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Preprint ARTICLE | doi:10.20944/preprints202007.0025.v1

COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study

Martin Scholz, Roland Derwand, Vladimir Zelenko

Subject: Medicine And Pharmacology, Pharmacy Keywords: SARS-CoV-2; COVID-19; outpatients; treatment; zinc; hydroxychloroquine; azithromycin

Online: 3 July 2020 (08:52:22 CEST)

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Objective: To describe outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low dose hydroxychloroquine, and azithromycin (the triple therapy) dependent on risk stratification. Design: Retrospective case series study. Setting: General practice. Participants: 141 COVID-19 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the year 2020. Main Outcome Measures: Risk-stratified treatment decision, rate of hospitalization and all-cause death. Results: Of 335 positively PCR-tested COVID-19 patients, 127 were treated with the triple therapy. 104 of 127 met the defined risk stratification criteria and were included in the analysis. In addition, 37 treated and eligible patients who were confirmed by IgG tests were included in the treatment group (total N=141). 208 of the 335 patients did not meet the risk stratification criteria and were not treated. After 4 days (median, IQR 3-6, available for N=66/141) of onset of symptoms, 141 patients (median age 58 years, IQR 40-67; 73% male) got a prescription for the triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control. 4 of 141 treated patients (2.8%) were hospitalized, which was significantly less (p<0.001) compared with 58 of 377 untreated patients (15.4%) (odds ratio 0.16, 95% CI 0.06-0.5). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated group. One patient (0.7%) died in the treatment group versus 13 patients (3.5%) in the untreated group (odds ratio 0.2, 95% CI 0.03-1.5; p=0.16). There were no cardiac side effects. Conclusions: Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset with the used triple therapy, including the combination of zinc with low dose hydroxychloroquine, was associated with significantly less hospitalizations and 5 times less all-cause deaths.

Preprint REVIEW | doi:10.20944/preprints202003.0235.v2

Evidence That Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths

William B. Grant, Henry Lahore, Sharon L. McDonnell, Carole A. Baggerly, Christine B. French, Jennifer L. Aliano, Harjit Pal Bhattoa

Subject: Medicine And Pharmacology, Dietetics And Nutrition Keywords: acute respiratory distress syndrome (ARDS); ascorbic acid; cathelicidin; coronavirus; COVID-19; cytokine storm; influenza; observational; pneumonia, prevention; respiratory tract infection; solar radiation; treatment; UVB; vitamin C; vitamin D

Online: 30 March 2020 (05:48:43 CEST)

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The world is in the grips of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increase concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D [25(OH)D] concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome, and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D₃ for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/ml (100–150 nmol/l). For treatment of people who become infected with COVID-19, higher vitamin D₃ doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.

Preprint ARTICLE | doi:10.20944/preprints202005.0057.v2

Early Hydroxychloroquine Is Associated with an Increase of Survival in COVID-19 Patients: An Observational Study

Francisco Javier Membrillo, Germán Ramírez-Olivencia, Miriam Estébanez, Begoña de Dios, María Dolores Herrero, Tatiana Mata, Alberto M. Borobia, Carlos Gutiérrez, María Simón, Ana Ochoa, Yolanda Martínez, Alejandro Aguirre, Francisco de Asís Alcántara, Pablo Fernández-González, Elena López, Paula Valle, Sergio Campos, María Navarro, Lucía Elena Ballester

Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: COVID-19; treatment; drug; survival; antiviral; hydroxychloroquine

Online: 9 May 2020 (04:45:37 CEST)

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Preprint CASE REPORT | doi:10.20944/preprints201912.0264.v2

4-Year Long Progression-Free and Symptom-Free Survival of a Patient with Recurrent Glioblastoma Multiforme: A Case Report of the Paleolithic Ketogenic Diet (PKD) Used as a Stand-Alone Treatment After Failed Standard Oncotherapy

Csaba Tóth, Andrea Dabóczi, Madhvi Chanrai, Mária Schimmer, Katalin Horváth, Zsófia Clemens

Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: glioblastoma; brain tumor; paleolithic diet; ketogenic diet; paleolithic ketogenic diet; metabolic therapy; intestinal permeability; cancer treatment

Online: 9 November 2020 (11:25:35 CET)

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Preprint HYPOTHESIS | doi:10.20944/preprints202004.0348.v3

Hydroxychloroquine; Why It Might Be Successful and Why It Might Not Be Successful in the Treatment of Covid-19 Pneumonia? Could It Be A Prophylactic Drug?

Omer Deniz

Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: hydroxychloroquine; COVID-19; pneumonia; prophylaxis; treatment

Online: 12 May 2020 (08:06:55 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202002.0061.v1

Deep Learning Based Drug Screening for Novel Coronavirus 2019-nCov

Haiping Zhang, Konda Mani Saravanan, Yang Yang, Md. Tofazzal Hossain, Junxin Li, Xiaohu Ren, Yanjie Wei

Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: Coronavirus; Deep learning; Drug screening; homology modeling; main protease

Online: 5 February 2020 (10:59:09 CET)

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Preprint ARTICLE | doi:10.20944/preprints202002.0047.v1

Possible Inhibitors of ACE2, the Receptor of 2019-nCoV

Qinghua Cui, Chuanbo Huang, Xiangwen Ji, Wanlu Zhang, Fenghong Zhang, Liang Wang

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: 2019-nCoV; therapeutic strategies; drug; ACE2

Online: 4 February 2020 (10:59:25 CET)

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Preprint ARTICLE | doi:10.20944/preprints202003.0360.v2

TMPRSS2 Transcriptional Inhibition as a Therapeutic Strategy for COVID-19

Xinchen Wang, Ryan Dhindsa, Gundula Povysil, Anthony Zoghbi, Joshua Motelow, Joseph Hostyk, Nicholas Nickols, Matthew Rettig, David B. Goldstein

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: SARS-CoV-2; transcriptional inhibition; COVID-19; drug repurposing; TMPRSS2

Online: 28 April 2020 (09:39:02 CEST)

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Preprint REVIEW | doi:10.20944/preprints202004.0122.v2

Can Melatonin Reduce the Severity of COVID-19 Pandemic?

Alex Shneider, Aleksandr Kudriavtsev, Anna Vakhrusheva

Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: melatonin; coronavirus; pandemic; SARS-CoV-2; bat; lung; apoptosis; programmed cell death; mortality; morbidity; COVID-19; drug

Online: 9 April 2020 (09:24:47 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202204.0296.v1

Efficacy of Short-Term High Dose Pulsed Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (PTLDS) and Associated Co-infections: A Report of Three Cases and Literature Review

Richard I. Horowitz, Phyllis R. Freeman

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: dapsone; disulfiram; chronic Lyme disease; Post-Treatment Lyme Disease Syndrome; babesia; bartonella; persisters; biofilms.

Online: 29 April 2022 (10:12:41 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202003.0349.v1

In Silico Identification of Potent COVID-19 Main Protease Inhibitors from FDA Approved Antiviral Compounds and Active Phytochemicals through Molecular Docking: A Drug Repurposing Approach

Vaishali Chandel, Sibi Raj, Brijesh Rathi, Dhruv Kumar

Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: novel coronavirus; COVID-19; protease; molecular docking; drug designing; ADME; drug repurposing

Online: 23 March 2020 (09:47:49 CET)

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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.

Preprint COMMUNICATION | doi:10.20944/preprints202002.0418.v2

Virtual Screening Based Prediction of Potential Drugs for COVID-19

Sekhar Talluri

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: virtual screening; molecular docking; drug repurposing; drug repositioning; anti-viral drugs; Coronavirus; COVID-19; 2019-nCoV; SARS-CoV-2

Online: 9 March 2020 (02:29:04 CET)

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Preprint ARTICLE | doi:10.20944/preprints202003.0413.v1

Ontological and Bioinformatic Analysis of Anti-Coronavirus Drugs and Their Implication for Drug Repurposing against COVID-19

Yingtong Liu, Wallace K.B. Chan, Zhigang Wang, Junguk Hur, Jiangan Xie, Hong Yu, Yongqun He

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: coronavirus; drug; COVID-19; SARS; MERS; ontology; ChEBI; NDF-RT; DrON; bioinformatics

Online: 29 March 2020 (01:58:40 CET)

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Coronavirus-infected diseases have posed great threats to human health. In past years, highly infectious coronavirus-induced diseases, including COVID-19, SARS, and MERS, have resulted in world-wide severe infections. Our literature annotations identified 110 chemical drugs and 26 antibodies effective against at least one human coronavirus infection in vitro or in vivo. Many of these drugs inhibit viral entry to cells and viral replication inside cells or modulate host immune responses. Many antimicrobial drugs, including antimalarial (e.g., chloroquine and mefloquine) and antifungal (e.g., terconazole and rapamycin) drugs as well as antibiotics (e.g., teicoplanin and azithromycin) were associated with anti-coronavirus activity. A few drugs, including remdesivir, chloroquine, favipiravir, and tocilizumab, have already been reported to be effective against SARS-CoV-2 infection in vitro or in vivo. After mapping our identified drugs to three ontologies ChEBI, NDF-RT, and DrON, many features such as roles and mechanisms of action (MoAs) of these drugs were identified and categorized. For example, out of 57 drugs with MoA annotations in NDF-RT, 47 have MoAs of different types of inhibitors and antagonists. A total of 29 anticoronaviral drugs are anticancer drugs with the antineoplastic role. Two clustering analyses, one based on ChEBI-based semantic similarity, the other based on drug chemical similarity, were performed to cluster 110 drugs to new categories. Moreover, differences in physicochemical properties among the drugs were found between those inhibiting viral entry and viral replication. A total of 163 host genes were identified as the known targets of 68 anti-coronavirus drugs, resulting in a network of 428 interactions among these drugs and targets. Chlorpromazine, dasatinib, and anisomycin are the hubs of the drug-target network with the highest number of connected target proteins. Many enriched pathways such as calcium signaling and neuroactive ligand-receptor interaction pathways were identified. These findings may be used to facilitate drug repurposing against COVID-19.

