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Tissue-resident macrophages are heterogeneous as a consequence of anatomical niche–specific functions. Many populations self-renew independently of bone marrow in the adult, but the molecular mechanisms of this are poorly understood. We determined a transcriptional profile for the major self-renewing population of peritoneal macrophages in mice. These cells specifically expressed the transcription factor Gata6. Selective deficiency of Gata6 in myeloid cells caused substantial alterations in the transcriptome of peritoneal macrophages. Gata6 deficiency also resulted in dysregulated peritoneal macrophage proliferative renewal during homeostasis and in response to inflammation, which was associated with delays in the resolution of inflammation. Our investigations reveal that the tissue macrophage phenotype is under discrete tissue-selective transcriptional control and that this is fundamentally linked to the regulation of their proliferation renewal.

Background and aims: Despite recent advances in advanced prostate cancer treatments, clinical biomarkers or treatments for men with such cancers are imperfect. Targeted therapies have shown promise, but there remain fewer actionable targets in prostate cancer than in other cancers. This work aims to characterise BRD9, currently understudied in prostate cancer, and investigate its co-expression with other genes to assess its potential as a biomarker and therapeutic target in human prostate cancer. Materials and methods: Omics data from a total of 2053 prostate cancer patients across 11 independent datasets were accessed via Cancertool and cBioPortal. mRNA M.expression and co-expression, mutations, amplifications, and deletions were assessed with respect to key clinical parameters including survival, Gleason grade, stage, progression, and treatment. Network and pathway analysis was carried out using Genemania, and heatmaps were constructed using Morpheus. Results: BRD9 is overexpressed in prostate cancer patients, especially those with metastatic disease. BRD9 expression did not differ in patients treated with second generation antiandrogens versus those who were not. BRD9 is co-expressed with many genes in the SWI/SNF and BET complexes, as well as those in common signalling pathways in prostate cancer. Summary and conclusions: BRD9 has potential as a diagnostic and prognostic biomarker in prostate cancer. BRD9 also shows promise as a therapeutic target, particularly in advanced prostate cancer, and as a co-target alongside other genes in the SWI/SNF and BET complexes, and those in common prostate cancer signalling pathways. These promising results highlight the need for wider experimental inhibition and co-targeted inhibition of BRD9 in vitro and in vivo, to build on the limited inhibition data available.

There is widespread transcriptional dysregulation in Huntington’s disease (HD) brain, but analysis is inevitably limited by advanced disease and postmortem changes. However, mutant HTT is ubiquitously expressed and acts systemically, meaning blood, which is readily available and contains cells that are dysfunctional in HD, could act as a surrogate for brain tissue. We conducted an RNA-Seq transcriptomic analysis using whole blood from two HD cohorts, and performed gene set enrichment analysis using public databases and weighted correlation network analysis modules from HD and control brain datasets. We identified dysregulated gene sets in blood that replicated in the independent cohorts, correlated with disease severity, corresponded to the most significantly dysregulated modules in the HD caudate, the most prominently affected brain region, and significantly overlapped with the transcriptional signature of HD myeloid cells. High-throughput sequencing technologies and use of gene sets likely surmounted the limitations of previously inconsistent HD blood expression studies. Our results suggest transcription is disrupted in peripheral cells in HD through mechanisms that parallel those in brain. Immune upregulation in HD overlapped with Alzheimer’s disease, suggesting a common pathogenic mechanism involving macrophage phagocytosis and microglial synaptic pruning, and raises the potential for shared therapeutic approaches.

The COVID-19 pandemic has led to restrictions such as social distancing and mandatory wearing of face masks. Singing and religious gatherings have been linked to infection clusters, and between 2020 and 2021 indoor congregational singing and chanting were prohibited in the United Kingdom. We evaluated attitudes to face mask use and their acceptability as well as changes within places of worship since their reopening in July up to autumn 2020. In this cross-sectional study, participants were recruited using convenience sampling through selective targeting of religious organisations and social media. Participants self-enrolled and completed an online questionnaire, which included open and closed questions. We used multivariable logistic regression to identify factors associated with face mask acceptability. We performed thematic analysis to evaluate responses to open questions. A total of 939 participants were included in the analysis. Median age was 52.7 years and 66.1% were female, while 80.7% identified as Christian. A majority (672/861; 78.0%) of participants would find it acceptable to wear a face mask and reduce their singing or chanting volume if required, even though 428/681 (49.1%) found face masks to be uncomfortable. Multivariable regression found that younger age was associated with a higher acceptability of face masks (adjusted OR (aOR): 0.98 (95% confidence interval (95% CI) 0.96–1.00), p = 0.0218). The majority of respondents stated that religious services had become shorter, attended by fewer people and with reduced singing or chanting. Most (869/893, 97.3%) stated their place of worship complied with government guidelines, with 803/887 (90.5%) reported that their place of worship enforced face mask wearing and 793/887 (89.4%) at least moderately happy with precaution measures. Our study demonstrates the significant impact of COVID-19 in places of worship but a high degree of compliance with guidelines. Face masks, despite practical difficulties, appeared to be more acceptable if there was an incentive of being able to sing and chant.

