Biology subjects

Sundararajan, A.

Publications and source records attributed to Sundararajan, A..

7 recordsLinked to original sources

bioRxiv2024

Predictive simulation of human movement in OpenSim using floating-base task space control

Task space control, also known as operational space control, is a useful paradigm for investigating neural control of human movement using predictive simulations. While some efforts have been made to implement task space control in the widely used open-source platform OpenSim, existing implementations do not support floating base kinematics, which is necessary for simulating gait and other types of human movement. Our aim in this work is to fill that gap. In this paper, we describe the theory and implementation of a floating base kinematics task space framework for torque- and muscle-driven simulations in OpenSim. Our framework builds on previous work that was limited to models with a base (i.e., root) segment fixed to ground. In addition, we integrate various algorithms from robotics in order to handle dynamically changing contacts and task prioritization. The framework can be used to generate realistic walking gaits by prescribing a small set of controller gains and gait parameters such as step length, step width and center of mass velocity. Task can be specified as desired positions, rotations, or higher-order feature such as base of support and whole-body angular momentum. We provide several examples to demonstrate how framework is successful in orchestrating a complex hierarchy of tasks that work in concert to perform both balance control and gait generation. The implementation is freely available for roboticists and biomechanists to use with OpenSim. Author summaryRecent advances in computational biomechanics have provided researchers with tools capable of predicting human movement. Previous approaches to simulating human movement required experimental data as input and the simulation would replicate the experimental motion. This conventional approach limited the scientific insights to the specific movement recorded in the laboratory. With predictive approaches, researchers can investigate how a person might respond to various factors, such as reduced muscle strength or an assistive device such as a robotic exoskeleton. Existing approaches for generating predictive simulations utilize optimization-based approaches, which can be time-consuming and difficult to troubleshoot. Task space control is an alternative approach which is widely used in robotics. Conceptually, task space control aims to generate a simulation by specifying "tasks", such as moving a hand or foot to a desired position, and computing the joint angles required to achieve the task. Here we aim to outline the mathematics behind task space control and demonstrate how task space control can be used to generate simulations of movements such as walking.

bioengineering↗

bioRxiv2023

An evolution-based framework for describing human gut bacteria

The human gut microbiome contains many bacterial strains of the same species ( strain-level variants). Describing strains in a biologically meaningful way rather than purely taxonomically is an important goal but challenging due to the genetic complexity of strain-level variation. Here, we measured patterns of co-evolution across >7,000 strains spanning the bacterial tree-of-life. Using these patterns as a prior for studying hundreds of gut commensal strains that we isolated, sequenced, and metabolically profiled revealed widespread structure beneath the phylogenetic level of species. Defining strains by their co-evolutionary signatures enabled predicting their metabolic phenotypes and engineering consortia from strain genome content alone. Our findings demonstrate a biologically relevant organization to strain-level variation and motivate a new schema for describing bacterial strains based on their evolutionary history. One Sentence SummaryDescribing bacterial strains in the human gut by a statistical model that captures their evolutionary history provides insight into their biology.

systems biology↗

bioRxiv2023

Structure-Activity Relationship Studies of Novel Gut-derived Lantibiotics Against Human Gut Commensals

Recent advances in sequencing techniques unveiled the vast potential of ribosomally synthesized and post-translationally modified peptides (RiPPs) encoded in microbiomes. Class I lantibiotics such as nisin A, widely used as a food preservative, have been investigated for their efficacy in killing pathogens. However, the impact of nisin and nisin-like class I lantibiotics on commensal bacteria residing in the human gut remains unclear. Here, we report six gut-derived class I lantibiotics that are close homologs of nisin, four of which are novel. We applied an improved lantibiotic expression platform to produce and purify these lantibiotics for antimicrobial assays. We determined their minimal inhibitory concentration (MIC) against both Gram-positive human pathogens and gut commensals, and profiled the lantibiotic resistance genes in these pathogens and commensals. SAR studies with variants revealed key regions and residues that impact their antimicrobial properties. Our characterization and SAR studies of nisin-like lantibiotics against both pathogens and human gut commensals could shed light on the future development of lantibiotic-based therapeutics and food preservatives.

bioengineering↗

bioRxiv2023

A ubiquitous mobile genetic element disarms a bacterial antagonist of the gut microbiota

