Biology subjects

Malik, R.

Publications and source records attributed to Malik, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Reversible hypervascularization drives cognitive decline and blood-brain barrier damage during aging

Cerebrovascular dysfunction emerges early in neurodegeneration, yet how vascular structure, blood-brain barrier (BBB) failure, and cognition are linked remains undefined. Using VesselPro, a whole-brain pipeline integrating perfusion-resolved 3D imaging with spatial proteomics, we mapped vascular aging across the mouse lifespan. We identify two discrete trajectories: a hypovascular state and a previously unrecognized hyper-vascular, BBB-compromised state, defined relative to a young-adult vascular baseline. The hyper-vascular trajectory, concentrated in the cortex and hippocampus, was associated with marked spatial memory impairment and pervasive BBB leakage. Spatial proteomics revealed a coordinated program involving angiogenic activation, endothelial stress, cytoskeletal remodeling, and inflammatory signaling. Cross-species comparison with human proteomic biomarkers from the UK Biobank showed strong alignment between the mouse hypervascular signature and vascular dementia risk, but minimal concordance with Alzheimers disease, defining a vascular-specific dementia endotype. Transient Tie2 activation with AKB-9778 attenuated this trajectory, improving vessel organization, BBB integrity, and memory performance. Our findings show that endothelial instability is a key mechanistic driver of this heterogeneous vascular aging state. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/720441v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@39494aorg.highwire.dtl.DTLVardef@faa4acorg.highwire.dtl.DTLVardef@1511dd5org.highwire.dtl.DTLVardef@7db29b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIVesselPro: we developed a pipeline for capturing perfused blood vessels in the brain: unexpected bifurcation in vascular aging: traditional hypovascular state and a novel, hypervascular, BBB-compromised state. C_LIO_LIHypervascular pathology: Linked the hypervascular profile in the cortex and hippocampus to spatial memory impairment, pervasive BBB leakage, and angiogenic inflammatory signaling. C_LIO_LIClinical endotype: Cross-species analysis via the UK Biobank confirms this hypervascular signature aligns with vascular dementia risk rather than Alzheimers disease. C_LIO_LIPharmacological stabilization: Demonstrated that Tie2 signaling activation (AKB-9778) improves the vessel organization, BBB integrity, and memory performance. C_LI

neuroscience↗

bioRxiv2026

A negatively charged unstructured loop autoinhibits mammalian Dicer and supports fidelity of miRNA biogenesis.

Dicer RNases produce small RNAs for RNA interference (RNAi) and microRNA (miRNA) pathways. Although vertebrate Dicers share a conserved overall architecture with other eukaryotic Dicers, they are uniquely adapted for the production of gene-regulating miRNAs. We report here this adaptation extends beyond the structured core of the enzyme and relies on an intrinsically disordered region (IDR) conserved across jawed vertebrates. This negatively charged IDR supports fidelity of miRNA biogenesis while inhibiting RNAi. The IDR projects into a positively charged substrate-binding groove of Dicer and stabilizes a pre-dicing state, which effectively licenses authentic miRNA precursors. Electron cryo-microscopy shows that removal of the IDR shifts the equilibrium from the pre-dicing to the dicing state, thus increasing enzymatic activity and broadening substrate accessibility. In cells, deletion, replacement or variations of the IDR affect fidelity of microRNA biogenesis, change substrate specificity, and enhance RNAi. Altogether, our work highlights functional relevance of unstructured protein parts, which escape attention in structural analyses, and introduces an autoinhibitory IDR element mimicking negative RNA charge as a component of the molecular grammar governing IDRs in RNA-binding proteins.

molecular biology↗

bioRxiv2025

Structural basis for ATP-driven double-ring assembly of the human mitochondrial Hsp60 chaperonin

The ATP-driven mHsp60:mHsp10 chaperonin system assists protein folding within the mitochondrial matrix of human cells. Substrate protein folding has been proposed to occur through interconnected single- and double-ring pathways. In the absence of nucleotide, mHsp60 exists in equilibrium between free protomers and heptameric single rings, while the formation of double rings requires ATP. Here, we present cryo-electron microscopy structures of mHsp60 in the apo state, bound to ATP, and bound to ATP in complex with the cochaperonin mHsp10. ATP binding to single-ring apo mHsp607 triggers coordinated conformational changes in the intermediate and apical domains, resulting in a highly dynamic apical region within the ring. Extensive inter-subunit rearrangements flatten the equatorial surface of each ring, thereby enabling inter-ring contacts that stitch the rings together to form double-ring mHsp6014. Collectively, these structures define the structural basis of ATP-driven double-ring assembly of a human mitochondrial chaperonin responsible for maintaining mitochondrial protein homeostasis.

biophysics↗

bioRxiv2025

The Role of SARS-CoV-2 Nucleocapsid Protein Persistence in Inducing Chronic Type I Interferon and Mitochondrial Dysfunction.

