Biology subjects

Goel, A.

Publications and source records attributed to Goel, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Multiscale Transcriptomic Architecture of the ALS Motor Cortex

Amyotrophic lateral sclerosis (ALS) exhibits marked clinical and molecular heterogeneity, but how this heterogeneity is organized within disease-relevant central nervous system regions remains incompletely understood. Because pooled cross-region analyses may confound regional variation with subtype structure, we focused on the motor cortex, a key site of ALS pathology, to resolve its internal transcriptomic organization. Using approximately 600 postmortem motor cortex transcriptomes from the Target ALS resource, we applied gene set variation analysis to generate sample-level pathway activity profiles and performed consensus clustering in pathway space. We identified seven reproducible ALS motor cortex subtypes characterized by distinct inflammatory, damage-response, metabolic, glial, and neuronal/synaptic programs. Donor-held-out projection recovered the seven subtype assignments with a mean balanced accuracy of 0.939, supporting the reproducibility of the pathway-defined subtype structure in unseen donors. Mapping these bulk-defined programs to an independent motor-cortex single-nucleus RNA-seq dataset revealed distinct cellular contexts, while cell-type marker adjustment showed that cellular differences contributed to, but did not fully account for, subtype-associated pathway variation. The seven subtypes also recapitulated major molecular programs reported in previous ALS subtype frameworks while resolving them into finer motor-cortex-specific states. Rather than forming isolated molecular classes, these subtypes occupied a structured pathway-space landscape with both discrete subtype-centered peaks and continuous biological gradients. Principal component analysis and representative pathway overlays defined a major axis from an upper inflammatory/damage region to a lower neuronal/metabolic/remodeling region, with C7 forming a neuronal/synaptic connector within the lower landscape. Co-expression network analysis further supported this multiscale organization, revealing family-level network backbones, subtype-specific modular refinements, and bridge-like rewiring. Metadata-informed analyses showed that this molecular architecture was not primarily organized by disease duration. Instead, the landscape was more clearly associated with clinical and genetic-background variables, including ALS/FTD family history and mutation-related signals. In particular, family-history-positive and C9orf72 repeat expansion-positive samples were more represented in the lower neuronal/metabolic/remodeling region, whereas family-history-negative samples and C9orf72-negative cases were more represented in the upper inflammatory/damage region. These findings support a model in which ALS motor cortex heterogeneity is organized as a multiscale transcriptomic architecture more closely associated with genetic-background variables than with disease duration. This framework provides a basis for subtype-aware biological comparison, future patient-stratification, biomarker, or therapeutic target-prioritization studies.

bioinformatics↗

bioRxiv2026

Intranasal adenovirus type 5 influenza vaccination enhances milk antibody responses and passive transfer to neonatal ferrets

Newborns and infants are particularly vulnerable to influenza, largely due to the immaturity of their immune systems. As such, maternal immunization is a valuable strategy to enhance influenza-neutralizing antibodies in both blood and breast milk, ensuring optimal passive immunity transfer to the infant. In our pregnant and lactating ferret maternal-neonatal model, we evaluated antibody responses to an adenovirus type 5-vectored H1N1 hemagglutinin vaccine delivered enterically, intranasally, or intramuscularly. While all three routes elicited a robust antibody response compared to saline-treated controls, intranasal vaccination significantly increased influenza-specific antibodies in dam serum, upper respiratory tract secretions, and milk, and subsequent transfer to suckling kits. Our results suggest that intranasal immunization was the most effective route for inducing functional influenza-specific antibodies in both dam serum and milk, with efficient passive transfer to suckling kits. Leveraging mucosal immune induction may enhance maternal antibody responses, transfer to offspring, and downstream neonatal protection.

microbiology↗

bioRxiv2026

AGPI: An AI-Powered Genomic Pathogen Intelligence Platform for Integrated Classification, Visualization, and Therapeutic Targeting

