Biology subjects

Nayak, R.

Publications and source records attributed to Nayak, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Longitudinal imaging of single cells in opaque tissue with cell chirp ultrasound

Small numbers of cells can determine the fate of an entire organism. For example, metastatic cancer cells seed distant organs, therapy-resistant clones repopulate tumors, and T cells infiltrate and expand in tissues with matching antigens. Visualizing the activity of such cells in living organisms requires highly sensitive, specific and repeatable imaging in optically opaque tissues. Here we introduce cell chirp, an ultrasound imaging method for real-time imaging of single cells in living organs inaccessible to light. Cell chirp exploits the harmonic response of genetically encoded gas vesicles to frequency-coded ultrasound to sensitively and specifically visualize single cells in scattering background. We first develop this method in tissue-mimicking phantoms, demonstrating the ability to quantitatively detect single cells as validated by optical cell counts. We then establish the ability of cell chirp to image thousands of genetically labeled cells within a million-cell background tissue, track reporter gene expression over days, and suppress background signals by more than two orders of magnitude. Finally, we use cell chirp to track the fate of antigen-positive or antigen-negative tumor-cell minorities during weeks-long T-cell engager treatments. Cell chirp reveals the dynamics of sparsely distributed, genetically defined cells in opaque tissues.

bioengineering↗

bioRxiv2026

Alternaria solani infection reprograms potato leaf metabolism and highlights potential defence and metabolic markers

Potato (Solanum tuberosum L.), the worlds fourth most cultivated crop, suffers yield losses of up to 40-50% from early blight caused by the necrotrophic fungal pathogen Alternaria solani. In this study we performed gas chromatography-mass spectrometry (GC-MS)-based untargeted metabolomics to characterize temporal alterations in metabolite composition, metabolic pathway regulation, and discriminatory biomarker metabolites in the susceptible Indian potato variety Kufri Jyoti, analyzing infected leaves, non-infected leaves, and lesion-associated necrotic tissues across four days post-inoculation (DPI).Metabolite annotation identified 58 compounds, including sugars, organic acids, amino acids, and secondary metabolites.. Multivariate analyses resolved distinct, largely non-overlapping metabolic clusters for control, infected leaves (1-4 DPI), and lesion tissue (Bs1-Bs3). A biphasic metabolic response was observed: early infection (1-2 DPI) was characterized by general suppression of primary metabolism, while late infection (3-4 DPI) showed pronounced upregulation of glycolysis, the TCA cycle, GS/GOGAT, and the shikimate pathway. Key discriminatory metabolites included asparagine, oxoproline, GABA, phenylalanine, and aromatic amino acids. Lesion tissues exhibited distinct metabolic fingerprints, with early disruption of amino acid recycling followed by a late rebound of defense-associated metabolites. Notably, defence-associated phenolics were detected exclusively within lesion tissue and were absent from whole-leaf profiles, demonstrating that spatially resolved lesion sampling captures defence chemistry that whole-leaf analysis alone would miss. The identified biomarker metabolites, particularly those linked to the shikimate and GS/GOGAT pathways, represent promising candidates for metabolite-assisted breeding and targeted crop protection strategies against early blight in potato. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/745268v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@100dd28org.highwire.dtl.DTLVardef@1b78326org.highwire.dtl.DTLVardef@103578corg.highwire.dtl.DTLVardef@68b214_HPS_FORMAT_FIGEXP M_FIG C_FIG

plant biology↗

bioRxiv2026

Decoding central metabolic rewiring induced by exogenous GABA shunt intermediates in Pea

