A Single Early Life Acetaminophen Exposure Causes Persistent Abnormalities in the Murine Lung.

Whether early life acetaminophen (APAP) exposures injure the developing lung is controversial. We sought to correlate murine pulmonary developmental expression profiles of to susceptibility to APAP exposure. P14 C57BL/6 mice were exposed to APAP (140 mg/kg x 1, IP) and assessed for evidence of a histologic, metabolic, functional, and/or transcriptional pulmonary response.

Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation.

Deubiquitinating enzymes (DUBs) are key regulators of cellular homoeostasis, and their dysregulation is associated with several human diseases. The ovarian tumour protease (OTU) family of DUBs are biochemically well-characterised and of therapeutic interest, yet only a few tool compounds exist to study their cellular function and therapeutic potential. Here we present a chemoproteomics fragment screening platform for identifying novel DUB-specific hit matter, that combines activity-based protein profiling with high-throughput chemistry direct-to-biology optimisation to enable rapid elaboration of initial fragment hits against OTU DUBs.

Robust proteome profiling of cysteine-reactive fragments using label-free chemoproteomics.

Identifying pharmacological probes for human proteins represents a key opportunity to accelerate the discovery of new therapeutics. High-content screening approaches to expand the ligandable proteome offer the potential to expedite the discovery of novel chemical probes to study protein function. Screening libraries of reactive fragments by chemoproteomics offers a compelling approach to ligand discovery, however, optimising sample throughput, proteomic depth, and data reproducibility remains a key challenge.

Association of Body Mass Index between Adolescents and their Parents in Mumbai and Kolkata: A Population-based Study.

Introduction: Adolescent overweight and obesity as measured by body mass index (BMI) seem to be increasing at an alarming rate in urban populations. Parental BMI plays an important role in their adolescent's BMI. Overweight and obesity coexisting with undernutrition in adolescents is an important public health challenge in low- and middle-income countries (LMICs).

The Sex Dependent and Independent Effects of Dietary Whey Proteins Are Passed from the Mother to the Offspring.

Scope: The study assesses the metabolic impact of dietary whey proteins across generations.

Method And Results: Virgin females are fed 20% energy whey proteins with 70% energy carbohydrates, which reduces body weight gain and visceral adipose compared to controls fed dietary casein. In contrast, the males are unresponsive.

Person explanatory multidimensional item response theory with the instrument package in R.

We present the new R package instrument to perform Bayesian estimation of person explanatory multidimensional item response theory. The package implements an exploratory multidimensional item response theory model and a higher-order multidimensional item response theory model, a type of confirmatory multidimensional item response theory. Explanation of person parameters is accomplished by fixed and random effect linear regression models.

A Fragment-Based Competitive F LB-NMR Platform For Hotspot-Directed Ligand Profiling.

Ligand binding hotspots are regions of protein surfaces that form particularly favourable interactions with small molecule pharmacophores. Targeting interactions with these hotspots maximises the efficiency of ligand binding. Existing methods are capable of identifying hotspots but often lack assays to quantify ligand binding and direct elaboration at these sites.

Covalent fragment-based drug discovery for target tractability.

An important consideration in drug discovery is the prioritization of tractable protein targets that are not only amenable to binding small molecules, but also alter disease biology in response to small molecule binding. Covalent fragment-based drug discovery has emerged as a powerful approach to aid in the identification of such protein targets. The application of irreversible binding mechanisms enables the identification of fragment hits for challenging-to-target proteins, allows proteome-wide screening in a cellular context, and makes it possible to determine functional effects with modestly potent ligands without the requirement for extensive compound optimization.

Chemical Validation of Phosphopantetheine Adenylyltransferase Using Fragment Linking and CRISPR Interference.

The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by (). Seeking to identify inhibitors of phosphopantetheine adenylyltransferase (PPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the PPAT active site, presenting a unique opportunity for fragment linking.

Implications of neonatal absence of innate immune mediated NFκB/AP1 signaling in the murine liver.

Background: The developmental immaturity of the innate immune system helps explains the increased risk of infection in the neonatal period. Importantly, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for the prevention of hepatocyte apoptosis in adult animals, yet whether developmental immaturity of these pathways increases the risk of hepatic injury in the neonatal period is unknown.

Methods: Using a murine model of endotoxemia (LPS 5 mg/kg IP x 1) in neonatal (P3) and adult mice, we evaluated histologic evidence of hepatic injury and apoptosis, presence of p65/NFκB and c-Jun/AP1 activation and associated transcriptional regulation of apoptotic genes.

GSK3β/NF-κB -dependent transcriptional regulation of homeostatic hepatocyte production.

Maintenance of hepatocyte homeostasis plays an important role in mediating the pathogenesis of many diseases. A growing body of literature has established a critical role played by tumor necrosis factor-α (TNFα) in maintaining hepatocyte homeostasis; however, the transcriptional mechanisms underlying constitutive expression are unknown. Whole liver fractions and primary hepatocytes from adult control C57BL/6 mice and the murine hepatocyte cell line AML12 were assessed for constitutive expression.

Consistency and Variation in Reasoning About Physical Assembly.

