• let-7 microRNAs: Their Role in Cerebral and Cardiovascular Diseases, Inflammation, Cancer, and Their Regulation

      Center for Substance Abuse Research (Temple University) (2021-05-26)
      The let-7 family is among the first microRNAs found. Recent investigations have indicated that it is highly expressed in many systems, including cerebral and cardiovascular systems. Numerous studies have implicated the aberrant expression of let-7 members in cardiovascular diseases, such as stroke, myocardial infarction (MI), cardiac fibrosis, and atherosclerosis as well as in the inflammation related to these diseases. Furthermore, the let-7 microRNAs are involved in development and differentiation of embryonic stem cells in the cardiovascular system. Numerous genes have been identified as target genes of let-7, as well as a number of the let-7’ regulators. Further studies are necessary to identify the gene targets and signaling pathways of let-7 in cardiovascular diseases and inflammatory processes. The bulk of the let-7’ regulatory proteins are well studied in development, proliferation, differentiation, and cancer, but their roles in inflammation, cardiovascular diseases, and/or stroke are not well understood. Further knowledge on the regulation of let-7 is crucial for therapeutic advances. This review focuses on research progress regarding the roles of let-7 and their regulation in cerebral and cardiovascular diseases and associated inflammation.
    • Lung transplantation and coronavirus disease 2019 (COVID-19): a roadmap for the enduring pandemic

      Shigemura, Norhisa; Cordova, Francis; Hayanga, Awori J.; Criner, Gerard; Toyoda, Yoshiya (2021-11-05)
      Due to the ongoing coronavirus disease 2019 (COVID-19) pandemic, organ transplant specialists remain uncertain of directions and goals before and after organ replacement therapy (1). Reports of COVID-19 outcomes in lung transplant recipients have been limited, comprising a small number of case series without a consistent approach between those infected post-transplant and those who became candidates for a transplant post-infection (2-5). Nonetheless, the pandemic has inspired new roles for lung failure specialists who must care for patients who develop acute respiratory distress syndrome (ARDS) and progressive pulmonary fibrosis due to COVID-19 (6). Specialists who can handle organ replacement therapy including extracorporeal membrane oxygenation (ECMO) and lung transplantation are an integral part of the multidisciplinary care team (2,7). In the midst of the first phase of the pandemic, we offered our insights regarding the direction of lung transplantation during the pandemic as specialists at a high-volume center in a geographical area with high COVID-19 infection rates (8). Herein, we expand our review of outcomes in lung transplant recipients with COVID-19 infections and offer our phased approach as well as insights for lung transplantation for post covid lung failure as the sequelae of COVID-19 infection in light of our large outcomes data for the recipients with positive covid after lung transplantation.
    • Males Receive Low-Tidal Volume Component of Lung Protective Ventilation More Frequently than Females in the Emergency Department

      Isenberg, Derek L.; Bloom, Benjamin; Gentile, Nina; Reimer, Hannah; Glaze, Owen D.; Palumbo, Paige; Fenstermacher, Rachel (2020)
      Introduction: Mechanical ventilation is a commonly performed procedure in the emergency department (ED). Approximately 240,000 patients per year receive mechanical ventilation in the ED representing 0.23% of ED visits. An ED-based trial published in 2017 showed that a bundle of interventions in mechanically ventilated patients, including low tidal volume ventilation, reduced the development of acute respiratory distress syndrome by nearly 50%. Prior literature has shown that as many as 40% of ED patients do not receive lung protective ventilation. Our goal was to determine whether differences exist between the percent of males vs females who are ventilated at ≥ 8 milliliters per kilogram (mL/kg) of predicted body weight. Methods: We conducted this study at Temple University Hospital, a tertiary care center located in Philadelphia, Pennsylvania. This was a planned subgroup analysis of study looking at interventions to improve adherence to recommended tidal volume settings. We used a convenience sample of mechanically ventilated patients in our ED between September 1, 2017, and September 30, 2018. All adult patient > 18 years old were eligible for inclusion in the study. Our primary outcome measure was the number of patients who had initial tidal volumes set at > 8 mL/kg of predicted body weight. Our secondary outcome was the number of patients who had tidal volumes set at ≥ 8 mL/kg at 60 minutes after initiation of mechanical ventilation. Results: A total of 130 patients were included in the final analysis. We found that significantly more females were initially ventilated with tidal volumes ≥ 8 mL/kg compared to men: 56% of females vs 9% of males (p=<0.001). Data was available for 107 patients (82%) who were in the ED at 60 minutes after initiation of mechanical ventilation. Again, a significantly larger percentage of females were ventilated with tidal volumes ≥ 8 mL/kg at 60 minutes: 56% of females vs 10% of males (p<0.001). Conclusion: The vast majority of tidal volumes ≥ 8 mL/kg during mechanical ventilation occurs in females. We suggest that objective measurements, such as a tape measure and tidal volume card, be used when setting tidal volumes for all patients, especially females.
    • Managing through a crisis: Managerial implications for business-to-business firms