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/741208v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1b38bfborg.highwire.dtl.DTLVardef@ab10b6org.highwire.dtl.DTLVardef@d65370org.highwire.dtl.DTLVardef@ffe08b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG Legume-rhizobium symbiosis is constrained by carbon allocation and nutrient exchanges between the host plant and symbiotic bacteroids, emphasizing the necessity of biostimulant-based strategies to improve symbiotic efficiency. Studies suggest that plants provide carbon substrates (mainly TCA cycle intermediates) and nitrogen assimilation precursors to support bacteroid metabolism and nitrogen fixation. The GABA shunt represents a conserved bypass, linking the GS/GOGAT cycle, TCA cycle, and broader nitrogen metabolism. In the present study, the metabolic phenotypes upon rhizospheric application of exogenous {gamma}-aminobutyric acid (GABA) and succinate were investigated in pea. Application of exogenous GABA and succinate primarily altered the morpho-biochemical properties and root nodule establishment of the plant. While GABA supplementation reduced the root length and increased stomatal density, succinate treatment alone inhibited nodule organogenesis with disrupted symbiosome zoning. Metabolic rewirings associated with these phenotypic changes begin at the root nodule compartment, where exogenous GABA altered endogenous tricarboxylic acid (TCA) cycle pools, leading to higher turnover of TCA cycle intermediates, including succinate, fumarate, and malate, as well as elevated levels of sugars (sucrose, glucose, and fructose) and polyols (pinitol, mannitol, and myo-inositol). Concurrently, the plants accumulated substantially higher levels of asparagine (+3.9 log10-fold higher), accompanied by altered shoot protein content and enhanced elemental nitrogen content (+0.8-1%). Collectively, these findings demonstrate the potential of GABA as a biostimulant capable of altering the carbon-nitrogen dynamics and enhancing symbiotic functioning in pea root nodules, whereas succinate alters the process of nodule formation.

plant biology↗

bioRxiv2026

Drought induced metabolomics of potato leaves highlight metabolic reprogramming and promising biomarkers for smart irrigation advisories

Smart irrigation management is essential for improving crop resilience under increasing drought frequency driven by climate change. Although satellite-based remote sensing provides valuable tools for monitoring crop water status at large spatial scales, its accuracy is often limited in mountainous and heterogeneous agricultural landscapes. In this study, we investigated drought-induced metabolic responses in potato (Solanum tuberosum L.) to identify biochemical biomarkers that could complement satellite-based irrigation advisories in the mid-Himalayan region of India. A field experiment was conducted using a gradient of soil moisture regimes corresponding to moderate (50% field capacity), critical (25% field capacity), and extreme drought stress (5-8% field capacity). Satellite-derived evapotranspiration-based irrigation advisories were validated against in situ soil moisture measurements, revealing discrepancies attributed to the inability of satellite estimates to capture actual water loss under drought stress conditions, highlighting the need for additional ground-truth biomarkers across heterogeneous field conditions. To capture plant-level physiological responses, untargeted metabolite profiling of potato leaves was performed using gas chromatography-mass spectrometry (GC-MS). Approximately fifty metabolites belonging to amino acids, organic acids, sugars, and sugar alcohols were detected. Multivariate statistical analyses revealed distinct metabolic signatures associated with progressive drought stress. Notably, accumulation of proline, serine, isoleucine, sucrose, fructose, glucose, and polyols such as mannitol and myo-inositol reflected key metabolic reprogramming associated with osmoprotection, redox homeostasis, and energy metabolism under drought conditions. Collectively, this ensemble of stress-responsive metabolites represents a robust panel of drought stress biomarkers. As a proof of concept, proline was validated as a qualitative biomarker of plant water status through a rapid and cost-effective colorimetric biochemical assay, demonstrating its practical applicability for field-level irrigation management. These findings demonstrate that metabolomics-derived biomarkers can provide sensitive plant-level indicators of drought stress that complement satellite-based monitoring systems. The integration of biochemical diagnostics with remote sensing platforms offers a promising approach for improving drought detection and developing low-cost, field-deployable tools for smart irrigation advisories in heterogeneous agricultural landscapes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/712810v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@5b4c6dorg.highwire.dtl.DTLVardef@1f6af44org.highwire.dtl.DTLVardef@6cd9f7org.highwire.dtl.DTLVardef@5a0f5a_HPS_FORMAT_FIGEXP M_FIG C_FIG

plant biology↗

bioRxiv2025

MicroRNA-mRNA Gene Regulatory Circuitry Orchestrates the Epigenetic and Transcriptional Reprogramming from Pluripotency to Murine Mammary Epithelial stem-like-Cells lactogenic differentiation

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression via mRNA degradation or translational repression. While miRNAs are established regulators of development and differentiation, their role in the dynamic mRNA transitions during lactogenic differentiation of mammary epithelial cells remains incompletely characterized. In this study, we profiled miRNA expression across four distinct developmental states: embryonic stem cells (ESCs), and three progressive stages of HC11 murine mammary epithelial differentiation, including undifferentiated growth factor-maintained cells (HC11-N), glucocorticoid-primed cells (HC11-P), and prolactin-induced lactogenic cells (HC11-PRL). By integrating these signatures with parallel mRNA expression profiles, we identified stage-specific miRNA-mRNA regulatory axes. Our analysis revealed miRNAs coordinate networks of transcription factors and epigenetic regulators to shape the lactogenic transcriptome. While ESCs and undifferentiated HC11 cells were characterized by pathways associated with pluripotency and oncogenic signalling, the pregnancy-like priming stage showed enrichment in, neurotrophin signalling. Crucially, the lactation-like state was dominated by PI3K-Akt and mTOR signalling-- critical drivers of epithelial proliferation and milk synthesis. Furthermore, the integration of miRNAs with transcriptional and epigenetic regulators highlighted the modulation of prolactin signalling and extracellular matrix-receptor interactions during lactation. This study provides a comprehensive map of the miRNA-associated post-transcriptional landscape of lactogenesis, offering a mechanistic framework for understanding mammary gland development and associated pathologies.

