Determination of Molecular Structures of HIV Envelope Glycoproteins using Cryo-Electron Tomography and Automated Sub-tomogram Averaging

Since its discovery nearly 30 years ago, more than 60 million people have been infected with the human immunodeficiency virus (HIV) (www.usaid.gov). The virus infects and destroys CD4+ T-cells thereby crippling the immune system, and causing an acquired immunodeficiency syndrome (AIDS) 2. Infection begins when the HIV Envelope glycoprotein "spike" makes contact with the CD4 receptor on the surface of the CD4+ T-cell. This interaction induces a conformational change in the spike, which promotes interaction with a second cell surface co-receptor 5,9. The significance of these protein interactions in the HIV infection pathway makes them of profound importance in fundamental HIV research, and in the pursuit of an HIV vaccine

Rare Variant Enrichment analysis Supports

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by aplasia of the female reproductive tract; the syndrome can include renal anomalies, absence or dysgenesis, and skeletal anomalies. While functional models have elucidated several candidate genes, onl

The impact of intermittent fasting during Ramadan on psychomotor and cognitive skills in adolescent athletes

IntroductionIntermittent fasting (IF) represents a dietary intervention similar to caloric restriction, characterized by the strategic limitation of food consumption. Among the diverse array of practices for IF, Ramadan IF (RIF), a religious observance in Islam, mandates that healthy adult Muslims abstain from both food and drinks during daylight hours. In sports, researchers have extensively studied IF effects on health, including sleep and physical performance, but its impact on cognitive functions during RIF remains understudied. Therefore, this study was conducted to evaluate the influence of RIF on psychomotor and cognitive performance among young female athletes.MethodsTo achieve this purpose, a cohort of 23 female handball players, aged 17.2 ± 0.5 years, participated in a series of six testing sessions: one conducted prior to Ramadan (R0), and others during the first (R1), second (R2), third (R3), and fourth (R4) weeks of Ramadan, followed by a session in the week after Ramadan (R5). Each session involved assessments using a Simple Reaction Time Test (SRT), Choice Reaction Time Test (CRT), Vigilance Test (VT), and Mental Rotation Test (MRT). Additionally, dietary intake, body composition, and Pittsburgh Sleep Quality Index (PSQI) scores were evaluated during these periods.Results and discussionThe obtained data illustrated that there was a decrease in SRT, CRT, VT, and MRT performances during R1 in comparison to R0 (all p < .001). This reduction was also observed in R2, R3, R4, and R5. Notably, during the fourth week of Ramadan (R4), these cognitive and psychomotor parameters were significantly lower than during the earlier weeks (R1, R2, R3; all p < .001). Furthermore, a gradual decrease in total PSQI scores, sleep quality, and sleep duration was observed throughout the Ramadan period, reaching the lowest levels during R4. These findings illustrate that RIF has a significantly detrimental impact on neuromuscular and cognitive abilities as well as sleep quality in young female athletes. The study also highlights a fluctuating pattern in cognitive function across the four weeks of Ramadan, with the most pronounced decline observed during the final week of fasting illustrating the importance of conducting similar studies on normal individuals from both genders with larger sample size

NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy

Abstract Background NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-β/NODAL signaling pathway have reproducibly been shown to cause laterality defects in humans. To further explore this association and improve genetic diagnosis, the study aims to identify and characterize a broader range of NODAL variants in a large number of individuals with laterality defects. Methods We re-analyzed a cohort of 321 proband-only exomes of individuals with clinically diagnosed laterality congenital heart disease (CHD) using family-based, rare variant genomic analyses. To this cohort we added 12 affected subjects with known NODAL variants and CHD from institutional research and clinical cohorts to investigate an allelic series. For those with candidate contributory variants, variant allele confirmation and segregation analysis were studied by Sanger sequencing in available family members. Array comparative genomic hybridization and droplet digital PCR were utilized for copy number variants (CNV) validation and characterization. We performed Human Phenotype Ontology (HPO)-based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Results Missense, nonsense, splice site, indels, and/or structural variants of NODAL were identified as potential causes of heterotaxy and other laterality defects in 33 CHD cases. We describe a recurrent complex indel variant for which the nucleic acid secondary structure predictions implicate secondary structure mutagenesis as a possible mechanism for formation. We identified two CNV deletion alleles spanning NODAL in two unrelated CHD cases. Furthermore, 17 CHD individuals were found (16/17 with known Hispanic ancestry) to have the c.778G > A:p.G260R NODAL missense variant which we propose reclassification from variant of uncertain significance (VUS) to likely pathogenic. Quantitative HPO-based analyses of the observed clinical phenotype for all cases with p.G260R variation, including heterozygous, homozygous, and compound heterozygous cases, reveal clustering of individuals with biallelic variation. This finding provides evidence for a genotypic-phenotypic correlation and an allele-specific gene dosage model. Conclusion Our data further support a role for rare deleterious variants in NODAL as a cause for sporadic human laterality defects, expand the repertoire of observed anatomical complexity of potential cardiovascular anomalies, and implicate an allele specific gene dosage model

