Biology subjects

Srinivasan, M.

Publications and source records attributed to Srinivasan, M..

27 records · Page 2Linked to original sources

bioRxiv2021

Exploration-based learning of a step to step controller predicts locomotor adaptation

Humans adapt their locomotion seamlessly in response to changes in the body or the environment. We do not understand how such adaptation improves performance measures like energy consumption or symmetry while avoiding falling. Here, we model locomotor adaptation as interactions between a stabilizing controller that reacts quickly to perturbations and a reinforcement learner that gradually improves the controllers performance through local exploration and memory. This model predicts time-varying adaptation in many settings: walking on a split-belt treadmill (i.e. with both feet at different speeds), with asymmetric leg weights, or using exoskeletons -- capturing learning and generalization phenomena in ten prior experiments and two model-guided experiments conducted here. The performance measure of energy minimization with a minor cost for asymmetry captures a broad range of phenomena and can act alongside other mechanisms such as reducing sensory prediction error. Such a model-based understanding of adaptation can guide rehabilitation and wearable robot control.

neuroscience↗

bioRxiv2021

Cryo-EM Structure of Bacterioferritin Nanocages Provides Insight into the Bio-mineralization of Ferritins

Iron is an essential element involved in various metabolic processes. The ferritin family of proteins forms nanocage assembly and are involved in iron oxidation, storage and mineralization. Although several structures of human ferritin and bacterioferritin subunits have been resolved, there is still no complete structure that shows both the trapped Fe-biomineral cluster along with the nanocage. Furthermore, whereas the mechanism of iron trafficking has been explained using various approaches, an atomic-level description of the pathway and the biomineralization that occurs inside the cavity are lacking. Here, we report three cryo-EM structures of different states of the Streptomyces coelicolor bacterioferritin nanocage (i.e., apo, holo) at 3.4 [A] to 4.6 [A] resolution and the subunit crystal structure at 2.6 [A] resolution. The holo forms show different stages of Fe-biomineral accumulation inside the nanocage and suggest the possibility of a different Fe biomineral accumulation process. The cryo-EM map shows connections between the Fe-biomineral cluster and residues such as Thr157 and Lys42 from the protein shell, which are involved in iron transport. Mutation and truncation of the bacterioferritin residues involved in these connections can significantly reduce iron binding as compared with wild type bacterioferritin. Moreover, S. coelicolor bacterioferritin binds to various DNA fragments, similar to Dps (DNA-binding protein from starved cells) proteins. Collectively, our results represent a prototype for the ferritin nanocage, revealing insight into its biomineralization and the potential channel for ferritin-associated iron trafficking.

biophysics↗

bioRxiv2020

Pre-crastination: Time deadlines increase walking speeds even when not constraining

In many circumstances, humans walk in a manner that approximately minimizes energy cost. Here, we performed human subject experiments to examine how having a time constraint affects the speeds at which humans walk. First, we measured subjects preferred walking speeds to travel a given distance in the absence of any time constraints. Then, we asked subjects to travel the same distance under different time constraints. That is, they had to travel the given distance within the time duration provided - they can arrive early, but not late. Under these constraints, subjects systematically arrived earlier than necessary. Surprisingly, even when the time duration provided was large enough to walk at their unconstrained preferred speeds, subjects walked systematically faster than their unconstrained preferred speed. We propose that this faster-than-energy optimal speeds may be due to human uncertainty in time estimation. We show that a model assuming that humans perform stochastic optimal feedback control to arrive on time with high probability while minimizing expected energy costs predicts walking speeds higher than energy optimal, as observed in experiment.

physiology↗

bioRxiv2020

Oral epithelial expression of angiotensin converting enzyme-2: Implications for COVID-19 diagnosis and prognosis.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses the angiotensin converting enzyme (ACE)-2 as the host receptor for target cell entry. The extent and distribution of ACE-2 has been associated with the clinical symptoms of coronavirus disease (COVID)-19. Here we show by immunofluorescence analysis that the ACE2 is abundantly expressed in oral mucosa, particularly in the surface epithelial cells suggesting that these cells could represent sites of entry for SARS-CoV-2. Further, together with the reports on ACE2 ectodomain shedding, we discuss the rationale for the hypothesis that the ACE-2 measurement in saliva could be a marker for COVID-19 infection during early phase following SARS-CoV-2 exposure.

microbiology↗

bioRxiv2019

Budgerigars adopt robust, but idiosyncratic flight paths

We have investigated the paths taken by Budgerigars while flying in a tunnel. The preferred flight trajectories of nine Budgerigars (Melopsittacus undulatus) were reconstructed in 3D from high speed stereo videography of their flights in an obstacle-free tunnel. Individual birds displayed highly idiosyncratic flight trajectories that were consistent from flight to flight over the course of several months. We then investigated the robustness of each birds trajectory by interposing a disk-shaped obstacle in its preferred flight path. We found that each bird continued to fly along its preferred trajectory up to a point very close to the obstacle before veering away rapidly, making a minimal deviation to avoid a collision, and subsequently returning to its original path. Thus, Budgerigars show a high propensity to stick to their individual, preferred flight paths even when confronted with a clearly visible obstacle, and do not adopt a substantially different, safer route. Detailed analysis of the last-minute avoidance manoeuvre suggests that a collision is avoided by restricting the magnitude of the optic flow generated by the obstacle to a maximum value of about 700 deg/sec. The robust preference for idiosyncratic flight paths, and the tendency to pass obstacles by flying above them, provide new insights into the strategies that underpin obstacle avoidance in birds. It could also have wide-ranging implications for conservation efforts to mitigate collisions of birds with man-made obstacles - especially obstacles that are poorly visible, such as wind turbines or buildings with glass facades. Our findings indicate that care needs to be exercised to ensure that newly planned structures are not located near major bird flyways, wherever possible, and to ensure that the positioning takes into consideration the cues and behaviours that birds use to avoid such obstacles.

