- The COVID-19 pandemic era impact on the incidence of the custodial death, due to illness in 36 states and union territories of India-A comparison study (2017–2022) -
Abstract: Mahatma Gandhi said that “crime is due to diseased mind and jail should have an environment like hospitals for prisoner’s treatment and care”. A lot of research is carried out globally during COVID-19, on the well being of peoples staying outside the prisons, but very few large scale researches are available to know about the well being of the prisoners during COVID-19 era. The data is provided by the Prison Section of all the 36 States/UTs in prearranged Performa of the NCRB, through an application made by NCRB. A total of 11,289 custodial death occurred among the prisoners residing in various prisons of India, during the study period, out of which 9,406 (83.32 percent, Total-9406 (Obs-216, Mean-43.55, Std. Dev.- 68.87, Min-0, Max-401, Std. Err.- 4.69, 95% Conf. Interval of mean-34.31 -52.78) mortalities were attributed due to illness. Compared to year 2020, our study revealed that the COVID-19 year 2021 has attributed to largest (16.47 percent increased illness custodial death and 12.14 percent increased total mortalities) number of custodial death due to illness. The study revealed that during the study period, majority of the mortalities were due to heart diseases in prisoners (27.28 percent, Total-2566 (Obs-216, Mean-11.88, Std. Dev.- 19.30, Min-0, Max-123, Std. Err.- 1.31, 95% Conf. Interval of mean-9.29 -14.47). Cholera / Diarrhoea attributed to the least number of mortalities during the study period (0.21 percent, Total-20 (Obs-216, Mean-0.09, Std. Dev. - 0.40, Min-0, Max-4, Std. Err. - 0.03, 95% Conf. Interval of mean-.04 -.15). This six years of study revealed that most of the custodial death (42%), due to illness in prisoners of India was due to CVDs and pulmonary diseases. This study also revealed that 27% of custodial deaths due to illness were not clearly categorized. Honourable Justice Lokur, of Supreme Court of India, said in a landmark judgment, in 2013, that “The distinction made by the NCRB [National Crime Records Bureau] between natural and unnatural custodial deaths is not clear. For example, if a prisoner dies due to a lack of proper medical attention or timely medical attention, would that be classified as a natural custodial death or an unnatural custodial death?” The policymakers and decision-makers must think on the necessity of developing Prisoners care policies following the COVID-19 pandemic, in light of the findings of this research study.
- Who has the flu? Early winter 2023-24 spread of flu and COVID-19 -
Winter 2023-24 has seen an unusual confluence of a variety of respiratory illnesses, ranging from flu to RSV (Respiratory Syncytial Virus) and COVID-19. Between December 21, 2023 and January 29, 2024, we surveyed 30,460 individuals aged 18 and older across all 50 states plus the District of Columbia. We asked them if they had experienced an Influenza-like Illness (ILI) defined as experiencing a fever and cough, or a fever and sore throat, and/or if they had been diagnosed with COVID-19, over the previous month. Amongst those who responded yes to such questions, we asked them whether or not they had sought medical attention. In this report, we summarize our findings across a variety of demographic subgroups, including age, race, education, income, gender, and geography.
