ARTICLE | doi:10.20944/preprints201610.0083.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: stroke; antioxidant; co-drug; animal model
Online: 20 October 2016 (08:46:38 CEST)
Background: Previously, our laboratory has provided evidence that pre-administration of the antioxidant, lipoic acid covalently bonded to various naturally occurring antioxidants, enhanced neuroprotective capacity compared to the administration of lipoic acid on its own. The naturally occurring compound scopoletin, a coumarin derivative, has been shown in various in vitro studies to have both antioxidant and anti-inflammatory mechanism of actions. To date, the effect of scopoletin on neuronal cell death in an in vivo model of ischemia or ischemia-reperfusion has not been investigated. Therefore, the present investigation was designed to determine if scopoletin on its own, or a co-drug consisting of lipoic acid and scopoletin covalent bond, named UPEI-400, would be capable of demonstrating a similar neuroprotective efficacy. Methods: Using a rodent model of stroke in male rats (anesthetized with Inactin®; 100 mg/kg, iv), the middle cerebral artery was permanently occluded for 6 hours (pMCAO), or in separate animals, occluded for 30 min followed by 5.5 hrs of reperfusion (ischemia/reperfusion; I/R). Results: Pre-administration of either scopoletin or UPEI-400 significantly decreased infarct volume in the I/R model (p<0.05), but not in the pMCAO model of stroke. However, UPEI-400 was ~1000 times more potent as compared to scopoletin on its own. The optimal dose of UPEI-400 was then injected during the occlusion and at several time points during reperfusion and significant neuroprotection was observed for up to 150 mins following the start of reperfusion (p<0.05). Conclusion: The data suggest that synthetic combination of scopoletin with lipoic acid (UPEI-400) is a more effective neuroprotectant that either compound on their own. Also, since UPEI-400 was only effective in a model of I/R, it is possible that it may act to enhance neuronal antioxidant capacity and/or upregulate anti-inflammatory pathways to prevent the neuronal cell death.
REVIEW | doi:10.20944/preprints202105.0143.v1
Subject: Life Sciences, Biochemistry Keywords: Co-infection; Drug resistance; Gut microbiota; Salmonellosis; Schistosoma
Online: 7 May 2021 (12:02:03 CEST)
Antibiotic inefficacy in treating bacterial infections is largely studied in the context of developing resistance mechanisms. However, little attention has been paid to combined diseases mechanisms, interspecies pathogenesis and the resulting impact on antimicrobial treatment. This review will consider the co-infections of Salmonella and Schistosoma mansoni. It summarises the protective mechanisms that the pathophysiology of the two infections confer, which leads to an antibiotic protection phenomenon. This review will elucidate the functional characteristics of the gut microbiota in the context of these co-infections, the pathogenicity of these infections in infected mice, and the efficacy of the antibiotics used in treatment of these co-infections over time. Salmonella-Schistosoma interactions and the mechanism for antibiotic protection are not well established. However, antimicrobial drug inefficacy is an existing phenomenon in these co-infections. The treatment of schistosomiasis to ensure the efficacy of antibiotic therapy for bacterial infections should be considered in co-infected patients.
ARTICLE | doi:10.20944/preprints202003.0393.v1
Subject: Life Sciences, Biophysics Keywords: SARS-CoV2; RNA depended RNA polymerase; Valproic acid Co-A; drug repurposing
Online: 26 March 2020 (15:04:22 CET)
SARS-CoV2 RNA depended RNA polymerase is an essential enzyme for the survival of the virus in hosts as it helps in the replication of viral RNA. There are no human polymerases that share either sequence or structural homology with viral RNA depended RNA polymerase. These make it a good target for inhibitor discovery, as a specific inhibitor cannot cross-react with the human polymerases. We have used virtual screening, docking, binding energy calculation and simulation to show that valproic acid Co-A, a metabolite from prodrug valproic acid, forms stable interaction with nsP12 of CoV. Our results suggest valproic acid Co-A could be a potential inhibitor of nsP12 of SARS-CoV2.
ARTICLE | doi:10.20944/preprints202212.0013.v1
Subject: Materials Science, Nanotechnology Keywords: poly(lactic-co-glycolic acid); silica; nanoparticles; enzymes; amino acid depletion; cancer; drug delivery; double emulsion; biocompatible
Online: 1 December 2022 (07:56:18 CET)
Some cancer cells rely heavily on non-essential biomolecules for survival, growth, and proliferation. Enzyme based therapeutics can eliminate these biomolecules, thus specifically targeting neoplastic cells; however, enzyme therapeutics are susceptible to immune clearance, exhibit short half-lives, and require frequent administration. Encapsulation of therapeutic cargo within biocompatible and biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) is a strategy for controlled release. Unfortunately, PLGA NPs exhibit burst release of cargo shortly after delivery or upon introduction to aqueous environments where they decompose via hydrolysis. Here we show the generation of hybrid silica-coated PLGA (SiLGA) NPs as viable drug delivery vehicles exhibiting sub-200 nm diameters, a metastable Zeta potential, and high loading efficiency and content. Compared to uncoated PLGA NPs, SiLGA NPs offer greater retention of enzymatic activity and slow the burst release of cargo. Thus, SiLGA encapsulation of therapeutic enzymes, such as asparaginase, could reduce frequency of administration, increase half-life, and improve efficacy for patients with a range of diseases.
ARTICLE | doi:10.20944/preprints202002.0143.v1
Subject: Mathematics & Computer Science, Information Technology & Data Management Keywords: ocean; big-data; cite-space; co-authorship analysis; co-citation analysis; keywords co-occurrence analysis; visualization
Online: 11 February 2020 (09:41:17 CET)
Ocean big data is the scientific practice of using big data technology in the marine field. Data from satellites, manned spacecraft, space stations, airship, unmanned aerial vehicles, shore-based radar and observation stations, exploration platforms, buoys, underwater gliders, submersibles, and submarine observation networks are seamlessly combined into the ocean’s big data. Increasing numbers of scholars have tried to fully analyze the ocean’s big data. To explore the key research technology knowledge graphs related to ocean big data, articles between 1990 and 2020 were collected from the “Web of Science”. By comparing bibliometric software and using the visualization software Cite-Space, the pivotal literature related to ocean big data, as well as countries, institutions, categories, and keywords, were visualized and recognized. Journal co-citation analysis networks can help determine the national distribution of core journals. Co-citation analysis networks for documents show authors who are influential at key technical levels. Key co-occurrence analysis network keywords can determine research hot spots and research frontiers. The three supporting elements of marine big data research are shown in the co-citation network. These elements are author, institution, and country. By examining the co-occurrence of keywords, the key technology research directions for future marine big data were determined.
REVIEW | doi:10.20944/preprints202208.0145.v1
Subject: Life Sciences, Microbiology Keywords: Leishmania; co-infections; mixed infections; co-culture; hybrid; intercellular communication
Online: 8 August 2022 (10:20:49 CEST)
Leishmania parasites present astonishing adaptative abilities that represent a matter of life or death within disparate environments during the heteroxenous parasite life cycle. From an evolutionary perspective, organisms develop methods of overcoming such challenges. Strategies that extend beyond the genetic diversity have been discussed and include variability between parasite cells during the infections of their hosts. The occurrence of Leishmania subpopulation fluctuations with variable structural genomic contents demonstrates that a single strain might shelter the variability required to overcome inconsistent environments. Such intrastrain variability provides parasites with an extraordinary ability to adapt and thus survive and propagate. However, different perspectives on this evolution have been proposed. Strains or species living in the same environment can cooperate but also compete. These interactions might increase the replication rate of some parasites but cause the loss of more aggressive competitors for others. Adaptive responses to intra- and interspecific competition can evolve as a fixed strategy (replication is adapted to the average genetic complexity of infections) or an optional strategy (replication varies according to the genetic complexity of the current infection). This review highlights the complexity of interspecies and intrastrain interactions among Leishmania parasites as well as the different factors that influence this interplay.
ARTICLE | doi:10.20944/preprints202201.0027.v1
Online: 5 January 2022 (10:24:32 CET)
New setting is introduced to study types of coloring numbers, degree of vertices, degree of hyperedges, co-degree of vertices, co-degree of hyperedges, neutrosophic degree of vertices, neutrosophic degree of hyperedges, neutrosophic co-degree of vertices, neutrosophic co-degree of hyperedges, neutrosophic number of vertices, neutrosophic number of hyperedges in neutrosophic hypergraphs. Different types of procedures including neutrosophic (r, n)−regular hypergraphs and neutrosophic complete r−partite hypergraphs are proposed in this way, some results are obtained. General classes of neutrosophic hypergraphs are used to obtain chromatic number, the representatives of the colors, degree of vertices, degree of hyperedges, co-degree of vertices, co-degree of hyperedges, neutrosophic degree of vertices, neutrosophic degree of hyperedges, neutrosophic co-degree of vertices, neutrosophic co-degree of hyperedges, neutrosophic number of vertices, neutrosophic number of hyperedges in neutrosophic hypergraphs. Using colors to assign to the vertices of neutrosophic hypergraphs and characterizing representatives of the colors are applied in neutrosophic (r, n)−regular hypergraphs and neutrosophic complete r−partite hypergraphs. Some questions and problems are posed concerning ways to do further studies on this topic. Using different ways of study on neutrosophic hypergraphs to get new results about number, degree and co-degree in the way that some number, degree and co-degree get understandable perspective. Neutrosophic (r, n)−regular hypergraphs and neutrosophic complete r−partite hypergraphs are studied to investigate about the notions, coloring, the representatives of the colors, degree of vertices, degree of hyperedges, co-degree of vertices, co-degree of hyperedges, neutrosophic degree of vertices, neutrosophic degree of hyperedges, neutrosophic co-degree of vertices, neutrosophic co-degree of hyperedges, neutrosophic number of vertices, neutrosophic number of hyperedges in neutrosophic (r, n)−regular hypergraphs and neutrosophic complete r−partite hypergraphs. In this way, sets of representatives of colors, degree of vertices, degree of hyperedges, co-degree of vertices, co-degree of hyperedges, neutrosophic degree of vertices, neutrosophic degree of hyperedges, neutrosophic co-degree of vertices, neutrosophic co-degree of hyperedges, neutrosophic number of vertices, neutrosophic number of hyperedges have key points to get new results but in some cases, there are usages of sets and numbers instead of optimal ones. Simultaneously, notions chromatic number, the representatives of the colors, degree of vertices, degree of hyperedges, co-degree of vertices, co-degree of hyperedges, neutrosophic degree of vertices, neutrosophic degree of hyperedges, neutrosophic co-degree of vertices, neutrosophic co-degree of hyperedges, neutrosophic number of vertices, neutrosophic number of hyperedges are applied into neutrosophic hypergraphs, especially, neutrosophic (r, n)−regular hypergraphs and neutrosophic complete r−partite hypergraphs to get sensible results about their structures. Basic familiarities with neutrosophic hypergraphs theory and hypergraph theory are proposed for this article.
REVIEW | doi:10.20944/preprints201910.0144.v6
Subject: Medicine & Pharmacology, Other Keywords: virus; antiviral drug; drug discovery; drug development; broad-spectrum antivirals
Online: 14 February 2020 (02:27:24 CET)
Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of general population from emerging and re-emerging viral diseases reinforcing the arsenal of available antiviral options. Here, we reviewed discovery and development of BSAAs and summarized the information on 120 safe-in-man agents in freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections.
REVIEW | doi:10.20944/preprints201805.0011.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: computational drug repositioning; drug repositioning; drug repurposing; machine learning; deep learning; crowdsourcing; open innovation; drug discovery
Online: 1 May 2018 (12:27:22 CEST)
Maximizing the indications potential and revenue from drugs that are already marketed offers a new take on the famous mantra of the Nobel Prize-winning pharmacologist, Sir James Black, “The most fruitful basis for the discovery of a new drug is to start with an old drug”. However, rational design of drug mixtures poses formidable challenges because of the lack of or limited information about in vivo cell regulation, mechanisms of genetic pathway activation, and in vivo pathway interactions. Most of the repositioned drugs therefore are the result of “serendipity” - based on late phase clinical studies of unexpected findings. One of the reasons that the connection between drug candidates and their potential adverse drug reactions or new applications could not be identified earlier is that the underlying mechanism associating them is either very intricate and unknown or dispersed and buried in a sea of information. Discovery of such multi-domain pharmacomodules - pharmacologically relevant sub-networks of biomolecules and/or pathways - from collection of databases by independent/simultaneous mining of multiple datasets is an active area of research. Here, while presenting some of the promising bioinformatics approaches and pipelines, we summarize and discuss the current and evolving landscape of computational drug repositioning.
REVIEW | doi:10.20944/preprints202006.0232.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: Adverse drug reactions; Anti-COVID drugs; Coronavirus; Drug repurposing; Drug toxicity; Pharmacotherapy
Online: 18 June 2020 (12:43:43 CEST)
Coronavirus disease (COVID-19) is the current global public health threat with no specific, effective, and approved treatment available till date. The outbreak of COVID-19 has led the world into an unimagined and uncertain situation by disrupting the economies, claiming human lives, and leaving many into secondary mental health problems. As per the latest WHO report, approximately 8.2 million people are infected, and nearly 0.44 million lives are lost to COVID. The infection has spread to over 200 countries and territories around the world. The world is in search of efficient diagnostics and therapeutics, including vaccines, biologics and drugs. With the rapid increase in rates of infection and time constraints, drug repurposing seems to be a potential and viable option to find the promising anti-COVID therapeutics. In the wake of a rapid increase in the number of clinical trials involving drugs for repurposing, we aim to provide information on the safety concerns related to the drugs currently investigated in trials. This review also highlights the possible mechanisms of actions, adverse drug reactions, and contraindications of the drugs under repurposing evaluation.
REVIEW | doi:10.20944/preprints202105.0036.v2
Subject: Chemistry, Analytical Chemistry Keywords: Electrophile; Drug Design; Covalent Drug; Chemical Biology
Online: 19 October 2021 (10:28:15 CEST)
Of the manifold concepts in drug discovery and design, covalent drugs have re-emerged as one of the most promising over the past 20-or so years. All such drugs harness the ability of a covalent bond to drive an interaction between a target biomolecule, typically a protein, and a small molecule. Formation of a covalent bond necessarily prolongs target engagement, opening avenues to targeting shallower binding sites, protein complexes, and other difficult to drug manifolds, amongst other virtues. This opinion piece discusses frameworks around which to develop covalent drugs. Our argument, based on results from our research program on natural electrophile signaling, is that targeting specific residues innately involved in native signaling programs are ideally poised to be targeted by covalent drugs. We outline ways to identify electrophile-sensing residues, and discuss how studying ramifications of innate signaling by endogenous molecules can provide a means to predict drug mechanism and function and assess on- versus off-target behaviors.
ARTICLE | doi:10.20944/preprints202210.0040.v1
Subject: Medicine & Pharmacology, Nursing & Health Studies Keywords: Value co-creation; Shared decision making; Stakeholder theory; Service-dominant logic; Co-created decision making
Online: 5 October 2022 (12:19:01 CEST)
Rare diseases are characterized by a wide diversity of signs and symptoms and vary not only from disease to disease, but also from person to person, and living with a disease leads patients to peculiar experiences and treatments, without limits of time and space, as they extend to various environments and relationships of their lives. The objective of this study is the theoretical interaction between Value Co-creation (VC) and the Stakeholder Theory (ST) with the Shared Decision Making (SDM) health care theory. It is configured as a multiparadigmatic proposal by enabling the analysis of multiple perspectives of different stakeholders in health care. Thus, Co-created Decision Making (CDM) emerges in a logic dominated by service, with emphasis on intangible aspects and the interactivity of the relationships. It goes beyond the clinical office and the doctor-patient relationships, as studied in SDM, extending to all environments and interactions that add value to the patient's treatment. It was concluded that the essence of this new theory proposed here is neither in patient-centered care nor in patient self-care, but in co-created relationships with and between stakeholders in both directions, including non-health care environments that are important to the patient, such as relationships with friends, family, other patients with the same disease, social media, public policies, and the practice of pleasurable activities.
