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Item Effects of cell size and bicarbonate on single photon response variability in retinal rods(Frontiers In Molecular Neuroscience, 2022-12-14) Geva, Polina; Caruso, Giovanni; Klaus, Colin; Hamm, Heidi E; Gurevich, Vsevolod V.; DiBenedetto, Emmanuele; Makino, Clint L.Accurate photon counting requires that rods generate highly amplified, reproducible single photon responses (SPRs). The SPR is generated within the rod outer segment (ROS), a multilayered structure built from membranous disks that house rhodopsin. Photoisomerization of rhodopsin at the disk rim causes a local depletion of cGMP that closes ion channels in the plasmalemma located nearby with relative rapidity. In contrast, a photoisomerization at the disk center, distant from the plasmalemma, has a delayed impact on the ion channels due to the time required for cGMP redistribution. Radial differences should be greatest in large diameter rods. By affecting membrane guanylate cyclase activity, bicarbonate could impact spatial inhomogeneity in cGMP content. It was previously known that in the absence of bicarbonate, SPRs are larger and faster at the base of a toad ROS (where the ROS attaches to the rest of the cell) than at the distal tip. Given that bicarbonate enters the ROS at the base and diffuses to the tip and that it expedites flash response recovery, there should be an axial concentration gradient for bicarbonate that would accentuate the base-to-tip SPR differences. Seeking to understand how ROS geometry and bicarbonate affect SPR variability, we used mathematical modeling and made electrophysiological recordings of single rods. Modeling predicted and our experiments confirmed minor radial SPR variability in large diameter, salamander rods that was essentially unchanged by bicarbonate. SPRs elicited at the base and tip of salamander rods were similar in the absence of bicarbonate, but when treated with 30 mM bicarbonate, SPRs at the base became slightly faster than those at the tip, verifying the existence of an axial gradient for bicarbonate. The differences were small and unlikely to undermine visual signaling. However, in toad rods with longer ROSs, bicarbonate somehow suppressed the substantial, axial SPR variability that is naturally present in the absence of bicarbonate. Modeling suggested that the axial gradient of bicarbonate might dampen the primary phototransduction cascade at the base of the ROS. This novel effect of bicarbonate solves a mystery as to how toad vision is able to function effectively in extremely dim light.Item REPLY TO TRAN ET AL.: Dimeric KRAS protein-protein interaction stabilizers(Proceedings of the National Academy of Sciences of the United States of America, 2020-02-18) Moser, Franziska; Phan, Jason; Sai, Jiqing; Sun, Qi; Waterson, Alex; Fesik, Stephen W.Item Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure(Nature Communications, 2020-01-09) Morgan, ThomasHeart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.Item A network analysis to identify mediators of germline-driven differences in breast cancer prognosis(Nature Communications, 2020-01-16) Blot, WilliamIdentifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.Item Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study(Nature Communications, 2020-02-03) Gwirtsman, Harry E.Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.Item Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility(Nature Communications, 2020-01-07) Aldrich, Melinda C.Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: r(g) = 0.098, p = 2.3 x 10(-8)) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: r(g) = 0.137, p = 2.0 x 10(-12)). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.Item Interactive Multiresolution Visualization of Cellular Network Processes(iScience, 2020-01-24) Ortega, Oscar O.; Lopez, Carlos F.Visualization plays a central role in the analysis of biochemical network models to identify patterns that arise from reaction dynamics and perform model exploratory analysis. To facilitate these analyses, we developed PyViPR, a visualization tool that generates static and dynamic representations of biochemical network processes within a Python-based environment. PyViPR embeds network visualizations within Jupyter notebooks, thus enabling integration with modeling, simulation, and analysis workflows. To present the capabilities of PyViPR, we explore execution