Biology subjects

Franklin, D.

Publications and source records attributed to Franklin, D..

9 recordsLinked to original sources

bioRxiv2026

Gradient-specified optimization based on muscle surface mesh and moment arm as an effect-oriented approach of automated musculotendon path modeling

There is more to musculotendon path modeling than aligning a cable to reflect the geometric features of a musculotendon unit. From the perspective of simulation accuracy, the key is to replicate the length- and moment arm-joint angle relations of the target muscle. In this study, we propose an effect-oriented approach of automated path modeling, via hybrid calibration based on muscle surface mesh and moment arm. The task is formulated as a least-squares optimization problem with a threefold objective for the path to: (1) pass through multiple ellipses representing muscle cross-sections, (2) yield moment arms that match experimental measurements, and (3) yield moment arms in the expected functional directions. We demonstrate the performance of our optimization framework with the musculoskeletal surface mesh from the Visible Human Male and moment arm datasets from literature--producing 42 paths that are anatomically realistic and biomechanically accurate within 20.1 minutes. Our optimization framework is gradient-specified, which is faster and more accurate than using the default numerical gradient, making it applicable for large-scale subject-specific uses.

bioengineering↗

bioRxiv2026

Community Curation of Microbial Metabolites Enables Biological Insights of Metabolomics Data

Microbial metabolites play a critical role in regulating ecosystems, including the human body and its microbiota. However, understanding the physiologically relevant role of these molecules, especially through liquid chromatography tandem mass spectrometry (LC-MS/MS)-based untargeted metabolomics, poses significant challenges and often requires manual parsing of a large amount of literature, databases, and webpages. To address this gap, we established the Collaborative Microbial Metabolite Center knowledgebase (CMMC-KB), a platform that fosters collaborative efforts within the scientific community to curate knowledge about microbial metabolites. The CMMC-KB aims to collect comprehensive information about microbial molecules originating from microbial biosynthesis, drug metabolism, exposure-related molecules, food, host-derived molecules, and, whenever available, their known activities. Molecules from other sources, including host-produced, dietary, and pharmaceutical compounds, are also included. By enabling direct integration of this knowledgebase with downstream analytical tools, including molecular networking, we can deepen insights into microbiota and their metabolites, ultimately advancing our understanding of microbial ecosystems.

bioinformatics↗

bioRxiv2024

Ethanolamine-induced assembly of microcompartments is required for Fusobacterium nucleatum virulence

Many bacteria metabolize ethanolamine as a nutrient source through cytoplasmic organelles named bacterial microcompartments (BMCs). Here we investigated the molecular assembly, regulation, and function of BMCs in Fusobacterium nucleatum - a Gram-negative oral pathobiont that is associated with adverse pregnancy outcomes. The F. nucleatum genome harbors a conserved ethanolamine utilization (eut) locus with 21 genes that encode several putative BMC shell proteins and a two-component signal transduction system (TCS), in addition to the enzymes for ethanolamine transport and catabolism. We show that the expression of most of these genes as well as BMC formation is highly increased in wild type fusobacteria when cultured in the presence of ethanolamine as a nutrient source. Deletion of the response regulator EutV eliminated this induction of eut mRNAs and BMCs, thus demonstrating that BMC formation is transcriptionally regulated by the TCS EutV-EutW in response to ethanolamine. Mass spectrometry of isolated BMCs unveiled the identity of the constituent proteins EutL, EutM1, EutM2, and EutN. Consistent with the role of these proteins in BMC assembly and metabolism, deletion of eutN, eutL/eutM1/eutM2, or eutL/eutM1/eutM2/eutN not only affected BMC formation, but also ethanolamine utilization, causing cell growth defects with ethanolamine as nutrient. BMCs also assembled in fusobacteria cultured with placental cells or the culture media, a process that is dependent on the BMC shell proteins. Significantly, we show that the eutN mutant is defective in inducing preterm birth in a mouse model. Together, these results establish that BMC-mediated metabolism of ethanolamine is critical for fusobacterial virulence. IMPORTANCEThe oral anaerobe Fusobacterium nucleatum can spread to distal internal organs, such as the colon and placenta, and thereby promote the development of colorectal cancer and induce preterm birth, respectively. Yet, how this opportunistic pathogen adapts to the various metabolically distinct host cellular niches remains poorly understood. We demonstrated here that this microbe assembles specialized metabolic organelles, termed bacterial microcompartments (BMCs), to utilize environmental ethanolamine (EA) as a key environmental nutrient source. The formation of F. nucleatum BMCs, containing BMC shell proteins EutLM1M2N, is controlled by a two-component system, EutV-EutW, responsive to EA. Significantly, this ability of F. nucleatum to form BMCs in response to EA is crucial for its pathogenicity evidenced by the fact that the genetic disruption of BMC formation reduces fusobacterial virulence in a mouse model of preterm birth.