The potential mechanisms that link SARS-CoV-2 infection to post-acute sequelae of SARS-CoV-2 symptoms and ultimately transition to new onset of autoimmune disease remain poorly understood. Here, we report the consequences of SARS-CoV-2 nucleocapsid (N) protein persistence in the absence of detectable SARS-CoV-2 replication in otherwise healthy individuals, a set of systemic lupus erythematosus (SLE) patients, and a case of a 60-year-old man who developed a new onset of lupus nephritis seven months following mild COVID-19 disease. We have identified that N protein persistence in peripheral blood mononuclear cells (PBMC) did not correlate with detectable SARS-CoV-2 RNA in blood but is associated with significantly increased secretion of type I interferons (IFN) and presence of tubuloreticular structures in peripheral leukocytes. We further demonstrate that the N protein colocalizes in the mitochondrial fraction of PBMCs from individuals positive for N protein alongside mitochondrial antiviral signaling protein (MAVS). In vitro expression of the N protein in a monocytic cell line showed that the N protein itself was directly capable of interacting with MAVS in the absence of viral RNA, and this interaction was enhanced if the cell was exposed to oxidative stress. We show that the type I IFN signature in the presence of N protein expression was MAVS, but not STING signaling pathway-dependent. Our findings suggest a mechanism for the onset and promotion of type I IFN signature after COVID-19; in our model, the SARS-CoV-2 N protein can independently trigger sustained type I IFN production via direct activation of MAVS and its spontaneous oligomerization. This long-lasting type I IFN generation may create a chronic inflammatory milieu, favoring autoimmunity with SLE-like symptoms in susceptible individuals. One Sentence SummaryThe persistence of SARS-CoV-2 nucleocapsid in the absence of viral replication is associated with an induction of mitochondria-mediated inflammatory milieu, which can favor autoimmunity in susceptible individuals.

immunology↗

bioRxiv2025

Identification and Characterization of PLUTO-201, a Novel Long Non-Coding RNA Associated with Poor Outcomes in Prostate Cancer

Background: Despite extensive investigation, the factors promoting aggressive prostate cancer are poorly understood. In particular, despite a few prominent examples, the role of long non-coding RNAs (lncRNAs) is largely unknown. Methods: We performed a comprehensive analysis of whole-genome transcriptome data to identify differential expression across 1,567 patients with prostate cancer, then correlated differential expression with risk of metastatic recurrence. We characterized the lncRNA most associated with metastasis in vitro and in vivo to investigate the mechanism by which it promotes aggressive prostate cancer. Results: We have identified a novel lncRNA, Prostate Cancer Associated hnRNPK Interacting Transcript (PCAHIT), which is strongly associated with metastasis and poor overall survival in men with prostate cancer. We find that overexpression/knockdown of PCAHIT in pre-clinical models of prostate cancer modulates proliferation rates and markers of an aggressive phenotype through regulation of steroid biosynthesis and expression of the MHC class I complex, driving increased growth in androgen-depleted conditions and decreased susceptibility to T cell-mediated cytotoxicity. We further find that the heterogeneous nuclear ribonucleoprotein hnRNPK directly binds PCAHIT and is indispensable for its activity. Conclusions: Overall, our findings indicate that PCAHIT is a driver of aggressive prostate cancer phenotypes and poor clinical outcomes through suppression of the immune response and increased androgen-independent cancer growth. PCAHIT is a potential biomarker of aggressive disease.

cancer biology↗

bioRxiv2024

Enhanced RNAi does not provide efficient innate antiviral immunity in mice in vivo.