Rapid and accurate pathogen detection remains a major challenge in modern bioinformatics, as existing tools are often fragmented and require multiple specialized workflows. We present AGPI (AI-powered Genomic Pathogen Intelligence), an integrated platform that combines genomic sequence classification, biological enrichment, three-dimensional structural visualization, and AI-guided therapeutic prioritization within a single interpretable pipeline. AGPI employs a hybrid convolutional-Bidirectional Gated Recurrent Unit (BiGRU) architecture trained on DNA sequences from 40 pathogen classes spanning viruses, bacteria, fungi, and protozoan pathogens. The model achieved 99.61% validation accuracy and 94.90% accuracy on an independent held-out evaluation of 600 pathogen sequences following iterative refinement. As a proof of concept, AGPI correctly classified a Zika virus genome with 96.14% confidence, retrieved curated biological context from 245 peer-reviewed studies, and identified Ribavirin as a leading therapeutic candidate against the Zika NS5 polymerase through AI-guided molecular docking. Multi-metric ligand similarity analysis further differentiated candidate compounds according to their structural and pharmacological properties. These results demonstrate that integrated AI-driven genomic pipelines can accelerate pathogen characterization and therapeutic hypothesis generation while providing an accessible and interpretable framework for infectious disease surveillance and computational drug repurposing.

bioinformatics↗

bioRxiv2026

Chromatin architecture sets origin licensing capacity

Replication origin licensing enables complete and faithful genome duplication, yet how chromatin regulates this process in vivo remains unclear. Using MCM-ChEC-seq to track helicase loading from metaphase through G1 in budding yeast, we find that licensing occurs in a rapid, synchronous burst at mitotic exit and then reaches an early plateau despite continued permissive cell-cycle conditions and persistent ORC binding at origins. Here we show that this plateau is imposed by chromatin architecture at replication origins, which limits the extent of origin licensing. Histone H3K56 acetylation marks newly replicated chromatin and is removed at S-phase exit by the deacetylases Hst3 and Hst4. Persistent H3K56ac severely impairs MCM loading without affecting ORC occupancy, indicating that chromatin limits licensing at the helicase-loading step. Strikingly, deletion or catalytic inactivation of the chromatin remodeler Isw2 increases licensing by approximately 40% in wild-type cells and fully suppresses the licensing defect in hst3{Delta} hst4{Delta} mutants, identifying Isw2 as a physiological inhibitor of origin licensing. Isw2-dependent nucleosome repositioning narrows the origin nucleosome-depleted region and restricts helicase loading. Together, these findings show that chromatin architecture at replication origins sets licensing capacity. Newly replicated chromatin transiently adopts an Isw2-dependent inhibitory configuration that is relieved, but not completely eliminated, by post-replicative chromatin maturation. Genome-wide licensing thus reflects integration of chromatin-imposed licensing capacity with cell cycle-dependent control of licensing timing.

genetics↗

bioRxiv2025

Aberrant Neural Entrainment to Word-Level Speech Patterns in Fragile X Syndrome: Evidence for a Statistical Learning Deficit

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder, causes significant language and cognitive impairments. Statistical learning refers to the ability to extract patterns from sensory input through mere exposure and plays a central role in language acquisition. Surprisingly, statistical learning in FXS has not been explored. Given that children with FXS typically follow a delayed developmental trajectory for language, we hypothesized that they would show impaired statistical learning. To test this hypothesis, we used an EEG measure of neural entrainment to index statistical learning of hidden trisyllabic words within a continuous speech stream in children with FXS (n = 17) and in typically developing controls (n = 31). Children with FXS showed significantly reduced neural entrainment to words compared to controls, particularly in the superior temporal gyrus and transverse temporal gyrus (primary auditory cortex), providing evidence of statistical learning impairment. Notably, syllable-level entrainment was preserved or even enhanced in FXS, indicating that word-level deficits cannot be attributed to general auditory processing impairments. In addition, while typically developing controls showed an increase in word-level entrainment over the course of learning, children with FXS failed to show a similar increase over time. Taken together, this pattern of results demonstrates that children with FXS can process rapid, lower-order acoustic structure but struggle to integrate these syllables into longer, chunk-like word representations. Overall, these findings suggest that statistical learning is impaired in FXS, and also suggest neural entrainment to statistical structure as a potential therapeutic target.

