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21:17 EST 18th February 2020 | BioPortfolio

The US National Library of Medicine and National Institutes of Health manage PubMed.gov which comprises of more than 29 million records, papers, reports for biomedical literature, including MEDLINE, life science and medical journals, articles, reviews, reports and  books.

BioPortfolio aims to cross reference relevant information on published papers, clinical trials and news associated with selected topics - speciality.

For example view all recent relevant publications on Epigenetics and associated publications and clincial trials.

Showing PubMed Articles 1–25 of 1,100+ from eLife

Mechanisms of chromosome biorientation and bipolar spindle assembly analyzed by computational modeling.

The essential functions required for mitotic spindle assembly and chromosome biorientation and segregation are not fully understood, despite extensive study. To illuminate the combinations of ingredients most important to align and segregate chromosomes and simultaneously assemble a bipolar spindle, we developed a computational model of fission-yeast mitosis. Robust chromosome biorientation requires progressive restriction of attachment geometry, destabilization of misaligned attachments, and attachment for...

The CHORD protein CHP-1 regulates EGF receptor trafficking and signaling in and human cells.

The intracellular trafficking of growth factor receptors determines the activity of their downstream signaling pathways. Here, we show that he putative HSP-90 co-chaperone CHP-1 acts as a regulator of EGFR trafficking in . Loss of causes the retention of the EGFR in the ER and decreases MAPK signaling. CHP-1 is specifically required for EGFR trafficking, as the localization of other transmembrane receptors is unaltered in mutants, and the inhibition of or other co-chaperones does not affect EGFR localiza...

Energy efficient synaptic plasticity.

Many aspects of the brain's design can be understood as the result of evolutionary drive towards metabolic efficiency. In addition to the energetic costs of neural computation and transmission, experimental evidence indicates that synaptic plasticity is metabolically demanding as well. As synaptic plasticity is crucial for learning, we examine how these metabolic costs enter in learning. We find that when synaptic plasticity rules are naively implemented, training neural networks requires extremely large am...

Paradoxical network excitation by glutamate release from VGluT3 GABAergic interneurons.

In violation of Dale's principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter 3 and cholecystokinin expressing cortical interneurons (CCKVGluT3INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCKVGluT3INT mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and o...

A large-scale resource for tissue-specific CRISPR mutagenesis in .

Genetic screens are powerful tools for the functional annotation of genomes. In the context of multicellular organisms, interrogation of gene function is greatly facilitated by methods that allow spatial and temporal control of gene abrogation. Here, we describe a large-scale transgenic short guide (sg) RNA library for efficient CRISPR-based disruption of specific target genes in a constitutive or conditional manner. The library consists currently of more than 2600 plasmids and 1700 fly lines with a focus o...

Regulation of mRNA translation by a photoriboswitch.

Optogenetic tools have revolutionized the study of receptor-mediated processes, but such tools are lacking for RNA-controlled systems. In particular, light-activated regulatory RNAs are needed for spatiotemporal control of gene expression. To fill this gap, we used selection to isolate a novel riboswitch that selectively binds the isoform of a stiff-stilbene (amino-SS)-a rapidly and reversibly photoisomerizing small molecule. Structural probing revealed that the RNA binds amino-SS about 100-times stronger...

The speed of GTP hydrolysis determines GTP cap size and controls microtubule stability.

Microtubules are cytoskeletal polymers whose function depends on their property to switch between states of growth and shrinkage. Growing microtubules are thought to be stabilized by a GTP cap at their ends. The nature of this cap, however, is still poorly understood. End Binding proteins (EBs) recruit a diverse range of regulators of microtubule function to growing microtubule ends. Whether the EB binding region is identical to the GTP cap is unclear. Using mutated human tubulin with blocked GTP hydrolysis...

Cohesin controls intestinal stem cell identity by maintaining association of Escargot with target promoters.

Intestinal stem cells (ISCs) maintain regenerative capacity of the intestinal epithelium. Their function and activity are regulated by transcriptional changes, yet how such changes are coordinated at the genomic level remains unclear. The Cohesin complex regulates transcription globally by generating topologically-associated DNA domains (TADs) that link promotor regions with distant enhancers. We show here that the Cohesin complex prevents premature differentiation of ISCs into enterocytes (ECs). Depletion...

Stochastic yield catastrophes and robustness in self-assembly.

