Spontaneous base flipping helps drive Nsp15's preferences in double stranded RNA substrates.

Coronaviruses evade detection by the host immune system with the help of the endoribonuclease Nsp15, which regulates levels of viral double stranded RNA by cleaving 3' of uridine (U). While prior structural data shows that to cleave double stranded RNA, Nsp15's target U must be flipped out of the helix, it is not yet understood whether Nsp15 initiates flipping or captures spontaneously flipped bases. We address this gap by designing fluorinated double stranded RNA substrates that allow us to directly relate a U's sequence context to both its tendency to spontaneously flip and its susceptibility to cleavage by Nsp15.

Refining breast cancer genetic risk and biology through multi-ancestry fine-mapping analyses of 192 risk regions.

Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant.

Proximity to petrochemical industry and risk of childhood asthma occurrence.

Adverse effects on the respiratory system were associated with intensive petroleum-related industrial activities. The study aimed to assess the impact of petrochemical exposure on childhood asthma using various surrogate indices. A singleton birth cohort from 2004 to 2017 was conducted, leveraging two linked nationwide databases in Taiwan.

A higher order PUF complex is central to regulation of C. elegans germline stem cells.

PUF RNA-binding proteins are broadly conserved stem cell regulators. Nematode PUF proteins maintain germline stem cells (GSCs) and, with key partner proteins, repress differentiation mRNAs, including gld-1. Here we report that PUF protein FBF-2 and its partner LST-1 form a ternary complex that represses gld-1 via a pair of adjacent FBF binding elements (FBEs) in its 3'UTR.

Estimated exposure to endotoxin and circulating immunological markers among male farmers in the Biomarkers of Exposure and Effect in Agriculture study.

Background: Occupational exposure to endotoxin has been associated with reduced lung cancer risk. The mechanisms underlying this association are unclear, though immunological alterations likely play a role. Farmers who perform certain tasks (eg, raising hogs) can be highly exposed to endotoxin.

Detection of Movement and Lead-Popping Artifacts in Polysomnography EEG Data.

Polysomnography (PSG) measures brain activity during sleep via electroencephalography (EEG) using six leads. Artifacts caused by movement or loose leads distort EEG measurements. We developed a method to automatically identify such artifacts in a PSG EEG trace.

Perineuronal nets on CA2 pyramidal cells and parvalbumin-expressing cells differentially regulate hippocampal dependent memory.

Perineuronal nets (PNNs) are a specialized extracellular matrix that surround certain populations of neurons, including (inhibitory) parvalbumin (PV) expressing-interneurons throughout the brain and (excitatory) CA2 pyramidal neurons in hippocampus. PNNs are thought to regulate synaptic plasticity by stabilizing synapses and as such, could regulate learning and memory. Most often, PNN functions are queried using enzymatic degradation with chondroitinase, but that approach does not differentiate PNNs on CA2 neurons from those on adjacent PV cells.

Concentrations, composition profiles, and in vitro-in silico-based mixture risk assessment of bisphenol A and its analogs in plant-based foods.

The substitution of bisphenol A (BPA) with structurally similar analogs has raised concerns due to their comparable estrogenic activities. Considering the high consumption of plant-based foods, assessing the risks posed by bisphenols (BPs) in such dietary sources is essential. However, limited exposure and animal toxicological data on BP analogs hinder comprehensive risk assessments.

Identification of a Potent CDK8 Inhibitor Using Structure-Based Virtual Screening.

Pulmonary fibrosis is excessive scarring of the lung tissues. Transforming growth factor-beta (TGF-β) has been implicated in pulmonary fibrosis due to its ability to induce the epithelial-to-mesenchymal transition (EMT) and promote epithelial cell migration. Cyclin-dependent kinase 8 (CDK8) can mediate the TGF-β signaling pathways and could function as an alternative therapeutic target for treating pulmonary fibrosis.

Association of early-life trauma with gestational diabetes and hypertensive disorders of pregnancy.

Background: Early-life trauma (before age 18) is hypothesized to increase risk for adverse pregnancy outcomes through stress pathways, yet epidemiologic findings are mixed.

Methods: Sister Study participants (U.S.

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.

