Duplex DNA from Sites of Helicase-Polymerase Uncoupling Links Non-B DNA Structure Formation to Replicative Stress

BACKGROUND: Replication impediments can produce helicase-polymerase uncoupling allowing lagging strand synthesis to continue for as much as 6 kb from the site of the impediment. MATERIALS AND METHODS: We developed a cloning procedure designed to recover fragments from lagging strand near the helicase halt site. RESULTS: A total of 62% of clones from a p53-deficient tumor cell line (PC3) and 33% of the clones from a primary cell line (HPS-19I) were within 5 kb of a G-quadruplex forming sequence. Analyses of a RACK7 gene sequence, that was cloned multiple times from the PC3 line, revealed multiple deletions in region about 1 kb from the cloned region that was present in a non-B conformation. Sequences from the region formed G-quadruplex and i-motif structures under physiological conditions. CONCLUSION: Defects in components of non-B structure suppression systems (e.g. p53 helicase targeting) promote replication-linked damage selectively targeted to sequences prone to G-quadruplex and i-motif formation

Bariatric surgery emphasizes biological sex differences in rodent hepatic lipid handling

Abstract Background Eighty percent of patients who receive bariatric surgery are women, yet the majority of preclinical studies are in male rodents. Because sex differences drive hepatic gene expression and overall lipid metabolism, we sought to determine whether sex differences were also apparent in these endpoints in response to bariatric surgery. Methods Two cohorts of age-matched virgin male and female Long-Evans rats were placed on a high fat diet for 3 weeks and then received either Sham or vertical sleeve gastrectomy (VSG), a surgery which resects 80% of the stomach with no intestinal rearrangement. Results Each sex exhibited significantly decreased body weight due to a reduction in fat mass relative to Sham controls (p < 0.05). Microarray and follow-up qPCR on liver revealed striking sex differences in gene expression after VSG that reflected a down-regulation of hepatic lipid metabolism and an up-regulation of hepatic inflammatory pathways in females vs. males after VSG. While the males had a significant reduction in hepatic lipids after VSG, there was no reduction in females. Ad lib-fed and fasting circulating triglycerides, and postprandial chylomicron production were significantly lower in VSG relative to Sham animals of both sexes (p < 0.01). However, hepatic VLDL production, highest in sham-operated females, was significantly reduced by VSG in females but not males. Conclusions Taken together, although both males and females lose weight and improve plasma lipids, there are large-scale sex differences in hepatic gene expression and consequently hepatic lipid metabolism after VSG.http://deepblue.lib.umich.edu/bitstream/2027.42/135948/1/13293_2017_Article_126.pd

Isotopic evidence for dominant secondary production of HONO in near-ground wildfire plumes

Nitrous acid (HONO) is an important precursor to hydroxyl radical (OH) that determines atmospheric oxidative capacity and thus impacts climate and air quality. Wildfire is not only a major direct source of HONO, it also results in highly polluted conditions that favor the heterogeneous formation of HONO from nitrogen oxides (NOx= NO + NO2) and nitrate on both ground and particle surfaces. However, these processes remain poorly constrained. To quantitatively constrain the HONO budget under various fire and/or smoke conditions, we combine a unique dataset of field concentrations and isotopic ratios (15N / 14N and 18O / 16O) of NOx and HONO with an isotopic box model. Here we report the first isotopic evidence of secondary HONO production in near-ground wildfire plumes (over a sample integration time of hours) and the subsequent quantification of the relative importance of each pathway to total HONO production. Most importantly, our results reveal that nitrate photolysis plays a minor role (\u3c5 %) in HONO formation in daytime aged smoke, while NO2-to-HONO heterogeneous conversion contributes 85 %–95 % to total HONO production, followed by OH + NO (5 %–15 %). At nighttime, heterogeneous reduction of NO2 catalyzed by redox active species (e.g., iron oxide and/or quinone) is essential (≥ 75 %) for HONO production in addition to surface NO2 hydrolysis. Additionally, the 18O / 16O of HONO is used for the first time to constrain the NO-to-NO2 oxidation branching ratio between ozone and peroxy radicals. Our approach provides a new and critical way to mechanistically constrain atmospheric chemistry and/or air quality models on a diurnal timescale

Urban-rural differences in immune responses to mycobacterial and tetanus vaccine antigens in a tropical setting: A role for helminths?

