ARTICLE | doi:10.20944/preprints202207.0058.v1
Subject: Life Sciences, Biophysics Keywords: human interferon gamma; human interferon gamma receptor; receptor binding; heparan sulfate; co-receptor; molecular dynamics simulations; sodium chlorate; kynurenine antiproliferative assays; hIFNγ signalling
Online: 5 July 2022 (04:43:05 CEST)
The extremely controversial conclusions about the function of human interferon-gamma (hIFNγ) C-terminus as well as the lack of a consistent model explaining its role in the receptor binding prompted us to scrutinize the interaction of hIFNγ with its extracellular receptor hIFNGR1 in different scenarios by means of molecular dynamics simulations. We find that the two molecules alone fail to form a stable complex but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity essay on cells depleted from surface sulfation confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.
ARTICLE | doi:10.20944/preprints202107.0585.v1
Subject: Medicine & Pharmacology, Other Keywords: Functional receptor; Hepatitis B virus; Polymorphism; Sodium taurocholate co-transporting polypeptide; hepatic fibrosis; Egypt
Online: 26 July 2021 (14:42:42 CEST)
Background: Single nucleotide polymorphisms (SNPs) in the SLC10A1 gene, coding for a functional receptor of hepatitis B virus (HBV), sodium taurocholate co-transporting polypeptide (NTCP), may influence the susceptibility, the outcome, and disease course of HBV infection in some populations. Aim: to determine the prevalence of SNPs of NTCP gene, rs2296651 and rs943277, and their relationship with chronic HBV infection in a group of Egyptian patients. Methods: 137 patients with HBV and 65 healthy controls were enrolled, and the patients were divided into two groups; group I chronic HBV infection (68 patients with normal ALT and minimal or no liver necroinflammation or fibrosis) and group II chronic hepatitis B (69 patients with elevated ALT and moderate or severe liver necroinflammation). They were subjected to full history taking, clinical examination, laboratory investigations, abdominal ultrasound, and liver stiffness measurement using both Echosens® Fibroscan and acoustic radiation force impulse (ARFI). Real time PCR TaqMan 5’ allelic discrimination assay was applied to detect the SNPs in NTCP gene, rs2296651 and rs943277. Results: On studying the rs2296651 variant, all controls and patients had genotype GG without any significant association with HBV infection or disease progression. However, the rs943277 variant in all controls and 98% of patients had genotype GA, except for two chronic HBV infection patients who had genotype AA, but no significant difference between patients and controls was found. The non-invasive methods for liver fibrosis assessment ARFI, AST/platelet's ratio (APRI), and fibrosis-4 score (FIB-4) could predict the stages of fibrosis in agreement with Fibroscan with AUCOR 0.8, 0.79, and 0.76, respectively. Conclusion: These findings may suggest that there is no relation between these SNPs of the NTCP gene and susceptibility or chronicity of HBV infection in the Egyptian population. We also suggest that the use of the non-invasive methods for liver fibrosis assessment, ARFI, FIB-4, and APRI may decrease the need for liver biopsies in prediction of significant hepatic fibrosis in chronic HBV patients.
ARTICLE | doi:10.20944/preprints202111.0396.v1
Subject: Biology, Ecology Keywords: Progesterone Receptor; Mineralocorticoid Receptor; Evolution; Zebrafish
Online: 22 November 2021 (13:52:50 CET)
There is much concern about disruption of endocrine physiology regulated by steroid hormones in humans, other terrestrial vertebrates and fish by industrial chemicals, such as bisphenol A, and pesticides, such as DDT. These endocrine-disrupting chemicals influence steroid-mediated physiology in humans and other vertebrates by competing with steroids for receptor binding sites, disrupting diverse responses involved in reproduction, development and differentiation. Here I discuss that due to evolution of the progesterone receptor (PR) and mineralocorticoid receptor (MR) after ray-finned fish and terrestrial vertebrates diverged from a common ancestor, each receptor evolved to respond to different steroids in ray-finned fish and terrestrial vertebrates. In elephant shark, a cartilaginous fish, ancestral to ray-finned fish and terrestrial vertebrates, both progesterone and 17,20-beta-dihydroxy-progesterone activate the PR. During the evolution of ray-finned fish and terrestrial vertebrates, the PR in terrestrial vertebrates continued responding to progesterone and evolved to weakly respond to 17,20-beta-dihydroxy-progesterone. In contrast, the physiological progestin for the PR in zebrafish and other ray-finned fish is 17,20-beta-dihydroxy-progesterone, and ray-finned fish PR responds weakly to progesterone. The MR in fish and terrestrial vertebrates also diverged to have different responses to progesterone. Progesterone is a potent agonist for elephant shark MR, zebrafish MR and other fish MRs, in contrast to progesterone’s opposite activity as an antagonist for aldosterone, the physiological mineralocorticoid for human MR. These different physiological ligands for fish and terrestrial vertebrate PR and MR need to be considered in applying data for their disruption by chemicals in fish and terrestrial vertebrates to each other.
REVIEW | doi:10.20944/preprints202112.0469.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: astrocyte; gamma-amino butyric acid (GABA); GABA transporter (GAT); GABAA receptor; glutamic acid decarboxylase (GAD); glycine; glycine receptor; glycine transporter (GlyT); K+-Cl- co-transporter 2 (KCC2); vesicular GABA transporter (VGAT)
Online: 29 December 2021 (14:27:41 CET)
Gamma-aminobutyric acid (GABA) and glycine act as inhibitory neurotransmitters. Three types of inhibitory neurons and terminals, GABAergic, GABA/glycine co-releasing, and glycinergic, are orchestrated in the spinal cord neural circuits and play key roles in the regulation of pain, locomotive movement, and respiratory rhythms. Herein, we first describe GABAergic and glycinergic transmission and inhibitory networks, which consist of three types of terminals, in the mature mouse spinal cord. Second, we describe the developmental formation of GABAergic and glycinergic networks, with specific focus on the differentiation of neurons, formation of synapses, maturation of removal systems, and changes in their action. GABAergic and glycinergic neurons are derived from the same domains of the ventricular zone. Initially, GABAergic neurons are differentiated and their axons form synapses. Some of these neurons remain GABAergic in lamina I and II. Many of GABAergic neurons convert to co-releasing state. The co-releasing neurons and terminals remain in the dorsal horn, whereas many of co-releasing ones ultimately become glycinergic in the ventral horn. During the development of terminals and the transformation from radial glia to astrocytes, GABA and glycine receptor subunit compositions markedly change, removal systems mature, and GABAergic and glycinergic action shifts from excitatory to inhibitory.
ARTICLE | doi:10.20944/preprints201807.0224.v2
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: pseudopterosin; triple negative breast cancer; glucocorticoid receptor alpha; dexamethasone; cell proliferation; 3D invasion; tumor spheroid; co-culture; interleukin 6; interleukin 8
Online: 2 August 2018 (06:08:31 CEST)
Pseudopterosin, produced by the sea whip of the genus Antillogorgia, possesses a variety of promising biological activities including potent anti-inflammatory effects. However, few studies examined pseudopterosin in the treatment of cancer cells and, to our knowledge, the ability to inhibit triple negative breast cancer (TNBC) proliferation or invasion has not been explored. Thus, we evaluated the as yet unknown mechanism of action of pseudopterosin: Pseudopterosin was able to inhibit proliferation of TNBC. Interestingly, analyzing breast cancer cell proliferation after knocking down glucocorticoid receptor α (GRα) revealed that anti-proliferative effects of pseudopterosin were significantly inhibited when GRα expression was reduced. Furthermore, pseudopterosin inhibited invasion of MDA-MB-231 3D tumor spheroids embedded in an extracellular-like matrix. Remarkably, the knockdown of GRα in 3D tumor spheroids revealed increased ability of cells to invade the surrounding matrix. In a co-culture, encompassing peripheral blood mononuclear cells (PBMC) and MDA-MB-231 cells, production of interleukin 6 (IL-6) and interleukin 8 (IL-8) significantly increased compared to monoculture. Notably, pseudopterosin proved to block cytokine elevation, representing key players in tumor progression, in the co-culture. Thus, our results reveal pseudopterosin treatment as a potential novel approach in TNBC therapy.
ARTICLE | doi:10.20944/preprints202002.0143.v1
Subject: Mathematics & Computer Science, Information Technology & Data Management Keywords: ocean; big-data; cite-space; co-authorship analysis; co-citation analysis; keywords co-occurrence analysis; visualization
Online: 11 February 2020 (09:41:17 CET)
Ocean big data is the scientific practice of using big data technology in the marine field. Data from satellites, manned spacecraft, space stations, airship, unmanned aerial vehicles, shore-based radar and observation stations, exploration platforms, buoys, underwater gliders, submersibles, and submarine observation networks are seamlessly combined into the ocean’s big data. Increasing numbers of scholars have tried to fully analyze the ocean’s big data. To explore the key research technology knowledge graphs related to ocean big data, articles between 1990 and 2020 were collected from the “Web of Science”. By comparing bibliometric software and using the visualization software Cite-Space, the pivotal literature related to ocean big data, as well as countries, institutions, categories, and keywords, were visualized and recognized. Journal co-citation analysis networks can help determine the national distribution of core journals. Co-citation analysis networks for documents show authors who are influential at key technical levels. Key co-occurrence analysis network keywords can determine research hot spots and research frontiers. The three supporting elements of marine big data research are shown in the co-citation network. These elements are author, institution, and country. By examining the co-occurrence of keywords, the key technology research directions for future marine big data were determined.
REVIEW | doi:10.20944/preprints202208.0145.v1
Subject: Life Sciences, Microbiology Keywords: Leishmania; co-infections; mixed infections; co-culture; hybrid; intercellular communication
Online: 8 August 2022 (10:20:49 CEST)
Leishmania parasites present astonishing adaptative abilities that represent a matter of life or death within disparate environments during the heteroxenous parasite life cycle. From an evolutionary perspective, organisms develop methods of overcoming such challenges. Strategies that extend beyond the genetic diversity have been discussed and include variability between parasite cells during the infections of their hosts. The occurrence of Leishmania subpopulation fluctuations with variable structural genomic contents demonstrates that a single strain might shelter the variability required to overcome inconsistent environments. Such intrastrain variability provides parasites with an extraordinary ability to adapt and thus survive and propagate. However, different perspectives on this evolution have been proposed. Strains or species living in the same environment can cooperate but also compete. These interactions might increase the replication rate of some parasites but cause the loss of more aggressive competitors for others. Adaptive responses to intra- and interspecific competition can evolve as a fixed strategy (replication is adapted to the average genetic complexity of infections) or an optional strategy (replication varies according to the genetic complexity of the current infection). This review highlights the complexity of interspecies and intrastrain interactions among Leishmania parasites as well as the different factors that influence this interplay.
ARTICLE | doi:10.20944/preprints202110.0304.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: 1,25-dihydroxyvitamin D; vitamin D receptor; vitamin D receptor; fibroblast growth factor receptor; signal transduction; differentiation
Online: 21 October 2021 (10:52:39 CEST)
(1) Background: Many malignancies are driven by mutations which affect the gene for fibroblast growth factor receptor (FGFR) 1. Previously we have documented that signal transduction from FOP2–FGFR1 fusion protein in KG1 cells downregulated the expression of vitamin D receptor (VDR) gene. In this paper we investigated if also other FGFRs were responsible for the regulation of the VDR expression. (2) Methods: We used human myeloid leukemia cells U937, and bone cancer cell line U2OS, and cell transfection methods in order to address the above questions. (3) Results: In myeloid leukemia cells overexpression of FGFR 1-4 caused shift to granulocytic differentiation, upregulated expression of VDR, and sensitized these cells to 1,25-dihydroxyvitamin D (1,25D)-induced monocytic differentiation, while in bone cells, signal transduction activated by FGF1 was not responsible for regulation of VDR expression and activity. (4) Conclusions: Since the overexpression of FGFRs occurs in many neoplasms, it may be reasonable to use 1,25D analogs in these cancers, in which overexpression of FGFRs leads to VDR upregulation.
ARTICLE | doi:10.20944/preprints202105.0087.v1
Subject: Life Sciences, Biochemistry Keywords: G-Protein Coupled Receptors; beta-3-adrenergic receptor; receptor desensitization
Online: 6 May 2021 (13:16:27 CEST)
Adrenergic receptor β3 (ADRβ3) is a member of the rhodopsin-like G protein-coupled receptor family. The binding of the ligand to ADRβ3 activates adenylate cyclase and increases cAMP in the cells. ADRβ3 is highly expressed in white and brown adipocytes and controls key regulatory pathways of lipid metabolism. Trp64Arg (W64R) polymorphism in the ADRβ3 has been associated with the early development of type 2 diabetes mellitus, lower resting metabolic rate, abdominal obesity, and insulin resistance. It is unclear how the substitution of W64R affects the functioning of ADRβ3. This study was initiated to functionally characterize this obesity-linked variant of ADRβ3. We evaluated in detail the expression, subcellular distribution, and post-activation behavior of the WT and W64R ADRβ3 using a single cell quantitative fluorescence microscopy. When expressed in HEK 293 cells, ADRβ3 shows a typical distribution displayed by other GPCRs with a predominant localization at the cell surface. Unlike Adrenergic receptor β2 (ADRβ2), agonist induced desensitization of ADRβ3 does not involve loss of cell surface expression. WT and W64R variant of ADRβ3 displayed comparable biochemical properties and there was no significant impact of the substitution of Tryptophan with Arginine on the expression, cellular distribution, signaling, and post-activation behavior of ADRβ3. The obesity-linked W64R variant of ADRβ3 is indistinguishable from the WT ADRβ3 in terms of expression, cellular distribution, signaling, and post-activation behavior.
ARTICLE | doi:10.20944/preprints201705.0126.v1
Subject: Biology, Other Keywords: amyloid peptides; androgen receptor; nuclear receptor; aggregation; atomic force microscopy
Online: 16 May 2017 (17:48:54 CEST)
The human androgen receptor (AR) is a ligand inducible transcription factor harboring an amino terminal domain (AR-NTD) hosting the ligand independent activation function. AR-NTD is intrinsically disordered and display aggregation properties conferred by the presence of a poly-glutamine (polyQ) sequence of 22 residues. The length of the polyQ sequence, as well as the presence of adjacent sequence motifs modulate this aggregation property. AR-NTD contains also a conserved sequence motif KELCKAVSVSM that displays an intrinsic property to form amyloid fibrils under mild oxidative conditions of its conserved cysteine residue. As peptide sequences with intrinsic ability to oligomerize are reported to have an impact on the aggregation of polyQ tract, we determined the effect of the KELCKAVSVSM on the polyQ stretch in the context of the AR NTD, using Atomic Force Microscopy (AFM). Here, we present evidence for a crosstalk between the amyloidogenic properties of the KELCKAVSVSM motif and the polyQ stretch at the AR NTD.
ARTICLE | doi:10.20944/preprints202201.0027.v1
Online: 5 January 2022 (10:24:32 CET)
New setting is introduced to study types of coloring numbers, degree of vertices, degree of hyperedges, co-degree of vertices, co-degree of hyperedges, neutrosophic degree of vertices, neutrosophic degree of hyperedges, neutrosophic co-degree of vertices, neutrosophic co-degree of hyperedges, neutrosophic number of vertices, neutrosophic number of hyperedges in neutrosophic hypergraphs. Different types of procedures including neutrosophic (r, n)−regular hypergraphs and neutrosophic complete r−partite hypergraphs are proposed in this way, some results are obtained. General classes of neutrosophic hypergraphs are used to obtain chromatic number, the representatives of the colors, degree of vertices, degree of hyperedges, co-degree of vertices, co-degree of hyperedges, neutrosophic degree of vertices, neutrosophic degree of hyperedges, neutrosophic co-degree of vertices, neutrosophic co-degree of hyperedges, neutrosophic number of vertices, neutrosophic number of hyperedges in neutrosophic hypergraphs. Using colors to assign to the vertices of neutrosophic hypergraphs and characterizing representatives of the colors are applied in neutrosophic (r, n)−regular hypergraphs and neutrosophic complete r−partite hypergraphs. Some questions and problems are posed concerning ways to do further studies on this topic. Using different ways of study on neutrosophic hypergraphs to get new results about number, degree and co-degree in the way that some number, degree and co-degree get understandable perspective. Neutrosophic (r, n)−regular hypergraphs and neutrosophic complete r−partite hypergraphs are studied to investigate about the notions, coloring, the representatives of the colors, degree of vertices, degree of hyperedges, co-degree of vertices, co-degree of hyperedges, neutrosophic degree of vertices, neutrosophic degree of hyperedges, neutrosophic co-degree of vertices, neutrosophic co-degree of hyperedges, neutrosophic number of vertices, neutrosophic number of hyperedges in neutrosophic (r, n)−regular hypergraphs and neutrosophic complete r−partite hypergraphs. In this way, sets of representatives of colors, degree of vertices, degree of hyperedges, co-degree of vertices, co-degree of hyperedges, neutrosophic degree of vertices, neutrosophic degree of hyperedges, neutrosophic co-degree of vertices, neutrosophic co-degree of hyperedges, neutrosophic number of vertices, neutrosophic number of hyperedges have key points to get new results but in some cases, there are usages of sets and numbers instead of optimal ones. Simultaneously, notions chromatic number, the representatives of the colors, degree of vertices, degree of hyperedges, co-degree of vertices, co-degree of hyperedges, neutrosophic degree of vertices, neutrosophic degree of hyperedges, neutrosophic co-degree of vertices, neutrosophic co-degree of hyperedges, neutrosophic number of vertices, neutrosophic number of hyperedges are applied into neutrosophic hypergraphs, especially, neutrosophic (r, n)−regular hypergraphs and neutrosophic complete r−partite hypergraphs to get sensible results about their structures. Basic familiarities with neutrosophic hypergraphs theory and hypergraph theory are proposed for this article.