Preprint ARTICLE | doi:10.20944/preprints202003.0440.v1

COVID-19: A Drug Repurposing and Biomarker Identification by Using Comprehensive Gene-Disease Associations through Protein-Protein Interaction Network Analysis

Suresh Kumar

Subject: Biology And Life Sciences, Virology Keywords: COVID-19; SARS-CoV-2; 2019-nCoV; novel corona virus; drug repurposing; chloroquine; high-risk group; asymptomatic

Online: 30 March 2020 (07:24:16 CEST)

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COVID-19 (2019-nCoV) is a pandemic disease with an estimated mortality rate of 3.4% (estimated by the WHO as of March 3, 2020). Until now there is no antiviral drug and vaccine for COVID-19. The current overwhelming situation by COVID-19 patients in hospitals is likely to increase in the next few months. About 15 percent of patients with serious disease in COVID-19 require immediate health services. Rather than waiting for new anti-viral drugs or vaccines that take a few months to years to develop and test, several researchers and public health agencies are attempting to repurpose medicines that are already approved for another similar disease and have proved to be fairly effective. This study aims to identify FDA approved drugs that can be used for drug repurposing and identify biomarkers among high- risk and asymptomatic groups. In this study gene-disease association related to COVID-19 reported mild, severe symptoms and clinical outcomes were determined. The high-risk group was studied related to SARS-CoV-2 viral entry and life cycle by using Disgenet and compared with curated COVID-19 gene data sets from the CTD database. The overlapped gene sets were enriched and the selected genes were constructed for protein-protein interaction networks. Through interactome, key genes were identified for COVID-19 and also for high risk and asymptomatic groups. The key hub genes involved in COVID-19 were VEGFA, TNF, IL-6, CXCL8, IL10, CCL2, IL1B, TLR4, ICAM1, MMP9. The identified key genes were used for drug-gene interaction for drug repurposing. The chloroquine, lenalidomide, pentoxifylline, thalidome, sorafenib, pacitaxel, rapamycin, cortisol, statins were proposed to be probable drug repurposing candidates for the treatment of COVID-19. However, these predicted drug candidates need to be validated through randomized clinical trials. Also, a key gene involved in high risk and the asymptomatic group were identified, which can be used as probable biomarkers for early identification.

Preprint REVIEW | doi:10.20944/preprints202005.0376.v1

Computational Strategies to Combat COVID-19: Useful Tools to Accelerate SARS-CoV-2 and Coronavirus Research

Franziska Hufsky, Kevin Lamkiewicz, Alexandre Almeida, Abdel Aouacheria, Cecilia Arighi, Alex Bateman, Jan Baumbach, Niko Beerenwinkel, Christian Brandt, Marco Cacciabue, Sara Chuguransky, Oliver Drechsel, Robert D. Finn, Adrian Fritz, Stephan Fuchs, Georges Hattab, Anne-Christin Hauschild, Dominik Heider, Marie Hoffmann, Martin Hölzer, Stefan Hoops, Lars Kaderali, Ioanna Kalvari, Max von Kleist, René Kmiecinski, Denise Kühnert, Gorka Lasso, Pieter Libin, Markus List, Hannah F. Löchel, Maria J. Martin, Roman Martin, Julian Matschinske, Alice C. McHardy, Pedro Mendes, Jaina Mistry, Vincent Navratil, Eric Nawrocki, Áine Niamh O'Toole, Nancy Palacios-Ontiveros, Anton I. Petrov, Guillermo Rangel-Piñeros, Nicole Redaschi, Susanne Reimering, Knut Reinert, Alejandro Reyes, Lorna Richardson, David L. Robertson, Sepideh Sadegh, Joshua B. Singer, Kristof Theys, Chris Upton, Marius Welzel, Lowri Williams, Manja Marz

Subject: Biology And Life Sciences, Virology Keywords: virus bioinformatics; SARS-CoV-2; sequencing; epidemiology; drug design; tools

Online: 23 May 2020 (11:01:11 CEST)

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Preprint REVIEW | doi:10.20944/preprints202012.0242.v1

Long-Haul COVID-19: Putative Pathophysiology, Risk Factors, and Treatments

Shin Jie Yong

Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: COVID-19; SARS-CoV-2; long-haul; inflammation; tissue damage; drug repurposing

Online: 10 December 2020 (09:42:20 CET)

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Preprint REVIEW | doi:10.20944/preprints202005.0234.v1

Epidemiological Challenges in Pandemic Coronavirus Disease (COVID-19): Role of Artificial Intelligence

Abhijit Dasgupta, Abhisek Bakshi, Srijani Mukherjee, Kuntal Das, Soumyajeet Talukdar, Pratyayee Chatterjee, Sagnik Mondal, Puspita Das, Subhrojit Ghosh, Archisman Som, Pritha Roy, Rima Kundu, Akash Sarkar, Arnab Biswas, Karnelia Paul, Sujit Basak, Krishnendu Manna, Chinmay Saha, Satinath Mukhopadhyay, Nitai P. Bhattacharyya, Rajat K. De

Subject: Computer Science And Mathematics, Artificial Intelligence And Machine Learning Keywords: SIRD; Twitter; GHSI; Pre-symptomatic; EHR; Contact tracing; On-line survey; qRT-PCR; X-ray; CT/HRCT; CNN; Autoencoder; Drug affinity; CPI; and Inflation.

Online: 14 May 2020 (11:25:57 CEST)

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Preprint REVIEW | doi:10.20944/preprints202007.0108.v1

COVID-19: Comprehensive Synopsis of Suggested Pathophysiological Mechanisms and Repurposed Drugs

Mathijs Binkhorst, Annette K. Offringa, Johannes G. van der Hoeven

Subject: Medicine And Pharmacology, Pharmacy Keywords: COVID-19; SARS-CoV-2; coronavirus; hypothesis; pathophysiology; drug repurposing

Online: 7 July 2020 (02:50:55 CEST)

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Preprint HYPOTHESIS | doi:10.20944/preprints202002.0147.v4

The clinically validated viral superinfection therapy (SIT) platform technology could cure early cases of COVID-19 disease

Imre Kovesdi, Volker Sandig, Shimon Slavin, Wolfgang Renz, Marc Van Ranst, Peter M. Chumakov, Tibor Bakács

Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Coronavirus; SARS-CoV-2; COVID-19; interferon; IFN; superinfection therapy; SIT; infectious bursal disease virus; IBDV; R903/78; safety; treatment

Online: 1 February 2021 (16:07:55 CET)

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Preprint ARTICLE | doi:10.20944/preprints202006.0293.v1

Doxycycline and Pentoxifylline for Mild and Mild-To-Moderate Covid-19

Emil Toma

Subject: Biology And Life Sciences, Virology Keywords: Covid-19; SARS-CoV-2; doxycycline; pentoxifylline; treatment; proposal

Online: 24 June 2020 (09:47:14 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202002.0071.v1

Drug and Vaccine Design against Novel Coronavirus (2019-nCoV) Spike Protein through Computational Approach

Suresh Kumar

Subject: Biology And Life Sciences, Virology Keywords: 2019-nCoV; novel corona virus; Wuhan virus; drug; vaccine; spike protein; epitope; vaccine design

Online: 5 February 2020 (15:34:15 CET)

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Preprint REVIEW | doi:10.20944/preprints201910.0144.v6

Discovery and Development of Safe-in-Man Broad-Spectrum Antiviral Agents

Petter I. Andersen, Aleksandr Ianevski, Hilde Lysvand, Astra Vitkauskiene, Valentyn Oksenych, Magnar Bjoras, Kaidi Telling, Irja Lutsar, Uga Dumpis, Yasuhiko Irie, Tanel Tenson, Anu Kantele, Denis E. Kainov

Subject: Biology And Life Sciences, Virology Keywords: virus; antiviral drug; drug discovery; drug development; broad-spectrum antivirals

Online: 14 February 2020 (02:27:24 CET)

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Preprint REVIEW | doi:10.20944/preprints202004.0077.v2

The Pathophysiology of Virulence of the COVID-19

Joseph De Soto, Shazia Hakim, Frederick Boyd

Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: COVID-19; native American Indian; treatment; ACE2 receptor; pathophysiology; virulence

Online: 15 April 2020 (08:08:52 CEST)

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Background: On Dec 19, 2019, the public health department of China reported that an outbreak of pneumonia was caused by a novel Coronavirus. The virulence of the new virus COVID-19 was much greater than either the SARs and MERSs viruses and on March 11, 2020, the World Health Department (WHO) declared a worldwide pandemic. Understanding the pathophysiology of virulence of the SARS-COV-2 virus is absolutely necessary for understanding the transmission, virulence factors, reduce risk factors, clinical presentation, predict outcomes of the disease and provide guidance for any current or future treatment protocols. Methodology: A comprehensive PubMed search was performed during December 20, 2019 and April 03, 2020, utilizing the words: 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: The SARS-COV-2 virus is much more virulent than either the SAR’s or MER’s virus and its ability to cause serious disease inversely corresponds to the person’s ability to produce T-cells which declines linearly with age. The ACE2 receptor binding site does not vary among different ethnic groups but do in ACE-2 expression levels. This variance in expression level may explain for different infectivity rates among men and women and predict and explain different susceptibilities to infection by different ethnic groups. Furthermore, by understanding the underlying pathophysiology one can explain and provide guidance to the clinical effectiveness of any treatment. Conclusions: The underlying pathophysiology of COVID-19 explains not only the virulence, and clinical presentation, but, explains at a molecular level the comorbidity risk factors such as hypertension, sex, and age. Ethnic and anatomic expression patterns of ACE-2 and associated pathophysiology suggests that Native Americans and Asians may be particularly susceptible to this disease.

