This is a post-hoc secondary analysis of a randomized controlled trial whose purpose was to analyze the effect of a supervised-combined aerobic and resistance exercise (concurrent exercise) training program during pregnancy on 1-month infant neuromotor skills based on maternal pre-pregnancy body mass index (BMI). Ninety-four pregnant women participated in this study, which was conducted at East Carolina University (Greenville, North Carolina, USA) between 2015 and 2018, and were allocated into concurrent exercise (n = 42) or stretching and breathing group (n = 52). The exercise group followed a 50-min 3 days/week moderate intensity concurrent exercise training program from the 16th gestational week until birth. Infant neuromotor skills were assessed with the Peabody Developmental Motor Scales, 2nd edition (PDMS-2). Per protocol analyses showed that infants from the exercise group and whose mothers were normal-weight, had higher PDMS-2 Stationary, Locomotion (borderline) and Gross Motor Quotient (GMQ) percentiles than infants of stretching and breathing participants (p = 0.022, ηp2 = 0.20; p = 0.054, ηp2 = 0.15; p = 0.022, ηp2 = 0.20, respectively). No differences between groups were found in infants whose mothers were normal-weight in reflexes percentiles in the adjusted model, or those infants whose mothers were overweight/obese in any of the outcomes (all p ≥ 0.05). Concurrent exercise training during pregnancy improves neuromotor skills in infants at 1 month of age in normal-weight women. Further studies are needed to understand the influence of concurrent exercise training during pregnancy on infants whose mothers are overweight or obese, and the potential mechanism behind the role of maternal BMI in the development of infant neuromotor skills. ClinicalTrials.gov Identifier: NCT03838146. Infants from normal-weight (but not overweight/obese) women who performed concurrent exercise during pregnancy presented better neuromotor skills than infants of stretching and breathing participants. The results of this study encourage the implementation of strategies to keep pregnant women active throughout pregnancy, to improve the neuromotor skills of future generations. Further studies are needed to understand the influence of concurrent exercise training during pregnancy on infants whose mothers are overweight or obese, which provides future lines of research necessary for society.

Background Fabry disease (FD) patients are known to be at high risk of developing neuropsychiatric symptoms such as anxiety, depression and cognitive deficits. Despite this, they are underdiagnosed and inadequately treated. It is unknown whether these symptoms arise from pathological glycosphingolipid deposits or from cerebrovascular abnormalities affecting neuronal functions in the central nervous system. We therefore aimed to fill this knowledge gap by exploring a transgenic FD mouse model with a combination of behavior, transcriptomic, functional and morphological assessments, with a particular focus on the hippocampus. Results Male FD mice exhibited increased anxiety-like behavior in the open field test, accompanied by a reduced exploratory drive in the Barnes maze, which could be related to the increased deposition of globotriaosylceramide (Gb3) identified in the dentate gyrus (DG). Hippocampus single-cell sequencing further revealed that Gb3 accumulation was associated with differential gene expression in neuronal and non-neuronal cell populations with granule, excitatory and interneurons, as well as microglia and endothelial cells as the main clusters with the most dysregulated genes. Particularly FD hippocampal neurons showed decreased electrical baseline activity in the DG and increased activity in the CA3 region of acutely dissected hippocampal slices. Conclusions Our study highlights transcriptional and functional alterations in non-neuronal and neuronal cell clusters in the hippocampus of FD mice, which are suggested to be causally related to anxiety-like behavior developing as a consequence of FD pathology in mouse models of the disease and in patients.

