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1.
Ann. New York Acad. Sci. C1L637734524&from=export ; 1510:79-99, 2022.
Article in English | EMBASE | ID: covidwho-1822055

ABSTRACT

Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome–lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium “Targeting protein degradation: from small molecules to complex organelles.” The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.

2.
Journal of Thrombosis and Haemostasis ; 20(5):1056-1066, 2022.
Article in English | EMBASE | ID: covidwho-1822054

ABSTRACT

Venous thromboembolism is a very common and costly health problem worldwide. Anticoagulant treatment for VTE is imperfect: all have the potential for significant bleeding, and none prevent the development of post thrombotic syndrome after deep vein thrombosis or chronic thromboembolic pulmonary hypertension after pulmonary embolism. For these reasons, alternate forms of therapy with improved efficacy and decreased bleeding are needed. Selectins are a family (P-selectin, E-selectin, L-selectin) of glycoproteins that facilitate and augment thrombosis, modulating neutrophil, monocyte, and platelet activity. P- and E-selectin have been investigated as potential biomarkers for thrombosis. Inhibition of P-selectin and E-selectin decrease thrombosis and vein wall fibrosis, with no increase in bleeding. Selectin inhibition is a promising avenue of future study as either a stand-alone treatment for VTE or as an adjunct to standard anticoagulation therapies.

3.
Influenza and other Respiratory Viruses ; 2022.
Article in English | EMBASE | ID: covidwho-1822050

ABSTRACT

Based on our national outpatient sentinel surveillance, we have developed a novel approach to determine respiratory syncytial virus (RSV) epidemic seasons in Germany by using RSV positivity rate and its lower limit of 95% confidence interval. This method was evaluated retrospectively on nine RSV seasons, and it is also well-suited to describe off-season circulation of RSV in near real time as observed for seasons 2020/21 and 2021/22 during the COVID-19 pandemic. Prospective application is of crucial importance to enable timely actions for health service delivery and prevention.

4.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821975

ABSTRACT

Considerable attention has been paid to immunological approaches to dealing with the Covid-19 pandemic. In addition, existing pharmaceuticals, such as the modified mononucleotide Remdesvir, have been studied in the context of the viral infection. This study looks at different classes of compounds, natural products, some already ingested by millions of people every day, and asks if there is evidence that they might bind to Covid19 viral proteins and possibly interfere with viral replication. In this study, the Universal Natural Products Database was used to search for compounds that bind to the SARS-CoV-2 3CL Protease. The database was interrogated using the Smina docking program, a branch of Autodock Vina. Those compounds that were predicted by Smina to bind better than -9 kcal/mole were then successively interrogated with LeDock, a program that gives results that are considerably different from Smina. The compounds with predicted binding values of -11 kcal/mole or lower by both programs were then studied by observing their predicted binding using several programs that enable the examination of ligand-protein interactions. While this study identified many compounds of potential interest, this report concentrates on compounds that are commonly found in foodstuffs. Some but not all of these compounds are structurally close to those compounds that have been classified by others as Pan-Assay Interference Compounds, PAINS.

