Anniston, Alabama was home to a major polychlorinated biphenyl (PCB) production facility from 1929 until 1971. The Anniston Community Health Survey I and II (ACHS-I 2005-2007, ACHS-II 2013-2014) were conducted to explore the effects of PCB exposures. In this report we examined associations between PCB exposure and DNA methylation in whole blood using EPIC arrays (ACHS-I, n = 518; ACHS-II, n = 299). For both cohorts, 35 PCBs were measured in serum. We modelled methylation versus PCB wet-weight concentrations for: the sum of 35 PCBs, mono-ortho substituted PCBs, di-ortho substituted PCBs, tri/tetra-ortho substituted PCBs, oestrogenic PCBs, and antiestrogenic PCBs. Using robust multivariable linear regression, we adjusted for age, race, sex, smoking, total lipids, and six blood cell-type percentages. We carried out a two-stage analysis; discovery in ACHS-I followed by replication in ACHS-II. In ACHS-I, we identified 28 associations (17 unique CpGs) at p ≤ 6.70E-08 and 369 associations (286 unique CpGs) at FDR p ≤ 5.00E-02. A large proportion of the genes have been observed to interact with PCBs or dioxins in model studies. Among the 28 genome-wide significant CpG/PCB associations, 14 displayed replicated directional effects in ACHS-II; however, only one in ACHS-II was statistically significant at p ≤ 1.70E-04. While we identified many novel CpGs significantly associated with PCB exposures in ACHS-I, the differential methylation was modest and the effect was attenuated seven years later in ACHS-II, suggesting a lack of persistence of the associations between PCB exposures and altered DNA methylation in blood cells.

RNA-binding proteins (RBPs) are key regulators of posttranscriptional processes such as RNA maturation, localization, turnover and translation. Despite their dysregulation in various diseases including cancer, the landscape of RBP expression in human cancer has not been well elucidated. Here, we built a comprehensive expression landscape of 1504 RBPs across 16 human cancer types, which revealed that RBPs are predominantly upregulated in tumours and this phenomenon is affected by the tumour immune subtypes and microenvironment. Across different cancer types, 109 RBPs are consistently upregulated while 41 RBPs are consistently downregulated. These up-regulated and down-regulated RBPs show distinct molecular characteristics and prognostic effects, whereas their dysregulation is mediated by distinct cis/trans-regulatory mechanisms. Finally, we validated one candidate PABPC1L that might promote colon tumorigenesis by regulating mRNA splicing. In summary, we built a comprehensive expression landscape of RBPs across different cancer types and identified consistently dysregulated RBPs which could be novel targets for developing broad-spectrum anticancer agents.

In the last decade, many research groups have reported predictions of jet noise using high-fidelity large-eddy simulations (LES) of the turbulent jet flow and these methods are beginning to be used more broadly. A brief overview of the publications since the review by Bodony & Lele (2008, AIAA J. 56, 346-380) is undertaken to assess the progress and overall contributions of LES towards a better understanding of jet noise. In particular, we stress the meshing, numerical and modelling advances which enable detailed geometric representation of nozzle shape variations intended to impact the noise radiation, and sufficiently accurate capturing of the turbulent boundary layer at the nozzle exit. Examples of how LES is currently being used to complement experiments for challenging conditions (such as highly heated pressure-mismatched jets with afterburners) and guide jet modelling efforts are highlighted. Some of the physical insights gained from these numerical studies are discussed, in particular on crackle, screech and shock-associated noise, impingement tones, acoustic analogy models, wavepackets dynamics and resonant acoustic waves within the jet core. We close with some perspectives on the remaining challenges and upcoming opportunities for future applications. This article is part of the theme issue 'Frontiers of aeroacoustics research: theory, computation and experiment'.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.

The roll-out of antiretroviral therapy (ART) has changed contexts of HIV risk, but the influence on HIV incidence among young women is not clear. We aimed to summarise direct estimates of HIV incidence among adolescent girls and young women since ART and before large investments in targeted prevention for those in sub-Saharan Africa.