      Pedersen, Carsten Lund; Ritter, Thomas; Di Benedetto, C. Anthony (2020-06-05)
    • Material Hardship Among Custodial Grandparents and Grandchildren's Physical and Mental Health in COVID-19

      Xu, Yanfeng; Zhao, Qianwei; Schuler, Brittany; Levkoff, Sue; Schuler|0000-0002-2869-6260 (2021-12-17)
      COVID-19 has increased economic hardship for many families, including custodial grandparent-headed families. We aim to examine latent classes of material hardship among custodial grandparent-headed families, to assess predictors associated with identified classes, and to investigate associations with grandchildren’s physical and mental health outcomes during COVID-19. Data was collected from a cross-sectional survey in June 2020. The sample comprised of 362 grandparents. Latent class analysis and logistic regression were conducted. Three latent classes of material hardship were identified: Class 1 (n = 232; 64.1%) low overall hardship with high medical hardship, class 2 (n = 52; 14.4%) moderate overall hardship with high utility hardship, and class 3 (n = 78; 21.5%) severe overall hardship. Factors, such as race, household income, labor force status, financial assistance status, and trigger events to raise grandchildren, were associated with class membership. Class 2 (OR = 0.19, p < 0.05) compared to Class 1 was significantly associated with grandchildren’s physical health. Our findings suggest that material hardship is heterogeneous among custodial grandparents during COVID-19, and children in households experiencing utility hardship have a higher risk for poorer physical health outcomes. Results highlight the needs to meet grandparents’ material needs and call for future research to examine the mechanism that explains the link between material hardship and grandchildren’s outcomes.
    • Mathematical model and simulations of COVID-19 2020 outbreak in New York: Predictions and implications for control measures

      Sinha, Durgesh; Tan, Peiwen; 0000-0001-7749-3710 (2020-05-01)
      The outbreak of the novel coronavirus has resulted in significant morbidity and mortality in the affected 210 countries with 2.4 million people infected and over 163 thousand deaths. The COVID-19 spike protein is effective at binding to human cells, but this COVID-19 backbone differed substantially from other, already known coronaviruses and mostly resembled viruses found in bats and pangolins. To help predict possible dynamics of COVID-19 as well as ways to contain it, this paper develops a mathematical model for the disease, which includes two different infectious routes. The model’s predictions are fitted to data from the outbreak in New York State from the first reported case from March 01, 2020 to April 19, 2020. The containment time and the severity of the outbreaks depend crucially on the contact coefficients and the isolation rate constant. When randomness is added to the model coefficients, the simulations show that the model is sensitive to the scaled contact rate among people and to the isolation rate. The model is analyzed using stability theory for ordinary differential equations and indicates that when using only isolation for control and advising self-recovery, the endemic steady state is locally stable and attractive. After reaching the peak of COVID-19 on April 14, 2020, new infections by the virus would slow down, particularly from the beginning of May at New York State if people keep the isolation. Numerical simulations with parameters estimated from New York State illustrate the analytical results and the model behavior, which may have important implications for the disease containment in other cities. Indeed, the model highlights the importance of isolation of infected individuals and advising self-recovery may be used to assess other control measures. The model is general and may be used to analyze outbreaks in other states of the United States and other countries.
    • Mathematical Modeling Study of the 2020 CoVID-19 Outbreak in the United States

