Biology subjects

Sharma, A. K.

Publications and source records attributed to Sharma, A. K..

52 records · Page 3Linked to original sources

bioRxiv2023

A GALLIUM-68-LABELED PEPTIDE RADIOTRACER FOR CD38-TARGETED IMAGING IN MULTIPLE MYELOMA WITH PET

PurposeThe limited availability of molecularly targeted low-molecular-weight imaging agents for monitoring multiple myeloma (MM)-targeted therapies has been a significant challenge in the field. In response, we developed [68Ga]Ga-AJ206, a peptide-based radiotracer that can be seamlessly integrated into the standard clinical workflow and is specifically designed to non-invasively quantify CD38 levels and pharmacodynamics by positron emission tomography (PET). Experimental designWe synthesized a high-affinity binder for quantification of CD38 levels. Affinity was tested using surface plasmon resonance, and In vitro specificity was evaluated using a gallium-68-labeled analog. Distribution, pharmacokinetics, and CD38 specificity of the radiotracer were assessed in MM cell lines and in primary patient-derived myeloma cells and xenografts (PDX) with cross-validation by flow cytometry and immunohistochemistry. Furthermore, we investigated the radiotracers potential to quantify CD38 pharmacodynamics induced by all-trans retinoic acid therapy (ATRA). Results[68Ga]Ga-AJ206 exhibited high CD38 binding specificity (KD: 19.1{+/-}0.99 nM) and CD38-dependent In vitro binding. [68Ga]Ga-AJ206-PET showed high contrast within 60 minutes and suitable absorbed dose estimates for clinical use. Additionally, [68Ga]Ga-AJ206 detected CD38 expression in xenografts, PDXs and disseminated disease models in a manner consistent with flow cytometry and immunohistochemistry findings. Moreover, [68Ga]Ga-AJ206-PET successfully quantified CD38 pharmacodynamics in PDXs, revealing increased CD38 expression in the tumor following ATRA therapy. Conclusions[68Ga]Ga-AJ206 exhibited the salient features required for clinical translation, providing CD38-specific high contrast images in multiple models of MM. [68Ga]Ga-AJ206-PET could be useful for quantifying total CD38 levels and pharmacodynamics during therapy to evaluate approved and new therapies in MM and other diseases with CD38 involvement. STATEMENT OF TRANSLATIONAL RELEVANCEThere is an unmet need for functional imaging agents to monitor the pharmacodynamic effects of new therapeutics targeting multiple myeloma (MM). MM is a challenging bone marrow plasma cell cancer that is associated with heterogenous responses and universal recurrence. While minimal residual disease monitoring by blood and invasive bone marrow samples have improved prognostication of disease recurrence, molecularly targeted, non-invasive imaging options that can assess therapy response early remain limited. To address this gap, we report the development of a high affinity, first-in-class gallium-68 labeled peptide radiotracer, [68Ga]Ga-AJ206, for CD38 protein, which is highly expressed on MM cells. [68Ga]Ga-AJ206 provides high-contrast CD38-specific images by PET within the standard clinical workflow of 60 minutes. Furthermore, the potential of [68Ga]Ga-AJ206 PET to measure pharmacodynamics of CD38 was demonstrated. Further development of this new radiotracer may complement existing technologies and improve prognostication and monitoring of therapy response in patients with MM.

