Biology subjects

Curtis, D.

Publications and source records attributed to Curtis, D..

At least 19 recordsLinked to original sources

bioRxiv2026

HIV remodels germinal centers through T follicular helper cell loss

T follicular helper cells (Tfh) within germinal centers are among the most permissive cells for HIV infection and serve as a critical part of the viral reservoir. Given the key role of Tfh in affinity maturation and the production of plasma cells and memory B cells, an understanding of this critical viral reservoir is fundamental not only for cure strategies but also for understanding immunodeficiency in people living with HIV (PLWH). Using rare clinical specimens from PLWH, we demonstrate that HIV causes both a change in the cellular composition of germinal centers and changes in their overall architecture in ways that are consistent with the immunodeficiency seen in PLWH, independent of their CD4 count. We note a significant decrease in the number of GC Tfh cells and an increase in the number of follicular CD8 T cells in lymphoid tissues obtained from PLWH. Our data further show that GC size is decreased both by HIV and with increased age. Single-cell RNA sequencing data demonstrate that HIV acutely decreases the expression of Tfh B-cell support pathways and disrupts Tfh expression of cell trafficking receptors. Additionally, in a lymphoid organoid model of acute infection that forms GC-like structures, these findings are recapitulated, suggesting that New Approach Methodologies could be germane to understanding the impact of HIV on the reservoir and immunodeficiency. This study describes previously undocumented remodeling of the germinal center niche in PLWH, providing insight into the immune microenvironment of a key HIV reservoir that may help inform future cure strategies.

microbiology↗

bioRxiv2026

Characterizing Industrial Pond Ecology Timeline in DISCOVR Cultivation Trials for Early Detection of Pond Crashes

For sustainable algal biomass cultivation, we need substantial improvement in annualized productivity by reducing the frequency of crop failure and improved growth in open raceway pond systems. In this study, high-performing strains were identified and optimized for biomass productivity. We utilized next-generation sequencing methods to quantify the ecological features of open raceway systems cultivated at in Arizona. We utilized data from several months of cultivation runs to construct a rich time-series of the ecology dynamics using amplicon sequencing and used custom anomaly detection, "PondSentry", for the early prediction of pond crashes. PondSentry uses tensor decomposition of higher-order joint moments to detect incipient anomalies in multivariate data and displays significant improvements from standard knowledge-based anomaly detection methods. The PondSentry strategy identifies signs of deteriorating pond health at an average of three days before an actual crash event, with rank order of the ecological features plausible for crop failures driven by organisms such as Amoeboaphelidium occidentale FD01. These findings are independently confirmed with PCR and microscopy studies at an Arizona cultivation site. PondSentrys time-series-based anomaly detection of crashes provides a suitable monitoring strategy for eukaryotic crash agents in unialgal culture. The early warnings can be used to time interventions or harvests to prevent biomass loss. The PondSentry strategy strengthens the role of data science and data-driven methods in algal cultivation and can increase the feasibility of algal-biomass based products.

ecology↗

bioRxiv2026

Protection of algae grown for biofuel using a consortium of environmentally harvested bacteria

Crop loss due to infection by pests and pathogens is a major barrier to the large-scale production of algal biofuels. Test systems have seen loss of green algae crops due to infection by the fungus-like Amoeboaphelidium occidentale FD01. While current antifungal compounds are effective in inhibiting the infection, their application raises the overall cost of the crop and lowers its economic viability as a biofuel source. Here we show that co-culturing environmentally harvested bacteria alongside algae crops can drastically lower the rate of infection in two different green algae species of interest for biofuel production. These bacteria-algae consortia increase the mean time to crop failure (MTTF) by up to 350% when tested under environmentally relevant conditions. While there was an increase in diversity over time, there was no statistically significant correlation between an increase in diversity and a longer MTTF. Community composition analysis reveals similarities between the bacterial genera growing alongside both green algae species even as bacterial harvest locations differed, although there was not a single dominant genus responsible for the increase in crop protection. These results show a promising new method of anti-fungal crop protection that can be applied to algal biofuels with no increase in fuel cost. HighlightsO_LIBacteria-algal cocultures protect against fungal pests without impact to productivity C_LIO_LIBacterial community composition is variable over time even as protection persists C_LIO_LIBacterial consortia can increase mean time to failure by 350% C_LI

microbiology↗

bioRxiv2026

Sequence effects on patterns of variation and DNA strand asymmetries observed from whole-genome sequenced UK Biobank participants

