Discovery of Potent, Highly Selective, and Efficacious SMARCA2 Degraders.

We describe the identification of selective SMARCA2, VHL-based heterobifunctional degraders. Structurally novel indolo[1,2-]quinazolin-5(7)-one SMARCA bromodomain binders were optimized and then converted to SMARCA2 degraders by linking them to well-defined VHL ligands. Our exploration led to the discovery of potent and selective degraders of SMARCA2 over the SMARCA4 paralog, leading to potent and selective growth inhibition of SMARCA4 mutant versus wild type cell lines.

Bad company? The pericardium microbiome in people investigated for tuberculous pericarditis in an HIV-prevalent setting.

Background: The site-of-disease microbiome and predicted metagenome were evaluated in a cross-sectional study involving people with presumptive tuberculous pericarditis. We also explored the interaction between C-reactive protein (CRP) and the microbiome.

Methods: People with effusions requiring diagnostic pericardiocentesis (n=139) provided pericardial fluid for sequencing and blood for CRP measurement.

Subtracting the background by reducing cell-free DNA's confounding effects on Mycobacterium tuberculosis quantitation and the sputum microbiome.

DNA characterisation in people with tuberculosis (TB) is critical for diagnostic and microbiome evaluations. However, extracellular DNA, more frequent in people on chemotherapy, confounds results. We evaluated whether nucleic acid dyes [propidium monoazide (PMA), PEMAX] and DNaseI could reduce this.

PneumoniaCheck, a novel aerosol collection device, permits capture of airborne Mycobacterium tuberculosis and characterisation of the cough aeromicrobiome in people with tuberculosis.

Background: Tuberculosis (TB), a major cause of disease and antimicrobial resistance, is spread via aerosols. Aerosols have diagnostic potential and airborne-microbes other than Mycobacterium tuberculosis complex (MTBC) may influence transmission. We evaluated whether PneumoniaCheck (PMC), a commercial aerosol collection device, captures MTBC and the aeromicrobiome of people with TB.

Latent Tuberculosis Infection Is Associated with an Enrichment of Short-Chain Fatty Acid-Producing Bacteria in the Stool of Women Living with HIV.

Latent tuberculosis infection (LTBI) is common in people living with HIV (PLHIV) in high-TB-burden settings. Active TB is associated with specific stool taxa; however, little is known about the stool microbiota and LTBI in PLHIV. We characterised the stool microbiota of PLHIV with [interferon- release assay (IGRA)- and tuberculin skin test (TST)-positive] or without (IGRA- and TST-negative) LTBI ( = 25 per group).

Bad company? The pericardium microbiome in people investigated for tuberculosis pericarditis in an HIV-prevalent setting.

Background: The microbiome likely plays a role in tuberculosis (TB) pathogenesis. We evaluated the site-of-disease microbiome and predicted metagenome in people with presumptive tuberculous pericarditis, a major cause of mortality, and explored for the first time, the interaction between its association with C-reactive protein (CRP), a potential diagnostic biomarker and the site-of-disease microbiome in extrapulmonary TB.

Methods: People with effusions requiring diagnostic pericardiocentesis (n=139) provided background sampling controls and pericardial fluid (PF) for 16S rRNA gene sequencing analysed using QIIME2 and PICRUSt2.

A novel aerosol collection method shows the cough aeromicrobiome of people with tuberculosis is phylogenetically distinct from respiratory tract specimens.

Background: Tuberculosis (TB), a major cause of disease and antimicrobial resistance, is spread via aerosols. Aerosols have diagnostic potential and airborne-microbes other than (MTBC) may influence transmission. We evaluated whether PneumoniaCheck (PMC), a commercial aerosol collection device, captures MTBC and the aeromicrobiome of people with TB.

Latent tuberculosis infection is associated with an enrichment of short chain fatty acid producing bacteria in the stool of women living with HIV.

