Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion, the molecular factors associated with heterogeneity along this spectrum require further characterization. Here, using a targeted NanoString molecular barcoding approach, we interrogate neuroinflammatory dysregulation and heterogeneity at the level of gene expression in post-mortem motor cortex tissue from a cohort of clinically heterogeneous C9-ALS-FTSD cases. We identified 20 dysregulated genes in C9-ALS-FTSD, with enrichment of microglial and inflammatory response gene sets. Two genes with significant correlations to available clinical metrics were selected for validation: FKBP5, a correlate of cognitive function, and brain-derived neurotrophic factor (BDNF), a correlate of disease duration. FKBP5 and its signalling partner, NF-κB, appeared to have a cell type-specific staining distribution, with activated (i.e. nuclear) NF-κB immunoreactivity in C9-ALS-FTSD. Expression of BDNF, a correlate of disease duration, was confirmed to be higher in individuals with long compared to short disease duration using BaseScope™ in situ hybridization. Our analyses also revealed two distinct neuroinflammatory panel signatures (NPS), NPS1 and NPS2, delineated by the direction of expression of proinflammatory, axonal transport and synaptic signalling pathways. We compared NPS between C9-ALS-FTSD cases and those from sporadic ALS and SOD1-ALS cohorts and identified NPS1 and NPS2 across all cohorts. Moreover, a subset of NPS was also able to separate publicly available RNA sequencing data from independent C9-ALS and sporadic ALS cohorts into two inflammatory subgroups. Importantly, NPS subgroups did not clearly segregate with available demographic, genetic, clinical or pathological features, highlighting the value of molecular stratification in clinical trials for inflammatory subgroup identification. Our findings thus underscore the importance of tailoring therapeutic approaches based on distinct molecular signatures that exist between and within ALS-FTSD cohorts.

Evidence-Based and Emerging Diet Recommendations for Small Bowel Disorders.

Diet plays a key role in the manifestation and severity of gastrointestinal symptoms, with increasing research interest on the role of diet in small bowel disorders. There are predominantly 3 small bowel conditions that have potential dietary interventions. Self-reported nonceliac gluten/wheat sensitivity is prevalent. Although gluten is believed to be a potential trigger for symptoms, other components of wheat may also be triggers, including fructans, alpha-amylase trypsin inhibitors, and wheat germ agglutinins. The diagnosis can be challenging, given the lack of validated biomarkers. A gluten-free diet that excludes the abovementioned triggers is the cornerstone of treatment; however, unlike celiac disease, there is uncertainty about the level of adherence or whether the gluten-free diet is a lifelong intervention. Several primary gastrointestinal disorders are associated with an increase in inflammatory cells including eosinophils. Diet seems to be an important driver of disease pathogenesis in eosinophilic gastroenteritis, with elimination and elemental diets showing promise in management, with further robust trials required. Small intestinal bacterial overgrowth is an example of microbial dysbiosis, with renewed interest in diet being postulated to cause an adaptive change of the microbes colonizing the small intestine. However, the diagnosis of small intestinal bacterial overgrowth is limited by a lack of sensitive and specific tests, with significant knowledge gaps in relation to therapeutic measures to manage and cure small intestinal bacterial overgrowth. Currently, antimicrobials are the established management option. There have been significant clinical advances in dietary interventions related to the small bowel, but this area is currently a novel and advancing field for both patients and clinicians.

Type 2 and type 17 effector cells are increased in the duodenal mucosa but not peripheral blood of patients with functional dyspepsia.