A guiding principle in self-assembly is that, for high production yield, nucleation of structures must be significantly slower than their growth. However, details of the mechanism that impedes nucleation are broadly considered irrelevant. Here, we analyze self-assembly into finite-sized target structures employing mathematical modeling. We investigate two key scenarios to delay nucleation: (i) by introducing a slow activation step for the assembling constituents and, (ii) by decreasing the dimerization rate...

Loss of flavin adenine dinucleotide (FAD) impairs sperm function and male reproductive advantage in .

Exposure to environmental stress is clinically established to influence male reproductive health, but the impact of normal cellular metabolism on sperm quality is less well-defined. Here we show that impaired mitochondrial proline catabolism, reduces energy-storing flavin adenine dinucleotide (FAD) levels, alters mitochondrial dynamics toward fusion, and leads to age-related loss of sperm quality (size and activity), which diminishes competitive fitness of the animal. Loss of the 1-pyrroline-5-carboxylate d...

Potential impact of outpatient stewardship interventions on antibiotic exposures of common bacterial pathogens.

The relationship between antibiotic stewardship and population levels of antibiotic resistance remains unclear. In order to better understand shifts in selective pressure due to stewardship, we use publicly available data to estimate the effect of changes in prescribing on exposures to frequently used antibiotics experienced by potentially pathogenic bacteria that are asymptomatically colonizing the microbiome. We quantify this impact under four hypothetical stewardship strategies. In one scenario, we estim...

Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation.

T cell expansion and differentiation are critically dependent on the transcription factor c-Myc (Myc). Herein we use quantitative mass-spectrometry to reveal how Myc controls antigen receptor driven cell growth and proteome restructuring in murine T cells. Analysis of copy numbers per cell of >7000 proteins provides new understanding of the selective role of Myc in controlling the protein machinery that govern T cell fate. The data identify both Myc dependent and independent metabolic processes in immune ac...

Defective lytic transglycosylase disrupts cell morphogenesis by hindering cell wall de--acetylation in .

Lytic transglycosylases (LT) are enzymes involved in peptidoglycan (PG) remodeling. However, their contribution to cell wall-modifying complexes and their potential as antimicrobial drug targets remain unclear. Here, we determined a high-resolution structure of the LT, an outer membrane lipoprotein from species with a disordered active site helix (alpha helix 30). We show that deletion of the conserved alpha-helix 30 interferes with the integrity of the cell wall, disrupts cell division, cell separation, a...

Gradients in the mammalian cerebellar cortex enable Fourier-like transformation and improve storing capacity.

Cerebellar granule cells (GCs) make up the majority of all neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs in mice. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs than GCs closer to the Purkinje cell layer (outer-zone GCs). Dynamic Clamp experiments showed that inner- and out...

Opposite changes in APP processing and human aβ levels in rats carrying either a protective or a pathogenic APP mutation.

Cleavage of APP by BACE1/b-secretase initiates the amyloidogenic cascade leading to Amyloid-b (Ab) production. a-Secretase initiates the non-amyloidogenic pathway preventing Ab production. Several mutations cause familial Alzheimer's disease (AD), while the Icelandic mutation near the BACE1-cleavage site protects from sporadic dementia, emphasizing APP's role in dementia pathogenesis. To study APP protective/pathogenic mechanisms, we generated knock-in rats carrying either the protective () or the pathoge...

Ser/Thr kinase Trc controls neurite outgrowth in by modulating microtubule-microtubule sliding.

Correct neuronal development requires tailored neurite outgrowth. Neurite outgrowth is driven in part by microtubule-sliding - the transport of microtubules along each other. We have recently demonstrated that a 'mitotic' kinesin-6 (Pavarotti in ) effectively inhibits microtubule-sliding and neurite outgrowth. However, mechanisms regulating Pavarotti itself in interphase cells and specifically in neurite outgrowth are unknown. Here, we use a combination of live imaging and biochemical methods to show that t...

A Fyn biosensor reveals pulsatile, spatially localized kinase activity and signaling crosstalk in live mammalian cells.

Cell behavior is controlled through spatio-temporally localized protein activity. Despite unique and often contradictory roles played by Src-family-kinases (SFKs) in regulating cell physiology, activity patterns of individual SFKs have remained elusive. Here, we report a biosensor for specifically visualizing active conformation of SFK-Fyn in live cells. We deployed combinatorial library screening to isolate a binding-protein (F29) targeting activated Fyn. Nuclear-magnetic-resonance (NMR) analysis provides ...

