• Canonical Secretomes, Innate Immune Caspase-1-, 4/11-Gasdermin D Non-Canonical Secretomes and Exosomes May Contribute to Maintain Treg-Ness for Treg Immunosuppression, Tissue Repair and Modulate Anti-Tumor Immunity via ROS Pathways

      Centers for Cardiovascular Research (Temple University); Metabolic Disease Research & Thrombosis Research (Temple University); Inflammation, Translational & Clinical Lung Research (Temple University) (2021-05-18)
      We performed a transcriptomic analyses using the strategies we pioneered and made the following findings: 1) Normal lymphoid Tregs, diseased kidney Tregs, splenic Tregs from mice with injured muscle have 3, 17 and 3 specific (S-) pathways, respectively; 2) Tumor splenic Tregs share 12 pathways with tumor Tregs; tumor splenic Tregs and tumor Tregs have 11 and 8 S-pathways, respectively; 3) Normal and non-tumor disease Tregs upregulate some of novel 2641 canonical secretomic genes (SGs) with 24 pathways, and tumor Tregs upregulate canonical secretomes with 17 pathways; 4) Normal and non-tumor disease tissue Tregs upregulate some of novel 6560 exosome SGs with 56 exosome SG pathways (ESP), tumor Treg ESP are more focused than other Tregs; 5) Normal, non-tumor diseased Treg and tumor Tregs upregulate some of novel 961 innate immune caspase-1 SGs and 1223 innate immune caspase-4 SGs to fulfill their tissue/SG-specific and shared functions; 6) Most tissue Treg transcriptomes are controlled by Foxp3; and Tumor Tregs had increased Foxp3 non-collaboration genes with ROS and 17 other pathways; 7) Immune checkpoint receptor PD-1 does, but CTLA-4 does not, play significant roles in promoting Treg upregulated genes in normal and non-tumor disease tissue Tregs; and tumor splenic and tumor Tregs have certain CTLA-4-, and PD-1-, non-collaboration transcriptomic changes with innate immune dominant pathways; 8) Tumor Tregs downregulate more immunometabolic and innate immune memory (trained immunity) genes than Tregs from other groups; and 11) ROS significantly regulate Treg transcriptomes; and ROS-suppressed genes are downregulated more in tumor Tregs than Tregs from other groups. Our results have provided novel insights on the roles of Tregs in normal, injuries, regeneration, tumor conditions and some of canonical and innate immune non-canonical secretomes via ROS-regulatory mechanisms and new therapeutic targets for immunosuppression, tissue repair, cardiovascular diseases, chronic kidney disease, autoimmune diseases, transplantation, and cancers.
    • Cardiomyocyte GSK-3β deficiency induces cardiac progenitor cell proliferation in the ischemic heart through paracrine mechanisms

      Yusuf, Ayesha M.; Qaisar, Rizwan; Al-Tamimi, Abaher O.; Jayakumar, Manju Nidagodu; Woodgett, James R.; Koch, Walter; Ahmad, Firdos; Koch|0000-0002-8522-530X; Ahmad|0000-0001-6530-6068 (2021-08-28)
      Cardiomyopathy is an irreparable loss and novel strategies are needed to induce resident cardiac progenitor cell (CPC) proliferation in situ to enhance the possibility of cardiac regeneration. Here we identify a potential role for glycogen synthase kinase-3β (GSK-3β), a critical regulator of cell proliferation and differentiation, in CPC proliferation that occurs after myocardial infarction (MI). Cardiomyocyte-specific conditional GSK-3β knockout (cKO) and littermate control mice were employed and challenged with MI. Though cardiac left ventricular chamber dimension (LVID) and contractile functions were comparable at two week post-MI, cKO mice displayed significantly preserved LV chamber and contractile function vs. control mice at four-weeks post-MI. Consistent with protective phenotypes, an increased percentage of c-kit positive cells (KPCs) were observed in the cKO hearts at four and six weeks post-MI which was accompanied by increased levels of cardiomyocyte proliferation. Further analysis revealed that the observed increased number of KPCs in the ischemic cKO hearts was mainly from a cardiac lineage as the majority of identified KPCs were negative for the hematopoietic lineage marker, CD45. Mechanistically, cardiomyocyte-GSK-3β profoundly suppresses the expression of growth factors (GFs), including basic-FGF angiopoietin-2, erythropoietin, stem cell factor (SCF), PDGF-BB, G-CSF, and VEGF, post-hypoxia. In conclusion, our findings strongly suggest that loss of cardiomyocyte-GSK-3β promotes cardiomyocyte and resident CPC proliferation post-MI. The induction of cardiomyocytes and CPC proliferation in the ischemic cKO hearts is potentially regulated by autocrine and paracrine signaling governed by dysregulated growth factors post-MI. A strategy to inhibit cardiomyocyte GSK-3β could be helpful for promotion of in-situ cardiac regeneration post-MI injury.
    • Cardiovascular Manifestations of COVID-19 Infection