ARTICLE | doi:10.20944/preprints201608.0027.v1
Subject: Mathematics & Computer Science, Analysis Keywords: Fuzzy implications; (S,N) implication; residuum t-norm; (T,N) co-implication; residual co-implication
Online: 3 August 2016 (08:29:47 CEST)
Recently, many authors have been interested to introduce fuzzy implications over t-norms and t-conorms. In this paper, we introduce (S,N) and residuum fuzzy implication for Dubois t-norm and Hamacher's t-norm. Also, new concepts so-called (T,N) and residual fuzzy co-implication in dual Heyting Algebra are investigated. Some examples as well as application are discussed as well.
ARTICLE | doi:10.20944/preprints201811.0561.v1
Subject: Keywords: cheminformatics, drugs, drug-likeness, drug discovery, natural products
Online: 23 November 2018 (13:56:32 CET)
We discuss further details on the concepts of “drug-likeness”, “lead-likeness”, and “natural product-likeness”. The discussion will first focus on natural products as drugs, then a discussion of previous studies in which the complexities of the scaffolds and chemical space of naturally occurring compounds have been compared with synthetic, semi-synthetic compounds and FDA-approved drugs. This is followed by guiding principles for designing “drug-like” natural product libraries for lead compound discovery purposes. We end up by presenting a tool for measuring “natural product-likeness” of compounds and a brief presentation of machine learning approaches and a binary quantitative structure-activity relationship (QSAR) for classifying drugs from non-drugs and natural compounds from non-natural ones, respectively.
ARTICLE | doi:10.20944/preprints201811.0429.v1
Subject: Biology, Other Keywords: drug repurposing; drug repositioning; computational biology; drug discovery; computational pharmacology; malaria; multitargeting; malaria treatment
Online: 19 November 2018 (07:31:08 CET)
Drug repurposing is a valuable tool for combating the slowing rates of novel therapeutic discovery. The Computational Analysis of Novel Drug Opportunities (CANDO) platform performs shotgun repurposing of 2030 indications/diseases using 3733 drugs/compounds to predict interactions with 46,784 proteins and relating them via proteomic interaction signatures. An accuracy is calculated by comparing interaction similarities of drugs approved for the same indications. We performed a unique subset analysis by breaking down the full protein library into smaller subsets and then recombining the best performing subsets into larger supersets. Up to 14% improvement in accuracy is seen upon benchmarking the supersets, representing a 100–1000 fold reduction in the number of proteins considered relative to the full library. Further analysis revealed that libraries comprised of proteins with more equitably diverse ligand interactions are important for describing compound behavior. Using one of these libraries to generate putative drug candidates against malaria results in more drugs that could be validated in the biomedical literature than the list suggested by the full protein library. Our work elucidates the role of particular protein subsets and corresponding ligand interactions that play a role in drug repurposing, with implications for drug design and machine learning approaches to improve the CANDO platform.
ARTICLE | doi:10.20944/preprints202207.0173.v1
Subject: Engineering, Energy & Fuel Technology Keywords: Cement; Co-process; Waste; Incineration; Landfill
Online: 12 July 2022 (04:32:38 CEST)
Recently, the amount of waste generated has been rapidly increasing, there have been difficulties disposing of waste in Korea. As a solution to this, treating waste using a cement kiln has suggested, but the environmental and economic effects have not been specifically studied. In this study, the effects of alternative resources, and reducing the social costs(Installation and Operation) associated with waste treatment facilities were analyzed. Through a co-processing method, a reduction of approximately 53kg of CO2 can be realized during the production of one ton of cement, and cost savings of about 3,815 milion USD. Another effect is an extension of the expiration date for landfills by 7.55 years.
ARTICLE | doi:10.20944/preprints202202.0100.v1
Subject: Mathematics & Computer Science, Applied Mathematics Keywords: Quasi-Co-Degree; Quasi-Degree; Vertex
Online: 7 February 2022 (16:23:20 CET)
New setting is introduced to study quasi-degree and quasi-co-degree arising from co-neighborhood. quasi-degree and quasi-co-degree is about a vertex which are applied into the setting of neutrosophic graphs. . The structure of set is studied and general results are obtained. Also, some classes of neutrosophic graphs namely path-neutrosophic graphs, cycle-neutrosophic graphs, complete-neutrosophic graphs and star-neutrosophic graphs, complete-bipartite-neutrosophic graphs and complete-multipartite-neutrosophic graphs are investigated in the terms of a vertex which is called either quasi-degree or quasi-co-degree. Neutrosophic number is reused in this way. It’s applied to use the type of neutrosophic number in the way that, three values of a vertex are used and they’ve same share to construct this number to compare with other vertices. Summation of three values of vertex makes one number and applying it to a comparison. This approach facilitates identifying vertices which form quasi-degree and quasi-co-degree. Quasi-degree is a value of a vertex which is maximum amid all values of vertices which are neighbors to a fixed vertex. Quasi-co-degree is a value of an edge which is maximum amid all values of edges which are neighbors to a fixed vertex but corresponded vertex is representative for this notion. Using different values which are related to a vertex inspire us to focus on edge and vertices which are corresponded to a fixed vertex. The notion of neighborhood is used to collect either vertices are titled neighbors or edges are incident to fixed vertex. In both settings, some classes of well-known neutrosophic graphs are studied. Some clarifications for each result and each definitions are provided. Using fixed vertex has key role to have these notions in the form of vertex or edge. The value of an edge has eligibility to call quasi-co-degree but the value of a vertex has eligibility to call quasi-degree. Some results get more frameworks and perspective about these definitions. The way in that, two vertices have connection together, open the way to define neighborhood and co-neighborhood. The maximum values in neighborhood and co-neighborhood introduces quasi-degree and quasi-co-degree, respectively. New name is chosen from degree. Since amid all vertices with different degrees, one vertex is chosen. In other words, one vertex is fixed and its degree turns out quasi-degree where two degrees could be assigned to a vertex. Degree of edges and degree of vertices. The number of edges which are incident to the vertex and the number of vertices which are neighbors to the vertex. Degree and co-degree are the notions which are transformed to use in quasi-style. Two neutrosophic values introduce two neutrosophic vertices separately in each settings. These notions are applied into neutrosophic graphs as individuals but not family of them as drawbacks for these notions. Finding special neutrosophic graphs which are well-known, is an open way to purse this study. Some problems are proposed to pursue this study. Basic familiarities with graph theory and neutrosophic graph theory are proposed for this article.
ARTICLE | doi:10.20944/preprints202107.0586.v1
Online: 26 July 2021 (14:49:51 CEST)
Potential of co-digestion mixing thickened secondary sludge (TS) from extended aeration wastewater treatment plant and locally available substrates (whey, grease and septage) has been studied using three steps. The first step was a batch test to determine biological methane potential (BMP) of different mixtures of the three co-substrates with TS. The second step has been carried out with lab-scale reactors (20 L) simulating anaerobic continuous stirred tank reactors fed by three mixtures of co-substrates determined according to previous step results. Modelling using ADM1 as a mechanistic model was applied in the third step to help understanding the co-digestion process. According to BMP step, septage used as co-substrate has a negative effect on performance and addition of 10 to 30% grease or 10% whey would lead to a higher production of biogas and with an increase of the methane content. The results from the reactor showed less evi-dence of the positive effects observed with the BMP assay. Protein and lipid fractions of particu-late biodegradable COD are important variables for digester stability and methane production as predicted by modelling. Results of simulations with ADM1 model adapted to co-digestion confirmed that this model is a powerful tool to optimize the process of biogas production.
REVIEW | doi:10.20944/preprints202107.0549.v1
Subject: Medicine & Pharmacology, Allergology Keywords: TRβ; tumor suppression; co-regulators; therapeutics
Online: 23 July 2021 (15:14:12 CEST)
There is compelling evidence that the nuclear receptor TRβ, a member of the thyroid hormone receptor (TR) family, is a tumor suppressor in thyroid, breast and other solid tumors. Cell-based and animal studies reveal that the liganded TRβ induces apoptosis, reduces an aggressive phenotype, decreases stem cell populations, and slows tumor growth through modulation of a complex interplay of transcriptional networks. TRβ-driven tumor suppressive transcriptomic signatures include repression of known drivers of proliferation such as PI3K/Akt pathway and activation of novel signaling (JAK1/STAT1) and metabolic reprogramming in both thyroid and breast cancers. The presence of TRβ is also correlated with a positive prognosis and response to therapeutics in BRCA+ and triple-negative breast cancers respectively. Ligand activation of TRβ enhances sensitivity to chemotherapeutics. TRβ co-regulators and bromodomain-containing chromatin remodeling proteins are emergent therapeutic targets. This review considers TRβ as a potential biomolecular diagnostic and therapeutic target.
Subject: Arts & Humanities, Anthropology & Ethnography Keywords: critical pedagogy; experiential learning; co-production
Online: 5 July 2021 (10:35:42 CEST)
The sense of uncertainty and fragility due to the effects and magnitude of global challenges we are facing (from pandemic circumstances to climate change impacts) requires – much more than in the past – the capacity to generate a visionary and forefront design approach in the young gen-erations aiming at stimulating their reaction attitude rather than providing consolidated tools from past conditions that no longer exist or will rapidly evolve. Within this general framework, we have investigated the effectiveness and impacts of experienced-based methods of learning and innovative educational tools in architecture aimed at shaping expertise in which the environ-mental dimension and the climate-change challenge dialogues with the context's complexity in terms of socio-cultural dynamics, real potentialities and constrains, addressing their transdisci-plinary trajectories. The paper analyses 5 international pioneering teaching experiences that provide the opportunity to understand the outcomes of collaborative and experiential learning processes in which the educational activities leverage a dialogue between diverse communities (academia-citizens-policymakers-practitioners). The study outcomes show that shifting the pedagogical paradigm towards in-field-experience-based models can improve the awareness of future practitioners for climate implications of architectural design, implement their analysis and project skills while triggering processes of knowledge transfer and co-production at community level, and allow them to better address the societal and cultural issues involved within decision making.
REVIEW | doi:10.20944/preprints202104.0608.v1
Online: 22 April 2021 (13:23:35 CEST)
The purpose of this study is to explore conceptual approaches in co-production studies and to examine current research trends of the study. The conceptual paper includes research articles related to co-production in public administration field. By thoroughly scrutinizing 32 research works of co-production, this study highlights major loopholes in the field of the study. The contributions of the study are: (1) identifying two common characteristics of co-production, (2) categorising three types of co-producing by end-users, and (3) finding that goals and success of co-production are more beneficial for service providers though its initial approach is citizen-centric approach. We suggest that future studies should be (1) to focus on reasons for co-production failures or success, (2) to discover further hindrances for co-production in service production, (3) to examine influencing factors on service providers as well as institutional impacts on co-production process, and (4) to include practical assessment in co-production study.
ARTICLE | doi:10.20944/preprints201801.0084.v1
Subject: Earth Sciences, Geochemistry & Petrology Keywords: antimony; ferrihydrite; silica; adsorption; co-precipitation
Online: 10 January 2018 (07:02:42 CET)
Elevated antimony concentrations in aqueous environments from anthropogenic sources is becoming of global concern, here iron oxides are known to strongly adsorb aqueous antimony species with different oxidation states, but the effect of silica on the removal characteristics is not well understood despite being a common component in the environment. In this study, ferrihydrite was synthesized at various Si/Fe molar ratios to investigate its adsorption and co-precipitation behaviors with aqueous antimony anionic species, Sb(III) and Sb(V). The XRD analyses of the precipitates showed two broad diffraction features at approximately 35° and 62° 2θ, which are characteristic of 2-line ferrihydrite, no significant shifts in peak positions in the ferrihydrite regardless of the Si/Fe ratios. The infrared spectra showed a sharp band at ~990 cm−1, corresponding to asymmetric stretching vibrations of Si-O-Fe bonds which increased in intensity with increasing Si/Fe molar ratios. Further, the surface charge on the precipitates became more negative with increasing Si/Fe molar ratios. The adsorption experiments indicated that Sb(V) was preferentially adsorbed at acidic conditions and decreased dramatically with increasing pH while the adsorption rate of Sb(III) ions was independent of pH, however, the presence of silica suppressed the adsorption of both Sb(III) and Sb(V) ions. The results showed that Sb(III) and Sb(V) ions were significantly inhibited by co-precipitation with ferrihydrite even in the presence of silica by isomorphous substitution in the ferrihydrite crystal structure.
ARTICLE | doi:10.20944/preprints201912.0267.v1
Subject: Chemistry, Electrochemistry Keywords: adsorption; coatings; poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate); corrosion tests; atomic force microscopy
Online: 20 December 2019 (07:00:55 CET)
Poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate) named further PVBA was investigated as protective coating for copper corrosion in 0.9 % NaCl solution using electrochemical measurements such as, electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization associated with Atomic Force Microscopy (AFM). The PVBA coating on the copper surface (Cu-PVBA) was modeled in methanol containing PVBA. Its inhibitory properties against corrosion was comparatively discussed with those of the copper sample treated in methanol without polymer (Cu-Me) and of untreated sample (standard copper). A protective performance of PVBA coating of 80 % was computed from electrochemical measurements, for copper corrosion in NaCl solution. Also, AFM images designed a specific surface morphology of coated surface with PVBA, clearly highlighting a polymer film adsorbed on the copper surface, which presents certain deterioration after corrosion, but metal surface was not significantly affected compared to those of untreated samples or treated in methanol, in the absence of PVBA.
REVIEW | doi:10.20944/preprints202202.0067.v1
Subject: Biology, Anatomy & Morphology Keywords: Antimalarial Drug; Malaria Vaccine; Drug Discovery; Artimisnine; K13; Malaria
Online: 4 February 2022 (10:22:34 CET)
Mosquitoes conveying Plasmodium store parasites into the skin of the mammalian host. Parasites make a trip through the circulation system to the liver, where they cross a few hepatocytes prior to building up a disease. Inside the last hepatocyte the parasite goes through morphogenesis and afterward abiogenetically partitions to become more than 20,000 blood-infective parasites, called merozoites. On account of P. vivax, P. ovale, and P. cynomolgi, the parasites can stay lethargic in the liver in structures called hypnozoites. The merozoites are delivered once again into the circulation system, where they start the repetitive blood stage. Inside erythrocytes, a little division of parasites separate into male or female gametocytes. These gametocytes are ingested by the mosquito during blood taking care of, where they will duplicate explicitly, in the long run prompting the arrangement of sporozoites
REVIEW | doi:10.20944/preprints202201.0440.v1
Subject: Life Sciences, Other Keywords: electrophiles; signaling; profiling; drug mechanism; drug discovery; T-REX
Online: 28 January 2022 (14:57:08 CET)
Our bodies produce a host of electrophilic species that can label specific endogenous proteins in cells. The signaling roles of these molecules are underactive debate. However, in our opinion it is becoming increasingly likely that electrophiles can rewire cellular signaling processes at endogenous levels. Attention is turning more to understanding how nuanced electrophile signaling in cells is. In this perspective, we describe recent work from our laboratory that has started to inform on different levels of context-specific regulation of proteins by electrophiles. We discuss the relevance of these data to the field, and to the broader application of electrophile signaling to precision medicine development, beyond the traditional views of their pleiotropic cytotoxic roles.
REVIEW | doi:10.20944/preprints202201.0146.v1
Subject: Materials Science, Nanotechnology Keywords: Nanomedicine; drug resistance; lung cancer; chemotherapeutic agents; drug delivery
Online: 11 January 2022 (13:48:22 CET)
Lung cancer (LC) is one of the leading causes of cancer occurrence and mortality worldwide. Treatment of patients with advanced and metastatic LC presents a significant challenge as malignant cells use different mechanisms to resist chemotherapy. Drug resistance (DR) is a complex process that occurs due to a variety of genetic and acquired factors. Identifying the mechanisms underlying DR in LC patients and possible therapeutic alternatives for more efficient therapy is a central goal of LC research. Advances in nanotechnology resulted in the development of targeted and multifunctional nanoscale drug constructs. The possible modulation of the components of nanomedicine, their surface functionalization, and encapsulation of various active therapeutics provide promising tools to bypass crucial biological barriers. These attributes enhance the delivery of multiple therapeutic agents directly to the tumor microenvironment (TME), resulting in reversal of LC resistance to anticancer treatment. This review provides a broad framework for understanding the different molecular mechanisms of DR in lung cancer; presents novel nanomedicine therapeutics aimed to improve the efficacy of treatment of various forms of resistant LC; outlines current challenges in using nanotechnology for reversing DR; and discusses the future directions for clinical application of nanomedicine in management of LC resistance.