Several vaccines elicit lower efficacy or impaired immune responses in rural compared to urban settings, and in tropical low-income countries compared to high-income countries. An unresolved hypothesis is that immunomodulation by parasitic infections such as helminths (prevalent in rural tropical settings) contributes to suppression of vaccine responses. Among 1-17-year-old Ugandan residents of rural Schistosoma mansoni (Sm)-endemic islands and proximate urban communities with lower helminth exposure, we assessed plasma antibody and whole blood assay cytokine responses to tetanus toxoid (TT) and purified protein derivative of Mycobacterium tuberculosis (PPD). These were taken to represent recall responses to tetanus and BCG vaccination in infancy. PPD-specific responses are additionally induced by tuberculous and non-tuberculous mycobacterial exposure. Urban-rural comparisons showed that PPD-specific IFN-? and IL-13 and TT-specific IL-13 and IgG concentrations were lower in the rural setting, but that PPD-specific IgE concentrations were higher. Among rural participants, Sm infection was inversely associated with PPD-specific IFN-?, while nematode infection was positively associated with PPD-specific IgG. Among urban participants, Sm infection was positively associated with PPD-specific responses but inversely associated with TT-specific responses, while nematode infection was inversely associated with TT-specific IgG and IgG4, but no associations were observed with PPD-specific responses. Despite these associations, for the urban-rural comparisons there were no notable changes in test statistics after adjusting for current helminth infections, suggesting that helminths were not the sole explanation for the urban-rural differences observed. Helminths likely work in concert with other environmental exposures and operational factors to influence vaccine response

Everyone on Radio

This adaptation of Everyman was scheduled for production on the main stage in the Kline Theatre of Gettysburg College. With the onset of COVID-19 and the ensuing advent of distance-learning, that could no longer happen, and originally that was a crushing disappointment. But the show must go on, especially when that show is “Everyman,” an especially apt theatrical choice for a pestilential year. Everyman offers exciting possibilities for audio drama, especially considering the play’s emphasis on the internal struggle of the individual facing death; Everyone on Radio attempts to make the most of these aspects of the play. Never willing to blink in the face of doom, the students in this class rose to the occasion with incredible pluck, optimism, and good humor. In particular, Lauren “Helping” Hand, the peer associate for this year’s course, led the pivot to the podcast platform, and this production is as much hers as anyone’s: She was chief cheerleader, coordinator, and executive producer, in tandem with Joey “Magic Fingers” Maguschak, who acted as senior sound engineer and producer

Mental illness and COVID-19 vaccination: a multinational investigation of observational & register-based data

Individuals with mental illness are at higher risk of severe COVID-19 outcomes. However, previous studies on the uptake of COVID-19 vaccination in this population have reported conflicting results. Using data from seven cohort studies (N = 325,298) included in the multinational COVIDMENT consortium, and the Swedish registers (N = 8,080,234), this study investigates the association between mental illness (defined using self-report measures, clinical diagnosis and prescription data) and COVID-19 vaccination uptake. Results from the COVIDMENT cohort studies were pooled using meta-analyses, the majority of which showed no significant association between mental illness and vaccination uptake. In the Swedish register study population, we observed a very small reduction in the uptake of both the first and second dose of a COVID-19 vaccine among individuals with vs. without mental illness; the reduction was however greater among those not using psychiatric medication. Here we show that uptake of the COVID-19 vaccine is generally high among individuals both with and without mental illness, however the lower levels of vaccination uptake observed among subgroups of individuals with unmedicated mental illness warrants further attention

The Impact of Intensive Versus Standard Anthelminthic Treatment on Allergy-related Outcomes, Helminth Infection Intensity, and Helminth-related Morbidity in Lake Victoria Fishing Communities, Uganda: Results From the LaVIISWA Cluster-randomized Trial.