cancer biology↗

bioRxiv2023

The role of intestine in metabolic dysregulation in murine Wilson disease

Background and aimsMajor clinical manifestations of Wilson disease (WD) are related to copper accumulation in the liver and the brain, and little is known about other tissues involvement in metabolic changes in WD. In vitro studies suggested that the loss of intestinal ATP7B could contribute to metabolic dysregulation in WD. We tested this hypothesis by evaluating gut microbiota and lipidome in two mouse models of WD and by characterizing a new mouse model with a targeted deletion of Atp7b in intestine. MethodsCecal content 16S sequencing and untargeted hepatic and plasma lipidome analyses in the Jackson Laboratory toxic-milk and the Atp7b null global knockout mouse models of WD were profiled and integrated. Intestine-specific Atp7b knockout mice (Atp7b{Delta}IEC) was generated using B6.Cg-Tg(Vil1-cre)997Gum/J mice and Atp7bLox/Lox mice, and characterized using targeted lipidome analysis following a high-fat diet challenge. ResultsGut microbiota diversity was reduced in animal models of WD. Comparative prediction analysis revealed amino acid, carbohydrate, and lipid metabolism functions to be dysregulated in the WD gut microbial metagenome. Liver and plasma lipidomic profiles showed dysregulated tri- and diglyceride, phospholipid, and sphingolipid metabolism in WD models. When challenged with a high-fat diet, Atp7b{Delta}IEC mice exhibited profound alterations to fatty acid desaturation and sphingolipid metabolism pathways as well as altered APOB48 distribution in intestinal epithelial cells. ConclusionCoordinated changes of gut microbiome and lipidome analyses underlie systemic metabolic manifestations in murine WD. Intestine-specific ATP7B deficiency affected both intestinal and systemic response to a high-fat challenge. WD is a systemic disease in which intestinal-specific ATP7B loss and diet influence phenotypic presentations.

molecular biology↗

bioRxiv2022

Methylglyoxal controls tomato fruit ripening by regulating ethylene biosynthesis

Methylglyoxal (MG), a toxic compound produced as a byproduct in several cellular processes such as respiration and photosynthesis, is well investigated for its deleterious effects, mainly through glycation of proteins during plant stress responses. However, very little is known about its impact on fruit ripening. In the present study, we report that MG levels are maintained at high level in green tomato fruits, which declines during fruit ripening inspite of a respiratory burst during this transition. We demonstrate that this decline is mainly mediated by glutathione-dependent MG detoxification pathway and primarily catalyzed by glyoxalase enzyme encoded by SlGLY14 gene. SlGLYI4 is a direct target of MADS-RIN and is induced during fruit ripening. Silencing of this gene leads to drastic MG overaccumulation at ripening-stages in the transgenic fruits and interferes with the ripening process. Further investigations show that MG plausibly glycates and inhibits key enzymes such as methionine synthase (MS) and S-adenosyl methionine synthase (SAMS) of ethylene biosynthesis pathway, thereby indirectly affecting fruit pigmentation and cell was metabolism. MG overaccumulation in several non-ripening or inhibited- ripening tomato mutant fruits suggests the tightly regulated MG detoxification process is crucial for normal ripening program. Overall, we underpin a SlGLYI4-mediated novel regulatory mechanism of MG detoxification controlling fruit ripening in tomato.

plant biology↗

bioRxiv2022

A ripening-associated ethylene response factor ERF.D7 activates ARF2 orthologs to regulate tomato fruit ripening

Despite the obligatory nature of ethylene to climacteric fruit ripening and the identification of 77 Ethylene Response Factors (ERFs) in the tomato genome, the role of only limited ERFs has been validated in the ripening process. Here, using a comprehensive morpho-physiological, molecular and biochemical approach, we demonstrate the regulatory role of SlERF.D7 in tomato fruit ripening. The expression of SlERF.D7 positively responds to exogenous ethylene and auxin treatments, most likely in a RIN-independent manner. Overexpression of SlERF.D7 promotes ripening and its silencing has the opposite effects. Alterations in its expression modulated ethylene production, pigment accumulation, and fruit firmness. Consistently, genes involved in ethylene biosynthesis and signalling, lycopene biosynthesis, and cell wall loosening were upregulated in the overexpression lines and downregulated in RNAi lines. These transgenic lines also accumulated altered levels of IAA at late-breaker stages. A positive correlation between ARF2 orthologs transcripts and SlERF.D7 mRNA levels and the fact that ARF2A and ARF2B are direct targets of SlERF.D7 underpinned the perturbed auxin-ethylene crosstalk for the altered ripening program observed in the transgenic fruits. Overall, this study uncovers that SlERF.D7 positively regulates SlARF2A/B abundance to amalgamate auxin and ethylene signalling pathways for controlling tomato fruit ripening. HighlightThe present study identifies a new ripening regulator, SlERF.D7, that controls tomato fruit ripening by activating other known-ripening regulators, SlARF2A and SlARF2B.