Background: Functional dyspepsia is characterised by chronic symptoms of post-prandial distress or epigastric pain not associated with defined structural pathology. Increased peripheral gut-homing T cells have been previously identified in patients. To date, it is unknown if these T cells were antigen-experienced, or if a specific phenotype was associated with FD. Objective: This study aimed to characterise T cell populations in the blood and duodenal mucosa of FD patients that may be implicated in disease pathophysiology. Methods: We identified duodenal T cell populations from 23 controls and 49 Rome III FD patients by flow cytometry using a surface marker antibody panel. We also analysed T cell populations in peripheral blood from 37 controls and 61 patients. Where available, we examined the number of duodenal eosinophils in patients and controls. Results: There was a shift in the duodenal T helper cell balance in FD patients compared to controls. For example, patients had increased duodenal mucosal Th2 populations in the effector (13.03 ± 16.11, 19.84 ± 15.51, p=0.038), central memory (23.75 ± 18.97, 37.52 ± 17.51, p=0.007) and effector memory (9.80±10.50 vs 20.53±14.15, p=0.001) populations. Th17 populations were also increased in the effector (31.74±24.73 vs 45.57±23.75, p=0.03) and effector memory (11.95±8.42 vs 18.44±15.63, p=0.027) subsets. Peripheral T cell populations were unchanged between FD and control. Conclusion: Our findings identify an association between lymphocyte populations and FD, specifically a Th2 and Th17 signature in the duodenal mucosa. The presence of effector and memory cells suggest that the microinflammation in FD is antigen driven.

Associations between major psychiatric disorder polygenic risk scores and blood-based markers in UK biobank.

Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors, and are associated with peripheral abnormalities. The relationships between such genetic architectures and blood-based markers are, however, unclear. We investigated relationships between polygenic risk scores (PRS) for these disorders and peripheral markers in the UK Biobank cohort. We calculated polygenic risk scores for n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) UK Biobank cohort subjects. We then examined associations between disorder PRS and 58 inflammatory/immune, hematological, bone, cardiovascular, hormone, liver, renal and diabetes-associated blood markers using two generalized linear regression models: 'minimally adjusted' controlling for variables such as age and sex, and 'fully adjusted' including additional lifestyle covariates: BMI, alcohol and smoking status, and medication intake. There were 38/58 MDD PRS, 32/58 SCZ PRS, and 20/58 BD PRS-blood marker associations detected for our minimally adjusted model. Of these, 13/38 (MDD PRS), 14/32 (SCZ PRS), and 10/20 (BD PRS) associations remained significant after controlling for lifestyle factors. Many were disorder-specific, with 8/13 unique MDD PRS associations identified. Several disorder-specific associations for MDD and SCZ were immune-related, with mostly positive and negative associations identified for MDD and SCZ PRS respectively. This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk. The results also implicate inflammatory dysfunction in MDD and SCZ, albeit with differences in patterns between the two conditions, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.

Synergies between local and climate-driven impacts on coral reefs in the Tropical Pacific: A review of issues and adaptation opportunities.

Coral reefs in the tropical Pacific region are exposed to a range of anthropogenic local pressures. Climate change is exacerbating local impacts, causing unprecedented declines in coral reef habitats and bringing negative socio-economic consequences to Pacific communities who depend heavily on coral reefs for food, income and livelihoods. Continued increases in greenhouse gas emissions will drive future climate change, which will accelerate coral reef degradation. Traditional systems of resource governance in Pacific island nations provide a foundation to address local pressures and build reef resilience to climate change. Management and adaptation options should build on the regional diversity of governance systems and traditional knowledge to support community-based initiatives and cross-sectoral cooperation to address local pressures and minimize climate change impacts. Such an inclusive approach will offer enhanced opportunities to develop and implement transformative adaptation solutions, particularly in remote and regional areas where centralized management does not extend.

Knowledge Gaps in the Biology, Ecology, and Management of the Pacific Crown-of-Thorns Sea Star Acanthaster sp. on Australia's Great Barrier Reef.

