Destination Area: Global Systems Science (GSS)

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https://hdl.handle.net/10919/78630

GSS fosters transdisciplinary study of the dynamic interplay between natural and social systems. Faculty in this area collaborate to discover creative solutions to critical social problems emergent from human activity and environmental change, in areas such as freshwater and coastal water systems, rural environments, infectious disease, and food production and safety. Work in this area also embraces equity in the human condition by seeking the equitable distribution and availability of physical safety and well-being, psychological well-being, respect for human dignity, and access to crucial material and social resources throughout the world’s diverse communities.

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Alpha 1 Antitrypsin is an Inhibitor of the SARS-CoV-2–Priming Protease TMPRSS2
Azouz, N. P.; Klingler, A. M.; Callahan, Victoria; Akhrymuk, Ivan V.; Elez, K.; Raich, L.; Henry, B. M.; Benoit, J. L.; Benoit, S. W.; Noé, F.; Kehn-Hall, Kylene; Rothenberg, M. E. (2021-01-01)
Background: Host proteases have been suggested to be crucial for dissemination of MERS, SARS-CoV, and SARS-CoV-2 coronaviruses, but the relative contribution of membrane versus intracellular proteases remains controversial. Transmembrane serine protease 2 (TMPRSS2) is regarded as one of the main proteases implicated in the coronavirus S protein priming, an important step for binding of the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor before cell entry. Methods: We developed a cell-based assay to identify TMPRSS2 inhibitors. Inhibitory activity was established in SARS-CoV-2 viral load systems. Results: We identified the human extracellular serine protease inhibitor (serpin) alpha 1 anti-trypsin (A1AT) as a novel TMPRSS2 inhibitor. Structural modeling revealed that A1AT docked to an extracellular domain of TMPRSS2 in a conformation that is suitable for catalysis, resembling similar serine protease inhibitor complexes. Inhibitory activity of A1AT was established in a SARS-CoV-2 viral load system. Notably, plasma A1AT levels were associated with COVID-19 disease severity. Conclusions: Our data support the key role of extracellular serine proteases in SARS CoV-2 infections and indicate that treatment with serpins, particularly the FDA-approved drug A1AT, may be effective in limiting SARS-CoV-2 dissemination by affecting the surface of the host cells.
Altered toxicological endpoints in humans from common quaternary ammonium compound disinfectant exposure
Hrubec, Terry C.; Seguin, Ryan P.; Xu, L.; Cortopassi, G. A.; Datta, S.; Hanlon, Alexandra L.; Lozano, A. J.; McDonald, V. A.; Healy, C. A.; Anderson, T. C.; Musse, N. A.; Williams, R. T. (Elsevier, 2021-01-01)
Humans are frequently exposed to Quaternary Ammonium Compounds (QACs). QACs are ubiquitously used in medical settings, restaurants, and homes as cleaners and disinfectants. Despite their prevalence, nothing is known about the health effects associated with chronic low-level exposure. Chronic QAC toxicity, only recently identified in mice, resulted in developmental, reproductive, and immune dysfunction. Cell based studies indicate increased inflammation, decreased mitochondrial function, and disruption of cholesterol synthesis. If these findings translate to human toxicity, multiple physiological processes could be affected. This study tested whether QAC concentrations could be detected in the blood of 43 human volunteers, and whether QAC concentrations influenced markers of inflammation, mitochondrial function, and cholesterol synthesis. QAC concentrations were detected in 80 % of study participants. Blood QACs were associated with increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose dependent manner. This is the first study to measure QACs in human blood, and also the first to demonstrate statistically significant relationships between blood QAC and meaningful health related biomarkers. Additionally, the results are timely in light of the increased QAC disinfectant exposure occurring due to the SARS-CoV-2 pandemic. Main Findings: This study found that 80 % of study participants contained QACs in their blood; and that markers of inflammation, mitochondrial function, and sterol homeostasis varied with blood QAC concentration.