DNA transfer is ubiquitous in the gut microbiota, especially among species of Bacteroidales. In silico analyses have revealed hundreds of mobile genetic elements shared between these species, yet little is known about the phenotypes they encode, their effects on fitness, or pleiotropic consequences for the recipients genome. Here, we show that acquisition of a ubiquitous integrative and conjugative element encoding an antagonistic system shuts down the native contact-dependent antagonistic system of Bacteroides fragilis. Despite inactivating the native antagonism system, mobile element acquisition increases fitness of the B. fragilis transconjugant over its progenitor by arming it with a new weapon. This DNA transfer causes the strain to change allegiances so that it no longer targets ecosystem members containing the same element yet is armed for communal defense.

microbiology↗

bioRxiv2023

Virulence and genomic diversity among clinical isolates of ST1 (BI/NAP1/027) Clostridioides difficile

Clostridioides difficile (C. difficile), a leading cause of nosocomial infection, produces toxins that damage the colonic epithelium and results in colitis that varies from mild to fulminant. Variation in disease severity is poorly understood and has been attributed to host factors (age, immune competence and intestinal microbiome composition) and/or virulence differences between C. difficile strains, with some, such as the epidemic BI/NAP1/027 (MLST1) strain, being associated with greater virulence. We tested 23 MLST1(ST1) C. difficile clinical isolates for virulence in antibiotic-treated C57BL/6 mice. All isolates encoded a complete Tcd pathogenicity locus and achieved similar colonization densities in mice. Disease severity varied, however, with 5 isolates causing lethal infections, 16 isolates causing a range of moderate infections and 2 isolates resulting in no detectable disease. The avirulent ST1 isolates did not cause disease in highly susceptible Myd88-/- or germ-free mice. Genomic analysis of the avirulent isolates revealed a 69 base-pair deletion in the N-terminus of the cdtR gene, which encodes a response regulator for binary toxin (CDT) expression. Genetic deletion of the 69 base-pair cdtR sequence in the highly virulent ST1 R20291 C. difficile strain rendered it avirulent and reduced toxin gene transcription in cecal contents. Our study demonstrates that a natural deletion within cdtR attenuates virulence in the epidemic ST1 C. difficile strain without reducing colonization and persistence in the gut. Distinguishing strains on the basis of cdtR may enhance the specificity of diagnostic tests for C. difficile colitis.

microbiology↗

bioRxiv2022

Exceptionally versatile respiratory metabolisms drive metabolite production by diverse gut bacteria

Respiratory reductases enable microbes to utilize molecules present in anaerobic ecosystems as energy-generating respiratory electron acceptors. Here we identify three taxonomically distinct families of human gut bacteria (Burkholderiaceae, Eggerthellaceae, Erysipelotrichaceae) that encode large arsenals of tens-to-hundreds of respiratory-like reductases per genome. Screening species from each family (Sutterella wadsworthensis, Eggerthella lenta, and Holdemania filiformis), we discover 22 metabolites used as respiratory electron acceptors in a species-specific manner. Identified reactions transform multiple classes of dietary- and host-derived metabolites, including bioactive molecules resveratrol and itaconate. Products of identified respiratory metabolisms highlight poorly characterized compounds, such as the itaconate-derived 2-methylsuccinate. Reductase substrate-profiling defines enzyme-substrate pairs and reveals a complex picture of reductase evolution, providing evidence that reductases with specificities for related cinnamate substrates independently emerged at least four times. These studies thus establish an exceptionally versatile form of anaerobic respiration that directly links microbial energy metabolism to the gut metabolome.

microbiology↗

bioRxiv2020

Mfd affects global transcription and the physiology of stressed Bacillus subtilis cells

For several decades, Mfd has been studied as the bacterial transcription-coupled repair factor. However, recent observations indicate that this factor influences cell functions beyond DNA repair. Our lab recently described a role for Mfd in disulfide stress that was independent of its function in nucleotide excision repair and base excision repair. Because reports showed that Mfd influenced transcription of single genes, we investigated the global differences in transcription in wild-type and mfd mutant growth-limited cells in the presence and absence of diamide. Surprisingly, we found 1,997 genes differentially expressed in Mfd- cells in the absence of diamide. Using gene knockouts, we investigated the effect of genetic interactions between Mfd and the genes in its regulon on the response to disulfide stress. Interestingly, we found that Mfd interactions were complex and identified additive, epistatic, and suppressor effects in the response to disulfide stress. Pathway enrichment analysis of our RNASeq assay indicated that major biological functions, including translation, endospore formation, pyrimidine metabolism, and motility, were affected by the loss of Mfd. Further, our RNASeq findings correlated with phenotypic changes in growth in minimal media, motility, and sensitivity to antibiotics that target the cell envelope, transcription, and DNA replication. Our results suggest that Mfd has profound effects on the modulation of the transcriptome and on bacterial physiology, particularly in cells experiencing nutritional and oxidative stress.

microbiology↗