Long read sequencing and expression studies of AHDC1 deletions in Xia-Gibbs syndrome reveal a novel genetic regulatory mechanism

Xia-Gibbs syndrome (XGS; MIM# 615829) is a rare mendelian disorder characterized by Development Delay (DD), intellectual disability (ID), and hypotonia. Individuals with XGS typically harbor de novo protein-truncating mutations in the AT-Hook DNA binding motif containing 1 (AHDC1) gene, although some missense mutations can also cause XGS. Large de novo heterozygous deletions that encompass the AHDC1 gene have also been ascribed as diagnostic for the disorder, without substantial evidence to support their pathogenicity. We analyzed 19 individuals with large contiguous deletions involving AHDC1, along with other genes. One individual bore the smallest known contiguous AHDC1 deletion (∼350 Kb), encompassing eight other genes within chr1p36.11 (Feline Gardner-Rasheed, IFI6, FAM76A, STX12, PPP1R8, THEMIS2, RPA2, SMPDL3B) and terminating within the first intron of AHDC1. The breakpoint junctions and phase of the deletion were identified using both short and long read sequencing (Oxford Nanopore). Quantification of RNA expression patterns in whole blood revealed that AHDC1 exhibited a mono-allelic expression pattern with no deficiency in overall AHDC1 expression levels, in contrast to the other deleted genes, which exhibited a 50% reduction in mRNA expression. These results suggest that AHDC1 expression in this individual is compensated by a novel regulatory mechanism and advances understanding of mutational and regulatory mechanisms in neurodevelopmental disorders

AHDC1 missense mutations in Xia-Gibbs syndrome

Xia-Gibbs syndrome (XGS; MIM: 615829) is a phenotypically heterogeneous neurodevelopmental disorder (NDD) caused by newly arising mutations in the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene that are predicted to lead to truncated AHDC1 protein synthesis. More than 270 individuals have been diagnosed with XGS worldwide. Despite the absence of an independent assay for AHDC1 protein function to corroborate potential functional consequences of rare variant genetic findings, there are also reports of individuals with XGS-like trait manifestations who have de novo missense AHDC1 mutations and who have been provided a molecular diagnosis of the disorder. To investigate a potential contribution of missense mutations to XGS, we mapped the missense mutations from 10 such individuals to the AHDC1 conserved protein domain structure and detailed the observed phenotypes. Five newly identified individuals were ascertained from a local XGS Registry, and an additional five were taken from external reports or databases, including one publication. Where clinical data were available, individuals with missense mutations all displayed phenotypes consistent with those observed in individuals with AHDC1 truncating mutations, including delayed motor milestones, intellectual disability (ID), hypotonia, and speech delay. A subset of the 10 reported missense mutations cluster in two regions of the AHDC1 protein with known conserved domains, likely representing functional motifs. Variants outside the clustered regions score lower for computational prediction of their likely damaging effects. Overall, de novo missense variants in AHDC1 are likely diagnostic of XGS when in silico analysis of their position relative to conserved regions is considered together with disease trait manifestations.Among >270 individuals diagnosed with Xia-Gibbs syndrome (XGS; MIM: 615829), almost all have de novo “truncating” mutations in AHDC1. There are now also 10 reports of XGS arising from de novo missense AHDC1 mutations. We mapped these to the AHDC1 protein domain structure and identified two critical, sensitive regions

Additional file 1 of NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy

Additional file 1: Table S1. Molecular, Cohort, and Phenotypic information on all cases with NODAL variants. Table S2. Inclusion criteria and description of included patient groups. Table S3. Detailed clinical information for all 33 CHD cases in the study. Table S4. CHD gene list analyzed in our cohort. Table S5. HPO terms used for all CHD cases in the study