Dysregulation of the angiotensin-II Type-I receptor (AT1R) and its pathway was reported to associate with poor-prognosis in several malignancies, including colorectal-cancer (CRC). We have explored the therapeutic-potential of targeting AT1R using valsartan, and its pharmacological-interaction with Fluorouracil (5-FU) in CRC. Anti-proliferative function was evaluated in 2-/3-dimensional cells and in vivo models. Anti-proliferative, anti-migratory, apoptotic function and effect on cell-cycle was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound-healing test, and Fluorescence-activated cell sorting (FACS), respectively, while gene-expression was determined at mRNA/protein levels. By histogical analysis and measuring of oxidative/antioxidant markers, we evaluated the anti-inflammatory properties of valsartan. Valsartan suppressed cell-growth and impacted the anti-tumor-activities of 5-FU by apoptosis-induction. Valsartan inhibited the cells migration by perturbation of Matrix metalloproteinase (MMP1). Furthermore, valsartan inhibited tumor-growth and metastasis, and this was more notable in valsartan/5-FU combination-treated-group. The mechanism was plausible to be via the induction of Reactive-oxygen-species (ROS) and down-regulation of Superoxide-dismutase (SOD), thiol/catalase (CAT) as well as Vascular endothelial growth factor (VEGF) and Transforming growth factor beta (TGF-β). Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory components include fibronectin, Interleukin) IL-1β (, Tumor necrosis factor alpha) TNF-α (, Interferon gamma) INF-γ (, and Monocyte Chemotactic Protein 1 (MCP-1). Our findings demonstrated that targeting the AT1R receptor may inhibit tumor-growth and ameliorate fibrosis and inflammation associated with CRC via modulation of AT1 and TGF-β pathways.

Androgen insensitivity syndrome (AIS) is the most common disorder of sex development in people with karyotype 46,XY. Mutations in AR (androgen receptor) gene are found in most individuals with AIS. Exons 4-8, which encode LBD, were shown to be a mutation hotspot. The aim of this study was the search of mutations in the sequence of exons 6-8 which encode LBD of AR gene in patients with different clinical AIS phenotypes from Ukraine. The investigated patients were 4 women with 46,XY karyotype, SRY-positive and clinical features of AIS (2 – CAIS, 2 – PAIS). Serum levels of T, LH, and FSH were quantified by electrochemiluminescence immunoassay (ECLIA) technology. Cytogenetic studies were performed on peripheral blood lymphocytes with further use of standard protocols of chromosomal analysis (GTG-banding). The presence of SRY sequence was confirmed by FISH with LSI SRY probe. Direct Sanger sequencing of 6-8 exons was performed in patients and family members on the PCR products on the matrix of DNA samples isolated from peripheral blood lymphocytes. Detected SNPs were analysed using gnomAD, VEP, MutationTaster, Human Splicing Finder, NetPhorest 2.1, Group-based Prediction System 5.0, and PhosphoPICK bioinformatical resources. Modelling of mutant proteins based on available 3D models was conducted using the open source software UCSF Chimera 1.14rc. We have detected 3 previously described mutations (missense mutation X:67722905 Т>С (rs9332970) in PAIS patient, missense mutation X:67722943 C>T (rs886041132) in CAIS patient and, samesense mutation X:67723745 C>T (rs137852594) in PAIS patient). We determined these mutations as pathogenic using SIFT, PolyPhen, MutationTaster, Human Splicing Finder. Moreover the synonymous mutation X:67723745 C>T (rs137852594) detected in patient with PAIS was determined as mutation affecting processes of splicing. In our study we have identified novel mutation X:67722884 T>G in CAIS patient and family members. This mutation was predicted as a pathogenic using aforementioned bioinformatical tools. STRUM calculations of the protein stability change caused by single-point mutation showed a destabilization effect of the Ile836Ser substitution ΔΔG=-2.6. Possible aberrant phosphorylation analysis revealed the ability of MAPK family, Akt family, CDK1, CDK7, CDK9, PKC kinases to phosphorylate Ser836. Results concerning the pathogenicity of X:67722905 Т>С (rs9332970), X:67722943 C>T (rs886041132), X:67723745 C>T (rs137852594) mutations detected in patients with AIS from Ukraine obtained using bioinformatical resources SIFT, PolyPhen, MutationTaster, Human Splicing Finder correlate with previously published data concerning weaker binding of androgens in patients with the same mutations. This approves informativity of using such resources for mutation pathogenicity analysis. Analysis of the ortholog proteins, subdomain structure, and aberrant phosphorylation of AR-LBD suggests novel X:67722884 T>G mutation to be pathogenic. Based on analysis of mutant protein modelling followed by assessment of free energy change using STRUM it was predicted that mutant protein binds androgens 460 times worse than wild type.

There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors. The A2BAR, coupled to both Gαi and Gαq G proteins, is one of the several G-protein-coupled receptors that are expressed in a significantly higher level in some cancer tissues in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are potentially novel attractive anticancer agents. Several antagonists targeting at the A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various types cancers, and the rationale of using A2BAR antagonists in cancer therapy

Luteinizing hormone receptor (LHR) is a member of the seven-transmembrane (TM) receptor family. Several mutations in LHR have been identified in many mammalian species, leading to either constitutive activation or inactivation of the receptor. Mutations in highly conserved regions of the TM domain have been reported. In this study, we analyzed signal transduction by three constitutively active mutants (designated M410T, L469R, and D590Y) and two inactivating mutants (D383N and Y546F) of eelLHR known as naturally occurring in human LHR . To directly assess the functional effects of these mutations, site-directed mutant receptors were transiently expressed in CHO-K1 cells and cAMP accumulation stimulated by recombinant eelLH (rec-eelLH) was measured by homogeneous time-resolved fluorescence (HTRF) assays. The cAMP response in cells expressing eelLHR wild-type (eLHR-WT) increased in a dose-dependent manner with rec-eelLH ligand stimulation. Cells expressing the activating eelLHR mutants, M410T, L469R, and D590Y, exhibited a 4.0-, 19.1-, and 7.8-fold increase in basal cAMP response, respectively. However, their maximal responses were approximately 73, 53, and 92%, respectively, of the maximal response of LHR-WT. The L469R mutant exhibited a particularly marked increase in cAMP production in the absence of agonist. The maximal responses of the inactivating mutants, D383N and Y546F, were 32 and 24% of LHR-WT, respectively. However, the inactivating mutations did not completely impair signal transduction. Thus, we report here the first characterization of activating and inactivating mutations in eelLHR and we show that these mutations have similar effects as those reported for mammalian LHRs. Moreover, eelLHR with activating mutations showed constitutive cAMP responses. These results provide important data on the signal transduction of constitutively active and inactive LHR mutants. Further studies should aim to identify the mechanism responsible for the significant increase in basal cAMP response in the constitutively activated eelLHR mutants.

Hyperandrogenism and insulin resistance are co-pathologies of polycystic ovary syndrome (PCOS). Recent evidence has suggested that elevated local cortisol levels are associated with ovarian and endometrial insulin resistance in hyperandrogenic PCOS patients, but the molecular mechanisms underlying these clinical findings remain unclear. We and others have used chronic treatment with human chorionic gonadotropin (hCG) and insulin to create an in vivo rodent model for the onset and development of PCOS-like phenotypes. Here, we aimed to determine whether the molecular mechanisms of glucocorticoid receptor (GR) signaling, mitochondrial function, and local inflammation in the ovary and uterus are intrinsically different in PCOS-like rats compared to controls. In both the ovary and the uterus, decreased expression of two GR protein isoforms was concurrent with increased expression of Fkbp51 but not Fkbp52 mRNA in PCOS-like rats compared to controls. However, PCOS-like rats exhibited an opposite regulation of Hsd11b1 or Hsd11b2 mRNAs in the two tissues. Further, the expression of several oxidative phosphorylation-related protein components was decreased in the PCOS-like ovary and uterus, but surprisingly the expression of many genes involved in mitochondrial function and homeostasis was increased in the same tissues and animals. Additionally, PCOS-like rats showed the increased expression of ovarian and uterine NFκB signaling proteins and Tnfaip3 mRNA. In PCOS-like rats, while similar decreased expression of Il1b, Il6, and Mmp2 mRNAs was seen in the ovary and uterus, the opposite regulation of Tnfa, Ccl2, Ccl5, and Mmp3 mRNA expression was observed in the two tissues. Both ovaries and uteri from PCOS-like animals showed increased collagen deposition compared to controls. Collectively, our observations suggest that hyperandrogenism and insulin resistance disrupt ovarian and uterine GR activation and trigger compensatory or adaptive effects for mitochondrial homeostasis, allowing tissue-level maintenance of mitochondrial function in order to limit ovarian and uterine dysfunction. Our study also suggests that hyperandrogenism and insulin resistance-induced activation of NFκB signaling resulting in aberrant regulation of inflammation-related gene expression might be tissue specific in female reproductive tissues.

Primary sclerosing cholangitis (PSC) is a cholestatic liver disorder frequently associated with ulcerative colitis (UC). Patients with PSC and UC have higher risk of colorectal neoplasia than patients with UC without PSC. Oncogenic properties of micro RNA 346 (miR-346) have been recently reported. In this study we investigated expressions of miR-346 and its two target genes i.e. the receptor of vitamin D (VDR) and the tumor necrosis factor α (TNF-α), which are known to modulate carcinogenesis. Biopsies from ascending and sigmoid colon were obtained from patients with PSC with and without UC, patients with UC and healthy controls. MiR-346 expression was increased in ascending but not sigmoid colon of patients with PSC and UC when compared to other analyzed groups (p<0.001 for all). In patients with UC an exceptionally low colonic expression of miRNA-346 was accompanied by the increase in VDR expression, and the extensive upregulation of TNF-α gene which protein product is known to be cytotoxic to tumor cells at high concentration. In summary, a substantial upregulation of miRNA-346 in ascending colon of patients with PSC and UC may be responsible for the inhibition of VDR and TNF-α signaling -pathway which may result in an inadequate suppression of neoplasia.

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, the metastatic breast cancer leaves a poor prognosis. In an era of personalized medicine, there is an urgent need for a better knowledge of the biology leading to the disease, which can lead to the design of always more accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the Fibroblast Growth Factor Receptor (FGFR) pathway, triggered by specific ligands. The FGFRs/FGFs axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of the FGFRs mutations leading to tumour formation and summarizes the state-of-the-art of therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.

The feed-forward loop (FFL) is an important and basic network motif to understand specific biological functions. Cyclic-AMP (cAMP) receptor protein (CRP), a transcription factor (TF), mediates catabolite repression and regulates more than 400 genes in response to changes in intracellular concentrations of cAMP in Escherichia coli. CRP participates in some FFLs like araBAD and araFGH operons and adapt to fluctuating environmental nutrients thus enhancing the survivability of E. coli. Although computational simulations have been used to explore the potential functionality of FFLs, a comprehensive study of the functions of all structural types based on in vivo data is lacking. Also, the regulatory role of CRP-mediated feed-forward loops (CRP-FFLs) remain unclear to date. Using EcoCyc and RegulonDB, we identified 393 CRP-FFLs in the E. coli. Dose-response genomic microarray of E. coli revealed dynamic gene expression of each target gene of CRP-FFLs in response to a range of cAMP dosages. All eight types of FFLs were present in CRP regulon with various expression patterns of each CRP-FFL, that were further divided into five functional groups. Microarray and reported regulatory relationships identified 202 CRP-FFLs which were directly regulated by CRP in these eight types of FFLs. Interestingly, 30% (147/482) of genes were directly regulated by CRP and CRP-regulated TFs, indicating that these CRP-regulated genes were also regulated by other CRP-regulated TFs responding to environmental signals through CRP-FFLs. Furthermore, we applied gene ontology annotation to reveal the biological functions of CRP-FFLs.

The rapid development of electric vehicles, unmanned aerial vehicles, and wearable electronic devices has led to a high interest in research related to the synthesis of graphene with a high specific surface area for energy applications. However, the problem of graphene synthesis scalability, as well as the lengthy duration and high energy intensity of the activation processes of carbon materials, are significant disadvantages. In this study, a reactor was developed for the green, simple, and scalable electrochemical synthesis of graphene oxide with a low oxygen content of 14.1 %. The resulting material was activated using a fast joule heating method. The processing of mildly oxidized graphene with a high–energy short electrical pulse (32 ms) made it possible to obtain a graphene–based porous carbon material with a specific surface area of up to 1984.5 m2/g. The low energy intensity, simplicity, and use of environmentally friendly chemicals render the proposed method scalable.

Non-alcoholic steatohepatitis (NASH) is a complex disease resulting from chronic liver injury associated with obesity, type 2 diabetes, and inflammation. Recently, multi-target drugs have been proposed to treat complex diseases including NASH; however, their manufacturing pro-cesses remain time- and cost-intensive and inefficient. Therefore, to overcome these limitations, we developed UniStac, a novel enzyme-mediated conjugation platform for multi-specific drug development. UniStac demonstrated high conjugation yields, optimal thermal stabilities, and robust biological activities. Through such platform, we designed a tetra-specific compound, C-192, targeting Glucagon-like peptide 1 (GLP-1), Glucagon (GCG), Fibroblast growth factor 21 (FGF21), and Interleukin-1 receptor antagonist (IL-1RA) simultaneously for the treatment of NASH. The biological activity and treatment efficacy of C-192 were confirmed both in vitro and in vivo using a methionine–choline-deficient (MCD) diet-induced mouse model. C-192 exhibited profound therapeutic efficacies compared to conventional drugs, including liraglutide and dulaglutide. C-192 significantly improved alanine transaminase levels, triglyceride accumula-tion, and the non-alcoholic fatty liver disease activity score. Our results collectively provide clin-ical feasibility of UniStac for developing multi-specific drugs, and C-192 as an innovative thera-peutic opportunity for severe NASH, as it exerts synergistic effects across multiple targets.

