Plasma amino acid concentrations after the ingestion of dairy and collagen proteins, in healthy active males

Introduction: Recent evidence suggests that the consumption of essential amino acids (AA) and/or those abundantly present in collagen may have the capacity to influence the synthesis of new collagen in ligaments and tendons, when tissue perfusion is optimized (e.g., during exercise). However, little is currently known about the bioavailability of these AAs in blood after the consumption of various collagen and diary protein sources: such information is needed to develop potentially useful dietary and supplement intake strategies. Objectives: The aim of the current study was to characterize blood AA concentrations in response to consumption of collagen and dairy protein sources; specifically, maximum concentrations, the timing of maximum concentration, and total (area under the curve) exposure above baseline. Methods: A 20 g serve of various dairy and collagen proteins, and a 300 mL serve of bone broth were consumed by healthy, recreationally active males after an overnight fast. Blood samples were drawn every 20 min for a total of 180 min, for analysis of plasma AA concentrations. Total AA, essential AA and collagen specific AAs were analyzed for maximum concentration, timing of peak, and area under the curve. Results: In general, protein intake was associated with a similar increase in total and collagen specific AAs, except for collagen proteins being a superior source of glycine (683 ± 166 μmol/L) compared to 260 ± 65 μmol/L for dairy proteins (P < 0.0001), whilst dairy proteins were a superior source of leucine (267 ± 77 μmol/L) compared to 189 ± μmol/L for collagen proteins (P < 0.04). Although there were several differences in the bioavailability of hydrolysed compared to non-hydrolysed proteins, this only reached statistical significance within the dairy proteins, but not for collagen proteins. Conclusions: The intake of collagen proteins result in higher plasma peaks of glycine, whilst the intake of dairy proteins result in higher plasma peaks of leucine. This information may support further investigations, and identification of key AAs that may support exercise in the synthesis of collagen

A strong sense of coherence associated with reduced risk of anxiety disorder among women in disadvantaged circumstances: British population study.

OBJECTIVE: Many patients receiving medical treatment for anxiety relapse or do not improve. Research has therefore been turning to coping mechanisms as a way to decrease anxiety rates. Previously, we showed that living in a deprived area significantly increases the risk of anxiety in women, but not in men. The objective of this study is to assess whether sense of coherence (coping mechanism) buffers the influence of area deprivation on women's risk of generalised anxiety disorder using data from the European Prospective Investigation of Cancer-Norfolk. DESIGN: Large, population study. SETTING: UK population-based cohort. PARTICIPANTS: 30 445 people over the age of 40 years were recruited through general practice registers in England. Of these, 20 919 completed a structured health and lifestyle questionnaire used to assess generalised anxiety disorder and sense of coherence. Area deprivation was measured using 1991 Census data, and sense of coherence and anxiety were examined in 1996-2000. 10 183 women had data on all variables. MAIN OUTCOME MEASURE: Past-year generalised anxiety disorder defined according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. RESULTS: In this study, 2.6% (260/10 183) of women had generalised anxiety disorder. In those with a strong sense of coherence, area deprivation was not significantly associated with anxiety (OR 1.29, 95% CI 0.77 to 2.17). However, among women with a weak sense of coherence, those living in deprived areas were almost twice as likely to have generalised anxiety disorder compared with those living in more affluent areas (OR 1.99, 95% CI 1.37 to 2.91). CONCLUSION: The number of women living in deprived conditions is large worldwide, and significant numbers are affected by generalised anxiety disorder. Sense of coherence moderates the association between area deprivation and anxiety in women; therefore, interventions targeting coping mechanisms may need to be considered for people with anxiety

Association of self-rated health with multimorbidity, chronic disease and psychosocial factors in a large middle-aged and older cohort from general practice: a cross-sectional study.

BACKGROUND: The prevalence of coexisting chronic conditions (multimorbidity) is rising. Disease labels, however, give little information about impact on subjective health and personal illness experience. We aim to examine the strength of association of single and multimorbid physical chronic diseases with self-rated health in a middle-aged and older population in England, and to determine whether any association is mediated by depression and other psychosocial factors. METHODS: 25 268 individuals aged 39 to 79 years recruited from general practice registers in the European Prospective Investigation of Cancer (EPIC-Norfolk) study, completed a survey including self-rated health, psychosocial function and presence of common physical chronic conditions (cancer, stroke, heart attack, diabetes, asthma/bronchitis and arthritis). Logistic regression models determined odds of "moderate/poor" compared to "good/excellent" health by condition and number of conditions adjusting for psychosocial measures. RESULTS: One-third (8252) reported one, around 7.5% (1899) two, and around 1% (194) three or more conditions. Odds of "moderate/poor" self-rated health worsened with increasing number of conditions (one (OR = 1.3(1.2-1.4)) versus three or more (OR = 3.4(2.3-5.1)), and were highest where there was comorbidity with stroke (OR = 8.7(4.6-16.7)) or heart attack (OR = 8.5(5.3-13.6)). Psychosocial measures did not explain the association between chronic diseases and multimorbidity with self-rated health.The relationship of multimorbidity with self-rated health was particularly strong in men compared to women (three or more conditions: men (OR = 5.2(3.0-8.9)), women OR = 2.1(1.1-3.9)). CONCLUSIONS: Self-rated health provides a simple, integrative patient-centred assessment for evaluation of illness in the context of multiple chronic disease diagnoses. Those registering in general practice in particular men with three or more diseases or those with cardiovascular comorbidities and with poorer self-rated health may warrant further assessment and intervention to improve their physical and subjective health.EPIC-Norfolk is supported by programme grants from Medical Research Council UK (G9502233, G0300128) and Cancer Research UK (C865/A2883), with additional support from the European Union, Stroke Association, Research into Ageing, British Heart Foundation, Department of Health and Wellcome Trust.This is the final version. It was first published by BioMed Central at http://www.biomedcentral.com/1471-2296/15/18