- Thymidine Phosphorylase Mediates SARS-CoV-2 Spike Protein Enhanced Thrombosis in K18-hACE2TG Mice -
COVID-19, caused by SARS-CoV-2, is associated with arterial and venous thrombosis, thereby increasing mortality. SARS-CoV-2 spike protein (SP), a viral envelope structural protein, is implicated in COVID-19-associated thrombosis. However, the underlying mechanisms remain unknown. Thymidine phosphorylase (TYMP), a newly identified prothrombotic protein, is upregulated in the plasma, platelets, and lungs of patients with COVID-19 but its role in COVID-19-associated thrombosis is not defined. In this study, we found that wild-type SARS-CoV-2 SP significantly promoted arterial thrombosis in K18-hACE2TG mice. SP-accelerated thrombosis was attenuated by inhibition or genetic ablation of TYMP. SP increased the expression of TYMP, resulting in the activation of signal transducer and activator of transcription 3 (STAT3) in BEAS-2B cells, a human bronchial epithelial cell line. A siRNA-mediated knockdown of TYMP inhibited SP-enhanced activation of STAT3. Platelets derived from SP-treated K18-hACE2TG mice also showed increased STAT3 activation, which was reduced by TYMP deficiency. Activated STAT3 is known to potentiate glycoprotein VI signaling in platelets. While SP did not influence ADP- or collagen-induced platelet aggregation, it significantly shortened activated partial thromboplastin time and this change was reversed by TYMP knockout. Additionally, platelet factor 4 (PF4) interacts with SP, which also complexes with TYMP. TYMP enhanced the formation of the SP/PF4 complex, which may potentially augment the prothrombotic and procoagulant effects of PF4. We conclude that SP upregulates TYMP expression, and TYMP inhibition or knockout mitigates SP-enhanced thrombosis. These findings indicate that inhibition of TYMP may be a novel therapeutic strategy for COVID-19-associated thrombosis.
- A specific phosphorylation-dependent conformational switch of SARS-CoV-2 nucleoprotein inhibits RNA binding -
The nucleoprotein (N) of SARS-CoV-2 encapsidates the viral genome and is essential for viral function. The central disordered domain comprises a serine-arginine-rich domain (SR) that is hyperphosphorylated in infected cells. This modification is thought to regulate function of N, although mechanistic details remain unknown. We use time-resolved NMR to follow local and long-range structural changes occurring during hyperphosphorylation by the kinases SRPK1/GSK-3/CK1, thereby identifying a conformational switch that abolishes interaction with RNA. When 8 approximately uniformly-distributed sites are phosphorylated, the SR domain competitively binds the same interface as single-stranded RNA, resulting in RNA binding inhibition. Phosphorylation by PKA does not prevent RNA binding, indicating that the pattern resulting from the physiologically-relevant kinases is specific for inhibition. Long-range contacts between the RNA-binding, linker and dimerization domains are also abrogated, phenomena possibly related to genome packaging and unpackaging. This study provides insight into recruitment of specific host kinases to regulate viral function.
- A pan-tissue, pan-disease compendium of human orphan genes -
Species-specific genes are ubiquitous in evolution, with functions ranging from prey paralysis to survival in subzero temperatures. Because they are typically expressed under limited conditions and lack canonical features, such genes may be vastly under-identified, even in humans. Here, we leverage terabytes of human RNA-Seq data to identify thousands of highly-expressed transcripts that do not correspond to any Gencode-annotated gene. Many may be novel ncRNAs although 80% of them contain ORFs that have the potential of encoding proteins unique to Homo sapiens (orphan genes). We validate our findings with independent strand-specific and single-cell RNA-seq datasets. Hundreds of these novel transcripts overlap with deleterious genomic variants; thousands show significant association with disease-specific patient survival. Most are dynamically regulated and accumulate selectively in particular tissues, cell-types, developmental stages, tumors, COVID-19, sex, and ancestries. As such, these transcripts hold potential as diagnostic biomarkers or therapeutic targets. To empower future discovery, we provide a compendium of these huge RNA-Seq expression data, and RiboSeq data, with associated metadata. Further, we supply the gene models for the novel genes as UCSC Genome Browser tracks.
- Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike -
The trimeric spike protein plays an essential role in the SARS-CoV-2 virus lifecycle, facilitating virus entry through binding to the cellular receptor angiotensin-converting enzyme 2 (ACE2) and mediating viral and host membrane fusion. The SARS-CoV-2 spike contains an allosteric fatty acid (FA) binding site at the interface between two neighbouring receptor-binding domains. This site, also found in some other coronaviruses, binds free fatty acids such as linoleic and oleic acid, and other small molecules. Understanding allostery and how this site modulates the behaviour of different regions in this protein could potentiate the development of promising alternative strategies for new coronavirus therapies. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to investigate allosteric effects and identify the communication pathways in the fully glycosylated spike in the original SARS-CoV-2 ancestral variant. The results reveal the allosteric networks that connect the FA site to important functional regions of the protein, including some more than 40 Angstroms away. These regions include the receptor binding motif, an antigenic supersite in the N-terminal domain, the furin cleavage site, the regions surrounding the fusion peptide and a second allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected connection between different allosteric sites. Notably, 65% of amino acid substitutions, deletions and insertions in the Alpha, Beta, Delta, Gamma and Omicron variants map onto or close to the identified allosteric pathways.
- The wide spectrum anti-inflammatory activity of andrographolide in comparison to NSAIDs: a promising therapeutic compound against the cytokine storm -
The challenges of the COVID-19 pandemic have highlighted an increasing clinical demand for safe and effective treatment options against an overzealous immune defence response, also known as the "cytokine storm". Andrographolide is a naturally derived bioactive compound with promising anti-inflammatory activity in many clinical studies. However, its cytokine-inhibiting activity, in direct comparison to commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), has not been extensively investigated in existing literature. The anti-inflammatory activities of andrographolide and common NSAIDs, such as diclofenac, aspirin, paracetamol and ibuprofen were measured on lipopolysaccharide (LPS) and interferon-{gamma} induced RAW264.7 cells. The levels of PGE2, nitric oxide (NO), TNF- & LPS-induced release of pro-inflammatory cytokines on differentiated human macrophage THP-1 cells were measured against increasing concentrations of andrographolide and aforementioned NSAIDs. The associated mechanistic pathway was examined on NF{kappa}B using flow cytometry on the human endothelial-leukocyte adhesion molecule (ELAM9) (E-selectin) transfected RAW264.7 cells with green fluorescent protein (GFP). Andrographolide exhibited broad and potent anti-inflammatory and cytokine-inhibiting activity in both cell lines by inhibiting the release of IL-6, TNF- and IFN-{gamma}, which are known to play a key role in the etiology of cytokine storm and the pathogenesis of inflammation. In comparison, the tested NSAIDs demonstrated weak or no activity against proinflammatory mediators except for PGE2, where the activity of andrographolide (IC50 = 8.8 M, 95% CI= 7.4 to 10.4 M) was comparable to that of paracetamol (IC50 = 7.73 M, 95% CI = 6.14 to 9.73 M). The anti-inflammatory action of andrographolide was associated with its potent downregulation of NF{kappa}B. The wide-spectrum anti-inflammatory activity of andrographolide demonstrates its therapeutic potential against cytokine storms as an alternative to NSAIDs.
- Early acquisition of S-specific Tfh clonotypes after SARS-CoV-2 vaccination is associated with the longevity of anti-S antibodies -
SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) {beta} sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). After the 2nd vaccination, T cell clonotypes highly responsive to recall S stimulation were polarized to follicular helper T (Tfh)-like cells in donors exhibiting sustained anti-S antibody titers (designated as “sustainers”), but not in “decliners”. Even before vaccination, S-reactive CD4+ T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic bacteria. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly-responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest that de novo acquisition of memory Tfh-like cells upon vaccination may contribute to the longevity of anti-S antibody titers.
- Integrating population-level and cell-based signatures for drug repositioning -
Genetics-informed drug repositioning presents a streamlined and cost-efficient way to broaden therapeutic options. However, leveraging the full spectrum of molecular signatures remains underexplored. We introduce TReD (Transcriptome-informed Reversal Distance), integrating population-level disease signatures robust to reverse causality and cell-based drug-induced response profiles. TReD embeds the disease signature and drug profile in a high-dimensional normed space, quantifying the reversal potential of candidate drugs in a disease-related cell screen assay. For illustration, we apply TReD to COVID-19 and type 2 diabetes (T2D). We identify 37 potential drugs against COVID-19, over 70% (27/37) with prior associations, and eight supported by clinical trials. For T2D, we observe reversal signals for 86 compounds on multiple disease signatures, with more than 40% supported by published literature. In summary, we propose a comprehensive genetics-anchored framework integrating population-level signatures and cell-based screens that can accelerate the search for new therapeutic strategies.