Modeling and assessing the sustainability of machining systems has been considered to be a crucial approach to improving the environmental performance of the machining processes. As the most common machining system, the computer numerical control (CNC) milling system is a typical man-machine cooperative system where the activities of the machine tool and operator generate material and energy consumption. However, the energy consumption of the operator in the CNC milling system has often been ignored in most existing research. Therefore, existing methods fail to provide a comprehensive understanding of the sustainability of the CNC milling system. To fill this gap, an exergy loss assessment method is proposed to investigate the sustainability of the CNC milling system, where the energy consumption of the operator, the energy consumption of the machine tool, and material consumption are taken into consideration. The key performance indexes of the energy consumption of the operator, the energy consumption of the machine tool, the exergy loss, and the specific exergy loss (SEL) are analyzed and modeled. To demonstrate the feasibility of the proposed method, a case study was carried out on a three-axis machining center (XH714D), in which SEL was found to be 88.04J/mm3. The proposed method is effective to assess the sustainability of the CNC milling system, and the established exergy loss models build a good basis for exergy efficiency optimization.

Initially introduced almost thirty years ago for the express purpose of providing electronic warfare systems the capabilities to detect, characterize, and identify radar emitters, Specific Emitter Identification (SEI) has recently received a lot of attention within the research community as a physical layer technique for securing Internet of Things (IoT) deployments. This attention is due in large part to SEI’s demonstrated success in passively and uniquely identifying wireless emitters using traditional machine learning and the success of Deep Learning (DL) within the natural language processing and computer vision areas. SEI exploits distinct and unintentional features present within an emitter’s transmitted signals. The existence of these distinctive and unintentional features is attributed to slight manufacturing and assembly variations that exist within and between the components, sub-systems, and systems that comprise an emitter’s Radio Frequency (RF) front end. Although sufficient to facilitate SEI, these features do not hinder normal operations such as detection, channel estimation, timing, and demodulation. However, despite the plethora of SEI publications, it has remained largely a focus of academic endeavors that primarily focus on proof-of-concept demonstration and little to no use in operational networks for various reasons. The focus of this survey is a review of SEI publications from the perspective of its use as a practical, effective, and usable IoT security mechanism, thus we use IoT requirements and constraints (e.g., wireless standard, nature of their deployment) as a lens through which each reviewed paper is analyzed. Previous surveys have not taken such an approach and have only used IoT as motivation, a setting, or a context. In this survey, we consider operating conditions, SEI threats, SEI at scale, publicly available data sets, and SEI considerations that are dictated by the fact that it is to be employed by IoT devices or IoT infrastructure.

For Convolutional Neural Network (CNN), Depthwise Separable CNN (DSCNN) is a preferred architecture for Application Specific Integrated Circuit (ASIC) implementation on edge devices. It can benefit from a multi-mode approximate multiplier proposed in this work. The proposed approximate multiplier uses two 4-bit multiplication operations to implement a 12-bit multiplication operation by reusing the same multiplier array. With this approximate multiplier, sequential multiplication operations are pipelined in a modified DSCNN to fully utilize the PE array in the convolutional layer. This Approximate (A-DSCNN) was implemented on TSMC 40-nm CMOS process with a supply voltage of 0.9 V. At the clock frequency of 200 MHz, the design achieves 4.78 GOPs/mW while occupying 1.24 mm x 1.24 mm silicon area. Compared to conventional DSCNN implemented in a similar process node, the chip area and power consumption were reduced by 53% and 25%, while the throughput was improved by 17%.

Autistic spectrum disease (ASD) is an increasingly common diagnosis nowadays with a prevalence of 1-2% in most countries. Its complex causality – a combination of genetic, immune, metabolic and environmental factors - is translated into pleiomorphic developmental disorders of various severity, which have in common two main aspects: repetitive, restrictive behaviors, and difficulties in social interaction varying from awkward habits and verbalization to complete lack of interest from the ASD child for the outside world. The wide variety of ASD causes also makes it very difficult to find a common denominator – a disease biomarker and medication – and currently there is no commonly used diagnostic and therapeutic strategy besides clinical evaluation and psychotherapy.It is known that inflammation is present in a majority of ASD children, and blood inflammatory markers, together with metabolic, electrophysiological markers and imagistics are useful for ASD diagnostic validation and treatment; however, they tend to leave out a sizeable proportion of ASD kids who do not have such modifications. Genetic testing – whole exome sequencing or targeted profiling on about 500 ASD-linked genes- may also provide good insight into pathophysiology, however many times its results are more restrictive rather than offering additional therapeutic options.Here we describe a new biomarker for ASD - the neuron-specific enolase (NSE) - which was elevated above the normal clinical range (less than 16.3 ng/mL) in the vast majority of ASD kids tested in our study (40 of 41, or 97.5%). This finding opens up a new direction for diagnostic confirmation, dynamic evaluation and therapeutic intervention for ASD kids.

Cross-species investigations on cancer invasiveness are a new approach that identified new biomarkers potentially useful for improving tumor diagnosis and prognosis in clinical medicine and veterinary science. In this study, we combined proteomic analysis of four experimental rat malignant mesothelioma (MM) tumors with analysis of ten patient-derived cell lines to identify common features associated to mitochondrial proteome rewiring. The comparison of significant abundance changes between invasive and non-invasive rat tumors rat tumors gave a list of 433 proteins, including twenty-six proteins reported to be exclusively located in mitochondria. Next, we analyzed the differential expression of genes encoding the mitochondrial proteins of interest in five primary epithelioid and five primary sarcomatoid human MM cell lines, and the most impressive increase was observed in the expression of the long-chain acyl coenzyme A dehydrogenase (ACADL). To evaluate the role of this enzyme in the migration/invasiveness, two epithelioid and two sarcomatoid human MM cell lines derived from patients with the highest and lowest overall survival were studied. Interestingly, sarcomatoid vs epithelioid cell lines were characterized by higher migration and fatty oxidation rates, in agreement with ACADL findings. These results suggest that evaluating mitochondrial proteins in MM specimens might identify tumors with higher invasiveness.

In this study, a numerical simulation of fluid flow through railway ballast in the time domain is presented, providing a model for unsteady-state flow. It is demonstrated that the position of the free surface with respect to time can also be used to solve the steady flow case. The effect of ballast fouling is included in the model to capture the realistic behavior of railway ballast, which is critical to understanding the impact of flooding. A thorough comparison with a range of previous studies, including theoretical and experimental approaches, is made and very close agreement is obtained. The significant impact of ballast fouling on fluid flow and its potential consequences for railway infrastructure are highlighted by the simulation. Valuable insights into the behavior of water flow through porous media and its relevance to railway ballast management are offered by this study.

Most existing cancer therapies negatively affect normal tissue as well as cancerous tissue. A potentially effective strategy for treating cancer that precludes off-target damage and could be an option for most patients would involve targeting one or more mutations that are ubiquitous in the given patient’s tumor(s). To effect this strategy, one would employ multi-region sequencing of a patient’s primary tumor and metastases to seek out mutations that are shared between all or at least most regions. Once the target or targets are known, one would ideally rapidly generate a molecular switch for at least one of said ubiquitous mutations that can distinguish the mutated DNA, RNA, or protein from the wild-type version and subsequently trigger a therapeutic response. I propose that the therapeutic response involve the replication of an oncolytic virus or intracellular bacterium, as any mutation can theoretically be detected by a vector that enters the cell - and automatic propagation could be very helpful. Moreover, the mutation “signal” can be easily enhanced through transcriptional and translational (if the target is an intracellular protein) enhancement. Importantly, RNA may make the best target for the molecular switches in terms of amplification of the signal and ease of targeting.

Recent advance in electric propulsion systems have demonstrated that these engines can be used for for long-duration interplanetary voyages. Constant specific impulse engine described as a thrust-limited engine is an example of this type of engine, processing the ability to operate at a constant level of impulse. The determination of minimum-fuel, planar heliocentric Earth-to-Mars low-thrust trajectories of spacecraft using a constant specific impulse is discussed considering the first-order necessary conditions derived from Lawden’s primer vector theory. The minimum-fuel low-thrust Earth-to-Mars optimization problem is then solved in two-dimensional, heliocentric frame using both indirect and direct methods. In the indirect method, two-point-boundary-value problems are derived to solve boundary value problems for ordinary differential equations. In the direct method, a general-purpose optimal control software called GPOPS-II is adopted to solve these optimal control problems. Numerical examples using two different optimization methods are presented to demonstrate the characteristics of minimum-fuel planar low-thrust trajectories with on-off-on thrust sequences at three chosen flight times and available maximum powers. The results are useful for broad trajectory search in the preliminary phase of mission designs.

The development of electric aircrafts is becoming an important technology for achieving the goals set by the European Commission for the reduction of gases emissions by 2050 in the aeronautical transportation system. However, there is a gap between the values of specific power in commercial electric machines and the ones required for aeronautical applications. Therefore, the search for alternative materials and non-conventional designs is mandatory. One emergent solution is using superconducting machines and systems to overcome the current limits of conventional electrical machines. This work reviews the new hybrid and all-electric aircraft tendencies, complementing it with recent research on the design and development of high specific power superconducting machines. This includes the main topologies for hybrid and all-electric aircraft, with an overview of the ongoing worldwide projects of these types of aircrafts, systematizing the main characteristics of their propulsion systems. It also includes the research on superconducting machines for the purpose of high specific power, considering the impact on the redesign of aircraft systems in the electrical, cooling, and fuel source sense.

In plant cells the conventional route to the vacuole involves the endoplasmic reticulum, the Golgi and the prevacuolar compartment. However, over the years, unconventional sorting to the vacuole, bypassing the Golgi, has been described, which is the case of the Plant Specific Insert (PSI) of the aspartic proteinase cardosin A. Interestingly, this Golgi-bypass ability is not a characteristic shared by all PSIs, since two related PSIs showed to have different sensitivity to ER-to-Golgi blockage. Given the high sequence similarity between the PSIs domains, we sought to depict the differences in terms of post-translational modifications. In fact, one feature that draws our attention is that one is N-glycosylated and the other one is not. Using site-directed mutagenesis to obtain mutated versions of the two PSIs, with and without the glycosylation motif, we observed that altering the glycosylation pattern interferes with the trafficking of the protein as the non-glycosylated PSI-B, unlike its native glycosylated form, is able to bypass ER-to-Golgi blockage and accumulate in the vacuole. This is also true when the PSI domain is analyzed in the context of the full-length cardosin. Regardless of opening exciting research gaps, the results obtained so far need a more comprehensive study of the mechanisms behind this unconventional direct sorting to the vacuole.

The Sentinel Application Platform (SNAP) architecture facilitates Earth Observation data processing (http://step.esa.int/main/toolboxes/snap/). In this work we present results from a new Snow Processor for SNAP. We also describe physical principles behind the developed snow property retrieval technique based on the analysis of Ocean and Land Colour Instrument (OLCI) onboard Sentinel-3A/B measurements over clean and polluted snow fields. Using OLCI spectral reflectance measurements in the range 400-1020nm, we derive important snow properties such as spectral and broadband albedo, snow specific surface area, snow extent and grain size on the spatial grid of 300m. The algorithm also incorporates cloud screening and atmospheric correction procedures over snow surfaces. We present validation results using ground measurements from Antarctica, the Greenland ice sheet and the French Alps. We find the spectral albedo retrieved with accuracy of better than 3% on average, making our retrievals sufficient for a variety of applications. Broadband albedo is retrieved with the average accuracy of about 5% over snow. Therefore, the uncertainties of satellite retrievals are close to experimental errors of ground measurements. The retrieved surface grain size shows good agreement with ground observations. Snow specific surface area observations are also consistent with our OLCI retrievals. We present snow albedo and grain size mapping over the inland ice sheet of Greenland for areas including dry snow, melted/melting snow and impurity rich bare ice. The algorithm can be applied to OLCI Sentinel-3 measurements providing an opportunity for creation of long – term snow property records essential for climate monitoring and data assimilation studies - especially in the Arctic region, where we face rapid environmental changes including reduction of snow/ice extent and, therefore, planetary albedo.

In Europe we can see a change in the social structure in the last period. Average life expectancy has increased dramatically over the last 50 years. Because of the improved life situation and advanced level of health care, older people are slower. With advancing age, the likelihood of experiencing a variety of constraints such as visual impairment, reduced hearing or physical ability increases. In such a life stage tenants are often forced to leave their long-term living space because these homes can not serve "new" individual needs and the resulting personal protection goal. This transition from the privacy of their home to the new environment often appears to be a painful change. They will take their familiar and well-known surroundings, because their homes can not be adapted to serve new needs. It must be the policy’s role to create a new inclusive social space and the requirement for architects and designers to create new goals for the design of an adaptable environment. This is a comprehensive approach to the design of the outer and inner space that could serve people even if there is an unexpected situation and changes in movement and physiological limitations of older people. The contribution shows the results of the survey conducted in Germany and Slovakia. In the survey respondents expressed their opinion on what they considered important in creating an adaptive environment. Results are processed graphically with explanation. The results were mainly for designers and developers of the indoor environment. Based on the results of the questionnaire survey, studies of possible modifications in the interior of the flats were then prepared. The contribution yielded these results in three age groups of respondents; i. people aged 35, 50 and over 50.

During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics. However, the BA detoxification-related enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) 2A1, and the nuclear receptors constitutive androstene receptor (CAR) and pregnane X receptor (PXR), were strongly suppressed in HFC fed males, and were only slightly changed in HFC-diet fed females. Expression levels of the farnesoid X receptor and its small heterodimer partner were similarly regulated in a gender-dependent fashion following HFC feeding. Hence, the pronounced female resistance to HFC-induced liver damage likely reflects sustained expression of the nuclear receptors CAR and PXR and the BA detoxification enzymes UGT and SULT.

