Biology subjects

Klein, C.

Publications and source records attributed to Klein, C..

7 recordsLinked to original sources

bioRxiv2018

Risky behaviors and Parkinson’s disease: A Mendelian randomization study in up to 1 million study participants

ObjectiveDopaminergic neurotransmission is known to be a potential modulator of risky behaviors including substance abuse, promiscuity, and gambling. Furthermore, observational studies have shown associations between risky behaviors and Parkinsons disease; however, the causal nature of these associations remains unclear. Thus, in this study, we examine causal associations between risky behavior phenotypes on Parkinsons disease using a Mendelian randomization approach.\n\nMethodsWe used two-sample Mendelian randomization to generate unconfounded estimates using summary statistics from two independent, large meta-analyses of genome-wide association studies on risk taking behaviors (n=370,771-939,908) and Parkinsons disease (cases: n=9581, controls: n = 33,245). We used inverse variance weighted as the main method for judging causality.\n\nResultsOur results support a strong protective association between the tendency to smoke and Parkinsons disease (OR=0.714 per log odds of ever smoking; 95% CI=0.568-0.897; p-value=0.0041; Cochran Q test; p-value=0.238; I2 index=6.3%). Furthermore, we observed risk association trends between automobile speed propensity as well as the number of sexual partners and Parkinsons disease after removal of overlapping loci with other risky traits (OR=1.986 for each standard deviation increase in normalized automobile speed propensity; 95% CI=1.215-3.243; p-value=0.0066, OR=1.635 for each standard deviation increase in number of sexual partners; 95% CI=1.165-2.293; p-value=0.0049).\n\nInterpretationThese findings provide support for a causal relationship between general risk tolerance and Parkinsons disease and may provide new insights in the pathogenic mechanisms leading to the development of Parkinsons disease.

genetics↗

bioRxiv2018

The Relationship Between the Cervical Microbiome, HIV Status, and Pre-Cancerous Lesions

Nearly all cervical cancers are causally associated with Human Papillomavirus (HPV). The burden of HPV-associated dysplasias in Sub-Saharan Africa is influenced by HIV. To investigate the role of the bacterial microbiome in cervical dysplasia, cytobrush samples were collected directly from cervical lesions of 144 Tanzanian women. The V4 hypervariable region of the 16S rRNA gene was amplified and deep-sequenced. Alpha diversity metrics; Chao1, PD whole tree, and operational taxonomic Unit (OTU) estimates, displayed significantly higher bacterial richness in HIV positive patients (P = 0.01) than in HIV negative patients. Within HIV positive patients, there was higher bacterial richness in patients with high grade squamous intraepithelial lesions (HSIL; P = 0.13) than those without lesions. The most abundant OTUs associated with high-grade squamous intraepitheilal lesions (HSIL) were Mycoplasmatales, Pseudomonadales, and Staphylococcus. We suggest that a chronic mycoplasma infection of the cervix can contribute to HPV-dependent dysplasia by sustained inflammatory signals.

cancer biology↗

bioRxiv2018

Active fluctuations modulate gene expression in mouse oocytes

In mammals, the nucleus is central in oocytes, not defining the future embryo axis. Nucleus centring depends on an F-actin mediated pressure gradient. In Fmn2-/- oocytes, lacking the F-actin nucleator Formin 2, the nucleus is off-centre and can be centred by re-expressing Formin 2. Here, we addressed the biological significance of nucleus positioning in mammalian oocytes. Using a dedicated computational 3D imaging approach, we observed nuclear architecture alterations in mouse Fmn2-/- oocytes. RNA sequencing of control versus Fmn2-/- oocytes detected 2285 mis-regulated genes. Rescue experiments showed that the process of nuclear positioning impacts nuclear architecture and gene expression. Using signal processing methods coupled to biophysical modelling allowing the extraction of in vivo mechanical properties of the nuclear envelope, we showed that F-actin-mediated activity promotes nuclear envelope shape fluctuations and chromatin motion. We thus propose a mechano-transduction model whereby nucleus positioning via microfilaments modulates oocyte transcriptome, essential for further embryo development.

cell biology↗

bioRxiv2018

Field synopsis and systematic meta-analyses of genetic association studies in isolated dystonia

