Biology subjects

Soni, N.

Publications and source records attributed to Soni, N..

16 recordsLinked to original sources

bioRxiv2026

An information-theoretic analysis of the tsetse fly (Glossina morsitans) antenna reveals trichoid sensilla as the main carriers of odor identity

Tsetse flies locate vertebrate hosts largely by smell, and odor-baited devices are central to tsetse and trypanosomiasis control. A published electrophysiological survey of the Glossina morsitans antenna defined seven classes of olfactory sensilla, but descriptive clustering cannot reveal how much information these classes carry or which odors they distinguish. We reanalyzed responses of 182 sensilla to 16-17 odorants using Fisher-Rao information geometry, bias-corrected mutual information, Bayesian decoding, and signal detection theory. In the fruit fly Drosophila melanogaster, trichoid sensilla are largely dedicated to pheromones. In tsetse, the three trichoid classes carried more information about odor identity than the four basiconic classes (1.92 vs. 1.14 bits, of a possible 4), a difference of 0.78 bits (95% confidence interval 0.44-1.10), and were strongly excited by the host attractant 1-octen-3-ol. Adding trichoid to basiconic sensilla raised decoding accuracy from 32% to 70% (23% to 55% for decoders tested on held-out sensilla) and identified 1-octen-3-ol on 98% of trials (92% held out). The basiconic code was nearly one-dimensional (participation ratio 1.71), organized along an axis of response strength with 1-octen-3-ol at its extreme. The CO2-sensitive ab4 class was the most sensitive detector for 11 of 16 odorants, whereas ab2 carried no detectable odor information. Classes shared up to 0.41 bits of their information with one another, an overlap only weakly predicted by the similarity of their mean tuning. On a shared odor panel, Drosophila receptors carried twice the information per channel and, with channel number matched, spanned about 1.5-fold more dimensions. These conclusions held in simulations at the real sample sizes, under alternative noise models, and when classes were defined on independent odorants. The tsetse antenna thus combines redundant, detection-oriented basiconic channels with trichoid sensilla that carry host-odor identity, principles relevant to the design of odor baits.

neuroscience↗

bioRxiv2026

Sparse Phosphorylatable Residues, Tuned by Agonist Chemotype, Shapes GPCR Signaling

GPCR signaling diversity is often attributed to an intracellular phosphorylation barcode, in which ligand-dependent modification of multiple receptor phosphoresidues encodes selective engagement of downstream transducers. However, whether such an extensive phosphorylation of the receptor is universally required remains unclear. Here, we show that the melanocortin-4 receptor (MC4R), a central regulator of energy homeostasis, achieves remarkably diverse and pathway-selective signaling through a sparse set of strategically positioned regulatory phosphoresidues. Systematic study of these phosphoresidues within helix 8 and the C-terminal tail revealed distinct, spatially segregated contributions to receptor function. Substitution of helix 8 residues S306 disrupted beta arrestin2 recruitment, early endosomal trafficking, and ERK1/2 activation, while visibly altering G alpha-cAMP signaling in all the receptor variants. In contrast, distal C-terminal substitutions had little effect on beta-arrestin2 coupling and trafficking, revealing that these regions are not functionally redundant. Surprisingly, signaling through G alpha q/11- and G alpha12/13-linked pathways remained largely constrained across receptor variants, further demonstrating pathway-specific control by these phosphoresidues. Notably, ligand chemotype reshaped the functional consequences of these substitutions: setmelanotide selectively restored or enhanced signaling through pathways that were compromised by specific receptor mutations. Together, our findings argue that GPCR signaling diversity does not necessarily require an extensive phosphorylation barcode. Instead, MC4R uses a minimal number of spatially organized phosphoresidue that can differentially control transducer engagement and downstream signaling, while ligand chemistry determines how this regulatory landscape is accessed.

pharmacology and toxicology↗

bioRxiv2026

Strain-specific response to pharmacological cold mimicking in aging mice

BackgroundAging impairs thermogenic and metabolic flexibility, increasing metabolic disease risk. We examined six aging male mouse strains for responses to chronic topical menthol, a pharmacological cold mimetic. Material and methodsMale (C57BL/6J, A/J, BALB/c, C3H/hej, DBA/2J, and FVB/NJ) mice were treated with 4g/kg of 10% menthol weight per volume cream once per day or vehicle as control using finger application for 15 days. After last application, core body temperature measurement, BAT thermography, Nesting behaviour, and metabolic tolerance test were performed, and gene expression was analysed in BAT. ResultsMenthol improved core temperature recovery via thermogenesis and enhanced insulin sensitivity across all strains. However, effects on BAT mass, nesting behaviour, and gluconeogenesis were strain-dependent. ConclusionCollectively, these findings highlight that genetic background modulates metabolic responses to cold mimetics, informing future precision strategies for age-related metabolic disorders.

