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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.
Synbiotics suppress colitis-induced tumorigenesis in a colon-specific cancer mouse model
(Plos One, 2019-06-26) Saito, Yasufumi; Hinoi, Takao; Adachi, Tomohiro; Miguchi, Masashi; Niitsu, Hiroaki; Kochi, Masatoshi; Sada, Haruki; Sotomaru, Yusuke; Sakamoto, Naoya; Sentani, Kazuhiro; Oue, Naohide; Yasui, Wataru; Tashiro, Hirotaka; Ohdan, Hideki
Although synbiotics may be effective in maintaining remission of inflammatory bowel disease, their anticarcinogenic effects are still debated. To address this issue, we evaluated the effects of synbiotics, probiotics, and prebiotics on tumorigenesis using a CDX2P-Cre; Apc(+/flox) mouse model harboring a colon-specific Apc knock out, which develops adenoma and adenocarcinoma of the colon. Dextran sodium sulfate (DSS)-administration promoted colonic tumor development in CDX2P-Cre; Apc(+/flox) mice, and these tumors were associated with loss of Apc heterozygosity, as confirmed by observation of well-differentiated adenocarcinomas with beta-catenin accumulation in tumor cell cytoplasm. Synbiotics-treatment suppressed dextran sodium sulfate-induced colitis in CDX2P-Cre; Apc(+/flox) mice, thereby reducing mortality, and inhibited tumorigenesis accelerated by DSS-administration. Conversely, neither probiotics nor prebiotics had any effect on inflammation and tumorigenesis. Lactobacillus casei and Bifidobacterium breve were detected in the fecal microbiota of probiotics-treated mice. Synbiotics-treatment suppressed DSS-induced expression of IL-6, STAT-3, COX-2, and TNF-alpha gene transcripts in normal colonic epithelium, indicating the possibility of suppressing tumor development. Importantly, these genes may be potential therapeutic targets in inflammation-associated colon cancer.
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.
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.
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.
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.
Multi-scale, numerical modeling of spatio-temporal signaling in cone phototransduction
(2019-07-25) Klaus, Colin; Caruso, Giovanni; Gurevich, Vsevolod V.; DiBenedetto, Emmanuele
Mammals 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.
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.
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.
Towards A Microbead Occlusion Model of Glaucoma for a Non-Human Primate
(2019-08-09) Lambert, Wendi S.; Carlson, Brian J.; Ghose, Purnima; Vest, Victoria D.; Yao, Vincent; Calkins, David J.
Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease causes vision loss through the degeneration of retinal ganglion cell neurons and their axons in the optic nerve. Using an inducible model of glaucoma, we elevated IOP in the squirrel monkey (Saimiri boliviensis) using intracameral injection of 35 mu m polystyrene microbeads and measured common pathogenic outcomes in the optic projection. A 42% elevation in IOP over 28 weeks reduced anterograde transport of fluorescently-labeled cholera toxin beta from retina to the lateral geniculate nucleus (60% decrease), and to the superior colliculus (49% decrease). Pressure also reduced survival of ganglion cellaxons in the optic nerve by 22%. The same elevation caused upregulation of proteins associated with glaucomatous neurodegeneration in the retina and optic nerve, including complement 1q, interleukin 6, and brain-derived neurotrophic factor. That axon degeneration in the nerve lagged deficits in anterograde transport is consistent with progression in rodent models, while the observed protein changes also occur in tissue from human glaucoma patients. Thus, microbead occlusion in a non-human primate with a visual system similar to our own represents an attractive model to investigate neurodegenerative mechanisms and therapeutic interventions for glaucoma.
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.
Racial/ethnic, age and sex disparities in leukemia survival among adults in the United States during 1973-2014 period
(PLoS One, 2019-08-19) Zheng, Wei; Shu, Xiao-Ou
There has been marked improvement in leukemia survival, particularly among children in recent time. However, the long-term trends in survival among adult leukemia patients and the associated sex and racial survival disparities are not well understood. We, therefore, evaluated the secular trends in survival improvement of leukemia patients from 1973 through 2014, using Surveillance Epidemiology and End-Result Survey Program (SEER) data. ICD-O-3 morphology codes were used to group leukemia into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML). Survival analysis for each leukemia type stratified by race/ethnicity, age, sex was performed to generate relative survival probability estimates for the baseline time period of 1973 through 1979. Hazard ratios (HR) and respective 95% confidence intervals (Cis) for survival within subsequent 10-year time periods by race, age and sex were calculated using Cox proportional hazard models. Of the 83,255 leukemia patients for the current analysis, the 5-year survival of patients with ALL, AML, CLL, and CML during 1973-1979 were 42.0%, 6.5%, 66.5%, and 20.9%, respectively. Compared to the baseline, there were substantial improvements of leukemia-specific survival in 2010-2014 among African-American (81.0%) and Asian (80.0%) patients with CML and among 20-49 year of age with CLL (96.0%). African-American patients, those with AML and those older than 75 years of age had the lowest survival improvements. Asians experienced some of the largest survival improvements during the study period. Others, including African American and the elderly, have not benefited as much from advances in leukemia
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, Kerri
Background 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.
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.
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.
