Self-reported pregnancy exposures and placental DNA methylation in the MARBLES prospective autism sibling study.

Human placenta is a fetal-derived tissue that offers a unique sample of epigenetic and environmental exposures present in utero. In the MARBLES prospective pregnancy study of high-risk younger siblings of children with autism spectrum disorder (ASD), pregnancy and environmental factors collected by maternal interviews were examined as predictors of placental DNA methylation, including partially methylated domains (PMDs), an embryonic feature of the placental methylome. DNA methylation data from MethylC-seq analysis of 47 placentas of children clinically diagnosed at 3 years with ASD or typical development using standardized assessments were examined in relation to: child's gestational age, birth-weight, and diagnosis; maternal pre-pregnancy body mass index, smoking, education, parity, height, prenatal vitamin and folate intake; home ownership; pesticides professionally applied to lawns or gardens or inside homes, pet flea/tick pouches, collars, or soaps/shampoos used in the 3 months prior to or during pregnancy. Sequencing run, order, and coverage, and child race and sex were considered as potential confounders. Akaike information criterion was used to select the most parsimonious among candidate models. Final prediction models used sandwich estimators to produce homoscadisticity-robust estimates of the 95% confidence interval (CI) and P-values controlled the false discovery rate at 5%. The strongest, most robust associations were between pesticides professionally applied outside the home and higher average methylation over PMDs [0.45 (95% CI 0.17, 0.72), P = 0.03] and a reduced proportion of the genome in PMDs [-0.42 (95% CI - 0.67 to -0.17), P = 0.03]. Pesticide exposures could alter placental DNA methylation more than other factors

Data extraction methods for systematic review (semi)automation: Update of a living systematic review [version 2; peer review: 3 approved]

Background: The reliable and usable (semi)automation of data extraction can support the field of systematic review by reducing the workload required to gather information about the conduct and results of the included studies. This living systematic review examines published approaches for data extraction from reports of clinical studies. Methods: We systematically and continually search PubMed, ACL Anthology, arXiv, OpenAlex via EPPI-Reviewer, and the dblp computer science bibliography. Full text screening and data extraction are conducted within an open-source living systematic review application created for the purpose of this review. This living review update includes publications up to December 2022 and OpenAlex content up to March 2023. Results: 76 publications are included in this review. Of these, 64 (84%) of the publications addressed extraction of data from abstracts, while 19 (25%) used full texts. A total of 71 (93%) publications developed classifiers for randomised controlled trials. Over 30 entities were extracted, with PICOs (population, intervention, comparator, outcome) being the most frequently extracted. Data are available from 25 (33%), and code from 30 (39%) publications. Six (8%) implemented publicly available tools Conclusions: This living systematic review presents an overview of (semi)automated data-extraction literature of interest to different types of literature review. We identified a broad evidence base of publications describing data extraction for interventional reviews and a small number of publications extracting epidemiological or diagnostic accuracy data. Between review updates, trends for sharing data and code increased strongly: in the base-review, data and code were available for 13 and 19% respectively, these numbers increased to 78 and 87% within the 23 new publications. Compared with the base-review, we observed another research trend, away from straightforward data extraction and towards additionally extracting relations between entities or automatic text summarisation. With this living review we aim to review the literature continually

Deficits in growth, muscle mass, and body composition following placental insufficiency-induced intrauterine growth restriction persisted in lambs at 60 d of age but were improved by daily clenbuterol supplementation

Low birthweight in livestock results from stress-induced intrauterine growth restriction (IUGR; Yates et al., 2018). IUGR fetuses exhibit diminished muscle growth that persists in the neonatal stage, leading to asymmetric body composition and decreased weight gain (Cadaret et al., 2019). Ultimately, low birthweight diminishes yield and carcass merit at harvest (Greenwood et al., 2000), making effective postnatal treatment strategies to improve IUGR growth outcomes necessary. In this study, we examined the benefits of injecting the β2 agonist clenbuterol daily to target adrenergic adaptations that we previously observed in IUGR muscle (Posont et al., 2018; Yates et al., 2018). We hypothesized that IUGRinduced growth deficits would persist at the juvenile stage, manifesting in inferior body composition and carcass traits. We also postulated that clenbuterol would at least partially recover growth and body symmetry. Our objective was to test this hypothesis by assessing growth metrics and body composition in IUGR-born lambs hand-reared to 60 d of age and supplemented daily with injectable clenbuterol

