Effects of different types of leisure activities on working memory across the adult lifespan.

The aim of the present study was to contrast the potential influence of five independent types of leisure activities (physical, mental, social, cultural, and passive) on working memory in a lifespan sample and in specific stages of adulthood (young, middle-aged, and older adults). A sample of 1652 healthy adults between 21 and 80 years of age participated in the study. Leisure activities were assessed through a lifestyle questionnaire created for the study. Working memory was measured in the verbal and spatial domains using a computerized n-back task that allowed us to reliably measure discrimination and reaction times. Across adulthood, mental (computer use and hobbies) and social leisure activities predicted greater verbal and spatial working memory discrimination; mental (reading) and social activities predicted faster verbal working memory; and mental (computer use) and physical activities predicted faster spatial working memory. In young adults, mental (computer use) and social activities were associated with greater verbal and spatial working memory performance. In middle-aged adults, physical and mental activities (computer use) were associated with greater working memory performance. In older adults, physical, mental (hobbies), and social activities were associated with greater working memory performance. Leisure activities can enhance working memory discrimination and speed independent of individuals' age.

Prediction of Cesarean Section for Intrapartum Fetal Compromise: A Multivariable Model from a Prospective Observational Approach.

OBJECTIVE: A cesarean section for intrapartum fetal compromise (IFC) is performed to avoid potential damage to the newborn. It is, therefore, crucial to develop an accurate prediction model that can anticipate, prior to labor, which fetus may be at risk of presenting this condition. MATERIAL AND METHODS: To calculate a prediction model for IFC, the clinical, epidemiological, and ultrasonographic variables of 538 patients admitted to the maternity of La Fe Hospital were studied and evaluated using univariable and multivariable logistic regression analysis, using the area under the curve (AUC) and the Akaike Information Criteria (AIC). RESULTS: In the univariable analysis, CPR MoM was the best single parameter for the prediction of CS for IFC (OR 0.043, p < 0.0001; AUC 0.72, p < 0.0001). Concerning the multivariable analysis, for the general population, the best prediction model (lower AIC) included the CPR multiples of the median (MoM), the maternal age, height, and parity, the smoking habits, and the type of labor onset (spontaneous or induction) (AUC 0.80, p < 0.0001). In contrast, for the pregnancies undergoing labor induction, the best prediction model included the CPR MoM, the maternal height and parity, and the smoking habits (AUC 0.80, p < 0.0001). None of the models included estimated fetal weight (EFW). CONCLUSIONS: CS for IFC can be moderately predicted prior to labor using maternal characteristics and CPR MoM. A validation study is pending to apply these models in daily clinical practice.

Prediction of Failure to Progress after Labor Induction: A Multivariable Model Using Pelvic Ultrasound and Clinical Data.

Objective: Labor induction is one of the leading causes of obstetric admission. This study aimed to create a simple model for predicting failure to progress after labor induction using pelvic ultrasound and clinical data. Material and Methods: A group of 387 singleton pregnant women at term with unruptured amniotic membranes admitted for labor induction were included in an observational prospective study. Clinical and ultrasonographic variables were collected at admission prior to the onset of contractions, and labor data were collected after delivery. Multivariable logistic regression analysis was applied to create several models to predict cesarean section due to failure to progress. Afterward, the most accurate and reproducible model was selected according to the lowest Akaike Information Criteria (AIC) with a high area under the curve (AUC). Results: Plausible parameters for explaining failure to progress were initially obtained from univariable analysis. With them, several multivariable analyses were evaluated. Those parameters with the highest reproducibility included maternal age (p < 0.05), parity (p < 0.0001), fetal gender (p < 0.05), EFW centile (p < 0.01), cervical length (p < 0.01), and posterior occiput position (p < 0.001), but the angle of descent was disregarded. This model obtained an AIC of 318.3 and an AUC of 0.81 (95% CI 0.76-0.86, p < 0.0001) with detection rates of 24% and 37% for FPRs of 5% and 10%. Conclusions: A simplified clinical and sonographic model may guide the management of pregnancies undergoing labor induction, favoring individualized patient management.

