Biology subjects

Morris, H.

Publications and source records attributed to Morris, H..

12 recordsLinked to original sources

bioRxiv2026

Beyond air-seeding: Dynamic, multiphase interactionsreveal a two-step mechanism of embolism propagation inangiosperm xylem

BackgroundThe mechanism underlying drought-induced embolism in angiosperm xylem has been attributed to air-seeding. This concept describes the bulk flow of gas from embolised to neighbouring conduits through the penetration of gas-liquid menisci across pores in interconduit pit membranes. While there is compelling evidence for the spatial propagation of embolism, air-seeding rests on various simplifying assumptions. Among others, air-seeding presumes that xylem sap has physical properties comparable to pure water, that pit membranes can be approximated as structures with simple pores, and that embolism occurs whenever a gas-liquid interface crosses a pit membrane. ScopeRecent experimental and theoretical work demonstrates that the biophysical conditions and processes governing gas-liquid interactions at interconduit pit membranes are fundamentally more dynamic and complex than assumed by air-seeding. These phenomena include: (1) gas movement through constriction pore networks, (2) insoluble, polar lipids at conduit surfaces and interfaces, (3) dynamic surface tension of xylem sap that depends on the local packing density of interfacial lipids, (4) bubble snap-off dynamics within pit membranes, (5) surfactant-stabilized nanobubbles in sap that is oversaturated with dissolved gas, and (6) electrostatic interactions between charged interfaces. Importantly, embolism propagation involves bubble generation and embolism formation as distinct, temporarily and spatially separated processes. Embolism formation occurs when nanobubbles become unstable, whereas nanobubbles below critical stability thresholds can remain stable in sap-filled conduits. ConclusionsTogether, these findings reconfirm that pit membranes function as safety valves enabling water transport according to the cohesion-tension theory, and provide mechanistic insights into embolism propagation. They address the question why plants do not suffer constant embolism formation despite negative xylem pressures. We conclude that a revised framework explicitly accounting for the 3D structure of pit membranes, and multiphase, dynamic processes operating within them are required to explain the biophysics underlying water transport and embolism resistance in angiosperm xylem.

plant biology↗

bioRxiv2026

Dimerisation and twist reversal of the Lewy fold in α-synuclein mutants with Parkinson's disease and dementia

Dominantly inherited missense and gene dosage mutations in SNCA, the -synuclein gene, cause familial forms of Parkinsons disease and dementia. Here we report the structures of -synuclein filaments from the brains of such individuals. Pathogenic mutations A53T and G51D in SNCA give rise to singlets and doublets of the Lewy fold with a left-handed helical twist in the absence of a peptide-like density for island A. By contrast, filaments from the non-pathogenic variant H50Q consist of singlets of the right-handed Lewy fold with a density for island A, like filaments of wild-type -synuclein. The structures of filaments from homozygous mice transgenic for human mutant A53T -synuclein (line M83) are unlike those from human brains. They are more similar to the multiple system atrophy folds than to the Lewy fold of Parkinsons disease, Parkinsons disease dementia and dementia with Lewy bodies

biophysics↗

bioRxiv2025

Longitudinal Proteomic Profiling Defines Robust Molecular Subtypes Underlying the Heterogeneity of Parkinson's Disease

Heterogeneity of Parkinsons disease (PD) pathology is a barrier to developing therapeutics and understanding progression and prognosis. High throughput proteomic measures can be used to better interpret PD pathophysiology and generate clusters to define disease subtypes. Identification of subtypes related to clinical phenotypes will help researchers understand PD progression. We analyzed longitudinal proteomic data from the Tracking Parkinsons Cohort, consisting of recent-onset PD patients across 72 UK sites. 794 patients were measured on the Somalogic platform (7596 proteins) for three time points. Weighted Gene Co-Expression Network Analysis (WGCNA) at each time point revealed consistent protein co-expression modules. Two modules were strongly preserved across all three time points and in validation in the Global Neurodegenerative Proteomics Consortia (GNPC) datasets. The brown module was enriched for metabolite pathways and the blue module with cellular signaling pathways and associated with quality of life scores. Conversely, the smaller red module had distinct cognitive function phenotypes and changed protein expression between visit time points. Using detailed characterization of proteomic clusters we have provided a comprehensive view of PD progression offering deeper insights into the conservation of proteomic expression, suggesting new module subsets and providing candidate target proteins for further study.

neuroscience↗

bioRxiv2025

17q21.31 locus regulates Parkinson's disease relevant pathways through KANSL1 activity

An inversion polymorphism at the 17q21.31 locus defines the H1 and H2 haplotypes, with the former linked to multiple neurodegenerative disorders, including an increased risk of Parkinsons disease (PD). Although the high linkage disequilibrium at this locus has made it difficult to decipher which gene(s) drive the PD association, there is increasing evidence to support the role of KANSL1 as a risk gene. KANSL1 has been shown to regulate the expression of some PD-associated genes and pathways, likely as part of the histone acetylating non-specific lethal (NSL) complex. Here for the first time, we studied the global effects of 17q21.31 haplotype variation using bulk and single-nuclear RNA-sequencing data from control and PD patient brain. We first analysed differential gene expression across haplotype groups, and then assessed the contribution of KANSL1 by comparing with the results of an siRNA knockdown in neuronal and glial human cell lines. We demonstrated that the PD risk-associated H1 haplotype downregulates autophagy, lysosomal and mitochondrial processes, all of which have already been implicated in PD aetiology. Furthermore, these effects were apparent in both neuronal and glial cell types, and in the case of the latter, appear to be associated with the modulation of innate and adaptive immune responses. Thus, we identify important links between NSL complex activity and PD pathophysiology that can be leveraged for novel therapeutic interventions.

