Biology subjects

Bowers, J.

Publications and source records attributed to Bowers, J..

6 recordsLinked to original sources

bioRxiv2026

Targeted editing of pericentromeric satellite DNA alters sensitivity to meiotic drive

Eukaryotic genomes are abundant in satellite DNA (satDNA): large blocks of tandemly-repeated sequences that accumulate in heterochromatic genome regions. SatDNAs are dynamic in their genomic location and abundance across species. Some satDNAs overlap essential genome regions such as centromeres and telomeres, but even pericentromeric satDNA can have effects on phenotypes, raising questions about their functional significance. However, it remains unclear whether these effects depend on satDNA sequence, copy number, higher-order structural organization, or genomic context. The highly repetitive nature of satDNA arrays has long hindered detailed genomic and genetic analyses. Recent advances in long-read sequencing now facilitate both the detailed characterization of satDNA structure and the development of more targeted approaches to genetic analysis. Here we present a sequential CRISPR/Cas9-based strategy to make mutations in satDNA arrays and demonstrate its utility using an autosomal pericentromeric satDNA in Drosophila melanogaster called Responder (Rsp). Rsp is the target of a sperm-killing male meiotic driver, Segregation Distorter (SD), where sensitivity to sperm killing positively correlates with Rsp copy number. Using our CRISPR/Cas9 approach, we generated an allelic series of Rsp deletion and expansion variants in two genetic backgrounds and examined their effects on spermatogenesis. Our approach produced precise satDNA variants efficiently, with minimal detectable off-target effects. The resulting mutations affect sensitivity to SD that scale with Rsp copy number. This work establishes a new framework for experimentally dissecting satDNA function and provides insights into the evolutionary and functional roles of satDNA in genome organization.

genetics↗

bioRxiv2022

The pitfalls of measuring representational similarityusing representational similarity analysis

Representational Similarity Analysis (RSA) is an innovative approach used to compare neural representations across individuals, species and computational models. Despite its popularity within neuroscience, psychology and artificial intelligence, this approach has led to difficult-to-reconcile and contradictory findings, particularly when comparing primate visual representations with deep neural networks (DNNs). Here, we demonstrate how such contradictory findings could arise due to incorrect inferences about mechanism when comparing complex systems processing high-dimensional stimuli. In a series of studies comparing computational models, primate cortex and human cortex we find two problematic phenomena: a "mimic effect", where confounds in stimuli can lead to high RSA-scores between provably dissimilar systems, and a "modulation effect", where RSA- scores become dependent on stimuli used for testing. Since our results bear on a number of influential findings, we provide recommendations to avoid these pitfalls and sketch a way forward to a more solid science of representation in cognitive systems.

neuroscience↗

bioRxiv2021

Can deep convolutional neural networks support relational reasoning in the same-different task?

Same-different visual reasoning is a basic skill central to abstract combinatorial thought. This fact has lead neural networks researchers to test same-different classification on deep convolutional neural networks (DCNNs), which has resulted in a controversy regarding whether this skill is within the capacity of these models. However, most tests of same-different classification rely on testing on images that come from the same pixel-level distribution as the testing images, yielding the results inconclusive. In this study we tested relational same-different reasoning DCNNs. In a series of simulations we show that models based on the ResNet-50 architecture are capable of visual same-different classification, but only when the test images are similar to the training images at the pixel-level. In contrast, even when there are only subtle differences between the testing and training images, the performance of DCNNs drops substantially. This is true even when DCNNs training regime is augmented with images from new versions of the same-different task or through multi-task learning on the test images. Furthermore, we show that the Relation Network, a deep learning architecture specifically designed to tackle visual relational reasoning problems, suffers the same kind of limitations than ResNet-50 classifiers.

animal behavior and cognition↗

bioRxiv2020

What do adversarial images tell us about human vision?

Deep convolutional neural networks (DCNNs) are frequently described as promising models of human and primate vision. An obvious challenge to this claim is the existence of adversarial images that fool DCNNs but are uninterpretable to humans. However, recent research has suggested that there may be similarities in how humans and DCNNs interpret these seemingly nonsense images. In this study, we reanalysed data from a high-profile paper and conducted four experiments controlling for different ways in which these images can be generated and selected. We show that agreement between humans and DCNNs is much weaker and more variable than previously reported, and that the weak agreement is contingent on the choice of adversarial images and the design of the experiment. Indeed, it is easy to generate images with no agreement. We conclude that adversarial images still challenge the claim that DCNNs constitute promising models of human and primate vision.

