Biology subjects

Hall, G.

Publications and source records attributed to Hall, G..

14 recordsLinked to original sources

bioRxiv2025

Baobab isotope records and rainfall forcing in southwest Madagascar over the last 700 years.

Highly resolved climate records for Madagascar are scarce but are essential for understanding of rainfall drivers over time and assessing the risks and likely trajectories of future climate change. We measured variation in the carbon isotopes of baobabs (Adansonia spp.) which reflect rainfall in southwest Madagascar. The record indicates a decreasing trend of rainfall over the last 700 years with high variability at a centennial-scale. The duration of wetter periods decreased over time with the wettest periods between 1350 - 1450 CE, after the onset of the Little Ice Age, while the driest period occurred between 1600 - 1750 CE, during the Maunder Minimum. The results suggest that decadal to centennial rainfall variability in southwest Madagascar is dominated by tropical forcing rather than subtropical forcing. Wetter periods are regulated by the movement and migration of easterly winds linked to the Intertropical Convergence Zone, while dry periods are influenced by the effect of the Pacific Decadal Oscillation linked to the El Nino Southern Oscillation and the sea surface temperature variation in the Southwestern Indian Ocean. The Southern Annular Mode is significantly correlated with the record, but its effect was only visible at the beginning of the record around 1300 CE. This evidence provides a new understanding of rainfall across southern Africa and the interaction of global forcing with regional factors. Further investigation is required to improve tree chronology from Southern Hemisphere and understand the migration of the westerlies and its potential future effect on the rainfall in Madagascar. Understanding the interplay between tropical and other rainfall forcings will be essential in assessing likely scenarios of resilience, and adaptive capacity of social-ecological systems in Madagascar.

ecology↗

bioRxiv2025

A Novel TRPC6 Mutation Causes Autosomal Dominant FSGS

FSGS is the most common primary glomerular lesion that causes kidney failure in the US. FSGS results from injury or loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic variants in TRPC6 can cause FSGS through dysregulated calcium conductance and associated disturbances in podocyte physiology. Here, we describe a 5-generation kindred with FSGS caused by a novel compound C-terminal TRPC6 mutation. Analysis of patient-specific iPSC-derived podocytes and glomerular capillary wall-on-a-chip systems revealed that the compound variants disrupt TRPC6 protein structure, intermolecular interactions, and membrane localization. Combined therapy with Sildenafil and Losartan ameliorated these disturbances compared to conventional immunosuppressive treatment.

genetics↗

bioRxiv2024

CRB2 Depletion Induces YAP Signaling and Disrupts Mechanosensing in Podocytes

Focal Segmental Glomerulosclerosis (FSGS) is a histologic lesion caused by a variety of injurious stimuli that lead to dysfunction/loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic mutations in CRB2, encoding the type 1 transmembrane protein Crumb 2 Homolog Protein, have been shown to cause early-onset corticosteroid-resistant nephrotic syndrome (SRNS)/FSGS. Here, we identified a 2-generation East Asian kindred (DUK40595) with biopsy-proven SRNS/FSGS caused by a compound heterozygous mutation in CRB2 comprised of the previously described truncating mutation p.Gly1036_Alafs*43 and a rare 9-bp deletion mutation p.Leu1074_Asp1076del. Because compound heterozygous mutations involving the truncating p.Gly1036_Alafs*43 variant have been associated with reduced CRB2 expression in podocytes and autosomal recessive SRNS/FSGS, we sought to define the pathogenic effects of CRB2 deficiency in podocytes. We show that CRB2 knockdown induces YAP activity and target gene expression in podocytes. It upregulates YAP-mediated mechanosignaling and increases the density of focal adhesion and F-actin. Using Elastic Resonator Interference Stress Microscopy (ERISM), we demonstrate that CRB2 knockdown also enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2 knockdown cells at low substrate stiffness. While the mechanical activation of CRB2 knockdown cells is associated with increased YAP activity, the enhanced cell contractility is not significantly reduced by the selective YAP inhibitors K-975 and verteporfin, suggesting that multiple pathways may be involved in mechanosignaling downstream of CRB2. Taken together, these studies provide the first evidence that CRB2 deficiency may impair podocyte mechanotransduction via disruption of YAP signaling in podocytes.

