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Ensemble-Based Mutational Profiling And Network Analysis Of The Sars-Cov-2 Spike Omicron Xbb Lineages For Interactions With The Ace2 Receptor And Antibodies: Cooperation Of Binding Hotspots In Mediating Epistatic Couplings Underlies Binding Mechanism And Immune Escape, Nishank Raisinghani, Mohammed Alshahrani, Grace Gupta, Gennady M. Verkhivker Apr 2024

Ensemble-Based Mutational Profiling And Network Analysis Of The Sars-Cov-2 Spike Omicron Xbb Lineages For Interactions With The Ace2 Receptor And Antibodies: Cooperation Of Binding Hotspots In Mediating Epistatic Couplings Underlies Binding Mechanism And Immune Escape, Nishank Raisinghani, Mohammed Alshahrani, Grace Gupta, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with the host cell receptor ACE2 and a panel of diverse class one antibodies. The central objective of this investigation was to examine the molecular factors underlying epistatic couplings among convergent evolution hotspots that enable optimal balancing of ACE2 binding and antibody evasion for Omicron variants BA.1, BA2, BA.3, BA.4/BA.5, BQ.1.1, XBB.1, XBB.1.5, and XBB.1.5 + L455F/F456L. By combining evolutionary analysis, molecular dynamics simulations, and ensemble-based mutational scanning of spike protein residues in complexes with ACE2, we identified structural stability and binding …


Comparative Analysis Of Conformational Dynamics And Systematic Characterization Of Cryptic Pockets In The Sars-Cov-2 Omicron Ba.2, Ba.2.75 And Xbb.1 Spike Complexes With The Ace2 Host Receptor: Confluence Of Binding And Structural Plasticity In Mediating Networks Of Conserved Allosteric Sites, Mohammed Alshahrani, Grace Gupta, Sian Xiao, Peng Tao, Gennady M. Verkhivker Oct 2023

Comparative Analysis Of Conformational Dynamics And Systematic Characterization Of Cryptic Pockets In The Sars-Cov-2 Omicron Ba.2, Ba.2.75 And Xbb.1 Spike Complexes With The Ace2 Host Receptor: Confluence Of Binding And Structural Plasticity In Mediating Networks Of Conserved Allosteric Sites, Mohammed Alshahrani, Grace Gupta, Sian Xiao, Peng Tao, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

In the current study, we explore coarse-grained simulations and atomistic molecular dynamics together with binding energetics scanning and cryptic pocket detection in a comparative examination of conformational landscapes and systematic characterization of allosteric binding sites in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 spike full-length trimer complexes with the host receptor ACE2. Microsecond simulations, Markov state models and mutational scanning of binding energies of the SARS-CoV-2 BA.2 and BA.2.75 receptor binding domain complexes revealed the increased thermodynamic stabilization of the BA.2.75 variant and significant dynamic differences between these Omicron variants. Molecular simulations of the SARS-CoV-2 Omicron spike full-length trimer complexes …


Exploring Conformational Landscapes And Cryptic Binding Pockets In Distinct Functional States Of The Sars-Cov-2 Omicron Ba.1 And Ba.2 Trimers: Mutation-Induced Modulation Of Protein Dynamics And Network-Guided Prediction Of Variant-Specific Allosteric Binding Sites, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta Sep 2023

Exploring Conformational Landscapes And Cryptic Binding Pockets In Distinct Functional States Of The Sars-Cov-2 Omicron Ba.1 And Ba.2 Trimers: Mutation-Induced Modulation Of Protein Dynamics And Network-Guided Prediction Of Variant-Specific Allosteric Binding Sites, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

A significant body of experimental structures of SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity of the spike protein and the emergence of druggable binding pockets. Understanding the interplay of conformational dynamics changes induced by the Omicron variants and the identification of cryptic dynamic binding pockets in the S protein is of paramount importance as exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In the current study, we explore conformational landscapes and characterize the universe of binding pockets in multiple open and closed functional spike states of the BA.1 and BA.2 Omicron …


The Impact Of Vaccinations And Chronic Disease On Covid Death Rates, James L. Doti Aug 2023

The Impact Of Vaccinations And Chronic Disease On Covid Death Rates, James L. Doti

