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  • Jo Bowyer
    replied
    Cross platform analysis of transcriptomic data identifies ageing has distinct and opposite effects on tendon in males and females

    https://www.nature.com/articles/s41598-017-14650-z



    New research from the University of Liverpool, published in the journal Scientific Reports, has identified that in tendon ageing has distinct and opposite effects on the genes expressed in males and females.

    Tendons are bundles or bands of strong fibres that attach muscles to bones. Tendons transfer force from the muscle to the bone to produce the movement of joints.

    Tendinopathy is a set of tendon disease that results in the tendons not functioning normally. Its development increases in frequency with age.

    Gene expression

    In this, the first study of its kind, researchers from the University's Institute of Ageing and Chronic Disease, analysed in parallel a number of gene datasets from male and females from two age groups (20-24 and 54-70 years) to identify sex-specific gene expression changes with age.

    Every cell in a human body contains a complete set of chromosomes with every gene needed to make every protein that that organism will ever make. However only a very small fraction of these genes are ever expressed in specific tissues at any one time.

    Each cell is specialised to carry out certain tasks and will only need to express certain genes. Gene expression is the process by which specific genes are activated to produce a required protein.

    Distinct

    The researchers analysed these genes and identified distinct molecular pathways which affect ageing in tendon dependent on gender.

    The results highlight the importance of gender differences which are frequently neglected in gene expression studies.

    Lead researcher Dr Mandy Peffers, said: "Our research highlights the possible need to treat tendon disease differently in males and females because alternative mechanisms may be involved.

    "Our findings could help in the treatment of more bespoke treatments for this large patient group."

    Dr Peffers is funded through a Wellcome Trust Clinical Intermediate fellowship. This work was supported by the MRC and Arthritis Research UK as part of the MRC -- Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing (CIMA).

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  • Jo Bowyer
    replied
    Development of a highly-accurate computational model of human metabolism

    https://www.sciencedaily.com/release...1026135241.htm

    Understanding personal metabolic phenotypes allows us to design effective therapeutic strategies for various chronic and infectious diseases. A human computational model called the genome-scale metabolic model (GEM) contains information on thousands of metabolic genes and their corresponding reactions and metabolites, and has played an important role in predicting metabolic phenotypes. Although several versions of human GEMs have been released, they had room for further development, especially as to incorporating biological information coming from a human genetics mechanism called "alternative splicing." Alternative splicing is a genetic mechanism that allows a gene to give rise to multiple reactions, and is strongly associated with pathology.

    To tackle this problem, Jae Yong Ryu (a Ph.D. student), Dr. Hyun Uk Kim (Research Fellow), and Distinguished Professor Sang Yup Lee, all from the Department of Chemical and Biomolecular Engineering at KAIST, developed a computational framework that systematically generates metabolic reactions, and adds them to the human GEM. The resulting human GEM was demonstrated to accurately predict metabolic phenotypes under varied environmental conditions. The research results were published online in Proceedings of the National Academy of Sciences(PNAS) on October 24, 2017, under the title "Framework and resource for more than 11,000 gene-transcript-protein-reaction associations in human metabolism."

    The research team first updated the biological contents of a previous version of the human GEM. The updated biological contents include metabolic genes and their corresponding metabolites and reactions. In particular, metabolic reactions catalyzed by already-known protein isoforms were additionally incorporated into the human GEM; protein isoforms are multiple variants of proteins generated from individual genes through the alternative splicing process. Each protein isoform is often responsible for the operation of a metabolic reaction. Although multiple protein isoforms generated from one gene can play different functions by having different sets of protein domains and/or subcellular localizations, such information was not properly considered in previous versions of human GEMs.

    Upon the initial update of the human GEM, named Recon 2M.1, the research team subsequently implemented a computational framework that systematically generates information on Gene-Transcript-Protein-Reaction Associations (GeTPRA) in order to identify protein isoforms that were previously not identified. This framework was developed in this study. As a result of the implementation of the framework for GeTPRA, more than 11,000 GeTPRA were automatically predicted, and thoroughly validated. Additional metabolic reactions were then added to Recon 2M.1 based on the predicted GeTPRA for the previously uncharacterized protein isoforms; Recon 2M.1 was renamed Recon 2M.2 from this upgrade. Finally, Recon 2M.2 was integrated with 446 sets of personal biological data (RNA-Seq data) in order to build patient-specific cancer models. These patient-specific cancer models were used to predict cancer metabolism activities and anticancer targets.