      Sinha, Durgesh; Klahn, Nicholas; 0000-0001-7749-3710 (2020-04-12)
      A mathematical model was developed for the currently evolving COVID-19 outbreak. Data analysis and model fitting using Latin Hypercube Sampling partial Correlation Coefficient Method was used to determine the model’s parameters and basic reproduction numbers. The infectivity values from symptomatic infectious people was 0.118461389 (95% CI [0.1136278, 0.12329497]), asymptomatic transmission was 0.100111427 (95% CI [0.1000297, 0.10019314]), and quarantined transmission was 0.057337278 (95% CI [0.0504738, 0.0642008]). The United states reached its peak basic reproduction number on March 10th where R0=58, but it has since lowered to 1.47 as of April 5th. Also, those in quarantine had contributed the most to the basic reproduction number, with asymptomatic people being second, and regular symptomatic people contributing the least. Our simulations showed that the United States has reached its peak occurred on April 11, 2020 with a total 461,700 number of cases and it will reach on June 12, 2020 where the confirmed case count would reach 1.439 million. As for the longevity of the virus, our prediction shows that it could be under preventive measure within two years by February 10, 2022, would be 14,130.
    • Mathematical Modeling to Estimate the Reproductive Number and the Outbreak Size of COVID-19: The case of India and the World

      Sinha, Durgesh; 0000-0001-7749-3710 (2020-05-04)
      Coronavirus disease (COVID-19) has become a global pandemic with more than 218,000 deaths in 211 different countries around the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for this deadliest disease. This paper describes a mathematical model for India, a country with the second highest population in the world with an extremely high population density of about 464 people per km2. This disease has multiphasic actions and reaction mode and our model SEIAQIm is based on six compartmental groups in the form of susceptible, exposed, infectious, asymptomatic, quarantine, and recovered immune factions. Latin Hypercube Sampling Partial Rank Correlation Coefficient method was used for the data analysis and model fitting. According to our model, India would reach its basic reproduction number R0=0.97 on May 14, 2020 with a total number of 73,800 estimated cases. Further, this study also equates the world's situation using the same model system and predicts by May 7, 2020 with a total number of 3,772,000 estimated confirmed cases. Moreover, the current mathematical model highlights the importance of social distancing as an effective method of containing spread of COVID-19.
    • Mechanism of a COVID-19 nanoparticle vaccine candidate that elicits a broadly neutralizing antibody response to SARS-CoV-2 variants

      Fels Institute for Cancer Research and Molecular Biology (Temple University) (2021-09-09)
      Vaccines that induce potent neutralizing antibody (NAb) responses against emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are essential for combating the coronavirus disease 2019 (COVID-19) pandemic. We demonstrated that mouse plasma induced by self-assembling protein nanoparticles (SApNPs) that present 20 rationally designed S2GΔHR2 spikes of the ancestral Wuhan-Hu-1 strain can neutralize the B.1.1.7, B.1.351, P.1, and B.1.617 variants with the same potency. The adjuvant effect on vaccine-induced immunity was investigated by testing 16 formulations for the multilayered I3-01v9 SApNP. Using single-cell sorting, monoclonal antibodies (mAbs) with diverse neutralization breadth and potency were isolated from mice immunized with the receptor binding domain (RBD), S2GΔHR2 spike, and SApNP vaccines. The mechanism of vaccine-induced immunity was examined in mice. Compared with the soluble spike, the I3-01v9 SApNP showed 6-fold longer retention, 4-fold greater presentation on follicular dendritic cell dendrites, and 5-fold stronger germinal center reactions in lymph node follicles.
    • Mechanism of a COVID-19 nanoparticle vaccine candidate that elicits a broadly neutralizing antibody response to SARS-CoV-2 variants