Economics Faculty Articles and Research

This study presents a theoretical and empirical regression model to measure the efficacy of vaccinations in reducing COVID death rates across states over the 3/10/21 to 12/28/22 period. During that period, it was estimated that the availability of vaccinations resulted in a reduction of 427,000 COVID deaths in the nation. To arrive at that estimate, other covariants were held constant. In particular, it was found that chronic disease should be included as an explanatory variable to arrive at unbiased measures of the efficacy of vaccinations in reducing deaths. In addition, the percentage of people over the age of 65 was …


Metapopulation Dynamics Of Sars-Cov-2 Transmission In A Small-Scale Amazonian Society, Thomas Kraft, Edmond Seabright, Sarah Alami, Samuel M. Jenness, Paul L. Hooper, Bret Beheim, Helen Davis, Daniel K. Cummings, Daniel Eid Rodriguez, Maguin Gutierrez Cayuba, Emily J. Miner, Xavier De Lamballerie, Lucia Inchauste, Stéphane Priet, Benjamin Trumble, Jonathan Stieglitz, Hillard Kaplan, Michael Gurven Aug 2023

Metapopulation Dynamics Of Sars-Cov-2 Transmission In A Small-Scale Amazonian Society, Thomas Kraft, Edmond Seabright, Sarah Alami, Samuel M. Jenness, Paul L. Hooper, Bret Beheim, Helen Davis, Daniel K. Cummings, Daniel Eid Rodriguez, Maguin Gutierrez Cayuba, Emily J. Miner, Xavier De Lamballerie, Lucia Inchauste, Stéphane Priet, Benjamin Trumble, Jonathan Stieglitz, Hillard Kaplan, Michael Gurven

ESI Publications

The severity of infectious disease outbreaks is governed by patterns of human contact, which vary by geography, social organization, mobility, access to technology and healthcare, economic development, and culture. Whereas globalized societies and urban centers exhibit characteristics that can heighten vulnerability to pandemics, small-scale subsistence societies occupying remote, rural areas may be buffered. Accordingly, voluntary collective isolation has been proposed as one strategy to mitigate the impacts of COVID-19 and other pandemics on small-scale Indigenous populations with minimal access to healthcare infrastructure. To assess the vulnerability of such populations and the viability of interventions such as voluntary collective isolation, we …


Balancing Functional Tradeoffs Between Protein Stability And Ace2 Binding In The Sars-Cov-2 Omicron Ba.2, Ba.2.75 And Xbb Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic And Energetic Changes, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta May 2023

Balancing Functional Tradeoffs Between Protein Stability And Ace2 Binding In The Sars-Cov-2 Omicron Ba.2, Ba.2.75 And Xbb Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic And Energetic Changes, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

Evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, structural stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2, BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and …


Coarse-Grained Molecular Simulations And Ensemble-Based Mutational Profiling Of Protein Stability In The Different Functional Forms Of The Sars-Cov-2 Spike Trimers: Balancing Stability And Adaptability In Ba.1, Ba.2 And Ba.2.75 Variants, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta Apr 2023

Coarse-Grained Molecular Simulations And Ensemble-Based Mutational Profiling Of Protein Stability In The Different Functional Forms Of The Sars-Cov-2 Spike Trimers: Balancing Stability And Adaptability In Ba.1, Ba.2 And Ba.2.75 Variants, Gennady M. Verkhivker, Mohammed Alshahrani, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

Evolutionary and functional studies have suggested that the emergence of Omicron variants can be determined by multiple fitness tradeoffs including immune escape, binding affinity, conformational plasticity, protein stability, and allosteric modulation. In this study, we embarked on a systematic comparative analysis of the conformational dynamics, electrostatics, protein stability, and allostery in the different functional states of spike trimers for BA.1, BA.2, and BA.2.75 variants. Using efficient and accurate coarse-grained simulations and atomistic reconstruction of the ensembles, we examined the conformational dynamics of the spike trimers that agree with the recent functional studies, suggesting that BA.2.75 trimers are the most stable …


Virtual And In Vitro Screening Of Natural Products Identifies Indole And Benzene Derivatives As Inhibitors Of Sars-Cov-2 Main Protease (MPro), Dony Ang, Riley Kendall, Hagop S. Atamian Mar 2023

Virtual And In Vitro Screening Of Natural Products Identifies Indole And Benzene Derivatives As Inhibitors Of Sars-Cov-2 Main Protease (MPro), Dony Ang, Riley Kendall, Hagop S. Atamian