biophysics↗

bioRxiv2023

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study

ObjectiveThe intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural MRI in 1,602 adults with epilepsy and 1,022 healthy controls across twenty-two sites from the global ENIGMA-Epilepsy working group. MethodsA state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in i) all epilepsies; ii) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS); iii) non-lesional temporal lobe epilepsy (TLE-NL); iv) genetic generalised epilepsy; and (v) extra-temporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. ResultsAcross all epilepsies, reduced total cerebellar volume was observed (d=0.42). Maximum volume loss was observed in the corpus medullare (dmax=0.49) and posterior lobe grey matter regions, including bilateral lobules VIIB (dmax= 0.47), Crus I/II (dmax= 0.39), VIIIA (dmax=0.45) and VIIIB (dmax=0.40). Earlier age at seizure onset ({eta}{rho}2max=0.05) and longer epilepsy duration ({eta}{rho}2max=0.06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. SignificanceWe provide robust evidence of deep cerebellar and posterior lobe subregional grey matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in non-motor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellum subregions into neurobiological models of epilepsy. Key pointsO_LICerebellar involvement in epilepsy is poorly understood within current cortico-centric models of this disease C_LIO_LIWe used a novel, deep learning segmentation tool to parcellate the cerebellum into 28 anatomical subunits using an international MRI dataset of 1,602 individuals with epilepsy (aged between 18 and 65 years old) including temporal lobe epilepsy with hippocampal sclerosis (TLE-HS, n=562), TLE non-lesional (TLE-NL, n=284), generalised genetic epilepsy (GGE, n=186) and extra temporal focal epilepsy (ETLE, n=251) and 1,022 controls. C_LIO_LIAcross all epilepsies (vs. controls) robust changes in the corpus medullare and posterior lobe "non-motor" regions were observed, with maximal differences in bilateral VIIB and Crus II lobules. Lower volume of these regions correlated with longer disease duration. Anterior "motor lobe" regions were relatively spared. C_LIO_LIFindings were most pronounced in TLE-HS and ETLE groups, with distinct neuroanatomical profiles observed. C_LIO_LICortical thinning was associated with pronounced cerebellar volume loss in TLE-HS epilepsy, relative to controls. C_LI ETHICAL PUBLICATION STATEMENTWe confirm that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

neuroscience↗

bioRxiv2022

Cost-efficient whole genome-sequencing using novel mostly natural sequencing-by-synthesis chemistry and open fluidics platform

We introduce a massively parallel novel sequencing platform that combines an open flow cell design on a circular wafer with a large surface area and mostly natural nucleotides that allow optical end-point detection without reversible terminators. This platform enables sequencing billions of reads with longer read length ([~]300bp) and fast runs times (<20hrs) with high base accuracy (Q30 > 85%), at a low cost of $1/Gb. We establish system performance by whole-genome sequencing of the Genome-In-A-Bottle reference samples HG001-7, demonstrating high accuracy for SNPs (99.6%) and Indels in homopolymers up to length 10 (96.4%) across the vast majority (>98%) of the defined high-confidence regions of these samples. We demonstrate scalability of the whole-genome sequencing workflow by sequencing an additional 224 selected samples from the 1000 Genomes project achieving high concordance with reference data.

genomics↗

bioRxiv2021

Antibiotic Resistance Genes from Mat and Planktonic Microbiomes of Antarctic Lake Fryxell and Lake Bonney, and a Mat-forming Culture of Rhodoferax antarcticus

The perennial ice-covered lakes of the Antarctic McMurdo Dry Valleys harbor oligotrophic microbial communities that are separated geographically from other aquatic systems. Their microbiomes include planktonic microbes as well as lift-off mat communities that emerge from the ice. We used ShortBRED to quantify the antibiotic resistance genes (ARGs) from metagenomes of lift-off mats emerging from ice, and from filtered water samples of Lake Fryxell and Lake Bonney. The overall proportion of ARG hits was similar to that found in temperate-zone rural water bodies with moderate human inputs. Specific ARGs showed distinct distributions for the two lakes, and for mat versus planktonic sources. Metagenomic taxa distributions showed that mat phototrophs consisted mainly of cyanobacteria or betaproteobacteria, whereas the water column phototrophs were mainly protists. An enrichment culture of the betaproteobacterium Rhodoferax antarcticus from a Lake Fryxell mat sample showed an unusual mat-forming phenotype not previously reported for this species. Its genome showed no ARGs associated with betaproteobacteria, but had ARGs consistent with a minor Pseudomonas component. The Antarctic lake mats and water showed specific ARGs distinctive to the mat and water sources, but overall ARG levels were similar to those of temperate water bodies with moderate human inputs.