microbiology↗

bioRxiv2024

The microbiome diversifies N-acyl lipid pools - including short-chain fatty acid-derived compounds

N-acyl lipids are important mediators of several biological processes including immune function and stress response. To enhance the detection of N-acyl lipids with untargeted mass spectrometry-based metabolomics, we created a reference spectral library retrieving N-acyl lipid patterns from 2,700 public datasets, identifying 851 N-acyl lipids that were detected 356,542 times. 777 are not documented in lipid structural databases, with 18% of these derived from short-chain fatty acids and found in the digestive tract and other organs. Their levels varied with diet, microbial colonization, and in people living with diabetes. We used the library to link microbial N-acyl lipids, including histamine and polyamine conjugates, to HIV status and cognitive impairment. This resource will enhance the annotation of these compounds in future studies to further the understanding of their roles in health and disease and highlight the value of large-scale untargeted metabolomics data for metabolite discovery.

bioinformatics↗

bioRxiv2024

Empirically establishing drug exposure records directly from untargeted metabolomics data

Despite extensive efforts, extracting information on medication exposure from clinical records remains challenging. To complement this approach, we developed the tandem mass spectrometry (MS/MS) based GNPS Drug Library. This resource integrates MS/MS data for drugs and their metabolites/analogs with controlled vocabularies on exposure sources, pharmacologic classes, therapeutic indications, and mechanisms of action. It enables direct analysis of drug exposure and metabolism from untargeted metabolomics data independent of clinical records. Our library facilitates stratification of individuals in clinical studies based on the empirically detected medications, exemplified by drug-dependent microbiota-derived N-acyl lipid changes in a cohort with human immunodeficiency virus. The GNPS Drug Library holds potential for broader applications in drug discovery and precision medicine.

bioinformatics↗

bioRxiv2024

Automated muscle path calibration with gradient-specified optimization based on moment arm

ObjectiveMuscle path modeling is more than just routing a cable that visually represents the muscle, but rather it defines how moment arms vary with different joint configurations. The muscle moment arm is the factor that translates muscle force into joint moment, and this property has an impact on the accuracy of musculoskeletal simulations. However, it is not easy to calibrate muscle paths based on a desired moment arm, because each path is configured by various parameters while the relations between moment arm and both the parameters and joint configuration are complicated. MethodsWe tackle this challenge in the simple fashion of optimization, but with an emphasis on the gradient; when specified in its analytical form, optimization speed and accuracy are improved. ResultsWe explain in detail how to differentiate the enormous cost function and how our optimization is configured, then we demonstrate the performance of this method by fast and accurate replication of muscle paths from a state-of-the-art shoulder-arm model. Conclusion and SignificanceAs long as the muscle is represented as a cable wrapping around obstacles, our method overcomes difficulties in path calibration, both for developing generic models and for customizing subject-specific models.

bioengineering↗

bioRxiv2023

Finding the rhythm: Humans exploit nonlinear intrinsic dynamics of compliant systems in periodic interaction tasks

Everyday activities, like jumping on a trampoline or using a swing-stick, show that humans seemingly effortless support systems in their intrinsically preferred motions. Although this observation seems obvious, data-based evidence proving that humans indeed match system dynamics has been lacking, since everyday objects usually exhibit complex, nonlinear dynamics, which are in general not analytically solvable. Recent insights in the field of nonlinear mode theory and the development of a tool to compute modes for nonlinear systems enabled us to investigate human strategies to excite periodic motions in the interaction with nonlinear systems. In the setup of a high score game, participants interacted with differently configured virtual compliant double pendulum systems through a haptic joystick. Through the joystick, the user could command positions to a motor link connected to the pendulum by a spring and received resulting spring forces in return to convey the feeling of holding a flexible stick. The participants were asked to alternately hit two targets located on the computed nonlinear mode of the system as often as possible. All participants intuitively exploited the elasticity of the system by choosing a holding strategy of the motor link and only compensate for energy losses with small motions. In this way, the intrinsic dynamics of the double pendulum system were exploited leading to the predicted fast motions along the nonlinear modes. The human strategy stayed consistent when decreasing the target size or increasing the mass of the lower pendulum link, i.e., changing the dynamics. Consequently, the presented research provides data-based evidence that humans can indeed estimate the nonlinear dynamics of system and intuitively exploit these. Additionally, the introduction to nonlinear modes and ways to compute them could be a powerful tool for further investigations on human capabilities and strategies in periodic interactions with nonlinear systems. Author summaryWithout thinking about it, humans interact with a wide variety of objects in everyday life. This includes objects with very complex nonlinear dynamics such as flexible rods or ropes. Since it is not trivial to enforce trajectories far away from the systems intrinsic motions and frequencies, it is likely that humans explore and, whenever possible, exploit the natural dynamics of the system. By using a tool to predict the trajectories of systems with nonlinear dynamics, we collected human user data to validate this hypothesis for repetitive tasks with a virtual double pendulum. Indeed our research showed that humans supported mechanical systems in their respective intrinsic motions and were able to intuitively match the systems eigenfrequencies. In doing so, only little control effort and motion was needed from the users, which could aids to save energy and mental resources. Since both these aspects are limiting factors in continuous tasks, it seems to have an evolutionary benefit that humans are very capable in estimating and exploiting the natural dynamics of compliant systems and tune their own control strategy to be be synchronized to the controlled system.