AbstractCrown-of-thorns sea stars (Acanthaster sp.) are among the most studied coral reef organisms, owing to their propensity to undergo major population irruptions, which contribute to significant coral loss and reef degradation throughout the Indo-Pacific. However, there are still important knowledge gaps pertaining to the biology, ecology, and management of Acanthaster sp. Renewed efforts to advance understanding and management of Pacific crown-of-thorns sea stars (Acanthaster sp.) on Australia's Great Barrier Reef require explicit consideration of relevant and tractable knowledge gaps. Drawing on established horizon scanning methodologies, this study identified contemporary knowledge gaps by asking active and/or established crown-of-thorns sea star researchers to pose critical research questions that they believe should be addressed to improve the understanding and management of crown-of-thorns sea stars on the Great Barrier Reef. A total of 38 participants proposed 246 independent research questions, organized into 7 themes: feeding ecology, demography, distribution and abundance, predation, settlement, management, and environmental change. Questions were further assigned to 48 specific topics nested within the 7 themes. During this process, redundant questions were removed, which reduced the total number of distinct research questions to 172. Research questions posed were mostly related to themes of demography (46 questions) and management (48 questions). The dominant topics, meanwhile, were the incidence of population irruptions (16 questions), feeding ecology of larval sea stars (15 questions), effects of elevated water temperature on crown-of-thorns sea stars (13 questions), and predation on juveniles (12 questions). While the breadth of questions suggests that there is considerable research needed to improve understanding and management of crown-of-thorns sea stars on the Great Barrier Reef, the predominance of certain themes and topics suggests a major focus for new research while also providing a roadmap to guide future research efforts.

Wheat Sensitivity and Functional Dyspepsia: A Pilot, Double-Blind, Randomized, Placebo-Controlled Dietary Crossover Trial with Novel Challenge Protocol.

Introduction: Functional dyspepsia (FD), characterised by symptoms of epigastric pain or early satiety and post prandial distress, has been associated with duodenal eosinophilia, raising the possibility that it is driven by an environmental allergen. Non-coeliac gluten or wheat sensitivity (NCG/WS) has also been associated with both dyspeptic symptoms and duodenal eosinophilia, suggesting an overlap between these two conditions. The aim of this study was to evaluate the role of wheat (specifically gluten and fructans) in symptom reduction in participants with FD in a pilot randomized double-blind, placebo controlled, dietary crossover trial. Methods: Patients with Rome III criteria FD were recruited from a single tertiary centre in Newcastle, Australia. All were individually counselled on a diet low in both gluten and fermentable oligo-, di-, mono-saccharides, and polyols (FODMAPs) by a clinical dietitian, which was followed for four weeks (elimination diet phase). Those who had a >30% response to the run-in diet, as measured by the Nepean Dyspepsia Index, were then re-challenged with 'muesli' bars containing either gluten, fructan, or placebo in randomised order. Those with symptoms which significantly reduced during the elimination diet, but reliably reappeared (a mean change in overall dyspeptic symptoms of >30%) with gluten or fructan re-challenge were deemed to have wheat induced FD. Results: Eleven participants were enrolled in the study (75% female, mean age 43 years). Of the initial cohort, nine participants completed the elimination diet phase of whom four qualified for the rechallenge phase. The gluten-free, low FODMAP diet led to an overall (albeit non-significant) improvement in symptoms of functional dyspepsia in the diet elimination phase (mean NDI symptom score 71.2 vs. 47.1, p = 0.087). A specific food trigger could not be reliably demonstrated. Conclusions: Although a gluten-free, low-FODMAP diet led to a modest overall reduction in symptoms in this cohort of FD patients, a specific trigger could not be identified. The modified Salerno criteria for NCG/WS identification trialled in this dietary rechallenge protocol was fit-for-purpose. However, larger trials are required to determine whether particular components of wheat induce symptoms in functional dyspepsia.

Declining abundance of coral reef fish in a World-Heritage-listed marine park.

One of the most robust metrics for assessing the effectiveness of protected areas is the temporal trend in the abundance of the species they are designed to protect. We surveyed coral-reef fish and living hard coral in and adjacent to a sanctuary zone (SZ: where all forms of fishing are prohibited) in the World Heritage-listed Ningaloo Marine Park during a 10-year period. There were generally more individuals and greater biomass of many fish taxa (especially emperors and parrotfish) in the SZ than the adjacent recreation zone (RZ: where recreational fishing is allowed) - so log response ratios of abundance were usually positive in each year. However, despite this, there was an overall decrease in both SZ and RZ in absolute abundance of some taxa by up to 22% per year, including taxa that are explicitly targeted (emperors) by fishers and taxa that are neither targeted nor frequently captured (most wrasses and butterflyfish). A concomitant decline in the abundance (measured as percentage cover) of living hard coral of 1-7% per year is a plausible explanation for the declining abundance of butterflyfish, but declines in emperors might be more plausibly due to fishing. Our study highlights that information on temporal trends in absolute abundance is needed to assess whether the goals of protected areas are being met: in our study, patterns in absolute abundance across ten years of surveys revealed trends that simple ratios of abundance did not.

