The anxiety and ethanol intake controlling GAL5.1 enhancer is epigenetically modulated by, and controls preference for, high-fat diet.

Excess maternal fat intake and obesity increase offspring susceptibility to conditions such as chronic anxiety and substance abuse. We hypothesised that environmentally modulated DNA methylation changes (5mC/5hmC) in regulatory regions of the genome that modulate mood and consumptive behaviours could contribute to susceptibility to these conditions. We explored the effects of environmental factors on 5mC/5hmC levels within the GAL5.1 enhancer that controls anxiety-related behaviours and alcohol intake. We first observed that 5mC/5hmC levels within the GAL5.1 enhancer differed significantly in different parts of the brain. Moreover, we noted that early life stress had no significant effect of 5mC/5hmC levels within GAL5.1. In contrast, we identified that allowing access of pregnant mothers to high-fat diet (> 60% calories from fat) had a significant effect on 5mC/5hmC levels within GAL5.1 in hypothalamus and amygdala of resulting male offspring. Cell transfection-based studies using GAL5.1 reporter plasmids showed that 5mC has a significant repressive effect on GAL5.1 activity and its response to known stimuli, such as EGR1 transcription factor expression and PKC agonism. Intriguingly, CRISPR-driven disruption of GAL5.1 from the mouse genome, although having negligible effects on metabolism or general appetite, significantly decreased intake of high-fat diet suggesting that GAL5.1, in addition to being epigenetically modulated by high-fat diet, also actively contributes to the consumption of high-fat diet suggesting its involvement in an environmentally influenced regulatory loop. Furthermore, considering that GAL5.1 also controls alcohol preference and anxiety these studies may provide a first glimpse into an epigenetically controlled mechanism that links maternal high-fat diet with transgenerational susceptibility to alcohol abuse and anxiety.

A history of opioid exposure in females increases the risk of metabolic disorders in their future male offspring.

Worldwide consumption of opioids remains at historic levels. Preclinical studies report intergenerational effects on the endogenous opioid system of future progeny following preconception morphine exposure. Given the role of endogenous opioids in energy homeostasis, such effects could impact metabolism in the next generation. Thus, we examined diet-induced modifications in F1 male progeny of morphine-exposed female rats (MORF1). When fed a high fat-sugar diet (FSD) for 6 weeks, MORF1 males display features of emerging metabolic syndrome; they consume more food, gain more weight, and develop fasting-induced hyperglycemia and hyperinsulinemia. In the hypothalamus, proteins involved in energy homeostasis are modified and RNA sequencing revealed down-regulation of genes associated with neuronal plasticity, coupled with up-regulation of genes associated with immune, inflammatory, and metabolic processes that are specific to FSD-maintained MORF1 males. Thus, limited preconception morphine exposure in female rats increases the risk of metabolic syndrome/type 2 diabetes in the next generation.

Prevalence and management of diabetic neuropathy in secondary care in Qatar.

AIMS: Diabetic neuropathy (DN) is a "Cinderella" complication, particularly in the Middle East. A high prevalence of undiagnosed DN and those at risk of diabetic foot ulceration (DFU) is a major concern. We have determined the prevalence of DN and its risk factors, DFU, and those at risk of DFU in patients with type 2 diabetes mellitus (T2DM) in secondary care in Qatar. MATERIALS AND METHODS: Adults with T2DM were randomly selected from the two National Diabetes Centers in Qatar. DN was defined by the presence of neuropathic symptoms and a vibration perception threshold (VPT) ≥ 15 V. Participants with a VPT ≥ 25 V were categorized as high risk for DFU. Painful DN was defined by a DN4 score ≥4. Logistic regression analysis was used to identify predictors of DN. RESULTS: In 1082 adults with T2DM (age 54 ± 11 years, duration of diabetes 10.0 ± 7.7 years, 60.6% males), the prevalence of DN was 23.0% (95% CI, 20.5%-25.5%) of whom 33.7% (95% CI, 27.9%-39.6%) were at high risk of DFU, and 6.3% had DFU; 82.0% of the patients with DN were previously undiagnosed. The prevalence of DN increased with age and duration of diabetes and was associated with poor glycaemic control (HbA1c ≥ 9%) AOR = 2.1 (95% CI, 1.3-3.2), hyperlipidaemia AOR = 2.7 (95% CI, 1.5-5.0), and hypertension AOR = 2.0 (95% CI, 1.2-3.4). CONCLUSIONS: Despite DN affecting 23% of adults with T2DM, 82% had not been previously diagnosed with one-third at high risk for DFU. This argues for annual screening and identification of patients with DN. Furthermore, we identify hyperglycaemia, hyperlipidaemia, and hypertension as predictors of DN.