      Fels Institute for Cancer Research and Molecular Biology (Temple University) (2021-10-20)
      Vaccines that induce potent neutralizing antibody (NAb) responses against emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are essential for combating the coronavirus disease 2019 (COVID-19) pandemic. We demonstrated that mouse plasma induced by self-assembling protein nanoparticles (SApNPs) that present 20 rationally designed S2GΔHR2 spikes of the ancestral Wuhan-Hu-1 strain can neutralize the B.1.1.7, B.1.351, P.1, and B.1.617 variants with comparable potency. The adjuvant effect on vaccine-induced immunity was investigated by testing 16 formulations for the multilayered I3-01v9 SApNP. Using single-cell sorting, monoclonal antibodies (mAbs) with diverse neutralization breadth and potency were isolated from mice immunized with the receptor binding domain (RBD), S2GΔHR2 spike, and SApNP vaccines. The mechanism of vaccine-induced immunity was examined in the mouse model. Compared with the soluble spike, the I3-01v9 SApNP showed sixfold longer retention, fourfold greater presentation on follicular dendritic cell dendrites, and fivefold stronger germinal center reactions in lymph node follicles.
    • Medication for Opioid Use Disorder Service Provision and Telephone Counseling: A Concurrent Mixed-Methods Approach

      Martin, Rosemarie; Kang, Augustine W.; DeBritz, Audrey A.; Walton, Mary R.; Hoadley, Ariel; DelaCuesta, Courtney; Hurley, Linda; Hoadley|0000-0003-1360-0358 (2021-06-07)
      Using quantitative and qualitative evidence, this study triangulates counselors’ perspectives on the use of telemedicine in the context of Opioid Use Disorder (OUD) treatment. A concurrent mixed-methods design examined counselors’ experiences with telephone counseling during the COVID-19 pandemic. N = 42 counselors who provided OUD counseling services completed a close-ended, quantitative survey examining their experiences in addressing clients’ anxiety, depression, anger, substance use, therapeutic relationship, and substance use recovery using telephone counseling. The survey also assessed comfort, convenience, and satisfaction with telephone counseling. Counselors also completed open-ended responses examining satisfaction, convenience, relationship with patients, substance use, and general feedback with telephone counseling. The synthesis of quantitative and qualitative evidence indicated that a majority of counselors had positive experiences with using telephone counseling to provide services to clients undergoing OUD treatment. Convenience, greater access to clients, and flexibility were among the reasons cited for their positive experience. However, counselors also expressed that the telephone counseling was impersonal, and that some clients may have difficulties accessing appropriate technology for telehealth adoption. Findings suggest that further research with counselors is needed to identify the key elements of an effective integration of telephone counseling with traditional in-person treatment approaches in the post-pandemic era.
    • Mental health solutions for domestic violence victims amid COVID-19: a review of the literature

      Su, Zhaohui; McDonnell, Dean; Roth, Stephanie; Li, Quanlei; Segalo, Sabina; Shi, Feng; Wagers, Shelly; Roth|0000-0001-5415-1718 (2021-06-28)
      Background: Due to COVID-19, domestic violence victims face a range of mental health challenges, possibly resulting in substantial human and economic consequences. However, there is a lack of mental health interventions tailored to domestic violence victims and in the context of COVID-19. In this study, we aim to identify interventions that can improve domestic violence victims’ mental health amid the COVID-19 pandemic to address the research gap. Main text: Drawing insights from established COVID-19 review frameworks and a comprehensive review of PubMed literature, we obtained information on interventions that can address domestic violence victims’ mental health challenges amid COVID-19. We identified practical and timely solutions that can be utilized to address mental health challenges domestic violence victims face amid COVID-19, mainly focusing on (1) decreasing victims’ exposure to the abuser and (2) increasing victims’ access to mental health services. Conclusion: Domestic violence is a public health crisis that affects all demographics and could result in significant morbidity and mortality. In addition to emphasizing mental health challenges faced by domestic violence victims, multidisciplinary interventions are identified that could provide timely and practical solutions to domestic violence victims amid the pandemic, which range from tailored shelter home strategies, education programs, escape plans, laws and regulations, as well as more technology-based mental health solutions. There is a significant need for more multipronged and multidisciplinary strategies to address domestic violence amid and beyond the pandemic, particularly interventions that could capitalize on the ubiquity and cost-effectiveness of technology-based solutions.
    • Mitigating saliva aerosol contamination in a dental school clinic

