Shikhar Saxena

Bio: Shikhar Saxena is an academic researcher from Indian Institute of Science. The author has contributed to research in topics: Metabolic network & Epidemiology. The author has an hindex of 2, co-authored 3 publications receiving 7 citations. Previous affiliations of Shikhar Saxena include Brandeis University.

Experience-Dependent Development of Dendritic Arbors in Mouse Visual Cortex.

Abstract: The dendritic arbor of neurons constrains the pool of available synaptic partners and influences the electrical integration of synaptic currents. Despite these critical functions, our knowledge of the dendritic structure of cortical neurons during early postnatal development and how these dendritic structures are modified by visual experience is incomplete. Here, we present a large-scale dataset of 849 3D reconstructions of the basal arbor of pyramidal neurons collected across early postnatal development in visual cortex of mice of either sex. We found that the basal arbor grew substantially between postnatal day 7 (P7) and P30, undergoing a 45% increase in total length. However, the gross number of primary neurites and dendritic segments was largely determined by P7. Growth from P7 to P30 occurred primarily through extension of dendritic segments. Surprisingly, comparisons of dark-reared and typically reared mice revealed that a net gain of only 15% arbor length could be attributed to visual experience; most growth was independent of experience. To examine molecular contributions, we characterized the role of the activity-regulated small GTPase Rem2 in both arbor development and the maintenance of established basal arbors. We showed that Rem2 is an experience-dependent negative regulator of dendritic segment number during the visual critical period. Acute deletion of Rem2 reduced directionality of dendritic arbors. The data presented here establish a highly detailed, quantitative analysis of basal arbor development that we believe has high utility both in understanding circuit development as well as providing a framework for computationalists wishing to generate anatomically accurate neuronal models.SIGNIFICANCE STATEMENT Dendrites are the sites of the synaptic connections among neurons. Despite their importance for neural circuit function, only a little is known about the postnatal development of dendritic arbors of cortical pyramidal neurons and the influence of experience. Here we show that the number of primary basal dendritic arbors is already established before eye opening, and that these arbors primarily grow through lengthening of dendritic segments and not through addition of dendritic segments. Surprisingly, visual experience has a modest net impact on overall arbor length (15%). Experiments in KO animals revealed that the gene Rem2 is positive regulator of dendritic length and a negative regulator of dendritic segments.

Experience-dependent development of dendritic arbors in mouse visual cortex

Abstract: Despite the importance of dendritic arbors for proper neuronal function, our knowledge of how sensory experience influences these structures during postnatal cortical development is incomplete. We present a large-scale dataset of 849 three-dimensional reconstructions of pyramidal neuron basal arbors collected across early postnatal development in the mouse visual cortex. We found that the basal arbor underwent a 45% increase in total length between postnatal day 7 (P7) and P30. Surprisingly, comparisons of dark-reared and typically-reared mice revealed that only 15% of arbor length could be attributed to visual experience. Furthermore, we characterized the role of the activity-regulated small GTPase Rem2, showing that Rem2 is an experience-dependent negative regulator of dendritic segment number during the visual critical period. These data establish a detailed, quantitative analysis of the basal arbor that has high utility for understanding circuit development and providing a framework for computationalists wishing to generate anatomically accurate neuronal models.

Modelling metabolic rewiring during melanoma progression using flux balance analysis

Abstract: Improvements in melanoma diagnosis, treatment and prognosis are urgently warranted, given that it causes 3 out of 4 skin cancer deaths. A large amount of genomic and molecular data indicate that alterations occur at multiple scales in different stages of melanoma. Metabolic rewiring is a characteristic feature of progressive cancers that facilitates sustenance of tumors, and caters to the changing energy requirements. Since such rewiring involves multiple variations in the metabolic network that are orchestrated, a systems perspective is necessary to understand the nature, significance, mechanisms and identification of the key steps. To address this, we integrate patient transcriptome data with a prior human reference metabolic model and construct stage-specific genome-scale metabolic models. Using flux balance analysis, we simulate the metabolic flows and compute the reaction fluxes specific to normal skin, primary melanoma and metastatic melanoma, from which the reactions with flux differences between conditions were identified. Reactions related to Warburg effect, as anticipated and in addition, ROS detoxification and tyrosine metabolism were largely altered in all stages of melanoma. Vitamin A and vitamin C sub-systems are identified to be involved in different stages, consistent with experimental studies from literature that indicate their support to cancer progression. Gene essentiality studies using the melanoma model identified 5 important genes NME2, CMPK1, HSD17B4, DTYMK and PRODH for the proliferation of melanoma cells, which can be explored as potential drug targets.