Better understanding and prediction of antiviral peptides through primary and secondary structure feature importance
Chowdhury, Abu Sayed; Reehl, Sarah M.; Kehn-Hall, Kylene; Bishop, Barney M.; Webb-Robertson, Bobbie-Jo M. (2020-11-06)
The emergence of viral epidemics throughout the world is of concern due to the scarcity of available effective antiviral therapeutics. The discovery of new antiviral therapies is imperative to address this challenge, and antiviral peptides (AVPs) represent a valuable resource for the development of novel therapies to combat viral infection. We present a new machine learning model to distinguish AVPs from non-AVPs using the most informative features derived from the physicochemical and structural properties of their amino acid sequences. To focus on those features that are most likely to contribute to antiviral performance, we filter potential features based on their importance for classification. These feature selection analyses suggest that secondary structure is the most important peptide sequence feature for predicting AVPs. Our Feature-Informed Reduced Machine Learning for Antiviral Peptide Prediction (FIRM-AVP) approach achieves a higher accuracy than either the model with all features or current state-of-the-art single classifiers. Understanding the features that are associated with AVP activity is a core need to identify and design new AVPs in novel systems. The FIRM-AVP code and standalone software package are available at https://github.com/pmartR/FIRM-AVP with an accompanying web application at https://msc-viz.emsl.pnnl.gov/AVPR.
Brucella abortus RB51 ΔleuB expressing Salmonella FliC conjugated gonadotropins reduces mouse fetal numbers: A possible feral swine brucellosis immunocontraceptive vaccine
Waldrop, Steven Grant; Smith, Garrett P.; Boyle, Stephen M.; Sriranganathan, Nammalwar (2021-02)
Population and health management of wildlife is a key to environmental health, domestic herd health, and ultimately public health. Many different methods including: surgical sterilization, poison baits, and sponsored hunting programs have been used in the attempt to control populations of various nuisance animal species. Particular interest has been given to immunocontraception through wildlife vaccination protocols. This study specifically looked at the potential immunocontraceptive and protective properties of a Brucella abortus RB51 Delta leuB vaccine expressing Salmonella typhimurium FliC conjugated to porcine follicle stimulating hormone beta subunit (FSH beta) or gonadotropin releasing hormone (GnRH) DNA sequences. B. abortus RB51 Delta leuB pNS4-TrcD-FliC-FSH beta (RB51LFSH beta) and B. abortus RB51 Delta leuB pNS4-TrcD-FliC-GnRH (RB51LGnRH) were tested in a pilot breeding study with BALB/c mice, and a significant reduction in fertility characteristics was observed in both male and female mice. Ultimately, this study provides support to test these vaccine candidates in feral swine, a destructive invasive species in the United States of America.
Conserving the Genetic Diversity of Domesticated Livestock
Sponenberg, D. Phillip (MDPI, 2020-07-17)
Domesticated animals live and produce in an environment influenced by both natural and human factors. These agricultural environments are important to maintain for human survival and also for their interactions with natural environments. Effective conservation of domesticated biodiversity can help to assure sustainable agricultural systems that minimize negative influences on natural environments. In addition, livestock biodiversity is a component of total biodiversity and for several species is the only remaining source of diversity because the wild ancestors are now extinct. Conservation of livestock biodiversity depends on cultural and biological approaches. Each of these has differential importance depending on the specific location of the genetic resource as well as the human culture in which it resides. Effective global conservation blends these in different measures to assure positive outcomes that succeed in securing the genetic resource as well as its contribution to human survival and well-being.
Defective viral genomes from chikungunya virus are broad-spectrum antivirals and prevent virus dissemination in mosquitoes
Levi, Laura I.; Rezelj, Veronica V.; Henrion-Lacritick, Annabelle; Erazo, Diana; Boussier, Jeremy; Vallet, Thomas; Bernhauerova, Veronika; Suzuki, Yasutsugu; Carrau, Lucia; Weger-Lucarelli, James; Saleh, Maria-Carla; Vignuzzi, Marco (2021-02)
Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo. Author summary Defective viral genomes (DVGs) are produced during virus replication. On their own they cannot replicate, but some of them can compete with wild-type virus for viral and/or cellular resources. For chikungunya virus, interference by DVGs has not been described. Here, we use a new approach based on experimental evolution and computational analysis to characterize all DVGs generated in a virus population and identify those with the highest antiviral potential. We confirm their antiviral activity in both mammalian and mosquito host environments and show that some can broadly interfere with other strains or related alphaviruses. Finally, we show that DVGs can inhibit virus dissemination in mosquitoes.