5.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821974

ABSTRACT

Symbiotic interaction between the human body and its microbiota is an important issue of modern biomedicine and personalized medicine. However, little is known on molecular mechanisms of that relationship. Bearing in mind the ubiquitous participation of peptides in biomolecular interactions and regulatory processes we attempted direct search of blood peptides originated from microbial proteins. LC-MS/MS analysis was carried out of blood serum and plasma samples taken from 20 healthy donors on Q Exactive HF-X Hybrid Quadrupole-Orbitrap mass-spectrometer. Sample preparation was carried out based on our previously developed method of peptide desorption from the surface of major blood plasma proteins followed by standard chromatographic steps. Mascot and X! Tandem search engines were used for peptide identification. Human protein sequences were taken from UniProt Knowledgebase and sequences of human microbiota proteins-from NIH Human Microbiome Project (HMP). As a result, out of 13625 identified peptides 912 were unique fragments of microbial precursors, which is 6.69% of the total amount of detected bloodstream peptides. In 30 cases peptide identification was confirmed by mass-spectral study of individual synthetic samples. Absolute quantification by the mass-spectrometric method of multiple reaction monitoring (MRM) confirmed the presence of bacterial peptides in plasma and serum in the range of approximately 0.1 nMol/L to 1 mkMol/L, which is comparable to physiologically significant hormone concentrations in human blood in normal conditions. Analysis of the in silico obtained hydrolyzates of microbiotic proteins showed that significant number of the identified peptides are derived from the precursor proteins as a result of hydrolysis with trypsin, chymotrypsin and pepsin, the main proteases of the gastrointestinal system. 60% of the identified “microbial” peptides are derived from the intestine flora, about 20% - from oral microbiota and 20% fall on the remaining microbiotic communities. Most of the precursor proteins refer to intracellular, cytoplasmic proteins. The isolated fraction of peripheral blood mononuclear cells showed increase secretion of proinflammatory cytokines, colony stimulating factors and chemoattractants as the response to the addition of some of the identified microbiotic peptides. The data obtained serve as a basis for the ongoing study of the functional properties of microbiome derived peptides.

6.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821960

ABSTRACT

Introduction and Objectives Novel SARS-CoV-2 virus has been implicated in prompting a bold immune response that leads to severe Coronavirus disease 2019 (COVID-19). Recent studies have shown that SARSCoV-2-infected monocytes and macrophages are stimulated to produce an overabundance of pro-inflammatory cytokines and chemokines to generate a cytokine storm. Cytokines in excess can contribute to local tissue inflammation and the pathogenesis of COVID-19. However, the mechanism by which SARS-CoV-2 signal macrophage-derived inflammatory response remains unclear. In the present study, we used RAW 264.7 cells, a wellcharacterized macrophage model, to study the in vitro effects of SARS-CoV-2 on reactive oxygen species (ROS) production and its potential role in the signal transduction of cytokine production. Methods The effect of SARS-CoV-2 on ROS and cytokine generation in macrophages was assessed by treating RAW 264.7 cells with SARS-CoV-2 heat inactivated virus (0-20 million viral particles) or recombinant proteins for 24 hours. 2',7'-Dichlorodihydrofluorescein (2',7'-DCF) fluorescence analysis was utilized to quantify ROS generation within the RAW 264.7 macrophage cell line. Cell culture medium was sampled to quantify the levels of tumor necrosis factor (TNF) using enzyme-linked immunosorbent assay (ELISA). To assess the effects of SARS-CoV-2 on mitochondrial function, cells were treated with SARS-CoV-2 heat inactivated virus (0-20 million viral particles) for 24 hrs. Mitochondria-derived superoxide was measured using the MitoSOX™ red mitochondrial superoxide indicator. Results Treatment of RAW 264.7 cells with inactivated SARS-CoV-2 viral particles or recombinant proteins stimulated ROS production. Mitochondria-derived superoxide and hydrogen peroxide production were increased in response to inactivated SARS-CoV-2 viral particles and recombinant protein exposure. The increased ROS generation is linked to macrophage activation induced by SARS-CoV-2 exposures. Along with the ROS generation, increased TNF production was observed. Conclusions The results of this study suggest that both SARS-CoV-2 viral proteins and heat-inactivated viral particle exposures cause significant generation of ROS and cytokines by RAW 264.7 cells. ROS generation and the subsequent cytokine release apparently play a significant role in the pathogenesis associated with the SARS-CoV-2 viral infection. The imbalanced cellular defense system against oxidative stress commonly associated with aging could explain the increased occurrence of more severe SARS-CoV-2 illness in seniors and in patients with underlying health conditions. Based on the results from this study, we propose that antioxidants such as N-acetyl-L-cysteine, resveratrol, or Vitamin E in combination with antiinflammatory drug could be used to control excess ROS and cytokines in patients with severe COVID-19.

