Biology subjects

Dicks, S.

Publications and source records attributed to Dicks, S..

4 recordsLinked to original sources

bioRxiv2026

Genome-scale functional mapping of the mammalian whole brain with in vivo Perturb-seq

Functional genomics studies have provided critical insights into cell type-specific gene regulatory programs, but to date most have been conducted in wild-type tissues or cell cultures. Here, we present a gene expression functional atlas across the mouse brain. We use an enhanced in vivo Perturb-seq platform to analyze transcriptome-wide responses to loss of 1,947 disease-associated genes, profiling over 7.7 million cells spanning major brain regions and neuronal populations. We find striking cell-type-specific essentiality and transcriptional programs and show that closely related disease genes such as two NMDA receptor subunits can drive opposing transcriptional programs. Together, this work reveals insights into the genetics and mechanisms of neurodevelopmental, psychiatric, and neurodegenerative diseases in vivo, paving the way for the design of future genetic medicine.

genomics↗

bioRxiv2020

Canonical TGFβ signaling induces collective invasion in colorectal carcinogenesis through a Snail1- and Zeb1-independent partial EMT

Local invasion is the initial step towards metastasis, the main cause of cancer mortality. In human colorectal cancer (CRC), malignant cells predominantly invade as cohesive collectives, and may undergo partial epithelial-mesenchymal transition (pEMT) at the invasive front. How this particular mode of stromal infiltration is generated is unknown. Here we investigated the impact of oncogenic transformation and the microenvironment on tumor cell invasion using genetically engineered organoids as CRC models. We found that inactivation of the Apc tumor suppressor combined with expression of oncogenic KrasG12D and dominant negative Trp53R172H did not cell-autonomously induce invasion in vitro. However, oncogenic transformation primed organoids for activation of a collective invasion program upon exposure to the prototypical microenvironmental factor TGF{beta}1. Execution of this program co-depended on a permissive extracellular matrix which was further actively remodeled by invading organoids. Although organoids shed some epithelial properties particularly at the invasive edge, TGF{beta}1-stimulated organoids largely maintained epithelial gene expression while additionally implementing a mesenchymal transcription pattern, resulting in a pEMT phenotype that did not progress to a fully mesenchymal state. Induction of this stable pEMT required canonical, Smad4-mediated TGF{beta} signaling, whereas the EMT master regulators Snail1 and Zeb1 were dispensable. Gene expression profiling provided further evidence for pEMT of TGF{beta}1-treated organoids and showed that their transcriptomes resemble those of human poor prognosis CMS4 cancers which likewise exhibit pEMT features. We propose that collective invasion in colorectal carcinogenesis is triggered by microenvironmental stimuli through activation of a novel, transcription-mediated form of non-progressive pEMT independently of classical EMT regulators.

cancer biology↗

bioRxiv2019

Enhancing senior high school student engagement and academic performance using an inclusive and scalable inquiry-based program

The multi-disciplinary nature of science, technology, engineering and math (STEM) careers often renders difficulty for high school students navigating from classroom knowledge to post-secondary pursuits. Discrepancies between the knowledge-based high school learning approach and the experiential approach of undergraduate studies leaves some students disillusioned by STEM. We present Discovery, a semester-long inquiry-focused learning model delivered by STEM graduate students in collaboration with high school educators, in the context of biomedical engineering. Entire classes of high school STEM students representing diverse cultural and socioeconomic backgrounds engaged in iterative, problem-based learning designed to emphasize critical thinking concomitantly within the secondary school and university environments. Assessment of grades and survey data suggested positive impact of this learning model on students STEM pursuits, notably in under-performing cohorts, as well as repeating cohorts that engage in the program on more than one occasion. Discovery presents a scalable platform blurring the divide between secondary and post-secondary learning, providing valuable learning opportunities and capturing cohorts of students that might otherwise be under-engaged in STEM.

scientific communication and education↗

bioRxiv2019

Modulated Zika virus NS1 conjugate offers advantages for accurate detection of Zika virus specific antibody in double antigen binding and Ig capture enzyme immunoassays

The accurate diagnosis and seroprevalence investigations of Zika virus (ZKV) infections remain complex due to cross reactivity with other flaviviruses. Two assay formats, both using labelled Zika virus NS1 antigen as a revealing agent (a double antigen binding assay, DABA, and an immunoglobulin Ig capture assay, IgG capture) were initially developed and compared with the indirect EuroimmunZ assay for the detection of anti-Zika antibody. Of 147 pre-Zika period serum samples, 39 (27%) were reactive in the EuroimmunZ or the DABA assays, 28 sera concordantly so. Such false reactivity was influenced by the serotype of Dengue virus (DV) to which individuals had been exposed to. Thus, of sera from patients undergoing secondary Dengue virus infection of known serotype, 91%, 45% and 28% of Dengue virus serotype 2, 3 and 4 respectively were reactive in one or more of the three assays. A novel method of quenching false sero-reactivity was therefore developed for the DABA and IgG capture assays. Initial addition of a single homologous Dengue virus serotype 3 NS1Ag quench significantly ablated false reactivities in the pre-Zika period sera. An equipotent quadrivalent quench comprising homologous Dengue virus serotypes 1 to 4 NS1Ag was shown to be optimum yet retained sensitivity for the detection of specific anti-Zika antibody. Comparing DABA and IgG capture assays using quenched and unquenched conjugates in comparison with EuroimmunZ early in the course of PCR-confirmed infection indicated that a significant component of the apparent early anti-ZIKA antibody response is likely to be due to a Zika virus-driven anamnestic anti-Dengue virus response. The increased specificity provided by homologous antigen quenching is likely to provide a significant improvement in sero-diagnostics and to be of clinical value.

microbiology↗