Preprint HYPOTHESIS | doi:10.20944/preprints202003.0341.v1

The AI-Discovered Aetiology of COVID-19 and Rationale of the Irinotecan+Etoposide Combination Therapy for Critically Ill COVID-19 Patients

Bragi Lovetrue

Subject: Biology And Life Sciences, Virology Keywords: Aetiology; Treatment; Cytokine Storm; ICU; COVID-19; ACE2; Irinotecan; Etoposide

Online: 23 March 2020 (06:56:57 CET)

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Preprint REVIEW | doi:10.20944/preprints202010.0179.v1

Explicit Treatment of Non Michaelis-Menten and Atypical Kinetics in Early Drug Discovery

Bharath Srinivasan

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Non Michaelis-Menten Kinetics; High-throughput screening; allostery; cooperativity; processive kinetics; distributive kinetics; single-molecule; auto-catalytic; drug discovery

Online: 8 October 2020 (13:34:16 CEST)

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Preprint ARTICLE | doi:10.3390/sci2020045

Antimalarial Drugs in Ghana: A Case Study on Personal Preferences

Prince Yeboah, Arnold Donkor Forkuo, Obed Kwabena Offe Amponsah, Nana Ofori Adomako, Ahmad Yaman Abdin, Muhammad Jawad Nasim, Pitsch Werner, Anto Berko Panyin, Eike Emrich, Claus Jacob

Subject: Medicine And Pharmacology, Tropical Medicine Keywords: adverse drug reactions; antimalarial; Ghana; herbal remedies; malaria; questionnaire; street sale; orthodox; unnatural medicines; patient preference

Online: 12 June 2020 (00:00:00 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202005.0397.v1

Genetic Uniformity of a Specific Region in SARS-CoV-2 Genome and In-Silico Target-Oriented Repurposing of N-Acetyl-D-Glucosamine

Omur Baysal, Ragip Soner Silme, Cagatay Karaaslan

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: SARS-CoV-2; Drug repurposing; N-acetyl-D-glucosamine; ORF1ab; Biodata mining; Protein modelling

Online: 24 May 2020 (18:49:41 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201608.0232.v2

ODK Scan: Digitizing Data Collection and Impacting Data Management Processes in the Tuberculosis Control Program of Pakistan

Syed Mustafa Ali, Rachel Powers, Jeffrey Beorse, Farah Naureen, Arif Noor, Naveed Anjum, Muhammad Ishaq, Javariya Aamir, Richard Anderson

Subject: Medicine And Pharmacology, Pulmonary And Respiratory Medicine Keywords: mHealth; ODK scan; mobile health application; digitizing data collection; data management processes; paper-to-digital system; technology-assisted data management; treatment adherence

Online: 2 September 2016 (03:17:38 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201610.0025.v1

A Protocol for Identifying Potentially Repurposable Drugs Using Online Tools and Databases

Aditi Chattopadhyay, Madhavi Ganapathiraju

Subject: Medicine And Pharmacology, Other Keywords: drug repurposing; translational bioinformatics; transcriptomics; transcriptome analysis; drug discovery; protocol; gene expression

Online: 9 October 2016 (08:42:23 CEST)

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Preprint REVIEW | doi:10.20944/preprints202006.0145.v1

Lessons for SARS-CoV-2 Study (COVID-19 Disease) From Its Exosome Relatives

Pierre Arsene

Subject: Biology And Life Sciences, Virology Keywords: SARS-CoV-2; COVID-19; Exosome; Extracellular Vesicle; Diagnostics; Vaccine; Treatment

Online: 12 June 2020 (09:01:02 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202010.0481.v1

Methylphenidate and Alprazolam Co-Abuse: Drug-DNA Interactions

Shweta Sharma, Meenu Dutt, Neha Sharma, Ravinder Naik Dharavath, Tanzeer Kaur

Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Drug-DNA interaction; FTIR; Polydrug-abuse; UV-visible spectrophotometer

Online: 23 October 2020 (10:36:07 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201611.0075.v3

A Robust Liquid Chromatographic Method for Confirmation of Drug Stability of Azithromycin in Bulk Samples, Tablets and Suspensions

Alex O. Okaru, Kennedy O. Abuga, Franco N. Kamau, Stanley N. Ndwigah, Dirk W. Lachenmeier

Subject: Chemistry And Materials Science, Analytical Chemistry Keywords: azithromycin; HPLC; robust; isocratic; drug stability; degradation products

Online: 4 January 2017 (10:08:52 CET)

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Preprint REVIEW | doi:10.3390/sci1010015.v1

Endocrine Disrupting Compounds Removal Methods from Wastewater in the United Kingdom: A Review

China K. Gadupudi, Louis Rice, Libin Xiao, Komali Kantamaneni

Subject: Environmental And Earth Sciences, Water Science And Technology Keywords: wastewater treatment; temperatures; systematic review; biofilms; endocrine disrupting compounds

Online: 21 March 2019 (00:00:00 CET)

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Preprint REVIEW | doi:10.20944/preprints202008.0225.v1

Heat Stability of Proteins and Its Exploitation for Purification of Heat-Stable Proteins

Muhammad Ahmad, Aisha Tahir, Rana Salman Anjum

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Heat-stable proteins; Heat treatment; Hyperthermophilic proteins; Heat stability; Protein purification

Online: 9 August 2020 (22:00:46 CEST)

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Working Paper ARTICLE

Short-Term Moderate-Dose Corticosteroid Plus Immunoglobulin Effectively Reverses COVID-19 Patients Who Have Failed Low-Dose Therapy

Zhi-Guo Zhou, Shu-Min Xie, Jing Zhang, Fang Zheng, Di-Xuan Jiang, Ke-Yu Li, Qi Zuo, Yu-Sheng Yan, Ji-Yang Liu, Yuan-Lin Xie, Hong Peng, Lei Zhang

Subject: Medicine And Pharmacology, Clinical Medicine Keywords: humans; infection control; therapy; coronavirus; immunoglobulins; drug therapy; therapeutic use; corticosteroid

Online: 8 March 2020 (17:04:19 CET)

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Background: The coronavirus disease-19 (COVID-19) has spread globally with more than 80,000 people infected, and nearly 3000 patients died. Currently, we are in an urgent need for effective treatment strategy to control the clinical deterioration of COVID-19 patients. Methods: The clinical data of 10 COVID-19 patients receiving short-term moderate-dose corticosteroid (160mg/d) plus immunoglobulin (20g/d) were studied in the North Yard of The First Hospital of Changsha, Hunan from January 17^th to February 27^th, 2020. Epidemiological, clinical, laboratory, radiological findings were analyzed. Results: After treatment with combination of low-dose corticosteroid (40-80mg/d) and immunoglobulin (10g/d), patients’ lymphocyte count (0.88±0.34 vs 0.59±0.18, P<0.05), oxygenation index including SPO₂ (94.90±2.51 vs 90.50±5.91, P<0.05) and PaO₂/FiO₂ (321.36±136.91 vs 129.30±64.97, P<0.05) were significantly lower than pre-treatment, and CT showed that the pulmonary lesion deteriorated in all patients. While after treatment of short-term moderate-dose corticosteroid plus immunoglobulin, patients’ APACHE Ⅱ score (9.10±6.15 vs 5.50±9.01, P<0.05), body temperature (37.59±1.16 vs 36.46±0.25, P<0.05), lymphocyte count (0.59±0.18 vs 1.36±0.51, P<0.05), Lactate dehydrogenase (419.24±251.31 vs 257.40±177.88, P<0.05), and C-reactive protein (49.94±26.21 vs 14.58±15.25, P<0.05) significantly improved compared with post-treatment with low-dose therapy. In addition, oxygenation index including SPO₂ (90.50±5.91 vs 97.50±1.18, P<0.05), PaO₂ (60.47±14.53 vs 99.07±34.31, P<0.05), and PaO₂/FiO₂ (129.30±64.97 vs 340.86±146.72, P<0.05) significant improved. Furthermore, CT showed that pulmonary lesions obviously improved in 7 patients. After systematic therapy, 4 out of 10 COVID-19 patients recovered and discharged. Conclusions: Short-term moderate-dose corticosteroid plus immunoglobulin is effective for reversing the continued deterioration of COVID-19 patients who failed to respond to the low-dose therapy. Funding: This work was supported by the Innovative Major Emergency Project Funding against the New Coronavirus Pneumonia in Hunan Province (Dr. Ji-Yang Liu, number 2020SK3014; Dr. Yuan-Lin Xie, number 2020SK3013).

Preprint REVIEW | doi:10.20944/preprints201805.0011.v1

Changing Trends in Computational Drug Repositioning

Jaswanth K. Yella, Suryanarayana Yaddanapudi, Yunguan Wang, Anil G. Jegga

Subject: Medicine And Pharmacology, Pharmacology And 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)

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Preprint REVIEW | doi:10.20944/preprints202105.0346.v1

Role of Artificial Intelligence and Machine Learning in Bioinformatics: Drug Discovery and Drug Repurposing

Sameer Quazi

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: drug discovery; drug repurposing; bioinformatics; machine learning; artificial intelligence; biomedical discoveries etc.