7.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821935

ABSTRACT

SARS-COV-2, or COVID-19, is a respiratory virus infecting over 86 million people worldwide. In addition to respiratory infections, SARS-COV-2 has been shown to include cardiovascular (CV) complications, including myocarditis and acute coronary syndrome. Risk of severe complications from SARS-COV-2 in individuals with existing CV and metabolic disease has been shown to be increased. Evidence indicates SARS-COV-2 enters tissues via the angiotensin-converting enzyme 2 (ACE2) receptor and that the virus is primed and activated by transmembrane protease, serine 2 (TMPRSS2). The goal of this study was to determine ACE2 and TMPRSS2 mRNA levels in pre-clinical swine models of heart failure (HF). We hypothesized sex, pressure-overload, and comorbidities would increase ACE2 and TMPRSS2 mRNA levels. A retrospective analysis was conducted in previously completed studies in our lab including: 1) Female, intact Ossabaw swine that were either lean control or western diet-fed aortic-banded (N=4-5/group);2) Female Yucatan mini-swine subject to ovariectomy and/or aortic banding (N=5-8/group);and 3) Sedentary and exercise trained male, intact Yucatan mini-swine that were aortic banded. ACE2 and TMPRSS2 mRNA levels were evaluated in the left ventricle (LV), right ventricle (RV), and coronary vasculature using qRT-PCR. Linear regression analysis was used to determine differences between the following variables: pig species, sex hormones, aortic banding, comorbidities, exercise training, and tissue. Data was log-transformed to meet linear regression assumptions. ACE2 and TMPRSS2 mRNA levels were significantly influenced by sex, comorbidity, and tissue type. TMPRSS2 mRNA levels were also influenced by species and disease status. Specifically, ACE2 mRNA levels decreased 57.1% in the LV and increased 169.9% in the RV of males compared to coronary vessels in intact females. TMPRSS2 mRNA levels increased in the LV and RV of males (1,218.6% and 5,479.8%, respectively) compared to coronary vessels in intact females. ACE2 and TMPRSS2 mRNA levels increased 344% and 453.4%, respectively, in the LV of Ossabaw swine fed a Western Diet compared to coronary vessels from Yucatan and Ossabaw swine without comorbidities. Species differences indicated TMPRSS2 mRNA levels increased 449.2% in the RV and 498.6% in the LV in Yucatan mini-swine compared to coronary vessels in Ossabaw swine. A 107.3% increase in TMPRSS2 mRNA level was observed in male swine without HF compared to female intact swine with HF highlighting the importance of sex and disease state. Exercise training did not impact ACE2 or TMPRSS2 mRNA levels irrespective of tissue. In conclusion, these results suggest differences in RV, LV and coronary mRNA levels of ACE2 and TMPRSS2 are dependent upon sex and comorbidities. TMPRSS2 levels are additionally influenced by pig species and pressureoverload. These results provide insight into how ACE2 and TMPRSS2 mRNA levels may influence the cardiovascular involvement of SARS-COV-2 infection in an experimental setting of pre-clinical HF incorporating different swine species, sex, and comorbidities.

8.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821901

ABSTRACT

The physiology of critical care patients is more complex than normally appreciated. Patients arrive at the intensive care unit (ICU) or the pediatric ICU (PICU) with a variety of infections, trauma, organ damage, and dysfunctional immune systems. This population is the prime target for testing and applying new precision medicine tools to decipher the unique biology occurring within each patient. This is particularly important as COVID-19 has made such an impact on the United States healthcare system. Thus, there is a need to develop strategies to find multiple levels of information while minimizing the number of tests performed, shifting the balance of testing to more proactive than reactive. With the collection of ∼2mL of blood (about half a teaspoon), our collaboration between Spectrum Health and Michigan State University has shown the ability to use PAXgene tubes and RNAseq to simultaneously map human gene/transcript signatures, score panels of corresponding risk genes, deconvolute immune cells, detect markers of organ/cell damage, detect RNA from bacteria/viruses/plants/fungi, profile the immune repertoire, address how patients are unique from other samples, and address common/rare genetic mutations. These tools have been applied to three cohorts of patients (and age matched controls) for critical care medicine physiology understanding for nearly all ages: 1) Infants with Respiratory syncytial virus (RSV);2) Kids with multiple organ dysfunction syndrome;and 3) Adults with hospitalized or lethal COVID-19. Our findings from these tools shows the complexity of immune system activation, secondary infections, and under appreciated interactions of the immune cell disorder overlapping COVID-19 pathology. The promise of blood-based transcriptomics to reveal cellular and cell free signatures opens a door for building more detailed physiological mechanisms from precision medicine.

