Biology subjects

Verma, A. K.

Publications and source records attributed to Verma, A. K..

At least 19 recordsLinked to original sources

bioRxiv2026

Spontaneous eye behavior is an objective marker of parkinsonian severity

Eye behavior disruption is reported in Parkinson's disease (PD), but its correlation with disease severity has not been well examined. Here, in a nonhuman primate model of PD, we show that spontaneous eye behavior is impaired in parkinsonism and correlates with clinical rating scores and subthalamic beta oscillatory activity. These findings suggest that spontaneous eye behavior could serve as an objective, non-invasive biomarker of parkinsonian severity.

neuroscience↗

bioRxiv2026

MPGEM: A harmonized and transcriptome-complete resource for large-scale reuse of legacy human microarray data

Abstract Background: Legacy microarray datasets provide an extensive record of human transcriptomic biology, but their reuse is constrained by differences in platform design, preprocessing, measurement scale, and gene coverage. Platforms measuring only subsets of genes cannot readily be integrated with higher-coverage platforms, limiting large-scale analysis and computational modeling. Results: We developed Multi-Platform Gene Expression Matrix (MPGEM), a computational framework and resource for harmonizing and completing gene-expression profiles across heterogeneous microarray platforms. MPGEM uses a Reference Quantile Distribution (RQD) and generalized Reference Subset Quantile Distribution (RSQD) framework to transform profiles with different gene coverage onto a common quantitative scale. The MPGEM Engine, a multilayer perceptron, predicts expression of unmeasured genes from genes shared across platforms. Applied to Affymetrix GPL570, GPL571, and GPL96, MPGEM uses GPL570 as a 19,320- gene reference space comprising 12,712 predictor and 6,608 target genes. The resulting resource contains 207,135 human gene-expression profiles across 19,320 genes. Evaluation using masked GPL570 profiles yielded mean sample-wise Pearson and Spearman correlations of 0.944 and 0.939, respectively, and mean gene-wise correlations of 0.830 and 0.825. The lowest-performing 5% of target genes achieved a mean Pearson correlation of 0.683. MPGEM showed comparable or higher predictive performance than baseline mean imputation and K-nearest-neighbor approaches. Conclusions: MPGEM transforms heterogeneous, partially measured legacy microarray profiles into a harmonized, transcriptome-complete representation, facilitating their reuse for large-scale transcriptomic analysis, biomarker discovery, systems biology, and machine learning. The framework, trained models, and expression resource are provided as open-source resources.

bioinformatics↗

bioRxiv2026

Distributions of threshold crossing times of messenger RNA

Within the studies of stochastic gene expression, apart from the variability of copy number of gene products, the problems of threshold crossing of those products are biologically important as they often lead to terminal cellular events. Here, we study the threshold crossing problem of the messenger ribonucleic acid (mRNA) and present an exact probability distribution of first passage times in Laplace space. The function furnishes moments of any order and also predicts the characteristic time of the exponential tail of the distribution, which we match against Gillespie simulations. We find that all the measures of relative fluctuations of the threshold crossing times show U-shapes within this simple model of mRNA, as was found earlier in more mathematically involved models of threshold crossing time statistics of proteins. Furthermore, we extend the exact formula to include the phenomenon of DNA duplication and the corresponding doubling of transcription rate. As expected, the distribution varies considerably depending on the onset of the duplication stage within the cell cycle.

biophysics↗

bioRxiv2026

Astrocytic ACSBG1 depletion improves lipid-cytokine signaling and attenuates α-Synuclein pathology in a Parkinson's disease mouse model