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  • Jo Bowyer
    replied
    Clock-dependent and system-driven oscillators interact in the suprachiasmatic nuclei to pace mammalian circadian rhythms


    http://journals.plos.org/plosone/art...l.pone.0187001

    Abstract


    Circadian clocks drive biological rhythms with a period of approximately 24 hours and keep in time with the outside world through daily resetting by environmental cues. While this external entrainment has been extensively investigated in the suprachiasmatic nuclei (SCN), the role of internal systemic rhythms, including daily fluctuations in core temperature or circulating hormones remains debated. Here, we show that lactating mice, which exhibit dampened systemic rhythms, possess normal molecular clockwork but impaired rhythms in both heat shock response gene expression and electrophysiological output in their SCN. This suggests that body rhythms regulate SCN activity downstream of the clock. Mathematical modeling predicts that systemic feedback upon the SCN functions as an internal oscillator that accounts for in vivo and ex vivo observations. Thus we are able to propose a new bottom-up hierarchical organization of circadian timekeeping in mammals, based on the interaction in the SCN between clock-dependent and system-driven oscillators.

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  • Jo Bowyer
    replied
    Navigation System of Brain Cells Decoded

    http://neurosciencenews.com/neural-n...n-system-7808/



    The human brain contains roughly 100 billion neurons. Information among them is transmitted via a complex network of nerve fibers. Hardwiring of most of this network takes place before birth according to a genetic blueprint, that is without external influences playing a role. Researchers of Karlsruhe Institute of Technology (KIT) have now found out more about how the navigation system guiding the axons during growth works. This is reported in eLife.

    Total length of the nerve fiber network in the brain is approximately 500,000 km, more than the distance between the earth and the moon. Growth of the nerve fibers is controlled by a navigation system to prevent incorrect hardwiring. But how exactly do the nerve fibers find their target region during growth? “This is similar to autonomous driving in road traffic,” says Franco Weth of the Cell and Neural Biology Division of the Zoological Institute. Vehicles exchange information with each other and with signal transmitters at the roadside to reach their destination. In case of nerve fibers, sensor molecules at their ends serve as antennas. With them, they receive guiding signals in the form of proteins that are positioned along the way, in the target area, and on other fibers crossing the path. Having arrived at the target, axons form interconnections with other neurons, the synapses.

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  • Jo Bowyer
    replied
    Scientists demonstrate path to linking the genome to healthy tissues, disease

    https://www.sciencedaily.com/release...1016102816.htm

    On Oct. 11, scientists came the closest yet to delivering an answer of "Yes." An international consortium of researchers in the Genotype-Tissue Expression (GTEx) Consortium published findings about how genetic variation effects gene regulation in 44 human tissue types. Reported in the journal Nature, the data help to establish a baseline understanding of the diversity of genetic roles in maintaining human tissues. The researchers said the work demonstrates that, in fact, multi-tissue, multi-individual data can be used to identify the mechanisms of gene regulation and help to study the genetic basis of complex diseases.

    The research that led to these findings is part of a larger effort to better understand gene regulation and expression, carried out by the GTEx Consortium, a National Institutes of Health-funded group that includes researchers from around 80 institutions founded in 2010.

    "The ultimate goal is to understand gene expression and gene regulation in a diversity of tissue types," said Barbara Engelhardt, an assistant professor in the Department of Computer Science at Princeton University, who is one of four corresponding authors of the paper and a GTEx principal investigator. "This is absolutely critical to understanding how dysregulation may lead to disease."

    Scientists are only beginning to reveal, for example, how genetic variation in our 22,000 genes -- as well as "non-coding" regions in the genome -- help to shape complex traits, from a person's height to whether he or she develops autism. Further, scientists seek to understand interactions between multiple genes and the environment. The same unknowns hold true for how genetic variation contributes to disorders such as schizophrenia and Parkinson's disease.

