Biology subjects

Senthilkumar, S.

Publications and source records attributed to Senthilkumar, S..

6 recordsLinked to original sources

bioRxiv2026

Signatures of selection in pleiotropic genes involved in insect neuronal and immune systems

Pleiotropy, where a single gene contributes to multiple biological functions, plays a central role in shaping evolutionary constraints. The nervous and immune systems are tightly integrated both functionally and genetically, but it is not clear whether pleiotropy constrains adaptation in each system or contributes to disease. Building on evidence that genes that are pleiotropic between development and immunity in Drosophila melanogaster evolve slower than immune-specific genes, we tested whether pleiotropic neuro-immune genes likewise exhibit reduced evolutionary rates compared to genes functioning solely in neuronal or immune processes, and whether such evolutionary constraint is associated with human neurological disease. We identified immune, neuronal, and neuro-immune genes in D. melanogaster using Gene Ontology annotations, estimated their evolutionary rates across 12 Drosophila species, and investigated the breadth of their expression across developmental stages as a complementary proxy for pleiotropy. We further curated associations between the human orthologs for these genes and neurological disease and tested whether their evolutionary rates and pleiotropic status predicted disease involvement. We found that pleiotropic genes exhibited significantly lower dN/dS values and were less stage-specific than non-pleiotropic immune genes. Slower-evolving genes were more likely to be associated with human neurological diseases but this pattern was strongest for non-pleiotropic neuronal genes, suggesting that pleiotropy alone is not the strongest predictor of disease. Our results therefore indicate that dN/dS could be a stronger predictor of disease association than pleiotropy, raising new questions about the maintenance of pleiotropy in evolutionarily dynamic physiological systems.

evolutionary biology↗

bioRxiv2025

Mapping the Metalloproteome of Deinococcus indicus DR1 through Integrative Structure and Function Annotation

Deinococcus indicus DR1 is a rod-shaped bacterium isolated from the Dadri wetlands (Uttar Pradesh, India) that tolerates ionizing radiation and arsenic. The molecular basis of its wider heavy-metal resilience, particularly among the 1017 out of 4128 proteins still annotated as hypothetical, remains unclear. We performed a proteome-wide structural and functional survey to address this gap. All the 4128 proteins were modeled with AlphaFold2, yielding very-high-confidence structures (pLDDT [≥] 90) for 2145 sequences. CATH/InterPro analysis assigned domains to 2735 proteins. Functions were predicted by combining DeepFRI (graph neural-network), MorphologFinder (Foldseek plus EggNOG-Mapper), and existing GenBank annotations. The integrated workflow suggests that more than 100 previously uncharacterized proteins may bind or transport arsenic, chromium, cobalt, copper, iron, manganese, molybdenum, nickel, or zinc, indicating a metal-handling capacity that extends beyond the known ars operon. Recurrent domain architectures that include P-loop NTPases, Rossmann folds, GNAT acetyl-transferases, and sensor modules (CHASE, PAS, GAF) point to coordinated redox regulation and efflux pathways. Twenty high-confidence metal-binding candidates have been prioritized for experimental validation through expression, mutagenesis, and knockout studies. All structural models, domain assignments, and query tools are available at https://deinococcus.in, providing a resource for future investigations of heavy-metal tolerance in this organism.

bioinformatics↗

bioRxiv2024

Mechanism of nucleus-chloroplast communication by alternative promoter usage and stromules to establish photomorphogenesis in Arabidopsis

Interorganellar communication is essential for maintaining cellular and organellar functions and adapting to dynamic environmental changes in eukaryotic cells. In plants, light triggers photomorphogenic development, including chloroplast biogenesis and the inhibition of hypocotyl elongation, through photoreceptors such as the red/far-red-sensing phytochromes and their downstream signaling pathways. However, the mechanism of interorganellar crosstalk underlying photomorphogenesis remains elusive. Here, we investigate the role of light-regulated alternative promoter usage in NUCLEAR CONTROL OF PEP ACTIVITY (NCP), a gene encoding a phytochrome signaling component that is dual-localized to the nucleus and chloroplasts. The long transcript variant (NCP-L) is upregulated under high red light, while the short variant (NCP-S) predominates in dark or low red light conditions. This light-regulated alternative transcription initiation of NCP is dependent on PHYTOCHROME-INTERACTING FACTORS (PIFs). The NCP-L isoform primarily localizes to chloroplasts, whereas the NCP-S isoform is found in the cytoplasm and nucleus. Notably, chloroplast-localized NCP-L translocates to the nucleus via stromules. Consequently, NCP-L, present in both chloroplasts and the nucleus, initiates chloroplast biogenesis and inhibits hypocotyl growth during photomorphogenesis, whereas NCP-S is nonfunctional and degraded by the 26S proteasome. Taken together, our findings elucidate the mechanisms by which light-regulated NCP alternative promoter usage and NCP retrotranslocation via stromules control photomorphogenesis in Arabidopsis. These mechanisms provide insights into interorganellar communication, orchestrating organ-specific developmental processes in response to fluctuating light environments.

plant biology↗

bioRxiv2024

A method for focused ultrasound (FUS) neuromodulation with simultaneous electroencephalogram recordings in awake, head-fixed mice with temporal lobe epilepsy