In RNA interference (RNAi), long double-stranded RNA (dsRNA) is cleaved by Dicer endonuclease into small RNA interfering RNAs (siRNAs), which guide degradation of complementary RNAs. While RNAi mediates antiviral innate immunity in plants and many invertebrates, vertebrates adopted sequence-independent response and their Dicer produces siRNAs inefficiently because it is adapted to process small hairpin microRNA precursors in the gene-regulating microRNA pathway. Mammalian RNAi is thus a rudimentary pathway of unclear significance. To investigate its antiviral potential, we modified mouse Dicer locus to express a truncated variant (Dicer{Delta}HEL1) known to stimulate RNAi. Next, we analyzed how Dicer{Delta}HEL1/wt mice respond to four RNA viruses: Coxsackievirus B3 (CVB3) and encephalomyocarditis virus (ECMV) from Picornaviridae; tick-borne encephalitis virus (TBEV) from Flaviviridae; and lymphocytic choriomeningitis virus (LCMV) from Arenaviridae. Increased Dicer activity in Dicer{Delta}HEL1/wt mice did not elicit any antiviral effect. supporting insignificant antiviral function of endogenous mammalian RNAi in vivo. However, we also report that sufficiently high expression of Dicer{Delta}HEL1 suppressed LCMV in embryonic stem cells and in a transgenic mouse model. Altogether, mice with increased Dicer activity offer a new benchmark for identifying and studying viruses susceptible to mammalian RNAi in vivo.

molecular biology↗

bioRxiv2024

Activated RNAi does not rescue piRNA pathway deficiency in testes

RNA interference (RNAi) and PIWI-associated RNAs (piRNA) pathways use small RNAs as sequence-specific guides to repress transposable elements. In mice, the loss of Mili, an essential piRNA pathway factor, causes male sterility associated with mobilization of LINE L1 retrotransposons while female mutants remain fertile. At the same time, mouse oocytes have exceptionally active RNAi thanks to an oocyte-specific variant of RNase III Dicer, which efficiently makes small RNAs from long dsRNA substrates. In oocytes of mice lacking functional MILI and the oocyte-specific Dicer variant, we previously observed that L1 retrotransposons are redundantly targeted by both, RNAi and piRNA pathways. To test whether enhanced RNAi may reduce the Mili mutant phenotype in testes, we used transgenic mice ectopically expressing the oocyte-specific Dicer variant during spermatogenesis. We report here that this genetic modification increases siRNA biogenesis and supports RNAi but is not sufficient to reduce spermatogenic defects caused by the loss of Mili.

molecular biology↗

bioRxiv2024

Selective inflammation of the tumor microenvironment and invigorated T cell-mediated tumor control upon induced systemic inactivation of TREX1

Therapeutic innate immune stimulation within the tumor microenvironment can potentiate endogenous antitumor T cell immunity. DNase 3-repair exonuclease 1 (TREX1) is essential for cellular DNA disposal which prevents autoimmunity ensuing from cGAS/STING activation by endogenous DNA. Optimal strategies to therapeutically leverage cGAS/STING signalling for cancer therapy are highly sought after. TREX1-deficient tumor cells elicit enhanced protective immunity in syngeneic models. Here we show that induced inactivation of the Trex1 gene in (non-malignant) host cells is well tolerated and yields improved type I IFN- and T cell-dependent control of established TREX1-competent tumors with selective immune cell infiltration of tumor, but not other tissues. Intra-tumoral T cell proliferation and numbers of effector and effector-like exhausted cells massively increased, enabling complete rejection in synergy with checkpoint inhibition. We conclude that systemic TREX1 inhibition is a promising approach to boost anti-tumor immunity, that can overcome immune evasion by cancer cell- intrinsic cGAS/STING inactivation.

immunology↗

bioRxiv2023

Genetic activation of canonical RNA interference in mice

Canonical RNA interference (RNAi) is sequence-specific mRNA degradation guided by small interfering RNAs (siRNAs) made from double-stranded RNA (dsRNA) by RNase III Dicer. RNAi has different roles including gene regulation, antiviral immunity or defense against transposable elements. In mammals, RNAi is constrained by Dicer, which is adapted to produce microRNAs, another class of small RNAs. However, RNAi exists in mouse oocytes, which employs a truncated Dicer variant. A homozygous mutation to express only the truncated variant ({Delta}HEL1) causes dysregulation of microRNAs and perinatal lethality in mice. Here, we report the phenotype and RNAi activity in Dicer{Delta}HEL1/wtmice, which are viable, show minimal miRNome changes but their endogenous siRNA levels are increased by an order of magnitude. We show that siRNA abundance is limited by available dsRNA but not by PKR, a dsRNA sensor of innate immunity. Expressing dsRNA from a transgene, functional RNAi in vivo was induced in heart. Dicer{Delta}HEL1/wt mice thus represent a new model for researching mammalian canonical RNAi in vivo and offer an unprecedented platform for addressing claims about its biological roles.