Detection of Q129H Immune Escape Mutation in Apparently Healthy Hepatitis B Virus Carriers in Southwestern Nigeria
Adesina, Olufisayo Adeyemi; Akanbi, Olusola Aanuoluwapo; Opaleye, Oladele Oluyinka; Japhet, Margaret Oluwatoyin; Wang, Bo; Oluyege, Adekemi Olubukunola; Klink, Patrycja; Bock, C.-Thomas (MDPI, 2021-06-29)
As the global effort to eradicate hepatitis B continues, immune escape mutations (IEMs) and drug resistance mutations (DRMs) affecting its diagnosis, treatment, and prevention are compromising this goal. However, knowledge about the prevalence and circulation of these mutations in Nigeria is scarce. Serum samples (n = 199) from apparently healthy prospective blood donors, pregnant women, and individuals presenting with fever in southwestern Nigeria were analyzed for the presence of IEMs and DRMs by means of nested PCR in the HBV S (HBs) and HBV polymerase (Pol) genes, followed by phylogenetic and mutational analyses. In total, 25.1% (n = 50/199) of samples were positive for HBV, as measured by PCR. In 41 samples (20.6%), both fragments could be amplified, whereas the HBs gene and the Pol gene fragment alone were detected in 0.5% (n = 1/199) and 4% (n = 8/199) of samples, respectively. Sequences were successfully obtained for all 42 HBs gene fragments but for only 31/49 Pol gene fragments (totaling 73 sequences from 44 individuals). All sequences were identified as HBV genotype E. IEMs were present in 18.2% (n = 8/44) of the sequences of HBV-positive individuals with available sequences. IEM Q129H was detected in eight out of the 44 (18.2%) HBV isolates sequenced in this study; however, no DRMs were observed. This study confirms the circulation of HBV IEMs and reports the presence of Q129H IEM for the first time in Nigeria. Intensified research on the dynamics of IEM is necessary in order to enhance the elimination of HBV.
Dielectrophoretic differentiation of mouse ovarian surface epithelial cells, macrophages, and fibroblasts using contactless dielectrophoresis
Salmanzadeh, Alireza; Kittur, Harsha; Sano, Michael B.; Roberts, Paul C.; Schmelz, Eva M.; Davalos, Rafael V. (American Institute of Physics, 2012-06-01)
Ovarian cancer is the leading cause of death from gynecological malignancies in women. The primary challenge is the detection of the cancer at an early stage, since this drastically increases the survival rate. In this study we investigated the dielectrophoretic responses of progressive stages of mouse ovarian surface epithelial (MOSE) cells, as well as mouse fibroblast and macrophage cell lines, utilizing contactless dielectrophoresis (cDEP). cDEP is a relatively new cell manipulation technique that has addressed some of the challenges of conventional dielectrophoretic methods. To evaluate our microfluidic device performance, we computationally studied the effects of altering various geometrical parameters, such as the size and arrangement of insulating structures, on dielectrophoretic and drag forces. We found that the trapping voltage of MOSE cells increases as the cells progress from a non-tumorigenic, benign cell to a tumorigenic, malignant phenotype. Additionally, all MOSE cells display unique behavior compared to fibroblasts and macrophages, representing normal and inflammatory cells found in the peritoneal fluid. Based on these findings, we predict that cDEP can be utilized for isolation of ovarian cancer cells from peritoneal fluid as an early cancer detection tool. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.3699973] Actual pdf downloaded from NCBI.