In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson's disease.

See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline.

Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats.

BACKGROUND AND OBJECTIVE: Maternal overnutrition has been implicated in affecting the offspring by programming metabolic disorders such as obesity and diabetes, by mechanisms that are not clearly understood. This study aimed to determine the long-term impact of maternal high-fat (HF) diet feeding on epigenetic changes in the offspring's hypothalamic Pomc gene, coding a key factor in the control of energy balance. Further, it aimed to study the additional effects of postnatal overnutrition on epigenetic programming by maternal nutrition. METHODS: Eight-week-old female Sprague-Dawley rats were fed HF diet or low-fat (LF) diet for 6 weeks before mating, and throughout gestation and lactation. At postnatal day 21, samples were collected from a third offspring and the remainder were weaned onto LF diet for 5 weeks, after which they were either fed LF or HF diet for 12 weeks, resulting in four groups of offspring differing by their maternal and postweaning diet. RESULTS: With maternal HF diet, offspring at weaning had rapid early weight gain, increased adiposity, and hyperleptinemia. The programmed adult offspring, subsequently fed LF diet, retained the increased body weight. Maternal HF diet combined with offspring HF diet caused more pronounced hyperphagia, fat mass, and insulin resistance. The ARC Pomc gene from programmed offspring at weaning showed hypermethylation in the enhancer (nPE1 and nPE2) regions and in the promoter sequence mediating leptin effects. Interestingly, hypermethylation at the Pomc promoter but not at the enhancer region persisted long term into adulthood in the programmed offspring. However, there were no additive effects on methylation levels in the regulatory regions of Pomc in programmed offspring fed a HF diet. CONCLUSION: Maternal overnutrition programs long-term epigenetic alterations in the offspring's hypothalamic Pomc promoter. This predisposes the offspring to metabolic disorders later in life.

Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396.

UNLABELLED: HIV-1 maturation inhibitors are a novel class of antiretroviral compounds that consist of two structurally distinct chemical classes: betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by similar modes of action to generate aberrant noninfectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study, we utilized a series of novel analogues with decreasing similarity to PF-46396 to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding, and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, and inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into wild-type (WT) immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, and CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert-butyl group is essential for antiviral activity but is not an absolute requirement for Gag binding, (ii) the trifluoromethyl group is optimal but not essential for antiviral activity, and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but is not essential, as its replacement is tolerated. IMPORTANCE: Combinations of antiretroviral drugs successfully treat HIV/AIDS patients; however, drug resistance problems make the development of new mechanistic drug classes an ongoing priority. HIV-1 maturation inhibitors are novel as they target the Gag protein, specifically by inhibiting CA-SP1 proteolytic cleavage. The lack of high-resolution structural information of the CA-SP1 target in Gag has hindered our understanding of the inhibitor-binding pocket and maturation inhibitor mode of action. Therefore, we utilized analogues of the maturation inhibitor PF-46396 as chemical tools to determine the chemical components of PF-46396 that contribute to antiviral activity and Gag binding and the relationship between these essential properties. This is the first study to report structure-activity relationships of the maturation inhibitor PF-46396. PF-46396 is chemically distinct from betulinic acid-derived maturation inhibitors; therefore, our data provide a foundation of knowledge that will aid our understanding of how structurally distinct maturation inhibitors act by similar modes of action.