- Changes in risk perception during the COVID-19 pandemic in Southeast Alaska: Self-identified determinants of risk and protective behaviors -
Social and cultural context shapes how communities perceive health, well-being, and risk. Risk perception can change over time as a product of new information and improved understanding. We investigate risk perception and protective behaviors in Southeast Alaska during the first year of the COVID-19 pandemic. Surveys were circulated at two time points: (1) April-June 2020, before COVID-19 reached epidemic levels in the region, and (2) November 2020-February 2021. Ordinary least squares (OLS) regression models were used to analyze how demographic characteristics of the respondent population influenced risk perception. OLS models were again used to predict how individuals engaged in protective behaviors while controlling for risk perceptions. Controlling for demographic characteristics, risk perception increased as age increased for perceived risk of getting sick and dying from COVID-19, males perceived lower risk in general for all tested variables, and Alaska Native respondents perceived higher risk than non-Alaska Native respondents. Controlling for risk perception, results for protective behaviors were mixed; however, the strongest association identified was that knowing someone with a positive COVID-19 diagnosis increased protective behaviors. Between the two time points, risk perceptions increased significantly for variables related to oneself, others, and community members becoming infected with COVID-19. Protective behaviors like traveling less than normal, buying more cleaning products, and engaging in more subsistence gathering significantly increased. Identifying patterns of risk perception and protective behaviors, and especially how they change over time, are critical to developing place-specific public health recommendations, action, and preparedness plans against future infectious threats.
- Physical distancing and the perception of interpersonal distance in the COVID-19 crisis -
In the wake of the COVID-19 pandemic, it has been mandated to keep enlarged distances from others. We interviewed 136 German subjects over five weeks from the end of March to the end of April 2020 during the first wave of infections about their preferred interpersonal distance (IPD) before, during, and after the COVID-19 pandemic. In response to the pandemic, subjects adapted to distance requirements and preferred a larger IPD. This enlarged IPD was judged to persist after the crisis partially. People anticipated keeping more IPD to others even if there was no longer any risk of a SARS-CoV-2 infection. We also sampled two follow-up measurements, one in August, after the first wave had been flattened, and one in October 2020, at the beginning of the second wave. We discuss our findings in light of proxemic theory and an indicator for socio-cultural adaptation beyond the course of the pandemic.
- Maturing neutrophils of lower density associate with thrombocytopenia in Puumala orthohantavirus-caused hemorrhagic fever with renal syndrome -
Puumala orthohantavirus-caused hemorrhagic fever with renal syndrome (PUUV-HFRS) is characterized by strong neutrophil activation. Neutrophils are the most abundant immune cell type in the circulation and are specially equipped to rapidly respond to infections. They are more heterogenous than previously appreciated, with specific neutrophil subsets recently implicated in inflammation and immunosuppression. Furthermore, neutrophils can be divided based on their density to either low-density granulocytes (LDGs) or "normal density" polymorphonuclear cell (PMN) fractions. In the current study we aimed to identify and characterize the different neutrophil subsets in the circulation of PUUV-HFRS patients. PMNs exhibited an activation of antiviral pathways, while circulating LDGs were increased in frequency following acute PUUV-HFRS. Furthermore, cell surface marker expression analysis revealed that PUUV-associated LDGs are primarily immature and most likely reflect an increased neutrophil production from the bone marrow. Interestingly, both the frequency of LDGs and the presence of a "left shift" in blood associated with the extent of thrombocytopenia, one of the hallmarks of severe HFRS, suggesting that immature neutrophils could play a role in disease pathogenesis. These results imply that elevated circulating LDGs might be a general finding in acute viral infections. However, in contrast to the COVID-19 associated LDGs described previously, the secretome of PUUV LDGs did not show significant immunosuppressive ability, which suggests inherent biological differences in the LDG responses that can be dependent on the causative virus or differing infection kinetics.
