Complex regulation of Gephyrin splicing is a determinant of inhibitory postsynaptic diversity.

Gephyrin (GPHN) regulates the clustering of postsynaptic components at inhibitory synapses and is involved in pathophysiology of neuropsychiatric disorders. Here, we uncover an extensive diversity of GPHN transcripts that are tightly controlled by splicing during mouse and human brain development. Proteomic analysis reveals at least a hundred isoforms of GPHN incorporated at inhibitory Glycine and gamma-aminobutyric acid A receptors containing synapses.

Widespread genomic signatures of reproductive isolation and sex-specific selection in the Eastern Yellow Robin, Eopsaltria australis.

How new species evolve is one of the most fundamental questions in biology. Population divergence, which may lead to speciation, may be occurring in the Eastern Yellow Robin, a common passerine that lives along the eastern coast of Australia. This species is composed of 2 parapatric lineages that have highly divergent mitochondrial DNA; however, similar levels of divergence have not been observed in the nuclear genome.

Targeted LC-MS/MS-based metabolomics and lipidomics on limited hematopoietic stem cell numbers.

Metabolism is important for the regulation of hematopoietic stem cells (HSCs) and drives cellular fate. Due to the scarcity of HSCs, it has been technically challenging to perform metabolome analyses gaining insight into HSC metabolic regulatory networks. Here, we present two targeted liquid chromatography-mass spectrometry approaches that enable the detection of metabolites after fluorescence-activated cell sorting when sample amounts are limited.

Developmental dynamics of two bipotent thymic epithelial progenitor types.

T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naive T cell production with age. Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved.

Neutrophils: Amoeboid Migration and Swarming Dynamics in Tissues.

Neutrophils are key cells of our innate immune response with essential roles for eliminating bacteria and fungi from tissues. They are also the prototype of an amoeboid migrating leukocyte. As one of the first blood-recruited immune cell types during inflammation and infection, these cells can invade almost any tissue compartment.

Specification of CNS macrophage subsets occurs postnatally in defined niches.

All tissue-resident macrophages of the central nervous system (CNS)-including parenchymal microglia, as well as CNS-associated macrophages (CAMs) such as meningeal and perivascular macrophages-are part of the CNS endogenous innate immune system that acts as the first line of defence during infections or trauma. It has been suggested that microglia and all subsets of CAMs are derived from prenatal cellular sources in the yolk sac that were defined as early erythromyeloid progenitors. However, the precise ontogenetic relationships, the underlying transcriptional programs and the molecular signals that drive the development of distinct CAM subsets in situ are poorly understood.

Regulation of neuronal RNA signatures by ELAV/Hu proteins.

The RNA-binding proteins encoded by the highly conserved elav/Hu gene family, found in all metazoans, regulate the expression of a wide range of genes, at both the co-transcriptional and posttranscriptional level. Nervous-system-specific ELAV/Hu proteins are prominent for their essential role in neuron differentiation, and mutations have been associated with human neurodevelopmental and neurodegenerative diseases. Drosophila ELAV, the founding member of the protein family, mediates the synthesis of neuronal RNA signatures by promoting alternative splicing and alternative polyadenylation of hundreds of genes.

automRm: An R Package for Fully Automatic LC-QQQ-MS Data Preprocessing Powered by Machine Learning.

Preprocessing of liquid chromatography-mass spectrometry (LC-MS) raw data facilitates downstream statistical and biological data analyses. In the case of targeted LC-MS data, consistent recognition of chromatographic peaks is a main challenge, in particular, for low abundant signals. Fully automatic preprocessing is faster than manual peak review and does not depend on the individual operator.

Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches.

Reinvigoration of exhausted CD8 T (Tex) cells by checkpoint immunotherapy depends on the activation of precursors of exhausted T (Tpex) cells, but the local anatomical context of their maintenance, differentiation, and interplay with other cells is not well understood. Here, we identified transcriptionally distinct Tpex subpopulations, mapped their differentiation trajectories via transitory cellular states toward Tex cells, and localized these cell states to specific splenic niches. Conventional dendritic cells (cDCs) were critical for successful αPD-L1 therapy and were required to mediate viral control.

100 Hz ROCS microscopy correlated with fluorescence reveals cellular dynamics on different spatiotemporal scales.

Fluorescence techniques dominate the field of live-cell microscopy, but bleaching and motion blur from too long integration times limit dynamic investigations of small objects. High contrast, label-free life-cell imaging of thousands of acquisitions at 160 nm resolution and 100 Hz is possible by Rotating Coherent Scattering (ROCS) microscopy, where intensity speckle patterns from all azimuthal illumination directions are added up within 10 ms. In combination with fluorescence, we demonstrate the performance of improved Total Internal Reflection (TIR)-ROCS with variable illumination including timescale decomposition and activity mapping at five different examples: millisecond reorganization of macrophage actin cortex structures, fast degranulation and pore opening in mast cells, nanotube dynamics between cardiomyocytes and fibroblasts, thermal noise driven binding behavior of virus-sized particles at cells, and, bacterial lectin dynamics at the cortex of lung cells.

Macrophage network dynamics depend on haptokinesis for optimal local surveillance.