REVIEW | doi:10.20944/preprints202109.0287.v1
Subject: Engineering, Biomedical & Chemical Engineering Keywords: drug screening; monodrug or combinatorial drug screening; anti-cancer
Online: 16 September 2021 (13:46:49 CEST)
The up-and-coming microfluidic technology is the most promising platform for designing anti-cancer drugs and new point-of-care diagnostics. Compared to conventional drug screening methods based on Petri dishes and animal studies, drug delivery in microfluidic systems has many advantages. For instance, these platforms offer high throughput drug screening, require a small amount of samples, provide an in vivo-like microenvironment for cells, and eliminate ethical issues associated with animal studies. Multiple cell cultures in microfluidic chips could better mimic the 3D tumor environment using low reagents consumption. The clinical experiments have shown that combinatorial drug treatments have a better therapeutic effect than monodrug therapy. So many attempts were performed in this field in the last decade. This review highlights the applications of microfluidic chips in anti-cancer drug screening and systematically categorizes these systems as a function of sample size and combination of drug screening. Finally, it provides a perspective on the future of the clinical applications of microfluidic systems for anti-cancer drug development.
ARTICLE | doi:10.20944/preprints202012.0770.v2
Subject: Life Sciences, Biochemistry Keywords: BRF2; cancer; molecular dynamics simulation; drug repurposing; drug discovery
Online: 16 July 2021 (11:40:34 CEST)
Overexpression of BRF2, a selective subunit of RNA polymerase III, has been shown to be crucial in the development of several types of cancers, including breast cancer and lung squamous cell carcinoma . Predominately, BRF2 acts as a central redox-sensing transcription factor (TF) and is involved in rescuing oxidative stress (OS) -induced apoptosis. Here, we showed a novel link between BRF2 and DNA damage response. Due to the lack of BRF2 specific inhibitors, through virtual and molecular dynamics screening, we identified potential drug candidates that interfere with BRF2-TATA-binding Protein (TBP)-DNA complex interactions based on binding energy, intermolecular, and torsional energy parameters. We experimentally tested Bexarotene as a potential BRF2 inhibitor. We found that Bexarotene (Bex) treatment resulted in a dramatic decline in oxidative stress (Tert-butylhydroquinone (tBHQ))-induced levels of BRF2 and consequently, lead to a decrease in cellular proliferation of cancer cells which may in part be due to drug pretreatment induced reduction of ROS generated by the oxidizing agent. Our data thus, provide the first experimental evidence that BRF2 is a novel player in DNA damage response pathway and Bexarotene can be used as a potential inhibitor to treat cancers with the specific elevation of oxidative stress.
Subject: Medicine & Pharmacology, Allergology Keywords: Drug Safety Surveillance; Adverse Drug Reaction; Ophthalmic; Ciprofloxacin; Dexamethasone
Online: 5 January 2021 (11:51:06 CET)
Background: drugs provide a significant benefit; however, their use implies an intrinsic potential danger, with the possibility to cause unwanted effects. These effects are known as adverse drug reactions (ADRs). Post-marketing drug safety surveillance detects unknown risks that have not been identified in clinical trials and it is necessary to monitor marketed medications under real-life practice. Due to the scarce information about fixed combination of ciprofloxacin 0.3% / dexamethasone 0.1% (SDO), we performed a drug safety surveillance study. (2) Methods: A prospective non-controlled drug safety surveillance study was conducted in Peruvian population. A total of 236 patients prescribed SDO were included derivates from 12 sites. Patients' standardized information was collected through two phone calls, including demographics, medical history, prescribing patterns of SDO, concomitant medication, and ADRs in detail. The ADRs were classified by causality and severity, followed by outcome measures to identify new risk. (3) Results: 236 patients prescribed with SDO participated in the study and 220 were included. A total of 82 ADRs/220 patients were reported after the use of SDO, presenting a ratio 0.37 ADR/patient. The most frequent ADR with SDO administration was eye irritation (30%). The totality of the ADR was classified as non-serious, and the 97.5% (n=80) was classified as mild and 2.5% as moderate (n=2). No cases under the severe category were identified. (4) Conclusion: No new risks were found in the population where this study was conducted.
ARTICLE | doi:10.20944/preprints202203.0248.v1
Subject: Mathematics & Computer Science, Applied Mathematics Keywords: Neutrosophic Quasi-Order; Neutrosophic Quasi-Size; Neutrosophic Quasi-Number; Neutrosophic Quasi-Co-Number; Neutrosophic Co-t-Neighborhood
Online: 17 March 2022 (08:48:38 CET)
New setting is introduced to study co-neighborhood, neutrosophic t-neighborhood, neutrosophic quasi-vertex set, neutrosophic quasi-order, neutrosophic neighborhood, neutrosophic co-t-neighborhood, neutrosophic quasi-edge set, neutrosophic quasi-size, Neutrosophic number, neutrosophic co-neighborhood, co-neutrosophic number, quasi-number and quasi-co-number. Some classes of neutrosophic graphs are investigated.
REVIEW | doi:10.20944/preprints202203.0032.v1
Subject: Chemistry, Medicinal Chemistry Keywords: artificial intelligence; machine learning; drug design; covid-19; structure-based drug design; ligand-based drug design
Online: 2 March 2022 (03:00:37 CET)
The recent covid crisis has proven important lessons for academia and industry regarding digital reorganization. Among fascinating lessons from these times is the huge potential of data analytics and artificial intelligence. The crisis exponentially accelerated the adoption of analytics and artificial intelligence, and this momentum is predicted to continue into the 2020s and over. Moreover, drug development is a costly and time-consuming business, and only a minority of approved drugs return the revenue that exceeds the research and development costs. As a result, there is a huge drive to make drug discovery cheaper and faster. With modern algorithms and hardware, it is not too surprising that the new technologies of artificial intelligence and other computational simulation tools can help drug developers. In only two years of covid research, many novel molecules have been designed/identified using artificial intelligence methods with astonishing results in terms of time and effectiveness. This paper will review the most significant research on artificial intelligence in the de novo drug design for COVID-19 pharmaceutical research.
ARTICLE | doi:10.20944/preprints202212.0245.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: cannabis; tobacco; co-use; simultaneous use; mixing
Online: 14 December 2022 (06:30:42 CET)
Introduction: Increasing cannabis legalization raises concerns that tobacco use, frequently used with cannabis, will also increase. This study investigated the association between legal status of cannabis in place of residence and prevalence of cannabis and tobacco co-use, simultaneous use, and mixing by comparing the prevalence among adults in Canada (prior to cannabis legalization) vs. adults in US states that had legalized recreational cannabis vs. US states that had not as of September 2018. Methods: Data were drawn from the 2018 International Cannabis Policy Study, conducted with respondents aged 16-65 in Canada and the US recruited from non-probability consumer panels. Differences in the prevalence of co-use, simultaneous use, and mixing between tobacco and different cannabis products were examined using logistic regression models by legal status of place of residence among past 12-month cannabis consumers (N=6744). Results: Co-use and simultaneous use in the past 12 months were most common among respondents in US legal states. Among cannabis consumers, co-use and simultaneous use were less common in US legal states, while mixing was less frequent in US states with both legal and illegal cannabis compared to Canada. Use of edibles was associated with lower odds of all three outcomes, while smoking dried herb or hash was associated with higher odds. Conclusions: The proportion of cannabis consumers who used tobacco was lower in legal jurisdictions despite higher prevalence of cannabis use. Edible use was inversely associated with co-use suggesting that edible use does not appear to be associated with increased tobacco use.
ARTICLE | doi:10.20944/preprints202208.0130.v1
Subject: Social Sciences, Organizational Economics & Management Keywords: crowdsourcing; value co-creation; business sustainability; stakeholder
Online: 8 August 2022 (04:09:12 CEST)
As a typical form of value co-creation, crowdsourcing has been increasingly applied by firms to generate business value. By engaging a crowd, a platform, and other stakeholders, a crowdsourcer can foster the co-creation of a portfolio of value for diverse stakeholders. In analyzing the value co-creation in crowdsourcing, we propose a framework by combining the theories and frameworks in value co-creation and crowdsourcing. The framework examines the key stakeholders, joint purpose, engaged value co-creation processes, contributions, bidirectional relationships of the engagement, and perceived value, exhibiting a holistic view of the value co-creation in a crowdsourcing project. Results of the analysis reveal the business performance of the crowdsourcing project and identify areas of improvement regarding business sustainability. This is a major theoretical contribution of this study. The research design applied a case study approach to empirically investigate a crowdsourcing project. Both the theoretical and practical implications are discussed.
ARTICLE | doi:10.20944/preprints202201.0337.v1
Online: 24 January 2022 (09:41:10 CET)
This pot-based study investigated the influence of co-composted wood-derived biochar on lettuce growth performance under salinity and drought stress conditions. Biochar of two particle sizes; > 2 mm and < 1 mm were co-composted with the mixture (1:1 ratio of dry weight) of cow and poultry manures. Co-composted biochars were applied at 5% and 7% rates in soil. Control treatments included the amendment of mixture of biochar with manure in soil. Pots were subjected to slight drought (48-55% water filled pore space (WFPS) of soil) and non-drought conditions (60% WFPS) and under 0 and 1.3 dS m-1 salinity. Results revealed that plants growth performance was significantly better under treatments of co-composted biochar and no salt stress conditions, than when mixture of biochar and manure was applied to soil as non-composted fertilizer. Under no stress condition, small particle-sized co-composted biochar increased root biomass by 786.2% than the large particle-sized co-composted biochar at same application rate. As compared to large-sized co-composted biochar, small sized co-composted biochar at high application rates increased root biomass by 167 – 245% but not leaf biomass under both stress conditions. Small particle-sized co-composted biochar amendment also increased the phosphorus use efficiency (PUE) of lettuce leaves than large particle-sized co-composted biochar under no stress condition. The amendment of small-sized co-composted biochar also increased significantly the concentration of Olsen phosphorus in soil than the amendment of large-particle-sized co-composted biochar. In conclusion, amendment of small particle-sized co-composted biochar has the potential of attenuating salinity and drought stress in lettuce and promoting P cycling in soil.
ARTICLE | doi:10.20944/preprints202109.0053.v1
Subject: Mathematics & Computer Science, Numerical Analysis & Optimization Keywords: Co-scheduling; HPC; scheduling theory; stochastic optimization
Online: 3 September 2021 (10:14:03 CEST)
Applications in high-performance computing (HPC) may not use all available computational resources, leaving some of them underutilized. By co-scheduling, i.e. running more than one application on the same computational node, it is possible to improve resource utilization and overall throughput. Some applications may have conflicting requirements on resources and co-scheduling may cause performance degradation, so it is important to take it into account in scheduling decisions. In this paper, we formalized co-scheduling problem and proposed multiple scheduling strategies to solve it: an optimal strategy, an online strategy and heuristic strategies. These strategies vary in terms of the optimality of the solution they produce and a priori information about the system they require. We showed theoretically that the online strategy provides schedules with a competitive ratio that has a constant upper limit. This allowed us to solve the co-scheduling problem using heuristic strategies that approximate this online strategy. Numerical simulations showed how heuristic strategies compare to the optimal strategy for different input systems. We proposed a method for measuring input parameters of the model in practice and evaluated this method on HPC benchmark applications. We showed high accuracy of measurement method, which allows to apply proposed scheduling strategies in scheduler implementation.
ARTICLE | doi:10.20944/preprints202004.0483.v1
Subject: Earth Sciences, Environmental Sciences Keywords: city; CO; COVID 19; emission; social distancing
Online: 28 April 2020 (07:36:53 CEST)
The social distancing as a response to COVID 19 pandemic has led to the exceptional reductions of daily routine people activities and vehicle uses mainly in city. This same situation was also experienced by several busy, large, and populous cities in Southeast Asia (SA) countries. Correspondingly, this study aimed to test the hypothesis that the social distancing implementation period has increased the air quality in the term of carbon monoxide (CO) emission reduction as drawn from Jakarta city as an example of the one of populated cities in SA region. The CO was measured in parts per billions (ppb) and monitored on the daily basis employing remote sensor platform. The monitor periods were started from January, February, March, and April 2020 with 10 measurement days for each month. The social distancing was implemented from mid of March to the recent April. The CO measurement data were statistically tested to justify the significant effects of social distancing on the CO levels. Based on the CO data analysis, the order of CO mean by months is February > January > March > April. The CO levels for January, February, March, and April were 87.46 ppb (95%CI: 83.54-91.37), 88.20 ppb (95%CI: 81.65-94.74), 86.38 (95%CI: 81.06-91.69), and 78.68 (95%CI: 74.03-83.32) respectively. This study also find significant difference (p<0.05) of CO levels especially in April when social distancing has been implemented. Hence, these findings illustrate the potential air pollutant reduction gained from implementing social distancing as can be seen in April.
ARTICLE | doi:10.20944/preprints201807.0536.v1
Subject: Materials Science, Nanotechnology Keywords: photocatalysis, co-catalysts, water splitting, metallic cluster
Online: 27 July 2018 (09:33:40 CEST)
Degussa P25 is a benchmark form of TiO2 used worldwide in photocatalysis studies. Currently no such benchmark exists for co-catalysts, which are essential for many photocatalytic reactions. Here, we present the preparation of Pt nanocluster co-catalysts on TiO2 using an unmodified commercial source and equipment that is commonly available. Transmission electron microscopy reveals that the procedure produces TiO2 decorated with Pt atom and nanoclusters (1-5 atoms). Optical reflectance and X-ray diffraction measurements show that the procedure does not affect the TiO2 polymorph or UV-Vis absorbance. Gas phase photocatalytic splitting of heavy water (D2O) shows that the Pt nanocluster decorated TiO2 outperforms Pt nanoparticle (produced by photodeposition) decorated TiO2 in D2 production. Pt nanoclusters, produced directly from a commercial source, with high co-catalyst activity are prime candidates to be used in benchmark photocatalytic reactions.
ARTICLE | doi:10.20944/preprints201710.0010.v1
Subject: Chemistry, Inorganic & Nuclear Chemistry Keywords: Bi2Te3; Thermoelectric properties; co-doping; n-type
Online: 2 October 2017 (15:33:35 CEST)
In order to understand the effect of Pb-CuI co-doping on the thermoelectric performance of Bi2Te3, n-type Bi2Te3 co-doped with x at% CuI and 1/2x at% Pb (x = 0, 0.01, 0.03, 0.05, 0.07, and 0.10) were prepared via high temperature solid state reaction and consolidated using spark plasma sintering. Electron and thermal transport properties, i.e., electrical conductivity, carrier concentration, Hall mobility, Seebeck coefficient, and thermal conductivity, of CuI-Pb co-doped Bi2Te3 were measured in the temperature range from 300 K to 523 K and compared to corresponding x% of CuI-doped Bi2Te3 and undoped Bi2Te3. The addition of a small amount of Pb significantly decreased the carrier concentration, which could be attributed to the holes from Pb atoms, thus the CuI-Pb co-doped samples show a lower electrical conductivity and a higher Seebeck coefficient compared to CuI-doped samples with similar x values. The incorporation of Pb into CuI-doped Bi2Te3 rarely changed the power factor because of the trade-off relationship between the electrical conductivity and the Seebeck coefficient. The total thermal conductivity(κtot) of co-doped samples (κtot ~1.4 W/m∙K at 300 K) is slightly lower than that of 1% CuI-doped Bi2Te3 (κtot~1.5 W/m∙K at 300 K) and undoped Bi2Te3 (κtot ~1.6 W/m∙K at 300 K) due to the alloy scattering. The 1% CuI-Pb co-doped Bi2Te3 sample shows the highest ZT value of 0.96 at 370 K. All data on electrical and thermal transport properties suggest that the thermoelectric properties of Bi2Te3 and its operating temperature can be controlled by co-doping.
