👤 Jessica Silva Fausto

Alzheimer's disease (AD) pathology disrupts functional brain connectivity long before symptoms emerge. African Americans face elevated AD risk, yet underlying mechanisms remain unclear. Genetic risk differs by ancestry: APOE-ε4 strongly predicts late-onset AD in European ancestry, whereas ABCA7 rs115550680 confers substantial risk in African ancestry. Yet, how these variants influence neural function in African Americans is unclear. The medial temporal lobe (MTL) is an early target of AD pathology and resting-state functional Magnetic Resonance Imaging (rs-fMRI) measures of dynamic network connectivity (hereafter "flexibility"), the brain's capacity to dynamically reconfigure connectivity, provide a sensitive metric of network adaptability, potentially preceding structural decline. However, comparative influence of APOE-ε4 and ABCA7 rs115550680 on MTL flexibility and subregional volumes in this population is unknown. 146 older African Americans (Mean Show less

Congenital hypogonadotropic hypogonadism (CHH) arises from defects in the synthesis, secretion, or action of gonadotropin-releasing hormone (GnRH), resulting in incomplete or absent pubertal development and various nonreproductive features. CHH is genetically heterogeneous, with over 50 genes implicated in its pathogenesis. This study aimed to elucidate the genetic variants of CHH in a cohort of patients from a single-center endocrinology unit. We used a targeted next-generation sequencing panel to analyze 52 CHH-related genes in 35 patients. Functional studies validated two of the identified variants. Molecular etiology was identified in 20 of 35 (57%) patients. Among these, 12 (39%) had variants in multiple CHH-related genes, with oligogenic inheritance confirmed in two cases. Novel pathogenic variants (both single nucleotide variants and copy number variants) were identified, including ANOS1 p.Gln238* and c.318+2T>C, CHD7 p.Ser734Ilefs5 and p.Gln592Serfs16, FGFR1 p.Ala36Profs67, c.1663+5G>A, and p.Tyr210*, DMXL2 deletion (83.1 Kb), and SOX2 deletion (1.1 Mb). In total, 21 pathogenic or likely pathogenic variants across 15 CHH-related genes were detected, including ANOS1, CHD7, FGFR1, PROKR2, and others. A functional study confirmed the loss of function in the KISS1R p.Ala203Asp variant. Our findings demonstrate the utility of a next-generation sequencing panel in diagnosing genetically complex conditions like CHH and underscore the role of oligogenic inheritance in its phenotypic diversity. The inclusion of genes previously associated with syndromic CHH forms such as CHARGE in the exome panel may highlight possible shared mechanisms with neurodevelopmental disorders, aiding early diagnosis, genetic counseling, and treatment. Show less

In contrast to mammals, lower vertebrates have a remarkable capacity to regenerate complex structures damaged by injury or disease. This process, termed epimorphic regeneration, involves progenitor cells created through the reprogramming of differentiated cells or through the activation of resident stem cells. Wnt/beta-catenin signaling regulates progenitor cell fate and proliferation during embryonic development and stem cell function in adults, but its functional involvement in epimorphic regeneration has not been addressed. Using transgenic fish lines, we show that Wnt/beta-catenin signaling is activated in the regenerating zebrafish tail fin and is required for formation and subsequent proliferation of the progenitor cells of the blastema. Wnt/beta-catenin signaling appears to act upstream of FGF signaling, which has recently been found to be essential for fin regeneration. Intriguingly, increased Wnt/beta-catenin signaling is sufficient to augment regeneration, as tail fins regenerate faster in fish heterozygous for a loss-of-function mutation in axin1, a negative regulator of the pathway. Likewise, activation of Wnt/beta-catenin signaling by overexpression of wnt8 increases proliferation of progenitor cells in the regenerating fin. By contrast, overexpression of wnt5b (pipetail) reduces expression of Wnt/beta-catenin target genes, impairs proliferation of progenitors and inhibits fin regeneration. Importantly, fin regeneration is accelerated in wnt5b mutant fish. These data suggest that Wnt/beta-catenin signaling promotes regeneration, whereas a distinct pathway activated by wnt5b acts in a negative-feedback loop to limit regeneration. Show less