Cerebroplacental Ratio as a Predictive Factor of Emergency Cesarean Sections for Intrapartum Fetal Compromise: A Systematic Review.

Background: This systematic review aimed to clarify the association between the cerebroplacental ratio (CPR) and emergency cesarean sections (CSs) due to intrapartum fetal compromise (IFC). Methods: Datasets of PubMed, ScienceDirect, CENTRAL, Embase, and Google Scholar were searched for studies published up to January 2024 regarding the relationship between the CPR and the rate of CS for IFC, as well as the predictive value of the CPR. Results: The search identified 582 articles, of which 16 observational studies were finally included, most of them with a prospective design. A total of 14,823 patients were involved. A low CPR was associated with a higher risk of CS for IFC. The predictive value of the CPR was very different among the studies due to substantial heterogeneity regarding the group of patients included and the time interval from CPR evaluation to delivery. Conclusions: A low CPR is associated with a higher risk of CS for IFC, although with a poor predictive value. The CPR could be calculated prior to labor in all patients to stratify the risk of CS due to IFC.

Sex bias in celiac disease: XWAS and monocyte eQTLs in women identify TMEM187 as a functional candidate gene.

BACKGROUND: Celiac disease (CeD) is an immune-mediated disorder that develops in genetically predisposed individuals upon gluten consumption. HLA risk alleles explain 40% of the genetic component of CeD, so there have been continuing efforts to uncover non-HLA loci that can explain the remaining heritability. As in most autoimmune disorders, the prevalence of CeD is significantly higher in women. Here, we investigated the possible involvement of the X chromosome on the sex bias of CeD. METHODS: We performed a X chromosome-wide association study (XWAS) and a gene-based association study in women from the CeD Immunochip (7062 cases, 5446 controls). We also constructed a database of X chromosome cis-expression quantitative trait loci (eQTLs) in monocytes from unstimulated (n = 226) and lipopolysaccharide (LPS)-stimulated (n = 130) female donors and performed a Summary-data-based MR (SMR) analysis to integrate XWAS and eQTL information. We interrogated the expression of the potentially causal gene (TMEM187) in peripheral blood mononuclear cells (PBMCs) from celiac patients at onset, on a gluten-free diet, potential celiac patients and non-celiac controls. RESULTS: The XWAS and gene-based analyses identified 13 SNPs and 25 genes, respectively, 22 of which had not been previously associated with CeD. The X chromosome cis-eQTL analysis found 18 genes with at least one cis-eQTL in naïve female monocytes and 8 genes in LPS-stimulated female monocytes, 2 of which were common to both situations and 6 were unique to LPS stimulation. SMR identified a potentially causal association of TMEM187 expression in naïve monocytes with CeD in women, regulated by CeD-associated, eQTL-SNPs rs7350355 and rs5945386. The CeD-risk alleles were correlated with lower TMEM187 expression. These results were replicated using eQTLs from LPS-stimulated monocytes. We observed higher levels of TMEM187 expression in PBMCs from female CeD patients at onset compared to female non-celiac controls, but not in male CeD individuals. CONCLUSION: Using X chromosome genotypes and gene expression data from female monocytes, SMR has identified TMEM187 as a potentially causal candidate in CeD. Further studies are needed to understand the implication of the X chromosome in the higher prevalence of CeD in women.