plant biology↗

bioRxiv2022

A salt bridge mediated resistance mechanism to FtsZ inhibitor PC190723 revealed by a single step cell-based screen

Bacterial cell division proteins, especially the tubulin homolog FtsZ, have emerged as strong targets for developing new antibiotics. Here, we have utilized the fission yeast heterologous expression system to develop a cell-based assay to screen for small molecules that directly and specifically target the bacterial cell division protein FtsZ. The strategy also allows for simultaneous assessment of the toxicity of the drugs to eukaryotic yeast cells. As a proof-of-concept of the utility of this assay, we demonstrate the effect of the inhibitors sanguinarine, berberine and PC190723 on FtsZ. Though sanguinarine and berberine affect FtsZ polymerization, they exert a toxic effect on the cells. Further, using this assay system, we show that PC190723 affects Helicobacter pylori FtsZ function and gain new insights into the molecular determinants of resistance to PC190723. Based on sequence and structural analysis and site-specific mutations, we demonstrate that the presence of salt-bridge interactions between the central H7 helix and beta-strands S9 and S10 mediate resistance to PC190723 in FtsZ. The single-step in vivo cell-based assay using fission yeast enabled us to dissect the contribution of sequence-specific features of FtsZ and cell permeability effects associated with bacterial cell envelopes. Thus, our assay serves as a potent tool to rapidly identify novel compounds targeting polymeric bacterial cytoskeletal proteins like FtsZ to understand how they alter polymerization dynamics and address resistance determinants in targets.

cell biology↗

bioRxiv2022

Functional Biomarkers of Ex-vivo Dental Caries Onset

BackgroundThe etiology of dental caries remains poorly understood. With the advent of next generation sequencing, a number of studies have focused on the microbial ecology of the disease. However, taxonomic associations with caries have not been consistent. Researchers have also pursued function-centric studies of the caries microbial communities aiming to identify consistently conserved functional pathways. A major question is whether changes in microbiome are a cause or a consequence of the disease. Thus, there is a critical need to define conserved functional biomarkers at the onset of dental caries. MethodsSince it is unethical to induce carious lesions clinically, we developed an innovative longitudinal ex-vivo model integrated with the advanced non-invasive multiphoton second harmonic generation bioimaging to spot the very early signs of dental caries, combined with 16S rRNA short amplicon sequencing and liquid chromatography-mass spectrometry-based targeted metabolomics. FindingsFor the first time, we induced longitudinally-monitored caries lesions validated with the scanning electron microscope. Consequently, we spotted the caries onset and, associated to it, distinguished five differentiating metabolites - Lactate, Pyruvate, Dihydroxyacetone phosphate, Glyceraldehyde 3-phosphate (upregulated) and Fumarate (downregulated). Those metabolites co-occurred with certain bacterial taxa; Streptococcus, Veillonella, Actinomyces, Porphyromonas, Fusobacterium, and Granulicatella, regardless of the abundance of other taxa. InterpretationThese findings are crucial for understanding the etiology and dynamics of dental caries, and devising targeted interventions to prevent disease progression. FundingThe study was funded by the National Institute for Dental and Craniofacial Research of the National Institutes of Health and the University of Minnesota. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSStudies have shown that dental caries, tooth decay, occurs as a result of disruptive imbalance in the oral ecosystem. Excessive dietary intake of fermentable carbohydrates is a critical contributor to disease progression by promoting bacterial production of acids, which shifts the microbial community to an imbalanced and a less diverse one. Studies have also shown that microbial associations with caries have not been consistent while their functions are relatively conserved across individuals. Still, the specific microbial functions associated with the dental caries onset is still unknown due to its infeasible clinical diagnosis. Added value of this studyThis study applied a novel longitudinal ex-vivo model, integrated with advanced non-invasive bioimaging, for experimental dental caries induction. This model enabled the detection of the exact onset of the disease, which is undetected clinically. Then, the microbial communities accompanying the caries onset were analyzed for their microbial composition and metabolic functions in comparison to normal conditions. Our study identified five metabolites differentiating the caries onset. Further, we investigated the co-occurrence of these metabolic biomarkers with certain oral bacteria. Implications of all the available evidenceOur study provides carefully validated evidence for biomarkers of the dental caries onset. These data are critical for early diagnostics and development of timely intervention strategies to interfere with the disease progression that otherwise requires invasive and costly health care expenses. Moreover, our data open new avenues for developing therapeutics to neutralize the identified metabolic biomarkers or target the accountable bacteria for caries prevention.