neuroscience↗

bioRxiv2024

Thermal acclimation of stem respiration reduces global carbon burden

Stem respiration is a key driver of carbon flux from ecosystems to the atmosphere, yet its response to global warming remains poorly constrained. In particular it has been proposed that stem respiration acclimates to changing temperatures, which could have large implications for carbon cycling under climate change, but no theory exists to predict acclimated respiration rates. Here, we hypothesized that stem respiration is physiologically linked to transpiration in order to maintain hydraulic continuity. We then use that linkage, combined with Eco-evolutionary optimality theory, to develop a theoretical prediction of the temperature sensitivity of both acclimated and instantaneous stem respiration. Leveraging an extensive global dataset, we observe temperature sensitivities of stem respiration across geographical and seasonal variations that are consistent with this prediction. Our findings reveal that stem respiration contributes approximately a quarter of the global above-ground auto-trophic respiration, with an estimated annual emission of around 11.20 {+/-} 5.88 Pg C--comparable to total anthropogenic emissions. Importantly, incorporating thermal acclimation of stem respiration into projections significantly reduces predicted land ecosystem carbon emissions by 4.41 and 9.56 Pg C under the SSP126 and SSP585 scenarios, respectively, for the 21st century.

ecology↗

bioRxiv2023

LRRK2 kinase dependent and independent function on endolysosomal repair promotes macrophage cell death

LRRK2 is commonly mutated in Parkinsons disease and has cell type-specific mechanisms of activation and function. In macrophages, LRRK2 is associated with lysosomes and is activated following lysosomal damage. However, effects of pathogenic LRRK2-G2019S in macrophages are unknown. Here, using primary mouse and human iPSC-derived macrophage (iPSDM) models of LRRK2-G2019S, we defined the substrates of LRRK2 after lysosomal damage. Using phosphoproteomics we found that LRRK2-G2019S and wild-type macrophages showed similar levels of Rab phosphorylation after lysosomal damage, with the exceptions of Rab12 and Rab35, which were increased and decreased, respectively, in LRRK2-G2019S. LRRK2-G2019S macrophages showed a LRRK2 kinase activity-independent deficit in lysosomal membrane repair which resulted in more cell death and increased apoptosis. Importantly, we recapitulated this phenotype in iPSDM from patients carrying the G2019S mutation, but not in isogenic control iPSDM. Altogether, we define here the signaling downstream of G2019S in macrophages and identify susceptibility to cell death after lysosomal damage as an important phenotype of this mutation.

cell biology↗

bioRxiv2023

Identification of 5-HT2A Receptor Signaling Pathways Responsible for Psychedelic Potential

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and {beta}-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT2A-selective ligands with varying Gq efficacies, including {beta}-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-{beta}-arrestin2 efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A-Gq efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists. We also demonstrate that {beta}-arrestin-biased 5-HT2A receptor agonists induce receptor downregulation and tachyphylaxis, and have an anti-psychotic-like behavioral profile. Overall, 5-HT2A receptor signaling can be fine-tuned to generate ligands with properties distinct from classical psychedelics.

neuroscience↗

bioRxiv2023

Evidence for deliberate burial of the dead by Homo naledi

In this study we describe new results of excavations in the Dinaledi Subsystem of the Rising Star cave system, South Africa. In two areas within the Hill Antechamber and the Dinaledi Chamber this work uncovered concentrations of abundant Homo naledi fossils including articulated, matrix-supported skeletal regions consistent with rapid covering by sediment prior to the decomposition of soft tissue. We additionally re-examine the spatial positioning of skeletal material and associated sediments within the Puzzle Box area, from which abundant H. naledi remains representing a minimum of six individuals were recovered in 2013 and 2014. Multiple lines of evidence exclude the hypothesis that skeletal remains from these three areas come from bodies that decomposed on the floor of the chamber or within a shallow depression prior to burial by sediments. The spatial positioning of skeletal material, the topography of the subsystem, and observations on sediments within and surrounding features exclude the hypothesis that rapid burial by sediment was a result of gravity-driven slumping or spontaneous movement of sediments. We present a minimal hypothesis of hominin cultural burial and test the evidence from all three areas, finding that this hypothesis is most compatible with the pattern of evidence. These results suggest that mortuary behavior including cultural burial was part of the repertoire of Homo naledi.

paleontology↗

bioRxiv2023

The clock transcription factor BMAL1 is a key regulator of extracellular matrix homeostasis and cell fate in the intervertebral disc