Resting lactate concentration in venous blood is a commonly used indicator of metabolic disease risk. Regular exercise during pregnancy improves maternal metabolic health; however, it is unknown if maternal exercise regulates resting lactate concentration. We aimed to elucidate the effects of three different modalities of exercise during pregnancy on blood lactate in pregnant women. This is a secondary analysis of data from three blinded, prospective, randomized controlled trials. Pregnant women were randomized to control or exercise. Exercisers underwent ~24 weeks of supervised aerobic, resistance, or combination exercise between 12–16 and 37–40 weeks gestation. Fasted resting maternal blood lactate was collected at 16 and 36 weeks of gestation. Although lactate increased 0.5 mmol/L in controls across gestation, this rise was blunted in exercisers ( p = 0.01). Pre‐pregnancy BMI was correlated with blood lactate in controls ( p < 0.05, R 2 = 0.20) but not in exercisers ( p > 0.05, R 2 = 0.01). Exercisers with overweight or obesity had lower 36‐week lactate ( p = 0.001), particularly in aerobic and combination ( p = 0.03; p = 0.006, respectively). These findings show that exercise helps control the BMI‐associated rise in maternal lactate seen in gestation and highlights the importance of exercise in women with overweight or obesity.

Background The current study examined whether risk factors for anorexia nervosa (AN) were related to different levels of severity based on (a) the DSM-5/body mass index (BMI) and (b) drive for thinness (DT) severity ratings. Methods The sample comprised 153 pairs of individuals with a lifetime diagnosis AN per DSM-IV criteria and their non-ED sisters ( N = 306, mean age = 26.53; mean current BMI = 20.42 kg/m 2 ). The Oxford risk factor interview was used to establish AN-related risk factors. Individuals were categorised into the DSM-5 severity groups based on their lowest BMI, while the DT subscale from the eating disorder inventory-2 was used to classify individuals with AN into low and high DT groups. Results Multinominal regression models showed similar risk factors (e.g., perfectionism, having a history of being teased about weight and shape) contributed to the development of AN using the DSM-5 and DT severity ratings. Follow-up analyses across the severity groups for both indices revealed that only childhood perfectionism was found to be more common in the extreme severe DSM-5 BMI severity group compared to the severe DSM-5 group. Conclusion Overall, this study found little evidence for AN risk factors being related to the DSM-5 and DT severity ratings. However, given the novelty of this study, replication of the current results is warranted.

Genome-wide association and the analysis of rare genetic variants has provided great insights into the genetic basis of schizophrenia, with over 250 variants now identified. Evidence suggests that genetic evidence for association between a gene and disease (even for low risk, common variants) increased the probability of success as a drug target by two-fold or more (Minikel et al., 2024). However, there are several barriers to drug development using this information, including variant-to-gene mapping, target prioritisation, the validity of disease models, target tractability and the development of a therapeutic hypothesis. On the plus side, mapping of the genes within these loci have identified the dopamine D2 receptor (DRD2) gene, a major target of typical antipsychotic drugs, as well as a number of other genes that produce druggable or potentially druggable proteins (Kraft et al., 2024). In this presentation, potential pathways to drug development and stratification using genetics and genomics will be explored.

To investigate relationships between weight loss and weight loss maintenance with cardiac autonomic function and exercise in obesity, 39 adults (45.7 ± 10.7 years; BMI: 34.2 ± 3.4 kg·m−2) participated in a 10-week, medical weight loss program combined with aerobic exercise. A subset ( n = 18) participated in an aerobic exercise weight loss maintenance program (550 or 970 MET min·week−1) for 18 additional weeks. Primary outcomes included markers of cardiac autonomic function assessed by heart rate variability (HRV) (i.e., SDNN, RMSSD, HFln). Following weight loss, we observed significant improvements for SDNN (48.2 [41.4–55.1] vs. 55.1 [45.7–64.4] ms, p = 0.03), RMSSD (37.7 [29.1–46.4] vs. 47.9 [37.4–58.4] ms, p = 0.002), and HFln (5.88 [5.39–6.36] vs. 6.32 [5.86–6.78] ms, p = 0.001). Regression analyses showed fasting insulin concentration predicted 24% and 27% of the variance in RMSSD ( r2 = 0.236, p = 0.007) and HFln ( r2 = 0.274, p = 0.004), respectively. Following weight loss maintenance, no significant changes in HRV were observed. Changes in LDL ( r=–0.54, p = 0.04) and non-HDL ( r=–0.77, p = 0.001) were inversely associated with RMSSD changes. Clinically significant weight loss via caloric restriction and aerobic exercise improved HRV markers of cardiac vagal modulation. Following weight loss maintenance, we did not observe any further changes in HRV. Thus, our data suggest that commonly prescribed exercise volumes contribute to maintenance of parasympathetic modulation following medical weight loss programming and exercise. Novelty Caloric restriction and exercise exert significant improvements in cardiac autonomic function as measured by HRV in overweight and obesity. Aerobic exercise training, within recommended guidelines coupled with weight loss maintenance, retains cardiac autonomic function benefits from weight loss in previously obese individuals.