Background: Latent tuberculosis infection (LTBI) is common in people living with HIV (PLHIV) in high TB burden settings. Active TB is associated with specific stool taxa; however, little is known about the stool microbiota and LTBI, including in PLHIV.

Method: Within a parent study that recruited adult females with HIV from Cape Town, South Africa into predefined age categories (18-25, 35-60 years), we characterised the stool microbiota of those with [interferon-γ release assay (IGRA)- and tuberculin skin test (TST)-positive] or without (IGRA- and TST- negative) LTBI (n=25 per group).

Oral vancomycin treatment suppresses gut trypsin activity and preserves intestinal barrier function during EAE.

Studies have reported increased intestinal permeability in multiple sclerosis (MS) patients and its mouse model experimental autoimmune encephalomyelitis (EAE). However, the mechanisms driving increased intestinal permeability that in turn exacerbate neuroinflammation during EAE remain unclear. Here we showed that vancomycin preserved the integrity of the intestinal barrier, while also suppressing gut trypsin activity, enhancing the relative abundance of specific and ameliorating disease during EAE.

Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare costs. Cigarette smoke is a causative factor; however, not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advanced stages.

Associations between Ileal Juice Bile Acids and Colorectal Advanced Adenoma.

Background: There is an urgent need to identify biomarkers for advanced adenoma, an important precursor of colorectal cancer (CRC). We aimed to determine alterations in ileal juice bile acids associated with colorectal advanced adenoma.

Methods: We quantified a comprehensive panel of primary and secondary bile acids and their conjugates using an ultraperformance liquid chromatography triple-quadrupole mass spectrometric assay in ileal juice collected at colonoscopy from 46 study subjects (i.

Gut and oral microbiome modulate molecular and clinical markers of schizophrenia-related symptoms: A transdiagnostic, multilevel pilot study.

Although increasing evidence links microbial dysbiosis with the risk for psychiatric symptoms through the microbiome-gut-brain axis (MGBA), the specific mechanisms remain poorly characterized. In a diagnostically heterogeneous group of treated psychiatric cases and nonpsychiatric controls, we characterized the gut and oral microbiome, plasma cytokines, and hippocampal inflammatory processes via proton magnetic resonance spectroscopic imaging (H-MRSI). Using a transdiagnostic approach, these data were examined in association with schizophrenia-related symptoms measured by the Positive and Negative Syndrome Scale (PANSS).

Effects of vaginal microbiota transfer on the neurodevelopment and microbiome of cesarean-born infants: A blinded randomized controlled trial.

The microbiomes of cesarean-born infants differ from vaginally delivered infants and are associated with increased disease risks. Vaginal microbiota transfer (VMT) to newborns may reverse C-section-related microbiome disturbances. Here, we evaluated the effect of VMT by exposing newborns to maternal vaginal fluids and assessing neurodevelopment, as well as the fecal microbiota and metabolome.

Dissemination, Implementation, and Evaluation of an Effective School-Based Intervention to Promote Physical Activity in Adolescents: A Study Protocol.

Adolescents around the world do not engage in sufficient physical activity and the Spanish context is no exception. Understanding the educational context as a complex system, school-based multi-level and multi-component interventions seem to be an effective strategy to reverse this trend. Moreover, a co-creational approach seems to facilitate the mobilization of community partnerships and the engagement of stakeholders in the intervention process.

Alterations in the cutaneous microbiome of patients with psoriasis and psoriatic arthritis reveal similarities between non-lesional and lesional skin.

Objectives: To investigate the cutaneous microbiome spanning the entire psoriatic disease spectrum, and to evaluate distinguishing features of psoriasis (PsO) and psoriatic arthritis (PsA).

Methods: Skin swabs were collected from upper and lower extremities of healthy individuals and patients with PsO and PsA. Psoriatic patients contributed both lesional (L) and contralateral non-lesional (NL) samples.

More than site-of-disease microbial communities, and their functional and clinical profiles in tuberculous lymphadenitis.