Online: 14 May 2021 (15:17:50 CEST)

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Preprint REVIEW | doi:10.20944/preprints202101.0503.v1

Central Nervous System Depressant Drugs: Updated Review

Abdullah Alkattan, Eman Alsalameen, Amr Ahmed

Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: CNS; Drug receptors; GABA; Cannabinoid; Opioid; Serotonin; Dopamine

Online: 25 January 2021 (14:15:20 CET)

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Preprint REVIEW | doi:10.20944/preprints202003.0345.v2

Widely Available Lysosome Targeting Agents Should Be Considered as a Potential Therapy for COVID-19

Jan Homolak, Ivan Kodvanj

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: COVID-19; lysosomotropic agents; endosome; antiviral; drug repurposing

Online: 24 March 2020 (06:26:54 CET)

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While the COVID-19 pandemic advances, the scientific community struggles in the search for treatments. Several improvements have been made, including the discovery of clinical efficacy of chloroquine (CQ) in COVID-19 patients, but the effective treatment protocols are still missing. In order to find novel treatment options many scientists utilize the in silico approach to identify compounds that could interfere with the key molecules involved in entrance, replication, or dissemination of the SARS-CoV-2. However, most of the identified molecules are currently not available as pharmacological agents, and assessing their safety and efficacy could take many months. Here, we took a different approach based on the proposed pharmacodynamic model of CQ in COVID-19. The main mechanism of action responsible for the favourable outcome of COVID-19 patients treated with CQ seems to be related to pH modulation-mediated effect on the endolysosomal trafficking, a characteristic of chemical compounds often called lysosomotropic agents because of the physico-chemical properties that enable them to passively diffuse through the endosomal membrane and undergo protonation-based trapping in the lumen of the acidic vesicles. In this review, we discuss lysosomotropic and lysosome targeting drugs that are already in clinical use and are characterized by good safety profiles, low cost, and wide availability. We emphasize that some of these drugs, in particular azithromycin and other macrolide antibiotics, indomethacin and some other non-steroidal anti-inflammatory drugs, proton pump inhibitors, and fluoxetine could provide additional therapeutic benefits in addition to the potential antiviral effect that still has to be confirmed by well-controlled clinical trials. As some of these drugs, mostly antibiotics, were already empirically used in the treatment of COVID-19, we encourage our colleagues all over the world to publish patient data so potential efficacy of these agents can be evaluated in the clinical context and rapidly implemented in the therapeutic protocols if the beneficial effect on clinical outcome is observed.

Preprint ARTICLE | doi:10.20944/preprints201701.0116.v3

Network Analysis: A Novel Approach to Understand Suicidal Behavior

Derek de Beurs

Subject: Medicine And Pharmacology, Psychiatry And Mental Health Keywords: suicide; network analysis; symptoms; personalized treatment

Online: 13 February 2017 (11:04:49 CET)

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Preprint REVIEW | doi:10.20944/preprints201812.0170.v1

Nanocellulose in Biotechnology and Medicine: Focus on Skin Tissue Engineering and Wound Healing

Lucie Bacakova, Julia Pajorova, Marketa Bacakova, Anne Skogberg, Pasi Kallio, Katerina Kolarova, Vaclav Svorcik

Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: bacterial nanocellulose; nanofibrillated nanocellulose; animal nanocellulose; algal nanocellulose; tissue engineering; tissue repair; wound dressing; cell delivery; drug delivery; antimicrobial properties

Online: 14 December 2018 (06:44:53 CET)

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Preprint ARTICLE | doi:10.20944/preprints201609.0109.v1

Plasma Polymerization SnOxCy Organic-like Films and Grafted PNIPAAm Composite Hydrogel with Nanogold Particles for Promotion Thermal Resistive Properties

Chin-Yen Chou, Ko-Shao Chen, Win-Li Lin, Ying-Cian Ye, Shu-Chuan Liao

Subject: Chemistry And Materials Science, Surfaces, Coatings And Films Keywords: nano-Au particles; NIPAAm hydrogel; plasma treatment; UV grafting

Online: 28 September 2016 (09:49:23 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202005.0199.v1

Revealing SARS-CoV-2 Functional Druggability Through Multi-Target Cadd Screening of Repurposable Drugs

Yash Gupta, Dawid Maciorowski, Raman Mathur, Catherine M. Pearce, David J. Ilc, Hamza Husein, Ajay Bharti, Daniel Becker, Rathi Brijesh, Steven B Bradfute, Ravi Durvasula, Prakasha Kempaiah

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: SARS-CoV-2; COVID-19; CADD; virtual screening; approved drugs; drug repurposing; essential targets; molecular docking; molecular dynamics simulations

Online: 11 May 2020 (13:14:18 CEST)

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The emergence of SARS/MERS drug resistant COVID-19 with high transmission and mortality has recently been declared a deadly pandemic causing economic chaos and significant health problems. Like all coronaviruses, SARS-CoV-2 is a large virus that has many druggable components within its proteome. In this study, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes within SARS-CoV-2. We shortlisted seven target proteins with enzymatic activities known to be essential at different stages of the virus life cycle. For virtual screening, the energy minimization of a crystal structure or modeled protein was carried out using Protein Preparation Wizard (Schrödinger LLC, 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are already approved by worldwide regulatory bodies including the FDA, using the ZINC database. Screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. A top lead from each target group was further subjected to molecular dynamics simulation (MDS) using the Desmond module to validate the efficacy of the screening pipeline. All of the simulated hit-target complexes were predicted to strongly interact and with highly stable binding. Thus, we have identified a number of approved and investigational drugs with high likelihood of inhibiting a variety of key SARS-CoV-2 proteins. Follow-up studies will continue to identify inhibitors suitable for combination therapy based on drug-drug synergy to thwart resistance. In addition, the screening hits that we have identified provide excellent probes for understanding the binding properties of the active sites of all seven targets, further enabling us to derive consensus molecules through computer-aided drug design (CADD). While infections are expanding at a rampant pace, it must be recognized that resistance will grow commensurately through either genetic shift and/or genetic drift to all small molecule drugs identified. Vaccines should provide a more permanent solution through prevention, but resistivity is still a possible scenario. Nevertheless, a persistent multi-target drug development program is essential to curb this ongoing pandemic and to keep reemergence in check.

Preprint REVIEW | doi:10.20944/preprints202012.0062.v1

Recent Advances in Trop 2 Targeted Therapy for Solid Tumors

Shutan Liao, Bing Wang, Rong Zeng, Haifeng Bao, Xiaomin Chen, Rakesh Dixit, Xiaoyan Xing

Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Trop 2; targeted therapy; antibody-drug conjugate; solid tumors

Online: 2 December 2020 (12:35:36 CET)

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Preprint ARTICLE | doi:10.20944/preprints202009.0459.v1

SARS-CoV-2 Infections - Gene Expression Omnibus (GEO) Data Mining, Pathway Enrichment Analysis, and Prediction of Repurposable Drugs/Compounds

Srilakshmi Chaparala, Carrie L Iwema, Ansuman Chattopadhyay

Subject: Biology And Life Sciences, Virology Keywords: COVID-19; coronavirus; drug repositioning; pathway enrichment

Online: 19 September 2020 (11:34:12 CEST)

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Preprint ESSAY | doi:10.20944/preprints201611.0142.v1

Seasonal Applicability of Three Plant Constructed Wetlands for Nutrient Removal in Pilot Scale

Farham Aminsharei, Seyed Mehdi Borghei, Reza Arjomandi, Jafar Nouri, Alireza Pendashteh

Subject: Environmental And Earth Sciences, Environmental Science Keywords: sub-surface flow constructed wetland; nutrient removal; wastewater treatment; Lactuca sativa; Medicago sativa; Phragmites australis

Online: 28 November 2016 (10:34:49 CET)

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Preprint REVIEW | doi:10.20944/preprints202004.0372.v1

Pathogenesis, Diagnosis and Possible Therapeutic Options for COVID-19

Yusha Araf

Subject: Biology And Life Sciences, Virology Keywords: COVID-19; Diagnosis; Pathogenesis; Treatment; SARS-CoV-2

Online: 21 April 2020 (04:44:40 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202004.0466.v1

Angiotensin Converting Enzyme 2 in Coronavirus Disease (COVID-19): Evidence from Bioinformatics Analysis

Xiaomei Yang, Hongjin Zhao, Yan Li, Peng Zhang

Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: COVID-19; coronavirus; ACE2; bioinformatics analysis; drug prediction

Online: 26 April 2020 (03:14:50 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201809.0544.v1

Peak Week and Competition Day Strategies of Competitive Natural Bodybuilders

Andrew J Chappell , Trevor Simper

Subject: Biology And Life Sciences, Food Science And Technology Keywords: Bodybuilding; Drug Free; Competing; Peaking; Carbohydrate Loading; Water Loading; Sodium Loading; Fat Loading: Vitamin C; Fibre Restriction

Online: 27 September 2018 (12:58:34 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201704.0019.v1

Influence of Plasma Treatment to the Performance of Amorphous IGZO based Flexible Thin Film Transistors

Long-long Chen, Xiang Sun, Ji-feng Shi, Xi-feng Li, Xing-wei Ding, Jian-Hua Zhang

Subject: Physical Sciences, Fluids And Plasmas Physics Keywords: TFTs; IGZO; flexible; plasma treatment

Online: 4 April 2017 (09:44:42 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201704.0023.v1

Effects of Biomimetic Shear Stress by Self-Assembled Gelatin Oleic Nanoparticles Containing Paclitaxel on the Behavior of Cancer Cell Lines in a Microfluidic System

Taehee Kang, Thuy Thi Thanh Tran, Kyung Taek Oh, Han-Gon Choi, Beom-Jin Lee

Subject: Chemistry And Materials Science, Nanotechnology Keywords: gelatin-oleic conjugate; self-assembled biodegradable nanoparticles; biomimetic shear stress; cell dynamic environment; cellular drug delivery; paclitaxel

Online: 4 April 2017 (10:59:02 CEST)

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Preprint REVIEW | doi:10.20944/preprints201702.0036.v1

Nanoparticle-Mediated Drug Delivery System for Pulmonary Arterial Hypertension

Kazufumi Nakamura, Hiromi Matsubara, Satoshi Akagi, Toshihiro Sarashina, Kentaro Ejiri, Norifumi Kawakita, Masashi Yoshida, Toru Miyoshi, Atsuyuki Watanabe, Nobuhiro NIshii, Hiroshi Ito

Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: pulmonary arterial hypertension; prostacyclin; nanoparticle; drug delivery system

Online: 13 February 2017 (09:27:09 CET)