The ability to reason about how things were made is a pervasive aspect of how humans make sense of physical objects. Such reasoning is useful for a range of everyday tasks, from assembling a piece of furniture to making a sandwich and knitting a sweater. What enables people to reason in this way even about novel objects, and how do people draw upon prior experience with an object to continually refine their understanding of how to create it? To explore these questions, we developed a virtual task environment to investigate how people come up with step-by-step procedures for recreating block towers whose composition was not readily apparent, and analyzed how the procedures they used to build them changed across repeated attempts.

EEG microstate quantifiers and state space descriptors during anaesthesia in patients with postoperative delirium: a descriptive analysis.

Postoperative delirium is a serious sequela of surgery and surgery-related anaesthesia. One recommended method to prevent postoperative delirium is using bi-frontal EEG recording. The single, processed index of depth of anaesthesia allows the anaesthetist to avoid episodes of suppression EEG and excessively deep anaesthesia.

Detecting emerald green in 19thC book bindings using vis-NIR spectroscopy.

Detection and identification of heavy metal-based pigments in 19th-century bookbindings is crucial to avoid human user exposure to toxic substances. Vibrant green bookbindings with arsenical emerald green are particularly problematic due to their friability. A pilot study at St Andrews University tested 800 green bookbindings for arsenic presence using visible near-infrared spectrometry, a technique not previously applied to the detection of heavy metals in bindings.

A statewide study of disparities in local policies and tobacco, vape, and cannabis retail environments.

The current study: (1) assesses sociodemographic disparities in local policies related to tobacco and cannabis retail, and (2) examines the cross-sectional association between policy strength and retailer densities of tobacco, e-cigarette (vape), and cannabis retailers within California cities and county unincorporated areas (N = 539). We combined (a) American Community Survey data (2019 5-year estimates), (b) 2018 tobacco, vape, and cannabis retailer locations from a commercial data provider, (c) 2017 tobacco and vape retail environment policy data from American Lung Association, and (d) 2018 cannabis policy data from California Cannabis Local Laws Database. Conditional autoregressive models examined policy strength associations with sociodemographic composition and retailer density in California jurisdictions.

Isolation and identification of chlorate-reducing sp. from milk.

Chlorate has become a concern in the food and beverage sector, related to chlorine sanitizers in industrial food production and water treatment. It is of particular concern to regulatory bodies due to the negative health effects of chlorate exposure. This study investigated the fate of chlorate in raw milk and isolated bacterial strains of interest responsible for chlorate breakdown.

Randomized Comparative Effectiveness Trial of 2 Federally Recommended Strategies to Reduce Excess Body Fat in Overweight, Low-Income Patients: MyPlate.gov vs Calorie Counting.

Purpose: Since 2011, US authorities have supported the following 2 approaches to healthier body fat composition: the Centers for Disease Control and Prevention National Diabetes Prevention Program's calorie counting (CC) approach and the US Department of Agriculture's MyPlate (adherence to federal nutrition guidelines). The purpose of this study was to compare the effect of CC vs MyPlate approaches on satiety/satiation and on achieving healthier body fat composition among primary care patients.

Methods: We conducted a randomized controlled trial comparing the CC and MyPlate approaches from 2015 to 2017.

Innate Immune Zonation in the Liver: NF-κB (p50) Activation and C-Reactive Protein Expression in Response to Endotoxemia Are Zone Specific.

Hepatic innate immune function plays an important role in the pathogenesis of many diseases. Importantly, a growing body of literature has firmly established the spatial heterogeneity of hepatocyte metabolic function; however, whether innate immune function is zonated remains unknown. To test this question, we exposed adult C57BL/6 mice to endotoxemia, and hepatic tissue was assessed for the acute phase response (APR).

Chemical Validation of Mycobacterium tuberculosis Phosphopantetheine Adenylyltransferase Using Fragment Linking and CRISPR Interference.

The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking.

"Ancestral recipes": a mixed-methods analysis of MyPlate-based recipe dissemination for Latinos in rural communities.

Background: The Latinx population experiences some of the highest rates of chronic disease, including obesity and type II diabetes. Such conditions may be especially burdensome in rural Latinx communities that often face barriers to accessing disease prevention resources and public health programs.

Methods: Diverse stakeholders (i.

Neonatal Selenium Deficiency Decreases Selenoproteins in the Lung and Impairs Pulmonary Alveolar Development.

Decreased selenium (Se) levels during childhood and infancy are associated with worse respiratory health. Se is biologically active after incorporation into Se-containing antioxidant enzymes (AOE) and proteins. It is unknown how decreased maternal Se during pregnancy and lactation impacts neonatal pulmonary selenoproteins, growth, and lung development.

Absence of IκBβ/NFκB signaling does not attenuate acetaminophen-induced hepatic injury.

Acetaminophen (N-acetyl-p-aminophenol [APAP]) toxicity is a common cause of acute liver failure. Innate immune signaling and specifically NFκB activation play a complex role in mediating the hepatic response to toxic APAP exposures. While inflammatory innate immune responses contribute to APAP-induced injury, these same pathways play a role in regeneration and repair.

Chronic, but not sub-chronic, stress increases binge-like alcohol consumption in male and female c57BL6 mice.

Stress is known to contribute to mental illness and alcohol use disorders, which are highly prevalent and lead to considerable disability. These stress-related disorders are characterized by significant sex differences, which remain poorly understood. Preclinical research comparing the effects of stress in males and females has the potential to provide new insights into the neurobiology of these conditions.