Oesophageal food bolus obstruction and eosinophilic oesophagitis.

Eosinophilic oesophagitis (EoE) is now a well-recognised cause of dysphagia and food bolus obstruction (FBO). The diagnosis requires histologic confirmation, and the yield is greatest when at least 4 to 6 oesophageal biopsies are taken from different sites. Previous case reports of FBO have demonstrated a low biopsy rate, and as such cases of EoE may have been missed. In this review, the medical records of 123 patients aged 18 years or older, who had presented with FBO over a 2 year period, were reviewed. EoE was the most common diagnosis, and was found in 81.3% of patients with FBO aged 40 years or less. 45.5% of patients with FBO were biopsied, and of those, 33.9% were confirmed to have had at least 4 biopsies. EoE is a common cause of FBO and requires appropriate oesophageal sampling to confirm the diagnosis. Cases of EoE may otherwise be missed.

Metabolic Profiling of Live Cancer Tissues Using NAD(P)H Fluorescence Lifetime Imaging.

Altered metabolism is a hallmark of cancer, both resulting from and driving oncogenesis. The NAD and NADP redox couples play a key role in a large number of the metabolic pathways involved. In their reduced forms, NADH and NADPH, these molecules are intrinsically fluorescent. As the average time for fluorescence to be emitted following excitation by a laser pulse, the fluorescence lifetime, is exquisitely sensitive to changes in the local environment of the fluorophore, imaging the fluorescence lifetime of NADH and NADPH offers the potential for label-free monitoring of metabolic changes inside living tumors. Here, we describe the biological, photophysical, and methodological considerations required to establish fluorescence lifetime imaging (FLIM) of NAD(P)H as a routine method for profiling the metabolism of living cancer cells and tissues.

A Serological Diagnosis of Coeliac Disease Is Associated with Osteoporosis in Older Australian Adults.

Previously thought to be mainly a disorder of childhood and early adult life, coeliac disease (CeD) is increasingly diagnosed in older adults. This may be important given the association between CeD and osteoporosis. The primary aim of this study was to determine the seroprevalence of undiagnosed CeD (‘at-risk serology’) in an older Australian community and relate this to a diagnosis of osteoporosis and fractures during a follow-up period of 12 years. We included participants from the Hunter Community Study (2004⁻2007) aged 55⁻85, who had anti-tissue transglutaminase (tTG) titres, human leukocyte antigen (HLA) genotypes, and bone mineral density measurements at baseline. Follow-up data included subsequent diagnosis of CeD and fractures using hospital information. ‘At-risk’ serology was defined as both tTG and HLA positivity. Complete results were obtained from 2122 patients. The prevalence of ‘at-risk’ serology was 5%. At baseline, 3.4% fulfilled criteria for a diagnosis of osteoporosis. During a mean of 9.7 years of follow-up, 7.4% of the cohort suffered at least one fracture and 0.7% were subsequently diagnosed with CeD. At-risk serology was significantly associated with osteoporosis in a multivariate model (odds ratio 2.83, 95% confidence interval 1.29⁻6.22); there was insufficient power to look at the outcome of fractures. The results of this study demonstrate that at-risk CeD serology was significantly associated with concurrent osteoporosis but not future fractures. Most individuals with a serological diagnosis of CeD were not diagnosed with CeD during the follow-up period according to medical records. Coeliac disease likely remains under-diagnosed.

Wheat Intolerance and Chronic Gastrointestinal Symptoms in an Australian Population-based Study: Association Between Wheat Sensitivity, Celiac Disease and Functional Gastrointestinal Disorders.

