Biology subjects

Adhikari, A.

Publications and source records attributed to Adhikari, A..

43 records · Page 3Linked to original sources

bioRxiv2020

Dorsal Periaqueductal gray ensembles represent approach and avoidance states

Animals must balance needs to approach threats for risk-assessment and to avoid danger. The dorsal periaqueductal gray (dPAG) controls defensive behaviors, but it is unknown how it represents states associated with threat approach and avoidance. We identified a dPAG threat-avoidance ensemble in mice that showed higher activity far from threats such as the open arms of the elevated plus maze and a live predator. These cells were also more active during threat-avoidance behaviors such as escape and freezing, even though these behaviors have antagonistic motor output. Conversely, the threat-approach ensemble was more active during risk-assessment behaviors and near threats. Furthermore, unsupervised methods showed approach/avoidance states were encoded with shared activity patterns across threats. Lastly, the relative number of cells in each ensemble predicted threat-avoidance across mice. Thus, dPAG ensembles dynamically encode threat approach and avoidance states, providing a flexible mechanism to balance risk-assessment and danger avoidance.

neuroscience↗

bioRxiv2020

Incorporation of a Biocompatible Nanozyme in Cellular Antioxidant Enzyme Cascade Reverses Huntington's Like Disorder in Preclinical Model

The potentiality of nano-enzymes in therapeutic use has directed contemporary research to develop a substitute for natural enzymes, which are suffering from several disadvantages including low stability, high cost, and difficulty in storage. However, inherent toxicity, inefficiency in the physiological milieu, and incompatibility to function in cellular enzyme networks limit the therapeutic use of nanozymes in living systems. Here, we have shown that citrate functionalized manganese-based biocompatible nanoscale material (C-Mn3O4 NP) efficiently mimics glutathione peroxidase enzyme in the physiological milieu and easily incorporates into the cellular multienzyme cascade for H2O2 scavenging. A detailed computational study reveals the mechanism of the nanozyme action. We further established the in vivo therapeutic efficacy of C-Mn3O4 nanozyme in a preclinical animal model of Huntingtons disease, a prevalent progressive neurodegenerative disorder, which has no effective medication till date. SUMMARYAlthough, nano-enzymes have shown lots of promises in the management of several diseases, two major concerns limit their clinical translation. Apart from the inherent toxicity of the constituent materials (e.g., cerium, vanadium, gold, etc.), activities of contemporary nanozymes are often inhibited in physiological milieu. Furthermore, most of them are incapable of incorporation into the cellular metabolic networks for functioning in tandem and parallel with natural enzymes, a major criteria for potential therapeutics. Here, we have shown that citrate-functionalized spherical Mn3O4 nanoparticles can efficiently mimic glutathione peroxidase (GPX) enzyme without the limitations of contemporary nanozymes, and effectively manage neurodegenerative Huntingtons disease in preclinical animal model. The choice of the material in the nanozyme lies on the fact that Mn is an essential micronutrient for mammals, and the stabilizing ligand citrate helps the nanoparticles to cross the blood-brain-barrier to reach brain. We have shown that the nanozyme can easily be incorporated in cellular antioxidant enzyme cascade. The specificity and efficacy of the nanozyme in the cascade was significantly higher compared to other reported nanozymes. We have justified our experimental findings with a detailed computational study. Understanding the mode of operation and management of Huntingtons disease in preclinical animal trial using a biocompatible (non-toxic) nanozyme as a part of the metabolic network may uncover a new paradigm in nanozyme based therapeutic strategy.

pharmacology and toxicology↗

bioRxiv2020

Emerging fungal pathogen on an invasive grass differentially affects native species

Infectious diseases and invasive species are strong drivers of biological systems that may interact to shift plant community composition. Disease and invasion can each directly suppress native populations, but variation in responses among native species to disease, invasion, and their combined effects are not well characterized. Here, we quantified the responses of three native North American grass species to experimental inoculation with the fungal pathogen Bipolaris gigantea, which has recently emerged in populations of the invasive grass Microstegium vimineum, causing leaf spot disease. In a greenhouse experiment, we examined the direct effects of disease on the native species and the indirect effects of disease on the native species through altered competition with M. vimineum, which was planted at a range of densities. Pathogen inoculation directly affected each of the three native species in unique ways, by increasing, decreasing, or not changing their biomass relative to mock inoculation. Higher M. vimineum densities, however, reduced the biomass of all three native species, regardless of inoculation treatment, suggesting that disease had no indirect effects through altered competition. In addition, competition with M. vimineum suppressed native plant biomass to a greater extent than disease. The differential impacts of B. gigantea and the consistent impacts of M. vimineum on native species biomass suggest that disease may modify native plant community composition while plant invasion may suppress multiple native plant species in systems where these drivers co-occur.