neuroscience↗

bioRxiv2025

Genome-wide screening reveals producer-cell modifications that improve virus-like particle production and delivery potency

Engineered virus-like particles (eVLPs) are promising vehicles for transient delivery of gene editing agents. While extensive particle engineering has yielded efficient eVLPs, it remains underexplored whether engineering the cells used to produce eVLPs could further improve eVLP properties. We developed a genome-wide screening approach to systematically investigate how genetic perturbations in producer cells influence eVLP production. This approach generates eVLPs loaded with guide RNAs that identify the genetic perturbation in the cell that produced a particular particle; the abundance of each guide RNA in eVLPs therefore reflects how the corresponding genetic perturbation influences eVLP production or cargo loading. We applied this approach to identify several genes that regulate eVLP cargo expression and loading into particles during the production process. Leveraging these insights, we engineered producer cells that support increased eVLP cargo packaging and a 2- to 9-fold increase in eVLP delivery potency across several cargo, particle, and target-cell types in cultured cells and in mice. Our findings suggest the potential of producer-cell engineering as a useful strategy for improving the utility of eVLPs and related delivery methods.

synthetic biology↗

bioRxiv2025

A Temporal Single-Cell Multi-Omics Atlas of Murine Pancreatic Islet Remodeling During Hyperglycaemia Progression

Pancreatic islets undergo coordinated cellular remodeling during obesity-induced insulin resistance (IR). However, the associated molecular changes across endocrine and non-endocrine compartments remain largely unexplored. Here, using longitudinal single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) on islets from C57BL/6 mice subjected to high-fat diet (HFD) feeding for 8, 16, and 24 weeks, along with age-matched controls on regular chow, we mapped dynamic changes in islet cell composition and transcriptional states. Beta cells demonstrated pronounced stress-induced reprogramming, with the emergence of proliferative and dysfunctional subsets. Alpha and delta cell fractions declined under HFD, despite increased polyhormonal biosynthesis, suggesting functional rather than numerical adaptation. Immune profiling showed robust expansion of proinflammatory M1 macrophages and upregulation of NF-{kappa}B and chemotaxis pathways, particularly at 16 weeks. Notably, cell-cell communication analyses revealed diet-specific disruption in signaling networks. Under HFD conditions, intercellular communication among beta cells, macrophages, and delta cells was markedly altered, leading to the disruption of key signaling pathways such as the gastric inhibitory polypeptide receptor (GIPR) and major histocompatibility complex-I (MHC-I). Notably, C-C motif chemokine ligand 27A (Ccl27a) expression and chromatin accessibility were significantly altered in a distinct subpopulation of beta cells under HFD condition, indicative of a niche-specific regulatory mechanism. Integration with human islet datasets from obese and type 2 diabetes (T2D) donors confirmed conserved shifts in beta cell identity and immune activation. This study presents a comprehensive high-resolution atlas of islet remodeling under metabolic stress, identifying key communication nodes and transcriptional programs pertinent to T2D pathogenesis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/656754v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@64aee0org.highwire.dtl.DTLVardef@150beborg.highwire.dtl.DTLVardef@1c19c6dorg.highwire.dtl.DTLVardef@4d1a0_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2025

Cytokine profiling identifies circulating IL-2, IL23 and sPD-L1 as prognostic biomarkers for treatment outcomes in Non-Small cell Lung Cancer patients undergoing anti-PD1 therapy