- Confirmation of Covid Infection Status and Reporting of Long Covid Symptoms in a Population-Based Birth Cohort: No Evidence of a Nocebo Effect -
Some patients with COVID-19 develop symptoms after the acute infection, known as ‘Long COVID’. We examined whether or not confirmation of COVID-19 infection status could act as a nocebo, using data from questionnaires distributed to the Avon Longitudinal Study of Parents and Children cohort. We examined associations between confirmation of COVID-19 infection status (confirmed by a positive test versus unconfirmed) and reporting of Long COVID symptoms. We explored the roles of sex and anxiety as potential moderators. There was no clear evidence of a strong association between confirmation of COVID-19 infection status and the Long COVID composite score, physical or psychological symptoms, or duration of symptoms. There was no clear evidence of moderation by sex or anxiety. We therefore found no evidence of a nocebo effect. Our data suggest that this psychological mechanism does not play a role in the medical symptomatology experienced by patients with Long COVID.
- Affordable private rental supply and demand: short-term disruption (2016–2021) and longer-term structural change (1996–2021) -
This research analyses the ABS Census to reveal changes in the supply of private rental housing affordable and available to lower-income households (Q1 and Q2 households) over both the short term (2016–21) and the longer term (1996–2021). It also provides analysis of how COVID-19 policy and population responses temporarily altered the long-run structural trajectory of the private rental sector (PRS) in Australia. In 2021, the Australian PRS housed more than 2.363 million households, a 17 per cent increase of nearly 340,000 households since the 2016 Census. This growth has been greater than total household growth in each intercensal period since 1996. Between 2016 and 2021 PRS growth was concentrated at mid-market levels; in dwellings renting from around $300–$530 per week ($2021). This continues a major change trend first established in 2011, reinforcing the structural shift to a market concentration of dwellings renting at mid-to-higher levels. The long-term shift in the national distribution of PRS household incomes reveals the growth of households with incomes at mid to high levels ($1,246 a week and above). In 1996, these ‘wealthier’ households comprised 40 per cent of all PRS households (or 489,000 households); in 2021, they comprised 64 per cent (or 1,519,000 households), a 211 per cent increase. In comparison, the total number of PRS households increased by 91 per cent between 1996 and 2021 (from 1,234,000 households to 2,362,000). Over the same time frame, there has been a relatively constant total number of lower income renters in the PRS; 508,000 households in1996 and 488,000 in 2024. Nevertheless, there was a shortage of 348,000 affordable and available private rental homes for very-low income (Q1) households in 2021 and that, as a result, 82 per cent of Q1 PRS households paid unaffordable rents.
- COVID-19 and Changes in Young Adults’ Weight Concerns -
The COVID-19 pandemic introduced fundamental challenges to nearly all aspects of college students’ lives, yet changes in key domains of their health, including weight concerns, remain untested. The current study utilized a longitudinal project comprised of 355 young-adult college students (Mage=19.5, 66.8% female, 33.2% male) oversampled for recent substance use behavior. Participants completed multiple assessments (mode=5) from September 2017 to September 2021. Piecewise growth-curve models tested whether COVID-19 onset was associated with changes in the trajectories of young adults’ weight concerns. Analyses also examined participants’ sex as a moderator of these trajectories. On average, participants reported a significant increase in weight concern levels around the start of COVID-19, although weight concern slopes were not significantly different before and after COVID-19. Additionally, moderation analyses showed that females (but not males) had a significant increase in weight concern levels after COVID-19 onset.
