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  • Jo Bowyer
    Grabbing a parasite by the tail: Team solves 'jumping gene' mystery

    Like a jungle cat, this parasite sports a long tail. But until now, little was known about what role that tail plays in this dangerous jumping.

    Today, scientists report that without a tail, this parasitic gene can't jump efficiently. The findings could help lead to new strategies for inhibiting the movement of the parasite, called a LINE-1 retrotransposon.

    The research, published in Molecular Cell by a team from the University of Michigan Medical School and the Howard Hughes Medical Institute, answers a key question about how "jumping genes" move to new DNA locations.

    The parasite in question isn't a foreign beast, but rather a piece of DNA that carries its own instructions for making a piece of "rogue" genetic material and two proteins that can help it jump. "Jumping" allows this rogue copy to land anywhere in the DNA of a cell, causing a change called a mutation.

    Jumping LINE-1s -- and other genetic parasites like it -- are responsible for about one in every 250 disease producing mutations in humans. They've been blamed for causing a number of diseases, including hemophilia, Duchenne muscular dystrophy, and cancer. Copies of this parasite litter our DNA, though most of them can no longer jump and cause damage.

    For these reasons, scientists want to understand as much as possible about how this process works. Perhaps someday, this new understanding could help fight the effects of these jumps -- or prevent the parasites from leaping in the first place.

    "Now, we have a mechanism to explain how sequences that comprise one-third of our genome have moved," says John Moran, Ph.D., senior author of the new paper and a longtime U-M and HHMI researcher studying jumping genes. "By understanding how LINE-1 jumps, we can understand how it contributes to disease."

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  • Jo Bowyer
    Complex grammar of the genomic language

    November 9, 2015
    Karolinska Institutet
    The 'grammar' of the human genetic code is more complex than that of even the most intricately constructed spoken languages in the world. The findings explain why the human genome is so difficult to decipher -- and contribute to the further understanding of how genetic differences affect the risk of developing diseases on an individual level.
    The cells in our body have almost identical genomes, but differ from each other because different genes are active (expressed) in different types of cells. Each gene has a regulatory region that contains the instructions controlling when and where the gene is expressed. This gene regulatory code is read by proteins called transcription factors that bind to specific 'DNA words' and either increase or decrease the expression of the associated gene.

    Under the supervision of Professor Jussi Taipale, researchers at Karolinska Institutet have previously identified most of the DNA words recognised by individual transcription factors. However, much like in a natural human language, the DNA words can be joined to form compound words that are read by multiple transcription factors. However, the mechanism by which such compound words are read has not previously been examined. Therefore, in their recent study in Nature, the Taipale team examines the binding preferences of pairs of transcription factors, and systematically maps the compound DNA words they bind to.

    Their analysis reveals that the grammar of the genetic code is much more complex than that of even the most complex human languages. Instead of simply joining two words together by deleting a space, the individual words that are joined together in compound DNA words are altered, leading to a large number of completely new words.

    "Our study identified many such words, increasing the understanding of how genes are regulated both in normal development and cancer," says Arttu Jolma. "The results pave the way for cracking the genetic code that controls the expression of genes. "

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  • Jo Bowyer
    Multi-Scale Molecular Deconstruction of the Serotonin Neuron System

    •5HT neuron RNA-seq across anatomy and sublineage at population and single-cell scales
    •Unbiased analyses identify 5HT neuron subtypes and organizing principles
    •Differential gene expression predicts subtype-specific functions and disease associations
    •In vitro drug responses, sensorimotor gating, and behaviors map to distinct subtypes

    Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity—from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance.

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  • Jo Bowyer
    Identification of Spinal Cord MicroRNA and Gene Signatures in a Model of Chronic Stress-Induced Visceral Hyperalgesia in Rat



    Animal studies have shown that stress could induce epigenetic and transcriptomic alterations essential in determining the balance between adaptive or maladaptive responses to stress. We tested the hypothesis that chronic stress in rats deregulates coding and non-coding gene expression in the spinal cord, which may underline neuroinflammation and nociceptive changes previously observed in this model.


