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  • #91
    Epigenetic regulation of lateralized fetal spinal gene expression underlies hemispheric asymmetries

    https://elifesciences.org/content/6/e22784

    Abstract
    Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-β signaling pathway and lateralized methylation of CpG islands. Our findings suggest that molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans.



    The Evolution of Lateralized Brain Circuits

    http://journal.frontiersin.org/artic...017.01021/full

    In the vast clade of animals known as the bilateria, cerebral and behavioral asymmetries emerge against the backdrop of bilateral symmetry, with a functional trade-off between the two. Asymmetries can lead to more efficient processing and packaging of internal structures, but at the expense of efficient adaptation to a natural world without systematic left-right bias. Asymmetries may arise through the fissioning of ancestral structures that are largely symmetrical, creating new circuits. In humans these may include asymmetrical adaptations to language and manufacture, and as one or other hemisphere gains dominance for functions that were previously represented bilaterally. This is best illustrated in the evolution of such functions as language and tool manufacture in humans, which may derive from the mirror-neuron system in primates, but similar principles probably apply to the many other asymmetries now evident in a wide range of animals. Asymmetries arise in largely independent manner with multi-genetic sources, rather than as a single over-riding principle.
    Introduction
    Part of the reason for the fascination with handedness and cerebral asymmetry is that they seem to arise from a system that is for the most part structurally symmetrical, suggesting the operation of some non-material force—and perhaps even encouraging a Cartesian notion of mind over matter (Corballis, 1980). Nevertheless lateral asymmetries can scarcely be understood or even defined except in relation to symmetry. Humans belong to the vast clade of animals known as the bilateria, going back some 550 million years, and characterized by near symmetry about the midsagittal plane. This bilateral symmetry makes us almost indistinguishable from our reflection in the mirror, and may be an adaptation to the fact that for freely moving animals, the natural world is essentially indifferent with respect to left and right. So it is that we have limbs and sense organs arranged in bilateral pairs, and even the brain is more obviously symmetrical than it is asymmetrical. You would be hard-pressed to decide whether a picture of the brain is normal or mirror-reversed, although there are a few small give-away signs.

    It is against this fundamentally symmetrical plan that asymmetries sometimes arise, and are of interest. Structural asymmetries are especially evident in the way internal organs are located, with the heart, stomach, and spleen displaced to the left, the liver and gall bladder to the right. Some asymmetries, such as the asymmetrical gallop of a horse, or human preference for one or other hand, are more apparent from function than from structure. This also seems to be true of the human brain, which functions in well-documented asymmetrical ways that are all the more remarkable given its apparent anatomical symmetry.

    The pressure toward asymmetry may have to do, at least in part, with packaging and efficiency, especially in internal structures that are largely independent of external constraints. It would simply be inefficient to pack a suitcase while retaining perfect symmetry of its contents; rather, you fit the contents in to make optimal use of the space. Similarly, an automobile retains external symmetry for efficient movement and maneuverability, while its internal parts are asymmetrically organized. Sheer efficiency may therefore have guided the placement of internal bodily organs such as the stomach, which processes food regardless of the manner of its arrival—or its departure. The heart, too, functions internally and is asymmetrical, but retains a degree of symmetry because it must pump blood to both sides of the body.

    There is greater pressure for the retention of symmetry in the brain than in the internal organs of the body, because it is involved in coordination of symmetrical actions such as walking or swimming, and the processing of input from symmetrical sense organs. As the brain increases in size and complexity, though, there would be increased demand for asymmetrical packaging, and this pressure would be enhanced by constraints on the size of the skull. This is especially true of bipedal animals, since the demands of upright walking constrains the size of the birth canal, which in turn restricts the size of the head. These constraints conflict with heightened demands for cognitive processing, especially in animals such as humans where survival depends on complex social interactions and the manufacture of tools and habitable environments. In humans, these competing pressures create what has been termed the “obstetrical dilemma,” a hypothesis to explain why childbirth is so difficult, and leads to dangerously early birth normally requiring assistance (Washburn, 1960)—yet we need large brains to cope with the complexities of our lives on the planet. The pressure for larger brains in a constrained skull can also explain why the human brain is exceptionally wrinkled and folded, like an old automobile crushed for infill. The same conflict might also explain why asymmetry seems especially pronounced in the human brain, since reducing redundancy and duplication makes better use of the restricted brain space.
    Update 17/06/2017
    Last edited by Jo Bowyer; 17-06-2017, 03:04 PM.
    Jo Bowyer
    Chartered Physiotherapist Registered Osteopath.
    "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

    Comment


    • #92
      Chronic pain, depression and cardiovascular disease linked through a shared genetic predisposition: Analysis of a family-based cohort and twin study

      http://journals.plos.org/plosone/art...l.pone.0170653

      Abstract

      Background

      Depression and chronic pain are the two most important causes of disability (Global Burden of Disease Study 2013). They occur together more frequently than expected and both conditions have been shown to be co-morbid with cardiovascular disease. Although shared socio-demographic risk factors (e.g. gender, deprivation) might explain the co-morbidity of these three conditions, we hypothesised that these three long-term, highly prevalent conditions co-occur and may be due to shared familial risk, and/or genetic factors.

