Biology subjects

Berger, D. J.

Publications and source records attributed to Berger, D. J..

8 recordsLinked to original sources

bioRxiv2025

TRPtracker: a community database for monitoring praziquantel sensitivity at TRPMPZQ variants

The anthelmintic praziquantel (PZQ) has been used for decades as the clinical therapy for schistosomiasis, and remains the only available drug. As a cheap and effective drug therapy for all human disease-causing Schistosoma species, usage of PZQ underpins mass drug administration strategies aimed at eliminating schistosomiasis as a public health problem by 2030. Concern over the potential emergence of resistance to PZQ is therefore warranted, as it would constitute a major threat to this approach. In terms of molecular adaptations conferring PZQ resistance, variation in the sequence and/or expression of the drug target is an obvious mechanism and should be a priority for surveillance efforts. The target of PZQ is a transient receptor potential ion channel, TRPMPZQ, which is established as a locus that regulates schistosome sensitivity to PZQ. Here, we describe the establishment of a community resource, TRPtracker, which coalesces data on TRPMPZQ natural variants together with measurements of individual variant sensitivity to PZQ. A compendium of laboratory-generated mutants in TRPMPZQ is also compiled in TRPtracker to map regions within TRPMPZQ critical for PZQ sensitivity. Aggregation of data from multiple research groups into TRPtracker permits rapid community-wide exchange of data, cataloguing which TRPMPZQ variants have been functionally profiled, where geographically these variants have been found, their frequency within populations and their potential impact on PZQ sensitivity.

microbiology↗

bioRxiv2025

A modular architecture for trial-by-trial learning of redundant muscle activity patterns in novel sensorimotor tasks

The coordination of the multiple degrees-of-freedom of the human body may be simplified by muscle synergies, motor modules which can be flexibly combined to achieve various goals. Studies investigating adaptation to novel relationships between muscle activity and task outcomes found that altering the recruitment of such modules is faster than the learning of their structures de novo. However, how learning new synergy recruitments or new synergy structures may occur remains unclear. While trial-by-trial learning of novel sensorimotor tasks has been successfully modeled at the level of task variables, few models accounted for the redundancy of the motor system, particularly at the muscular level. However, these models either did not consider a modular architecture of the motor system, or assumed a priori knowledge of the sensorimotor task. Here, we present a computational model for the generation of redundant muscle activity where explicitly defined modules, implemented as spatial muscle synergies, can be updated together with their recruitment coefficients through an error-based learning process dependent on a forward model of the sensorimotor task, which is not assumed to be known a priori. Our model can qualitatively reproduce the experimental observations of slower learning and larger changes in the structure of the muscle activity under sensorimotor tasks that require the learning of novel patterns of muscle activity, providing further insights into the modular organization of the human motor system. Author summaryIt has been proposed that muscles are recruited in modules, called muscle synergies, rather than on a muscle-by-muscle basis. This modular organization was shown to affect the learning of novel tasks, where simulated remapping of the forces generated by the muscles ("virtual surgeries") that make the synergies ineffective are more difficult to learn. Previous models of trial-by-trial learning in a modular architecture have assumed prior knowledge of the motor task (in particular, how to modify the muscles / synergies recruitment given an error), which might not be the case for tasks in which novel patterns of muscle activity are required. In contrast, models which assumed no prior knowledge of the task have not investigated the role of modularity. Here, we propose a computational model of the trial-by-trial adaptation of muscle synergies, their recruitment, and the concurrent learning of the internal model of the musculoskeletal system responsible for error correction. Our results show that this model replicates experimental observations of slower learning and larger changes in the structure of the muscle activity in sensorimotor tasks that require the learning of novel patterns of muscle activity, providing insight into learning-related changes of muscle activity in novel sensorimotor tasks.

neuroscience↗

bioRxiv2024

Changes in Muscle Synergy Structure and Activation Patterns Underlie Force Field Adaptation, Retention, and Generalization