genomics↗

bioRxiv2025

Mapping function in the tree shrew visual system using functional ultrasound imaging.

We adapted functional ultrasound imaging (fUSI) for awake, head-fixed northern tree shrews and used it to produce functional maps of visual processing at [~]100 {micro}m spatial resolution and [~]100 ms temporal resolution. Using classical retinotopic stimuli, full-field noise, motion localizers, and object versus scrambled object contrasts, we demonstrate robust, spatially specific hemodynamic responses across primary and extrastriate visual cortex, superior colliculus and subcortical structures. fUSI reliably reveals retinotopic reversals, laterality, and stimulus-selective modules, and yields high signal-to-noise %CBV changes that enable single-session mapping and targeting of electrophysiology or perturbations. These mesoscale maps provide a systems-level complement to recent high-density electrophysiological surveys of tree shrew visual cortex, which reported a compressed ventral-stream hierarchy and surprisingly early emergence of object coding in V2 (Lanfranchi et al., 2025). Together, our results establish fUSI as a powerful, scalable tool for functional mapping in the tree shrew, bridging large-scale circuit measurement and single-neuron electrophysiology and accelerating this species utility as a bridge between rodent genetics and primate vision.

neuroscience↗

bioRxiv2025

Harmonic Amplitude-Modulated Singular Value Decomposition for Ultrafast Ultrasound Imaging of Gas Vesicles

Ultrafast nonlinear ultrasound imaging of gas vesicles (GV) contrast agents promises high-sensitivity biomolecular visualization with applications such as targeted molecular imaging of tumor markers or real-time tracking of gene expression. However, separating GV-specific signal from tissue remains challenging and requires the implementation of complex transmit schemes. In this work we introduce harmonic amplitude-modulated singular value decomposition (HAM-SVD), which synergizes pulse inversion (PI) with amplitude-modulated singular value decomposition (AM-SVD) to isolate GV-specific second-harmonic signals. In HAM-SVD, single-cycle plane waves at 9.6 MHz and five tilted angles (at a pulse repetition frequency of 2500 Hz) are transmitted under four duty cycles with alternating polarity. Beamformed IQ data are reshaped along a "space x pressure" matrix and decomposed via SVD; tissue background is cancelled by discarding the first and lowest singular modes, yielding an image comprised solely of pressure-dependent second harmonic signals. HAM-SVD sequence enables wide-field, ultrafast imaging without complex transmit sequences. Validation via simulations, in vitro phantoms, and in vivo rat lower limb experiments demonstrates HAM-SVDs outperformance compared to PI and AM-SVD. HAM-SVD is shown to achieve a 19.16 {+/-} 1.63 dB signal-to-background ratio (SBR) in vivo, surpassing PI (14.19 {+/-} 1.41 dB) and AM-SVD (15.79 {+/-} 1.38 dB). HAM-SVD overcomes limitations of conventional nonlinear techniques (e.g., depth restrictions, tissue clutter) by combining PIs harmonic sensitivity with AM-SVDs adaptive clutter filtering of tissue signals. This approach enhances molecular imaging specificity for GVs and holds potential for ultrasound localization microscopy of slow-flowing agents.

bioengineering↗

bioRxiv2025

Dysregulation of Multiple Solute Carrier genes and Metabolic Deficits in SLC1A4-Mutant Human iPSC-Derived Hippocampal Neurons