UK Biobank has released whole genome sequence data for 500,000 participants, including allele counts for hundreds of millions of variants and these were considered in the context of the pentanucleotide background on which they occurred. Variants with an allele count of 25 were found to closely mirror previously reported de novo mutations (DNMs) in terms of the frequencies of variant types. Therefore these variants, referred to as AC25 variants, were used to investigate factors relevant to mutation frequency. The counts of AC25 variant types in a trinucleotide context could be well approximated by combining seven mutational signatures previously obtained from studies of cancer cells. Frequencies of variants were strongly influenced by context. C>T variants occurred more often in the CpG context but other features of the trinucleotide context also had marked effects. Although the trinucleotide context was a very strong predictor of the variant frequencies for the full pentanucleotide context, there were examples where the more distant nucleotides did have marked effects. Here, the configuration of bases two upstream or downstream could have a more than two-fold effect on variant frequencies, presumed to reflect mutation rates. For some variants frequencies varied between non-transcribed and transcribed regions and variants with higher frequencies in transcripts of protein coding genes also demonstrated strand asymmetry, being more frequent on the coding than template strand. Genes with high frequencies of these variants showed enrichment for basic cellular processes, meaning that they could have arisen as a result of transcriptional events during embryogenesis prior to entering the germline. Investigating the molecular mechanisms whereby contexts moderate mutation rates could lead to a better understanding of variant pathogenicity and how DNA fidelity is conserved in normal tissue. This research has been conducted using the UK Biobank Resource. Article summaryWe analysed hundreds of millions of variations in DNA code observed in 500,000 UK Biobank participants. For each change of a single DNA base, we also considered the two bases either side. We found that the set of variants which each occurred exactly 25 times in the sample, termed AC25 variants, had a frequency distribution which almost exactly matched that of a set of previously reported variants which occurred as new mutations. Therefore, we used these AC25 variants to study the effect of DNA context on mutation rates and to compare mutation types with those previously observed in cancer patients.

genetics↗

bioRxiv2024

Mesoscale Modelling of Fibrin Clots: The Interplay between Rheology and Microstructure at the Gel Point

This study presents a numerical model for incipient fibrin-clot formation that captures characteristic rheological and microstructural features of the clot at the gel point. Using a mesoscale-clustering framework, we evaluate the effect of gel concentration or gel volume fraction and branching on the fractal dimension, the gel time, and the viscoelastic properties of the clots. We show that variations in the gel concentration of our model can reproduce the effect of thrombin in the formation of fibrin clots. In particular, the model reproduces the fractal dimensions dependency on gel concentration and the trends in elasticity and gelation time with varying thrombin concentrations. This approach allows us to accurately recreate the gelation point of fibrin-thrombin gels, highlighting the intricate process of fibrin polymerization and gel network formation. This is critical for applications in the clinical and bioengineering fields where precise control over the gelation process is required.

biophysics↗

bioRxiv2022

EcoFun-MAP: An Ecological Function Oriented Metagenomic Analysis Pipeline

Annotating ecological functions of environmental metagenomes is challenging due to a lack of specialized reference databases and computational barriers. Here we present the Ecological Function oriented Metagenomic Analysis Pipeline (EcoFun-MAP) for efficient analysis of shotgun metagenomes in the context of ecological functions. We manually curated a reference database of EcoFun-MAP which is used for GeoChip design. This database included [~]1,500 functional gene families that were catalogued by important ecological functions, such as carbon, nitrogen, phosphorus, and sulfur cycling, metal homeostasis, stress responses, organic contaminant degradation, antibiotic resistance, microbial defense, electron transfer, virulence and plant growth promotion. EcoFun-MAP has five optional workflows from ultra-fast to ultra-conservative, fitting different research needs from functional gene exploration to stringent comparison. The pipeline is deployed on High Performance Computing (HPC) infrastructure with a highly accessible web-based interface. We showed that EcoFun-MAP is accurate and can process multi-million short reads in a minute. We applied EcoFun-MAP to analyze metagenomes from groundwater samples and revealed interesting insights of microbial functional traits in response to contaminations. EcoFun-MAP is available as a public web server at http://iegst1.rccc.ou.edu:8080/ecofunmap/.

bioinformatics↗

bioRxiv2020

Multiple linear regression allows weighted burden analysis of rare coding variants in an ethnically heterogeneous population