molecular biology↗

bioRxiv2023

Nucleic Acid Mediated Activation of a Short Prokaryotic Argonaute Immune System

The continual pressure of invading DNA has led bacteria to develop numerous immune systems, including a short prokaryotic Argonaute (pAgo) TIR-APAZ system (SPARTA) that is activated by invading DNA to unleash its TIR domain for NAD(P)+ hydrolysis. To gain a molecular understanding of this activation process, we resolved a crystal structure of SPARTA heterodimer in the absence of guide RNA/target ssDNA at 2.66[A] resolution and a cryo-EM structure of the SPARTA oligomer (tetramer of heterodimers) bound to guide RNA/target ssDNA at nominal 3.15-3.35[A] resolution. The crystal structure provides a high-resolution view of the TIR-APAZ protein and the MID-PIWI domains of short pAgo - wherein, the APAZ domain emerges as equivalent to the N, L1 and L2 regions of long pAgos and the MID domain has a unique insertion (insert57). A comparison to cryo-EM structure reveals regions of the PIWI (loop10-9) and APAZ (helix N) domains that reconfigure to relieve auto-inhibition to permit nucleic acid binding and transition to an active oligomer. Oligomerization is accompanied by the nucleation of the TIR domains in a parallel-strands arrangement for catalysis. Together, the structures provide a visualization of SPARTA before and after RNA/ssDNA binding and reveal the basis of SPARTAs active assembly leading to NAD(P)+ degradation and abortive infection.

biophysics↗

bioRxiv2023

Aberrant activation of the innate immune sensor PKR by self dsRNA is prevented by direct interaction with ADAR1

Loss of dsRNA editing by Adar1 leads to aberrant interferon induction in Adar null mouse embryos. Adar Mavs mutants, in which this interferon induction is prevented, die within two weeks of birth. We show here that early death of pups is reduced in Adar Mavs EIF2k2 (Pkr) mutants, identifying PKR as the second aberrantly activated dsRNA sensor in Adar mutant mice. In intestines of Adar Mavs pups transit amplifying progenitor cells in intestinal crypts die and intestinal villi are lost in pups before death; intestinal defects are prevented in Adar Mavs Eifak2. In human A549 lung cancer cells ADAR1 forms a complex with PKR. AlphaFold modelling predicts a direct inhibitory interaction of ADAR1 dsRBDIII with the PKR near the kinase active site and a new mode for ADAR1 dsRNA-binding. Mutations at residues required for ADAR1 dsRNA binding or for predicted PKR contacts, prevent interaction with PKR.

immunology↗

bioRxiv2023

Single-cell multiome regression models identify functional and disease-associated enhancers and enable chromatin potential analysis

We present a novel gene-level regulatory model called SCARlink that predicts single-cell gene expression from single-cell chromatin accessibility within and flanking (+/-250kb) the genic loci by training on multiome (scRNA-seq and scATAC-seq co-assay) sequencing data. The approach uses regularized Poisson regression on tile-level accessibility data to jointly model all regulatory effects at a gene locus, avoiding the limitations of pairwise gene-peak correlations and dependence on a peak atlas. SCARlink significantly outperformed existing gene scoring methods for imputing gene expression from chromatin accessibility across across high-coverage multiome data sets while giving comparable to improved performance on low-coverage data sets. Shapley value analysis on trained models identified cell-type-specific gene enhancers that are validated by promoter capture Hi-C and are 8x-35x enriched in fine-mapped eQTLs and 22x-35x enriched in fine-mapped GWAS variants across 83 UK Biobank traits. We further show that SCARlink-predicted and observed gene expression vectors provide a robust way to compute a chromatin potential vector field to enable developmental trajectory analysis.

bioinformatics↗

bioRxiv2022

Angie-LAMP for diagnosis of human eosinophilic meningitis using dog as proxy: A LAMP assay for Angiostrongylus cantonensis DNA in cerebrospinal fluid

