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Gregory, S.

Publications and source records attributed to Gregory, S..

15 recordsLinked to original sources

Ancient DNA reveals matrilineal organisation and recurrent unions between dominant matrilines in Iron Age Britain

Kinship practices underpin all traditional societies, forming the basis for socially sanctioned reproductive unions, residence patterns and the inheritance of rights and property1,2. Although the relationship between biological relatedness and kinship is not always straightforward, ancient DNA studies are increasingly used to examine the extent to which biological relatedness underpinned social constructs of kinship in prehistoric societies3-6. Here, we report the analysis of genome-wide data for 534 individuals from the Arras Culture of Middle Iron Age northeast England (including 390 from Wetwang Slack, 100 from Pocklington, and 29 from Melton), finding evidence for communities with kinship systems structured along matrilineal lines. At Wetwang Slack, we reconstruct a 13-generation pedigree comprising 195 individuals structured around female-line connections: matrilineal transmissions greatly outnumbered patrilineal ones and male reproductive partners were largely absent from the cemetery, plausibly because they were buried in their own natal communities. Furthermore, the three main sites with robust sample sizes were characterised by non-overlapping dominant mitochondrial haplogroups, implying a maternal clan-based structure. Reproductive unions at Wetwang Slack suggest a recurrent alliance between two dominant maternal descent groups, with members of each group never reproducing with members of their own maternal lineage. Meanwhile, three individuals from lavishly furnished chariot burials at Wetwang Slack were close maternal relatives belonging to a lineage with consecutive generations of close kin unions, a pattern largely absent among other individuals at the site. These results indicate highly distinctive social practices among an elite group embedded in the wider kinship network of the Arras community.

genetics↗

Anti-malaria RTS,S/AS01 vaccine generates a limited pool of memory B cells expressing specificities associated with protection

RTS,S/AS01, an adjuvanted subunit malaria vaccine, induces protective but short-lived anti- Plasmodium falciparum circumsporozoite protein (CSP) antibody titers. To better understand the lack of sustained protection post-vaccination, we analyzed CSP-specific B cells over time in malaria-naive individuals following immunization with RTS,S/AS01. Longitudinal analyses of the cellular responses revealed a shift in the specificity of CSP-specific B cells over time. Early post- vaccine responses were dominated by plamsablasts and class-switched memory B cells (MBCs) specific for the NANP-repeat region of CSP, epitopes associated with protective antibodies. However, the frequency of NANP-repeat-specific MBCs declines, while longer-term memory specific for the C-terminus of CSP persists. Despite being class-switched and affinity matured, C- term monoclonal antibodies derived from these MBCs failed to protect mice against a transgenic parasite challenge. Taken together, these findings suggest that RTS,S/AS01 induces a transient, protective NANP repeat-specific B cell response that is subsequently replaced by memory B cells with non-protective reactivities, potentially explaining its limited long-term efficacy and limited response to subsequent challenges or boosters.

immunology↗

Nociceptin receptor and ligand in Alzheimer's disease:Implications for psychiatric symptoms and circadianregulation

BackgroundNociceptin (N/OFQ) and its receptor OPRL1 play crucial roles in emotional processing, reward-related behaviors, learning, and neurotransmitter regulation, but their involvement in Alzheimers disease (AD) pathology remains poorly understood. This study investigated possible relationships between prepronociceptin (PNOC) and OPRL1 expression and psychiatric symptoms in AD, utilizing Natural Language Processing (NLP) to assess Research Domain Criteria (RDoC) domains. MethodsPost-mortem brain tissue from the dorsal anterior cingulate gyrus (BA32) was analyzed in 61 donors across different Braak and Braak (B&B) stages. RNA expression of PNOC and OPRL1 was quantified and correlated with RDoC scores derived from medical records using NLP. Sex-stratified analyses, circadian rhythmicity analysis, and cell-type specific expression patterns were examined. ResultsBoth genes showed significant downregulation in AD cases (PNOC: p = 0.024; OPRL1: p < 0.001), with notable sex differences. Men displayed higher post-mortem PNOC (Cohens d = -0.482) and OPRL1 (Cohens d = -0.237) expression compared to women. In adjusted models controlling for B&B stage and post-mortem interval, PNOC expression significantly correlated with dimensional scores of positive valence ({beta} = -0.38, p = 0.035) and arousal regulatory systems ({beta} = -0.43, p = 0.015) derived from a text classification algorithm applied to medical records. OPRL1 showed disrupted circadian rhythmicity in AD cases (p = 0.151 vs. p = 0.020 in controls). ConclusionsThese findings suggest distinct roles for PNOC and OPRL1 in AD pathology, with PNOC primarily associated with psychiatric symptoms and OPRL1 showing disrupted circadian regulation. Sex-specific expression patterns further indicate the need for personalized therapeutic approaches targeting the nociceptin system.