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The rapid spread of the coronavirus disease 2019 (COVID-19) resulted in serious health, social, and economic consequences. While the development of effective vaccines substantially reduced the severity of symptoms and the associated deaths, we still urgently need effective drugs to further reduce the number of casualties associated with SARS-CoV-2 infections. Machine learning methods both improved and sped up all the different stages of the drug discovery processes by performing complex analyses with enormous datasets. Natural products (NPs) have been used for treating diseases and infections for thousands of years and represent a valuable resource for drug discovery when combined with …


The Effectiveness Of Pay-It-Forward In Addressing Hpv Vaccine Delay And Increasing Uptake Among 15–18-Year-Old Adolescent Girls Compared To User-Paid Vaccination: A Study Protocol For A Two-Arm Randomized Controlled Trial In China, Yifan Li, Chuanyu Qin, Shengyue Qiu, Yu He, Linchuan Pang, Xiaolan Xu, Vivian Wan-Cheong Yim, Shenglan Tang, Heng Du, Wenfeng Gong, Fan Yang, Joseph D. Tucker, Weiming Tang, Yun Wang, Leesa Lin, Mark Jit, Wei Song, Chunrong Li, Jennifer Smith, Jing Li, Dan Wu Jan 2023

The Effectiveness Of Pay-It-Forward In Addressing Hpv Vaccine Delay And Increasing Uptake Among 15–18-Year-Old Adolescent Girls Compared To User-Paid Vaccination: A Study Protocol For A Two-Arm Randomized Controlled Trial In China, Yifan Li, Chuanyu Qin, Shengyue Qiu, Yu He, Linchuan Pang, Xiaolan Xu, Vivian Wan-Cheong Yim, Shenglan Tang, Heng Du, Wenfeng Gong, Fan Yang, Joseph D. Tucker, Weiming Tang, Yun Wang, Leesa Lin, Mark Jit, Wei Song, Chunrong Li, Jennifer Smith, Jing Li, Dan Wu

Pharmacy Faculty Articles and Research

Background

Human papillomavirus (HPV) vaccination could prevent cervical and other HPV-associated cancers attributable to vaccine-associated HPV types. However, HPV vaccination coverage among women aged 9–18 years old is low in China. Common barriers include poor financial affordability, minimal public engagement, and low confidence in domestically produced HPV vaccines. Pay-it-forward offers an individual a free or subsidized service then an opportunity to voluntarily donate and/or create a postcard message to support future people. This study aims to assess the effectiveness of pay-it-forward as compared to standard-of-care self-paid vaccination to improve HPV vaccine uptake among adolescent girls aged 15–18 years, who are …


Probing Mechanisms Of Binding And Allostery In The Sars-Cov-2 Spike Omicron Variant Complexes With The Host Receptor: Revealing Functional Roles Of The Binding Hotspots In Mediating Epistatic Effects And Communication With Allosteric Pockets, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan Sep 2022

Probing Mechanisms Of Binding And Allostery In The Sars-Cov-2 Spike Omicron Variant Complexes With The Host Receptor: Revealing Functional Roles Of The Binding Hotspots In Mediating Epistatic Effects And Communication With Allosteric Pockets, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we performed all-atom MD simulations of RBD–ACE2 complexes for BA.1, BA.1.1, BA.2, and BA.3 Omicron subvariants, conducted a systematic mutational scanning of the RBD–ACE2 binding interfaces and analysis of electrostatic effects. The binding free energy computations of the Omicron RBD–ACE2 complexes and comprehensive examination of the electrostatic interactions quantify the driving forces of binding and provide new insights into energetic mechanisms underlying evolutionary differences between Omicron variants. A systematic mutational scanning of the RBD residues determines the protein stability centers and binding energy hotpots in the Omicron RBD–ACE2 complexes. By employing the ensemble-based global network analysis, we …


Men’S Stories: An Account Of Translating Vaccine Decision Narratives From Young Men In The U.S. Into A Targeted Public Health Intervention, Michelle Miller-Day, Erin S. Craw, Diana Harris, Michael L. Hecht Jul 2022

Men’S Stories: An Account Of Translating Vaccine Decision Narratives From Young Men In The U.S. Into A Targeted Public Health Intervention, Michelle Miller-Day, Erin S. Craw, Diana Harris, Michael L. Hecht

Communication Faculty Articles and Research

Effective interventions to promote human papillomavirus (HPV) vaccination are needed for all young adults across the globe. Yet, most public health efforts focus on HPV-related risks for females. Unfortunately, HPV-related cancers in men are also a concern, as is the potential for men to spread HPV to their partners. The HPV vaccine is highly effective in reducing risks related to these cancers. Yet, vaccination rates among young males are low and their vaccination concerns are not well understood. This project conducted 15 in-depth qualitative interviews with U.S. males aged 18–22 to hear their vaccine decision stories. Themes of HPV vaccination …