LPA3 receptors were expressed in TREx HEK 293 cells, and their signaling and phosphorylation were studied. The agonist, lysophosphatidic acid (LPA), increased intracellular calcium and ERK phosphorylation through pertussis toxin-insensitive processes. Phorbol myristate acetate, but not LPA, desensitizes LPA3-mediated calcium signaling. The agonists and the phorbol ester-induced LPA3 internalization. Pitstop 2 (clathrin heavy chain inhibitor) markedly reduced LPA-induced receptor internalization; in contrast, phorbol ester-induced internalization was only delayed. LPA induced rapid β-arrestin-LPA3 receptor association. The agonist and the phorbol ester induced marked LPA3 receptor phosphorylation, and phosphorylation sites were detected using mass spectrometry. Phosphorylated residues were detected in the intracellular loop 3 (S221, T224, S225, and S229) and in the carboxyl terminus (S321, S325, S331, T333, S335, Y337, and S343). Interestingly, phosphorylation sites are within sequences predicted to constitute β-arrestin binding sites. These data provide insight into LPA3 receptor signaling and regulation.

Cadmium (Cd) is a metal with no nutritional or physiological value, but is found in most people because it is a contaminant in nearly all food types. The intestinal absorption rate determines the body burden of Cd because humans lack a physiologic mechanism for excretion of the metal. Most acquired Cd accumulates in the kidneys, in which the Cd content increases through age 50 but falls thereafter. The decline from maximal kidney content is probably due to release of Cd from injured tubular cells into urine and replacement of destroyed nephrons by scar tissue. Chronic kidney disease is diagnosed when the estimated glomerular filtration rate (eGFR) falls below 60 mL/min/1.73 m2, or when albuminuria is present. Albuminuria is defined as an albumin-to-creatinine ratio ≥ 30 mg/g creatinine in women or ≥ 20 mg/g creatinine in men that persists for at least 3 months. Generally, Cd-induced reductions in eGFR are not reversible, and Cd nephropathy may progress to end-stage kidney disease. There is no evidence that elimination of current environmental exposure can reverse Cd nephropathy, and no theoretical reason to believe that such a reversal is possible. This review provides an update of knowledge concerning CKD in population environmentally exposed to Cd. Special attention is devoted to mechanisms of Cd-induced albuminuria concurrently with eGFR reductions, and the difficult challenge of exposure guidelines sufficient to eliminate the risk of Cd-induced CKD is addressed.

Recent events concerning jet fuel contamination of drinking water have shown that we need a better understanding of the effects of ingested jet fuel. To this end, a reproductive study with in-gested jet fuel in rats was undertaken with relatively high concentrations of Jet Propellant (JP)-5 along with a human estrogen receptor activation in vitro assay using JP-5, JP-8, and an alternative jet fuel derived from the camelina plant to help evaluate potential effects of ingested jet fuel. Results of the in vivo study provided evidence that JP-5 can act as an endocrine disruptor, with specific observations including altered hormone levels with JP-5 exposure (significantly lower estradiol levels in male rats and significantly increased Dehydroepiandrosterone levels in females), indi-cations of abnormal estrous cycles, and a decreased male/female offspring ratio. The in vitro hormone receptor activation assay indicated JP-5 and JP-8 are capable of upregulating human estrogen receptor (ER) activity, while the alternative jet fuel derived from the camelina plant was not active in the ER assay. The jet fuels were not able to activate androgen or glucocorticoid re-ceptors in further in vitro assays. These results infer potential endocrine disruption associated with JP-5, with activation of the estrogen receptor as one potential mechanism of action.

Breast cancer is the most common cancer among women worldwide, and estrogen receptor-positive (ER+) breast cancer accounts for a significant proportion of cases. While various treatments are available, endocrine therapies are often the first-line treatment for this type of breast cancer. However, the development of drug resistance poses a significant challenge in managing this disease. ESR1 mutations have been identified as a common mechanism of endocrine therapy resistance in ER+ breast cancer. The first-generation selective estrogen receptor degrader (SERD) fulvestrant has shown some activity against ESR1 mutant tumors. However, due to its poor bioavailability and need for intramuscular injection, it may not be the optimal therapy for patients. Second-generation SERDs have been developed to overcome these limitations. These newer drugs have improved oral bioavailability and pharmacokinetics, making them more convenient and effective for patients. Several oral SERDs are now in phase III trials for early and advanced ER+ breast cancer. This review summarizes the background of oral SERD development, the current status, and future perspectives.

Piceatannol (PIC), a natural analog of resveratrol, has various biological functions. We previously reported that PIC had an anti-obesity effect only in ovariectomized mice. While ovariectomized mice have low phosphorylation levels of hormone-sensitive lipase (pHSL) at Ser563, we found that PIC increased those levels. Here, we investigated the effect of PIC using 3T3-L1 adipocytes to clarify the mechanism by which PIC activates HSL. First, PIC was confirmed to induce HSL phosphorylation at Ser563 in 3T3-L1 cells as in vivo experiments showed. pHSL (Ser563) is believed to be activated through the β-adrenergic receptor (β-AR) and protein kinase A (PKA) pathway; however, the addition of a selective inhibitor of β-AR did not inhibit the effect of PIC. The addition of PKA inhibitor with PIC blocked pHSL (Ser563), suggesting that PIC’s effects are mediated by PKA from a different pathway than β-AR. The addition of G15, a selective inhibitor of the G protein-coupled estrogen receptor (GPER), lowered HSL activation by PIC. Furthermore, PIC inhibited insulin signaling and did not induce pHSL (Ser565), which represents its inactive form. This study is the first to suggest that the GPER pathway might regulate HSL activation in adipocytes.

Abstract Forensic institutions throughout the country house patients with severe psychiatric illness and history of criminal violations. Improved medical care, hygiene, and nutrition led to unmatched longevity in this population which previously lived on average 15 to 20 years shorter than the public at large. On the other hand, longevity has contributed to increased prevalence of age-related diseases, including neurodegenerative disorders, which complicate clinical management. Forensic institutions, originally intended for the treatment of younger individuals, are ill-equipped for the growing number of older offenders. Moreover, as antipsychotic drugs became available in 1950s and 1960s, we are observing the first generation of forensic detainees who had aged on dopamine blockers. Although the consequences of long-term treatment with these agents are unclear, schizophrenia-associated gray matter loss, may contribute to the development of early dementia. Taken together, increased lifespan and subsequent cognitive deficit observed in long-term psychiatric institutions brought forth questions and dilemmas unencountered by the previous generations of clinicians, such as: 1. Does the presence of neurocognitive dysfunction justify antipsychotic dose reduction or discontinuation despite a lifelong history of schizophrenia and violent behavior? 2. Should neurolipidomic interventions become the standard of care in elderly individuals with lifelong schizophrenia and dementia? 3. Can patients with schizophrenia and dementia meet the Dusky standard and stand trial? 4. Should neurocognitive disorders in elderly with lifelong schizophrenia be treated differently than age-related neurodegeneration? In this article, we describe strategies for potentially slowing the development of neurocognitive disorders in forensic patients with chronic mental illness by adopting a three-prong strategy: 1. Approaching lifelong psychosis from microbial and immunological perspective. 2. Identify modifiable risk factors for age-related diseases in forensic institutions. 3. Utilizing novel receptor-independent treatments for chronic psychosis.

The conventional phytopathogen Pseudomonas syringae has been identified several significant virulence determinants against Caenorhabditis elegans, but their mechanisms of action remain elusive. Here, we report the nematicidal activity and action receptor of a methyl-accepting chemotaxis protein (MCP03) of a wild-type P. syringae MB03 against C. elegans. Purified MCP03 exhibited significant nematicidal toxicity against C. elegans, with a half-lethal concentration of 124.4 μg mL1, and detrimental effects on the growth and brood size of C. elegans. Additionally, MCP03-treated worms showed severe pathological destruction of the intestine and ovary, and depressed wrinkles of the cuticle. Through yeast two-hybrid assays, we identified a subunit of a COP9 signalosome, namely CSN-5, functionated as an action receptor of MCP03. In vitro pull-down and in vivo co-localization assays verified the binding interaction between MCP03 and CSN-5. RNA interference assays confirmed that MCP03 acts on CSN-5 to adversely affect the brood size, growth, and cuticle integrity of C. elegans. Following MCP03 infection, the expression of several genes relative to reproduction, growth, and cuticle formation, such as kgb-1, unc-98, and col-117, were significantly downregulated, which implicated the pathological changes of MCP03-treated nematodes. Thus, this study demonstrates that MCP03 acted on the receptor protein CSN-5 causing lethality and detrimental effects on the fertility, growth, and morphogenesis of C. elegans, which will provide new insights into the signaling pathways and mechanism underlying the nematicidal action of MCP03 towards C. elegans.

The objective of the present study is to isolate phages targeting multidrug resistant (MDR), extended spectrum beta lactamase (ESBL) positive clinical isolate of E. coli ( U1007), sequence and analyze the phage genome and use machine learning tools to predict host cell surface receptor and finally evaluate the efficiency of monophage and phage cocktail in vitro and in vivo in a zebrafish model. Phage specific for E. coli U1007 was isolated from Ganges River (designated as U1G), Cuoom River (designated as CR) and Hospital waste water (designated as M phage). The obtained phages were triple purified and enriched. U1G phages had a greater burst size of 124 PFU/cell and a latent time of 25 min.M phage had a burst size of 150 PFU/cell with a shortlatent time of 20min. Similarly CR phage has a short latent 20 min and a burst size of 115 PFU/cell. Based on capsid architecture, U1G phage resembles Podoviridae, CR phage is structurally similar to Myoviridae and M phage has morphology that resembles Siphoviridae. Genome sequencing and analysis revealed that the size of the U1G phage genome is 73275 bp Whereas that of CR phage and M phage are 45236 bp and 45294 bp, respectively. All three genomes were marked by the absence of genes encoding tRNA sequence, antibiotic resistant or virulent genes. A machine learning (ML) based multi-class classification model using algorithms such as Random Forest, Logistic Regression, and Decision Tree were employed to predict the host receptor targeted by all 3 phages and the best performing algorithm Random Forest predicted LPS O antigen , LamB or OmpC for U1G FhuA, OmpC for CR phage and FhuA, LamB, TonB or OmpF for the M phage as the host receptor targeted by the receptor binding protein (RBP) of the phages. In vitro time kill assay showed that treatment with monophages alone and along with colistin resulted in regrowth whereas phage combinations significantly reduced the regrowth and by 24h the phage cocktail along with colistin produced a significant 3 log declinein cell counts relative to the untreated control. In vivo intramuscular infection study in zebrafish showed that phages were non toxic and a cocktail of dual (U1G +M) phage along with colsitin resulted in a significant 3.5 log decline in cell counts whereas triple phage combination along with colistin resulted in 3 log decline in cell counts probably due to host receptor competition. Our study highlights the potential of phage cocktail therapy in mitigating MDR clinical isolate of E. coli in vitro and in vivo.

Porcine epidemic diarrhea virus (PEDV) has caused great damage to the global pig industry. The innate immunity plays a significant role in resisting viral infection, however, the exact role of innate immunity in the anti-PEDV response has not been fully elucidated. In this study, we observed that various porcine innate immune signaling adaptors are involved in the anti-PEDV activity. Among these, TRIF and MAVS showed the strongest anti-PEDV activity. The endogenous TRIF, MAVS and STING were selected for further examination of anti-PEDV activity. Agonist stimulation experiments showed that TRIF, MAVS and STING signaling all have obvious anti-PEDV activity. The siRNA knockdown assay showed that TRIF, MAVS and STING are also all involved in anti-PEDV response, and their remarkable effects on PEDV replication were confirmed in TRIF-/-, MAVS-/- and STING-/- Vero cells. For further verification, the anti-PEDV activity of TRIF, MAVS and STING could be reproduced in porcine IPEC-DQ cells. In summary, this study reveals that multiple pattern recognition receptor (PRR) signaling pathways of porcine innate immunity play an important role in the anti-PEDV infection, providing new and useful antiviral knowledge for prevention and control of PEDV spreading.

Gram-negative bacterial infections pose a significant threat to public health. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and induces innate immune responses, autophagy and cell death, which have major impacts on the body physiological homeostasis. However, the role of TLR4 in bacterial LPS-induced autophagy and apoptosis in large mammals remains unknown, which are closer to humans than rodents in many physiological characteristics. So far, few reports focus on the relationship between TLR, autophagy and apoptosis in large mammal levels. We urgently need more tools to further explore their crosstalk. Here, we generated a TLR4-enriched mammal model (sheep) and found that a high-dose LPS treatment blocked autophagic degradation and caused strong innate immune responses and severe apoptosis in PBMCs of transgenic offspring. Excessive accumulation of autophagosomes/autolysosomes might contribute to LPS-induced apoptosis in PBMCs of transgenic animals. Further study demonstrated that inhibiting TLR4 downstream NF-κB or p38 MAPK signaling pathways reversed the LPS-induced autophagy activity and apoptosis. These results indicate that the elevated TLR4 aggravates LPS-induced PBMCs apoptosis by leading to lysosomal dysfunction and impaired autophagic flux, which is associated with TLR4 downstream NF-κB and MAPK signaling pathways. This study provides a novel TLR4-enriched mammal model to study its potential effects on autophagy activity, inflammation, oxidative stress and cell death. These findings also enriched the biological functions of TLR4 and provided powerful evidence for bacterial infection.

Among the five human senses, light, sound, and force perceived by eye, ear, and skin, respectively are physical actions, and therefore can be easily measured and expressed as objective, univocal, and simple digital data with physical quantity. However, taste and odor molecules perceived by tongue and nose are chemical actions, it has been difficult to express them as objective and univocal digital data, since no reference chemicals can be defined. Therefore, while the recording, saving, transmitting to remote locations, and replaying human visual, auditory, and tactile information as digital data in digital devices has been realized (this series of data flow is defined as DX (digital transformation) in this review), the DX of human taste and odor information is not yet in the realization stage. Particularly, since there are at least 400,000 types of odor molecules and an infinite number of complex odors that are mixtures of these molecules, it has been considered extremely difficult to realize "human olfactory DX" by converting all odors perceived by the human olfaction into digital data. In this review, we discuss the current status and future prospects of the development of "human olfactory DX," which we believe can be realized by utilizing odor sensors that employ the olfactory receptors (ORs) that support human olfaction as sensing molecules (i.e., human OR sensor).