      Methods and findings

      We employed three different study designs in two independent cohorts, namely Generation Scotland and TwinsUK, having standardised, validated questionnaire data on the three traits of interest. First, we estimated the prevalence and co-occurrence of chronic pain, depression and angina among 24,024 participants of a population-based cohort of extended families (Generation Scotland: Scottish Family Health Study), adjusting for age, gender, education, smoking status, and deprivation. Secondly, we compared the odds of co-morbidity in sibling-pairs with the odds in unrelated individuals for the three conditions in the same cohort. Lastly, examination of similar traits in a sample of female twins (TwinsUK, n = 2,902), adjusting for age and BMI, allowed independent replication of the findings and exploration of the influence of additive genetic (A) factors and shared (C) and non-shared (E) environmental factors predisposing to co-occurring chronic widespread pain (CWP) and cardiovascular disease (hypertension, angina, stroke, heart attack, elevated cholesterol, angioplasty or bypass surgery). In the Generation Scotland cohort, individuals with depression were more than twice as likely to have chronic pain as those without depression (adjusted OR 2·64 [95% CI 2·34–2·97]); those with angina were four times more likely to have chronic pain (OR 4·19 [3·64–4·82]); those with depression were twice as likely to have angina (OR 2·20 [1·90–2·54]). Similar odds were obtained when the outcomes and predictors were reversed and similar effects seen among sibling pairs; depression in one sibling predicted chronic pain in the other (OR 1·34 [1·05–1·71]), angina predicted chronic pain in the other (OR 2·19 [1·63–2·95]), and depression, angina (OR 1·98 [1·49–2·65]). Individuals with chronic pain and angina showed almost four-fold greater odds of depression compared with those manifesting neither trait (OR 3·78 [2·99–4·78]); angina showed seven-fold increased odds in the presence of chronic pain and depression (OR 7·76 [6·05–9·95]) and chronic pain nine-fold in the presence of depression and angina (OR 9·43 [6·85–12·98]). In TwinsUK, the relationship between CWP and depression has been published (R = 0.34, p<0.01). Considering the CWP-cardiovascular relationship, the most suitable model to describe the observed data was a combination of A, C and E, with a small but significant genetic predisposition, shared between the two traits (2·2% [95% CI 0·06–0·23]).

      Conclusion

      We found an increased co-occurrence of chronic pain, depression and cardiovascular disease in two independent cohorts (general population-based cohort, twins cohort) suggesting a shared genetic contribution. Adjustment for known environmental influences, particularly those relating to socio-economic status (Generation Scotland: age, gender, deprivation, smoking, education; Twins UK: age,BMI) did not explain the relationship observed between chronic pain, depression and cardiovascular disease. Our findings from two independent cohorts challenge the concept of traditional disease boundaries and warrant further investigation of shared biological mechanisms.
      Jo Bowyer
      Chartered Physiotherapist Registered Osteopath.
      "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

      Comment


      • #93
        Impacts of Neanderthal-Introgressed Sequences on the Landscape of Human Gene Expression

        http://www.cell.com/cell/fulltext/S0092-8674(17)30128-9

        Highlights
        •We devised a flexible method to quantify allele-specific expression across samples

        One-quarter of Neanderthal-introgressed haplotypes show cis-regulatory effects

        •Introgressed regulatory variants add to genomic complexity and phenotypic diversity

        •Neanderthal alleles are downregulated in genes expressed in the brain and testes
        Summary
        Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes.

        Neanderthal-Derived Genetic Variation Shapes Modern Human Cranium and Brain

        https://www.nature.com/articles/s41598-017-06587-0 Abstract

        Before their disappearance from the fossil record approximately 40,000 years ago, Neanderthals, the ancient hominin lineage most closely related to modern humans, interbred with ancestors of present-day humans. The legacy of this gene flow persists through Neanderthal-derived variants that survive in modern human DNA; however, the neural implications of this inheritance are uncertain. Here, using MRI in a large cohort of healthy individuals of European-descent, we show that the amount of Neanderthal-originating polymorphism carried in living humans is related to cranial and brain morphology. First, as a validation of our approach, we demonstrate that a greater load of Neanderthal-derived genetic variants (higher “NeanderScore”) is associated with skull shapes resembling those of known Neanderthal cranial remains, particularly in occipital and parietal bones. Next, we demonstrate convergent NeanderScore-related findings in the brain (measured by gray- and white-matter volume, sulcal depth, and gyrification index) that localize to the visual cortex and intraparietal sulcus. This work provides insights into ancestral human neurobiology and suggests that Neanderthal-derived genetic variation is neurologically functional in the contemporary population.
        Update 27/07/2017
        Last edited by Jo Bowyer; 27-07-2017, 01:26 PM.
        Jo Bowyer
        Chartered Physiotherapist Registered Osteopath.
        "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