The Impact Of Hpv Vaccine Narratives On Social Media: Testing Narrative Engagement Theory With A Diverse Sample Of Young Adults, Amy E. Leader, Michelle Miller-Day, Rikishi T. Rey, Preethi Selvan, Anne E. Pezalla, Michael L. Hecht Jul 2022

The Impact Of Hpv Vaccine Narratives On Social Media: Testing Narrative Engagement Theory With A Diverse Sample Of Young Adults, Amy E. Leader, Michelle Miller-Day, Rikishi T. Rey, Preethi Selvan, Anne E. Pezalla, Michael L. Hecht

Communication Faculty Articles and Research

Rates of human papillomavirus (HPV) infection are highest in young adults, who can be vaccinated against HPV if they were not vaccinated as adolescents. Since young adults increasingly access health information on social media, we tested the impact of a social media campaign with narrative-based health information on intentions related to HPV vaccination. We also aimed to understand which ads resonated most with young adults and led to higher survey completion rates. We created social media posts featuring videos promoting HPV vaccination. We launched a sponsored ad campaign on Facebook to reach young women, ages 18–26, across the country. Participants …


Integrating Conformational Dynamics And Perturbation-Based Network Modeling For Mutational Profiling Of Binding And Allostery In The Sars-Cov-2 Spike Variant Complexes With Antibodies: Balancing Local And Global Determinants Of Mutational Escape Mechanisms, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan Jul 2022

Integrating Conformational Dynamics And Perturbation-Based Network Modeling For Mutational Profiling Of Binding And Allostery In The Sars-Cov-2 Spike Variant Complexes With Antibodies: Balancing Local And Global Determinants Of Mutational Escape Mechanisms, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

n this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, and perturbation-based network profiling of allosteric interactions in the SARS-CoV-2 spike complexes with a panel of cross-reactive and ultra-potent single antibodies (B1-182.1 and A23-58.1) as well as antibody combinations (A19-61.1/B1-182.1 and A19-46.1/B1-182.1). Using this approach, we quantify the local and global effects of mutations in the complexes, identify protein stability centers, characterize binding energy hotspots, and predict the allosteric control points of long-range interactions and communications. Conformational dynamics and distance fluctuation analysis revealed the antibody-specific signatures of protein stability and flexibility of the …


Total Prevention: A History Of Schistosomiasis In Japan, Alexander Bay Jul 2022

Total Prevention: A History Of Schistosomiasis In Japan, Alexander Bay

History Faculty Articles and Research

In Japan, schistosomiasis was endemic in Yamanashi Prefecture and a few other hotspot areas where the Miya’iri snail lived. The parasite’s lifecycle relied on the intermediary Miya’iri snail as well as the human host. Parasite eggs passed into the agrarian environment through untreated night soil used as fertiliser or through the culture of open defecation in rural Japan. Manmade rice fields and irrigation ditches, night soil covered paddies and highly refined growing seasons put people in flooded rice paddies to intensively work the land in the spring and summer. The disease was equally dependent on human intervention in the natural …


Biophysical Insight Into The Sars-Cov2 Spike–Ace2 Interaction And Its Modulation By Hepcidin Through A Multifaceted Computational Approach, Hamid Hadi-Alijanvand, Luisa Di Paola, Guang Hu, David M. Leitner, Gennady M. Verkhivker, Peixin Sun, Humanath Poudel, Alessandro Giuliani May 2022

Biophysical Insight Into The Sars-Cov2 Spike–Ace2 Interaction And Its Modulation By Hepcidin Through A Multifaceted Computational Approach, Hamid Hadi-Alijanvand, Luisa Di Paola, Guang Hu, David M. Leitner, Gennady M. Verkhivker, Peixin Sun, Humanath Poudel, Alessandro Giuliani

Mathematics, Physics, and Computer Science Faculty Articles and Research

At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its diffusion, but the need of purposed drugs is emerging as a core target of the fight against COVID19. In this respect, the repurposing of drugs has already led to discovery of drugs thought to reduce the effects of the cytokine storm, but still a drug targeting the spike protein, in the infection …


