miR-193b-365 microcluster downstream of coordinates neuron-subtype identity and dendritic morphology in cortical projection neurons.

Different neuron types develop characteristic axonal and dendritic arborizations that determine their inputs, outputs, and functions. Expression of fate-determinant transcription factors is essential for specification of their distinct identities. However, the mechanisms downstream of fate-determinant factors coordinating different aspects of neuron identity are not understood.

Dynamic human gut microbiome and immune shifts during an immersive psychosocial intervention program.

Background: Although depression is a leading cause of disability worldwide, the pathophysiological mechanisms underlying this disorder-particularly those involving the gut microbiome-are poorly understood.

Method: To investigate, we conducted a community-based observational study to explore complex associations between changes in the gut microbiome, cytokine levels, and depression symptoms in 52 participants (M = 49.56, SD = 13.

Interindividual Variability in Postprandial Plasma Fructose Patterns in Adults.

High fructose consumption is associated with an increased risk of cardiometabolic disease, and fructose feeding dose-dependently induces markers reflective of poor metabolic health. However, unlike glucose, surprisingly little is known about person-to-person differences in postprandial plasma fructose patterns. Herein, we performed post hoc analyses of two published studies to address this question.

Nonlinear dynamics of multi-omics profiles during human aging.

Aging is a complex process associated with nearly all diseases. Understanding the molecular changes underlying aging and identifying therapeutic targets for aging-related diseases are crucial for increasing healthspan. Although many studies have explored linear changes during aging, the prevalence of aging-related diseases and mortality risk accelerates after specific time points, indicating the importance of studying nonlinear molecular changes.

Genome-wide transcription response of to heat shock and medically relevant glucose levels.

Skin serves as both barrier and interface between body and environment. Skin microbes are intermediaries evolved to respond, transduce, or act in response to changing environmental or physiological conditions. We quantified genome-wide changes in gene expression levels for one abundant skin commensal, , in response to an internal physiological signal, glucose levels, and an external environmental signal, temperature.

Reversal of injury-associated retinal ganglion cell gene expression by a phosphodiesterase anchoring disruptor peptide.

Loss of retinal ganglion cells (RGCs) is central to the pathogenesis of optic neuropathies such as glaucoma. Increased RGC cAMP signaling is neuroprotective. We have shown that displacement of the cAMP-specific phosphodiesterase PDE4D3 from an RGC perinuclear compartment by expression of the modified PDE4D3 N-terminal peptide 4D3(E) increases perinuclear cAMP and protein kinase A activity in cultured neurons and in vivo RGC survival after optic nerve crush (ONC) injury.

Dynamic Human Gut Microbiome and Immune Shifts During an Immersive Psychosocial Therapeutic Program.

Background: Depression is a leading cause of disability worldwide yet its underlying factors, particularly microbial associations, are poorly understood.

Methods: We examined the longitudinal interplay between the microbiome and immune system in the context of depression during an immersive psychosocial intervention. 142 multi-omics samples were collected from 52 well-characterized participants before, during, and three months after a nine-day inquiry-based stress reduction program.

Structure and topography of the synaptic V-ATPase-synaptophysin complex.

Synaptic vesicles are organelles with a precisely defined protein and lipid composition, yet the molecular mechanisms for the biogenesis of synaptic vesicles are mainly unknown. Here we discovered a well-defined interface between the synaptic vesicle V-ATPase and synaptophysin by in situ cryo-electron tomography and single-particle cryo-electron microscopy of functional synaptic vesicles isolated from mouse brains. The synaptic vesicle V-ATPase is an ATP-dependent proton pump that establishes the proton gradient across the synaptic vesicle, which in turn drives the uptake of neurotransmitters.

People living with HIV display increased anti-apolipoprotein A1 auto-antibodies, inflammation, and kynurenine metabolites: a case-control study.

Objective: This study aimed to study the relationship between auto-antibodies against apolipoprotein A1 (anti-apoA1 IgG), human immunodeficiency virus (HIV) infection, anti-retroviral therapy (ART), and the tryptophan pathways in HIV-related cardiovascular disease.

Design: This case-control study conducted in South Africa consisted of control volunteers ( = 50), people living with HIV (PLWH) on ART ( = 50), and untreated PLWH ( = 44). Cardiovascular risk scores were determined, vascular measures were performed, and an extensive biochemical characterisation (routine, metabolomic, and inflammatory systemic profiles) was performed.

Repopulated spinal cord microglia exhibit a unique transcriptome and contribute to pain resolution.

Microglia are implicated as primarily detrimental in pain models; however, they exist across a continuum of states that contribute to homeostasis or pathology depending on timing and context. To clarify the specific contribution of microglia to pain progression, we take advantage of a temporally controlled transgenic approach to transiently deplete microglia. Unexpectedly, we observe complete resolution of pain coinciding with microglial repopulation rather than depletion.

SMYD3: a new regulator of adipocyte precursor proliferation at the early steps of differentiation.

Background: In obesity, adipose tissue undergoes a remodeling process characterized by increased adipocyte size (hypertrophia) and number (hyperplasia). The ability to tip the balance toward the hyperplastic growth, with recruitment of new fat cells through adipogenesis, seems to be critical for a healthy adipose tissue expansion, as opposed to a hypertrophic growth that is accompanied by the development of inflammation and metabolic dysfunction. However, the molecular mechanisms underlying the fine-tuned regulation of adipose tissue expansion are far from being understood.