neuroscience↗

Repertoire, function, and structure of serological antibodies induced by the R21/Matrix-M malaria vaccine

The World Health Organization recently recommended the programmatic use of R21/Matrix-M vaccine for Plasmodium falciparum malaria prevention in children living in malaria-endemic areas. To determine its effects on humoral immunity, we conducted a proteomic analysis of polyclonal IgG antibodies directed against the NANP tetrapeptide of the circumsporozoite protein (CSP) which comprises the vaccines core immunogen. In ten malaria-naive adult volunteers, R21/Matrix-M induced polarized IgG anti-NANP repertoires, heavily skewed for IGHV3-30/3-33 genes bearing minimal somatic mutation, which remained static in composition following a controlled human malaria infection challenge. Notably, these vaccine-generated antibodies cross-reacted with another protective CSP epitope, the N-terminal junction region, despite its absence from the R21 construct. NANP-specific IGHV3-30/3-33 monoclonal antibodies mined from polyclonal IgG repertoires blocked sporozoite invasion in vitro and prevented parasitemia in vivo. Overall, R21/Matrix-M elicits polarized, minimally mutated, polyclonal IgG responses that can target multiple protective CSP epitopes, offering molecular insight into the serological basis for its demonstrated efficacy against P. falciparum malaria.

immunology↗

Ambient Temperature Bacterial Large Ribosomal Subunit Structure Enabled by Serial Femtosecond X-ray Crystallography

Ribosomes are the supramolecular complexes responsible for protein synthesis. The large 50S ribosomal subunit catalyzes the peptidyl transferase reaction and peptide bond formation between amino acids. The 50S is targeted by many known clinically effective antibiotics. Available structures, obtained at cryogenic temperatures (CT), are used for drug discovery despite that active or important target sites may display a structural configuration that is CT-induced. The introduction of ultrafast and ultrabright X-ray free electron laser (XFEL) pulses has enabled the structural observation of biological macro- and supramolecules at previously unattainable, near-physiological temperatures. In this study, we use ultrafast and ultrabright XFEL pulses to solve the apo form of 50S ribosomal subunit isolated from the extremely thermophilic bacterium Thermus thermophilus at ambient temperature (AT). The dimeric structure of the 50S subunit presented in this work is among the largest ([~]3 megadalton) structures determined using an XFEL source to date. This study demonstrates the ability to obtain new information about ribosome structural dynamics at AT through serial femtosecond X-ray crystallography (SFX). This allowed us to capture previously unobserved dynamics of ribosomal protein uL23 and coordination by hexahydrated magnesium cations at a hitherto unseen resolution at near-physiological temperature. Also, residue A2602, at the core of the peptidyl transferase center (PTC), shows a rather different orientation of the sugar moiety if compared to CT structures. In addition, our structure highlights the importance of flexible residues at both the PTC and in the binding sites for antibiotics erythromycin and chloramphenicol. The method implemented here may also serve as a starting point for future structural research involving the 50S subunit complexes by employing time-resolved mix-inject and probe kineto-crystallography experiments at XFELs. Unveiling ligand-dependent 50S dynamics at physiological temperatures shall guide further development of next-generation antibiotics that target the translation machinery.