Mutations in SLC1A4, which encodes the neuronal amino acid transporter ASCT1, disrupt metabolic and synaptic homeostasis, contributing to neurodevelopmental deficits commonly observed in autism spectrum disorder (ASD). To investigate the underlying molecular mechanisms of SLC1A4-related disorders, we utilized human iPSC-derived hippocampal neurons and applied an integrated multi-omics approach, combining electrophysiology, calcium imaging, metabolomics, proteomics, and transcriptomics. Our findings reveal an initial phase of early neuronal hyperexcitability, driven by increased sodium and potassium currents, followed by a progressive decline in synaptic activity at later stages. Metabolomic analysis identified elevated glycine, serine, and glutamate levels during early differentiation, contributing to excitotoxicity, whereas later glutamate depletion and extracellular matrix (ECM) disruption were associated with synaptic dysfunction. Proteomics data further showed dysregulation in metabolic pathways, amino acid biosynthesis, and fatty acid metabolism pathways during early time points, and in later stage dysregulation in metabolic and ECM-receptor interactions. Additionally, transcriptomic analysis revealed dysregulation in calcium signaling, amino acid metabolism pathways such as valine, leucine and isoleucine degradation, tryptophan metabolism, and glycine, serine, and threonine metabolism. Further investigation of SLC-family transporter genes uncovered disruptions in glutamate and glycine transport, establishing a direct link between amino acid transport dysfunction and neuronal deficits. Collectively, our study demonstrates that SLC1A4 mutations lead to dysregulation of multiple solute carrier protein genes causing metabolic stress, excitability defects, and synaptic abnormalities, providing a molecular framework for understanding SLC1A4-related neurodevelopmental disorders and identifying potential therapeutic targets.

neuroscience↗

bioRxiv2024

Morphogenic, molecular, and cellular adaptations for unidirectional airflow in the chicken lung

Unidirectional airflow in the avian lung enables gas exchange during both inhalation and exhalation. The underlying developmental process and how it deviates from that of the bidirectional mammalian lung are poorly understood. Sampling key developmental stages with multiscale 3D imaging and single-cell transcriptomics, we delineate morphogenic, molecular, and cellular features that accommodate the unidirectional airflow in the chicken lung. Primary termini of hyper-elongated branches are eliminated via proximal-short and distal-long fusions, forming parabronchi. Neoform termini extend radially through parabronchial smooth muscle to form gas-exchanging alveoli. Supporting this radial alveologenesis, branch stalks halt their proximalization, defined by SOX9-SOX2 transition, and become SOX9low parabronchi. Primary and secondary vascular plexi interface with primary and neoform termini, respectively. Single-cell and Stereo-seq spatial transcriptomics reveal a third, chicken-specific alveolar cell type expressing KRT14, hereby named luminal cells. Luminal, alveolar type 2, and alveolar type 1 cells sequentially occupy concentric zones radiating from the parabronchial lumen. Our study explores the evolutionary space of lung diversification and lays the foundation for functional analysis of species-specific genetic determinants.

developmental biology↗

bioRxiv2024

Harmonic imaging for nonlinear detection of acoustic biomolecules

Gas vesicles (GVs) based on acoustic reporter genes have emerged as potent contrast agents for cellular and molecular ultrasound imaging. These air-filled, genetically encoded protein nanostructures can be expressed in a variety of cell types in vivo to visualize cell location and activity or injected systemically to label and monitor tissue function. Distinguishing GVs from tissue signal deep inside intact organisms requires imaging approaches such as amplitude modulation (AM) or collapse-based pulse sequences, however they have limitations in sensitivity or require irreversible collapse of the GVs that restricts its scope for imaging dynamic cellular processes. To address these limitations, this study explores the utility of harmonic imaging to enhance the sensitivity of non-destructive imaging of GVs and cellular processes. Traditional fundamental-frequency imaging utilizing cross-wave AM (xAM) sequences has been deemed optimal for GV imaging. Contrary to this, we hypothesize that harmonic imaging, integrated with xAM could significantly elevate GV detection sensitivity. To verify our hypothesis, we conducted imaging on tissue-mimicking phantoms embedded with purified GVs, mammalian cells genetically modified to express GVs, and live mice after systemic GV infusion. Our findings reveal that harmonic xAM (HxAM) imaging markedly surpasses traditional xAM in isolating GVs nonlinear acoustic signature, showcasing significant enhancements in signal-to-background and contrast-to-background ratios across all tested samples. Further investigation into the backscattered spectra elucidates the efficacy of harmonic imaging in conjunction with xAM. HxAM imaging enables the detection of lower concentrations of GVs and cells with ultrasound and extends the imaging depth in vivo by up to 20% and imaging performance metrics by up to 10dB. These advancements bolster the capabilities of ultrasound for molecular and cellular imaging, underscoring the potential of using harmonic signals to amplify GV detection.