Ticks home in on body heat: A new understanding of Haller's organ and repellent action
(PLoS One, 2019-08-23) Carr, Ann L.; Salgado, Vincent L.
Ticks are second only to mosquitoes as vectors of disease to humans and animals. Tick host detection is mainly ascribed to Haller's organ, a complex sensory structure on the tick foreleg that detects odors, carbon dioxide and heat, but these host detection mechanisms are not well understood. There is anecdotal evidence that ticks and other ectoparasites are attracted to heat, but it has never been demonstrated that they use radiant heat to detect hosts at a distance. In fact, previous attempts to do this have concluded that radiant heat was not used by ticks. Here we use a novel thermotaxis assay to investigate the detection range, temperature dependence and repellent sensitivity of heat perception in ticks and to identify the sensory organ responsible for this sense. We show that Amblyomma americanum and Dermacentor variabilis ticks can locate a human from several meters away by radiant heat sensed by the part of Haller's organ known as the capsule, a covered spherical pit organ. An aperture in the capsule cover confers directionality and highly reflective interior surfaces of the capsule concentrate radiation on the sensilla to sharpen directionality and increase sensitivity. Commercial insect repellents provide an effective means of personal protection against potentially infectious tick bites by hindering host-seeking behavior. Low concentrations of the insect repellents DEET, picaridin, 2-undecanone, citronellal and nootkatone eliminate thermotaxis without affecting olfaction-stimulated host-seeking behavior. Our results demonstrate that the tick Haller's organ capsule is a radiant heat sensor used in host-finding and that repellents disrupt this sense at concentrations that do not disrupt olfaction. We anticipate that this discovery will significantly aid insect repellent research and provide novel targets for the development of innovative integrated pest management programs and personal protection strategies for ectoparasites and vector-borne disease.
Probing the solution structure of the E. coli multidrug transporter MdfA using DEER distance measurements with nitroxide and Gd(III) spin labels
(Scientific Reports, 2019-08-29) Yardeni, Eliane H.; Bahrenberg, Thorsten; Stein, Richard A.; Mishra, Smriti; Zomot, Elia; Graham, Bim; Tuck, Kellie L.; Huber, Thomas; Bibi, Eitan; Mchaourab, Hassane S.; Goldfarb, Danielle
Methodological and technological advances in EPR spectroscopy have enabled novel insight into the structural and dynamic aspects of integral membrane proteins. In addition to an extensive toolkit of EPR methods, multiple spin labels have been developed and utilized, among them Gd(III)-chelates which offer high sensitivity at high magnetic fields. Here, we applied a dual labeling approach, employing nitroxide and Gd(III) spin labels, in conjunction with Q-band and W-band double electron-electron resonance (DEER) measurements to characterize the solution structure of the detergent-solubilized multidrug transporter MdfA from E. coli. Our results identify highly flexible regions of MdfA, which may play an important role in its functional dynamics. Comparison of distance distribution of spin label pairs on the periplasm with those calculated using inward- and outward-facing crystal structures of MdfA, show that in detergent micelles, the protein adopts a predominantly outward-facing conformation, although more closed than the crystal structure. The cytoplasmic pairs suggest a small preference to the outward-facing crystal structure, with a somewhat more open conformation than the crystal structure. Parallel DEER measurements with the two types of labels led to similar distance distributions, demonstrating the feasibility of using W-band spectroscopy with a Gd(III) label for investigation of the structural dynamics of membrane proteins.
Two truncating variants in FANCC and breast cancer risk
(Scientific Reports, 2019-08-29) Beeghly-Fadiel, Alicia; Brauch, Hiltrud; Long, Jirong; Mulligan, Anna Marie; Shu, Xiao-Ou; Xiao-Ou, Wei
Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95% CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Thermal Perceptual Thresholds are typical in Autism Spectrum Disorder but Strongly Related to Intra-individual Response Variability
(Scientific Reports, 2019-08-29) Williams, Zachary J.; Failla, Michelle D.; Davis, Samona L.; Heflin, Brynna H.; Okitondo, Christian D.; Moore, David J.; Cascio, Carissa J.
Individuals with autism spectrum disorder (ASD) are often reported to exhibit an apparent indifference to pain or temperature. Leading models suggest that this behavior is the result of elevated perceptual thresholds for thermal stimuli, but data to support these assertions are inconclusive. An alternative proposal suggests that the sensory features of ASD arise from increased intra-individual perceptual variability. In this study, we measured method-of-limits warm and cool detection thresholds in 142 individuals (83 with ASD, 59 with typical development [TD], aged 7-54 years), testing relationships with diagnostic group, demographics, and clinical measures. We also investigated the relationship between detection thresholds and a novel measure of intra-individual (trial-to-trial) threshold variability, a putative index of "perceptual noise." This investigation found no differences in thermal detection thresholds between individuals with ASD and typical controls, despite large differences between groups in sensory reactivity questionnaires and modest group differences in intra-individual variability. Lower performance IQ, male sex, and higher intra-individual variability in threshold estimates were the most significant predictors of elevated detection thresholds. Although no psychophysical measure was significantly correlated with questionnaire measures of sensory hyporeactivity, large intra-individual variability may partially explain the elevated psychophysical thresholds seen in a subset of the ASD population.
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.

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