Astrocytes are key regulators of lipid metabolism, and dysregulated astrocytic lipid processing is implicated in Parkinsons disease (PD) pathogenesis. Our prior genome-wide screens identified ACSBG1, an astrocyte-enriched acyl-CoA synthetase, as a candidate regulator of -synuclein (-Syn) levels. However, how ACSBG1 links lipid reprogramming to inflammatory astrocyte activation and -Syn pathology remains unknown. We compared the transcriptomic, cytokine, and lipid secretomes of TNF- and IL-1 stimulated primary astrocytes from wild-type (WT) and Acsbg1 knockout (KO) mice. In vivo, we crossed Acsbg1 KO mice with a Thy1--Syn PD model to assess behavior, neuroinflammation, synaptic integrity, and -Syn levels. Following cytokine exposure, Acsbg1 KO astrocytes mounted an attenuated inflammatory transcriptional response, secreting significantly fewer inflammatory mediators (e.g., IL-6, RANTES, MIP-3) and less long-chain Sphingosine 20:1 than WT astrocytes. Importantly, exogenous Sphingosine 20:1 or cytokines from WT reactive astrocytes induced neuronal -Syn phosphorylation (pS129). In vivo, Acsbg1 deletion in Thy1--Syn mice reduced astrogliosis, rescued synaptic and behavioral deficits, and decreased total and pS129--Syn. These findings establish ACSBG1 as a key regulator of inflammatory astrocyte signaling that contributes to -Syn phosphorylation via specific cytokine and lipid mediators, identifying ACSBG1 as a novel therapeutic target for modulating astrocyte-neuron communication in PD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/726454v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@150a3e3org.highwire.dtl.DTLVardef@137b5caorg.highwire.dtl.DTLVardef@7fe373org.highwire.dtl.DTLVardef@2d996e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Longitudinal analysis reveals myeloid cell contributions to neuroPASC pathogenesis

Neurological and neuropsychiatric symptoms, collectively termed neuroPASC, are among the most prevalent Post-Acute Sequelae of COVID-19 (PASC). Neuroinflammation - particularly microglia reactivity - has been implicated in neuroPASC. Current insights are largely derived from post-mortem tissues of acutely infected patients and may not reflect PASC-related neuropathology. We previously established a PASC model in which SARS-CoV-2-infected mice developed persistent behavioral alterations and prolonged neuroinflammation for up to 120 days post-infection (dpi) in the absence of viral neuroinvasion. Here, we extended these results to a longitudinal single-cell RNA sequencing analysis of brain immune cells collected at 0, 6, 30, and 100 dpi. We identified a coordinated contribution of infiltrating and resident myeloid cells to the initiation and persistence of neuroinflammation. In specific, microglia displayed sustained expansion of subclusters characterized by inflammatory, stress response, and metabolic signatures. Border-associated macrophages upregulated monocyte attractants during acute infection. Concurrently, monocytes and neutrophils showed marked brain recruitment and mounted transient inflammatory responses at 6 dpi, potentially triggering long-term microglial reactivity. Together, these findings provide a high-resolution atlas of brain myeloid immune dynamics during neuroPASC and highlight a central role for microglia in sustaining chronic neuroinflammation.

immunology↗

bioRxiv2026

Causal Dissociation of Frontoparietal Control Mechanisms in Automatic Alcohol Approach Tendencies Using Continuous Theta Burst Stimulation

Compulsive alcohol intake is often sustained by approach tendencies that automatically orient individuals toward alcohol-related cues, even when they intend to avoid them. Converging evidence implicates the frontoparietal regions in regulating such automatic behavior; however, the specific contributions of the right dorsolateral prefrontal cortex (rDLPFC) and right posterior parietal cortex (rPPC), and the underlying neurocognitive mechanisms, remain unclear. To determine the specific contributions of these regions, we applied continuous theta burst stimulation (cTBS) to the rDLPFC or rPPC in separate groups of non-clinical alcohol users (rDLPFC: n = 29; rPPC: n = 28) using a within-subject, active-sham counterbalanced design. Alcohol approach tendencies were assessed using the Alcohol Approach-Avoidance Task at baseline and following active and sham stimulation. Active rDLPFC cTBS selectively slowed alcohol push responses without affecting pull responses, whereas rPPC cTBS produced a bidirectional, alcohol-specific shift in which push responses slowed and pull responses simultaneously accelerated. Although stimulation at either site shifted automatic tendencies toward greater alcohol approach, the behavioral profiles were dissociable. The findings suggest that rDLPFC contributes to sustaining the regulatory signal that drives avoidance over prepotent alcohol approach responses, whereas rPPC determines whether that signal is successfully expressed in behavior when competing cue-driven influences are present. These findings provide node-specific evidence for functional specialization within the frontoparietal network and identify a potential parietal mechanism linking cue salience to overt alcohol approach behavior.

neuroscience↗

bioRxiv2026

Modulation of Automatic Alcohol Approach Tendencies using Single-Session 10 Hz rTMS over the Right dLPFC

