Biology subjects

Ahmed, F.

Publications and source records attributed to Ahmed, F..

At least 19 recordsLinked to original sources

bioRxiv2026

Enhanced cortical tracking of unfamiliar languages in both monolinguals and bilinguals

Humans routinely encounter speech in languages they have never heard, yet how the brain responds to such input and whether bilingual experience shapes this response remains unknown. Here, we used electroencephalography (EEG) and temporal response function (TRF) modeling to examine cortical tracking of the speech envelope in 24 English-monolingual and 24 English-Mandarin bilingual adults. Participants listened to naturally produced continuous speech in three languages: English (familiar to all), Mandarin (familiar to bilinguals only), and Vietnamese (unfamiliar to all). We report two main findings. First, both monolinguals and bilinguals showed enhanced cortical tracking for unfamiliar relative to familiar languages, evidenced by higher EEG prediction accuracy (PA). Monolinguals showed enhanced tracking for both Mandarin and Vietnamese, whereas bilinguals showed enhancement only for Vietnamese, consistent with Mandarin being a familiar language for this group. This finding suggests that enhanced cortical encoding of unfamiliar speech is a general property of the listening brain, not a signature of listening to a non-native language or reduced language proficiency. Second, bilinguals strikingly showed stronger cortical tracking than monolinguals overall, in both PA and TRF peak weights, with the TRF peak weight advantage present across all three languages, suggesting a difference in how bilingual experience shapes the neural encoding of speech. These findings have implications for understanding how the brain navigates the linguistic diversity of everyday life in an increasingly global, multilingual world.

neuroscience↗

bioRxiv2026

Structural Basis for Dimeric Genome Selection by HIV-1

HIV-1 packages a dimeric RNA genome into assembling virions, a requirement for replication. To understand the mechanism of dimer selection, we conducted cryogenic electron microscopy (cryoEM) studies of nascent assemblies formed between HIV-1 Gag protein constructs and genomic RNA elements that promote dimerization and packaging. CryoEM maps revealed structural architectures in which the helical dimer initiation signal (DIS) of the RNA packaging signal bridges two 6-helix bundles (6HBs) that protrude from adjacent Gag hexamers. Conserved guanosines that sandwich the DIS are located beneath the 6HBs and poised to interact with clusters of nucleocapsid domains. Mutation of these guanosines severely impairs RNA packaging into virus-like particles. Our findings suggest that DIS functions as a molecular ruler, organizing Gag hexamers into structures optimized for Gag lattice expansion.

molecular biology↗

bioRxiv2026

Exclusive liquid repellency isolation (ELRi) microliter scale isolation technique unmasks T-cell migration defects to CCL21 in pediatric asthma

Exclusive Liquid Repellency Isolation (ELRi) is a novel, chip-free platform designed for efficient microscale immune cell isolation. Leveraging the inherent exclusive liquid repellency (ELR) properties of polypropylene tubes with an oil overlay, ELRi ensures that small sample volumes, as low as 8 L, have no contact with container walls, preventing cell loss. Here we describe ELRi and demonstrate magnetic bead-based isolation of diverse immune cells, including T cells, and monocytes, from whole blood. The platforms utility is highlighted in its application to pediatric asthma research, where sample volume is highly restricted. It has been reported that the T cell homing receptor CCR7 is downregulated in cells from asthmatic patients, but a direct functional link to impaired cell migration remains unconfirmed (1, 2). Using ELRi-isolated cells, we provide the first functional evidence that T cells from asthmatic children exhibit significantly impaired chemotaxis toward the CCR7 ligand, CCL21. By simplifying RBC depletion and enabling such functional assays alongside RNA sequencing from the same tiny sample, ELRi overcomes the limitations of large-volume flow cytometry or cell-specific sorting methods. Easily integrated into lab workflows and scalable for various needs, ELRi facilitates more frequent, minimally invasive, and functionally informative immune profiling of restricted volume samples.

immunology↗

bioRxiv2026

One-Pot NADH-Mediated Physiological Redox-Controlled Synthesis of Papain-Stabilized Copper Nanoclusters with Preserved Bioactivity for Efficient Drug Delivery