BACKGROUND: The prevalence of allergy-related diseases is increasing in low-income countries. Parasitic helminths, common in these settings, may be protective. We hypothesized that intensive, community-wide, anthelminthic mass drug administration (MDA) would increase allergy-related diseases, while reducing helminth-related morbidity. METHODS: In an open, cluster-randomized trial (ISRCTN47196031), we randomized 26 high-schistosomiasis-transmission fishing villages in Lake Victoria, Uganda, in a 1:1 ratio to receive community-wide intensive (quarterly single-dose praziquantel plus albendazole daily for 3 days) or standard (annual praziquantel plus 6 monthly single-dose albendazole) MDA. Primary outcomes were recent wheezing, skin prick test positivity (SPT), and allergen-specific immunoglobulin E (asIgE) after 3 years of intervention. Secondary outcomes included helminths, haemoglobin, and hepatosplenomegaly. RESULTS: The outcome survey comprised 3350 individuals. Intensive MDA had no effect on wheezing (risk ratio [RR] 1.11, 95% confidence interval [CI] 0.64-1.93), SPT (RR 1.10, 95% CI 0.85-1.42), or asIgE (RR 0.96, 95% CI 0.82-1.12). Intensive MDA reduced Schistosoma mansoni infection intensity: the prevalence from Kato Katz examinations of single stool samples from each patient was 23% versus 39% (RR 0.70, 95% CI 0.55-0.88), but the urine circulating cathodic antigen test remained positive in 85% participants in both trial arms. Hookworm prevalence was 8% versus 11% (RR 0.55, 95% CI 0.31-1.00). There were no differences in anemia or hepatospenomegaly between trial arms. CONCLUSIONS: Despite reductions in S. mansoni intensity and hookworm prevalence, intensive MDA had no effect on atopy, allergy-related diseases, or helminth-related pathology. This could be due to sustained low-intensity infections; thus, a causal link between helminths and allergy outcomes cannot be discounted. Intensive community-based MDA has a limited impact in high-schistosomiasis-transmission fishing communities, in the absence of other interventions. CLINICAL TRIALS REGISTRATION: ISRCTN47196031

Introduction to “Binary Binds”: Deconstructing Sex and Gender Dichotomies in Archaeological Practice

YesGender archaeology has made significant strides toward deconstructing the hegemony of binary categorizations. Challenging dichotomies such as man/woman, sex/gender, and biology/culture, approaches informed by poststructuralist, feminist, and queer theories have moved beyond essentialist and universalist identity constructs to more nuanced configurations. Despite the theoretical emphasis on context, multiplicity, and fluidity, binary starting points continue to streamline the spectrum of variability that is recognized, often reproducing normative assumptions in the evidence. The contributors to this special issue confront how sex, gender, and sexuality categories condition analytical visibility, aiming to develop approaches that respond to the complexity of theory in archaeological practice. The papers push the ontological and epistemological boundaries of bodies, personhood, and archaeological possibility, challenging a priori assumptions that contain how sex, gender, and sexuality categories are constituted and related to each other. Foregrounding intersectional approaches that engage with ambiguity, variability, and difference, this special issue seeks to “de-contain” categories, assumptions, and practices from “binding” our analytical gaze toward only certain kinds of persons and knowledges, in interpretations of the past and practices in the present

Biometric conversion factors as a unifying platform for comparative assessment of invasive freshwater bivalves

