Search results for "APT"

Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer

2016

Background & Aims Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. Methods We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability (CIN); we investigated associations with overall survival time and cancer recurrence using Kaplan–Meier curves. We analyze…

Long-term genomic coevolution of host-parasite interaction in the natural environment

2017

Antagonistic coevolution of parasite infectivity and host resistance may alter the biological functionality of species, yet these dynamics in nature are still poorly understood. Here we show the molecular details of a long-term phage–bacterium arms race in the environment. Bacteria (Flavobacterium columnare) are generally resistant to phages from the past and susceptible to phages isolated in years after bacterial isolation. Bacterial resistance selects for increased phage infectivity and host range, which is also associated with expansion of phage genome size. We identified two CRISPR loci in the bacterial host: a type II-C locus and a type VI-B locus. While maintaining a core set of conse…

2018

Abstract To function properly, organisms must adjust their physiology, behavior and metabolism in response to a suite of varying environmental conditions. One of the central regulators of these changes is organisms’ internal circadian clock, and recent evidence has suggested that the clock genes are also important in the regulation of seasonal adjustments. In particular, thermosensitive splicing of the core clock gene timeless in a cosmopolitan fly, Drosophila melanogaster, has implicated this gene to be involved in thermal adaptation. To further investigate this link we examined the splicing of timeless in a northern malt fly species, Drosophila montana, which can withstand much colder cli…

Genome Mutational and Transcriptional Hotspots Are Traps for Duplicated Genes and Sources of Adaptations

2017

Gene duplication generatesnewgeneticmaterial,which has been shownto lead tomajor innovations in unicellular andmulticellular organisms.Awhole-genome duplication occurred in the ancestor of Saccharomyces yeast species but 92%of duplicates returned to single-copy genes shortly after duplication. The persisting duplicated genes in Saccharomyces led to the origin of major metabolic innovations, which have been the source of the unique biotechnological capabilities in the Baker's yeast Saccharomyces cerevisiae. What factors have determined the fate of duplicated genes remains unknown. Here,we report the first demonstration that the local genome mutation and transcription rates determine the fate…

Brain Control of Plasma Cholesterol Involves Polysialic Acid Molecules in the Hypothalamus

2017

IF 3.566; International audience; The polysialic acid (PSA) is a large glycan that is added to cell-surface proteins during their post-translational maturation. In the brain, PSA modulates distances between cells and controls the plasticity of the nervous system. In the hypothalamus, PSA is involved in many aspects of energy balance including food intake, osmoregulation, circadian rhythm, and sleep. In this work, we investigated the role of hypothalamic PSA in the regulation of plasma cholesterol levels and distribution. We report that HFD consumption in mice rapidly increased plasma cholesterol, including VLDL, LDL, and HDL-cholesterol. Although plasma VLDL-cholesterol was normalized withi…

2019

VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved resid…

Transient Confinement of CaV2.1 Ca2+-Channel Splice Variants Shapes Synaptic Short-Term Plasticity

2019

Summary The precision and reliability of synaptic information transfer depend on the molecular organization of voltage-gated calcium channels (VGCCs) within the presynaptic membrane. Alternative splicing of exon 47 affects the C-terminal structure of VGCCs and their affinity to intracellular partners and synaptic vesicles (SVs). We show that hippocampal synapses expressing VGCCs either with exon 47 (CaV2.1+47) or without (CaV2.1Δ47) differ in release probability and short-term plasticity. Tracking single channels revealed transient visits (∼100 ms) of presynaptic VGCCs in nanodomains (∼80 nm) that were controlled by neuronal network activity. Surprisingly, despite harboring prominent bindin…

A study on time discretization and adaptive mesh refinement methods for the simulation of cancer invasion: The urokinase model

2016

In the present work we investigate a model that describes the chemotactically and proteolytically driven tissue invasion by cancer cells. The model is a system of advection-reaction-diffusion equations that takes into account the role of the serine protease urokinase-type plasminogen activator. The analytical and numerical study of such a system constitutes a challenge due to the merging, emerging, and traveling concentrations that the solutions exhibit. Classical numerical methods applied to this system necessitate very fine discretization grids to resolve these dynamics in an accurate way. To reduce the computational cost without sacrificing the accuracy of the solution, we apply adaptive…

A systems-wide understanding of photosynthetic acclimation in algae and higher plants

2017

The ability of phototrophs to colonise different environments relies on robust protection against oxidative stress, a critical requirement for the successful evolutionary transition from water to land. Photosynthetic organisms have developed numerous strategies to adapt their photosynthetic apparatus to changing light conditions in order to optimise their photosynthetic yield, which is crucial for life on Earth to exist. Photosynthetic acclimation is an excellent example of the complexity of biological systems, where highly diverse processes, ranging from electron excitation over protein protonation to enzymatic processes coupling ion gradients with biosynthetic activity, interact on drasti…

New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated acti…

2021

International audience; Purpose: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority.Methods: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC.Results: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-ass…