pharmacology and toxicology↗

bioRxiv2026

Role of brown adipose tissue-specific sympathetic and sensory innervations in menthol-induced energy-expending phenotype

Menthol, a TRPM8 agonist and pharmacological cold mimic, activates brown adipose tissue (BAT) to increase adaptive thermogenesis and whole-body energy expenditure. BAT is highly innervated with sensory and sympathetic nerve fibers. There is existing literature that sympathetic nerves have a critical role in regulating menthols (or cold) effect on energy homeostasis, but there is minimal literature about the involvement of somatosensory innervations. Here, we ought to investigate whether short-term topical application (3 days) of menthol elicits sympathetic and sensory nerves. We used chemical denervation models of complete (100 mg/kg; 6-OHDA and 125 mg/kg; capsaicin, s.c.) and localized (in BAT, 20 {micro}L of 6-OHDA (20 mg/ml) and 20{micro}L of capsaicin (20{micro}g/{micro}L) in each BAT lobe) ablation of sympathetic (6-OHDA) and sensory (capsaicin) innervations to explore their roles in menthol induced BAT activation and energy expanding phenotype. In the present study we have shown that (i) short-term topical application of menthol (10 % menthol for 3 consecutive days) elicits sympathetic and sensory innervations, and induces thermogenesis, lipolysis and mitochondrial biogenesis in mice BAT; (ii) localized ablation of sympathetic innervation prevented menthol induced BAT activation and lipolysis (iii) localized ablation of sensory neurons augments sympathetic innervations induced BAT activation and modulated thermoregulation. Collectively, our results suggest that BAT activation following short-term topical application of menthol is dependent primarily but not exclusively on centrally mediated SNS activation. TRPV1-positive sensory neurons are partially necessary for thermoregulation and efficient BAT activation.

pharmacology and toxicology↗

bioRxiv2025

Dysregulated Microglial Synaptic Engulfment in Diffuse Midline Glioma

Diffuse midline glioma (DMG) is a near-universally lethal form of pediatric high-grade glioma, driven by neuronal activity-regulated paracrine signaling and synaptic integration of malignant cells into neural circuits. In turn, DMG increases neuronal excitability, augmenting neuron-to-glioma signaling. In the healthy brain, microglia, the resident immune cells of the central nervous system (CNS), regulate neuronal excitability and synaptic connectivity. However, the role of microglia in promoting tumor-associated hyperexcitable neural networks in glioma remains unknown. Here, we investigate the activity-regulated engulfment of neuronal synapses by microglia in both healthy and glioma-bearing mice, and further explore how glioma cells alter microglia-mediated circuit refinement, contributing to pathogenic neuronal hyperexcitability. Microglia-mediated circuit refinement in the glioma microenvironment was characterized through synaptic engulfment analysis of both excitatory and inhibitory synapses by microglia in healthy mice and patient-derived DMG xenograft models, paired with optogenetic stimulation in the neocortex. We found that glutamatergic neuronal activity in the healthy brain increased excitatory synaptic engulfment by microglia in a previously unappreciated negative feedback mechanism that may guard against hyperexcitability. In contrast, this activity-regulated increase in excitatory synaptic engulfment was abrogated in DMG-infiltrated brains. Instead, inhibitory synaptic engulfment was significantly increased in DMG in response to glutamatergic neuronal activity. Together, these dysregulated synaptic engulfment mechanisms may create imbalance in the excitatory to inhibitory (E:I) synapse ratio predicted to increase neuronal excitability. Complementary single-nuclei sequencing studies revealed concordant tumor-specific, activity-regulated changes in microglia-neuron signaling showing reduced expression of excitatory synaptic refinement gene programs in microglia, potentially mediating the aberrant synaptic engulfment observed in DMG. These findings reveal novel cancer-neuron-immune interactions in DMG and provide an opportunity to potentially modulate tumor-associated neuronal hyperexcitability by targeting aberrant microglial synaptic engulfment. HIGHLIGHTSO_LIExcitatory synaptic engulfment by microglia increases in a glutamatergic neuronal activity-dependent manner in the healthy brain. C_LIO_LIIn the glioma-infiltrated brain, this feedback regulatory mechanism is inverted, with loss of activity-regulated excitatory synaptic engulfment and aberrant increased inhibitory synaptic engulfment. C_LIO_LITranscriptomic changes in glioma-associated microglia contribute to differential excitatory and inhibitory synaptic engulfment, with reduced excitatory synaptic refinement gene programs in tumor-associated microglia. C_LIO_LIActivity-regulated soluble factors drive this imbalanced excitatory-inhibitory postsynaptic engulfment by glioma-associated microglia. C_LI