Selenium (Se) plays a vital role in reactive oxygen species (ROS) homeostasis and redox regulation in intracellular signaling via selenocysteine (Sec), known as the 21st proteinogenic amino acid, but its specific biological functions in development and disease remain undiscovered. In this study, we explored the role of selenophosphate synthetase 1 (SEPHS1) in the pluripotency maintenance and reprogramming. We found that high level of SEPHS1 is retained in undifferentiated embryonic stem cells (ESCs), which is decreased during their differentiation. SEPHS1 knockdown significantly reduced reprogramming efficiency, proving that SEPHS1 is required for acquisition of pluripotency. However, SEPHS1 knockdown did not affect the expression of significant pluripotency genes, suggesting that SEPHS1 may be involved in the survival of pluripotent stem cells rather than in the regulation of pluripotency genes. Transcriptome analysis revealed altered expression of the gene set related to the ROS pathway and apoptosis in SEPHS1-knockdown cells. We also demonstrated the role of SEPHS1 in human ESC clonogenicity, and we found improved single-cell survival of hESCs by selenium treatment in a concentration-dependent manner. Our study implies that hSEPHS1 is a regulator of selenium-mediated redox-signaling in human pluripotent stem cells and plays a role in their survival.

Ectodysplasin is a ligand of the TNF family that plays a key role in ectodermal differentiation. EDA-A1 and EDA-A2 are two isoforms of ectodysplasin that differ only by the insertion of two amino acids and bind to two different receptors, ectodysplasin A receptor (EDAR) and ectodysplasin A2 receptor (EDA2R), respectively. Mutations of EDA-A1 and its receptor EDAR have been associated with hypohidrotic ecodermal dysplasia (HED). However, the role of EDA-A2 and the expression pattern of EDA2R in human hair follicles and in the mouse hair growth cycle have not been reported. In this study, we first investigated the expression of EDA2R in human hair follicles and in cultured follicular cells. EDA2R was strongly expressed in outer root sheath (ORS) cells and weakly expressed in dermal papilla (DP) cells. EDA-A2 induced the apoptosis of both ORS cells and DP cells via the activation of cleaved caspase-3. In addition, EDA2R was highly expressed in the late anagen phase compared with other phases in the hair growth cycle. Moreover, EDA-A2 induced apoptosis in cultured human hair follicle cells and in the mouse hair growth cycle, causing the premature onset of the catagen phase. Collectively, our results suggest that EDA-A2/EDA2R signaling could inhibit hair growth, and an inhibitor of EDA-A2/EDA2R signaling may be a promising agent for the treatment and prevention of hair loss.

The development of muscle in the embryo, which is crucial for postnatal skeletal muscle growth, has been investigated widely. Much has been learned during the past several decades about the role of maternal nutrition in the outcome of pregnancy. Protein and carbohydrate levels during pregnancy have been shown to be important in the development of offspring, especially muscle development. However, the maternal effects of steroids were still not clear. Phytosterol esters (PEs) are produced by the esterification of phytosterols and fatty acids and have many beneficial functions, such as anti-inflammation and hypolipemic functions. Through the effect of regulation on lipid metabolism, can pregnant mice fed with PEs show any programming effect on the muscle development of offspring? In our study, PEs were supplied to the maternal diet, and changes in maternal lipid metabolism and the development of offspring skeletal muscle were detected. As a result, the amniotic fluid total bile acid (TBA) and total cholesterol (TC) levels were decreased; the growth of offspring was significantly faster than that of the control group until 6 weeks of age. Adult offspring had a higher lean mass index and grip strength. In skeletal muscle, the proportion of myosin heavy chain (MHC) 1 was significantly decreased, while the proportion of MHC 2 b was increased. In conclusion, maternal PEs significantly reduced sterols in the amniotic fluid, while skeletal muscle development was promoted in the offspring.

Hippocampus CA1 pyramidal cells receive γ-aminobutyric acid (GABA) release from multiple GABAergic interneurons. Combining optogenetic strategy and whole-cell recordings, we demonstrate that baclofen, a specific GABAB receptor agonist, depresses monosynaptic GABAA receptor-mediated transmission from parvalbumin (PV)-expressing interneuron terminals onto pyramidal cells with less efficacy than that from the unspecific GABAergic terminals. The depression from PV neuron terminals is mainly mediated by presynaptic P/N type calcium channels. The results suggest that GABAB receptors are widely expressed on GABAergic interneurons, where they exert inhibition onto pyramidal cells by GABA release with different efficacy. The data strengthen the proposal that diverse GABA neurons play different roles in modulating CA1 pyramidal cell excitability.

The Trento screening program transitioned to digital breast tomosynthesis (DBT) screening based on evidence that DBT improves breast cancer (BC) detection compared to mammography; an evaluation of the transition to DBT is reported in this pilot study.