1Humans can adapt their motor commands in response to errors when they perform reaching movements in new dynamic conditions, a process called motor adaptation. They acquire knowledge about the new dynamics, which they can use when they are re-exposed and, limitedly, generalize to untrained reaching directions. While force field adaptation, retention, and generalization have been thoroughly investigated at a kinematic and kinetic task level, the underlying coordination at a muscular level remains unclear. Many studies propose that the central nervous system uses low- dimensional control, i.e., coordinates muscles in functional groups: so-called muscle synergies. Accordingly, we hypothesized that changes in muscle synergy structure and activation patterns represent the acquired knowledge underlying force field adaptation, retention, and generalization. To test this, 36 male humans practiced reaching to a single target in a viscous force field and were tested for retention and generalization to new directions, while we simultaneously measured muscle activity from 13 upper-body muscles. We found that muscle synergies used for unperturbed reaching cannot explain the muscle patterns when adapted. Instead, muscle synergies specific to this adapted state were necessary, alongside a novel four-phasic pattern of muscle synergy activation. Furthermore, these structural changes and patterns were also evident during retention and generalization. Our results suggest that reaching in an environment with altered dynamics requires structural changes to muscle synergies compared to unperturbed reaching, and that these changes facilitate retention and generalization. These findings provide new insights into how the central nervous system coordinates the muscles underlying motor adaptation, retention, and generalization. 2 Significance StatementHumans can adapt their reaching movements to new dynamic conditions. They acquire knowledge about the new dynamics and can use it not only when re-exposed to these conditions but also, in part, to generalize unpracticed reaching directions. While adaptation, retention, and generalization in a force field with new dynamics have been thoroughly investigated at a kinematic and kinetic task level, coordination of the underlying muscles remains elusive. Our results show how muscle synergies - functional groupings of co-activated muscles - underlie adaptation, retention, and generalization. In particular, we observed structural changes in the muscle synergies after adaptation compared to unperturbed reaching. These changes facilitate retention and spatial generalization. Thus, muscle synergies provide new insights into human motor adaptation.

neuroscience↗

bioRxiv2024

Extensive transmission and variation in a functional receptor for praziquantel resistance in endemic Schistosoma mansoni

Mass-drug administration (MDA) of human populations using praziquantel monotherapy has become the primary strategy for controlling and potentially eliminating the major neglected tropical disease schistosomiasis. To understand how long-term MDA impacts schistosome populations, we analysed whole-genome sequence data of 570 Schistosoma mansoni samples (and the closely related outgroup species, S. rodhaini) from eight countries incorporating both publicly-available sequence data and new parasite material. This revealed broad-scale genetic structure across countries but with extensive transmission over hundreds of kilometres. We characterised variation across the transient receptor potential melastatin ion channel, TRPMPZQ, a target of praziquantel, which has recently been found to influence praziquantel susceptibility. Functional profiling of TRPMPZQ variants found in endemic populations identified four mutations that reduced channel sensitivity to praziquantel, indicating standing variation for resistance. Analysis of parasite infrapopulations sampled from individuals pre- and post-treatment identified instances of treatment failure, further indicative of potential praziquantel resistance. As schistosomiasis is targeted for elimination as a public health problem by 2030 in all currently endemic countries, and even interruption of transmission in selected African regions, we provide an in-depth genomic characterisation of endemic populations and an approach to identify emerging praziquantel resistance alleles. One Sentence SummaryPopulation genomics and functional genetics of praziquantel resistance in Schistosoma mansoni

genomics↗

bioRxiv2023

Development of the Pneumococcal Genome Library, a core genome multilocus sequence typing scheme, and a taxonomic life identification number barcoding system to investigate and define pneumococcal population structure

Investigating the genomic epidemiology of major bacterial pathogens is integral to understanding transmission, evolution, colonisation, disease, antimicrobial resistance, and vaccine impact. Furthermore, the recent accumulation of large numbers of whole genome sequences for many bacterial species enhances the development of robust genome-wide typing schemes to define the overall bacterial population structure and lineages within it. Using previously published data, we developed the Pneumococcal Genome Library (PGL), a curated dataset of 30,976 genomes and contextual data for carriage and disease pneumococci recovered between 1916-2018 in 82 countries. We leveraged the size and diversity of the PGL to develop a core genome multilocus sequence typing (cgMLST) scheme comprised of 1,222 loci. Finally, using multilevel single-linkage clustering, we stratified pneumococci into hierarchical clusters based on allelic similarity thresholds, and defined these with a taxonomic life identification number (LIN) barcoding system. The PGL, cgMLST scheme, and LIN barcodes represent a high-quality genomic resource and fine-scale clustering approaches for the analysis of pneumococcal populations, which support the genomic epidemiology and surveillance of this leading global pathogen. Impact statementMany thousands of pneumococcal genomes are available in the public domain, and this creates opportunities for the scientific community to re-use existing data; however, these data are most useful when the contextual data (provenance and phenotype) are also linked to the genomes. Therefore, we created a curated, open-access database in PubMLST that contained nearly 31,000 published pneumococcal genomes and the corresponding contextual data for each genome. This large and diverse pneumococcal database was used to create a novel cgMLST scheme and multilevel clustering method to define genetic lineages with high resolution and a standardised nomenclature. These are open-access resources for all to use and provide a unified framework for the characterisation of global pneumococcal populations.