Protein-protected copper nanoclusters are promising candidates for bioimaging and therapeutic applications. However, harsh reducing conditions required for their synthesis, compromising the proteins structural integrity and bioactivity. Here, we report a one-pot, physiologically compatible aqueous synthesis for papain-protected copper nanoclusters (Pap-CuNCs) with blue photoluminescence and excellent photostability using nicotinamide adenine dinucleotide (NADH) as a biological reducing agent. The mild conditions (ambient temperature, neutral pH) enable the simultaneous formation of a metallic Cu0 core while stabilizing the helical content of the protein. This approach introduces a physiologically redox-controlled strategy for nanocluster formation, establishing physiological redox chemistry as a governing principle for controlling nanoscale structure and protein conformational stability. Spectroscopic and microscopic studies have demonstrated the presence of crystalline nanoclusters with a protein corona that undergoes -helical stabilization as revealed by circular dichroism. Notably, atomistic simulation studies reveal preferential binding of the copper core in the proteins active site, enhancing the -helical content of papain, consistent with experimental observations. Functionally, the Pap-CuNCs possess biocompatibility and serve as an effective delivery platform for 5-fluorouracil, leading to a 50-fold decrease in IC50 for HeLa cells without causing cytotoxicity to normal cells. This establishes a generalizable framework for bio-integrated nanocluster design under biologically compatible conditions. TOC Text O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=44 SRC="FIGDIR/small/719779v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1ca9292org.highwire.dtl.DTLVardef@5cd82aorg.highwire.dtl.DTLVardef@173ed2forg.highwire.dtl.DTLVardef@1d8c30c_HPS_FORMAT_FIGEXP M_FIG C_FIG NADH-mediated physiological redox synthesis of papain-stabilized copper nanoclusters with enhanced -helical stability. This bio-integrated nanoplatform facilitates drug loading and delivery, resulting in a [~]50-fold increase in cytotoxicity in cancer cells while maintaining excellent biocompatibility toward normal cells.

bioengineering↗

bioRxiv2026

Molecular basis for ligand-gating of the human GluD1 receptor

The delta-type ionotropic glutamate receptors (iGluRs) GluD1 and GluD2 are ligand-gated ion channels that are fundamental for regulating both excitatory and inhibitory synapses. Rising evidence points to the role of GluD1 in the development of neurological diseases. However, the ultrastructure of human GluD1 (hGluD1) and the molecular basis for its ligand-gating remain unclear. Here, we define the structure of hGluD1 and resolve its ligand-gating mechanism using cryo-electron microscopy (cryoEM) and single channel bilayer recording. While hGluD1 exhibits a non-swapped architecture, it contains conserved iGluR moieties that enable ligand-gating, such as a ligand-binding domain (LBD) tethered to a transmembrane ion channel. Binding of the neurotransmitter {gamma}-aminobutyric acid (GABA) or D-serine to the LBD enables cation influx through the hGluD1 ion channel. Our findings delineate the molecular architecture and function of hGluD1, provide foundations for understanding patient mutations in hGluD1, and will invigorate therapeutic development against hGluD1.

biophysics↗

bioRxiv2026

In silico transcriptomic analysis reveals shared molecular signatures and immune-associated pathways between Hashimotos thyroiditis and type 2 diabetes with exploratory drug repurposing