ARTICLE | doi:10.20944/preprints202209.0198.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Cholecystokinin-2 receptor; minigastrin; peptide receptor radionuclide therapy; lutetium-177, theranostics
Online: 14 September 2022 (08:39:42 CEST)
Minigastrin (MG) analogs for therapy of CCK2R-expressing malignancies are limited by low stability in vivo or excessive accumulation in non-target organs. By modifying the C-terminal receptor-binding sequence, metabolization could be prevented and tumor targeting significantly improved. In this work, N-terminal changes of the peptide length were evaluated. Based on the amino acid sequence of DOTA-MGS5 (DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2), two new MG analogs were synthesized, by either introduction of a penta-DGlu moiety or depletion of the four N-terminal amino acids and introduction of a non-charged hydrophilic linker. Two CCK2R-expressing cell lines were used to demonstrate receptor interaction. Stability of the 177Lu-labeled peptide analogs was evaluated in human serum up to 24 h after incubation and in BALB/c mice up to 30 min after injection. The biodistribution profile and tumor targeting potential was evaluated in xenografted BALB/c nude mice. For both new MG analogs, the combination of strong receptor-specific cell interaction, high stability and enhanced tumor targeting could be demonstrated. Shortening of the peptide sequence lowered the absorption in the dose-limiting organs, whereas elongation increased uptake in renal tissue.
ARTICLE | doi:10.20944/preprints201903.0001.v1
Subject: Biology, Physiology Keywords: shark steroids; steroid receptor evolution; mineralocorticoid receptor evolution; progesterone; aldosterone; cortisol
Online: 1 March 2019 (06:37:37 CET)
We report the analysis of activation by corticosteroids and progesterone of full-length mineralocorticoid receptor (MR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates. Based on their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fishes. Because progesterone is a precursor for corticosteroids that activate elephant shark MR, we propose that progesterone was an ancestral ligand for elephant shark MR. Although progesterone activates ray-finned fish MRs, progesterone does not activate human, amphibian or alligator MRs, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Comparison of RNA-sequence analysis of elephant shark MR with that of human MR suggests that MR expression in the human brain, heart, ovary, testis and other non-epithelial tissues evolved in cartilaginous fishes. Together, these data suggest that progesterone-activated MR may have unappreciated functions in elephant shark ovary and testis.
REVIEW | doi:10.20944/preprints202207.0180.v1
Subject: Medicine & Pharmacology, Behavioral Neuroscience Keywords: plasma membrane; membrane domains; nanodomains; neurotransmitter receptors; cannabinoids; acetylcholine receptor; cannabinoid receptor.
Online: 12 July 2022 (09:17:01 CEST)
Fifty years on from the classical fluid-mosaic model of Singer and Nicolson, current views of the plasma membrane portray a much more complex view of this interface region. Compartmentalization, together with transbilayer and lateral asymmetries, provide the structural foundation for functional specializations at the cell surface, including the active role of the lipid microenvironment in the modulation of membrane-bound proteins. The chemical synapse, the site where neurotransmitter-coded signals are decoded by neurotransmitter receptors, adds another layer of complexity to the plasma membrane architectural intricacy, mainly due to the need to accommodate a sizeable number of molecules in a minute subcellular compartment with dimensions barely reaching the micrometer. In this review, we discuss how Nature has developed suitable adjustments to accommodate different types of membrane-bound receptors and scaffolding proteins via membrane microdomains, and how this “efford-sharing” mechanism has evolved to optimize crosstalk or separation or coupling where/when appropriate. To this end, we use a fast ligand-gated neurotransmitter receptor, the nicotinic acetylcholine receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as paradigmatic example.
ARTICLE | doi:10.20944/preprints202012.0513.v1
Subject: Life Sciences, Biochemistry Keywords: apoferritin nanocarriers; controlled drug delivery; idarubicin; ferritin receptor targeting; folate receptor targeting
Online: 21 December 2020 (11:28:08 CET)
The interactions of chemotherapeutic drugs with nanocage protein apoferritin (APO) are the key features in the effective encapsulation and release of highly toxic drugs in APO-based controlled drug delivery systems. The encapsulation enables mitigating the drugs side effects, collateral damage to healthy cells, and adverse immune reactions. Herein, the interactions of anthracycline drugs with APO were studied to assess the effect of drug lipophilicity on their encapsulation excess n and in vitro activity. Anthracycline drugs, including doxorubicin (DOX), epirubicin (EPI), daunorubicin (DAU), and idarubicin (IDA), with lipophilicity P from 0.8 to 15, were investigated. We have found that in addition to hydrogen-bonded supramolecular ensemble formation with n = 24, there are two other competing contributions that enable increasing n under strong polar interactions (APO(DOX)) or under strong hydrophobic interactions (APO(IDA) of the highest efficacy). The encapsulation/release processes were investigated using UV-Vis, fluorescence, circular dichroism, and FTIR spectroscopies. In vitro cytotoxicity/growth inhibition tests and flow cytometry corroborate high apoptotic activity of APO(drugs) against targeted MDA-MB-231 adenocarcinoma and HeLa cancer cells, and low activity against non-tumorigenic MCF10A cells, demonstrating targeting ability of nanodrugs. A model for molecular interactions between anthracyclines and APO nanocarriers was developed, and the relationships derived compared with experimental results.
ARTICLE | doi:10.20944/preprints202105.0525.v1
Subject: Medicine & Pharmacology, Allergology Keywords: COVID-19; glycyrrhizin; mineralocorticoid receptor; toll like receptor 4; angiotensin converting enzyme; aldosterone
Online: 21 May 2021 (15:11:30 CEST)
Angiotensin converting enzyme 2 (ACE2) is a key entry point of SARS-CoV-2 virus known to induce COVID-19. We have recently outlined the concept to reduce ACE2 expression by the administration of glycyrrhizin, a component of Glycyrrhiza glabra extract, via its inhibitory activity on 11beta hydroxysteroid dehydrogenase type 2 (11betaHSD2) and resulting activation of mineralocorticoid receptor (MR). We hypothesized that in organs, such as the intestine, which co-express 11betaHSD2, MR and ACE2, the expression of ACE2 would be suppressed. We studied organ tissues from an experiment originally designed to address the effects of Glycyrrhiza glabra extract on the stress response. Male Sprague Dawley rats were left undisturbed or exposed to chronic mild stress for five weeks. For the last two weeks, animals continued with a placebo diet or received a diet containing extract of Glycyrrhiza glabra root at a dose of 150 mg/kg of body weight/day. Quantitative PCR measurements showed a significant decrease in gene expression of ACE2 in the small intestine of rats fed with diet containing Glycyrrhiza glabra extract. This effect was independent of the stress condition and failed to be observed in non-target tissues, namely the heart and the brain cortex. In the small intestine we confirmed the reduction of ACE2 also at the protein level. Present findings provide first evidence to support the hypothesis that Glycyrrhiza glabra extract may reduce an entry point of SARS-CoV-2. Whether this phenomenon, when confirmed in additional studies, is linked to the susceptibility of cells to the virus requires further studies.
ARTICLE | doi:10.20944/preprints201901.0320.v1
Subject: Medicine & Pharmacology, Other Keywords: Acanthamoeba sp.; eyes; toll-like receptor 2 (TLR2); toll-like receptor 4 (TLR4)
Online: 31 January 2019 (07:00:38 CET)
Toll-like receptors (TLRs) play a key role in the innate immune response to numerous pathogens, including Acanthamoeba sp. The aim of this study was to determine the expression of TLR2 and TLR4 in the eyes of mice following intranasal infection with Acanthamoeba sp. Amoebae used in this study were isolated from the bronchial aspirate of a patient with acute myeloid leukemia (AML) and atypical symptoms of pneumonia. We found statistically significant differences in the expression of TLR2 and TLR4 in the eyes of immunocompetent mice at 8, 16, and 24 days post Acanthamoeba sp. infection (dpi) compared to control. Immunosuppressed mice showed significant differences in the expression of TLR2 at 16 and 24 dpi compared to uninfected animals. Our results indicate that TLR2 and TLR4 are upregulated in the eyes of mice in response to Acanthamoeba sp. We suggest that it is possible for trophozoites to migrate through the optic nerve from the brain to the eyes.
ARTICLE | doi:10.20944/preprints201610.0027.v1
Subject: Biology, Physiology Keywords: Liver X receptor (LXR); Peroxisome proliferator-activated receptor (PPARγ); Adipose expansion; Insulin resistance
Online: 10 October 2016 (07:56:30 CEST)
Liver X receptors (LXR) are deemed as potential drug targets for atherosclerosis, whereas a role in adipose tissue expansion and its relation to insulin sensitivity remains unclear. To assess the metabolic effects of LXR activation, C57BL/6 mice on a high-fat diet (HFD) were treated with the dual LXRα/β agonist T0901317 (30 mg/kg per day) for 3 weeks. Differentiated 3T3-L1 was used for analysing the effect of T0901317 on glucose uptake.T0901317 reduced fat mass, accompanied by a massive fatty liver and lower adipokine levels in circulation of HFD mice. Increased adipocyte apoptosis and macrophage infiltration were found in epididymal fat of T0901317-treated HFD mice. In addition, T0901317 treatment promoted basal lipolysis, but blunted the anti-lipolytic action of insulin. Furthermore, LXR activation antagonized PPARγ target genes in epididymal fat and PPARγ-PPRE binding activity in 3T3-L1 adipocytes. Although the glucose tolerance was comparable to that in vehicle-treated HFD mice, the insulin tolerance was significantly decreased in T0901317-treated HFD mice, indicating decreased insulin sensitivity by T0901317 administration, and which was further supported by impaired insulin signalling found in epididymal fat and decreased insulin-induced glucose uptake in 3T3-L1 by T0901317administration. These findings reveal that LXR activation impairs adipose expansion which contributes to decreased insulin sensitivity.
ARTICLE | doi:10.20944/preprints202009.0374.v1
Subject: Life Sciences, Other Keywords: aldosterone; apoptosis; cardiac myocyte; eplerenone; fibrosis; finerenone; G protein-coupled receptor kinase (GRK)-5; mineralocorticoid receptor; mineralocorticoid receptor antagonist (MRA); signal transduction
Online: 17 September 2020 (05:24:29 CEST)
Background: In the heart, aldosterone (Aldo) binds the mineralocorticoid receptor (MR) to exert damaging, adverse remodeling-promoting effects. We recently showed that G protein-coupled receptor (GPCR)-kinase (GRK)-5 blocks the cardiac MR by directly phosphorylating it, thereby repressing its transcriptional activity. MR antagonist (MRA) drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure. Non-steroidal MRAs, such as finerenone, may provide better cardio-protection against Aldo than classic, steroidal MRAs, like spironolactone and eplerenone. Herein, we sought to investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. Methods: We used the cardiomyocyte cell line H9c2 and neonatal rat ventricular myocytes (NRVMs). Results: GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone. Unlike eplerenone, finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity, thus displaying inverse agonism. GRK5 is necessary for finerenone`s inverse agonism, since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity. Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels. Finally in NRVMs, GRK5 is necessary for the anti-apoptotic and anti-fibrotic effects of both finerenone and eplerenone against Aldo, as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis and fibrosis. Conclusions: Finerenone, but not eplerenone, induces GRK5-dependent cardiac MR inhibition, which underlies, at least in part, its higher potency and efficacy, compared to eplerenone, as an MRA in the heart. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.
ARTICLE | doi:10.20944/preprints201608.0027.v1
Subject: Mathematics & Computer Science, Analysis Keywords: Fuzzy implications; (S,N) implication; residuum t-norm; (T,N) co-implication; residual co-implication
Online: 3 August 2016 (08:29:47 CEST)
Recently, many authors have been interested to introduce fuzzy implications over t-norms and t-conorms. In this paper, we introduce (S,N) and residuum fuzzy implication for Dubois t-norm and Hamacher's t-norm. Also, new concepts so-called (T,N) and residual fuzzy co-implication in dual Heyting Algebra are investigated. Some examples as well as application are discussed as well.
ARTICLE | doi:10.20944/preprints202107.0665.v1
Subject: Biology, Anatomy & Morphology Keywords: cannabinoid receptor; inflammation; astrocytes; immunohistochemistry
Online: 29 July 2021 (14:11:55 CEST)
HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in brain specimens of HAND donors. Immunoblot revealed CB1 and CB2 were differentially expressed in frontal cortices from HAND brains compared to neurocognitively unimpaired (NUI) brains from PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution on neuronal processes of NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.
ARTICLE | doi:10.20944/preprints202002.0194.v1
Online: 14 February 2020 (10:52:21 CET)
Recently, it was confirmed that ACE2 is the receptor of 2019-nCoV, the pathogen causing the recent outbreak of severe pneumonia in China. It is confused that ACE2 is widely expressed across a variety of organs and is expressed moderately but not highly in lung, which, however, is the major infected organ. It remains unclear why it is the lung but not other tissues among which ACE2 highly expressed is mainly infected. We hypothesized that there could be some other genes playing key roles in the entry of 2019-nCoV into human cells. Here we found that AGTR2 (angiotensin II receptor type 2), a G-protein coupled receptor, has interaction with ACE2 and is highly expressed in lung with a high tissue specificity. More importantly, simulation of 3D structure based protein-protein interaction reveals that AGTR2 shows a higher binding affinity with the Spike protein of 2019-nCov than ACE2 (energy score: -15.7 vs. -6.9 [kcal/mol]). Given these observations, we suggest that AGTR2 could be a putative novel gene for the the entry of 2019-nCoV into human cells but need further confirmation by biological experiments. Finally, a number of compounds, biologics and traditional Chinese medicine that could decrease the expression level of AGTR2 were predicted.
REVIEW | doi:10.20944/preprints201705.0212.v1
Subject: Biology, Physiology Keywords: cancer; cell-surface receptor; EGFR; molecular mechanism; phosphorylation; receptor tyrosine kinase; transmembrane signal transduction
Online: 30 May 2017 (08:34:04 CEST)
The epidermal growth factor receptor (EGFR) plays vital roles in cellular processes including cell proliferation, survival, motility and differentiation. Dysregulated activation of the receptor is often implicated in human cancers. EGFR is synthesized as a single-pass transmembrane protein, which consists of an extracellular ligand-binding domain and an intracellular kinase domain separated by a single transmembrane domain. The receptor is activated by a variety of polypeptide ligands such as epidermal growth factor and transforming growth factor α. It has long been thought that EGFR is activated by ligand-induced dimerization of the receptor monomer, which brings intracellular kinase domains into close proximity for trans-autophosphorylation. An increasing number of diverse studies, however, demonstrate that EGFR is present as a pre-formed, yet inactive, dimer prior to ligand binding. Furthermore, recent progress in structural studies has provided insight into conformational changes during the activation of a pre-formed EGFR dimer. Upon ligand binding to the extracellular domain of EGFR, its transmembrane domains rotate or twist parallel to the plane of the cell membrane, resulting in reorientation of the intracellular kinase domain dimer from a symmetric inactive configuration to an asymmetric active form (the “rotation model”). This model is also able to explain how oncogenic mutations activate the receptor in the absence of ligand without assuming that the mutations induce receptor dimerization. In this review, we discuss mechanisms underlying ligand-induced activation of the preformed EGFR dimer, as well as how oncogenic mutations constitutively activate the receptor dimer, based on the rotation model.