Epidemiological trend and clinical profile of COVID-19 patients: Experience from a designated COVID-19 center in Delhi

Abstract: Objective: To study the epidemiological characteristics of the pandemic by describing the clinical profile of the COVID-19 patients presenting to a super specialty hospital. Methods: This was a descriptive study using medical records of patients who tested positive for SARS-CoV-2 RNA using reverse transcription-polymerase chain reaction between 17th March and 15th January 2021 while maintaining confidentiality. The clinical and demographic data of all the patients were entered in a Microsoft Excel and statistical analysis was done using SPSS 21 software. Regression analysis was performed and a P value < 0.05 was considered to be statistically significant. Results: A total of 3534 patients were enrolled in this study aged 9–96 years. Among patients with symptoms, fever and cough were the most common presenting symptoms, while 5.6% of the patients were asymptomatic. Hypertension was the most common comorbidity (37%), while no comorbidities were present in 43.0% of the participants and this was statistically significant for age (P = 0.000). Among patient outcomes, >50% of patients were in home isolation, while 11% of patients had a fatal outcome. Elder age group had a higher proportion of expiry among outcomes (P <= 0.001). Most patients had a hospital stay of 9–11 days. A total of 63 health workers were included with male: female ratio being 3.5:1. Conclusion: Our study reflects that majority of the positive cases that presented to the hospital had mild/moderate symptoms. We believe that appropriate triaging of patients followed by early institution of medicine and good critical care services may help to control this epidemic.

Brain tumor based mri image enhancement using entropy and clahe based intuitionistic fuzzy method with deep learning

Abstract: The inner area of the human brain is where abnormal brain cells gather when they become a mass. These are known as brain tumors, and based on the location and size of the tumor, they can produce a wide range of symptoms. Accurate segmentation and classification of brain tumors are critical for effective diagnosis and treatment planning. In this paper, we present a novel approach for the segmentation and classification of brain tumors using Entropy and CLAHE Based Intuitionistic Fuzzy Method with Deep Learning. Entropy and CLAHE (Contrast Limited Adaptive Histogram Equalization) based Intuitionistic Fuzzy Method with Deep Learning is a technique that combines several image processing and machine learning algorithms to enhance the quality of images. By applying entropy-based techniques to an image, we can identify and highlight the most significant features or patterns in the image. Our study provides a thorough evaluation of the proposed technique and its performance compared to other methods, showing its effectiveness and potential for use in real-world applications. Our method separates the tumor regions from the healthy tissue and provides accurate results in comparison with traditional methods. The results of this study demonstrate the potential of this approach to improve the diagnosis and treatment of brain tumors and provide a foundation for future research in this field. The proposed technique holds significant promise for improving the prognosis and quality of life for patients with brain tumors.

Extracellular and intracellular signaling for neuronal polarity

Abstract: Neurons are one of the highly polarized cells in the body. One of the fundamental issues in neuroscience is how neurons establish their polarity; therefore, this issue fascinates many scientists. Cultured neurons are useful tools for analyzing the mechanisms of neuronal polarization, and indeed, most of the molecules important in their polarization were identified using culture systems. However, we now know that the process of neuronal polarization in vivo differs in some respects from that in cultured neurons. One of the major differences is their surrounding microenvironment; neurons in vivo can be influenced by extrinsic factors from the microenvironment. Therefore, a major question remains: How are neurons polarized in vivo? Here, we begin by reviewing the process of neuronal polarization in culture conditions and in vivo. We also survey the molecular mechanisms underlying neuronal polarization. Finally, we introduce the theoretical basis of neuronal polarization and the possible involvement of neuronal polarity in disease and traumatic brain injury.