BackgroundMaladaptive drinking is often sustained by automatic approach tendencies toward alcohol cues that override conscious self-control. While cognitive and behavioral modification techniques show some promise, their effects remain limited, highlighting the need for alternative neuromodulatory strategies. The current study examined the feasibility of a single session of 10 Hz repetitive transcranial magnetic stimulation (rTMS) to the right dorsolateral prefrontal cortex (dLPFC) as a targeted approach to reduce automatic alcohol approach tendencies. MethodForty-five healthy alcohol-using participants completed an alcohol approach- avoidance task (A-AAT) with concurrent electroencephalographic recording before and after active or sham stimulation. Primary analyses focused on participants with baseline alcohol approach tendencies (n = 35). ResultsAt baseline, individuals with approach tendencies exhibited attenuated N2 and P3b amplitudes to alcohol relative to non-alcohol cues, indicating reduced cognitive control and attentional mechanisms irrespective of group. Following stimulation, active rTMS selectively facilitated alcohol avoidance responses and enhanced prefrontal N2 amplitudes, suggesting strengthened top-down control and protection against repetition-induced automaticity, which was evident in the sham group. ConclusionThese findings suggest that high-frequency rTMS over the right dLPFC can modulate automatic alcohol-related action tendencies by strengthening neural control mechanisms, supporting its further evaluation as a neuromodulatory adjunct for maladaptive drinking. Baseline motivational profiles may additionally influence rTMS response and warrant consideration when tailoring such approaches.

neuroscience↗

bioRxiv2026

Reprogramming BCMA-Targeted CAR-T Cells through γ-Secretase Modulation Blocks Antigen Shedding and Extends CAR-T Longevity

B-cell maturation antigen (BCMA) shedding by {gamma}-secretase generates soluble BCMA (sBCMA), which diminishes membrane antigen density, and limits the durability of BCMA-directed immunotherapies in multiple myeloma (MM). Here, using AI-driven diffusion modeling, we identify peptide inhibitors that selectively block {gamma}-secretase-mediated BCMA cleavage, stabilizing membrane-bound BCMA (mBCMA) without compromising cellular viability. The lead peptide, P5, suppresses sBCMA and restores mBCMA in vitro and in xenograft models. To create sustained, cell-intrinsic inhibition, we engineered Shedding Deterrent Locked-in (SHEDLOCK) CAR-T cells that locally secrete {gamma}-secretase-modulatory peptides. SHEDLOCK-1 CAR-T cells secreting P5 exhibits enhanced cytotoxicity and persistence relative to conventional CAR-T cells. Building on this, SHEDLOCK-2 CAR-T cells were generated, which secrete a modified, naturally derived peptide (nxP) that directly engages the {gamma}-secretase catalytic site, concurrently preventing BCMA shedding, and surprisingly enhancing CAR-T cell longevity by preserving telomere integrity and metabolic fitness. In MM xenograft and patient-derived models, SHEDLOCK-2 CAR-T cells demonstrate durable antitumor activity with a favorable safety profile. Together, these findings establish SHEDLOCK as a next-generation CAR-T platform and provide a strong preclinical foundation for Phase I clinical evaluation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/700575v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@3cd38aorg.highwire.dtl.DTLVardef@164167borg.highwire.dtl.DTLVardef@1ffed21org.highwire.dtl.DTLVardef@1294d06_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Counterconditioning Alcohol Cues: Neural and Behavioral Modulation of Automatic Tendencies and Pavlovian-to-Instrumental Transfer in Male Alcohol Users

ObjectiveRepeated alcohol-cue pairings with rewarding experiences establish automatic response tendencies that bias instrumental behavior through Pavlovian-to-instrumental transfer (PIT). How individual differences in approach and avoidance tendencies shape PIT and intervention responsiveness remains poorly understood. This study examined whether automatic tendencies differentially modulate PIT, and whether counterconditioning (CC) combined with retrieval cues can attenuate approach biases and cue-driven instrumental interference. MethodThirty-nine male alcohol users completed an Alcohol Approach-Avoidance Task and PIT task before and after CC, classified into approach or avoidance groups based on their baseline Alcohol Approach Index. Alcohol cues were paired with monetary loss during CC, with retrieval cues introduced to facilitate reactivation of newly formed aversive associations. Right frontal N2 and centroparietal P3 were examined as indices of early evaluative and attentional processing. ResultsDespite comparable behavioral PIT performance, approach-oriented individuals showed attenuated right frontal N2 during push actions at baseline, reflecting reduced frontal regulatory engagement during cue-incongruent responding. CC selectively reduced approach biases in the approach group, with retrieval cues producing additional reductions, accompanied by N2 and P3 restoration. CC recalibrated PIT interference by reducing push and increasing pull interference, particularly with retrieval cues. CC-induced changes in approach bias did not predict PIT interference, suggesting modulation through partially dissociable pathways. ConclusionsCC with retrieval cues selectively reduced approach biases and recalibrated cue-driven instrumental interference in approach-oriented individuals, providing proof-of-concept for retrieval cue-integrated CC as a targeted associative intervention and highlighting the importance of individual tendency profiles in intervention responsiveness.

