Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal ...dementia. However, the cellular function of the C9ORF72 protein remains unknown. Here, we demonstrate that C9ORF72 regulates endosomal trafficking. C9ORF72 colocalized with Rab proteins implicated in autophagy and endocytic transport: Rab1, Rab5, Rab7 and Rab11 in neuronal cell lines, primary cortical neurons and human spinal cord motor neurons, consistent with previous predictions that C9ORF72 bears Rab guanine exchange factor activity. Consistent with this notion, C9ORF72 was present in the extracellular space and as cytoplasmic vesicles. Depletion of C9ORF72 using siRNA inhibited transport of Shiga toxin from the plasma membrane to Golgi apparatus, internalization of TrkB receptor and altered the ratio of autophagosome marker light chain 3 (LC3) II:LC3I, indicating that C9ORF72 regulates endocytosis and autophagy. C9ORF72 also colocalized with ubiquilin-2 and LC3-positive vesicles, and co-migrated with lysosome-stained vesicles in neuronal cell lines, providing further evidence that C9ORF72 regulates autophagy. Investigation of proteins interacting with C9ORF72 using mass spectrometry identified other proteins implicated in ALS; ubiquilin-2 and heterogeneous nuclear ribonucleoproteins, hnRNPA2/B1 and hnRNPA1, and actin. Treatment of cells overexpressing C9ORF72 with proteasome inhibitors induced the formation of stress granules positive for hnRNPA1 and hnRNPA2/B1. Immunohistochemistry of C9ORF72 ALS patient motor neurons revealed increased colocalization between C9ORF72 and Rab7 and Rab11 compared with controls, suggesting possible dysregulation of trafficking in patients bearing the C9ORF72 repeat expansion. Hence, this study identifies a role for C9ORF72 in Rab-mediated cellular trafficking.
Probiotic mechanisms of action Halloran, Katrina; Underwood, Mark A.
Early human development,
August 2019, 2019-08-00, 20190801, Volume:
135
Journal Article
Peer reviewed
Intestinal dysbiosis is associated with a large number of disease processes including necrotizing enterocolitis and late-onset sepsis in preterm infants and colic and antibiotic-associated diarrhea ...in term infants. Probiotic microbes are increasingly administered to infants with the intent of decreasing risk of these acute diseases as well as chronic diseases of childhood such as asthma and atopic disease. The mechanisms by which probiotics decrease inflammation, decrease intestinal permeability, alter the intestinal microbiota, and influence metabolism have been discovered through both in vitro studies and in vivo in animal models. We review key mechanisms by which probiotic microbes improve health with emphasis on recent discoveries in the field.
•Several probiotics dampen inflammation by inhibiting TLR4 and TLR2 and by stimulating expression of anti-inflammatory mediators•Several probiotics improve intestinal barrier function by strengthening the mucus layer and tight junctions between enterocytes•Many probiotics increase energy harvest by producing short chain fatty acids, amino acids, vitamins, and secondary bile acids•Many probiotics alter the intestinal microbiota by selectively competing for human milk oligosaccharides and by producing bacteriocins
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes.
RG analysis was ...conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants.
Fifteen critical RGs are summarised below:
: Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment;
: Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk;
: Pressing need for prevention trials;
: Lack of integration of different prevention approaches;
: Lack of optimal strategies for CRC screening;
: Lack of effective triage systems for invasive investigations;
: Imprecise pathological assessment of CRC;
: Lack of qualified personnel in genomics, data sciences and digital pathology;
: Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices;
: Need for novel technologies/interventions to improve curative outcomes;
: Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment;
: Lack of reliable biomarkers to guide stage IV treatment;
: Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution;
: Lack of coordination of CRC research/funding;
: Lack of effective communication between relevant stakeholders.
Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years.
In extremely premature infants, postnatal growth restriction (PNGR) is common and increases the risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Mechanisms by ...which poor nutrition impacts lung development are unknown, but alterations in the gut microbiota appear to play a role. In a rodent model, PNGR plus hyperoxia causes BPD and PH and increases intestinal Enterobacteriaceae, Gram-negative organisms that stimulate Toll-like receptor 4 (TLR4). We hypothesized that intestinal dysbiosis activates intestinal TLR4 triggering systemic inflammation which impacts lung development.