Background: Lymphadenitis is the most common extrapulmonary tuberculosis (EPTB) manifestation. The microbiome is important to human health but uninvestigated in EPTB. We profiled the site-of-disease lymph node microbiome in tuberculosis lymphadenitis (TBL).

Mining the microbiota to identify gut commensals modulating neuroinflammation in a mouse model of multiple sclerosis.

Background: The gut microbiome plays an important role in autoimmunity including multiple sclerosis and its mouse model called experimental autoimmune encephalomyelitis (EAE). Prior studies have demonstrated that the multiple sclerosis gut microbiota can contribute to disease, hence making it a potential therapeutic target. In addition, antibiotic treatment has been shown to ameliorate disease in the EAE mouse model of multiple sclerosis.

Novel technologies to characterize and engineer the microbiome in inflammatory bowel disease.

We present an overview of recent experimental and computational advances in technology used to characterize the microbiome, with a focus on how these developments improve our understanding of inflammatory bowel disease (IBD). Specifically, we present studies that make use of flow cytometry and metabolomics assays to provide a functional characterization of microbial communities. We also describe computational methods for strain-level resolution, temporal series, mycobiome and virome data, co-occurrence networks, and compositional data analysis.

Patient-reported exposures and outcomes link the gut-brain axis and inflammatory pathways to specific symptoms of severe mental illness.

Unlabelled: We developed a "gut-brain-axis questionnaire" (GBAQ) to obtain standardized person-specific "review of systems" data for microbiome-gut-brain-axis studies. Individual items were compared to PANSS symptom measures using dimensional, transdiagnostic and traditional categorical approaches.

Method: Forty psychotic participants, independent of diagnoses, and 42 without psychosis (18 nonpsychotic affective disorders, 24 healthy controls) completed the GBAQ and underwent research diagnostic and symptom assessments.

Impaired central tolerance induces changes in the gut microbiota that exacerbate autoimmune hepatitis.

Medullary thymic epithelial cells (mTECs) induce T cell tolerance in the thymus through the elimination of self-reactive thymocytes. Commensal bacteria are also critical for shaping T cell responses in the gut and distal organs. We previously showed that mice depleted of mTECs (Traf6ΔTEC) generated autoreactive T cells and developed autoimmune hepatitis (AIH).

Identifying correlations driven by influential observations in large datasets.

Although high-throughput data allow researchers to interrogate thousands of variables simultaneously, it can also introduce a significant number of spurious results. Here we demonstrate that correlation analysis of large datasets can yield numerous false positives due to the presence of outliers that canonical methods fail to identify. We present Correlations Under The InfluencE (CUTIE), an open-source jackknifing-based method to detect such cases with both parametric and non-parametric correlation measures, and which can also uniquely rescue correlations not originally deemed significant or with incorrect sign.

Traditional Farming Lifestyle in Old Older Mennonites Modulates Human Milk Composition.

Background: In addition to farming exposures in childhood, maternal farming exposures provide strong protection against allergic disease in their children; however, the effect of farming lifestyle on human milk (HM) composition is unknown.

Objective: This study aims to characterize the maternal immune effects of Old Order Mennonite (OOM) traditional farming lifestyle when compared with Rochester (ROC) families at higher risk for asthma and allergic diseases using HM as a proxy.

Methods: HM samples collected at median 2 months of lactation from 52 OOM and 29 ROC mothers were assayed for IgA and IgA antibodies, cytokines, endotoxin, HM oligosaccharides (HMOs), and targeted fatty acid (FA) metabolites.

An integrative study of the microbiome gut-brain-axis and hippocampal inflammation in psychosis: Persistent effects from mode of birth.

Unlabelled: The mechanism producing psychosis appears to include hippocampal inflammation, which could be associated with the microbiome-gut-brain-axis (MGBS). To test this hypothesis we are conducting a multidisciplinary study, herein described. The procedures are illustrated with testing of a single subject and group level information on the impact of C-section birth are presented.