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Prenatal stress is known to epigenetically program offspring physiology and behaviour, and may become a risk factor for adult complex diseases. To gain insight into the underlying environment-gene interactions, we used proton nuclear magnetic resonance spectroscopy to analyze urinary metabolomes of male and female adolescents who were in utero during the 1998 Quebec Ice Storm. Metabolomic profiles in adolescent groups were found to be significantly different. Higher prenatal stress exposure generated alterations in metabolic pathways involved in energy metabolism and protein biosynthesis, such as branched-chain amino acid synthesis, alanine metabolism, and ketone body metabolism. Dysregulation of energy and protein metabolism suggests an increased risk of metabolic diseases like insulin resistance, diabetes, and obesity. These findings are consistent with prior observations of physiological phenotypes from this cohort. Understanding the impact of natural disasters on health risks will provide new and improved therapeutic strategies to mitigate stress-associated adverse health outcomes. Using metabolomic biomarkers may also assist in the prediction and prevention of these adverse outcomes.

Metabolic risk factors are among the most common causes of noncommunicable diseases, and stress critically contributes to metabolic risk. In particular, social isolation during pregnancy may represent a salient stressor that affects offspring metabolic health, with potentially adverse consequences for future generations. Here, we used proton nuclear magnetic resonance (1H NMR) spectroscopy to analyze the blood plasma metabolomes of the third filial (F3) generation of rats born to lineages that experienced either transgenerational or multigenerational maternal social isolation stress. We show that maternal social isolation induces distinct and robust metabolic profiles in the blood plasma of adult F3 offspring, which are characterized by critical switches in energy metabolism, such as upregulated formate and creatine phosphate metabolisms and downregulated glucose metabolism. Both trans- and multigenerational stress altered plasma metabolomic profiles in adult offspring when compared to controls. Social isolation stress increasingly affected pathways involved in energy metabolism and protein biosynthesis, particularly in branched-chain amino acid synthesis, the tricarboxylic acid cycle (lactate, citrate), muscle performance (alanine, creatine phosphate), and immunoregulation (serine, threonine). Levels of creatine phosphate, leucine, and isoleucine were associated with changes in anxiety-like behaviours in open field exploration. The findings reveal the metabolic underpinnings of epigenetically heritable diseases and suggest that even remote maternal social stress may become a risk factor for metabolic diseases, such as diabetes, and adverse mental health outcomes. Metabolomic signatures of transgenerational stress may aid in the risk prediction and early diagnosis of non-communicable diseases in precision medicine approaches.

Persistent post-traumatic headache (PTH) after mild traumatic brain injury is one of the most prominent and highly reported persistent post-concussion symptoms (PPCS). Non-pharmacological treatments, including non-invasive neurostimulation technologies, have been proposed for use. Our objective was to evaluate headache characteristics at 1 month after repetitive transcranial magnetic stimulation (rTMS) treatment in participants with PTH and PPCS. A double-blind, randomized, sham-controlled, pilot clinical trial was performed on 20 participants (18–65 years) with persistent PTH (International Classification of Headache Disorders, 3rd edition) and PPCS (International Classification of Diseases, Tenth Revision). Ten sessions of rTMS therapy (10 Hz, 600 pulses, 70% resting motor threshold amplitude) were delivered to the left dorsolateral pre-frontal cortex. The primary outcome was a change in headache frequency or severity at 1 month post-rTMS. Two-week-long daily headache diaries and clinical questionnaires assessing function, PPCS, cognition, quality of life, and mood were completed at baseline, post-treatment, and at 1, 3, and 6 months post-rTMS. A two-way (treatment × time) mixed analyisis of variance indicated a significant overall time effect for average headache severity (F (3,54) = 3.214; p = 0.03) and a reduction in headache frequency at 1 month post-treatment (#/2 weeks, REAL −5.2 [standard deviation {SD} = 5.8]; SHAM, −3.3 [SD = 7.7]). Secondary outcomes revealed an overall time interaction for headache impact, depression, post-concussion symptoms, and quality of life. There was a significant reduction in depression rating in the REAL group between baseline and 1 month post-treatment, with no change in the SHAM group (Personal Health Questionnaire-9; REAL, −4.3 [SD = 3.7[ p = 0.020]; SHAM, −0.7 [SD = 4.7; p = 1.0]; Bonferroni corrected). In the REAL group, 60% returned to work whereas only 10% returned in the SHAM group (p = 0.027). This pilot study demonstrates an overall time effect on headache severity, functional impact, depression, PPCS, and quality of life after rTMS treatment in participants with persistent PTH; however, findings were below clinical significance thresholds. There was a 100% response rate, no dropouts, and minimal adverse effects, warranting a larger phase II study. Clinicaltrials.gov: NCT03691272.

