Biology subjects

Hodges, F.

Publications and source records attributed to Hodges, F..

4 recordsLinked to original sources

bioRxiv2026

Validated Semantic Scoring Improves Filtering Generic Concepts from Knowledge-Graphs for Drug Repurposing Queries

When an ontology-based biomedical knowledge graph (a KG, containing information about genes, pathways, phenotypes, and molecular interactions) is analyzed using a computational reasoning system, the system can return unwanted generic concepts. Such generic concepts, in the context of a query about potential drug treatments for a disease, might include 'pharmaceutical preparations' or 'antibiotics'. Answers can be filtered based on hand-curated block-lists or ontology Information Content (IC), but to our knowledge, (1) neither filtering method has been validated against expert judgments of generality, and (2) IC is not available for the majority of nodes in the representative KG used in this work. In this study, three domain experts rated representative lists of KG concepts for generality. We built a semantic precision score (SPS) from a concept's name and description alone, using a biomedical language model (BioLORD). For the purpose of filtering generic answers from biomedical query results, we compared (using queries for 200 diseases) the SPS against a curated concept block-list and two IC thresholds. IC agreed moderately with the experts (Spearman's {rho} = 0.59), but correlations were negligible or negative within IC bands. The SPS was well-correlated with the experts ({rho} = 0.76) globally and within SPS bands, and remained informative on concepts without IC ({rho} = 0.59). Hard filtering of query results using the SPS removed 1,502 of 33,161 query answers, nearly three times the block-list's 513, while removing fewer of the query-specific DrugCentral indications. Hard filtering by IC removed either few answers or many approved drugs. We additionally compared the filtering methods' performance on an independent evaluation set of queries for 200 diseases. The SPS filter removed 5,135 of 91,203 answers compared with the block-list's 1,419 and lost none of 1,296 indications compared with 17. Further, SPS filtering removed approved drugs no more often from the half of DrugCentral not used in training than from the half used in training. Semantic meaning captures expert judgments of specificity more faithfully than ontology position, and semantic scoring can replace IC and manually maintained block-lists for filtering drug-repurposing results.

bioinformatics↗

bioRxiv2024

Identification of new genes on a whole genome scale using saturated reporter transposon mutagenesis

Small or overlapping genes are prevalent across all domains of life but are often overlooked for annotation and function because of challenges in their detection. The advent of high-density mutagenesis and data-mining studies suggest the existence of further coding potential within bacterial genomes. To overcome limitations in existing protein detection methods, we applied a genetics-based approach. We combined transposon insertion sequencing with a translation reporter to identify translated open reading frames throughout the genome at scale, independent of genome annotation. We applied our method to the well-characterised species Escherichia coli and identified [~]200 putative novel protein coding sequences (CDS). These are mostly short CDSs (<50 amino acids) and in some cases highly conserved. We validated the expression of selected CDSs demonstrating the utility of this approach. Despite the extensive study of E. coli, this method revealed proteins that have not been described previously, including proteins that are conserved and neighbour functionally important genes, suggesting significant functional roles of these small proteins. We present this as a complementary method to whole cell proteomics and ribosome trapping for condition-dependent identification of protein CDSs, and as a high-throughput method for testing conditional gene expression. We anticipate this technique will be a starting point for future high-throughput genetics investigations to determine the existence of unannotated genes in multiple bacterial species.

microbiology↗

bioRxiv2020

Glycine acylation and trafficking of a new class of bacterial lipoprotein by a composite secretion system

Protein acylation is critical for many cellular functions including signal transduction, cell division and development. In bacteria, such lipoproteins have important roles in virulence and are therefore potential targets for the development of novel antimicrobials and vaccines. To date, all known bacterial lipoproteins are secreted from the cytosol via the Sec pathway, acylated on an N-terminal cysteine residue through the action of Lgt, Lsp and Lnt, and then targeted to the appropriate cellular location. In the case of Gram-negative bacteria, the lipoprotein trafficking Lol pathway transports the lipoproteins to the outer membrane where most substrate molecules are retained within the cell. Here we identify a new secretion pathway that displays the substrate lipoprotein on the cell surface. We demonstrate that the previously identified E. coli Aat secretion system is a composite system that shares similarity with type I secretion systems and elements of the Lol pathway. Remarkably, during secretion by the Aat system, the AatD subunit acylates the substrate CexE on a highly conserved N-terminal glycine residue (rather than the canonical cysteine). Mutations in AatD or CexE that disrupt glycine acylation interfere with membrane incorporation and trafficking. Our data suggest that CexE is the first member of a new class of glycine-acylated bacterial lipoprotein, while Aat represents a new secretion system that we propose be defined as a lipoprotein secretion system (LSS).

microbiology↗

bioRxiv2020

Direct Continuous EMG control of a Powered Prosthetic Ankle for Improved Postural Control after Guided Physical Training: a Case Study

BackgroundDespite the promise of powered lower limb prostheses, the existing control of these modern devices is insufficient to assist many daily activities, such as postural control while lifting weight, that require continuous control of prosthetic joints according to human states and environments. The objective of this case study was to investigate the feasibility and potential of direct, continuous electromyographic (dEMG) control of a powered ankle prosthesis, combined with physical therapist (PT)-guided training, for improved standing postural control in an individual with transtibial amputation. MethodsA powered prosthetic ankle was directly controlled by EMG signals of the residual lateral gastrocnemius and tibialis anterior muscles. The participant with transtibial amputation received 4-week PT-guided training on posture while using the dEMG control of powered ankle. A subset of activities in the mini-BESTest (a clinical balance assessment tool) were used in the training and evaluation protocol. We quantified EMG signals in the bilateral shank muscles, biomechanics that captures postural control and stability, and score for the clinical balance evaluation. ResultsCompared to the participants daily passive prosthesis, the dEMG-controlled ankle, combined with the training, yielded improved clinical balance score and reduced compensation from the intact joints. In addition, cross correlation coefficient of bilateral CoP excursions, a metric for quantifying standing postural control, increased to 0.83({+/-}0.07) when using dEMG ankle control, compared with 0.39({+/-}0.29) when using the passive device. Between-limb coordination was also observed as synchronized activation of homologous muscles in the shank. We witnessed rapid improvement in performance on the first day of the training for load transfer tasks, where bilateral CoP synchronization improvement was significantly related to repetition order (R=0.459, p = 0.045). Finally, the participant further improved this performance significantly across training days. ConclusionThis case study showed the feasibility of dEMG control of powered prosthetic ankle by a transtibial amputee after a PT-guided training to assist postural control. This studys training protocol and dEMG control method that lays the foundation for future study to extend these results through the inclusion of more participants and activities.

bioengineering↗