Rat pups were assigned to litters of 17 (PNGR) or 10 (normal growth) at birth and exposed to room air or 75% oxygen for 14 days. Half of the pups were treated with the TLR4 inhibitor TAK-242 from birth or beginning at day 3. After 14 days, pulmonary arterial pressure was evaluated by echocardiography and hearts were examined for right ventricular hypertrophy (RVH). Lungs and serum samples were analyzed by western blotting and immunohistochemistry.
Postnatal growth restriction + hyperoxia increased pulmonary arterial pressure and RVH with trends toward increased plasma IL1β and decreased IκBα, the inhibitor of NFκB, in lung tissue. Treatment with the TLR4 inhibitor attenuated PH and inflammation.
Postnatal growth restriction induces an increase in intestinal Enterobacteriaceae leading to PH. Activation of the TLR4 pathway is a promising mechanism by which intestinal dysbiosis impacts the developing lung.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from the death of upper and lower motor neurons. Due to a lack of effective treatment, it is imperative to understand ...the underlying mechanisms and processes involved in disease progression. Regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in disease. Here we discuss the possible involvement of redox dysregulation in the pathophysiology of ALS, either as a cause of cellular abnormalities or a consequence. We focus on its possible role in oxidative stress, protein misfolding, glutamate excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagic stress, and endoplasmic reticulum (ER) stress. We also speculate that an ER chaperone protein disulphide isomerase (PDI) could play a key role in this dysregulation. PDI is essential for normal protein folding by oxidation and reduction of disulphide bonds, and hence any disruption to this process may have consequences for motor neurons. Addressing the mechanism underlying redox regulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The aim in the present study was to assess the effect of small-moderate red wine ingestion on the level of serum insulin and plasma glucose when nutritional status is varied. Twenty nondiabetic males ...(19-22 years) participated in the study. In the fasting trial, all participants underwent a 6 h fast prior to consuming 4 standard units of red wine (40 g alcohol) or the equivalent amount of placebo as dealcoholized wine (containing <0.5% alcohol, 0% resveratrol) over a 135 min period. Alternatively, in the feeding trial, participants consumed food for 45 min prior to ingesting 4 standard units of red wine (40 g alcohol) or placebo over 135 min. Serum insulin and plasma glucose were assessed at regular 45 min intervals during all trials. The results showed a significant decrease in the level of serum insulin and no significant change in plasma glucose concentration in the fasting trial. Alternatively, a significant alcohol-induced decrease in plasma glucose and no change in serum insulin occurred when red wine alone was consumed after food. It was concluded that red wine can alter the glucose-insulin relationship and ingesting red wine alone (without food) should not be encouraged in nondiabetic individuals.
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DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In the BEST-CLI trial (Best Endovascular Versus Best Surgical Therapy for Patients With Chronic Limb-Threatening Ischemia), a prespecified secondary objective was to assess the effects of ...revascularization strategy on health-related quality of life (HRQoL).
Patients with chronic limb-threatening ischemia were randomized to surgical bypass (Bypass) or endovascular intervention (Endo) in 2 parallel trials. Cohort 1 included patients with single-segment great saphenous vein; cohort 2 included those lacking suitable single-segment great saphenous vein. HRQoL was assessed over the trial duration using Vascular Quality-of-Life (VascuQoL), European Quality-of-Life-5D (EQ-5D), the Short Form-12 (SF-12) Physical Component Summary (SF-12 PCS), SF-12 Mental Component Summary (SF-12 MCS), Utility Index Score (SF-6D R2), and numeric rating scales of pain. HRQoL was summarized by cohort and compared within and between groups using mixed-model linear regression.