Weighted burden analysis has been used in exome-sequenced case-control studies to identify genes in which there is an excess of rare and/or functional variants associated with phenotype. Implementation in a ridge regression framework allows simultaneous analysis of all variants along with relevant covariates such as population principal components. In order to apply the approach to a quantitative phenotype, a weighted burden score is derived for each subject and included in a linear regression analysis. The weighting scheme is adjusted in order to apply differential weights to rare and very rare variants and a score is derived based on both the frequency and predicted effect of each variant. When applied to an ethnically heterogeneous dataset consisting of 49,790 exome-sequenced UK Biobank subjects and using BMI as the phenotype the method produces a very inflated test statistic. However this is almost completely corrected by including 20 population principal components as covariates. When this is done the top 30 genes include a few which are quite plausibly associated with the phenotype, including LYPLAL1 and NSDHL. This approach offers a way to carry out gene-based analyses of rare variants identified by exome sequencing in heterogeneous datasets without requiring that data from ethnic minority subjects be discarded. This research has been conducted using the UK Biobank Resource.

genetics↗

bioRxiv2019

Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for involvement of PSEN1 and demonstrates protective role for variants in tyrosine phosphatase genes

Previous studies have implicated common and rare genetic variants as risk factors for late onset Alzheimers disease (AD, LOAD). Here, weighted burden analysis was applied to over 10,000 exome sequenced subjects from the Alzheimers Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7 and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 x 10-6) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Since PIK3R1 variants are expected to impair PI3K/Akt/GSK-3{beta} signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models suggesting that this pathway is protective against AD.

genetics↗

bioRxiv2019

LD scores are associated with differences in allele frequencies between populations but LD score regression can still distinguish confounding from polygenicity

The LD score regression method tests whether there is an association between the LD score and allele frequency differences between cases and controls. It makes the assumption that there is no association between LD score and allele frequency differences between populations and hence that any observed association is due to a polygenic effect rather than population stratification. This assumption has not previously been tested. In comparisons between HapMap populations we observe that there is indeed an association between the LD score and allele frequency differences. However this effect is small and when we carry out simulations of large case-control samples the effect becomes negligible. We conclude that if the intercept is small then any increase in mean chi-squared does indeed reflect a polygenic effect rather than population stratification.

genetics↗

bioRxiv2019

Do damaging variants of SLC6A9, the gene for the glycine transporter 1 (GlyT-1), protect against schizophrenia?

AimsTo test whether genetic variants predicted to impair the functionality of SLC6A9, which codes for the GlyT-1 glycine transporter, are protective against schizophrenia. MethodIn an exome sequenced sample of 4225 schizophrenia cases and 5834 controls variants occurring in SLC6A9 were annotated and weights were assigned using GENEVARASSOC. Genotype counts were compared using SCOREASSOC. ResultsVariants predicted to be deleterious by SIFT and damaging by PolyPhen were examined. Genotypes at 1:44466494-G/A seemed likely to be erroneous. If these were ignored then there were 15 damaging variants in controls and 5 in cases. ConclusionsThe results are consistent with the hypothesis that variants which damage SLC6A9 are protective against schizophrenia but a larger sample would be required to confirm this. Declaration of interestThe author declares no conflict of interest.

genetics↗

bioRxiv2018

In silico investigation of coding variants potentially affecting the functioning of the glutamatergic N-methyl-D-aspartate receptor in schizophrenia

BackgroundSeveral lines of evidence support the hypothesis that impaired function of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) might be involved in the aetiology of schizophrenia. NMDAR is activated by phosphorylation by Fyn and there is also some evidence to suggest that abnormalities in Fyn functionality could also be involved in susceptibility to schizophrenia. In a recent weighted burden analysis of exome sequenced schizophrenia cases and controls we noted modest statistical evidence for an enrichment of rare, functional variants in FYN, GRIN1 and GRIN2B in schizophrenia cases.\n\nAimsTo test the plausibility of the hypothesis that schizophrenia susceptibility might be associated with genetic variants predicted to cause impaired functioning of NMDAR, either directly or indirectly through impairment of the kinases which phosphorylate it.\n\nMethodIn an exome sequenced sample of 4225 schizophrenia cases and 5834 controls rare variants occurring in genes for the NMDAR subunits and for the kinases acting on it were annotated. The counts of disruptive and damaging variants were compared between cases and controls and the distribution of amino acids affected by damaging variants were visualised in ProteinPaint and the RCSB Protein Data Bank. Special attention was paid to tyrosine residues subject to phosphorylation.\n\nResultsThere was no suggestion that abnormalities of the serine-threonine kinases or of Src were associated with schizophrenia. 3 cases and no controls had a disruptive variant in GRIN2A and 2 cases and no controls had a disruptive variant in FYN. 14 cases and 3 controls had damaging variants in FYN and all the variants in controls affected amino acid residues in the N-terminal region outside of any known functional domains. By contrast, 10 variants in cases affected amino acids in functional domains and in the 3D structure of Fyn two of the amino acid substitions, A376T and Q517E, were adjacent to each other. 8 cases and 1 control had damaging variants in GRIN1 but there was no obvious pattern with respect to particular functional domains being affected in this or other genes. A single case had a variant in GRIN2A affecting a well-supported phosphorylation site, Y943C, and three cases had a variant which produce an amino acid change, T216S, which lies two residues away from two well-supported phosphorylation sites. Aside from this, there was no suggestion that tyrosine phosphorylation sites in Fyn or NMDAR were affected.\n\nConclusionsThe numbers of variants involved are too small for firm conclusions to be drawn. The results are consistent with the hypothesis that about 0.5% of subjects with schizophrenia have disruptive or damaging genetic variants which could plausibly impair functioning of NMDAR directly or indirectly through impairing Fyn function.

