Biology subjects

Saha, G.

Publications and source records attributed to Saha, G..

9 recordsLinked to original sources

bioRxiv2026

A New Disease Gene for Hypokalemic Periodic Paralysis, KCNA7, Established in a Multigenerational Family

Hypokalemic periodic paralysis (HypoPP) is an inherited skeletal muscle ion channelopathy of CACNA1S or SCN4A characterized by recurrent episodes of weakness, often triggered by rest after exercise or by reduced K+ (carbohydrate ingestion, stress). Here, we describe a multigenerational family in whom a KCNA7 missense variant [c.834A>C (p.Arg278Ser)] co-segregated with susceptibility to recurrent attacks of weakness in association with hypokalemia as low as 1.3 mEq/L and a 40% decrement of the compound muscle action potential after exercise, suggesting an additional HypoPP gene. Arg278 is the outermost positively charged residue (R1) within the S4 transmembrane segment of the voltage-sensor domain of KV1.7, orthologous to the canonical patten of arginine missense mutations at R1 or R2 in S4 segments for HypoPP-mutant CaV1.1 and NaV1.4 channels. To determine the functional consequences of Arg278Ser, we expressed wild-type and mutant KV1.7 channels in Xenopus oocytes and HEK293 cells. Arg278Ser, but not wild-type KV1.7, generated an anomalous inwardly rectifying current at hyperpolarized membrane potentials that was nonselective Na+ or K+, consistent with the anomalous gating pore conductance that causes susceptibility to HypoPP. Other pathogenic variants of KCNA7 have previously been implicated only in inherited cardiac arrhythmias. Collectively, the genetic, structural and electrophysiological findings support KCNA7 Arg278Ser as a pathogenic variant underlying HypoPP and implicate KCNA7 as a disease gene for periodic paralysis, extending the established gating-pore mechanism of HypoPP to KV1.7.

genetics↗

bioRxiv2024

EmbedSimScore: Advancing Protein Similarity Analysis with Structural and Contextual Embeddings

Accurately computing protein similarity is challenging due to the intricate interplay between local substructures and the global structure within protein molecules. Traditional metrics like TM-score often focus on aligning the global structures of the proteins in a rather geometry-based algorithmic way, potentially overlooking critical local-global relations and contextual comparisons. We introduce Embed-SimScore, a novel self-supervised method that generates structural and contextual embeddings by jointly considering both local substructures and global proteins structures. Utilizing contrastive language-structure pre-training (CLSP) and structural contrastive learning, EmbedSimScore captures comprehensive features across different scales of protein structure. These embeddings provide a more precise and holistic means of computing protein similarities, resulting in the identification of intrinsic relations among proteins that traditional approaches overlook.

bioinformatics↗

bioRxiv2023

Parallel nonfunctionalization of CK1δ/ϵ kinase ohnologs following a whole-genome duplication event

Whole genome duplication (WGD) followed by speciation allows us to examine the parallel evolution of ohnolog pairs. In the yeast family Saccharomycetaceae, HRR25 is a rare case of repeated ohnolog maintenance. This gene has reverted to a single copy in S. cerevisiae where it is now essential, but has been maintained as pairs in at least 7 species post WGD. In S. cerevisiae, HRR25 encodes the casein kinase (CK) 1{delta}/{varepsilon} and plays a role in a variety of functions through its kinase activity and protein-protein interactions (PPIs). We hypothesized that the maintenance of duplicated HRR25 ohnologs could be a result of repeated subfunctionalization. We tested this hypothesis through a functional complementation assay in S. cerevisiae, testing all pairwise combinations of 25 orthologs (including 7 ohnolog pairs). Contrary to our expectations, we observed no cases of pair-dependent complementation, which would have supported the subfunctionalization hypothesis. Instead, most post-WGD species have one ohnolog that failed to complement, suggesting their nonfunctionalization or neofunctionalization. The ohnologs incapable of complementation have undergone more rapid protein evolution, lost most PPIs that were observed for their functional counterparts and singletons from post and non-WGD species, and have non-conserved cellular localization, consistent with their ongoing loss of function. The analysis in N. castelli shows that the non-complementing ohnolog is expressed at a lower level and has become non-essential. Taken together, our results indicate that HRR25 orthologs are undergoing gradual nonfunctionalization.