A total of 1193 and 335 patients in cohorts 1 and 2 with a mean follow-up of 2.9 and 2.0 years, respectively, were analyzed. In cohort 1, HRQoL significantly improved from baseline to follow-up for both groups across all measures. For example, mean (SD) VascuQoL scores were 3.0 (1.3) and 3.0 (1.2) for Bypass and Endo at baseline and 4.7 (1.4) and 4.8 (1.5) over follow-up. There were significant group differences favoring Endo when assessed with VascuQoL (difference, -0.14 95% CI, -0.25 to -0.02;
=0.02), SF-12 MCS (difference, -1.03 95% CI, -1.89 to -0.18;
=0.02), SF-6D R2 (difference, -0.01 95% CI, -0.02 to -0.001;
=0.03), numeric rating scale pain at present (difference, 0.26 95% CI, 0.03 to 0.49;
=0.03), usual level during previous week (difference, 0.26 95% CI, 0.04 to 0.48;
=0.02), and worst level during previous week (difference, 0.29 95% CI, 0.02 to 0.56;
=0.04). There was no difference between treatment arms on the basis of EQ-5D (difference, -0.01 95% CI, -0.03 to 0.004;
=0.12) or SF-12 PCS (difference, -0.41 95% CI, -1.2 to 0.37;
=0.31). In cohort 2, HRQoL also significantly improved from baseline to the end of follow-up for both groups based on all measures, but there were no differences between Bypass and Endo on any measure.
Among patients with chronic limb-threatening ischemia deemed eligible for either Bypass or Endo, revascularization resulted in significant and clinically meaningful improvements in HRQoL. In patients with an available single-segment great saphenous vein for bypass, but not among those without one, Endo was statistically superior on some HRQoL measures; however, these differences were below the threshold of clinically meaningful difference.
Objective. To evaluate the prevalence of atypical antipsychotic use in privately insured children and the diagnoses associated with treatment. Study design. Claims were used to conduct a ...retrospective cohort study of children aged 2 through 18 years in the Midwest, covered by private insurance between 2002 and 2005 (n = 172 766). The 1-year prevalence of children receiving atypical antipsychotics was determined along with associated diagnoses. Results. The 1-year prevalence of atypical antipsychotics ranged from 7.9 per 1000 in 2002 to 9.0 in 2005. The leading diagnoses were disruptive behavior disorders (67%), mood disorders (65%), and anxiety disorders (43%).The authors found that 75% of children on atypical antipsychotics had more than one psychiatric diagnosis. Conclusions. Atypical antipsychotic use is primarily seen in children who have multiple psychiatric diagnoses. Studies are needed to assess the long-term safety and effectiveness in such patients with multiple diagnoses.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Coral reefs face multiple anthropogenic threats, from pollution and overfishing to the dual effects of greenhouse gas emissions: rising sea temperature and ocean acidification 1. While the abundance ...of coral has declined in recent decades 2, 3, the implications for humanity are difficult to quantify because they depend on ecosystem function rather than the corals themselves. Most reef functions and ecosystem services are founded on the ability of reefs to maintain their three-dimensional structure through net carbonate accumulation 4. Coral growth only constitutes part of a reef’s carbonate budget; bioerosion processes are influential in determining the balance between net structural growth and disintegration 5, 6. Here, we combine ecological models with carbonate budgets and drive the dynamics of Caribbean reefs with the latest generation of climate models. Budget reconstructions using documented ecological perturbations drive shallow (6–10 m) Caribbean forereefs toward an increasingly fragile carbonate balance. We then projected carbonate budgets toward 2080 and contrasted the benefits of local conservation and global action on climate change. Local management of fisheries (specifically, no-take marine reserves) and the watershed can delay reef loss by at least a decade under “business-as-usual” rises in greenhouse gas emissions. However, local action must be combined with a low-carbon economy to prevent degradation of reef structures and associated ecosystem services.
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•Many Caribbean reefs are expected to experience continued structural decline by 2080•Avoiding decline necessitates local management and vastly reduced CO2 emissions•Reconstructed carbonate budgets reveal high sensitivity to ecological perturbations•Climate policy should aim for the most aggressive IPCC emission scenario (RCP2.6)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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