Macrophages are key immune cells with important roles for tissue surveillance in almost all mammalian organs. Cellular networks made up of many individual macrophages allow for optimal removal of dead cell material and pathogens in tissues. However, the critical determinants that underlie these population responses have not been systematically studied.

The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming.

Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling.

Exploring the biological behavior of Heat shock protein (HSPs) for understanding the Anti-ischemic stroke in humans.

Background: An ischemic stroke can be caused by thrombosis and ischemia, which is a major public health problem around the world, resulting in severe disability and a high death rate. The goal of this work is to examine and target various heat shock proteins (HSPs) via their interacting partners, which may have an anti-ischemic stroke impact.

Methods: Various heat shock proteins are identified and used for construction of PPI network through STRING webserver.

How to resist Notch-targeted T-leukemia therapy: Lineage- and MYC enhancer switch.

Gain-of-function NOTCH1 mutations drive oncogenic MYC expression in T-ALL cells. Zhou et al. (2022) reveal that Notch-targeted therapy-resistant T-ALL cells activate EBF1, which promotes a T-to-B lineage shift and maintains oncogenic MYC expression in the absence of Notch signaling.

Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N-carboxymethyllysine.

Microglial function declines during aging. The interaction of microglia with the gut microbiota has been well characterized during development and adulthood but not in aging. Here, we compared microglial transcriptomes from young-adult and aged mice housed under germ-free and specific pathogen-free conditions and found that the microbiota influenced aging associated-changes in microglial gene expression.

Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.

Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, myelination, and synapse formation. Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity.

Transposable Elements in the Genome of the Lichen-Forming Fungus and Their Distribution in Different Climate Zones along Elevation.

Transposable elements (TEs) are an important source of genome plasticity across the tree of life. Drift and natural selection are important forces shaping TE distribution and accumulation. Fungi, with their multifaceted phenotypic diversity and relatively small genome size, are ideal models to study the role of TEs in genome evolution and their impact on the host's ecological and life history traits.

Modulation of cellular processes by histone and non-histone protein acetylation.

Lysine acetylation is a widespread and versatile protein post-translational modification. Lysine acetyltransferases and lysine deacetylases catalyse the addition or removal, respectively, of acetyl groups at both histone and non-histone targets. In this Review, we discuss several features of acetylation and deacetylation, including their diversity of targets, rapid turnover, exquisite sensitivity to the concentrations of the cofactors acetyl-CoA, acyl-CoA and NAD, and tight interplay with metabolism.

Cold case: The disappearance of Egypt bee virus, a fourth distinct master strain of deformed wing virus linked to honeybee mortality in 1970's Egypt.

In 1977, a sample of diseased adult honeybees (Apis mellifera) from Egypt was found to contain large amounts of a previously unknown virus, Egypt bee virus, which was subsequently shown to be serologically related to deformed wing virus (DWV). By sequencing the original isolate, we demonstrate that Egypt bee virus is in fact a fourth unique, major variant of DWV (DWV-D): more closely related to DWV-C than to either DWV-A or DWV-B. DWV-A and DWV-B are the most common DWV variants worldwide due to their close relationship and transmission by Varroa destructor.

Stress - Regulation of SUMO conjugation and of other Ubiquitin-Like Modifiers.

Stress is unavoidable and essential to cellular and organismal evolution and failure to adapt or restore homeostasis can lead to severe diseases or even death. At the cellular level, stress drives a plethora of molecular changes, of which variations in the profile of protein post-translational modifications plays a key role in mediating the adaptative response of the genome and proteome to stress. In this context, post-translational modification of proteins by ubiquitin-like modifiers, (Ubl), notably SUMO, is an essential stress response mechanism.

Defective Allelic Exclusion by IgD in the Absence of Autoantigen.

A considerable proportion of peripheral B cells is autoreactive, and it is unclear how the activation of such potentially harmful cells is regulated. In this study, we show that the different activation thresholds or IgM and IgD BCRs adjust B cell activation to the diverse requirements during development. We rely on the autoreactive 3-83 model BCR to generate and analyze mice expressing exclusively autoreactive IgD BCRs on two different backgrounds that determine two stages of autoreactivity, depending on the presence or absence of the cognate Ag.

Gab2 deficiency prevents Flt3-ITD driven acute myeloid leukemia in vivo.

Internal tandem duplications (ITD) of the FMS-like tyrosine kinase 3 (FLT3) predict poor prognosis in acute myeloid leukemia (AML) and often co-exist with inactivating DNMT3A mutations. In vitro studies implicated Grb2-associated binder 2 (GAB2) as FLT3-ITD effector. Utilizing a Flt3-ITD knock-in, Dnmt3a haploinsufficient mouse model, we demonstrate that Gab2 is essential for the development of Flt3-ITD driven AML in vivo, as Gab2 deficient mice displayed prolonged survival, presented with attenuated liver and spleen pathology and reduced blast counts.

Sensing Stemness.

Purpose Of Review: Hematopoietic stem cells (HSCs) are formed embryonically during a dynamic developmental process and later reside in adult hematopoietic organs in a quiescent state. In response to their changing environment, HSCs have evolved diverse mechanisms to cope with intrinsic and extrinsic challenges. This review intends to discuss how HSCs and other stem cells co-opted DNA and RNA innate immune pathways to fine-tune developmental processes.