Physiology and diseases of tissue-resident macrophages.

Embryo-derived tissue-resident macrophages are the first representatives of the haematopoietic lineage to emerge in metazoans. In mammals, resident macrophages originate from early yolk sac progenitors and are specified into tissue-specific subsets during organogenesis-establishing stable spatial and functional relationships with specialized tissue cells-and persist in adults. Resident macrophages are an integral part of tissues together with specialized cells: for instance, microglia reside with neurons in brain, osteoclasts reside with osteoblasts in bone, and fat-associated macrophages reside with white adipocytes in adipose tissue.

Targeting GITR in cancer immunotherapy - there is no perfect knowledge.

Glucocorticoid-induced TNFR-related protein (GITR) belongs to the TNFR superfamily (TNFRSF) and stimulates both the acquired and innate immunity. GITR is broadly expressed on immune cells, particularly regulatory T cells (Tregs) and natural killer (NK) cells. Given its potential to promote T effector function and impede Treg immune suppression, GITR is an attractive target for cancer immunotherapy.

Vitamin A and retinoid signaling in the kidneys.

Vitamin A (VA, retinol) and its metabolites (commonly called retinoids) are required for the proper development of the kidney during embryogenesis, but retinoids also play key roles in the function and repair of the kidney in adults. Kidneys filter 180-200 liters of blood per day and each kidney contains approximately 1 million nephrons, which are often referred to as the 'functional units' of the kidney. Each nephron consists of a glomerulus and a series of tubules (proximal tubule, loop of Henle, distal tubule, and collecting duct) surrounded by a network of capillaries.

Metabolism along the life journey of T cells.

T cells are one of few cell types in adult mammals that can proliferate extensively and differentiate diversely upon stimulation, which serves as an excellent example to dissect the metabolic basis of cell fate decisions. During the last decade, there has been an explosion of research into the metabolic control of T-cell responses. The roles of common metabolic pathways, including glycolysis, lipid metabolism, and mitochondrial oxidative phosphorylation, in T-cell responses have been well characterized, and their mechanisms of action are starting to emerge.

A transposase-derived gene required for human brain development.

DNA transposable elements and transposase-derived genes are present in most living organisms, including vertebrates, but their function is largely unknown. PiggyBac Transposable Element Derived 5 (PGBD5) is an evolutionarily conserved vertebrate DNA transposase-derived gene with retained nuclease activity in human cells. Vertebrate brain development is known to be associated with prominent neuronal cell death and DNA breaks, but their causes and functions are not well understood.

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.

Application of a Hermite-based measure of non-Gaussianity to normality tests and independent component analysis.

In the analysis of neural data, measures of non-Gaussianity are generally applied in two ways: as tests of normality for validating model assumptions and as Independent Component Analysis (ICA) contrast functions for separating non-Gaussian signals. Consequently, there is a wide range of methods for both applications, but they all have trade-offs. We propose a new strategy that, in contrast to previous methods, directly approximates the shape of a distribution via Hermite functions.

Human pluripotent-stem-cell-derived organoids for drug discovery and evaluation.

Human pluripotent stem cells (hPSCs) and three-dimensional organoids have ushered in a new era for disease modeling and drug discovery. Over the past decade, significant progress has been in deriving functional organoids from hPSCs, which have been applied to recapitulate disease phenotypes. In addition, these advancements have extended the application of hPSCs and organoids for drug screening and clinical-trial safety evaluations.

TAP-ing into the cross-presentation secrets of dendritic cells.

Viral blockade of the transporter associated with antigen processing (TAP) diminishes surface and endosomal recycling compartment levels of major histocompatibility complex class-I (MHC-I) in dendritic cells (DCs), and compromises both classical MHC-I presentation and canonical cross-presentation during infection to impair CD8 T-cell immunity. Virus-specific CD8 T cells are thought to be cross-primed mostly by uninfected TAP-sufficient DCs through cross-presentation of viral peptides from internalized virus-infected dying cells. The dilemma is that CD8 T cells primed to TAP-dependent viral peptides are mismatched to the TAP-independent epitopes presented on tissues infected with immune-evasive viruses.

Single-cell analysis of bidirectional reprogramming between early embryonic states reveals mechanisms of differential lineage plasticities.

Two distinct fates, pluripotent epiblast (EPI) and primitive (extra-embryonic) endoderm (PrE), arise from common progenitor cells, the inner cell mass (ICM), in mammalian embryos. To study how these sister identities are forged, we leveraged embryonic (ES) and etraembryonic doderm (XEN) stem cells - counterparts of the EPI and PrE. Bidirectional reprogramming between ES and XEN coupled with single-cell RNA and ATAC-seq analyses uncovered distinct rates, efficiencies and trajectories of state conversions, identifying drivers and roadblocks of reciprocal conversions.

Power spectral analysis can determine language laterality from resting-state functional MRI data in healthy controls.

Background And Purpose: Resting-state functional magnetic resonance imaging (rsfMRI) has been proposed as an alternative to task-based fMRI including clinical situations such as preoperative brain tumor planning, due to advantages including ease of performance and time savings. However, one of its drawbacks is the limited ability to accurately lateralize language function.

Methods: Using the rsfMRI data of healthy controls, we carried out a power spectra analysis on three regions of interest (ROIs): Broca's area (BA) in the frontal cortex for language, hand motor (HM) area in the primary motor cortex, and the primary visual cortex (V1).

ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer.

