Biology subjects

Adler, C.

Publications and source records attributed to Adler, C..

8 recordsLinked to original sources

bioRxiv2024

Combined aerobic and resistance exercise training alters the spatial transcriptome of skeletal muscle in young adults

Chronic exercise training substantially improves skeletal muscle function and performance. The repeated demands and stressors of each exercise bout drive coordinated molecular adaptations within multiple cell types in muscle tissue, leading to enhanced neuromuscular recruitment and contractile function, stem cell activation, myofiber hypertrophy, mitochondrial biogenesis, and angiogenesis, among others. To comprehensively profile molecular changes induced by combined resistance and endurance exercise training, we employed spatial transcriptomics coupled with immunofluorescence and computational approaches to resolve effects on myofiber and mononuclear cell populations in human muscle. By computationally identifying fast and slow myofibers using immunofluorescence data of spatially sequenced tissue sections, we identified fiber type-specific, exercise-induced gene expression changes that correlated with muscle functional improvements. Additionally, spatial transcriptome profiling and integration of human muscle single cell RNAseq data identified an exercise-induced shift in interstitial cell populations coincident with angiogenesis. Overall, these data provide a unique spatial molecular profiling resource for exploring muscle adaptations to exercise, and provide a pipeline and rationale for future studies in human muscle.

physiology↗

bioRxiv2022

Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade

Here, we leveraged a large neoadjuvant PD-1 blockade trial in patients with hepatocellular carcinoma (HCC) to search for correlates of response to immune checkpoint blockade (ICB) within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+ CH25H+ IL-21+ PD-1+ CD4 T helper cells (CXCL13+ Th) and Granzyme K+ PD-1+ effector-like CD8 T cells, whereas terminally exhausted CD39hi TOXhi PD-1hi CD8 T cells dominated in non-responders. Strikingly, most T cell receptor (TCR) clones that expanded post-treatment were found in pre-treatment biopsies. Notably, PD-1+ TCF-1+ progenitor-like CD8 T cells were present in tumors of responders and non-responders and shared clones mainly with effector-like cells in responders or terminally differentiated cells in non-responders, suggesting that local CD8 T cell differentiation occurs upon ICB. We found that these progenitor CD8 T cells interact with CXCL13+ Th cells within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". Receptor-ligand analysis revealed unique interactions within these triads that may promote the differentiation of progenitor CD8 T cells into effector-like cells upon ICB. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ Th cells control the differentiation of tumor-specific progenitor CD8 T cell clones in patients treated with ICB.

immunology↗

bioRxiv2022

Two independent loss-of-function mutations in anthocyanidin synthase homeologous genes make sweet basil all green

Sweet basil, Ocimum basilicum L., is an important culinary herb grown worldwide. Although basil is green, many landraces, breeding lines and exotic cultivars have purple stems and flowers. This anthocyanins pigmentation is unacceptable in the traditional Italian basil. We used the recently published sweet basil genome to map quantitative trait loci (QTL) for flower and stem color in a bi-parental F2 population. It was found that the pigmentation is governed by a single QTL, harboring an anthocyanidin synthase (ANS) gene. Further analysis revealed that the basil genome harbors two homeologous ANS genes, each carrying a loss-of-function mutation. ObANS1 carries a 1-bp insertion, and ObANS2 carries a missense mutation within the active site. In the purple-flower parent, ANS1 is functional and ANS2 carries a nonsense mutation. The functionality of the active allele was validated by complementation in an Arabidopsis ANS mutant. Moreover, we have restored the functionality of the missense-mutated ANS2 using site-directed activation. We found that the non-functional alleles were expressed to similar levels as the functional allele, suggesting polyploids invest futile effort in expressing non-functional genes, harming their superior redundancy. We show here we can harness basils genomics and genetics to understand the basic mechanism of metabolic traits.

plant biology↗

bioRxiv2021

Convergent evolution of genome guardian functions in a parasite-specific p53 homolog

SignificanceP53 is a widely studied tumor suppressor that is found throughout metazoans, including invertebrates that do not develop malignancies. The prevailing theory for why this is the case is that P53 originally evolved to protect the germline of early metazoans from genotoxic stress such as UV radiation. In this study, we examine the function of two P53 homologs in the parasitic flatworm Schistosoma mansoni. The first is orthologous to canonical P53, and regulates stem cell maintenance and differentiation. The second P53 gene is a parasite-specific paralog that is required for the normal response to genotoxic stress. This implies that the ability to respond to genotoxic stress in parasitic flatworms may have arisen from convergent evolution.

evolutionary biology↗

bioRxiv2020

AdRoit: an accurate and robust method to infer complex transcriptome composition

Bulk RNA sequencing technology provides the opportunity to understand biology at the whole transcriptome level without the prohibitive cost of single cell profiling. Advances in spatial transcriptomics enable to dissect tissue organization and function by genome-wide gene expressions. However, the readout of both technologies is the overall gene expression across potentially many cell types without directly providing the information of cell type constitution. Although several in-silico approaches have been proposed to deconvolute RNA-Seq data composed of multiple cell types, many suffer a deterioration of performance in complex tissues. Here we present AdRoit, an accurate and robust method infer the cell composition from transcriptome data comprised of multiple cell types. AdRoit uses gene expression profile obtained from single cell RNA sequencing as a reference. It employs an adaptive learning approach to correct the sequencing technique difference between the single cell data and the bulk or spatial transcriptome data, enabling cross-platform readout comparability. Our systematic benchmarking and applications, which include deconvoluting complex mixtures that encompass 30 cell types, demonstrate its superior sensitivity and specificity compared to other existing methods as well as its utilities. In addition, AdRoit is computationally efficient and runs orders of magnitude faster than many existing methods.

