321 research outputs found
The Glial Regenerative Response to Central Nervous System Injury Is Enabled by Pros-Notch and Pros-NFΞΊB Feedback
Organisms are structurally robust, as cells accommodate changes preserving structural integrity and function. The molecular mechanisms underlying structural robustness and plasticity are poorly understood, but can be investigated by probing how cells respond to injury. Injury to the CNS induces proliferation of enwrapping glia, leading to axonal re-enwrapment and partial functional recovery. This glial regenerative response is found across species, and may reflect a common underlying genetic mechanism. Here, we show that injury to the Drosophila larval CNS induces glial proliferation, and we uncover a gene network controlling this response. It consists of the mutual maintenance between the cell cycle inhibitor Prospero (Pros) and the cell cycle activators Notch and NFΞΊB. Together they maintain glia in the brink of dividing, they enable glial proliferation following injury, and subsequently they exert negative feedback on cell division restoring cell cycle arrest. Pros also promotes glial differentiation, resolving vacuolization, enabling debris clearance and axonal enwrapment. Disruption of this gene network prevents repair and induces tumourigenesis. Using wound area measurements across genotypes and time-lapse recordings we show that when glial proliferation and glial differentiation are abolished, both the size of the glial wound and neuropile vacuolization increase. When glial proliferation and differentiation are enabled, glial wound size decreases and injury-induced apoptosis and vacuolization are prevented. The uncovered gene network promotes regeneration of the glial lesion and neuropile repair. In the unharmed animal, it is most likely a homeostatic mechanism for structural robustness. This gene network may be of relevance to mammalian glia to promote repair upon CNS injury or disease
Weight management interventions in adults with intellectual disabilities and obesity: a systematic review of the evidence
o evaluate the clinical effectiveness of weight management interventions in adults with intellectual disabilities (ID) and obesity using recommendations from current clinical guidelines for the first line management of obesity in adults. Full papers on lifestyle modification interventions published between 1982 to 2011 were sought by searching the Medline, Embase, PsycINFO and CINAHL databases. Studies were evaluated based on 1) intervention components, 2) methodology, 3) attrition rate 4) reported weight loss and 5) duration of follow up. Twenty two studies met the inclusion criteria. The interventions were classified according to inclusion of the following components: behaviour change alone, behaviour change plus physical activity, dietary advice or physical activity alone, dietary plus physical activity advice and multi-component (all three components). The majority of the studies had the same methodological limitations: no sample size justification, small heterogeneous samples, no information on randomisation methodologies. Eight studies were classified as multi-component interventions, of which one study used a 600 kilocalorie (2510 kilojoule) daily energy deficit diet. Study durations were mostly below the duration recommended in clinical guidelines and varied widely. No study included an exercise program promoting 225β300Β minutes or more of moderate intensity physical activity per week but the majority of the studies used the same behaviour change techniques. Three studies reported clinically significant weight loss (≥ 5%) at six months post intervention. Current data indicate weight management interventions in those with ID differ from recommended practice and further studies to examine the effectiveness of multi-component weight management interventions for adults with ID and obesity are justified
LLM3D: a log-linear modeling-based method to predict functional gene regulatory interactions from genome-wide expression data
All cellular processes are regulated by condition-specific and time-dependent interactions between transcription factors and their target genes. While in simple organisms, e.g. bacteria and yeast, a large amount of experimental data is available to support functional transcription regulatory interactions, in mammalian systems reconstruction of gene regulatory networks still heavily depends on the accurate prediction of transcription factor binding sites. Here, we present a new method, log-linear modeling of 3D contingency tables (LLM3D), to predict functional transcription factor binding sites. LLM3D combines gene expression data, gene ontology annotation and computationally predicted transcription factor binding sites in a single statistical analysis, and offers a methodological improvement over existing enrichment-based methods. We show that LLM3D successfully identifies novel transcriptional regulators of the yeast metabolic cycle, and correctly predicts key regulators of mouse embryonic stem cell self-renewal more accurately than existing enrichment-based methods. Moreover, in a clinically relevant in vivo injury model of mammalian neurons, LLM3D identified peroxisome proliferator-activated receptor Ξ³ (PPARΞ³) as a neuron-intrinsic transcriptional regulator of regenerative axon growth. In conclusion, LLM3D provides a significant improvement over existing methods in predicting functional transcription regulatory interactions in the absence of experimental transcription factor binding data
Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination
Brain-derived neurotrophic factor (BDNF) is involved in neuronal and glial development and survival. While neurons and astrocytes are its main cellular source in the central nervous system (CNS), bioactive BDNF is also expressed in immune cells and in lesions of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Previous data revealed that BDNF exerts neuroprotective effects in myelin oligodendrocyte glycoprotein-induced EAE. Using a conditional knock-out model with inducible deletion of BDNF, we here show that clinical symptoms and structural damage are increased when BDNF is absent during the initiation phase of clinical EAE. In contrast, deletion of BDNF later in the disease course of EAE did not result in significant changes, either in the disease course or in axonal integrity. Bone marrow chimeras revealed that the deletion of BDNF in the CNS alone, with no deletion of BDNF in the infiltrating immune cells, was sufficient for the observed effects. Finally, the therapeutic effect of glatiramer acetate, a well-characterized disease-modifying drug with the potential to modulate BDNF expression, was partially reversed in mice in which BDNF was deleted shortly before the onset of disease. In summary, our data argue for an early window of therapeutic opportunity where modulation of BDNF may exert neuroprotective effects in experimental autoimmune demyelination
Health, not weight loss, focused programmes versus conventional weight loss programmes for cardiovascular risk factors:A systematic review and meta-analysis
Β© 2019 The Authors. Published by BMC. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisherβs website:Background: Obesity is a cardiovascular disease risk factor. Conventional weight loss (CWL) programmes focus on weight loss, however 'health, not weight loss, focused' (HNWL) programmes concentrate on improved health and well-being, irrespective of weight loss. What are the differences in CVD risk outcomes between these programmes? Aim: To conduct a systematic review and meta-analysis to compare the effects of HNWL with CWL programmes on cardiovascular disease risk factors. Methods: We searched CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, ASSIA, clinical trial registers, commercial websites and reference lists for randomised controlled trials comparing the two programmes (initially searched up to August 2015 and searched updated to 5 April 2019). We used the Mantel-Haneszel fixed-effect model to pool results. Sub-group and sensitivity analyses that accounted for variations in length of follow-up, enhanced programmes and risk of bias dealt with heterogeneity. Results: Eight randomised controlled trials of 20,242 potential studies were included. Improvements in total cholesterol-HDL ratio (mean difference-0.21 mmol/L, 95% confidence interval [-3.91, 3.50]) and weight loss (-0.28 kg [-2.00, 1.44]) favoured HNWL compared to CWL programmes in the long term (53-104 week follow-up), whereas improvements in systolic (-1.14 mmHg, [-5.84, 3.56]) and diastolic (-0.15 mmHg, [-3.64, 3.34]) blood pressure favoured CWL programmes. These differences did not reach statistical significance. Statistically significant improvements in body satisfaction (-4.30 [-8.32,-0.28]) and restrained eating behaviour (-4.30 [-6.77,-1.83]) favoured HNWL over CWL programmes. Conclusions: We found no long-term significant differences in improved CVD risk factors; however, body satisfaction and restrained eating behaviour improved more with HNWL compared to CWL programmes. Yet firm conclusions cannot be drawn from small studies with high losses to follow-up and data sometimes arising from a single small study.Published versio
Disabling knee pain β another consequence of obesity: Results from a prospective cohort study
BACKGROUND: Obesity is linked to knee osteoarthritis (OA) and knee pain. These are disabling problems that are more prevalent in older adults. No prospective study has estimated the impact of excess weight avoidance on the occurrence of knee pain in the general older population. The aim of this study was to investigate the influence of overweight and obesity on the onset and progression of knee pain and disability in older adults living in the community. METHODS: A prospective cohort study of people aged 50 and over registered with three general practices in North Staffordshire, UK. 5784 people who had responded to a survey in March 2000 were mailed a follow-up questionnaire in March 2003. The main outcome measures were self-reported knee pain and severe knee pain and disability at 3 years measured by the Western Ontario and McMaster Universities Osteoarthritis index. RESULTS: Adjusted response to follow-up was 75%. Among responders with no knee pain at baseline, obesity predicted onset of severe knee pain (relative risk 2.8; 95% CI 1.8, 4.5 compared to normal body mass index (BMI) category). Considering overweight and obese categories together, 19% of new cases of severe knee pain over a 3-year period could potentially be avoided by a one-category shift downwards in BMI; this includes almost half of the new cases that arose in the obese group. CONCLUSION: Obesity accounts for a substantial proportion of severe disabling knee pain. As knee pain is a common disabling condition in older adults living in the community, effective public health interventions about avoidance of excess weight could have a major impact on future lower limb disability in older adults