        Comment


        • #94
          Fat mass and obesity associated (FTO) gene influences skeletal muscle phenotypes in non-resistance trained males and elite rugby playing position

          https://bmcgenet.biomedcentral.com/a...ource=Teradata

          Abstract

          Background
          FTO gene variants have been associated with obesity phenotypes in sedentary and obese populations, but rarely with skeletal muscle and elite athlete phenotypes.

          Methods
          In 1089 participants, comprising 530 elite rugby athletes and 559 non-athletes, DNA was collected and genotyped for the FTO rs9939609 variant using real-time PCR. In a subgroup of non-resistance trained individuals (NT; n = 120), we also assessed structural and functional skeletal muscle phenotypes using dual energy x-ray absorptiometry, ultrasound and isokinetic dynamometry. In a subgroup of rugby athletes (n = 77), we assessed muscle power during a countermovement jump.

          Results
          In NT, TT genotype and T allele carriers had greater total body (4.8% and 4.1%) and total appendicular lean mass (LM; 3.0% and 2.1%) compared to AA genotype, with greater arm LM (0.8%) in T allele carriers and leg LM (2.1%) for TT, compared to AA genotype. Furthermore, the T allele was more common (94%) in selected elite rugby union athletes (back three and centre players) who are most reliant on LM rather than total body mass for success, compared to other rugby athletes (82%; P = 0.01, OR = 3.34) and controls (84%; P = 0.03, OR = 2.88). Accordingly, these athletes had greater peak power relative to body mass than other rugby athletes (14%; P = 2 x 10-6).

          Conclusion
          Collectively, these results suggest that the T allele is associated with increased LM and elite athletic success. This has implications for athletic populations, as well as conditions characterised by low LM such as sarcopenia and cachexia.
          Keywords

          RugbyGene project IRX3 Lean mass

          Environmental lifestyle factors (diet and physical activity) have also been investigated for FTO gene-environment interactions. Risk allele carriers are more likely to choose a high fat diet than protective allele carriers [11, 14, 15]. However, with administration of a high protein diet (25% energy intake) risk allele carriers demonstrated a greater reduction in body mass, fat mass and percentage body fat [16], due to greater appetite suppression than in protective allele carriers [17]. Additionally, physically active risk allele carriers have a 30% reduction in likelihood of becoming obese and have 36% less body fat compared to inactive risk allele carrying individuals [18]. In contrast, data from the HERITAGE Family Study showed that following 20 weeks of endurance training, protective allele carriers exhibited reductions in fat mass three times greater than risk allele homozygotes [19]. Interestingly, when comparing normal weight and obese individuals who participate in sport, no differences in FTO genotype were observed (P = 0.97), which was contrasted by those not participating P = 0.02; [20]. Considering the attenuation of FTO-associated obesity with environmental factors and the greater FTO-associated LM reported in obese populations [9, 12], investigating LM and associated phenotypes in healthy, non-obese, non-resistance trained individuals and habitually trained elite athletes would be worthwhile.
          These data suggest the relevance of the FTO rs9939609 T allele to muscle-related phenotypes and subsequently, athletic success. When considering the possible molecular mechanism from FTO via IRX3 to OLIG2 resulting in greater lifelong motor neuron availability, this may have implications for muscle size-related disorders such as sarcopenia and cachexia.
          Jo Bowyer
          Chartered Physiotherapist Registered Osteopath.
          "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

          Comment


          • #95
            Gene found to cause sudden death in young people

            https://www.sciencedaily.com/release...0309150637.htm

            A new gene that can lead to sudden death among young people and athletes has now been identified by an international team of researchers. The gene, called CDH2, causes arrhythmogenic right ventricle cardiomyopathy (ARVC), which is a genetic disorder that predisposes patients to cardiac arrest and is a major cause of unexpected death in seemingly healthy young people.
            Jo Bowyer
            Chartered Physiotherapist Registered Osteopath.
            "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

            Comment


            • #96
              War in the womb

              https://aeon.co/essays/why-pregnancy...cd029-69418129

              A ferocious biological struggle between mother and baby belies any sentimental ideas we might have about pregnancy
              Jo Bowyer
              Chartered Physiotherapist Registered Osteopath.
              "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