evolutionary biology↗

bioRxiv2023

PRIEST - Predicting viral mutations with immune escape capability of SARS-CoV-2 using temporal evolutionary information

The dynamic evolution of the SARS-CoV-2 virus is largely driven by mutations in its genetic sequence, culminating in the emergence of variants with increased capability to evade host immune responses. Accurate prediction of such mutations is fundamental in mitigating pandemic spread and developing effective control measures. In this study, we introduce a robust and interpretable deep-learning approach called PRIEST. This innovative model leverages time-series viral sequences to foresee potential viral mutations. Our comprehensive experimental evaluations underscore PRIESTs proficiency in accurately predicting immune-evading mutations. Our work represents a substantial step forward in the utilization of deep-learning methodologies for anticipatory viral mutation analysis and pandemic response.

bioinformatics↗

bioRxiv2023

Molecular Dynamics studies of Long Neurotoxins against nAChR provide key insights towards design of therapeutic peptides for Dyskinesia

Peptide-based drugs are widely used as therapeutic products that exhibit strong binding affinities with high specificity and low toxicity. To develop novel therapeutics against severe involuntary muscle movement and trembling disorder (Dyskinesia), the study explored the design of peptides that could target the nicotine acetylcholine receptor (nAChR) as antagonistic leads. The work aimed to suggest that the pharmacological interaction of snake venom toxins and its associated peptides with nAChRs could be exploited as plausible solutions for PD. Molecular docking and Molecular dynamics exercises were carried out using long chain neurotoxins (-BTx, 1NTN) to analyze the efficacies of their binding to nAChRs, with both the entire toxin and short peptide moieties. The study demonstrated that the novel-peptide (F8J2D7) system appears to possess better affinity with the nAChR than the entire toxin, which is a first step towards designing peptide-based drugs from snake venom proteins that could facilitate further research in the peptide-engineering and drug designing prospects for various neurodegenerative diseases.

bioinformatics↗

bioRxiv2023

PLGA-based dual-loaded nanoformulation of DIM and TMZ - An advanced clinical strategy for brain cancer treatment in a combinatorial approach

Glioblastoma multiforme (GBM) is a highly aggressive form of primary brain tumor in adults, which unfortunately has an abysmal prognosis and poor survival rates. Even though several FDA-approved multimodal treatments for targeting GBM are available, the effectiveness in most patients are not satisfactory. The reason behind this poor success rate is mainly attributed to insufficient drug distribution to the tumor site across the blood-brain barrier (BBB) and induction of resistance for single-drug based therapies. Chemotherapy with Temozolomide (TMZ) having a median overall survival of around 12-15 months, envisages the urgent necessity for more effective treatment strategies. Based upon these facts, in this study, we have developed a novel approach for repurposing TMZ along with inhibition of EGFR, which overexpressed in GBM, to achieve our goal. PLGA-based nanoencapsulation of both TMZ and 3,3-diindoyl methane (DIM), an EGFR inhibitor, in a combinatorial approach enhances the delivery of them together. Their synergistic mode of actions, significantly enhances the cytotoxic effect of TMZ in vitro and in vivo. Moreover, the dual-loaded nanoformulation works more efficiently than their individually packed nanoparticles on DNA damage and apoptosis, resulting in a several-fold reduction in tumor burden, systemic drug toxicity, and increased survival. These findings suggest the preclinical potential of this new treatment strategy.

cancer biology↗

bioRxiv2021

Identification and validation of E3 ubiquitin ligase XIAP as a novel substrate of deubiquitinase USP7 (HAUSP) - Implication towards oncogenesis