9.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821823

ABSTRACT

The SARS-CoV-2 virus is responsible for the COVID-19 pandemic which continues to impact nearly every person on Earth, having caused over 1.8 million deaths. Two anti-SARS-CoV monoclonal antibodies (MAbs) 80R and 362 are known to bind to epitopes on the spike protein receptor-binding domain (RBD) and neutralize the virus. To investigate this further and hypothesize structures for potentially more effective antibodies, undergraduate students cooperated in teams as part of the CREST (Connecting Researchers, Educators, and STudents) Program with the Center for Biological Modeling. Working collaboratively, students from eight universities nationwide applied their knowledge to build 3-D printed models to explain a particular protein-based molecular story using crystal structures of proteins described in the literature. The Nova Southeastern University (NSU) CREST team modeled and compared the 80R antibody that binds to SARS-CoV-1 and the MAb362 antibody that can bind to both SARS-CoV-1 and SARS-CoV-2. Students developed skills with protein visualization software including Pymol and Jmol to design models which showed the 80R and 362 antibodies binding to the RBD of the corresponding proteins. By studying the point mutation differences between the two antibodies (80R and 362), a potentially more universal antibody (named NSU1 in this study) was modeled. This hypothesized antibody was expected to bind more effectively to future mutations in the SARS spike protein. At the binding interface between these antibodies and the SARS spike protein, MAb362 mutations trend smaller and less polar including: Arg149Ser, Asn151Ser, Asp170Gly, and Trp213Ser. Due to the trend of smaller amino acids appearing in the MAb362 binding interface, it was hypothesized that more space in this area could allow antibodies to be more resistant to future SARS-CoV spike protein structure variations. NSU1 was modeled based on MAb362 with the following four additional mutations: Asp103Gly, Trp104Leu, Gly170Ser, and Arg211Val. All of these except for Gly170 are mutations that decreased size and polarity of amino acid residues within the binding interface. Position 170 is Asp on the 80R structure and thus a mutation to Ser is still expected to maintain this trend of smaller residues in the antibody. Due to the additional space created due to these amino acid substitutions in the binding region between the antibody and RBD of the spike protein, NSU1 was predicted to be more resistant to spike protein mutations. These models allowed for deeper understanding of the impact that mutations in antibodies can have on binding interactions with viral proteins. Additionally, the modeling process also provided insight into the molecular structure of a potentially more universal antibody against variations in SARS-CoV.

10.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821817

ABSTRACT

Background The novel SARS-CoV-2 virus inflicts far-reaching health decrements, both directly and through secondary inflammatory stimulation. To date, there is little information regarding the effects of COVID-19 on the heart after infection, especially among young healthy adults. Purpose We sought to determine whether contracting SARS-CoV-2 affects cardiac function in young, otherwise healthy adults and whether these alterations recede after testing positive for SARS-CoV-2. Methods Transthoracic echocardiography was performed on 7 subjects with SARS-CoV-2 (3F/4M, 21±1y, 24±2 kg m ) who tested positive 3-4 weeks prior to baseline testing followed by 1- month and 2-month follow-up testing. A parasternal long-axis view was utilized to measure septal and left ventricular posterior wall thickness, left ventricular volume, and left ventricular outflow tract dimensions. A four-chamber view was utilized to measure mitral and tricuspid valve, left ventricular, and pulmonary vein function. Data are mean±SD. Results Stroke volume (Baseline: 44±11ml, 1-month: 42±13ml, 2-month: 54±12ml) and stroke index (Baseline: 24±6ml/m