neuroscience↗

bioRxiv2025

Sertraline enhances bacterial control by improving the pharmacodynamic -pharmacokinetic properties of frontline TB drugs

Given the need for innovative interventions for tackling the burden of TB, host directed therapies have emerged as a promising alternative in recent times. The combination of sertraline with frontline TB drugs has shown excellent promise in the murine models of infection in imparting better bacterial control and increasing host survival. We tested if the addition of sertraline worked to increase bacterial clearance in the random bred guinea pig model of TB infection that mimics the inter individual heterogeneity observed in the human response to infection. The combination of sertraline and frontline TB drugs effectively reduced bacterial burdens in the tissues of guinea pigs significantly better than the drugs alone with a marked betterment of lung histopathology. In order to evaluate the effect of sertraline on the pharmacodynamic properties of TB drugs, concentrations of the drugs were estimated in tissues at different time intervals over a period of 24h of administration to rats. Overall, addition of sertraline did not alter TB drug distribution or clearance from the animals, although enriching drug amounts transiently between 3-6 h in the different tissues. We thus highlight the advantage of an adjunct TB therapy with the inclusion of sertraline, an FDA approved antidepressant, in improving the PKPD of TB drugs and imparting better infection control in diverse models of infection.

microbiology↗

bioRxiv2025

Neural Mechanisms Underlying Approach and Avoidance Tendencies in Alcohol Use: An Electrophysiological Investigation

Background: A growing body of research highlights the differential role of approach and avoidance tendencies toward alcohol cues in the development and maintenance of harmful drinking behavior. Some individuals involved in alcohol consumption show an automatic approach towards alcohol-related stimuli, whereas others demonstrate avoidance, suggesting the need to understand the neurocognitive mechanisms underlying these automatic tendencies. Methods: The current study employed an Alcohol Approach-Avoidance Task (A-AAT) with electroencephalography (EEG) to investigate neural responses among individuals with alcohol approach and avoidance tendencies. Alcohol group participants were categorized into approach and avoidance subgroups based on their behavioral tendencies following A-AAT administration. Findings: Results revealed significant attenuation in P3 and FN400 amplitudes at frontal and parietal sites, respectively, in the alcohol-approach participants compared to both the alcohol-avoidance and non-alcohol participants. These findings suggest weakened controlled cue processing and impaired stimulus-response conflict resolution in individuals with stronger approach tendencies. Notably, right prefrontal activity exhibited prominent differences between the approach and avoidance groups, highlighting its potential role in regulating automatic alcohol-related responses. Implications: The identified ERP markers provide clinical utility for assessing alcohol approach tendencies and monitoring the progress of intervention. Findings further emphasize the importance of individually tailored targeted interventions aimed at reducing harmful alcohol consumption behavior by altering alcohol approach tendencies.

neuroscience↗

bioRxiv2025

Sleep firing rate homeostasis is disrupted in mild parkinsonism

Sleep-associated downscaling of neuronal firing, i.e., firing rate homeostasis (FRH), is essential for restorative sleep. Sleep dysfunction is common in Parkinsons disease (PD), but FRH has not been investigated. Here, using a within-subject design in the nonhuman primate model of PD, we report that thalamocortical FRH is disrupted in parkinsonism. These findings can inform therapeutic approaches tailored towards normalizing FRH to reestablish restorative sleep in PD.

neuroscience↗

bioRxiv2025

The abundance of potential B12 producers in gut microbiome is inversely associated with serum vitamin B12 levels: A putative role of Host-microbiome feedback regulation