neuroscience↗

bioRxiv2019

Scc2 counteracts a Wapl-independent mechanism that releases cohesin from chromosomes during G1 but is unnecessary during S phase for establishing cohesion

Cohesins association with chromosomes is determined by loading dependent on the Scc2/4 complex and release due to Wapl. We show here that Scc2/4 is not merely a loading complex and that it actively maintains cohesin on chromosomes during G1. It does so by blocking a Wapl-independent release reaction that requires opening the cohesin ring at its Smc3/Scc1 interface as well as the D loop of Smc1s ATPase. The Wapl-independent release mechanism is switched off as cells activate Cdk1 and enter G2/M and cannot be turned back on without cohesins dissociation from chromosomes. The latter phenomenon enabled us to show that cohesin that has already captured DNA in a Scc2-dependent manner before replication no longer requires Scc2 to capture sister DNAs during S phase.

molecular biology↗

bioRxiv2018

Differential Profiles of Soluble and Cellular Toll-like Receptors (TLRs) 2 and 4 in Chronic Periodontitis.

Chronic periodontitis is a common inflammatory disease initiated by a complex microbial biofilm and mediated by the host response causing destruction of the supporting tissues of the teeth. Host recognition of pathogens is mediated by toll-like receptors (TLRs) that bind conserved molecular patterns shared by groups of microorganisms. The oral epithelial cells respond to most periodontopathic bacteria via TLR-2 and TLR-4. Many studies have previously reported the presence of elevated numbers of viable exfoliated epithelial cells (SEC) in the saliva of patients with chronic periodontitis. In addition to the membrane-associated receptors, soluble forms of TLR-2 (sTLR-2) and TLR-4 (sTLR-4) have been identified and are thought to play a regulatory role by binding microbial ligands. sTLR-2 has been shown to arise from ectodomain shedding of the extracellular domain of the membrane receptor and sTLR-4 is thought to be an alternate spliced form. The objective of this study was to investigate the potential value of salivary sTLR-2/4 and the paired epithelial cell-associated TLR-2/4 mRNA as diagnostic markers for chronic periodontitis. Unstimulated whole saliva was collected after obtaining informed consent from 40 individuals in either periodontitis or gingivitis cohorts. The levels of sTLR-2/4 were measured by enzyme-linked immunosorbent assay (ELISA). SEC TLR-2/4 transcripts were quantitated by real time polymerase chain reaction. While levels of sTLR-2 exhibited an inverse correlation, sTLR-4 positively correlated with clinical parameters in the gingivitis cohort. Interestingly, both correlations were lost in the periodontitis cohort indicating a dysregulated host response. On the other hand, while sTLR-2 and the paired SEC associated TLR-2 mRNA exhibited a direct correlation (r2=0.62), that of sTLR4 and SEC TLR-4 mRNA exhibited an inverse correlation (r2=0.53) in the periodontitis cohort. Collectively, assessments of salivary sTLR2 and sTLR4 together with the respective transcripts in SECs could provide clinically relevant markers of disease progression from gingivitis to periodontitis.

immunology↗

bioRxiv2017

The cohesin ring uses its hinge to organize DNA using non-topological as well as topological mechanisms

As predicted by the notion that sister chromatid cohesion is mediated by entrapment of sister DNAs inside cohesin rings, there is a perfect correlation between co-entrapment of circular minichromosomes and sister chromatid cohesion in a large variety of mutants. In most cells where cohesin loads onto chromosomes but fails to form cohesion, loading is accompanied by entrapment of individual DNAs. However, cohesin with a hinge domain whose positively charged lumen has been neutralized not only loads onto and translocates along chromatin but also organizes it into chromatid-like threads, despite largely failing to entrap DNAs inside its ring. Thus, cohesin engages chromatin in a non-topological as well as a topological manner. Our finding that hinge mutations, but not fusions between Smc and kleisin subunits, abolish entrapment suggests that DNAs may enter cohesin rings through hinge opening. Lastly, mutation of three highly conserved lysine residues inside the Smc1 moiety of Smc1/3 hinges abolishes all loading without affecting cohesins initial recruitment to CEN loading sites or its ability to hydrolyze ATP. We suggest that loading and translocation are mediated by conformational changes in cohesins hinge driven by cycles of ATP hydrolysis.

molecular biology↗

bioRxiv2017

STRT-seq-2i: dual-index 5′ single cell and nucleus RNA-seq on an addressable microwell array

Single-cell RNA-seq has become routine for discovering cell types and revealing cellular diversity, but currently no high-throughput platform has been used successfully on archived human brain samples. We present STRT-seq-2i, an addressable 9600-microwell array platform, combining sampling by limiting dilution or FACS, with imaging and high throughput at competitive cost. We applied the platform to fresh single mouse cortical cells and to frozen post-mortem human cortical nuclei, matching the performance of a previous lower-throughput platform.

molecular biology↗