The induction of apoptosis upon USP7 (HAUSP) inhibition is established in cancers that contain a wild-type p53 (p53Wt) through the USP7-Mdm2-p53 axis, but no clear explanation has yet been reported for the same to occur in cancers containing mutant 53 (p53Mut) or even p53 null (p53Null) systems. Instead of this USP7-Mdm2-p53 axis USP7 also works through an alternative new pathway identified in this study. Here in this study, we observed that the magnitude of apoptosis induction in response to USP7 inhibition was remarkably similar between cancer cells showing p53Null or p53Mut and those with p53Wt. Through a proteomics-based approach, we were able to identify XIAP as a novel interacting partner for USP7. XIAP is a potent and well-characterized member of the inhibitor of apoptosis proteins (IAPs), which function through caspase inhibition. We successfully identified USP7 as a positive regulator of XIAP at post-translational but not at its transcriptional level. Using molecular modelling coupled with domain deletion studies, we show that the first three Ubl domains in association with the catalytic domain of USP7 interact with the BIR2 and the linker region between BIR2 and BIR3 domains of XIAP. Modulation of expression and catalytic activity of USP7 in multiple type of cancer cell lines showed that USP7 stabilizes XIAP through its deubiquitinase activity. We have also observed that USP7 sensitizes cells against chemotherapeutic drugs through stabilization of XIAP. Thus, USP7 promotes tumorigenesis in multiple cancers, via stabilization of XIAP that results in apoptosis inhibition in caspase dependent pathway. Moreover, we observed that combinatorial inhibition of USP7 and XIAP can induce cellular apoptosis in a higher magnitude than their individual inhibition. Additionally, our results indicates that nanoformulated P5091 and P22077 showed higher potency for killing C6 cells in comparison to normal drugs. To the best of our knowledge, this is the first report on identification and validation of XIAP, a crucial E3 ubiquitin ligase, as a novel substrate of the deubiquitinase USP7 and they together involve in empowerment of the tumorigenic potential of cancer cells.

cancer biology↗

bioRxiv2020

Linking flexibility of brain networks to cognitive development in preschool children

Recent studies of functional connectivity networks (FCNs) suggest that the reconfiguration of brain network across time, both at rest and during task, is linked with cognition in human adults. In this study, we tested this prediction, i.e. cognitive ability is associated with a flexible brain network in preschool children of 3-4 years - a critical age, representing a blossoming period for brain development. We recorded magnetoen-cephalogram (MEG) data from 88 preschoolers, and assessed their cognitive ability by a battery of cognitive tests. We estimated FCNs obtained from the source reconstructed MEG recordings, and characterized the temporal variability at each node using a novel path-based measure of temporal variability; the latter captures reconfiguration of the nodes interactions to the rest of the network across time. Using connectome predictive modeling, we demonstrated that the temporal variability of fronto-temporal nodes in the dynamic FCN can reliably predict out-of-scanner performance of short-term memory and attention distractability in novel participants. Further, we observed that the network-level temporal variability increased with age, while individual nodes exhibited an inverse relationship between temporal variability and node centrality. These results demonstrate that functional brain networks, and especially their reconfiguration ability, are important to cognition at an early but a critical stage of human brain development.

neuroscience↗

bioRxiv2019

Draft genome sequence of a popular Indian tea genotype TV-1

Camellia assamica L. (O). Kuntze. var. TV-1 from Assam, India is one of the most important tea cultivar of Indian Tea Industry which botanically belongs to Assam type and has distinct morphological as well as chemical constituent in leaf than China type of tea. We here present the first draft genome sequence of TV-1, assembled in 2.93 Gb size comprising of 14,824 scaffolds and covering 97.66% of the predicted genome size (3.0 Gb) as determined by flow cytometry. The N50 value, longest and average contig size for this draft genome was found to be as 538.96 Kb, 3.64 Mb and 197.99 Kb, respectively. There were 495,747 SSRs (Di- to Hexa-mers) in the genome and the repeat contents accounted for 71.87% of the genome. About 94.40% genome completeness was predicted with BUSCO, maximum among the published and reported tea genomes. The clustering of the assembled genome with Hi-C data resulted in 15 clusters ranging from the size of 631.46 Mb to 14.39 Mb and accounting 99.32% of assembled genome. This data will act as the starting point for unravelling the important genes and differentiating Indian tea from other commercially available tea varieties.

plant biology↗