Celiac disease (CeD) is an immune-related condition triggered by gluten consumption in genetically susceptible individuals. Women present higher prevalence of CeD than men, but the biological explanation of such difference has not been elucidated. In this study, we investigated whether specific genetic variations on the X chromosome were associated with CeD in each sex. Surprisingly, we found 13 genetic variants and 25 genes significantly linked to CeD in women, but not in men. Additionally, we identified genetic variants on the X chromosome associated with gene expression of monocytes, a type of immune cells that is activated in CeD after gluten intake. Integrating these data with our previous findings, we found that lower expression of a gene termed TMEM187 might be associated with a potential increase in CeD risk in women. Finally, validation experiments confirmed higher TMEM187 levels in blood cells from female CeD patients compared to non-celiac women, while no such difference was seen in males. In summary, our study suggests that the X-chromosome gene TMEM187 may play a key role in CeD development, providing insights into the higher prevalence of CeD in females.

Intestinal permeability assessment using lactulose and mannitol in celiac disease.

Alterations in intestinal permeability can lead to increased uptake of luminal antigens, which has been linked to several intestinal diseases, such as inflammatory bowel diseases, celiac disease, and irritable bowel syndrome, but also to extra-intestinal diseases. Promising therapies that target intestinal permeability could be developed, for instance tight junction modulators. Consequently, permeability assays are increasingly being used as treatment endpoints in clinical studies. Therefore, reliable, reproducible, and feasible methods for measuring intestinal permeability in the clinical setting are necessary. Currently, a variety of in vivo, ex vivo, and in vitro tests are available, some of which are only applicable to basic research. Despite the various options available to measure gut permeability, their use in clinical setting is still limited because of their heterogeneity. Here, we describe a clinical method to measure intestinal permeability using two non-metabolizable sugars.

Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity.

De novo heterozygous loss-of-function mutations in phosphatase and tensin homolog (PTEN) are strongly associated with autism spectrum disorders; however, it is unclear how heterozygous mutations in this gene affect different cell types during human brain development and how these effects vary across individuals. Here, we used human cortical organoids from different donors to identify cell-type specific developmental events that are affected by heterozygous mutations in PTEN. We profiled individual organoids by single-cell RNA-seq, proteomics and spatial transcriptomics and revealed abnormalities in developmental timing in human outer radial glia progenitors and deep-layer cortical projection neurons, which varied with the donor genetic background. Calcium imaging in intact organoids showed that both accelerated and delayed neuronal development phenotypes resulted in similar abnormal activity of local circuits, irrespective of genetic background. The work reveals donor-dependent, cell-type specific developmental phenotypes of PTEN heterozygosity that later converge on disrupted neuronal activity.

Deciphering the underlying mechanisms of the oxidative perturbations and impaired meat quality in Wooden breast myopathy by label-free quantitative MS-based proteomics.

The study aimed to investigate biochemical mechanisms occurred in Wooden breast (WB) chicken meat, with attention to the impact on meat quality. Commercial chicken breasts were classified as Normal (N, n = 12), WB-M (moderate degree; focal hardness on cranial region, n = 12) and WB-S (severe degree; extreme and diffused hardness over the entire surface, n = 12). Samples were analyzed for physico-chemical properties, oxidative damage to lipids and proteins, and discriminating sarcoplasmic proteins by using a Q-Exactive mass spectrometer. WB meat presented impaired composition and functionality and higher levels of lipid and protein oxidation markers than N meat. The proteomic profile of WB-S presents a dynamic regulation of the relevant proteins involved in redox homeostasis, carbohydrate, protein and lipid metabolisms. Proteomics results demonstrate that the physiological and metabolic processes of muscles affected by WB myopathy are involved in combating the inflammatory process and in repairing the damaged tissue by oxidative stress.

Nutrient effects on working memory across the adult lifespan.

OBJECTIVE: To identify the nutrients that influence the performance of working memory, which is greatly affected as age progresses. METHOD: A total of 1646 healthy adults between 21 and 80 years old participated in the study. The daily consumption of 64 nutrients was examined using a food frequency questionnaire that assessed food intake during the previous year. Working memory was measured in the verbal and spatial domains using a computerized task. We examined which nutrients influence working memory across the entire adult lifespan and whether the influence of any of these nutrients on working memory is moderated by individuals' ages. RESULTS: Working memory, across the entire adult lifespan, benefits from the intake of cholesterol, alcohol, gamma- and delta-tocopherol, vitamin B6, and palmitoleic, oleic, alpha linoleic and linoleic acids. Moderator analyses revealed that fats, energy, lactose and sodium negatively influenced working memory in middle-aged and older adults, whereas vitamin D and vitamin C had positive effects on memory beyond 70 years of age. CONCLUSION: Nutrients have the ability to positively or negatively affect working memory, which varies as a function of age.