Effects of exercise on adolescent and adult hypothalamic and hippocampal neuroinflammation.

Adolescence is a period of significant brain plasticity that can be affected by environmental factors, including the degree of physical activity. Here we hypothesized that adolescent rats would be more sensitive to the beneficial metabolic and anti-inflammatory effects of voluntary exercise than adult rats, whose more mature brains have less capacity for plasticity. We tested this by giving adolescent and adult Wistar rats four weeks' voluntary access to running wheels. At the end of this period we assessed metabolic effects, including weight and circulating leptin and ghrelin, as well as performance in a novel object recognition test of memory and central changes in neuronal proliferation, survival, synaptic density, and inflammatory markers in hippocampus. We found exercise reduced fat mass and circulating leptin levels in both adults and adolescents but suppressed total weight gain and lean mass in adults only. Exercise stimulated neuronal proliferation in the suprapyramidal blade of the dentate gyrus in both adults and adolescents without altering the number of mature neurons during this time frame. Exercise also increased dentate microglial numbers in adolescents alone and microglial numbers in this region were inversely correlated with performance in the novel object recognition test. Together these data suggest that adolescent hippocampal microglia are more sensitive to the effects of exercise than those of adults, but this leads to no apparent improvement in recognition memory. © 2016 Wiley Periodicals, Inc.

Social stress during lactation, depressed maternal care, and neuropeptidergic gene expression.

Depression and anxiety can be severely detrimental to the health of both the affected woman and her offspring. In a rodent model of postpartum depression and anxiety, chronic social stress exposure during lactation induces deficits in maternal care and increases anxiety. Here, we extend previous findings by expanding the behavioral analyses, assessing lactation, and examining several neural systems within amygdalar and hypothalamic regions involved in the control of the stress response and expression of maternal care that may be mediating the behavioral changes in stressed dams. Compared with control dams, those exposed to chronic social stress beginning on day 2 of lactation show impaired maternal care and lactation and increased maternal anxiety on day 9 of lactation. Saccharin-based anhedonia and maternal aggression were increased and lactation was also impaired on day 16 of lactation. These behavioral changes were correlated with a decrease in oxytocin mRNA expression in the medial amygdala, and increases in the expressions of corticotrophin-releasing hormone mRNA in the central nucleus of the amygdala, glucocorticoid receptor mRNA in the paraventricular nucleus, and orexin 2 receptor mRNA in the supraoptic nucleus of stressed compared with control dams. The increase in glucocorticoid receptor mRNA in the paraventricular nucleus was negatively correlated with methylation of a CpG site in the promoter region. In conclusion, the data support the hypothesis that social stress during lactation can have profound effects on maternal care, lactation, and anxiety, and that these behavioral effects are mediated by central changes in stress and maternally relevant neuropeptide systems.

Sex-differential markers of psychiatric risk and treatment response based on premature aging of functional brain network dynamics and peripheral physiology.

BACKGROUND: Aging is a multilevel process of gradual decline that predicts morbidity and mortality. Independent investigations have implicated senescence of brain and peripheral physiology in psychiatric risk, but it is unclear whether these effects stem from unique or shared mechanisms. METHODS: To address this question, we analyzed clinical, blood chemistry and resting state functional neuroimaging data in a healthy aging cohort (N= 427; age 36-100 years) and two disorder-specific samples encompassing patients with early psychosis (100 patients, 16-35 years) and major depressive disorder (MDD) (104 patients, 20-76 years). RESULTS: We identified sex-dependent coupling between blood chemistry markers of metabolic senescence (i.e., homeostatic dysregulation), functional brain network aging, and psychiatric risk. In females, premature aging of frontoparietal and somatomotor networks was linked to greater homeostatic dysregulation. It also predicted the severity and treatment resistance of mood symptoms (depression/anxiety [all three samples], anhedonia [MDD]) and social withdrawal/behavioral inhibition (avoidant personality disorder [healthy aging]; negative symptoms [early psychosis]). In males, premature aging of the default mode, cingulo-opercular, and visual networks was linked to reduced homeostatic dysregulation and predicted severity and treatment resistance of symptoms relevant to hostility/aggression (antisocial personality disorder [healthy aging]; mania/positive symptoms [early psychosis]), impaired thought processes (early psychosis, MDD) and somatic problems (healthy aging, MDD). CONCLUSIONS: Our findings identify sexually dimorphic relationships between brain dynamics, peripheral physiology, and risk for psychiatric illness, suggesting that the specificity of putative risk biomarkers and precision therapeutics may be improved by considering sex and other relevant personal characteristics.

Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice.

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer's disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.

Maternal Immune Activation Induces Adolescent Cognitive Deficits Preceded by Developmental Perturbations in Cortical Reelin Signalling.

Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developing schizophrenia and other neurodevelopmental disorders. To understand the biological mechanisms underlying the link between MIA and increased risk, preclinical animal models have focussed on specific signalling pathways in the brain that mediate symptoms associated with neurodevelopmental disorders such as cognitive dysfunction. Reelin signalling in multiple brain regions is involved in neuronal migration, synaptic plasticity and long-term potentiation, and has been implicated in cognitive deficits. However, how regulation of Reelin expression is affected by MIA across cortical development and associated cognitive functions remains largely unclear. Using a MIA rat model, here we demonstrate cognitive deficits in adolescent object-location memory in MIA offspring and reductions in Reln expression prenatally and in the adult prefrontal cortex. Further, developmental disturbances in gene/protein expression and DNA methylation of downstream signalling components occurred subsequent to MIA-induced Reelin dysregulation and prior to cognitive deficits. We propose that MIA-induced dysregulation of Reelin signalling contributes to the emergence of prefrontal cortex-mediated cognitive deficits through altered NMDA receptor function, resulting in inefficient long-term potentiation. Our data suggest a developmental window during which attenuation of Reelin signalling may provide a possible therapeutic target.

DNA methylation patterns respond to thermal stress in the viviparous cockroach Diploptera punctata.

It is increasingly recognized that epigenetic mechanisms play a key role in acclimatization and adaptation to thermal stress in invertebrates. DNA methylation and its response to temperature variation has been poorly studied in insects. Here, we investigated DNA methylation and hydroxymethylation patterns in the viviparous cockroach Diploptera punctata at a global and gene specific level in response to variation in temperature. We specifically studied methylation percentage in the heat shock protein 70 (Hsp70), whose function is linked to thermal plasticity and resistance. We found high levels of DNA methylation in several tissues but only low levels of DNA hydroxymethylation in the brain. Hsp70 methylation patterns showed significant differences in response to temperature. We further found that global DNA methylation variation was considerably lower at 28°C compared to higher or lower temperatures, which may be indicative of the optimal temperature for this species. Our results demonstrate that DNA methylation could provide a mechanism for insects to dynamically respond to changing temperature conditions in their environment.

Biopsychosocial correlates of psychological distress in Latina mothers.

