Biology subjects

Brenner, E.

Publications and source records attributed to Brenner, E..

9 recordsLinked to original sources

bioRxiv2025

Beyond the core: endemic microbiota drive functional and microdiversity differences across salamander populations

Population-specific variation in animal microbiomes is well documented, yet the functional consequences and underlying mechanisms remain poorly understood. To address this, we conducted genome-resolved metagenomic analyses on gut and skin microbiomes from four populations of Pyrenean brook salamanders (Calotriton asper) inhabiting two distinct environments (Pyrenean subalpine brooks and Atlantic montane streams). From paired faecal and skin swab samples, we reconstructed 539 and 43 metagenome-assembled genomes (MAGs), respectively, and examined taxonomic composition, metabolic capacity, and microdiversity across environments. While alpha diversity remained consistent, both gut and skin microbiomes exhibited significant differences in community composition and functional potential between environments. Partitioning the gut microbiome into core, endemic, and marginal fractions revealed a dominant core community--shared across environments and accounting for over 85% of reads--that did not drive functional divergence. Instead, functional differences were primarily shaped by low-abundance, population-specific endemic bacteria. Atlantic salamanders hosted endemic taxa with significantly greater metabolic potential and higher strain-level microdiversity than those at the Pyrenees. These patterns were not explained by dietary differences and may reflect environmental influences such as temperature and nutrient availability. Our findings highlight the relevance of rare, endemic bacteria in driving microbiome function and underscore the power of genome-resolved metagenomics to uncover functional and evolutionary dynamics in wild host-microbe systems.

microbiology↗

bioRxiv2025

The interaction between aging and DNA damage influences the accumulation of APP in Alzheimer's disease

DNA damage is a major driver of the aging process, and the progression of Alzheimers disease (AD) worsens the situation. Neurons of the AD brain show significantly elevated levels of DNA damage compared to controls. AD is also associated with altered processing of the amyloid precursor protein (APP), best known for its A{beta} proteolytic peptide fragment. In the current work we find that these three elements - age, DNA damage, and APP - are associated with each other. We present evidence from the mouse brain supporting the hypothesis that DNA damage drives increased levels of APP. Using the TUNEL reaction to track DNA damage, we show that TUNEL staining increases significantly with age (6 months to 24 months, 8 females and 14 males total in this study), in lockstep with intracellular APP. To separate correlation from causality we analyzed tissue from mice genetically deficient in ATM (ataxia-telangiectasia mutated), a protein kinase that promotes DNA damage repair. Compared to 6-month wild type mice, the increased TUNEL signal in neurons of 6-month Atm-/- animals was equivalent to that seen in 24-month wild type. Significantly, the APP signal in the Atm-/- cells was also increased, and this correlation was found in both neuronal and non-neuronal cells. These results suggest that the loss of genomic integrity associated with aging is a cellular stressor that increases the levels of APP and thus increases vulnerability to the pathogenesis of AD. SIGNIFICANCE STATEMENTOur work links the genetics of Alzheimers disease (dominant disease-causing mutations in the APP gene) with DNA damage and aging - two factors known as risk factors in AD. The evidence suggests that the enhanced DNA damage associated with the normal aging process, increases the levels of APP thus potentially contributing to A{beta} production and plaque formation.

neuroscience↗

bioRxiv2024

Gaze when walking to grasp an object in the presence of obstacles

People generally look at positions that are important for their current actions, such as objects they intend to grasp. What if there are obstacles on their path to such objects? We asked participants to walk into a room and pour the contents of a cup placed on a table into another cup elsewhere on the table. There were two small obstacles on the floor between the door and the table. There was a third obstacle on the table near the target cup. Participants mainly looked at the items on the table, but as they approached and entered the room they often looked at the floor near the obstacles, although there was nothing particularly informative to see there. They relied on peripheral vision and memory of where they had seen obstacles to avoid kicking the obstacles. From well before participants crossed the obstacles, they primarily looked at the object that they intended to grasp. We conclude that people look at positions at which they plan to interact with the environment in a specific manner, rather than at items that constrain such interactions.

neuroscience↗

bioRxiv2024

Integrative genomics approach identifies glial transcriptomic dysregulation and risk in the cortex of individuals with Alcohol Use Disorder

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disorder that is a major global health concern, affecting millions of people worldwide. Past molecular studies of AUD used underpowered single cell analysis or bulk homogenates of postmortem brain tissue, which obscures gene expression changes in specific cell types. Here we performed single nuclei RNA-sequencing analysis of 73 post-mortem samples from individuals with AUD (N=36, Nnuclei= 248,873) and neurotypical controls (N=37, Nnuclei= 210,573) in both sexes across two institutional sites. We identified 32 clusters and found widespread cell type-specific transcriptomic changes across the cortex in AUD, particularly affecting glia. We found the greatest dysregulation in novel microglial and astrocytic subtypes that accounted for the majority of differential gene expression and co-expression modules linked to AUD. Analysis for cell type-specific enrichment of aggregate genetic risk for AUD identified subtypes of microglia and astrocytes as potential key players not only affected by but causally linked to the progression of AUD. These results highlight the importance of cell-type specific molecular changes in AUD and offer opportunities to identify novel targets for treatment.

neuroscience↗

bioRxiv2020

Girding the loins? Direct evidence of the use of a medieval parchment birthing girdle from biomolecular analysis