Metamemory Mediates the Effects of Age on Episodic and Working Memory across the Adult Lifespan.

BACKGROUND: Previous studies have examined the direct relationship between metamemory and memory performance in young and older adults, but the results of these studies have been inconsistent. Therefore, we examined whether metamemory mediates the effects of age on memory performance. METHODS: We examined episodic memory and working memory through computerized tasks performed by a lifespan sample of 1554 healthy adults. Seven metamemory traits were measured with the Metamemory in Adulthood (MIA) questionnaire. Separate structural equation modeling analyses were conducted to investigate potential metamemory mediators that intervened between age and the accuracy and speed of accessing information from episodic and working memory. RESULTS: The use of internal or external strategies mediated the effects of age on episodic memory and spatial working memory performance. The perception of one's own memory capacity and the experience of anxiety when using memory functions mediated the effects of age on working memory performance in both domains. CONCLUSIONS: Metamemory traits have the power to strengthen or weaken the course of episodic and working memory decline throughout adulthood.

Modeling brain disorders using transplanted organoids: Beyond the short circuit.

Human cortical organoids transplanted into the somatosensory cortex of rats integrate into the host neural circuits, receive inputs from host cells, and can produce behavioral responses. In a publication in Nature, Revah et al.1 highlight the potential of this platform for modeling circuit defects associated with neurodevelopmental disorders.

Ellagic Acid Triggers the Necrosis of Differentiated Human Enterocytes Exposed to 3-Nitro-Tyrosine: An MS-Based Proteomic Study.

To study the molecular basis of the toxicological effect of a dietary nitrosated amino acid, namely, 3-nitrotyrosine (3-NT), differentiated human enterocytes were exposed to dietary concentrations of this species (200 µM) and analyzed for flow cytometry, protein oxidation markers and MS-based proteomics. The possible protective role of a dietary phytochemical, ellagic acid (EA) (200 µM), was also tested. The results revealed that cell viability was significantly affected by exposure to 3-NT, with a concomitant significant increase in necrosis (p < 0.05). 3-NT affected several biological processes, such as histocompatibility complex class II (MHC class II), and pathways related to type 3 metabotropic glutamate receptors binding. Addition of EA to 3-NT-treated cells stimulated the toxicological effects of the latter by reducing the abundance of proteins involved in mitochondrial conformation. These results emphasize the impact of dietary nitrosated amino acids in intestinal cell physiology and warn about the potential negative effects of ellagic acid when combined with noxious metabolites.

Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex.

Realizing the full utility of brain organoids to study human development requires understanding whether organoids precisely replicate endogenous cellular and molecular events, particularly since acquisition of cell identity in organoids can be impaired by abnormal metabolic states. We present a comprehensive single-cell transcriptomic, epigenetic, and spatial atlas of human cortical organoid development, comprising over 610,000 cells, from generation of neural progenitors through production of differentiated neuronal and glial subtypes. We show that processes of cellular diversification correlate closely to endogenous ones, irrespective of metabolic state, empowering the use of this atlas to study human fate specification. We define longitudinal molecular trajectories of cortical cell types during organoid development, identify genes with predicted human-specific roles in lineage establishment, and uncover early transcriptional diversity of human callosal neurons. The findings validate this comprehensive atlas of human corticogenesis in vitro as a resource to prime investigation into the mechanisms of human cortical development.

Ruxolitinib as a treatment strategy for SARS-CoV-2 pneumonia: clinical experience in a real-world setting.