neuroscience↗

bioRxiv2025

Magnetic Resonance Imaging for Improved Brain Tumor Detection

Precise demarcation of brain tumor boundaries is critical for optimizing treatment strategies and improving patient outcomes. In vivo characterization of tumor using PET/CT and MRI is clinical standard. PET/CT highlights the metabolic aspects of the tumor, while MRI provides information on functional, metabolic and structural changes. Even with technological advancements in both PET/CT and MRI, a method that can precisely delineate infiltrative tumor boundaries from normal-appearing brain regions (NABR) in vivo is still lacking. To address this limitation, we explored a relatively new MR imaging method, the Nuclear Overhauser Effect Magnetization Transfer Ratio (NOEMTR), in conjunction with a gadolinium-based contrast agent (Gd-DOTA), to precisely delineate the tumor boundaries in a rat model of infiltrative gliosarcoma. NOEMTR imaging was performed in the rat model (n=5) before and after Gd-DOTA administration. The post-Gd-DOTA NOEMTR map was subtracted from the pre-Gd-DOTA map and compared with contrast-enhanced T1-weighted images and immuno-histological findings. The resulting NOEMTR difference map clearly highlighted both the tumor core and infiltrative boundaries, which was not discernible on the post-contrast T1-weighted images. The extended tumor boundaries observed on the NOEMTR difference map corroborated with the IHC image, which confirmed the presence of infiltrative tumor cells and macrophages in these regions. Guided by the NOEMTR difference map, regions of interest (ROI) were drawn to quantify NOEMTR signal changes in the tumor core, tumor boundaries, and NABR post-Gd-DOTA. Tumor core showed a significant [~]43% reduction in NOEMTR signal (plJ=lJ0.003), while the tumor periphery exhibited a moderate reduction of [~]10%, (plJ=lJ0.045). No appreciable change in was observed in the NABR (plJ=lJ0.371). In contrast, the post contrast T1-weighted signal changes in tumor core, tumor periphery and NABR were, 33.32% (p = 0.092), 3.8% (p = 0.478), and 8.7% (p = 0.464) respectively. These findings suggest that NOEMTR imaging provides enhanced tumor contrast, particularly at the infiltrative tumor margins, where conventional contrast enhanced T1-weighted MRI may underestimate tumor extent. Histological validation confirmed the presence of infiltrative tumor cells and macrophages in the tumor periphery, as highlighted by the NOEMTR difference map. Overall, NOEMTR imaging, in combination with Gd-DOTA administration, demonstrates superior delineation of brain tumor boundaries compared to conventional MRI. As NOEMTR imaging is a fast acquisition scan (under 10 minutes) and performed on standard 3 Tesla, it can be easily integrated into clinical protocols. By improving visualization of tumor infiltration and distinguishing tumor regions from NABR, NOEMTR imaging holds promise for advancing neuro-oncological diagnostics and treatment planning.

bioengineering↗

bioRxiv2024

A transposable element insertion in IAA16 interrupts normal splicing and generates a novel dicamba resistance allele in Bassia scoparia