Invasive bivalves continue to spread and negatively impact freshwater ecosystems worldwide. As different metrics for body size and biomass are frequently used within the literature to standardise bivalve-related ecological impacts (e.g. respiration and filtration rates), the lack of broadly applicable conversion equations currently hinders reliable comparison across bivalve populations. To facilitate improved comparative assessment among studies originating from disparate geographical locations, we report body size and biomass conversion equations for six invasive freshwater bivalves (or species complex members) worldwide: Corbicula fluminea, C. largillierti, Dreissena bugensis, D. polymorpha, Limnoperna fortunei and Sinanodonta woodiana, and tested the reliability (i.e. precision and accuracy) of these equations. Body size (length, width and height) and biomass metrics of living-weight (LW), wet-weight (WW), dry-weight (DW), dry shell-weight (SW), shell free dry-weight (SFDW) and ash-free dry-weight (AFDW) were collected from a total of 44 bivalve populations located in Asia, the Americas and Europe. Relationships between body size and individual biomass metrics, as well as proportional weight-to-weight conversion factors, were determined. For most species, although inherent variation existed between sampled populations, body size directional measurements were found to be good predictors of all biomass metrics (e.g. length to LW, WW, SW or DW: R2 = 0.82–0.96), with moderate to high accuracy for mean absolute error (MAE): ±9.14%–24.19%. Similarly, narrow 95% confidence limits and low MAE were observed for most proportional biomass relationships, indicating high reliability for the calculated conversion factors (e.g. LW to AFDW; CI range: 0.7–2.0, MAE: ±0.7%–2.0%). Synthesis and applications. Our derived biomass prediction equations can be used to rapidly estimate the biologically active biomass of the assessed species, based on simpler biomass or body size measurements for a wide range of situations globally. This allows for the calculation of approximate average indicators that, when combined with density data, can be used to estimate biomass per geographical unit-area and contribute to quantification of population-level effects. These general equations will support meta-analyses, and allow for comparative assessment of historic and contemporary data. Overall, these equations will enable conservation managers to better understand and predict ecological impacts of these bivalves.Fil: Coughlan, Neil E.. The Queens University of Belfast; Irlanda. University College Cork; IrlandaFil: Cunningham, Eoghan M.. The Queens University of Belfast; IrlandaFil: Cuthbert, Ross N.. The Queens University of Belfast; Irlanda. Geomar-Helmholtz Centre for Ocean Research Kiel; AlemaniaFil: Joyce, Patrick W. S.. The Queens University of Belfast; IrlandaFil: Anastácio, Pedro. Universidade de Évora; PortugalFil: Banha, Filipe. Universidade de Évora; PortugalFil: Bonel, Nicolás. Université Montpellier II; Francia. Centre National de la Recherche Scientifique; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; ArgentinaFil: Bradbeer, Stephanie J.. University of Leeds; Reino UnidoFil: Briski, Elizabeta. Geomar-Helmholtz Centre for Ocean Research Kiel; AlemaniaFil: Butitta, Vince L.. University of Wisconsin; Estados UnidosFil: Cadková, Zuzana. Czech University of Life Sciences; República ChecaFil: Dick, Jaimie T. A.. The Queens University of Belfast; IrlandaFil: Douda, Karel. Czech University of Life Sciences; República ChecaFil: Eagling, Lawrence E.. The Queens University of Belfast; IrlandaFil: Ferreira Rodríguez, Noé. Universidad de Vigo; EspañaFil: Hünicken, Leandro Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; ArgentinaFil: Johansson, Mattias L.. University of North Georgia; Estados UnidosFil: Kregting, Louise. The Queens University of Belfast; IrlandaFil: Labecka, Anna Maria. Jagiellonian University; PoloniaFil: Li, Deliang. Hunan Agricultural University; ChinaFil: Liquin, Florencia Fernanda. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Instituto para el Estudio de la Biodiversidad de Invertebrados; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta; ArgentinaFil: Marescaux, Jonathan. University of Namur; Bélgica. e-biom; BélgicaFil: Morris, Todd J.. Fisheries and Ocean Canada; CanadáFil: Nowakowska, Patrycja. University of Gdansk; PoloniaFil: Ozgo, Malgorzata. Kazimierz Wielki University; PoloniaFil: Paolucci, Esteban Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; ArgentinaFil: Peribáñez, Miguel A.. Universidad de Zaragoza; EspañaFil: Riccardi, Nicoletta. Consiglio Nazionale delle Ricerche; ItaliaFil: Smith, Emily R. C.. University College London; Estados UnidosFil: Sylvester, Francisco. Universidad Nacional de Salta. Facultad de Ciencias Naturales. Instituto para el Estudio de la Biodiversidad de Invertebrados; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta; Argentin