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Preprint REVIEW | doi:10.3390/sci2030068

Perspectives on Topical Medical Research in the COVID-19 Era

Michael McAleer

Subject: Medicine And Pharmacology, Tropical Medicine Keywords: COVID-19; pooling clinical trials; hyperinfection; steroids; treatment; targeted healthcare; population health management; cancer treatment; clinical research; clinical trials; developing vaccines; ranking and rating hospital quality; school closures; interventions for delirium; assessments of COVID-19 death inequities; regulatory safeguards; preventing child abuse and maltreatment; prevalence of health care worker burnout; nursing home ratings; challenging oncology practice; addressing racial; ethnic; social and economic divides; violence against sexual minority adolescents; primary tumors; metastasis; stages of cancer; reforming cancer clinical trials; supporting carers; protection and prevention; benign and malignant tumors; reforming cancer clinical trials; protection of healthcare personnel; comparing excess deaths in NYC; 1918 influenza pandemic; the possibility of full recovery from COVID-19; mental health impact of COVID-19 on young adults; ranking and rating nursing home quali

Online: 21 August 2020 (00:00:00 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201610.0083.v1

UPEI-400, a Conjugate of Lipoic Acid and Scopoletin, Mediates Neuroprotection in a Rat Model of Ischemia/Reperfusion

Barry J. Connell, Monique C. Saleh, Desikan Rajagopal, Tarek M. Saleh

Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: stroke; antioxidant; co-drug; animal model

Online: 20 October 2016 (08:46:38 CEST)

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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.

Preprint REVIEW | doi:10.20944/preprints202006.0027.v1

Artificial Intelligence and Drones to Combat COVID - 19

T Preethika, P Vaishnavi, J Agnishwar, K Padmanathan, S Umashankar, S Annapoorani, M Subash, K Aruloli

Subject: Engineering, Control And Systems Engineering Keywords: COVID-19; pandemic; Artificial Intelligence; prevention; testing; treatment

Online: 4 June 2020 (06:30:35 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202006.0358.v1

In-Silico Analysis of Natural Products That Modulates Enzymes of Diabetic Target

Babita Aryal, Saroj Basnet, Bishnu P. Marasini, Karan Khadayat, Darbin Kumar Poudel, Ganesh Lamichhane, Prakriti Budhathoki, Purushottam Niraula, Sonika Dawadi, Rishab Marahatha, Sitaram Phuyal, Niranjan Parajuli

Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: Enzyme inhibition; Secondary Metabolites; In-silico Analysis; Molecular docking; Drug candidates

Online: 30 June 2020 (08:11:28 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202003.0393.v1

Virtual Screening and Molecular Dynamics Simulation Suggest Valproic Acid Co-A could Bind to SARS-CoV2 RNA Depended RNA Polymerase

Neel Sarovar Bhavesh, Anupam Patra

Subject: Biology And Life Sciences, Biophysics Keywords: SARS-CoV2; RNA depended RNA polymerase; Valproic acid Co-A; drug repurposing

Online: 26 March 2020 (15:04:22 CET)

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Preprint ARTICLE | doi:10.20944/preprints201706.0116.v1

Fog Computing in Medical Internet-of-Things: Architecture, Implementation and Applications

Harishchandra Dubey

Subject: Computer Science And Mathematics, Computer Networks And Communications Keywords: big data； body area network；body sensor network；edge computing；Fog Computing； Medical Cyberphysical Systems； medical internet-of-things；telecare； tele-treatment；wearable devices

Online: 26 June 2017 (06:24:07 CEST)

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In the era when the market segment of Internet of Things (IoT) tops the chart in various business reports, it is apparently envisioned that the field of medicine expects to gain a large benefit from the explosion of wearables and internet-connected sensors that surround us to acquire and communicate unprecedented data on symptoms, medication, food intake, and daily-life activities impacting one’s health and wellness. However, IoT-driven healthcare would have to overcome many barriers, such as: 1) There is an increasing demand for data storage on cloud servers where the analysis of the medical big data becomes increasingly complex; 2) The data, when communicated, are vulnerable to security and privacy issues; 3) The communication of the continuously collected data is not only costly but also energy hungry; 4) Operating and maintaining the sensors directly from the cloud servers are non-trial tasks.This book chapter defined Fog Computing in the context of medical IoT. Conceptually, Fog Computing is a serviceoriented intermediate layer in IoT, providing the interfaces between the sensors and cloud servers for facilitating connectivity, data transfer, and queryable local database. The centerpiece of Fog computing is a low-power, intelligent, wireless, embedded computing node that carries out signal conditioning and data analytics on raw data collected from wearables or other medical sensors and offers efficient means to serve telehealth interventions. We implemented and tested an fog computing system using the Intel Edison and Raspberry Pi that allows acquisition, computing, storage and communication of the various medical data such as pathological speech data of individuals with speech disorders, Phonocardiogram (PCG) signal for heart rate estimation, and Electrocardiogram (ECG)-based Q, R, S detection. The book chapter ends with experiments and results showing how fog computing could lessen the obstacles of existing cloud-driven medical IoT solutions and enhance the overall performance of the system in terms of computing intelligence, transmission, storage, configurable, and security. The case studies on various types of physiological data shows that the proposed Fog architecture could be used for signal enhancement, processing and analysis of various types of bio-signals.

Preprint ARTICLE | doi:10.20944/preprints201704.0028.v1

Synthesis of Europium-doped Fluorapatite Nanorods and Their Multifunctional Biomedical Applications

Hai Feng Zeng, Mu Yang Sun, Su Fan Wu, Hai Feng Chen

Subject: Chemistry And Materials Science, Nanotechnology Keywords: lanthanides; fluorapatite; drug loading; nano carrier

Online: 5 April 2017 (11:26:48 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201702.0091.v1

A Novel Methods for Fracture Toughness Evaluation of Tool Steels with Post-Tempering Cryogenic Treatment

Ramona Sola, Roberto Giovanardi, Paolo Veronesi, Giovanni Parigi

Subject: Chemistry And Materials Science, Metals, Alloys And Metallurgy Keywords: fracture toughness, scratch test, residual stress, tool steel, cryogenic treatment

Online: 24 February 2017 (14:46:47 CET)

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Preprint ARTICLE | doi:10.20944/preprints201612.0039.v1

The Wear Resistance of Cryogenically Treated Diamond-Like Carbon Films

Lee-Long Han, Chun-Ming Lin, Yih-Shiun Shih

Subject: Chemistry And Materials Science, Surfaces, Coatings And Films Keywords: Cryogenic treatment; wear resistance; Raman intensity rate

Online: 7 December 2016 (11:13:10 CET)

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Preprint REVIEW | doi:10.20944/preprints202008.0312.v1

Virion Structure and Mechanism of Propagation of Coronaviruses including SARS-CoV 2 (COVID -19 ) and some Meaningful Points for Drug or Vaccine Development

Swapan Ghosh

Subject: Biology And Life Sciences, Virology Keywords: SARS-CoV-2(COVID-19); + ssRNA; ribosomal – framshift; Pseudoknot; replication; model; drug; vaccine

Online: 14 August 2020 (08:26:31 CEST)

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SARS-CoV-2 or COVID-19, a new seventh human corona virus, has out-broken in Wuhan, China since 31^st December 2019, and quickly escalated to take the form of pandemic which killed many human beings throughout almost all countries across continents. The rapidity of its transmission from human to human is far greater than all previous human corona viruses which came into existence like SARS-CoV, MERS-CoV, etc. The nucleotide sequence of SARS-CoV-2 (isolates Wuhan-Hu-1) is 29,875 bp in ss-RNA. Symptoms of SARS-CoV-2 infected pneumonia include from asymptomatic to high fever and/or respiratory illnesses. Coronavirus virion (spherical/round /elliptical in shape) consists of three parts- outer membrane or envelope, nucleocapsid and genome (RNA). SARS-CoV-2 was shown to use receptor, angiotensin converting enzyme 2 (ACE2) for attachment to the cells through its surface spike (S) protein (S1), and the virion enters into the host cell through two routes- direct membrane fusion and endocytotic pathway. The RNA of SARS-CoV acts directly as mRNA and here minus(-) 1 programmed ribosomal frameshift (-1PRF) is being operated by slippery sequence and pseudoknot, so it translates 16 nonstructural proteins including RNA dependent RNA replicase. Then genomic RNA replicated continuously on – strand RNA template and subgenomic RNA transcribed discontinuously on –RNA template to sgmRNA. Subgenomic RNAs/sgmRNAs synthesize all structural proteins. This article takes into consideration the details of established theories of viral structure, viral attachment, mode of entry into human cells, different models of replication and transcription of virus genome proposed by eminent scientists over the years, and makes an in depth examination highlighting meaningful points or important target cites of viral propagation or synthesis, which are conserved, for prompt development of potent drugs or vaccine to counter COVID-19 for which human race is anxiously and eagerly waiting.