Volatile hydrocarbon exposures and immune-related illnesses among Deepwater Horizon oil spill workers.

Background: Despite evidence from experimental studies linking some petroleum hydrocarbons to markers of immune suppression, limited epidemiologic research exists on this topic.

Objective: The aim of this cross-sectional study was to examine associations of oil spill related chemicals (benzene, toluene, ethylbenzene, xylene, and n-hexane (BTEX-H)) and total hydrocarbons (THC) with immune-related illnesses as indicators of potential immune suppression.

Methods: Subjects comprised 8601 Deepwater Horizon (DWH) oil spill clean-up and response workers who participated in a home visit (1-3 years after the DWH spill) in the Gulf Long-term Follow-up (GuLF) Study.

Long-term exposure to multiple air pollutants and risk of Parkinson's disease: a population-based multipollutant model study.

Background: Recent evidence suggests brain-first Parkinson's disease (PD) may start from the olfactory system, indicating potential inhalational exposure to causal agents. We investigated the impact of long-term exposure to various air pollutants on PD incidence using both single- and multi-pollutant models to account for interactions between pollutants.

Methods: This retrospective population study used data from Taiwan's National Health Insurance Research Database (2006 and 2018) and included individuals aged 40-65 without PD.

Genetic Variants Associated With Preeclampsia and Maternal Serum sFLT1 Levels.

Background: Elevated maternal serum sFLT1 (soluble fms-like tyrosine kinase 1) has a key role in the pathophysiology of preeclampsia. We sought to determine the relationship between the maternal and fetal genome and maternal levels of sFLT1 at 12, 20, 28, and 36 weeks of gestational age (wkGA).

Methods: We studied a prospective cohort of nulliparous women (3968 mother-child pairs).

Pooling Biospecimens for Efficient Exposure Assessment When Using Case-Cohort Analysis in Cohort Studies.

Background: Large prospective cohort studies have been fruitful for identifying exposure-disease associations. In a cohort where biospecimens (e.g.

Protocol for X-ray irradiation of C57BL/6J recipient mice followed by the transplantation of mTomato-expressing bone marrow cells.

Bone marrow chimera is a useful tool to determine the pathophysiological contributions of hematopoietic versus stromal compartments. Here, we present a protocol for lethal irradiation of wild-type C57BL/6J recipient mice followed by the transplantation of bone marrow from mTomato-expressing donors. We then detail procedures for animal distress scoring and assessment of reconstitution efficiency.

Effects of gravity, microgravity or microgravity simulation on early mouse embryogenesis: A review of the first two space embryo studies.

Many simulated micro-gravity (micro-G) experiments on earth suggest that micro-G conditions are not compatible with early mammalian embryo development. Recently, the first two "space embryo" studies have been published showing that early mouse embryo development can occur in real microgravity (real micro-G) conditions in orbit. In the first of these studies, published in 2020, Lei and collaborators developed automated mini-incubator (AMI) devices for mouse embryos facilitating cultivation, microscopic observation, and fixation.

Association of exposure to second-hand smoke during childhood with blood DNA methylation.

Introduction: By recent estimates, 40% of children worldwide are exposed to second-hand smoke (SHS), which has been associated with adverse health outcomes. While numerous studies have linked maternal smoking during pregnancy (MSDP) to widespread differences in child blood DNA methylation (DNAm), research specifically examining postnatal SHS exposure remains sparse. To address this gap, we conducted epigenome-wide meta-analyses to identify associations of postnatal SHS and child blood DNAm.

Interactions of VMAT2 with CDCrel-1 and Parkin in Methamphetamine Neurotoxicity.

In recent years, methamphetamine (METH) misuse in the US has been rapidly increasing, and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including the dysfunction of the neuroprotective protein parkin.

Influence of occupational stress on breast cancer incidence in the Women's Health Initiative.

Objective: Psychological stress has long been posited as a potential risk factor for breast cancer. We aimed to examine the relationship between occupational stress and the incidence of invasive breast cancer among postmenopausal women from the Women's Health Initiative Observational Study.

Method: Occupational stress was characterized through linkage of Standard Occupational Classification codes for participants' jobs to the Occupational Information Network.