Background Early detection of esophageal cancer is critical to improve survival. Whilst studies have identified biomarkers, their interpretation and validity is often confounded by cell-type heterogeneity. Results Here we applied systems-epigenomic and cell-type deconvolution algorithms to a discovery set encompassing RNA-Seq and DNA methylation data from esophageal adenocarcinoma (EAC) patients and matched normal-adjacent tissue, in order to identify robust biomarkers, free from the confounding effect posed by cell-type heterogeneity. We identify 12 gene-modules that are epigenetically deregulated in EAC, and are able to validate all 12 modules in 4 independent EAC cohorts. We demonstrate that the epigenetic deregulation is present in the epithelial compartment of EAC-tissue. Using single-cell RNA-Seq data we show that one of these modules, a proto-cadherin module centered around CTNND2, is inactivated in Barrett’s Esophagus, a precursor lesion to EAC. By measuring DNA methylation in saliva from EAC cases and controls, we identify a chemokine module centered around CCL20, whose methylation patterns in saliva correlate with EAC status. Conclusions Given our observations that a CCL20 chemokine network is overactivated in EAC tissue and saliva from EAC patients, and that in independent studies CCL20 has been found to be overactivated in EAC tissue infected with the bacterium F. nucleatum , a bacterium that normally inhabits the oral cavity, our results highlight the possibility of using DNAm measurements in saliva as a proxy for changes occurring in the esophageal epithelium. Both the CTNND2/CCL20 modules represent novel promising network biomarkers for EAC that merit further investigation.

Background The YAC128 model of Huntington’s disease (HD) shows substantial deficits in motor, learning and memory tasks and alterations in its transcriptional profile. We examined the changes in the transcriptional profile in the YAC128 mouse model of HD at 6, 12 and 18 months and compared these with those seen in other models and human HD caudate. Results Differential gene expression by genotype showed that genes related to neuronal function, projection outgrowth and cell adhesion were altered in expression. A Time-course ANOVA revealed that genes downregulated with increased age in wild-type striata were likely to be downregulated in the YAC128 striata. There was a substantial overlap of concordant gene expression changes in the YAC128 striata compared with those in human HD brain. Changes in gene expression over time showed fewer striatal YAC128 RNAs altered in abundance than in the HdhQ150 striata but there was a very marked overlap in transcriptional changes at all time points. Despite the similarities in striatal expression changes at 18 months the HdhQ150 mice showed widespread mHTT and ubiquitin positive inclusion staining in the striatum whereas this was absent in the YAC128 striatum. Conclusions The gene expression changes in YAC128 striata show a very closely matched profile to that of HdhQ150 striata and are already significantly different between genotypes by six months of age, implying that the temporal molecular gene expression profiles of these models match very closely, despite differences in the prevalence of brain inclusion formation between the models. The YAC128 gene expression changes appear to correlate well with gene expression differences caused by ageing. A relatively small number of genes showed significant differences in expression between the striata of the two models and these could explain some of the phenotypic differences between the models.

BackgroundWhile the central nervous system is considered to be the primary site of Huntington’s disease (HD) pathology, patients exhibit a wide range of peripheral abnormalities. Indeed, there is much interest in the systemic innate immune system as a modifier of disease progression, with HD myeloid cells exhibiting numerous functional abnormalities, but the molecular mechanisms underpinning these changes remain only partially understood.AimTo investigate alterations in transcriptional regulation that are associated with HD myeloid cell hyper-reactivity.MethodsRNA deep-sequencing was performed for whole transcriptome analysis of primary monocytes isolated from HD patients and control subjects cultured with and without a proinflammatory stimulus and various bioinformatic analyses were carried out. ChIP-seq was undertaken to identify changes in histone modifications or transcription factor binding that are associated with altered transcription. ResultsSignificant transcriptional differences in HD monocytes in their basal, unstimulated state were observed, including elevated expression of genes encoding proinflammatory cytokines. That such differences are observed under basal conditions contrasts with previous studies that have required stimulation to elicit phenotypic abnormalities. Pathway analysis of differentially expressed genes reveals an enrichment of genes associated with innate immunity and the inflammatory response, while analysis of upstream regulators suggests that abnormal activation of particular intracellular signalling pathways plays a major causative role in mediating this transcriptional dysregulation. The precise mechanism by which mutant huntingtin exerts these effects may reside in particular histone modifications and/or altered transcription factor binding to increase the expression of specific sets of genes.ConclusionsHD myeloid cells are intrinsically abnormal, with a proinflammatory phenotype in the absence of stimulation that is consistent with a priming effect of mutant huntingtin such that an exaggerated inflammatory response is produced when a stimulus is encountered. This is associated with transcriptional dysregulation, which may be a key mechanism causing innate immune dysfunction in Huntington’s disease.

Vehicle and Traffic Law (VTL) section 1194 establishes the procedures governing the arrest and testing of an individual suspected of driving while under the influence of drugs or alcohol. As a result of a 1970 change to the enabling statute, conflict emerged as to the current application of the two-hour rule. The original two-hour rule contained in VTL section 70(5) provided that chemical evidence of the amount of alcohol in a driver's blood was only admissible if the test was performed within two hours of his arrest. This rule, as a matter of construction, applied to the entire statute, serving as a rule of an evidentiary nature. In 1970, however, the New York legislature changed the statutory placement of the two-hour rule, relocating it from the VTL's evidentiary provision to its deemed consent provision. In People v. Zawacki, the Fourth Department recognized the (New York) Court of Appeals (as holding) the two-hour limit inapplicable to chemical tests administered pursuant to (a) defendant's actual consent.

Sensory perception is an inextricable part of Fourth Amendment jurisprudence. As a legal matter, it is undisputed that the \"alert\" of a trained dog to contraband generates probable cause for a search or seizure. State v. Rabb was decided incorrectly: a dog sniff is a non-search so long as it is performed from a constitutionally unprotected launching pad. First, the court's focus on Kyllo is misplaced. Provided that the sniff is performed from constitutionally unprotected ground, it infringes no legitimate privacy interest. This is consistent with the idea that the Fourth Amendment does not validate privacy expectations in per se unlawful property or activity. The dog sniff is a unique and vital law enforcement technique, and its Fourth Amendment character is generally unaffected by the location in which it occurs.

The effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtin's polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the \"polyglutamine disorders\".