genomics↗

bioRxiv2023

Control limitations in the null-space of the wrist muscle system

The redundancy present within the musculoskeletal system may offer a non-invasive source of signals for movement augmen tation, where the muscle-to-force null-space could be controlled simultaneously to the natural limbs. Here, we investigated the viability of extracting movement augmentation control signals from the muscles of the wrist complex. Our study assessed i) if controlled variation of the muscle activation patterns in the wrist joints null-space is possible; and ii) whether force and null-space targets could be reached simultaneously. During the null-space target reaching condition, participants used EMG-to-force null-space muscle activation to move their cursor towards a displayed target while minimising the exerted force as visualised through the cursors size. Initial targets were positioned to require natural co-contraction in the null-space and if participants showed a consistent ability to reach for their current target, they would rotate 5{degrees} incrementally to generate muscle activation patterns further away from their natural co-contraction. In contrast, during the concurrent target reaching condition participants were required to match a target position and size, where their cursor position was instead controlled by their exerted flexion-extension and radial-ulnar deviation, while its size was changed by their natural co-contraction magnitude. The results collected from 10 participants suggest that while there was variation in each participants co-contraction behaviour, most did not possess the ability to control this variation for muscle-to-force null-space reaching. In contrast, participants did show a direction and target size dependent ability to vary isometric force and co-contraction activity concurrently. Our results show the limitations of using null-space activity in joints with a low level of redundancy.

neuroscience↗

bioRxiv2021

Assembled chromosomes of the blood fluke Schistosoma mansoni provide insight into the evolution of its ZW sex-determination system

BackgroundSchistosoma mansoni is a flatworm that causes a neglected tropical disease affecting millions worldwide. Most flatworms are hermaphrodites but schistosomes have genotypically determined male (ZZ) and female (ZW) sexes. Sex is essential for pathology and transmission, however, the molecular determinants of sex remain unknown and is limited by poorly resolved sex chromosomes in previous genome assemblies. ResultsWe assembled the 391.4 Mb S. mansoni genome into individual, single-scaffold chromosomes, including Z and W. Manual curation resulted in a vastly improved gene annotation, resolved gene and repeat arrays, trans-splicing, and almost all UTRs. The sex chromosomes each comprise pseudoautosomal regions and single sex-specific regions. The Z-specific region contains 932 genes, but on W all but 29 of these genes have been lost and the presence of five pseudogenes indicates that degeneration of W is ongoing. Synteny analysis reveals an ancient chromosomal fusion corresponding to the oldest part of Z, where only a single gene--encoding the large subunit of pre-mRNA splicing factor U2AF--has retained an intact copy on W. The sex-specific copies of U2AF have divergent N-termini and show sex-biased gene expression. ConclusionOur assembly with fully resolved chromosomes provides evidence of an evolutionary path taken to create the Z and W sex chromosomes of schistosomes. Sex-linked divergence of the single U2AF gene, which has been present in the sex-specific regions longer than any other extant gene with distinct male and female specific copies and expression, may have been a pivotal step in the evolution of gonorchorism and genotypic sex determination of schistosomes.

genomics↗

bioRxiv2021

Task space exploration improves adaptation after incompatible virtual surgeries

Humans have a remarkable capacity to learn new motor skills, a process that requires novel muscle activity patterns. Muscle synergies may simplify the generation of muscle patterns through the selection of a small number of synergy combinations. Learning new motor skills may then be achieved by acquiring novel muscle synergies. In a previous study, we used myoelectric control to construct virtual surgeries that altered the mapping from muscle activity to cursor movements. After compatible virtual surgeries, which could be compensated by recombining subject-specific muscle synergies, participants adapted quickly. In contrast, after incompatible virtual surgeries, which could not be compensated by recombining existing synergies, participants explored new muscle patterns, but failed to adapt. Here, we tested whether task space exploration can promote learning of novel muscle synergies, required to overcome an incompatible surgery. Participants performed the same reaching task as in our previous study, but with more time to complete each trial, thus allowing for exploration. We found an improvement in trial success after incompatible virtual surgeries. Remarkably, improvements in movement direction accuracy after incompatible surgeries occurred faster for corrective movements than for the initial movement, suggesting that learning of new synergies is more effective when used for feedback control. Moreover, reaction time was significantly higher after incompatible than after compatible virtual surgeries, suggesting an increased use of an explicit adaptive strategy to overcome incompatible surgeries. Taken together, these results indicate that exploration is important for skill learning and suggest that human participants, with sufficient time can learn new muscle synergies. NEW & NOTEWORTHYMotor skill learning requires the acquisition of novel muscle patterns, a slow adaptive process. Here we show that learning to control a cursor after an incompatible virtual surgery, a complex skill requiring new muscle synergies, is possible when enough time for task space exploration is provided. Our results suggest that learning new synergies is related to the exceptional human capacity to acquire a wide variety of novel motor skills with practice.

neuroscience↗