              Comment


              • #97
                Pain in the Neck: Using CRISPR to Prevent Tissue Damage and Neck Pain

                http://neurosciencenews.com/crispr-neck-pain-6241/

                Summary:
                Researchers use CRISPR to modulate genes in order to reduce tissue damage and inflammation for people with neck and back pain.
                Jo Bowyer
                Chartered Physiotherapist Registered Osteopath.
                "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                Comment


                • #98
                  Have you seen this:
                  intrauterine cannibalism
                  (of sharks)
                  Marcel

                  "Evolution is a tinkerer not an engineer" F.Jacob
                  "Without imperfection neither you nor I would exist" Stephen Hawking

                  Comment


                  • #99
                    Yeurch!!!!!!..........but at the same time amazing!
                    Jo Bowyer
                    Chartered Physiotherapist Registered Osteopath.
                    "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                    Comment


                    • FROM SKIN TO BRAIN: STEM CELLS WITHOUT GENETIC MODIFICATION

                      http://neurosciencenews.com/stem-cel...fication-6248/

                      Stem cells have been derived from adult cells before, but not without adding genes to alter the cells. The new process yields neural crest cells without addition of foreign genetic material. The reprogrammed neural crest cells can become smooth muscle cells, melanocytes, Schwann cells or neurons.
                      Jo Bowyer
                      Chartered Physiotherapist Registered Osteopath.
                      "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                      Comment


                      • Human evolution is more a muddy delta than a branching tree


                        https://aeon.co/ideas/human-evolutio...6e0dc-69418129

                        Until recently, anthropologists drew the human family tree in the same way that my 10-year-old son solves a maze. He finds it much easier to work from the end to the beginning, because blind alleys lead with depressing sameness away from the start. In just this way, scientists once traced our own lineage from the present into the past, moving backward through a thicket of fossil relatives, each perched upon its own special branch to extinction.

                        This approach yielded the now-ubiquitous image of the human family tree, with Homo sapiens – the one and only living hominid – sitting alone, seemingly inevitable, at the top. It’s a powerful metaphor, but it also turns out to be a deeply mistaken one. Where once we saw each branch in isolation, DNA evidence now reveals a network of connections. From an African origin more than 1.8 million years ago, human ancestors flowed into different populations, following separate paths for hundreds of thousands of years, yet still coming together to mix their genes.

                        The recovery of ancient DNA from ancient hominins, first by Svante Pääbo’s research group at the Max Planck Institute in Leipzig and later by others, has started to bring unknown populations into view. Neanderthals provided a proof of principle, showing the recovery of whole-genome evidence from small fragments.
                        Once geneticists knew what to look for, they began documenting more such lineages from the scattered traces of their genes in living people, even without DNA from ancient bones. Geneticists began to call these ‘ghost populations’, and quickly showed that many Africans, too, carry a legacy of unknown populations.

                        Even ancient genomes have ghosts within them. The Denisovan genome bears the traces of ancient mixture, not only from Neanderthals but with another even more divergent group – some speculate it might have been Homo erectus. Everywhere geneticists look, they see populations more different than any living people, mixing with each other in small fractions. It is no evolutionary tree. Our evolutionary history is like a braided stream.


                        Human spit contains ancestral surprises

                        http://science.sciencemag.org/conten...
                        Last edited by Jo Bowyer; 19-08-2017, 02:26 PM.
                        Jo Bowyer
                        Chartered Physiotherapist Registered Osteopath.
                        "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                        Comment


                        • Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors


                          http://journals.plos.org/plosone/art...l.pone.0181556


                          Abstract

                          Objective


                          Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown.

                          Methods


                          To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating) to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating.

                          Results


                          An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p<0.0001) for genes involved in neuropeptide/neurotrophic pathways implicated in appetite regulation, including neurotensin-, glucagon-like peptide 1- and BDNF-signaling. Administration of the glucagon-like peptide 1 receptor agonist exendin-4 significantly reduced food intake in a mouse model of ‘binge-like’ eating.

                          Conclusions


                          These findings implicate ultra-rare and novel damaging variants in neuropeptide/neurotropic factor signaling pathways in the development of eating disorder behaviors and identify glucagon-like peptide 1-receptor agonists as a potential treatment for binge eating.
                          Jo Bowyer
                          Chartered Physiotherapist Registered Osteopath.
                          "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                          Comment


                          • 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.
                            Jo Bowyer
                            Chartered Physiotherapist Registered Osteopath.
                            "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                            Comment


                            • 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.
                              Jo Bowyer
                              Chartered Physiotherapist Registered Osteopath.
                              "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                              Comment


                              • 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.
                                Jo Bowyer
                                Chartered Physiotherapist Registered Osteopath.
                                "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

                                Comment

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