    Teasing apart these complexities first requires characterizing how healthy tissues function, which in turn requires tissue samples. To obtain those samples, GTEx researchers requested consent from family members to collect small pieces of up to 50 different tissues immediately after a donor's death. Samples range from various organs and blood, and include ten brain sub-regions. This work represents data across 449 donors.

    "These types of tissue are incredibly difficult to get from healthy living donors," Engelhardt said. "With endless thanks to the donors, we have these samples as a resource. We can now explain observed relationships between genotype and disease by looking at the effects of the genotypes that lead to higher risk of the disease on gene expression levels in disease-specific tissues, including brain."

    While the research is still ongoing, this latest study represents the largest analysis to date, including over 7,000 tissue samples. Engelhardt's group was responsible for mapping associations between genetic variants and gene expression levels on different chromosomes, a connection known as "trans-expression quantitative trait loci (trans-eQTLS)." In contrast, cis-eQTLs -- which account for the majority of genetic variation that affects gene expression -- regulate genes located nearby on the same chromosome. Trans-eQTLs in particular have proven especially difficult to identify because of their biological and statistical complexity, Engelhardt said, but they might hold clues for explaining complex traits in a more comprehensive way than cis-eQTLs.
    The database is growing.

    The clinical trial of which I'm a member/number has funding for collecting blood saliva and tears from the participants. We have regular gatherings which are just as good as the multidisciplinary meetings I attend as a clinician, they don't give us alcohol though

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  • Jo Bowyer
    commented on 's reply
    2017 Nobel Prize in Physiology or Medicine Awarded to Circadian Rhythm Researchers

    http://neurosciencenews.com/nobel-pr...n-rhythm-7649/

  • Jo Bowyer
    commented on 's reply
    Our muscles measure the time of day

    https://www.sciencedaily.com/release...1002084843.htm

  • Jo Bowyer
    commented on 's reply
    2017 Nobel Prize in Physiology or Medicine: Molecular mechanisms controlling the circadian rhythm

    https://www.sciencedaily.com/release...1002092603.htm

  • Jo Bowyer
    replied
    Timing is everything: U.S. trio earns Nobel for work on the body’s biological clock

    http://www.sciencemag.org/news/2017/...et_cid=1577514

    Leave a comment:


  • Jo Bowyer
    replied
    Transcriptome profiling reveals expression signatures of cranial neural crest cells arising from different axial levels

    https://bmcdevbiol.biomedcentral.com...ource=Teradata


    Abstract

    Background


    Cranial neural crest cells (NCCs) are a unique embryonic cell type which give rise to a diverse array of derivatives extending from neurons and glia through to bone and cartilage. Depending on their point of origin along the antero-posterior axis cranial NCCs are rapidly sorted into distinct migratory streams that give rise to axial specific structures. These migratory streams mirror the underlying segmentation of the brain with NCCs exiting the diencephalon and midbrain following distinct paths compared to those exiting the hindbrain rhombomeres (r). The genetic landscape of cranial NCCs arising at different axial levels remains unknown. Results


    Here we have used RNA sequencing to uncover the transcriptional profiles of mouse cranial NCCs arising at different axial levels. Whole transcriptome analysis identified over 120 transcripts differentially expressed between NCCs arising anterior to r3 (referred to as r1-r2 migratory stream for simplicity) and the r4 migratory stream. Eight of the genes differentially expressed between these populations were validated by RT-PCR with 2 being further validated by in situ hybridisation. We also explored the expression of the Neuropilins (Nrp1and Nrp2) and their co-receptors and show that the A-type Plexins are differentially expressed in different cranial NCC streams. Conclusions


    Our analyses identify a large number of genes differentially regulated between cranial NCCs arising at different axial levels. This data provides a comprehensive description of the genetic landscape driving diversity of distinct cranial NCC streams and provides novel insight into the regulatory networks controlling the formation of specific skeletal elements and the mechanisms promoting migration along different paths.
    Keywords