ARTICLE | doi:10.20944/preprints202207.0173.v1
Subject: Engineering, Energy & Fuel Technology Keywords: Cement; Co-process; Waste; Incineration; Landfill
Online: 12 July 2022 (04:32:38 CEST)
Recently, the amount of waste generated has been rapidly increasing, there have been difficulties disposing of waste in Korea. As a solution to this, treating waste using a cement kiln has suggested, but the environmental and economic effects have not been specifically studied. In this study, the effects of alternative resources, and reducing the social costs(Installation and Operation) associated with waste treatment facilities were analyzed. Through a co-processing method, a reduction of approximately 53kg of CO2 can be realized during the production of one ton of cement, and cost savings of about 3,815 milion USD. Another effect is an extension of the expiration date for landfills by 7.55 years.
ARTICLE | doi:10.20944/preprints202202.0100.v1
Subject: Mathematics & Computer Science, Applied Mathematics Keywords: Quasi-Co-Degree; Quasi-Degree; Vertex
Online: 7 February 2022 (16:23:20 CET)
New setting is introduced to study quasi-degree and quasi-co-degree arising from co-neighborhood. quasi-degree and quasi-co-degree is about a vertex which are applied into the setting of neutrosophic graphs. . The structure of set is studied and general results are obtained. Also, some classes of neutrosophic graphs namely path-neutrosophic graphs, cycle-neutrosophic graphs, complete-neutrosophic graphs and star-neutrosophic graphs, complete-bipartite-neutrosophic graphs and complete-multipartite-neutrosophic graphs are investigated in the terms of a vertex which is called either quasi-degree or quasi-co-degree. Neutrosophic number is reused in this way. It’s applied to use the type of neutrosophic number in the way that, three values of a vertex are used and they’ve same share to construct this number to compare with other vertices. Summation of three values of vertex makes one number and applying it to a comparison. This approach facilitates identifying vertices which form quasi-degree and quasi-co-degree. Quasi-degree is a value of a vertex which is maximum amid all values of vertices which are neighbors to a fixed vertex. Quasi-co-degree is a value of an edge which is maximum amid all values of edges which are neighbors to a fixed vertex but corresponded vertex is representative for this notion. Using different values which are related to a vertex inspire us to focus on edge and vertices which are corresponded to a fixed vertex. The notion of neighborhood is used to collect either vertices are titled neighbors or edges are incident to fixed vertex. In both settings, some classes of well-known neutrosophic graphs are studied. Some clarifications for each result and each definitions are provided. Using fixed vertex has key role to have these notions in the form of vertex or edge. The value of an edge has eligibility to call quasi-co-degree but the value of a vertex has eligibility to call quasi-degree. Some results get more frameworks and perspective about these definitions. The way in that, two vertices have connection together, open the way to define neighborhood and co-neighborhood. The maximum values in neighborhood and co-neighborhood introduces quasi-degree and quasi-co-degree, respectively. New name is chosen from degree. Since amid all vertices with different degrees, one vertex is chosen. In other words, one vertex is fixed and its degree turns out quasi-degree where two degrees could be assigned to a vertex. Degree of edges and degree of vertices. The number of edges which are incident to the vertex and the number of vertices which are neighbors to the vertex. Degree and co-degree are the notions which are transformed to use in quasi-style. Two neutrosophic values introduce two neutrosophic vertices separately in each settings. These notions are applied into neutrosophic graphs as individuals but not family of them as drawbacks for these notions. Finding special neutrosophic graphs which are well-known, is an open way to purse this study. Some problems are proposed to pursue this study. Basic familiarities with graph theory and neutrosophic graph theory are proposed for this article.
ARTICLE | doi:10.20944/preprints202107.0586.v1
Online: 26 July 2021 (14:49:51 CEST)
Potential of co-digestion mixing thickened secondary sludge (TS) from extended aeration wastewater treatment plant and locally available substrates (whey, grease and septage) has been studied using three steps. The first step was a batch test to determine biological methane potential (BMP) of different mixtures of the three co-substrates with TS. The second step has been carried out with lab-scale reactors (20 L) simulating anaerobic continuous stirred tank reactors fed by three mixtures of co-substrates determined according to previous step results. Modelling using ADM1 as a mechanistic model was applied in the third step to help understanding the co-digestion process. According to BMP step, septage used as co-substrate has a negative effect on performance and addition of 10 to 30% grease or 10% whey would lead to a higher production of biogas and with an increase of the methane content. The results from the reactor showed less evi-dence of the positive effects observed with the BMP assay. Protein and lipid fractions of particu-late biodegradable COD are important variables for digester stability and methane production as predicted by modelling. Results of simulations with ADM1 model adapted to co-digestion confirmed that this model is a powerful tool to optimize the process of biogas production.
REVIEW | doi:10.20944/preprints202107.0549.v1
Subject: Medicine & Pharmacology, Allergology Keywords: TRβ; tumor suppression; co-regulators; therapeutics
Online: 23 July 2021 (15:14:12 CEST)
There is compelling evidence that the nuclear receptor TRβ, a member of the thyroid hormone receptor (TR) family, is a tumor suppressor in thyroid, breast and other solid tumors. Cell-based and animal studies reveal that the liganded TRβ induces apoptosis, reduces an aggressive phenotype, decreases stem cell populations, and slows tumor growth through modulation of a complex interplay of transcriptional networks. TRβ-driven tumor suppressive transcriptomic signatures include repression of known drivers of proliferation such as PI3K/Akt pathway and activation of novel signaling (JAK1/STAT1) and metabolic reprogramming in both thyroid and breast cancers. The presence of TRβ is also correlated with a positive prognosis and response to therapeutics in BRCA+ and triple-negative breast cancers respectively. Ligand activation of TRβ enhances sensitivity to chemotherapeutics. TRβ co-regulators and bromodomain-containing chromatin remodeling proteins are emergent therapeutic targets. This review considers TRβ as a potential biomolecular diagnostic and therapeutic target.
Subject: Arts & Humanities, Anthropology & Ethnography Keywords: critical pedagogy; experiential learning; co-production
Online: 5 July 2021 (10:35:42 CEST)
The sense of uncertainty and fragility due to the effects and magnitude of global challenges we are facing (from pandemic circumstances to climate change impacts) requires – much more than in the past – the capacity to generate a visionary and forefront design approach in the young gen-erations aiming at stimulating their reaction attitude rather than providing consolidated tools from past conditions that no longer exist or will rapidly evolve. Within this general framework, we have investigated the effectiveness and impacts of experienced-based methods of learning and innovative educational tools in architecture aimed at shaping expertise in which the environ-mental dimension and the climate-change challenge dialogues with the context's complexity in terms of socio-cultural dynamics, real potentialities and constrains, addressing their transdisci-plinary trajectories. The paper analyses 5 international pioneering teaching experiences that provide the opportunity to understand the outcomes of collaborative and experiential learning processes in which the educational activities leverage a dialogue between diverse communities (academia-citizens-policymakers-practitioners). The study outcomes show that shifting the pedagogical paradigm towards in-field-experience-based models can improve the awareness of future practitioners for climate implications of architectural design, implement their analysis and project skills while triggering processes of knowledge transfer and co-production at community level, and allow them to better address the societal and cultural issues involved within decision making.
REVIEW | doi:10.20944/preprints202104.0608.v1
Online: 22 April 2021 (13:23:35 CEST)
The purpose of this study is to explore conceptual approaches in co-production studies and to examine current research trends of the study. The conceptual paper includes research articles related to co-production in public administration field. By thoroughly scrutinizing 32 research works of co-production, this study highlights major loopholes in the field of the study. The contributions of the study are: (1) identifying two common characteristics of co-production, (2) categorising three types of co-producing by end-users, and (3) finding that goals and success of co-production are more beneficial for service providers though its initial approach is citizen-centric approach. We suggest that future studies should be (1) to focus on reasons for co-production failures or success, (2) to discover further hindrances for co-production in service production, (3) to examine influencing factors on service providers as well as institutional impacts on co-production process, and (4) to include practical assessment in co-production study.
ARTICLE | doi:10.20944/preprints201801.0084.v1
Subject: Earth Sciences, Geochemistry & Petrology Keywords: antimony; ferrihydrite; silica; adsorption; co-precipitation
Online: 10 January 2018 (07:02:42 CET)
Elevated antimony concentrations in aqueous environments from anthropogenic sources is becoming of global concern, here iron oxides are known to strongly adsorb aqueous antimony species with different oxidation states, but the effect of silica on the removal characteristics is not well understood despite being a common component in the environment. In this study, ferrihydrite was synthesized at various Si/Fe molar ratios to investigate its adsorption and co-precipitation behaviors with aqueous antimony anionic species, Sb(III) and Sb(V). The XRD analyses of the precipitates showed two broad diffraction features at approximately 35° and 62° 2θ, which are characteristic of 2-line ferrihydrite, no significant shifts in peak positions in the ferrihydrite regardless of the Si/Fe ratios. The infrared spectra showed a sharp band at ~990 cm−1, corresponding to asymmetric stretching vibrations of Si-O-Fe bonds which increased in intensity with increasing Si/Fe molar ratios. Further, the surface charge on the precipitates became more negative with increasing Si/Fe molar ratios. The adsorption experiments indicated that Sb(V) was preferentially adsorbed at acidic conditions and decreased dramatically with increasing pH while the adsorption rate of Sb(III) ions was independent of pH, however, the presence of silica suppressed the adsorption of both Sb(III) and Sb(V) ions. The results showed that Sb(III) and Sb(V) ions were significantly inhibited by co-precipitation with ferrihydrite even in the presence of silica by isomorphous substitution in the ferrihydrite crystal structure.
ARTICLE | doi:10.20944/preprints201610.0083.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: stroke; antioxidant; co-drug; animal model
Online: 20 October 2016 (08:46:38 CEST)
Background: Previously, our laboratory has provided evidence that pre-administration of the antioxidant, lipoic acid covalently bonded to various naturally occurring antioxidants, enhanced neuroprotective capacity compared to the administration of lipoic acid on its own. The naturally occurring compound scopoletin, a coumarin derivative, has been shown in various in vitro studies to have both antioxidant and anti-inflammatory mechanism of actions. To date, the effect of scopoletin on neuronal cell death in an in vivo model of ischemia or ischemia-reperfusion has not been investigated. Therefore, the present investigation was designed to determine if scopoletin on its own, or a co-drug consisting of lipoic acid and scopoletin covalent bond, named UPEI-400, would be capable of demonstrating a similar neuroprotective efficacy. Methods: Using a rodent model of stroke in male rats (anesthetized with Inactin®; 100 mg/kg, iv), the middle cerebral artery was permanently occluded for 6 hours (pMCAO), or in separate animals, occluded for 30 min followed by 5.5 hrs of reperfusion (ischemia/reperfusion; I/R). Results: Pre-administration of either scopoletin or UPEI-400 significantly decreased infarct volume in the I/R model (p<0.05), but not in the pMCAO model of stroke. However, UPEI-400 was ~1000 times more potent as compared to scopoletin on its own. The optimal dose of UPEI-400 was then injected during the occlusion and at several time points during reperfusion and significant neuroprotection was observed for up to 150 mins following the start of reperfusion (p<0.05). Conclusion: The data suggest that synthetic combination of scopoletin with lipoic acid (UPEI-400) is a more effective neuroprotectant that either compound on their own. Also, since UPEI-400 was only effective in a model of I/R, it is possible that it may act to enhance neuronal antioxidant capacity and/or upregulate anti-inflammatory pathways to prevent the neuronal cell death.
ARTICLE | doi:10.20944/preprints201912.0267.v1
Subject: Chemistry, Electrochemistry Keywords: adsorption; coatings; poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate); corrosion tests; atomic force microscopy
Online: 20 December 2019 (07:00:55 CET)
Poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate) named further PVBA was investigated as protective coating for copper corrosion in 0.9 % NaCl solution using electrochemical measurements such as, electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization associated with Atomic Force Microscopy (AFM). The PVBA coating on the copper surface (Cu-PVBA) was modeled in methanol containing PVBA. Its inhibitory properties against corrosion was comparatively discussed with those of the copper sample treated in methanol without polymer (Cu-Me) and of untreated sample (standard copper). A protective performance of PVBA coating of 80 % was computed from electrochemical measurements, for copper corrosion in NaCl solution. Also, AFM images designed a specific surface morphology of coated surface with PVBA, clearly highlighting a polymer film adsorbed on the copper surface, which presents certain deterioration after corrosion, but metal surface was not significantly affected compared to those of untreated samples or treated in methanol, in the absence of PVBA.
ARTICLE | doi:10.20944/preprints202203.0248.v1
Subject: Mathematics & Computer Science, Applied Mathematics Keywords: Neutrosophic Quasi-Order; Neutrosophic Quasi-Size; Neutrosophic Quasi-Number; Neutrosophic Quasi-Co-Number; Neutrosophic Co-t-Neighborhood
Online: 17 March 2022 (08:48:38 CET)
New setting is introduced to study co-neighborhood, neutrosophic t-neighborhood, neutrosophic quasi-vertex set, neutrosophic quasi-order, neutrosophic neighborhood, neutrosophic co-t-neighborhood, neutrosophic quasi-edge set, neutrosophic quasi-size, Neutrosophic number, neutrosophic co-neighborhood, co-neutrosophic number, quasi-number and quasi-co-number. Some classes of neutrosophic graphs are investigated.
ARTICLE | doi:10.20944/preprints202010.0504.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: glycine transporter; glycine receptor; analgesics; lipids
Online: 26 October 2020 (08:46:31 CET)
Reduced inhibitory glycinergic neurotransmission is implicated in a number of neurological conditions such as neuropathic pain, schizophrenia, epilepsy and hyperekplexia. Restoring glycinergic signalling may be an effective method of treating these pathologies. Glycine transporters (GlyTs) control synaptic and extra-synaptic glycine concentrations and slowing the reuptake of glycine using specific GlyT inhibitors will increase glycine extracellular concentrations and increase glycine receptor (GlyR) activation. Glycinergic neurotransmission can also be improved through positive allosteric modulation (PAM) of GlyRs. Despite efforts to manipulate this synapse, no therapeutics currently target it. We propose that dual action modulators of both GlyTs and GlyRs may show greater therapeutic potential than those targeting individual proteins. To show this, we have characterized a co-expression system in Xenopus laevis oocytes consisting of GlyT1 or GlyT2 co-expressed with GlyRα1. We use two electrode voltage clamp recording techniques to measure the impact of GlyTs on GlyRs and the effects of modulators of these proteins. We show that increases in GlyT density in close proximity to GlyRs diminish receptor currents. Reductions in GlyR mediated currents are not observed when non-transportable GlyR agonists are applied or when Na+ is not available. GlyTs reduce glycine concentrations across different concentration ranges, corresponding with their ion-coupling stoichiometry, and full receptor currents can be restored when GlyTs are blocked with selective inhibitors. We show that partial inhibition of GlyT2 and modest GlyRα1 potentiation using a dual action compound, is as useful in restoring GlyR currents as a full and potent single target GlyT2 inhibitor or single target GlyRα1 PAM.
REVIEW | doi:10.20944/preprints201704.0006.v1
Subject: Medicine & Pharmacology, Allergology Keywords: fibromyalgia; drugs; NMDA receptor; ketamine; memantine.
Online: 3 April 2017 (16:43:53 CEST)
Activation of the N-methyl D-aspartate receptor (NMDAR) results in increased sensitivity of spinal cord and brain pathways that process sensory information, particularly that which relates pain. The NMDAR shows increased activity in fibromyalgia and hence modulation of the NMDAR is a target for therapeutic intervention. A literature review of interventions impacting on the NMDAR shows a number of drugs to be active on the NMDAR mechanism in fibromyalgia patients, with variable clinical effects. Low-dose intravenous ketamine and oral memantine both show clinically useful benefit in fibromyalgia. However, consideration of side-effects, logistics and cost need to be factored into management decisions regarding use of these drugs in this clinical setting. Overall benefits with current NMDAR antagonists appear modest and there is a need for better strategy trials to clarify optimal dose schedules and to delineate potential longer –term adverse events. Further investigation of the role of the NMDAR in fibromyalgia and the effect of other molecules that modulate this receptor appear important to enhance treatment targets in fibromyalgia.
ARTICLE | doi:10.20944/preprints202208.0130.v1
Subject: Social Sciences, Organizational Economics & Management Keywords: crowdsourcing; value co-creation; business sustainability; stakeholder
Online: 8 August 2022 (04:09:12 CEST)
As a typical form of value co-creation, crowdsourcing has been increasingly applied by firms to generate business value. By engaging a crowd, a platform, and other stakeholders, a crowdsourcer can foster the co-creation of a portfolio of value for diverse stakeholders. In analyzing the value co-creation in crowdsourcing, we propose a framework by combining the theories and frameworks in value co-creation and crowdsourcing. The framework examines the key stakeholders, joint purpose, engaged value co-creation processes, contributions, bidirectional relationships of the engagement, and perceived value, exhibiting a holistic view of the value co-creation in a crowdsourcing project. Results of the analysis reveal the business performance of the crowdsourcing project and identify areas of improvement regarding business sustainability. This is a major theoretical contribution of this study. The research design applied a case study approach to empirically investigate a crowdsourcing project. Both the theoretical and practical implications are discussed.