The management of Hashimotos thyroiditis (HT), one of the most prevalent autoimmune disorders worldwide, becomes more complex when it coexists with type 2 diabetes (T2D) compared with the management of either disease alone. This complexity may arise from overlapping genetic, metabolic, and immune dysregulation, as well as potential therapeutic conflicts. Although HT and T2D are known to co-occur and share immune and metabolic features, the molecular characteristics underlying these overlaps have not been systematically explored. This study aimed to identify shared gene expression signatures and associated biological pathways between HT and T2D using an in silico, hypothesis-generating approach, and to explore candidate compounds that may be relevant to both conditions. Independent transcriptomic datasets (GSE138198 for control/HT and GSE29231 for control/T2D) were analyzed, leading to the identification of 59 genes that were differentially expressed in both HT and T2D compared with control samples. Protein-protein interaction (PPI) network analysis prioritized five shared key genes (sKGs): CDC42, CD74, FOS, RAC2, and YWHAB. Functional enrichment analysis of these sKGs revealed overlapping biological processes, molecular functions, cellular components, and immune-related signaling pathways, as well as shared regulatory networks involving transcription factors (FOXC1 and HNF4A) and microRNAs (hsa-miR-221-3p and hsa-miR-29a-3p). Immune infiltration analysis demonstrated broadly similar patterns of immune dysregulation in both diseases, providing additional biological context for the observed shared molecular signatures. Finally, an exploratory in silico drug repurposing pipeline incorporating molecular docking, ADMET profiling, drug-likeness assessment, and molecular dynamics simulations prioritized three candidate compounds: gliquidone, oleanolic acid, and glipizide for further investigation. Overall, this study provides a hypothesis-generating framework highlighting shared molecular features between HT and T2D, which may inform future experimental validation and clinical research. Author SummaryIn this work, we wanted to better understand why Hashimotos thyroiditis, an autoimmune condition that affects the thyroid gland, is often seen in people who also have type 2 diabetes. Treating patients who live with both conditions can be difficult, and we were interested in finding out whether they share common biological causes. To do this, we examined genetic data from individuals with each disease and looked for patterns that appeared in both groups. We discovered several genes that seem to act in similar ways in the two conditions, particularly genes linked to immune system activity and associated pathways. This finding suggests that shared molecular signatures and immune-associated pathways may play a role in the development of both diseases. We also explored how these shared genetic features influence larger biological processes and immune responses. The similarities we found support the idea that the two diseases may be connected through related biological pathways. In addition, we used computer-based screening methods to identify existing drugs that might influence these shared pathways. While these results need further testing, we hope our findings help open new directions for research and eventually contribute to better care for patients affected by both conditions.

bioinformatics↗

bioRxiv2026

Infant cortical tracking of speech shows emerging spatial release from masking in the first year of life

Natural listening environments are filled with competing sounds. One mechanism that helps overcome this challenge is spatial release from masking (SRM), whereby spatial separation between a target signal and interfering sounds improves perception of the target. SRM has been observed in a wide range of species including songbirds, crocodilians, ferrets, and human adults, suggesting an evolutionarily conserved strategy for listening in noise. However, an important question remains: Is an infants developing brain able to tap into the same mechanism to cope with the noisy world? To address this question, we recorded electroencephalography (EEG) from 7- and 11-month-old infants (N = 53) and adults (N = 20) as they listened to natural speech in quiet, collocated noise, and spatially segregated noise. Our results revealed that both infants and adults showed robust cortical tracking of speech across quiet and noisy listening conditions. For adults, spatial separation between the target speaker and distracting talkers led to enhanced cortical tracking of the target speech, consistent with SRM. Infants also showed SRM, with stronger tracking in segregated than collocated noise, although the effect was confined to a frontal-central region rather than broadly distributed across the scalp as in adults. These findings provide the first neurophysiological evidence that, although still immature, the developing brain can benefit from spatial cues in the first year of life. Together, these results add new insight into how the infant brain solves a fundamental perceptual problem - identifying a relevant voice in a noisy environment - using a mechanism that is evolutionarily grounded.

neuroscience↗

bioRxiv2025

Oral administration of engineered recombinant outer membrane vesicles-based nano-vaccine formulation triggers robust mucosal and systemic humoral immunity against poultry pathogens

Although vaccination is an integral part of poultry health management, affordable, scalable, and easily administrable new-generation vaccine discovery platforms are required to combat emerging infectious diseases. Oral vaccines offer an alternative to injectable options owing to their ease of administration; however, existing platforms fail to confer robust protective systemic and mucosal immunity. Here, we used engineered outer membrane vesicles (rOMVs) displaying the desired vaccine antigens, and derived from hypervesiculating probiotic E coli Nissle 1917 (EcN) [36], which elicits both mucosal and systemic immunity when administered orally. Using such approach, we attempted to formulate rOMV based single Oral vaccine against Newcastle Disease Virus (NDV) and Infectious Bursal Disease Virus (IBDV), which pose significant risks to the poultry sector. We engineered rOMVs to display the antigenic regions of immunodominant Hemagglutinin-Neuraminidase (HN) and Viral Protein 2 (VP2) of NDV and IBDV, respectively, on their surface, with sizes less than 150 nm and considerable polydispersity. The Oral administration of these rOMVs expressing the HN and VP2 induced a robust immune response which shows enhanced production of high-titer antigen-specific sIgA and IgG, which were able to neutralize the virus effectively in an in-vitro infection model system. While the poultry pathogens such as NDV and IBDV served as a model, the rOMV-based platforms hold considerable potential for the development of a multivalent oral biotherapeutic agent, including vaccines against a wide range of emerging human and animal pathogens by engineering rOMVs to display immunodominant antigenic portions, demonstrating its capability as a next-generation oral vaccine discovery platform.

immunology↗

bioRxiv2025

MYC-induced oncogenesis is dependent on acidic patches within its N-terminal intrinsically disordered domain.