biophysics↗

Genomics of secondarily temperate adaptation in the only non-Antarctic icefish

AO_SCPLOWBSTRACTC_SCPLOWWhite-blooded Antarctic icefishes, a family within the adaptive radiation of Antarctic notothenioid fishes, are an example of extreme biological specialization to both the chronic cold of the Southern Ocean and life without hemoglobin. As a result, icefishes display derived physiology that limits them to the cold and highly oxygenated Antarctic waters. Against these constraints, remarkably one species, the pike icefish Champsocephalus esox, successfully colonized temperate South American waters. To study the genetic mechanisms underlying secondarily temperate adaptation in icefishes, we generated chromosome-level genome assemblies of both C. esox and its Antarctic sister species, Champsocephalus gunnari. The C. esox genome is similar in structure and organization to that of its Antarctic congener; however, we observe evidence of chromosomal rearrangements coinciding with regions of elevated genetic divergence in pike icefish populations. We also find several key biological pathways under selection, including genes related to mitochondria and vision, highlighting candidates behind temperate adaptation in C. esox. Substantial antifreeze glycoprotein (AFGP) pseudogenization has occurred in the pike icefish, likely due to relaxed selection following ancestral escape from Antarctica. The canonical AFGP locus organization is conserved in C. esox and C. gunnari, but both show a translocation of two AFGP copies to a separate locus, previously unobserved in cryonotothenioids. Altogether, the study of this secondarily temperate species provides an insight into the mechanisms underlying adaptation to ecologically disparate environments in this otherwise highly specialized group.

genomics↗

Genomics analysis of Drosophila sechellia response to Morinda citrifolia fruit diet

Drosophila sechellia is an island endemic host specialist that has evolved to consume the toxic fruit of Morinda citrifolia, also known as noni fruit. Recent studies by our group and others have examined genome-wide gene expression responses of fruit flies to individual highly abundant compounds found in noni responsible for the fruits unique chemistry and toxicity. In order to relate these reductionist experiments to the gene expression responses to feeding on noni fruit itself, we fed rotten noni fruit to adult female D. sechellia and performed RNA-sequencing. Combining the reductionist and more wholistic approaches, we have identified candidate genes that may contribute to each individual compound and those that play a more general role in response to the fruit as a whole. Using the compound specific and general responses, we used transcription factor prediction analyses to identify the regulatory networks and specific regulators involved in the responses to each compound and the fruit itself. The identified genes and regulators represent the possible genetic mechanisms and biochemical pathways that contribute to toxin resistance and noni specialization in D. sechellia.

genomics↗

Genomics analysis of hexanoic acid exposure in Drosophila species

Drosophila sechellia is a dietary specialist endemic to the Seychelles islands that has evolved to consume the fruit of Morinda citrifolia. When ripe, the fruit of M. citrifolia contains octanoic acid and hexanoic acid, two medium chain fatty acid volatiles that deter and are toxic to generalist insects. D. sechellia has evolved resistance to these volatiles allowing it to feed almost exclusively on this host plant. The genetic basis of octanoic acid resistance has been the focus of multiple recent studies, but the mechanisms that govern hexanoic acid resistance in D. sechellia remain unknown. To understand how D. sechellia has evolved to specialize on M. citrifolia fruit and avoid the toxic effects of hexanoic acid, we exposed adult D. sechellia, D. melanogaster and D. simulans to hexanoic acid and performed RNA sequencing comparing their transcriptional responses to identify D. sechellia specific responses. Our analysis identified many more genes responding transcriptionally to hexanoic acid in the susceptible generalist species than in the specialist D. sechellia. Interrogation of the sets of differentially expressed genes showed that generalists regulated the expression of many genes involved in metabolism and detoxification whereas the specialist primarily downregulated genes involved in the innate immunity. Using these data we have identified interesting candidate genes that may be critically important in aspects of adaptation to their food source that contains high concentrations of HA. Understanding how gene expression evolves during dietary specialization is crucial for our understanding of how ecological communities are built and how evolution shapes trophic interactions.