The Impact Of The Covid-19 Pandemic On Care Delivery And Quality Of Life In Lung Cancer Surgery, Dede K. Teteh, Jovani Barajas, Betty Ferrell, Ziaoke Zhou, Loretta Erhunmwunsee, Dan J. Raz, Jae Y. Kim, Virginia Sun Apr 2022

The Impact Of The Covid-19 Pandemic On Care Delivery And Quality Of Life In Lung Cancer Surgery, Dede K. Teteh, Jovani Barajas, Betty Ferrell, Ziaoke Zhou, Loretta Erhunmwunsee, Dan J. Raz, Jae Y. Kim, Virginia Sun

Health Sciences and Kinesiology Faculty Articles

Background

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (COVID-19) pandemic and associated restrictions have altered the delivery of surgical care. The purpose of this study was to explore the impact of COVID-19 on care delivery and quality of life (QOL) from the perspectives of lung cancer surgery patients, family caregivers (FCGs), and thoracic surgery teams.

Methods

Patients/FCGs enrolled in a randomized trial of a self-management intervention for lung cancer surgery preparation/recovery were invited to participate in this qualitative study. Patients/FCGs data were collected separately 1-month postdischarge. Interviews were also conducted with thoracic surgery team members. Content analysis approaches were …


Obesogenic Environments And Cardiovascular Disease: A Path Analysis Using Us Nationally Representative Data, Fangqi Guo, Georgiana Bostean, Vincent Berardi, Alfredo J. Velasquez, Jennifer W. Robinette Apr 2022

Obesogenic Environments And Cardiovascular Disease: A Path Analysis Using Us Nationally Representative Data, Fangqi Guo, Georgiana Bostean, Vincent Berardi, Alfredo J. Velasquez, Jennifer W. Robinette

Psychology Faculty Articles and Research

Introduction

People living in obesogenic environments, with limited access to healthful food outlets and exercise facilities, generally have poor health. Previous research suggests that behavioral risk factors and indicators of physiological functioning may mediate this link; however, no studies to date have had the requisite data to investigate multi-level behavioral and physiological risk factors simultaneously. The present study conducted serial and parallel mediation analyses to examine behavioral and physiological pathways explaining the association between environmental obesogenicity and cardiovascular disease (CVD).

Methods

This cross-sectional observational study used data from the 2012–2016 Health and Retirement Study, a representative survey of US older …


Allosteric Determinants Of The Sars-Cov-2 Spike Protein Binding With Nanobodies: Examining Mechanisms Of Mutational Escape And Sensitivity Of The Omicron Variant, Gennady M. Verkhivker Feb 2022

Allosteric Determinants Of The Sars-Cov-2 Spike Protein Binding With Nanobodies: Examining Mechanisms Of Mutational Escape And Sensitivity Of The Omicron Variant, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric …


Development Of A Bamlanivimab Infusion Process In The Emergency Department For Outpatient Covid-19 Patients, Danny Pham, Sandy Wong, Christina T. Nguyen, Stephen C. Lee, Kimberly J. Won Dec 2021

Development Of A Bamlanivimab Infusion Process In The Emergency Department For Outpatient Covid-19 Patients, Danny Pham, Sandy Wong, Christina T. Nguyen, Stephen C. Lee, Kimberly J. Won

Pharmacy Faculty Articles and Research

The coronavirus disease 2019 (COVID-19) pandemic has prompted the creation of new therapies to help fight against the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Bamlanivimab is a SARS-CoV-2 monoclonal antibody that is administered as an intravenous infusion to ambulatory patients with mild or moderate COVID-19, but a concern that arose was deciding the optimal location for patients to receive the medication. This report describes the development and implementation of a bamlanivimab infusion center in the emergency department of three hospitals in Orange County, California, shortly after bamlanivimab received emergency use authorization. As a result, a total of 601 …


Atomistic Simulations And In Silico Mutational Profiling Of Protein Stability And Binding In The Sars-Cov-2 Spike Protein Complexes With Nanobodies: Molecular Determinants Of Mutational Escape Mechanisms, Gennady M. Verkhivker, Steve Agajanian, Deniz Yasar Oztas, Grace Gupta Sep 2021