ARTICLE | doi:10.20944/preprints202204.0224.v1
Subject: Life Sciences, Biochemistry Keywords: COVID-19; SARS-CoV-2; drug discovery; multitargeting; computational drug repurposing
Online: 26 April 2022 (03:39:06 CEST)
The worldwide outbreak of SARS-CoV-2 in early 2020 caused numer- ous deaths and unprecedented measures to control its spread. We employed our Computational Analysis of Novel Drug Opportunities (CANDO) multiscale therapeutic discovery, repurposing, and design platform to identify small molecule inhibitors of the virus to treat its resulting indication, COVID-19. Initially, few experimental studies existed on SARS-CoV-2, so we optimized our drug candidate prediction pipelines using results from two independent high-throughput screens against prevalent human coronaviruses. Ranked lists of candidate drugs were generated using our open source cando.py software based on viral protein inhibition and proteomic interaction similarity. For the former viral protein inhibition pipeline, we computed interaction scores between all compounds in the corresponding candidate library and eighteen SARS-CoV proteins using an interaction scoring protocol with extensive parameter optimization which was then applied to the SARS-CoV-2 proteome for prediction. For the latter similarity based pipeline, we computed interaction scores between all compounds and human protein structures in our libraries then used a consensus scoring approach to identify candidates with highly similar proteomic interaction signatures to multiple known anti-coronavirus actives. We published our ranked candidate lists at the very beginning of the COVID-19 pandemic. Since then, 51 of our 276 predictions have demonstrated anti-SARS-CoV-2 activity in published clinical and experimental studies. These results illustrate the ability our platform to rapidly respond to emergent pathogens and provide greater evidence that treating compounds in a multitarget context more accurately describes their behavior in biological systems.
ARTICLE | doi:10.20944/preprints202202.0327.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: pregnancy; medicines; drug information; drug safety; pharmacovigilance; pharmacoepidemiology; pharmaceutical industry; stakeholders
Online: 25 February 2022 (08:54:01 CET)
Although marketing authorization holders (MAHs) are involved in monitoring medication safety, it was unclear how they experience their role and current monitoring activities in pregnancy. Therefore, a qualitative study using online focus groups with MAHs and the Belgian umbrella organisation of MAHs was conducted in June-July 2021. In total, 38 representatives of nine organisations participated. Overall, participants reported multiple difficulties with data collection, including underreporting, collection of incomplete information and loss to follow-up. The limited number of high-quality data collected, the unknown denominator and the lack of comparator data complicate MAHs’ data processing activities, preventing them to timely provide evidence in the pregnancy label. Three ‘conflicts’ inherent to the specific position of MAHs were identified explaining the difficulties they experience, i.e., 1) mistrust from patients and healthcare professionals (HCPs); 2) MAHs’ legal obligations and regulatory framework; 3) MAHs’ position outside the healthcare context. To overcome these barriers, MAHs suggested that data registration should occur in close collaboration with patients and HCPs, organized within the healthcare context and performed by using a user-friendly system. In conclusion, the reported difficulties and underlying conflicts of MAHs highlight the need for more effective, collaborative data collection strategies to generate new evidence on this topic.
ARTICLE | doi:10.20944/preprints202202.0208.v1
Subject: Biology, Physiology Keywords: aging; intestinal microbiota; dysbiosis; probiotics; microbial co-occurrences
Online: 17 February 2022 (10:59:55 CET)
Age-related alterations in the gut microbiome composition and its impacts on the host’s health have been well described; however, detailed analyses of the gut microbial structure defining ecological microbe-microbe interactions is limited. One of the ways to determine these interactions is by understanding microbial co-occurrence patterns. We previously showed promising abilities of Lactobacillus acidophilus DDS-1 on the aging gut microbiome and immune system. However, the potential of the DDS-1 strain to modulate microbial co-occurrence patterns is unknown. Hence, we aimed to investigate the ability of L. acidophilus DDS-1 to modulate the fecal, mucosal and cecal-related microbial co-occurrence networks in young and aging C57BL/6J mice. Our Kendall’s tau correlation measures of co-occurrence revealed age-related changes in the gut microbiome, which were characterized by reduced number of nodes and associations across sample types when compared to younger mice. After four-week supplementation, L. acidophilus DDS-1 differentially modulated the overall microbial community structure in fecal and mucosal samples as compared to cecal samples. Beneficial bacteria such as Lactobacillus and Akkermansia acted as connectors in aging networks in response to L. acidophilus DDS-1 supplementation. Our findings provided the first evidence of the DDS-1-induced gut microbial ecological interactions revealing the complex structure of microbial ecosystems with age.
ARTICLE | doi:10.20944/preprints202108.0571.v1
Subject: Biology, Plant Sciences Keywords: Arabidopsis thaliana; plastid; co-maturation; post-transcriptional; Nanopore
Online: 31 August 2021 (11:48:48 CEST)
Plastid gene expression involves many post-transcriptional maturation steps resulting in a complex transcriptome composed of multiple isoforms. Although short read RNA-seq has considerably improved our understanding of the molecular mechanisms controlling these processes, it is unable to sequence full-length transcripts. This information is however crucial when it comes to understand the interplay between the various steps of plastid gene expression. Here, the study of the Arabidopsis leaf plastid transcriptome using Nanopore sequencing showed that many splicing and editing events were not independent but co-occurring. For a given transcript, maturation events also appeared to be chronologically ordered with splicing happening after most sites are edited.
ARTICLE | doi:10.20944/preprints202108.0562.v1
Subject: Medicine & Pharmacology, Veterinary Medicine Keywords: female reproductive tract; organoid; co-culture; crosstalk; blastocyst
Online: 31 August 2021 (11:19:56 CEST)
Hormones must be balanced and dynamically controlled for the Female Reproductive Tract (FRT) to function correctly during the menstrual cycle, pregnancy, and delivery. Gamete selection and successful transfer to the uterus, where it implants and pregnancy occurs, is supported by the mucosal epithelial lining of the FRT ovaries, uterus, cervix, fallopian tubes, and vagina. Successful implantation and placentation in humans and other animals rely on complex interactions between the embryo and a receptive female reproductive system. The FRT's recent breakthroughs in three-dimensional (3D) organoid systems now provide critical experimental models that match the organ's physiological, functional, and anatomical characteristics in vitro. This article summarizes the current state of the art on organoids generated from various parts of the FRT. The current analysis examines recent developments in the creation of organoid models of reproductive organs, as well as their future directions.
ARTICLE | doi:10.20944/preprints202104.0216.v1
Subject: Life Sciences, Biochemistry Keywords: SARS-CoV-2; variants; co-circulation; dominance; vaccines
Online: 7 April 2021 (17:24:38 CEST)
Some emergent SARS-CoV-2 variants raise concerns due to their altered biological properties. For both B.1.1.7 and B.1351 variants, named as variants of concern (VOC), increased transmissibility was reported, whereas B.1.351 was more resistant to multiple monoclonal antibodies (mAbs), as well as convalescent and vaccination sera. To test this hypothesis, we examined the proportion of VOC over time across different geographic areas where the two VOC, B.1.1.7 and B.1.351, co-circulate. Our comparative analysis was based on the number of SARS-CoV-2 sequences on GISAID database. We report that B.1.1.7 dominates over B.1.351 in geographic areas where both variants co-circulate and the B.1.1.7 was the first variant introduced in the population. The only areas where B.1.351 was detected at higher proportion were South Africa and Mayotte in Africa, where this strain was associated with increased community transmission before the detection of B.1.1.7. The dominance of B.1.1.7 over B.1.351 could be important since B.1.351 was more resistant to certain mAbs, as well as heterologous convalescent and vaccination sera, thus suggesting that it may be transmitted more effectively in people with pre-existing immunity to other VOC. This scenario would lessen the effectiveness of vaccine and urge the need to update them with new strains.
ARTICLE | doi:10.20944/preprints202007.0711.v1
Subject: Life Sciences, Molecular Biology Keywords: co-expression network; residual feed intake; RNA-Seq
Online: 30 July 2020 (09:39:36 CEST)
Long non-coding RNA (lncRNA) can regulate several aspects of gene expression, being associated with complex phenotypes in humans and livestock species. In taurine beef cattle, recent evidence points to the involvement of lncRNA in feed efficiency (FE), a proxy for increased productivity and sustainability. Here, we hypothesized specific regulatory roles of lncRNA in FE of indicine cattle. Using RNA-Seq data from liver, muscle, hypothalamus, pituitary and adrenal gland from Nellore bulls with divergent FE, we submitted new transcripts to a series of filters to confidently predict lncRNA. Then, we identified lncRNA that were differentially expressed (DE) and/or key regulators of FE. Finally, we explored lncRNA genomic location and interactions with miRNA and mRNA to infer potential function. We were able to identify 126 relevant lncRNA for FE in Bos indicus, some with high homology to previously identified lncRNA in Bos taurus and some possible specific regulators of FE in indicine cattle. Moreover, lncRNA identified here were linked to previously described mechanisms related to FE in hypothalamus-pituitary-adrenal axis and are expected to help elucidate this complex phenotype. This study contributes to expanding the catalogue of lncRNA, particularly in indicine cattle, and identifies candidates for further studies in animal selection and management.
ARTICLE | doi:10.20944/preprints202003.0291.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: co-infection; coronavirus disease 2019; COVID-19; influenza
Online: 19 March 2020 (02:00:47 CET)
Background: On late December 2019, a viral pneumonia known as coronavirus disease 2019 (COVID-19), was originated from China and spread very rapidly in the world. Therefore, COVID-19 became a global concern and health problem. Methods: We presented four patients in this study. They were selected from patients who presented with pneumonia symptoms and were suspicious for COVID-19 and referred to the intended centers for COVID-19 diagnosis and management of Shiraz University of Medical Sciences in the south of Iran. Two nasopharyngeal and oropharyngeal throat swab samples were collected from each patient and tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection by real-time reverse-transcriptase–polymerase-chain-reaction (RT-PCR), and also samples were sent for influenza viruses and all the respiratory panel. Results: In the present report, four patients were diagnosed in the starting days of COVID-19 disease in our center in south of Iran with co-infection of SARS-CoV-2 and influenza virus. Conclusions: This co-infection of COVID-19 and influenza highlights the importance of considering SARS-CoV-2 PCR assay regardless of other positive findings for other pathogens in the primary test during the epidemic.
ARTICLE | doi:10.20944/preprints202002.0430.v2
Subject: Life Sciences, Biotechnology Keywords: Co-culture; Reduced-serum; Wound bed; Fibroblasts; Keratinocytes
Online: 12 March 2020 (13:24:46 CET)
Contact-based co-culture of fibroblasts and keratinocytes is important to study the structure and functions of the wound bed. Co-culture of these two cell types in direct contact with each other has been challenging, requiring high serum concentrations (up to 10%), feeder systems and a range of supplemental factors. These approaches are not only technically demanding, but also present scientific, cost and ethical limitations associated with high-serum concentrations. We have developed two reduced-serum approaches (1-2%) to support contact-based co-culture of human dermal fibroblasts (HDFa) and human epidermal keratinocytes (HaCaT). The two approaches include (1) Specialized cell culture media for each cell type mixed in a 1:1 ratio (KGM+FGM), and (2) Minimal media supplemented with cell-specific growth factors (MEM+GF). Co-culture could be successfully achieved by co-seeding (two cell types were introduced simultaneously), or in a layered fashion (keratinocytes seeded on top of confluent fibroblasts). With wound scratch assays, the co-cultured platforms could demonstrate cell proliferation, migration and wound closure. The reduced-serum conditions developed are simple, easy to formulate and adopt, and based on commonly-available media components. These contact-based co-culture approaches can be leveraged for wound and skin studies, and tissue bioengineering applications, potentially reducing concerns with high-serum formulations.
CASE REPORT | doi:10.20944/preprints201811.0254.v1
Subject: Medicine & Pharmacology, Other Keywords: dengue; chikungunya; Leptospira; co-infection; Colombia; Latin America
Online: 12 November 2018 (03:21:38 CET)
Background: The febrile patient from tropical areas, in which emerging arboviruses are endemic, represent a diagnostic challenge and potential co-infections with other pathogens (i.e bacteria or parasites) are usually overlooked. Objectives: We present a case of an elderly woman diagnosed with dengue, chikungunya and Leptospira interrogans co-infection. Study Design: Case report. Results: An 87-year old woman from Colombia complained of upper abdominal pain, arthralgia, myalgia, hyporexia, malaise and intermittent fever accompanied with progressive jaundice. She had a medical history of chronic heart failure (Stage C, NYHA III), without documented cardiac murmurs, right bundle branch block, non-valvular atrial fibrillation, hypertension, and chronic venous disease. Her cardiac and pulmonary status quickly deteriorated after 24 hours of her admission without electrocardiographic changes and she required ventilatory and vasopressor support. In the next hours the patient evolved to pulseless electrical activity and then she died. Dengue IgM, NS1 ELISA, MAT for Leptospira interrogans and RT-PCR for chikungunya, were positive. Discussion: This case illustrates a multiple co-infection in a febrile patient from a tropical area of Latin America that evolved to death.
ARTICLE | doi:10.20944/preprints201704.0014.v1
Subject: Materials Science, Nanotechnology Keywords: tin oxide pellets; doping; HRTEM analysis; CO; sensitivity
Online: 4 April 2017 (08:16:13 CEST)
In this work, we report synthesis of Cu, Pt and Pd doped SnO2 powders and their comparative CO gas sensing studies. Dopants were incorporated into SnO2 nanostructures using chemical and impregnation methods by using urea and ammonia as precipitation agents. The synthesized samples were characterized using X-ray diffraction (XRD), Raman spectroscopy, Scanning electron microscopy (SEM) and High resolution transmission electron microscopy (HR-TEM). The presence of dopants within the SnO2 nanostructures was evidenced from HR-TEM. Doped powders utilizing chemical methods with urea as precipitation agent presented higher sensitivities compared to the remaining, which is due to the formation of uniform and homogeneous particles resulted from the temperature assisted synthesis. The particle sizes of doped SnO2 nanostructures were in the range of 40-100 nm. An enhanced sensitivity around 1783 was achieved with Cu doped SnO2 when compared with two other dopants i.e., Pt (1200) and Pd: SnO2(502). The high sensitivity of Cu: SnO2 is due to formation of CuO and its excellent association and dissociation in the presence of CO with adsorbed atmospheric oxygen at sensor operation temperatures resulted in high conductance. Cu: SnO2 may be an alternative and cost effective sensor for industrial applications.
ARTICLE | doi:10.20944/preprints201611.0123.v1
Subject: Biology, Forestry Keywords: co-management; livelihoods; conflicts; biodiversity conservation; sustainable development
Online: 24 November 2016 (11:25:34 CET)
Good governance in natural resource management (NRM) is one of the most challenging issues in developing countries that often inappropriately embedded in national policies and political agendas. It is, in fact, even more important for countries like Bangladesh with exceptionally high pressure and dependence on its natural resources for sustaining rural livelihoods. Globally, nowadays, good governance is considered as one of the key factor for achieving the goal of sustainable development and biodiversity conservation. Bangladesh, of late has responded to that global zeal by involving local communities in the management of country’s declining forest and other natural resources. The colonial legacy of the forestry sector of Bangladesh was planned and, managed as interim projects through donors’ prescriptions. Thus, institutions, management processes and conservation outcomes were problematic. The conventional approach adopted by colonial and post-colonial regimes for forest management also proved to be inefficient due to its top-down management system. The absolute dependency on donor support, and their prescription sometimes worsened the situation both ecologically and socially. Global, regional and local trends supported the need for a different dimension in the governance paradigms. The introduction of a pluralistic approach, known as co-management in protected areas (PAs) is an example of an attempt whereby shared governance mechanism are implemented to attain the desired goals of conservation that will also address the livelihoods and aspirations of communities living in and around PAs of the country. However, in designing future forest and PA regimes the concern of the external aid support and attached conditions remain a reality that needs to be addressed. Adequate attention should be given to our vanishing biodiversity, culture and community livelihoods through devising an appropriate governance mechanism recognizing and supporting local rights, access and participation in the environmental management. It is now time to mainstream the adhoc nature of governance according to our national conservation strategy and policy frameworks in order to achieve the goals and objectives of the Bangladesh NRM sector addressing the human and community right of people in the specific context of forest protected areas management.