We aimed to evaluate the magnesium content in human cirrhotic liver and its correlation with serum AST levels, expression of hepatocellular injury, and MELDNa prognostic score. In liver biopsies obtained at liver transplantation we measured the magnesium content in liver tissue in 27 cirrhotic patients (CIRs) and 16 deceased donors with healthy liver (CTRLs) by atomic absorption spectrometry and within hepatocytes in 15 CIRs using synchrotron-based X-ray Fluorescence Microscopy. In 31 CIRs and 10 CTRLs we evaluated the immunohistochemical expression in hepatocytes of the transient receptor potential melastatin 7 (TRPM7), a magnesium influx chanzyme also involved in inflammation. CIRs showed a lower hepatic magnesium content [117.2 (IQR 110.5-132.9) vs 162.8 (IQR 155.9-169.8) μg/g; p&lt;0.001] and a higher percentage of TRPM7 positive hepatocytes [53.0 (IQR 36.8-62.0) vs 20.7 (10.7-32.8) %; p&lt;0.001) than CTRLs. In CIRs, MELDNa and serum AST at transplant correlated: a) inversely with the magnesium content both in liver tissue and hepatocytes; b) directly with the percentage of hepatocytes stained intensely for TRPM7. The latter also directly correlated with worsening of MELDNa at transplant compared to waitlisting. Magnesium depletion and overexpression of its influx chanzyme TRPM7 in hepatocytes are associated with severity of hepatocyte injury and prognosis in cirrhosis. These data represent the pathophysiological basis for a possible beneficial effect of magnesium supplementation in cirrhotic patients.

Studies on the neurobiological causes of anxiety disorders suggest that the GABA system in-creases synaptic concentration and enhances the affinity of GABAA (type A) receptors for ben-zo-diazepine ligands. Flumazenil antagonizes the benzodiazepine binding site of the GABA (γ-aminobutyric acid) type /benzodiazepine receptor (BZR) complex in the central nervous sys-tem (CNS). The integration of the metabolites of flumazenil by LC-tandem mass spectrometry will complete understanding of the in vivo metabolism of flumazenil and accelerate radio-pharmaceutical inspection and registration. The main goal of our study was to investigate using reversed-phase HPLC (PR-HPLC) coupled with electrospray ionization triple quadrupole tan-dem mass spectrometry (ESI-QqQ MS) for the identification of flumazenil and its metabolites in a hepatic matrix. And a carrier-free nucleophilic fluorination with automatic synthesizer for [18F]flumazenil which applied to in vivo nano-positron emission tomography (Nano-PET)/computed tomography (CT) imaging and ex vivo bio-distribution used to analyze in normal rats. The study showed that 50% of the flumazenil was bio-transformed at 60 min by the rat liver homogenate, while one metabolite (M1) was a methyl transesterification product of flumazenil. In a rat liver microsomes system, two metabolites were identified (M2 and M3) as its carboxylic acid and hydroxylated ethylester forms, respectively. [18F]flumazenil in vivo nanoPET/CT imag-ing and ex vivo bio-distribution assay also showed significant effects on GABAA receptor availa-bility in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, worriless about the formation of metabolites. We showed completion of the bio-transformed course of flumazenil by the hepatic system; and [18F]flumazenil can be a good ligand and serve as a PET agent for determination of GABAA/BZR complex for multiplex neurological syndromes in the clinical stage.

Abstract: The SARS-CoV-2 pandemic has significantly impacted world health and economic status. In response, much work has been undertaken to provide effective, safe vaccines, antibodies and antiviral drugs with which to address this pandemic. Treatment of a pandemic population presents multiple challenges in addition to the primary issue of drug efficacy and safety, such as large scale drug manufacture and distribution, drug stability, oral dosing and pharmacoeconomic considerations. Ideally, these factors must be addressed if new candidate drugs are to be advanced for treatment of large (pandemic) populations. Subsequently, new antivirals have reached the market but choices are few. According to the NIH Covid Treatment Guidelines, only three small molecule antiviral drugs are available to treat COVID-19 disease. As such, a significant part of the research towards discovery of new antiviral drugs has focused on screening and evaluation of ‘repurposed drugs’ or previously approved or clinical stage drugs. Yet, in spite of this increased research activity, one promising clinical stage candidate drug has received little attention regarding its potential as a monotherapy or component of combination therapy for treatment of COVID-19 disease. Tucaresol, with documented human safety and pharmacokinetic data, is an orally active, stable, small molecule amenable to large scale manufacture by a proprietary two-step synthesis developed by us. Tucaresol functions as a host-targeted antiviral by selective protection/reconstitution of CD4+ T helper cells as demonstrated in HIV patients and SIV macaques. In view of similarities between HIV and SARS-CoV-2, especially with respect to host CD4+ T helper cells, and the suitability of Tucaresol for facile treatment of pandemic populations, Tucaresol is presented herein for treatment of mild-to-moderate COVID-19 patients but may also be useful for treatment of advanced disease accompanied by lymphopenia.

The endocannabinoid system (eCB) began to be studied from the identification of the molecular structures present in the cannabis sativa plant. The ECS is constituted of cannabinoid receptors, endogenous ligands and all the associated enzymatic apparatus responsible for maintaining homeostasis. Several physiological effects of cannabinoids are exerted through interaction with various receptors such as CB1 and CB2 receptors, vanilloid receptors, and the recently discovered [GPCRs (GPR55, GPR3, GPR6, GPR12 and GPR19). Endogenous ligands such anandamide and 2-arachidonoylglycerol might modulate these receptors. eCB has proved to play a critical role in some human diseases and has been extensively studied due to its wide therapeutic potential and because it is a promising target for the development of new drugs. Phytocannabinoids and synthetic cannabinoids have shown varied affinities to eCB, which are relevant to the treatment of various diseases. They may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases. Furthermore, Integrative and Complementary Health Practices (ICHP) appear to influence the endocannabinoid system through modulation. This review will show a description of ECS components and discuss how phytocannabinoids, other exogenous compounds, and PICS may operate the eCB balance.

The different cell subsets of the immune system express vitamin D receptor (VDR). Through VDR, vitamin D exerts different functions which influences on immune responses, as previously shown in different preclinical models. Based on this background, retrospective studies have explored the impact of vitamin D levels on the outcome of patients undergoing allogeneic hematopoietic stem cell transplantation, showing that vitamin D deficiency is related to an increased risk of complications, especially graft-versus-host disease. These results have been confirmed in a prospective cohorts trial, although further studies are required to confirm this data. In addition, the role of vitamin D on the treatment of hematologic malignancies has also been explored. Considering this dual effect both on the immune system as well as on tumor cells in patients with hematologic malignancies, vitamin D might be useful in this setting both to decrease graft-versus-host disease and relapse rates.

The ryanodine receptor (RyR) is a Ca2+ release channel in the sarcoplasmic reticulum of skeletal and cardiac muscles and plays a key role in excitation-contraction coupling. The activity of the RyR is regulated by many intracellular factors such as divalent cations (Ca2+ and Mg2+), nucleotides, associated proteins, and reactive oxygen species. Since these intracellular factors change depending on the condition of the muscle, e.g., exercise, fatigue, or disease states, the RyR channel activity will be altered accordingly. In this review, we describe how the RyR channel is regulated under various conditions and discuss the possibility that the RyR acts as a sensor for change in the cellular environment of muscles.

The New World (NW) mammarenavirus group includes several zoonotic highly pathogenic viruses, such as Junin (JUNV) or Machupo (MACV). Contrary to Old World mammarenavirus, these viruses are not able to completely suppress the innate immune response, and trigger a robust interferon (IFN)-I response via retinoic acid-inducible gene I (RIG-I). Nevertheless, pathogenic NW mammarenaviruses trigger a weaker IFN response than their non-pathogenic relatives do. RIG-I activation leads to upregulation of a plethora of IFN-stimulated genes (ISGs), which exert a characteristic antiviral effect either as lone effectors, or resulting from the combination with other ISGs or cellular factors. The dsRNA sensor-protein kinase receptor (PKR) is an ISG that plays a pivotal role in the control of the mammarenavirus infection. In addition to its well-known protein synthesis inhibition, PKR further modulates the overall IFN-I response against different viruses, including mammarenaviruses. For this study, we employed Tacaribe virus (TCRV), the closest relative of the human pathogenic JUNV. Our findings indicate that PKR does not only increase IFN-I expression against TCRV infection, but also affects the kinetic expression and the extent of induction of Mx1 and ISG15 at both levels, mRNA and protein expression. Moreover, TCRV fails to prevent the effect of PKR on viral protein translation and its viral titer is inhibited when PKR is pre-stimulated via IFN-I. Here, we provide first evidence of the specific immunomodulatory role of PKR over selected ISGs, altering the dynamic of the innate immune response course against TCRV. IMPORTANCE: The mechanisms for innate immune evasion are key for emergence and adaptation of human pathogenic arenaviruses, and highly pathogenic mammarenaviruses such as JUNV or MACV trigger a weaker IFN response than non-pathogenic mammarenaviruses. Within the innate immune response context, PKR plays an important role in sensing and restricting the infection of TCRV virus. Although the mechanism of PKR for protein synthesis inhibition is well described, its immunomodulatory role is less understood. In this study, we found that TCRV protein expression and viral propagation are inhibited from early times after infection, and when externally activated, PKR inhibits TCRV viral progeny production. Our present findings further characterize the innate immune response in absence of PKR, unveiling the role of PKR in defining the ISG profile after viral infection.

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

Substances that can modify the androgen receptor pathway in humans and animals are entering the environment and food chain with the proven ability to disrupt hormonal systems and leading to toxicity and adverse effects on reproduction, brain development, and prostate cancer, among others. State-of-the-art databases with experimental data of human, chimp, and rat effects by chemicals have been used to build machine learning classifiers and regressors and evaluate these on independent sets. Different featurizations, algorithms, and protein structures lead to dif- ferent results, with deep neural networks (DNNs) on user-defined physicochemically-relevant features developed for this work outperforming graph convolutional, random forest, and large featurizations. The results show that these user-provided structure-, ligand-, and statistically-based features and specific DNNs provided the best results as determined by AUC (0.87), MCC (0.47), and other metrics and by their interpretability and chemical meaning of the descriptors/features. In addition, the same features in the DNN method performed better than in a multivariate logistic model: validation MCC = 0.468 and training MCC = 0.868 for the present work compared to evalu- ation set MCC = 0.2036 and training set MCC = 0.5364 for the multivariate logistic regression on the full, unbalanced set. Techniques of this type may improve AR and toxicity description and predic- tion, improving assessment and design of compounds. Source code and data are available at https://github.com/AlfonsoTGarcia-Sosa/ML

Novel severe acute respiratory syndrome coronavirus 2 infection (SARS-Cov-2) is an acute respiratory and infectious disease. This perspective aims to provide the basic understanding of the inflammation caused by SARS-Cov-2 and relation to trigeminal ganglion (TG). Virus enters through the mucous membranes of orofacial region and reach the TG where it resides and take control of its peptides including Substance P (SP).SP is the main neuropeptide, neuromodulator and neuro-hormone of TG, associated with nociception and inflammation under noxious stimulus. SP release is triggered and consequently, it affects the immune cells, blood vessels to release the mediators for inflammation. Cytokine storming is initiated and cause respiratory distress, bronchoconstriction and death in complicated cases. Neurokinin-1 Receptor (NK-1R) antagonist and glucocorticoids may be used to alleviate the symptoms and treat this infection. SP is the main culprit seem to be involved in the triggering of inflammatory pathways in SARS-Cov-2 infection. It has direct association with cardiorespiratory rhythm, sleep-wake cycle, nociception, ventilator responses and regulates many important physiological and pathological roles. Its over-secretion should be blocked by NK-1R antagonist. However, experimental work leading to clinical trials are mandatory for further confirmation.

As the world grapples with a pandemic with various and expanding epicenters, a flurry of medical and scientific activity has gained speed and momentum in a race to halt COVID-19. A controversial topic has been the connection between COVID-19 and the Renin-Angiotensin system (RAS). COVID-19, like Sars before it, enters by way of the Angiotensin Converting Enzyme 2 (ACE2). ACE2 is ubiquitously expressed in many tissues in the body serving as the doorway by which the virus can enter and spread causing inflammatory havoc. Demographic evidence coming out of China and other locations make it clear that the elderly and those suffering cardiovascular complications such as hypertension etc are most at risk. The connection to RAS and the demographic nature of the data coming out has led many to advance hypothesis, recommendations and even therapies based on existing RAS inhibitors and other components of the renin-Angiotensin system. It is pertinent to review the literature in the context of our understanding of the renin-angiotesnin system to allow better judgements to be made as well as lines of research initiated advancing a quick resolution to COVID-19. Covid-19 appears invincible as if dipped in the river Styx, but even Achilles had a vulnerable heel. Understanding the homeostatic balance that the coronavirus disrupts, we can discover the arrow in corona’s heel.

The transnational spread of coronavirus (2019-nCoV) first detected in Wuhan is causing global panic; thus, accelerated research into clinical intervention is of high necessity. The spike glycoprotein structure has been resolved, and its affinity to human angiotensin-converting enzyme 2 (ACE-2) has been experimentally validated. Here, using computational methods, a metastable conformation of 2019-nCoV-RBD/ACE-2 complex has been revealed and FDA-database of approved drugs have been docked into the interface. Darunavir has been discovered as high ligand affinity candidate capable of disrupting communication between 2019-nCoV-RBD and ACE-2. Darunavir, in addition to its previously known anti-HIV protease inhibitor is now repurposeable for the treatment 2019-nCoV disease acting via disruption of cellular recognition, binding and invasion.