microbiology↗

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↗

bioRxiv2021

Experimental safety testing shows that the NSAID tolfenamic acid is not toxic to Gyps vultures in India at concentrations likely to be encountered in cattle carcasses

Population declines of Gyps vultures across the Indian subcontinent were caused by unintentional poisoning by the non-steroidal anti-inflammatory drug (NSAID) diclofenac. Subsequently, a number of other NSAIDs have been identified as toxic to vultures, while one, meloxicam, is safe at concentrations likely to be encountered by vultures in the wild. Other vulture-safe drugs need to be identified to reduce the use of those toxic to vultures. We report on safety-testing experiments on the NSAID tolfenamic acid on captive vultures of three Gyps species, all of which are susceptible to diclofenac poisoning. Firstly, we estimated the maximum level of exposure (MLE) of wild vultures and gave this dose to 38 Near Threatened G. himalayensis by oral gavage, with 15 control birds dosed with benzyl alcohol (the carrier solution for tolfenamic acid). Two birds given tolfenamic acid died with elevated uric acid levels and severe visceral gout, while the remainder showed no adverse clinical or biochemical signs. Secondly, four G. himalayensis were fed tissues from water buffaloes which had been treated with double the recommended veterinary dose of tolfenamic acid prior to death and compared to two birds fed uncontaminated tissue; none suffered any clinical effects. Finally, two captive Critically Endangered vultures, one G. bengalensis and one G. Indicus, were given the MLE dose by gavage and compared to two control birds; again, none suffered any clinical effects. The death of two G. himalayensis may have been an anomaly due to i) the high dose level used and ii) the high ambient temperatures at the time of the experiment. Tolfenamic acid is likely to be safe to Gyps vultures at concentrations encountered by wild birds and could therefore be promoted as a safe alternative to toxic NSAIDs. It is manufactured in the region, and is increasingly being used to treat livestock.

pharmacology and toxicology↗

bioRxiv2021

Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A

The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed an increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/453259v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@bc3332org.highwire.dtl.DTLVardef@1c533b0org.highwire.dtl.DTLVardef@1c4a852org.highwire.dtl.DTLVardef@6aec2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Deep phylogenetic analysis of Orthocoronavirinae genomes traces the origin, evolution and transmission route of 2019 novel coronavirus

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan city, China in December 2019 and thereafter its spillover across the world has created a global pandemic and public health crisis. Researchers across the world are involved in finding the origin and evolution of SARS-CoV-2, its transmission route, molecular mechanism of interaction between SARS-CoV-2 and host cells, and the cause of pathogenicity etc. In this paper, we shed light on the origin, evolution and adaptation of SARS-CoV-2 into human systems. Our phylogenetic/evolutionary analysis supported that bat-CoV-RaTG13 is the closest relative of human SARS-CoV-2, outbreak of SARS-CoV-2 took place via inter-intra species mode of transmission, and host-specific adaptation occurred in SARS-CoV-2. Furthermore, genome recombination analysis found that Sarbecoviruses, the subgenus containing SARS-CoV and SARS-CoV-2, undergo frequent recombination. Multiple sequence alignment (MSA) of spike proteins revealed the insertion of four amino acid residues "PRRA" (Proline-Arginine-Arginine-Alanine) into the SARS-CoV-2 human strains. Structural modeling of spike protein of bat-CoV-RaTG13 also shows a high number of mutations at one of the receptor binding domains (RBD). Overall, this study finds that the probable origin of SARS-CoV-2 is the results of intra-species recombination events between bat coronaviruses belonging to Sarbecovirus subgenus and the insertion of amino acid residues "PRRA" and mutations in the RBD in spike protein are probably responsible for the adaptation of SARS-CoV-2 into human systems. Thus, our findings add strength to the existing knowledge on the origin and adaptation of SARS-CoV-2, and can be useful for understanding the molecular mechanisms of interaction between SARS-CoV-2 and host cells which is crucial for vaccine design and predicting future pandemics.

