• Effects of the COVID‐19 Pandemic on Patients Living With Vasculitis

      Vasculitis Patient‐Powered Research Network (2020-12-08)
      This study aimed to analyze the concerns and health‐related behaviors in patients with vasculitis during the early phase of the coronavirus disease 2019 (COVID‐19) pandemic in North America. Patients with vasculitis in North America were invited to complete an online survey through the Vasculitis Patient‐Powered Research Network in collaboration with the Vasculitis Foundation and the Relapsing Polychondritis Foundation. Questions focused on concerns and behaviors related to doctors’ visits, tests, medication, and telehealth use. Factors affecting their concern and health‐related behaviors were determined. Data from 662 patients were included: 90% of patients were White, 78% were women, 83% expressed moderate or high levels of concern about COVID‐19, and 87% reported that their vasculitis moderately or extremely affected their level of concern. Older age, female sex, lung disease, and immunosuppression were associated with greater concern. Doctors’ visits, laboratory tests, and other tests were avoided by 66%, 46%, and 40% of patients, respectively. Younger age, urban location, higher income, higher concern levels, and prednisone use (>10 mg/day) were associated with greater likelihood of avoiding visits or tests. Ten percent of patients on immunosuppressive therapy stopped their medication. Twenty‐nine percent patients on rituximab avoided an infusion. Forty‐four percent of patients had telehealth visits; more visits were reported for younger patients, for patients on glucocorticoids, and in Canada versus the United States. During the COVID‐19 pandemic, patients with vasculitis have high levels of concern and exhibit potentially harmful health‐related behaviors. Health care use varies across different demographic groups and geographic regions. Specific strategies are warranted to facilitate engagement of these patients with the health care system during the pandemic.
    • Elite Athletes and COVID-19 Lockdown: Future Health Concerns for an Entire Sector

      Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine (Temple University) (2020-05-07)
      In this editorial, we focused our attention on elite athletes during the COVID-19 lockdown. A high level of physical fitness is required by elite athletes irrespective of the specific type of sport. Generally speaking, elite athletes avoid long periods of rest during and at the end of the competitive season. Normally, elite athletes stop training or reduce training volume and intensity for a period that ranges from two weeks to a maximum of four weeks.
    • Embracing Diversity in Dermatology: Creation of a Culture of Equity and Inclusion in Dermatology

      Desai, Seemal R.; Khanna, Rayva; Glass, Donald; Alam, Murad; Barrio, Vicky; French, Lars E.; Gohara, Mona; McKinley-Grant, Lynn; Harvey, Valerie; Heath, Candrice; Mariwalla, Kavita; Pentland, Alice; Piliang, Melissa; Pourciau, Crystal; Taylor, Susan; Wu, Peggy; Grimes, Pearl; Lim, Henry W.; Heath|0000-0002-2687-5468 (2021-08-05)
    • Endothelial Immunity Trained by Coronavirus Infections, DAMP Stimulations and Regulated by Anti-Oxidant NRF2 May Contribute to Inflammations, Myelopoiesis, COVID-19 Cytokine Storms and Thromboembolism