ARTICLE | doi:10.20944/preprints202201.0337.v1
Online: 24 January 2022 (09:41:10 CET)
This pot-based study investigated the influence of co-composted wood-derived biochar on lettuce growth performance under salinity and drought stress conditions. Biochar of two particle sizes; > 2 mm and < 1 mm were co-composted with the mixture (1:1 ratio of dry weight) of cow and poultry manures. Co-composted biochars were applied at 5% and 7% rates in soil. Control treatments included the amendment of mixture of biochar with manure in soil. Pots were subjected to slight drought (48-55% water filled pore space (WFPS) of soil) and non-drought conditions (60% WFPS) and under 0 and 1.3 dS m-1 salinity. Results revealed that plants growth performance was significantly better under treatments of co-composted biochar and no salt stress conditions, than when mixture of biochar and manure was applied to soil as non-composted fertilizer. Under no stress condition, small particle-sized co-composted biochar increased root biomass by 786.2% than the large particle-sized co-composted biochar at same application rate. As compared to large-sized co-composted biochar, small sized co-composted biochar at high application rates increased root biomass by 167 – 245% but not leaf biomass under both stress conditions. Small particle-sized co-composted biochar amendment also increased the phosphorus use efficiency (PUE) of lettuce leaves than large particle-sized co-composted biochar under no stress condition. The amendment of small-sized co-composted biochar also increased significantly the concentration of Olsen phosphorus in soil than the amendment of large-particle-sized co-composted biochar. In conclusion, amendment of small particle-sized co-composted biochar has the potential of attenuating salinity and drought stress in lettuce and promoting P cycling in soil.
ARTICLE | doi:10.20944/preprints202109.0053.v1
Subject: Mathematics & Computer Science, Numerical Analysis & Optimization Keywords: Co-scheduling; HPC; scheduling theory; stochastic optimization
Online: 3 September 2021 (10:14:03 CEST)
Applications in high-performance computing (HPC) may not use all available computational resources, leaving some of them underutilized. By co-scheduling, i.e. running more than one application on the same computational node, it is possible to improve resource utilization and overall throughput. Some applications may have conflicting requirements on resources and co-scheduling may cause performance degradation, so it is important to take it into account in scheduling decisions. In this paper, we formalized co-scheduling problem and proposed multiple scheduling strategies to solve it: an optimal strategy, an online strategy and heuristic strategies. These strategies vary in terms of the optimality of the solution they produce and a priori information about the system they require. We showed theoretically that the online strategy provides schedules with a competitive ratio that has a constant upper limit. This allowed us to solve the co-scheduling problem using heuristic strategies that approximate this online strategy. Numerical simulations showed how heuristic strategies compare to the optimal strategy for different input systems. We proposed a method for measuring input parameters of the model in practice and evaluated this method on HPC benchmark applications. We showed high accuracy of measurement method, which allows to apply proposed scheduling strategies in scheduler implementation.
ARTICLE | doi:10.20944/preprints202004.0483.v1
Subject: Earth Sciences, Environmental Sciences Keywords: city; CO; COVID 19; emission; social distancing
Online: 28 April 2020 (07:36:53 CEST)
The social distancing as a response to COVID 19 pandemic has led to the exceptional reductions of daily routine people activities and vehicle uses mainly in city. This same situation was also experienced by several busy, large, and populous cities in Southeast Asia (SA) countries. Correspondingly, this study aimed to test the hypothesis that the social distancing implementation period has increased the air quality in the term of carbon monoxide (CO) emission reduction as drawn from Jakarta city as an example of the one of populated cities in SA region. The CO was measured in parts per billions (ppb) and monitored on the daily basis employing remote sensor platform. The monitor periods were started from January, February, March, and April 2020 with 10 measurement days for each month. The social distancing was implemented from mid of March to the recent April. The CO measurement data were statistically tested to justify the significant effects of social distancing on the CO levels. Based on the CO data analysis, the order of CO mean by months is February > January > March > April. The CO levels for January, February, March, and April were 87.46 ppb (95%CI: 83.54-91.37), 88.20 ppb (95%CI: 81.65-94.74), 86.38 (95%CI: 81.06-91.69), and 78.68 (95%CI: 74.03-83.32) respectively. This study also find significant difference (p<0.05) of CO levels especially in April when social distancing has been implemented. Hence, these findings illustrate the potential air pollutant reduction gained from implementing social distancing as can be seen in April.
ARTICLE | doi:10.20944/preprints201807.0536.v1
Subject: Materials Science, Nanotechnology Keywords: photocatalysis, co-catalysts, water splitting, metallic cluster
Online: 27 July 2018 (09:33:40 CEST)
Degussa P25 is a benchmark form of TiO2 used worldwide in photocatalysis studies. Currently no such benchmark exists for co-catalysts, which are essential for many photocatalytic reactions. Here, we present the preparation of Pt nanocluster co-catalysts on TiO2 using an unmodified commercial source and equipment that is commonly available. Transmission electron microscopy reveals that the procedure produces TiO2 decorated with Pt atom and nanoclusters (1-5 atoms). Optical reflectance and X-ray diffraction measurements show that the procedure does not affect the TiO2 polymorph or UV-Vis absorbance. Gas phase photocatalytic splitting of heavy water (D2O) shows that the Pt nanocluster decorated TiO2 outperforms Pt nanoparticle (produced by photodeposition) decorated TiO2 in D2 production. Pt nanoclusters, produced directly from a commercial source, with high co-catalyst activity are prime candidates to be used in benchmark photocatalytic reactions.
ARTICLE | doi:10.20944/preprints201710.0010.v1
Subject: Chemistry, Inorganic & Nuclear Chemistry Keywords: Bi2Te3; Thermoelectric properties; co-doping; n-type
Online: 2 October 2017 (15:33:35 CEST)
In order to understand the effect of Pb-CuI co-doping on the thermoelectric performance of Bi2Te3, n-type Bi2Te3 co-doped with x at% CuI and 1/2x at% Pb (x = 0, 0.01, 0.03, 0.05, 0.07, and 0.10) were prepared via high temperature solid state reaction and consolidated using spark plasma sintering. Electron and thermal transport properties, i.e., electrical conductivity, carrier concentration, Hall mobility, Seebeck coefficient, and thermal conductivity, of CuI-Pb co-doped Bi2Te3 were measured in the temperature range from 300 K to 523 K and compared to corresponding x% of CuI-doped Bi2Te3 and undoped Bi2Te3. The addition of a small amount of Pb significantly decreased the carrier concentration, which could be attributed to the holes from Pb atoms, thus the CuI-Pb co-doped samples show a lower electrical conductivity and a higher Seebeck coefficient compared to CuI-doped samples with similar x values. The incorporation of Pb into CuI-doped Bi2Te3 rarely changed the power factor because of the trade-off relationship between the electrical conductivity and the Seebeck coefficient. The total thermal conductivity(κtot) of co-doped samples (κtot ~1.4 W/m∙K at 300 K) is slightly lower than that of 1% CuI-doped Bi2Te3 (κtot~1.5 W/m∙K at 300 K) and undoped Bi2Te3 (κtot ~1.6 W/m∙K at 300 K) due to the alloy scattering. The 1% CuI-Pb co-doped Bi2Te3 sample shows the highest ZT value of 0.96 at 370 K. All data on electrical and thermal transport properties suggest that the thermoelectric properties of Bi2Te3 and its operating temperature can be controlled by co-doping.
Subject: Medicine & Pharmacology, Allergology Keywords: histamine; histamine H1 receptor; histamine H4 receptor; itch; TRPV1; TRPA1; dorsal root ganglion neurons (DRG); Ca2+-imaging
Online: 15 July 2021 (10:12:01 CEST)
Two histamine receptor subtypes (HR), namely H1R and H4R, as key components, are involved in the transmission of histamine-induced itch. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. Aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo and in vitro via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons. The TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch and reduced Ca2+ influx into the neurons. The TRPA1 inhibitor reduced H4R-induced itch and both H1R- and H4R-induced Ca2+ influx. In conclusion, these results indicate that both channels, TRPV1 and TRPA1 are involved in the transmission of histamine-induced pruritus.
ARTICLE | doi:10.20944/preprints202012.0376.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Desipramine; Autophagy; Apoptosis; Death receptor-5; TRAIL
Online: 15 December 2020 (12:09:09 CET)
Autophagy, an alternative cell death mechanism, is also termed programmed cell death type II. Autophagy in cancer treatment needs to be regulated. In our study, autophagy inhibition by desipramine or the autophagy inhibitor chloroquine (CQ) enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 [death receptor (DR5)] expression and subsequently TRAIL-induced apoptosis in TRAIL-resistant A549 lung cancer cells. Genetic inhibition of DR5 substantially reduced desipramine-enhanced TRAIL-mediated apoptosis, proving that DR5 was required to increase TRAIL sensitivity in TRAIL-resistant cancer cells. Desipramine treatment upregulated p62 expression and promoted conversion of light chain 3 (LC3)-I to its lipid-conjugated form, LC3-II, indicating that autophagy inhibition occurred at the final stages of autophagic flux. Transmission electron microscopy analysis showed the presence of condensed autophagosomes, which resulted from the late stages of autophagy inhibition by desipramine. TRAIL, in combination with desipramine or CQ, augmented the expression of apoptosis-related proteins cleaved caspase-8 and cleaved caspase-3. Our results contributed to the understanding of the mechanism underlying the synergistic anti-cancer effect of desipramine and TRAIL and presented a novel mechanism of DR5 upregulation. These findings demonstrated that autophagic flux inhibition by desipramine potentiated TRAIL-induced apoptosis, suggesting that appropriate regulation of autophagy is required for sensitizing TRAIL-resistant cancer cells to TRAIL-mediated apoptosis.
REVIEW | doi:10.20944/preprints202001.0231.v1
Online: 21 January 2020 (03:19:47 CET)
The progesterone receptor (PR) mediates progesterone regulation of female reproductive physiology, as well as gene transcription in non-reproductive tissues, such as brain, bone, lung and vasculature, in both women and men. An unusual property of progesterone is its high affinity for the mineralocorticoid receptor (MR), which regulates electrolyte transport in the kidney in humans and other terrestrial vertebrates. In humans, rats, alligators and frogs, progesterone antagonizes activation of the MR by aldosterone, the physiological mineralocorticoid in terrestrial vertebrates. In contrast, in elephant shark, ray-finned fishes and chickens, progesterone activates the MR. Interestingly, cartilaginous fishes and ray-finned fishes do not synthesize aldosterone, raising the question of which steroid(s) activate the MR in cartilaginous fishes and ray-finned fishes. The simpler synthesis of progesterone, compared to cortisol and other corticosteroids, makes progesterone a candidate physiological activator of the MR in elephant sharks and ray-finned fishes. Elephant shark and ray-finned fish MRs are expressed in diverse tissues, including heart, brain and lung, as well as, ovary and testis, two reproductive tissues that are targets for progesterone, which together suggests a multi-faceted physiological role for progesterone activation of the MR in elephant shark and ray-finned fish. The functional consequences of progesterone as an antagonist of some terrestrial vertebrate MRs and as an agonist of fish and chicken MRs are not fully understood. Indeed, little is known of physiological activities of progesterone via any vertebrate MR.
ARTICLE | doi:10.20944/preprints201905.0356.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Influenza A virus, immunology, immunotherapy, receptor; tumors
Online: 29 May 2019 (16:16:49 CEST)
Dewetting transition - a concept borrowed from fluid mechanics - is a physiological process which takes place inside the hydrophobic pores of ion channels. This transient phenomenon causes a metastable state which forbids water molecules to cross the microscopic receptors’ cavities. This leads to a decrease of conductance, a closure of the hole and, subsequently, severe impairment of cellular performance. We suggest that artificially-provoked dewetting transition in ion channels’ hydrophobic pores could stand for a molecular candidate to erase detrimental organisms, such as viruses, bacteria and cancer cells. We describe a novel type of high-affinity monoclonal antibody, which: a) targets specific trans-membrane receptor structures of harmful or redundant cells; b) is equipped with lipophilic and/or hydrophobic fragments that prevent physiological water flows inside ion channels. Therefore, we achieve an artificial dewetting transition inside receptors’ cavities which causes transmembrane ionic flows discontinuity, channel blockage and subsequent damage of morbid cells. As an example, we describe dewetting monoclonal antibodies targeting the M2 channel of the Influenza A virus: they might prevent water to enter the pores, thus leading to virion impairment.
ARTICLE | doi:10.20944/preprints201904.0176.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: depression; cytokines; inflammation; endogenous opioid; opioid receptor
Online: 16 April 2019 (09:49:14 CEST)
Background: There is now evidence that immune and opioid systems show functional reciprocal relationships and that both systems may participate in the pathophysiology of major depression (MDD). Objective: The present study was carried out to delineate differences between MDD patients and healthy controls in dynorphin and kappa opioid receptor (KORs) in association with levels of β-endorphins and mu opioid receptors (MORs), interleukin-6 (IL-6) and IL-10. Method: The present study recruited 60 drug-free male participants with MDD aged 24-70 year and 30 age-matched healthy males as control group and measured serum levels of dynorphin, KOR, β-endorphin, MOR, IL-6 and IL-10. Results: Serum dynorphin, KOR, β-endorphin and MOR are significantly increased in MDD as compared with controls. The increases in the dynorphin/KOR system and β-endorhin/MOR system are significantly intercorrelated and are both strongly associated with increased IL-6 and IL-10 levels. Dynorphin, β-endorphin, KOR and both cytokines showed a good diagnostic performance for MDD versus controls, whereby both opioid peptides and cytokines show a bootstrapped (n=2000) area under the receiver operating curve of 0.972. KOR and the dynorphin/KOR system are both significantly decreased in depressed subjects with comorbid nicotine dependence. Conclusion: Our findings suggest that in MDD, immune activation is associated with a simultaneous activation of dynorphin/KOR and β-endorhin/MOR signaling and that these opioid systems may participate in the pathophysiology of depression by a) exerting immune regulatory activities attenuating the primary immune response; and b) modulating reward responses and mood as well as emotional and behavioral responses to stress.
ARTICLE | doi:10.20944/preprints201804.0033.v1
Subject: Life Sciences, Endocrinology & Metabolomics Keywords: cordycepin; adenosine A1 receptor; prolactin; anti-obesity
Online: 3 April 2018 (07:53:24 CEST)
Cordycepin is an extract from the insect fungus Cordyceps. militaris, which is a traditional medicine with various biological function. In previous studies, cordycepin had been reported with excellent anti-obesity effect, but the mechanism is unclear. A large quantity of evidences showed that prolactin plays an important part in body weight regulation, hyperprolactinemia can promote appetite and accelerate fat deposition. In this study, we explored the molecular mechanism of the anti-obesity effect of cordycepin by reducing prolactin release via an adenosine A1 receptor. In vivo, obese rats model was induced by high fat diet for 5 weeks, the serum and liver lipids coupling with serum prolactin were reduced by treatment of cordycepin, the results suggested that cordycepin is a potential drug for therapying obesity which could be related with prolactin. In vitro, cordycepin could inhibit prolactin secretion in GH3 cells via upregulating the expression of adenosine A1 receptor, the inhibition effect could be blocked by an antagonist of adenosine receptor A1 DPDPX, prolactin induced the upregulation of lipogenesis genes PRLR, and P-JAK2 in 3T3-L1 cells. Intriguingly, cordycepin would down-regulate the expression of prolactin receptor (PRLR). Thus, we concluded that cordycepin modulate body weight by reducing prolactin release via an adenosine A1 receptor.
ARTICLE | doi:10.20944/preprints202012.0635.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Free fatty acid receptor 2; microbiota; metabolite; sensor; G-coupled protein receptor; signaling; Alzheimer’s disease; senescence; C. elegans
Online: 24 December 2020 (14:56:00 CET)
Gut microbiota and its metabolites like short chain fatty acids (SCFAs) are linked with pathology of Alzheimer’s disease (AD)- a debilitating public health problem in older adults. However, strategies to beneficially modulate gut microbiota and its sensing signaling pathways remain largely unknown. Here, we screened, validated and established the agonists of free fatty acid receptor 2 (FFAR2) signaling, which senses beneficial signals from SCFAs produced by microbiota in the gut. We demonstrated that inhibition of FFAR2 signaling increases amyloid-beta (Aβ) stimulated neuronal toxicity. Thus, we screened FFAR2 agonists, using in-silico library of more than 144,000 natural compounds, and 15 compounds were selected based on binding with FFAR2 agonist sites. Further, cell culture toxicity and FFAR2 stimulatory experiments demonstrated that Fenchol (a natural compound commonly present in basil) was potent FFAR2 agonist in neuronal cells. Interestingly, we also demonstrated that Fenchol protects Aβ-stimulated neurodegeneration in FFAR2 dependent manner. In addition, Fenchol reduced AD like phenotypes such as Aβ-accumulation and, learning and memory behaviors in Caenorhabditis (C.) elegans. Fenchol increased Aβ-clearance by increasing proteasome/lysosome activity and reduced senescence in neuronal cells. These results demonstrated that the inhibition of FFAR2 signaling promotes Aβ-induced neurodegeneration, while activating it by Fenchol as a natural agonist reverse it by promoting Aβ-clearance and reducing cellular senescence; thus stimulation of FFAR2 signaling can be a therapeutic approach to prevent/ treat AD.