BackgroundAngiostrongylus cantonensis (rat lungworm) is recognised as the leading cause of human eosinophilic meningitis, a serious condition observed when nematode larvae migrate through the CNS. Canine Neural Angiostrongyliasis (CNA) is the analogous disease in dogs. Both humans and dogs are accidental hosts, and rapid diagnosis is warranted. A highly sensitive PCR based assay is available but often not readily accessible in many jurisdictions. An alternative DNA amplification assay that would further improve the accessibility is needed. This study aimed to assess the diagnostic utility of a newly designed LAMP assay to detect DNA of globally distributed and invasive A. cantonensis and Angiostrongylus mackerrasae, the only other neurotropic Angiostrongylus species, which is native to Australia. Methodology/Principal FindingsCerebrospinal fluid (CSF) from dogs (2020-2022) with a presumptive diagnosis of A. cantonensis infection were received for confirmatory laboratory testing and processed for DNA isolation and ultrasensitive Angiostrongylus qPCR. A newly designed LAMP assay targeting AcanR3390 in a diagnostic laboratory setting was directly compared to the reference ultrasensitive qPCR for determination of presence of A. cantonensis DNA to aid the diagnosis of CNA. The LAMP assay (Angie-LAMP) allowed the sensitive detection of A. cantonensis DNA from archived DNA specimens (Kappa=0.81, 95%CI 0.69-0.92; n=93) and rapid single-step lysis of archived CSF samples (Kappa=0.77, 95%CI 0.59-0.94; n=52). Only A. cantonensis DNA was detected in canine CSF samples, and co-infection with A. mackerrasae using amplicon deep sequencing (ITS-2 rDNA) was not demonstrated. Both SYD.1 and AC13 haplotypes were detected using sequencing of partial cox1. Conclusions/SignificanceThe Angie-LAMP assay is a useful molecular tool for detecting Angiostrongylus DNA in CSF of dogs and performs comparably to laboratory Angiostrongylus qPCR. Adaptation of single-step sample lysis improved potential applicability for effective diagnosis of angiostrongyliasis in a clinical setting for dogs and by extension for humans. Authors summaryA potentially fatal disease, neural angiostrongyliasis, is caused by the rat lungworm (Angiostrongylus cantonensis). The parasite migrates into the spinal cord and brain of accidental hosts, such as humans and dogs, after ingestion of infective larvae. Recently, an ultrasensitive molecular assay which can detect tiny fragments of the parasites DNA was developed and has been used for confirmatory diagnosis. Although this assay outperforms previously developed assays, it requires clean DNA with specialised equipment in a laboratory setting. There is an urgent need for an alternative diagnostic method which is sensitive and portable, for deployment in the field and in the hospitals in remote areas or in low-income countries. The authors developed a fast and portable loop-mediated isothermal amplification (LAMP) assay that compares favourably to the ultra-sensitive PCR assay when tested using cerebrospinal fluid from dogs on the Australian east coast with presumptive neural angiostrongyliasis. Considering a One Health approach to diagnostics, this assay enables portable emergency diagnostics equally suitable to humans, dogs and wildlife. The newly developed assay will also enable water supplies to be screened, as well as crustaceans and molluscs used as potential food sources, for presence of the parasite.

microbiology↗

bioRxiv2022

Vasoactive Endothelial Growth Factor and Heat Shock Protein Gene Expression Response in Kawasaki Disease Associated Coronary Arteritis

Kawasaki Disease (KD) is a childhood vasculitis primarily affecting medium-sized arteries, which can lead to severe complications, particularly with respect to coronary artery disease (CAD). The impact of thermal stress on KD coronary artery pathogenesis, in association with prolonged fever and inflammation, remains unclear. In this study, we hypothesized that altered gene expression (GE) of angiogenesis-inducing Heat Shock Proteins (HSPs) is associated with KD-CAD through pro-inflammation. Transcriptomic analysis was performed using the three largest KD peripheral blood studies in the clinical literature (KD1-KD3), and one study direct from coronary artery tissue (KD4). The analysis revealed a significant increase in TNF and NFKB1 GE, indicating the presence of inflammation based on gene expression profiles. Gene set enrichment analysis (GSEA) of KD1-KD3 datasets identified inflammatory pathways, including TNFA signaling via NFKB, IL6 JAK STAT 3 Signalling, and p53 (Heat Shock Protein 90). The study also focused on specific HSPs known to be associated with angiogenesis, namely HSPB1, HSPA1A, and HSP90AB1. The temporal transcript model (TTM) consistently showed up-regulation of pro-inflammatory genes VEGF-A, TNF, and NFKB1, as well as up-regulation of HSPA1A. GSEA revealed gene ontology pathways associated with VEGF production. These findings suggest that the binding of VEGF-A or VEGF-B to their receptors could potentially impact the coronary artery in KD. Additionally, the up-regulation of the gene HSPAB1 in KD has not been described previously. In contrast, KD4 showed no differential GE for the studied genes potentially related to end-stage KD. This study provides valuable insights into VEGF and HSPs in KD-associated inflammation. Future research should focus on developing a VEGF-HSP CAD model to explore implications for KD biomarking as well as developing precision management strategies.