      Centers of Cardiovascular Research, Inflammation, Translational & Clinical Lung Research (Temple University); Metabolic Disease Research, Thrombosis Research (Temple University) (2021-06-25)
      To characterize transcriptomic changes in endothelial cells (ECs) infected by coronaviruses, and stimulated by DAMPs, the expressions of 1311 innate immune regulatomic genes (IGs) were examined in 28 EC microarray datasets with 7 monocyte datasets as controls. We made the following findings: The majority of IGs are upregulated in the first 12 hours post-infection (PI), and maintained until 48 hours PI in human microvascular EC infected by middle east respiratory syndrome-coronavirus (MERS-CoV) (an EC model for COVID-19). The expressions of IGs are modulated in 21 human EC transcriptomic datasets by various PAMPs/DAMPs, including LPS, LPC, shear stress, hyperlipidemia and oxLDL. Upregulation of many IGs such as nucleic acid sensors are shared between ECs infected by MERS-CoV and those stimulated by PAMPs and DAMPs. Human heart EC and mouse aortic EC express all four types of coronavirus receptors such as ANPEP, CEACAM1, ACE2, DPP4 and virus entry facilitator TMPRSS2 (heart EC); most of coronavirus replication-transcription protein complexes are expressed in HMEC, which contribute to viremia, thromboembolism, and cardiovascular comorbidities of COVID-19. ECs have novel trained immunity (TI), in which subsequent inflammation is enhanced. Upregulated proinflammatory cytokines such as TNFα, IL6, CSF1 and CSF3 and TI marker IL-32 as well as TI metabolic enzymes and epigenetic enzymes indicate TI function in HMEC infected by MERS-CoV, which may drive cytokine storms. Upregulated CSF1 and CSF3 demonstrate a novel function of ECs in promoting myelopoiesis. Mechanistically, the ER stress and ROS, together with decreased mitochondrial OXPHOS complexes, facilitate a proinflammatory response and TI. Additionally, an increase of the regulators of mitotic catastrophe cell death, apoptosis, ferroptosis, inflammasomes-driven pyroptosis in ECs infected with MERS-CoV and the upregulation of pro-thrombogenic factors increase thromboembolism potential. Finally, NRF2-suppressed ROS regulate innate immune responses, TI, thrombosis, EC inflammation and death. These transcriptomic results provide novel insights on the roles of ECs in coronavirus infections such as COVID-19, cardiovascular diseases (CVD), inflammation, transplantation, autoimmune disease and cancers.
    • Entangling COVID-19 associated thrombosis into a secondary antiphospholipid antibody syndrome: Diagnostic and therapeutic perspectives (Review)

      Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine (Temple University) (2020-06-25)
      The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a novel β coronavirus that is the etiological agent of the pandemic coronavirus disease 2019 (COVID‑19) that at the time of writing (June 16, 2020) has infected almost 6 million people with some 450,000 deaths. These numbers are still rising daily. Most (some 80%) cases of COVID‑19 infection are asymptomatic, a substantial number of cases (15%) require hospitalization and an additional fraction of patients (5%) need recovery in intensive care units. Mortality for COVID‑19 infection appears to occur globally between 0.1 and 0.5% of infected patients although the frequency of lethality is significantly augmented in the elderly and in patients with other comorbidities. The development of acute respiratory distress syndrome and episodes of thromboembolism that may lead to disseminated intravascular coagulation (DIC) represent the primary causes of lethality during COVID‑19 infection. Increasing evidence suggests that thrombotic diathesis is due to multiple derangements of the coagulation system including marked elevation of D‑dimer that correlate negatively with survival. We propose here that the thromboembolic events and eventually the development of DIC provoked by SARS‑CoV‑2 infection may represent a secondary anti‑phospholipid antibody syndrome (APS). We will apply both Baconian inductivism and Cartesian deductivism to prove that secondary APS is likely responsible for coagulopathy during the course of COVID‑19 infection. Diagnostic and therapeutic implications of this are also discussed.
    • Epigallocatechin gallate from green tea effectively blocks infection of SARS-CoV-2 and new variants by inhibiting spike binding to ACE2 receptor