Preprint ESSAY | doi:10.20944/preprints201704.0120.v2

Synthesis and Anti-Tumor Activity of Oleanolic Acid Derivatives

Kuai ZhenYu, Lei Li, Shengwen Zhan, Chunlin Li, Yuwei Zhao, Hongrong Chen, Yanqiu Meng

Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: oleanolic acid derivatives; synthesis; anti-tumor activity; molecular docking; computer-aided drug design

Online: 24 April 2017 (12:08:36 CEST)

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Preprint REVIEW | doi:10.20944/preprints202004.0207.v1

Chinese Guidelines Related to Novel Coronavirus Pneumonia

Tingting Qiu, Shuyao Liang, Monique Dabbous, Yitong Wang, Ru Han, Mondher Toumi

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Chinese Guidelines; COVID-19; pharmaceutical treatment

Online: 13 April 2020 (03:43:37 CEST)

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Background and Objective: China has managed to control the coronavirus disease (COVID-19) with confinement measurements and treatment strategies, while other countries are struggling to contain the spread. This study discusses the guidelines related to COVID-19 in China in order to provide important references for other countries in the fight against COVID-19. Methods: Chinese guidelines relevant to COVID-19 were systematically searched via the China National Knowledge Infrastructure database, YiMaiTong database, and World Health Organization (WHO) COVID-19 database on March 20^th, 2020. Guideline information was extracted, including date of publication, source, objectives and the target population. Guidelines specific to the pharmacological treatment of COVID-19 were further investigated to identify the types of antivirus drugs recommended and to report on how treatment recommendations for COVID-19 have evolved overtime. Results: A total of 114 guidelines were identified, of which 87 were national guidelines and 27 were regional guidelines. The scope of included guidelines consisted of: the diagnosis and treatment of COVID-19, the management of hospital departments and specific diseases during the outbreak of COVID-19. Sixty-four of the included guidelines targeted all COVID-19 patients, while the remaining guidelines concentrated on special patient populations (i.e., geriatric population, pediatric population, and pregnant population) or patients with coexisting diseases. Twenty-three guidelines focused on the pharmacological treatments for all COVID-19 patients. Interferon, Lopinavir/Ritonavir, Ribavirin, Chloroquine, and Umifenovir represented the most recommended antivirus drugs. With the emergence of encouraging results from preclinical and preliminary clinical studies, Chloroquine Phosphate was recommended in the national Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (6^th version) on February 19^th, 2020. Thereafter, more detailed guidelines regarding the adjustment of dosage regimens and the monitoring of adverse events of Chloroquine Phosphate were published. To date, 8 Chinese guidelines have recommended Chloroquine Phosphate or Hydroxychloroquine as mainstream antivirus drug for the treatment of COVID-19. Conclusions: China has generated a plethora of guidelines covering almost all aspects of COVID-19. Chloroquine, as one widely affordable treatment, holds great potential to become the gold standard choice as more clinical evidence is shared by researchers from China as well as other countries.

Preprint ARTICLE | doi:10.20944/preprints201703.0228.v1

Hydrogen Storage Characteristics and Corrosion Behavior of V-rich Ti-V-Cr-Fe Alloy

Jimoh Mohammed Abdul, Lesley Hearth Chown, Jamiu K. Odusote, Jean Nei, Kwo-Hsiung Young, Woli Taiye Olayinka

Subject: Chemistry And Materials Science, Chemical Engineering Keywords: Ti-V-Cr-Fe alloy; hydrogen storage characteristics; metal corrosion; heat treatment; crystal structure

Online: 31 March 2017 (09:19:32 CEST)

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Preprint REVIEW | doi:10.20944/preprints202310.0637.v1

A Systematic Analysis of the Effectiveness of Mitochondrial-Based Therapies for the Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Leif Gerrit Keferstein

Subject: Medicine And Pharmacology, Clinical Medicine Keywords: Myalgic Encephalomyelitis; chronic fatigue syndrome; therapeutic strategies; personalized treatment; pathophysiology; pharmacological treatments; nutritional supplements; dietary changes; physical therapies; lifestyle modifications

Online: 10 October 2023 (11:23:01 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201706.0132.v1

In Silico Screening and Analysis of Potential Inhibitors of Arylamine N-Acetyltransferases (NATs) from the Traditional Chinese Medicine: A Study Using Free Available Tools

Francisco Azevedo, Joveline Richardt, Mayrla Oliveira, Inês Araujo, Ricardo Oliveira, Luis Baptista, Hermes Amorim

Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: arylamine N-acetyltransferases; cancer; tuberculosis; drug discovery; traditional Chinese medicine; virtual screening; molecular dynamics simulation; MM-PBSA

Online: 30 June 2017 (11:36:22 CEST)

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Preprint REVIEW | doi:10.20944/preprints202006.0232.v1

Repurposing of FDA Approved Drugs as COVID-19 Therapeutics: Safety Concerns and Contraindications of Drugs in Clinical Trials

Ravinder Naik Dharavath, Meenu Dutt, Sunil Kumar, Priya Badyal, Nitin Rawat, Tanzeer Kaur, Shweta Sharma, Mahendra Bishnoi, Kanwaljit Chopra

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Adverse drug reactions; Anti-COVID drugs; Coronavirus; Drug repurposing; Drug toxicity; Pharmacotherapy

Online: 18 June 2020 (12:43:43 CEST)

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Preprint REVIEW | doi:10.20944/preprints201801.0218.v1

Biodegradable and Biocompatible Polyhydroxyalkanoates (PHA): Auspicious Microbial Macromolecules for Pharmaceutical and Therapeutic Applications

Martin Koller

Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: Biocompatibility; Biodegradability; Biopolyesters; Biopolymers; Composites; Drug Release; Implants; Polyhydroxyalkanoates; Scaffolds; Tissue Engineering

Online: 23 January 2018 (16:49:05 CET)

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Preprint ARTICLE | doi:10.20944/preprints201902.0011.v1

Eradicating Metastatic Cancer and the Evolutionary Dynamics of Extinction

Robert Gatenby, Joel S. Brown

Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Cancer treatment, resistance to treatment, evolution of resistance, background extinctions

Online: 1 February 2019 (10:29:06 CET)

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Preprint REVIEW | doi:10.20944/preprints202104.0022.v2

Immunomodulation as a Potent COVID-19 Pharmacotherapy: Past, Present and Future

Decsa Medika Hertanto, Bayu Satria Wiratama, Henry Sutanto, Citrawati Dyah Kencono Wungu

Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: COVID-19; immunomodulation; immunology; immune system; pharmacotherapy; coronavirus; drug repurposing

Online: 1 July 2021 (12:59:44 CEST)

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Preprint REVIEW | doi:10.20944/preprints202102.0265.v1

Current Advances in Therapeutic Peptides: Past and Future Trends

Ramachandran Chelliah, Eric Banan-Mwine Daliri, Fazle Elahi, Su-Jung Yeon, Akanksha Tyagi, Deog-Hwan Oh

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Peptides; Clinical Practice; Drug Therapy; Therapeutic

Online: 10 February 2021 (15:51:13 CET)

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Preprint REVIEW | doi:10.20944/preprints202002.0198.v1

Suggestion of an Alternative Approach of Inhalation of Volatile Chemicals from Onion and Garlic for Isolated Patient of Mild Onset Infected Flu: Review and Communication

Huibing Tan, Ganqiu Wu, Xiaotong Li, Wei Hou

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: mild virus-infected flu; home-based treatment; inhalation of volatile chemicals; onion; garlic

Online: 15 February 2020 (14:38:20 CET)

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Preprint ARTICLE | doi:10.20944/preprints202004.0441.v1

Pulmonary Vesicle and Bullae Formation in Patients With COVID-19: Experiences from Wuhan

Hexiao Tang, Li Zhang, Yanhong Wei, Changsheng Li, Bo Hu, Jinping Zhao, Nahush A Mokadam, Hua Zhu, Jun Lin, Sufang Tian, Xuefeng Zhou

Subject: Medicine And Pharmacology, Pulmonary And Respiratory Medicine Keywords: Corona Virus Disease 2019; pulmonary vesicle; prognosis; surgical treatment

Online: 24 April 2020 (12:06:33 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201803.0222.v1

Microstructure and Properties of 2219 Aluminum Alloy under Compound Technologies of Friction-Stir-Welding, Heat-Treatment and Electromagnetic Forming

Zeyu Wang, Liang Huang, Jianjun Li, Xiaoxia Li, Hui Zhu, Fei Ma, Huijuan Ma, Junjia Cui

Subject: Chemistry And Materials Science, Metals, Alloys And Metallurgy Keywords: aluminum alloy; electromagnetic forming; friction stir welding; heat treatment; secondary phase

Online: 27 March 2018 (11:11:35 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201901.0026.v2

Life Perceptions, Problems and Psychological Wellbeing in Preadolescent and Adolescent Patients in Treatment for Leukemia Compared with Healthy Peers

Marta Tremolada, Ilaria Tamara Chiavetta

Subject: Social Sciences, Psychology Keywords: children; adolescents; leukemia; in treatment; healthy peers; life perceptions; psychological wellbeing; reported problems

Online: 4 February 2019 (13:52:19 CET)

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Preprint ARTICLE | doi:10.20944/preprints201705.0174.v1

Inhibitory Effects of Diclofenac on Steroid Glucuronidation in Vivo Do not Affect Hair-Based Doping Tests for Stanozolol

Gergely Zachár, Nawed I. K. Deshmukh, Andrea Petróczi, Andrea D. Székely, Iltaf Shah, James Barker, Declan P. Naughton

Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: steroid; metabolism; anti-inflammatory drug; inhibition

Online: 24 May 2017 (08:25:26 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201710.0143.v1

Thiopurine Drugs Repositioned as Tyrosinase Inhibitors

Joonhyuck Choi, You-Mie Lee, Jun-Goo Jee

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: cheminformatics; docking simulation; drug repositioning; thiopurine; tyrosinase

Online: 22 October 2017 (14:03:13 CEST)

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Preprint REVIEW | doi:10.20944/preprints202008.0320.v1

Data Science in Unveiling COVID-19 Pathogenesis and Diagnosis: Evolutionary Origin to Drug Repurposing

Jayanta Kumar Das, Giuseppe Tradigo, Pierangelo Veltri, Pietro H Guzzi, Swarup Roy

Subject: Computer Science And Mathematics, Artificial Intelligence And Machine Learning Keywords: Data Science; Machine Learning; Deep Learning; Genomics; COVID-19; Drug Discovery; Image Analysis; Interactomics; Epidemiology

Online: 14 August 2020 (11:01:56 CEST)

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Preprint REVIEW | doi:10.20944/preprints201807.0369.v1

Microbial Electrochemical Technologies for Wastewater Treatment: Principles and Evolution from Microbial Fuel Cells to Bioelectrochemical-Based Constructed Wetlands