BackgroundThis study investigates the predictive potential of circulating cytokines for response and survival outcomes in patients with advanced non-small cell lung cancer (NSCLC) undergoing immune checkpoint inhibitor (ICI) therapy. Materials and MethodsA cohort of 64 patients with advanced NSCLC receiving ICI therapy were included. Baseline serum samples were collected prior to ICI initiation and profiled using a multiplex cytokine panel. Logistic regression, Cox regression, and Kaplan-Meier survival analysis were employed to assess associations between cytokine levels, therapeutic response, progression-free survival (PFS), and overall survival (OS). Gene expression levels of key cytokines were validated in peripheral blood mononuclear cells (PBMCs) using quantitative real-time PCR. ResultsElevated baseline levels of IL-2, IL-23, and sPD-L1 were significantly associated with clinical response to ICI therapy. Among these, sPD-L1 emerged as an independent predictor of response (AUC = 0.87). Multivariate Cox regression showed IL-2 (HR = 0.67), sPD-L1 (HR = 0.15), and IL-23 (HR = 1.18) were significantly associated with PFS and also predictive of OS. Notably, combined profiling of IL-2 and sPD-L1 enhanced predictive power (AUC = 0.95 for both PFS and OS). RT-PCR analysis of PBMCs corroborated these findings, confirming upregulation of IL-2 in responders and elevated IL-23 expression in non-responders. ConclusionBaseline cytokine profiling particularly of IL-2, sPD-L1, and IL-23 provides important prognostic and predictive information in advanced NSCLC patients undergoing ICI therapy. These biomarkers may facilitate more personalized approaches to immunotherapy and guide clinical decision-making.

cancer biology↗

bioRxiv2024

Learning Impairments in Fmr1-/- mice on an Audio-Visual Temporal Pattern Discrimination Task.

Estimating time and making predictions is integral to our experience of the world. Given the importance of timing to most behaviors, disruptions in temporal processing and timed performance are reported in a number of neuropsychiatric disorders such as Schizophrenia, Autism Spectrum Disorder (ASD), Fragile X Syndrome (FXS), and Attention-deficit Hyperactivity Disorder (ADHD). Symptoms that implicitly include disruption in timing are atypical turn-taking during social interactions, unusual verbal intonations, poor reading, speech and language skills, inattention, delays in learning, and difficulties making predictions. Currently, there are no viable treatments for these symptoms, the reason being the underlying neural dysfunction that contributes to timing deficits in neuropsychiatric disorders is unknown. To address this unknown, we have designed a novel Temporal Pattern Discrimination Task (TPSD) for awake-behaving mice. Stimuli consist of audiovisual stimuli that differ in duration. Compared to Wild-Type (WT) mice, Fmr1-/- mice, a well-established mouse model of FXS, showed significant impairment in learning the TPSD task, as evidenced by reduced discriminability indices and atypical licking patterns. Often sensory information is multimodal and indeed studies show that learning in humans and rodents improves with multimodal stimuli than with unimodal stimuli. To test how the multimodal nature of stimuli impacted performance of Fmr1-/- mice, following training on the audiovisual stimuli, we tested mice on audio-only or visual-only stimuli. While WT mice showed significant disruption in performance when tested on unimodal stimuli, Fmr1-/- mice displayed equivalent performance on visual-only stimuli when compared to the multimodal task. Our novel task captures timing difficulties and multisensory integration issues in Fmr1-/- mice and provides an assay to examine the associated neural dysfunction.

animal behavior and cognition↗

bioRxiv2024

Towards a Health-Associated Core Keystone (HACK) index for the human gut microbiome