MYC is one of the most enticing therapeutic targets for cancer but clinical-grade inhibitors are still lacking. By site-saturation mutagenesis screening, we identified several evolutionarily conserved acidic patches within the intrinsically-disordered MYC N-terminus that were confirmed to be functionally essential in different cell models and in vivo. Beyond modulating MYCs global transcriptional activity, these negatively charged patches regulate the interaction with chromatin-modifying complexes including those with histone acetyl-transferase activity. One of the key interactions is established with the co-factor TRRAP, a subunit shared between several Histone Acetyl-Transferase complexes. The protein-protein binding between MYC and TRRAP predominantly relies on two of the N-terminal negative clusters that are located outside MYC-Box-II (MBII) and drive oncogenesis. Our work identifies a new multivalent MYC subdomain that presents new therapeutic vulnerabilities providing invaluable insights for the development of new therapeutic approaches.

cancer biology↗

bioRxiv2025

ALOX12B overexpression in the skin drives inflammasome/Th17 signaling axis to promote inflammation in the mouse model and human patients

Inflammation plays a pivotal role in the etiopathogenesis of chronic inflammatory skin diseases. However, the underlying mechanism remains unclear. Here, we employed Gene expression meta-analysis and clinical validation strategy to dissect the global architecture of immune dysregulation responsible for inflammatory conditions in the skin. Using such approaches, we identified a gene signature comprising of ALOX12B, which is significantly upregulated in psoriatic and atopic dermatitis patient skin samples, and correlates with increased levels of pathological IL-1{beta} and Th17 responses. Surprisingly, ALOX12B is predominantly expressed in the skin. Furthermore, skin-specific overexpression of human ALOX12B in transgenic mice resulted in psoriasis-like inflammatory symptoms, including epidermal hyperplasia, immune cell infiltration, and elevated IL-1{beta}/Th17 responses. ALOX12B is a non-heme iron-containing enzyme that catalyses the production of 12R-HETE from polyunsaturated fatty acids such as arachidonic acid. Mechanistically, we found that ALOX12B/12R-HETE accumulation in the skin acts as an intrinsic danger signal that triggers enhanced IL-1{beta} processing and secretion via ROS generation and NLRP3 inflammasome activation. Increased IL-1{beta} levels in turn drive IL-17 producing T-cell polarization. We further designed a novel first-in-class, potent ALOX12B inhibitor, 6a, which exhibited favorable topical pharmacokinetic and safety profiles. The topical application of 6a reduced inflammation-associated pathologies in Tg-hALOX12B mice by suppressing 12R-HETE-induced IL-1{beta} production and ROS generation. These findings revealed a novel mechanism mediated by ALOX12B/12R-HETE overexpression that controls skin inflammation, thereby providing a promising therapeutic target for treating inflammatory skin diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/658245v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@13cdf3forg.highwire.dtl.DTLVardef@164cac3org.highwire.dtl.DTLVardef@3c0364org.highwire.dtl.DTLVardef@2ca91_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO The proposed mechanism through which ALOX12B modulates the inflammatory pathway in psoriasiform-like inflammatory conditions in the skin. The study provides insight into the role of ALOX12B in skin inflammation. Increased levels of ALOX12B expression in the skin result in 12R-HETE accumulation, which subsequently triggers the IL-1/Th17 inflammatory cascade through ROS generation and inflammasome activation. IL-1 produced by the activated inflammasome leads to the polarization of naive T-cells to activated IL-17 producing CD4+ T-cells, which are involved in the skin-inflammation related pathologies such as keratinocyte proliferation, and cellular infiltration. Hence, we propose ALOX12B as a novel potential therapeutic target for psoriasis-like inflammatory skin disorders. Additionally, we designed a novel first-in-class ALOX12B inhibitor, 6a; which shows a substantial alleviation in ALOX12B enzymatic activity, thereby reducing cellular ROS, which in turn results in reduced levels of IL-1, as a result inhibiting IL-1/Th17 inflammatory pathway and subsequent reduction in pathological inflammatory skin conditions. A portion of the image was created using Biorender.com C_FIG HighlightsO_LIALOX12B is a key gene upregulated in the skin during psoriasis and atopic dermatitis. C_LIO_LITransgenic mice overexpressing ALOX12B in the skin developed Psoriasis-like inflammatory symptoms. C_LIO_LIMechanistically, ALOX12B, through 12R-HETE, enhanced IL-1{beta} production via ROS generation and NLRP3 inflammasome activation. Further elevated IL-1{beta} production promotes Th17 cell polarization. C_LIO_LINovel first-in-class ALOX12B inhibitor alleviates inflammatory symptoms in a transgenic mouse model. C_LIO_LIStudy reveals a crucial ALOX12B/12R-HETE-inflammasome-IL-17 axis involvement in inflammatory skin diseases. C_LI