Evaluation of ebselen in resolving a methicillin-resistant Staphylococcus aureus infection of pressure ulcers in obese and diabetic mice
Mohammad, Haroon; Abutaleb, Nader S.; Dieterly, Alexandra M.; Lyle, L. Tiffany; Seleem, Mohamed N. (2021-02-22)
Pressure ulcers (PUs) are a source of morbidity in individuals with restricted mobility including individuals that are obese or diabetic. Infection of PUs with pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), impairs ulcers from healing. The present study evaluated ebselen as a topical antibacterial to treat MRSA-infected PUs. Against two different S. aureus strains, including MRSA USA300, resistance to ebselen did not emerge after 14 consecutive passages. Resistance to mupirocin emerged after only five passages. Additionally, ebselen was found to exert a modest postantibiotic effect of five hours against two MRSA strains. Ebselen was subsequently evaluated in MRSA-infected PUs in two models using obese and diabetic mice. In obese mice, topical ebselen (89.2% reduction) and oral linezolid (84.5% reduction) similarly reduced the burden of MRSA in infected PUs. However, in diabetic mice, topical ebselen (45.8% reduction in MRSA burden) was less effective. Histopathological evaluation of ulcers in diabetic mice determined that ebselen treatment resulted in fewer bacterial colonies deep within the dermis and that the treatment exhibited evidence of epithelial regeneration. Topical mupirocin was superior to ebselen in reducing MRSA burden in infected PUs both in obese (98.7% reduction) and diabetic (99.3% reduction) mice. Ebselen's antibacterial activity was negatively impacted as the bacterial inoculum was increased from 10(5) CFU/mL to 10(7) CFU/mL. These results suggest that a higher dose of ebselen, or a longer course of treatment, may be needed to achieve a similar effect as mupirocin in topically treating MRSA-infected pressure ulcers.
Evaluation of the 50% Infectious Dose of Human Norovirus Cin-2 in Gnotobiotic Pigs: A Comparison of Classical and Contemporary Methods for Endpoint Estimation
Ramesh, Ashwin; Parreño, Viviana; Schmidt, Philip J.; Lei, Shaohua; Zhong, Weiming; Jiang, Xi; Emelko, Monica B.; Yuan, Lijuan (MDPI, 2020-08-28)
Human noroviruses (HuNoVs) are the leading causative agents of epidemic and sporadic acute gastroenteritis that affect people of all ages worldwide. However, very few dose–response studies have been carried out to determine the median infectious dose of HuNoVs. In this study, we evaluated the median infectious dose (ID₅₀) and diarrhea dose (DD₅₀) of the GII.4/2003 variant of HuNoV (Cin-2) in the gnotobiotic pig model of HuNoV infection and disease. Using various mathematical approaches (Reed–Muench, Dragstedt–Behrens, Spearman–Karber, exponential, approximate beta-Poisson dose–response models, and area under the curve methods), we estimated the ID₅₀ and DD₅₀ to be between 2400–3400 RNA copies, and 21,000–38,000 RNA copies, respectively. Contemporary dose–response models offer greater flexibility and accuracy in estimating ID₅₀. In contrast to classical methods of endpoint estimation, dose–response modelling allows seamless analyses of data that may include inconsistent dilution factors between doses or numbers of subjects per dose group, or small numbers of subjects. Although this investigation is consistent with state-of-the-art ID₅₀ determinations and offers an advancement in clinical data analysis, it is important to underscore that such analyses remain confounded by pathogen aggregation. Regardless, challenging virus strain ID₅₀ determination is crucial for identifying the true infectiousness of HuNoVs and for the accurate evaluation of protective efficacies in pre-clinical studies of therapeutics, vaccines and other prophylactics using this reliable animal model.