genomics↗

Timing of selective basal ganglia white matter loss in Huntington's disease

ObjectivesTo investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (WM) loss begins in premanifest Huntingtons disease (preHD), and which striatal and thalamic sub-region WM tracts are most vulnerable. MethodsWe performed fixel-based analysis, which allows resolution of crossing WM fibres at the voxel level, on diffusion tractography derived WM tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. ResultsWe found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntingtons disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. ConclusionsOur findings suggest that the initiation of disease modifying therapies 25 years before onset could protect these important brain networks from undergoing neurodegeneration and highlight selectively vulnerable sub-regions of the striatum and thalamus that may be important targets for future therapies.

neuroscience↗

Single-cell characterization of transcriptomic heterogeneity in lymphoblastoid cell lines

Lymphoblastoid Cell Lines (LCLs) are generated by transforming primary B cells with Epstein-Barr Virus (EBV) and are used extensively as model systems in viral oncology, immunology, and human genetics research. In this study, we characterized single-cell transcriptomic profiles of five LCLs and present a simple discrete-time simulation to explore the influence of stochasticity on LCL clonal evolution. Single-cell RNA sequencing revealed substantial phenotypic heterogeneity within and across LCLs with respect to immunoglobulin isotype; virus-modulated host pathways involved in survival, proliferation, and differentiation; viral replication state; and oxidative stress. This heterogeneity is likely attributable to intrinsic variance in primary B cells and host-pathogen dynamics. Stochastic simulations demonstrate that initial primary cell heterogeneity, random sampling, time in culture, and even mild differences in phenotype-specific fitness can contribute substantially to dynamic diversity in populations of nominally clonal cells.

immunology↗

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

Adaptation of cancer cells to targeted therapy follows ecological paradigms observed in natural populations that encounter resource depletion and changing environments, including activation of pro-survival mechanisms, migration to new locations, and escape of predation. We identified the p38 MAPK pathway as a common molecular driver of these three responses during the adaptation to hormone therapy resistance in prostate cancer. The p38 pathway is activated in therapy-resistant cells and mechanistically drives these three convergent responses through sustained AR activity, enhanced invasion and metastasis, and immune evasion. Targeting p38 signaling may represent a new therapeutic strategy to treat men with metastatic, hormone therapy-resistant prostate cancer.

cancer biology↗

Dynamics of cortical degeneration over a decade in Huntington's Disease

The neurodegenerative process is typically slowly progressive and complex. While simple models of neurodegeneration suggest that brain changes progress at a near constant rate, previous research shows regional variation within the temporal progression of atrophy, indicating that over the course of neurodegeneration, different regions may undergo changing rates of atrophy. Characterization of long-term dynamic brain changes in neurodegeneration requires both extensive longitudinal MRI datasets and an advanced modeling framework. Until recently, both of these elements were not available. Here, we implement a novel dynamic systems approach to infer patterns of regional progression spatially and temporally in a unique longitudinal dataset with up to seven annual individual brain scans per participant from 49 Huntingtons Disease (HD) gene-carriers. We map participant-and group-level trajectories of cortical atrophy in HD using a decade of data that encompasses motor symptom onset and, for the first time, show that neurodegenerative brain changes exhibit complex temporal dynamics of atrophy with substantial regional variation in progressive cortical atrophy. Some fronto-occipital cortical areas show an almost constant rate of atrophy, while medial-inferior temporal areas undergo only minor change. Interestingly, cortical sensory-motor areas were found to show a noticeable acceleration of atrophy following HD diagnosis. Furthermore, we establish links between individual atrophy and genetic markers of HD (CAG repeat length), as well as showing that cortical motor network changes predict subsequent decline in task-based motor performance, demonstrating face-validity of the model. Our findings highlight the complex pattern of dynamic cortical change occurring in HD that can help to resolve the biological underpinnings of HD progression.