neuroscience↗

bioRxiv2023

An ancient respiratory enzyme metabolically modulates Fusobacterium nucleatum virulence

A prominent oral commensal and opportunistic pathogen, Fusobacterium nucleatum can traverse to extra-oral sites such as placenta and colon, promoting adverse pregnancy outcomes and colorectal cancer, respectively. How this anaerobe sustains many metabolically changing environments enabling its virulence potential remains unclear. Informed by our genome-wide transposon mutagenesis, we report here that the highly conserved Rnf complex, encoded by the rnfCDGEAB gene cluster, is key to fusobacterial metabolic adaptation and virulence. Genetic disruption of the Rnf complex via non-polar, in-frame deletion of rnfC ({Delta}rnfC) abrogates polymicrobial interaction (or coaggregation) associated with adhesin RadD and biofilm formation. The defect in coaggregation is not due to reduced cell surface of RadD, but rather an increased level of extracellular lysine, which binds RadD and inhibits coaggregation. Indeed, removal of extracellular lysine via washing {Delta}rnfC cells restores coaggregation, while addition of lysine inhibits this process. These phenotypes mirror that of a mutant ({Delta}kamA) that fails to metabolize extracellular lysine. Strikingly, the {Delta}rnfC mutant is defective in ATP production, cell growth, cell morphology, and expression of the enzyme MegL that produces hydrogen sulfide from cysteine. Targeted metabolic profiling demonstrated that catabolism of many amino acids, including histidine and lysine, is altered in {Delta}rnfC cells, thereby reducing production of ATP and metabolites including H2S and butyrate. Most importantly, we show that the {Delta}rnfC mutant is severely attenuated in a mouse model of preterm birth. The indispensable function of Rnf complex in fusobacterial pathogenesis via modulation of bacterial metabolism makes it an attractive target for developing therapeutic intervention. IMPORTANCEAlthough viewed as an oral commensal, the Gram-negative F. nucleatum is an opportunistic pathogen that can spread to extra-oral sites such as placenta and colon, promoting adverse pregnancy outcomes and colorectal cancer, respectively. How this anaerobe sustains various metabolically changing environments enabling its virulence potential remains unclear. We demonstrate here that the highly conserved Rnf complex is key to fusobacterial metabolic adaptation and virulence. Genetic disruption of this Rnf complex causes global defects in polymicrobial interaction, biofilm formation, cell growth and morphology, H2S production, and ATP synthesis. Targeted metabolomic profiling demonstrates that the loss of this respiratory enzyme significantly diminishes catabolism of numerous amino acids, which negatively impacts fusobacterial virulence as tested in a preterm birth model in mice.

microbiology↗

bioRxiv2019

Time-to-target explains task-dependent modulation of temporal feedback gain evolution

Visuomotor feedback responses vary in intensity throughout a reach, commonly explained by optimal control. Here we show that the optimal control for a range of movements with the same goal can be simplified to a time-to-target dependent control scheme. We measure participants visuomotor responses in five reaching conditions, each with different hand or cursor kinematics. Participants only produced different feedback responses when these kinematic changes resulted in different times-to-target. We complement our experimental data with a range of finite and non-finite horizon optimal feedback control models, finding that only the model with time-to-target as one of the input parameters can successfully replicate the experimental data. Overall, this suggests that time-to-target is a critical control parameter in online feedback control. Moreover, we propose that for a specific task and known dynamics, humans can instantly produce a control signal without any computation allowing rapid response onset and close to optimal control.

neuroscience↗