11.
Viral Immunology ; 35(1):4, 2022.
Article in English | EMBASE | ID: covidwho-1821680
13.
Journal of Experimental Nanoscience ; 17(1):297-314, 2022.
Article in English | EMBASE | ID: covidwho-1821664

ABSTRACT

A simple low-cost one-pot photodeposition synthesis with no hazardous reactants or products is used to make silver nanoparticles-activated carbon composite (SNPs@AC). The SNPs are homogenously and photodeposited and absorbed into the activated carbon matrix. Both SNPs and SNPs@AC composite have particle sizes around 10 nm and 100 nm, respectively. The SNPs@AC composite showed good antiviral activity to VERO (ATCC ccl-81) cells. Zeta potential of SNPs@AC composite is −25 mV, showing that this colloidal system is electrically stable and resistant to coagulation. For many Gram-positive and Gram-negative bacteria, the SNPs@AC composite demonstrated strong antibacterial efficacy. The SNPs@AC composite has 75.72 percent anti-inflammatory effect at concentration 500 µg/mL. This composite has a maximum non-toxic concentration (MNTC) of 78.125 g/mL, which corresponds to antiviral activity of up to 96.7 percent against hepatitis A. virus (HAV). It is suggested as a candidate for pharmaceutical formulations, such as integration into the manufacture of N95 masks for COVID-19 infection protection. Concentration 160 μg/mL SNPs@AC composite has antioxidant activity 42.74% percent. The SNPs@AC composite exhibited selective catalytic activity for the organosynthesis hydrazination reaction of 4-chloro-3, 5-di-nitro-benzo-triflouride, giving 1-hydroxy-4-nitro-6-trifluoro-methyl benzotriazole, a common antiviral drug for severe acute respiratory syndrome (SARS). SNPs@composite's well-defined pores provide suitable active sites for binding reactants: 4-Cl-3, 5-di-NO2-benzotriflouride, and hydrazine, which react to create 1-hydroxy-4-nitro-6-trifluoromethyl benzotriazole, which diffuses into solution away from the catalyst surface, leaving the catalyst surface unaffected.

14.
Trends in Biochemical Sciences ; 47(5):372-374, 2022.
Article in English | EMBASE | ID: covidwho-1821500

ABSTRACT

Modifications of cysteine residues in redox-sensitive proteins are key to redox signaling and stress response in all organisms. A novel type of redox switch was recently discovered that comprises lysine and cysteine residues covalently linked by an nitrogen–oxygen–sulfur (NOS) bridge. Here, we discuss chemical and biological implications of this discovery.

15.
Journal of Epidemiology and Global Health ; 2022.
Article in English | EMBASE | ID: covidwho-1821089

ABSTRACT

Introduction: Following the first year of the COVID-19 pandemic, a complete analysis of the characteristics of the deceased hospitalized patients was performed, to identify factors related to premature mortality and to compare patient profiles according to the epidemic periods. Methods: Retrospective analysis of 1104 deceased patients in two University Hospitals in South-eastern France, between March 1, 2020 and March 12, 2021 from Hospital’s electronic medical records was performed. Results: Mean age was 80 years (± 11.1) and 10% of the deceased were younger than 65 years with specific comorbidities, e.g., genetic conditions, metastatic cancer, or massive obesity. Among the three clusters identified, two clusters (75% of deceased patients) include very elderly patients with numerous comorbidities, and differ by their proportion of dependent institutionalized patients. The third cluster is made up of younger patients with fewer but severe comorbidities. Deceased patients’ profiles varied according to the epidemic periods: during the first period (March–June 2020), more patients were institutionalized. The second period (September–December2020) coincided with a higher mortality rate. Conclusions: This study confirmed that most patients hospitalized and dying from COVID-19 were frail, i.e., elderly and/or highly comorbid and that the small proportion of young patients had severe comorbidities.