Nitrosylcobalamin Potentiates the Anti-Neoplastic Effects of Chemotherapeutic Agents via Suppression of Survival Signaling

Nitrosylcobalamin (NO-Cbl) is a chemotherapeutic pro-drug derived from vitamin B12 that preferentially delivers nitric oxide (NO) to tumor cells, based upon increased receptor expression. NO-Cbl induces Apo2L/TRAIL-mediated apoptosis and inhibits survival signaling in a variety of malignant cell lines. Chemotherapeutic agents often simultaneously induce an apoptotic signal and activation of NF-kappaB, which has the undesired effect of promoting cell survival. The specific aims of this study were to 1) measure the anti-tumor effects of NO-Cbl alone and in combination with conventional chemotherapeutic agents, and to 2) examine the mechanism of action of NO-Cbl as a single agent and in combination therapy.Using anti-proliferative assays, electrophoretic mobility shift assay (EMSA), immunoblot analysis and kinase assays, we demonstrate an increase in the effectiveness of chemotherapeutic agents in combination with NO-Cbl as a result of suppressed NF-kappaB activation.Eighteen chemotherapeutic agents were tested in combination with NO-Cbl, in thirteen malignant cell lines, resulting in a synergistic anti-proliferative effect in 78% of the combinations tested. NO-Cbl pre-treatment resulted in decreased NF-kappaB DNA binding activity, inhibition of IkappaB kinase (IKK) enzymatic activity, decreased AKT activation, increased caspase-8 and PARP cleavage, and decreased cellular XIAP protein levels.The use of NO-Cbl to inhibit survival signaling may enhance drug efficacy by preventing concomitant activation of NF-kappaB or AKT

Angiogenic gene expression and vascular density are reflected in ultrasonographic features of synovitis in early Rheumatoid Arthritis: an observational study.

INTRODUCTION: Neovascularization contributes to the development of sustained synovial inflammation in the early stages of Rheumatoid Arthritis. Ultrasound (US) provides an indirect method of assessing synovial blood flow and has been shown to correlate with clinical disease activity in patients with Rheumatoid Arthritis. This study examines the relationship of US determined synovitis with synovial vascularity, angiogenic/lymphangiogenic factors and cellular mediators of inflammation in a cohort of patients with early Rheumatoid Arthritis (RA) patients prior to therapeutic intervention with disease modifying therapy or corticosteroids. METHODS: An ultrasound guided synovial biopsy of the supra-patella pouch was performed in 12 patients with early RA prior to treatment. Clinical, US and biochemical assessments were undertaken prior to the procedure. Ultrasound images and histological samples were obtained from the supra-patella pouch. Histological samples were stained for Factor VIII and a-SMA (a-smooth muscle actin). Using digital imaging analysis a vascular area score was recorded. QT-PCR (quantitative-PCR) of samples provided quantification of angiogenic and lymphangiogenic gene expression and immunohistochemistry stained tissue was scored for macrophage, T cell and B cell infiltration using an existing semi-quantitative score. RESULTS: Power Doppler showed a good correlation with histological vascular area (Spearman r--0.73) and angiogenic factors such as vascular endothelial growth factor-A (VEGF-A), Angiopoietin 2 and Tie-2. In addition, lymphangiogenic factors such as VEGF-C and VEGF-R3 correlated well with US assessment of synovitis. A significant correlation was also found between power Doppler and synovial thickness, pro-inflammatory cytokines and sub-lining macrophage infiltrate. Within the supra-patella pouch there was no significant difference in US findings, gene expression or inflammatory cell infiltrate between any regions of synovium biopsied. CONCLUSION: Ultrasound assessment of synovial tissue faithfully reflects synovial vascularity. Both grey scale and power Doppler synovitis in early RA patients correlate with a pro-angiogenic and lymphangiogenic gene expression profile. In early RA both grey scale and power Doppler synovitis are associated with a pro-inflammatory cellular and cytokine profile providing considerable validity in its use as an objective assessment of synovial inflammation in clinical practice