Variations in the normal gut microbiome and the existence of context-dependent disease associations have confounded the identification of microbiome markers of health. A reliable indexing of taxa based on their association with host health and microbiome resilience could accelerate development of microbiome-based therapeutics including selection of live biotherapeutics and facilitate microbiome comparisons in diverse study populations. Here we first investigated 196 taxa for their association with three hallmark properties of health and microbiome-resilience, namely prevalence/community-influence in non-diseased subjects, longitudinal stability and host health, using a discovery cohort of 39,926 publicly available adult (> 18 years) gut microbiomes from 127 studies spanning 42 countries and 28 disease conditions (including 9,434 longitudinal samples). We identified 18 species-level-taxa, referred to as Health-Associated Core Keystones (HACKs), with association-strengths in the top 30 percentile for all three properties. We integrated these association-strengths into a single value, the HACK-index, that ranks taxa based on their estimated contribution to both microbiome stability and host health. We then demonstrate the reproducibility of these indices for the taxon associations with the three properties, using a validation cohort of 4,500 gut microbiomes (from 11 studies with various demographics and diseases). Specific consortia of high HACK-index taxa are also associated with positive response to Mediterranean Diet interventions and Immuno-Checkpoint-Inhibitor therapies. We finally identify the distinguishing microbial genomic functions associated with high HACK-indices/HACK-taxa that can be investigated using targeted mechanistic studies to identify microbiome effectors of improved health. The availability of HACK-indices provides a rational basis for microbiome comparisons and will facilitate the selection and design of microbiome-based therapeutics.

microbiology↗

bioRxiv2024

Development and tissue specific expression of RAPGEF1 (C3G) transcripts having exons encoding disordered segments with predicted regulatory function.

The ubiquitously expressed RAPGEF1(C3G), regulates differentiation, and is essential for development of mouse embryos. While multiple transcripts have been predicted, evidence of their expression and function is scarce. We demonstrate tissue and development specific expression of novel transcripts with exons 12-14 in various combinations, in the mouse. These exons encode an intrinsically disordered serine-rich polypeptide, that undergoes phosphorylation. Isoform switching occurred during differentiation of myoblasts and mouse embryonic stem cells. In silico structure and docking studies indicated that the additional exons alter intra-molecular interactions keeping it in a closed confirmation, and interaction with its target, RAP1A. Our results demonstrate the expression of novel RAPGEF1 isoforms, and suggest cassette exon inclusion as an additional means of regulating RAPGEF1 activity during differentiation.

molecular biology↗

bioRxiv2024

Temporal information of subsecond sensory stimuli in primary visual cortex is encoded via high dimensional population vectors.

Whether in music, language, baking, or memory, our experience of the world is fundamentally linked to time. However, it is unclear how temporal information is encoded, particularly in the range of milliseconds to seconds. Temporal processing at this scale is critical to prediction and survival, such as in a prey anticipating not only where a charging predator will go but also when the predator will arrive at that location. Several models of timing have been proposed that suggest that either time is encoded intrinsically in the dynamics of a network or that time is encoded by mechanisms that are explicitly dedicated to temporal processing. To determine how temporal information is encoded, we recorded neural activity in primary visual cortex (V1) as mice (male and female) performed a goal directed sensory discrimination task, in which patterns of subsecond stimuli differed only in their temporal profiles. We found that temporal information was encoded in the changing population vector of the network and that the space between these vectors was maximized in learned sessions. Our results suggest that temporal information in the subsecond range is encoded intrinsically and does not rely upon specialized timing mechanisms. SIGNIFICANCE STATEMENTOur experience of the world is fundamentally linked to time, but it is unclear how temporal information is encoded, particularly in the range of milliseconds to seconds. Using a sensory discrimination task in which patterns of subsecond stimuli differed in their temporal profiles, we found that primary visual cortex encodes temporal information via the changing population vector of the network. As temporal processing via population encoding has been shown to rely on inhibitory activity in computational models, our results may provide insight into temporal processing deficits in disorders such as autism spectrum disorder in which there is inhibitory-excitatory imbalance. Furthermore, our results may underlie processing of higher-order sensory stimuli, such as language, that are characterized by complex temporal sequences.

neuroscience↗

bioRxiv2023

An integrative proteomics approach identifies tyrosine kinase KIT as a novel therapeutic target for SPINK1-positive prostate cancer.

