Biology subjects

Moss, S.

Publications and source records attributed to Moss, S..

6 recordsLinked to original sources

bioRxiv2026

Distinct Motor Cortex Somatotopy in Experimental Alzheimers Disease

Alzheimers Disease (AD) and related dementias (AD/RDs) impact cortical motor and sensory biology whereas the precise changes to these systems, and their clinical relevance, remain under debate. We hypothesized that cortical representations of complex and simple movements are differently altered during disease progression in 5XFAD mice, a well-established model of AD. Motor cortex somatotopy was determined in 5XFAD and Wild-Type Control (WT Control) mice at 6 and 12 months (mos.) of age using long-duration intracortical microstimulation (LD-ICMS) to systematically identify cortical sites evoking complex and simple forelimb movements. At 6 mos. of age, 5XFAD mice exhibited a significant expansion of motor cortical sites representing simple movements, specifically Elbow Flexion (p=0.0004) and Wrist Flexion (p=0.024). The over-sized territory for Elbow Flexion significantly distinguished 5XFAD from WT mice (Receiver Operating Characteristic [ROC] area under the curve [AUC]= 0.94, p= 0.0009) whereas discriminative performance of Wrist Flexion was a non-significant trend (AUC=0.75, p=0.059). By 12 mos. of age, motor cortex organization was markedly reorganized in 5XFAD mice, with significantly fewer cortical sites evoking complex Advance movement (p<0.0001) as well as simple Shoulder (p=0.0001), Elbow Extension (p=0.024), and Wrist Extension (p=0.003) movements. The number of sites for simple Wrist Flexion was significantly increased (p=0.011) in 12 mo. old 5XFAD mice. At 12 mos., territory size of several of these movement zones highly distinguished 5XFAD from WT mice, including Advance (AUC= 0.96, p= 0.0005), Shoulder (AUC= 0.97, p= 0.0004), Elbow Extension (AUC=0.78, p=0.034), Wrist Extension (AUC=0.85, p= 0.0082), and Wrist Flexion (AUC=0.80, p= 0.023). These findings demonstrate progressive, age-dependent remodeling of motor cortex somatotopy in 5XFAD mice, characterized by early expansion of specific simple movement cortical sites followed by deterioration of both complex and simple motor cortical maps as disease advances. Motor cortex somatotopic remodeling may provide a sensitive biomarker of AD/RDs progression.

neuroscience↗

bioRxiv2024

Association between mosaic loss of chromosome Y and pulmonary fibrosis susceptibility and severity

Background Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and multiple interconnected underlying biological mechanisms. Mosaic loss of chromosome Y (mLOY) is one of the most common forms of acquired chromosome abnormality in men, which has been reported to be associated with increased risk of various chronic progressive diseases including fibrotic diseases. However, the exact role of mLOY in the development of PF remains elusive and to be elucidated. MethodsWe adopted three complementary approaches to explore the role of mLOY in the pathogenesis of PF. We used copy number on chromosome Y to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. We performed Mendelian randomisation to examine the causal relationship between mLOY, IPF, and telomere length. ResultsThe genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (P = 0.0032). mLOY is related to age (P = 0.00021) and shorter telomere length (P = 0.0081) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells and appears to be related to presence and severity of fibrosis. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY. ConclusionOur study confirms the existence of mLOY in PF patients and suggests that mLOY is not a major driver of IPF. The combined evidence suggests a triangulation model where telomere shortening leads to both IPF and mLOY.

genomics↗

bioRxiv2024

Conditional language models enable the efficient design of proficient enzymes

The design of functional enzymes holds promise for transformative solutions across various domains but presents significant challenges. Inspired by the success of language models in generating nature-like proteins, we explored the potential of an enzyme-specific language model in designing catalytically active artificial enzymes. Here, we introduce ZymCTRL (enzyme control), a conditional language model trained on the enzyme sequence space, capable of generating enzymes based on user-defined specifications. Experimental validation at diverse data regimes and for different enzyme families demonstrated ZymCTRLs ability to generate active enzymes across various sequence identity ranges. Specifically, we describe the design of carbonic anhydrases and lactate dehydrogenases in zero-shot, without requiring further training of the model, and showcasing activity at sequence identities below 40% compared to natural proteins. Biophysical analysis confirmed the globularity and well-folded nature of the generated sequences. Furthermore, fine-tuning the model enabled the generation of lactate dehydrogenases outside of natural sequence space but with activity comparable to their natural counterparts. Two of the artificial lactate dehydrogenases were selected for scale production and successfully lyophilised, maintaining activity and demonstrating preliminary conversion in one-pot enzymatic cascades under extreme conditions. Our findings open a new door towards the rapid and cost-effective design of artificial proficient enzymes. The model and dataset are freely available to the community.

bioinformatics↗

bioRxiv2021

Two microbiota subtypes identified in Irritable Bowel Syndrome with distinct responses to the low-FODMAP diet