    Male Wistar rats were exposed to daily stress or handled, for 10 days. At day 11, lumbar spinal segments were collected and processed for mRNA/miRNA isolation followed by expression profiling using Agilent SurePrint Rat Exon and Rat miRNA Microarray platforms. Differentially expressed gene lists were generated using the dChip program. Microarrays were analyzed using the Ingenuity Pathways Analysis (IPA) tool from Ingenuity Systems. Multiple methods were used for the analysis of miRNA-mRNA functional modules. Quantitative real time RT-PCR for Interleukin 6 signal transducer (gp130), the Signal Transducer And Activator Of Transcription 3 (STAT3), glial fibrillary acidic protein and mir-17-5p were performed to confirm levels of expression.


    Gene network analysis revealed that stress deregulated different inflammatory (IL-6, JAK/STAT, TNF) and metabolic (PI3K/AKT) signaling pathways. MicroRNA array analysis revealed a signature of 39 deregulated microRNAs in stressed rats. MicroRNA-gene network analysis showed that microRNAs are regulators of two gene networks relevant to inflammatory processes. Specifically, our analysis of miRNA-mRNA functional modules identified miR-17-5p as an important regulator in our model. We verified miR-17-5p increased expression in stress using qPCR and in situ hybridization. In addition, we observed changes in the expression of gp130 and STAT3 (involved in intracellular signaling cascades in response to gp130 activation), both predicted targets for miR-17-5p. A modulatory role of spinal mir17-5p in the modulation of visceral sensitivity was confirmed in vivo.


    Using an integrative high throughput approach, our findings suggest a link between miR-17-5p increased expression and gp130/STAT3 activation providing new insight into the possible mechanisms mediating the effect of chronic stress on neuroinflammation in the spinal cord.

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  • Jo Bowyer
    A big belly isn’t necessarily a pain in the back

    According to our new research investigating twins it could be our genes – not those extra kilos – that are causing back pain. We have recently published two novel twin studies, in The Spine Journal and in The European Spine Journal that debunk the direct link between obesity and low back pain. The articles show that the relationship between obesity and low back pain is more likely the result of shared genetic factors.

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  • Jo Bowyer
    Gene expression atlas for human embryogenesis

    Human embryogenesis is believed to involve an integrated set of complex yet coordinated development of different organs and tissues mediated by the changes in the spatiotemporal expression of many genes. Here, we report a genome-wide expression analysis during wk 4–9 of human embryogenesis, a critical period when most organs develop. About half of all human genes are expressed, and 18.6% of the expressed genes were significantly regulated during this important period. We further identified >5000 regulated genes, most of which previously were not known to be associated with animal development. Our study fills an important gap in mammalian developmental studies by identifying functional pathways involved in this critical but previously not studied period. Our study also revealed that the genes involved here are distinct from those during early embryogenesis, which include three groups of maternal genes. Furthermore, we discovered that genes in a given developmental process are regulated coordinately. This led us to develop an easily searchable database of this entire collection of gene expression profiles, allowing for the identification new genes important for a particular developmental process/pathway and deducing the potential function of a novel gene. The validity of the predictions from the database was demonstrated with two examples through spatiotemporal analyses of the two novel genes. Such a database should serve as a highly valuable resource for the molecular analysis of human development and pathogenesis.—Yi, H., Xue, L., Guo, M.-X. Ma, J., Zeng, Y., Wang, W., Cai, J.-Y. Hu, H.-M., Shu, H.-B. Shi, Y.-B., Li, W.-X. Gene expression atlas for human embryogenesis.
    Keywords: human embryonic development, gene regulation database, organogenesis, microarrays, maternal genes

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  • Jo Bowyer
    The Role of G-Protein Receptor 84 in Experimental Neuropathic Pain