      Center for Translational Medicine (Temple University) (2020-11-19)
      SARS-CoV-2 induced the novel coronavirus disease (COVID-19) outbreak, the most significant medical challenge in the last century. COVID-19 is associated with notable increases in morbidity and death worldwide. Preexisting conditions, like cardiovascular disease (CVD), diabetes, hypertension, and obesity, are correlated with higher severity and a significant increase in the fatality rate of COVID-19. COVID-19 induces multiple cardiovascular complexities, such as cardiac arrest, myocarditis, acute myocardial injury, stress-induced cardiomyopathy, cardiogenic shock, arrhythmias and, subsequently, heart failure (HF). The precise mechanisms of how SARS-CoV-2 may cause myocardial complications are not clearly understood. The proposed mechanisms of myocardial injury based on current knowledge are the direct viral entry of the virus and damage to the myocardium, systemic inflammation, hypoxia, cytokine storm, interferon-mediated immune response, and plaque destabilization. The virus enters the cell through the angiotensin-converting enzyme-2 (ACE2) receptor and plays a central function in the virus’s pathogenesis. A systematic understanding of cardiovascular effects of SARS-CoV2 is needed to develop novel therapeutic tools to target the virus-induced cardiac damage as a potential strategy to minimize permanent damage to the cardiovascular system and reduce the morbidity. In this review, we discuss our current understanding of COVID-19 mediated damage to the cardiovascular system.
    • Cardiovascular Manifestations of COVID-19 Infection

      Center for Translational Medicine (Temple University) (2020-11-19)
      SARS-CoV-2 induced the novel coronavirus disease (COVID-19) outbreak, the most significant medical challenge in the last century. COVID-19 is associated with notable increases in morbidity and death worldwide. Preexisting conditions, like cardiovascular disease (CVD), diabetes, hypertension, and obesity, are correlated with higher severity and a significant increase in the fatality rate of COVID-19. COVID-19 induces multiple cardiovascular complexities, such as cardiac arrest, myocarditis, acute myocardial injury, stress-induced cardiomyopathy, cardiogenic shock, arrhythmias and, subsequently, heart failure (HF). The precise mechanisms of how SARS-CoV-2 may cause myocardial complications are not clearly understood. The proposed mechanisms of myocardial injury based on current knowledge are the direct viral entry of the virus and damage to the myocardium, systemic inflammation, hypoxia, cytokine storm, interferon-mediated immune response, and plaque destabilization. The virus enters the cell through the angiotensin-converting enzyme-2 (ACE2) receptor and plays a central function in the virus’s pathogenesis. A systematic understanding of cardiovascular effects of SARS-CoV2 is needed to develop novel therapeutic tools to target the virus-induced cardiac damage as a potential strategy to minimize permanent damage to the cardiovascular system and reduce the morbidity. In this review, we discuss our current understanding of COVID-19 mediated damage to the cardiovascular system.
    • Case series: Failure of imaging & biochemical markers to capture disease progression in COVID-19

      Dorey-Stein, Zachariah L.; Myers, Catherine; Kumaran, Maruti; Mamary, Albert; Criner, Gerard J.; 0000-0002-3761-153X; 0000-0002-0909-5048 (2020-09-19)
      We report four individuals admitted for acute respiratory failure due to COVID-19 who demonstrated significant clinical improvement prior to discharge and subsequently were readmitted with worsening respiratory failure, elevated inflammatory markers and worsening chest imaging. We propose a multi-disciplinary discharge criterion to establish a safer discharge process including trending inflammatory markers, daily imaging and pursuing follow up CT chest, particularly in individuals with significant morbidities and health disparities.
    • Cast Face Shield Process & User Manual