ObjectiveReducing FODMAPs can be clinically beneficial in IBS but the mechanism is poorly understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action. DesignWe used metagenomics to determine high-resolution taxonomic and functional profiles of the stool microbiota from IBS cases and household controls (n=56 pairs) on their usual diet. Clinical response and microbiota changes were studied in 41 pairs after 4 weeks on a low FODMAP diet. ResultsUnsupervised analysis of baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBSP (pathogenic-like) and IBSH (health-like) subtypes. IBSP microbiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species. IBSH microbiomes were similar to controls. On the low FODMAP diet IBSH and control microbiota were unaffected, but the IBSP signature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalization of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBSP subjects compared to IBSH (p = 0.02). Conclusion50% of IBS cases manifested a pathogenic gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBSP cases showed an enhanced clinical responsiveness to the dietary therapy. The effectiveness of FODMAP exclusion in IBSP may result from the alterations in gut microbiota and metabolites produced. Microbiota signatures could be useful as biomarkers to guide IBS treatment; and investigating IBSP species and metabolic pathways might yield insights regarding IBS pathogenic mechanisms. O_TEXTBOXSignificance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSO_LIIBS subjects often respond to a low FODMAP diet. C_LIO_LIThe gut microbiota has been implicated in IBS. C_LIO_LIThe microbiota in IBS subjects may change with diet. C_LI What are the new findings?O_LIWe were able to stratify patients with IBS according to their gut microbiota species and metabolic gene signatures. C_LIO_LIWe identified a distinct gut microbiota subtype with an enhanced clinical response to a low FODMAP diet compared to other IBS subjects. C_LI How might it impact on clinical practice in the foreseeable future?O_LIThe potential development of a microbiota signature as a biomarker to manage IBS cases with a low FODMAP diet recommendation. C_LIO_LIIf the bacteria represented in the IBSP subtype are shown to play a pathogenic role in IBS, perhaps through the metabolic activity this provides a target for new therapies and an intermediate phenotype by which to assess them. C_LI C_TEXTBOX

microbiology↗

bioRxiv2019

Genomic investigation reveals contaminated detergent as the source of an ESBL-producing Klebsiella michiganensis outbreak in a neonatal unit

BackgroundKlebsiella species are problematic pathogens in neonatal units and may cause outbreaks, for which sources of transmission can be challenging to elucidate. We describe the use of whole genome sequencing (WGS) to investigate environmental sources of transmission during an outbreak of extended-spectrum-{beta}-lactamase (ESBL)-producing Klebsiella michiganensis colonizing neonates. MethodsCeftriaxone-resistant Klebsiella spp. isolated from neonates (or their mothers) and the hospital environment were included. Short-read (Illumina) and long-read (MinION, Oxford Nanopore Technologies) sequencing was used to confirm species taxonomy, define antimicrobial resistance genes and determine phylogenetic relationships using single nucleotide polymorphism (SNP) profiling. ResultsA total of 21 organisms (10 patient-derived and 11 environmental isolates) were sequenced. Standard laboratory methods identified the outbreak strain as an ESBL-producing Klebsiella oxytoca, but taxonomic assignment from WGS data suggested closer identity to Klebsiella michiganensis. Strains isolated from baby bath drains and multiple detergent dispensing bottles were either identical or closely related by SNP comparison. Detergent bottles contaminated by K. michiganensis had been used for washing milk-expressing equipment. No new cases were identified once the detergent bottles were removed and the baby baths decommissioned. ConclusionsEnvironmental reservoirs may be an important source in outbreaks of multi-drug resistant organisms. WGS, in conjunction with traditional epidemiological investigation, can be instrumental in revealing routes of transmission and guiding infection control responses. Key pointsO_LIK. michiganensis can be misidentified as K. oxytoca and is probably under-recognized as a nosocomial pathogen C_LIO_LIWhole genome sequencing of neonatal and environmental isolates during an outbreak of ESBL-producing K. michiganensis confirmed contaminated detergent and sinks to be the source C_LI

microbiology↗

bioRxiv2018

Inactive USP14 and inactive UCHL5 cause accumulation of distinct ubiquitinated proteins in mammalian cells

USP14 is a cysteine-protease deubiquitinase associated with the proteasome and plays important catalytic and allosteric roles in proteasomal degradation. USP14 inhibition has been considered a therapeutic strategy for accelerating degradation of aggregation-prone proteins in neurodegenerative diseases and for inhibiting proteasome function to induce apoptotic cell death in cancers. Here we studied the effects of USP14 inhibition in mammalian cells using small molecule inhibitors and an inactive USP14 mutant C114A. Neither the inhibitors nor USP14 C114A changed the level of TDP-43, tau or -synuclein in HEK293T cells. However, USP14 C114A led to an accumulation of ubiquitinated proteins, which were isolated by ubiquitin immunoprecipitation and identified by mass spectrometry. Among these proteins we confirmed that ubiquitinated {beta}-catenin was accumulated in the cells expressing USP14 C114A with biochemistry and molecular biology experiments. The proteasome binding of USP14 C114A is required for its effect on ubiquitinated proteins. UCHL5 is the other cysteine-protease deubiquitinase associated with the proteasome. Interestingly, the inactive mutant of UCHL5 C88A also caused an accumulation of ubiquitinated proteins in HEK293T cells but did not affect {beta}-catenin. Using ubiquitin immunoprecipitation and mass spectrometry, we identified the accumulated ubiquitinated proteins in UCHL5 C88A expressing cells which are mostly distinct from those accumulated in USP14 C114A expressing cells. Among the identified proteins are well established proteasome substrates and proteasome subunits. Together our data suggest that USP14 and UCHL5 can deubiquitinate distinct substrates at the proteasome and regulate the ubiquitination of the proteasome itself which is tightly linked to its function.

molecular biology↗