Heat stress and β-adrenergic agonists alter the adipose transcriptome and fatty acid mobilization in ruminant livestock

Growth and feed efficiency of cattle are improved by supplementation with the beta-adrenergic agonists (βAA), ractopamine hydrochloride (RH; β1AA) or zilpaterol hydrochloride (ZH; β2AA) (Elam et al., 2009). βAA supplementation alters adipose deposition by inhibiting fatty acid biosynthesis and promoting lipolysis of stored triacylglycerols into free fatty acids (FFAs) (Johnson et al., 2014). However, β2 adrenoceptors (βAR) desensitize with chronic activation (Re et al., 1997); supplementation is thus limited to the last 20 to 40 d of feeding. The annual economic impact of heat stress (HS) has been estimated to exceed $2.4 billion (St-Pierre et al., 2003). Heat-stressed livestock have reduced growth rates, dry matter intake, and average daily gain (Mitlöhner et al., 2001; St-Pierre et al., 2003). In response to acute stress, signaling pathways for lipolysis of circulating and stored triglycerides are activated, while chronic stress increases lipogenesis and adipogenesis (Campbell et al., 2009; Peckett et al., 2011). In cattle, HS also increases the responsiveness of adipocytes to lipolytic signals, increasing lipolysis (Faylon et al., 2015). The objective of this study was to understand how HS and βAA independently and interactively affect adipose tissue. Prior work identified minimal impact of RH on metabolic properties (Barnes et al., 2019) and on the transcriptome of skeletal muscle (Kubik et al., 2018). We therefore hypothesized that RH may be primarily affecting adipose; specifically, that lipolytic activity is increased due to heat and βAA in an additive fashion. We tested this hypothesis in RH-supplemented lambs and ZH-supplemented cattle exposed to HS for 30 and 21 d, respectively

Data extraction methods for systematic review (semi)automation: Update of a living systematic review [version 2; peer review: 3 approved]

Background: The reliable and usable (semi)automation of data extraction can support the field of systematic review by reducing the workload required to gather information about the conduct and results of the included studies. This living systematic review examines published approaches for data extraction from reports of clinical studies. Methods: We systematically and continually search PubMed, ACL Anthology, arXiv, OpenAlex via EPPI-Reviewer, and the dblp computer science bibliography. Full text screening and data extraction are conducted within an open-source living systematic review application created for the purpose of this review. This living review update includes publications up to December 2022 and OpenAlex content up to March 2023. Results: 76 publications are included in this review. Of these, 64 (84%) of the publications addressed extraction of data from abstracts, while 19 (25%) used full texts. A total of 71 (93%) publications developed classifiers for randomised controlled trials. Over 30 entities were extracted, with PICOs (population, intervention, comparator, outcome) being the most frequently extracted. Data are available from 25 (33%), and code from 30 (39%) publications. Six (8%) implemented publicly available tools Conclusions: This living systematic review presents an overview of (semi)automated data-extraction literature of interest to different types of literature review. We identified a broad evidence base of publications describing data extraction for interventional reviews and a small number of publications extracting epidemiological or diagnostic accuracy data. Between review updates, trends for sharing data and code increased strongly: in the base-review, data and code were available for 13 and 19% respectively, these numbers increased to 78 and 87% within the 23 new publications. Compared with the base-review, we observed another research trend, away from straightforward data extraction and towards additionally extracting relations between entities or automatic text summarisation. With this living review we aim to review the literature continually

Game fence presence and permeability influences the local movement and distribution of South African mammals