ARTICLE | doi:10.20944/preprints202009.0185.v1
Subject: Life Sciences, Endocrinology & Metabolomics Keywords: eel luteinizing hormone receptor; constitutively activating mutation; inactivating mutation; cyclic adenosine monophosphate response; cell surface loss of receptor
Online: 8 September 2020 (10:56:48 CEST)
We analyzed signal transduction of three constitutively activating mutants (M410T, L469R, and D590Y) and two inactivating mutants (D417N and Y558F) of the eel luteinizing hormone receptor (eel LHR), known to occur in human LHR. The objective of this study was to assess the functional effects of these mutations in signal transduction and cell surface loss of receptor. Mutant receptors were transiently expressed in Chinese hamster ovary (CHO-K1) cells. Eel LH-stimulated accumulation of cyclic adenosine monophosphate (cAMP) was measured by homogeneous time-resolved fluorescence (HTRF) assays. The loss of receptors from the cells surface was measured using an enzyme-linked immunosorbent assay (ELISA) in human embryonic kidney (HEK) 293 cells. The cAMP response in cells expressing the wild type eel LHR was increased in a dose-dependent manner using eel LH ligand stimulation. Compared with the wild type, cells expressing the activating mutants (M410T, L469R, and D590Y), exhibited a 4.0-, 19.1-, and 7.8-fold increase in basal cAMP response without agonist stimulation, respectively. Their maximal responses to agonist stimulation were approximately 65%, 52%, and 98%, respectively, of those of the wild type. The inactivating mutants (D417N and Y558F) did not completely impair signal transduction, and their maximal responses were only 33% and25 % of those of wild type. These data clearly showed that the eel LHR-L469R and D590Y, activating mutants enhanced the rate of the loss of cell surface receptors following treatment with eel LH. Thus, the loss of cell surface receptors in cells expressing mutant eel LHRs was consistent with the eel LH agonist-induced production of cAMP. Our results suggested that the activation of the eel LHR requires appropriate loss of LHR-ligand complexes from the cell surface.
REVIEW | doi:10.20944/preprints202008.0017.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: μ opioid receptor; receptor model; biased ligands; dependence; pain therapy; neonatal opioid withdrawal syndrome; naltrexone; 6β-naltrexol; buprenorphine
Online: 2 August 2020 (11:27:40 CEST)
Opioid analgesics are effective pain therapeutics but cause various adverse effects and addiction. For safer pain therapy, biased opioid agonists selectively target distinct m opioid receptor (MOR) conformations, while the potential of biased opioid antagonists has been neglected. Agonists convert a dormant receptor form (MOR-m) to a ligand-free active form (MOR-m*), which mediates MOR signaling. Moreover, MOR-m converts spontaneously to MOR-m* (basal signaling). Persistent upregulation of MOR-m* has been invoked as a hallmark of opioid dependence. Contrasting interactions with both MOR-m and MOR-m* can account for distinct pharmacological characteristics of inverse agonists (naltrexone), neutral antagonists (6b-naltrexol), and mixed opioid agonist-antagonists (buprenorphine). Upon binding to MOR-m*, naltrexone but not 6b-naltrexol suppresses MOR-m*signaling. Naltrexone blocks opioid analgesia non-competitively at MOR-m*with high potency, whereas 6BN must compete with agonists at MOR-m, accounting for ~100-fold lower in vivo potency. Buprenorphine’s bell-shaped dose-response curve may also result from opposing effects on MOR-m and MOR-m*. In contrast, we find that 6b-naltrexol potently prevents dependence, below doses affecting analgesia or causing withdrawal, possibly binding to MOR conformations relevant to opioid dependence. We propose that 6b-naltrexol is a biased opioid antagonist modulating opioid dependence at low doses, opening novel avenues for opioid pain therapy and use management.
ARTICLE | doi:10.20944/preprints202202.0208.v1
Subject: Biology, Physiology Keywords: aging; intestinal microbiota; dysbiosis; probiotics; microbial co-occurrences
Online: 17 February 2022 (10:59:55 CET)
Age-related alterations in the gut microbiome composition and its impacts on the host’s health have been well described; however, detailed analyses of the gut microbial structure defining ecological microbe-microbe interactions is limited. One of the ways to determine these interactions is by understanding microbial co-occurrence patterns. We previously showed promising abilities of Lactobacillus acidophilus DDS-1 on the aging gut microbiome and immune system. However, the potential of the DDS-1 strain to modulate microbial co-occurrence patterns is unknown. Hence, we aimed to investigate the ability of L. acidophilus DDS-1 to modulate the fecal, mucosal and cecal-related microbial co-occurrence networks in young and aging C57BL/6J mice. Our Kendall’s tau correlation measures of co-occurrence revealed age-related changes in the gut microbiome, which were characterized by reduced number of nodes and associations across sample types when compared to younger mice. After four-week supplementation, L. acidophilus DDS-1 differentially modulated the overall microbial community structure in fecal and mucosal samples as compared to cecal samples. Beneficial bacteria such as Lactobacillus and Akkermansia acted as connectors in aging networks in response to L. acidophilus DDS-1 supplementation. Our findings provided the first evidence of the DDS-1-induced gut microbial ecological interactions revealing the complex structure of microbial ecosystems with age.
ARTICLE | doi:10.20944/preprints202108.0571.v1
Subject: Biology, Plant Sciences Keywords: Arabidopsis thaliana; plastid; co-maturation; post-transcriptional; Nanopore
Online: 31 August 2021 (11:48:48 CEST)
Plastid gene expression involves many post-transcriptional maturation steps resulting in a complex transcriptome composed of multiple isoforms. Although short read RNA-seq has considerably improved our understanding of the molecular mechanisms controlling these processes, it is unable to sequence full-length transcripts. This information is however crucial when it comes to understand the interplay between the various steps of plastid gene expression. Here, the study of the Arabidopsis leaf plastid transcriptome using Nanopore sequencing showed that many splicing and editing events were not independent but co-occurring. For a given transcript, maturation events also appeared to be chronologically ordered with splicing happening after most sites are edited.
ARTICLE | doi:10.20944/preprints202108.0562.v1
Subject: Medicine & Pharmacology, Veterinary Medicine Keywords: female reproductive tract; organoid; co-culture; crosstalk; blastocyst
Online: 31 August 2021 (11:19:56 CEST)
Hormones must be balanced and dynamically controlled for the Female Reproductive Tract (FRT) to function correctly during the menstrual cycle, pregnancy, and delivery. Gamete selection and successful transfer to the uterus, where it implants and pregnancy occurs, is supported by the mucosal epithelial lining of the FRT ovaries, uterus, cervix, fallopian tubes, and vagina. Successful implantation and placentation in humans and other animals rely on complex interactions between the embryo and a receptive female reproductive system. The FRT's recent breakthroughs in three-dimensional (3D) organoid systems now provide critical experimental models that match the organ's physiological, functional, and anatomical characteristics in vitro. This article summarizes the current state of the art on organoids generated from various parts of the FRT. The current analysis examines recent developments in the creation of organoid models of reproductive organs, as well as their future directions.
REVIEW | doi:10.20944/preprints202105.0143.v1
Subject: Life Sciences, Biochemistry Keywords: Co-infection; Drug resistance; Gut microbiota; Salmonellosis; Schistosoma
Online: 7 May 2021 (12:02:03 CEST)
Antibiotic inefficacy in treating bacterial infections is largely studied in the context of developing resistance mechanisms. However, little attention has been paid to combined diseases mechanisms, interspecies pathogenesis and the resulting impact on antimicrobial treatment. This review will consider the co-infections of Salmonella and Schistosoma mansoni. It summarises the protective mechanisms that the pathophysiology of the two infections confer, which leads to an antibiotic protection phenomenon. This review will elucidate the functional characteristics of the gut microbiota in the context of these co-infections, the pathogenicity of these infections in infected mice, and the efficacy of the antibiotics used in treatment of these co-infections over time. Salmonella-Schistosoma interactions and the mechanism for antibiotic protection are not well established. However, antimicrobial drug inefficacy is an existing phenomenon in these co-infections. The treatment of schistosomiasis to ensure the efficacy of antibiotic therapy for bacterial infections should be considered in co-infected patients.
ARTICLE | doi:10.20944/preprints202104.0216.v1
Subject: Life Sciences, Biochemistry Keywords: SARS-CoV-2; variants; co-circulation; dominance; vaccines
Online: 7 April 2021 (17:24:38 CEST)
Some emergent SARS-CoV-2 variants raise concerns due to their altered biological properties. For both B.1.1.7 and B.1351 variants, named as variants of concern (VOC), increased transmissibility was reported, whereas B.1.351 was more resistant to multiple monoclonal antibodies (mAbs), as well as convalescent and vaccination sera. To test this hypothesis, we examined the proportion of VOC over time across different geographic areas where the two VOC, B.1.1.7 and B.1.351, co-circulate. Our comparative analysis was based on the number of SARS-CoV-2 sequences on GISAID database. We report that B.1.1.7 dominates over B.1.351 in geographic areas where both variants co-circulate and the B.1.1.7 was the first variant introduced in the population. The only areas where B.1.351 was detected at higher proportion were South Africa and Mayotte in Africa, where this strain was associated with increased community transmission before the detection of B.1.1.7. The dominance of B.1.1.7 over B.1.351 could be important since B.1.351 was more resistant to certain mAbs, as well as heterologous convalescent and vaccination sera, thus suggesting that it may be transmitted more effectively in people with pre-existing immunity to other VOC. This scenario would lessen the effectiveness of vaccine and urge the need to update them with new strains.
ARTICLE | doi:10.20944/preprints202007.0711.v1
Subject: Life Sciences, Molecular Biology Keywords: co-expression network; residual feed intake; RNA-Seq
Online: 30 July 2020 (09:39:36 CEST)
Long non-coding RNA (lncRNA) can regulate several aspects of gene expression, being associated with complex phenotypes in humans and livestock species. In taurine beef cattle, recent evidence points to the involvement of lncRNA in feed efficiency (FE), a proxy for increased productivity and sustainability. Here, we hypothesized specific regulatory roles of lncRNA in FE of indicine cattle. Using RNA-Seq data from liver, muscle, hypothalamus, pituitary and adrenal gland from Nellore bulls with divergent FE, we submitted new transcripts to a series of filters to confidently predict lncRNA. Then, we identified lncRNA that were differentially expressed (DE) and/or key regulators of FE. Finally, we explored lncRNA genomic location and interactions with miRNA and mRNA to infer potential function. We were able to identify 126 relevant lncRNA for FE in Bos indicus, some with high homology to previously identified lncRNA in Bos taurus and some possible specific regulators of FE in indicine cattle. Moreover, lncRNA identified here were linked to previously described mechanisms related to FE in hypothalamus-pituitary-adrenal axis and are expected to help elucidate this complex phenotype. This study contributes to expanding the catalogue of lncRNA, particularly in indicine cattle, and identifies candidates for further studies in animal selection and management.
ARTICLE | doi:10.20944/preprints202003.0291.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: co-infection; coronavirus disease 2019; COVID-19; influenza
Online: 19 March 2020 (02:00:47 CET)
Background: On late December 2019, a viral pneumonia known as coronavirus disease 2019 (COVID-19), was originated from China and spread very rapidly in the world. Therefore, COVID-19 became a global concern and health problem. Methods: We presented four patients in this study. They were selected from patients who presented with pneumonia symptoms and were suspicious for COVID-19 and referred to the intended centers for COVID-19 diagnosis and management of Shiraz University of Medical Sciences in the south of Iran. Two nasopharyngeal and oropharyngeal throat swab samples were collected from each patient and tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection by real-time reverse-transcriptase–polymerase-chain-reaction (RT-PCR), and also samples were sent for influenza viruses and all the respiratory panel. Results: In the present report, four patients were diagnosed in the starting days of COVID-19 disease in our center in south of Iran with co-infection of SARS-CoV-2 and influenza virus. Conclusions: This co-infection of COVID-19 and influenza highlights the importance of considering SARS-CoV-2 PCR assay regardless of other positive findings for other pathogens in the primary test during the epidemic.
ARTICLE | doi:10.20944/preprints202002.0430.v2
Subject: Life Sciences, Biotechnology Keywords: Co-culture; Reduced-serum; Wound bed; Fibroblasts; Keratinocytes
Online: 12 March 2020 (13:24:46 CET)
Contact-based co-culture of fibroblasts and keratinocytes is important to study the structure and functions of the wound bed. Co-culture of these two cell types in direct contact with each other has been challenging, requiring high serum concentrations (up to 10%), feeder systems and a range of supplemental factors. These approaches are not only technically demanding, but also present scientific, cost and ethical limitations associated with high-serum concentrations. We have developed two reduced-serum approaches (1-2%) to support contact-based co-culture of human dermal fibroblasts (HDFa) and human epidermal keratinocytes (HaCaT). The two approaches include (1) Specialized cell culture media for each cell type mixed in a 1:1 ratio (KGM+FGM), and (2) Minimal media supplemented with cell-specific growth factors (MEM+GF). Co-culture could be successfully achieved by co-seeding (two cell types were introduced simultaneously), or in a layered fashion (keratinocytes seeded on top of confluent fibroblasts). With wound scratch assays, the co-cultured platforms could demonstrate cell proliferation, migration and wound closure. The reduced-serum conditions developed are simple, easy to formulate and adopt, and based on commonly-available media components. These contact-based co-culture approaches can be leveraged for wound and skin studies, and tissue bioengineering applications, potentially reducing concerns with high-serum formulations.
CASE REPORT | doi:10.20944/preprints201811.0254.v1
Subject: Medicine & Pharmacology, Other Keywords: dengue; chikungunya; Leptospira; co-infection; Colombia; Latin America
Online: 12 November 2018 (03:21:38 CET)
Background: The febrile patient from tropical areas, in which emerging arboviruses are endemic, represent a diagnostic challenge and potential co-infections with other pathogens (i.e bacteria or parasites) are usually overlooked. Objectives: We present a case of an elderly woman diagnosed with dengue, chikungunya and Leptospira interrogans co-infection. Study Design: Case report. Results: An 87-year old woman from Colombia complained of upper abdominal pain, arthralgia, myalgia, hyporexia, malaise and intermittent fever accompanied with progressive jaundice. She had a medical history of chronic heart failure (Stage C, NYHA III), without documented cardiac murmurs, right bundle branch block, non-valvular atrial fibrillation, hypertension, and chronic venous disease. Her cardiac and pulmonary status quickly deteriorated after 24 hours of her admission without electrocardiographic changes and she required ventilatory and vasopressor support. In the next hours the patient evolved to pulseless electrical activity and then she died. Dengue IgM, NS1 ELISA, MAT for Leptospira interrogans and RT-PCR for chikungunya, were positive. Discussion: This case illustrates a multiple co-infection in a febrile patient from a tropical area of Latin America that evolved to death.
ARTICLE | doi:10.20944/preprints201704.0014.v1
Subject: Materials Science, Nanotechnology Keywords: tin oxide pellets; doping; HRTEM analysis; CO; sensitivity
Online: 4 April 2017 (08:16:13 CEST)
In this work, we report synthesis of Cu, Pt and Pd doped SnO2 powders and their comparative CO gas sensing studies. Dopants were incorporated into SnO2 nanostructures using chemical and impregnation methods by using urea and ammonia as precipitation agents. The synthesized samples were characterized using X-ray diffraction (XRD), Raman spectroscopy, Scanning electron microscopy (SEM) and High resolution transmission electron microscopy (HR-TEM). The presence of dopants within the SnO2 nanostructures was evidenced from HR-TEM. Doped powders utilizing chemical methods with urea as precipitation agent presented higher sensitivities compared to the remaining, which is due to the formation of uniform and homogeneous particles resulted from the temperature assisted synthesis. The particle sizes of doped SnO2 nanostructures were in the range of 40-100 nm. An enhanced sensitivity around 1783 was achieved with Cu doped SnO2 when compared with two other dopants i.e., Pt (1200) and Pd: SnO2(502). The high sensitivity of Cu: SnO2 is due to formation of CuO and its excellent association and dissociation in the presence of CO with adsorbed atmospheric oxygen at sensor operation temperatures resulted in high conductance. Cu: SnO2 may be an alternative and cost effective sensor for industrial applications.