The mechanisms underlying -driven prostate cancer initiation and progression remain poorly understood due to a lack of model systems that recapitulate this phenotype. We generated a genetically engineered mouse with prostate-specific expression of the factor, ETV4, at lower and higher protein dosage through mutation of its degron. Lower-level expression of ETV4 caused mild luminal cell expansion without histologic abnormalities, and higher-level expression of stabilized ETV4 caused prostatic intraepithelial neoplasia (mPIN) with 100% penetrance within 1 week.

Immunoglobulins at the interface of the gut mycobiota and anti-fungal immunity.

The dynamic and complex community of microbes that colonizes the intestines is composed of bacteria, fungi, and viruses. At the mucosal surfaces, immunoglobulins play a key role in protection against bacterial and fungal pathogens, and their toxins. Secretory immunoglobulin A (sIgA) is the most abundantly produced antibody at the mucosal surfaces, while Immunoglobulin G (IgG) isotypes play a critical role in systemic protection.

Evolution of promoter-proximal pausing enabled a new layer of transcription control.

Promoter-proximal pausing of RNA polymerase II (Pol II) is a key regulatory step during transcription. Despite the central role of pausing in gene regulation, we do not understand the evolutionary processes that led to the emergence of Pol II pausing or its transition to a rate-limiting step actively controlled by transcription factors. Here we analyzed transcription in species across the tree of life.

Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors.

Immunotherapy is the standard of care for several cancers and the field continues to advance at a rapid pace, with novel combinations leading to indications in an increasing number of disease settings. Durable responses and long-term survival with immunotherapy have been demonstrated in some patients, though lack of initial benefit and recurrence after extended disease control remain major hurdles for the field. Many new combination regimens are in development for patients whose disease progressed on initial immunotherapy.

P-selectin-targeted nanocarriers induce active crossing of the blood-brain barrier via caveolin-1-dependent transcytosis.

Medulloblastoma is the most common malignant paediatric brain tumour, with ~30% mediated by Sonic hedgehog signalling. Vismodegib-mediated inhibition of the Sonic hedgehog effector Smoothened inhibits tumour growth but causes growth plate fusion at effective doses. Here, we report a nanotherapeutic approach targeting endothelial tumour vasculature to enhance blood-brain barrier crossing.

Drosophila Tropomodulin is required for multiple actin-dependent processes within developing myofibers.

Proper muscle contraction requires the assembly and maintenance of sarcomeres and myofibrils. Although the protein components of myofibrils are generally known, less is known about the mechanisms by which they individually function and together synergize for myofibril assembly and maintenance. For example, it is unclear how the disruption of actin filament (F-actin) regulatory proteins leads to the muscle weakness observed in myopathies.

L-type calcium channels and neuropsychiatric diseases: Insights into genetic risk variant-associated genomic regulation and impact on brain development.

Recent human genetic studies have linked a variety of genetic variants in the and genes to neuropsychiatric and neurodevelopmental disorders. This is not surprising given the work from multiple laboratories using cell and animal models that have established that Ca1.2 and Ca1.

Principles of regulatory T cell function.

Regulatory T (Treg) cells represent a distinct lineage of cells of the adaptive immune system indispensable for forestalling fatal autoimmune and inflammatory pathologies. The role of Treg cells as principal guardians of the immune system can be attributed to their ability to restrain all currently recognized major types of inflammatory responses through modulating the activity of a wide range of cells of the innate and adaptive immune system. This broad purview over immunity and inflammation is afforded by the multiple modes of action Treg cells exert upon their diverse molecular and cellular targets.

Bone marrow Adipoq-lineage progenitors are a major cellular source of M-CSF that dominates bone marrow macrophage development, osteoclastogenesis, and bone mass.

M-CSF is a critical growth factor for myeloid lineage cells, including monocytes, macrophages, and osteoclasts. Tissue-resident macrophages in most organs rely on local M-CSF. However, it is unclear what specific cells in the bone marrow produce M-CSF to maintain myeloid homeostasis.

Screening for bilayer-active and likely cytotoxic molecules reveals bilayer-mediated regulation of cell function.

A perennial problem encountered when using small molecules (drugs) to manipulate cell or protein function is to assess whether observed changes in function result from specific interactions with a desired target or from less specific off-target mechanisms. This is important in laboratory research as well as in drug development, where the goal is to identify molecules that are unlikely to be successful therapeutics early in the process, thereby avoiding costly mistakes. We pursued this challenge from the perspective that many bioactive molecules (drugs) are amphiphiles that alter lipid bilayer elastic properties, which may cause indiscriminate changes in membrane protein (and cell) function and, in turn, cytotoxicity.

Novel extragenic genomic safe harbors for precise therapeutic T-cell engineering.

Cell therapies that rely on engineered immune cells can be enhanced by achieving uniform and controlled transgene expression in order to maximize T-cell function and achieve predictable patient responses. Although they are effective, current genetic engineering strategies that use γ-retroviral, lentiviral, and transposon-based vectors to integrate transgenes, unavoidably produce variegated transgene expression in addition to posing a risk of insertional mutagenesis. In the setting of chimeric antigen receptor (CAR) therapy, inconsistent and random CAR expression may result in tonic signaling, T-cell exhaustion, and variable T-cell persistence.

Optimized M24B Aminopeptidase Inhibitors for CARD8 Inflammasome Activation.

Inflammasomes are innate immune signaling platforms that trigger pyroptotic cell death. NLRP1 and CARD8 are related human inflammasomes that detect similar danger signals, but NLRP1 has a higher activation threshold and triggers a more inflammatory form of pyroptosis. Both sense the accumulation of intracellular peptides with Xaa-Pro N-termini, but Xaa-Pro peptides on their own without a second danger signal only activate the CARD8 inflammasome.