mechanisms of extrinsic apoptosis in HeLa cells. We show that community-detection algorithms identify groups of molecular species that capture key biological functions and ease exploration of the apoptosis network. We then show how different kinetic parameter sets that fit the experimental data equally well exhibit significantly different signal-execution dynamics as the system progresses toward mitochondria! outermembrane permeabilization. Therefore, PyViPR aids the conceptual understanding of dynamic network processes and accelerates hypothesis generation for further testing and validation.Item Countermanding Perceptual Decision-Making(iScience, 2020-01-24) Middlebrooks, Paul G.; Zandbelt, Bram B.; Logan, Gordon D.; Palmeri, Thomas J.; Schall, Jeffrey D.We investigated whether a task requiring concurrent perceptual decision-making and response control can be performed concurrently, whether evidence accumulation and response control are accomplished by the same neurons, and whether perceptual decision-making and countermanding can be unified computationally. Based on neural recordings in a prefrontal area of macaque monkeys, we present behavioral, neural, and computational results demonstrating that perceptual decision-making of varying difficulty can be countermanded efficiently, that single prefrontal neurons instantiate both evidence accumulation and response control, and that an interactive race between stochastic GO evidence accumulators for each alternative and a distinct STOP accumulator fits countermanding choice behavior and replicates neural trajectories. Thus, perceptual decision-making and response control, previously regarded as distinct mechanisms, are actually aspects of a common neuro-computational mechanism supporting flexible behavior. KeywordsItem Profiling of the plasma proteome across different stages of human heart failure(Nature Communications, 2019-12-20) Wells, Quinn S.Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development.Item Can Mentoring Promote Self-esteem and School Connectedness? An Evaluation of the Mentor-UP Project(Psychological Inervention, 2020-04) Marino, Claudia; Santinello, Massimo; Lenzi, Michela; Santoro, Paolo; Bergamin, Marisa; Gaboardi, Marta; Calcagni, Antonio; Altoe, Gianmarco; Perkins, Douglas D.Research in the United States has shown that youth mentoring is a promising strategy for increasing self-esteem and school connectedness in at-risk youth. There has been little confirmation of those findings internationally. The current study evaluates the impact of mentoring by trained university students on children's self-esteem and school connectedness compared to schoolmates not involved in the program. Mentor-UP is a school- and community-based weekly mentoring program implemented in northern Italy over a period of seven months. Participants (209 students - 34 in the experimental group and 175 in the comparison group - aged between 11 and 13,56% male, 27% immigrants) reported their levels of self-esteem and school connectedness at the beginning and at the end of the program. Results showed a significant increase in mentees' self-esteem compared to the control group, while the difference in school-connectedness was nonsignificant. The findings support the effectiveness of Mentor-UP in nurturing youth's self-esteem.Item GWAS of QRS duration identifies new loci specific to Hispanic/Latino populations(PLoS One, 2019-06-28) Petty, Lauren E.; Below, Jennifer E.Background The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies ( GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored. Methods We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations ( n = 15,124) from four studies using 1000 Genomes imputed genotype data ( adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis. Results We identified six loci associated with QRS ( P<5x10(-8)), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency ( MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 ( P = 1.19x10(-24)) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos. Conclusions Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.Item Innate CD8 alpha alpha(+) cells promote ILC1-like intraepithelial lymphocyte homeostasis and intestinal inflammation(PLoS One, 2019-07-10) Nazmi, Ali; Hoek, Kristen L.; Greer, Michael J.; Piazuelo, Maria B.; Minato, Nagahiro; Olivares-Villagomez, DanyvidInnate CD8 alpha alpha(+) cells, also referred to as iCD8 