      Yang, Maobin; Chaghtai, Asad; Melendez, Marc; Hasson, Hana; Whitaker, Eugene; Badi, Mustafa; Sperrazza, Leona; Godel, Jeffrey; Yesilsoy, Cemil; Tellez, Marisol; Orrego, Santiago; Montoya, Carolina; Ismail, Amid (2021-02-05)
      Background: Transmission of COVID-19 via salivary aerosol particles generated when using handpieces or ultrasonic scalers is a major concern during the COVID-19 pandemic. The aim of this study was to assess the spread of dental aerosols on patients and dental providers during aerosol-generating dental procedures. Methods: This pilot study was conducted with one volunteer. A dental unit used at the dental school for general dental care was the site of the experiment. Before the study, three measurement meters (DustTrak 8534, PTrak 8525 and AeroTrak 9306) were used to measure the ambient distribution of particles in the ambient air surrounding the dental chair. The volunteer wore a bouffant, goggles, and shoe covers and was seated in the dental chair in supine position, and covered with a surgical drape. The dentist and dental assistant donned bouffant, goggles, face shields, N95 masks, surgical gowns and shoe covers. The simulation was conducted by using a high-speed handpiece with a diamond bur operating in the oral cavity for 6 min without touching the teeth. A new set of measurement was obtained while using an ultrasonic scaler to clean all teeth of the volunteer. For both aerosol generating procedures, the aerosol particles were measured with the use of saliva ejector (SE) and high-speed suction (HSS) followed a separate set of measurement with the additional use of an extra oral high-volume suction (HVS) unit that was placed close to the mouth to capture the aerosol in addition to SE and HSS. The distribution of the air particles, including the size and concentration of aerosols, was measured around the patient, dentist, dental assistant, 3 feet above the patient, and the floor. Results: Four locations were identified with elevated aerosol levels compared to the baseline, including the chest of the dentist, the chest of patient, the chest of assistant and 3 feet above the patient. The use of additional extra oral high volume suction reduced aerosol to or below the baseline level. Conclusions: The increase of the level of aerosol with size less than 10 µm was minimal during dental procedures when using SE and HSS. Use of HVS further reduced aerosol levels below the ambient levels.
    • MK2a inhibitor CMPD1 abrogates chikungunya virus infection by modulating actin remodeling pathway

      Center for Translational Medicine (Temple University) (2021-05-26)
      Chikungunya virus (CHIKV) epidemics around the world have created public health concern with the unavailability of effective drugs and vaccines. This emphasizes the need for molecular understanding of host-virus interactions for developing effective targeted antivirals. Microarray analysis was carried out using CHIKV strain (Prototype and Indian) infected Vero cells and two host isozymes, MK2 and MK3 were selected for further analysis. Gene silencing and drug treatment were performed in vitro and in vivo to unravel the role of MK2/MK3 in CHIKV infection. Gene silencing of MK2 and MK3 abrogated around 58% CHIKV progeny release from the host cell and a MK2 activation (a) inhibitor (CMPD1) treatment demonstrated 68% inhibition of viral infection suggesting a major role of MAPKAPKs during the late phase of CHIKV infection in vitro. Further, it was observed that the inhibition in viral infection is primarily due to the abrogation of lamellipodium formation through modulation of factors involved in the actin cytoskeleton remodeling pathway that is responsible for releasing the virus from the infected cells. Moreover, CHIKV-infected C57BL/6 mice demonstrated reduction in the viral copy number, lessened disease score and better survivability after CMPD1 treatment. In addition, reduction in expression of key pro-inflammatory mediators such as CXCL13, RAGE, FGF, MMP9 and increase in HGF (a CHIKV infection recovery marker) was observed indicating the effectiveness of this drug against CHIKV. Additionally, CMPD1 also inhibited HSV1 and SARS CoV2-19 infection in vitro. Taken together it can be proposed that MK2 and MK3 are crucial host factors for CHIKV infection and can be considered as key targets for developing effective anti-CHIKV strategies in future.
    • Mobilization and Preparation of a Large Urban Academic Center During the COVID-19 Pandemic