Genome Number and Size Polymorphism in Zika Virus Infectious Units
Sexton, Nicole R.; Bellis, Eric D.; Murrieta, Reyes A.; Spangler, Mark Cole; Cline, Parker J.; Weger-Lucarelli, James; Ebel, Gregory D. (2021-03)
Zika virus (ZIKV; Flaviviridae, Flavivirus) is an arthropod-borne infection that can result in severe outcomes, particularly in fetuses infected in utero. It has been assumed that infection by ZIKV, as well as other viruses, is largely initiated by individual virus particles binding to and entering a cell. However, recent studies have demonstrated that multiple virus particles are frequently delivered to a cell simultaneously and that this collective particle delivery enhances infection. ZIKV is maintained in nature between Aedes aegypti mosquitos and vertebrate hosts, including humans. Human infection is initiated through the injection of a relatively small initial inoculum comprised of a genetically complex virus population. Since most mutations decrease virus fitness, collective particle transmission could benefit ZIKV and other arthropod-borne diseases by facilitating the maintenance of genetic complexity and adaptability during infection or through other mechanisms. Therefore, we utilized a barcoded ZIKV to quantify the number of virus genomes that initiate a plaque. We found that individual plaques contain a mean of 10 infecting viral genomes (range, 1 to 212). Few plaques contained more than two dominant genomes. To determine whether multigenome infectious units consist of collectively transmitting virions, infectious units of ZIKV were then separated mechanically by centrifugation, and heavier fractions were found to contain more genomes per plaque-forming unit, with larger diameters. Finally, larger/heavier infectious units reformed after removal. These data suggest that ZIKV populations consist of a variety of infectious unit sizes, likely mostly made up of aggregates, and only rarely begin with a single virus genome. IMPORTANCE The arthropod-borne Zika virus (ZIKV) infects humans and can cause severe neurological sequelae, particularly in fetuses infected in utero. How this virus has been able to spread across vast geological ranges and evolve in new host populations is not yet understood. This research demonstrates a novel mechanism of ZIKV transmission through multigenome aggregates, providing insight into ZIKV evolution, immunologic evasion, and better future therapeutic design. This study shows that ZIKV plaques result from collections of genomes rather than individual genomes, increasing the potential for interactions between ZIKV genotypes.
Hydrogel particles improve detection of SARS-CoV-2 RNA from multiple sample types
Barclay, R. A.; Akhrymuk, Ivan V.; Patnaik, A.; Callahan, Victoria; Lehman, C.; Andersen, P.; Barbero, R.; Barksdale, S.; Dunlap, R.; Goldfarb, D.; Jones-Roe, T.; Kelly, R.; Kim, B.; Miao, S.; Munns, A.; Munns, D.; Patel, S.; Porter, E.; Ramsey, R.; Sahoo, S.; Swahn, O.; Warsh, J.; Kehn-Hall, Kylene; Lepene, Benjamin (Springer, 2020-12-01)
Here we present a rapid and versatile method for capturing and concentrating SARS-CoV-2 from contrived transport medium and saliva samples using affinity-capture magnetic hydrogel particles. We demonstrate that the method concentrates virus from 1 mL samples prior to RNA extraction, substantially improving detection of virus using real-time RT-PCR across a range of viral titers (100–1,000,000 viral copies/mL) and enabling detection of virus using the 2019 nCoV CDC EUA Kit down to 100 viral copies/mL. This method is compatible with commercially available nucleic acid extraction kits (i.e., from Qiagen) and a simple heat and detergent method that extracts viral RNA directly off the particle, allowing a sample processing time of 10 min. We furthermore tested our method in transport medium diagnostic remnant samples that previously had been tested for SARS-CoV-2, showing that our method not only correctly identified all positive samples but also substantially improved detection of the virus in low viral load samples. The average improvement in cycle threshold value across all viral titers tested was 3.1. Finally, we illustrate that our method could potentially be used to enable pooled testing, as we observed considerable improvement in the detection of SARS-CoV-2 RNA from sample volumes of up to 10 mL.