      TUCAT (Temple University) (2020-05-05)
    • Cellular mechanisms underlying neurological/neuropsychiatric manifestations of COVID‐19

      Center for Metabolic Disease Research (Temple University) (2020-12-10)
      Patients with severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection manifest mainly respiratory symptoms. However, clinical observations frequently identified neurological symptoms and neuropsychiatric disorders related to COVID‐19 (Neuro‐SARS2). Accumulated robust evidence indicates that Neuro‐SARS2 may play an important role in aggravating the disease severity and mortality. Understanding the neuropathogenesis and cellular mechanisms underlying Neuro‐SARS2 is crucial for both basic research and clinical practice to establish effective strategies for early detection/diagnosis, prevention, and treatment. In this review, we comprehensively examine current evidence of SARS‐CoV‐2 infection in various neural cells including neurons, microglia/macrophages, astrocytes, pericytes/endothelial cells, ependymocytes/choroid epithelial cells, and neural stem/progenitor cells. Although significant progress has been made in studying Neuro‐SARS2, much remains to be learned about the neuroinvasive routes (transneuronal and hematogenous) of the virus and the cellular/molecular mechanisms underlying the development/progression of this disease. Future and ongoing studies require the establishment of more clinically relevant and suitable neural cell models using human induced pluripotent stem cells, brain organoids, and postmortem specimens.
    • Challenges Experienced by Older People During the Initial Months of the COVID-19 Pandemic

      Siminoff Research Group (Temple University) (2020-09-21)
      Background and Objectives: The coronavirus disease 2019 (COVID-19) pandemic has created unique stressors for older people to manage. Informed by the Stress Process Model and the Transactional Model of Stress and Coping, we examined the extent to which older people are adhering to physical distancing mandates and the pandemic-related experiences that older people find most challenging. Research Design and Methods: From May 4 to May 17, 2020, a web-based questionnaire focused on the COVID-19 pandemic was completed by 1,272 people (aged 64 and older) who were part of an ongoing research panel in New Jersey recruited in 2006. Frequencies for endorsement of physical distancing behaviors were tabulated, and open-ended responses to the biggest challenge of the pandemic were systematically coded and classified using content analysis. Results: More than 70% of participants reported adhering to physical distancing behaviors. Experiences appraised as most difficult by participants fell into 8 domains: Social Relationships, Activity Restrictions, Psychological, Health, Financial, Global Environment, Death, and Home Care. The most frequently appraised challenges were constraints on social interactions (42.4%) and restrictions on activity (30.9%). Discussion and Implications: In the initial weeks of the pandemic, the majority of older adults reported adhering to COVID-19 physical distancing mandates and identified a range of challenging experiences. Results highlight the factors having the greatest impact on older adults, informing quantitative modeling for testing the impact of the pandemic on health and well-being outcomes, and identifying how intervention efforts may be targeted to maximize the quality of life of older adults.
    • Clinical Impact of the Early Use of Monoclonal Antibody LY-CoV555 (Bamlanivimab) on Mortality and Hospitalization Among Elderly Nursing Home Patients: A Multicenter Retrospective Study