neuroscience↗

bioRxiv2020

Dual blockade of IL-6 and CTLA-4 regresses pancreatic tumors in a CD4+ T cell-dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) is exceptionally resistant to immune checkpoint inhibition (ICI). We previously reported that elevated systemic interleukin-6 (IL-6) and increased numbers of T cells positive for circulating cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) correlate with worse overall survival in patients with PDAC. We postulated that combined blockade of IL-6 and CTLA-4 would significantly enhance anti-tumor immune responses to PDAC. Dual blockade of IL-6 and CTLA-4 in immune competent mice bearing subcutaneously injected pancreatic tumors significantly inhibited tumor growth, accompanied by overwhelming T cell infiltration. Therapeutic efficacy was confirmed in an orthotopic murine model of pancreatic cancer and T cell depletion studies unveiled a unique dependence on CD4+ T cells for anti-tumor activity of dual IL-6 and CTLA-4 blockade. In vitro studies utilizing T cells from a TRP-1 transgenic mouse as an antigen-specific model system demonstrate this combination therapy elicits increased IFN-{gamma} production by activated CD4+ T cells. Additionally, IFN-{gamma} stimulation of pancreatic tumor cells in vitro profoundly increased tumor cell production of CXCR3 specific chemokines (CXCL10 and CXCL9). Further studies blocking CXCR3 in the presence of combined IL-6 and CTLA-4 blockade prevented orthotopic tumor regression, demonstrating a dependence on the CXCR3 axis for anti-tumor efficacy. We also found combination therapy increased intratumoral CD4+ T cells and elicited systemic changes in T-helper subsets. These data represent the first report of IL-6 and CTLA-4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy. Given these results, this therapeutic combination has potential for immediate clinical translation. One Sentence SummaryBlockade of interleukin-6 in pancreatic cancer enhances CTLA-4 immune checkpoint inhibition to regress tumors in a CD4+ T cell and CXCR3-dependent manner.

cancer biology↗

bioRxiv2018

Reduced central and peripheral inflammatory responses and increased mitochondrial activity contribute to diet-induced obesity resistance in WSB/EiJ mice.

ObjectivesEnergy balance disruption due to excess of calorie-rich food is considered to be one of the major players in the current worldwide obesity pandemic. In rodents, a high fat diet (HFD) induces not only obesity, but also inflammation and mitochondrial dysfunctions. To identify factors underlying diet-induced obesity (DIO) resistance we compared the wild-derived mouse strain WSB/EiJ, characterized by a striking resistance to DIO, with the more DIO-sensitive C57BL/6J strain.\n\nMethodsWe analysed circulating levels of lipids, cytokines and adipokines as well as hypothalamic markers of inflammatory status and mitochondrial activity in both strains exposed to HFD for three days (3d) or eight weeks (8wk). To identify hypothalamic genes potentially involved in these differential regulations, we selected 86 genes related to inflammation and mitochondrial pathways. We analysed their expression levels by high throughput microfluidic qPCR on RNA extracted from laser micro-dissected arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei of the two strains of mice, under the different HFD treatments.\n\nResultsAfter 3d and 8wk HFD, C57BL/6J mice, in contrast to WSB/EiJ, displayed significantly increased body weight gain, and also increased circulating levels of leptin, cholesterol, HDL and LDL. WSB/EiJ mice displayed a lower inflammatory status, both peripherally (lower levels of circulating cytokines) and centrally (less activated microglia in the hypothalamus) as well as more reactive mitochondria in the hypothalamus. Principal Component Analysis and gene ontology analysis of gene expression data showed, first, that datasets segregated as a function of strain and second, allowed to identify the metabolic pathways involved. These results were reinforced by the identification of strain-specific differential expression of several individual hypothalamic genes as well as differential effects of HFD between strains.\n\nConclusionsAdaptation to metabolic stress in the DIO-resistant WSB/EiJ strain implicates enhanced lipid metabolism, lower peripheral and hypothalamic inflammatory status and higher mitochondrial activity than in the C57BL/6J strain. These results point to the implication of the hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO.\n\nDeclarations of interest: none\n\nHighlightsO_LIDiet-induced-obesity resistance of WSB/EiJ implicates enhanced lipid metabolism\nC_LIO_LIWSB/EiJ mice are protected from HFD-induced peripheral and central inflammation\nC_LIO_LIEnhanced hypothalamic transport and signalling of endocrine molecules in WSB/EiJ\nC_LIO_LIWSB/EiJ hypothalamic mitochondria dynamics differ from C57BL/6J\nC_LIO_LIDifferential regulation of hypothalamic inflammatory/mitochondria genes in WSB/EiJ\nC_LI

physiology↗