In vitro and in vivo activities of the carbonic anhydrase inhibitor, dorzolamide, against vancomycin-resistant enterococci
Abutaleb, Nader S.; Elhassanny, Ahmed E. M.; Flaherty, Daniel P.; Seleem, Mohamed N. (PeerJ, 2021-03-30)
Vancomycin-resistant enterococci (VRE) are a serious public health threat and a leading cause of healthcare-associated infections. Bacterial resistance to antibiotics recommended for the treatment of enterococcal infections complicates the management of these infections. Hence, there is a critical need for the discovery of new anti-VRE agents. We previously reported carbonic anhydrase inhibitors (CAIs) as new potent VRE inhibitors. In the present study, the activity of the CAI, dorzolamide was evaluated against VRE both in vitro and in vivo. Dorzolamide exhibited potent activity against a panel of clinical VRE isolates, with minimum inhibitory concentration (MIC) values ranging from 1 µg/mL to 8 µg/mL. A killing kinetics experiment determined that dorzolamide exhibited a bacteriostatic effect against VRE, which was similar to the drug of choice (linezolid). Dorzolamide interacted synergistically with gentamicin against four strains of VRE, and exhibited an additive interaction with gentamicin against six VRE strains, reducing gentamicin’s MIC by several folds. Moreover, dorzolamide outperformed linezolid in an in vivo VRE colonization reduction mouse model. Dorzolamide significantly reduced the VRE burden in fecal samples of mice by 2.9-log10 (99.9%) and 3.86-log10 (99.99%) after 3 and 5 days of treatment, respectively. Furthermore, dorzolamide reduced the VRE count in the cecal (1.74-log10 (98.2%) reduction) and ileal contents (1.5-log10 (96.3%)) of mice, which was superior to linezolid. Collectively, these results indicate that dorzolamide represents a promising treatment option that warrants consideration as a supplement to current therapeutics used for VRE infections.
Investigating dielectric properties of different stages of syngeneic murine ovarian cancer cells
Salmanzadeh, Alireza; Sano, Michael B.; Gallo-Villanueva, R. C.; Roberts, Paul C.; Schmelz, Eva M.; Davalos, Rafael V. (American Institute of Physics, 2013-01-01)
In this study, the electrical properties of four different stages of mouse ovarian surface epithelial (MOSE) cells were investigated using contactless dielectrophoresis (cDEP). This study expands the work from our previous report describing for the first time the crossover frequency and cell specific membrane capacitance of different stages of cancer cells that are derived from the same cell line. The specific membrane capacitance increased as the stage of malignancy advanced from 15.39 +/- 1.54 mF m(-2) for a non-malignant benign stage to 26.42 +/- 1.22 mF m(-2) for the most aggressive stage. These differences could be the result of morphological variations due to changes in the cytoskeleton structure, specifically the decrease of the level of actin filaments in the cytoskeleton structure of the transformed MOSE cells. Studying the electrical properties of MOSE cells provides important information as a first step to develop cancer-treatment techniques which could partially reverse the cytoskeleton disorganization of malignant cells to a morphology more similar to that of benign cells. (C) 2013 American Institute of Physics. [http://dx.doi.org/10.1063/1.4788921] Actual pdf downloaded from NCBI.
La Crosse Virus Shows Strain-Specific Differences in Pathogenesis
Wilson, Sarah N.; López, Krisangel; Coutermarsh-Ott, Sheryl; Auguste, Dawn I.; Porier, Danielle L.; Armstrong, Philip M.; Andreadis, Theodore G.; Eastwood, Gillian; Auguste, A. Jonathan (MDPI, 2021-03-29)
La Crosse virus (LACV) is the leading cause of pediatric viral encephalitis in North America, and is an important public health pathogen. Historically, studies involving LACV pathogenesis have focused on lineage I strains, but no former work has explored the pathogenesis between or within lineages. Given the absence of LACV disease in endemic regions where a robust entomological risk exists, we hypothesize that some LACV strains are attenuated and demonstrate reduced neuroinvasiveness. Herein, we compared four viral strains representing all three lineages to determine differences in neurovirulence or neuroinvasiveness using three murine models. A representative strain from lineage I was shown to be the most lethal, causing >50% mortality in each of the three mouse studies. However, other strains only presented excessive mortality (>50%) within the suckling mouse neurovirulence model. Neurovirulence was comparable among strains, but viruses differed in their neuroinvasive capacities. Our studies also showed that viruses within lineage III vary in pathogenesis with contemporaneous strains, showing reduced neuroinvasiveness compared to an ancestral strain from the same U.S. state (i.e., Connecticut). These findings demonstrate that LACV strains differ markedly in pathogenesis, and that strain selection is important for assessing vaccine and therapeutic efficacies.