Fences are utilized throughout the world to restrict the movements of wildlife, protecting them from threats and reducing human-wildlife conflict. In South Africa the number of privately-owned fenced game reserves has greatly increased in recent years, but little is known about how fencing affects the distribution and movements of target and non-target mammals. We surveyed 2m either side of the complete fence line of a recently established commercial game reserve in South Africa, identifying signs of animal presence (spoor, scat, foraging or other field signs) while also recording damage (holes) to the fence. Every 250m we carried out 100m perpendicular transects either side of the fence, recording vegetation cover and height at 10m intervals along the transect. We found that livestock (largely cattle) were excluded from the reserve. However, 12% of records of large animal species were recorded outside of the fence line. These species had been introduced to the reserve, strongly suggesting that they had crossed the boundary into the surrounding farmland. Sixteen naturally present wild species were found on both sides of the fence, but we found more evidence of their presence inside the reserve. Observational evidence suggests that they were regularly crossing the boundary, particularly where the fence was damaged, with hole size affecting species recorded. We also found evidence that the construction of the fence had led to a difference in vegetation structure with plant diversity and percentage of non-woody plant cover significantly higher inside the fence. While fencing was highly effective at preventing movement of livestock, introduced and wild animals were able to cross the boundary, via holes in the fence. This work shows that the efficacy of the most common approach to preventing animal movement around protected areas depends on the species being considered and fence condition

Exploring the effectiveness of the output-based aid voucher program to increase uptake of gender-based violence recovery services in Kenya: a qualitative evaluation

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Few studies in Africa have explored in detail the ability of output-based aid (OBA) voucher programs to increase access to gender-based violence recovery (GBVR) services. Methods: A qualitative study was conducted in 2010 and involved: (i) in-depth interviews (IDIs) with health managers, service providers, voucher management agency (VMA) managers and (ii) focus group discussions (FGDs) with voucher users, voucher non-users, voucher distributors and opinion leaders drawn from five program sites in Kenya. Results: The findings showed promising prospects for the uptake of OBA GBVR services among target population. However, a number of factors affect the uptake of the services. These include lack of general awareness of the GBVR services vouchers, lack of understanding of the benefit package, immediate financial needs of survivors, as well as stigma and cultural beliefs that undermine reporting of cases or seeking essential medical services. Moreover, accreditation of only hospitals to offer GBVR services undermines access to the services in rural areas. Poor responsiveness from law enforcement agencies and fear of reprisal from perpetrators also undermine treatment options and access to medical services. Low provider knowledge on GBVR services and lack of supplies also affect effective provision and management of GBVR services. Conclusions: The above findings suggest that there is a need to build the capacity of health care providers and police officers, strengthen the community strategy component of the OBA program to promote the GBVR services voucher, and conduct widespread community education programs aimed at prevention, ensuring survivors know how and where to access services and addressing stigma and cultural barriers.The Bill and Melinda Gates Foundatio

Hard Two-Photon Contribution to Elastic Lepton-Proton Scattering: Determined by the OLYMPUS Experiment

The OLYMPUS collaboration reports on a precision measurement of the positron-proton to electron-proton elastic cross section ratio, $R_{2\gamma}$, a direct measure of the contribution of hard two-photon exchange to the elastic cross section. In the OLYMPUS measurement, 2.01~GeV electron and positron beams were directed through a hydrogen gas target internal to the DORIS storage ring at DESY. A toroidal magnetic spectrometer instrumented with drift chambers and time-of-flight scintillators detected elastically scattered leptons in coincidence with recoiling protons over a scattering angle range of $\approx 20\degree$ to $80\degree$. The relative luminosity between the two beam species was monitored using tracking telescopes of interleaved GEM and MWPC detectors at $12\degree$, as well as symmetric M{\o}ller/Bhabha calorimeters at $1.29\degree$. A total integrated luminosity of 4.5~fb$^{-1}$ was collected. In the extraction of $R_{2\gamma}$, radiative effects were taken into account using a Monte Carlo generator to simulate the convolutions of internal bremsstrahlung with experiment-specific conditions such as detector acceptance and reconstruction efficiency. The resulting values of $R_{2\gamma}$, presented here for a wide range of virtual photon polarization $0.456<\epsilon<0.978$, are smaller than some hadronic two-photon exchange calculations predict, but are in reasonable agreement with a subtracted dispersion model and a phenomenological fit to the form factor data.Comment: 5 pages, 3 figures, 2 table