genomics↗

bioRxiv2022

Molecular basis of indispensable accuracy of mammalian miRNA biogenesis

Mammalian Dicer is the gatekeeper into the essential gene-regulating miRNA pathway. What is committing mammalian Dicer to the miRNA pathway remains unknown. We report that Dicers highly conserved DExD/H helicase domain is the key structural element supporting accurate miRNA biogenesis. While ATPase activity of the domain is non-essential, its loss is lethal in mice. It is required during canonical miRNA biogenesis for efficient recognition, high-fidelity cleavage, and strand selection. Structure of Dicer-miRNA precursor complexes showed that the DExD/H domain acquired helicase-unrelated function defining Dicer conformations, which affect substrate loading and facilitate pre-selection of miRNA precursors. Dicer lacking the DExD/H domain favors conformations enabling reduced substrate selectivity and supporting RNA interference, a different small RNA pathway. Therefore, Dicers DExD/H domain ensures indispensable high-fidelity precursor processing of mammalian miRNAs, which constitutes a structural "mold" for adaptive miRNA evolution.

molecular biology↗

bioRxiv2021

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

To study how the 22q11.2 deletion predisposes to psychiatric disease, we generated induced pluripotent stem cells from deletion carriers and controls, as well as utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Upon differentiation into neural progenitor cells, we found the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including Autism Spectrum Disorder. In more differentiated excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common (per-SNP heritability p ({tau}c)= 4.2 x 10-6) and rare, loss of function variants (p = 1.29x10-12). These findings suggest a potential relationship between cellular states, developmental windows and susceptibility to psychiatric conditions with different ages of onset. To understand how the deletion contributed to these observed changes in gene expression, we developed and applied PPItools, which identifies the minimal protein-protein interaction network that best explains an observed set of gene expression alterations. We found that many of the genes in the 22q11.2 interval interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways that underlie the broader alterations in psychiatric risk gene expression we identified. Our findings suggest that the 22q11.2 deletion impacts genes and pathways that may converge with risk loci implicated by psychiatric genetic studies to influence disease manifestation in each deletion carrier.

neuroscience↗

bioRxiv2021

Physical localization of 45S rDNA in Cymbopogon and the analysis of differential distribution of rDNA in homologous chromosomes of Cymbopogon winterianus.

Cymbopogon, commonly known as lemon grass, is one of the most important aromatic grasses having therapeutic and medicinal values. FISH signals on somatic chromosome spreads off Cymbopogon species indicated the localization of 45S rDNA on the terminal region of short arms of a chromosome pair. A considerable interspecific variation in the intensity of 45S rDNA hybridization signals was observed in the cultivars of Cymbopogon winterianus and Cymbopogon flexuosus. Furthermore, in all the varieties of Cymbopogon winterianus namely Bio-13, Manjari and Medini, a differential distribution of 45S rDNA was observed in a heterologous pair of chromosome 1. The development of Cymbopogon winterianus var. Manjari through gamma radiation may be responsible for breakage of fragile rDNA site from one of the chromosomes of this heterologous chromosome pair. While, in other two varieties of Cymbopogon winterianus (Bio-13 and Medini), this variability may be because of evolutionary speciation due to natural cross among two species of Cymbopogon which was fixed through clonal propagation. However, in both the situations these changes were fixed by vegetative method of propagation which is general mode of reproduction in the case of Cymbopogon winterianus.

genetics↗

bioRxiv2021

Top-down control of hippocampal signal-to-noise by prefrontal long-range inhibition

The prefrontal cortex (PFC) is postulated to exert top-down control by modulating information processing throughout the brain to promote specific actions based on current goals. However, the pathways mediating top-down control remain poorly understood. In particular, knowledge about direct prefrontal connections that might facilitate top-down prefrontal control of information processing in the hippocampus remains sparse. Here we describe novel monosynaptic long-range GABAergic projections from PFC to hippocampus. These preferentially inhibit vasoactive intestinal polypeptide expressing interneurons, which are known to disinhibit hippocampal microcircuits. Indeed, stimulating prefrontal-hippocampal GABAergic projections increases hippocampal feedforward inhibition and reduces hippocampal activity in vivo. The net effect of these actions is to specifically enhance the signal-to-noise ratio for hippocampal representations of objects. Correspondingly, stimulation of PFC-to-hippocampus GABAergic projections promotes object exploration. Together, these results elucidate a novel top-down pathway in which long-range GABAergic projections target disinhibitory microcircuits, thereby enhancing signals and network dynamics underlying exploratory behavior.

neuroscience↗