Atomistic Simulations And In Silico Mutational Profiling Of Protein Stability And Binding In The Sars-Cov-2 Spike Protein Complexes With Nanobodies: Molecular Determinants Of Mutational Escape Mechanisms, Gennady M. Verkhivker, Steve Agajanian, Deniz Yasar Oztas, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structure-functional studies have recently revealed a spectrum of diverse high-affinity nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this study, we combine atomistic simulations with the ensemble-based mutational profiling of binding for the SARS-CoV-2 S-RBD complexes with a wide range of nanobodies to identify dynamic and binding affinity fingerprints and characterize the energetic determinants of nanobody-escaping mutations. Using an in silico mutational profiling approach for probing the protein stability and binding, we examine dynamics and energetics of the SARS-CoV-2 complexes with single nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E + …


Landscape-Based Mutational Sensitivity Cartography And Network Community Analysis Of The Sars-Cov-2 Spike Protein Structures: Quantifying Functional Effects Of The Circulating D614g Variant, Gennady M. Verkhivker, Steve Agajanian, Deniz Yasar Oztas, Grace Gupta Jun 2021

Landscape-Based Mutational Sensitivity Cartography And Network Community Analysis Of The Sars-Cov-2 Spike Protein Structures: Quantifying Functional Effects Of The Circulating D614g Variant, Gennady M. Verkhivker, Steve Agajanian, Deniz Yasar Oztas, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

We developed and applied a computational approach to simulate functional effects of the global circulating mutation D614G of the SARS-CoV-2 spike protein. All-atom molecular dynamics simulations are combined with deep mutational scanning and analysis of the residue interaction networks to investigate conformational landscapes and energetics of the SARS-CoV-2 spike proteins in different functional states of the D614G mutant. The results of conformational dynamics and analysis of collective motions demonstrated that the D614 site plays a key regulatory role in governing functional transitions between open and closed states. Using mutational scanning and sensitivity analysis of protein residues, we identified the stability …


Computational Analysis Of Protein Stability And Allosteric Interaction Networks In Distinct Conformational Forms Of The Sars Cov 2 Spike D614g Mutant: Reconciling Functional Mechanisms Through Allosteric Model Of Spike Regulation, Gennady M. Verkhivker, Steve Agajanian, Deniz Oztas, Grace Gupta Jun 2021

Computational Analysis Of Protein Stability And Allosteric Interaction Networks In Distinct Conformational Forms Of The Sars Cov 2 Spike D614g Mutant: Reconciling Functional Mechanisms Through Allosteric Model Of Spike Regulation, Gennady M. Verkhivker, Steve Agajanian, Deniz Oztas, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we used an integrative computational approach to examine molecular mechanisms underlying functional effects of the D614G mutation by exploring atomistic modeling of the SARS-CoV-2 spike proteins as allosteric regulatory machines. We combined coarse-grained simulations, protein stability and dynamic fluctuation communication analysis with network-based community analysis to examine structures of the native and mutant SARS-CoV-2 spike proteins in different functional states. Through distance fluctuations communication analysis, we probed stability and allosteric communication propensities of protein residues in the native and mutant SARS-CoV-2 spike proteins, providing evidence that the D614G mutation can enhance long-range signaling of the allosteric spike …


Very Low Prevalence And Incidence Of Atrial Fibrillation Among Bolivian Forager-Farmers, Christopher J. Rowan, Michael A. Eskander, Edmond Seabright, Daniel Eid Rodriguez, Edhitt Cortez Linares, Raul Quispe Gutierrez, Juan Copajira Adrian, Daniel Cummings, Bret Beheim, Kirsten Tolstrup, Abinash Achrekar, Thomas Kraft, David E. Michalik, Michael I. Miyamoto, Adel H. Allam, L. Samuel Wann, Jagat Narula, Benjamin C. Trumble, Jonathan Stieglitz, Randall C. Thompson, Gregory S. Thomas, Hillard S. Kaplan, Michael D. Gurven Feb 2021

Very Low Prevalence And Incidence Of Atrial Fibrillation Among Bolivian Forager-Farmers, Christopher J. Rowan, Michael A. Eskander, Edmond Seabright, Daniel Eid Rodriguez, Edhitt Cortez Linares, Raul Quispe Gutierrez, Juan Copajira Adrian, Daniel Cummings, Bret Beheim, Kirsten Tolstrup, Abinash Achrekar, Thomas Kraft, David E. Michalik, Michael I. Miyamoto, Adel H. Allam, L. Samuel Wann, Jagat Narula, Benjamin C. Trumble, Jonathan Stieglitz, Randall C. Thompson, Gregory S. Thomas, Hillard S. Kaplan, Michael D. Gurven

ESI Publications

Background: Atrial fibrillation is the most common arrhythmia in post-industrialized populations. Older age, hypertension, obesity, chronic inflammation, and diabetes are significant atrial fibrillation risk factors, suggesting that modern urban environments may promote atrial fibrillation.

