The Genetics and Learning Disorders of the Syndromes Involving Craniosynostosis

Prenatal genetic vehicles that lead to facial and cranial dysmorphias, specifically craniosynostosis, are seen in a spectrum of synostotic syndromes that include apert, crouzon, Kleeblattschadel deformity, saethre-chotzen, muenke, cranio-fronto-nasal syndrome, Robinow-Sorauf syndrome and beare-stevenson-cutis-gyrata syndrome. Specific genes involved in cranio-synostotic syndromes include: TWIST1, EFNB1, GLI2, DMD, YWHAE, IRAK2, FGFR1, FGFR2, FGFR3, CNTNAP2, ADAMTS18, SKI, MECP2, KIFBP, TCF12, H2AL1P, GAGE12D and possibly HDAC9. Regarding protein expression, conserved domains found in rpsblast for craniosynostosis using the NCBI homologene tool show IGc2 (smart00408) immunoglobulin C-2 Type, PKc_like (cl09925) Protein Kinases, catalytic domain, Ig (cl11960) Immunoglobulin domain. A discussion of all the syndromes involving craniosynostosis is beyond the scope of this paper. We will discuss the clinical features, genetics, cognitive development and associated psychiatric conditions of the more common syndromes involving craniosynostosis. We theorize that the clinical features and genetics of craniosynostosis involve a spectrum of syndromes on which there is variable severity and involvement of impaired cognition and developmental disorders.

VSIG10 expression associates with survival in triple negative breast cancer.

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of V-set and immunoglobulin domain-containing 10, encoded by VSIG10 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, VSIG10 expression was significantly correlated with recurrence-free survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. VSIG10 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

B7 Family Molecule VSIG4 Regulates Intestinal Anti-Enterohemorrhagic Escherichia coli Immunity by Altering Gut Flora Diversity

As an essential member of the B7 family, V-set and immunoglobulin domain-containing 4 (VSIG4) is expressed explicitly in tissue-resident macrophages (TRMs) and plays an essential role in maintaining the homeostasis of the environmental immune system. Here, we demonstrate that gene-targeted VSIG4-deficient mice infected with Enterohemorrhagic Escherichia coli (EHEC) display reduced bacterial burden. To reveal the role of VSIG4 in the fight against EHEC infection, we collected mice feces and used high-throughput 16S rRNA gene amplicons to detect changes in the flora. A total of 657330 sequences were sequenced on the PacBio platform, with an average length of 1498 bp. We found that VSIG4 deficiency could alter the gut microbiota by increasing diversity and shifting community composition. In particular, G_Akkermansia and G_Oscillo spiraceae increased significantly. These findings expand upon a prior observation that VSIG4 deficiency reduced EHEC colonization by changing the gut microbiota diversity and shifting community composition.

Diagnostic potential of serum extracellular vesicles expressing prostate-specific membrane antigen in urologic malignancies

We aimed to develop a sandwich ELISA to detect prostate-specific membrane antigen (PSMA) on small extracellular vesicles (EVs) using T-cell immunoglobulin domain and mucin domain-containing protein 4 (Tim4) as a capture molecule for EVs and to evaluate its diagnostic potential in urologic malignancies. First, we optimized the conditions for sandwich ELISA measuring the PSMA level on EVs captured from serum by Tim4 and found that the use of highly-purified EVs released from Tim4 that had captured EVs in serum reduced the background. Second, we confirmed its validity by studying mouse xenograft model for prostate cancer (PC). Lastly, we measured PSMA-EVs in serum of patients with urologic malignancies. The PSMA-EV levels were significantly higher in metastatic PC and castration-resistant PC (CRPC) patients than in therapy-naïve PC patients. In renal cell carcinoma (RCC) patients, PSMA-EVs were elevated in those with metastasis compared with those without metastasis, which may reflect the development of the neovasculature positive for PSMA in tumors. In conclusion, we developed a sandwich ELISA for detection of PSMA-EVs using highly-purified EVs isolated from serum by Tim4. Our results suggest that PSMA-EVs may be useful to diagnose and monitor not only PC but also RCC and possibly other hypervascular solid tumors.

Holosteans contextualize the role of the teleost genome duplication in promoting the rise of evolutionary novelties in the ray-finned fish innate immune system

Over 99% of ray-finned fishes (Actinopterygii) are teleosts, a clade that comprises half of all living vertebrates that have diversified across virtually all fresh and saltwater ecosystems. This ecological diversity raises the question of how the immunogenetic diversity required to persist under heterogeneous pathogen pressures evolved. The teleost genome duplication (TGD) has been hypothesized as the evolutionary event that provided the genomic substrate for rapid genomic evolution and innovation. However, studies of putative teleost-specific innate immune receptors have been largely limited to comparisons either among teleosts or between teleosts and distantly related vertebrate clades such as tetrapods. Here we describe and characterize the receptor diversity of two clustered innate immune gene families in the teleost sister lineage: Holostei (bowfin and gars). Using genomic and transcriptomic data, we provide a detailed investigation of the phylogenetic history and conserved synteny of gene clusters encoding diverse immunoglobulin domain-containing proteins (DICPs) and novel immune-type receptors (NITRs). These data demonstrate an ancient linkage of DICPs to the major histocompatibility complex (MHC) and reveal an evolutionary origin of NITR variable-joining (VJ) exons that predate the TGD by at least 50 million years. Further characterizing the receptor diversity of Holostean DICPs and NITRs illuminates a sequence diversity that rivals the diversity of these innate immune receptor families in many teleosts. Taken together, our findings provide important historical context for the evolution of these gene families that challenge prevailing expectations concerning the consequences of the TGD during actinopterygiian evolution.

VISTA regulates microglia homeostasis and myelin phagocytosis, and is associated with MS lesion pathology

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) that is involved in T-cell quiescence, inhibition of T-cell activation, and in myeloid cells regulates cytokine production, chemotaxis, phagocytosis, and tolerance induction. In the central nervous system (CNS), VISTA is expressed by microglia, the resident macrophage of the parenchyma, and expression is decreased during neuroinflammation; however, the function of VISTA in microglia is unknown. Here, we extensively analyzed VISTA expression in different MS lesion stages and characterized the function of VISTA in the CNS by deleting VISTA in microglia. VISTA is differentially expressed in distinct MS lesion stages. In mice, VISTA deletion in Cx3Cr1-expressing cells induced a more amoeboid microglia morphology, indicating an immune-activated phenotype. Expression of genes associated with cell cycle and immune-activation was increased in VISTA KO microglia. In response to LPS and during experimental autoimmune encephalomyelitis (EAE), VISTA KO and WT microglia shared similar transcriptional profiles and VISTA deletion did not affect EAE disease progression or microglia responses. VISTA KO in microglia in vitro decreased the uptake of myelin. This study demonstrates that VISTA is involved in microglia function, which likely affects healthy CNS homeostasis and neuroinflammation.