alpha cells, are TCR-negative intraepithelial lymphocytes (IEL) possessing cytokine and chemokine profiles and functions related to innate immune cells. iCD8 alpha cells constitute an important source of osteopontin in the intestinal epithelium. Osteopontin is a pleiotropic cytokine with diverse roles in bone and tissue remodeling, but also has relevant functions in the homeostasis of immune cells. In this report, we present evidence for the role of iCD8 alpha cells in the homeostasis of TCR-negative NKp46(+)NK1.1(+)IEL (ILC1-like). We also show that the effect of iCD8 alpha cells on ILC1-like IEL is enhanced in vitro by osteopontin. We show that in the absence of iCD8 alpha cells, the number of NKp46(+)NK1.1(+)IEL is significantly reduced. These ILC1-like cells are involved in intestinal pathogenesis in the anti-CD40 mouse model of intestinal inflammation. Reduced iCD8 alpha cell numbers results in a milder form of intestinal inflammation in this disease model, whereas treatment with osteopontin increases disease severity. Collectively, our results suggest that iCD8 alpha cells promote survival of NKp46(+)NK1.1(+)IEL, which significantly impacts the development of intestinal inflammation.Item Engaging policy in science writing: Patterns and strategies(PLoS One, 2019-08-01) Ruhl, J. B.; Posner, Stephen M.; Ricketts, Taylor H.Many scientific researchers aspire to engage policy in their writing, but translating scientific research and findings into policy discussion often requires an understanding of the institutional complexities of legal and policy processes and actors. To examine how researchers have undertaken that challenge, we developed a set of metrics and applied them to articles published in one of the principal academic publication venues for science and policy-Science magazine's Policy Forum. We reviewed each Policy Forum article published over a five-year period (2011-15), 220 in all. For each article, we assessed the level of policy content based on presence of a stated policy proposal or position and identification of the relevant policy actors and actions, and recorded attributes such as field of science, field of policy, number of references to legal and policy sources, number of authors from law and policy institutions, and number of citations. We find that a handful of science fields dominate publication frequency, but that all fields have produced publications with high policy engagement. Of the attributes, number of references to law and policy sources is correlated positively with level of engagement, whereas number of law and policy authors was fairly constant across all depths of engagement. Surprisingly, level of policy engagement was negatively correlated with the number of citations an article subsequently received. We offer possible explanations for these results and thoughts for authors, editors, and research institutions interested in facilitating robust engagement of policy in scientific writing.Item Normal Saline solutions cause endothelial dysfunction through loss of membrane integrity, ATP release, and inflammatory responses mediated by P2X7R/p38 MAPK/MK2 signaling pathways(PLoS One, 2019-08-14) Cheung-Flynn, Joyce; Alvis, Bret D.; Hocking, Kyle M.; Guth, Christy M.; Luo, Weifeng; McCallister, Reid; Chadalavada, Kalyan; Polcz, Monica; Komalavilas, Padmini; Brophy, Colleen M.Resuscitation with 0.9% Normal Saline (NS), a non-buffered acidic solution, leads to increased morbidity and mortality in the critically ill. The goal of this study was to determine the molecular mechanisms of endothelial injury after exposure to NS. The hypothesis of this investigation is that exposure of endothelium to NS would lead to loss of cell membrane integrity, resulting in release of ATP, activation of the purinergic receptor (P2X7R), and subsequent activation of stress activated signaling pathways and inflammation. Human saphenous vein endothelial cells (HSVEC) incubated in NS, but not buffered electrolyte solution (Plasma-Lyte, PL), exhibited abnormal morphology and increased release of lactate dehydrogenase (LDH), adenosine triphosphate (ATP), and decreased transendothelial resistance (TEER), suggesting loss of membrane integrity. Incubation of intact rat aorta (RA) or human saphenous vein in NS but not PL led to impaired endothelial-dependent relaxation which was ameliorated by apyrase (hydrolyzes ATP) or SB203580 (p38 MAPK inhibitor). Exposure of HSVEC