      Alam, Mohammud M.; Mahmud, Saborny; Aggarwal, Sandeep; Fathma, Sawsan; Al Mahi, Naim; Shibli, Mohammed S.; Haque, Siddiqi M.; Mahmud, Sharothy; Ahmed, Ziauddin (2021-05-10)
      Importance: Coronavirus disease 2019 (COVID-19) outbreaks are frequent occurrences in nursing homes and long-term care facilities (LTCFs), resulting in subsequent hospitalization and death. Rationale: Virus-neutralizing monoclonal antibodies demonstrate a significant decrease in both viral load and hospital transfer rate among patients with mild-to-moderate COVID-19 infection. Objective: To assess the clinical outcomes of COVID-19 patients with mild-to-moderate symptoms in LTCFs who received LY-CoV555 as compared to those who did not receive this treatment. Design: Retrospective case-control study and logistic regression analysis. Setting: LTCFs in New York. Participants: Two-hundred forty-six (246) LTCF patients diagnosed with mild-to-moderate COVID-19 infection with positive COVID-19 polymerase chain reaction (PCR) from November 15, 2020, to January 31, 2021. Methods: Two-hundred forty-six (246) COVID-19 patients were identified from electronic medical records, out of which 160 cases were exposed to LY-CoV555 treatment (700 mg single dose, intravenous infusion). Eighty-six (86) patients were unexposed controls who did not receive monoclonal antibodies, LY-CoV555. Outcome: We assessed the odds of death and hospitalization of exposed cases as compared to unexposed controls. Using logistic regression analysis, we also assessed the risk factors associated with these outcomes in the entire sample population. Results: The mean age of the entire sample was 82.4 years. Fifty-two percent (52%) of patients (n = 129) were female and 48% (n = 117) were male. The mean ages of the exposed group and the unexposed group were 81 years and 84 years, respectively. At the end of the study, 92% (148/160) of the exposed group were alive or not transferred to the hospital as compared to 79% (68/86) patients of the unexposed group (OR 3.23, 95% CI: (1.48, 7.31), p-value = 0.0032). Three percent (3%; 5/160) of patients died in the exposed group compared to 10% (9/86) of patients who died in the unexposed group (OR = 0.25, 95% CI: (0.1, 0.85), p-value = 0.0257). Four point thirty-seven percent (4.37%; 7/160) of patients in the exposed group and 10.46% (9/86) of patients in the unexposed group were transferred to the hospital (OR = 0.35, 95% CI: (0.15, 1.08), p-value = 0.0793). Conclusion: Early treatment with monoclonal antibody LY-CoV555 is associated with decreased mortality among high-risk patients with mild-to-moderate COVID-19 infection in LTCFs. Although not statistically significant, there was a trend towards a lower risk of hospitalization in patients treated with LY-CoV555.
    • Comprehensive mapping of local and diaspora scientists: A database and analysis of 63,951 Greek scientists

      Center for Translational Medicine (Temple University) (2021-07-15)
      Research policy and planning for a given country may benefit from reliable data on both its scientific workforce as well as the diaspora of scientists for countries with a substantial brain drain. Here we use a systematic approach using Scopus to generate a comprehensive country-level database of all scientists in Greece. Moreover, we expand that database to include also Greek diaspora scientists. The database that we have compiled includes 63,951 scientists who have published at least five papers indexed in Scopus. Of those, 35,116 have an affiliation in Greece. We validate the sensitivity and specificity of the database against different control sets of scientists. We also analyze the scientific disciplines of these scientists according to the Science Metrix classification (174 subfield disciplines) and provide detailed data on each of the 63,951 scientists using multiple citation indicators and a composite thereof. These analyses demonstrate differential concentrations in specific subfields for the local versus the diaspora cohorts, as well as an advantage of the diaspora cohort in terms of citation indicators, especially among top-impact researchers. The approach that we have taken can also be applied to map the scientific workforce of other countries and nations for evaluation, planning, and policy purposes.
    • Computerized Assessment of Psychosis Risk

      Mittal, Vijay A.; Ellman, Lauren M.; Strauss, Gregory P.; Walker, Elaine F.; Corlett, Philip R.; Schiffman, Jason; Woods, Scott W.; Powers, Albert R.; Silverstein, Steven M.; Waltz, James A.; Zinbarg, Richard; Chen, Shuo; Williams, Trevor; Kenney, Joshua; Gold, James M. (2021-06-29)
      Early detection and intervention with young people at clinical high risk (CHR) for psychosis is critical for prevention efforts focused on altering the trajectory of psychosis. Early CHR research largely focused on validating clinical interviews for detecting at-risk individuals; however, this approach has limitations related to: (1) specificity (i.e., only 20% of CHR individuals convert to psychosis) and (2) the expertise and training needed to administer these interviews is limited. The purpose of our study is to develop the computerized assessment of psychosis risk (CAPR) battery, consisting of behavioral tasks that require minimal training to administer, can be administered online, and are tied to the neurobiological systems and computational mechanisms implicated in psychosis. The aims of our study are as follows: (1A) to develop a psychosis-risk calculator through the application of machine learning (ML) methods to the measures from the CAPR battery, (1B) evaluate group differences on the risk calculator score and test the hypothesis that the risk calculator score of the CHR group will differ from help-seeking and healthy controls, (1C) evaluate how baseline CAPR battery performance relates to symptomatic outcome two years later (i.e., conversion and symptomatic worsening). These aims will be explored in 500 CHR participants, 500 help-seeking individuals, and 500 healthy controls across the study sites. This project will provide a next-generation CHR battery, tied to illness mechanisms and powered by cutting-edge computational methods that can be used to facilitate the earliest possible detection of psychosis risk.
    • Contracting COVID: Private Order and Public Good