Elevated Serine Peptidase Inhibitor, Kazal type 1 (SPINK1) levels in [~]10-25% of prostate cancer (PCa) patients associate with aggressive phenotype, for which there are limited treatment choices and dismal clinical outcomes. Using an integrative proteomics approach involving label-free phosphoproteome and proteome profiling, we delineated the downstream signaling pathways involved in SPINK1-mediated tumorigenesis in PCa, and identified tyrosine kinase KIT as a highly enriched kinase. Furthermore, high to moderate levels of KIT expression was detected in [~]85% of SPINK1-positive PCa specimens. KIT signaling regulates SPINK1-associated oncogenesis, and treatment with KIT inhibitor reduces tumor growth and distant metastases in preclinical mice models. Mechanistically, KIT signaling modulates WNT/{beta}-catenin pathway and confers stemness-related features in PCa. Notably, inhibiting KIT signaling restores AR/REST levels, forming a feedback loop enabling SPINK1 repression. Overall, we uncover the role of KIT signaling downstream of SPINK1 in maintaining lineage plasticity and provide new treatment modalities for advanced-stage SPINK1-positive subtype.

cancer biology↗

bioRxiv2023

Distinct senescence mechanisms restrain progression of dysplastic nevi

TERT promoter mutations (TPMs) are frequently found in different cancer types, including approximately 70% of sun-exposed skin melanomas. In melanoma, TPMs are among the earliest mutations and can be present during the transition from nevus to melanoma. However, the specific factors that contribute to the selection of TPMs in certain nevi subsets are not well understood. To investigate this, we analyzed a group of dysplastic nevi (DN) by sequencing genes commonly mutated in melanocytic neoplasms. We examined the relationship between the identified mutations, patient age, telomere length, histological features, and the expression of p16. Our findings reveal that TPMs are more prevalent in DN from older patients and are associated with shorter telomeres. Importantly, these TPMs were not found in nevi with BRAF V600E mutations. Conversely, DN with BRAF V600E mutations were observed in younger patients, had longer telomeres, and a higher proportion of p16-positive cells. This suggests that these nevi arrest growth independently of telomere shortening through a mechanism known as oncogene-induced senescence (OIS). These characteristics extend to melanoma sequencing data sets, where melanomas with BRAF V600E mutations were more likely to have CDKN2A inactivation, overriding OIS. In contrast, melanomas without BRAF V600E mutations showed a higher frequency of TPMs. Our data imply that TPMs are selected to bypass replicative senescence (RS) in cells that were not arrested by OIS. Overall, our results indicate that a subset of melanocytic neoplasms face constraints from RS, while others encounter OIS and RS. The order in which these barriers are overcome during progression to melanoma depends on the mutational context.

cancer biology↗

bioRxiv2023

Hypersensitivity to distractors in Fragile X syndrome from loss of modulation of cortical VIP interneurons.

Attention deficit is one of the most prominent and disabling symptoms in Fragile X Syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in both humans and mice with FXS, but not their typically developing controls. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the post-stimulus period during early distractor trials in WT mice, consistent with their known role as error signals. Strikingly, however, VIP cells from Fmr1-/- mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells, could be a potential therapeutic target for attentional difficulties in FXS.

neuroscience↗

bioRxiv2022

Hyperactive mTOR in Lung Mesenchyme Induces Endothelial Dysfunction and Pulmonary Vascular Remodeling

Pulmonary vascular remodeling is the key structural abnormality in pulmonary hypertension (PH). Mechanistic target of rapamycin (mTOR) has long been suspected to play a role in the development of pulmonary vascular remodeling. However, underlying cellular and molecular mechanisms leading to this pathophysiological condition remain incompletely understood. To elucidate the crosstalk between lung mesenchyme with activated mTOR and endothelial cells (ECs), we focused on a monogenic lung disease, pulmonary lymphangioleiomyomatosis (LAM). LAM is a progressive cystic lung disease caused by a mutational inactivation of tuberous sclerosis complex (TSC1/TSC2), which results in constitutive mTOR activation in mesenchymal LAM cells. ECs derived from LAM lung explants showed increased proliferation, migration, and defective angiogenesis compared to age- and sex-matched ECs from control human lung. In LAM cells, we found increased WNT2 ligand expression. We also identified corresponding Frizzled 4 (FZD) receptors on ECs isolated from distal LAM lung, suggesting cellular crosstalk between LAM cells and ECs. In endothelial-fibroblast cocultures, treatment of normal ECs with WNT2 ligands recapitulated LAM EC phenotype and morphology. We observed transcriptomic upregulation in metabolic, angiogenic and growth pathways in ECs of young mice, while 1-year-old Tsc2KO mice spontaneously developed pulmonary vascular remodeling with concurrent elevation in right ventricular systolic pressure. Our study demonstrates that LAM cells are not just a pathological mesenchymal cell state but a signaling hub that contributes to dysregulated cellular response in the surrounding vasculature, eventual pulmonary vascular remodeling and PH.