The rodent collecting duct (CD) expresses a 24p3/NGAL/lipocalin-2 (Lcn2) receptor (Slc22a17) apically to possibly mediate high-affinity reabsorption of filtered proteins by endocytosis, yet its functions remain uncertain. Recently, we showed that hyperosmolarity/-tonicity upregulates Slc22a17 in cultured mouse inner medullary CD cells, whereas activation of toll-like receptor 4 (TLR4) via bacterial lipopolysaccharides (LPS) downregulates Slc22a17. This is similar to the upregulation of Aqp2 by hyperosmolarity/-tonicity and arginine vasopressin (AVP) and downregulation by TLR4 signaling that occur via the transcription factors Nfat5 (TonEBP or OREBP), cAMP-responsive element binding protein (CREB), and nuclear factor-kappa B, respectively. The aim of the study was to determine the effects of osmolarity/tonicity via Nfat5, AVP via CREB and TLR4 signaling on the expression of Slc22a17 and its ligand Lcn2 in the mouse (m) cortical collecting duct cell line mCCD(cl.1). Normosmolarity/-tonicity was 300 mosmol/l whereas addition of 50-100 mmol/l NaCl for up to 72 h induced hyperosmolarity/-tonicity (400-500 mosmol/l). RT-PCR, qPCR, immunoblotting and immunofluorescence microscopy detected Slc22a17 and Lcn2 expression. RNAi silenced Nfat5, and the pharmacological agent 666-15 blocked CREB. Activation of TLR4 occurred with LPS. Similar to Aqp2, hyperosmotic/-tonic media and AVP upregulated Slc22a17 via activation of Nfat5 and CREB, respectively, and LPS/TLR4 signaling downregulated Slc22a17. Conversely, though Nfat5 mediated hyperosmolarity/-tonicity induced downregulation of Lcn2 expression, AVP reduced Lcn2 expression and predominantly apical Lcn2 secretion evoked by LPS, but through a posttranslational mode of action that was independent of cAMP signaling. In conclusion, the hyperosmotic/-tonic upregulation of Slc22a17 in mCCD(cl.1) cells via Nfat5 and by AVP via CREB suggests a contribution of Slc22a17 to adaptive osmotolerance, whereas Lcn2 downregulation could counteract increased proliferation and permanent damage of osmotically stressed cells.

Abstract: With the availability of an increasing number of 3D structures of bacteriophage components, combined with powerful in silico predictive tools, it has become possible to decipher the structural assembly and functionality of phage adhesion devices. In the current study, we examined 113 members of the 936 group of lactococcal siphophages, and identified a number of Carbohydrate Binding Modules (CBMs) in the neck passage structure and major tail protein, on top of evolved Dit proteins as recently reported by us. The binding ability of such CBM-containing proteins was assessed through the construction of green fluorescent protein fusion proteins and subsequent binding assays. Two CBMs, one from the phage tail and another from the neck, demonstrated definite binding to their phage-specific host. Bioinformatic analysis of the structural proteins of 936 phages reveals that they incorporate binding modules which exhibit structural homology to those found in other lactococcal phage groups and beyond, indicating that phages utilize common structural “bricks” to enhance host binding capabilities. The omnipresence of CBMs in Siphophages supports their beneficial role in the infection process, as they can be combined in various ways to form appendages with different shapes and functionalities, ensuring their success in host detection in their respective ecological niches.

Cardiac β₂-adrenergic receptors (ARs) are known to inhibit collagen production and fibrosis in cardiac fibroblasts and myocytes. The β₂AR is a Gs protein-coupled receptor (GPCR) and, upon its activation, stimulates generation of cyclic 3', 5'-adenosine monophosphate (cAMP). cAMP has two effectors: protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac). Epac1 has been shown to inhibit cardiac fibroblast activation and fibrosis. Osteopontin (OPN) is a ubiquitous pro-inflammatory cytokine, mediating also fibrosis in several tissues, including the heart. OPN underlies several cardiovascular pathologies, including atherosclerosis and cardiac adverse remodeling. We have found that the cardiotoxic hormone aldosterone transcriptionally upregulates OPN in H9c2 rat cardiac myoblasts, an effect prevented by endogenous β₂AR activation. Additionally, CRISPR-mediated OPN deletion enhances cAMP generation in response to both b₁AR and β₂AR activation in H9c2 cardiomyocytes, leading to upregulation of Epac1 protein levels. These effects render β₂AR stimulation capable of completely abrogating transforming growth factor (TGF)-β-dependent fibrosis in OPN-lacking H9c2 cardiomyocytes. Finally, OPN interacts constitutively with G_as subunits in H9c2 cardiac cells. Thus, we have uncovered a direct inhibitory role of OPN in cardiac β₂AR anti-fibrotic signaling via cAMP/Epac1. OPN blockade could be of value in the treatment and/or prevention of cardiac fibrosis.

Single-particle tracking with quantum dots (QDs) constitutes a powerful tool to track the nanoscopic dynamics of individual cell membrane components unveiling their membrane diffusion characteristics. Here we tested the possibility of extracting from the nano-resolved (16 ms and 30 nm) population dynamics of several quantum dots, time-binned at the second time-scale, the rapid structural changes of the cell membrane surface. We used for this proof-of-concept study bright, small and stable biofunctional QD nanoconstructs recognizing the neuronal cannabinoid type 1 (CB1) receptor and a commercial point-localization microscope to reconstruct in 3D the dynamics of the plasma membrane surface of cultured cells with a spatial resolution of tens of nanometers. CB1 receptor was chosen because it’s a highly expressed and fast diffusing membrane protein. Therefore, rapid QD diffusion on the axonal plasma membrane of cultured hippocampal neurons allowed highly precise reconstruction of the membrane surface in less than one minute. QD nanoconstructs diffused into the membrane of synaptic clefts allowing the entire topological reconstruction of the presynaptic component. In addition, we demonstrated successful reconstruction of the remarkably high dynamics of membrane surface topology at the second time-scale both in HEK-293 cell filopodia and axons. Our results show that this novel technique, which we named nanoPaint, is a powerful precision tool for the study of the structural plasticity of cell membrane surfaces.

The theory says that the first things to exist in the universe and the current moment were driven by an imperative need; that is, the intensities of the physical concept specify influence the existence of elements and facts based on the countless observations in physical spaces in relation to elements and facts. The existence of mandatory elements in space is motivated by the characteristics of the spaces that offer conditions for such an obligation. The theory states that the universe did not arise by chance; that is, the universe emerged through determination influenced by its surroundings. The objective of the study is to help explain the elements and facts of the universe from its origins to the present.

This study employs molecular docking simulations using Autodock Vina with the Pyrx program to investigate the binding interactions between Human prostate-specific antigen (PSA) and natural compounds, namely Amentoflavone, Ginketin, Rutin, and Hypericin. The evaluation reveals excellent binding energy values, averaging around -10 kcal/mol, suggesting robust and favorable interactions between the selected compounds and PSA. The results provide valuable insights into the potential therapeutic applications of these natural compounds in the context of prostate cancer treatment or management. Further experimental validation is warranted to confirm these findings and explore the viability of these compounds as promising candidates for innovative therapeutic strategies. This research contributes to the growing body of knowledge in the field of molecular docking and its applications in drug discovery and bioinformatics.

Ubiquitin-Specific-peptidase 22 (Usp22) cleaves ubiquitin moieties from numerous proteins, in particular transcription factors. Recently, it was reported that Usp22 acts as negative regulator of interferon-dependent responses. In the current study, we investigated the role of Usp22 deficiency upon acute viral infection with lymphocytic choriomeningitis (LCMV) virus. We found that lack of Usp22 on bone marrow derived cells (Usp22 fl/fl Vav1-Cre mice) reduced induction of type I and II interferons. Limited type I interferon response did not influence virus replication. However, restricted expression of PD-L1 led to increased frequencies of functional virus-specific CD8+ T cells and rapid death of Usp22 deficient mice. CD8+ T cell depletion experiments revealed that accelerated CD8+ T cells were responsible for enhanced lethality in Usp22 deficient mice. In conclusion, we found that the lack of Usp22 generated a pathological CD8+ T cell response, which gave rise to severe disease in mice.

The fishmeal production industry is essential for providing protein for animal feed in the aquaculture sector. However, the industry faces challenges related to energy consumption and environmental sustainability. This study evaluates the energy efficiency and environmental benefits of waste heat recovery (WHR) technologies in a fishmeal production plant in Vietnam. Data were collected from the plant between 2016 and 2022, and a specific energy consumption (SEC) indicator and a comprehensive methodology were utilized. Implementing an economizer as a WHR technology resulted in a 55.5% decrease in SEC compared to the state before installation. The enhanced energy efficiency also translated to reduced energy consumption per output unit. Moreover, the economizer contributed to annual energy savings of 4,537.57 GJ/year and cost savings of $26,474.49. Additionally, carbon dioxide (CO2) emissions associated with producing one ton of fishmeal decreased by 58.37%. These findings highlight the potential for WHR technologies to improve energy efficiency and reduce the environmental footprint of fishmeal production. The study's results provide valuable insights for practitioners and policymakers in promoting energy efficiency practices and reducing environmental impact in the industry.

In recent years, the number of open preservation surgeries for treatment of laryngeal Cancer has increased. The purpose of this surgery is to avoid the highly mutilating intervention of a total laryngectomy (TL) and to maintain laryngeal function while ensuring oncological radicality. The aim of this study was to assess the oncologic results of OPHL I and II and to identify prognostic factors that could impact patient survival and local failure rates. This study was conducted on 182 patients with laryngeal squamous cell carcinoma treated with OPHLs between 2005 and 2015. The survival rates of a group of patients treated with TL between 2004 and 2014 were taken into con-sideration to compare survival outcomes. The DSS in pT2 and pT3 tumors in relation to the type of surgery showed no statistically significant difference between OPHLs and TL (p=0.54 and p=0.63 respectively). The 5-years T-recurrence free survival showed that pT4 tumors, perineural/vascular positive invasion and OPHL IIb + ARY treated tumors were associated with a higher risk of tumor recurrence (p<0.0001, p=0.0005 and p=0.016 respectively). OPHLs represent an excellent alterna-tive to TL considering the characteristics of the tumor and the general conditions of the patient.

Prostate-specific membrane antigen (PSMA) is a well validated prostate cancer marker, but reported PSMA-targeted tracers derived from the Lys-urea-Glu pharmacophore including the clinically validated [99mTc]Tc-EDDA/HYNIC-iPSMA have high off-target uptake in kidneys, spleen and salivary glands. In this study, we synthesized and evaluated three novel 99mTc-labeled PSMA-targeted tracers and investigated if the tracers derived from the Lys-urea-Aad pharmacophore could have minimized uptake in off-target organs/tissues. In vitro competition binding assays showed that compared with HYNIC-iPSMA, the three novel ligands had slightly weaker PSMA binding affinity (average Ki = 3.11 vs 8.96 - 11.6 nM). Imaging and ex vivo biodistribution studies in LNCaP tumor-bearing mice showed that [99mTc]Tc-EDDA/HYNIC-iPSMA and the three novel tracers successfully visualized LNCaP tumor xenografts in SPECT images and were excreted mainly via the renal pathway. The average tumor uptake at 1 h post-injection varied from 5.40 to 18.8 %ID/g, and the tracers derived from the Lys-urea-Aad pharmacophore had much lower uptake in spleen and salivary glands. Compared with the clinical tracer [99mTc]Tc-EDDA/HYNIC-iPSMA, the Lys-urea-Aad derived [99mTc]Tc-EDDA-KL01127 had lower background uptake and superior tumor-to-background contrast ratios, and is therefore promising for clinical translation to detect prostate cancer lesions with SPECT.

Knowledge of the biological effects of molecular hydrogen (H2), hydrogen gas, is constantly expanding giving a reason for optimism for several healthcare practitioners regarding management of multiple diseases, including socially significant ones. However, mechanisms underlying the biological effects of H2 are still being actively argued. In this review, we focus on mast cells as a potential target for H2 at the level of a specific tissue microenvironment. H2 regulates processing of pro-inflammatory components of the mast cell secretome and their entry into the extracellular matrix; this can significantly affect the state of the integrated-buffer metabolic environment and the structure of the immune landscape of the local tissue microenvironment. The analysis performed highlights several potential mechanisms for developing the biological effects of H2 and offers great opportunities for translating the obtained findings into clinical practice.

Malignancy is a fatal disease with an increasing incidence with each passing year, and the early diagnosis of malignancy can significantly improve the cure rate of patients, which has profound implications for saving patients' lives. The changes of miRNA are closely related to the occurrence of malignant tumors. The expression of miRNA in many malignant tumors is obviously different and unique from that in normal tissues. In this study, a strategy for amplifying microRNA (miRNA) signal was designed using duplex specific nuclease (DSN), which was then combined with Peptide nucleic acid (PNA) probe hybridization technology to prepare a sensitive and efficient paper-based lateral flow biosensor (LFB) for the detection of pancreatic cancer (PC) associated microRNA-10b. The performance evaluation results of the LFB showed that the detection limit of miR-NA-10b is 5 nM/mL, and carries demonstrated well specificity, stability, reproducibility. The biosensor prepared in this paper can provide accurate and rapid detection of miRNA-10b. The detection results play a guiding role in the early diagnosis of PC. Meeting the clinical need for largescale screening of individuals at high risk of PC. Providing new avenues to achieve early mass screening in individuals at high risk of PC.