Transporting epithelial cells, like those that line the intestinal tract, are specialized for solute processing and uptake. One defining feature is the brush border, an array of microvilli that serves to amplify apical membrane surface area and increase functional capacity. During differentiation, upon exit from stem-cell-containing crypts, enterocytes build thousands of microvilli, each supported by a parallel bundle of actin filaments several microns in length. Given the high concentration of actin residing in mature brush borders, we sought to determine whether enterocytes were resource (i.e., actin monomer) limited in assembling this domain. To examine this possibility, we inhibited Arp2/3, the ubiquitous branched actin nucleator, to increase G-actin availability during brush border assembly. In native intestinal tissues, Arp2/3 inhibition led to increased microvilli length on the surface of crypt, but not villus, enterocytes. In a cell culture model of brush border assembly, Arp2/3 inhibition accelerated the growth and increased the length of microvilli; it also led to a redistribution of F-actin from cortical lateral networks into the brush border. Effects on brush border growth were rescued by treatment with the G-actin sequestering drug, latrunculin A. G-actin binding protein, profilin-1, colocalized in the terminal web with G-actin, and knockdown of this factor compromised brush border growth in a concentration-dependent manner. Finally, the acceleration in brush border assembly induced by Arp2/3 inhibition was abrogated by profilin-1 knockdown. Thus, brush border assembly is limited by G-actin availability, and profilin-1 directs unallocated actin monomers into microvillar core bundles during enterocyte differentiation.

Trust and betrayal are central to our social world, and adaptive responses to generous and selfish behavior are crucial to our economic and social well-being [1]. We learn about others' trustworthiness through trial and error during repeated interactions [2]. By reinforcing and suppressing behavior during positive and negative interactions with conspecifics, rodent research has established a crucial role for the basolateral amygdala (BLA) in social experiential learning [3, 4]. The human BLA has undergone a reorganization with massive expansion relative to other amygdala nuclei [5], and there is no translational research on its role in experiential learning. The human amygdala is traditionally researched as a single structure [6], neglecting the sub-nuclei's structural und functional differences [7], which might explain inconsistent findings in research on social interactions [8, 9]. Here, we study whether the human BLA is necessary for social and non-social experiential learning by testing a group of five humans with selective bilateral damage to the BLA. We compared their learning behavior in a repeated trust game, and a non-social control task, to healthy, matched controls. Crucially, BLA-damaged subjects, unlike control subjects, completely failed to adapt their investments when interacting with a trustworthy and an untrustworthy partner. In the non-social task, BLA-damaged subjects learned from positive outcomes but differed from the controls by not learning from negative outcomes. Our data extend findings in rodent research by showing that the human BLA is essential for social experiential learning and provide confirmatory evidence of divergent mechanisms for differentially valenced outcomes in non-social learning.

Abscission, the final step of cytokinesis, cleaves the thin intercellular bridge connecting the two daughter cells [1-6]. The scaffold protein ALIX is a core component of the abscission machinery with an evolutionarily conserved role in midbody recruitment of ESCRT-III [7-11], which mediates the final cut [1-5, 8-10, 12-14]. In mammalian cells, the centralspindlin complex recruits the major midbody organizer CEP55 that directly binds and recruits ALIX and ESCRT-I [7-9, 15-17], which in turn cooperatively recruit ESCRT-III [8, 9, 18]. However, CEP55 is missing in Drosophila melanogaster and other invertebrates [6, 9, 19], and it is unknown how the abscission machinery is recruited to the midbody in the absence of CEP55. Here, we address how Drosophila ALIX is recruited to the midbody. Surprisingly, ALIX localizes to the midbody via its V-domain, independently of the GPPX3Y motif in the proline-rich region that recruits human ALIX [8, 9]. We elucidate that the centralspindlin component Pavarotti (H.s.MKLP1) interacts with the V-domain of ALIX to recruit it to the midbody. Specifically, our results indicate that an LxxLF motif in Pavarotti directly interacts with a conserved hydrophobic pocket in the ALIX V-domain, which in human ALIX binds (L)YPXnL/LxxLF motifs of virus proteins [20-28]. Thus, our study identifies that ALIX is recruited by an analogous mechanism during abscission in Drosophila as during virus budding in mammalian cells and an ancestral role for centralspindlin in recruiting the abscission machinery to the midbody.