OBJECTIVES: Wheat avoidance in the absence of celiac disease (CD) is common but occurrence of concurrent functional gastrointestinal disorders (FGIDs) in this group is uncertain. The aims of this study were to determine the prevalence of self-reported wheat or gluten sensitivity and doctor diagnosed CD in an Australian population, define the associated gastrointestinal (GI) symptoms and FGIDs, and determine the relationship between self-reported wheat sensitivity, demographic and medical factors. METHODS: A total of 3542 people randomly selected from the Australian population returned a mail survey which contained questions on wheat avoidance, GI symptoms, demographic, medical, and lifestyle factors. We defined self-reported wheat sensitivity as people who reported gastrointestinal symptoms on ingestion of wheat based foods, but did not suffer from celiac disease, inflammatory bowel disease or colorectal cancer. Functional dyspepsia (FD) and irritable bowel syndrome (IBS) were diagnosed by Rome III criteria. CD status was self-reported. RESULTS: The prevalence of self-reported wheat sensitivity in this cohort was 14.9% (95% CI 13.7-16.2). The prevalence of CD was 1.2% (95%CI 0.8-1.6). Doctor diagnosed CD was significantly associated with a diagnosis of FD (OR 3.35, 95%CI 1.72-6.52) and IBS (OR 2.28, 95%CI 1.08-4.81). Those with self-reported wheat sensitivity were more likely to report multiple abdominal symptoms (of the 18 assessed) than those without (3.9 symptoms with self-reported wheat sensitivity vs. 1.6 without, p = 0.0001). In a multivariate analysis, self-reported wheat sensitivity was independently associated with IBS (OR 3.55, 95%CI 2.71-4.65) and FD (1.48, 95%CI 1.13-1.94). CONCLUSIONS: Self-reported wheat sensitivity is common, with a prevalence of 14.9% in this cohort. There is a strong association between both celiac disease and self-reported wheat sensitivity, and chronic gastrointestinal symptoms, as well as a diagnosis of FD and IBS.

Loss of coral reef growth capacity to track future increases in sea level.

Sea-level rise (SLR) is predicted to elevate water depths above coral reefs and to increase coastal wave exposure as ecological degradation limits vertical reef growth, but projections lack data on interactions between local rates of reef growth and sea level rise. Here we calculate the vertical growth potential of more than 200 tropical western Atlantic and Indian Ocean reefs, and compare these against recent and projected rates of SLR under different Representative Concentration Pathway (RCP) scenarios. Although many reefs retain accretion rates close to recent SLR trends, few will have the capacity to track SLR projections under RCP4.5 scenarios without sustained ecological recovery, and under RCP8.5 scenarios most reefs are predicted to experience mean water depth increases of more than 0.5 m by 2100. Coral cover strongly predicts reef capacity to track SLR, but threshold cover levels that will be necessary to prevent submergence are well above those observed on most reefs. Urgent action is thus needed to mitigate climate, sea-level and future ecological changes in order to limit the magnitude of future reef submergence.

Challenges of transferring models of fish abundance between coral reefs.

Reliable abundance estimates for species are fundamental in ecology, fisheries, and conservation. Consequently, predictive models able to provide reliable estimates for un- or poorly-surveyed locations would prove a valuable tool for management. Based on commonly used environmental and physical predictors, we developed predictive models of total fish abundance and of abundance by fish family for ten representative taxonomic families for the Great Barrier Reef (GBR) using multiple temporal scenarios. We then tested if models developed for the GBR (reference system) could predict fish abundances at Ningaloo Reef (NR; target system), i.e., if these GBR models could be successfully transferred to NR. Models of abundance by fish family resulted in improved performance (e.g., 44.1%  0.05). High spatio-temporal variability of patterns in fish abundance at the family and population levels in both reef systems likely affected the transferability of these models. Inclusion of additional predictors with potential direct effects on abundance, such as local fishing effort or topographic complexity, may improve transferability of fish abundance models. However, observations of these local-scale predictors are often not available, and might thereby hinder studies on model transferability and its usefulness for conservation planning and management.