evolutionary biology↗

bioRxiv2020

Computed tomography reveals hip dysplasia in Smilodon: Implications for social behavior in an extinct Pleistocene predator

Reconstructing the behavior of extinct species is challenging, particularly for those with no living analogues. However, damage preserved as paleopathologies on bone can record how an animal moved in life, potentially reflecting behavioral patterns. Here, we assess hypothesized etiologies of pathology in a pelvis and associated right femur of a Smilodon fatalis saber-toothed cat, one of the best-studied species from the Pleistocene-age Rancho La Brea asphalt seeps, California, USA, using visualization by computed tomography (CT). The pelvis exhibits massive destruction of the right hip socket that was interpreted, for nearly a century, to have developed from trauma and infection. CT imaging reveals instead that the pathological distortions characterize chronic remodeling that began at birth and led to degeneration of the joint over the animals life. These results suggest that this individual suffered from hip dysplasia, a congenital condition common in domestic dogs and cats. This individual reached adulthood but could not have hunted properly nor defended territory on its own, likely relying on a social group for feeding and protection. While extant social felids are rare, these fossils and others with similar pathologies are consistent with a spectrum of social strategies in Smilodon supported by a predominance of previous studies.

paleontology↗

bioRxiv2019

A charge-dependent phase transition determines interphase chromatin organization

An emerging principle of cellular compartmentalization is that liquid unmixing results in formation of compartments by phase separation. We used electron spectroscopic Imaging (ESI), a transmission electron microscopy technology, to distinguish chromatin and nucleoplasmic phases of mammalian cell lines and their responses towards different environmental changes. We tested the hypothesis that charge-dependent phase separation mediated by the histone N-termini could explain the organization of chromatin. 3D images of nuclear chromatin with electron spectroscopic imaging (ESI) demonstrates that the amount of chromatin proximal to the interchromatin compartment (IC) differs between cell types, reflecting major differences in chromatin organization. These differences were lost when cells were treated overnight with a histone deacetylase inhibitor. We show that drastic, reversible changes in chromatin mixing or unmixing with the nucleoplasm/interchromatin space can be induced by modulating osmolarity of the medium or acetylation status of the chromatin. In vitro phase separation experiments demonstrated that chromatin separated from solution through a phase transition towards a more solid chromatin state.

cell biology↗

bioRxiv2018

Combinations of slow translating codon clusters can increase mRNA half-life

The introduction of a single, non-optimal codon cluster into a transcript was found to cause ribosomes to queue upstream of it and decrease the transcripts half-life through the action of the dead box protein Dhh1p, which interacts with stalled ribosomes and promotes transcript degradation. Naturally occurring transcripts often contain multiple slow codon clusters, but the influence of these combinations of clusters on a transcripts half-life is unknown. Using a kinetic model that describes translation and mRNA degradation, we find that the introduction of a second slow codon cluster into a transcript near the 5'-end can have the opposite effect than that of the first cluster by increasing the mRNAs half-life. We experimentally validate this finding by showing that S. cerevisiae transcripts that only have a slow codon cluster towards the 3'-end of the coding sequence have shorter half-lives than transcripts with non-optimal clusters at both 3' and 5' -ends. The origin of this increase in half-life arises from the 5'-end cluster suppressing the formation of ribosome queues upstream of the second cluster, thereby decreasing the opportunities for translation-dependent degradation machinery, such as the Dhh1p protein, to interact with stalled ribosomes. We also find in the model that in the presence of two slow codon clusters the cluster closest to 5'-end is the primary determinant of mRNA half-life. These results identify two of the rules governing the influence of slow codon clusters on mRNA half-life, demonstrate that multiple slow codon clusters can have synergistic effects, and indicate that codon usage bias can play a more nuanced role in controlling cellular protein levels than previously thought.