ecology↗

bioRxiv2020

Potential Impact of Climate Change on One-Horned Rhinoceros (Rhinoceros unicornis) in Nepal

Abrupt change in climate or simply termed as climate change is considered to be one of the major challenges in biodiversity. Change in climate has impacted many species around the world, particularly threatened species like One-Horned Rhinoceros (Rhinoceros unicornis). Rhinoceros unicornis is placed as an endangered species by International Union for Conservation of Nature (IUCN). Being an endangered species, studies regarding the impact of climate on the distribution of Rhinoceros unicornis is very rare in Nepal. Thus, the present study focuses on identifying the potential impact of climate change on the suitable habitat of Rhinoceros unicornis in Nepal using Species Distribution Modelling (SDM). For this, we used the present climatic scenarios and two greenhouse concentration trajectories (RCP 4.5 and RCP 8.5) for two different time periods (2050 and 2070) using different bioclimatic variables. Our model demonstrated the loose of the suitable habitat of Rhincoeros unicornis by 51.87% and 56.54% in RCP 4.5 for year 2050 and 2070 respectively. Under RCP 8.5 for year 2050 and 2070, the model demonstrated the loose of present suitable habitat by 54.25% and 49.51% respectively. Likewise, our result also predicted elevation as an important bioclimatic variable. This study would provide an information to the policy makers, conservationist and government officer of Nepal for the management and protection of habitat of Rhinoceros unicornis in present and future climatic context.

ecology↗

bioRxiv2020

Effective Biophysical Modeling of Cell Free Transcription and Translation Processes

Transcription and translation are at the heart of metabolism and signal transduction. In this study, we developed an effective biophysical modeling approach to simulate transcription and translation processes. We tested this approach by simulating the dynamics of two cell free synthetic circuits. First, we considered a simple circuit in which sigma factor 70 induced the expression of green fluorescent protein. This relatively simple case was then followed by a more complex negative feedback circuit in which two control genes were coupled to the expression of a third reporter gene, green fluorescent protein. While many of the model parameters were estimated from previous biophysical literature, the remaining unknown model parameters for each circuit were estimated from messenger RNA (mRNA) and protein measurements using multi-objective optimization. In particular, either the literature parameter estimates were used directly in the model simulations, or characteristic literature values were used to establish feasible ranges for the multiobjective parameter search. Next, global sensitivity analysis was used to determine the influence of individual model parameters on the expression dynamics. Taken together, the effective biophysical modeling approach captured the expression dynamics, including the transcription dynamics, for the two synthetic cell free circuits. While we considered only two circuits here, this approach could potentially be extended to simulate other genetic circuits in both cell free and whole cell biomolecular applications. The model code, parameters, and analysis scripts are available for download under an MIT software license from the Varnerlab GitHub repository.

systems biology↗

bioRxiv2019

Deletion of a non-canonical promoter regulatory element causes loss of Scn1a expression and epileptic phenotypes in mice

Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the NaV1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet Syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency, however putative causal non-coding promoter mutations have been identified. To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. Mice harboring a deletion of the extended evolutionarily-conserved 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and NaV1.1 expression in brain with accompanying electroencephalographic seizures and behavioral deficits. This work identified the 1b region as a critical disease-relevant regulatory element and provides evidence that non-canonical and seemingly redundant promoters can have essential function.

neuroscience↗

bioRxiv2019

Pediatric and adult-onset HCM mutations in the myosin motor domain have similar properties

Hypertrophic Cardiomyopathy (HCM) is a common genetic disorder that typically involves left ventricular hypertrophy and cardiac hypercontractility. Mutations in {beta} cardiac myosin heavy chain ({beta}-MyHC) are a major cause of HCM, but the specific mechanistic changes to myosin function that lead to the disease remain incompletely understood. Predicting the severity of any single {beta}-MyHC mutation is hindered by a lack of detailed evaluation at the molecular level. In addition, since the cardiomyopathy can take 20 or more years to develop, the severity of the mutations must be somewhat subtle. We hypothesized that mutations which result in early onset disease may show more severe molecular changes in function compared to later onset mutations. In this work, we performed steady-state and transient kinetic analyses of myosins carrying 1 of 7 missense mutations in the motor domain. Of these 7, 4 have been identified in early onset cardiomyopathy screens. The derived parameters were used to model the ATP driven cross-bridge cycle. Contrary to our hypothesis, the results show no clear differences between early and late onset HCM mutations. Despite the lack of distinction between early and late onset HCM, the predicted occupancy of the force-holding actin.myosin.ADP complex at [Actin] = 3 Kapp along with the closely related Duty Ratio (DR; fraction of myosin in strongly attached force-holding states) and the measured ATPases all change in parallel (in both sign and degree of change) compared to wild type (WT) values. Six of the 7 HCM mutations are clearly distinct from a set of DCM mutations previously characterized.

biophysics↗