    Neural crest Fate RNA-seq Neuropilin Cranial neural crest

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  • Jo Bowyer
    replied
    Diversity amongst trigeminal neurons revealed by high throughput single cell sequencing


    http://journals.plos.org/plosone/art...l.pone.0185543

    Introduction


    Somatosensory neurons have cell-bodies in the trigeminal and dorsal root ganglia and respond to a diverse array of thermal, mechanical and chemical stimuli to generate a wide variety of distinct sensations and behavioral responses [1, 2]. These primary sensory neurons differ widely in the morphology of their peripheral and central projections, have a range of axon diameters and conduction velocities and exhibit diverse functional tuning [1, 2]. Many genes have been linked to the detection specificity and response properties of somatosensory neurons. For example, cells expressing the heat sensitive ion channel, Trpv1, are required for normal responses to high temperature [3, 4], whereas those expressing the cool-temperature activated channel, Trpm8, appear dedicated sensors of cold [47]. However, functional imaging experiments have hinted at far greater diversity even within these thermosensory populations [8]. For example, four classes of cooling responsive neurons (including one group that only respond after injury) were very recently identified in recordings from the trigeminal ganglion [8]. Does molecular diversity amongst Trpm8-neurons explain this level of functional variability?
    OK, it's a mouse study, but it's interesting with regards to the trigeminal nerve which may feature in head and neck pain salience.

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  • Jo Bowyer
    replied
    HOW THE BRAIN DEVELOPS BEFORE BIRTH IS TIGHTLY CONTROLLED BY RNA MODIFICATIONS

    http://neurosciencenews.com/rna-brain-development-7608/

    Leave a comment:


  • Jo Bowyer
    replied
    Genes are controlled by 'Nano footballs,' scientists discover

    https://www.sciencedaily.com/release...0925111215.htm



    By placing tiny glowing probes on transcription factors -- special chemicals inside cells which control whether a gene is switched 'on' or 'off' -- researchers gained a remarkable new insight into the way in which genes are controlled.

    Crucially, they discovered that transcription factors operate not as single molecules as was previously thought, but as a spherical football-like cluster of around seven to ten molecules of roughly 30 nanometres in diameter.

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  • Jo Bowyer
    replied
    Identifying novel transcription factors involved in the inflammatory response by using binding site motif scanning in genomic regions defined by histone acetylation


    http://journals.plos.org/plosone/art...l.pone.0184850

    Abstract

    The innate immune response to pathogenic challenge is a complex, multi-staged process involving thousands of genes. While numerous transcription factors that act as master regulators of this response have been identified, the temporal complexity of gene expression changes in response to pathogen-associated molecular pattern receptor stimulation strongly suggest that additional layers of regulation remain to be uncovered. The evolved pathogen response program in mammalian innate immune cells is understood to reflect a compromise between the probability of clearing the infection and the extent of tissue damage and inflammatory sequelae it causes. Because of that, a key challenge to delineating the regulators that control the temporal inflammatory response is that an innate immune regulator that may confer a selective advantage in the wild may be dispensable in the lab setting. In order to better understand the complete transcriptional response of primary macrophages to the bacterial endotoxin lipopolysaccharide (LPS), we designed a method that integrates temporally resolved gene expression and chromatin-accessibility measurements from mouse macrophages. By correlating changes in transcription factor binding site motif enrichment scores, calculated within regions of accessible chromatin, with the average temporal expression profile of a gene cluster, we screened for transcriptional factors that regulate the cluster. We have validated our predictions of LPS-stimulated transcriptional regulators using ChIP-seq data for three transcription factors with experimentally confirmed functions in innate immunity. In addition, we predict a role in the macrophage LPS response for several novel transcription factors that have not previously been implicated in immune responses. This method is applicable to any experimental situation where temporal gene expression and chromatin-accessibility data are available.

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  • Jo Bowyer
    replied
    Migration bound to neurotransmitter

    http://science.sciencemag.org/conten...et_cid=1546016

    Interneurons in the brain that use GABA (γ-aminobutyric acid) as a neurotransmitter are essential for functional circuits. During development, these interneurons migrate tangentially from their birthplace in embryonic ganglionic eminences to their functional homes in the neocortex. In mice lacking the distal-less homeobox genes (Dlx1 and -2), this migration is disrupted. Studying mouse brain development, Le et al.now show that Dlx1 and -2 regulate not only interneuron migration but also production of GABA. These genes bind to and regulate promotors of genes encoding GAD (glutamic acid decarboxylase), which converts the excitatory neurotransmitter glutamate into the inhibitory neurotransmitter GABA.

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