16.
Journal of Nephrology ; 35(3):715-716, 2022.
Article in English | EMBASE | ID: covidwho-1821076
17.
Ophthalmology and Therapy ; 2022.
Article in English | EMBASE | ID: covidwho-1821036

ABSTRACT

Purpose: To evaluate the effect of COVID-19 on retinal tissues by conducting a systematic review and meta-analysis of the current literature. Background: The novel coronavirus disease is not yet well understood. The orbit provides a window into the body's microvasculature, and as such, it is a non-invasive opportunity to analyse the systemic circulation in vivo. By analysing the current literature, we test the hypothesis that non-invasive imaging of the retina could provide insight into the effect of COVID-19 on the retinal microvasculature. Methods: For this systematic review and meta-analysis, we screened PubMed databases and LitCOVID19 using the search criteria: (OCTA or Optical Coherence Tomography Angiography) AND (COVID-19 or corona or SARS-CoV-2) AND (retina or fundus). Databases were searched on 11 January 2022. The primary study outcomes were studies that utilised OCTA to analyse the retina;secondary outcomes involved studies that involved other imaging modalities such as OCT, fundus photography, and fundus autofluorescence. Findings: The total number of studies included in this review was 32. Optical coherence tomography angiography scans show reduced central retinal vascular density, a thinner ganglion cell layer, a thicker retinal nerve fibre layer, and an enlarged foveal avascular zone. Optical coherence tomography scans demonstrate a thicker central macular thickness and other changes to the macula, ganglion cell, and inner nuclear layers. Many fundus photographs depicted cotton wool spots, microhaemorrhages, and vascular occlusions. Non-invasive imaging technology has demonstrated that COVID-19 can profoundly affect the retina. Therefore, there is a requirement for long-term follow-up of COVID-19 patients to assess whether the retinal damage caused by COVID-19 is reversible.

18.
Infection ; 2022.
Article in English | EMBASE | ID: covidwho-1821023

ABSTRACT

Objective: The aim of our study was to build a predictive model able to stratify the risk of bacterial co-infection at hospitalization in patients with COVID-19. Methods: Multicenter observational study of adult patients hospitalized from February to December 2020 with confirmed COVID-19 diagnosis. Endpoint was microbiologically documented bacterial co-infection diagnosed within 72 h from hospitalization. The cohort was randomly split into derivation and validation cohort. To investigate risk factors for co-infection univariable and multivariable logistic regression analyses were performed. Predictive risk score was obtained assigning a point value corresponding to β-coefficients to the variables in the multivariable model. ROC analysis in the validation cohort was used to estimate prediction accuracy. Results: Overall, 1733 patients were analyzed: 61.4% males, median age 69 years (IQR 57–80), median Charlson 3 (IQR 2–6). Co-infection was diagnosed in 110 (6.3%) patients. Empirical antibiotics were started in 64.2 and 59.5% of patients with and without co-infection (p = 0.35). At multivariable analysis in the derivation cohort: WBC ≥ 7.7/mm3, PCT ≥ 0.2 ng/mL, and Charlson index ≥ 5 were risk factors for bacterial co-infection. A point was assigned to each variable obtaining a predictive score ranging from 0 to 5. In the validation cohort, ROC analysis showed AUC of 0.83 (95%CI 0.75–0.90). The optimal cut-point was ≥2 with sensitivity 70.0%, specificity 75.9%, positive predictive value 16.0% and negative predictive value 97.5%. According to individual risk score, patients were classified at low (point 0), intermediate (point 1), and high risk (point ≥ 2). CURB-65 ≥ 2 was further proposed to identify patients at intermediate risk who would benefit from early antibiotic coverage. Conclusions: Our score may be useful in stratifying bacterial co-infection risk in COVID-19 hospitalized patients, optimizing diagnostic testing and antibiotic use.

20.
Cerebellum ; 2022.
Article in English | EMBASE | ID: covidwho-1820999
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