immunology↗

bioRxiv2025

WNK1 kinase activity is required for maintenance of podocyte structure

The filtration-function of glomeruli requires slit diaphragms formed by interdigitating podocyte foot processes, which are actin-based membrane protrusions. Dysregulation of mechanisms that maintain these membrane extensions lead to foot process effacement, proteinuria, and progression to chronic kidney disease. Building on our previous work that showed WNK1 kinase activity is necessary for the maintenance of normal biomechanical properties of glomeruli and podocyte foot process architecture, we tested the hypothesis that WNK1 kinase activity affects the structure of podocyte foot processes through modulation of actomyosin activity and focal adhesion complexes. Using a WNK1 kinase specific inhibitor, we determined by immunofluorescence microscopy of nascent focal adhesions, podocyte membrane spreading/extensions, and NMII paralog localization and extent of activation calculated from quantification of phosphorylated myosin, that all were sensitive to WNK1 kinase activity. Moreover, biochemical evidence of WNK1 kinase activity-dependent signalosomes supports a role for WNK1 in the maintenance of podocyte foot processes, and sarcomere-like structures (SLSs) that are induced in models of podocyte injury. Using primary and immortalized podocyte cell lines developed from control and Col4a3-/-Alport Syndrome model mice, we measured WNK1 kinase activity-dependent improvement in properties of injured podocytes in vitro. Physiological relevance of WNK1 kinase activity-dependent structural maintenance of podocyte foot processes was confirmed by significant acute proteinuria measured in response to WNK1 inhibition in vivo. Collectively, the results provide evidence that WNK1 kinase signalosome activity that includes formation of nascent focal adhesions and regulation of NMII localization and activity at membrane protrusions and extensions, are necessary for physiological maintenance of slit diaphragms. SignificanceTerminally differentiated podocytes are arborized cells with interdigitating foot processes that form the renal filtration barrier. Loss of foot process structural integrity causes progressive proteinuria, which can lead to irreversible renal injury, but the mechanisms that maintain foot process structure are incompletely understood. We report evidence that WNK1 kinase activity is required for maintenance of normal glomerular filtration in vivo, and this is mediated in part through WNK1 activity-dependent modulation of non-muscle myosin II activity, and formation of nascent focal adhesions that are necessary for lamellipodial extensions. Using glomeruli and podocyte cell lines developed from an Alport Syndrome podocyte injury model, we show that aspects of abnormal podocyte structure associated with chronic kidney disease can be suppressed through increased WNK1 activation.

cell biology↗

bioRxiv2025

Programing Immunogenicity of Dengue EDIII Vaccine Antigens Using Engineered Outer Membrane Vesicles (OMVs)

Dengue is a mosquito-borne viral infection and is more prevalent in the world with no therapeutics and suboptimal vaccine performance against all four serotypes of the dengue virus. Hence, there is an urgent requirement for a non-infectious and non-replicative vaccine candidate that can elicit a balanced and serotype-specific immune response. In this study, we have engineered bacterial outer membrane vesicles (rOMVs) that display EDIII antigens (EDIII rOMVs). The current formulation modulates the expression of costimulatory molecules on antigen-presenting cells (APCs) as well as enhances the uptake and presentation. Subsequently, the EDIII rOMVs elicited a strong antigen-specific polyfunctional response from CD4+ and CD8+ T cells. The robust antibody response was facilitated by a germinal center reaction characterized by high T follicular helper (Tfh) and B cell response levels in the mice that received EDIII rOMVs. Notably, the produced antibodies demonstrated the ability to neutralize all four dengue virus serotypes in an in vitro infection model, indicating its potential role in protective immunity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/640071v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@689d81org.highwire.dtl.DTLVardef@3c878aorg.highwire.dtl.DTLVardef@1e6b1aaorg.highwire.dtl.DTLVardef@9a5180_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Mechanisms of maternal antibody interference to rotavirus vaccination