REVIEW | doi:10.20944/preprints201611.0101.v1
Subject: Earth Sciences, Environmental Sciences Keywords: biodiversity conservation, livelihood, co-management, stakeholder, law enforcement
Online: 18 November 2016 (15:20:07 CET)
Despite of being an exceptionally biodiversity rich country, the forest coverage of Bangladesh is declining at an alarming rate. Declaration and management of protected areas in this regard is one of the efforts from government side to tackle the loss of biodiversity. The limited numbers of forest-protected areas (FPA), established to conserve the dwindling forest biodiversity of the country with high pressure on them for timber, non-timber forest products, and fuelwood - makes their management challenging. Moreover, most of the FPAs of the country declared only in the recent decades with very limited infrastructure, manpower and policy support for monitoring and governance. Some people-centred approaches for the management of FPAs and alternative livelihood and income generation subsidies although made available through a few project interventions, their number are still inadequate and performance remains less than satisfactory. This chapter provides a critical review of the FPAs of Bangladesh looking at their role in biodiversity conservation, management challenges, and key lessons from previous management interventions with recommendations for the future. It has been revealed that the FPA system of Bangladesh still poorly represents the diverse forest ecosystems with relatively small forest size and lack of corridors for the movement of wildlife. There are ample opportunities to render co-management of FPAs an effective strategy to minimize the conflicts in FPAs management in the country. It is, however, important to ensure the access of local forest-dependent people to different alternative income generating options that may adequately support their livelihoods.
REVIEW | doi:10.20944/preprints202105.0346.v1
Subject: Life Sciences, Biochemistry Keywords: drug discovery; drug repurposing; bioinformatics; machine learning; artificial intelligence; biomedical discoveries etc.
Online: 14 May 2021 (15:17:50 CEST)
Artificial intelligence AI or machine learning has proven to be a potential activity in the health and biomedical sciences. Previous research it has found that AI can learn new data and transform it into the useful knowledge. In the field of pharmacology, the aim is to design more efficient and novel vaccines using this method which are also cost effective. The underlying fact is to predict the molecular mechanism and structure for increased likelihood of developing new drugs. Clinical, electronic and high resolution imaging datasets can be used as inputs to aid the drug development niche. Moreover, the use of comprehensive target activity has been performed for repurposing a drug molecule by extending target profiles of drugs which also include off targets with therapeutic potential providing a new indication.
ARTICLE | doi:10.20944/preprints202101.0316.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Valproic acid; Drug-induced liver injury; Adverse drug reaction; Case-control study
Online: 18 January 2021 (11:11:04 CET)
Introduction: Valproic acid (VPA) is an antiepileptic drug extensively used for treating partial and generalised seizures, acute mania and as prophylaxis for bipolar disorder. Drug-induced liver injury (DILI) persists as a significant issue related to fatal outcomes by VPA. The aim of this study was to increase our knowledge about this condition and to better identify patients affected. Methods: We conducted an observational retrospective case-control study that identified cases of DILI by VPA from the Pharmacovigilance Programme from our Laboratory Signals at La Paz University Hospital from January 2007 to December 2019. From the Therapeutic VPA Monitoring Programme, two control groups were assigned, VPA-tolerant patients and the other with patients who developed mild VPA-related hepatitis but who did not meet the DILI criteria, matched for date, age and sex. Results: A total of 60 patients were included in the study: 15 cases of DILI, 30 VPA-tolerant controls and 15 controls with mild hepatitis. Mean age for the cases was 45.7 years, 4(26.7%) were women and 5(33.34%) were children under 18 years, of them 3(20%) were fatal. Polytherapy with other antiepileptic drugs (p=0.047) and alcohol consumption (p<0.001) were associated with a greater risk of developing DILI by VPA. A diagnosis of epileptic seizure was more frequently related to DILI when compared with the VPA-tolerant controls (p<0.001). The cases developed hepatocellular hepatitis (p<0.001), while the mild hepatitis controls had a higher rate of cholestatic hepatitis (p<0.001). The laboratory lactate dehydrogenase values were statistically higher (even at baseline) in patients with DILI than in both control groups (p= 0.033 and p=0.039). Conclusions: VPA hepatotoxicity remains a considerable problem. This study offers interesting findings for characterising VPA-induced liver injury and at-risk patients.
ARTICLE | doi:10.20944/preprints202003.0349.v1
Subject: Life Sciences, Biotechnology Keywords: novel coronavirus; COVID-19; protease; molecular docking; drug designing; ADME; drug repurposing
Online: 23 March 2020 (09:47:49 CET)
The Novel Coronavirus (COVID-19) is a positive-sense single-stranded RNA ((+)ssRNA) virus. The COVID-19 Main Proteases play very important role in the propagation of the Novel Coronavirus (COVID-19). It has already killed more than 8000 people around the world and thousands of people are getting infected every day. Therefore, it is very important to identify a potential inhibitor against COVID-19 Main Proteases to inhibit the propagation of the Novel Coronavirus (COVID-19). We have applied a drug repurposing approach of computational methodology, depending on the synergy of molecular docking and virtual screening techniques, aimed to identify possible potent inhibitors against Novel Coronavirus (COVID-19) from FDA approved antiviral compounds and from the library of active phytochemicals. On the basis of recently resolved COVID-19 Main Protease crystal structure (PDB:6LU7), the library of 100 FDA approved antiviral compounds and 1000 active components of Indian Medicinal Plants extracted for screening against COVID-19 Main Protease. The compounds were further screened using Pyrex virtual screening tool and then best inhibitors, top 19 compounds optimally docked to the COVID-19 Main Protease structure to understand the participation of specific amino acids with inhibitors at active sites. Total 19 best compounds were identified after screening based on their highest binding affinity with respect to the other screened compounds. Out of 19, 6 best compounds were further screened based on their binding affinity and best ADME properties. Nelfinavir exhibited highest binding energy -8.4 kcal/mol and strong stability with the TRP207, ILE281, LEU282, PHE3, PHE291, GLN127, ARG4, GLY283, GLU288, LYS5, LYS137, TYR126, GLY138, TYR126, SER139 and VAL135 amino acid residues of COVID-19 Main Protease participating in the interaction at the binding pocket. In addition to Nelfinavir (-8.4), Rhein (-8.1), Withanolide D (-7.8), Withaferin A (-7.7), Enoxacin (-7.4), and Aloe-emodin (-7.4) also showed good binding affinity and best ADME properties. Our findings suggest that these compounds can be used as potential inhibitors against COVID-19 Main Protease, which could be helpful in inhibiting the propagation of the Novel Coronavirus (COVID-19). Moreover, further in vitro and in vivo validation of these findings would be very helpful to bring these inhibitors to next level study.
REVIEW | doi:10.20944/preprints201810.0507.v1
Subject: Life Sciences, Other Keywords: liposomes, exosomes, extracellular vesicles, drug delivery, drug targeting, bioinspired systems, engineered systems.
Online: 22 October 2018 (15:35:20 CEST)
The similarities between exosomes and liposomes, together with the high organotropism of several types of exosomes, have recently prompted the development of engineered-exosomes or exosome-mimetics, which may be artificial (liposomal) or cell-derived vesicles, as advanced platforms for targeted drug delivery. Here we provide the current state-of-the-art of using exosome or exosome-inspired systems for drug delivery. We review the various approaches investigated and the shortcomings of each approach. Finally the challenges identified up-to-date in this field are summarized.
ARTICLE | doi:10.20944/preprints201610.0025.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: drug repurposing; translational bioinformatics; transcriptomics; transcriptome analysis; drug discovery; protocol; gene expression
Online: 9 October 2016 (08:42:23 CEST)
Traditional methods for discovery and development of new drugs can be a very time-consuming and expensive process because it includes several stages such as compound identification, pre-clinical and clinical trials before the drug is approved by the US Food and Drug Administration (FDA). Therefore, drug repurposing, namely using currently FDA-approved drugs as therapeutics for other diseases than what they are originally prescribed for, is emerging to be a faster and more cost-effective alternative to current drug discovery methods. In this paper, we have described a three-step in silico protocol for analyzing transcriptomics data using online databases and bioinformatics tools for identifying potentially repurposable drugs. The efficacy of this protocol was evaluated by comparing its predictions with the findings of two case studies of recently reported repurposed drugs: HIV treating drug Zidovudine for the treatment of Dry Age-Related Macular Degeneration and the antidepressant Imipramine for Small-Cell Lung Carcinoma. The proposed protocol successfully identified the published findings, thus demonstrating the efficacy of this method. In addition, it also yielded several novel predictions that have not yet been published, including the finding that Imipramine could potentially treat Severe Acute Respiratory Syndrome (SARS), a disease that currently does not have any treatment or vaccine. Since this in-silico protocol is simple to use and does not require advanced computer skills, we believe any motivated participant with access to these databases and tools would be able to apply it to large datasets to identify other potentially repurposable drugs in the future.
ARTICLE | doi:10.20944/preprints202208.0213.v1
Subject: Life Sciences, Biophysics Keywords: intermolecular binding affinity; drug target binding affinity; computer-aided drug design (CADD); artificial intelligence-integrated drug discovery (AIDD); machine learning
Online: 11 August 2022 (08:40:37 CEST)
Thanks to the continued development of experimental structural biology and the half-a-century old Protein Data Bank, 2021 saw a big step forward in the development of protein structure prediction with deep learning algorithms. Recently, DeepMinds AlphaFold has determined the structures of ∼ 200 million proteins from 1 million species. The speed of this progress raise the question of what becomes possible for computational drug discovery and design when we have a systems-wide account of the structures and motions of most proteins. Therefore, this article puts forward the concept of a general intermolecular binding affinity calculator (GIBAC): Kd = f(molA, molB, envPara), towards the acceleration of traditional computer-aided drug design (CADD) and artificial intelligence-integrated drug discovery (AIDD), for both small molecules and biologics such as therapeutic proteins.
ARTICLE | doi:10.20944/preprints202209.0179.v1
Subject: Medicine & Pharmacology, Other Keywords: polypharmacy; duplicate therapy; digital health; inappropriate prescribing; contraindicated drugs; drug-drug interactions; pharmacoepidemiology
Online: 13 September 2022 (12:25:42 CEST)
The primary purpose of this study was to determine the prevalence of drug-drug interaction (DDI) and duplicate therapy in chronic patients in a completely random study population engaged in digital health apps. In this cross-sectional study, polypharmacy checks for 100 completely anonymous patients were analyzed for the occurrence of DDIs and duplicate therapy. Logistic regression models were used to identify factors associated with DDIs and duplicate therapy. DDIs and duplicate therapy prevalence were 34% and 33%, respectively. Chi-Square test discovered a significant association between the DDIs and duplicate therapy variables. Logistic regression models showed a strong association between the number of medications taken and higher odds of DDIs occurring in our population only. In conclusion, our study shows that polypharmacy is a determining factor for the occurrence of unwanted DDIs, and the prevalence of duplicate therapy and DDIs is around 33%, increasing an issue regarding patient safety and its burden to the healthcare system.
ARTICLE | doi:10.20944/preprints202106.0717.v1
Subject: Medicine & Pharmacology, Allergology Keywords: hyperthyroidism; thyrotoxicosis; Graves’ disease; pregnancy; antithyroid drug; drug withdrawal; postpartum recurrence; birth defects
Online: 30 June 2021 (00:09:17 CEST)
Overt hyperthyroidism during pregnancy is associated with risk of maternal-fetal complications. The antithyroid drugs (ATD) have a potential risk for teratogenic effects and fetal–neonatal hy-pothyroidism. This study evaluated ATD treatment and thyroid function control during preg-nancy, and pregnancy outcome in women with hyperthyroidism. Patients and methods: retro-spective analysis of 36 single fetus pregnancies in 29 consecutive women (median age 30.3 ± 4.7 years) with hyperthyroidism diagnosed before or during pregnancy; a control group of 39 healthy euthyroid pregnant women was used. Results: 26 women had Graves’ disease (GD, 33 pregnan-cies), 1 had a hyperfunctioning autonomous nodule, 2 had gestational transient thyrotoxicosis (GTT). Methimazole (MMI) was administered in 22 pregnancies (78.5%), Propylthiouracil (PTU) in 2 (7.1%), switch from MMI to PTU in 4 (14.2%), no treatment in 8 pregnancies (3 with subclinical hyperthyroidism, 5 euthyroid with previous GD remission before conception). One spontaneous abortion at 5 weeks (3.4% of pregnancies) and 1 premature delivery at 32 weeks with perinatal death in 24h (3.4%) were recorded in 2 of the 8 pregnancies of GD patients diagnosed shortly before (< 6 weeks) or during gestation. In women treated more than 6 months until conception (20 pregnancies): a) median ATD doses were lower than those in women diagnosed shortly before or during pregnancy; b) ATD was withdrawn in 40% of pregnancies in trimester (T) I, all on MMI < 10 mg/day (relapse in 14.2%), and in up to 55% in TIII; c) TSH level was below normal in 37%, 35% and 22% of pregnancies in T I, II and III respectively; FT4 was increased in 5.8% (T I) and sub-normal in 11.75% in TII and III; d) one fetal death due to a true umbilical cord knot was recorded. Hyperthyroidism relapsed postpartum in 83% of GD patients (at median 3 ± 2.6 months). One child had neonatal hyperthyroidism (3.3% of live children in GD women) and a small atrial sept defect (4% of live children in ATD treated women). Mean birth weight did not differ from that of the control group. Conclusion. In hyperthyroid women with long-term ATD control before con-ception, drugs could be withdrawn in TI in a third of them, and fetal complications were rare. Frequent serum TSH and FT4 monitoring is needed in order to maintain optimal thyroid function during pregnancy.
ARTICLE | doi:10.20944/preprints202010.0196.v2
Subject: Medicine & Pharmacology, Allergology Keywords: drug discovery; artificial intelligence; protein discovery; binding prediction; synthetic molecule generation; synthetic drug
Online: 20 November 2020 (11:30:03 CET)
In this paper we propose the generation of synthetic small and more sophisticated molecule structures that optimize the binding affinity to a target (ASYNT-GAN). To achieve this we leverage on three important achievements in A.I.: Attention, Deep Learning on Graphs and Generative Adversarial Networks. Similar to text generation based on parts of text we are able to generate a molecule architecture based on an existing target. By adopting this approach, we propose a novel way of searching for existing compounds that are suitable candidates. Similar to question and answer Natural Language solutions we are able to find drugs with highest relevance to a target. We are able to identify substructures of the molecular structure that are the most suitable for binding. In addition, we are proposing a novel way of generating the molecule in 3D space in such a way that the binding is optimized. We show that we are able to generate compound structures and protein structures that are optimised for binding to a target.
REVIEW | doi:10.20944/preprints201907.0286.v1
Subject: Life Sciences, Virology Keywords: HIV-1 Gag; Gag inhibitors; Protease; Protease inhibitors; drug resistance mutations; drug design
Online: 25 July 2019 (10:05:03 CEST)
HIV treatment strategies against viral enzymes are continuously hampered by viral drug resistance. Recent findings show that viral substrate Gag contributes to HIV-1 Protease Inhibitor (PI) resistance, leading to demands for new strategies in HIV treatment where Gag is recognized as a drug target. To successfully target Gag, there is a need of in-depth understanding of the Gag polyprotein and the effects of Gag mutations. Here, we propose new strategies in designing novel Gag inhibitors against existing and novel emerging Gag mutations via a structural understanding of the Gag-Protease relationship in PI resistance. In this review, we discuss the role of both novel and previously reported mutations, revealing insights to how they aid in PI resistance, and how new Gag inhibitors can be designed.
ARTICLE | doi:10.20944/preprints202212.0304.v1
Subject: Biology, Other Keywords: Mitochondria; Co-translational import; BioID; Protein identification; Mass spectrometry
Online: 16 December 2022 (10:29:37 CET)
The majority of mitochondrial proteins are encoded by the nuclear genome and must be imported into the mitochondria. There are two main paths for mitochondrial protein import: post-translational and co-translational import. Co-translational import couples the translation and the translocation of the mitochondrial proteins, alleviating the energy cost typically associated with the post-translational import relying on chaperone systems. The mitochondrial co-translational import mechanisms are still unclear with few actors identified but none have been described in mammals yet. We thus profiled the TOM20 proxisome using BioID, assuming that some of identified proteins could be molecular actors of the co-translational import in human cells. The obtained results showed a high enrichment of RNA binding proteins close to the TOM complex. However, for the few selected candidates, we could not demonstrate a role in the mitochondrial co-translational import process. Nonetheless, we were able to demonstrate a new mitochondrial localization for nuclear proteins. Besides, additional analyses revealed a negative correlation between the abundance of mitochondrial proteins and their reported half-life. This experimental approach is thus proposed to potentially characterize mitochondrial co-translational import effectors in human cells and to monitor protein entry inside mitochondria with a potential application in the prediction of mitochondrial protein half-life.