to NS but not PL led to activation of p38 MAPK and its downstream substrate, MAPKAP kinase 2 (MK2). Treatment of HSVEC with exogenous ATP led to interleukin 113 (IL-1 beta) release and increased vascular cell adhesion molecule (VCAM) expression. Treatment of RA with IL-1 beta led to impaired endothelial relaxation. IL-1 beta treatment of HSVEC led to increases in p38 MAPK and MK2 phosphorylation, and increased levels of arginase II. Incubation of porcine saphenous vein (PSV) in PL with pH adjusted to 6.0 or less also led to impaired endothelial function, suggesting that the acidic nature of NS is what contributes to endothelial dysfunction. Volume overload resuscitation in a porcine model after hemorrhage with NS, but not PL, led to acidosis and impaired endothelial function. These data suggest that endothelial dysfunction caused by exposure to acidic, non-buffered NS is associated with loss of membrane integrity, release of ATP, and is modulated by P2X7R-mediated inflammatory responses.Item Abnormal sodium and water homeostasis in mice with defective heparan sulfate polymerization(PLoS One, 2019-07-31) Engberink, Rik H. G. Olde; de Vos, Judith; van Weert, Angela; Zhang, Yahua; van Vlies, Naomi; van den Born, Bert-Jan H.; Titze, Jens M.); van Bavel, Ed; Vogt, LiffertGlycosaminoglycans in the skin interstitium and endothelial surface layer have been shown to be involved in local sodium accumulation without commensurate water retention. Dysfunction of heparan sulfate glycosaminoglycans may therefore disrupt sodium and water homeostasis. In this study, we investigated the effects of combined heterozygous loss of heparan sulfate polymerization genes (exostosin glycosyltransferase 1 and 2; Ext1(+/-)Ext2(+/-)) on sodium and water homeostasis. Sodium storage capacity was decreased in Ext1(+/-)Ext2(+/-) mice as reflected by a 77% reduction in endothelial surface layer thickness and a lower skin sodium-to-glycosaminoglycan ratio. Also, these mice were characterized by a higher heart rate, increased fluid intake, increased plasma osmolality and a decreased skin water and sodium content, suggesting volume depletion. Upon chronic high sodium intake, the initial volume depletion was restored but no blood pressure increase was observed. Acute hypertonic saline infusion resulted in a distinct blood pressure response: we observed a significant 15% decrease in control mice whereas blood pressure did not change in Ext1(+/-)Ext2(+/-) mice. This differential blood pressure response may be explained by the reduced capacity for sodium storage and/or the impaired vasodilation response, as measured by wire myography, which was observed in Ext1(+/-)Ext2(+/-) mice. Together, these data demonstrate that defective heparan sulfate glycosaminoglycan synthesis leads to abnormal sodium and water homeostasis and an abnormal response to sodium loading, most likely caused by inadequate capacity for local sodium storage.Item Association between alcohol use and inflammatory biomarkers over time among younger adults with HIV-The Russia ARCH Observational Study(PLoS One, 2019-08-22) Freiberg, Matthew S.Background Biomarkers of monocyte activation (soluble CD14 [sCD14]), inflammation (interleukin-6 [IL-6]), and altered coagulation (D-dimer) are associated with increased mortality risk in people with HIV. The objective of the Russia Alcohol Research Collaboration on HIV/AIDS (ARCH) study was to evaluate the association between heavy alcohol use and inflammatory biomarkers over time. Methods The study sought antiretroviral therapy naive participants with HIV (n = 350) and assessed them at baseline, 12 and 24 months. Linear mixed effects models were used to determine whether heavy drinking (self-report augmented by phosphatidylethanol [PEth], an alcohol biomarker) was longitudinally associated with IL-6, sCD14 and D-dimer adjusting for potential confounders (e.g., demographics, HIV factors, comorbid conditions). Results Participants' baseline characteristics were as follows: 71% male; mean age of 34 years; 87% self-reported hepatitis C; and 86% current smokers. Mean log(10) (HIV RNA) was 4.3 copies/mL. Heavy alcohol use, based on National Institute of Alcohol Abuse and Alcoholism risky drinking criteria and PEth (versus non-heavy alcohol use) was associated with higher sCD14 (adjusted mean difference 125 ng/mL [95% CI: 42, 209]), IL-6 (ratio of means 1.35 [95% CI: 1.17, 1.55] pg/mL), and D-dimer (ratio of means 