GS-441524 for COVID-19 SAD, FE, and MAD Study in Healthy Subjects - Conditions: COVID-19
Interventions: Drug: GS-441524; Drug: Placebo
Sponsors: National Center for Advancing Translational Sciences (NCATS); Leidos Biomedical Research, Inc.; ICON Government and Public Health Solutions, Inc
Not yet recruiting
UNAIR Inactivated COVID-19 Vaccine INAVAC as Heterologue Booster (Immunobridging Study) in Adolescent Subjects - Conditions: COVID-19 Pandemic; COVID-19 Vaccines
Interventions: Biological: INAVAC (Vaksin Merah Putih - UA- SARS CoV-2 (Vero Cell Inactivated) 5 μg
Sponsors: Dr. Soetomo General Hospital; Indonesia-MoH; Universitas Airlangga; PT Biotis Pharmaceuticals, Indonesia
Active, not recruiting
The Aerobic Exercise Capacity and Muscle Strenght in Individuals With COVID-19 - Conditions: COVID-19 Pneumonia; COVID-19
Interventions: Device: Kardiopulmonary exercise test (Quark KPET C12x/T12x device connected to the Omnia version 1.6.8 COSMED system); Device: Peripheral muscle strength measurement (microFET3 (Hoggan Health Industries, Fabrication Enterprises, lnc) and JAMAR hydraulic hand dynamometer (Sammons Preston, Rolyon, Bolingbrook).; Device: Standard exercise tolerance test (a bicycle ergometer and recorded through the ergoline rehabilitation system 2 Version 1.08 SPI.); Device: Aerobic exercise training (a bicycle ergometer and recorded through the ergoline rehabilitation system 2 Version 1.08 SPI.)
Sponsors: Selda Sarıkaya; Zonguldak Bulent Ecevit University
Completed
World Health Organization (WHO) , COVID19 Case Series of Post Covid 19 Rhino Orbito Cerebral Mucormycosis in Egypt - Conditions: Mucormycosis; Rhinocerebral (Etiology); COVID-19
Interventions: Procedure: debridment
Sponsors: Nasser Institute For Research and Treatment
Completed
Treatment of Post-COVID-19 With Hyperbaric Oxygen Therapy: a Randomized, Controlled Trial - Conditions: Post-COVID-19 Syndrome; Post-COVID Syndrome; Post COVID-19 Condition; Post-COVID Condition; Post COVID-19 Condition, Unspecified; Long COVID; Long Covid19
Interventions: Drug: Hyperbaric oxygen
Sponsors: Erasmus Medical Center; Da Vinci Clinic; HGC Rijswijk
Not yet recruiting
Mindfulness-based Mobile Applications Program - Conditions: COVID-19; Cell Phone Use; Nurse; Mental Health
Interventions: Device: mindfulness-based mobile applications program
Sponsors: Yu-Chien Huang
Completed
Attention Training for COVID-19 Related Distress - Conditions: Anxiety
Interventions: Behavioral: Attention Bias Modification; Behavioral: Attention Control Training; Behavioral: Neutral training
Sponsors: Palo Alto University
Not yet recruiting
Correlation of Antibody Response to COVID-19 Vaccination in Pregnant Woman and Transplacental Passage Into Cord Blood. - Conditions: Covid-19
Interventions: Diagnostic Test: COVID-19 Spike Protein IgG Quantitative Antibody (CMIA)
Sponsors: Vachira Phuket Hospital
Recruiting
UNAIR Inactivated COVID-19 Vaccine as Homologue Booster (Immunobridging Study) - Conditions: COVID-19 Pandemic; COVID-19 Vaccines; COVID-19 Virus Disease