BackgroundThe human gut microbiome is a natural source of essential micronutrients like B-vitamins, which are utilized by both the host and other community members. The prevalence and abundance of known B-vitamin producers and B-vitamin biosynthesis pathways have already been reported in gut microbiome cohorts of a few countries including India. ObjectiveTo test whether the presence of B-vitamin producers/biosynthetic pathways translates into serum B-vitamin levels, taking B12 as a case example. MethodsFecal samples were collected from non-deficient (serum B12 level > 210 pg/mL, n=29) and B12 deficient (serum B12 level < 210 pg/mL, n=30) children from a tribal region of central India. Whole metagenomic DNA was extracted, sequenced, and analyzed for taxonomic profiling and diversity comparisons. Differentially abundant taxa between two groups were identified. The prevalence and abundance of potential B12 producers were compared, and their association with serum B12 level was established. ResultsA comparison of within-sample diversity between the two groups didnt show any difference; however, between-sample diversity was significantly less in the B12 deficient group. Differential abundance testing also showed different microbiome structure in the B12 deficient group, where an increased abundance of B12 transporter-carrying Bacteroides thetaiotaomicron, a few pathogenic species, and ten known B12 producers was observed. Potential B12 producers were also significantly prevalent and abundant in the deficient group. Their cumulative abundance was also significantly higher in the deficient group and showed a negative association with serum B 12 levels. ConclusionA higher abundance of potential B12 producers in the deficient group suggested an adaptive mechanism by the gut microbiome to meet the communitys B12 requirements, by selectively promoting the growth of B12 producers.

genomics↗

bioRxiv2025

Unveiling BPDE Induced Carcinogenic Signaling: Computational Insights into NF-κB, MAPK, and PI3K/Akt Pathway Activation

AbstractThe Carcinogen benzo[a]pyran-7, 8 dihydrodiol 9, 10 epoxide(BaP-DNP) the active metabolite of benzo[a]pyrene has been postulated to induce carcinogenesis through formation of adduct with DNA and through alteration of critical pathways involved in signaling. Besides genotoxicity, BPDE has more recently been reported to alter the NF-{kappa}B, MAPK, and PI3K/Akt, that are involved in inflammation, cell survival and cell proliferation. From the above molecular docking analysis of BPDE binding to the potential proteins of these pathways, the mechanism of action of the compound is examined. The studies conducted on docking reveal moderate binding affinity of BPDE with NF-{kappa}B, that is, -6.11 kcal/mol, which points out its role in inflammation and oncogenic signaling. In addition, BPDE has more protein-binding affinities within the MAPK and PI3K/Akt pathway for CDK1 (-7.46 kcal/mol), LOX (-7.47 kcal/mol), and CDK6 (-6.84 kcal/mol). These indicate that influence of BPDE in tumour progression should not be only through the activation of NF-{kappa}B but would rather be supported by significant inputs of pathways that include PI3K/Akt and MAPK. This interaction would seem to favor cell survival, proliferation, and apoptosis resistance. Broader analysis of the data presented allows defining NF-{kappa}B as one of the key molecules contributing to BPDE-induced carcinogenesis; however, the data also point to the significant participation of the MAPK and PI3K/Akt pathways in this process. Future work should also more fully detail how these pathways interconnect and also evaluate the effectiveness of inhibiting NF-{kappa}B and related pathways in preventing BPDEs carcinogenic action. This study adds to understanding of molecular mechanisms and therapeutic targets of BPDE. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/631754v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@d157e0org.highwire.dtl.DTLVardef@1e061b4org.highwire.dtl.DTLVardef@2ea4acorg.highwire.dtl.DTLVardef@3d50b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

In Silico Toxicity Assessment of Organophosphates: A DFT and Molecular Docking Study on Their Interaction with Human Serum Albumin (HSA)

This study presents an in silico analysis of the toxicity of Organophosphates (OPs) through their interaction with Human Serum Albumin (HSA) protein using density functional theory (DFT) and molecular docking approaches. Organophosphates, known for their widespread use as pesticides, have raised significant concerns due to their potential toxicological effects. To investigate the molecular mechanisms underlying OP toxicity, we conducted DFT calculations to determine the electronic properties and reactivity of selective OP compounds. Molecular docking simulations were performed to explore the binding affinity, interaction sites, and conformational changes of HSA upon exposure to OPs. The DFT analysis revealed key electronic descriptors, such as HOMO-LUMO gap and electrostatic potential, that indicate high reactivity of OPs with biological molecules. Docking results showed strong binding affinities between OPs and HSA, particularly at sites involved in metabolite and drug transport, suggesting potential interference with the proteins native function. The interaction of OPs with HSA was further supported by molecular dynamics simulations, which confirmed the stability of the OP-HSA complex over time. These findings provide critical insights into the molecular basis of organophosphate toxicity, emphasizing the importance of their interaction with HSA. The combined DFT and molecular docking approach offers a valuable framework for predicting the toxicological behavior of OPs and lays the foundation for further in vitro and in vivo studies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/628551v3_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@881814org.highwire.dtl.DTLVardef@e4cb5forg.highwire.dtl.DTLVardef@e3cb74org.highwire.dtl.DTLVardef@1426bb4_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