neuroscience↗

Evaluating DNA methylation age on the Illuminas methylationEPIC BeadChip

DNA methylation age (DNAm age) has become a widely utilized epigenetic biomarker for the aging process. The Horvath method for determining DNAm age is perhaps the most widely utilized and validated DNA methylation age assessment measure. Horvath DNAm age is calculated based on methylation measurements at 353 loci which were present on Illuminas 450k and 27k DNA methylation microarrays. With the increasing use of the more recently developed Illumina MethylationEPIC (850k) microarray, it is worth revisiting this widely used aging measure to evaluate differences in DNA methylation age estimation based on array design. Of the requisite 353 loci, 17 are missing from the current 850k microarray. Using 17 datasets with 27k, 450k, and/or 850k methylation data, we calculated and compared each samples epigenetic age estimated from all 353 loci required from the Horvath DNAm age calculator (full), and using only the 336 loci present on the 27k, 450k, and 850k arrays (reduced). In 450k/27k data, missing loci caused underestimation of epigenetic age when compared with the full clock. Underestimation of full epigenetic age grew from ages 0 to ~20, remaining stable thereafter (mean= -3.46 y, SD=1.13) years for individuals [&ge;]20 years. Underestimation of DNAm age by the reduced 450k/27k data was similar to the underestimation observed in the 850k data indicating that array differences in DNAm age estimation are primarily driven by missing probes. Correlations between age and DNAm age were not dependent on missing probes or on array designs and consequently associations between DNAm age and outcomes such as sex remained the same independent of missing probes and probe design. In conclusion, DNAm age estimations are array dependent driven by missing probes between arrays. Though correlations and associations with DNAm age may remain the same, researchers should exercise caution when interpreting results based on absolute differences in DNAm age or when mixing samples assayed on different arrays.\n\nDisclaimerThis paper has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. EPA, and is approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The authors declare they have no competing financial interests.

bioinformatics↗

Stability and sensitivity of structural connectomes: effect of thresholding and filtering and demonstration in neurodegeneration

Structural connectomes derived using diffusion tractography are increasingly used to investigate white matter connectivity in neurological diseases. However inherent biases in diffusion tractography algorithms may lead to both false negatives and false positives in connectome construction. A range of graph thresholding approaches and more recently several streamline filtering algorithms have been developed to address these issues. However there is no consensus in the literature regarding the best available approach. Using a cohort of Huntingtons disease patients and healthy controls we compared the effect of several graph thresholding strategies: proportional, absolute, consensus and consistency thresholding, with and without streamline filtering, using Spherical Deconvolution Informed Filtering of tractograms (SIFT2) algorithm. We examined the effect of thresholding strategies on the stability of graph theory metrics and the sensitivity of these measures in neurodegeneration. We show that while a number of graph thresholding procedures result in stable metrics across thresholds, the detection of group differences is highly variable. We also showed that the application of streamline filtering using SIFT2 resultes in better detection of group differences and stronger clinical correlations. We therefore conclude that the application of SIFT2 streamline filtering without graph thresholding may be sufficient for structural connectome construction.

neuroscience↗

Assessment of Functional Connectome Construction Strategies in Neurodegeneration

Connectomics can be used to investigate functional brain networks in neurodegenerative diseases including Huntingtons disease (HD). In this developing field, different connectome construction strategies have emerged in parallel. However, there is a need to understand the influences of different strategies on subsequent analyses when constructing a connectome. This study systematically compares connectome construction strategies based on their biological relevance to functional networks in neurodegeneration.\n\nWe asked which functional connectome construction strategy was best able to discriminate HD gene carriers from healthy controls, and how such a strategy affected modular organization of the network. The major factors compared were principal component-based correction versus wavelet decomposition for physiological noise correction, the type of parcellation atlas (functional, structural and multi-modal), weighted versus binarized networks, and unthresholded versus proportionally thresholded networks. We found that principal component-based correction generated the most discriminatory connectomes, while binarization and proportional thresholding did not increase discrimination between HD gene carriers and healthy controls. When a functional parcellation atlas was used, the highest discrimination rates were obtained. We observed that the group differences in modular organization of the functional connectome were greatly affected by binarization and thresholding, showing no consistent pattern of modularity.\n\nThis study suggests that functional connectome construction strategies using principal component-based correction and weighted unthresholded connectivity matrices may outperform other strategies.

neuroscience↗