In this paper we describe a dry non-invasive extraction method to detect palaeoproteomic evidence from stained manuscripts. The manuscript analysed in this study is a medieval parchment birth girdle (Wellcome Collection Western MS. 632) made in England and thought to be used by pregnant women while giving birth. Using a dry non-invasive sampling method we were able to extract both human and non-human peptides from the stains, including evidence for the use of honey, cereals, ovicaprine milk and legumes. In addition, a large number of human peptides were detected on the birth roll, many of which are found in cervico-vaginal fluid. This suggests that the birth roll was actively used during childbirth. This study is the first to extract and analyse non-collagenous peptides from a parchment document using a dry non-invasive sampling method and demonstrates the potential of this type of analysis for stained manuscripts, providing direct biomolecular evidence for active use.

molecular biology↗

bioRxiv2020

Integrating multimodal data sets into a mathematical framework to describe and predict therapeutic resistance in cancer

A significant challenge in the field of biomedicine is the development of methods to integrate the multitude of dispersed data sets into comprehensive frameworks to be used to generate optimal clinical decisions. Recent technological advances in single cell analysis allow for high-dimensional molecular characterization of cells and populations, but to date, few mathematical models have attempted to integrate measurements from the single cell scale with other data types. Here, we present a framework that actionizes static outputs from a machine learning model and leverages these as measurements of state variables in a dynamic mechanistic model of treatment response. We apply this framework to breast cancer cells to integrate single cell transcriptomic data with longitudinal population-size data. We demonstrate that the explicit inclusion of the transcriptomic information in the parameter estimation is critical for identification of the model parameters and enables accurate prediction of new treatment regimens. Inclusion of the transcriptomic data improves predictive accuracy in new treatment response dynamics with a concordance correlation coefficient (CCC) of 0.89 compared to a prediction accuracy of CCC = 0.79 without integration of the single cell RNA sequencing (scRNA-seq) data directly into the model calibration. To the best our knowledge, this is the first work that explicitly integrates single cell clonally-resolved transcriptome datasets with longitudinal treatment response data into a mechanistic mathematical model of drug resistance dynamics. We anticipate this approach to be a first step that demonstrates the feasibility of incorporating multimodal data sets into identifiable mathematical models to develop optimized treatment regimens from data.

cancer biology↗

bioRxiv2019

Why some size illusions affect grip aperture

There is an extensive literature debating whether perceived size is used to guide grasping. A possible reason for not using judged size is that using judged positions might lead to more precise movements. As this argument does not hold for small objects, and all studies showing an effect of the Ebbinghaus illusion on grasping used small objects, we hypothesized that size information is used for small objects but not for large ones. Using a modified diagonal illusion, we obtained an effect of about 10% on perceptual judgements, without an effect on grasping, irrespective of object size. We therefore reject our precision hypothesis. We discuss the results in the framework of grasping as moving digits to positions on an object. We conclude that the reported disagreement on the effect of illusions is because the Ebbinghaus illusion not only affects size, but -unlike most size illusions- also affects perceived positions.

neuroscience↗

bioRxiv2019

Single cell transcriptome profiling of the human alcohol-dependent brain

BackgroundAlcoholism remains a prevalent health concern throughout the world. Previous studies have identified transcriptomic patterns in the brain associated with alcohol dependence in both humans and animal models. But none of these studies have systematically investigated expression within the unique cell types present in the brain.\n\nResultsWe utilized single nucleus RNA sequencing (snRNA-seq) to examine the transcriptomes of over 16,000 nuclei isolated from prefrontal cortex of alcoholic and control individuals. Each nucleus was assigned to one of seven major cell types by unsupervised clustering. Cell type enrichment patterns varied greatly among neuroinflammatory-related genes, which are known to play roles in alcohol dependence and neurodegeneration. Differential expression analysis identified cell type-specific genes with altered expression in alcoholics. The largest number of differentially expressed genes (DEGs), including both protein-coding and non-coding, were detected in astrocytes, oligodendrocytes, and microglia.\n\nConclusionsTo our knowledge, this is the first single cell transcriptome analysis of alcohol-associated gene expression in any species, and the first such analysis in humans for any addictive substance. These findings greatly advance understanding of transcriptomic changes in the brain of alcohol-dependent individuals.

neuroscience↗

bioRxiv2019

Expressed barcodes enable clonal characterization of chemotherapeutic responses in chronic lymphocytic leukemia

The remarkable evolutionary capacity of cancer is a major challenge to current therapeutic efforts. Fueling this evolution is its vast clonal heterogeneity and ability to adapt to diverse selective pressures. Although the genetic and transcriptional mechanisms underlying these responses have been independently evaluated, the ability to couple genetic alterations present within individual clones to their respective transcriptional or functional outputs has been lacking in the field. To this end, we developed a high-complexity expressed barcode library that integrates DNA barcoding with single-cell RNA sequencing through use of the CROP-seq sgRNA expression/capture system, and which is compatible with the COLBERT clonal isolation workflow for subsequent genomic and epigenomic characterization of specific clones of interest. We applied this approach to study chronic lymphocytic leukemia (CLL), a mature B cell malignancy notable for its genetic and transcriptomic heterogeneity and variable disease course. Here, we demonstrate the clonal composition and gene expression states of HG3, a CLL cell line harboring the common alteration del(13q), in response to front-line cytotoxic therapy of fludarabine and mafosfamide (an analog of the clinically used cyclophosphamide). Analysis of clonal abundance and clonally-resolved single-cell RNA sequencing revealed that only a small fraction of clones consistently survived therapy. These rare highly drug tolerant clones comprise 94% of the post-treatment population and share a stable, pre-existing gene expression state characterized by upregulation of CXCR4 and WNT signaling and a number of DNA damage and cell survival genes. Taken together, these data demonstrate at unprecedented resolution the diverse clonal characteristics and therapeutic responses of a heterogeneous cancer cell population. Further, this approach provides a template for the high-resolution study of thousands of clones and the respective gene expression states underlying their response to therapy.

cancer biology↗