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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, Liffert
Glycosaminoglycans 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.
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.
Biomineralization by particle attachment in early animals
(Proceedings of the National Academy of Sciences of the United States of America, 2019-09-03) Gilbert, Pupa U. P. A.; Porter, Susannah M.; Sun, Chang-Yu; Xiao, Shuhai; Gibson, Brandt M.; Shenkar, Noa; Knoll, Andrew H.
Crystallization by particle attachment (CPA) of amorphous precursors has been demonstrated in modern biomineralized skeletons across a broad phylogenetic range of animals. Precisely the same precursors, hydrated (ACC-H2O) and anhydrous calcium carbonate (ACC), have been observed spectromicroscopically in echinoderms, mollusks, and cnidarians, phyla drawn from the 3 major clades of eumetazoans. Scanning electron microscopy (SEM) here also shows evidence of CPA in tunicate chordates. This is surprising, as species in these clades have no common ancestor that formed a mineralized skeleton and appear to have evolved carbonate bio-mineralization independently millions of years after their late Neoproterozoic divergence. Here we correlate the occurrence of CPA from ACC precursor particles with nanoparticulate fabric and then use the latter to investigate the antiquity of the former. SEM images of early biominerals from Ediacaran and Cambrian shelly fossils show that these early calcifiers used attachment of ACC particles to form their biominerals. The convergent evolution of biomineral CPA may have been dictated by the same thermodynamics and kinetics as we observe today.
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.
Cell-specific image-guided transcriptomics identifies complex injuries caused by ischemic acute kidney injury in mice
(Communications Biology, 2019-09-02) Page-McCaw, Patrick S.
The kidney's inherent complexity has made identifying cell-specific pathways challenging, particularly when temporally associating them with the dynamic pathophysiology of acute kidney injury (AKI). Here, we combine renal cell-specific luciferase reporter mice using a chemoselective luciferin to guide the acquisition of cell-specific transcriptional changes in C57BL/6 background mice. Hydrogen peroxide generation, a common mechanism of tissue damage, was tracked using a peroxy-caged-luciferin to identify optimum time points for immunoprecipitation of labeled ribosomes for RNA-sequencing. Together, these tools revealed a profound impact of AKI on mitochondrial pathways in the collecting duct. In fact, targeting the mitochondria with an antioxidant, ameliorated not only hydrogen peroxide generation, but also significantly reduced oxidative stress and the expression of the AKI biomarker, LCN2. This integrative approach of coupling physiological imaging with transcriptomics and drug testing revealed how the collecting duct responds to AKI and opens new venues for cell-specific predictive monitoring and treatment.
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. Keywords
Data on the negative regulation of invadopodia activity by MLCK
(Data in Brief, 2019-06) Jerrell, Rachel J.; Parekh, Aron
Actomyosin contractility can promote extracellular matrix (ECM) degradation by invadopodia in cancer cells. However, we previously found that inhibiting myosin light chain kinase (MLCK) with siRNA did not change force generation by the head and neck squamous cell carcinoma (HNSCC) cell line SCC-61. We provide data here that this targeted method of MLCK knockdown (KD) resulted in a significant increase in the amount of ECM degradation, number of actively degrading invadopodia, and the number of total invadopodia formed. These data are related to the research article entitled "Matrix rigidity differentially regulates invadopodia activity through ROCK1 and ROCK2" Jerrell and Parekh, 2016. (C) 2019 The Author(s). Published by Elsevier Inc.
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.
Energetic costs regulated by cell mechanics and confinement are predictive of migration path during decision-making
(Nature Communications, 2019-09-13) Zanotelli, Matthew R.; Rahman-Zaman, Aniqua; VanderBurgh, Jacob A.; Taufalele, Paul V.; Jain, Aadhar; Erickson, David; Bordeleau, Francois; Reinhart-King, Cynthia A.
Cell migration during the invasion-metastasis cascade requires cancer cells to navigate a spatially complex microenvironment that presents directional choices to migrating cells. Here, we investigate cellular energetics during migration decision-making in confined spaces. Theoretical and experimental data show that energetic costs for migration through confined spaces are mediated by a balance between cell and matrix compliance as well as the degree of spatial confinement to direct decision-making. Energetic costs, driven by the cellular work needed to generate force for matrix displacement, increase with increasing cell stiffness, matrix stiffness, and degree of spatial confinement, limiting migration. By assessing energetic costs between possible migration paths, we can predict the probability of migration choice. Our findings indicate that motility in confined spaces imposes high energetic demands on migrating cells, and cells migrate in the direction of least confinement to minimize energetic costs. Therefore, therapeutically targeting metabolism may limit cancer cell migration and metastasis.