bioengineering↗

bioRxiv2024

Predicting Suicide Risk in Bipolar Disorder patients from Lymphoblastoid Cell Lines genetic signatures

This research investigates the genetic signatures associated with a high risk of suicide in Bipolar disorder (BD) patients through RNA sequencing analysis of lymphoblastoid cell lines (LCLs). By identifying differentially expressed genes (DEGs) and their enrichment in pathways and disease associations, we uncover insights into the molecular mechanisms underlying suicidal behavior. LCL gene expression analysis reveals significant enrichment in pathways related to primary immunodeficiency, ion channel, and cardiovascular defects. Notably, genes such as LCK, KCNN2, and GRIA1 emerged as pivotal in these pathways, suggesting their potential roles as biomarkers. Machine learning models trained on a subset of the patients and then tested on other patients demonstrate high accuracy in distinguishing low and high-risk of suicide in BD patients. Moreover, the study explores the genetic overlap between suicide-related genes and several psychiatric disorders. This comprehensive approach enhances our understanding of the complex interplay between genetics and suicidal behavior, laying the groundwork for future prevention strategies.

neuroscience↗

bioRxiv2024

Fertilization by short-term stored sperm alters DNA methylation patterns in common carp (Cyprinus carpio) embryos at single-base resolution

Short-term storage of sperm in vitro is widely used for artificial fertilization in aquaculture. It has been shown that short-term storage affects sperm motility characteristics, resulting in diminished fertility. However, the detrimental effects of short-term sperm storage on embryos development have remained largely unexplored in single-base methylome resolution. The main aim of the present study was to investigate DNA methylation in the offspring of common carp (Cyprinus carpio) derived from short-term stored sperm. Sperm were stored in artificial seminal plasma on ice (0-2{degrees}C) for 0, 3 and 6 days in vitro, fertilization was performed using oocytes from a single female, and embryos were collected at the mid-blastula stage. Sperm and embryo DNA was extracted, analysed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and whole genome bisulfite sequencing (WGBS). DNA methylation was then assessed. Sperm storage showed negative effects on motility, viability and DNA integrity, but had no effect on global DNA methylation of spermatozoa and resulting embryos. Results from the WGBS showed that methylation of 3313 genes was affected in the embryos fertilized with the 6-day-stored sperm, and the differentially methylated regions (DMRs) identified were mainly involved in cell adhesion, calcium, mitogen-activated protein kinase and adrenergic signalling, melanogenesis, metabolism and RNA transport. Such results suggest that prolongation of storage time may have certain impacts on embryonic development. These initial results provide valuable information for future consideration of the DNA methylome in embryos generated from short-term stored sperm, which is widely used for genetic management of broodstock in aquaculture.

molecular biology↗

bioRxiv2022

Upregulated extracellular matrix-related genes and impaired synaptic activity in dopaminergic and hippocampal neurons derived from Parkinson's disease patients with PINK1 and PARK2 mutations

Parkinsons disease (PD) is the second most prevalent neurodegenerative disease. Primary symptoms of PD arise with the loss of dopaminergic (DA) neurons in the Substantia Nigra Pars Compacta, but it affects the hippocampus and cortex also, usually in its later stage. Approximately 15% of PD cases familial with a genetic mutation. Two of the most associated genes with autosomal recessive (AR) early-onset familial PD are PINK1 and PARK2. There is a need for in-vitro studies of these genetic mutations in order to understand the neurophysiological changes in patients neurons that may contribute to neurodegeneration. In this work, we generated and differentiated DA and hippocampal neurons from iPSCs derived from two patients with a double mutation in their PINK1 and PARK2 (one homozygous and one heterozygous) genes and assessed their neurophysiology compared to two healthy controls. We showed that the synaptic activity of PD neurons generated from patients with the PINK1 and PARK2 mutations is impaired in the hippocampus and dopaminergic neurons. Mutant dopaminergic neurons had enhanced excitatory post-synaptic activity. In addition, DA neurons with the homozygous mutation of PINK1 exhibited more pronounced electrophysiological differences compared to the control neurons. Signaling network analysis of RNA sequencing results revealed that Focal adhesion and ECM receptor pathway were the top 2 upregulated pathways in the mutant PD neurons. These phenotypes are reversed to PD phenotypes of other mutations, suggesting that the interaction of the two mutations may yield different mechanisms of PD.