The circadian clock in mammals temporally coordinates physiological and behavioural processes to anticipate daily rhythmic changes in their environment. Chronic disruption to circadian rhythms (e.g., through ageing or shift work) is thought to contribute to a multitude of diseases, including degeneration of the musculoskeletal system. The intervertebral disc (IVD) in the spine contains circadian clocks which control [~]6% of the transcriptome in a rhythmic manner, including key genes involved in extracellular matrix (ECM) homeostasis. However, it remains largely unknown to what extent the local IVD molecular clock is required to drive rhythmic gene transcription and IVD physiology. In this work, we identified profound age-related changes of ECM microarchitecture and an endochondral ossification-like phenotype in the annulus fibrosus (AF) region of the IVD in the Col2a1-Bmal1 knockout mice. Circadian time series RNA-Seq of the whole IVD in Bmal1 knockout revealed loss of circadian patterns in gene expression, with an unexpected emergence of 12-hour ultradian rhythms, including FOXO transcription factors. Further RNA sequencing of the AF tissue identified region-specific changes in gene expression, evidencing a loss of AF phenotype markers and a dysregulation of ECM and FOXO pathways in Bmal1 knockout mice. Consistent with an up-regulation of FOXO1 mRNA and protein levels in Bmal1 knockout IVDs, inhibition of FOXO1 in AF cells suppressed their osteogenic differentiation. Collectively, these data highlight the importance of the local molecular clock mechanism in the maintenance of the cell fate and ECM homeostasis of the IVD. Further studies may identify potential new molecular targets for alleviating IVD degeneration.

physiology↗

bioRxiv2020

Whole genome sequencing for diagnosis of neurological repeat expansion disorders

BackgroundRepeat expansion (RE) disorders affect ~1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in under diagnosis of atypical clinical presentations, especially in paediatric patients without a prior positive family history. Whole genome sequencing (WGS) is emerging as a first-line test for rare genetic disorders, but until recently REs were thought to be undetectable by this approach. MethodsWGS pipelines for RE disorder detection were deployed by the 100,000 Genomes Project and Illumina Clinical Services Laboratory. Performance was retrospectively assessed across the 13 most common neurological RE loci using 793 samples with prior orthogonal testing (182 with expanded alleles and 611 with alleles within normal size) and prospectively interrogated in 13,331 patients with suspected genetic neurological disorders. FindingsWGS RE detection showed minimum 97{middle dot}3% sensitivity and 99{middle dot}6% specificity across all 13 disease-associated loci. Applying the pipeline to patients from the 100,000 Genomes Project identified pathogenic repeat expansions which were confirmed in 69 patients, including seven paediatric patients with no reported family history of RE disorders, with a 0.09% false positive rate. InterpretationWe show here for the first time that WGS enables the detection of causative repeat expansions with high sensitivity and specificity, and that it can be used to resolve previously undiagnosed neurological disorders. This includes children with no prior suspicion of a RE disorder. These findings are leading to diagnostic implementation of this analytical pipeline in the NHS Genomic Medicine Centres in England. FundingMedical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, Illumina Inc

genomics↗

bioRxiv2020

Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes

OBJECTIVETo discover genetic determinants of Parkinson disease (PD) motor subtypes, including Tremor Dominant (TD) and Postural Instability/Gait Difficulty (PIGD) forms. METHODSIn 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining two complementary outcome traits derived from the Unified Parkinsons Disease Rating Scale (UPDRS), including dichotomous motor subtype (TD vs. PIGD) or a continuous tremor / PIGD score ratio. Logistic or linear regression models were adjusted for sex, age of onset, disease duration, and 5 ancestry principal components, followed by meta-analysis. RESULTSAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199347, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, {beta} = -0.04, 95% CI = -0.07, 0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, pratio = 6.6x10-7), which harbors an independent risk allele for essential tremor. CONCLUSIONSMultiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.

genomics↗

bioRxiv2019

The Parkinsons Disease Mendelian Randomization Research Portal

BackgroundMendelian randomization (MR) is a method for exploring observational associations to find evidence of causality.\n\nObjectiveTo apply MR between multiple risk factors/phenotypic traits (exposures) and Parkinsons disease (PD) in a large, unbiased manner, and to create a public resource for research.\n\nMethodsWe used two-sample MR in which the summary statistics relating to SNPs from genome wide association studies (GWASes) of 5,839 exposures curated on MR Base were used to assess causal relationships with PD. We selected the highest quality exposure GWASes for this report (n=401). For the disease outcome, summary statistics from the largest published PD GWAS were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted (IVW) method, followed by a range of sensitivity analyses. We used a false discovery rate (FDR) corrected p-value of <0.05 from the IVW analysis to prioritize traits of interest.\n\nResultsWe observed evidence for causal associations between twelve exposures and risk of PD. Of these, nine were causal effects related to increasing adiposity and decreasing risk of PD. The remaining top exposures that affected PD risk were tea drinking, time spent watching television and forced vital capacity, but the latter two appeared to be biased by violations of underlying MR assumptions.\n\nDiscussionWe present a new platform which offers MR analyses for a total of 5,839 GWASes versus the largest PD GWASes available (https://pdgenetics.shinyapps.io/pdgenetics/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD.

neuroscience↗