N-(1,3,4-Oxadiazol-2-yl)Benzamides as Antibacterial Agents against Neisseria gonorrhoeae
Naclerio, George A.; Abutaleb, Nader S.; Alhashimi, Marwa; Seleem, Mohamed N.; Sintim, Herman O. (2021-03)
The Centers for Disease Control and Prevention (CDC) recognizes Neisseria gonorrhoeae as an urgent-threat Gram-negative bacterial pathogen. Additionally, resistance to frontline treatment (dual therapy with azithromycin and ceftriaxone) has led to the emergence of multidrug-resistant N. gonorrhoeae, which has caused a global health crisis. The drug pipeline for N. gonorrhoeae has been severely lacking as new antibacterial agents have not been approved by the FDA in the last twenty years. Thus, there is a need for new chemical entities active against drug-resistant N. gonorrhoeae. Trifluoromethylsulfonyl (SO2CF3), trifluoromethylthio (SCF3), and pentafluorosulfanyl (SF5) containing N-(1,3,4-oxadiazol-2-yl)benzamides are novel compounds with potent activities against Gram-positive bacterial pathogens. Here, we report the discovery of new N-(1,3,4-oxadiazol-2-yl)benzamides (HSGN-237 and -238) with highly potent activity against N. gonorrhoeae. Additionally, these new compounds were shown to have activity against clinically important Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Listeria monocytogenes (minimum inhibitory concentrations (MICs) as low as 0.25 mu g/mL). Both compounds were highly tolerable to human cell lines. Moreover, HSGN-238 showed an outstanding ability to permeate across the gastrointestinal tract, indicating it would have a high systemic absorption if used as an anti-gonococcal therapeutic.
Natural, incidental, and engineered nanomaterials and their impacts on the Earth system
Hochella, Michael F. Jr.; Mogk, David W.; Ranville, James; Allen, Irving C.; Luther, George W.; Marr, Linsey C.; McGrail, B. Peter; Murayama, Mitsuhiro; Qafoku, Nikolla P.; Rosso, Kevin M.; Sahai, Nita; Schroeder, Paul A.; Vikesland, Peter J.; Westerhoff, Paul; Yang, Yi (2019-03-29)
Nanomaterials are critical components in the Earth system's past, present, and future characteristics and behavior. They have been present since Earth's origin in great abundance. Life, from the earliest cells to modern humans, has evolved in intimate association with naturally occurring nanomaterials. This synergy began to shift considerably with human industrialization. Particularly since the Industrial Revolution some two-and-a-half centuries ago, incidental nanomaterials (produced unintentionally by human activity) have been continuously produced and distributed worldwide. In some areas, they now rival the amount of naturally occurring nanomaterials. In the past half-century, engineered nanomaterials have been produced in very small amounts relative to the other two types of nanomaterials, but still in large enough quantities to make them a consequential component of the planet. All nanomaterials, regardless of their origin, have distinct chemical and physical properties throughout their size range, clearly setting them apart from their macroscopic equivalents and necessitating careful study. Following major advances in experimental, computational, analytical, and field approaches, it is becoming possible to better assess and understand all types and origins of nanomaterials in the Earth system. It is also now possible to frame their immediate and long-term impact on environmental and human health at local, regional, and global scales.