      Chowdhury, Junad M.; Patel, Maulin; Zheng, Matthew; Abramian, Osheen; Criner, Gerard J. (2020-04-21)
    • Monitoring Non-indigenous Species in Port Habitats: First Application of a Standardized North American Protocol in the Mediterranean Sea

      Tamburini, Marco; Keppel, Erica; Marchini, Agnese; Repetto, Michele F.; Ruiz, Gregory M.; Ferrario, Jasmine; Occhipinti-Ambrogi, Anna (2021-07-16)
      Baseline port monitoring for fouling communities is an essential tool to assess non-indigenous species (NIS) introduction and spread, but a standardized and coordinated method among Mediterranean and European countries has not yet been adopted. In this context, it is important to test monitoring protocols that allow for the collection of standardized and directly comparable data, replicated across time and space. Here, for the first time in the Mediterranean Sea, we tested a standardized protocol developed by the Smithsonian Environmental Research Center (SERC) and used now in several countries. The 3-year monitoring survey (2018–2020) was conducted in the Gulf of La Spezia (Ligurian Sea, Italy), with the deployment of a total of 50 PVC panels per year in five different sites (a commercial harbor, three marinas and a site in the proximity of a shellfish farm). A total of 79 taxa were identified, including 11 NIS, ranging from zero to seven NIS for each panel. In comparison with previous surveys, new NIS arrivals were observed in the Gulf of La Spezia: Botrylloides cf. niger, Branchiomma sp., Branchiomma luctuosum, Paraleucilla magna, and Watersipora arcuata. At the end of the 3-year monitoring, mean richness? and percent cover of NIS were measured, and both measures differed across the monitoring sites, with higher values in two marinas and in the commercial harbor. Among years, richness of NIS was relatively stable at each monitoring site. The structure of the fouling was influenced more by native and cryptogenic species than by NIS. Moreover, among the monitoring sites, the density of artificial structures was not a reliable predictor or proxy for local NIS abundance. This first application of the SERC method in the Mediterranean Sea, demonstrates both pros and cons, including the detection of new NIS reported here. Further direct comparisons with other NIS monitoring tools are recommended, and additional tests to assess its effectiveness in this biogeographical area are encouraged. A broader application of this and other standard methods across temporal and spatial scales in the Mediterranean basin should be implemented, providing critical data needed to assess changes in the structure of fouling communities.
    • Monitoring the global COVID-19 impact on tourism: The COVID19tourism index

      Yang, Yang; Altschuler, Benjamin; Liang, Zhengkang; Li, Xiang (Robert) (2020-12-15)
      The COVID-19 virus is highly transmittable, wreaking havoc on the world's economy with the travel and tourism industry one of the most ravaged sectors. Given the impacts of COVID-19 and the intricacies of the global tourism economy, it is critical for policymakers to monitor recovery across numerous destinations. In this research note, we describe the development and calibration of an analytical tool named the “COVID19tourism index” to monitor the pandemic's tourism effects. As a powerful numerical and visual tool, the index provides important information related to the potential travel and tourism recovery at the global, regional, and country levels. Compared to a benchmark of “normal” levels (equal to 100 in this case), the COVID19tourism index offers insight into the tourism industry's recovery process along with the pandemic's impacts on numerous aspects of tourism.
    • More than just smell - COVID-19 is associated with severe impairment of smell, taste, and chemesthesis

