Biology subjects

Parihar, M.

Publications and source records attributed to Parihar, M..

9 recordsLinked to original sources

bioRxiv2026

Molecular Mechanism of Lipid Recognition and Membrane-Guided Gating in Plant Minimal START Proteins

The hydrophobic nature of lipids requires specialized transport mechanisms, and one such non-vesicular transport mechanism involves START (StAR-related lipid transfer) domain proteins. START domains either occur as a part of multidomain proteins or occur solo as in minimal START proteins. Unlike well-studied multidomain variants, plant minimal START proteins remain poorly understood, leaving their ligand specificity, structural dynamics, and biological roles largely uncharacterized. Integrating structural screening with experimental validation, we analyzed representative plant minimal START proteins and confirmed their specific binding to amphipathic lipids, primarily myristic acid and lysophosphatidylcholine. The ligand binding involves a bipartite mechanism, in which basic residues within the cavity interact with polar lipid headgroups, while the hydrophobic tails are accommodated deeper within the cavity. Mechanistically, ligand binding induced closure of a lid-like gate at the cavity entrance, whereas membrane proximity promoted reopening of the gate and ligand release, collectively suggesting a membrane-guided gating mechanism for lipid exchange. Consistent with this model, localization studies show that these proteins associate with the endoplasmic reticulum, plastids, Golgi apparatus, and plasma membrane, major sites of lipid metabolism. Together, our findings establish plant minimal START proteins as bona fide lipid-binding proteins that utilize a bipartite ligand-binding mechanism coupled with membrane-responsive gating dynamics.

biochemistry↗

bioRxiv2026

Liquidity of gene co-expression trajectories across the lifespan highlights delayed maturation and the perinatal GABA switch in schizophrenia risk

Schizophrenia genetic and environmental risk factors play out largely in early life, biasing development toward a pathogenic trajectory that becomes clinically apparent in early adulthood, when the disorder typically onsets. Here, we convert snapshots of gene expression in postmortem brain at a moment in time into a dynamic lifetime series employing the "liquidity" metric, a novel tool to track the evolution of networks across time from a multi-systemic perspective. The landscape of normal prefrontal cortical development becomes increasingly "liquid" during the first two decades of post-natal life, with sharp discontinuities in known critical periods such as birth and adolescence. Neurotypical individuals free of apparent neuropathology with relatively elevated polygenic risk scores for schizophrenia exhibit a generalized delay in the dynamics of liquidity across these trajectories compared to below-average-risk individuals. Impacted biological processes strongly converge on delayed GABA-A receptor functional maturation, involved in establishing Excitatory/Inhibitory balance in brain during early development. Similar to patients with schizophrenia, neurotypical high-risk individuals show an increased expression ratio between the genes SLC12A2 (protein NKCC1) and SLC12A5 (protein KCC2) relative to low-risk, involved in the control of the equilibrium potential of chloride ions that regulates GABA-A function. These results provide evidence that genetic risk for schizophrenia is associated with a delayed maturational profile and delayed maturation of GABAergic signaling without detectable neuropathology and well before the age of clinical onset. Interestingly, the same effect is not observed in the hippocampus and is not observed with genetic risk for other neuropsychiatric and immune conditions. The dynamics of maturation of GABA-A signaling in the dorsolateral prefrontal cortex emerge as an early contributor to translating genetic risk into an altered developmental trajectory associated with schizophrenia.

genomics↗

bioRxiv2026

History of Traumatic Brain Injury with Loss of Consciousness and APOE ϵ4 Carriers Synergistically Increase Late-Life Amyloid PET Burden

BackgroundTraumatic brain injury with loss of consciousness (TBI-LOC) is an established risk factor for dementia, yet the pathways linking remote TBI to Alzheimers disease (AD) biology remain incompletely defined. APOE {varepsilon}4 is the strongest genetic predictor of amyloid accumulation in late-onset AD, it may moderate the long-term consequences of head injury. This study investigates whether history TBI-LOC independently contributes or synergistically interacts with APOE {varepsilon}4 to amplify late-life amyloid and tau burden. Methods429 participants completed the Ohio State University TBI screening tool and an amyloid PET scan (centiloids). A subcohort (n=352) also underwent tau PET. TBI history was classified by recency (<10 vs >10 years) and severity (no TBI, dazing/confusion [TBI-DZ], TBI-LOC). Analyses were stratified by degree of clinical impairment as assessed by Clinical Dementia Rating (CDR=0 vs CDR>0). Logistic and linear regression models examined associations between TBI and amyloid, adjusting for age, sex, education, and APOE {varepsilon}4, including an APOE*TBI-LOC status interaction term, while Fishers exact tests evaluated TBI recency and biomarker positivity. ResultsIn CDR=0 participants (n=365), 119 reported a history of TBI, comprising 56 TBI-DZ and 63 TBI-LOC. TBI-LOC but not TBI-DZ, correlated with elevated amyloid PET levels (p<0.001; [4.6-17]). Furthermore, an interaction between APOE {varepsilon}4 and TBI-LOC indicated that TBI-LOC augmented the amyloid-related risk associated with the APOE {varepsilon}4 allele (p=0.003; [4.3-21]). The interaction persisted when stratified by TBI recency with only remote TBI-LOC (occurring more than 10 years prior) associated with increased amyloid PET (p=0.003 [5.2-25]). No association between TBI and tau was identified in a subset with tau PET, and no TBI-amyloid correlations were observed among symptomatic participants (CDR>0; n=64) suggesting a ceiling effect of pathology once clinical dementia is present. ConclusionsHistory of remote TBI-LOC is linked to elevated amyloid PET levels in later life, particularly among APOE {varepsilon}4 carriers with a CDR=0. The robust findings for amyloid, contrasted with null tau results and the reduced association in symptomatic cases underscore the importance of considering TBI history when screening for preclinical AD and assessing early-stage risk.