A 61-year-old man sustained a mild traumatic brain injury (mTBI) following a pedestrian versus vehicle traffic accident. Post injury, he began to experience symptoms including light-headedness, spatial disorientation, nausea, fatigue and prominent dizziness brought on by postural change, physical activity or eye movements. Symptoms of dizziness persisted for over 5 years, despite numerous extensive and rigorous vestibular and vision therapy regimens. All investigations suggested normal peripheral and central vestibular functioning. The patient underwent 10 sessions of repetitive transcranial magnetic stimulation (rTMS) treatment, with stimulation of the left dorsolateral prefrontal cortex at 70% of resting motor threshold and a frequency of 10 Hz. Dizziness symptom severity and frequency were reduced by greater than 50% at 3 months post treatment, with a clinically significant reduction of dizziness disability from 40 to 21 points on the Dizziness Handicap Inventory. We propose rTMS as a safe, effective and cost-effective treatment option for patients who experience persistent post-traumatic dizziness secondary to mTBI.

Abstract Determinants of lifetime health are complex and emphasize the need for robust predictors of disease risk. Allostatic load (AL) has become a clinical framework to estimate the cumulative biological burden associated with chronic stress. To assist knowledge translation in the developmental origins of health and disease field, clinically valid methods for reliable AL assessment in experimental models are urgently needed. Here, we introduce the rat cumulative allostatic load measure (rCALM), as a new preclinical knowledge translation tool to assess the burden of chronic stress. First, we identified an array of stress-associated physiological markers that are particularly sensitive to hypothalamic–pituitary–adrenal axis dysregulation by ancestral prenatal stress. Second, we determined which of these markers are susceptible to an intervention by environmental enrichment (EE) to mitigate AL. The markers most responsive to stress and EE therapy were assembled to become operationalized in the rCALM. Third, the new rCALM was validated for the ability to indicate future disease risks. The results show that the rCALM estimates the burden of chronic stress and serves as a proxy to estimate stress resilience and vulnerability to disease. Using the rCALM we showed that enrichment therapy can offset the adverse health outcomes linked to a high AL. Thus, the rCALM provides a model for the development of new test strategies that facilitate knowledge translation in preclinical animal models.

Stress in utero causes epigenetic changes that manifest in offspring physiology and behaviour, becoming risk factors for complex adult diseases. Here we used 1H NMR spectroscopy to analyze two novel cohorts; first, we assessed urine metabolomes of adolescents in utero during the largest natural disaster in Canadian history; second, we investigated blood plasma metabolomes of offspring that were transgenerationally or multigenerationally-stressed in utero. Metabolomic profiles in offspring of high PNMS mothers were significantly altered. Higher PNMS generated significant alterations in metabolic pathways involving energy metabolism and protein biosynthesis in both rats and humans, particularly in BCAA synthesis, TCA cycle, muscle performance, and immunoregulation. Dysregulation of energy and protein metabolism suggests an increased risk of metabolic diseases, such as insulin resistance, diabetes, and obesity. The present findings provide a novel approach to PNMS outcomes and HPA-axis dysregulation by taking a metabolomics perspective and utilizing novel stressors in animal and human models.

What you'll need - 1x non-stick 60/90com shallow baking tray Ingredients - 500g Butter melted 8 Cups sugar 8 eggs 1 and half cups dark coco powder 1 split vanilla pod 2/3 of a cup plain flour Half-teaspoon baking powder 1-teaspoon salt 420g Dark chocolate chips 2 cups roasted and peeled hazelnuts How to make them - Add all the in gradients to the melted butter in a bowl.

ObjectiveTo determine if 1H NMR spectroscopy of urine and a quantitative metabolomics approach can aid diagnostic and prognostic outcomes in patients who have suffered acute sport concussion.DesignPre-concussion urine samples were collected from WinSport athletes at the beginning of the sport season. Any athlete who experienced a head injury reported to a brain injury clinic to be tested within 72 hours of head injury. This testing included collection of a post-concussion urine sample for metabolomic analysis.SettingBrain injury clinic and metabolomics laboratory.Participants167 athletes entered the study with a total of 39 concussions occurring. Inclusion criteria: at least 18 years old, diagnosis of concussion, and concussion sustained within 72 hours. Exclusion criteria: multiple injuries coinciding with concussion and a past history of neurological pathology.Outcome measuresMetabolite concentrations were calculated in pre- and post-concussion urine samples and compared using a paired t-test and partial least squares discriminant analysis (PLS-DA) to determine which metabolites led to significant variation between samples.Main resultsThe PLS-DA model showed significant variation between baseline and post-injury sample groups and passed all permutation and cross-validation testing. A paired t-test, with cross-validation, isolated five significant metabolites of interest in the concussion group (p<0.05).ConclusionsUsing NMR spectroscopy we quantified urinary metabolites in patients before and after concussion. This revealed several metabolites that were shown to be significantly altered following injury, opening up future inquiry into both the pathways and processes involved in concussion and new avenues for personalized diagnosis and treatment.Competing interestsNone.