Carlos A. Ramírez-Vargas, Amanda Prado, Carlos A. Arias, Pedro N. Carvalho, Abraham Esteve-Núñez, Hans Brix

Subject: Biology And Life Sciences, Plant Sciences Keywords: bioelectrochemical systems (BES); electroactive bacteria (EAB); extracelullar electron transfer (EET); microbial fuel cells (MFC); treatment wetlands

Online: 20 July 2018 (04:03:11 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201902.0037.v1

The Effect of Chemical Character of Ionic Liquids on Biomass Pre-Treatment and Posterior Enzymatic Hydrolysis

Joana R. Bernardo, Francisco M. Girio, Rafal Lukasik

Subject: Engineering, Energy And Fuel Technology Keywords: Biomass, valorisation, ionic liquid, crystallinity, enzymatic hydrolysis, pre-treatment

Online: 4 February 2019 (13:57:18 CET)

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Preprint REVIEW | doi:10.20944/preprints201705.0129.v1

Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory

Dongya Jia, Mohit Kumar Jolly, Prakash Kulkarni, Herbert Levine

Subject: Biology And Life Sciences, Biophysics Keywords: cell fate decision; cancer attractors; gene network dynamics; EMT; drug resistance; intrinsically disordered proteins

Online: 17 May 2017 (06:25:17 CEST)

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Waddington’s epigenetic landscape, a famous metaphor in developmental biology, depicts how a stem cell progresses from an undifferentiated phenotype to a differentiated one. The concept of “landscape” in the context of dynamical system theory represents a high-dimensional cell state space, in which each cell phenotype is considered as an “attractor” that is determined by interactions among multiple variables (molecular players), and is buffered against environmental fluctuations. Further, biological noise is thought to play an important role during these cell-fate decisions and in fact controls transitions between different phenotypes. Here, we discuss these phenotypic transitions in cancer from a dynamical systems perspective and invoke the concept of “cancer attractors” – hidden stable states of the underlying regulatory network that are not occupied by normal cells. Using epithelial-to-mesenchymal transition (EMT), cancer stem-like properties, metabolic reprogramming and the emergence of drug/hormone resistance as examples, we illustrate how phenotypic plasticity in cancer cells enables them to acquire hybrid phenotypes (such as hybrid epithelial/mesenchymal and hybrid metabolic phenotypes) that tend to be more aggressive and notoriously resilient to drug/hormone treatment. Furthermore, we highlight multiple factors that may give rise to phenotypic plasticity in cancer cells, such as (a) multi-stability or oscillatory behaviors governed by underlying regulatory networks involved in cell-fate decisions in cancer cells, and (b) network rewiring due to conformational dynamics of intrinsically disordered proteins (IDPs) that are highly enriched in cancer cells. We conclude by discussing why a therapeutic approach that promotes ‘recanalization’, i.e. the exit from “cancer attractors” and re-entry into “normal attractors”, is more likely to succeed rather than a conventional approach that targets individual molecules/pathways.

Preprint REVIEW | doi:10.20944/preprints201908.0271.v1

Insights from Molecular Dynamics Simulations for GPCR Drug Discovery

Ye Zou, John Ewalt, Ho-Leung Ng

Subject: Biology And Life Sciences, Biophysics Keywords: GPCRs; membrane protein; molecular dynamics; protein structure; drug design; biased-signaling pathway; allosteric sites

Online: 26 August 2019 (15:34:57 CEST)

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Preprint REVIEW | doi:10.20944/preprints202206.0147.v3

The DARPin Encyclopedia: from Basic Research towards Therapeutics

Philipp Wild, Rohan Eapen, Patrik Forrer, Christian Jost

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Designed Ankyrin Repeat protein; DARPin; drug development; ensovibep; abicipar pegol

Online: 21 June 2022 (10:21:27 CEST)

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The adaptive immune system in vertebrates comes in two flavors. Historically, adaptive immunity focused on the study of immunoglobulins (also referred to as Ig-based antibodies herein); more recently, jawless vertebrates were found to use an entirely different class of proteins for their adaptive immunesystem. Specifically, these organisms express variable lymphocyte receptors (so called VLR antibodies) that create diversity based on the rearrangement of leucine-rich repeats. Meanwhile, various, naturally occurring repeat motifs have been used as building blocks for the design of artificial binding scaffolds which, among others, include designed ankyrin repeat proteins (DARPins). Such binding scaffolds are also referred to as non-Ig-based antibodies or non-Ig scaffolds herein). DARPins display several benefits such as a low molecular weight (~15 kDa), high thermal stability, high specificity and affinity, versatility (e.g., in terms of valency and multi-specificity), speedy preclinical development, low production costs and, thus, bear the potential to not only complement existing therapeutic Ig-based antibodies but also open up novel therapeutic strategies. The first generation DARPin therapeutic abicipar pegol has completed two Phase III studies in 2020 while several other DARPin drug candidates are currently undergoing clinical validation. Most recently, the rapid development of tri-specific SARSCoV-2 DARPin therapeutics showcases the immense potential of recombinant repeat proteins in adopting quickly e.g., new forms of target neutralization that a single Ig-based antibody cannot afford. Here, we highlight the design principles of repeat proteins in general and summarize in detail the continuous advancements of the DARPin scaffold that made it one of the most promising antibody mimetics to date. This review provides an overview of current and emerging applications of DARPins as both a research tool and therapeutic drug that can match or even surpass Ig-based antibody applications.

Preprint ARTICLE | doi:10.20944/preprints202104.0395.v1

SynPred: Prediction of Drug Combination Effects in Cancer using Full-Agreement Synergy Metrics and Deep Learning

António J. Preto, Pedro Matos-Filipe, Joana Mourão, and Irina S. Moreira

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Deep-Learning; Interpretability; Omics; Biophysics; Drug Synergy; Cancer

Online: 14 April 2021 (17:44:40 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201712.0024.v1

Characterization of HIV-1 near Full-Length Proviral Genome Quasispecies from Patients with Undetectable Viral Load Undergoing First-Line HAART Therapy

Brunna M. Alves, Juliana D. Siqueira, Marianne M. Garrido, Ornella M. Botelho, Isabel M. Prellwitz, Sayonara R. Ribeiro, Esmeralda A. Soares, Marcelo A. Soares

Subject: Biology And Life Sciences, Virology Keywords: HIV-1; quasispecies; minority resistance mutations; HAART; drug resistance; undetectable viral load

Online: 4 December 2017 (09:34:16 CET)

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Preprint ARTICLE | doi:10.20944/preprints201612.0093.v1

The Effect of Membrane Material and Surface Pore Size on the Fouling Properties of Submerged Membranes

Sungil Jeon, Saeid Rajabzadeh, Ryo Okamura, Toru Ishigami, Susumu Hasegawa, Noriaki Kato, Hideto Matsuyama

Subject: Engineering, Chemical Engineering Keywords: membrane bioreactor (MBR); membrane fouling; hollow fiber membrane; hydrophilicity; hydrophobicity; wastewater treatment

Online: 18 December 2016 (10:04:27 CET)

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Preprint REVIEW | doi:10.20944/preprints202004.0526.v1

A snapshot on COVID-19: A review

Mahfuz Al Mamun, Kaiissar Mannoor, Tahmina Shirin, Meerjady Sabrina Flora, Firdausi Qadri, Lili Ren, Jianwei Wang

Subject: Biology And Life Sciences, Virology Keywords: COVID-19; SARS-CoV-2; origin; transmission; epidemiology; signs and symptoms; diagnosis; treatment and prevention.

Online: 30 April 2020 (10:47:14 CEST)

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Preprint ARTICLE | doi:10.20944/preprints202107.0229.v1

Isocratic Reverse-Phase HPLC Method for Determination of Aspirin, Paracetamol, and Naproxen

Md. Mynul Hassan, Sung-Wook Nam

Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: HPLC; NSAIDs; Isocratic; Short column; Drug mixture

Online: 9 July 2021 (15:23:57 CEST)

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Preprint ARTICLE | doi:10.20944/preprints201901.0250.v1

Nano PGE1 Enhances Phosphorylation of ERK1/2 and Akt to Promote Recovery from Motor Dysfunction and Muscle Atrophy Induced by Sciatic Nerve Injury

Mitsuko Takenaga, Tsutomu Ishihara, Jun Niimi, Akemi Hamaguchi, Teita Asano, Reiko Tsuchiya, Yuki Ohta, Tohru Mizushima, Kazuo Yudoh

Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: drug delivery system, muscle atrophy, nanoparticle, prostaglandin E1, sciatic nerve injury

Online: 24 January 2019 (08:51:02 CET)

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Preprint REVIEW | doi:10.20944/preprints202102.0619.v1

Smart Nanoparticles in Biomedicine: An Overview of Recent Developments and Applications

Simona Campora, Giulio Ghersi

Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: Nanotechnology 1; Nanomedicine 2; organic and inorganic nanoparticles 3; drug delivery 4; antitumour therapy5; tissue engineering 6.