    G-protein receptor 84 (GPR84) is an orphan receptor that is induced markedly in monocytes/macrophages and microglia during inflammation, but its pathophysiological function is unknown. Here, we investigate the role of GPR84 in a murine model of traumatic nerve injury. Naive GPR84 knock-out (KO) mice exhibited normal behavioral responses to acute noxious stimuli, but subsequent to partial sciatic nerve ligation (PNL), KOs did not develop mechanical or thermal hypersensitivity, in contrast to wild-type (WT) littermates. Nerve injury increased ionized calcium binding adapter molecule 1 (Iba1) and phosphorylated p38 MAPK immunoreactivity in the dorsal horn and Iba1 and cluster of differentiation 45 expression in the sciatic nerve, with no difference between genotypes. PCR array analysis revealed that Gpr84 expression was upregulated in the spinal cord and sciatic nerve of WT mice. In addition, the expression of arginase-1, a marker for anti-inflammatory macrophages, was upregulated in KO sciatic nerve. Based on this evidence, we investigated whether peripheral macrophages behave differently in the absence of GPR84. We found that lipopolysaccharide-stimulated KO macrophages exhibited attenuated expression of several proinflammatory mediators, including IL-1β, IL-6, and TNF-α. Forskolin-stimulated KO macrophages also showed greater cAMP induction, a second messenger associated with immunosuppression. In summary, our results demonstrate that GPR84 is a proinflammatory receptor that contributes to nociceptive signaling via the modulation of macrophages, whereas in its absence the response of these cells to an inflammatory insult is impaired.
    May be of interest to those who deal with patients referred by rheumatologists and gastroenterologists, this pathway has also been noted in patients post meningitis.

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  • Jo Bowyer
    Novel SCN9A Mutations Underlying Extreme Pain Phenotypes: Unexpected Electrophysiological and Clinical Phenotype Correlations


    The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype–phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.

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  • Jo Bowyer
    Inflammatory and Metabolic Alterations of Kager's Fat Pad in Chronic Achilles Tendinopathy



    Achilles tendinopathy is a painful inflammatory condition characterized by swelling, stiffness and reduced function of the Achilles tendon. Kager’s fat pad is an adipose tissue located in the area anterior to the Achilles tendon. Observations reveal a close physical interplay between Kager’s fat pad and its surrounding structures during movement of the ankle, suggesting that Kager’s fat pad may stabilize and protect the mechanical function of the ankle joint.


    The aim of this study was to characterize whether Achilles tendinopathy was accompanied by changes in expression of inflammatory markers and metabolic enzymes in Kager’s fat pad.


    A biopsy was taken from Kager’s fat pad from 31 patients with chronic Achilles tendinopathy and from 13 healthy individuals. Gene expression was measured by reverse transcription-quantitative PCR. Focus was on genes related to inflammation and lipid metabolism.


    Expression of the majority of analyzed inflammatory marker genes was increased in patients with Achilles tendinopathy compared to that in healthy controls. Expression patterns of the patient group were consistent with reduced lipolysis and increased fatty acid β-oxidation. In the fat pad, the pain-signaling neuropeptide substance P was found to be present in one third of the subjects in the Achilles tendinopathy group but in none of the healthy controls.


    Gene expression changes in Achilles tendinopathy patient samples were consistent with Kager’s fat pad being more inflamed than in the healthy control group. Additionally, the results indicate an altered lipid metabolism in Kager’s fat pad of Achilles tendinopathy patients.


    To the best of our knowledge we here report the first investigation of gene expression changes in Kager’s fat pad of AT patients. The main finding of the present study is an increased expression of inflammatory marker genes as well as altered expression of genes involved in lipid and energy metabolism in AT patients.


