Biology subjects

Sedaghat, A.

Publications and source records attributed to Sedaghat, A..

3 recordsLinked to original sources

bioRxiv2025

Characterization of the hemodynamic response function in default mode network subregions for task-evoked negative BOLD responses

While the hemodynamic response function (HRF) of the positive blood oxygenated level dependent (BOLD) signal is well characterized in the functional magnetic resonance imaging (fMRI) field, studies investigating the shape and properties of the negative BOLD HRF, often observed in the default mode network (DMN) regions, are rare. In this study, we first investigated the linearity of the task-evoked negative BOLD response (NBR) with respect to stimulus duration. Then, we obtained the shape of the HRF from each region of the DMN, using an in-house developed unbiased and robust iterative deconvolution technique. Our results demonstrated that each region of the DMN represented a unique HRF, which was not only substantially different from the HRF of the positive BOLD signal, but also different from the HRF extracted from the other DMN regions. We replicated these findings using different fMRI datasets with distinct task paradigms. When comparing the HRF across DMN sub-regions and across tasks, our results demonstrated a significantly higher inter-regional variability compared to inter-task variability. Furthermore, our performance correlation analysis illustrated that the HRFs in the DMN sub-regions extracted by our iterative FIR method were not biased by the task performance level. Altogether, we demonstrated the linearity of the NBR, introduced a robust HRF extraction approach to obtain a distinct HRF for each DMN sub-regions, which were different from the HRF of the positive BOLD signal. The results suggest there is possibility that each node of the DMN might have different underlying neural and/or vascular mechanisms.

neuroscience↗

bioRxiv2022

In Silico Analysis of Novel VHL Germline Mutations in Iranian RCH Patients

Von Hippel-Lindau (VHL) syndrome is an autosomal dominant inherited multisystem neoplasia disorder caused by the VHL tumor suppressor gene, coding for VHL protein (pVHL), variants. Various types of VHL variants present different clinical phenotypes that later lead to events resulting in benign or malignant lesions including Retinal Capillary Hemangioblastoma (RCH). We reported on 3 novel mutation sites observed in 3 families (5 RCH patients), including c.511A>C, c.514C>T, and c.511A>T in exon 3 of the VHL gene. According to the ACMG classifications, c.514C>T and c.511A>T variations are likely pathogenic, and c.511A>C is a variant of uncertain significance (VUS) and in accordance with autosomal dominant inheritance. The location and impact of the incidence mutations on pVHL were computed using in silico analysis. The obtained structural information and computational analysis showed that the studied mutations induce conformational changes that limit the flexibility of the pVHL interaction interface with elonginB/C, elongin C/B, and cullin2, which is necessary for HIF1 alpha binding. The recently added gene variants and their related clinical phenotypes will improve the VHL diagnosis accuracy and the patients population carrying VHL gene mutations. These pioneering results could be a model for future functional studies.

genetics↗

bioRxiv2020

Biallelic mutation of CLRN2 causes non-syndromic hearing loss in humans

Deafness, the most frequent sensory deficit in humans, is extremely heterogenous with hundreds of genes probably involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 15.2 Mb locus on chromosome 4p15.32p15.1 containing a missense pathogenic variant in CLRN2 (c.494C>A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C>A mutation leads to two events: 1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and 2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.

genetics↗