Background and objectivesDystonia is a genetically complex disease with both monogenic and polygenic causes. For the latter, numerous genetic associations studies have been performed with largely inconsistent results. The aim of this study was to perform a field synopsis including systematic meta-analyses of genetic association studies in isolated dystonia\n\nMethodsFor the field synopsis we systematically screened and scrutinized the published literature using NCBIs PubMed database. For genetic variants with sufficient information in at least two independent datasets, random-effects meta-analyses were performed, including meta-analyses stratified by ethnic descent and dystonia subtypes.\n\nResultsA total of 3,575 articles were identified and scrutinized resulting in the inclusion of 42 independent publications allowing 134 meta-analyses on 45 variants across 17 genes. While our meta-analyses pinpointed several significant association signals with variants in TOR1A, DRD1, and ARSG, no single variant displayed compelling association with dystonia in the available data.\n\nConclusionsOur study provides an up-to-date summary of the status of dystonia genetic association studies. Additional large-scale studies are needed to better understand the genetic causes of isolated dystonia.

neuroscience↗

bioRxiv2017

Atf3 links loss of epithelial polarity to defects in cell differentiation and cytoarchitecture

Interplay between apicobasal cell polarity modules and the cytoskeleton is critical for differentiation and integrity of epithelia. However, this coordination is poorly understood at the level of gene regulation by transcription factors. Here, we establish the Drosophila activating transcription factor 3 (atf3) as a cell polarity response gene acting downstream of the membrane-associated Scribble polarity complex. Loss of the tumor suppressors Scribble or Dlg1 induces atf3 expression via aPKC but independent of Jun-N-terminal kinase (JNK) signaling. Strikingly, removal of Atf3 from Dlg1 deficient cells restores polarized cytoarchitecture, levels and distribution of endosomal trafficking machinery, and differentiation. Conversely, excess Atf3 alters microtubule network, vesicular trafficking and the partition of polarity proteins along the apicobasal axis. Genomic and genetic approaches implicate Atf3 as a regulator of cytoskeleton organization and function, and identify Lamin C as one of its bona fide target genes. By affecting structural features and cell morphology, Atf3 functions in a manner distinct from other transcription factors operating downstream of disrupted cell polarity.\n\nAuthor summaryEpithelial cells form sheets and line both the outside and inside of our body. Their proper development and function require the asymmetric distribution of cellular components from the top to the bottom, known as apicobasal polarization. As loss of polarity hallmarks a majority of cancers in humans understanding how epithelia respond to a collapse of the apicobasal axis is of great interest. Here, we show that in the fruit fly Drosophila melanogaster, the breakdown of epithelial polarity engages Activating transcription factor 3 (Atf3), a protein that directly binds the DNA and regulates gene expression. We demonstrate that many of the pathological consequences of disturbed polarity require Atf3, as its loss in this context results in normalization of cellular architecture, vesicle trafficking and differentiation. Using unbiased genome-wide approaches we identify the genetic program controlled by Atf3 and experimentally verify select candidates. Given the evolutionary conservation of Atf3 between flies and man, we believe that our findings in the Drosophila model will contribute to a better understanding of diseases stemming from compromised epithelial polarity.

genetics↗

bioRxiv2017

DNA-Demethylating Agents enhance cytolytic activity of CD8+ T Cells and anti-tumor immunity

Recent studies have shown that DNA methyltransferase inhibitors (DNMTi) can induce IRF7 activation and Type I/III interferon signaling through dsRNA-mediated viral mimicry in cancer cells. By performing a large pan-cancer analysis using TCGA data, we determined that IRF7 activation is associated with higher CD8+ T cell tumor infiltration and higher cytolytic activity across multiple cancer types. Accordingly, we demonstrate that DNMTi treatment results in increased CD8+ T cell tumor infiltration, enhanced cytolytic activity and CD8+ T cell dependent tumor growth inhibition. Finally, we show that DNMTi triggers a process marked by the induction of viral mimicry directly on CD8+ T cells, leading to activation of dsRNA sensing pathway, and up-regulation of T cell activation markers, effector cytokines, and Granzyme B. Taken together, our findings suggest that dsRNA sensing pathway activation in the immune compartment, through pharmacological DNA demethylation, is a viable strategy for boosting anti-tumor immune response.

cancer biology↗

bioRxiv2017

Decoding The Brain: Neural Representation And The Limits Of Multivariate Pattern Analysis In Cognitive Neuroscience

Since its introduction, multivariate pattern analysis (MVPA), or \"neural decoding\", has transformed the field of cognitive neuroscience. Underlying its influence is a crucial inference, which we call the Decoders Dictum: if information can be decoded from patterns of neural activity, then this provides strong evidence about what information those patterns represent. Although the Dictum is a widely held and well-motivated principle in decoding research, it has received scant philosophical attention. We critically evaluate the Dictum, arguing that it is false: decodability is a poor guide for revealing the content of neural representations. However, we also suggest how the Dictum can be improved on, in order to better justify inferences about neural representation using MVPA.

neuroscience↗