murine-mesenteric-lymphadenectomy-for-selective-disruption-lymphatic

Murine Mesenteric Lymphadenectomy for Selective Disruption of Lymphatic Communication with Region-Specific Gut

Immunosurveillance versus antigen-tolerance is a fine balance within the gut microenvironment, during which the critical role of circulating T cell ...

Yale University School of Medicine

The aim of this study is to evaluate the application of magnetic resonance imaging (MRI) to assess ovarian maturation in live female Rhinogobio ventralis (Sauvage & Dabry de Thiersant, 1874). The fish were randomly collected from the Jiangjin area of the Yangtze River between January and April 2014. Magnetic resonance imaging was performed using a 3.0 T clinical MRI scanner with a brain coil and two pulse sequences (IDEAL and 3D CUBE) were employed. Magnetic resonance and histologic images at different stages of ovarian maturation (I-IV) were acquired. An empirical equation (y = -0.1 + 1.56 × x) was derived by traditional method to describe the relationship between the gonadosomatic index (y) and the percentage volume of the ovary (x). A significant correlation (R(2) = 0.977, P < 0.01, N = 53) was found between measurements of the percentage volume of the ovary by MRI and traditional methods. The research findings suggested that MRI was a reliable, rapid, and noninvasive method to assess stages of ovarian maturity in female R. ventralis.

Use of magnetic resonance imaging to assess ovarian maturation in live Rhinogobio ventralis (Sauvage & Dabry de Thiersant, 1874).

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

In vivo models that recapitulate human erythropoiesis with persistence of circulating red blood cells (RBCs) have remained elusive. We report an immunodeficient murine model in which combined human liver and cytokine humanization confer enhanced human erythropoiesis and RBC survival in the circulation. We deleted the fumarylacetoacetate hydrolase () gene in MISTRG mice expressing several human cytokines in place of their murine counterparts. Liver humanization by intrasplenic injection of human hepatocytes (huHep) eliminated murine complement C3 and reduced murine Kupffer cell density. Engraftment of human sickle cell disease (SCD)-derived hematopoietic stem cells in huHepMISTRG  mice resulted in vaso-occlusion that replicated acute SCD pathology. Combined liver-cytokine-humanized mice will facilitate the study of diseases afflicting RBCs, including bone marrow failure, hemoglobinopathies, and malaria, and also preclinical testing of therapies.

Combined liver-cytokine humanization comes to the rescue of circulating human red blood cells.

Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context. The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping, but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry and microfluidic deterministic barcoding. Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease.

Spatial profiling of chromatin accessibility in mouse and human tissues.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Although the role of cellular immunity in checkpoint immunotherapy (CPI) for cancer is well established, the effect of antibody-mediated humoral immunity is comparably underexplored. Here we used rapid extracellular antigen profiling to map the autoantibody reactome within a cohort of 374 patients with cancer treated with CPIs and 131 healthy control participants for autoantibodies to 6,172 extracellular and secreted proteins (the 'exoproteome'). Globally, patients with cancer treated with CPIs had diverse autoreactivities that were elevated relative to control individuals but changed minimally with treatment. Autoantibody signatures in patients treated with CPI strikingly distinguished them from healthy individuals. Although associations of specific autoantibodies with immune-related adverse events were sparse, we detected numerous individual autoantibodies that were associated with greatly altered odds ratios for response to therapy. These included autoantibodies to immunomodulatory proteins, such as cytokines, growth factors and immunoreceptors, as well as tumour surface proteins. Functional evaluation of several autoantibody responses indicated that they neutralized the activity of their target proteins, which included type I interferons (IFN-I), IL-6, OSM, TL1A, and BMPR1A and BMPR2. Modelling the effects of autoantibodies to IFN-I and TL1A in preclinical mouse tumour models resulted in enhanced CPI efficacy, consistent with their effects in patients. In conclusion, these findings indicate that autoantibodies to the exoproteome modify CPI responses and highlight therapeutically actionable pathways that can be exploited to augment immunotherapy.

Article	Year
Use of magnetic resonance imaging to assess ovarian maturation in live Rhinogobio ventralis (Sauvage & Dabry de Thiersant, 1874). Theriogenology\| PubMed ID: 27481814	2016
International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci. Nature communications\| PubMed ID: 31594949	2019
Combined liver-cytokine humanization comes to the rescue of circulating human red blood cells. Science (New York, N.Y.)\| PubMed ID: 33674488	2021
Spatial profiling of chromatin accessibility in mouse and human tissues. Nature\| PubMed ID: 35978191	2022
Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder. Nature genetics\| PubMed ID: 38637617	2024
Humoral determinants of checkpoint immunotherapy. Nature\| PubMed ID: 40702172	2025

Y. Qin

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