neuroscience↗

bioRxiv2022

Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-causing mutations

Autism Spectrum Disorder (ASD) is characterized mainly by social and sensory-motor abnormal and repetitive behavior patterns. Over hundreds of genes and thousands of genetic variants were reported to be highly penetrant and causative of ASD. Many of these mutations cause comorbidities such as epilepsy and intellectual disabilities (ID). In this study, we measured cortical neurons derived from induced pluripotent stem cells (iPSCs) of patients with four mutations in the genes GRIN2B, SHANK3, UBTF, as well as chromosomal duplication in the 7q11.23 region and compared them to neurons derived from a first-degree relative without the mutation. Using a whole-cell patch-clamp, we observed that the mutant cortical neurons demonstrated hyperexcitability and early maturation compared to control lines. These changes were characterized by increased sodium currents, increased amplitude and rate of excitatory postsynaptic currents (EPSCs), and more evoked action potentials in response to current stimulation in early-stage cell development (3-5 weeks post differentiation). These changes that appeared in all the different mutant lines, together with previously reported data, indicate that an early maturation and hyperexcitability may be a convergent phenotype of ASD cortical neurons.

neuroscience↗

bioRxiv2022

Prioritizing landscapes to reconcile biodiversity conservation, ecosystem services, and human well-being in India

Biodiversity conservation and human well-being are tightly interlinked; yet mismatches in the scale at which both priorities are planned and implemented have exacerbated biodiversity loss, erosion of ecosystem services, and declining human quality of life. India houses the second largest human population on the planet, while <5% of the countrys land area is effectively protected for conservation. This warrants landscape-level conservation planning through a judicious mix of land-sharing and land-sparing approaches, and co-production of ecosystem services. Through a multi-faceted assessment, we prioritize spatial extents of land parcels that, in the face of anthropogenic threats, can safeguard conservation landscapes across Indias biogeographic zones. We find that only a fraction (~15%) of such priority areas identified here are encompassed under Indias extant PA network, and several landscapes of high importance were omitted in all previous global-scale assessments. We then examined the spatial congruence of priority areas with administrative units earmarked for economic development by the Indian government, and propose management-zoning through state-driven and participatory approaches. Our spatially explicit insights can help meet the twin goals of biodiversity conservation and sustainable development in India and other countries across the Global South.

ecology↗

bioRxiv2022

Current progress in understanding Schizophrenia using genomics and pluripotent stem cells: A Meta-analytical overview

Schizophrenia (SCZ) is a highly heritable, polygenic neuropsychiatric disease, which disables the patients as well as decreases their life expectancy and quality of life. Common and Rare variants studies on SCZ subjects have provided more than 100 genomic loci that hold importance in the context of SCZ pathophysiology. Transcriptomic studies from clinical samples have informed about the differentially expressed genes (DEGs) and non-coding RNAs in SCZ patients. Despite these advancements, no causative genes for SCZ were found and hence SCZ is difficult to recapitulate in animal models. In the last decade, induced Pluripotent Stem Cells (iPSCs)-based models have helped in understanding the neural phenotypes of SCZ by studying patient iPSC-derived 2D neuronal cultures and 3D brain organoids. Here, we have aimed to provide a simplistic overview of the current progress and advancements after synthesizing the enormous literature on SCZ genetics and SCZ iPSC-based models. Although further understanding of SCZ genetics and mechanisms using these technological advancements is required, the recent approaches have allowed to delineate important cellular mechanisms and biological pathways affected in SCZ.

neuroscience↗

bioRxiv2022

Generation and characterization of iPSC lines (UOHi001-A, UOHi002-A)From a patient with SHANK3 mutation and her healthy mother

Phelan-McDermid syndrome (PMS) is a rare genetic condition that causes global developmental disability, delayed or absent speech, and autism spectrum disorder. The loss of function of one copy of SHANK3, which codes for a scaffolding protein found in the postsynaptic density of synapses, has been identified as the main cause of PMS. We report the generation and characterization of two induced pluripotent stem cell (iPSC) lines derived from one patient with a SHANK3 mutation and the patients mother as a control. Both lines expressed pluripotency markers, differentiated into the three germ layers, retained the disease-causing mutation, and displayed normal karyotypes.

cell biology↗

bioRxiv2022

Reduced synaptic activity and dysregulated extracellular matrix pathways are common phenotypes in midbrain neurons derived from sporadic and mutation-associated Parkinson's disease patients

Several mutations that cause Parkinsons disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: Neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, shows changes that are central and convergent to PD and suggests a strong involvement of the tetra-partite synapse in PD pathophysiology.

neuroscience↗