A dicamba-resistant population of kochia (Bassia scoparia) identified in Colorado, USA in 2012 was used to generate a synthetic mapping population that segregated for dicamba resistance. Linkage mapping associating dicamba injury with genotype derived from restriction-site-associated DNA sequencing identified a single locus in the kochia genome associated with resistance on chromosome 4. A mutant version of Auxin/Indole-3-Acetic Acid 16 (AUX/IAA16; a gene previously implicated in dicamba resistance in kochia) was found near the middle of this locus in resistant plants. Long read sequencing of dicamba-resistant plants identified a recently inserted Ty1/Copia retrotransposon near the beginning of the second exon of AUX/IAA16, leading to disruption of normal splicing. A molecular marker for this insertion allows for rapid detection of resistance. Stable transgenic lines of Arabidopsis thaliana ectopically expressing the mutant and wildtype alleles of AUX/IAA16 were developed. Arabidopsis thaliana plants expressing the mutant AUX/IAA16 allele grew shorter roots on control media. However, transgenic root growth was less inhibited on media containing either dicamba (5 M) or IAA (0.5 M) when compared to non-transgenic plants or those expressing the wildtype allele of AUX/IAA16. In vitro assays indicate reduced binding affinity and more rapid dissociation of the mutant AUX/IAA with TIR1 in the presence of several auxins, and protein modeling suggests the substitution of the glycine residue in the degron domain of AUX/IAA16 is especially important for resistance. A fitness cost associated with the mutant allele of AUX/IAA16 has implications for resistance evolution and management of kochia populations with this resistance mechanism. SignificanceAuxin mimics are amongst the most important herbicides in modern agriculture. Evolution of weeds that are resistant to these herbicides threatens sustainable crop production. Understanding the basis of auxin herbicide resistance informs the development of improved weed control technologies. Additionally, auxin-resistant mutations and their pleotropic effects help us understand auxin perception and signalling. We describe a transposable element insertion within an herbicide target site gene that alters splicing and reduces synthetic and natural auxin perception.

plant biology↗

bioRxiv2024

COCONUT: An analysis of coiled-coil regions in proteins

MotivationThe molecular rules determine the strength and orientation (parallel or antiparallel) of interacting coiled-coil helices in protein-protein interactions. Interpreting these rules is crucial for identifying novel protein-protein interactions, designing competitive binders, and constructing large assemblies containing coiled-coil domains. This study establishes the molecular principles that dictate the strength and orientation of coiled-coil interactions, providing insights relevant to these applications. ResultsWe examined how hydrophobic contacts determine structural specificity within coiled-coil dimers. Our analysis revealed that the hydrophobic core densities differ between parallel and antiparallel dimer confirmations, highlighting their importance in stabilizing different structural arrangements. We developed COiled-COil aNalysis UTility (COCONUT), a computational platform with machine learning models, validated for predictive capabilities in various applications. Using COCONUTs pipeline for coiled-coil analysis and modeling, we predicted the orientation of substitution-sensitive coiled-coil dimer, identified residue pairings in non-canonical coiled-coil heterodimer, and constructed n-stranded coiled-coil model. These results demonstrate COCONUTs utility as a computational framework for interpreting and modeling coiled-coil structures. Availability and implementationCOCONUT is an open-source and free Python package available here https://github.com/neeleshsoni21/COCONUT. The documentation is available in the source code and here: https://neeleshsoni21.github.io/COCONUT/

bioinformatics↗

bioRxiv2024

The Molecular Architecture of the Nuclear Basket

The nuclear pore complex (NPC) is the sole mediator of nucle-ocytoplasmic transport. Despite great advances in understanding its conserved core architecture, the peripheral regions can exhibit considerable variation within and between species. One such structure is the cage-like nuclear basket. Despite its crucial roles in mRNA surveillance and chromatin organization, an architectural understanding has remained elusive. Using in-cell cryo-electron tomography and subtomogram analysis, we explored the NPCs structural variations and the nuclear basket across fungi (yeast; S. cerevisiae), mammals (mouse; M. musculus), and protozoa (T. gondii). Using integrative structural modeling, we computed a model of the basket in yeast and mammals that revealed how a hub of Nups in the nuclear ring binds to basket-forming Mlp/Tpr proteins: the coiled-coil domains of Mlp/Tpr form the struts of the basket, while their unstructured termini constitute the basket distal densities, which potentially serve as a docking site for mRNA preprocessing before nucleocytoplasmic transport

biophysics↗

bioRxiv2023

The International Weed Genomics Consortium: Community Resources for Weed Genomics Research

The International Weed Genomics Consortium is a collaborative group of researchers focused on developing genomic resources for the study of weedy plants. Weeds are attractive systems for basic and applied research due to their impacts on agricultural systems and capacity to swiftly adapt in response to anthropogenic selection pressures. Our goal is to use genomic information to develop sustainable and effective weed control methods and to provide insights about biotic and abiotic stress tolerance to assist crop breeding. Here, we outline resources under development by the consortium and highlight areas of research that will be impacted by these enabling resources.

genomics↗

bioRxiv2022

The novel compensatory reciprocal interplay between neutrophils and monocytes drives cancer progression