Takotsubo syndrome (TTS), recognized as stress’s cardiomyopathy, or better as left ventricular apical balloon syndrome in the recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and by the strong predominance in postmenopausal women. The clear causes of these TTS features are uncertain, given the reduced understanding of this intriguing syndrome until now. However, the increasing frequency of TTS cases in the last years, and particularly correlated to SARS-CoV-2 pandemic, leads us to imperative necessity both of a complete knowledge of TTS pathophysiology for identifying biomarkers facilitating its management, and targets for specific and effective treatments. The suspect of a genetic basis in TTS pathogenesis has been evidenced. Accordingly, familial form of TTS has been described. But a systematic and comprehensive characterization of the genetic or epigenetic factors significantly associated with TTS is lacking. Thus, we, here, conducted a systematic review of literature before June 2021, to contribute to identify potential genetic and epigenetic factors associated with TTS. Interesting data were evidenced, but of reduced number and with diverse limitations. Consequently, we concluded further work is needed to address the gaps discussed, and probably a clear evidence may arrive using multi-omics investigations.

The ubiquitin-specific protease 2 (USP) belongs to the family of deubiquitinases and plays a critical role in tumors cells’ survival and therefore signifies an important therapeutic target. Previous studies have indicated promising efficacies of potent human USP2 inhibitors including, thiopurine analogues against SARS-CoV papain-like proteases (PLpro). The PLpro have significant functional implications in the innate immune response during SARS-CoV-2 infection and considered an important antiviral target. Both proteases share strikingly similar USP fold with right-handed thumb–palm–fingers structural scaffold and conserved catalytic triad Cys-His-Asp/Asn. In this urgency situation of COVID-19 outbreak, there is a lack of in-vitro facilities readily available to test SARS-CoV-2 inhibitors in whole-cell assays. Therefore, we adopted an alternate route to identify potential USP2 inhibitor through integrated structure-based virtual screening efforts. After a subsequent virtual screening protocol, the best compounds were selected and tested. The compound Z93 showed significant IC₅₀ value against Jurkat (9.67 µM) and MOTL-4 cells (11.8 µM). The binding mode of Z93 was extensively analyzed through molecular docking, followed by MD simulations, and molecular interactions were compared with SARS-CoV-2. The relative binding poses of Z93 fitted well in the binding site of both proteases and showed consensus π-π stacking and H-bond interactions with histidine and aspartate/asparagine residues of the catalytic triad. These results led us to speculate that compound Z93 might be the first potential chemical lead against SARS-CoV-2 PLpro, which warrants in-vitro evaluations.

Research in various fields of evolutionary biology has shown that divergence in gene expression is a key driver for phenotypic variation. An exceptional contribution of cis-regulatory evolution has for instance been found to contribute to morphological diversification. In the light of these findings, the analysis of genome-wide expression data has become one of the central tools to link genotype and phenotype information on a more mechanistic level. However, in many studies, especially if general conclusions are drawn from such data, a key feature of gene regulation is often neglected. With our article, we want to raise awareness that gene regulation and thus gene expression is highly context dependent. Genes show tissue- and developmental stage-specific expression. We argue that the regulatory context must be considered when studying evolution of gene expression.

Types of DNA recombination include homologous recombination and nonhomologous recombination. Homologous DNA recombination is a general term that includes exchange of information between chromatids: (reciprocal) crossing-over, gene conversion, and post-meiotic segregation. Gene conversion is now thought to be a type of non-Mendelian segregation of heterozygous markers near the recombination initiation site. Thus, it includes both gene conversion and post-meiotic segregation previously described. DNA non-HR including transpositional recombination and site-specific recombination. Our understanding of the molecular mechanism by which DNA recombination occurs has significantly increased in the past decades. Currently The synthesis-dependent strand annealing model is now thought to give rise to most or all noncrossovers, with the double-strand-break repair model forming mainly crossovers. The Shapiro model proposed by Dr. J. Shapiro explains the molecular mechanism of transpositional recombination. Site-specific recombination results from another distinct model. We previously proposed a novel theory which can provide a more reasonable and simpler explanation accounting for DNA HR including the 3 classes of recombinogenic events described above. In the new supplementedly molecular model, DNA meiotic recombination can be initiated by a copy choice mechanism, that is, copying part of 1 single-stranded DNA template, followed by DNA polymerase switching to another single-stranded DNA template, and then resuming the following DNA synthesis along the new template. The current review suggests that transpositional recombination and site-specific recombination should be initiated by copy choice during DNA synthesis rather than break/join mechanism. The work indicates that review of DNA nonhomologous recombination are very necessary. The novel theory would challenge earlier models accounting for transpositional recombination and site-specific recombination and would be critical to the understanding of the mechanisms. We hope copy choice initiating DNA nonhomologous recombination will be one of the concepts that are explored. Proper and specific experiments are required to reconstruct the detailed mechanism described here.

Abstract: Kiwifruit, a perennial horticultural crop known for its nutritional value, faces significant challenges due to biotic and abiotic stresses, affecting its yield and quality. Leucine-rich repeat receptor-like proteins (LRR-RLPs), a major group of receptor-like proteins in plants, have diverse functions in plant physiology, including growth, development, signal transduction, and stress responses. Despite their importance, the specific roles of kiwifruit LRR-RLPs in response to biotic and abiotic stresses remain poorly understood. In this study, we investigated the expression patterns of kiwifruit LRR-RLPs under various stress conditions, including pathogen stress, heat stress, waterlogging stress, and copper stress. Through genome and transcriptome analyses, we identified a total of 101, 164, and 105 LRR-RLPs in Actinidia Chinensis 'Hongyang', Actinidia eriantha 'Huate', and Actinidia chinensis 'Red5' kiwifruit, respectively, classified into 9 subgroups based on phylogenetic relationships. Synteny analysis revealed that the expansion of kiwifruit LRR-RLPs was primarily attributed to segmental duplication events. Using RNA-seq data from pathogen-infected kiwifruits, we identified specific LRR-RLP genes potentially involved in different stages of pathogen infection. Additionally, we observed the potential involvement of kiwifruit LRR-RLPs in abiotic stress responses, with upstream transcription factors possibly regulating their expression. Furthermore, protein interaction network analysis unveiled the participation of kiwifruit LRR-RLP genes in the regulatory network of abiotic stress responses. These findings highlight the crucial roles of LRR-RLPs in mediating both biotic and abiotic stress responses in kiwifruit, offering valuable insights for the breeding of stress-resistant kiwifruit varieties.

N-methyl-D-aspartate receptors (NMDARs) are the main class of ionotropic receptor for the ex-citatory neurotransmitter glutamate. It plays a crucial role in the permeability of Ca2+ ions and excitatory neurotransmission in the brain. Being heteromeric receptors, they are composed of sev-eral subunits, including two obligatory GluN1 subunits (eight splice variants) and regulatory GluN2 (GluN2A~D) and/or GluN3 (GluN3A~B) subunits. Widely distributed in the brain, they regulate other neurotransmission systems and are therefore involved in essential functions such as synaptic transmission, learning and memory, plasticity, excitotoxicity. The present review will discuss the physiopathological impacts of NMDAR and particularly GluN2A and GluN2B subu-nits in cognitive processes and neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease). The pharmacology of different NMDAR antagonists and their po-tentialities will be presented. In particular, a focus will be given on fluoroethylnormemantine (FENM), an investigational drug with very promising developments as a tomography radiotracer for NMDARs, an anxiolytic in post-traumatic stress disorder and a neuroprotective agent in Alzheimer's disease.

The expedited development of drugs targeting gene products associated with insulin resistance holds the potential to enhance our comprehension of type 2 diabetes mellitus (T2DM). The virtual screening based on a three-dimensional (3D) protein structure has been expected as potential technique to accelerate a development of molecular target drugs. Among the targets implicated in insulin resistance, genetic characterization and protein function of Grb14 have been clarified without contradiction. The Grb14 gene displays notable variations in T2DM, and its gene product known to inhibit the function of the insulin receptor (IR) by directly binding to the tyrosine kinase domain. In the present study, a virtual screening, based on 3D structure of IR tyrosine kinase domain (IRβ) in complex with part of Grb14, was conducted to find compounds that can disrupt the complex formation between Grb14 and IRβ. First, ten compounds were selected from 154,118 compounds via hierarchical in silico structure-based drug screening, composed of grid docking-based and genetic algorithm-based programs. The experimental validations suggested that the one compound can affect blood glucose level. The molecular dynamics simulations and co-immunoprecipitation analysis showed that the compound did not completely suppress the protein–protein interaction between Grb14 and IR, though competitively bound to IR with the tyrosine kinase pseudosubstrate region in Grb14.

Tocilizumab against interleukin-6 receptor (IL-6R) has been demonstrated to inhibit the progression of diverse cancers in vitro and in vivo. Nonetheless, evidence regarding the anti-tumor effects of Tocilizumab on human colorectal carcinoma (CRC) corresponding to IL-6R expression levels re-mains scarce. To investigate the influence of IL-6R expression, SW480 and HT-29 cells inoculated subcutaneously into NU/NU mice were used as our human CRC xenograft models with anti-IL-6R antibody (Tocilizumab) therapy. IL-6R expression levels, the histology of CRC growth/ invasiveness and tumor growth-related signaling pathway were estimated by H&E and immunohistochemical staining. SW480 tumor cells with higher IL-6R expression levels exerted better responsiveness in Tocilizumab therapy than the treated HT-29 group. Likewise, therapeutic effects of Tocilizumab on the proliferative ability with mitotic index and Ki-67 expressions, the invasiveness with MMP-9 proteinase expressions, ERK 1/2 and STAT3 signaling transduction in SW480 treatment group were superior to HT-29 treatment group. In light of our results, IL-6R is the key indicator for the efficacy of Tocilizumab treatment in CRC xenografts. From the perspective of precision medicine, tumor response to anti-IL-6R antibody therapy could be predicted on the basis of IL-6R expression levels. In this manner, Tocilizumab may serve as a targeted and promising anti-CRC therapy.

Background and Objectives: Previous studies revealed anti-angiogenic, antiproliferative and anti-inflammatory effects of Vitamin D on cancer cells. Although this body of evidence supported the correlation of high Vitamin D levels with reduced incidence rates for various malignancies, contradictory results were reported regarding non-melanoma skin cancer (NMSC). Aim of this overview was to summarize the available evidence from the existing pool of systematic reviews and meta-analyses, focusing on Vitamin D serum status, dietary intake, and Vitamin D receptor (VDR) polymorphisms in correlation to NMSC incidence. Materials and Methods: A literature search in electronic databases was conducted from inception to January 2023. Inclusion criteria were systematic reviews and meta-analyses published in peer-reviewed journals, evaluating Vitamin D serum levels, dietary and/or supplementary intake, or VDR gene polymorphisms, and reporting data on NMSC. Results: A total of 10 studies were included in the data analysis models. A positive association between Vitamin D serum levels and NMSC is highlighted. However, dietary/supplementation of Vitamin D doesn’t exhibit a likewise strong linkage to NMSC. Despite the contradictory findings, VDR polymorphisms may play a crucial role in the intricate NMSC pathogenesis. Conclusions: This umbrella review showed that high Vitamin D levels are associated with increased NMSC incidence, potentially due to its direct correlation with increased sun exposure. Further research on VDR polymorphisms is suggested to explore their true effect size on NMSC risk.

Background. The type-2 sodium-glucose cotransporters inhibitors (SGLT2i) are a new relevant therapeutic option for patients affected by chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate, in a real-world population from a single center, the feasibility of introducing SGLT2i and their interaction with other recommended drug classes. Methods. We evaluated the consecutive patients affected by chronic heart failure (CHF) since January 2022. At baseline clinical visit the therapy taken by the patients as well as that prescribed were accurately collected. During a 6-12 month follow-up the the changes in concomitant therapy were analyzed. Results. At baseline, among 350 patients evaluated, only 17 (5%) were already taking SGLT2i, 13 with HFrEF, 2 with CHF with mild reduced (HFmrEF) and 2 with preserved ejection fraction (HFpEF). After baseline evaluation, SGLT2i were prescribed to 220 (63%) of all the patients enrolled, among whom 178 (84%) of HFrEF patients, 25 (42%) of HFmrEF and 17 (22%) of HFpEF. After follow-up, SGLT2i therapy was highly tolerated and it was associated with a significant increased prescription of sacubitril/valsartan and a reduced use of diuretics. Finally, a significant improvement in functional status and left ventricular systolic function after SGLT2i therapy was observed. Conclusions. In this single center “real world” study, SGLT2i were prescribed in HFrEF patients most of all already in therapy with the other classes of drugs currently recommended for their treatment. Moreover, a further optimization in prescribed ther-apy was observed during a short term follow-up. These data further support the use of this thera-peutic approach in routine clinical practice.

Febrile seizures (FS) are a relatively common early-life condition that can cause CNS developmental disorders, but the specific mechanisms of action of FS are poorly understood. In this work, we used hyperthermia-induced FS in 10-day-old rats. By recording local field potentials, we showed that the efficiency of glutamatergic synaptic transmission decreased 15 min after FS. This effect was transient, and after 2 days there were no differences between control and post-FS groups. During early ontogeny, the proportion of calcium-permeable (CP)-AMPA receptors in the synapses of principal cortical and hippocampal neurons is high. Therefore, rapid internalization of CP-AMPA receptors may be one of the mechanisms underlying this phenomenon. Using the whole-cell patch clamp method and the selective CP-AMPA receptor blocker IEM-1460, we tested whether the proportion of CP-AMPA receptors changes. We have demonstrated that FS rapidly reduces synaptic CP-AMPA receptors in both the hippocampus and the entorhinal cortex. This process was accompanied by a sharp decrease in calcium permeability of the membrane of principal neurons, which we revealed in experiments with kainate-induced cobalt uptake. Our experiments show that FSs cause rapid changes in the function of the glutamatergic system, which may have compensatory effects that prevent excessive excitotoxicity and neuronal death.