BACKGROUND: Few studies have explored the relationship between psychological, psychosocial and biological factors among Latinas. An integrated understanding of how these factors associate with psychological distress is necessary for the development of culturally relevant screening tools and interventions. The study aim was to examine the relationships among (a) psychological distress symptoms, (b) psychosocial factors (discrimination, acculturation, acculturative stress, economic hardship), and (c) biological (DNA methylation of stress-related genes) factors among Latinas during pregnancy and postpartum period. METHODS: A sample of 150 pregnant Latinas completed the Inventory of Depression and Anxiety Symptoms II (IDAS-II), psychosocial questionnaires (discrimination, acculturation, acculturative stress, economic hardship) before (24-32 weeks) and after gestation (4-6 weeks postpartum). Blood samples were collected between 24-32 weeks gestation. Correlations were determined between psychosocial and biological measures and psychological distress measures. Multivariable linear regression models were conducted to assess the relationships between IDAS and stressors. RESULTS: Several correlations among psychosocial measures,DNA methylation factors and IDAS-II variables were identified. Among the psychosocial measures, everyday discrimination was the most strongly and consistently associated with IDAS-II. DNA methylation of NR3C1 affects the associations between psychological and psychosocial distress. LIMITATIONS: We only assessed DNA methylation during pregnancy and focused on four HPA-related genes. Longitudinal assessment of DNA methylation and genome-wide analysis can provide a better picture of the role of methylation in psychological distress. CONCLUSIONS: This work may assist clinicians and policy makers in effectively recognizing and preventing maternal mental health disparities based on discrimination and other psychosocial stressors in at-risk groups.

Prevalence and risk factors for diabetic neuropathy and painful diabetic neuropathy in primary and secondary healthcare in Qatar.

AIMS/INTRODUCTION: This study determined the prevalence and risk factors for diabetic peripheral neuropathy (DPN) and painful DPN (pDPN) in patients with type 2 diabetes in primary healthcare (PHC) and secondary healthcare (SHC) in Qatar. MATERIALS AND METHODS: This was a cross-sectional multicenter study. Adults with type 2 diabetes were randomly enrolled from four PHC centers and two diabetes centers in SHC in Qatar. Participants underwent assessment of clinical and metabolic parameters, DPN and pDPN. RESULTS: A total of 1,386 individuals with type 2 diabetes (297 from PHC and 1,089 from SHC) were recruited. The prevalence of DPN (14.8% vs 23.9%, P = 0.001) and pDPN (18.1% vs 37.5%, P < 0.0001) was significantly lower in PHC compared with SHC, whereas those with DPN at high risk for diabetic foot ulceration (31.8% vs 40.0%, P = 0.3) was comparable. The prevalence of undiagnosed DPN (79.5% vs 82.3%, P = 0.66) was comparably high, but undiagnosed pDPN (24.1% vs 71.5%, P < 0.0001) was lower in PHC compared with SHC. The odds of DPN and pDPN increased with age and diabetes duration, and DPN increased with poor glycemic control, hyperlipidemia and hypertension, whereas pDPN increased with obesity and reduced physical activity. CONCLUSIONS: The prevalence of DPN and pDPN in type 2 diabetes is lower in PHC compared with SHC, and is attributed to overall better control of risk factors and referral bias due to patients with poorly managed complications being referred to SHC. However, approximately 80% of patients had not been previously diagnosed with DPN in PHC and SHC. Furthermore, we identified a number of modifiable risk factors for PDN and pDPN.

Associations of sperm telomere length with semen parameters, clinical outcomes and lifestyle factors in human normozoospermic samples.

BACKGROUND: Many studies have demonstrated that lifestyle factors can affect sperm quality and fertility. Sperm telomere length (STL) has been reported as potential biomarker or sperm quality. However, no studies have investigated how lifestyle factors can affect STL and associated clinical outcomes. OBJECTIVES: The purpose of this manuscript is to investigate any association between STL with lifestyle factors, semen parameters and clinical outcomes. MATERIALS AND METHODS: Sperm telomere length was measured using real-time PCR in normozoospermic male partners (n = 66) of couples undergoing ART treatment. Each participant also completed a detailed questionnaire about general lifestyle. Linear regression univariate analysis and ANCOVA were performed to respectively determine correlations between STL and study parameters or identify statistically significant differences in STL while controlling for age, BMI and other factors. RESULTS: Using a linear regression model, STL is positively correlated with in vitro fertilization success (n = 65, r = 0.37, P = .004) but not with embryo cleavage rates and post-implantation clinical outcomes including gestational age-adjusted birth weight. No associations were observed between STL and sperm count, concentration or progressive motility. We further found that STL did not associate age, BMI, health or lifestyle factors. DISCUSSION: In somatic cells, the rate of telomere shortening is influenced by a number of lifestyle factors such as smoking, diet and occupation. However, little is known about how lifestyle factors affect STL and subsequently reproductive outcome. Out data suggest that STL might have an important role mechanistically for fertilization rate regardless of sperm parameters and lifestyle factors. CONCLUSION: The results of this study demonstrate that STL is associated with in vitro fertilization rates, but not with semen parameters nor lifestyle factors. Further investigations are warranted to identify the potential variation of STL overtime to clarify its significance as a potential biomarker in ART.