Noble Metal Organometallic Complexes Display Antiviral Activity against SARS-CoV-2
Chuong, Christina; DuChane, Christine M.; Webb, Emily M.; Rai, Pallavi; Marano, Jeffrey M.; Bernier, Chad M.; Merola, Joseph S.; Weger-Lucarelli, James (MDPI, 2021-05-25)
SARS-CoV-2 emerged in 2019 as a devastating viral pathogen with no available preventative or treatment to control what led to the current global pandemic. The continued spread of the virus and increasing death toll necessitate the development of effective antiviral treatments to combat this virus. To this end, we evaluated a new class of organometallic complexes as potential antivirals. Our findings demonstrate that two pentamethylcyclopentadienyl (Cp*) rhodium piano stool complexes, Cp*Rh(1,3-dicyclohexylimidazol-2-ylidene)Cl₂ (complex 2) and Cp*Rh(dipivaloylmethanato)Cl (complex 4), have direct virucidal activity against SARS-CoV-2. Subsequent in vitro testing suggests that complex 4 is the more stable and effective complex and demonstrates that both 2 and 4 have low toxicity in Vero E6 and Calu-3 cells. The results presented here highlight the potential application of organometallic complexes as antivirals and support further investigation into their activity.
Proteomic Discovery of VEEV E2-Host Partner Interactions Identifies GRP78 Inhibitor HA15 as a Potential Therapeutic for Alphavirus Infections
Barrera, Michael D.; Callahan, Victoria; Akhrymuk, Ivan V.; Bhalla, Nishank; Zhou, Weidong; Campbell, Catherine; Narayanan, Aarthi; Kehn-Hall, Kylene (MDPI, 2021-03-02)
Alphaviruses are a genus of the Togaviridae family and are widely distributed across the globe. Venezuelan equine encephalitis virus (VEEV) and eastern equine encephalitis virus (EEEV), cause encephalitis and neurological sequelae while chikungunya virus (CHIKV) and Sindbis virus (SINV) cause arthralgia. There are currently no approved therapeutics or vaccines available for alphaviruses. In order to identify novel therapeutics, a V5 epitope tag was inserted into the N-terminus of the VEEV E2 glycoprotein and used to identify host-viral protein interactions. Host proteins involved in protein folding, metabolism/ATP production, translation, cytoskeleton, complement, vesicle transport and ubiquitination were identified as VEEV E2 interactors. Multiple inhibitors targeting these host proteins were tested to determine their effect on VEEV replication. The compound HA15, a GRP78 inhibitor, was found to be an effective inhibitor of VEEV, EEEV, CHIKV, and SINV. VEEV E2 interaction with GRP78 was confirmed through coimmunoprecipitation and colocalization experiments. Mechanism of action studies found that HA15 does not affect viral RNA replication but instead affects late stages of the viral life cycle, which is consistent with GRP78 promoting viral assembly or viral protein trafficking.
PSGL-1 Inhibits the Incorporation of SARS-CoV and SARS-CoV-2 Spike Glycoproteins into Pseudovirions and Impairs Pseudovirus Attachment and Infectivity
He, Sijia; Waheed, Abdul A.; Hetrick, Brian; Dabbagh, Deemah; Akhrymuk, Ivan V.; Kehn-Hall, Kylene; Freed, Eric O.; Wu, Yuntao (MDPI, 2020-12-30)
P-selectin glycoprotein ligand-1 (PSGL-1) is a cell surface glycoprotein that binds to P-, E-, and L-selectins to mediate the tethering and rolling of immune cells on the surface of the endothelium for cell migration into inflamed tissues. PSGL-1 has been identified as an interferon-γ (INF-γ)-regulated factor that restricts HIV-1 infectivity, and has recently been found to possess broad-spectrum antiviral activities. Here we report that the expression of PSGL-1 in virus-producing cells impairs the incorporation of SARS-CoV and SARS-CoV-2 spike (S) glycoproteins into pseudovirions and blocks pseudovirus attachment and infection of target cells. These findings suggest that PSGL-1 may potentially inhibit coronavirus replication in PSGL-1⁺ cells

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Browsing Destination Area: Global Systems Science (GSS) by Department "Biomedical Sciences and Pathobiology"

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