Antigen 43 (Ag43) expression induces aggregation and biofilm formation that has consequences for bacterial colonisation and infection. Ag43 is secreted through the Type 5 subtype “a” secretion system (T5aSS) and is a prototypical member of the family of self-associating autotransporters (SAATs). As a T5aSS protein, Ag43 has a modular architecture comprised of (i) a signal peptide, (ii) a passenger domain that can be subdivided into three subdomains (SL, EJ, and BL), (iii) an autochaperone (AC) domain, and (iv) an outer membrane translocator. The cell-surface SL subdomain is directly involved in the “Velcro-handshake” mechanism resulting in bacterial autoaggregation. Ag43 is considered to have a ubiquitous distribution in E. coli genomes and many strains harbour multiple agn43 genes. However, recent phylogenetic analyses indicated the existence of four distinct Ag43 classes exhibiting different propensities for autoaggregation and interactions. Given the knowledge of the diversity and distribution of Ag43 in E. coli genomes is incomplete, we have performed a thorough in silico investigation across bacterial genomes. Our comprehensive analyses indicate that Ag43 passenger domains cluster in six phylogenetic classes associated with different SL subdomains. The diversity of Ag43 passenger domains is a result of the association of the SL subtypes with two different EJ-BL-AC modules. We reveal that agn43 is almost exclusively present among bacterial species of the Enterobacteriaceae family and essentially in the Escherichia genus (99.6%) but that it is not ubiquitous in E. coli. The gene is typically present as a single copy but up to five copies of agn43 with different combinations of classes can be observed. The presence of agn43 as well as its different classes appeared to differ between Escherichia phylogroups. Strikingly, agn43 is present in 90% of E. coli from E phylogroup. Our results shed light on Ag43 diversity and provide a rational framework for investigating its role in E. coli ecophysiology and physiopathology.

From January 2011 to December 2013, we constructed a comprehensive pCO2 data set based on voluntary observing ship (VOS) measurements in the western English Channel (WEC). We subsequently estimated surface pCO2 and air–sea CO2 fluxes in northwestern European continental shelf waters using multiple linear regressions (MLRs) from remotely sensed sea surface temperature (SST), chlorophyll a concentration (Chl a), wind speed (WND), photosynthetically active radiation (PAR) and modeled mixed layer depth (MLD). We developed specific MLRs for the seasonally stratified northern WEC (nWEC) and the permanently well-mixed southern WEC (sWEC) and calculated surface pCO2 with uncertainties of 17 and 16 µatm, respectively. We extrapolated the relationships obtained for the WEC based on the 2011–2013 data set (1) temporally over a decade and (2) spatially in the adjacent Celtic and Irish seas (CS and IS), two regions which exhibit hydrographical and biogeochemical characteristics similar to those of WEC waters. We validated these extrapolations with pCO2 data from the SOCAT and LDEO databases and obtained good agreement between modeled and observed data. On an annual scale, seasonally stratified systems acted as a sink of CO2 from the atmosphere of -0.6 ± 0.3, -0.9 ± 0.3 and -0.5 ± 0.3 mol C m-2 yr-1 in the northern Celtic Sea, southern Celtic sea and nWEC, respectively, whereas permanently well-mixed systems acted as source of CO2 to the atmosphere of 0.2 ± 0.2 and 0.3 ± 0.2 mol C m-2 yr-1 in the sWEC and IS, respectively. Air–sea CO2 fluxes showed important inter-annual variability resulting in significant differences in the intensity and/or direction of annual fluxes. We scaled the mean annual fluxes over these provinces for the last decade and obtained the first annual average uptake of -1.11 ± 0.32 Tg C yr-1 for this part of the northwestern European continental shelf. Our study showed that combining VOS data with satellite observations can be a powerful tool to estimate and extrapolate air–sea CO2 fluxes in sparsely sampled area.