A predominately pulmonary activation of complement in a mouse model of severe COVID-19

Evidence from in vitro studies and observational human disease data suggest the complement system plays a significant role in SARS-CoV-2 pathogenesis, although how complement dysregulation develops in patients with severe COVID-19 is unknown. Here, using a mouse-adapted SARS-CoV-2 virus (SARS2-N501YMA30) and a mouse model of severe COVID-19, we identify significant serologic and pulmonary complement activation following infection. We observed C3 activation in airway and alveolar epithelia, and in pulmonary vascular endothelia. Our evidence suggests that while the alternative pathway is the primary route of complement activation, components of both the alternative and classical pathways are produced locally by respiratory epithelial cells following infection, and increased in primary cultures of human airway epithelia in response to cytokine exposure. This locally generated complement response appears to precede and subsequently drive lung injury and inflammation. Results from this mouse model recapitulate findings in humans, which suggest sex-specific variance in complement activation, with predilection for increased C3 activity in males, a finding that may correlate with more severe disease. Our findings indicate that complement activation is a defining feature of severe COVID-19 in mice and lay the foundation for further investigation into the role of complement in COVID-19.

immunology↗

bioRxiv2024

Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations

Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological dysfunction in mice infected with a virulent mouse-adapted SARS-CoV-2 that does not infect the brain. Long after recovery from nasal infection, we observed loss of tyrosine hydroxylase (TH) expression in olfactory bulb glomeruli and neurotransmitter levels in the substantia nigra (SN) persisted. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased levels of proinflammatory cytokines and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, as found in human neurodegenerative diseases. Early treatment with antivirals (nirmatrelvir and molnupiravir) reduced virus titers and lung inflammation but failed to prevent neurological abnormalities, as observed in patients. Together these results show that chronic deficiencies in neuronal function in SARS-CoV-2-infected mice are not directly linked to ongoing olfactory epithelium dysfunction. Rather, they bear similarity with neurodegenerative disease, the vulnerability of which is exacerbated by chronic inflammation.

microbiology↗

bioRxiv2024

Cytosolic Class I J-domain proteins aid mitochondrial protein import and influence homeostasis in Arabidopsis thaliana.

Mitochondrial homeostasis heavily relies on import of numerous nuclear encoded proteins. Multiple chaperone machineries operate at the cytosolic and mitochondrial side of the bilayer to ensure the efficacy of this process. While the mechanisms and components involved in translocation of polypeptides into the mitochondria are known in great detail, the cytosolic events of mitochondrial protein import are poorly understood in plants. This study explores the role of two cytosolic Class I J-domain proteins (JDPs), atDjA1 and atDjA2, in mitochondrial homeostasis in Arabidopsis thaliana. We show that atDjA1 and atDjA2 uniquely interacted with outer mitochondrial surface receptors, Tom9, Metaxin, and OM64, which guide the import of numerous mitochondrial precursors. Knockout of atDjA1 or atDjA2 impeded seed germination under multiple abiotic stress conditions, with atDjA1 mutant being more sensitive. Both the mutants demonstrated decreased respiratory rates and enhanced accumulation of reactive oxygen species (ROS), indicating compromised mitochondrial function. Further, knockout of atDjA1 resulted in a significant decline in the number of active mitochondria as well as import of MTS-GFP. While atDjA2 mutants did not show a reduction in mitochondrial number, both the mutants had an activated mitochondrial retrograde signaling (MRS) further underscoring compromised mitochondrial homeostasis in these mutants. Our findings suggest that evolutionarily conserved cytosolic Class I JDPs preserve mitochondrial homeostasis by targeting specific receptors on the outer mitochondrial surface, facilitating the import of cytosolically synthesized mitochondrial precursors in Arabidopsis thaliana.

plant biology↗