    We have previously investigated several inflammatory markers in Achilles tendon tissue and have observed that inflammation was absent in tendon tissue of chronic AT patients [18,19]. This result concurs with the generally accepted notion that tendinopathy is an ongoing tendon degenerative process [20–22]. Nevertheless, despite the absence of tendon inflammation, corticosteroid injections are often used as a treatment, providing a short-term relief of symptoms [23]. The corticosteroid-mediated relief of symptoms is difficult to explain if tendinopathy is considered solely a degenerative process [24] and indicates that inflammation plays a role. Since it is well known that adipose tissue in itself has immunological functions [25] and has been proposed to play important roles in other tendon pathologies including Hoffa’s disease [26] and osteoarthritis [27], we considered it important to investigate the inflammatory status of Kager’s fat pad in chronic AT patients. We provide evidence for an inflammatory phenotype in the Kager’s fat pad of patients, as documented by increased expression of TNF-α, IL-1R1, IL-6, IL-10, MCP1 and CD68. The existence of paracrine interactions between the inflammatory response of tenocytes in the tendon and adipocytes in the fat pad is likely. However, in the present study we analyzed the inflammatory markers of the Kager’s fat pad only, and our data therefore cannot provide definitive conclusions about this possibility. ADIPOQ has been suggested to be pro-inflammatory in joint diseases [16], but in our study, we find lower ADIPOQ mRNA levels in patients than in healthy controls, arguing against a pro-inflammatory function in AT. A previous study by Shaw et al. identified CD68 positive cells in the retromalleolar fat pad in rats using immunohistochemistry, and suggested that these cells might play a role combating infection and/or removal of cell debris [28]. Another reason for the presence of macrophages and inflammatory markers could be fat tissue fibrosis. It has been shown that the development of fibrosis of adipose tissue in obesity is tightly associated with tissue inflammation and the infiltration of macrophages [29] and mast cells [30]. In addition, it has been shown that increased collagen formation in the IFP might contribute to the development of synovial fibrosis [31]. Whether fibrosis is present in Kager’s fat pad of AT patients has yet to be investigated. It has been suggested that the fat pads are filling dead spaces in joints and thereby maintaining the joint cavity and promoting efficient lubrication [32]. The tip of Kager’s fat pad is associated with the Achilles tendon and minimizes pressure changes in the bursa by moving in and out of the retrocalcaneal bursa during plantar and dorsiflexion of the foot [6]. However, in case of fat pad hypertrophy, the space filling properties might contribute to symptoms of tendinopathy [33]. It has been shown previously that the size of the IFP is associated with patellar tendinopathy. Magnetic resonance imaging showed that patellar tendinopathy patients had a significantly larger fat pad compared to the control subjects when controlled for height [34]. Whether the size of Kager’s fat pad is increased in AT patients needs further investigation.

    In the knee joint there is an intimate relationship between the patellar tendon and the fat pad, and a shared neurovascular supply has been observed [35]. Kager’s fat pad is related to the Achilles tendon in a similar manner [6]. In patellar tendinopathy, neurovascular infiltration into the patellar tendon has been observed [36]. Neurovascular ingrowth is associated with tendon pathology and pain. In addition, the IFP has been shown to have a nociceptive function in the anterior knee pain syndrome [37]. Shaw et al. also identified nerve fibers and the nociceptive marker substance P in the fat tissue [28]. Another study showed an increased number of nociceptive fibers in ‘jumpers knee’ patients [38]. Since there is growing evidence that the fat pad is involved in pain mechanisms of tendon pathologies, it is relevant to mention that expression of the TAC1 gene, encoding substance P, was below the detection limit in most subjects of the present study. However, TAC1 mRNA was detectable in about one third (n = 11) of the AT patients, but could not be detected in any healthy control subjects. This may indicate that Kager’s fat pad mediates pain in Achilles tendinopathy.

    Lipid and energy metabolism

    In the present study, gene expression was analyzed in Kager’s fat pad only. Reduced expression of ATGL, HSL and MGL in Kager’s fat pad of AT patients as compared to control subjects indicates decreased lipolysis in the patient group [39]. CACT and CPT2 mRNAs were increased in AT patients suggesting that the Kager’s fat pad of patients has an increased capacity for β-oxidation. By contrast, CPT1B, catalyzing the first and rate-limiting step of transport of fatty acids into mitochondria [40], showed no difference in expression between the AT patients and the control group. ACC2 expression was lower in AT patients, indicative of diminished malonyl-CoA synthesis and thereby higher activity of CPT1B in AT patients, despite unchanged expression levels [41]. Combined, this is supportive of increased β-oxidation in Kager’s fat pad of AT patients. The gene expression analysis thus creates an apparent paradox, as lipolysis appears to be decreased, whereas fatty acid oxidation appears to increase in AT patients. Although mRNA levels need not reflect enzyme activities, one possible explanation is that in Kager’s fat pad from AT patients, more fatty acid are taken up from the circulation. This could be studied by measuring levels of fatty acid transport proteins. In AT patients, we found a decrease in expression of GLUT4, suggesting decreased insulin-stimulated glucose uptake in Kager’s fad pad-resident adipocytes of AT patients. Therefore, it remains possible that Kager’s fad pad of AT patients metabolizes relatively more fatty acids and less glucose than in healthy controls.