Inhibitory Dendrite Dynamics as a General Feature of the Adult Cortical Microcircuit

Abstract: The mammalian neocortex is functionally subdivided into architectonically distinct regions that process various types of information based on their source of afferent input. Yet, the modularity of neocortical organization in terms of cell type and intrinsic circuitry allows afferent drive to continuously reassign cortical map space. New aspects of cortical map plasticity include dynamic turnover of dendritic spines on pyramidal neurons and remodeling of interneuron dendritic arbors. While spine remodeling occurs in multiple cortical regions, it is not yet known whether interneuron dendrite remodeling is common across primary sensory and higher-level cortices. It is also unknown whether, like pyramidal dendrites, inhibitory dendrites respect functional domain boundaries. Given the importance of the inhibitory circuitry to adult cortical plasticity and the reorganization of cortical maps, we sought to address these questions by using two-photon microscopy to monitor interneuron dendritic arbors of thy1-GFP-S transgenic mice expressing GFP in neurons sparsely distributed across the superficial layers of the neocortex. We find that interneuron dendritic branch tip remodeling is a general feature of the adult cortical microcircuit, and that remodeling rates are similar across primary sensory regions of different modalities, but may differ in magnitude between primary sensory versus higher cortical areas. We also show that branch tip remodeling occurs in bursts and respects functional domain boundaries.

Highly Specific Structural Plasticity of Inhibitory Circuits in the Adult Neocortex

Abstract: Inhibitory neurons are known to play a vital role in defining the window for critical period plasticity during development, and it is increasingly apparent that they continue to exert powerful control over experience-dependent cortical plasticity in adulthood. Recent in vivo imaging studies demonstrate that long-term plasticity of inhibitory circuits is manifested at an anatomical level. Changes in sensory experience drive structural remodeling in inhibitory interneurons in a cell-type and circuit-specific manner. Inhibitory synapse formation and elimination can occur with a great deal of spatial and temporal precision and are locally coordinated with excitatory synaptic changes on the same neuron. We suggest that the specificity of inhibitory synapse dynamics may serve to differentially modulate activity across the dendritic arbor, to selectively tune parts of a local circuit, or potentially discriminate between activities in distinct local circuits. We further review evidence suggesting that inhibitory ...

Dendritic branch structure compartmentalizes voltage-dependent calcium influx in cortical layer 2/3 pyramidal cells

Abstract: Back-propagating action potentials (bAPs) regulate synaptic plasticity by evoking voltage-dependent calcium influx throughout dendrites. Attenuation of bAP amplitude in distal dendritic compartments alters plasticity in a location-specific manner by reducing bAP-dependent calcium influx. However, it is not known if neurons exhibit branch-specific variability in bAP-dependent calcium signals, independent of distance-dependent attenuation. Here, we reveal that bAPs fail to evoke calcium influx through voltage-gated calcium channels (VGCCs) in a specific population of dendritic branches in cortical layer 2/3 pyramidal cells, despite evoking substantial VGCC-mediated calcium influx in sister branches. These branches contain VGCCs and successfully propagate bAPs in the absence of synaptic input; nevertheless, they fail to exhibit bAP-evoked calcium influx due to a branch-specific reduction in bAP amplitude. We demonstrate that these branches have more elaborate branch structure compared to sister branches, which causes a local reduction in electrotonic impedance and bAP amplitude. Finally, we show that bAPs still amplify synaptically-mediated calcium influx in these branches because of differences in the voltage-dependence and kinetics of VGCCs and NMDA-type glutamate receptors. Branch-specific compartmentalization of bAP-dependent calcium signals may provide a mechanism for neurons to diversify synaptic tuning across the dendritic tree.

Dendritic branch structure compartmentalizes voltage-dependent calcium influx in cortical layer 2/3 pyramidal cells

Abstract: Back-propagating action potentials (bAPs) regulate synaptic plasticity by evoking voltage-dependent calcium influx throughout dendrites. Attenuation of bAP amplitude in distal dendritic compartments alters plasticity in a location-specific manner by reducing bAP-dependent calcium influx. However, it is not known if neurons exhibit branch-specific variability in bAP-dependent calcium signals, independent of distance-dependent attenuation. Here, we reveal that bAPs fail to evoke calcium influx through voltage-gated calcium channels (VGCCs) in a specific population of dendritic branches in mouse cortical layer 2/3 pyramidal cells, despite evoking substantial VGCC-mediated calcium influx in sister branches. These branches contain VGCCs and successfully propagate bAPs in the absence of synaptic input; nevertheless, they fail to exhibit bAP-evoked calcium influx due to a branch-specific reduction in bAP amplitude. We demonstrate that these branches have more elaborate branch structure compared to sister branches, which causes a local reduction in electrotonic impedance and bAP amplitude. Finally, we show that bAPs still amplify synaptically-mediated calcium influx in these branches because of differences in the voltage-dependence and kinetics of VGCCs and NMDA-type glutamate receptors. Branch-specific compartmentalization of bAP-dependent calcium signals may provide a mechanism for neurons to diversify synaptic tuning across the dendritic tree.