Interventions: Biological: INAVAC (Vaksin Merah Putih - UA- SARS CoV-2 (Vero Cell Inactivated) 5 μg
Sponsors: Dr. Soetomo General Hospital; Universitas Airlangga; Biotis Pharmaceuticals, Indonesia; Indonesia-MoH
Recruiting
Safety and Immunogenicity of a Sub-unit Protein CD40.RBDv Bivalent COVID-19 Vaccine, Adjuvanted or Not, as a Booster in Volunteers. - Conditions: COVID-19
Interventions: Drug: CD40.RBDv vaccin (SARS-Cov2 Vaccin)
Sponsors: ANRS, Emerging Infectious Diseases; LinKinVax; Vaccine Research Institute (VRI), France
Not yet recruiting
High-definition Transcranial Direct Current Ctimulation and Chlorella Pyrenoidosa to Reduce Cardiovascular Risk - Conditions: Cardiovascular Diseases; Long Covid19
Interventions: Other: High Definition-transcranial Direct Current Stimulation; Dietary Supplement: Chlorella Pyrenoidosa
Sponsors: Federal University of Paraíba; City University of New York
Recruiting
SGB for COVID-induced Parosmia - Conditions: COVID-19-Induced Parosmia
Interventions: Drug: Stellate Ganglion Block; Drug: Placebo Sham Injection
Sponsors: Washington University School of Medicine
Recruiting
Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1 - Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and…
Sulfated Glycans Inhibit the Interaction of MERS-CoV Receptor Binding Domain with Heparin - Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic virus with high contagion and mortality rates. Heparan sulfate proteoglycans (HSPGs) are ubiquitously expressed on the surface of mammalian cells. Owing to its high negatively charged property, heparan sulfate (HS) on the surface of host cells is used by many viruses as cofactor to facilitate viral attachment and initiate cellular entry. Therefore, inhibition of the interaction between viruses and HS could be a promising…
The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses - Although the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on (+)- and (-)-usnic acid and studied their ability to inhibit the main protease of SARS-CoV-2. Substances containing unsubstituted thiophene groups or methyl- or bromo-substituted thiophene moieties showed…
Human Betacoronavirus OC43 Interferes with the Integrated Stress Response Pathway in Infected Cells - Viruses evolve many strategies to ensure the efficient synthesis of their proteins. One such strategy is the inhibition of the integrated stress response-the mechanism through which infected cells arrest translation through the phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2α). We have recently shown that the human common cold betacoronavirus OC43 actively inhibits eIF2α phosphorylation in response to sodium arsenite, a potent inducer of oxidative…
Feasibility Study of Developing a Saline-Based Antiviral Nanoformulation Containing Lipid-Soluble EGCG: A Potential Nasal Drug to Treat Long COVID - CONCLUSION: Nanoformulations containing EC16 showed properties compatible with nasal application to rapidly inactivate SARS-CoV-2 residing in the olfactory mucosa and to reduce inflammation in the CNS, pending additional formulation and safety studies.