REVIEW | doi:10.20944/preprints202212.0236.v1
Subject: Biology, Animal Sciences & Zoology Keywords: Microsporidia, Metchnikovellida, hyperparasites, co-occurring infections, host-parasite relationships
Online: 13 December 2022 (09:48:50 CET)
Metchnikovellids (Microsporidia: Metchnikovellida) are poorly studied hyperparasitic micro-sporidia that live in gregarines inhabiting the intestines of marine invertebrates, mostly poly-chaetes. Our recent studies showed that the diversity of the metchnikovellids might be signifi-cantly higher than previously thought, even within a single host. Four species of metchnikovellids were found in the gregarines inhabiting the gut of the polychaete Pygospio elegans from littoral populations of the White and Barents Seas: the eugregarine Polyrhabdina pygospionis is the host for Metchnikovella incurvata and M. spiralis, while the archigregarine Selenidium pygospionis is the host for M. dogieli and M. dobrovolskiji. The most common species in the White Sea is M. in-curvata, while M. dobrovolskiji prevails in the Barents Sea. The gregarines within a single worm could be infected with different metchnikovellid species. However, co-infection of one and the same gregarine with several species of metchnikovellids has never been observed. The difference in prevalence and intensity of metchnikovellid invasion apparently depends on the features of the life cycle and on the development strategies of individual species.
ARTICLE | doi:10.20944/preprints202209.0143.v1
Subject: Life Sciences, Microbiology Keywords: Salmonella; novel antibacterial agents; cannabidiol; co-therapy; bacterial genetics
Online: 12 September 2022 (09:55:22 CEST)
New generation antibiotics are needed to combat the development of resistance to antimicrobials. One of the most promising new classes of antibiotics is cannabidiol (CBD). It is a non-toxic and low-resistance chemical that can be used to treat bacterial infections. The antibacterial activity of Cannabis sativa L. byproducts, specifically CBD, has been of growing interest in the field of novel therapeutics. As research continues to define and characterize the antibacterial activity that CBD possesses against a wide variety of bacterial species it is important to examine potential interaction between CBD and common therapeutics such as broad-spectrum antibiotics. Here, we show that CBD-antibiotic co-therapy can effectively fight S. typhimurium via membrane integrity disruption. This research serves to examine the potential synergy between CBD and three broad-spectrum antibiotics for potential antibiotic-CBD co-therapy. In this study, we reveal that Salmonella typhimurium (S. typhimurium) growth is inhibited at very low dosages of CBD-antibiotic. This interesting finding demonstrates that CBD and CBD-antibiotic co-therapies are viable novel alternatives to combating Salmonella typhimurium.
REVIEW | doi:10.20944/preprints202208.0530.v1
Subject: Engineering, Civil Engineering Keywords: Resource recovery; circular economy; food waste; anaerobic co-digestion
Online: 31 August 2022 (03:10:30 CEST)
The emergence of the circular economy, and the evolving paradigms in the treatment and management of wastewater, have opened up an opportunity for co-digestion of organic waste (i.e., food waste) with sewage sludges to enhance resource recovery at wastewater treatment plants (WWTPs). This paper reviewed the potential for anaerobic co-digestion of food waste and sewage sludges, as well as alternative sustainable food waste handling systems in South Africa. The promotion of the circular economy by the latest national solid waste management strategy and the ongoing efforts for resource recovery by the wastewater sector suggests that anaerobic co-digestion of food waste and sewage sludge is possible in South Africa. Furthermore, an integrated food waste disposer (FWD) system was identified as a sustainable alternative for food waste handling. To formulate a roadmap for future food waste and sewage sludge co-digestion implementation, a multi-disciplinary investigation is required to bridge the literature gap.
ARTICLE | doi:10.20944/preprints202201.0282.v1
Subject: Social Sciences, Organizational Economics & Management Keywords: Project management; geothermal; co-benefits; sustainable development; innovation, operationalization
Online: 19 January 2022 (16:08:41 CET)
Despite knowledge concerning stakeholders and the economic advantages of consultation, collaboration and innovation, analysis of the sustainability implications of the geothermal industry has tended to take a high-level or systemic overview of national performance. This study seeks to begin to fill this gap in the academic and grey literature, investigating the following research question: how do projects in the Icelandic geothermal energy sector create co-benefits with stakeholders and reflect the integration of sustainable energy development (SED)? The focus of its analysis is on identifying who are the stakeholders, what are the sustainability benefits co-created with stakeholders, and when in the project lifecycle do these occur. Based on eleven semi-structured interviews with project managers in Iceland’s geothermal industry, the study identifies a broad array of stakeholders in the sector, including national and municipal governments and public sector institutions, businesses, the public, employees and landowners. The sustainability co-benefits of Iceland’s geothermal power projects are broad and cut cross all six themes of SED and multiple phases of the project lifecycle. Although the sustainability benefits are very apparent, trade-offs are reported between the pursuit of an economically efficient energy system and nature conservation. This relates to unsustainable utilization of the resources and the environmental externalities of power production and consumption. Efforts to mitigate these effects are ongoing and the further pursuit of SED is likely in Iceland given its recognition within the nation’s new energy policy and to meet ambitious greenhouse gas emissions reduction targets in the government’s climate action plan. These are issues that are prominent in other nations seeking to decarbonize energy systems through increased utilization of geothermal resources.
ARTICLE | doi:10.20944/preprints202112.0319.v1
Subject: Earth Sciences, Environmental Sciences Keywords: Waste water; Phosphate co-product; Adsorption; Red Acid 52
Online: 21 December 2021 (09:15:16 CET)
Water is essential for all living things however its pain has become serious. Many industrial activities cause its pollution by the release of polluting byproduct. Waste water treatment is hence necessary. In this context, the waste water of the textile industry containing Red Acid 52 was treated by the solid waste of the washed natural phosphate byproduct. Natural phosphate was also studied. The solid materials were first characterized by chemical analysis, Fourier Transform Infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The phosphate materials were after that, tested in the adsorption of the Red Acid 52. The experimental data indicated that the phosphate waste rock allowed the removal of Red Acid 52. Its maximum retention capacity attained 18.4 mg.g-1. Calcinations of materials inhibits the removal capacity found reduced by 60 to 70%. The adsorption kinetics of the Red Acid 52 on the material is well described by the pseudo second order model while the adsorption isotherms are identified by the Langmuir model. Hereafter, the thermodynamic study revealed that the adsorption process is spontaneous and exothermic. Keywords: Waste water, Phosphate co-product, Adsorption, Red Acid 52.
REVIEW | doi:10.20944/preprints202112.0029.v1
Subject: Materials Science, Nanotechnology Keywords: carbon nanomaterials; nitrogen doping; sulphur doping; co-doping; electrocatalysts
Online: 2 December 2021 (10:18:53 CET)
In recent years, hetero atom incorporated specially structured metal-free carbon nanomaterials have drawn huge attention among researchers. In comparison to the un-doped carbon nanomaterials, hetero atoms like nitrogen, sulphur, boron, phosphorous etc. incorporated nanomaterials become well-accepted as potential electrocatalysts in water splitting, supercapacitors and dye-sensitized solar cells. This review emphasizes on the mostly popular synthetic strategies utilized in last two decades and their excellent performance in electrocatalytic studies.
ARTICLE | doi:10.20944/preprints202012.0085.v1
Subject: Biology, Anatomy & Morphology Keywords: allosteric ligands; AutoDock; cognate ligands; Tanimoto co-efficient; GPCRs
Online: 3 December 2020 (13:08:24 CET)
G-protein coupled receptors (GPCRs) are large protein families known to be important in many cellular processes. They are well known for their allosteric activation mechanisms. They are drug targets for several FDA-approved drugs. We have investigated the diversity of the ligand binding site for these class of proteins against their cognate ligands using computational docking, even if their structures are known in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site, with better score than the binding at the conservative site. Further, ligands obtained from GLASS database, which consists of experimentally verified GPCR ligands, also show allosteric binding to GPCRs. The allosteric binders show strong affinity to the binding site, though the residues at the binding site are not conserved across GPCR subfamilies.
ARTICLE | doi:10.20944/preprints202009.0375.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: co-infection; SARS-CoV-2; pike glycoprotein; stop mutations
Online: 17 September 2020 (05:33:59 CEST)
There is a rising global concern for the ongoing outbreak of SARS-CoV-2 due to its high transmission rate and unavailability of treatment. Through the binding of its spike glycoprotein with angiotensin type 2 (ACE2), SARS-CoV-2 can efficiently get in the cells of patients and start its pandemic cycle. Herein, the biological diversity of SARS-CoV-2 infection was assessed in Babylon province of Iraq by investigating the possible genetic variations of the spike glycoprotein. A specific coding region of 795 bp within the viral spike (S) gene was amplified from 19 patients who suffered from obvious symptoms of SARS-CoV-2 infection. Sequencing results identified fifteen novel nucleic acid variations with a variety of distributions within the investigated samples. The electropherograms of all the identified variations showed obvious co-infections with at least two different viral strains per sample. Within these co-infections, the majority of samples exhibited three nonsense single nucleotide polymorphism (SNP)s, p.301Cdel, p.380Ydel, and p.436del, which yielded three truncated SARS-CoV-2 spike glycoproteins of 301, 380, and 436 amino acids length, respectively. The network and phylogenetic analyses indicated that for all viral infections were derived from multi-ancestral origins. Results inferred from the specific clade-based tree entailed that some viral strains were derived from European G-clade sequences. In conclusion, our data demonstrated the absence of any single strain infection among all investigated viral samples in the studied area, which may entail a higher risk of SARS-CoV-2 in this country. Through the identified high frequency of truncated spike proteins, we suggest that defective SARS-CoV-2 may depend on helper strains having intact spikes in its infection. Alternatively, another putative ACE2-independent route of viral infection way also suggested. To the best of our knowledge, this is the first report to describe the co-infection of multiple strains of SARS-CoV-2 in patients with COVID-19.
ARTICLE | doi:10.20944/preprints202007.0252.v1
Subject: Life Sciences, Immunology Keywords: SARS-Co-V2; Paediatric hyperinflammation; MIS-C; PIMS-TS
Online: 12 July 2020 (12:09:35 CEST)
We describe the innate and adaptive immune system trajectory in Multi-system inflammatory syndrome of childhood (MIS-C), at acute(within 72 hours of hospitalization), resolution (at clinical improvement) and convalescent phase. In our cohort, in the acute phase, 68% of the children were SARS-CoV-2 seropositive, with hypercytokinenemia (high interleukin(IL)-1beta,IL-6,IL-8,IL-10,IL-17, interferon gamma), procoagulant state, myocardial dysfunction, activated neutrophils and monocytes; differential T and B cell subset lymphopenia; activated chemokine receptor type-7 positive and gamma-delta T cell subsets; antigen presenting cells had reduced HLA-DR expression; and B-cell class-switch responses occurred with illness resolution. MIS-C is an immunopathogenic illness associated with SARS-CoV-2 infections in children.
REVIEW | doi:10.20944/preprints202004.0217.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; Indigenous Tribes; Co-morbidities; Corona Virus; Navaho
Online: 14 April 2020 (08:43:11 CEST)
Introduction The COVID-19 virus was initially reported in Dec 2019 as the causative agent of a pneumonia breakout in Wuhan China. This virus rapidly spread from China to Europe and the East Coast of the United States eventually reaching the South West United States and indigenous tribes in mid -March. Since, then the indigenous tribes have been devasted by the virus which the Governor of New Mexico has likened as an existential threat. Methodology A PubMed search was performed utilizing the words: Navajo Indian, Indigenous Indian, Wuhan Virus, COVID-19, SARs coronavirus, ACE2, S protein, virulence, clinical presentation, epidemiology, genome, treatment, structure, MERs, pathogenesis and/or pathology alone and in combination with other terms. Each paper was evaluated by three content experts for quality, reproducibility, credibility and reputation of the journal Results: Navajo’s and other indigenous peoples may have elevated levels of ACE2 receptors in their lungs and other tissues allowing greater susceptibility to the COVID-19 virus. Increased levels of diabetes and protein nutrition are directly related to increased morbidity and mortality in this group while obesity, COPD, and heart diseas are not. The increased morbidity and mortality is exasperated by an inability to test for COVID-19 Conclusion: The infectivity rate of Navaho’s on the reservation is 22 times higher than the national average with a death rate near 4%. Comorbidites account for some of the increased morbidity and mortality while lack of access to adequate health care unnecessarily magnifies the poor outcome. The threat to indigenous tribes in the Southwest of COVID-19 is dire.
ARTICLE | doi:10.20944/preprints202002.0406.v1
Subject: Chemistry, Applied Chemistry Keywords: Environmental chemistry; Oxyfuel Combustion; NO-CO reaction; Heterogeneous catalysis.
Online: 27 February 2020 (12:25:57 CET)
Carbon dioxide has become a global challenge, where the emissions have become more than what could be handled. In this regard, conversion of CO2 to value added chemicals and thus recycling CO2 became a viable option. One of these options is the use of a process in strong development: oxycombustion. However, the gases resulting from this process contain some traces of impurities that can hinder the recovery of CO2 such as NO and CO. This work has therefore focused on the study of the reaction of NO reduction by CO in an oxidizing medium, using catalytic materials based on various supported noble metals. These materials were extensively characterized by a variety of methods including BET surface area measurements, hydrogen chemisorption, Transmission Electron Microscopy (TEM) and H2 temperature programmed reduction (H2-TPR). The obtained results show that the catalytic behaviour of M/Al2O3 catalysts in CO oxidation and NO reduction with CO in oxidative conditions depends mainly on the nature of the metal. The best result for these both reactions is obtained with Pt/Al2O3 catalyst. The Pt nanoparticles existing in the metallic form (Pt°) showed by TPR could explain the activity.
ARTICLE | doi:10.20944/preprints201812.0299.v1
Subject: Social Sciences, Business And Administrative Sciences Keywords: European Parliament , Ordinary Legislative Procedure, Co-decision, Efficiency,Effectiveness
Online: 25 December 2018 (08:44:35 CET)
On the eve of the Brexit process, in the context of a rising Euroscepticism that fuels the modest confidence of European citizens in their national and European institutions, the article assesses the efficiency and effectiveness of the European Parliament within the framework of the ordinary legislative procedure (co-decision). After defining and formulating the main indicators, the paper analyses the micro- and macro-performance of the European Parliament within the decision-making process from a quantitative-qualitative and a qualitative-quantitative perspective, highlighting the relativizing factors and the responsiveness of the European decision-making process to the Europeans’ needs.
ARTICLE | doi:10.20944/preprints201812.0298.v1
Subject: Materials Science, Surfaces, Coatings & Films Keywords: Ti doped ZnO, Thin film, Co-Sputtering, UV-Visible
Online: 25 December 2018 (08:40:43 CET)
ZnO films with Ti atoms incorporated (TZO) in a wide range (0-18 at. %) have been grown by reactive co-sputtering on silicon and glass substrates. The influence of the titanium incorporation in the ZnO matrix on the structural and optical characteristics of the samples has been determined by Rutherford backscattering spectroscopy (RBS), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD). The results indicate that the samples with low Ti content (< 4 at. %) exhibit the wurtzite-like structure, with the Ti+4 ions substitutionally incorporated into the ZnO structure, forming Ti-doped ZnO films. In particular, very low concentration of Ti (<0.9 at. %) leads to a significant increase of the crystallinity of the TZO samples. Higher Ti contents give rise to a progressive amorphization of the wurtzite-like structure so samples with high Ti content (≥18at. %), displays an amorphous structure indicating the XPS analysis a predominance of Ti-O-Zn mixed oxides. The energy gap, obtained from absorption spectrophotometry, increases from 3.2 eV for pure ZnO films to 3.6 eV for those with the highest Ti content. Ti incorporation in the ZnO samples below 0.9 at. % rises both, the blue (380 nm) and green (550 nm) bands of the photoluminescence (PL) emission, thereby indicating a significant improvement of PL efficiency of the samples.