      Liu, Jinbiao; Bodnar, Brittany; Meng, Fengzhen; Khan, Adil I.; Wang, Xu; Saribas, Sami; Wang, Tao; Lohani, Saroj Chandra; Wang, Peng; Wei, Zhengyu; Luo, Jinjun; Zhou, Lina; Wu, Jianguo; Luo, Guangxiang; Li, Qingsheng; Hu, Wenhui; Ho, Wenzhe; Bodnar|0000-0003-0467-5219 (2021-08-31)
      Background: As the COVID-19 pandemic rages on, the new SARS-CoV-2 variants have emerged in the different regions of the world. These newly emerged variants have mutations in their spike (S) protein that may confer resistance to vaccine-elicited immunity and existing neutralizing antibody therapeutics. Therefore, there is still an urgent need of safe, effective, and affordable agents for prevention/treatment of SARS-CoV-2 and its variant infection. Results: We demonstrated that green tea beverage (GTB) or its major ingredient, epigallocatechin gallate (EGCG), were highly effective in inhibiting infection of live SARS-CoV-2 and human coronavirus (HCoV OC43). In addition, infection of the pseudoviruses with spikes of the new variants (UK-B.1.1.7, SA-B.1.351, and CA-B.1.429) was efficiently blocked by GTB or EGCG. Among the 4 active green tea catechins at noncytotoxic doses, EGCG was the most potent in the action against the viruses. The highest inhibitory activity was observed when the viruses or the cells were pre-incubated with EGCG prior to the infection. Mechanistic studies revealed that EGCG blocked infection at the entry step through interfering with the engagement of the receptor binding domain (RBD) of the viral spikes to angiotensin-converting enzyme 2 (ACE2) receptor of the host cells. Conclusions: These data support further clinical evaluation and development of EGCG as a novel, safe, and cost-effective natural product for prevention/treatment of SARS-CoV-2 transmission and infection.
    • Essential requirement for JPT2 in NAADP-evoked Ca2+ signaling

      Center for Substance Abuse Research (Temple University) (2021-03-23)
      Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca2+ from acidic organelles through the activation of two-pore channels (TPCs) to regulate endolysosomal trafficking events. NAADP action is mediated by NAADP-binding protein(s) of unknown identity that confer NAADP sensitivity to TPCs. Here, we used a “clickable” NAADP-based photoprobe to isolate human NAADP-binding proteins and identified Jupiter microtubule-associated homolog 2 (JPT2) as a TPC accessory protein required for endogenous NAADP-evoked Ca2+ signaling. JPT2 was also required for the translocation of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus through the endolysosomal system. Thus, JPT2 is a component of the NAADP receptor complex that is essential for TPC-dependent Ca2+ signaling and control of coronaviral entry.
    • Etoposide as Salvage Therapy for Cytokine Storm due to COVID-19

      COVID-19 Research Group (Temple University) (2020-09-12)
      Coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality because of a lack of effective therapies. Therapeutic strategies under investigation target the overactive cytokine response with anti-cytokine or immunomodulators therapies. We present a unique case of severe cytokine storm resistant to multiple anti-cytokine therapies, but eventually responsive to etoposide. Thus, etoposide may have a role as salvage therapy in treatment of cytokine storm in COVID-19. To our knowledge, this is the first reported case of use of etoposide in COVID-19.
    • Evaluating the neutralizing ability of a CpG-adjuvanted S-2P subunit vaccine against SARS-CoV-2 Variants of Concern

      Lien, Chia-En; Kuo, Tsun-Yung; Lin, Yi-Jiun; Lian, Wei-Cheng; Lin, Meei-Yun; Liu, Luke Tzu-Chi; Chou, Yu-Chi; Chen, Charles (2021-03-22)
      Vaccination is currently the best weapon to control the COVID-19 pandemic. However, an alarming number of novel variants termed Variants of Concern (VoC) were found to harbor mutations that diminished the neutralizing capacity of antibodies elicited by the vaccines. We have investigated the neutralizing titers of antibodies from sera of humans and rats immunized with the MVC-COV1901 vaccine against pseudoviruses coated with the wildtype, D614G, B.1.1.7, or B.1.351 spike proteins. Rats vaccinated with two doses of adjuvanted S-2P retained neutralization activities against the B.1.351 variant, albeit with a slight reduction compared to wildtype. Phase 1 vaccinated subjects showed more reduced neutralization abilities against the B.1.351 variant. The study is among the first, to our knowledge, to demonstrate dose-dependent neutralizing responses against VoCs, particularly against B.1.351, from different doses of antigen in a clinical trial for a subunit protein COVID-19 vaccine. The appearance of vaccine escape variants is a growing concern facing many current COVID-19 vaccines and therapeutics. Strategies should be adopted against the ever-changing nature of these variants. The observations of this study grant us valuable insight into preemptive strikes against current and future variants.
    • Evidence of significant natural selection in the evolution of SARS-CoV-2 in bats, not humans