Maternal antibodies (MatAbs) are transferred transplacentally during pregnancy and through breast milk after birth to provide protection whilst the neonatal immune response is immature. However, MatAbs also suppress the development of neonatal B cell responses via mechanisms that are not well defined. MatAbs can therefore result in poor vaccine performance in the infant, placing them at risk against potentially life-threatening pathogens such as rotavirus. It is essential we understand the mechanisms by which MatAbs interact with neonatal immunity, so that strategies can be developed to overcome this major vaccine issue. To investigate mechanisms of interference we developed a mouse model of neonatal oral rotavirus vaccination in the presence and absence of MatAbs. Oral vaccination with attenuated murine rotavirus induced robust neonatal antibody responses, whereas vaccination failed to induce seroconversion in the presence of MatAbs. Vaccination with heterologous strains, reduced MatAb titers and vaccination in Fc{gamma}RIIB knockout mice did not overcome interference. However, live vaccine replication was blocked in the presence of MatAbs and more rapid waning of MatAbs was observed following vaccination. This is indicative of premature vaccine clearance and likely reduced antigen encounter by B cells. Single-cell RNA sequencing of mesenteric lymph nodes revealed diminished plasma and germinal center B cell subpopulations as well as global reduction of interferon-stimulated genes in the presence of MatAbs. Our model has also enabled identification of strategies to reduce the effects of interference. In summary, we have tested multiple hypotheses for MatAb-mediated interference to rotavirus vaccination in a mouse model, and demonstrated that premature Fc{gamma}RIIB signaling and epitope masking are not the primary mechanisms of vaccine failure. Rather our data supports the conclusion that MatAb-mediated vaccine clearance is a key mechanism of interference to oral rotavirus vaccine.

immunology↗

bioRxiv2025

Metabolic reprogramming in the spinal cord drives the transition to pain chronicity

Acute injuries can progress into painful states that endure long after healing. The mechanisms underlying this transition remain unclear, but metabolic adaptations to the bioenergy demands imposed by injury are plausible contributors. Here we show that peripheral injury activates AKT/mTORC1 in afferent segments of the mouse spinal cord, redirecting local core metabolism toward biomass production while simultaneously suppressing autophagy-mediated biomass reclamation. This metabolic shift supports neuroplasticity, but creates a resource bottleneck that depletes critical spinal cord nutrients. Preventing this depletion with a modified diet normalizes biomass generation and autophagy and halts the transition to chronic pain. This effect, observed across multiple pain models, requires activation of the nutrient sensors, sirtuin-1 and AMPK, as well as restoration of autophagy. The findings identify metabolic reprogramming and consequent autophagy suppression as key drivers of the progression to pain chronicity and highlight nutritional and pharmacological interventions that could prevent this progression after surgery or other physical traumas.

neuroscience↗

bioRxiv2025

Argonaute proteins regulate the timing of the spermatogenic transcriptional program

Argonaute proteins are best known for their role in microRNA-mediated post-transcriptional gene silencing. Here, we show that AGO3 and AGO4, but not AGO2, localize to the sex chromatin of pachytene spermatocytes where they are required for transcriptional silencing of XY-linked genes, known as Meiotic Sex Chromosome Inactivation (MSCI). Using an Ago413-/- mouse, we show that AGO3 and AGO4 are key regulators of spermatogenesis, orchestrating expression of meiosis-related genes during prophase I while maintaining silencing of spermiogenesis genes. Premature overexpression of spermiogenesis genes during prophase I in Ago413-/- mice results in subfertility, altered sperm morphology and reduced fertilization capability. We also identify BRG1, a BAF complex subunit, as an AGO3 interactor. Loss of AGO3 and AGO4 results in increased BRG1 in spermatocytes, suggesting that AGO3 aids in removing BRG1 from the XY chromatin to achieve MSCI and demonstrating a meiotic role for AGO3 in transcriptional control through the chromatin remodeling machinery.