1.20 [95% CI: 1.06, 1.37] ug/mL) across the two-year follow-up. Conclusion Among HIV+ adults, current heavy alcohol use is associated with higher sCD14, IL-6 and D-dimer over time. Since these biomarkers are associated with mortality, interventions to mitigate effects of heavy drinking on these immune processes merit consideration.Item Primary care physicians' perceptions of barriers and facilitators to management of chronic kidney disease: A mixed methods study(PLoS One, 2019-08-22) Abdel-Kader, Khaled; Cavanaugh, KerriBackground Given the high prevalence of chronic kidney disease (CKD), primary care physicians (PCPs) frequently manage early stage CKD. Nonetheless, there are challenges in providing optimal CKD care in the primary care setting. This study sought to understand PCPs' perceptions of barriers and facilitators to the optimal management of CKD. Study design Mixed methods study Settings and participants Community-based PCPs in four US cities: Baltimore, MD; St. Louis, MO; Raleigh, NC and San Francisco, CA. Methodology We used a self-administered questionnaire and conducted 4 focus groups of PCPs (n = 8 PCPs/focus group) in each city to identify key barriers and facilitators to management of patients with CKD in primary care. Analytic approach We conducted descriptive analyses of the survey data. Major themes were identified from audio-recorded interviews that were transcribed and coded by the research team. Results Of 32 participating PCPs, 31 (97%) had been in practice for >10 years, and 29 (91%) practiced in a non-academic setting. PCPs identified multiple barriers to managing CKD in primary care including at the level of the patient (e.g., low awareness of CKD, poor adherence to treatment recommendations), the provider (e.g., staying current with CKD guidelines), and the health care system (e.g., inflexible electronic medical record, limited time and resources). PCPs desired electronic prompts and lab decision support, concise guidelines, and healthcare financing reform to improve CKD care. Conclusions PCPs face substantial but modifiable barriers in providing care to patients with CKD. Interventions that address these barriers and promote facilitative tools may improve PCPs' effectiveness and capacity to care for patients with CKD.Item The long-term consequences of antibiotic therapy: Role of colonic short-chain fatty acids (SCFA) system and intestinal barrier integrity(PLoS One, 2019-08-22) Holota, Yuliia; Dovbynchuk, Taisa; Kaji, Izumi; Vareniuk, Igor; Dzyubenko, Natalia; Chervinska, Tetiana; Zakordonets, Liudmyla; Stetska, Viktoria; Ostapchenko, Liudmyla; Serhiychuk, Tetiana; Tolstanova, GannaEpidemiological studies revealed that antibiotics exposure increases a risk of inflammatory bowel diseases (IBD) development. It remained largely unknown how antibiotic-induced dysbiosis confers the risk for enhanced inflammatory response. The aim of the present study was to test the hypothesis that SCFAs, their receptors and transporters mediate the antibiotic long-term effects on the functional state of colonic mucosa and susceptibility to the experimental colitis. Male Wistar rats were treated daily for 14 days with antibiotic ceftriaxone (300 mg/kg, i.m.) or vehicle; euthanized by CO2 inhalation followed by cervical dislocation in 1, 14 or 56 days after antibiotic withdrawal. We found increased cecum weight and sustained changes in microbiota composition after ceftriaxone treatment with increased number of conditionally pathogenic enterobacteria, E. coli, Clostridium, Staphylococcus spp. and hemolytic bacteria even at 56 days after antibiotic withdrawal. The concentration of SCFAs was decreased after ceftriaxone withdrawal. We found decreased immunoreactivity of the FFA2, FFA3 receptors, SMCT1 and increased MCT1 & MCT4 transporters of SCFAs in colon mucosa. These changes evoked a significant shift in colonic mucosal homeostasis: the disturbance of oxidant-antioxidant balance; activation of redox-sensitive transcription factor HIF1 alpha and ERK1/2 MAP kinase; increased colonic epithelial permeability and bacterial translocation to blood; morphological remodeling of the colonic tissue. Ceftriaxone pretreatment significantly reinforced inflammation during experimental colitis 56 days after ceftriaxone withdrawal, which was confirmed by increased histopathology of colitis, Goblet cell dysfunction, colonic dilatation and wall thickening, and increased serum levels