ARTICLE | doi:10.20944/preprints201808.0203.v1
Subject: Materials Science, Nanotechnology Keywords: Titanium dioxide nanotube, photoelectric properties, co-doping, magnetron sputtering
Online: 10 August 2018 (09:43:33 CEST)
Cu,N-TiO2 nanotube (Cu,N-TNT) is prepared through a novel magnetron sputtering and anodic oxidation method. Then the morphology, structure and physicochemical property of Cu,N-TNT was analyzed by XRD, SEM, TEM, EDX and UV-vis-DR. The results indicate that the evenly doped copper is beneficial to the transformation of the TNT from anatase to rutile and play a key role in the morphology of the Cu,N-TNT. The doped Cu and N in the TNT influence the growth orientation of the TiO2 crystals, which result in the lattice distortion and wider the interplanar spacing 60s-Cu,N-TNT has less band gap and stronger absorption intensity in visible region than other Cu,N-TNT samples, which make the combination rate of photogenerated electron and photogenerated hole decrease greatly, thus beneficial to its physicochemical property.
ARTICLE | doi:10.20944/preprints201807.0021.v1
Subject: Materials Science, Biomaterials Keywords: biomaterials; cobalt ferrites; poly(hydroxybutyrate-co-hydroxyvalerate); tissue engineering
Online: 3 July 2018 (05:12:53 CEST)
Polymer-based piezoelectric biomaterials have already proven their relevance for tissue engineering applications. Further, the morphology of the scaffolds plays also an important role in cell proliferation and differentiation. The present work reports on poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV), a biocompatible, biodegradable and piezoelectric biopolymer that has been processed in different morphologies, including films, fibres, microspheres and 3D scaffolds. Further, the corresponding magnetically active PHBV-based composites were also produced. The effect of the morphology on physico-chemical, thermal, magnetic and mechanical properties of pristine and composites samples was evaluated, as well as their cytotoxicity. It was observed that the morphology does not strongly affect the properties of the pristine samples but the introduction of cobalt ferrites induces changes in the degree of crystallinity that could affect the applicability of prepared biomaterials. Young modulus is dependent of the morphology and also increases with the addition of cobalt ferrites. Both, pristine and PHBV/cobalt ferrite composite samples are no cytotoxic, indicating their suitability for tissue engineering applications.
ARTICLE | doi:10.20944/preprints201806.0132.v1
Subject: Earth Sciences, Environmental Sciences Keywords: subplinian eruption; co-occurrence matrix; wavelet transform; similarity metrics
Online: 8 June 2018 (12:33:49 CEST)
This paper presents a new methodology that provides the analysis of surface texture changes in areas adjacent to the volcano and its impact product of volcanic activity. To do this, algorithms from digital image processing such as the co-occurrence matrix and the wavelet transform are used. These methods are working on images taken by the Landsat satellite platform sensor 5 TM and Landsat 7 ETM + sensor, and implemented with the purpose of evaluating superficial changes that can warn of surface movements of the volcano. The results were evaluated by similarity metrics for grayscale images, and validated in two different scenarios that have the same type of eruption, but differ, essentially, in climate and vegetation. Finally, the proposed algorithm is presented, setting the parameters and constraints for implementation and use.
ARTICLE | doi:10.20944/preprints201805.0165.v1
Subject: Biology, Animal Sciences & Zoology Keywords: infectious bronchitis virus; protection; co-expressing; subunit vaccine; challenge
Online: 10 May 2018 (12:02:08 CEST)
Avian infectious bronchitis virus (IBV) is the causative agent of infectious bronchitis, which causes considerable economic losses to the poultry industry worldwide. It is imperative to develop safe and efficient candidate vaccines to control IBV infection. In the current study, recombinant baculoviruses co-expressing S1 and N proteins, mono-expressing S1 or N proteins alone of IBV were constructed and prepared into subunit vaccines rHBM-S1-N, rHBM-S1 and rHBM-N. The levels of immune protection of these subunit vaccines were evaluated by inoculating specific pathogen-free (SPF) chickens at 14 days of age, boosting with the same dose 14 days later, and following challenge with a virulent GX-YL5 strain of IBV 14 days post-booster (dpb). The commercial vaccine strain H120 was used as a control. The IBV-specific antibody levels as well as the percentages of CD4+ and CD8+ T lymphocytes were detected within 28 days post-vaccination (dpv). The morbidity, mortality, and re-isolation of virus from the tracheas and kidneys of challenged birds were evaluated at 5 days post-challenge (dpc). The results showed that the IBV-specific antibody levels and the percentages of CD4+ and CD8+ T lymphocyte in rHBM-S1-N group were higher than those of rHBM-S1 and rHBM-N groups, especially the cellular immunity response. At 5 dpc, the mortality, morbidity and virus re-isolation rate of rHBM-S1-N were slightly higher than those of H120 group, but were lower than those of rHBM-S1 group and rHBM-N group. The present study demonstrated that the protection of recombinant baculovirus co-expressing S1 and N proteins was better than that of recombinant baculoviruses mono-expressing S1 or N protein alone. Thus, the recombinant baculovirus co-expressing S1 and N proteins could serve as a potential IBV vaccine and this demonstrates that the bivalent subunit vaccine including the S1 and N proteins might be a strategy for the development of an IBV subunit vaccine.
REVIEW | doi:10.20944/preprints202210.0270.v1
Online: 19 October 2022 (07:28:11 CEST)
Both Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are main injurious cutaneous medication reactions that mostly affect the epidermis and mucus membranes. TEN and SJS affecting nearly 1 or 2/1,000,000 people per year, and can recognized as medical crises since they may be deadly. Mucocutaneous discomfort, hemorrhagic erosions, erythema, and more or less severe epidermal separation that appear as ulcer and patches of dermic loss are their defining characteristics. The sole difference between TEN and SJS at this time is the degree of skin detachment, making them two extremes of a spectrum of severe cutaneous adverse drug reactions (cADRs). In the majority of cases, drugs are considered as the principal reason of SJS/TEN, but herpes simplex virus and Mycoplasma pneumoniae infections are also recognized causes, along with lesser number of cases in which the cause is still unknown. Among the drugs with a "high" likelihood of producing TEN/SJS are carbamazepine (CBZ), trimethoprim-sulfamethoxazole, phenytoin, aminopenicillins, allopurinol, cephalosporins, other sulfonamide antibiotics, quinolones, phenobarbital, and NSAIDs of the oxicam variety. There is strong genetic evidence for SJS and TEN in Han Chinese due to the substantial association between the human leukocyte antigen (HLA-B*1502) and SJS brought on by CBZ. The diagnosis is made mostly based on clinical symptoms and the histological study of a dermal biopsy. Pemphigus vulgaris, bullous pemphigoid, linear IgA dermatosis, paraneoplastic pemphigus, disseminated fixed bullous drug eruption, acute generalized exanthematous pustulosis (AGEP), and staphylococcal scalded skin syndrome (SSSS) are among the differential diagnoses. The management of patients with SJS/TEN is complicated by the high risk of mortality, necessitating early diagnosis, estimation of the SCORTEN prognosis, identification and discontinuation of the causative drug, specialized supportive care, and high-dose injectable Ig therapeutic interventions. The reported fatality rates for SJS are 1-5% on average and 25-35% for TEN; it can be even higher in patients who are elderly or who have a significant amount of epidermal detachment on their skin. More than 50% of TEN patients who survive the disease experience long-term consequences.
REVIEW | doi:10.20944/preprints202112.0315.v1
Online: 20 December 2021 (14:18:53 CET)
Nanotechnology is making significant transformation to our world, especially in healthcare and the treatment of diseases. It is widely used in different medical applications, such as in treatment and detection. Targeting diseased cell with nanomedicines is one of the numerous applications of nanotechnology. Targeted drug delivery systems for delivering various types of drugs to specific sites are such a dynamic area in pharmaceutical biotechnology and nanotechnology. Compared to conventional drugs, nanomedicines have a higher absorption and bioavailability rate, improving efficacy and minimizing side effects. There are several drug delivery systems including metallic nanoparticles, polymers, liposomes, and microspheres, but one of the most important is the niosomes, which are produced by nonionic surfactants. Because of the amphiphilic nature and structure, hydrophilic or hydrophobic drugs can be loaded into niosome structures. Other compounds, including cholesterol, can also be applied to the niosomes' backbone to rigidize the structure. Several variables such as the type of surfactant in niosome production, the preparation method, and the hydration temperature can affect the structure of the niosomes. Nevertheless, in-silico design of drug delivery formulations requires molecular dynamic simulation tools, molecular docking, and ADME (absorption; distribution; excretion; metabolism) properties, which evaluate physicochemical features of formulation and ADME attitudes before synthesis, investigating the interaction between nano-carriers and specific targets. Hence, experimenting in-vitro and in-vivo is essential. In this review, the basic aspects of niosomes are described including their structure, characterization, preparation methods, optimization with in-silico tools, factors affecting their formation, and limitations.
REVIEW | doi:10.20944/preprints202107.0506.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Drug repositioning; Molecular modelling; Beauvericin
Online: 22 July 2021 (07:48:33 CEST)
Drug discovery has been initially attributed to coincidence or trial and error where the traditional approach was complex, lengthy, and expensive. Conventional drug discovery methods require the costly random screening of synthesized compounds or natural products. Another downside for this approach is the wide dependency on the experimental use of animals for in vi-vo testing. Currently, in silico modeling has become a vital tool for drug discovery and repurposing, and molecular docking is being used to find the best matching between a ligand and a molecule. Practical application of in silico docking will predict the biomolecular interactions between the drug and the target host. Beauvericin (BEA) is an emerging mycotoxin produced by the entomopathogenic fungus Beauveria bassiana. Originally investigated for its pesticide capability, BEA is now considered as a molecule of interest for its potentially diverse biotechnological applications in the pharmacological industry and the field of medicine. In this manuscript, we will provide an overview of the repurposing of BEA into a potentially superior therapeutic molecule in a broad range of diseases. Furthermore, considerable attention has been given to the fundamental role of in silico techniques to i) further investigate the spectrum of this secondary metabolite and ii) elucidate the pathways of BEA for its promising therapeutic action
REVIEW | doi:10.20944/preprints202105.0084.v1
Subject: Medicine & Pharmacology, Allergology Keywords: peritoneal, HIPEC, intraperitoneal, drug transport
Online: 6 May 2021 (12:58:55 CEST)
With increasing awareness amongst physicians and improved radiological imaging techniques, the peritoneal cavity is increasingly recognized as an important metastatic site in various malignancies. Prognosis of these patients is usually poor as traditional treatment including surgical resection or systemic treatment is relatively ineffective. Intraperitoneal delivery of chemotherapeutic agents is thought to be an attractive alternative as this results in high tumor tissue concentrations with limited systemic exposure. The addition of hyperthermia aims to potentiate the anti-tumor effects of chemotherapy, resulting in the concept of heated intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal metastases as it was developed about 3 decades ago. With increasing experience, HIPEC has become a safe and accepted treatment offered in many centers around the world. However, standardization of the technique has been poor and results from clinical trials have been equivocal. As a result, the true value of HIPEC in the treatment of peritoneal metastases remains a matter of debate. The current review aims to provide a critical overview of the theoretical concept and preclinical and clinical study results, to outline areas of persisting uncertainty, and to propose a framework to better define the role of HIPEC in the treatment of peritoneal malignancies.
ARTICLE | doi:10.20944/preprints202011.0327.v1
Online: 12 November 2020 (08:24:40 CET)
Introduction Tuberculosis is common in Pakistan. Due to various factors including socioeconomic factors, compliance is poor to anti-tuberculosis drugs, leading to resistance. We aim to determine the prevalence of Multidrug resistance (MDR) tuberculosis in Pakistani population.Methods A prospective observational study was conducted from April 1, 2019, to December 31, 2019, in the Pulmonology department of a tertiary care hospital in Pakistan. Culture and sensitivity were assessed using a sputum sample or, in cases of an absent sputum sample, from Broncho alveolar lavage.ResultsApproximately 71.3% percent patients who had tuberculosis were found to be resistant to Isoniazid and around 48.6% did not respond to Rifampin. Multi-drug resistant was found in 29.4% participants.ConclusionMulti-drug resistance tuberculosis is very prevalent in Pakistan, which may increase burden on health care system and may lead to various complications of tuberculosis.
ARTICLE | doi:10.20944/preprints201905.0297.v1
Subject: Materials Science, Polymers & Plastics Keywords: lignin; drug release; paracetamol; disintegration
Online: 24 May 2019 (12:40:01 CEST)
The influence of lignin modification on drug release and pH-dependent releasing behaviour of oral solid dosage form was investigated using three different formulations. The first formulation contains microcrystalline cellulose (MCC101) as excipient and paracetamol as active pharmaceutical ingredient (API). The second formulation includes Alcell lignin and MCC 101 as excipient and paracetamol, and the third formulation consists of carboxylated Alcell lignin, MCC 101 and paracetamol. Direct compaction was carried out in order to prepare the tablets. Lignin can be readily chemically modified due to the existence of different functional groups in its structure. The focus of this investigation is on lignin carboxylation and its influence on paracetamol control release behaviour at varying pH. Results suggest that carboxylated lignin tablets had the highest drug release, which is linked to their faster disintegration and lower tablet hardness.
ARTICLE | doi:10.20944/preprints201810.0752.v1
Online: 31 October 2018 (11:13:37 CET)
Objective: To evaluate the status of receiving education on rational drug use, the criteria in medical drug selection, and level of knowledge of dentists working in a dentistry faculty in Turkey. Material and Methods: This was a descriptive study based on a questionnaire. One hundred seventeen (74%) dentists volunteered to participate in the study. The questionnaire consisted of 20 questions investigating sociodemographic features and rational drug use. Results: The mean age of the dentists was 30.8 ± 7.2 years, and 62.4% were men. The mean period of professional experience was 8.9±7.1 years. The most frequently used resources of references while prescribing medicine were Vademecum (medical drug guide) (61.5%), the internet (59.0%), and colleagues (49.6%). The most frequently reported condition described as ‘good’ was drug indications (43.6%). The dentists had a moderate level of information about posology, and administration route (48.7%), pharmacologic features (48.7%), and contraindications (46.2%). The number of dentists who stated that they considered cost while prescribing was low [always (6%), and frequently (15.4%)]. Rational drug use education had been received by 23.9% of the dentists. Conclusions: The dentists were found to have a lack of adequate and effective education on rational use of drugs. Regular and continuous education before and after graduation is a necessity for dentists and for their patients.
REVIEW | doi:10.20944/preprints202212.0112.v1
Subject: Materials Science, Nanotechnology Keywords: Gastro retentive drug delivery systems; non-effervescent systems; floating drug delivery systems; microballoons; CRDDS
Online: 7 December 2022 (02:26:58 CET)
Gastro-retentive floating microspheres were developed as a result of the recent advancements in floating delivery systems for drugs (FDDS), which included the uniform dispersion of multiparticulate dosage forms along the GIT. This could lead to more consistent drug absorption and a lower risk of local irritation. Microballoons (MB), a multi-unit extended release with a sphere-shaped cavity encased in a tough polymer shell, have been developed as a dosage form with exceptional buoyancy in the stomach. This preparation for constrained intestinal absorption is made to float on top of gastric acid, that has a relative density lower than 1.By using enteric acrylic polymers and the emulsion solvent diffusion method, microballoons are prepared and filled to drug in one‘s outer polymer casings. Enteric acrylic plastics are used to generate microballoons that are drug-loaded in one‘s external polymer casings and dissipate in a solution of dichloromethane and ethanol. Cavity development in microparticles seems to be particularly correlated with dichloromethane evaporation. Microballoons with a drug distributed or dispersed all through the particle-matrix have the potential for a controlled drug release and float continuously for more than 12 hours in vitro out over the surface of an acidified dissolution medium with surfactant. The drug is released slowly and at the desired rate as the microballoons glide over the components of the stomach, increasing gastro-retention time and lowering fluctuations in plasma concentration.