Additional file 4. Upstream regulators inferred from causal reasoning across different algorithms/networks and the frequency of their occurrence.

Background A key histopathological hallmark of Alzheimer’s disease (AD) is the presence of neurofibrillary tangles of aggregated microtubule-associated protein tau in neurons. Anle138b is a small molecule which has previously shown efficacy in mice in reducing tau aggregates and rescuing AD disease phenotypes. Methods In this work, we employed bioinformatics analysis—including pathway enrichment and causal reasoning—of an in vitro tauopathy model. The model consisted of cultured rat cortical neurons either unseeded or seeded with tau aggregates derived from human AD patients, both of which were treated with Anle138b to generate hypotheses for its mode of action. In parallel, we used a collection of human target prediction models to predict direct targets of Anle138b based on its chemical structure. Results Combining the different approaches, we found evidence supporting the hypothesis that the action of Anle138b involves several processes which are key to AD progression, including cholesterol homeostasis and neuroinflammation. On the pathway level, we found significantly enriched pathways related to these two processes including those entitled “Superpathway of cholesterol biosynthesis” and “Granulocyte adhesion and diapedesis”. With causal reasoning, we inferred differential activity of SREBF1/2 (involved in cholesterol regulation) and mediators of the inflammatory response such as NFKB1 and RELA. Notably, our findings were also observed in Anle138b-treated unseeded neurons, meaning that the inferred processes are independent of tau pathology and thus represent the direct action of the compound in the cellular system. Through structure-based ligand-target prediction, we predicted the intracellular cholesterol carrier NPC1 as well as NF-κB subunits as potential targets of Anle138b, with structurally similar compounds in the model training set known to target the same proteins. Conclusions This study has generated feasible hypotheses for the potential mechanism of action of Anle138b, which will enable the development of future molecular interventions aiming to reduce tau pathology in AD patients.

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Background Non-Hispanic black (NHB) pregnant women disproportionately experience adverse birth outcomes compared to Non-Hispanic white (NHW) pregnant women. The positive effects of prenatal exercise on maternal and neonatal health may mitigate these disparities. This study evaluated the influence of prenatal exercise on racial/ethnic disparities in gestational age (GA), birthweight (BW), and risks of preterm birth (PTB), cesarean section (CS), and low-birthweight (LBW) neonates. Methods This study performed a secondary data analysis using data from a 24-week, two-arm exercise intervention trial (ENHANCED by Mom). Women with singleton pregnancies (< 16 weeks), aged 18–40 years, BMI between 18.5–34.99 kg/m 2 , and no preexisting health conditions were eligible. The aerobic exercisers (EX) participated in 150 min of moderate-intensity weekly exercise while non-exercising controls (CON) attended low-intensity stretching/breathing sessions. Data on GA, PTB (< 37 weeks), BW, LBW (< 2.5 kg), and delivery mode were collected. Poisson, median and linear regressions were performed. Results Participants with complete data ( n = 125) were eligible for analyses (EX: n = 58, CON: n = 67). NHB pregnant women delivered lighter neonates (β = − 0.43 kg, 95% CI: − 0.68, − 0.18, p = 0.001). After adjusting for prenatal exercise, racial/ethnic disparities in BW were reduced (β = − 0.39 kg, 95% CI: − 0.65, − 0.13, p = 0.004). Prenatal exercise reduced borderline significant racial/ethnic disparities in PTB ( p = 0.053) and GA ( p = 0.07) with no effects found for CS and LBW. Conclusions The findings of this study demonstrate that prenatal exercise may attenuate the racial/ethnic disparities observed in neonatal BW, and possibly GA and PTB. Larger, diverse samples and inclusion of maternal biomarkers (e.g., cytokines) are encouraged to further evaluate these relationships.