The Prospective Study of Epigenetic Regulatory Profiles in Sport and Exercise Monitored Through Chromosome Conformation Signatures.

The integration of genetic and environmental factors that regulate the gene expression patterns associated with exercise adaptation is mediated by epigenetic mechanisms. The organisation of the human genome within three-dimensional space, known as chromosome conformation, has recently been shown as a dynamic epigenetic regulator of gene expression, facilitating the interaction of distal genomic regions due to tight and regulated packaging of chromosomes in the cell nucleus. Technological advances in the study of chromosome conformation mean a new class of biomarker-the chromosome conformation signature (CCS)-can identify chromosomal interactions across several genomic loci as a collective marker of an epigenomic state. Investigative use of CCSs in biological and medical research shows promise in identifying the likelihood that a disease state is present or absent, as well as an ability to prospectively stratify individuals according to their likely response to medical intervention. The association of CCSs with gene expression patterns suggests that there are likely to be CCSs that respond, or regulate the response, to exercise and related stimuli. The present review provides a contextual background to CCS research and a theoretical framework discussing the potential uses of this novel epigenomic biomarker within sport and exercise science and medicine.

Neuroinflammation in mild cognitive impairment and Alzheimer's disease: A meta-analysis.

BACKGROUND: Increasingly, evidence from brain imaging supports the role of neuroinflammation in dementia progression. Yet, it is not clear if there are patterns of spatial and temporal susceptibility to neuroinflammatory processes in the brain that may correspond to dementia staging or symptom expression. METHODS: We searched literature databases for case-control studies examining levels of translocator protein (TSPO) levels using positron emission tomography, representing neuroinflammation, in regional analyses between healthy controls and mild cognitive impairment (MCI) or Alzheimer's disease (AD) subjects. Standardised mean differences (SMDs) were calculated and results meta-analysed using random-effects models. Quality assessments, sensitivity analysis, subgroup analysis and meta-regressions were also performed. RESULTS: Twenty-eight studies comprising 755 (HC = 318, MCI = 168, AD = 269) participants and 37 brain regions were included. Compared to HCs, AD participants had increased TSPO levels throughout the brain (SMD range: 0.43-1.76), especially within fronto-temporal regions. MCI subjects also had increased TSPO levels, mainly within the neocortex, with more modest effects (SMD range: 0.46 - 0.90). Meta-regression analysis identified an inverse association between TSPO levels in the parietal region and Mini-Mental State Examination scores, a proxy for disease severity, in AD subjects (estimate: -0.11, 95% confidence interval: -0.21 to -0.02; P = 0.024). CONCLUSIONS: Our findings support the association of increased neuroinflammation during the progression of MCI and AD, relative to HCs.

Maternal social environment affects offspring cognition through behavioural and immune pathways in rats.