    In terms of energy metabolism, we detected decreased expression of CS and increased expression of RB1 in the Kager’s fat pad of AT patients compared to healthy controls. RB1 is a tumor suppressor, but is also an established inhibitor of oxidative metabolism in both white and brown adipose tissue [42,43]. Therefore, these data suggest that oxidative metabolism is lower in the fat pad of AT patients. RB1 is also inhibiting expression of the brown fat-specific UCP1 gene [42,43]. The very low expression of UCP1 mRNA strongly suggests that Kager’s fat pad is a white adipose tissue depot.

    The influence of BMI and age on gene expression

    The possible effect of BMI and age on gene expression was analyzed. Of the 16 genes differentially expressed between the healthy control group and the AT patients, seven genes were significantly affected by BMI. For five of the seven genes, there was still a significant difference in mRNA expression between control subjects and AT patients when accounting for BMI. Thus, differences in BMI between the healthy control group and the AT patients could only explain two out of 16 differentially expressed genes. With respect to age, six of the 16 genes differentially expressed between healthy controls and AT patients were significantly influenced by age. Three of the six genes still displayed differential expression with respect to health status when accounting for age. Thus, differences in age between the healthy control group and the AT group could only explain three out of 16 differentially expressed genes.

    Limitations of the present study

    A limitation of the present study is that gene expression was analyzed only by RT-qPCR. Obviously, an altered mRNA level does not necessarily reflect a change in protein level or protein activity. However, as very little tissue was available for analysis, we were limited to studying gene regulation at the mRNA level. Another limitation is that differences in cell type composition of Kager’s fat pad between healthy control subjects and AT patients might have influenced the outcome of our gene expression analysis. The inflammatory gene expression profile of AT patients most likely means an increased prevalence of immune cells in their fat pad, which again might have affected the relative expression of some of the metabolism-related genes analyzed.


    The contribution of Kager’s fat pad to Achilles tendinopathy is unknown. The present study reveals that Kager’s fat pad might play an important role in the pathology of disease. Expression of several inflammatory markers was up-regulated in the Kager’s fat pad of AT patients. In addition, the gene expression data are consistent with substantial alterations in lipid and energy metabolism of the fat pad of AT patients. Delineating the contribution of the inflammatory state and the altered metabolism of Kager’s fat pad to Achilles tendinopathy requires more and dedicated investigations.

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  • Jo Bowyer
    Applying Personal Genetic Data to Injury Risk Assessment in Athletes


    Recent studies have identified genetic markers associated with risk for certain sports-related injuries and performance-related conditions, with the hope that these markers could be used by individual athletes to personalize their training and diet regimens. We found that we could greatly expand the knowledge base of sports genetic information by using published data originally found in health and disease studies. For example, the results from large genome-wide association studies for low bone mineral density in elderly women can be re-purposed for low bone mineral density in young endurance athletes. In total, we found 124 single-nucleotide polymorphisms associated with: anterior cruciate ligament tear, Achilles tendon injury, low bone mineral density and stress fracture, osteoarthritis, vitamin/mineral deficiencies, and sickle cell trait. Of these single nucleotide polymorphisms, 91% have not previously been used in sports genetics.

    We conducted a pilot program on fourteen triathletes using this expanded knowledge base of genetic variants associated with sports injury. These athletes were genotyped and educated about how their individual genetic make-up affected their personal risk profile during an hour-long personal consultation. Overall, participants were favorable of the program, found it informative, and most acted upon their genetic results.

    This pilot program shows that recent genetic research provides valuable information to help reduce sports injuries and to optimize nutrition. There are many genetic studies for health and disease that can be mined to provide useful information to athletes about their individual risk for relevant injuries.
    There is an interest in this in UK sports science teams as a baseline marker. The home and training environment is considered to be of far greater significance.

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  • Jo Bowyer
    Or perhaps not............

