Biology subjects

Mishra, A. P.

Publications and source records attributed to Mishra, A. P..

8 recordsLinked to original sources

bioRxiv2026

A single BRCA2 BRC repeat supports viability while multiple repeats ensure resilience under stress

BRC repeats are integral to BRCA2 function and mediate RAD51 loading during homologous recombination (HR). Their number varies across species, but mammals, including mice and humans, harbor eight repeats. Prior studies have suggested functional redundancy among these repeats, but the biological significance of maintaining multiple repeats remains unresolved. Here, we demonstrate that the presence of a single BRC repeat, either BRC2 or BRC4, is sufficient for mouse embryonic stem cell (mESC) viability, RAD51 loading, PARP inhibitor resistance and protection of stalled replication forks. Consistent with these findings, we show that knock-in mice with a single BRC repeat 2 or 4 are viable and exhibit normal growth and fertility. In contrast, embryonic fibroblasts from these mice display genomic instability and impaired RAD51 recruitment. Notably, this defect is rescued under low oxygen culture conditions, which mimics physoxic levels, whereas exposure to oxidative stress impairs RAD51 recruitment in mESCs harboring a single BRC repeat. Together, our findings indicate that while a single BRC repeat is sufficient under physiological conditions, the evolutionary retention of multiple BRC repeats likely ensures robust genome stability under extreme oxidative stress.

genetics↗

bioRxiv2024

5hmC enhances PARP trapping and restores PARP inhibitor sensitivity in chemoresistant BRCA1/2-deficient cells

Mutations in BRCA1 and BRCA2 genes are the leading cause of hereditary breast and ovarian cancer. BRCA1/2-mutant cells are defective in repairing damaged DNA by homologous recombination and are characterized by hypersensitivity to PARP inhibitors. PARP inhibitors can trap PARP proteins on the chromatin, a mechanism that can contribute to the death of BRCA1/2-deficient cells. The FDA has approved multiple PARP inhibitors for the treatment of metastatic breast and ovarian cancers, but despite the success of PARP inhibitors in treating BRCA1/2-mutant cancers, drug resistance is a major challenge. Here, we report that 5hmC enhances PARP1 trapping on the chromatin in olaparib-treated cells. Elevated PARP trapping generates replication gaps, leading to the restoration of PARP inhibitor sensitivity in chemoresistant BRCA1/2-deficient cells. Our findings suggest that combining 5hmC with olaparib can restore the sensitivity of chemoresistant BRCA1/2-deficient cells.

cancer biology↗

bioRxiv2023

Dissociable roles of the auditory midbrain and cortex in processing the statistical features of natural sound textures

It is well established that sound texture perception takes advantage of a hierarchy of time-averaged statistical features of acoustic stimuli, but much remains unclear about how these statistical features are processed in auditory subcortical and cortical regions. Here, we compared the neural representation of sound textures in the inferior colliculus (IC), and primary and non-primary auditory cortex (AC) of anesthetized rats with texture morph stimuli which gradually add statistical features of increasingly higher order. We generated texture morphs for a representative subset of 13 sound textures, chosen to span the three principal component dimensions of a corpus of 200 natural texture recordings. For each of the 13 texture types, six different exemplar morphs were synthesized using different random seeds. All exemplars of each texture type have the same long term statistics, but they differ in their acoustic waveforms. Meanwhile, different texture types differ in statistical features as well as waveforms. An analysis of transient and ongoing multi-unit responses to our stimulus set showed that the IC units were sensitive to every type of statistical feature, albeit to a varying extent, but only a small proportion of AC units were overtly sensitive to any statistical features. Differences in texture types explained more of the variance of IC neural responses than did differences in exemplars, indicating a degree of "texture-type tuning" in the IC, but this was, perhaps surprisingly, not the case for AC responses. We also evaluated the accuracy of texture type classification from single-trial population activity and found that IC responses became more informative as more summary statistics were included in the texture morphs, while for AC population responses classification performance remained constant, and consistently lower, than for the IC. These results argue against the idea that AC plays an important role in encoding statistical features of natural sound textures.

physiology↗

bioRxiv2022

Intracortical remodelling increases in highly-loaded bone after exercise cessation

Resorption within cortices of long bones removes excess mass and damaged tissue, and increases during periods of reduced mechanical loading. Returning to high-intensity exercise may place bones at risk of failure due to increased porosity caused by bone resorption. We used microradiographs of bone slices from highly-loaded (metacarpal, tibia) and minimally-loaded (rib) bones from 12 racehorses, 6 that died during a period of high-intensity exercise and 6 that had a period of intense exercise followed by at least 35 days of rest prior to death, and measured intracortical canal cross-sectional area (Ca.Ar) and number (N.Ca) to infer remodelling activity across sites and exercise groups. Large canals that are the consequence of bone resorption (Ca.Ar > 0.04 mm2) were 1.4x to 18.7x greater in number and area in the third metacarpal bone from rested than exercised animals (p = 0.005- 0.008), but were similar in number and area in ribs from rested and exercised animals (p = 0.575-0.688). An intermediate relationship was present in the tibia, and when large canals and smaller canals that result from partial bony infilling (Ca.Ar > 0.002 mm2) were considered together. The mechanostat may override targeted remodelling during periods of high mechanical load by enhancing bone formation, reducing resorption and suppressing turnover. Both systems may work synergistically in rest periods to remove excess and damaged tissue.