neuroscience↗

bioRxiv2024

Structural Insights into the Assembly and Regulation of 2'-O RNA Methylation by SARS-CoV-2 nsp16/nsp10

2-O-ribose methylation of the first transcribed base (adenine or A1 in SARS-CoV-2) of viral RNA mimics the host RNAs and subverts the innate immune response. How nsp16, with its obligate partner nsp10, assembles on the 5-end of SARS-CoV-2 mRNA to methylate the A1 has not been fully understood. We present a [~] 2.4 [A] crystal structure of the heterotetrameric complex formed by the cooperative assembly of two nsp16/nsp10 heterodimers with one 10-mer Cap-1 RNA (product) bound to each. An aromatic zipper-like motif in nsp16 and the N-terminal regions of nsp10 and nsp16 orchestrate an oligomeric assembly for efficient methylation. The front catalytic pocket of nsp16 stabilizes the upstream portion of the RNA while the downstream RNA remains unresolved, likely due to its flexibility. An inverted nsp16 dimer extends the positively charged surface area for longer RNA to influence the catalysis. Additionally, a non-specific nucleotide-binding pocket on the backside of nsp16 plays a critical role in catalysis, further contributing to its enzymatic activity.

microbiology↗

bioRxiv2024

Transcriptomics and proteomics of projection neurons in a circuit linking hippocampus with dorsolateral prefrontal cortex in human brain

Transcriptome and proteome sequencing of brain tissue homogenate has helped unravel processes underlying schizophrenia (SCZ). However, most studies have lacked granularity at the cell type level and have focused on individual brain regions, rather than examining expression dynamics across multiple regions or illness-relevant circuitries. We used laser capture microdissection to collect excitatory neuron-enriched samples from hippocampal subregions CA1 and presubiculum (SUB), and from dorsolateral prefrontal cortex (DLPFC), a circuit prominently implicated in schizophrenia. Using RNA sequencing and quantitative proteomics, we show significantly superior discrimination of brain regional identity in the transcriptomic (>90% accuracy) and proteomic data (>97% accuracy) compared with gene-level expression data (<70% in bulk). Patients with SCZ show hippocampal-specific differential protein phosphorylation. SCZ risk co-expression gene-sets that replicate across transcript and protein networks are enriched for transmembrane transporters in the DLPFC and CA1 and postsynaptic processes in the SUB. We demonstrate a strong directional connectivity effect of SCZ risk in that excitatory synaptic genes in CA1 unidirectionally predict gene expression in SUB. Finally, parallel CA1 snRNA-seq results suggest that in SCZ excitatory efferents in CA1 are affected by interactions with glia and by downregulation of inhibitory neuropeptide inputs. Our study proposes molecular mechanisms by which hippocampal communication, previously associated with SCZ at the macroscopic level, may be altered at the inter-field and interregional circuit level.

neuroscience↗

bioRxiv2023

Dopamine and schizophrenia from bench to bedside: Discovery of a striatal co-expression risk gene set that predicts in vivo measures of striatal function.