      Institute for Genomics and Evolutionary Medicine (Temple University) (2020-05-29)
      RNA viruses are proficient at switching to novel host species due to their fast mutation rates. Implicit in this assumption is the need to evolve adaptations in the new host species to exploit their cells efficiently. However, SARS-CoV-2 has required no significant adaptation to humans since the pandemic began, with no observed selective sweeps to date. Here we contrast the role of positive selection and recombination in the Sarbecoviruses in horseshoe bats to SARS-CoV-2 evolution in humans. While methods can detect some evidence for positive selection in SARS-CoV-2, we demonstrate these are mostly due to recombination and sequencing artefacts. Purifying selection is also substantially weaker in SARS-CoV-2 than in the related bat Sarbecoviruses. In comparison, our results show evidence for positive, specifically episodic selection, acting on the bat virus lineage SARS-CoV-2 emerged from. This signature of selection can also be observed among synonymous substitutions, for example, linked to ancestral CpG depletion on this bat lineage. We show the bat virus RmYN02 has recombinant CpG content in Spike pointing to coinfection and evolution in bats without involvement of other species. Our results suggest the non-human progenitor of SARS-CoV-2 was capable of human-human transmission as a consequence of its natural evolution in bats.
    • Exploring the natural origins of SARS-CoV-2 in the light of recombination

      Institute for Genomics and Evolutionary Medicine (iGEM) (Temple University) (2021-05-27)
      The lack of an identifiable intermediate host species for the proximal animal ancestor of SARS-CoV-2, and the large geographical distance between Wuhan and where the closest evolutionary related coronaviruses circulating in horseshoe bats (Sarbecoviruses) have been identified, is fuelling speculation on the natural origins of SARS-CoV-2. We have comprehensively analysed phylogenetic relations between SARS-CoV-2, and the related bat and pangolin Sarbecoviruses sampled so far. Determining the likely recombination events reveals a highly reticulate evolutionary history within this group of coronaviruses. Clustering of the inferred recombination events is non-random with evidence that Spike, the main target for humoral immunity, is beside a recombination hotspot likely driving antigenic shift in the ancestry of bat Sarbecoviruses. Coupled with the geographic ranges of their hosts and the sampling locations, across southern China, and into Southeast Asia, we confirm horseshoe bats, Rhinolophus, are the likely SARS-CoV-2 progenitor reservoir species. By tracing the recombinant sequence patterns, we conclude that there has been relatively recent geographic movement and co-circulation of these viruses’ ancestors, extending across their bat host ranges in China and Southeast Asia over the last 100 years or so. We confirm that a direct proximal ancestor to SARS-CoV-2 is yet to be sampled, since the closest relative shared a common ancestor with SARS-CoV-2 approximately 40 years ago. Our analysis highlights the need for more wildlife sampling to (i) pinpoint the exact origins of SARS-CoV-2’s animal progenitor, and (ii) survey the extent of the diversity in the related Sarbecoviruses’ phylogeny that present high risk for future spillover.
    • Expression of SARS-CoV-2 Entry Factors in Human Alveolar Type II Cells in Aging and Emphysema