Objective: Here we assess atrial fibrillation prevalence and incidence among tropical horticulturalists of the Bolivian Amazon with high levels of physical activity, a lean diet, and minimal coronary atherosclerosis, but also high infectious disease burden and associated inflammation.

Methods: Between 2005–2019, 1314 Tsimane aged 40–94 years (52% female) and 534 Moseten Amerindians aged 40–89 years (50% female) underwent resting 12-lead electrocardiograms to assess atrial fibrillation prevalence. …


Healthcare Of Indigenous Amazonian Peoples In Response To Covid-19: Marginality, Discrimination And Revaluation Of Ancestral Knowledge In Ucayali, Peru, Doreen Montag, Marco Barboza, Lizardo Cauper, Ivan Brehaut, Isaac Alva, Aoife Bennett, José Sanchez-Choy, Juan Pablo Sarmiento Barletti, Pilar Valenzuela, José Manuyama, Italo García Murayari, Miguel Guimaraes Vásquez, Celso Aguirre Panduro, Angela Giattino, Edwin Julio Palomino Cadenas, Rodrigo Lazo, Carlos A. Delgado, Alfonso Nino, Elaine C. Flores, Maria Amalia Pesantes, Juan Pablo Murillo, Luisa Elvira Belaunde, Sergio Recuenco, Robert Chuquimbalqui, Carol Zavaleta-Cortijo Jan 2021

Healthcare Of Indigenous Amazonian Peoples In Response To Covid-19: Marginality, Discrimination And Revaluation Of Ancestral Knowledge In Ucayali, Peru, Doreen Montag, Marco Barboza, Lizardo Cauper, Ivan Brehaut, Isaac Alva, Aoife Bennett, José Sanchez-Choy, Juan Pablo Sarmiento Barletti, Pilar Valenzuela, José Manuyama, Italo García Murayari, Miguel Guimaraes Vásquez, Celso Aguirre Panduro, Angela Giattino, Edwin Julio Palomino Cadenas, Rodrigo Lazo, Carlos A. Delgado, Alfonso Nino, Elaine C. Flores, Maria Amalia Pesantes, Juan Pablo Murillo, Luisa Elvira Belaunde, Sergio Recuenco, Robert Chuquimbalqui, Carol Zavaleta-Cortijo

World Languages and Cultures Faculty Articles and Research

"Systematic and persistent discrimination against Indigenous Peoples translates into differential health outcomes when analysed through ethnicity and/or mother tongue.1 In Peru, morbidity and mortality rates among Indigenous Peoples for COVID-19 appear to confirm this.2 The COVID-19 pandemic has highlighted the historical structural violence against Indigenous Peoples that currently takes a disproportionate toll in the Peruvian Amazon. This equally applies to Indigenous Andean Peoples and Afro Peruvians. Indigenous Peoples in voluntary isolation and those in initial contact are at highest health risk in this pandemic as they have no previous immunity against common infectious diseases, and lack access to public healthcare …


Decomposing Differences In Coronavirus Disease 2019-Related Case-Fatality Rates Across Seventeen Nations, Ashley Wendell Kranjac, Dinko Kranjac Dec 2020

Decomposing Differences In Coronavirus Disease 2019-Related Case-Fatality Rates Across Seventeen Nations, Ashley Wendell Kranjac, Dinko Kranjac

Sociology Faculty Articles and Research

As of 1 November 2020, estimated case-fatality rates associated with coronavirus disease 2019 are not uniformly patterned across the world and differ substantially in magnitude. Given the global spatial heterogeneity in case-fatality rates, we applied the Blinder-Oaxaca regression decomposition technique to identify how putative sociodemographic, structural, and environmental sources influence variation in case-fatality rates. We show that compositional and associational differences in country-level risk factors explain a substantial proportion of the coronavirus disease 2019-related case-fatality rate gap across nations. Asian countries fair better vis-à-vis case-fatality rate differences mainly due to variation in returns to sociodemographic, structural, and environmental sources among …


The Physiological Interaction Of Sleep Deprivation And Zoledronate On Distal Femur Trabecular Thickness Of Ovariectomized Rats, Erin Nolte, Frank Frisch, Oliver Lopez Dec 2020