Neuroimmunology and Neuroinflammation is an open access journal, with focuses on neuroimmunology and neuroinflammation research, and coverage extending to other basic and clinical studies related to neuroscience.

Human asthma, obesity, MetS, overt Type 2 diabetes, and related sequelae such as cardiovascular diseases, account for much of the mortality and morbidity worldwide. The etiology and complex physiological mechanisms underlying these pathological states intersect within the human body – and within Rhesus macaques. Much like humans, these animals (in captivity) often develop spontaneous, age‐related obesity. Hence, these animals are ideally suited for investigations of obesity and metabolism, as well as chronic allergic asthma.

ABSTRACT Objective Psychosis - a complex and heterogeneous neuropsychiatric condition characterized by hallucinations and delusions - is a common feature of schizophrenia. There is evidence for altered DNA methylation (DNAm) associated with schizophrenia in both brain and peripheral tissues. We aimed to undertake a systematic analysis of variable DNAm associated with psychosis, schizophrenia, and treatment-resistant schizophrenia, also exploring measures of biological ageing, smoking, and blood cell composition derived from DNAm data to identify molecular biomarkers of disease. Methods We quantified DNAm across the genome in blood samples from 4,483 participants from seven case-control cohorts including patients with schizophrenia or first-episode psychosis. Measures of biological age, cellular composition and smoking status were derived from DNAm data using established algorithms. DNAm and derived measures were analyzed within each cohort and the results combined by meta-analysis. Results Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNAm data, with the largest differences seen in treatment-resistant schizophrenia patients. DNAm at 95 CpG sites was significantly different between psychosis cases and controls, with 1,048 differentially methylated positions (DMPs) identified between schizophrenia cases and controls. Schizophrenia-associated DMPs colocalize to regions identified in genetic association studies, with genes annotated to these sites enriched for pathways relevant to disease. Finally, a number of the schizophrenia associated differences were only present in the treatment-resistant schizophrenia subgroup. Conclusions We show that DNAm data can be leveraged to derive measures of blood cell counts and smoking that are strongly associated with psychosis. Our DNAm meta-analysis identified multiple DMPs associated with both psychosis and a more refined diagnosis of schizophrenia, with evidence for differential methylation associated with treatment-resistant schizophrenia that potentially reflects exposure to clozapine.

Despite increased reimbursement for registered dietitian nutritionists (RDNs), few studies have assessed the potential of integrating them into primary care clinics to support pediatric weight management. To assess the feasibility and effectiveness of this approach, RDNs were introduced into 8 primary care practices in North Carolina. This mixed-methods study combined (1) interviews and focus groups with RDNs and clinic personnel, (2) comparison of change in body mass index (BMI) z-score in study practices to change in historical comparison groups, and (3) analysis of behavior and BMI change for RDN utilizers. Qualitative data were coded thematically, and McNemar's and Wilcoxon signed-rank tests were used for quantitative data. RDN integration was good, but average referral rate for eligible children was 19.4%; 48.4% of those referred utilized the RDN (most fewer than 3 times). Using the full analysis set, there was no difference in change in BMI z-score for intervention and comparison groups. For RDN utilizers, the average change in BMI z-score was -0.089 (P < .001), and there was statistically significant improvement in 7 of 8 health behaviors. Integrating RDNs into primary care practices was feasible and possibly effective for utilizers. Reaping potential benefits of RDN co-location would require increasing low referral and utilization rates.

An increasing number of studies implicate a role for alternative splicing in the development and neuropathology of Alzheimer’s disease (AD). However, it has been historically challenging to characterise splicing events, due to the limitations of short‐read RNA‐sequencing (RNA‐Seq) for the capture full‐length transcripts critical for transcriptome assembly. In this study, we used Pacific Biosciences long‐read isoform sequencing (Iso‐Seq) to enrich and comprehensively characterise isoform diversity for AD‐associated genes in entorhinal cortex samples from a well‐validated AD transgenic mouse model.

We present a consensus atlas of the human brain transcriptome in Alzheimer’s disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington’s disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.