Myeloid cells comprise the majority of immune cells in tumors, contributing to tumor growth and therapeutic resistance. Incomplete understanding of myeloid cells response to tumor driver mutation and therapeutic intervention impedes effective therapeutic design. Here, by leveraging CRISPR/Cas9-based genomic editing, we generated a mouse model that is deficient of all monocyte chemoattractant proteins (MCP). Using this strain, we effectively abolished monocyte infiltration in glioblastoma (GBM) and hepatocellular carcinoma (HCC) murine models, which were enriched for monocytes or neutrophils, respectively. Remarkably, eliminating monocyte chemoattraction invokes a significant compensatory neutrophil influx in GBM, but not in HCC. Single-cell RNA sequencing revealed that intratumoral neutrophils promoted proneural-to-mesenchymal transition in GBM, and supported tumor aggression by facilitating hypoxia response via TNF production. Importantly, genetic or pharmacological inhibiting neutrophil in HCC or qMCP-KO GBM extended the survival of tumor-bearing mice. Our findings emphasize the importance of targeting both monocytes and neutrophils simultaneously for cancer immunotherapy. In BriefEliminating monocyte chemoattraction invokes compensatory neutrophil influx in tumor, and vice versa, rendering current myeloid-targeted therapies ineffective. Using genetic and pharmacological approaches combined with novel mouse models of GBM and HCC, we provide credence advocating for combinational therapies aiming at inhibiting both monocytes and neutrophils simultaneously. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/500690v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@bbbae5org.highwire.dtl.DTLVardef@eb3eecorg.highwire.dtl.DTLVardef@702696org.highwire.dtl.DTLVardef@f54734_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights* Blocking monocyte chemoattraction results in increased neutrophil infiltration. * Increased neutrophil recruitment induces GBM PN to MES transition. * Inhibiting neutrophil infiltration in monocyte-deficient tumors improves mouse GBM survival. * Blocking neutrophil, but not monocyte, infiltration in HCC prolongs mouse survival.

immunology↗

bioRxiv2022

GLT8D1 mutations cause amyotrophic lateral sclerosis via disruption of neurotrophin signalling within membrane lipid rafts

Mutations within GLT8D1 contribute to familial amyotrophic lateral sclerosis. Pathogenic mutations impair GLT8D1 glycosyltransferase enzymatic function via a dominant negative mechanism, yet the downstream mechanism leading to neurotoxicity is unclear. Here we show that a p.R92C mutation causes fragmentation of the Golgi network and reduces ganglioside expression within membrane lipid rafts (MLRs), leading to impaired neurotrophin signalling. Expression of p.R92C-GLT8D1 in HEK293 cells and mouse primary neurons reduces expression of GM1 gangliosides within the cell plasma membrane leading to disruption of MLRs. Furthermore, p.R92C-GLT8D1 reduces TrkB-mediated pro-survival signalling in MLRs isolated from primary neurons. Interestingly, up-regulation of wild-type GLT8D1 enhances MLRs and promotes pro-survival signalling through TrkB. This closely mirrors findings for another ALS gene, CAV1, suggesting convergence on a common pathogenic pathway. Other ALS genes have been associated with Golgi dysfunction and may disrupt the same pathway, suggesting a potential new therapeutic approach via upregulation of GLT8D1. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/497990v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1992dc4org.highwire.dtl.DTLVardef@18be04eorg.highwire.dtl.DTLVardef@333216org.highwire.dtl.DTLVardef@11d76c5_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

The master energy homeostasis regulator PGC-1alpha couples transcriptional co-activation and mRNA nuclear export

PGC-1 plays a central role in maintaining the mitochondrial and energy metabolism homeostasis, linking external stimuli to the transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and a putative RNA recognition motif, however potential RNA-processing role(s) have remained elusive for the past 20 years. Here, we show that the RS domain of human PGC-1 directly interacts with RNA and the nuclear RNA export factor NXF1. Inducible depletion of endogenous PGC-1 and expression of RNAi-resistant RS-deleted PGC-1 further demonstrate that the RNA-binding activity is required for nuclear export of co-activated transcripts and mitochondrial homeostasis. Moreover, a quantitative proteomics approach confirmed PGC-1-dependent RNA transport and mitochondrial-related functions, identifying also novel mRNA nuclear export targets in age-related telomere maintenance. Discovering a novel function for a major cellular homeostasis regulator provides new directions to further elucidate the roles of PGC-1 in gene expression, metabolic disorders, ageing and neurodegenerative diseases.