The social environment of lactation is a key etiological factor for the occurrence of postpartum disorders affecting women and their children. Postpartum depression and anxiety disorders are highly prevalent in new mothers and negatively affect offspring's cognitive development through mechanisms which are still unclear. Here, using a rat model, we manipulated the maternal social environment during lactation and explored the pathways through which social isolation (vs. the opportunity for limited social interaction with another lactating female, from 1 day before parturition to postpartum day 16) and chronic social conflict (daily exposure to a male intruder from postpartum day 2 to day 16) affect offspring learning and memory, measured at 40 to 60 days of age. We specifically explored the consequences of these social treatments on two main hypothesized mediators likely to affect offspring neurophysiological development: the quality of maternal care and maternal inflammation factors (brain-derived neurotrophic factor, granulocyte-macrophage colony-stimulating factor, intercellular adhesion molecule 1, tissue inhibitor of metalloproteinases 1 and vascular endothelial growth factor) likely to influence offspring development through lactation. Maternal rats which had the opportunity to interact with another lactating female spent more time with their pups which, in turn, displayed improved working and reference memory. Social stress affected maternal plasma levels of cytokines that were associated with cognitive deficits in their offspring. However, females subjected to social stress were protected from these stress-induced immune changes and associated offspring cognitive impairment by increased social affiliation. These results underscore the effects of social interaction for new mothers and their offspring and can be used to inform the development of clinical preventative measures and interventions.

Prevalence and risk factors for painful diabetic neuropathy in secondary healthcare in Qatar.

AIMS/INTRODUCTION: Painful diabetic peripheral neuropathy (PDPN) has a significant impact on the patient's quality of life. The prevalence of PDPN in the Middle East and North Africa region has been reported to be almost double that of populations in the UK. We sought to determine the prevalence of PDPN and its associated factors in type 2 diabetes mellitus patients attending secondary care in Qatar. MATERIALS AND METHODS: This was a cross-sectional study of 1,095 participants with type 2 diabetes mellitus attending Qatar's two national diabetes centers. PDPN and impaired vibration perception on the pulp of the large toes were assessed using the Douleur Neuropathique en 4 questionnaire with a cut-off ≥4 and the neurothesiometer with a cut-off ≥15 V, respectively. RESULTS: The prevalence of PDPN was 34.5% (95% confidence interval [CI] 31.7-37.3), but 80% of these patients had not previously been diagnosed or treated for this condition. Arabs had a higher prevalence of PDPN compared with South Asians (P < 0.05). PDPN was associated with impaired vibration perception adjusted odds ratio (AOR) 4.42 (95% CI 2.92-6.70), smoking AOR 2.43 (95% CI 1.43-4.15), obesity AOR 1.74 (95% CI 1.13-2.66), being female AOR 1.65 (95% CI: 1.03-2.64) and duration of diabetes AOR 1.08 (95% CI 1.05-1.11). Age, poor glycemic control, hypertension, physical activity and proteinuria showed no association with PDPN. CONCLUSIONS: PDPN occurs in one-third of type 2 diabetes mellitus patients attending secondary care in Qatar, but the majority have not been diagnosed. Arabs are at higher risk for PDPN. Impaired vibration perception, obesity and smoking are associated with PDPN in Qatar.

Discrimination exposure and DNA methylation of stress-related genes in Latina mothers.

Latina mothers, who have the highest fertility rate among all ethnic groups in the US, are often exposed to discrimination. The epigenetic changes related to this discrimination are largely unknown. This study is the first to explore the relationship between discrimination and DNA methylation of stress regulatory genes in Latinas. Our sample was Latina women (n = 147) with a mean age of 27.6 years who were assessed at 24-32 weeks' gestation (T1) and 4-6 weeks postpartum (T2) and reside in the U.S. Blood was collected at T1, and the Everyday Discrimination Scale (EDS) was administered at T1 and T2. DNA Methylation at candidate gene regions was determined by bisulphite pyrosequencing. Associations between EDS and DNA methylation were assessed via zero-inflated Poisson models, adjusting for covariates and multiple-test comparisons. Discrimination was negatively associated with methylation at CpG sites within the glucocorticoid receptor (NR3C1) and brain-derived neurotrophic factor (BDNF) genes that were consistent over time. In addition, discrimination was negatively associated with methylation of a CpG in the glucocorticoid binding protein (FKBP5) at T1 but not at T2. This study underscores associations between discrimination and epigenetic markers of DNA methylation in Latinas that warrant further investigation to better understand the biological pathways and psychopathological effects of discrimination on Latina mothers and their families.