<p> Over 40 years since the emergence of the AIDS epidemic and still no cure exists for AIDS or its causative HIV-1 infection. Protease inhibitors are an integral part of the most effective treatment regimen for HIV-1 infected patients known as combination antiretroviral therapy (cART), which is extremely effective at decreasing viral loads to nearly undetectable levels. One of the most alarming issues with current treatments is the emergence of multi-drug resistant strains. Even darunavir, which has shown exceptional activity against drug resistant strains, has experienced this issue. Herein we designed a novel series of heterocyclic based P2 ligand HIV-1 protease inhibitors based on kinase inhibitors such as imatinib and dasatinib. These inhibitors were designed to promote hydrogen bonding with the peptide backbone atoms of HIV-1 protease. Compounds were synthesized, biologically evaluated, and underwent X-ray structural studies. Inhibitors displayed activity as low as sub-nanomolar potency and low nanomolar antiviral activity. Important ligand-binding site interactions were determined through two X-ray crystal structures.</p> <p>Emergence of SARS-CoV-2 at the end of 2019 resulted in a global pandemic that has affected millions. Researchers all over the world turned their attention to developing drug therapies aimed at preventing and treating the viral infection. One such target became the main viral protease, or 3-chymotrypsin like protease (3CLpro). 3CLpro is an essential viral enzyme responsible for polypeptide cleavage during the viral replication cycle to produce 16 nonstructural proteins (nsps). Thus, it has been a highly researched area for effective SARS-CoV-2 drug therapies. Therefore, we designed, synthesized, and biologically evaluated a series of competitive reversible SARS-CoV-2 3CLpro inhibitors. </p>

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a global pandemic with an unprecedented death toll worldwide. Although it primarily affects the respiratory tract presenting as pneumonia or acute respiratory failure, it is also known to cause significant cardiovascular complications, including acute coronary syndrome (ACS), arrhythmia, myopericarditis, cardiomyopathy, venous thromboembolism, heart failure, and cardiogenic shock. Morbidity and mortality secondary to cardiovascular complications are higher in patients with preexisting cardiovascular risk factors. Here, we present a case report of a 69-year-old male who was recently diagnosed with COVID-19 illness presenting with ST-elevation myocardial infarction (STEMI) and eventually with Takotsubo cardiomyopathy (TTC), and the course was complicated by right atrial thrombus and a pulmonary embolism (PE).

This policy paper reviews the history, use and significance of telehealth in primary care. The emergence of telehealth as a primary strategy to continue to deliver value based, timely primary care during COVID-19 is discussed with recommendations for future applications, payment and preparation of providers to continue to provide quality care of clients in the future using telehealth.

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Beginning in 2019 and quickly spreading internationally, the Coronavirus disease Covid-19 became the first pandemic that many people have witnessed firsthand along with the severe disruption to their daily lives. A key field of research for Covid-19 that is studied by epidemiologists, biologists, and computer scientists alike is modeling the spread of Covid-19 in order to better predict future outbreaks of the pandemic and evaluate potential strategies to reduce infections, hospitalizations, and deaths. This thesis proposes a method of modeling Covid-19 spread and interventions for local environments based on different levels of perspective. The goal for this thesis is to be able to present a model of Covid-19 in terms of surrounding areas in San Luis Obispo including the unique mobility dynamic currently held in the global pandemic. Furthermore, we use our model to explore different methods of ensuring a low infection rate such as isolation methods and mobility restrictions.

Infectious diseases caused by viruses such as influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pose major threats to human health. Glycosylation, a post-translational modification critical for biological functions including receptor recognition and binding, cell adhesion, and protein folding, is a key mediator of the interaction between viruses and host cells. IAV and SARS-CoV-2 recognize and bind to glycans on host cells prior to uptake by the cells; by the same token, the glycoproteins hemagglutinin of IAV and the spike protein of SARS-CoV-2 are the targets of both host immune molecules and vaccines. The diversity of glycans, structures made up of oligosaccharide residues in complex, branched configurations, can in part be attributed to the push and pull of evolutionary pressures from infectious disease agents such as these viral pathogens. Evolving host glycans may gain the ability to evade recognition by viruses, and likewise, the evolution of viral glycans may result in viral evasion from immune responses. Thus, for a complete understanding of host-pathogen interactions, detailed characterization of glycoproteins that quantitatively measures changes in glycosylation is necessary. However, a number of factors makes quantitative characterization of glycoproteins difficult. Firstly, glycans are highly heterogeneous with dozens of possible glycans at a given glycosylation site and different occupancy levels at each site. Secondly, a particular glycoform may have very low abundance, making the signals difficult to detect. Thirdly, it is difficult to achieve deep, quantitative measurement of glycoprotein glycans using conventional liquid chromatography-mass spectrometry experiments. The usual mass spectrometry methods are not adequate because they are biased towards selecting higher abundance precursors, which leave many glycopeptide glycoforms undetected. This dissertation begins with an assessment of the current state-of-the-art of glycoproteomics using mass spectrometry to give context to our primary research discussed in subsequent chapters. Chapter 2 describes the use of a modified Tanimoto similarity coefficient to quantify the glycosylation similarity between two variants of a strain of IAV, wild-type and mutant, both expressed in embryonated chicken eggs. Our results indicate that even subtle changes in the amino acid sequence of hemagglutinin can result in measurably distinct glycosylation. Chapter 3 expands the number of comparisons of IAV strains made in the previous chapter to include strains produced in a mammalian expression vector, Madin-Darby canine kidney cells. We show that the choice of expression system can change the population of glycoforms at some but not necessarily all glycosylation sites. In addition, we explore data-independent acquisition mass spectrometry to improve upon sensitivity and selectivity of glycopeptide identification. In Chapter 4, this data-independent acquisition method is applied to the quantitative characterization of SARS-CoV-2 spike protein. The work presented here provides a significant contribution toward improving the confident detection and assignment of site-specific glycopeptides. Furthermore, understanding how to measure changes in glycosylation in related viral glycoprotein variants offers opportunities to include consideration of specific glycosylations in the design of vaccines to potentially improve efficacy against continually evolving viruses.