Mimicking the Neurotrophic Factor Profile of Embryonic Spinal Cord Controls the Differentiation Potential of Spinal Progenitors into Neuronal Cells
Recent studies have indicated that the choice of lineage of neural progenitor cells is determined, at least in part, by environmental factors, such as neurotrophic factors. Despite extensive studies using exogenous neurotrophic factors, the effect of endogenous neurotrophic factors on the differentiation of progenitor cells remains obscure. Here we show that embryonic spinal cord derived-progenitor cells express both ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) mRNA before differentiation. BDNF gene expression significantly decreases with their differentiation into the specific lineage, whereas CNTF gene expression significantly increases. The temporal pattern of neurotrophic factor gene expression in progenitor cells is similar to that of the spinal cord during postnatal development. Approximately 50% of spinal progenitor cells differentiated into astrocytes. To determine the effect of endogenous CNTF on their differentiation, we neutralized endogenous CNTF by administration of its polyclonal antibody. Neutralization of endogenous CNTF inhibited the differentiation of progenitor cells into astrocytes, but did not affect the numbers of neurons or oligodendrocytes. Furthermore, to mimic the profile of neurotrophic factors in the spinal cord during embryonic development, we applied BDNF or neurotrophin (NT)-3 exogenously in combination with the anti-CNTF antibody. The exogenous application of BDNF or NT-3 promoted the differentiation of these cells into neurons or oligodendrocytes, respectively. These findings suggest that endogenous CNTF and exogenous BDNF and NT-3 play roles in the differentiation of embryonic spinal cord derived progenitor cells into astrocytes, neurons and oligodendrocytes, respectively
Adult Spinal Cord Radial Glia Display a Unique Progenitor Phenotype
Radial glia (RG) are primarily embryonic neuroglial progenitors that express Brain Lipid Binding Protein (Blbp a.k.a. Fabp7) and Glial Fibrillary Acidic Protein (Gfap). We used these transcripts to demarcate the distribution of spinal cord radial glia (SCRG) and screen for SCRG gene expression in the Allen Spinal Cord Atlas (ASCA). We reveal that neonatal and adult SCRG are anchored in a non-ventricular niche at the spinal cord (SC) pial boundary, and express a βsignatureβ subset of 122 genes, many of which are shared with βclassicβ neural stem cells (NSCs) of the subventricular zone (SVZ) and SC central canal (CC). A core expressed gene set shared between SCRG and progenitors of the SVZ and CC is particularly enriched in genes associated with human disease. Visualizing SCRG in a Fabp7-EGFP reporter mouse reveals an extensive population of SCRG that extend processes around the SC boundary and inwardly (through) the SC white matter (WM), whose abundance increases in a gradient from cervical to lumbar SC. Confocal analysis of multiple NSC-enriched proteins reveals that postnatal SCRG are a discrete and heterogeneous potential progenitor population that become activated by multiple SC lesions, and that CC progenitors are also more heterogeneous than previously appreciated. Gene ontology analysis highlights potentially unique regulatory pathways that may be further manipulated in SCRG to enhance repair in the context of injury and SC disease
Regenerative endodontics: a true paradigm shift or a bandwagon about to be derailed?
Aims: Regenerative endodontic techniques (RETs) have been hailed as a paradigm shift for the management of traumatised non-vital immature permanent anterior teeth. In this article the aim was to critically appraise the literature with regards to the outcome of regenerative endodontics on root development. Methods: Critical review of the literature where regenerative endodontic techniques have been used in the management of immature non-vital teeth with continuation of root development as the main outcome reported. Results: Most studies published were in the form of case reports and series with very few randomised controlled trials with a high risk of bias. Continuation of root development following the use of RET has been shown to be unpredictable at best with lower success in those teeth losing vitality as a result of dental trauma. Conclusions: Despite the high success of regenerative endodontics in terms of periodontal healing including resolution of clinical and radiographic signs and symptoms of infection, continuation of root development remains an unpredictable outcome. The use of a blood clot as a scaffold in regenerative endodontics should be reviewed carefully as that might offer an environment for repair rather than regeneration. In addition, preservation of structures, such as Hertwigβs epithelial root sheath, may have an important bearing on the success of this approach and should be further investigated
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