      Parma, Valentina; Ohla, Kathrin; Veldhuizen, Maria G.; Nim, Masha Y.; Kelly, Christine E.; Global Consortium for Chemosensory Research; Reed, Danielle R.; Hummel, Thomas; Munger, Steven; Hayes, John E.; 0000-0003-0276-7072 (2020-05-24)
      Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, generally lacked quantitative measurements, were mostly restricted to data from single countries. Here, we report the development, implementation and initial results of a multi-lingual, international questionnaire to assess self-reported quantity and quality of perception in three distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, 8 other, ages 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change+/-100) revealed a mean reduction of smell (-79.7+/- 28.7, mean+/- SD), taste (-69.0+/- 32.6), and chemesthetic (-37.3+/- 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell, but also affects taste and chemesthesis. The multimodal impact of COVID-19 and lack of perceived nasal obstruction suggest that SARS-CoV-2 infection may disrupt sensory-neural mechanisms.
    • Multiple Recombination Events and Strong Purifying Selection at the Origin of SARS-CoV-2 Spike Glycoprotein Increased Correlated Dynamic Movements

      Tagliamonte, Massimiliano S.; Abid, Nabil; Borocci, Stefano; Sangiovanni, Elisa; Ostrov, David A.; Pond, Sergei; Salemi, Marco; Chillemi, Giovanni; Mavian, Carla; Pond|0000-0003-4817-4029 (2020-12-23)
      Our evolutionary and structural analyses revealed that the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) spike gene is a complex mosaic resulting from several recombination events. Additionally, the fixation of variants has mainly been driven by purifying selection, suggesting the presence of conserved structural features. Our dynamic simulations identified two main long-range covariant dynamic movements of the novel glycoprotein, and showed that, as a result of the evolutionary duality, they are preserved. The first movement involves the receptor binding domain with the N-terminal domain and the C-terminal domain 2 and is maintained across human, bat and pangolin coronaviruses. The second is a complex network of long-range dynamics specific to SARS-CoV-2 involving the novel PRRA and the conserved KR*SF cleavage sites, as well as conserved segments in C-terminal domain 3. These movements, essential for host cell binding, are maintained by hinges conserved across human, bat, and pangolin coronaviruses glycoproteins. The hinges, located around Threonine 333 and Proline 527 within the N-terminal domain and C-terminal domain 2, represent candidate targets for the future development of novel pan-coronavirus inhibitors. In summary, we show that while recombination created a new configuration that increased the covariant dynamic movements of the SARS-CoV-2 glycoprotein, negative selection preserved its inter-domain structure throughout evolution in different hosts and inter-species transmissions.
    • Nanovesicles displaying functional linear and branched oligomannose self-assembled from sequence-defined Janus glycodendrimers

      Institute of Computational Molecular Science (Temple University) (2020-06-02)
      Cell surfaces are often decorated with glycoconjugates that contain linear and more complex symmetrically and asymmetrically branched carbohydrates essential for cellular recognition and communication processes. Mannose is one of the fundamental building blocks of glycans in many biological membranes. Moreover, oligomannoses are commonly found on the surface of pathogens such as bacteria and viruses as both glycolipids and glycoproteins. However, their mechanism of action is not well understood, even though this is of great potential interest for translational medicine. Sequence-defined amphiphilic Janus glycodendrimers containing simple mono- and disaccharides that mimic glycolipids are known to self-assemble into glycodendrimersomes, which in turn resemble the surface of a cell by encoding carbohydrate activity via supramolecular multivalency. The synthetic challenge of preparing Janus glycodendrimers containing more complex linear and branched glycans has so far prevented access to more realistic cell mimics. However, the present work reports the use of an isothiocyanate-amine “click”-like reaction between isothiocyanate-containing sequence-defined amphiphilic Janus dendrimers and either linear or branched oligosaccharides containing up to six monosaccharide units attached to a hydrophobic amino-pentyl linker, a construct not expected to assemble into glycodendrimersomes. Unexpectedly, these oligoMan-containing dendrimers, which have their hydrophobic linker connected via a thiourea group to the amphiphilic part of Janus glycodendrimers, self-organize into nanoscale glycodendrimersomes. Specifically, the mannose-binding lectins that best agglutinate glycodendrimersomes are those displaying hexamannose. Lamellar “raft-like” nanomorphologies on the surface of glycodendrimersomes, self-organized from these sequence-defined glycans, endow these membrane mimics with high biological activity.