Short-Term Carbohydrate Restriction Impairs Bone Formation at Rest and During Prolonged Exercise to a Greater Degree than Low Energy Availability

Bone stress injuries are common in athletes, resulting in time lost from training and competition. Diets that are low in energy availability have been associated with increased circulating bone resorption and reduced bone formation markers, particularly in response to prolonged exercise. However, studies have not separated the effects of low energy availability per se from the associated reduction in carbohydrate availability. The current study aimed to compare the effects of these two restricted states directly. In a parallel group design, 28 elite racewalkers completed two 6-day phases. In the Baseline phase, all athletes adhered to a high carbohydrate/high energy availability diet (CON). During the Adaptation phase, athletes were allocated to one of three dietary groups: CON, low carbohydrate/high fat with high energy availability (LCHF), or low energy availability (LEA). At the end of each phase, a 25-km racewalk was completed, with venous blood taken fasted, pre-exercise, and 0, 1, 3 hours postexercise to measure carboxyterminal telopeptide (CTX), procollagen-1 N-terminal peptide (P1NP), and osteocalcin (carboxylated, gla-OC; undercarboxylated, glu-OC). Following Adaptation, LCHF showed decreased fasted P1NP (~26%; p < 0.0001, d = 3.6), gla-OC (~22%; p = 0.01, d = 1.8), and glu-OC (~41%; p = 0.004, d = 2.1), which were all significantly different from CON (p < 0.01), whereas LEA demonstrated significant, but smaller, reductions in fasted P1NP (~14%; p = 0.02, d = 1.7) and glu-OC (~24%; p = 0.049, d = 1.4). Both LCHF (p = 0.008, d = 1.9) and LEA (p = 0.01, d = 1.7) had significantly higher CTX pre-exercise to 3 hours post-exercise but only LCHF showed lower P1NP concentrations (p < 0.0001, d = 3.2). All markers remained unchanged from Baseline in CON. Short-term carbohydrate restriction appears to result in reduced bone formation markers at rest and during exercise with further exercise-related increases in a marker of bone resorption. Bone formation markers during exercise seem to be maintained with LEA although resorption increased. In contrast, nutritional support with adequate energy and carbohydrate appears to reduce unfavorable bone turnover responses to exercise in elite endurance athletes. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)

Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism

Global changes in transcriptional regulation and RNA metabolism are crucial features of cancer development. However, little is known about the role of the core promoter in defining transcript identity and post-transcriptional fates, a potentially crucial layer of transcriptional regulation in cancer. In this study, we use CAGE-seq analysis to uncover widespread use of dual-initiation promoters in which non-canonical, first-base-cytosine (C) transcription initiation occurs alongside first-base-purine initiation across 59 human cancers and healthy tissues. C-initiation is often followed by a 5' terminal oligopyrimidine (5'TOP) sequence, dramatically increasing the range of genes potentially subjected to 5'TOP-associated post-transcriptional regulation. We show selective, dynamic switching between purine and C-initiation site usage, indicating transcription initiation-level regulation in cancers. We additionally detail global metabolic changes in C-initiation transcripts that mark differentiation status, proliferative capacity, radiosensitivity, and response to irradiation and to PI3K-Akt-mTOR and DNA damage pathway-targeted radiosensitization therapies in colorectal cancer organoids and cancer cell lines and tissues.</p

Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder with variable expressivity and a predisposition to tumorigenesis, results from disordered expression and/or function of imprinted genes at chromosome 11p15.5. There are no generally agreed clinical diagnostic criteria, with molecular studies commonly performed to confirm diagnosis. In particular, methylation status analysis at two 11p15.5 imprinting control centres (IC1 and IC2) detects up to 80% of BWS cases (though low-level mosaicism may not be detected). In order to evaluate the relationship between the clinical presentation of suspected BWS and IC1/2 methylation abnormalities we reviewed the results of >1,000 referrals for molecular diagnostic testing. RESULTS: Out of 1,091 referrals, 507 (46.5%) had a positive diagnostic test for BWS. The frequency of tumours was 3.4% in those with a molecular diagnosis of BWS. Previously reported genotype-phenotype associations with paternal uniparental disomy, IC1, and IC2 epimutation groups were confirmed and potential novel associations detected. Predictive values of previously described clinical diagnostic criteria were compared and, although there were differences in their sensitivity and specificity, receiver operating characteristic (ROC) analysis demonstrated that these were not optimal in predicting 11p15.5 methylation abnormalities. Using logistic regression, we identified clinical features with the best predictive value for a positive methylation abnormality. Furthermore, we developed a weighted scoring system (sensitivity 75.9%, and specificity 81.8%) to prioritise patients presenting with the most common features of BWS, and ROC analysis demonstrated superior performance (area under the curve 0.85, 95% CI 0.83 to 0.87) compared to previous criteria. CONCLUSIONS: We suggest that this novel tool will facilitate selection of patients with suspected BWS for routine diagnostic testing and so improve the diagnosis of the disorder.We thank Action Medical Research and the Cambridge NIHR Biomedical Research Centre for financial support.This is the final published version. It first appeared at http://www.clinicalepigeneticsjournal.com/content/6/1/11

Six days of low carbohydrate, not energy availability, alters the iron and immune response to exercise in elite athletes

Purpose To quantify the effects of a short-term (6-d) low carbohydrate (CHO) high fat (LCHF), and low energy availability (LEA) diet on immune, inflammatory, and iron-regulatory responses to exercise in endurance athletes. Methods Twenty-eight elite male race walkers completed two 6-d diet/training phases. During phase 1 (Baseline), all athletes consumed a high CHO/energy availability (CON) diet (65% CHO and ~40 kcal·kg−1 fat-free mass (FFM)·d−1). In phase 2 (Adaptation), athletes were allocated to either a CON (n = 10), LCHF (n = 8; <50 g·d−1 CHO and ~40 kcal·kg−1·FFM−1·d−1), or LEA diet (n = 10; 60% CHO and 15 kcal·kg−1·FFM−1·d−1). At the end of each phase, athletes completed a 25-km race walk protocol at ~75% V˙O2max. On each occasion, venous blood was collected before and after exercise for interleukin-6, hepcidin, cortisol, and glucose concentrations, as well as white blood cell counts. Results The LCHF athletes displayed a greater IL-6 (P = 0.019) and hepcidin (P = 0.011) response to exercise after Adaptation, compared with Baseline. Similarly, postexercise increases in total white blood cell counts (P = 0.026) and cortisol levels (P 0.05). No differences between CON and LEA were evident for any of the measured biological markers (all P > 0.05). Conclusions Short-term adherence to a LCHF diet elicited small yet unfavorable iron, immune, and stress responses to exercise. In contrast, no substantial alterations to athlete health were observed when athletes restricted energy availability compared with athletes with adequate energy availability. Therefore, short-term restriction of CHO, rather than energy, may have greater negative impacts on athlete health

Germline Mutation in NLRP2 (NALP2) in a Familial Imprinting Disorder (Beckwith-Wiedemann Syndrome)

Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centres (IC1 and IC2). However, rare familial cases may be associated with germline 11p15.5 deletions causing abnormal imprinting in cis. We report a family with BWS and an IC2 epimutation in which affected siblings had inherited different parental 11p15.5 alleles excluding an in cis mechanism. Using a positional-candidate gene approach, we found that the mother was homozygous for a frameshift mutation in exon 6 of NLRP2. While germline mutations in NLRP7 have previously been associated with familial hydatidiform mole, this is the first description of NLRP2 mutation in human disease and the first report of a trans mechanism for disordered imprinting in BWS. These observations are consistent with the hypothesis that NLRP2 has a previously unrecognised role in establishing or maintaining genomic imprinting in humans

Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL.

A subset of individuals diagnosed with cerebral palsy will have an underlying genetic diagnosis. Previously, a missense variant in GAD1 was described as a candidate mutation in a single family diagnosed with autosomal recessive spastic cerebral palsy-1 (CPSQ1; OMIM 603513). Following the ascertainment of a further branch of the CPSQ1 kindred, we found that the previously reported GAD1 variant did not segregate with the neurological disease phenotype in the recently ascertained branch of the kindred. Following genetic linkage studies to map autozygous regions and whole-exome sequencing, a missense variant (c.527 T > C; p. Leu176Pro, rs773333490) in the HPDL gene was detected and found to segregate with disease status in both branches of the kindred. HPDL encodes a 371-amino acid protein (4-Hydroxyphenylpyruvate Dioxygenase Like) that localizes to mitochondria but whose function is uncertain. Recently, biallelic loss of function variants and missense substitution-causing variants in HPDL were reported to cause a childhood onset progressive spastic movement disorder with a variable presentation. These findings suggest that HPDL-related neurological disease may mimic spastic cerebral palsy and that GAD1 should not be included in diagnostic gene panels for inherited cerebral palsy.NIH