      Center for Inflammation, Translational and Clinical Lung Research (Temple University) (2021-07-06)
      Alveolar type II (ATII) cells proliferate and restore the injured epithelium. It has been described that SARS-CoV-2 infection causes diffuse alveolar damage in the lungs. However, host factors facilitating virus infection in ATII cells are not well known. We determined the SARS-CoV-2-related genes and protein expression using RT-PCR and Western blotting, respectively, in ATII cells isolated from young and elderly non-smokers, smokers, and ex-smokers. Cells were also obtained from lung transplants of emphysema patients. ACE2 has been identified as the receptor for SARS-CoV-2, and we found significantly increased levels in young and elderly smokers and emphysema patients. The viral entry depends on TMPRSS2 protease activity, and a higher expression was detected in elderly smokers and ex-smokers and emphysema patients. Both ACE2 and TMPRSS2 mRNA levels were higher in this disease in comparison with non-smokers. CD209L serves as a receptor for SARS-CoV-2, and we found increased levels in ATII cells obtained from smokers and in emphysema patients. Also, our data suggest CD209L regulation by miR142. Endoplasmic reticulum stress was detected in ATII cells in this disease. Our results suggest that upregulation of SARS-CoV-2 entry factors in ATII cells in aging, smokers, and emphysema patients may facilitate infection.
    • Extended Reality Technologies in Nutrition Education and Behavior: Comprehensive Scoping Review and Future Directions

      Center for Obesity Research and Education (Temple University) (2020-09-22)
      The use of Extended Reality (XR) (i.e. Virtual and Augmented Reality) for nutrition education and behavior change has not been comprehensively reviewed. This paper presents findings from a scoping review of current published research. Articles (n = 92) were extracted from PubMed and Scopus using a structured search strategy and selection approach. Pertinent study information was extracted using a standardized data collection form. Each article was independently reviewed and coded by two members of the research team, who then met to resolve any coding discrepancies. There is an increasing trend in publication in this area, mostly regarding Virtual Reality. Most studies used developmental testing in a lab setting, employed descriptive or observational methods, and focused on momentary behavior change like food selection rather than education. The growth and diversity of XR studies suggest the potential of this approach. There is a need and opportunity for more XR technology focused on children and other foundational theoretical determinants of behavior change to be addressed within nutrition education. Our findings suggest that XR technology is a burgeoning approach in the field of nutrition, but important gaps remain, including inadequate methodological rigor, community application, and assessment of the impact on dietary behaviors.
    • Fast and accurate genome-wide predictions and structural modeling of protein-protein interactions using Galaxy

      Institute for Genomics and Evolutionary Medicine (iGEM) (Temple University) (2021-04-14)
      Protein-protein interactions play a crucial role in almost all cellular processes. Identifying interacting proteins reveals insight into living organisms and yields novel drug targets for disease treatment. Here, we present a publicly available, automated pipeline to predict genome-wide protein-protein interactions and produce high-quality multimeric structural models. Application of our method to the Human and Yeast genomes yield protein-protein interaction networks similar in quality to common experimental methods. We identified and modeled Human proteins likely to interact with the papain-like protease of SARS-CoV2’s non-structural protein 3 (Nsp3). We also produced models of SARS-CoV2’s spike protein (S) interacting with myelin-oligodendrocyte glycoprotein receptor (MOG) and dipeptidyl peptidase-4 (DPP4). The presented method is capable of confidently identifying interactions while providing high-quality multimeric structural models for experimental validation. The interactome modeling pipeline is available at usegalaxy.org and usegalaxy.eu.
    • First-in-Human Trial of a Recombinant Stabilized Prefusion SARS-CoV-2 Spike Protein Vaccine with Adjuvant of Aluminum Hydroxide and CpG 1018