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.
Evaluation of Synthetic Cytochrome P-450-Mimetic Metalloporphyrins To Facilitate "Biomimetic" Biotransformation of a Series of mGlu(5) Allosteric Ligands
(ACS Omega, 2019-07) Presley, Christopher C.; Perry, Charles K.; Childress, Elizabeth S.; Mulder, Matthew J.; Luscombe, Vincent B.; Rodriguez, Alice L.; Niswender, Colleen M.; Conn, P. Jeffrey; Lindsley, Craig W.
Allosteric ligands within a given chemotype can have the propensity to display a wide range of pharmacology, as well as unexpected changes in GPCR subtype selectivity, typically mediated by single-atom modifications to the ligand. Due to the unexpected nature of these "molecular switches", chemotypes with this property are typically abandoned in lead optimization. Recently, we have found that in vivo oxidative metabolism by CYP(450)s can also engender molecular switches within allosteric ligands, changing the mode of pharmacology and leading to unwanted toxicity. We required a higher-throughput approach to assess in vivo metabolic molecular switches, and we turned to a "synthetic liver", a 96 well kit of biomimetic catalysts (e.g., metalloporphyrins) to rapidly survey a broad panel of synthetic CYP(450)s' ability to oxidize/"metabolize" an mGlu(5) PAM (VU0403602) known to undergo an in vivo CYP450-mediated molecular switch. While the synthetic CYP(450)s did generate a number of oxidative "metabolites" at known "hot spots", several of which proved to be pure mGlu(5) PAMs comparable in potency to the parent, the known CYP450-mediated in vivo ago-PAM metabolite, namely, VU0453103, was not formed. Thus, this technology platform has potential to identify hot spots for oxidative metabolism and produce active metabolites of small-molecule ligands in a high-throughput, scalable manner.
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.
Experimentally-driven mathematical modeling to improve combination targeted and cytotoxic therapy for HER2+breast cancer
(Scientific Reports, 2019-09-06) Jarrett, Angela M.; Shah, Alay; Bloom, Meghan J.; McKenna, Matthew T.; Hormuth, David A., II; Yankeelov, Thomas E.; Sorace, Anna G.
The goal of this study is to experimentally and computationally investigate combination trastuzumab-paclitaxel therapies and identify potential synergistic effects due to sequencing of the therapies with in vitro imaging and mathematical modeling. Longitudinal alterations in cell confluence are reported for an in vitro model of BT474 HER2+ breast cancer cells following various dosages and timings of paclitaxel and trastuzumab combination regimens. Results of combination drug regimens are evaluated for drug interaction relationships based on order, timing, and quantity of dose of the drugs. Altering the order of treatments, with the same total therapeutic dose, provided significant changes in overall cell confluence (p < 0.001). Two mathematical models are introduced that are constrained by the in vitro data to simulate the tumor cell response to the individual therapies. A collective model merging the two individual drug response models was designed to investigate the potential mechanisms of synergy for paclitaxel-trastuzumab combinations. This collective model shows increased synergy for regimens where trastuzumab is administered prior to paclitaxel and suggests trastuzumab accelerates the cytotoxic effects of paclitaxel. The synergy derived from the model is found to be in agreement with the combination index, where both indicate a spectrum of additive and synergistic interactions between the two drugs dependent on their dose order. The combined in vitro results and development of a mathematical model of drug synergy has potential to evaluate and improve standard-of-care combination therapies in cancer.
Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
(Nature Communications, 2020-01-09) Morgan, Thomas
Heart 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.
Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
(Nature Communications, 2019-09-11) Giri, Ayush; Shaffer, Christian M.; Carroll, Robert J.; McMullen, Barbara; Hung, Adriana M.; Wilson, Otis D; Edwards, Todd L.
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n =192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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.
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.
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, Danyvid
Innate 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.
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.
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, Ganna
Epidemiological 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.

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