molecular biology↗

bioRxiv2021

Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

Microglia, the brains resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using sustained colony-stimulating factor 1 receptor inhibition, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from an important neurogenic niche, the subventricular zone, and associated white matter areas. These cells exhibit tremendous chemotaxis potential, migrating radially and tangentially in a dynamic wave and filling the brain in a distinct pattern, to fully replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit distinct phenotypic and functional profiles to endogenous microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into myeloid cell dynamics in an empty microglial niche without contributions from bone marrow-derived cells.

immunology↗

bioRxiv2020

Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms

Circadian clocks regulate [~]24 hour oscillations in gene expression, behavior, and physiology. While the molecular and neural mechanisms of circadian rhythms are well characterized, how cellular organization of clock components controls circadian clock regulation remains poorly understood. Here, we elucidate how clock proteins regulate circadian rhythms by controlling the spatiotemporal organization of clock genes. Using high-resolution live imaging techniques we demonstrate that Drosophila clock proteins are concentrated in a few discrete foci and are organized at the nuclear envelope; these results are in contrast to longstanding expectations that clock proteins are diffusely distributed in the nucleus. We also show that clock protein foci are highly dynamic and change in number, size, and localization over the circadian cycle. Further, we demonstrate that clock genes are positioned at the nuclear periphery by the clock proteins precisely during the circadian repression phase, suggesting that subnuclear localization of clock genes plays an important role in the control of rhythmic gene expression. Finally, we show that Lamin B receptor, a nuclear envelope protein, is required for peripheral localization of clock protein foci and clock genes and for normal circadian rhythms. These results reveal that clock proteins form dynamic nuclear foci and play a hitherto unexpected role in the subnuclear reorganization of clock genes to control circadian rhythms, identifying a novel mechanism of circadian regulation. Our results further suggest a new role for clock protein foci in the clustering of clock-regulated genes during the repression phase to control gene co-regulation and circadian rhythms. SIGNIFICANCEAlmost all living organisms have evolved circadian clocks to tell time. Circadian clocks regulate [~]24-hour oscillations in gene expression, behavior and physiology. Here, we reveal the surprisingly sophisticated spatiotemporal organization of clock proteins and clock genes and its critical role in circadian clock function. We show, in contrast to current expectations, that clock proteins are concentrated in a few discrete, dynamic nuclear foci at the nuclear envelope during the repression phase. Further, we uncovered several unexpected features of clock protein foci, including their role in positioning the clock genes at the nuclear envelope precisely during the repression phase to enable circadian rhythms. These studies provide fundamental new insights into the cellular mechanisms of circadian rhythms and establish direct links between nuclear organization and circadian clocks.

neuroscience↗

bioRxiv2019

Predicting and Designing therapeutics against the Nipah virus

Though every outbreak of the Nipah Virus has resulted in high mortality rates (>70% in Southeast Asia), there are no licensed drugs against it. In this study we have considered all 9 Nipah proteins as potential therapeutic targets and computationally identified putative peptides (against G, F, and M proteins) and small molecules inhibitors (against F, G, M, N, and P proteins). The computations include extensive homology/ab initio modelling, peptide design and small molecule docking. An important contribution of this study is the increased structural characterization of Nipah proteins by approximately 90% of what is deposited in the PDB. In addition, we have carried out molecular dynamics simulations on all the designed protein-peptide complexes to check for stability and to estimate binding strengths. Details, including atomic coordinates of all the proteins and their ligand bound complexes, can be accessed at http://cospi.iiserpune.ac.in/Nipah. Our strategy was to tackle the development of therapeutics on a proteome wide scale and the lead compounds identified could be attractive starting points for drug development. To this end, we have designed 4 peptide inhibitors and predicted 70 small molecules (13 with high confidence) against 3 and 5 Nipah proteins respectively. To counter the threat of drug resistance, we have analyzed the sequences of the viral strains from different outbreaks, to check whether they would be sensitive to the binding of the proposed inhibitors.\n\nAuthor SummaryNipah virus infections have killed 72-86% of the infected individuals in Bangladesh and India. The infections are spread via bodily secretions of bats, pigs and other infected individuals. Even though, the disease was first detected in the human population in 1998, there are no approved drugs/vaccines against it. In this study, we have tried to model the 3D structures of the Nipah virus proteins. We have then used these models to design/predict small inhibitory molecules that would bind them and prevent their function. We have also analyzed the different strains of the virus to identify conservation patterns of amino acids in the proteins, which in turn informs us of the efficacy of the drugs. The designed/docked compounds as well as the protein models are freely accessible for experimental validation and hypothesis testing.

bioinformatics↗