bioinformatics↗

bioRxiv2020

Molecular taxonomy of human ocular outflow tissues defined by single cell transcriptomics

The conventional outflow pathway is a complex tissue responsible for maintaining intraocular pressure (IOP) homeostasis. The coordinated effort of multiple cells with differing responsibilities ensure healthy outflow function and IOP maintenance. Dysfunction of one or more resident cell type results in ocular hypertension and risk for glaucoma, a leading cause of blindness. In this study, single cell RNA sequencing was performed to generate a comprehensive cell atlas of human conventional outflow tissues. We obtained 17757 genes expression profiles from 8758 cells from eight eyes of four donors representing the outflow cell transcriptome. Upon clustering analysis, 12 distinct cell types were identified, and region-specific expression of candidate genes were mapped in human tissues. Significantly, we identified two distinct expression patterns (myofibroblast and fibroblast) from cells located in the trabecular meshwork (TM), the primary structural component of the conventional outflow pathway. We also located neuron and macrophage signatures in the TM. The second primary component structure, Schlemms canal displayed a unique combination of lymphatic/blood vascular gene expression. Other expression clusters corresponded to cells from neighboring tissues, predominantly in the ciliary muscle/scleral spur, which together correspond to the uveoscleral outflow path. Importantly, the utility of our atlas was demonstrated by mapping glaucoma-relevant genes to outflow cell clusters. Our study provides a comprehensive molecular and cellular classification of conventional and unconventional outflow pathway structures responsible for IOP homeostasis. Significance statementOcular hypertension is the primary, and only modifiable risk factor for glaucoma, the leading cause of irreversible blindness. Intraocular pressure is regulated homeostatically by resistance to aqueous humor outflow through an architecturally complex tissue, the conventional/trabecular pathway. In this study, we generated a comprehensive cell atlas of the human trabecular meshwork and neighboring tissues using single cell, RNA sequencing. We identified 12 distinct cell types, and mapped region-specific expression of candidate genes. The utility of our atlas was demonstrated by mapping glaucoma-relevant genes to conventional outflow cell clusters. Our study provides a comprehensive molecular and cellular classification of tissue structures responsible for intraocular pressure homeostasis in health, and dysregulation in disease.

cell biology↗

bioRxiv2018

Laboratory contamination over time during low-biomass sample analysis

Bacteria are not only ubiquitous on earth but can also be incredibly diverse within clean laboratories and reagents. The presence of both living and dead bacteria in laboratory environments and reagents is especially problematic when examining samples with low endogenous content (e.g. skin swabs, tissue biopsies, ice, water, degraded forensic samples, or ancient material), where contaminants can outnumber endogenous microorganisms within samples. The contribution of contaminants within high-throughput studies remains poorly understood because of the relatively low number of contaminant surveys. Here, we examined 144 negative control samples (extraction blank and no-template amplification controls) collected in both typical molecular laboratories and an ultraclean ancient DNA laboratory over five years to characterize long-term contaminant diversity. We additionally compared the contaminant content within a homemade silica-based extraction method, commonly used to analyse low-endogenous samples, with a widely used commercial DNA extraction kit. The contaminant taxonomic profile of the ultraclean ancient DNA laboratory was unique compared to the modern molecular biology laboratories, and changed over time according to researchers, month, and season. The commercial kit contained higher microbial diversity and several human-associated taxa in comparison to the homemade silica extraction protocol. We recommend a minimum of two strategies to reduce the impacts of laboratory contaminants within low-biomass metagenomic studies: 1) extraction blank controls should be included and sequenced with every batch of extractions and 2) the contributions of laboratory contamination should be assessed and reported in each high-throughput metagenomic study.

microbiology↗

bioRxiv2017

Ancient symbiosis confers desiccation resistance to stored grain pest beetles

Microbial symbionts of insects provide a range of ecological traits to their hosts that are beneficial in the context of biotic interactions. However, little is known about insect symbiont-mediated adaptation to the abiotic environment, e.g. temperature and humidity. Here we report on an ancient (~400 Mya) clade of intracellular, bacteriome-located Bacteroidetes symbionts that are associated withgrain and wood pest beetles of the phylogenetically distant families Silvanidae and Bostrichidae. In the saw-toothed grain beetle Oryzaephilus surinamensis, we demonstrate that the symbionts affect cuticle thickness, melanization and hydrocarbon profile, enhancing desiccation resistance and thereby strongly improving fitness under dry conditions. Together with earlier observations on symbiont contributions to cuticle biosynthesis in weevils, our findings indicate that convergent acquisitions of bacterial mutualists represented key adaptations enabling diverse pest beetle groups to survive and proliferate under the low ambient humidities that characterize dry grain storage facilities.

evolutionary biology↗