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which has now become a severe public health problem worldwide. β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous study has demonstrated that Bruton's tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-β related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by β-AR overactivation;(2) Methods: In vivo: Male C57BL/6J mice were treated with or without the β-AR agonist isoproterenol (ISO) to establish cardiac fibrosis animal model. Here, results showed that BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by β-AR. In vitro: Results showed that ZB alleviated β-AR-induced cardiac fibroblast activation and macrophage proinflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited β-AR-induced cardiac fibrosis and inflammation by BTK、STAT3、NF-κB and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates β-AR-induced cardiac fibrosis and inflammation.

The natural product Salvinorin A (SalA) was the first nitrogen-lacking agonist discovered for the opioid receptors and exhibits high selectivity for the kappa opioid receptor (KOR) turning SalA into a promising analgesic to overcome the current opioid crisis. Since SalA’s suffers from poor pharmacokinetic properties, particularly the absence of gastrointestinal bioavailability, fast metabolic inactivation and subsequent short duration of action, the rational design of new tailored analogs with improved clinical usability is highly desired. Despite being known for decades, the binding mode of SalA within the KOR remains elusive as several conflicting binding modes of SalA were proposed hindering the rational design of new analgesics. In this study, we rationally determined the binding mode of SalA to the active state KOR by in silico experiments (docking, molecular dynamics simulations, dynophores) in the context of all available mutagenesis studies and structure-activity relationship (SAR) data. To the best of our knowledge this is the first comprehensive evaluation of SalA’s binding mode since the determination of the active state KOR crystal structure. SalA binds above the morphinan binding site with its furan pointing towards the intracellular core while the C2-acetoxy group is oriented towards the extracellular loop 2 (ECL2). SalA is solely stabilized within the binding pocket by hydrogen bonds (C210ECL2, Y3127.35, Y3137.36) and hydrophobic contacts (V1182.63, I1393.33, I2946.55, I3167.39). With the disruption of this interaction pattern or the establishment of additional interactions within the binding site we were able to rationalize the experimental data for selected analogs. We surmise the C2-substituent interactions as important for SalA and its analogs to be experimentally active, albeit moderate frequency within MD simulations of SalA. We further identified the non-conserved residues 2.63, 7.35, and 7.36 responsible for the KOR subtype selectivity of SalA. We are confident that the elucidation of the SalA binding mode will promote the understanding of KOR activation and the facilitate the development of novel analgesics that are urgently needed.

Up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse despite the improvement achieved by the introduction of HER2-targeted therapy. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown an improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). One strategy has been to target the cyclin-dependent kinases 4/6 (CDK4/6) as they are downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies play a key role in cell cycle and proliferation. Different trials have explored these strategies with encouraging results, but definitive results are needed. In addition, HER2+ BC is known to be more immunogenic than other BC subgroups, with high variability between tumors. Different immunotherapeutic agents have been investigated in this setting, with promising but controversial results obtained to date.

Even brief epileptic seizures can lead to activity-dependent structural remodeling of neural circuitry. Animal models show that the functional plasticity of synapses and changes in the intrinsic excitability of neurons can be crucial for epileptogenesis. However, the exact mechanisms underlying epileptogenesis remain unclear. We induced epileptiform activity in rat hippocampal slices for 15 min using a 4-aminopyridine (4-AP) in vitro model and observed hippocampal hyperexcitability for at least 1 hour. We tested several possible mechanisms of this hyperexcitability, including changes in intrinsic membrane properties of neurons, presynaptic and postsynaptic alterations. Neither input resistance nor other essential biophysical properties of hippocampal CA1 pyramidal neurons were affected by epileptiform activity. The glutamate release probability also remained unchanged, as the frequency of miniature EPSCs and the paired amplitude ratio of evoked responses did not change after epileptiform activity. However, we found an increase in the AMPA/NMDA ratio, suggesting alterations in the properties of postsynaptic glutamatergic receptors. Thus, the increase in excitability of hippocampal neural networks is realized through postsynaptic mechanisms. In contrast, the intrinsic membrane properties of neurons and the probability of glutamate release from presynaptic terminals are not affected in a 4-AP model.

Several studies have demonstrated that the p75NTR low-affinity receptor of Nerve Growth Factor (NGF), is produced in abnormally large amounts in several human cancer types. However, the role of p75NTR varies substantially depending on cell context, so that a dual role of this receptor protein in tumor cell survival and invasion, as well as cell death, has been supported in recent studies. Herein we explored for the first time the expression of p75NTR in human specimens (nr=40) from testicular germ cell tumors (TGCTs), mostly seminomas. Nuclear overexpression of p75NTR was detected by immunohistochemistry in tumor tissue as compared to normal tissue, whereas neither NGF nor its high-affinity TrkA receptor was detected. An increased nuclear staining of phospho-JNK, belonging to the p75NTR signaling pathway, and its pro-apoptotic target gene, p53, was concomitantly observed. Interestingly, our analysis revealed that decreased expression frequency of p75NTR, p-JNK, and p53 was related to staging progression, thus suggesting that p75NTR may represent a specific marker of differentiation in TGCTs.

Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds, are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.

Vitamin D is a nutrient with anti-inflammatory properties whose role is currently being evaluated in COVID-19. Although studies are conflicting, they seem to suggest a role for vitamin D in reducing disease susceptibility but not in improving clinical outcome. In order to understand why vitamin D does not seem to have much effect on decreasing disease severity, it is essential to appreciate pulmonary vitamin D metabolism. To reach the pulmonary compartment, vascular endothelial cells would need to take up vitamin D from the blood stream, but they lack vitamin D receptor (VDR) and the activating enzyme CYP27B1. Endothelialitis – an important disease manifestation of COVID-19 – is therefore not expected to be directly affected by vitamin D. Bronchial epithelial cells are usually among the first to be infected with SARS-CoV-2. They do express both VDR and CYP27B1, but circulating vitamin D may not reach bronchial epithelial cells without transportation from the blood stream through the blood vessel wall. Inhalation therapy with vitamin D has therefore been suggested as an alternative for oral administration to bypass endothelial cells and efficaciously target bronchial epithelium. In conclusion, based on the principles of pulmonary vitamin D metabolism, it is not expected that vitamin D administration has a significant effect on COVID-19 severity. Vitamin D is more likely to reduce SARS-CoV-2 susceptibility, but reaching the airways with oral supplementation will be difficult and vitamin D inhalation therapy should be considered.

Neurokinin-1 receptor (NK-1R) antagonists exert an antitumor action, are safe and do not cause serious side-effects. These antagonists (via the NK-1R) exerted multiple actions against cancer: antiproliferative and anti-Warburg effects, apoptosis, anti-angiogenic and antimetastatic. These multiple effects have been shown in a broad-spectrum of cancers. The drug aprepitant (an NK-1R antagonist) is currently used in clinical practice as antiemetic. In in vivo and in vitro studies, aprepitant also showed the aforementioned multiple antitumor actions against many types of cancer. A successful combination therapy (aprepitant and radiotherapy) has recently been reported in a patient suffering from lung carcinoma: the tumor mass disappeared and side-effects were not observed. Aprepitant could be considered as an intelligent bullet against cancer. The administration of aprepitant in cancer patients to prevent recurrence and metastasis after surgical procedures, thrombosis and thromboembolism is discussed as well as the possible link, through the SP/NK-1R system, between cancer and depression. Our main aim is to review the multiple antitumor actions exerted by aprepitant and the use of this drug is suggested in cancer patients. Altogether, the data support the reprofiling of aprepitant for a new therapeutic use as an antitumor agent.

Life-threatening inflammatory conditions such as acute respiratory distress syndrome or sepsis often go hand in hand with severe vascular leakage. During inflammation, endothelial cell integrity and intact barrier function are crucial to limit leukocyte and plasma extravasation. Prostaglandin D₂ (PGD₂) is a potent inflammatory lipid mediator with vasoactive properties. It has been suggested that PGD^­₂ is involved in the regulation of endothelial barrier function; however, it is unclear whether this is also true for primary human pulmonary microvascular endothelial cells. Furthermore, as PGD₂ is a highly promiscuous ligand, we set out to determine which receptors are important in human pulmonary endothelial cells. In the current study, we found that PGD₂ and the DP1 agonist BW245c potently strengthened pulmonary and dermal microvascular endothelial cell barrier function and protected against thrombin-induced barrier disruption. Yet surprisingly, these effects were mediated only to a negligible extent via DP1 receptor activation. In contrast, we observed that the EP4 receptor was most important and mediated the barrier enhancement by PGD₂ and BW245c. These data demonstrate a novel mechanism by which PGD₂ may modulate inflammation and emphasizes the role of EP4 receptors in human endothelial cell function.

SARS-CoV-2, the newly identified human coronavirus causing severe pneumonia epidemic, was probably originated from Chinese horseshoe bats. However, direct transmission of the virus from bats to humans is unlikely due to lack of direct contact, implying the existence of unknown intermediate hosts. Angiotensin converting enzyme 2 (ACE2) is the receptor of SARS-CoV-2, but only ACE2s of certain species can be utilized by SARS-CoV-2. Here, we evaluated and ranked the receptor-utilizing capability of ACE2s from various species by phylogenetic clustering and sequence alignment with the currently known ACE2s utilized by SARS-CoV-2, predicting potential intermediate hosts of SARS-CoV-2.

Acute ischemic strokes are the third leading cause of death and the leading cause of neurological disability worldwide. The oxygen and glucose deprivation associated with ischemic strokes not only leads to neuronal cell death, but also increases the inflammatory response and decreases functional output of the brain. The only intervention approved by US Federal Drug and Food Administration for treatment of ischemic strokes is tissue plasminogen activator (tPA), however, such treatment can only be given within 4.5 hours of the onset of stroke-like symptoms. This narrow time-range limits its application, and it also might induce detrimental rather than beneficial effects to stroke patients by treatment of the tPA. In order to reduce the infarct volume of an acute ischemic stroke while increasing the time period for treatment, emerging therapies reveal great potential by targeting inflammation, growth factors, ion channels, and neurotransmitter receptors with monoclonal antibody (MAB). With successfully application in the treatment of cancer patient by MAB, in this review, we will focus on recent advances on stroke therapy by using MAB on the treatment of stroke by targeting inflammation, growth factors, ion channels, and neurotransmitter receptors. Therefore, developing specific MAB targeting the signaling pathway of stroke will contribute to stroke therapy.

Natural and synthetic small molecules from the NCI Developmental Therapeutics Program (DTP) were employed in molecular dynamics-based docking with DNA repair proteins whose RNA-Seq based expression was associated with overall cancer survival (OS) after adjustment for the PCNA metagene. The compounds employed were required to elicit a sensitive response (vs. resistance) in more than half of the cell lines tested for each cancer. Methodological approaches included peptide sequence alignments and homology modeling for 3D protein structure determination, ligand preparation, docking, toxicity and ADME prediction. Docking was performed for unique lists of DNA repair proteins which predict OS for AML, cancers of the breast, lung, colon, and ovaries, GBM, melanoma, and renal papillary cancer. Results indicate hundreds of drug-like and lead-like ligands with best-pose binding energies less than -6 kcal/mol. Ligand solubility for the top 20 drug-like hits approached lower bounds, while lipophilicity was acceptable. Most ligands were also blood-brain barrier permeable with high intestinal absorption rates. While the majority of ligands lacked positive prediction for Herg channel blockage and Ames carcinogenicity, there was considerable variation for predicted fathead minnow, honey bee, and Tetrahymena pyriformis toxicity. The computational results suggest the potential for new targets and mechanisms of repair inhibition and can be directly employed for in vitro and in vivo confirmatory laboratory experiments to identify new targets of therapy for cancer survival.

The exploitation of lipid membranes in biosensors has provided the ability to reconstitute a considerable part of their functionality to detect trace of food toxicants and environmental pollutants. Nanotechnology enabled sensor miniaturization and extended the range of biological moieties that could be immobilized within a lipid bilayer device. This chapter reviews recent progress in biosensor technologies based on lipid membranes suitable for environmental applications and food quality monitoring. Numerous biosensing applications are presented, putting emphasis on novel systems, new sensing techniques and nanotechnology-based transduction schemes. The range of analytes that can be currently detected include, insecticides, pesticides, herbicides, metals, toxins, antibiotics, microorganisms, hormones, dioxins, etc. Technology limitations and future prospects are discussed, focused on the evaluation/ validation and eventually commercialization of the proposed sensors.

The exploitation of lipid membranes in biosensors has provided the ability to reconstitute a considerable part of their functionality to detect trace of food toxicants and environmental pollutants. Nanotechnology enabled sensor miniaturization and extended the range of biological moieties that could be immobilized within a lipid bilayer device. This chapter reviews recent progress in biosensor technologies based on lipid membranes suitable for environmental applications and food quality monitoring. Numerous biosensing applications are presented, putting emphasis on novel systems, new sensing techniques and nanotechnology-based transduction schemes. The range of analytes that can be currently detected include, insecticides, pesticides, herbicides, metals, toxins, antibiotics, microorganisms, hormones, dioxins, etc. Technology limitations and future prospects are discussed, focused on the evaluation/ validation and eventually commercialization of the proposed sensors.

Many agonists for the estrogen receptor are known to disrupt endocrine functioning. We have developed a computational model that predicts agonists for the estrogen receptor ligand-binding domain in an assay system. Our model was entered into the Tox21 Data Challenge 2014, a computational toxicology competition organized by the National Center for Advancing Translational Sciences. This competition aims to find high-performance predictive models for various adverse-outcome pathways, including the estrogen receptor. Our predictive model, which is based on the random forest method, delivered the best performance in its competition category. In the current study, the predictive performance of the random forest models was improved by strictly adjusting the hyperparameters to avoid overfitting. The random forest models were optimized from 4,000 descriptors simultaneously applied to 10,000 activity assay results for the estrogen receptor ligand-binding domain, which have been measured and compiled by Tox21. At this time, our model delivers the highest predictive power on estrogen receptor agonists in the world. Furthermore, analysis of the optimized model revealed some important features of the agonists, such as the number of hydroxyl groups in the molecules.