INTRODUCTION: Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) infection is characterised by a viral phase and a severe pro-inflammatory phase. The inhibition of the JAK/STAT pathway limits the pro-inflammatory state in moderate to severe COVID-19. METHODOLOGY: We analysed the data obtained by an observational cohort of patients with SARS-CoV-2 pneumonia treated with ruxolitinib in 22 hospitals of Mexico. The applied dose was determined based on physician's criteria. The benefit of ruxolitinib was evaluated using the 8-points ordinal scale developed by the NIH in the ACTT1 trial. Duration of hospital stay, changes in pro-inflammatory laboratory values, mortality, and toxicity were also measured. RESULTS: A total of 287 patients were reported at 22 sites in Mexico from March to June 2020; 80.8% received ruxolitinib 5 mg BID and 19.16% received ruxolitinib 10 mg BID plus standard of care. At beginning of treatment, 223 patients were on oxygen support and 59 on invasive ventilation. The percentage of patients on invasive ventilation was 53% in the 10 mg and 13% in the 5 mg cohort. A statistically significant improvement measured as a reduction by 2 points on the 8-point ordinal scale was described (baseline 5.39 ± 0.93, final 3.67± 2.98, p = 0.0001). There were 74 deaths. Serious adverse events were presented in 6.9% of the patients. CONCLUSIONS: Ruxolitinib appears to be safe in COVID-19 patients, with clinical benefits observed in terms of decrease in the 8-point ordinal scale and pro-inflammatory state. Further studies must be done to ensure efficacy against mortality.

Autism genes converge on asynchronous development of shared neuron classes.

Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1-6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes-SUV420H1 (also known as KMT5B), ARID1B and CHD8-in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages-γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons-but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.

Effects of hypotension and hypertension on source memory and working memory.

OBJECTIVES: The effects of chronic low and high blood pressure on memory are unclear due to divergent results, originating in part due to participant misclassifications. The aim of this study was to compare source memory and working memory performance in individuals diagnosed with hypotension or hypertension with the performance of normotensive participants. Hypertensive and hypotensive individuals were receiving medical treatment. METHOD: From a sample of 1656 participants, 219 were identified as hypertensive, and 37 were identified as hypotensive. Each of these two groups was compared with normotensive individuals matched by age, education and sex. Source memory performance and working memory performance were assessed through computerized tasks. RESULTS: Source memory accuracy was poorer in hypotensive and hypertensive individuals than in normotensive individuals, and spatial working memory discrimination was inferior in hypertensive participants compared to normotensive individuals. CONCLUSION: Blood pressure impairment should be considered a major concern because it has been linked to severe cardiovascular and cerebrovascular diseases. Furthermore, here we show that it has negative effects on the two types of memory that are most essential for preserving a self-sufficient lifestyle.

Protein carbonylation in food and nutrition: a concise update.

Protein oxidation is a topic of indisputable scientific interest given the impact of oxidized proteins on food quality and safety. Carbonylation is regarded as one of the most notable post-translational modifications in proteins and yet, this reaction and its consequences are poorly understood. From a mechanistic perspective, primary protein carbonyls (i.e. α-aminoadipic and γ-glutamic semialdehydes) have been linked to radical-mediated oxidative stress, but recent studies emphasize the role alternative carbonylation pathways linked to the Maillard reaction. Secondary protein carbonyls are introduced in proteins via covalent linkage of lipid carbonyls (i.e. protein-bound malondialdehyde). The high reactivity of protein carbonyls in foods and other biological systems indicates the intricate chemistry of these species and urges further research to provide insight into these molecular mechanisms and pathways. In particular, protein carbonyls are involved in the formation of aberrant and dysfunctional protein aggregates, undergo further oxidation to yield carboxylic acids of biological relevance and establish interactions with other biomolecules such as oxidizing lipids and phytochemicals. From a methodological perspective, the routine dinitrophenylhydrazine (DNPH) method is criticized not only for the lack of accuracy and consistency but also authors typically perform a poor interpretation of DNPH results, which leads to misleading conclusions. From a practical perspective, the biological relevance of protein carbonyls in the field of food science and nutrition is still a topic of debate. Though the implication of carbonylation on impaired protein functionality and poor protein digestibility is generally recognized, the underlying mechanism of such connections requires further clarification. From a medical perspective, protein carbonyls are highlighted as markers of protein oxidation, oxidative stress and disease. Yet, the specific role of specific protein carbonyls in the onset of particular biological impairments needs further investigations. Recent studies indicates that regardless of the origin (in vivo or dietary) protein carbonyls may act as signalling molecules which activate not only the endogenous antioxidant defences but also implicate the immune system. The present paper concisely reviews the most recent advances in this topic to identify, when applicable, potential fields of interest for future studies.