REVIEW | doi:10.20944/preprints202112.0380.v2
Subject: Medicine & Pharmacology, General Medical Research Keywords: sex differences; drug repurposing; sex-bias; sex-aware; review; therapeutics; pharmaceuticals; computational drug repurposing
Online: 8 March 2022 (10:34:42 CET)
Sex differences are essential factors in disease etiology and manifestation in many diseases such as cardiovascular disease, cancer, and neurodegeneration (1). The biological influence of sex differences (including genomic, epigenetic, hormonal, immunological, and metabolic differences between males and females) and the lack of biomedical studies considering sex differences in their study design has led to several policies. For example, the National Institute of Health’s (NIH) sex as a biological variable (SABV) and Sex and Gender Equity in Research (SAGER)) policies to motivate researchers to consider sex differences (2). However, drug repurposing, a promising alternative to traditional drug discovery by identifying novel uses for FDA-approved drugs, lacks sex-aware methods that can improve the identification of drugs that have sex-specific responses (1,3–5). Sex-aware drug repurposing methods either select drug candidates that are more efficacious in one sex or deprioritize drug candidates based on if they are predicted to cause a sex-bias adverse event (SBAE), unintended therapeutic effects that are more likely to occur in one sex. Computational drug repurposing methods are encouraging approaches to develop for sex-aware drug repurposing because they can prioritize sex-specific drug candidates or SBAEs at lower cost and time than traditional drug discovery. Sex-aware methods currently exist for clinical, genomic, and transcriptomic information (3,6,7). They have not expanded to other data types, such as DNA variation, which has been beneficial in other drug repurposing methods that do not consider sex (8). Additionally, some sex-aware methods suffer from poorer performance because a disproportionate number of male and female samples are available to train computational methods (3). However, there is development potential for several different categories (i.e., data mining, ligand binding predictions, molecular associations, and networks). Low-dimensional representations of molecular association and network approaches are also especially promising candidates for future sex-aware drug repurposing methodologies because they reduce the multiple hypothesis testing burden and capture sex-specific variation better than the other methods (9,10). Here we review how sex influences drug response, the current state of drug repurposing including with respect to sex-bias drug response, and how model organism study design choices influence drug repurposing validation.
REVIEW | doi:10.20944/preprints202201.0303.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Inflammation; NF-κB; drug repurposing; drug development; autoimmunity; COVID-19; multiple sclerosis; rheumatoid arthritis
Online: 20 January 2022 (11:16:25 CET)
NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Thus, modulation of NF-κB signaling is being widely investigated as an approach to treat chronic inflammatory diseases, autoimmunity and cancer. The emergence of COVID-19 in late 2019, the subsequent pandemic and the huge clinical burden of patients with life-threatening SARS-CoV-2 pneumonia led to a massive scramble to repurpose existing medicines to treat lung inflammation in a wide range of healthcare systems. These efforts continue and these efforts continue to be con-troversial. Drug repurposing strategies are a promising alternative to de-novo drug development, as they minimize drug development timelines and reduce the risk of failure due to unexpected side effects. Different experimental approaches have been applied to identify existing medicines which inhibit NF-κB that could be repurposed as anti-inflammatory drugs.
ARTICLE | doi:10.20944/preprints202104.0222.v1
Subject: Medicine & Pharmacology, Allergology Keywords: ocular surface disease; dry eye disease; antioxidant; Xanthohumol; drug delivery; drug formulation; PLGA; nanoparticles
Online: 8 April 2021 (09:09:24 CEST)
Elevated levels of oxidative stress in the corneal epithelium contribute to the progression of dry eye disease pathology. Previous studies have shown that antioxidant therapeutic intervention is a promising avenue to reduce disease burden and slow disease progression. In this study, we evaluated the pharmacological efficacy of Xanthohumol in preclinical models for dry eye disease. Xanthohumol is a naturally occurring prenylated chalconoid that promotes the transcription of phase II antioxidant enzymes. Xanthohumol exerted a dose-response in preventing tert-butylhydroxide-induced loss of cell viability in human corneal epithelial (HCE-T) cells and resulted in a significant increase in expression of nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of the endogenous antioxidant system. Xanthohumol-encapsulating poly(lactic-co-glycolic acid) nanoparticles (PLGA NP) were cytoprotective against oxidative stress in vitro, and significantly reduced corneal fluorescein staining in the mouse desiccating stress/ scopolamine model for dry eye disease in vivo by reducing oxidative stress-associated DNA damage in corneal epithelial cells. PLGA NP represent a safe and efficacious drug delivery vehicle for hydrophobic small molecules to the ocular surface. Optimization of NP-based antioxidant formulations with the goal to minimize instillation frequency may represent future therapeutic options for dry eye disease and related ocular surface disease.
ARTICLE | doi:10.20944/preprints202004.0161.v2
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: COVID-19; docking; drug repurposing; natural products; in silico drug design; viral replication inhibition
Online: 1 June 2020 (02:42:54 CEST)
We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the SARS-CoV-2 virus causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top- ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.
REVIEW | doi:10.20944/preprints201812.0032.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: cannabis; cannabinoids; THC; CBD, drug-drug interactions; pharmacokinetic; cytochrome P450; UDP- glucuronosyltransferases; glucoprotein-P
Online: 3 December 2018 (16:07:43 CET)
Endocannbinoids system (ECS) engrossed a considerable interest as potential therapeutic targets in various carcinomas and cancer related conditions alongside with neurodegenerative diseases. Cannabinoids are implemented in several physiological processes such as appetite stimulation, energy balance, pain modulation and the control of chemotherapy induced nausea and vomiting (CINV). However, pharmacokinetics and pharmacodynamics interactions could be perceived in drug combinations, so in this short review we tried to shed the light over the potential drug interactions of medicinal cannabis. Hitherto, few data have been provided to the healthcare practitioners about the drug-drug interactions of cannabinoids with other prescription medications. In general, cannabinoids are usually well tolerated, but the bidirectional effects may be expected with concomitant administered agents via affected membrane transporters (glycoprotein p, breast cancer resistance proteins) and metabolizing enzymes (Cytochrome P450 and UDP- glucuronosyltransferases). The caveats should be undertaken to closely monitor the responses of cannabis users with certain drugs to guard their safety, especially for the elderly and people with chronic diseases or kidney and liver conditions.
REVIEW | doi:10.20944/preprints201807.0518.v1
Subject: Life Sciences, Virology Keywords: virus; antiviral agent; drug target; drug side effect; innate immunity; precision medicine; systems biology
Online: 26 July 2018 (15:33:03 CEST)
There are dozens of approved, investigational and experimental antiviral agents. Many of these agents cause serious side effects, which can be revealed only after drug administration. Identification of the side effects prior to drug administration is challenging. Here we describe an ex vivo approach for studying immuno- and neuro-modulatory properties of antiviral agents, which could be associated with potential side effects of these therapeutics. The approach combines drug toxicity/efficacy tests and transcriptomics, which is followed by cytokine and metabolite profiling. We demonstrated the utility of this approach with several examples of antiviral agents. We also showed that the approach can utilize different immune stimuli and cell types. It can also include other omics techniques, such as genomics and epigenomics, to allow identification of individual markers associated with adverse reactions to antivirals with immuno- and neuro-modulatory properties.
ARTICLE | doi:10.20944/preprints202212.0107.v2
Subject: Earth Sciences, Environmental Sciences Keywords: green infrastructure; transdisciplinary; water systems; Costa Rica; co-design; prototype
Online: 27 December 2022 (01:55:16 CET)
The management of urban water has evolved from single-function systems to more sustainable designs promoting society and nature as inputs to engineer novel infrastructure. In transdisciplinary research, co-design refers to a design thinking strategy in which people jointly frame a problem-solution. This article presents a conceptual framework to assess a case study focusing on the process of co-design and implementation of green infrastructure as a prototype for stormwater management. The evaluation is carried out from a self-reflective post-implementation perspective. Research activities are translated into the framework to evaluate conditions shaping the trajectory of the prototype. As a result, key aspects driving the research regarding levels of stakeholder participation and dimensions of power are identified. Planning resilient co-design strategies to retrofit urban spaces is necessary to avoid unintended consequences, especially at the initial experimental stages. This study aims to contribute to the continuous improvement of pilot strategies in urban spaces by providing a framework for a structured evaluation of research experiences.
ARTICLE | doi:10.20944/preprints202212.0078.v1
Subject: Medicine & Pharmacology, Other Keywords: mHealth; pregnancy; app; first 1000 days; co-design; expectant parents
Online: 5 December 2022 (14:43:03 CET)
Background. To improve maternal and child health, it is essential to adhere to health-promoting and preventive measures. However, reliable information as well as effective tools are not easy to identify in this field. Our cross-sectional study investigated the needs and expectations of expectant and new mothers and fathers -primary users of an app supporting the first 1000 days of life. Methods. Between May and August 2022, we recruited expectant and new parents by administering a 71-item 5-point Likert scale questionnaire related to content, functionalities, and technical features of a hypothetical app. We stratified responses by sociodemographic characteristics and then performed ward hierarchical clustering. Results. The 94 women and 69 men involved in our study generally agreed with the proposed content, but expressed low interest in certain app functionalities, especially those related to interaction mechanism and interactivity. Women were generally more demanding than men, and family income declined as the needs and expectations increased. Conclusions. Our findings, resulting from the engagement of end-users, may be useful for designers and technology providers to implement mHealth solutions that, in addition to conveying reliable information, are tailored to the needs and preferences of end-users in the first 1000 days of life.
REVIEW | doi:10.20944/preprints202206.0014.v1
Subject: Life Sciences, Other Keywords: pharmaceutical toxicants; recalcitrant pollutants; co-metabolic pathways; biostimulation; bioaug-mentation
Online: 1 June 2022 (10:29:47 CEST)
Pharmaceutically active compounds and organic pollutants are becoming a major environmental dispute possessing serious threat to the water bodies and terrestrial ecosystem. Microorganisms are capable of the self-purification process, and hence the microbial degradation is considered a lucrative method to counteract the therapeutic and recalcitrant pollutants. Pharmaceutical toxicants in aquatic system can be treated by conventional wastewater treatment, but slow sludge settling, presence of mixture of pharmaceuticals and recalcitrant compounds often pose a potential ecological risk. Some microbial strains are very effective in reducing the chemical oxygen demand (COD), biological oxygen demand (BOD), total dissolved solids (TDS), and turbidity in pharmaceutical industrial wastewater treatment. The natural microbial community has a significant role in the ecological processes of pharmaceutical and organic compounds, including non-steroidal anti-inflammatory drugs, analgesics, blood lipid regulators and other micropollutants. Specific bacterial isolates can act as biodegraders, and fungal treatment could offer protection to the ecosystem. These microorganisms use the pollutants as their sole carbon source and transform the contaminants by co-metabolic pathways. Natural attenuation by native microorganisms, biostimulation and bioaugmentation are the processes employed to degrade the target contaminant. Microorganisms may also be genetically engineered to improve the neutralization efficiency, which would assist in the mineralization of the pollutants. Thus, employing microorganisms to detoxify the pollutants probably enhances the sustainable potential biodegradability, improves water quality standards and ensures eco-friendly alternative bioremediation strategy.
ARTICLE | doi:10.20944/preprints202205.0123.v1
Subject: Engineering, Energy & Fuel Technology Keywords: wind energy; digitalisation; collaboration; co-innovation; machine learning; fault detection
Online: 10 May 2022 (03:05:25 CEST)
In the next decade, further digitalisation of the entire wind energy project lifecycle is expected to be a major driver for reducing project costs and risks. In this paper, a literature review on the challenges related to implementation of digitalisation in the wind energy industry is first carried out, showing that there is a strong need for new solutions that enable co-innovation within and between organisations. Therefore, a new collaboration method called the WeDoWind Ecosystem is developed and demonstrated. The method is centred around specific "challenges", which are defined by "challenge providers" within a topical "space" and made available to participants via a digital platform. The data required in order to solve a particular "challenge" is provided by the "challenge providers" under the confidentiality conditions they specify. The method is demonstrated via a case study, the EDP Wind Turbine Fault Detection Challenge. Six submitted solutions using diverse approaches are evaluated. Two of the methods perform significantly better than EDP’s existing method in terms of Total Prediction Costs (saving up to €120,000). The WeDoWind Ecosystem is found to be a promising solution for enabling co-innovation in wind energy, providing a number of tangible benefits for both challenge and solution providers.
HYPOTHESIS | doi:10.20944/preprints202204.0185.v3
Subject: Medicine & Pharmacology, General Medical Research Keywords: case fatality rate; co-infection; control; COVID-19; pandemic; policy; risk; vaccination
Online: 6 May 2022 (03:38:30 CEST)
There are two contrary opinions regarding the risk if mainland China (MC) moves away from its zero-COVID policy. Some experts think the risk shall be much lower than influenza as per MC’s own COVID-19 case fatality rate (CFR), while some other experts think the risk shall be much higher than influenza as per the COVID-19 CFRs of other regions. We elucidate here that this and multiple other striking differences in the CFR between various scenarios all support and substantially resulted from the view that good IDM is highly powerful to mitigate COVID-19, where IDM (isolation-disinfection-maintenance) means isolation of COVID-19 cases from other people, disinfection of their living environments, and health maintenance (e.g., rest, nutrition, breathing). The high effect of good IDM is also supported by the theoretic functions of IDM in minimizing co-infections and maintaining body functions, and the fact that all the 505 COVID-19 deaths reported in MC in 2022 before May 5 died directly of severe underlying diseases with COVID-19. Although it is tough for people in poverty to obtain good IDM, good IDM can be feasible at home for the most mild cases and in hospitals for the most severe cases. Therefore, good IDM can be crucial to mitigating COVID-19 worldwide. It also suggests that the risk for China to end its zero-COVID policy depends on China’s control policies or measures. Based on the effect of IDM, the cautious co-existence policy was proposed for COVID-19 control. This policy could reduce the whole death toll in MC because good IDM is non-specific and can reduce deaths of various other diseases. The cautious co-existence policy (non-specific) and the vaccination policy (specific) aid each other to mitigate COVID-19, and they cannot replace each other. Those who are qualified in health for vaccination should be vaccinated against COVID-19 timely.
ARTICLE | doi:10.20944/preprints202201.0165.v1
Subject: Mathematics & Computer Science, Probability And Statistics Keywords: HIV/TB co-infected Mortality; Residential Variations; Multilevel Logistic Regression
Online: 12 January 2022 (13:34:06 CET)
The purpose of this study was to identify the factors that affect the mortality among adult HIV/TB co-infected patients and to see the nutritional difference among mortality in residence level. Retrospective cohort studies of 417 patients which fulfill our criteria were included. Multilevel logistic regression models were used. MLwiN and SPSS software are used to estimate the parameter. The variance of the random factor in the empty model was significant which indicates that there were residential differences in TB-HIV co-infected mortality and it shows multilevel analysis was an appropriate approach for further analysis. The prevalence of HIV/TB co-infected patients' death was 12.9% in study time. Functional status, age of patients, WHO clinical stages, nutritional status, CD4 counts, regimen, and BMI were found to be significant determinants of HIV/TB co-infected mortality. In our study, patients with the bedridden category of functional status, the fourth stages of WHO clinical stages (stage IV), patients with higher age, patients whose treatments were second-line regimen and low CD4 cell counts were more at risk of death. The study also revealed that; poor nutritional status increased the risk of mortality among HIV/TB co-infected patients and it varies among the residence of the patients (rural area were more at risk).
REVIEW | doi:10.20944/preprints202110.0057.v1
Subject: Earth Sciences, Environmental Sciences Keywords: impacts; microplastics; marine environment; single-use plastics; co-management initiatives
Online: 4 October 2021 (12:23:39 CEST)
Threats emerging from microplastics pollution in the marine environment have received much global attention. This review assessed sources, fate, and impacts of microplastics in marine ecosystems and identified gaps. Most studies document ubiquity of microplastics and associated environmental effects. Effects include impacts to marine ecosystems, risks to biodiversity, and threats to human health. Microplastic leakage into marine ecosystems arises from plastic waste mismanagement and a lack of effective mitigative strategies. This review identified a scarcity of microplastics mitigation strategies across different stakeholders. Lack of community involvement in microplastic monitoring or ecosystem conservation exists due to limited existence of stakeholder co-management initiatives. Although some management strategies exist for controlling the effects of microplastics (often implemented by local and global environmental groups); a standardized management strategy to mitigate microplastics in coastal areas is urgently required. There is a need to identify focal causes of microplastic pollution in the marine environment through further environmental research. This would extend to creating more effective policies as well as harmonized and extended efforts of educational campaigns and incentives for counteraction and plastic waste reduction, while mandating stringent penalties for polluting the marine environment. This will help reduce microplastic leakage into the environment.