microbiology↗

bioRxiv2020

Deep mining of early antibody response in COVID-19 patients yields potent neutralisers and reveals high level of convergence

Passive immunisation using monoclonal antibodies will play a vital role in the fight against COVID-19. Until now, the majority of anti-SARS-CoV-2 antibody discovery efforts have relied on screening B cells of patients in the convalescent phase. Here, we describe deep-mining of the antibody repertoires of hospitalised COVID-19 patients using a combination of phage display technology and B cell receptor (BCR) repertoire sequencing to isolate neutralising antibodies and gain insights into the early antibody response. This comprehensive discovery approach has yielded potent neutralising antibodies with distinct mechanisms of action, including the identification of a novel non-ACE2 receptor blocking antibody that is not expected to be affected by any of the major viral variants reported. The study highlighted the presence of potent neutralising antibodies with near germline sequences within both the IgG and IgM pools at early stages of infection. Furthermore, we highlight a highly convergent antibody response with the same sequences occurring both within this study group and also within the responses described in previously published anti-SARS-CoV-2 studies.

immunology↗

bioRxiv2020

Patterns of within-host genetic diversity in SARS-CoV-2

Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around the world. The modest mutation rate and rapid transmission of SARS-CoV-2 prevents the reconstruction of transmission chains from consensus genome sequences, but within-host genetic diversity could theoretically help identify close contacts. Here we describe the patterns of within-host diversity in 1,181 SARS-CoV-2 samples sequenced to high depth in duplicate. 95% of samples show within-host mutations at detectable allele frequencies. Analyses of the mutational spectra revealed strong strand asymmetries suggestive of damage or RNA editing of the plus strand, rather than replication errors, dominating the accumulation of mutations during the SARS-CoV-2 pandemic. Within and between host diversity show strong purifying selection, particularly against nonsense mutations. Recurrent within-host mutations, many of which coincide with known phylogenetic homoplasies, display a spectrum and patterns of purifying selection more suggestive of mutational hotspots than recombination or convergent evolution. While allele frequencies suggest that most samples result from infection by a single lineage, we identify multiple putative examples of co-infection. Integrating these results into an epidemiological inference framework, we find that while sharing of within-host variants between samples could help the reconstruction of transmission chains, mutational hotspots and rare cases of superinfection can confound these analyses.

genomics↗

bioRxiv2020

Improvements to the ARTIC multiplex PCR method for SARS-CoV-2 genome sequencing using nanopore

Genome sequencing has been widely deployed to study the evolution of SARS-CoV-2 with more than 90,000 genome sequences uploaded to the GISAID database. We published a method for SARS-CoV-2 genome sequencing (https://www.protocols.io/view/ncov-2019-sequencing-protocol-bbmuik6w) online on January 22, 2020. This approach has rapidly become the most popular method for sequencing SARS-CoV-2 due to its simplicity and cost-effectiveness. Here we present improvements to the original protocol: i) an updated primer scheme with 22 additional primers to improve genome coverage, ii) a streamlined library preparation workflow which improves demultiplexing rate for up to 96 samples and reduces hands-on time by several hours and iii) cost savings which bring the reagent cost down to {pound}10 per sample making it practical for individual labs to sequence thousands of SARS-CoV-2 genomes to support national and international genomic epidemiology efforts.

genomics↗

bioRxiv2020

Fungi are more dispersal-limited than bacteria among flowers

Variation in dispersal ability among taxa affects community assembly and biodiversity maintenance within metacommunities. Although fungi and bacteria frequently coexist, their relative dispersal abilities are poorly understood. Nectar-inhabiting microbial communities affect plant reproduction and pollinator behavior, and are excellent models for studying dispersal of bacteria and fungi in a metacommunity framework. Here, we assay dispersal ability of common nectar bacteria and fungi in an insect-based dispersal experiment. We then compare these results to the incidence and abundance of culturable flower-inhabiting bacteria and fungi within naturally occurring flowers across two coflowering communities in California across two flowering seasons. Our microbial dispersal experiment demonstrates that bacteria disperse among habitat patches more readily than fungi via thrips. Across all flowers, bacterial and fungal incidence and abundance were positively correlated but bacteria were much more widespread, suggesting shared dispersal routes or habitat requirements but differences in dispersal and colonization frequency. The finding that bacteria are more common among flowers sampled here, in part due to superior insect-mediated dispersal, may have broad relevance for microbial life-history, community assembly of microbes and plant-pollinator interactions.

