New Horizons: Translational Aspects of Osteomorphs.

Osteomorphs are a newly described osteoclast lineage cell in mice, which are suggested to play a significant role in the maintenance of bone resorption. Preclinical investigations revealed that osteomorphs are generated through the fission of multinucleated bone-resorbing osteoclasts and can also re-fuse with existing osteoclasts. Modifications to RANKL signaling have been shown to alter cycles of fission and re-fusion of osteomorphs in mice.

Epinephrine inhibits PI3Kα via the Hippo kinases.

The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes.

3D Enhancer-promoter networks provide predictive features for gene expression and coregulation in early embryonic lineages.

Mammalian embryogenesis commences with two pivotal and binary cell fate decisions that give rise to three essential lineages: the trophectoderm, the epiblast and the primitive endoderm. Although key signaling pathways and transcription factors that control these early embryonic decisions have been identified, the non-coding regulatory elements through which transcriptional regulators enact these fates remain understudied. Here, we characterize, at a genome-wide scale, enhancer activity and 3D connectivity in embryo-derived stem cell lines that represent each of the early developmental fates.

T1-Weighted, Dynamic Contrast-Enhanced MR Perfusion Imaging Can Differentiate between Treatment Success and Failure in Spine Metastases Undergoing Radiation Therapy.

Background And Purpose: Current imaging techniques have difficulty differentiating treatment success and failure in spinal metastases undergoing radiation therapy. This study investigated the correlation between changes in dynamic contrast-enhanced MR imaging perfusion parameters and clinical outcomes following radiation therapy for spinal metastases. We hypothesized that perfusion parameters will outperform traditional size measurements in discriminating treatment success and failure.

A cholesterol switch controls phospholipid scrambling by G protein-coupled receptors.

Class A G protein-coupled receptors (GPCRs), a superfamily of cell membrane signaling receptors, moonlight as constitutively active phospholipid scramblases. The plasma membrane of metazoan cells is replete with GPCRs, yet has a strong resting trans-bilayer phospholipid asymmetry, with the signaling lipid phosphatidylserine confined to the cytoplasmic leaflet. To account for the persistence of this lipid asymmetry in the presence of GPCR scramblases, we hypothesized that GPCR-mediated lipid scrambling is regulated by cholesterol, a major constituent of the plasma membrane.

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission.

Cofilin, an actin severing protein, plays critical roles in muscle sarcomere addition and maintenance. Our previous work has shown cofilin () knockdown causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy (NM) caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by knockdown would impact other aspects of muscle development, and, thus, conducted an RNA sequencing analysis which unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes.

Optimization of a cardiomyocyte model illuminates role of increased in repolarization reserve.

Cardiac ion currents may compensate for each other when one is compromised by a congenital or drug-induced defect. Such redundancy contributes to a robust repolarization reserve that can prevent the development of lethal arrhythmias. Most efforts made to describe this phenomenon have quantified contributions by individual ion currents.

Bridging the Translational Gap in Heart Failure Research: Using Human iPSC-derived Cardiomyocytes to Accelerate Therapeutic Insights.

Heart failure (HF) remains a leading cause of death worldwide, with increasing prevalence and burden. Despite extensive research, a cure for HF remains elusive. Traditionally, the study of HF's pathogenesis and therapies has relied heavily on animal experimentation.

The show and tell of cross-presentation.

Cross-presentation is the culmination of complex subcellular processes that allow the processing of exogenous proteins and the presentation of resultant peptides on major histocompatibility class I (MHC-I) molecules to CD8 T cells. Dendritic cells (DCs) are a cell type that uniquely specializes in cross-presentation, mainly in the context of viral or non-viral infection and cancer. DCs have an extensive network of endovesicular pathways that orchestrate the biogenesis of an ideal cross-presentation compartment where processed antigen, MHC-I molecules, and the MHC-I peptide loading machinery all meet.

Essential roles of the ANKRD31-REC114 interaction in meiotic recombination and mouse spermatogenesis.

Meiotic DNA double-strand breaks (DSBs) initiate homologous recombination and are crucial for ensuring proper chromosome segregation. In mice, ANKRD31 recently emerged as a regulator of DSB timing, number, and location, with a particularly important role in targeting DSBs to the pseudoautosomal regions (PARs) of sex chromosomes. ANKRD31 interacts with multiple proteins, including the conserved and essential DSB-promoting factor REC114, so it was hypothesized to be a modular scaffold that "anchors" other proteins together and to meiotic chromosomes.

Reprogramming tumor-associated macrophages to outcompete endovascular endothelial progenitor cells and suppress tumor neoangiogenesis.

Tumors develop by invoking a supportive environment characterized by aberrant angiogenesis and infiltration of tumor-associated macrophages (TAMs). In a transgenic model of breast cancer, we found that TAMs localized to the tumor parenchyma and were smaller than mammary tissue macrophages. TAMs had low activity of the metabolic regulator mammalian/mechanistic target of rapamycin complex 1 (mTORC1), and depletion of negative regulator of mTORC1 signaling, tuberous sclerosis complex 1 (TSC1), in TAMs inhibited tumor growth in a manner independent of adaptive lymphocytes.

Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

Ovarian-derived estrogen is a key modulator of numerous physiological processes via genomic and nongenomic mechanisms, including signaling non-canonically at membrane-associated estrogen receptors in the brain to rapidly regulate neuronal function. However, the mechanisms mediating estrogen regulation of behaviors such as alcohol consumption remain unclear. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen levels, but a causal role for estrogen signaling in driving alcohol drinking in gonadally-intact animals has not been established.

Decoding Heterogenous Single-cell Perturbation Responses.

Understanding diverse responses of individual cells to the same perturbation is central to many biological and biomedical problems. Current methods, however, do not precisely quantify the strength of perturbation responses and, more importantly, reveal new biological insights from heterogeneity in responses. Here we introduce the perturbation-response score (PS), based on constrained quadratic optimization, to quantify diverse perturbation responses at a single-cell level.

Sex differences in binge alcohol drinking and the behavioral consequences of protracted abstinence in C57BL/6J mice.

Background: Binge alcohol drinking is a risk factor linked to numerous disease states including alcohol use disorder (AUD). While men binge drink more alcohol than women, this demographic gap is quickly shrinking, and preclinical studies demonstrate that females consistently consume more alcohol than males. Further, women are at increased risk for the co-expression of AUD with neuropsychiatric diseases such as anxiety and mood disorders.

Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders.

DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through stimulator of interferon genes (STING) activation. IFN-I cytokines are essential in mediating neuroinflammation, which is widely observed in CNS injury, neurodegeneration, and aging, suggesting an upstream role for the cGAS DNA sensing pathway.

Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma.

Unlabelled: Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but the clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells.

Molecular basis for Nse5-6 mediated regulation of Smc5/6 functions.

The Smc5/6 complex (Smc5/6) is important for genome replication and repair in eukaryotes. Its cellular functions are closely linked to the ATPase activity of the Smc5 and Smc6 subunits. This activity requires the dimerization of the motor domains of the two SMC subunits and is regulated by the six non-SMC subunits (Nse1 to Nse6).

Structural titration reveals Ca-dependent conformational landscape of the IP receptor.

Inositol 1,4,5-trisphosphate receptors (IPRs) are endoplasmic reticulum Ca channels whose biphasic dependence on cytosolic Ca gives rise to Ca oscillations that regulate fertilization, cell division and cell death. Despite the critical roles of IPR-mediated Ca responses, the structural underpinnings of the biphasic Ca dependence that underlies Ca oscillations are incompletely understood. Here, we collect cryo-EM images of an IPR with Ca concentrations spanning five orders of magnitude.

A Survey of Publicly Available MRI Datasets for Potential Use in Artificial Intelligence Research.

Artificial intelligence (AI) has the potential to bring transformative improvements to the field of radiology; yet, there are barriers to widespread clinical adoption. One of the most important barriers has been access to large, well-annotated, widely representative medical image datasets, which can be used to accurately train AI programs. Creating such datasets requires time and expertise and runs into constraints around data security and interoperability, patient privacy, and appropriate data use.

Impaired T cell IRE1α/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune pathophysiology. Using a 2-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occurred concomitantly with cardiac pathology and that diastolic dysfunction, cardiomyocyte hypertrophy, and cardiac phospholamban phosphorylation were T cell dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the inositol-requiring enzyme 1α/X-box-binding protein 1 (IRE1α/XBP1) arm of the unfolded protein response.

Fungal microbiota sustains lasting immune activation of neutrophils and their progenitors in severe COVID-19.

Gastrointestinal fungal dysbiosis is a hallmark of several diseases marked by systemic immune activation. Whether persistent pathobiont colonization during immune alterations and impaired gut barrier function has a durable impact on host immunity is unknown. We found that elevated levels of Candida albicans immunoglobulin G (IgG) antibodies marked patients with severe COVID-19 (sCOVID-19) who had intestinal Candida overgrowth, mycobiota dysbiosis and systemic neutrophilia.

Dectin-1/CARD9 induction of the TFEB and TFE3 gene network is dispensable for phagocyte anti- activity in the lung.

Myeloid phagocytes of the respiratory immune system, such as neutrophils, monocytes, and alveolar macrophages, are essential for immunity to , the most common etiologic agent of mold pneumonia worldwide. Following the engulfment of conidia, fusion of the phagosome with the lysosome is a critical process for killing conidia. TFEB and TFE3 are transcription factors that regulate lysosomal biogenesis under stress and are activated by inflammatory stimuli in macrophages, but it is unknown whether TFEB and TFE3 contribute to anti- immunity during infection.

Cardinal features of immune memory in innate lymphocytes.

The ability of vertebrates to 'remember' previous infections had once been attributed exclusively to adaptive immunity. We now appreciate that innate lymphocytes also possess memory properties akin to those of adaptive immune cells. In this Review, we draw parallels from T cell biology to explore the key features of immune memory in innate lymphocytes, including quantity, quality, and location.

Oncogenic context shapes the fitness landscape of tumor suppression.

Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R.