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Human ITGAV variants are associated with immune dysregulation, brain abnormalities, and colitis.

Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three independent families (two patients and four fetuses) that either caused abnormal mRNA and the loss of functional protein or caused mistargeting of the integrin. This led to eye and brain abnormalities, inflammatory bowel disease, immune dysregulation, and other developmental issues. Mechanistically, the reduction of functional Integrin αV resulted in the dysregulation of several pathways including TGF-β-dependent signaling and αVβ3-regulated immune signaling. These effects were confirmed using immunostaining, RNA sequencing, and functional studies in patient-derived cells. The genetic deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Taken together, the ITGAV variants identified in this report caused a previously unknown human disease characterized by brain and developmental defects in the case of complete loss-of-function and atopy, neurodevelopmental defects, and colitis in cases of incomplete loss-of-function.

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Validation study of the Spanish brief version of TEMPS-A.

Identifying affective temperaments could be useful both for understanding the normal behavioral variations in the general population and to establish if there is a clinical predisposition to certain disorders. Five affective temperaments have been proposed: depressive, cyclothymic, hyperthymic, irritable and anxious. Original instrument for measuring them (TEMPS-A) is a 110-item scale but many short versions in different languages have been validated. The aim of this study was to obtain a short self-administered Spanish version of TEMPS-A with good psychometric properties. A sample of 550 students who answered the argentinean version of TEMPS-A was included, after psychometric analysis a comparison between inpatients with major depression and their matched controls by sex and age who answered the brief version was performed to get an external validation. The sample was composed by 298 (54.2%) women. The mean age was 23.3 year (SD=6.2). A forced five factor analysis was performed. The 7 items with the highest factorial load (more than 0.350) for each subscale were included in the brief version. The Cronbach alpha's ranged from 0.690 to .800. The most prevalent temperament was hyperthymic followed by cyclothymic for students sample. Similarities between students and controls sample were observed, but not with patients with major depression. This brief Spanish version of TEMPS-A (35 items) has good psychometric properties and can be used in general and clinical population.

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Dissipative dark cosmology: From early matter dominance to delayed compact objects

We demonstrate a novel mechanism for producing dark compact objects and black holes through a dark sector, where all the dark matter can be dissipative. Heavy dark sector particles with masses above 104 GeV can come to dominate the Universe and yield an early matter-dominated era before big bang nucleosynthesis (BBN). Density perturbations in this epoch can grow and collapse into tiny dark matter halos, which cool via self-interactions. The typical halo size is set by the Hubble length once perturbations begin growing, offering a straightforward prediction of the halo size and evolution depending on one’s choice of dark matter model. Once these primordial halos have formed, a thermal phase transition can then shift the Universe back into radiation domination and standard cosmology. These halos can continue to collapse after BBN, resulting in the late-time formation of fragmented dark compact objects and sub-solar-mass primordial black holes. We find that these compact objects can constitute a sizable fraction of all of dark matter. The resulting fragments can have masses between 1020 and 1032 g, with radii ranging from 10−2 to 105 m, while the black holes can have masses between 108 and 1034 g. Furthermore, a unique feature of this model is the late-time formation of black holes which can evaporate today. We compare where these objects lie with respect to current primordial black hole and massive (astrophysical) compact halo object constraints. Published by the American Physical Society 2024

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Endocannabinoids and their receptors modulate endometriosis pathogenesis and immune response.

Endometriosis (EM), characterized by the presence of endometrial-like tissue outside the uterus, is the leading cause of chronic pelvic pain and infertility in females of reproductive age. Despite its high prevalence, the molecular mechanisms underlying EM pathogenesis remain poorly understood. The endocannabinoid system (ECS) is known to influence several cardinal features of this complex disease including pain, vascularization, and overall lesion survival, but the exact mechanisms are not known. Utilizing CNR1 knockout (k/o), CNR2 k/o, and wild-type (WT) mouse models of EM, we reveal contributions of ECS and these receptors in disease initiation, progression, and immune modulation. Particularly, we identified EM-specific T cell dysfunction in the CNR2 k/o mouse model of EM. We also demonstrate the impact of decidualization-induced changes on ECS components, and the unique disease-associated transcriptional landscape of ECS components in EM. Imaging mass cytometry (IMC) analysis revealed distinct features of the microenvironment between CNR1, CNR2, and WT genotypes in the presence or absence of decidualization. This study, for the first time, provides an in-depth analysis of the involvement of the ECS in EM pathogenesis and lays the foundation for the development of novel therapeutic interventions to alleviate the burden of this debilitating condition.

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Open Access