ecology↗

bioRxiv2020

Nutrient parsimony shapes diversity and functionality in hyper-oligotrophic Antarctic soils

The balance of nutrients in soil is critical for microbial growth and function, and stoichiometric values below the Redfield ratio for C:N:P can negatively affect microbial ecosystem services. However, few studies have assessed the relationships between nutrient balance and biological productivity in extremely nutrient-poor habitats. The Mackay Glacier region of Eastern Antarctica is a hyper-oligotrophic ice-free desert and is an appropriate landscape to evaluate the effects of nutrient deficiency and imbalance on microbial community ecology. In a survey of multiple, widely dispersed soil samples from this region, we detected only low rates of microbial respiration, and observed that C:N:P ratios were well below those required for optimal activity. In silico metagenomic and soil isotopic ratio ({delta}15N) analyses indicated that the capacity for nitrogen fixation was low, but that soil microbial communities were enriched for soil nitrate assimilation processes, mostly associated with heterotrophic taxa.{delta} 13C isotope ratio data suggested that carbon dioxide was fixed principally via the Calvin cycle. Genes involved in this pathway were common to all metagenomes and were primarily attributed to members of the dominant soil bacterial phyla: Bacteroidetes and Acidobacteria. The identification of multiple genes encoding non-photoautotrophic RUBISCO and carbon dioxide dehydrogenase enzymes in both the metagenomic sequences and assembled MAGs is suggestive of a trace-gas scavenging physiology in members of these soil communities.

ecology↗

bioRxiv2019

Multi-proxy analyses of a mid-15th century Middle Iron Age Bantu-speaker palaeo-faecal specimen elucidates the configuration of the ancestral sub-Saharan African intestinal microbiome

The archaeological incidence of ancient human faecal material provides a rare opportunity to explore the taxonomic composition and metabolic capacity of the ancestral human intestinal microbiome (IM). Following the recovery of a single desiccated palaeo-faecal specimen from Bushman Rock Shelter in Limpopo Province, South Africa, we applied a multi-proxy analytical protocol to the sample. Our results indicate that the distal IM of the Neolithic Middle Iron Age (c. AD 1485) Bantu-speaking individual exhibits features indicative of a largely mixed forager-agro-pastoralist diet. Subsequent comparison with the IMs of the Tyrolean Iceman (Otzi) and contemporary Hadza hunter-gatherers, Malawian agro-pastoralists and Italians, reveals that this IM precedes recent adaptation to Western diets, including the consumption of coffee, tea, chocolate, citrus and soy, and the use of antibiotics, analgesics and also exposure to various toxic environmental pollutants. Our analyses reveal some of the causes and means by which current human IMs are likely to have responded to recent dietary changes, prescription medications and environmental pollutants, providing rare insight into human IM evolution following the advent of the Neolithic c. 12,000 years ago.

microbiology↗

bioRxiv2019

Brain Aging in Major Depressive Disorder: Results from the ENIGMA Major Depressive Disorder working group

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset. MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain predicted age difference (brain-PAD). FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohens d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004). InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates. FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

neuroscience↗

bioRxiv2019

Assessing the potential impact of Medicaid work requirements on African-Americans via a welfare reform analysis: A systematic review

The Centers for Medicare and Medicaid Services are currently approving Medicaid demonstration projects involving work and community engagement requirements. The fear among public health professionals and policymakers is that these work requirements will disproportionately limit access to health insurance for African-Americans. To investigate these new work requirements for Medicaid, we conducted a systematic review of the Temporary Assistance for Needy Families program, the last major welfare program to have such work requirements. We used the ProQuest database and selected scholarly journal studies in English and published between January 1991-August 2018. Our selection strategy yielded 14 eligible studies, eight of which focused on caseload movements and six focused on sanctions. We found that African-Americans entered TANF at a higher rate than Whites, remained on TANF longer, and were subject to sanctions more frequently and stringently than Whites were. These results suggest that African-Americans may disproportionately experience reduced access to care through sanctioning such as lockout periods. Recommended policy changes include prohibiting work activities as a condition of Medicaid coverage, strengthening Medicaid in other ways, combating discriminatory hiring practices, and easing burdensome reporting requirements.

scientific communication and education↗