      Hsieh, Szu-Min; Liu, Wang-Da; Huang, Yu-Shan; Lin, Yi-Jiun; Hsieh, Erh-Fang; Lian, Wei-Cheng; Chen, Charles; Tai, I-Chen; Chang, Shan-Chwen (2021-04-06)
      Design: This is a phase 1, dose-escalation open-label trial to evaluate the safety and immunogenicity of MVC-COV1901, a recombinant stabilized prefusion SARS-CoV-2 spike (S-2P) protein vaccine with adjuvant of aluminum hydroxide and CpG 1018. Methods: We enrolled 45 healthy adults from 20 to 49 years of age to be administered with two vaccinations of MVC-COV1901 in a low dose (LD), middle dose (MD), and high dose (HD) of spike protein at 28 days apart. There were 15 participants in each dose group, and all of them were followed up for 28 days after the second vaccination at the time of interim analysis. Adverse events (AEs) and laboratory data were recorded for safety evaluation. Blood samples were collected for wild-type SARS-CoV-2 and pseudovirus neutralization assays as well as SARS-CoV-2 spike-specific immunoglobulin G (IgG) at various times. Overall, the study duration will be 7 months. Results: Solicited events were mostly mild and similar in the participants of all three dose groups. No subject experienced fever. There were no serious nor adverse events of special interest at the time point of this interim report. After the second vaccination, the SARS-CoV-2 spike specific IgG titers increased with peak geometric mean titers at 7178.245 (LD), 7746.086 (MD), and 11220.58 (HD), respectively. Serum neutralizing activity was detected by two methods in all participants of MD and HD groups, with geometric mean values generally comparable to those of a panel of control convalescent serum specimens. All of the participants in the MD and HD groups were seroconverted after the second vaccination. Conclusions: The MVC-COV1901 vaccine is safe and elicits remarkable immune responses especially in the MD and HD groups.
    • Fondaparinux: Should It Be Studied in Patients with COVID-19 Disease?

      Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine (Temple University) (2020-10-01)
      We have read with interest the review article by Bikdeli et al recently published in Thrombosis and Haemostasis on the priority in planning studies on the different anticoagulants in coronavirus disease 2019 (COVID-19) infection.[1] The authors describe the characteristics of both the anticoagulants available today and in the future. Antiplatelets drugs have been also considered. Surprisingly, fondaparinux (FPX) has reached a lower priority research mean (4.89) than unfractionated heparin (UFH) and low-molecular weight heparin (LMWH) at intermediate (7.82) or therapeutic (7.53) dosage for hospitalized ward and intensive care unit patients. We believe that properties of these drugs have been overlooked by the scientific panel of the Global COVID-19 Thrombosis Collaborative Group.
    • Freely accessible ready to use global infrastructure for SARS-CoV-2 monitoring

      Maier, Wolfgang; Bray, Simon; van den Beek, Marius; Bouvier, Dave; Coraor, Nathaniel; Miladi, Milad; Singh, Babita; Rambla De Argila, Jordi; Baker, Dannon; Roach, Nathan; Gladman, Simon; Coppens, Frederik; Martin, Darren P.; Lonie, Andrew; Grüning, Björn; Pond, Sergei; Nekrutenko, Anton; Pond|0000-0003-4817-4029 (2021-03-25)
      The COVID-19 pandemic is the first global health crisis to occur in the age of big genomic data. Although data generation capacity is well established and sufficiently standardized, analytical capacity is not. To establish analytical capacity it is necessary to pull together global computational resources and deliver the best open source tools and analysis workflows within a ready to use, universally accessible resource. Such a resource should not be controlled by a single research group, institution, or country. Instead it should be maintained by a community of users and developers who ensure that the system remains operational and populated with current tools. A community is also essential for facilitating the types of discourse needed to establish best analytical practices. Bringing together public computational research infrastructure from the USA, Europe, and Australia, we developed a distributed data analysis platform that accomplishes these goals. It is immediately accessible to anyone in the world and is designed for the analysis of rapidly growing collections of deep sequencing datasets. We demonstrate its utility by detecting allelic variants in high-quality existing SARS-CoV-2 sequencing datasets and by continuous reanalysis of COG-UK data. All workflows, data, and documentation is available at https://covid19.galaxyproject.org.
    • From examining the relationship between (corona)viral adhesins and galectins to glyco-perspectives

      Institute of Computational Molecular Science (Temple University) (2021-03-16)
      Glycan-lectin recognition is vital to processes that impact human health, including viral infections. Proceeding from crystallographical evidence of case studies on adeno-, corona-, and rotaviral spike proteins, the relationship of these adhesins to mammalian galectins was examined by computational similarity assessments. Intrafamily diversity among human galectins was in the range of that to these viral surface proteins. Our findings are offered to inspire the consideration of lectin-based approaches to thwart infection by present and future viral threats, also mentioning possible implications for vaccine development.