physiology↗

bioRxiv2021

The precedence effect in spatial hearing emerges only late in the auditory pathway

BackgroundTo localize sound sources accurately in a reverberant environment, human binaural hearing strongly favors analyzing the initial wave front of sounds. Behavioral studies of this "precedence effect" have so far largely been confined to human subjects, limiting the scope of complementary physiological approaches. Similarly, physiological studies have mostly looked at neural responses in the inferior colliculus, or used modeling of cochlear mechanics in an attempt to identify likely underlying mechanisms. Studies capable of providing a direct comparison of neural coding and behavioral measures of sound localization under the precedence effect are lacking. ResultsWe adapted a "temporal weighting function" paradigm for use in laboratory rats. The animals learned to lateralize click trains in which each click in the train had a different interaural time difference. Computing the "perceptual weight" of each click in the train revealed a strong onset bias, very similar to that reported for humans. Follow-on electrocorticographic recording experiments revealed that onset weighting of ITDs is a robust feature of the cortical population response, but interestingly it often fails to manifest at individual cortical recording sites. ConclusionWhile previous studies suggested that the precedence effect may be caused by cochlear mechanics or inhibitory circuitry in the brainstem and midbrain, our results indicate that the precedence effect is not fully developed at the level of individual recording sites in auditory cortex, but robust and consistent precedence effects are observable at the level of cortical population responses. This indicates that the precedence effect is significantly "higher order" than has hitherto been assumed.

neuroscience↗

bioRxiv2021

Interaural Time Difference Tuning in the Rat Inferior Colliculus is Predictive of Behavioral Sensitivity

Recent studies have shown that rats are a useful model for binaural cochlear implant (CI) research, with behavioral sensitivity to interaural time differences (ITDs) of CI stimuli which are better than those of human patients. Here, we characterize ITD tuning in the rat inferior colliculus (IC) and explore whether quality of tuning can predict behavioral performance. We recorded IC responses to stimuli of varying pulse rates and envelope types and quantified both mutual information (MI) and neural d' as measures of ITD sensitivity. Neural d' values paralleled behavioral ones, declining with increasing click rates or when envelopes changed from rectangular to Hanning windows. While MI values increased with experience, neural d' did not. However, neural d' values correlated much better with behavioral performance than MI. Thus, neural d' appears to be a particularly well suited to predicting how stimulus parameters will impact behavioral performance.

neuroscience↗

bioRxiv2020

Exploring the distribution of statistical feature parameters for natural sound textures

Sounds like "running water" and "buzzing bees" are classes of sounds which are a collective result of many similar acoustic events and are known as "sound textures". Recent psychoacoustic study using sound textures by [1] reported that natural sounding textures can be synthesized from white noise by imposing statistical features such as marginals and correlations computed from the outputs of cochlear models responding to the textures. The outputs being the envelopes of bandpass filter responses, the cochlear envelope. This suggests that the perceptual qualities of many natural sounds derive directly from such statistical features, and raises the question of how these statistical features are distributed in the acoustic environment. To address this question, we collected a corpus of 200 sound textures from public online sources and analyzed the distributions of the textures marginal statistics (mean, variance, skew, and kurtosis), cross-frequency correlations and modulation power statistics. A principal component analysis of these parameters revealed a great deal of redundancy in the texture parameters. For example, just two marginal principal components, which can be thought of as measuring the sparseness or burstiness of a texture, capture as much as 66% of the variance of the 128 dimensional marginal parameter space, while the first two principal components of cochlear correlations capture as much as 90% of the variance in over 1000 correlation parameters. Knowledge of the statistical distributions documented here may help guide the choice of acoustic stimuli with high ecological validity in future research.

neuroscience↗

bioRxiv2019

Impaired liver regeneration and lipid homeostasis in CCl4 treated WDR13 deficient mice

Background and AimWDR13 - a WD repeat protein, is abundant in pancreas, liver, ovary and testis. Absence of this protein in mice has been seen to be associated with pancreatic {beta}-cell proliferation, hyperinsulinemia and age dependent mild obesity. Previously, we have reported that the absence of WDR13 in diabetic Leprdb/db mice helps in amelioration of fatty liver phenotype along with diabetes and systemic inflammation. This intrigued us to study direct liver injury and hepatic regeneration in Wdr13-/0 mice using hepatotoxin CCl4.\n\nMethodsMice were injected with CCl4 twice a week for 8 consecutive weeks. Controls were injected with vehicle (olive oil) similarly. After the last injection, mice were given a 10-days of recovery period and then sacrificed for physiological and molecular analyses.\n\nResultsIn the present study we report slower hepatic regeneration in Wdr13-/0 mice as compared to their wild type littermates after CCl4 administration. Interestingly, during the regeneration phase, hepatic hypertriglyceridemia was observed in Wdr13-/0 mice. Further analyses revealed an upregulation of PPAR pathway in the liver of CCl4-administered Wdr13-/0 mice, causing de novo lipogenesis.\n\nConclusionsThe slower hepatic regeneration observed in CCl4 administered Wdr13-/0 mice, may be linked to liver hypertriglyceridemia because of activation of PPAR pathway.

pharmacology and toxicology↗