Online: 26 February 2021 (13:31:45 CET)

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Preprint ARTICLE | doi:10.20944/preprints201705.0068.v1

Treated Greywater Reuse for Hydroponic Lettuce Production in a Green Wall System – Quantitative Health Risk Assessment

Fasil Ejigu Eregno, Melesse Eshetu Moges, Arve Heistad

Subject: Environmental And Earth Sciences, Environmental Science Keywords: Source separation system; Greywater treatment; Water reuse; Hydroponic system; Green wall; Heavy metals bioaccumulation; QMRA; Health risk assessment

Online: 8 May 2017 (17:39:16 CEST)

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Preprint REVIEW | doi:10.20944/preprints201711.0204.v1

Pediatric Thermal Burns and Treatment: A Review of Progress and Future Prospects

Elton Mathias, Madhu Srinivas Murthy

Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: burns; treatment; pediatric; autograft; biological skin substitute; thermal

Online: 30 November 2017 (14:12:10 CET)

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Preprint REVIEW | doi:10.20944/preprints202012.0452.v1

An Update on Self-Amplifying mRNA Vaccine Development

Anna Blakney, Andrew Geall, Shell Ip

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: RNA; self-amplifying RNA; replicon; vaccine; drug delivery

Online: 18 December 2020 (11:12:44 CET)

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Preprint ARTICLE | doi:10.20944/preprints202106.0169.v1

CD133 Promotes Resistance to Trametinib in Melanoma Stem Cells by Activating an AKT / BCL-2 Survival Pathway

Cynthia Marie Simbulan-Rosenthal, Yogameenakshi Haribabu, Sahar Vakili, Li-Wei Kuo, Havens Clark, Ryan Dougherty, Ryyan Alobaidi, Bonnie C. Carney, Peter Sykora, Dean Scott Rosenthal

Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: melanoma initiating cells; CD133; drug resistance; apoptosis; caspase activation; CRISPR-Cas9 knockout; AKT; BAD; BCL-2 family

Online: 7 June 2021 (12:11:10 CEST)

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Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MIC), implicated in tumorigenesis, invasion, and drug resistance, and characterized by elevated expression of stem cell markers, such as CD133. We previously showed that siRNA knockdown of CD133 enhances apoptosis induced by the MEK inhibitor trametinib in melanoma cells. The current study investigates underlying mechanisms of CD133’s anti-apoptotic activity in patient-derived BAKP and POT cells, harboring difficult-to-treat NRASQ61K and NRASQ61R drivers, after CRISPR-Cas9 CD133 knockdown or Dox-inducible expression of CD133. To maintain stable expression of CD133, MACS-sorted CD133(+) positive cells were expanded by ROCK-mediated conditional reprogramming of BAKP melanoma cells (BAKR). BAKR showed increased survival via reduced apoptosis after exposure to trametinib or DTIC, compared to BAKP. CRISPR-Cas9- mediated CD133 knockdown in BAKR cells (BAKR-T3) re-sensitized the cells, while CRISPR-Cas9 knockdown of CD133 in parental BAKP and POT cells even further increased trametinib-induced apoptosis (cleaved PARP) by reducing levels of anti-apoptotic BCL-xL, p-AKT, and p-BAD, and increasing pro-apoptotic BAD and active BAX. Dox-induced CD133 overexpression had the opposite effect, and blocked trametinib-induced apoptosis in both cell lines, coincident with elevated p-AKT, p-BAD, BCL-2 and BCL-xL and decreased levels of the active form of BAX and caspases-3 and -9. The roles of CD133 in AKT and BAD phosphorylation, or in the upregulation of anti-apoptotic BCL-2 family members, was further investigated by AKT knockout with siRNA, or inhibition of BCL-2 family members with navitoclax (ABT-263). Similar to CD133 knockdown, AKT1/2 siRNA knockdown in BAKP cells also reduced p-BAD. CD133 knockdown (T3)-mediated reduction of pBAD levels was equivalent in AKT-knockdown or AKT control cells indicating that CD133 may be upstream of AKT signaling. In BAKP cells treated with trametinib and/or ABT-263, effects of ABT-263 mirrored CD133 knockdown, since levels of active BAX and cleaved-PARP in BAKP-SC (CD133-) cells increased to the same level as that exhibited by BAKP-T3 cells (CD133+). CD133 may therefore activate a survival pathway where 1) increased phosphorylation of AKT induces 2) phosphorylation and inactivation of BAD, 3) decrease in the active form of BAX, and 4) reduction in caspase-mediated PARP cleavage, indicating apoptosis suppression leading to drug resistance in melanomas. Targeting survival pathways by which CD133 may confer chemoresistance in MICs can contribute to development of more effective treatments for patients with high-risk melanoma.

Preprint ARTICLE | doi:10.20944/preprints201904.0093.v1

Identification of Research Priorities in Infertility and Assisted Reproduction: An International, Multicenter Study in Partnership with Patients

D García, F Lindenberg, E Toft, A La Marca, R Borrás, AR Lorenzon, MB Chehin, L Silva, ELA Motta, M Ripero, j Madero, RM Marinho, CA Oliveira, JPJ Caetano, A Bolívar, S Brazal, A Rodríguez, R Vassena

Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: Patients involvement; research interests; ART treatments; treatment personalization; psychological effects; healthy habits; fertility protection; infertility prevention; lifestyle; diet

Online: 8 April 2019 (12:46:17 CEST)

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STUDY QUESTION: Which are the main research interests among patients of assisted reproductive technologies (ART)? SUMMARY ANSWER: Patients identified as research priorities that deserve further investigation: success rates and risks of ART, side-effects of treatments, resources to cope with infertility, effectiveness of alternative therapies, lifestyle habits to protect fertility, oocyte quality and ovarian reserve, and causes of genetic or hereditary infertility. WHAT IS KNOWN ALREADY: The involvement of patients and caregivers in setting research agendas in medicine has gathered significant momentum in the last decade. Patients’ involvement in setting research priorities offers several benefits: improved patient knowledge and awareness of their condition; greater understanding of the medical professionals of the impact of the condition on patients’ quality of life; reduced costs associated with redundant research activities. This is may be also applicable to research in infertility and ART, where patients’ interests have never been explored before. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional study that consists of an anonymous online survey, which was sent up to three times to 2112 patients from 11 fertility centers in 5 countries between January-December 2018. The study design was based on the James Lind Alliance priority setting partnership model, which comprises the identification of patients groups, the exploration of the research agenda, the analysis of collected data and identification of priorities. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 2112 patients were contacted, and 945 surveys were answered (RR: 44.7%). Patients were asked to identify research questions relevant to them in the areas of infertility causes and prevention, fertility treatments (medication and ART), and the emotional aspects of infertility. Answers were categorized in topics and ranked by frequency. A long list of the top-30 research topics was extracted from the aggregate results, from which, a short list of the top-10 research topics was created. At the end, 10 research questions related to each of the 10 research topics were constructed, based on the answers given by patients. MAIN RESULTS AND THE ROLE OF CHANCE: Female (845, 89.4%) and male (100, 10.6%) patients were included. The mean age of patients was 37.8 (SD 1.74). Most of the patients did not have children at the time of the survey (523, 59%), while 51 (5.7%) were pregnant. Sixty (6.3%) patients did not start treatment, 579 (61.3%) were performing a treatment with their own gametes and 304 (32.2%) were treated through gamete donation. Patients were mainly interested in the effectiveness of ART -especially per clinical profile-, side effects of drugs, protection of fertility and prevention of infertility –especially through diet and exercise-, and psychological aspects of the infertility journey. The top-10 research questions (and weight) obtained were: 1) What are the side-effects of ART treatments? (41.6%); 2) What are the most effective methods to cope with infertility from the psychological point of view? (37.2%); 3) What effects could diet have on fertility? (25.9%); 4) What are ART success rates per clinical profile? (25.9%); 5) Are there habits and lifestyle factors that could prevent infertility? (20.0%); 6) What are the long-term risks associated to ART? (18.5%); 7) Are alternative therapies such as acupuncture, yoga, and meditation effective to treat/prevent infertility? (18.5%); 8) What is the impact of exercise on fertility? (15.4%); 9) How does oocytes quantity and quality affect fertility? (9.5%); 10) What are the genetic patterns or hereditary conditions causing/related to infertility? (9.5%). LIMITATIONS, REASONS FOR CAUTION: Although all respondents had attended a fertility center, not all of them were diagnosed as infertile (i.e. single women) and had started treatment at the time of response, while a few were pregnant; their priorities for research might have been influenced by their infertility journey. Also, all participants attended private fertility centers: areas of interest may be different in public settings. WIDER IMPLICATIONS FOR THE FINDINGS: Researchers and clinicians should keep in mind that, in addition to improvement of treatments’ success rates and side-effects, patients greatly value research on causes, prevention and emotional aspects of infertility. As their views might differ from those of medical professionals, patients’ voices should be incorporated in setting infertility research priorities.

Preprint REVIEW | doi:10.20944/preprints201808.0155.v1

Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms

Sofia Giorgetti, Claudio Greco, Paolo Tortora, Francesco Antonio Aprile

Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: amyloid diseases; biocomputing; drug design; natural antiamyloids

Online: 8 August 2018 (04:27:10 CEST)

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Preprint REVIEW | doi:10.20944/preprints201703.0093.v1

Potential Impact of Diet on Treatment Effect from Anti-TNF Drugs in Inflammatory Bowel Disease

Vibeke Andersen, Axel Kornerup Hansen, Berit Lilienthal Heitmann

Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: lifestyle factors; chronic inflammatory diseases; treatment result; treatment response; diet; meat intake; dietary pattern; food; mucosa associated bacteria; epithelium-associated bacteria; microbiome; fibre intake; personalized medicine; mucus; sulphate-reducing bacteria; mucin-degrading bacteria; Western style diet; anti-TNF

Online: 15 March 2017 (07:29:13 CET)

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Preprint REVIEW | doi:10.20944/preprints202111.0271.v1

Review On Progress of 7xxx Series Aluminum Alloy Materials

Yuxin Dai, Liangming Yan, Jianpeng Hao

Subject: Chemistry And Materials Science, Materials Science And Technology Keywords: 7xxx superhard aluminum; Heat treatment technological; Alloy microstructure; Future direction

Online: 15 November 2021 (19:14:37 CET)

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Preprint ARTICLE | doi:10.20944/preprints201704.0170.v1

Cellular Morphology-Mediated Proliferation and Drug Sensitivity of Breast Cancer Cells

Ryota Domura, Rie Sasaki, Yuma Ishikawa, Masami Okamoto

Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: Spreading parameter; Cellular proliferation; Drug sensitivity; Substrates; Cancer cells

Online: 26 April 2017 (17:38:07 CEST)

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