    Injury-Dependent and Disability-Specific Lumbar Spinal Gene Regulation following Sciatic Nerve Injury in the Rat


    Allodynia, hyperalgesia and spontaneous pain are cardinal sensory signs of neuropathic pain. Clinically, many neuropathic pain patients experience affective-motivational state changes, including reduced familial and social interactions, decreased motivation, anhedonia and depression which are severely debilitating. In earlier studies we have shown that sciatic nerve chronic constriction injury (CCI) disrupts social interactions, sleep-wake-cycle and endocrine function in one third of rats, a subgroup reliably identified six days after injury. CCI consistently produces allodynia and hyperalgesia, the intensity of which was unrelated either to the altered social interactions, sleep-wake-cycle or endocrine changes. This decoupling of the sensory consequences of nerve injury from the affective-motivational changes is reported in both animal experiments and human clinical data. The sensory changes triggered by CCI are mediated primarily by functional changes in the lumbar dorsal horn, however, whether lumbar spinal changes may drive different affective-motivational states has never been considered. In these studies, we used microarrays to identify the unique transcriptomes of rats with altered social behaviours following sciatic CCI to determine whether specific patterns of lumbar spinal adaptations characterised this subgroup. Rats underwent CCI and on the basis of reductions in dominance behaviour in resident-intruder social interactions were categorised as having Pain & Disability, Pain & Transient Disability or Pain alone. We examined the lumbar spinal transcriptomes two and six days after CCI. Fifty-four ‘disability-specific’ genes were identified. Sixty-five percent were unique to Pain & Disability rats, two-thirds of which were associated with neurotransmission, inflammation and/or cellular stress. In contrast, 40% of genes differentially regulated in rats without disabilities were involved with more general homeostatic processes (cellular structure, transcription or translation). We suggest that these patterns of gene expression lead to either the expression of disability, or to resilience and recovery, by modifying local spinal circuitry at the origin of ascending supraspinal pathways.

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  • Jo Bowyer
    started a topic CT Gene genie

    Gene genie

    Yesterday I saw a patient for complex/persistent neck pain, we had a productive session and she was a joy to work with. She writes copy for science based journals and I was therefore able to introduce advanced material without the preamble required by lay members of the public.

    As she was getting dressed she began talking about other therapies that had helped her and her family in the past and wondered aloud whether it might speed things up if she had some myofascial release or reiki. I have had countless similar conversations over the years with physicists,surgeons,GPs etc:, it is as if someone has flicked a switch and it fascinates me.

    This morning I revisited this

    No matter what you do to a patient, from whatever level you focus, changes in
    gene expression will occur if the patient makes some changes.
    That every
    practitioner is ultimately a gene therapist is a nice idea, is unifying, and is, as
    far as I can see, quite rational. Also, if you are a patient you can be your own
    gene manipulator if you get involved in self help. Every therapist could argue
    (and perhaps one day soon should argue) that fundamental to their ‘technique’
    or ‘input’ is the modulation of gene expression.
    I might be no different in my
    influence as a physiotherapy practitioner from a healer, a medicine man, a
    magnetic or copper arm band with healing properties, a session of Reiki, a
    cranial manipulation, a grade II p-a on a zygapophyseal joint, a muscle
    rebalance session, a McKenzie extension exercise, an education session that
    changes the patient’s perspective on their pain to a less fearful one, a successful
    rehabilitation session where a formerly feared movement is conquered, or a
    positively negotiated arrangement with a patient’s employer that results in a
    comfortable stress free return to work. Based on this type of logic it
    seems unwise to criticise therapies that you find unusual/different/unorthodox.
    If patients have improved in some way from a therapy, there must be a
    mechanism underlying that improvement.
    my bolds

    Imo it is useful to know as much as possible about the therapies which appeal to patients and if possible something about their history. Chances are they will stay with you anyway, science is currently flavour of the month and it's starting to show in patient feedback forms.

    Climbing Brain Levels of Organisation from Genes to Consciousness

    Given the tremendous complexity of brain organisation, here I propose a strategy that dynamically links stages of brain organisation from genes to consciousness, at four privileged structural levels: genes; transcription factors (TFs)–gene networks; synaptic epigenesis; and long-range connectivity. These structures are viewed as nested and reciprocally inter-regulated, with a hierarchical organisation that proceeds on different timescales during the course of evolution and development. Interlevel bridging mechanisms include intrinsic variation-selection mechanisms, which offer a community of bottom-up and top-down models linking genes to consciousness in a stepwise manner.

    The proposed approach is to nest the various intertwined structural and functional levels that compose the brain into a coherent and open ‘brain models community’ covering multiple timescales.