ARTICLE | doi:10.20944/preprints201611.0123.v1
Subject: Biology, Forestry Keywords: co-management; livelihoods; conflicts; biodiversity conservation; sustainable development
Online: 24 November 2016 (11:25:34 CET)
Good governance in natural resource management (NRM) is one of the most challenging issues in developing countries that often inappropriately embedded in national policies and political agendas. It is, in fact, even more important for countries like Bangladesh with exceptionally high pressure and dependence on its natural resources for sustaining rural livelihoods. Globally, nowadays, good governance is considered as one of the key factor for achieving the goal of sustainable development and biodiversity conservation. Bangladesh, of late has responded to that global zeal by involving local communities in the management of country’s declining forest and other natural resources. The colonial legacy of the forestry sector of Bangladesh was planned and, managed as interim projects through donors’ prescriptions. Thus, institutions, management processes and conservation outcomes were problematic. The conventional approach adopted by colonial and post-colonial regimes for forest management also proved to be inefficient due to its top-down management system. The absolute dependency on donor support, and their prescription sometimes worsened the situation both ecologically and socially. Global, regional and local trends supported the need for a different dimension in the governance paradigms. The introduction of a pluralistic approach, known as co-management in protected areas (PAs) is an example of an attempt whereby shared governance mechanism are implemented to attain the desired goals of conservation that will also address the livelihoods and aspirations of communities living in and around PAs of the country. However, in designing future forest and PA regimes the concern of the external aid support and attached conditions remain a reality that needs to be addressed. Adequate attention should be given to our vanishing biodiversity, culture and community livelihoods through devising an appropriate governance mechanism recognizing and supporting local rights, access and participation in the environmental management. It is now time to mainstream the adhoc nature of governance according to our national conservation strategy and policy frameworks in order to achieve the goals and objectives of the Bangladesh NRM sector addressing the human and community right of people in the specific context of forest protected areas management.
REVIEW | doi:10.20944/preprints201611.0101.v1
Subject: Earth Sciences, Environmental Sciences Keywords: biodiversity conservation, livelihood, co-management, stakeholder, law enforcement
Online: 18 November 2016 (15:20:07 CET)
Despite of being an exceptionally biodiversity rich country, the forest coverage of Bangladesh is declining at an alarming rate. Declaration and management of protected areas in this regard is one of the efforts from government side to tackle the loss of biodiversity. The limited numbers of forest-protected areas (FPA), established to conserve the dwindling forest biodiversity of the country with high pressure on them for timber, non-timber forest products, and fuelwood - makes their management challenging. Moreover, most of the FPAs of the country declared only in the recent decades with very limited infrastructure, manpower and policy support for monitoring and governance. Some people-centred approaches for the management of FPAs and alternative livelihood and income generation subsidies although made available through a few project interventions, their number are still inadequate and performance remains less than satisfactory. This chapter provides a critical review of the FPAs of Bangladesh looking at their role in biodiversity conservation, management challenges, and key lessons from previous management interventions with recommendations for the future. It has been revealed that the FPA system of Bangladesh still poorly represents the diverse forest ecosystems with relatively small forest size and lack of corridors for the movement of wildlife. There are ample opportunities to render co-management of FPAs an effective strategy to minimize the conflicts in FPAs management in the country. It is, however, important to ensure the access of local forest-dependent people to different alternative income generating options that may adequately support their livelihoods.
REVIEW | doi:10.20944/preprints202105.0414.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: : mineralocorticosteroid receptor antagonist (MRA); angiotensin converting enzyme 2 (ACE2); SARS-CoV-2; transmembrane protease receptor serine 2; furin; plasmin
Online: 18 May 2021 (10:39:03 CEST)
Aims: Spironolactone is a steroidal mineralocoricosteroid receptor antagonist (MRA) used for treatment of resistant hypertension, heart failure and edema. It exerts class specific adverse effects that are shared by other MRAs. Additionally, it exerts unique “off target” steroidal effects that include gynecomastia, impotence and loss of libido in males and menstrual irregularity in females. Together, these have led to a poor tolerability and limited use despite positive results in many randomized, controlled clinical trials. We review the off-target effects of spironolactone that may summate with its MRA action to provide an advantageous profile for prevention or treatment of patients with COVID-19. Methods: Literature review using PubMed Central. Results: The blockade by spironolactone of the androgen receptor should diminish the expression of transmembrane protease serine 2 (TMPRSS2) that has an androgen promoter while its MRA action should enhance the expression of protease nexin1 (PN1) that inhibits furin and plasmin. TMPRSS2, furin and plasmin cooperated to process the SARS-CoV-2 spike protein to increase its high affinity binding to the angiotensin converting enzyme 2 (ACE2) and thereby promote viral cell entry. Its actions as an MRA may reduce inflammation and preserve pulmonary, cardiac and vascular functions. Its anti-plasmin action may combat hemostatic dysfunction. Conclusion: The hypothesis that the off-target effects of spironolactone summate with its MRA actions to provide special benefits for COVID-19 is worthy of direct investigation and clinical trial.
REVIEW | doi:10.20944/preprints202205.0290.v1
Subject: Life Sciences, Other Keywords: Cholesterol; PCSK9 inhibitors; HMG-CoA; LDL receptor; statins
Online: 23 May 2022 (10:01:24 CEST)
Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a proteolytic enzyme that indirectly regulates serum LDL cholesterol by destroying LDL receptors. In clinical studies, the main role of the proprotein convertase subtilisin/Kexin type9 (PCSK9) inhibitor in cholesterol regulation was elucidated. It is produced in the liver but is also present in the kidney and intestine. It prevents HMGCo from synthesizing cholesterol. SREBP-2 is a reductase that is induced by statins. In a dose-dependent manner, increasing SREBP-2 levels enhanced LDL-R and PCSK9 gene expression. At the minimum, two procedures have been developed to overcome the plasma level of PCSK9. This is the LDLR test, polyclonal antibodies, and sentience oligonucleotide. Lower dosage statin treatment with a proprotein convertase subtilisin/Kexin type9 inhibitor will be most efficient in lowering LDL and avoiding statin adverse effects. In multiple long-term trials, statins have been found to reduce cardiovascular mortality by 30% and stroke incidence by 20%. In this way, we conclude the role of PCSK9 in hypercholesterolemia.
REVIEW | doi:10.20944/preprints202205.0269.v1
Subject: Medicine & Pharmacology, Other Keywords: inflammation; calcium-sensing receptor; burns; chemokines; NLRP3 inflammasome
Online: 20 May 2022 (04:01:33 CEST)
Burn injury serves as an example of a condition with a robust inflammatory response. The elevation of circulating interleukins (IL)- 1 beta and -6 in children with severe burn injury up-regulate the parathyroid calcium sensing receptor (CaSR) resulting in hypocalcemic hypoparathyroidism with urinary calcium wasting. This effect protects the body from the hypercalcemia resulting from bone resorption liberating calcium into the circulation. Extracellular calcium can exacerbate and prolong the inflammatory response by stimulating mononuclear cell chemokine production as well as the NLRP3 inflammasome of the innate immune system, resulting in increased IL-1 production by monocytes and macrophages. Interestingly, the CaSR response to inflammatory cytokines disappears with age, potentially trapping calcium from bone resorption in the circulation and allowing it to contribute to increased inflammation and possibly increased calcium deposition in small arteries, , such as the coronaries, as conditions with increased chronic inflammation, such as spinal cord injury, osteoarthritis and rheumatoid arthritis have an incidence of cardiovascular disease and coronary artery calcium deposition significantly higher than the unaffected age-matched population.
ARTICLE | doi:10.20944/preprints202202.0082.v1
Online: 7 February 2022 (11:57:16 CET)
Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet® model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to develop further more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.
ARTICLE | doi:10.20944/preprints202108.0007.v1
Subject: Life Sciences, Biochemistry Keywords: receptor; distribution; BMP; BMPR; center of mass; micropattern
Online: 2 August 2021 (09:29:25 CEST)
At the plasma membrane, transmembrane receptors are at the interface between cells and their environment. They allow sensing and transduction of chemical and mechanical extracellular signals. The spatial distribution of receptors and the specific recruitment of receptor subunits to the cell membrane is crucial for the regulation of signaling and cell behavior. However, it is challenging to define what regulates such spatial patterns for receptor localization, as cell shapes are extremely diverse when cells are maintained in standard culture conditions. Bone morphogenic protein receptors (BMPRs) are serine-threonine kinases, which build heteromeric complexes of BMPRI and II. These are especially interesting targets for receptor distribution studies, since the signaling pathways triggered by BMPR-complexes depends on their dimerization mode. They might exist as pre-formed complexes, or assemble upon binding of BMP, triggering cell signaling which leads to differentiation or migration. In this work we analyzed BMPR receptor distributions in single cells grown on micropatterns, which allows not only to control cell shape, but also the distribution of intracellular organelles and protein assemblies. We developed a script called ComRed (Center Of Mass Receptor Distribution), which uses center of mass calculations to analyze the shift and spread of receptor distributions according to the different cell shapes. ComRed was tested by simulating changes in experimental data, showing that shift and spread of distributions can be reliably detected. Our ComRed-based analysis of BMPR-complexes indicates that receptor distribution depends on cell polarization. The absence of a coordinated internalization after addition of BMP suggests that a rapid and continual recycling of BMPRs occurs. Receptor complexes formation and localization in cells induced by BMP might yield insights into the local regulation of different signaling pathways.
ARTICLE | doi:10.20944/preprints202106.0030.v1
Online: 1 June 2021 (11:59:27 CEST)
Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.
ARTICLE | doi:10.20944/preprints202105.0634.v1
Subject: Medicine & Pharmacology, Allergology Keywords: silica; nanoparticles; ATP; purinergic receptor; airway; epithelial cell
Online: 26 May 2021 (11:45:50 CEST)
Because of their low cost and easy production silica nanoparticles (NPs) are amply used in multiple manufactures as anti-caking, densifying and hydrophobic agents. However, this has increased the exposure levels of the general population and has raised concerns about possible toxicity of this nanomaterial. NPs are known to affect the function of the airway epithelium, but the biochemical pathways targeted by these particles remain largely unknown. Here we investigated the effects of NPs on the responses of cultured human bronchial epithelial (16HBE) cells to the damage-associated molecular pattern ATP, using fluorometric measurements of intracellular Ca2+ concentration. Upon stimulation with extracellular ATP these cells displayed a concentration-dependent increase in intracellular Ca2+, which was mediated by release from intracellular stores. Silica NPs inhibited the Ca2+ responses to ATP within minutes of application and at low micromolar concentrations, which are significantly faster and more potent than those previously reported for the induction of cellular toxicity and pro-inflammatory responses. NPs-induced inhibition appeared to be independent from the increase in intracellular Ca2+ they produce, and via a non-competitive mechanism. These findings suggest that NPs reduce the ability of airway epithelial cells to mount ATP-dependent protective responses such as the increase in mucociliary clearance and cough.
REVIEW | doi:10.20944/preprints202105.0625.v1
Online: 26 May 2021 (08:17:01 CEST)
Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) family that identify pathogen-associated molecular patterns derived from microbes and activate immune cell response. Following TLRs ligation, different adaptor and transcription molecules such as myeloid differentiation primary response gene 88 (MyD88) and nuclear factor kappa B (NF-kB) are recruited that initiate inflammatory signaling pathways. The human Toll-like receptor 10 (hTLR10) is a novel member of the PRRs family with a regulatory function of immune responses because of unique cytoplasmic domains which lead to induction of both inflammatory and anti-inflammatory properties. Recent studies have reported the association of TLR10 polymorphisms with many inflammatory diseases and human cancer. Engagement of TLR10 on the surface of the epithelium and macrophages leads to the production of proinflammatory cytokines and chemokines, while other studies have proven an anti-inflammatory role of TLR10. Accordingly, TLR10 suppresses proinflammatory cytokine production via negative regulation of MyD88 and the Akt (protein kinase B) and MAPK (mitogen-activated protein kinase) signaling pathways. This review aimed to provide answers for these conflicting findings (Inflammatory and anti-inflammatory properties of TLR10) to further identify distinct biological functions of TLR10.
Subject: Life Sciences, Biochemistry Keywords: glucocorticoid receptor; allosteric; elephant shark; nuclear receptors; evolution
Online: 19 October 2020 (10:03:00 CEST)
Orthologs of human glucocorticoid receptor (GR) and human mineralocorticoid receptor (MR) first appear in cartilaginous fishes. Subsequently, the MR and GR diverged to respond to different steroids: the MR to aldosterone and the GR to cortisol and corticosterone. We report that cortisol, corticosterone and aldosterone activate full-length elephant shark GR, and progesterone, which activates elephant shark MR, does not activate elephant shark GR. However, progesterone inhibits steroid binding to elephant shark GR, but not to human GR. Together, this indicates partial functional divergence of elephant shark GR from the MR. Deletion of the N-terminal domain (NTD) from elephant shark GR (truncated GR) reduced the response to corticosteroids, while truncated and full-length elephant shark MR had similar responses to corticosteroids. Swapping of NTDs of elephant shark GR and MR yielded an elephant shark MR chimera with full-length GR-like increased activation by corticosteroids and progesterone compared to full-length elephant shark MR. Elephant shark MR NTD fused to GR DBD+LBD had similar activation as full-length MR, indicating that the MR NTD lacked GR-like NTD activity. We propose that NTD activation of human GR evolved early in GR divergence from the MR.
ARTICLE | doi:10.20944/preprints202008.0083.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: scavenger receptor CD36; inflammation; vascular calcification; diabetes; atherosclerosis
Online: 4 August 2020 (10:37:01 CEST)
Diabetes mellitus entails increased atherosclerotic burden and medial arterial calcification but the precise mechanisms are not fully elucidated. Our aim was to investigate the implication of CD36 in inflammation and calcification processes orchestrated by vascular smooth muscle cells (VSMCs) under hyperglycemic and atherogenic conditions. We examined the expression of CD36, pro-inflammatory cytokines, endoplasmic reticulum (ER) stress markers and mineralization-regulating enzymes by RT-PCR in human VSMCs, cultured in medium containing normal (5 mM) or high glucose (22 mM) for 72 h with or without oxLDL (24 h). The uptake of DiI-labelled oxLDL was quantified by flow citometry and fluorimetry and calcification assays were performed in VSMC cultured in osteogenic medium and stained by alizarin red. We observed an induction in the expression of CD36, cytokines, calcification markers and ER stress markers under high glucose that was exacerbated by oxLDL. These results were confirmed in carotid plaques from subjects with diabetes versus non-diabetic subjects. Accordingly, the uptake of DiI-labelled oxLDL was increased after exposure to high glucose. Silencing of CD36 abolished the induction of CD36 and reduced the expression of calcification enzymes and mineralization of VSMC. Our results indicate that CD36 signaling is involved in hyperglycemia and oxLDL-induced vascular calcification in diabetes.
BRIEF REPORT | doi:10.20944/preprints202005.0006.v1
Online: 2 May 2020 (12:11:38 CEST)
The recent 2019-nCoV outbreak, spreading infection around the globe is jeopardizing the public health and global economy. The virus was reported to have emerged from an animal market in Wuhan, China at the end of 2019 and presumed to have originated from bats and eventually transmitted in humans. The entry of the virus into human cells is triggered by a series of molecular events initiated with the binding of a receptor-binding domain of viral spike protein to human Ace2 cell surface receptor. Based on the comparative sequence analysis of the well-known binding hotspots of human Ace2, cross-interacting potential of 2019-nCoV was predicted, which suggests Ace2 of wild animals like tiger, bear, orangutan, etc.; aquatic mammals like whale and dolphins; and domestic animals like cat, horse, goat, sheep, dog etc. as potential target. However, the recognition of Ace2 of bats, rats and mice by the 2019-nCoV spike protein remains under question. The study indicates that 2019-nCoV might have broad host range and may thus intensify the gravity of 2019-nCoV outbreak
Subject: Life Sciences, Cell & Developmental Biology Keywords: SARS-CoV2; spike; receptor–ligand docking; super infection
Online: 20 March 2020 (08:30:40 CET)
SARS-CoV2 (corona virus) has spread globally at an unprecedented rate; so far, increasing SARS-CoV2-infected individuals have been identified. Although the situation in China is improving and is currently under control, the outbreak in other countries and its pandemic management is only beginning to develop. Based on 154 SARS-CoV2 genome sequence analyses, we used receptor–ligand docking to identify one potential point mutation (V354F) on the spike structure which enhances spike binding to ACE2 receptors underlying potential super infection. Importantly, the V354F site on spike S1 had been identified in 5/10 infected French patients living in Paris, who sharing 100% identical SARS-CoV2 genomes. With Covid-19 cases increasing rapidly in France that could lead to a new explosion, we suggest that the French government should identify all potential super spreaders and treat them accordingly. In summary, our study provides on of the measures to avoid the potential second worldwide explosion of SARS-CoV2.