Identification of SARS-CoV-2 Main Protease Inhibitors Using Chemical Similarity Analysis Combined with Machine Learning - SARS-CoV-2 Main Protease (Mpro) is an enzyme that cleaves viral polyproteins translated from the viral genome, which is critical for viral replication. Mpro is a target for anti-SARS-CoV-2 drug development. Herein, we performed a large-scale virtual screening by comparing multiple structural descriptors of reference molecules with reported anti-coronavirus activity against a library with >17 million compounds. Further filtering, performed by applying two machine learning algorithms, identified…
Discovery of Pyrano[2,3-c]pyrazole Derivatives as Novel Potential Human Coronavirus Inhibitors: Design, Synthesis, In Silico, In Vitro, and ADME Studies - The SARS-CoV-2 pandemic at the end of 2019 had major worldwide health and economic consequences. Until effective vaccination approaches were created, the healthcare sectors endured a shortage of operative treatments that might prevent the infection’s spread. As a result, academia and the pharmaceutical industry prioritized the development of SARS-CoV2 antiviral medication. Pyranopyrazoles have been shown to play a prominent function in pharmaceutical chemistry and drug sighting because of their…
Silver Nanoparticles In Situ Synthesized and Incorporated in Uniaxial and Core-Shell Electrospun Nanofibers to Inhibit Coronavirus - In the present study, we sought to develop materials applicable to personal and collective protection equipment to mitigate SARS-CoV-2. For this purpose, AgNPs were synthesized and stabilized into electrospinning nanofiber matrices (NMs) consisting of poly(vinyl alcohol) (PVA), chitosan (CHT), and poly-ε-caprolactone (PCL). Uniaxial nanofibers of PVA and PVA/CHT were developed, as well as coaxial nanofibers of PCL[PVA/CHT], in which the PCL works as a shell and the blend as a core. A crucial…
The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19 - The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms of action and some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. The most effective small-molecule drug approved to date for the…
An Antiherpesviral Host-Directed Strategy Based on CDK7 Covalently Binding Drugs: Target-Selective, Picomolar-Dose, Cross-Virus Reactivity - The repertoire of currently available antiviral drugs spans therapeutic applications against a number of important human pathogens distributed worldwide. These include cases of the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), human immunodeficiency virus type 1 (HIV-1 or AIDS), and the pregnancy- and posttransplant-relevant human cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit,…
The Role of Extracellular Vesicles in SARS-CoV-2-Induced Acute Kidney Injury: An Overview - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions worldwide since its outbreak in the winter of 2019. While extensive research has primarily focused on the deleterious respiratory effects of SARS-CoV-2 in recent years, its pan-tropism has become evident. Among the vital organs susceptible to SARS-CoV-2 infection is the kidney. Post SARS-CoV-2 infection, patients have developed coronavirus disease 19 (COVID-19), with reported incidences of COVID-19 patients…
SARS-CoV-2 Spike Protein Stimulates Macropinocytosis in Murine and Human Macrophages via PKC-NADPH Oxidase Signaling - Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While recent studies have demonstrated that SARS-CoV-2 may enter kidney and colon epithelial cells by inducing receptor-independent macropinocytosis, it remains unknown whether this process also occurs in cell types directly relevant to SARS-CoV-2-associated lung pneumonia, such as alveolar epithelial cells and macrophages. The goal of our study was to investigate…
Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes - Predicting the potency of inhibitors is key to in silico screening of promising synthetic or natural compounds. Here we describe a predictive workflow that provides calculated inhibitory values, which concord well with empirical data. Calculations of the free interaction energy ΔG with the YASARA plugin FoldX were used to derive inhibition constants K(i) from PDB coordinates of protease-inhibitor complexes. At the same time, corresponding K(D) values were obtained from the PRODIGY server. These…
The Sphingolipid-Modulating Drug Opaganib Protects against Radiation-Induced Lung Inflammation and Fibrosis: Potential Uses as a Medical Countermeasure and in Cancer Radiotherapy - Fibrosis is a chronic pathology resulting from excessive deposition of extracellular matrix components that leads to the loss of tissue function. Pulmonary fibrosis can follow a variety of diverse insults including ischemia, respiratory infection, or exposure to ionizing radiation. Consequently, treatments that attenuate the development of debilitating fibrosis are in desperate need across a range of conditions. Sphingolipid metabolism is a critical regulator of cell proliferation, apoptosis,…
Isolation and Identification of a Tibetan Pig Porcine Epidemic Diarrhoea Virus Strain and Its Biological Effects on IPEC-J2 Cells - Porcine epidemic diarrhoea virus (PEDV) is a coronavirus that can cause severe watery diarrhoea in piglets, with high morbidity and mortality rates, seriously hindering the healthy development of the global swine industry. In this study, we isolated a strain of PEDV from Tibetan pigs and named it CH/GS/2022. Subsequently, we screened the apoptosis signals of PEDV-infected IPEC-J2 cells and studied the correlation between apoptosis signals and cell apoptosis. The results showed that different…