A molecular switch for neuroprotective astrocyte reactivity.

The intrinsic mechanisms that regulate neurotoxic versus neuroprotective astrocyte phenotypes and their effects on central nervous system degeneration and repair remain poorly understood. Here we show that injured white matter astrocytes differentiate into two distinct C3-positive and C3-negative reactive populations, previously simplified as neurotoxic (A1) and neuroprotective (A2), which can be further subdivided into unique subpopulations defined by proliferation and differential gene expression signatures. We find the balance of neurotoxic versus neuroprotective astrocytes is regulated by discrete pools of compartmented cyclic adenosine monophosphate derived from soluble adenylyl cyclase and show that proliferating neuroprotective astrocytes inhibit microglial activation and downstream neurotoxic astrocyte differentiation to promote retinal ganglion cell survival.

Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2) and persistent pulmonary hypertension.

Arsenic induces metabolome remodeling in mature human adipocytes.

Human lifetime exposure to arsenic through drinking water, food supply or industrial pollution leads to its accumulation in many organs such as liver, kidneys, lungs or pancreas but also adipose tissue. Recently, population-based studies revealed the association between arsenic exposure and the development of metabolic diseases such as obesity and type 2 diabetes. To shed light on the molecular bases of such association, we determined the concentration that inhibited 17% of cell viability and investigated the effects of arsenic acute exposure on adipose-derived human mesenchymal stem cells differentiated in vitro into mature adipocytes and treated with sodium arsenite (NaAsO, 10 nM to 10 µM).

Plasmodium falciparum infection of human erythroblasts induces transcriptional changes associated with dyserythropoiesis.

During development down the erythroid lineage, hematopoietic stem cells undergo dramatic changes to cellular morphology and function in response to a complex and tightly regulated program of gene expression. In malaria infection, Plasmodium spp parasites accumulate in the bone marrow parenchyma, and emerging evidence suggests erythroblastic islands are a protective site for parasite development into gametocytes. Although it has been observed that Plasmodium falciparum infection in late-stage erythroblasts can delay terminal erythroid differentiation and enucleation, the mechanism(s) underlying this phenomenon are unknown.

Age-dependent Microglial Disease Phenotype Results in Functional Decline in Gut Macrophages.

Background And Aims: Muscularis macrophages (MMs) are tissue-resident macrophages in the gut muscularis externa which play a supportive role to the enteric nervous system. We have previously shown that age-dependent MM alterations drive low-grade enteric nervous system inflammation, resulting in neuronal loss and disruption of gut motility. The current studies were designed to identify the MM genetic signature involved in these changes, with particular emphasis on comparison to genes in microglia, the central nervous system macrophage population involved in age-dependent cognitive decline.

Effects of biomechanical and biochemical stimuli on angio- and vasculogenesis in a complex microvasculature-on-chip.

The endothelium of blood vessels is a vital organ that reacts differently to subtle changes in stiffness and mechanical forces exerted on its environment (extracellular matrix (ECM)). Upon alteration of these biomechanical cues, endothelial cells initiate signaling pathways that govern vascular remodeling. The emerging organs-on-chip technologies allow the mimicking of complex microvasculature networks, identifying the combined or singular effects of these biomechanical or biochemical stimuli.

Multi-omics microsampling for the profiling of lifestyle-associated changes in health.

Current healthcare practices are reactive and use limited physiological and clinical information, often collected months or years apart. Moreover, the discovery and profiling of blood biomarkers in clinical and research settings are constrained by geographical barriers, the cost and inconvenience of in-clinic venepuncture, low sampling frequency and the low depth of molecular measurements. Here we describe a strategy for the frequent capture and analysis of thousands of metabolites, lipids, cytokines and proteins in 10 μl of blood alongside physiological information from wearable sensors.

KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress.

Physiologic laminar shear stress (LSS) induces an endothelial gene expression profile that is vasculo-protective. In this report, we delineate how LSS mediates changes in the epigenetic landscape to promote this beneficial response. We show that under LSS, KLF4 interacts with the SWI/SNF nucleosome remodeling complex to increase accessibility at enhancer sites that promote the expression of homeostatic endothelial genes.

Deep learning-based pseudo-mass spectrometry imaging analysis for precision medicine.

Liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics provides systematic profiling of metabolic. Yet, its applications in precision medicine (disease diagnosis) have been limited by several challenges, including metabolite identification, information loss and low reproducibility. Here, we present the deep-learning-based Pseudo-Mass Spectrometry Imaging (deepPseudoMSI) project (https://www.

Immunofluorescent and molecular characterization of effusion tumor cells reveal cancer site-of-origin and disease-driving mutations.

Background: Effective cancer treatment relies on precision diagnostics. In cytology, an accurate diagnosis facilitates the determination of proper therapeutics for patients with cancer. Previously, the authors developed a multiplexed immunofluorescent panel to detect epithelial malignancies from pleural effusion specimens.

Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis.

Objective: Chronic pancreatitis (CP) is a potentially fatal disease of the exocrine pancreas, with no specific or effective approved therapies. Due to difficulty in accessing pancreas tissues, little is known about local immune responses or pathogenesis in human CP. We sought to characterise pancreatic immune responses using tissues derived from patients with different aetiologies of CP and non-CP organ donors in order to identify key signalling molecules associated with human CP.