    A critical bridging role between the gene and neuronal levels is assigned to regulatory proteins termed ‘TFs’.

    TFs regulate disparate genes into coherent assemblies.

    The impact of the environment on brain synaptogenesis is modelled as activity-dependent selective stabilisation pruning of synapses.

    Long-range connectivity, subject to developmental shaping through interactions with the physical, social, and cultural environment, is proposed to form the bridge between neuronal microcircuitry and higher cognitive functions by globally integrating the underlying neural organisations.

    A novel allosteric pharmacology of TFs is proposed for neuropsychiatric diseases.
    It makes me smile to think that Louis was thinking along these lines 17 years ago


    MiR-183 cluster scales mechanical pain sensitivity by regulating basal and neuropathic pain genes

    Nociception is protective and prevents tissue damage but can also facilitate chronic pain. Whether a general principle governs these two types of pain is unknown. Here we show that both basal mechanical and neuropathic pain are controlled by the microRNA-183 cluster in mice. This single cluster controls more than 80% of neuropathic pain–regulated genes and scales basal mechanical sensitivity and mechanical allodynia by regulating auxiliary voltage-gated calcium channel subunits α2δ-1 and α2δ-2. Basal sensitivity is controlled in nociceptors, and allodynia involves TrkB+ light-touch mechanoreceptors. These light-touch–sensitive neurons, which normally do not elicit pain, produce pain during neuropathy that is reversed by gabapentin. Thus, a single microRNA cluster continuously scales acute noxious mechanical sensitivity in nociceptive neurons and suppresses neuropathic pain transduction in a specific, light-touch–sensitive neuronal type recruited during mechanical allodynia.
    Update 02/06/2017

    Unexpected mechanism behind chronic nerve pain

    It has long been assumed that chronic nerve pain is caused by hypersensitivity in the neurons that transmit pain. Researchers now show that another kind of neuron that normally allows us to feel pleasant touch sensation can switch function and instead signal pain after nerve damage. The results can eventually lead to more effective pain treatments, say the researchers.
    Severe, treatment-demanding chronic nerve pain is a common condition but the drugs available have, at best, only some efficacy. Since the mechanisms behind nerve pain are largely unknown, the pharmaceutical industry has encountered major setbacks in the development of new drugs.

    It was previously assumed that certain sensory neurons only transmit pleasant tactile sensations, while other specializes to transmit pain. During chronic nerve pain, normal touch can cause pain, but how this happens has remained a mystery. Scientists at Karolinska Institutet have now discovered that a small RNA molecule (microRNA) in sensory neurons regulates how touch is perceived. Upon nerve damage, levels of this molecule drop in the sensory neurons, which results in raised levels of a specific ion channel that makes the nerve cells sensitive to pain.

    "Our study shows that touch-sensitive nerves switch function and start producing pain, which can explain how hypersensitivity arises," says Professor Patrik Ernfors at Karolinska Institutet's Department of Medical Biochemistry and Biophysics. "MicroRNA regulation could also explain why people have such different pain thresholds."

    The drug substance gabapentin is often used to treat nerve pain, even though the mechanism of action has not been known. The new study shows that gabapentin operates in the touch-sensitive neurons and blocks the ion channel that increases when microRNA levels decrease. Yet it is still around only half of all patients who respond positively to the treatment.

    "Nerve pain is a complex condition with several underlying mechanisms," says Professor Ernfors. "What's interesting about our study is that we can show that the RNA molecule controls the regulation of 80 per cent of the genes that are known to be involved in nerve pain. My hope, therefore, is that microRNA-based drugs will one day be a possibility."

    The research was primarily conducted on mice but also verified in tests on human tissue, where low microRNA levels could be linked to high levels of the specific ion channel and vice versa, suggesting that the mechanism is the same in humans.

    "It's vital that we understand the mechanisms that lead to chronic nerve pain so that we can discover new methods of treatment," says Professor Ernfors. "The pharmaceutical companies have concentrated heavily on substances that target ion channels and receptors in pain neurons, but our results show that they might have been focusing on the wrong type of neuron."
    Today's follow up on the above paper by Science Direct.

    Update 03/06/2017
    Last edited by Jo Bowyer; 03-06-2017, 03:36 PM.