genetics↗

bioRxiv2018

A weighted burden test using logistic regression for integrated analysis of sequence variants, copy number variants and polygenic risk score

Previously described methods of analysis allow variants in a gene to be weighted more highly according to rarity and/or predicted function and then for the variant contributions to be summed into a gene-wise risk score which can be compared between cases and controls using a t test. However this does not allow incorporating covariates into the analysis. Schizophrenia is an example of an illness where there is evidence that different kinds of genetic variation can contribute to risk, including common variants contributing to a polygenic risk score (PRS), very rare copy number variants (CNVs) and sequence variants. A logistic regression approach has been implemented to compare the gene-wise risk scores between cases and controls while incorporating as covariates population principal components, the PRS and the presence of pathogenic CNVs and sequence variants. A likelihood ratio test is performed comparing the likelihoods of logistic regression models with and without this score. The method was applied to an ethnically heterogeneous exome-sequenced sample of 6000 controls and 5000 schizophrenia cases. In the raw analysis the test statistic is inflated but inclusion of principal components satisfactorily controls for this. In this dataset the inclusion of the PRS and effect from CNVs and sequence variants had only small effects. The set of genes which are FMRP targets showed some evidence for enrichment of rare, functional variants among cases (p=0.0005). This approach can be applied to any disease in which different kinds of genetic and non-genetic risk factors make contributions to risk.

genetics↗

bioRxiv2018

Polygenic risk score for schizophrenia is more strongly associated with ancestry than with schizophrenia

BackgroundThe polygenic risk score (PRS) for schizophrenia, derived from very large numbers of weakly associated genetic markers, has been repeatedly shown to be robustly associated with schizophrenia in independent samples and also with other diseases and traits.\n\nAimsTo explore the distribution of the schizophrenia PRS in subjects of different ancestry.\n\nMethodThe schizophrenia PRS derived from the large genome-wide association study carried out by the Psychiatric Genetics Consortium was calculated using the downloaded genotypes of HapMap subjects from eleven different ancestral groups. It was also calculated using downloaded genotypes of European schizophrenia cases and controls from the CommonMind Consortium.\n\nResultsThe PRS for schizophrenia varied significantly between ancestral groups (p < 2*10-16) and was much higher in African than European HapMap subjects. The mean difference between these groups was ten times as high as the mean difference between European schizophrenia cases and controls. The distributions of scores for African and European subjects hardly overlapped.\n\nConclusionsThe PRS cannot be regarded as simply a measure of the polygenic contribution to risk of schizophrenia and clearly contains a strong ancestry component. It is possible that this could be controlled for to some extent by incorporating principal components as covariates but doubts remain as to how it should be interpreted. The PRS derived from European subjects cannot be applied to non-Europeans, limiting its potential usefulness and raising issues of inequity. Previous studies which have used the PRS should be re-examined in the light of these findings.\n\nDeclaration of interestThe author declares he has no conflict of interest.

genetics↗

bioRxiv2017

Polygenic risk score for schizophrenia is not strongly associated with the expression of specific genes or gene sets