Bacterial interspecies interactions modulate pH-mediated antibiotic tolerance.

Predicting antibiotic efficacy within microbial communities remains highly challenging. Interspecies interactions can impact antibiotic activity through many mechanisms, including alterations to bacterial physiology. Here, we studied synthetic communities constructed from the core members of the fruit fly gut microbiota. Co-culturing of with species altered its tolerance to the transcriptional inhibitor rifampin. By measuring key metabolites and environmental pH, we determined that species counter the ac...

Notochord vacuoles absorb compressive bone growth during zebrafish spine formation.

The vertebral column or spine assembles around the notochord rod which contains a core made of large vacuolated cells. Each vacuolated cell possesses a single fluid-filled vacuole, and loss or fragmentation of these vacuoles in zebrafish leads to spine kinking. Here, we identified a mutation in the kinase gene that causes fragmentation of notochord vacuoles and a severe congenital scoliosis-like phenotype in zebrafish. Live imaging revealed that Dstyk regulates fusion of membranes with the vacuole. We fi...

Microtubule plus-end dynamics link wound repair to the innate immune response.

The skin protects animals from infection and physical damage. In C. elegans, wounding the epidermis triggers an immune reaction and a repair response, but it is not clear how these are coordinated. Previous work implicated the microtubule cytoskeleton in the maintenance of epidermal integrity (Chuang et al, 2016). Here, by establishing a simple wounding system, we show that wounding provokes a reorganisation of plasma membrane subdomains. This is followed by recruitment of the microtubule plus end-binding p...

The p75 neurotrophin receptor in AgRP neurons is necessary for homeostatic feeding and food anticipation.

Networks of neurons control feeding and activity patterns by integrating internal metabolic signals of energy balance with external environmental cues such as time-of-day. Proper circadian alignment of feeding behavior is necessary to prevent metabolic disease, and thus it is imperative that molecular players that maintain neuronal coordination of energy homeostasis are identified. Here, we demonstrate that mice lacking the p75 neurotrophin receptor, p75NTR, decrease their feeding and food anticipatory beha...

Distinct roles for innexin gap junctions and hemichannels in mechanosensation.

Mechanosensation is central to a wide range of functions, including tactile and pain perception, hearing, proprioception, and control of blood pressure, but identifying the molecules underlying mechanotransduction has proved challenging. In , the avoidance response to gentle body touch is mediated by 6 touch receptor neurons (TRNs), and is dependent on MEC-4, a DEG/ENaC channel. We show that hemichannels containing the innexin protein UNC-7 are also essential for gentle touch in the TRNs, as well as harsh t...

SIRT6 is a DNA double-strand break sensor.

DNA double strand breaks are the most deleterious type of DNA damage. In this work, we show that SIRT6 directly recognizes DNA damage through a tunnel-like structure, with high affinity for double strand breaks. SIRT6 relocates to sites of damage independently of signalling and known sensors. It activates downstream signalling for double strand break repair by triggering ATM recruitment, H2AX phosphorylation and the recruitment of proteins of Homologous Recombination and Non-Homologous End Joining pathways....

Stepwise polarisation of developing bilayered epidermis is mediated by aPKC and E-cadherin in zebrafish.

The epidermis, a multilayered epithelium, surrounds and protects the vertebrate body. It develops from a bilayered epithelium formed of the outer periderm and underlying basal epidermis. How apicobasal polarity is established in the developing epidermis has remained poorly understood. We show that both the periderm and the basal epidermis exhibit polarised distribution of adherens junctions in zebrafish. aPKC, an apical polarity regulator, maintains the robustness of polarisation of E-cadherin- an adherens ...

Human Neocortical Neurosolver (HNN), a new software tool for interpreting the cellular and network origin of human MEG/EEG data.

Magneto- and electro-encephalography (MEG/EEG) non-invasively record human brain activity with millisecond resolution providing reliable markers of healthy and disease states. Relating these macroscopic signals to underlying cellular- and circuit-level generators is a limitation that constrains using MEG/EEG to reveal novel principles of information processing or to translate findings into new therapies for neuropathology. To address this problem, we built Human Neocortical Neurosolver (HNN, https://hnn.bro...


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