The Physiological Interaction Of Sleep Deprivation And Zoledronate On Distal Femur Trabecular Thickness Of Ovariectomized Rats, Erin Nolte, Frank Frisch, Oliver Lopez

Health Sciences and Kinesiology Faculty Articles

Osteoporosis, a disease resulting in an increased risk of fracture due to compromised bone, affects 1 in 3 postmenopausal women. Discontinuities in the microarchitecture of bone, such as trabeculae, are seen in postmenopausal osteoporosis. This study aimed to evaluate how sleep deprivation affects the distal femur trabecular thickness of estrogen-deficient rats treated with Zoledronate. 29 ovariectomized Wistar female rats were separated into 4 groups. The control group (C) was housed in standard housing with a 12-hour light/dark cycle and was given an intravenous injection of 0.45 mL of 0.9% saline. The Zoledronate group (Z) were also housed in standard conditions …


Covid-19 Viral Testing Disparities In Los Angeles City, Laura Cyphers Dec 2020

Covid-19 Viral Testing Disparities In Los Angeles City, Laura Cyphers

Student Scholar Symposium Abstracts and Posters

Hispanic and Black communities have been disproportionately impacted by COVID-19-related morbidity and mortality (California Department of Public Health, 2020). Inequitable access to viral testing resources may have exacerbated these COVID-19-related racial and ethnic health disparities. For example, reports from the Los Angeles Department of Public Health revealed glaring viral testing disparities in April 2020 (early pandemic), with predominantly White communities in Los Angeles County receiving 65% more tests than Hispanic and Black communities. In response, California statewide testing was expanded for communities of color (Vann et al., 2020). To investigate access to viral testing in Los Angeles City, the current …


Understanding Covid-19: From Origin To Potential Therapeutics, Muhammad Moazzam, Muhammad Imran Sajid, Hamza Shahid, Jahanzaib Butt, Irfan Bashir, Muhammad Jamshaid, Amir Nasrolahi Shirazi, Rakesh Kumar Tiwari Aug 2020

Understanding Covid-19: From Origin To Potential Therapeutics, Muhammad Moazzam, Muhammad Imran Sajid, Hamza Shahid, Jahanzaib Butt, Irfan Bashir, Muhammad Jamshaid, Amir Nasrolahi Shirazi, Rakesh Kumar Tiwari

Pharmacy Faculty Articles and Research

Currently, a global pandemic era of public health concerns is going on with the Coronavirus Disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The first case of COVID-19 was reported from Wuhan’s Huanan seafood market in China late December 2019. Bats, pangolins, and snakes have been nominated as salient carriers of the virus. Thanks to its high pathogenicity, it can cause severe respiratory infections. Fever, dry cough, sore throat, pneumonia, septic shock, and ground-glass opacities are the foremost clinical manifestations of COVID-19. Immunocompromised patients are at high risk for COVID-19 infection and may lead to …


Prospects For Rnai Therapy Of Covid-19, Hasan Uludağ, Kylie Parent, Hamidreza Montazeri Aliabadi, Azita Haddadi Jul 2020

Prospects For Rnai Therapy Of Covid-19, Hasan Uludağ, Kylie Parent, Hamidreza Montazeri Aliabadi, Azita Haddadi

Pharmacy Faculty Articles and Research

COVID-19 caused by the SARS-CoV-2 virus is a fast emerging disease with deadly consequences. The pulmonary system and lungs in particular are most prone to damage caused by the SARS-CoV-2 infection, which leaves a destructive footprint in the lung tissue, making it incapable of conducting its respiratory functions and resulting in severe acute respiratory disease and loss of life. There were no drug treatments or vaccines approved for SARS-CoV-2 at the onset of pandemic, necessitating an urgent need to develop effective therapeutics. To this end, the innate RNA interference (RNAi) mechanism can be employed to develop front line therapies against …


We Are Not Alone In Trying To Be Alone, Patricia C. Lopes Jun 2020

We Are Not Alone In Trying To Be Alone, Patricia C. Lopes

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Certain diseases, like colds, tend not to stop us. A paracetamol here, an ibuprofen there, and we are on the go. That is, until we, as a species, are faced with a virus that not only spreads through social contact, but has an estimated reproductive number of 2 to 2.5 and potentially kills 3–4% of those infected (WHO, 2020). To reduce transmission probability of COVID-19, governmental agencies around the world have recommended or enforced measures to decrease social contact; early evidence suggests these measures produce the intended effect (Kucharski et al., 2020).