      Lipson, Jonathan C. (2020-09-02)
      The novel Coronavirus (2019) (COVID) has created a dilemma: Open the economy and spread disease; quarantine and choke the economy. Thus far, the response has looked to government for health-safety standards and financial subsidies. Although these are necessary steps, they have become politicized, thereby exacerbating severe uncertainties created by the pandemic. While we will surely halt it, we do not know how, when, or what comes next. Many writers are exploring litigation that will flow from COVID. This Article considers the flip side: the important but under-appreciated role that ex ante contracting plays in addressing the COVID dilemma. Liability waivers, for example, will be ubiquitous, but might be misused to shelter poor risk management. This essay argues that these waivers should be enforceable only when coupled with reasonable health-safety precautions, which may appear in contracts such as workplace rules or supply chain agreements. Without such balance—or worse, when imposed by fiat, as President Trump did in the meat processing industry—they can inflame the public health crisis. At the same time, the COVID-induced shutdown has caused most contracts to be in or near breach. This has resulted in responses such as litigation, bankruptcy, and bailouts. While these may be inevitable, second-order contracts such as standstill agreements provide certainty that enables parties to adjust commercial relationships in ways that may preserve more value at lower cost than public interventions. Contract in this context is thus doing more than creating private order; it is also producing public good. This hearkens to Depression-era scholarship which argued that contract had public ramifications. Although modern writers have largely abandoned that view, it reflected a change in mindset that cleared the way for sweeping New Deal reforms. While we do not yet know whether COVID will be as disruptive as the Depression, the uses of contract described here may signal a comparably dramatic realignment of private and public.
    • Coronavirus 2019 Infectious Disease Epidemic: Where We Are, What Can Be Done and Hope For

      Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine (Temple University) (2021-01-07)
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads mainly by means of aerosols (microdroplets) in enclosed environments, especially those in which temperature and humidity are regulated by means of air-conditioning. About 30% of individuals infected with SARS-CoV-2 develop coronavirus disease 2019 (COVID-19) disease. Among them, approximately 25% require hospitalization. In medicine, cases are identified as those who become ill. During this pandemic, cases have been identified as those with a positive SARS-CoV-2 polymerase chain reaction test, including approximately 70% who were asymptomatic—this has caused unnecessary anxiety. Individuals more than 65 years old, those affected by obesity, diabetes, asthma, or are immune-depressed owing to cancer and other conditions, are at a higher risk of hospitalization and of dying of COVID-19. Healthy individuals younger than 40 years very rarely die of COVID-19. Estimates of the COVID-19 mortality rate vary because the definition of COVID-19–related deaths varies. Belgium has the highest death rate at 154.9 per 100,000 persons, because it includes anyone who died with symptoms compatible with COVID-19, even those never tested for SARS-CoV-2. The United States includes all patients who died with a positive test, whether they died because of, or with, SARS-CoV-2. Countries that include only patients in which COVID-19 was the main cause of death, rather than a cofactor, have lower death rates. Numerous therapies are being developed, and rapid improvements are anticipated. Because of disinformation, only approximately 50% of the U.S. population plans to receive a COVID-19 vaccine. By sharing accurate information, physicians, health professionals, and scientists play a key role in addressing myths and anxiety, help public health officials enact measures to decrease infections, and provide the best care for those who become sick. In this article, we discuss these issues.
    • Coronavirus Disease (Covid-19): What Are We Learning in a Country With High Mortality Rate?

      Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine (Temple University) (2020-05-28)
    • Coronavirus Outbreak in Italy: Physiological Benefits of Home-Based Exercise During Pandemic

      Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine (Temple University) (2020-05-07)
      The Coronavirus Disease 2019 (COVID-19) pandemic has forced the hardest-hit populations, like Italians, to radically change their daily habits, starting with social distancing, strict preventive measures, and self-isolation. These precautions also apply to sport-related facilities and activities. The difficulty to practice physical activity during this dramatic moment in time adds to the risks associated with sedentary habits, due to staying all the time at home. Here, the importance and the benefits of maintaining exercise routine, even at home, are emphasized in order to avoid the consequences of inactivity.
    • Coronaviruses and the Chemical Senses: Past, Present, and Future

      Pellegrino, Robert; Cooper, Keiland W.; Di Pizio, Antonella; Joseph, Paule V.; Bhutani, Surabhi; Parma, Valentina; 0000-0003-0276-7072 (2020-05-14)
      A wealth of rapidly evolving reports suggests that olfaction and taste disturbances may be manifestations of the novel COVID-19 pandemic. While otolaryngological societies worldwide have started to consider chemosensory evaluation as a screening tool for COVID-19 infection, the true nature of the relationship between the changes in chemosensory ability and COVID-19 is unclear. Our goal with this review is to provide a brief overview of published and archived literature, as well as the anecdotal reports and social trends related to this topic up to April 29, 2020. We also aim to draw parallels between the clinical/chemosensory symptomology reported in association to past coronavirus pandemics (such as SARS and MERS) and the novel COVID-19. This review also highlights current evidence on persistent chemosensory disturbances after the infection has resolved. Overall, our analysis pinpoints the need for further studies: (1) to better quantify olfaction and taste disturbances associated with SARS-CoV-2 infection, compared to those of other viral and respiratory infections, (2) to understand the relation between smell, taste, and chemesthesis disturbances in COVID-19, and (3) to understand how persistent are these disturbances after the infection has resolved.
    • Correlation of vaccine-elicited antibody levels and neutralizing activities against SARS-CoV-2 and its variants

      Center for Metabolic Disease Research (Temple University) (2021-05-31)
      Both Pfizer-BNT162b2 and Moderna-mRNA-1273 vaccines can elicit an effective immune response against SARS-CoV-2 infection. However, the elicited serum antibody levels vary substantially and longitudinally decrease after vaccination. We examined the correlation of vaccination-induced IgG levels and neutralization titers against newly emerged variants remains and demonstrate a significant reduction of neutralization activities against the variants (B.1.1.7, B.1.525, and B.1.351) in Pfizer or Moderna vaccined sera. There was a significant and positive correlation between serum IgG levels and ID50 titers for not only SARS-CoV-2 WT but also the variants. These findings indicate that a high level of anti-spike IgG may offer better protection against infection from SARS-CoV-2 and its variants. Therefore, it is necessary to longitudinally monitor specific serum IgG level for evaluating the protective efficacy of the vaccines against SARS-CoV-2 and its new variants.
    • COVID Moonshot: Open Science Discovery of SARS-CoV-2 Main Protease Inhibitors by Combining Crowdsourcing, High-Throughput Experiments, Computational Simulations, and Machine Learning

      The COVID Moonshot Consortium (2020-10-30)
      Herein we provide a living summary of the data generated during the COVID Moonshot project focused on the development of SARS-CoV-2 main protease (Mpro) inhibitors. Our approach uniquely combines crowdsourced medicinal chemistry insights with high throughput crystallography, exascale computational chemistry infrastructure for simulations, and machine learning in triaging designs and predicting synthetic routes. This manuscript describes our methodologies leading to both covalent and non-covalent inhibitors displaying protease IC50 values under 150 nM and viral inhibition under 5 uM in multiple different viral replication assays. Furthermore, we provide over 200 crystal structures of fragment-like and lead-like molecules in complex with the main protease. Over 1000 synthesized and ordered compounds are also reported with the corresponding activity in Mpro enzymatic assays using two different experimental setups. The data referenced in this document will be continually updated to reflect the current experimental progress of the COVID Moonshot project, and serves as a citable reference for ensuing publications. All of the generated data is open to other researchers who may find it of use.