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: CYP3A5; androgen receptor; African American; CYP3A5 inhibitors/inducers
Online: 6 March 2020 (03:33:52 CET)
Androgen receptor signaling is crucial for prostate cancer growth and is positively regulated in part by intratumoral CYP3A5. As African American (AA) men often carry the wild type CYP3A5 and express high level of CYP3A5 protein, we blocked the wild type CYP3A5 in AA origin prostate cancer cells and tested its effect on androgen receptor signaling. q-PCR based profiler assay identified several AR regulated genes known to regulate AR nuclear translocation, cell cycle progression and cell growth. CYP3A5 processes several commonly prescribed drugs and many of these are CYP3A5 inducers or inhibitors. In this study, we test the effect of these commonly prescribed CYP3A5 inducers/inhibitors on AR signaling. The results show that the CYP3A5 inducers promoted AR nuclear translocation, downstream signaling and cell growth whereas CYP3A5 inhibitors abrogated them. The observed changes in AR activity is specific to alterations in CYP3A5 activity. Both the inducers tested demonstrated increased cell growth of prostate cancer cells, whereas the inhibitors showed reduced cell growth. Further, characterization and utilization of the observation that CYP3A5 inducers and inhibitors alter AR signaling may provide guidance to physicians prescribing CYP3A5 modulating drugs to treat comorbidities in elderly patients undergoing ADT, particularly AA.
ARTICLE | doi:10.20944/preprints201810.0746.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: aryl hydrocarbon receptor; polyphenols; inflammation; urolithin; AHR antagonist
Online: 31 October 2018 (10:08:59 CET)
Urolithins (e.g., UroA and B) are gut microbiota-derived metabolites of the natural polyphenol ellagic acid. Urolithins are associated with various health benefits, including attenuation of inflammatory signaling, anti-cancer effects and repression of lipid accumulation. The molecular mechanisms underlying the beneficial effects of urolithins remain unclear. We hypothesize that some of the human health benefits of urolithins are mediated through the aryl hydrocarbon receptor (AHR). Utilizing a cell-based reporter system, we tested urolithins for the capacity to modulate AHR activity. Cytochrome P450 1A1 (CYP1A1) mRNA levels were assessed by real-time quantitative polymerase chain reaction. Competitive ligand binding assays were performed to determine whether UroA is a direct ligand for the AHR. Subcellular AHR protein levels were examined utilizing immunoblotting analysis. AHR expression was repressed in Caco-2 cells by siRNA transfection to investigate AHR-dependency. UroA and B were able to antagonize 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AHR-mediated transcriptional activity. Furthermore, UroA and B attenuated TCCD-mediated stimulation of CYP1A1 mRNA levels. In addition, competitive ligand binding assays characterized UroA as a direct AHR ligand. Consistent with other AHR antagonists, UroA failed to induce AHR retention in the nucleus. AHR is necessary for UroA-mediated attenuation of cytokine-induced interleukin 6 (IL6) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in Caco-2 cells. Here we identified UroA as the first dietary-derived human selective AHR antagonist produced by the gut microbiota through multi-step metabolism. Furthermore, previously reported anti-inflammatory activity of UroA may at least in part be mediated through AHR.
ARTICLE | doi:10.20944/preprints201807.0401.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: lung cancer; environment; EE2; NP; estrogen receptor; EGFR
Online: 22 July 2018 (11:23:02 CEST)
Lung cancer has been the leading cause of cancer death in the world. In addition to smoking, estrogen is supposed to play an important role in the lung cancer development because women have a higher proportion of adenocarcinoma than men. In the environment, there are many metabolites and wastes that mimic human estrogen structurally and functionally. As an oral contraceptive, 17α-ethynylestradiol (EE2) is released to wastewater after being utilized. Moreover, 4-nonylphenol (NP) exiting in the petrochemical products and air pollutants has estrogenic activity. In our study, 17β-estradiol (E2), EE2, and NP are administered to stimulate A549 male lung adenocarcinoma cells and H1435 female lung adenocarcinoma cells. The results demonstrate that EE2 and NP stimulate A549 and H1435 cells proliferation in a dose- and time-dependent trend. Both estrogen receptor α and β are activated simultaneously during these processes. Up-regulation of epidermal growth factor receptor (EGFR) and ERK expression is involved in response to estrogens. In conclusion, we first time report that EE2 and NP exert biotoxic effect to stimulate the proliferation of both male and female lung cancer cells in a dose- and time- response manner. New challenges from environmental hormones to lung cancer deserved further investigation.
ARTICLE | doi:10.20944/preprints201612.0107.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: apoptosis; gynecologic cancer; lipopolysaccharide; proliferation; Toll-like receptor
Online: 20 December 2016 (11:12:07 CET)
Toll-like receptor 4 (TLR4) is a member of the TLR family. Members of the TLR family play an important role in innate immune responses and are induced by recognition of pathogen-associated molecular patterns. They are also involved in cell proliferation and apoptosis in cancer. We investigated the role of TLR4 in apoptotic cell death in gynecological cancer cells; gynecological cancer is associated with infertility and spontaneous abortion. To examine the effect of TLR4 activation on apoptotic signaling in cancer cells, cultured primary cancer cells were treated with the TLR4 agonist lipopolysaccharide (LPS). The morphology of cancer cells was compared with normal myometrial cells. Enhanced growth rate and loss of contact inhibition with cellular overlap was observed in the cancer cells. The molecular mechanism analysis revealed differential expression of tumor suppressor genes in LPS-treated cancer cells. The expression of apoptosis-related caspase-3 was increased significantly in cancer cells with TLR4 activation after exposure to LPS. Taken together, these results suggest the pro-apoptotic activity of TLR4 as a potential therapeutic target for the treatment of gynecological cancers.
ARTICLE | doi:10.20944/preprints202209.0143.v1
Subject: Life Sciences, Microbiology Keywords: Salmonella; novel antibacterial agents; cannabidiol; co-therapy; bacterial genetics
Online: 12 September 2022 (09:55:22 CEST)
New generation antibiotics are needed to combat the development of resistance to antimicrobials. One of the most promising new classes of antibiotics is cannabidiol (CBD). It is a non-toxic and low-resistance chemical that can be used to treat bacterial infections. The antibacterial activity of Cannabis sativa L. byproducts, specifically CBD, has been of growing interest in the field of novel therapeutics. As research continues to define and characterize the antibacterial activity that CBD possesses against a wide variety of bacterial species it is important to examine potential interaction between CBD and common therapeutics such as broad-spectrum antibiotics. Here, we show that CBD-antibiotic co-therapy can effectively fight S. typhimurium via membrane integrity disruption. This research serves to examine the potential synergy between CBD and three broad-spectrum antibiotics for potential antibiotic-CBD co-therapy. In this study, we reveal that Salmonella typhimurium (S. typhimurium) growth is inhibited at very low dosages of CBD-antibiotic. This interesting finding demonstrates that CBD and CBD-antibiotic co-therapies are viable novel alternatives to combating Salmonella typhimurium.
REVIEW | doi:10.20944/preprints202208.0530.v1
Subject: Engineering, Civil Engineering Keywords: Resource recovery; circular economy; food waste; anaerobic co-digestion
Online: 31 August 2022 (03:10:30 CEST)
The emergence of the circular economy, and the evolving paradigms in the treatment and management of wastewater, have opened up an opportunity for co-digestion of organic waste (i.e., food waste) with sewage sludges to enhance resource recovery at wastewater treatment plants (WWTPs). This paper reviewed the potential for anaerobic co-digestion of food waste and sewage sludges, as well as alternative sustainable food waste handling systems in South Africa. The promotion of the circular economy by the latest national solid waste management strategy and the ongoing efforts for resource recovery by the wastewater sector suggests that anaerobic co-digestion of food waste and sewage sludge is possible in South Africa. Furthermore, an integrated food waste disposer (FWD) system was identified as a sustainable alternative for food waste handling. To formulate a roadmap for future food waste and sewage sludge co-digestion implementation, a multi-disciplinary investigation is required to bridge the literature gap.
ARTICLE | doi:10.20944/preprints202201.0282.v1
Subject: Social Sciences, Organizational Economics & Management Keywords: Project management; geothermal; co-benefits; sustainable development; innovation, operationalization
Online: 19 January 2022 (16:08:41 CET)
Despite knowledge concerning stakeholders and the economic advantages of consultation, collaboration and innovation, analysis of the sustainability implications of the geothermal industry has tended to take a high-level or systemic overview of national performance. This study seeks to begin to fill this gap in the academic and grey literature, investigating the following research question: how do projects in the Icelandic geothermal energy sector create co-benefits with stakeholders and reflect the integration of sustainable energy development (SED)? The focus of its analysis is on identifying who are the stakeholders, what are the sustainability benefits co-created with stakeholders, and when in the project lifecycle do these occur. Based on eleven semi-structured interviews with project managers in Iceland’s geothermal industry, the study identifies a broad array of stakeholders in the sector, including national and municipal governments and public sector institutions, businesses, the public, employees and landowners. The sustainability co-benefits of Iceland’s geothermal power projects are broad and cut cross all six themes of SED and multiple phases of the project lifecycle. Although the sustainability benefits are very apparent, trade-offs are reported between the pursuit of an economically efficient energy system and nature conservation. This relates to unsustainable utilization of the resources and the environmental externalities of power production and consumption. Efforts to mitigate these effects are ongoing and the further pursuit of SED is likely in Iceland given its recognition within the nation’s new energy policy and to meet ambitious greenhouse gas emissions reduction targets in the government’s climate action plan. These are issues that are prominent in other nations seeking to decarbonize energy systems through increased utilization of geothermal resources.
ARTICLE | doi:10.20944/preprints202112.0319.v1
Subject: Earth Sciences, Environmental Sciences Keywords: Waste water; Phosphate co-product; Adsorption; Red Acid 52
Online: 21 December 2021 (09:15:16 CET)
Water is essential for all living things however its pain has become serious. Many industrial activities cause its pollution by the release of polluting byproduct. Waste water treatment is hence necessary. In this context, the waste water of the textile industry containing Red Acid 52 was treated by the solid waste of the washed natural phosphate byproduct. Natural phosphate was also studied. The solid materials were first characterized by chemical analysis, Fourier Transform Infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The phosphate materials were after that, tested in the adsorption of the Red Acid 52. The experimental data indicated that the phosphate waste rock allowed the removal of Red Acid 52. Its maximum retention capacity attained 18.4 mg.g-1. Calcinations of materials inhibits the removal capacity found reduced by 60 to 70%. The adsorption kinetics of the Red Acid 52 on the material is well described by the pseudo second order model while the adsorption isotherms are identified by the Langmuir model. Hereafter, the thermodynamic study revealed that the adsorption process is spontaneous and exothermic. Keywords: Waste water, Phosphate co-product, Adsorption, Red Acid 52.
REVIEW | doi:10.20944/preprints202112.0029.v1
Subject: Materials Science, Nanotechnology Keywords: carbon nanomaterials; nitrogen doping; sulphur doping; co-doping; electrocatalysts
Online: 2 December 2021 (10:18:53 CET)
In recent years, hetero atom incorporated specially structured metal-free carbon nanomaterials have drawn huge attention among researchers. In comparison to the un-doped carbon nanomaterials, hetero atoms like nitrogen, sulphur, boron, phosphorous etc. incorporated nanomaterials become well-accepted as potential electrocatalysts in water splitting, supercapacitors and dye-sensitized solar cells. This review emphasizes on the mostly popular synthetic strategies utilized in last two decades and their excellent performance in electrocatalytic studies.
ARTICLE | doi:10.20944/preprints202012.0085.v1
Subject: Biology, Anatomy & Morphology Keywords: allosteric ligands; AutoDock; cognate ligands; Tanimoto co-efficient; GPCRs
Online: 3 December 2020 (13:08:24 CET)
G-protein coupled receptors (GPCRs) are large protein families known to be important in many cellular processes. They are well known for their allosteric activation mechanisms. They are drug targets for several FDA-approved drugs. We have investigated the diversity of the ligand binding site for these class of proteins against their cognate ligands using computational docking, even if their structures are known in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site, with better score than the binding at the conservative site. Further, ligands obtained from GLASS database, which consists of experimentally verified GPCR ligands, also show allosteric binding to GPCRs. The allosteric binders show strong affinity to the binding site, though the residues at the binding site are not conserved across GPCR subfamilies.
ARTICLE | doi:10.20944/preprints202009.0375.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: co-infection; SARS-CoV-2; pike glycoprotein; stop mutations
Online: 17 September 2020 (05:33:59 CEST)
There is a rising global concern for the ongoing outbreak of SARS-CoV-2 due to its high transmission rate and unavailability of treatment. Through the binding of its spike glycoprotein with angiotensin type 2 (ACE2), SARS-CoV-2 can efficiently get in the cells of patients and start its pandemic cycle. Herein, the biological diversity of SARS-CoV-2 infection was assessed in Babylon province of Iraq by investigating the possible genetic variations of the spike glycoprotein. A specific coding region of 795 bp within the viral spike (S) gene was amplified from 19 patients who suffered from obvious symptoms of SARS-CoV-2 infection. Sequencing results identified fifteen novel nucleic acid variations with a variety of distributions within the investigated samples. The electropherograms of all the identified variations showed obvious co-infections with at least two different viral strains per sample. Within these co-infections, the majority of samples exhibited three nonsense single nucleotide polymorphism (SNP)s, p.301Cdel, p.380Ydel, and p.436del, which yielded three truncated SARS-CoV-2 spike glycoproteins of 301, 380, and 436 amino acids length, respectively. The network and phylogenetic analyses indicated that for all viral infections were derived from multi-ancestral origins. Results inferred from the specific clade-based tree entailed that some viral strains were derived from European G-clade sequences. In conclusion, our data demonstrated the absence of any single strain infection among all investigated viral samples in the studied area, which may entail a higher risk of SARS-CoV-2 in this country. Through the identified high frequency of truncated spike proteins, we suggest that defective SARS-CoV-2 may depend on helper strains having intact spikes in its infection. Alternatively, another putative ACE2-independent route of viral infection way also suggested. To the best of our knowledge, this is the first report to describe the co-infection of multiple strains of SARS-CoV-2 in patients with COVID-19.
ARTICLE | doi:10.20944/preprints202007.0252.v1
Subject: Life Sciences, Immunology Keywords: SARS-Co-V2; Paediatric hyperinflammation; MIS-C; PIMS-TS
Online: 12 July 2020 (12:09:35 CEST)
We describe the innate and adaptive immune system trajectory in Multi-system inflammatory syndrome of childhood (MIS-C), at acute(within 72 hours of hospitalization), resolution (at clinical improvement) and convalescent phase. In our cohort, in the acute phase, 68% of the children were SARS-CoV-2 seropositive, with hypercytokinenemia (high interleukin(IL)-1beta,IL-6,IL-8,IL-10,IL-17, interferon gamma), procoagulant state, myocardial dysfunction, activated neutrophils and monocytes; differential T and B cell subset lymphopenia; activated chemokine receptor type-7 positive and gamma-delta T cell subsets; antigen presenting cells had reduced HLA-DR expression; and B-cell class-switch responses occurred with illness resolution. MIS-C is an immunopathogenic illness associated with SARS-CoV-2 infections in children.
REVIEW | doi:10.20944/preprints202004.0217.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; Indigenous Tribes; Co-morbidities; Corona Virus; Navaho
Online: 14 April 2020 (08:43:11 CEST)
Introduction The COVID-19 virus was initially reported in Dec 2019 as the causative agent of a pneumonia breakout in Wuhan China. This virus rapidly spread from China to Europe and the East Coast of the United States eventually reaching the South West United States and indigenous tribes in mid -March. Since, then the indigenous tribes have been devasted by the virus which the Governor of New Mexico has likened as an existential threat. Methodology A PubMed search was performed utilizing the words: Navajo Indian, Indigenous Indian, Wuhan Virus, COVID-19, SARs coronavirus, ACE2, S protein, virulence, clinical presentation, epidemiology, genome, treatment, structure, MERs, pathogenesis and/or pathology alone and in combination with other terms. Each paper was evaluated by three content experts for quality, reproducibility, credibility and reputation of the journal Results: Navajo’s and other indigenous peoples may have elevated levels of ACE2 receptors in their lungs and other tissues allowing greater susceptibility to the COVID-19 virus. Increased levels of diabetes and protein nutrition are directly related to increased morbidity and mortality in this group while obesity, COPD, and heart diseas are not. The increased morbidity and mortality is exasperated by an inability to test for COVID-19 Conclusion: The infectivity rate of Navaho’s on the reservation is 22 times higher than the national average with a death rate near 4%. Comorbidites account for some of the increased morbidity and mortality while lack of access to adequate health care unnecessarily magnifies the poor outcome. The threat to indigenous tribes in the Southwest of COVID-19 is dire.