The polygenic risk score (PRS) is derived from SNPs including both those which are genome-wide significant and also a large number of others more weakly associated with schizophrenia. Such variants are widely dispersed, though concentrated near genes expressed in the brain, and it has been proposed that these SNP associations result from impacts on cell regulatory networks which ultimately affect the expression or function of a modest number of \"core\" genes. A previous study demonstrated association of some GWAS-significant variants with expression of a number of genes, by examining pair-wise correlations of gene expression with SNP genotypes. The present study used data downloaded from the CommonMind Consortium site, consisting of SNP genotypes and RNAseq expression data from the dorsolateral prefrontal cortex, to examine whether the expression of individual genes or sets of genes correlated with PRS in 207 controls and 209 schizophrenia cases. Although the PRS was significantly associated with phenotype, the correlations with genes and genes sets followed distributions expected by chance. Thus, this analysis failed to demonstrate that the PRS captures a cumulative effect of multiple variants impacting the expression of a small number of genes and it failed to focus attention on a small number of genes of biological relevance. The multiple SNP associations observed in schizophrenia may result from other mechanisms, including effects mediated indirectly through environmental risk factors.

genetics↗

bioRxiv2017

Weighted burden analysis of exome-sequenced case-control sample implicates synaptic genes in schizophrenia aetiology

A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive variants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish contribution to ancestry. We have reanalysed the same dataset after removal of these subjects and we have also included non-singleton variants of all types using a weighted burden test which assigns higher weights to variants predicted to have a greater effect on protein function. We investigated the same 31 gene sets as previously and also 1454 GO gene sets. The reduced dataset consisted of 4225 cases and 5834 controls. No individual variants or genes were significantly enriched in cases but 13 out of the 31 gene sets were significant after Bonferroni correction and the \"FMRP targets\" set produced a signed log p value (SLP) of 7.1. The gene within this set with the highest SLP, equal to 3.4, was FYN, which codes for a tyrosine kinase which phosphorylates glutamate metabotropic receptors and ionotropic NMDA receptors, thus modulating their trafficking, subcellular distribution and function. In the most recent GWAS of schizophrenia it was identified as a \"prioritized candidate gene\". Two of the subunits of the NMDA receptor which are substrates of FYN are coded for by GRIN1 (SLP=1.7) and GRIN2B (SLP=2.1). Of note, for some sets there was a substantial enrichment of non-singleton variants. Of 1454 GO gene sets, 3 were significant after Bonferroni correction. Identifying specific genes and variants will depend on genotyping them in larger samples and/or demonstrating that they cosegregate with illness within pedigrees.

genetics↗

bioRxiv2017

KCC1 Activation protects Mice from the Development of Experimental Cerebral Malaria.

Plasmodium falciparum malaria causes half a million deaths per year, with up to 9% of this mortality caused by cerebral malaria (CM). One of the major processes contributing to the development of CM is an excess of host inflammatory cytokines. Recently K+ signaling has emerged as an important mediator of the inflammatory response to infection; we therefore investigated whether mice carrying an ENU induced activation of the electroneutral K+ channel KCC1 had an altered response to Plasmodium berghei. Here we show that Kcc1M935K/M935K mice are protected from the development of experimental cerebral malaria, and that this protection is associated with an increased CD4+ T cells and TNF- response. This is the first description of a K+ channel affecting the development of experimental cerebral malaria.

microbiology↗

bioRxiv2017

Common variants of NRXN1, LRP1B and RORA are associated with increased ventricular volumes in psychosis - GWAS findings from the B-SNIP deep phenotyping study

Schizophrenia, Schizoaffective, and Bipolar Disorders share common illness traits, intermediate phenotypes and a partially overlapping polygenic basis. We performed GWAS on deep phenotyping data, including structural MRI and DTI, clinical, and behavioral scales from 1,115 cases and controls. Significant associations were observed with two cerebrospinal fluid volumes: the temporal horn of left lateral ventricle was associated with NRXN1, and the volume of the cavum septum pellucidum was associated with LRP1B and RORA. Both volumes were associated with illness. Suggestive associations were observed with local gyrification indices, fractional anisotropy and age at onset. The deep phenotyping approach allowed unexpected genetic sharing to be found between phenotypes, including temporal horn of left lateral ventricle and age at onset.

genetics↗

bioRxiv2017

Association study of schizophrenia with variants in miR-137 binding sites

There is strong cumulative evidence for the involvement of miR-137 and its targets in the aetiology of schizophrenia. Here we test whether variants, especially rare variants, in miR137 binding sites are associated with schizophrenia in an exome-sequenced sample of 4225 cases and 5834 controls. A weighted burden test using 372 variants was significant at p=0.024. The sample size is too small to implicate individual variants or genes but overall this finding provides further support for the hypothesis that disruption of miR-137 binding sites can increase the risk of schizophrenia, perhaps by leading to over-expression of the target gene. These findings could be followed up by genotyping these variants in larger samples and by experimentally testing whether they do indeed effect expression. When carrying out exome sequencing it is important to include UTRs so that disruption of microRNA bindings sites can be detected.

genetics↗