Schizophrenia (SCZ) is characterized by a polygenic risk architecture implicating diverse molecular pathways important for synaptic function. However, how polygenic risk funnels through these pathways to translate into syndromic illness is unanswered. To evaluate biologically meaningful pathways of risk, we used tensor decomposition to characterize gene co-expression in post-mortem brain (of neurotypicals: N=154; patients with SCZ: N=84; and GTEX samples N=120) from caudate nucleus (CN), hippocampus (HP), and dorsolateral prefrontal cortex (DLPFC). We identified a CN-predominant gene set showing dopaminergic selectivity that was enriched for genes associated with clinical state and for genes associated with SCZ risk. Parsing polygenic risk score for SCZ based on this specific gene set (parsed-PRS), we found that greater pathway-specific SCZ risk predicted greater in vivo striatal dopamine synthesis capacity measured by [18F]-FDOPA PET in three independent cohorts of neurotypicals and patients (total N=235) and greater fMRI striatal activation during reward anticipation in two additional independent neurotypical cohorts (total N=141). These results reveal a bench to bedside translation of dopamine-linked genetic risk variation in driving in vivo striatal neurochemical and hemodynamic phenotypes that have long been implicated in the pathophysiology of SCZ.

neuroscience↗

bioRxiv2020

Asymmetric robustness in the feedback control of the retinoic acid network response to environmental disturbances

Robustness is a feature of regulatory pathways to ensure signal consistency in light of environmental changes or genetic polymorphisms. The retinoic acid (RA) pathway, is a central developmental and tissue homeostasis regulatory signal, strongly dependent on nutritional sources of retinoids and affected by environmental chemicals. This pathway is characterized by multiple proteins or enzymes capable of performing each step and their integration into a self-regulating network. We studied RA network robustness by transient physiological RA signaling disturbances followed by kinetic transcriptomic analysis of the recovery during embryogenesis. The RA metabolic network was identified as the main regulated module to achieve signaling robustness using an unbiased pattern analysis. We describe the network-wide responses to RA signal manipulation and found the feedback autoregulation to be sensitive to the direction of the RA perturbation: RA knockdown exhibited an upper response limit, whereas RA addition had a minimal feedback-activation threshold. Surprisingly, our robustness response analysis suggests that the RA metabolic network regulation exhibits a multi-objective optimization, known as Pareto optimization, characterized by trade-offs between competing functionalities. We observe that efficient robustness to increasing RA is accompanied by worsening robustness to reduced RA levels and vice versa. This direction-dependent trade-off in the network-wide feedback response, results in an uneven robustness capacity of the RA network during early embryogenesis, likely a significant contributor to the manifestation of developmental defects.

developmental biology↗

bioRxiv2018

Chromosome-wide evolution and sex determination in a nematode with three sexes

The free-living nematode Auanema rhodensis is a rare example of a species with three sexes, in which males, females and hermaphrodites coexist. A. rhodensis males have only one X chromosome (XO), whereas females and hermaphrodites have two (XX). The A. rhodensis X chromosome is unusual: it does not recombine in hermaphrodites and is transmitted from father to son. The mechanism that controls the production of females versus hermaphrodites is unknown but is dependent on maternal and larval environmental factors. Here we report the genome sequence and genetic map of A. rhodensis, placing over 95% of the sequence in seven linkage groups. Comparison of the seven A. rhodensis chromosomes to chromosomal assemblies of Caenorhabditis elegans and three other rhabditine nematodes identified deeply conserved linkage groups we call Nigon units, some of which have been maintained in all species analysed. Others have undergone breakage and fusion, and the A. rhodensis karyotype is the product of a unique set of rearrangements involving three Nigon units. The A. rhodensis X chromosome is much smaller than the autosomes, is less gene dense and is 3 to 4 times more polymorphic, reflecting its unique transmission history. Differential expression analyses comparing females and hermaphrodites, identified several candidate genes, including orthologues of C. elegans gld-1, tra-1 and dmd-10/11, that are potentially involved in the female-hermaphrodite sexual decision.

genetics↗

bioRxiv2017

Gender- and gamete-specific patterns of X chromosome segregation in a three-gendered nematode

Meiosis is at the core of sexual reproduction and alterations to its program can have dramatic effects. In this study, we investigate the segregation pattern of the X chromosome in Auanema rhodensis, a three-gendered nematode. This species has an atypical pattern of X chromosome segregation during male spermatogenesis that results in the exclusive production of haplo-X sperm. Here we use a combination of genetic and cytological approaches to show that while XX females undergo conventional meiosis to produce mostly haplo-X oocytes, hermaphrodites undergo atypical meiosis to produce nullo-X oocytes and mostly diplo-X sperm. Gender- and gamete-specific alterations of the normal meiotic program include non-pairing of the X homologs and precocious separation of X chromatids. Given these intra-species, intra-individual and intra-gametogenesis variations in meiotic program of A. rhodensis, we argue that it is an ideal model to study the plasticity of meiosis and how it can be modulated.\n\nHighlights- Matings between A. rhodensis hermaphrodites and males generate only male crossprogeny.\n- Hermaphrodites generate mostly nullo-X oocytes and diplo-X sperm.\n- Following normal Mendelian genetics, XX females produce haplo-X oocytes.\n- In cross-progeny, sons always inherit the X chromosome from the father.

genetics↗