ARTICLE | doi:10.20944/preprints202002.0406.v1
Subject: Chemistry, Applied Chemistry Keywords: Environmental chemistry; Oxyfuel Combustion; NO-CO reaction; Heterogeneous catalysis.
Online: 27 February 2020 (12:25:57 CET)
Carbon dioxide has become a global challenge, where the emissions have become more than what could be handled. In this regard, conversion of CO2 to value added chemicals and thus recycling CO2 became a viable option. One of these options is the use of a process in strong development: oxycombustion. However, the gases resulting from this process contain some traces of impurities that can hinder the recovery of CO2 such as NO and CO. This work has therefore focused on the study of the reaction of NO reduction by CO in an oxidizing medium, using catalytic materials based on various supported noble metals. These materials were extensively characterized by a variety of methods including BET surface area measurements, hydrogen chemisorption, Transmission Electron Microscopy (TEM) and H2 temperature programmed reduction (H2-TPR). The obtained results show that the catalytic behaviour of M/Al2O3 catalysts in CO oxidation and NO reduction with CO in oxidative conditions depends mainly on the nature of the metal. The best result for these both reactions is obtained with Pt/Al2O3 catalyst. The Pt nanoparticles existing in the metallic form (Pt°) showed by TPR could explain the activity.
ARTICLE | doi:10.20944/preprints201812.0299.v1
Subject: Social Sciences, Business And Administrative Sciences Keywords: European Parliament , Ordinary Legislative Procedure, Co-decision, Efficiency,Effectiveness
Online: 25 December 2018 (08:44:35 CET)
On the eve of the Brexit process, in the context of a rising Euroscepticism that fuels the modest confidence of European citizens in their national and European institutions, the article assesses the efficiency and effectiveness of the European Parliament within the framework of the ordinary legislative procedure (co-decision). After defining and formulating the main indicators, the paper analyses the micro- and macro-performance of the European Parliament within the decision-making process from a quantitative-qualitative and a qualitative-quantitative perspective, highlighting the relativizing factors and the responsiveness of the European decision-making process to the Europeans’ needs.
ARTICLE | doi:10.20944/preprints201812.0298.v1
Subject: Materials Science, Surfaces, Coatings & Films Keywords: Ti doped ZnO, Thin film, Co-Sputtering, UV-Visible
Online: 25 December 2018 (08:40:43 CET)
ZnO films with Ti atoms incorporated (TZO) in a wide range (0-18 at. %) have been grown by reactive co-sputtering on silicon and glass substrates. The influence of the titanium incorporation in the ZnO matrix on the structural and optical characteristics of the samples has been determined by Rutherford backscattering spectroscopy (RBS), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). The results indicate that the samples with low Ti content (< 4 at. %) exhibit the wurtzite-like structure, with the Ti+4 ions substitutionally incorporated into the ZnO structure, forming Ti-doped ZnO films. In particular, very low concentration of Ti (<0.9 at. %) leads to a significant increase of the crystallinity of the TZO samples. Higher Ti contents give rise to a progressive amorphization of the wurtzite-like structure so samples with high Ti content (≥18at. %), displays an amorphous structure indicating the XPS analysis a predominance of Ti-O-Zn mixed oxides. The energy gap, obtained from absorption spectrophotometry, increases from 3.2 eV for pure ZnO films to 3.6 eV for those with the highest Ti content. Ti incorporation in the ZnO samples below 0.9 at. % rises both, the blue (380 nm) and green (550 nm) bands of the photoluminescence (PL) emission, thereby indicating a significant improvement of PL efficiency of the samples.
ARTICLE | doi:10.20944/preprints201808.0203.v1
Subject: Materials Science, Nanotechnology Keywords: Titanium dioxide nanotube, photoelectric properties, co-doping, magnetron sputtering
Online: 10 August 2018 (09:43:33 CEST)
Cu,N-TiO2 nanotube (Cu,N-TNT) is prepared through a novel magnetron sputtering and anodic oxidation method. Then the morphology, structure and physicochemical property of Cu,N-TNT was analyzed by XRD, SEM, TEM, EDX and UV-vis-DR. The results indicate that the evenly doped copper is beneficial to the transformation of the TNT from anatase to rutile and play a key role in the morphology of the Cu,N-TNT. The doped Cu and N in the TNT influence the growth orientation of the TiO2 crystals, which result in the lattice distortion and wider the interplanar spacing 60s-Cu,N-TNT has less band gap and stronger absorption intensity in visible region than other Cu,N-TNT samples, which make the combination rate of photogenerated electron and photogenerated hole decrease greatly, thus beneficial to its physicochemical property.
ARTICLE | doi:10.20944/preprints201807.0021.v1
Subject: Materials Science, Biomaterials Keywords: biomaterials; cobalt ferrites; poly(hydroxybutyrate-co-hydroxyvalerate); tissue engineering
Online: 3 July 2018 (05:12:53 CEST)
Polymer-based piezoelectric biomaterials have already proven their relevance for tissue engineering applications. Further, the morphology of the scaffolds plays also an important role in cell proliferation and differentiation. The present work reports on poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV), a biocompatible, biodegradable and piezoelectric biopolymer that has been processed in different morphologies, including films, fibres, microspheres and 3D scaffolds. Further, the corresponding magnetically active PHBV-based composites were also produced. The effect of the morphology on physico-chemical, thermal, magnetic and mechanical properties of pristine and composites samples was evaluated, as well as their cytotoxicity. It was observed that the morphology does not strongly affect the properties of the pristine samples but the introduction of cobalt ferrites induces changes in the degree of crystallinity that could affect the applicability of prepared biomaterials. Young modulus is dependent of the morphology and also increases with the addition of cobalt ferrites. Both, pristine and PHBV/cobalt ferrite composite samples are no cytotoxic, indicating their suitability for tissue engineering applications.
ARTICLE | doi:10.20944/preprints201806.0132.v1
Subject: Earth Sciences, Environmental Sciences Keywords: subplinian eruption; co-occurrence matrix; wavelet transform; similarity metrics
Online: 8 June 2018 (12:33:49 CEST)
This paper presents a new methodology that provides the analysis of surface texture changes in areas adjacent to the volcano and its impact product of volcanic activity. To do this, algorithms from digital image processing such as the co-occurrence matrix and the wavelet transform are used. These methods are working on images taken by the Landsat satellite platform sensor 5 TM and Landsat 7 ETM + sensor, and implemented with the purpose of evaluating superficial changes that can warn of surface movements of the volcano. The results were evaluated by similarity metrics for grayscale images, and validated in two different scenarios that have the same type of eruption, but differ, essentially, in climate and vegetation. Finally, the proposed algorithm is presented, setting the parameters and constraints for implementation and use.
ARTICLE | doi:10.20944/preprints201805.0165.v1
Subject: Biology, Animal Sciences & Zoology Keywords: infectious bronchitis virus; protection; co-expressing; subunit vaccine; challenge
Online: 10 May 2018 (12:02:08 CEST)
Avian infectious bronchitis virus (IBV) is the causative agent of infectious bronchitis, which causes considerable economic losses to the poultry industry worldwide. It is imperative to develop safe and efficient candidate vaccines to control IBV infection. In the current study, recombinant baculoviruses co-expressing S1 and N proteins, mono-expressing S1 or N proteins alone of IBV were constructed and prepared into subunit vaccines rHBM-S1-N, rHBM-S1 and rHBM-N. The levels of immune protection of these subunit vaccines were evaluated by inoculating specific pathogen-free (SPF) chickens at 14 days of age, boosting with the same dose 14 days later, and following challenge with a virulent GX-YL5 strain of IBV 14 days post-booster (dpb). The commercial vaccine strain H120 was used as a control. The IBV-specific antibody levels as well as the percentages of CD4+ and CD8+ T lymphocytes were detected within 28 days post-vaccination (dpv). The morbidity, mortality, and re-isolation of virus from the tracheas and kidneys of challenged birds were evaluated at 5 days post-challenge (dpc). The results showed that the IBV-specific antibody levels and the percentages of CD4+ and CD8+ T lymphocyte in rHBM-S1-N group were higher than those of rHBM-S1 and rHBM-N groups, especially the cellular immunity response. At 5 dpc, the mortality, morbidity and virus re-isolation rate of rHBM-S1-N were slightly higher than those of H120 group, but were lower than those of rHBM-S1 group and rHBM-N group. The present study demonstrated that the protection of recombinant baculovirus co-expressing S1 and N proteins was better than that of recombinant baculoviruses mono-expressing S1 or N protein alone. Thus, the recombinant baculovirus co-expressing S1 and N proteins could serve as a potential IBV vaccine and this demonstrates that the bivalent subunit vaccine including the S1 and N proteins might be a strategy for the development of an IBV subunit vaccine.
ARTICLE | doi:10.20944/preprints202110.0384.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: thiadizines; serotonin transporter (SERT); serotonin-1A receptor; serotonin-3 receptor; docking; docking energy; binding affinity; binding mechanism; c-Fos; immunohistochemistry; electrophysiology
Online: 26 October 2021 (12:32:43 CEST)
L-17 is a thiadiazine derivative with putative anti-inflammatory, neuroprotective, and antidepressant-like properties. In this study, we applied combined in silico, ex vivo, and in vivo electrophysiology techniques to reveal the potential mechanism of action of L-17. PASS 10.4 Professional Extended software suggested that L-17 might have pro-cognitive, antidepressant, and antipsychotic effects. Docking energy assessment with AutoDockVina predicted that the binding affinities of L-17 to the serotonin transporter (SERT) and serotonin receptors 3 and 1A (5-HT3 and 5-HT1A) receptors are compatible to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and selective antagonists of 5-HT3 and 5-HT1A receptors, granisetron and WAY100135, respectively. Acute pre-treatment with L-17 robustly increased c-Fos immunoreactivity in the amygdala (central nucleus), suggesting increased neuronal excitability in this brain area after L-17 administration. Acute L-17 also dose-dependently inhibited of 5-HT neurons of the dorsal raphe nucleus (DRN). This inhibition was partially reversed by subsequent administration of WAY100135, suggesting the involvement of extracellular 5-HT. Based on in silico predictions, c-Fos immunohistochemistry, and in vivo electrophysiology, we suggest that L-17 is a potent 5-HT reuptake inhibitor and/or partial 5-HT1A receptor antagonist. Thus, L-17 might be a representative of a new class of antidepressant drugs. Since L-17 also possesses neuro- and cardio-protective properties, it can be useful in post-stroke and post-myocardial infarction (MI) depression. In general, combined in silico predictions and ex vivo neurochemical and in vivo electrophysiological assessment might be a useful strategy for early preclinical assessment of the affectivity and neural mechanism in action of the novel CNS drugs.
REVIEW | doi:10.20944/preprints202012.0795.v1
Subject: Life Sciences, Biochemistry Keywords: T cells; chimeric antigen receptor; transgenic T-cell receptor; tumor-infiltrating lymphocytes; exhaustion; terminal differentiation; senescence; apoptosis; adoptive cell transfer; immunotherapy
Online: 31 December 2020 (12:16:55 CET)
Over the last decades, cellular immunotherapy has revealed its curative potential. However, the inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes, in addition to the various strategies put in place to circumvent these effects. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer are discussed. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features is key to the development of improved cellular immunotherapies.
REVIEW | doi:10.20944/preprints202001.0171.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: Dipeptidyl peptidase-4; Fibroblast growth factor; Gastrointestinal peptide; Glucagon-like peptide 1; Glucagon receptor; Peroxisome proliferator-activated receptor; Sodium glucose cotransporter
Online: 16 January 2020 (11:44:49 CET)
Liver related diseases are the 3rd leading causes (9.3%) of mortality in type 2 diabetes mellitus (T2DM) in Japan. T2DM is closely associated with nonalcoholic fatty liver disease (NAFLD) which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. There are no established pharmacotherapies for NASH patients with T2DM. Though vitamin E is established as a 1st line agent in NASH without T2DM, its efficacy was recently denied in NASH with T2DM. The effects of pioglitazone on NASH histology with T2DM have extensively been established, but several concerns exist such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium/glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin have already entered phase 3 trials (DEAN study). A key clinical question is what kinds of anti-diabetic drugs are the most appropriate for the treatment of NASH to prevent progression of hepatic fibrosis resulting in HCC/liver-related mortality without increasing risk at cardiovascular or renal events. The combination therapies such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide /GLP-1 will be under development. This review focuses on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2DM.
ARTICLE | doi:10.20944/preprints202209.0253.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Abdominal aortic aneurysm; Type I interferon receptor, Leukocytes; Angiogenesis
Online: 19 September 2022 (02:08:07 CEST)
Objective: Type I interferon receptor (IFNAR) signaling contributes to several autoimmune and vascular diseases such as atherosclerosis and stroke. The purpose of this study was to assess the influence of IFNAR1 deficiency on the formation and progression of experimental abdominal aortic aneurysms (AAAs). Methods: AAAs were induced in type I interferon receptor subunit 1 (IFNAR1) deficient and wild type control male mice via intra-infrarenal aortic infusion of porcine pancreatic elastase. Immunostaining for IFNAR1 was evaluated in experimental and clinical aneurysms. The initiation and progression of experimental AAAs was assessed via ultrasound imaging prior to (day 0) and 3-, 7-, and 14-days following elastase infusion. Aneurysmal histopathology was analyzed at sacrifice. Results: Increased aortic medial and adventitial IFNAR1 expression was present in both clinical AAAs harvested at surgery and experimental AAAs. Following AAA initiation, wild type mice experienced progressive, time-dependent infrarenal aortic enlargement. This progression was substantially attenuated in IFNAR1 deficient mice. On histological analyses, medial elastin degradation, smooth muscle cell depletion, leukocyte accumulation and neoangiogenesis were markedly diminished in IFNAR1 deficient as compared to wild type mice. Conclusion: IFNAR1 deficiency limited experimental AAA progression in response to intra-aortic elastase infusion. Combined with clinical observations, these results suggest a regulatory role for IFNAR1 activity in AAA pathogenesis.
REVIEW | doi:10.20944/preprints202107.0551.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: epidermal growth factor receptor; ErbB; biomarker; meningioma; intracranial tumor
Online: 23 July 2021 (22:06:24 CEST)
Meningioma (MGM) is the most common type of intracranial tumor in adults. The validation of novel prognostic biomarkers to better inform tumor stratification and clinical prognosis is urgently needed. Many molecular and cellular alterations have been described in MGM tumors over the past few years, providing a rational basis for the identification of biomarkers and therapeutic targets. The role of receptor tyrosine kinase (RTKs), including those of the ErbB family of receptors, as oncogenes has been well established in several cancer types. Here, we review histological, molecular, and clinical evidence suggesting that RTKs, including the epidermal growth factor receptor (EGFR, ErbB 1), as well as other members of the ErbB family, may be useful as biomarkers in MGM.
Subject: Medicine & Pharmacology, Allergology Keywords: cannabinoid receptor 2; epilepsy; cAMP, M-current; anti-inflammatory
Online: 6 July 2021 (17:09:20 CEST)
Epilepsy is characterized by repeated spontaneous reactions caused by hyper-excitability and neurons firing in high synchronization in the central nervous system. It seriously affects the quality of life of epileptic patients and nearly 30% of individuals are refractory to treatment of antiepileptic drugs. Therefore, there is an urgent need to develop new medicines to manage and control the refractory epilepsy. Cannabinoid ligands including selective cannabinoid receptor subtype (CB1 or CB2 receptor) ligands and non-selective cannabinoid (synthetic and endogenous) ligands may serve as the novel candidates for this need. Cannabinoid systems appear to regulating seizure activity in the brain through the activation of CB1 and CB2 cannabinoid receptors (CB1R and CB2R). An abundant series of cannabinoid analogues have been tested in various animal models, including a rat pilocarpine model of acquired epilepsy, in vitro hippocampal neuronal culture models of acquired epilepsy and status epilepticus, a pentylenetetrazole model of myoclonic seizures in mice and a penicillin-induced model of epileptiform activity in the rats. The accumulating lines of evidence show that cannabinoid ligands exhibit significant benefits to control seizure activity in different epileptic models. For this reason, we summarize the relationship between brain CB2 receptors and seizures, and emphasize the potential mechanisms of their therapeutic effects involving affecting neurons, astrocytes, and microglia cells. The unique features of CB2Rs, such as lower expression levels under physiological conditions and high inducibility under epileptic conditions, make it an important target for future research on drug-resistant epilepsy.