molecular biology↗

bioRxiv2022

Cortical Circuit Mechanisms of Multimodal Temporal Pattern Discrimination

Discriminating between temporal features in sensory stimuli is critical to complex behavior and decision making. However, how sensory cortical circuit mechanisms contribute to discrimination between subsecond temporal components in sensory events is unclear. To elucidate the mechanistic underpinnings of timing in primary visual cortex (V1), we recorded from V1 using 2-photon calcium imaging in awake-behaving mice performing a go/no-go discrimination timing task, which was composed of patterns of subsecond audio-visual stimuli. In both conditions, activity during the early stimulus period was temporally coordinated with the preferred stimulus. However, while network activity increased in the preferred condition, network activity was increasingly suppressed in the nonpreferred condition over the stimulus period. Our results demonstrate that discrimination between subsecond intervals that are contained in rhythmic patterns can be accomplished by local networks and suggest the contribution of neural resonance as a mechanism.

neuroscience↗

bioRxiv2022

Development of duplex real time PCR for quick detection of Cryptosporidia in goats

Cryptosporidium spp. is the most important foodborne and waterborne pathogens and the leading cause of mortality from foodborne and waterborne gastrointestinal disease. In neonates of domestic animals it is associated with consistent diarrhoea and dehydration. Cryptosporidium infection begins with the ingestion of sporulated oocytes disseminated by carrier animals that consistently contaminate the environment. Many diagnostic tests are available including microscopy, antigen trap ELISA, but none of the diagnostic tests available currently cannot differentiate between active and passive infection in the host. In the current study, to address this challenge an mRNA based duplex TaqMan(R) probe PCR (dRT-qPCR) was developed to target the Cryptosporidium oocyst wall protein (COWP) gene and 18ssu rRNA gene in a single tube that can detect metabolically active Cryptosporidial oocysts. The mRNA transcripts are the direct indicator of any actively replicating cell and it will help decipher the active stages of its lifecycle in host. This diagnostic assay was standardized by computing transcript copy number-based limit of detection. For COWP and 188ssu rRNA genes the limit of detection was 7.08x1004 and 5.95x1005 respectively. During active infections the oocyst wall protein will be active and so its COWP gene transcripts will act as marker for active infection. While transcripts for 18SSU rRNA are constitutively expressing in Cryptosporidial life cycle. This current diagnostic assay will be a quantitative marker that will help assess active stages of Cryptosporidium infection in neonates. The disease dynamics will help better understand to formulate the control strategies and contain infection among the healthy animals. ImportanceCryptosporidiosis is an important neonatal disease affecting goats causing diarrhoea, dehydration and stunted growth. For diagnosing this condition, many diagnostic tests are available including microscopy, immunological tests, but none of the diagnostic tests available currently can differentiate between active and passive infection in the host. The mRNA transcripts are the direct indicator of any actively replicating cell and especially in intracellular parasites it will help decipher the infective stages of a lifecycle in the host, and hence the test was developed in a reverse transcriptional format in a duplex mode. The currently developed diagnostic assay for cryptosporidiosis was evaluated for sensitivity using Limit of detection (LOD). This diagnostic test will act as a quantitative marker to aid in detecting active stages of Cryptosporidium infection in neonatal goats and will eventually lead to better control strategies for managing cryptosporidial infections in the future.

molecular biology↗