The mechanical properties of the materials stored inside agricultural silos influence the loads generated inside them. The different silo calculation methodologies allow predicting these loads under static and dynamic conditions if the mechanical properties of the stored materials are known. It has been known for many years that these properties are highly dependent on the moisture content of the material. However, to date there are not many studies focused on its determination. The goal of this research is the determination of the angle of internal friction, apparent cohesion, dilatancy angle and apparent specific weight of maize subjected to different moisture contents. Direct shear and oedometer assay devices were used for this purpose. In addition, the maize samples used were moistened using a climatic chamber. Moisture contents applied to maize sample ranged from 9.3% to 17.4%. The results obtained for the angle of internal friction and apparent cohesion, as well as those obtained for the apparent specific weight, were similar to those reported in the literature. However, the values obtained for the dilatancy angle of maize as a function of moisture content could not be compared because nothing has been published so far. The values obtained for this parameter overlap with those published for this material under ambient conditions. In addition, no direct relationship between the values obtained for this parameter and the moisture content of the sample could be found. Finally, the apparent specific weight increased with increasing moisture content of the samples, which differed from that published in the literature. The values provided here can be used for the optimization of storage and handling structures for granular agricultural materials using numerical methods.

This study investigates the impacts of climate change policies on businesses across various sectors, aiming to understand how these regulations affect operational, financial, and strategic aspects of business management. Utilizing a mixed-methods approach, data was collected from 500 businesses through surveys and interviews, encompassing a wide range of industries, sizes, and geographic locations. The findings reveal a complex landscape where 30% of businesses report positive impacts, primarily in the renewable energy and technology sectors, citing increased demand for green products and improvements in energy efficiency. Conversely, 45% of businesses, especially from manufacturing and agriculture, experience negative impacts, including increased operational costs and regulatory compliance challenges. Notwithstanding, a significant majority of businesses are committed to enhancing their sustainability practices, viewing climate change policies as an opportunity for innovation and long-term growth. The study highlights the nuanced effects of climate change policies, emphasizing the need for sector-specific support measures to alleviate financial and operational burdens on negatively impacted businesses. Moreover, it points to a broader shift towards sustainability within the business community, suggesting that climate policies, despite their varied impacts, are driving significant changes in business strategies towards environmental stewardship.

The loads generated inside agricultural silos under static and dynamic conditions depend on the mechanical properties of the materials stored inside them. The silo calculation methodologies are based on these mechanical properties. Although it is known that moisture content greatly influences the values reached by these mechanical properties, just few studies have been conducted to determine them. The present work determines the angle of internal friction, the apparent cohesion, the dilatancy angle and the apparent specific weight of wheat when subjected to different moisture contents. Direct shear and oedometer assay devices were used. In addition, a climatic chamber was used to moisten the wheat samples used in this work. The moisture content applied to the samples ranged from 7.5% to 15.5%. From the different assays carried out it could be observed that the values of the angle of internal friction and apparent cohesion obtained from direct shear assays, as well as those related to the apparent specific weight obtained from oedometer assays were like those found in the literature. The apparent specific weight increased as moisture content increased, reaching a peak value at a moisture content of 13.4%, followed by a drop at a moisture content of 15.5%. The values here provided can be used in silo load calculations involving numerical methods.

This study is based on the fatty acid and amino acid profile of 7 edible insect species: Acheta domesticus, Alphitobius diaperinus, Blaptica dubia, Galleria mellonella, Locusta migratoria, Tenebrio molitor and Zophobas morio. The fatty acid distribution within lipid classes (neutral lipids, glycolipids and phospholipids) was studied, while the amino acid profile was used to calculate the species-specific nitrogen-protein conversion factor (Kp). The profiles were used to evaluate the nutritional quality of the lipids and proteins. Oleic acid was the predominant fatty acid in all insects except for A. domesticus, in which a larger percentage of linoleic acid was found. The majority of the lipids were neutral lipids. L. migratoria showed a remarkably high content of α-linolenic acid in its phospholipid fraction, while T. molitor phospholipids were the only fraction in which a measurable amount of docosahexaenoic acid was found. Overall, in most insects, the phospholipid fraction had the highest polyunsaturated fatty acid content compared to the other classes, which may be protective in terms of autoxidative stability. Kp values in the range of 4.17 to 6.43 were obtained. Within the nutritional quality indices, all insects showed healthy fatty acid and high quality amino acid profiles.

Electroencephalography (EEG) signals are the primary source for discriminating the preictal from the interictal stage, enabling early warnings before the seizure onset. The epileptic seizure prediction models face significant challenges due to data scarcity, diversity, and privacy. This paper proposes a three-tier architecture for epileptic seizure prediction associated with the Federated Learning (FL) model that enhances the capability by utilizing the significant amount of seizure patterns from globally distributed patients with data privacy. The determination of the preictal state is influenced by global and local model-assisted decision-making by modeling the two-level edge layer. Integrating the Spiking Encoder (SE) with Graph Convolutional Neural Network (Spiking-GCNN) works as the local model trained using the bi-timescale approach. Each local model utilizes the aggregated seizure knowledge from the different medical centers through FL and determines the preictal probability in the coarse-grained personalization. The Adaptive Neuro-Fuzzy Inference System (ANFIS) is utilized in fine-grained personalization to recognize epileptic seizure patients by examining the outcomes of the FL model, heart rate variability features, and patient-specific clinical features. The proposed seizure prediction is evaluated using benchmark datasets by comparing them with the existing works to demonstrate the potential results.

In the last decade, we have witnessed an upsurge in nuclei-based studies, particularly coupled with next-generation sequencing. Such studies aim at understanding the molecular states that exist in heterogeneous cell populations by applying increasingly more affordable sequencing approaches, in addition to optimized methodologies developed to isolate and select nuclei. Although these powerful new methods promise unprecedented insights, it is important to understand and critically consider the associated challenges. Here, we provide a comprehensive overview of the rise of nuclei-based studies and elaborate on their advantages and disadvantages. Improved designs and appropriate use of the various experimental strategies will result in acquiring biologically accurate and meaningful information.

We continue in this paper to illustrate the implications of the Dual Model of Liquids (DML) by deriving the expression for the isochoric specific heat as function of the collective degrees of freedom available at a given temperature and analyzing its dependence on temperature. Two main tasks will be accomplished. First, we show that the expression obtained for the isochoric specific heat in the DML is in line with the experimental results. Second, the expression will be compared with the analogous one obtained in another theoretical dual model of the liquid state, the Phonon Theory of Liquid Thermodynamics. This comparison will allow to get interesting insights about the number of collective degrees of freedom available in a liquid and on the value of the isobaric thermal expansion coefficient, two quantities that are related to each other in this framework.

Background: The present retrospective study was designed to evaluate the relative diagnostic utility of breast-specific gamma imaging (BSGI) and breast magnetic resonance imaging (MRI) as means of evaluating female breast cancer patients in China. Methods: A total of 229 malignant breast cancer patients underwent ultrasound, mammography, BSGI, and MRI between January 2015 and December 2018 for initial tumor staging. Of these patients, 73 were subsequently treated via definitive breast surgery following neoadjuvant chemotherapy (NAC), of whom 17 exhibited a complete pathologic response (pCR) to NAC. Results: BSGI and MRI were associated with respective 76.8% and 69.6% sensitivity values as a means of detecting residual tumors following NAC, while both of these approaches exhibited comparable specificity in this diagnostic context (58.8% vs 70.6%, P=0.473). Conclusion: These results demonstrate that BSGI is a useful auxiliary approach to evaluating pCR to NAC treatment.

The coevolution of species drives diversity in animals and plants and contributes to natural selection, whereas in host–parasite coevolution, a parasite may complete an incomplete evolutionary/developmental function by utilizing the host cell’s machinery. Analysis of related older data suggests that Plasmodium falciparum (P. falciparum), the pathogen of malaria tropica, cannot survive outside its human host because it is unable to perform the evolutionarily first protein glycosylation of serologically A-like, O-GalNAcα1-Ser/Thr-R, Tn antigen (“T nouvelle”) formation, owing to its inability for synthesizing the amino sugar N-acetyl-d-galactosamine (GalNAc). This parasite breaks the species barrier via hijacking the host's physiological A-like/Tn formation through abundantly expressing serine residues and creating hybrid A-like/Tn structures, which in the human blood group O(H) are attacked by the germline-encoded nonimmune polyreactive immunoglobulin M (IgM), exerting the highly anti-A/B/H-aggressive isoagglutinin activities. These activities physiologically undergo the ABO(H) blood group phenotype formation, occurring on the surfaces of red blood cells (RBC), epithelial and endothelial cells and on plasma proteins by identical glycosylation, performed by the ABO(H)-allelic glycotransferases, phenotypically downregulating the anti-A/B/H-reactive IgM (isoagglutinin) activities in the non-O blood groups. ABO(H) phenotype diversity, this way glycosidically linked and molecularly connected to humoral immunity, becomes exposed to the evolution.

No research to date has explored the possibility of context-specific, within-relationship fluctuation in attachment security. In this present article, two cross-sectional studies were designed (1) to develop and validate context-specific attachment scales in Traditional-Chinese, and (2) to explore fluctuations in within-parent attachment security between the contexts of sport and academics, in relation to global attachment patterns and indicators of psychological wellbeing. Results indicated that youth can and do perceive within-parent attachment patterns differently depending upon context but that the relationship of such differences to context-specific outcomes is complex. Of particular interest was that the degree of within-parent attachment variability between contexts was clearly and negatively related to indices of psychological wellbeing. This suggests that contextual variation may be a meaningful and useful way to explore within-parent attachment fluctuation.

Aiming at the industrial scale development of a Scandium (Sc)-selective leaching process of Bauxite Residue (BR), a sufficiently numerous set of process design aspects has been investigated, by appropriate exploitation of available experimental data. The interpretation of experimental data for Sc leaching yield, with sulfuric acid as the leaching solvent, has shown significant impact from acid feed concentration, mixing residence time, liquid to solids ratio, and times of leachate re-usage onto fresh BR. The thin film diffusion model, as the fundamental theory for leaching, either with constant particle size for selective leaching, or with shrinking particle size for less-, or non-, selective leaching, interprets sufficiently well the relevant experimental data. In both cases, a concept for an unyielding core supplements the basic model. Especially for the selective leaching mild conditions, the simplest model version keeps step with the experiments, since both prove 1^st order kinetics, while especially for the extreme conditions including very low solvent excess, it is proposed a combined conversion rate model with diffusion and chemical reaction inside particles. The maximization of Sc recovery per unit of consumed solvent (i.e., specific recovery) emerged as highly critical for the process economics.

Understory plants are important components of forest ecosystem productivity and diversity. Compared to biomass models of overstory canopy trees, few are available for understory saplings and shrubs and therefore their roles in estimation of forest carbon pools are often ignored. In this study, we harvested 24 understory species including 4 saplings, 9 tree-like shrubs and 11 typical shrubs in coniferous and broadleaved mixed forest in northeastern China and developed the best fit allometric equations of above- and below-ground and total biomass by species-specific or multispecies using morphological measurements of basal diameter, height and crown area as independent variables. The result showed that single basal diameter, height or crown area had good explanatory power for both species-specific and multispecies (p<0.001). The best-fit models included only basal diameter in sapling and tree-like shrubs, and combinations of crown area, height, and basal diameter in typical shrubs. The logarithmic model was most desired among the 4 model forms of linear, quadratic, multiple linear and logarithmic, for species-specific and multispecies. The models we developed should help the estimation of forest ecosystem carbon stocks, especially for belowground component, and provide tools for quantification of individual species biomass of understory plants.

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.

Developing sustainability competences is an important endeavor for education, as competence development can be complex and requires appropriate approaches. In the case of preparing future educators, this becomes even more important, because of their multiplier role. The current study presents how a project, based on living-lab methodology, helped preservice preschool teachers, attending a course on sustainability issues, develop sustainability-specific professional action competence. Students collaborated with an organization and a school and were trained to deliver to 6-year-old pupils, activities concerning the protection of sea turtles. The process included reflection, based on a given template. After the intervention, the preservice preschool teachers reflected upon their role and professional performance and discussed how they, benefited from this project. They further analyzed through a group interview, how the Living Lab methodology raised their professional confidence and self-efficacy, and helped them develop content knowledge, pedagogical content knowledge, and a sense of purpose and motivation for teaching about sustainability. Outcomes indicate that participants felt confident and efficacious to teach about sustainability, and developed their content knowledge, pedagogy content knowledge, motivation, and volition due to a strong sense of purpose and responsibility. The overall process facilitated the development of critical thinking, systemic thinking, reflection, and collaboration..

Through the use of Smart Sensor Networks (SSN), Marine Observatories (MO) provide continuous ocean monitoring. Deployed sensors may not perform as intended due to the heterogeneity of SSN devices’ hardware and software when combined with the Internet. Hence, SSN are regarded as complex distributed systems. As such, SSN designers will encounter challenges throughout the design phase related to time, complexity, sharing diverse domain experiences (viewpoints), and ensuring optimal performance for the deployed SSN. To this end, we describe in this article how we extended our previously proposed ArchiMO meta-model and design tool by extending an Enterprise Architecture Framework based on the ArchiMate Modeling Language. This extension proposes the incorporation of new Underwater Environmental Constraints (UEC) for SSN in ArchiMO which is coupled with the fusion of sensors with Artificial Intelligence. This serves as the basis for generating a new version of our ArchiMO design tool, which incorporates the new added constraints and invokes the AI created Database. To illustrate our proposal, we use the newly generated ArchiMO to create a model in the MO domain. Furthermore, we use our self-developed domain-specific model compiler to produce the relevant simulation code. Throughout the design phase, our approach contributes to handle and control the uncertainties and variances of the provided quality of service that may occur during the performance of the SSN, hence reducing the design activity’s complexity and time. It provides a way to share the different viewpoints of the designers in the domain of SSN.