Biology subjects

Worth, A.

Publications and source records attributed to Worth, A..

5 recordsLinked to original sources

bioRxiv2025

Variants in glycine decarboxylase activate mechanisms of mitochondrial energy metabolism in the brain.

Brain energy metabolism is produced from glucose by mitochondrial oxidative phosphorylation. Variants in the mitochondrial enzyme glycine decarboxylase (GLDC) cause a rare neurological disease, non-ketotic hyperglycinemia (NKH), with expected hallmarks of brain glycine elevation and responsiveness to folate deficiency that are equivalent to the severity of Gldc mutations. We remarkably find that brains of young- attenuated mutant mice with a 1.5-fold increase in glycine are reduced > 5-fold in GLDC, show a decline in both the mitochondrial lipoyl-transfer protein GCSH and lipoylation of the pyruvate dehydrogenase (PDH) complex, as well as concomitant rise in signatures of astrocyte mitochondrial {beta}-oxidation of fatty acids and activation of neuronal PDH. Our findings suggest a novel GLDC mechanism of remodeling mitochondrial energy systems throughout the brain, established early in and sustained throughout post-natal NKH disease.

neuroscience↗

bioRxiv2022

Environmental DNA reveals invasive crayfish microbial associates and ecosystem-wide biodiversity before and after eradication

Biodiversity monitoring in conservation projects is essential to understand environmental status and recovery. However, traditional field surveys can be expensive, time-consuming, biased towards visual detection, and focused on measuring a limited set of taxa. Environmental DNA (eDNA) methods provide a new approach to biodiversity monitoring that has the potential to sample a taxonomically broader set of organisms with similar effort, but many of these approaches are still in the early stages of development and testing. Here, we use multilocus eDNA metabarcoding to understand how the removal of invasive red swamp crayfish impacts local biodiversity of a desert oasis ecosystem, as well as to detect crayfish both directly and indirectly. We tracked crayfish DNA signatures, microbial DNA associated with crayfish, and biodiversity of plant, fungal, animal, and bacterial communities through time. We were unsuccessful in detecting crayfish directly in either control tanks or oases using targeted metabarcoding primers for invertebrates and eukaryotes, similar to previous studies which have shown variable levels of success in detecting crayfish from environmental samples. However, we were successful in discerning a suite of 90 crayfish-associated taxa to serve as candidate bioindicators of invasive presence using 16S and Fungal ITS2 metabarcoding. Ranking these 90 taxa by their geographic distribution in eDNA surveys and by evidence of crayfish-associations in the literature, we support 9 taxa to be high-ranking, and suggest they be prioritized in future biomonitoring. Biodiversity analyses from five metabarcode loci including plants, animals, and both prokaryotic and eukaryotic microbes showed that communities differed but that species richness remained relatively similar between oases through time. Our results reveal that, while there are limitations of eDNA approaches to detect crayfish and other invasive species, microbial bioindicators offer a largely untapped biomonitoring opportunity for invasive species management, adding a valuable resource to a conservation managers toolkit.

ecology↗

bioRxiv2020

Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitution in vitro and in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.

physiology↗

bioRxiv2018

Whole Genome Sequencing of Primary Immunodeficiency reveals a role for common and rare variants in coding and non-coding sequences

Primary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent, and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 participants. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 10.3%, while a Bayesian approach (BeviMed4) identified multiple potential new candidate genes, including IVNS1ABP. Exploration of the non-coding genome revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to variable penetrance and phenotypic complexity in PID. Thus, a cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening our understanding of the key pathways influencing human immune responsiveness.

immunology↗

bioRxiv2018

Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here eleven new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that six of eighteen (33%) protein-coding mutations and the two (100%) 5-UTR mutations display incomplete penetrance. Three mutations were identified in 2 independent kindreds, due to a hotspot or a founder effect. Lastly, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.

genetics↗