Yes / The on-going COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) has posed an extraordinary threat to global public health, wealth and well-being. As the carrier of human life and production, infrastructures need to be upgraded to mitigate and prevent the spread of viral diseases. Developing multifunctional/smart civil engineering materials to fight viruses is a promising approach to achieving this goal. In this perspective, the basic introduction on virus and its structure is provided. Then, the current design principles of antiviral materials and structures are examined. Subsequently, the possibility of developing active/passive antiviral civil engineering materials (including cementitious composites, ceramics, polymers and coatings) is proposed and envisaged. Finally, the future research needs and potential challenges to develop antiviral civil engineering materials are put forward. The proposed strategies to develop multifunctional/smart antiviral civil engineering materials will aid in the construction of smart infrastructures to prevent the spread viruses, thus improving human life and health as well as sustainability of human society. / The authors would like to thank the National Science Foundation of China (51978127, 52178188, and 51908103) and the Fundamental Research Funds for the Central Universities (DUT21RC(3)039) for providing funding to carry out this investigation.

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Contemporary diagnostics rely on expensive, time-consuming, and optically-limited mechanisms that prevent at-home point-of-care molecular diagnostics with the accuracy of laboratory tools and the convenience of affordability. In this Thesis, biosensing was explored with commercial two-dimensional (2D) materials which have been investigated extensively over the last two decades yielding a variety of sensor metrics for detecting biomolecules. 2D materials have intrinsic properties that depend on the quality of material and substrate surface being employed. Here, graphene/SiO2 and monolayer hexagonal boron nitride (hBN) capping layer on graphene/SiO2 field-effect transistors (FETs) were used. Until recently, monolayer hBN has not been commercially available at the wafer-scale and has been observed in the literature to augment the properties of graphene-based devices and better control of processing repeatability. The work in this Thesis combines biochemistry with the wafer-scale production and surface-dependent properties of graphene and monolayer hBN/graphene via a FET fabrication process circumventing the use of photoresist. This was done to avoid photoresist resin that may contaminate the transducer surface and contribute to repeatability issues when studying biochemistry with 2D materials. Briefly, surface engineering of graphene/SiO2 and hBN/graphene/SiO2 was done, and the transfer characteristics were measured as a function of either the concentration of protons, genes, or proteins. Compared to bare 2D materials, the pH sensitivity of the shift in Dirac voltage was enhanced to -99 mV/pH when using 8.6 nm of Al2O3 on hBN/graphene/SiO2 FET. Graphene devices were then engineered for sensing SARS-CoV-2 genome with a signal-to-noise ratio of 3 at 100 aM and a linearized sensitivity of +22 mV/molar decade of SARS-CoV-2 ribonucleic acid and a dynamic range of four orders of magnitude. This was done by conjugating single-stranded deoxyribonucleic acid to sub-percolation threshold gold nanofilms deposited directly on the graphene sensing mesa. Finally, the 2D devices were studied for detecting SARS-CoV-2 spike protein after being functionalized with rabbit immunoglobulin G (IgG) monoclonal antibody (mAb). Additionally, preliminary work was done regarding the partial reduction and fragmentation of anti-SARS-CoV-2 spike protein human mAb IgG in an approach to leverage gold-thiol chemistry for covalently bonding the IgG to the 2D sensing mesa. In summary, the utilization of wide- and zero-bandgap nanomaterials may have profound implications in augmenting molecular diagnosis and treatment of disease through economically decentralizing biosensing. / 2024-01-20T00:00:00Z