developmental biology↗

bioRxiv2024

Causality Mapping Using Resting-state fMRI Reveals Hyperactivity and Hypoconnectivity in Schizophrenia Patients

Schizophrenia (SZ) is a debilitating disorder in which patients exhibit psychotic behavior due to aberrant connectivity between different regions of the brain. Advances in neuroimaging have now enabled the diagnosis and analysis of SZ in order to elucidate the whole brain functional connectivity networks. In the present study, we have used resting-state functional magnetic resonance imaging (rs-fMRI) to elucidate the causal relationships amongst the differentially activated brain regions between SZ patients (n=10) and healthy controls (n=10). Vector auto-regression (VAR) model and Granger causality (GC) were then applied to construct a functional connectivity network and analyze the causal effects in SZ patients. Our results revealed that the average voxel activation in the frontal lobe (FL), basal ganglia (BG), and ventricular system (VS) was significantly higher in patients indicating hyper-activity as compared to controls. Conversely, cerebellum white matter (CBWM) showed higher activation in the controls as compared to patients. A higher Pearson correlation was observed between the controls as compared to patients while VAR and GC showed higher functional connectivity among all the regions of interest (ROIs) along with more causal relations in the controls. Finally, mediation analysis showed that right middle superior frontal gyrus acts as a strong partial mediator between left accumbens area and left middle superior frontal gyrus. Taken together, this study decodes the dysregulated brain activity in schizophrenia showing hyperactivation in patients when compared with the healthy controls which leads to alterations in neural connections resulting in hypoconnectivity.

neuroscience↗

bioRxiv2023

The effect of gaze on EEG measures of multisensory integration in a cocktail party scenario

Seeing the speakers face greatly improves our speech comprehension in noisy environments. This is due to the brains ability to combine the auditory and the visual information around us, a process known as multisensory integration. Selective attention also strongly influences what we comprehend in scenarios with multiple speakers - an effect known as the cocktail-party phenomenon. However, the interaction between attention and multisensory integration is not fully understood, especially when it comes to natural, continuous speech. In a recent electroencephalography (EEG) study, we explored this issue and showed that multisensory integration is enhanced when an audiovisual speaker is attended compared to when that speaker is unattended. Here, we extend that work to investigate how this interaction varies depending on a persons gaze behavior, which affects the quality of the visual information they have access to. To do so, we recorded EEG from 31 healthy adults as they performed selective attention tasks in several paradigms involving two concurrently presented audiovisual speakers. We then modeled how the recorded EEG related to the audio speech (envelope) of the presented speakers. Crucially, we compared two classes of model - one that assumed underlying multisensory integration (AV) versus another that assumed two independent unisensory audio and visual processes (A+V). This comparison revealed evidence of strong attentional effects on multisensory integration when participants were looking directly at the face of an audiovisual speaker. This effect was not apparent when the speakers face was in the peripheral vision of the participants. Overall, our findings suggest a strong influence of attention on multisensory integration when high fidelity visual (articulatory) speech information is available. More generally, this suggests that the interplay between attention and multisensory integration during natural audiovisual speech is dynamic and is adaptable based on the specific task and environment.

neuroscience↗

bioRxiv2023

Integration of genetic fine-mapping and multi-omics data reveals candidate effector genes for hypertension

Genome-wide association studies of blood pressure (BP) have identified >1000 loci but the effector genes and biological pathways at these loci are mostly unknown. Using published meta-analysis summary statistics, we conducted annotation-informed fine-mapping incorporating tissue-specific chromatin segmentation to identify causal variants and candidate effector genes for systolic BP, diastolic BP, and pulse pressure. We observed 532 distinct signals associated with [≥]2 BP traits and 84 with all three. For >20% of signals, a single variant accounted for >75% posterior probability, 65 were missense variants in known (SLC39A8, ADRB2, DBH) and previously unreported BP candidate genes (NRIP1, MMP14). In disease-relevant tissues, we colocalized >80 and >400 distinct signals for each BP trait with cis-eQTLs, and regulatory regions from promoter capture Hi-C, respectively. Integrating mouse, human disorder, tissue expression data and literature review, we provide consolidated evidence for 394 BP candidate genes for future functional validation and identifies several new drug targets.

genetics↗