Recessive forms of catecholaminergic polymorphic ventricular tachycardia (CPVT) are induced by mutations in genes encoding triadin or calsequestrin, two proteins that belong to the Ca2+ release complex, responsible for intracellular Ca2+ release triggering cardiac contractions. To better understand the mechanisms of triadin-induced CPVT and to assay multiple therapeutic interventions, we used a triadin knockout mouse model presenting a CPVT-like phenotype associated with a decrease in calsequestrin protein level. We assessed different approaches to rescue protein expression and to correct intracellular Ca2+ release and cardiac function: pharmacological treatment with kifunensine or a viral gene transfer-based approach, using adeno-associated virus serotype 2/9 (AAV2/9) encoding the triadin or calsequestrin. We observed that the levels of triadin and calsequestrin are intimately linked, and that reduction of both proteins contributes to the CPVT phenotype. Different combinations of triadin and calsequestrin expression level were obtained using these therapeutic approaches. A full expression of each is not necessary to correct the phenotype; a fine-tuning of the relative re-expression of both triadin and calsequestrin is required to correct the CPVT phenotype and rescue the cardiac function. AAV-mediated gene delivery of calsequestrin or triadin and treatment with kifunensine are potential treatments for recessive forms of CPVT due to triadin mutations.

Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HTT CAG/CAA glutamine-encoding repeat, and DNA repair genes.

Tissue folding is a fundamental process that shapes epithelia into complex 3D organs. The initial positioning of folds is the foundation for the emergence of correct tissue morphology. Mechanisms forming individual folds have been studied, but the precise positioning of folds in complex, multi-folded epithelia is less well-understood. We present a computational model of morphogenesis, encompassing local differential growth and tissue mechanics, to investigate tissue fold positioning. We use the Drosophila wing disc as our model system and show that there is spatial-temporal heterogeneity in its planar growth rates. This differential growth, especially at the early stages of development, is the main driver for fold positioning. Increased apical layer stiffness and confinement by the basement membrane drive fold formation but influence positioning to a lesser degree. The model successfully predicts the in vivo morphology of overgrowth clones and wingless mutants via perturbations solely on planar differential growth in silico.

There are limited data on fetal and early life development of human intestinal immunity. Using mass cytometry (CyTOF) and next-generation sequencing of B and T cell receptor (BCR and TCR) repertoires, we demonstrate complex intestinal immunity from 16 weeks' gestational age (GA). Both BCR and TCR repertoires are diverse with CDRH and CDR3β length increasing with advancing GA. The difference-from-germline, CDR insertions and/or deletions, similarly occur in utero for TCR but not BCR, suggesting earlier mucosal T than B cell maturity. Innate immunity is dominated by macrophages, dendritic cells (DCs), innate lymphoid cells (ILCs), and natural killer (NK) cells. Follicular and transitional B cells are enriched in fetuses while CD69+IgM+ B cells are abundant in infants. Both CD4+ and CD8+ T cells are abundant, capable of secreting cytokines and are phenotypically of the tissue resident memory state in utero. Our data provide the foundation for a 2nd trimester and infant intestinal immune atlas and suggest that a complex innate and adaptive immune landscape exists significantly earlier than previously reported.

Nucleus position in cells can act as a developmental cue. Mammalian oocytes position their nucleus centrally using an F-actin-mediated pressure gradient. The biological significance of nucleus centering in mammalian oocytes being unknown, we sought to assess the F-actin pressure gradient effect on the nucleus. We addressed this using a dedicated computational 3D imaging approach, biophysical analyses, and a nucleus repositioning assay in mouse oocytes mutant for cytoplasmic F-actin. We found that the cytoplasmic activity, in charge of nucleus centering, shaped the nucleus while promoting nuclear envelope fluctuations and chromatin motion. Off-centered nuclei in F-actin mutant oocytes were misshaped with immobile chromatin and modulated gene expression. Restoration of F-actin in mutant oocytes rescued nucleus architecture fully and gene expression partially. Thus, the F-actin-mediated pressure gradient also modulates nucleus dynamics in oocytes. Moreover, this study supports a mechano-transduction model whereby cytoplasmic microfilaments could modulate oocyte transcriptome, essential for subsequent embryo development.

Tumour immune microenvironment (TIME) of gastrointestinal stromal tumours (GISTs) is largely unknown.

To estimate the prevalence of frailty and evaluate the relationship with the social determinants of health in elderly residents in urban and rural areas of Colombia.