biophysics↗

bioRxiv2018

Predicting natural behavior from whole-brain neural dynamics

The activity of an animals brain contains information about that animals actions and movements. We investigated the neural representation of locomotion in the nematode C. elegans by recording population calcium activity during unrestrained movement. We report that a neural population more accurately decodes locomotion than any single neuron. Relevant signals are distributed across neurons with diverse tunings to locomotion. Two distinct subpopulations are informative for decoding velocity and body curvature, and different neurons activities contribute features relevant for different instances of behavioral motifs. We labeled neurons AVAL and AVAR and found their activity was highly correlated with one another. They exhibited expected transients during backward locomotion, although they were not always the most informative neurons for decoding velocity. Finally, we compared population neural activity during movement and immobilization. Immobilization alters the correlation structure of neural activity and its dynamics. Some neurons previously correlated with AVA become anti-correlated and vice versa. The activity of an animals brain contains information about that animals actions and movements. We investigated the neural representation of locomotion in the nematode C. elegans by recording brain-wide neural dynamics in freely moving animals. We report that a population of neurons more accurately decodes the animals locomotion than any single neuron. Neural signals are distributed across neurons in the population with a diversity of tuning to locomotion. Two distinct subpopulations are most informative for decoding velocity and body curvature, and different neurons activities contribute features relevant for different instances of behavioral motifs within these subpopulations. We additionally labeled the AVA neurons within our population recordings. AVAL and AVAR exhibit activity that is highly correlated with one another, and they exhibit the expected responses to locomotion, although we find that AVA is not always the most informative neuron for decoding velocity. Finally, we compared brain-wide neural activity during movement and immobilization and observe that immobilization alters the correlation structure of neural activity and its dynamics. Some neurons that were previously correlated with AVA become anti-correlated and vice versa during immobilization. We conclude that neural population codes are important for understanding neural dynamics of behavior in moving animals.

neuroscience↗

bioRxiv2018

Genome Sequence of Indian Peacock Reveals the Peculiar Case of a Glittering Bird

The unique ornamental features and extreme sexual traits of Peacock have always intrigued the scientists. However, the genomic evidence to explain its phenotype are yet unknown. Thus, we report the first genome sequence and comparative analysis of peacock with the available high-quality genomes of chicken, turkey, duck, flycatcher and zebra finch. The candidate genes involved in early developmental pathways including TGF-{beta}, BMP, and Wnt signaling pathway, which are also involved in feather patterning, bone morphogenesis, and skeletal muscle development, showed signs of adaptive evolution and provided useful clues on the phenotype of peacock. The innate and adaptive immune components such as complement system and T-cell response also showed signs of adaptive evolution in peacock suggesting their possible role in building a robust immune system which is consistent with the between species predictions of Hamilton-Zuk hypothesis. This study provides novel genomic and evolutionary insights into the molecular understanding towards the phenotypic evolution of Indian peacock.

genomics↗

bioRxiv2017

SCGN Administration prevents Insulin Resistance and Diabetic Complications in High-Fat Diet Fed Animals

Secretagogin (SCGN) is poorly-studied secretory/cytosolic CaBP enriched in pancreatic {beta}-cells. Recent studies implicated SCGN in diabetes; however, its function and therapeutic prospect remain uncharted. Based on the apparent synchrony of SCGN and insulin secretion (and its disruption in HFD-fed animals) and considering SCGN downregulation in Type 2 diabetes, we hypothesized that SCGN is a key regulator of insulin response. To test this, we administered rSCGN to HFD-fed animals. We here report that a novel SCGN-insulin interaction stabilizes insulin and potentiates insulin action. Moreover, a chronic rSCGN administration improves insulin response and alleviates obesity associated risk factors such as weight gain, liver steatosis and cholesterol imbalance in DIO animals. Beside the anti-diabetic effects, prolonged rSCGN treatment also induces {beta}-cell regeneration. These effects seem to originate from SCGN mediated regulation of insulin concentration & function as validated in insulin-deficient STZ animals. Our results demonstrate the prospects of the therapeutic potential of SCGN against diabetes.

physiology↗