Transcranial focused ultrasound (FUS) may be a promising neuromodulation technology for treating people with epilepsy whose seizures are drug resistant. Prior studies have shown seizure suppression in animal studies using FUS. However, most of these studies were performed in evoked seizure models and not in animal models of epilepsy. Evoked seizure models do not exhibit the pathophysiology of epilepsy and do not exhibit spontaneous recurrent seizures, which define epilepsy. For translation to humans, there is a critical need to determine the specific FUS stimulation parameters that reduce spontaneous recurrent seizures in a chronic disease model of epilepsy. To achieve this goal, we developed and optimized an approach to determine the effects of ultrasonic stimulation on metrics of seizure-like events (SLEs) in awake, head-fixed mice within the intrahippocampal kainate (IHK) mouse model of temporal lobe epilepsy (TLE). A proof-of-principle study demonstrated that two target (bilateral and contralateral to the kainic acid injection site) stimulation conditions and two FUS parameter sets (low and high pressure) could be combined with the ability to simultaneously record hippocampal electroencephalograms. We also provide a method for analysis of the effects of FUS stimulation on the metrics of SLEs (interevent duration, SLE duration, and spike frequency).

bioengineering↗

bioRxiv2023

Development of an MR-guided focused ultrasound (MRgFUS) lesioning approach for small and deep structures in the rat brain

ObjectiveHigh-intensity magnetic resonance-guided focused ultrasound (MRgFUS) is a noninvasive therapy to lesion brain tissue, used clinically in patients and preclinically in several animal models. Challenges with focused ablation in rodent brains can include skull and near-field heating and accurately targeting small and deep brain structures. We overcame these challenges by creating a novel method consisting of a craniectomy skull preparation, a high-frequency transducer (3 MHz) with a small ultrasound focal spot, a transducer positioning system with an added manual adjustment of [~]0.1 mm targeting accuracy, and MR acoustic radiation force imaging for confirmation of focal spot placement. MethodsThe study consisted of two main parts. First, two skull preparation approaches were compared. A skull thinning approach (n=7 lesions) was compared to a craniectomy approach (n=22 lesions), which confirmed a craniectomy was necessary to decrease skull and near-field heating. Second, the two transducer positioning systems were compared with the fornix chosen as a subcortical ablation target. We evaluated the accuracy of targeting using a high-frequency transducer with a small ultrasound focal spot and MR acoustic radiation force imaging. ResultsComparing a motorized adjustment system ([~]1 mm precision, n=17 lesions) to the motorized system with an added micromanipulator ([~]0.1 mm precision, n=14 lesions), we saw an increase in the accuracy of targeting the fornix by 133%. The described work allows for repeatable and accurate targeting of small and deep structures in the rodent brain, such as the fornix, enabling the investigation of neurological disorders in chronic disease models.

bioengineering↗

bioRxiv2023

Oral Streptococci S. anginosus and S. mitis induce distinct morphological, inflammatory, and metabolic signatures in macrophages

Oral streptococci are the pioneer colonizer and structural architect of the complex oral biofilm. Disruption of this architectural framework causes oral dysbiosis associated with various clinical conditions, including dental caries, gingivitis, and oral cancer. Among the genus Streptococcus, S. anginosus is associated with esophageal, gastric, and pharyngeal cancer tissues, while S. mitis is correlated with oral cancer. However, no study has investigated mechanistic links between these Streptococcus species and cancer-related inflammatory responses. To explore the underlying involvement of S. anginosus and S. mitis in inflammation-associated cancer development, we investigated the innate immune response elicited by S. anginosus versus S. mitis using the RAW264.7 macrophage cell line. Compared to untreated or S. mitis infected macrophages, S. anginosus infected macrophages exhibited a robust proinflammatory response characterized by significantly increased levels of inflammatory cytokines and mediators, including TNF, IL-6, IL-1{beta}, NOS2, and COX2, accompanied by enhanced NF-{kappa}B activation. Mitostress analysis revealed an increased extracellular acidification rate in macrophages infected with S. anginosus compared to S. mitis. Further, macrophages infected with S. anginosus for 6h displayed upregulated aconitate decarboxylase, which catalyzes itaconate production. In contrast, no significant alterations were observed in succinate dehydrogenase that converts succinate to fumarate. At 24h, S. anginosus induced significant shifts in succinate and itaconate, emphasizing a unique macrophage metabolic profile, and an augmented inflammatory response in response to S. anginosus. This study underscores the capacity of S. anginosus to elicit a robust proinflammatory response in macrophages and opens new avenues of secretory immune metabolites in response to oral streptococci. ImportanceThe surge in head and neck cancer cases among individuals devoid of typical risk factors such as HPV infection, tobacco and alcohol use sparks an argumentative discussion around the emerging role of oral microbiota as a novel risk factor in oral squamous cell carcinoma (OSCC). While substantial research has dissected the gut microbiomes influence on physiology, the oral microbiome, notably oral streptococci, a gatekeeper of systemic health, has been underappreciated in mucosal immunopathogenesis. S. anginosus, a viridans streptococci group, has been linked to abscess formation and an elevated presence in esophageal cancer and OSCC. The current study aims to probe the innate immune response to S. anginosus compared to the early colonizer S. mitis as an initial ride towards understanding the impact of distinct oral Streptococcus species on the host immune response in the progression of OSCC.

microbiology↗