Influence of Dietary Nutrient Intake on Episodic Memory Across the Adult Life Span.

The aim of the study was to identify nutrients that have the ability to impact brain functioning and, as a consequence, influence episodic memory. In particular, we examined recollection, the ability to recall details of previous experiences, which is the episodic memory process most affected as age advances. A sample of 1,550 healthy participants between 21 and 80 years old participated in the study. Nutritional intake was examined through a food frequency questionnaire and software developed to determine the daily consumption of 64 nutrients based on food intake during the last year. Recollection was measured through a computerized source memory paradigm. First, we identified which nutrients influence recollection across the entire adult life span. Then, moderator analyses were conducted by dividing the sample into young (21-40 years old), middle-aged (41-60 years old) and older (61-80 years old) adults to establish in which life stage nutrients influence episodic memory. Across the adult life span, recollection accuracy was shown to benefit from the intake of sodium, heme, vitamin E, niacin, vitamin B6, cholesterol, alcohol, fat, protein, and palmitic, stearic, palmitoleic, oleic, gadoleic, alpha-linoleic and linoleic acid. The effects of energy, maltose, lactose, calcium and several saturated fatty acids on recollection were modulated by age; in older adults, the consumption of these nutrients negatively influenced episodic memory performance, and in middle-aged adults, only lactose had negative effects. Several brain mechanisms that support episodic memory were influenced by specific nutrients, demonstrating the ability of food to enhance or deteriorate episodic memory.

Microglial synaptic pruning on axon initial segment spines of dentate granule cells: Sexually dimorphic effects of early-life stress and consequences for adult fear response.

Axon initial segments (AIS) of dentate granule cells in the hippocampus exhibit prominent spines (AISS) during early development that are associated with microglial contacts. In the present study, we investigated whether developmental changes in AISS could be modified by early-life stress (ELS), specifically neonatal maternal separation (MS), through stress hormones and microglial activation and examined the potential behavioural consequences. We examined AISS at postnatal day (PND)5, 15 and 50, using Golgi-Cox staining and anatomical analysis. Neurone-microglial interaction was assessed using antibodies against ankyrin-G, PSD-95 and Iba1, for AIS, AISS and microglia visualisation, respectively, in normally reared and neonatal maternally separated male and female rats. We observed a higher density of AISS in ELS rats at both PND15 and PND50 compared to controls. Effects were more pronounced in females than males. AIS-associated microglia in ELS rats showed a hyper-ramified morphology and less co-localisation with PSD-95 compared to controls at PND15. ELS-associated alteration in microglial morphology and synaptic pruning was mimicked by treatment of acute hippocampal slices of normally reared rats with vasopressin. ELS rats exhibited increased freezing behaviour during auditory fear memory testing, which was more pronounced in female subjects and corresponded with increased Fos expression in dorsal and ventral dentate granule cells. Thus, microglial synaptic pruning in dentate AIS of hippocampus is influenced by ELS, with demonstrable sex bias regarding its anatomical characteristics and subsequent fear-induced defensive behaviours.