of inflammatory cytokines (TNF-alpha and IL-10). Since the recognition of the importance of microbiota metabolic activity rather than their composition in the development of inflammatory disorders, e.g. IBD, the present study is the first report on the role of the SCFA system in the long lasting side effects of antibiotic treatment and its implication in IBD development.Item Zinc deficiency and advanced liver fibrosis among HIV and hepatitis C co-infected anti-retroviral naive persons with alcohol use in Russia(PLoS One, 2019-06-27) Barocas, Joshua A.; So-Armah, Kaku; Cheng, Debbie M.; Lioznov, Dmitry; Baum, Marianna; Gallagher, Kerrin; Fuster, Daniel; Gnatienko, Natalia; Krupitsky, Evgeny; Freiberg, Matthew S.; Samet, Jeffrey H.Background and aims Liver disease in people living with HIV co-infected with hepatitis C virus is a source of morbidity and mortality in Russia. HIV accelerates liver fibrosis in the setting of HCV co-infection and alcohol use. Zinc deficiency is common among people living with HIV and may be a factor that facilitates the underlying mechanisms of liver fibrosis. We investigated the association between zinc deficiency and advanced liver fibrosis in a cohort of HIV/HCV co-infected persons reporting heavy drinking in Russia. Methods This is a secondary data analysis of baseline data from 204 anti-retroviral treatment naive HIV/HCV co-infected Russians with heavy drinking that were recruited into a clinical trial of zinc supplementation. The primary outcome of interest in this cross-sectional study was advanced liver fibrosis. Zinc deficiency, the main independent variable, was defined as plasma zinc <0.75 mg/L. Exploratory analyses were performed examining continuous zinc levels and fibrosis scores. Analyses were conducted using multivariable regression models adjusted for potential confounders. Results The prevalence of advanced liver fibrosis was similar for those with zinc deficiency compared to those with normal zinc levels, (27.7% vs. 23.0%, respectively). We did not detect an association between zinc deficiency and advanced liver fibrosis in the adjusted regression model (aOR: 1.28, 95% CI: 0.62-2.61, p = 0.51) nor in exploratory analyses.Item Multi-scale, numerical modeling of spatio-temporal signaling in cone phototransduction(2019-07-25) Klaus, Colin; Caruso, Giovanni; Gurevich, Vsevolod V.; DiBenedetto, EmmanueleMammals have two types of photoreceptors, rods and cones. While rods are exceptionally sensitive and mediate vision at very low illumination levels, cones operate in daylight and are responsible for the bulk of visual perception in most diurnal animals, including humans. Yet the mechanisms of phototransduction in cones is understudied, largely due to unavailability of pure cone outer segment (COS) preparations. Here we present a novel mathematical model of cone phototransduction that explicitly takes into account complex cone geometry and its multiple physical scales, faithfully reproduces features of the cone response, and is orders of magnitude more efficient than the standard 3D diffusion model. This is accomplished through the mathematical techniques of homogenization and concentrated capacity. The homogenized model is then computationally implemented by finite element method. This homogenized model permits one to analyze the effects of COS geometry on visual transduction and lends itself to performing large numbers of numerical trials, as required for parameter analysis and the stochasticity of rod and cone signal transduction. Agreement between the nonhomogenized, (i.e., standard 3D), and homogenized diffusion models is reported along with their simulation times and memory costs. Virtual expression of rod biochemistry on cone morphology is also presented for understanding some of the characteristic differences between rods and cones. These simulations evidence that 3D cone morphology and ion channel localization contribute to biphasic flash response, i.e undershoot. The 3D nonhomogenized and homogenized models are contrasted with more traditional and coarser well-stirred and 1D longitudinal diffusion models. The latter are single-scale and do not explicitly account for the multi-scale geometry of the COS, unlike the 3D homogenized model. We show that simpler models exaggerate the magnitude of the current suppression, yield accelerated time to peak, and do not predict the local concentration of cGMP at the ionic channels.