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The metabotropic glutamate receptor 7 (mGlu7) is a G protein–coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay. One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu7 ligand-binding domain. Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu7-I154T mutant reveal that this substitution resulted in significant loss of mGlu7 protein expression in HEK293A cells and in mice. We show that this occurred posttranscriptionally at the level of protein expression and trafficking. Similar to mGlu7–global KO mice, mGlu7-I154T animals exhibited reduced motor coordination, deficits in contextual fear learning, and seizures. This provides functional evidence that a disease-associated mutation affecting the mGlu7 receptor was sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population.

Aerobic and respiratory cultivations provide benefits for some lactic acid bacteria (LAB). Growth, metabolites, enzymatic activities (lactate dehydrogenase; pyruvate and NADH oxidases, NADH peroxidase; catalase), antioxidant capability and stress tolerance of Lactobacillus casei N87 were evaluated in anaerobic, aerobic and respiratory (aerobiosis with heme and menaquinone supplementation) batch cultivations with different dissolved oxygen (DO) concentrations. The expression of pox (pyruvate oxidase) and cydABCD operon (cytochrome bd oxidase complex) was quantified by quantitative Real Time polymerase chain reaction. Respiration increased biomass production compared to anaerobiosis and unsupplemented aerobiosis, and altered the central metabolism rerouting pyruvate away from lactate accumulation. All enzymatic activities, except lactate dehydrogenase, were higher in respiratory cultures, while unsupplemented aerobiosis with 60% of DO promoted H2O2 and free radical accumulation. Respiration improved the survival to oxidative and freeze-drying stresses, while significant numbers of dead, damaged and viable but not cultivable cells were found in unsupplemented aerobic cultures (60% DO). Analysis of gene expression suggested that the activation of aerobic and respiratory pathways occurred during the exponential growth phase, and that O2 and hemin induced, respectively, the transcription of pox and cydABCD genes. Respiratory cultivation might be a natural strategy to improve functional and technological properties of L. casei.

Gender-variant-based victimization is victimization based on the way others perceive an individual to convey masculine, feminine, and androgynous characteristics through their appearance, mannerisms, and behaviors. Previous work identifies gender-variant-based victimization as a risk factor for health-risking outcomes among same-sex attracted youths. The current study seeks to examine this relationship among other-sex attracted youths and same-sex attracted youth, and determine if gender-variant-based victimization is similarly or differentially associated with poor outcomes between these two groups. Anonymous data from a school-based survey of 2,438 racially diverse middle and high school students in the Eastern U.S. was examined. For other-sex attracted adolescents, gender-variant-based victimization was associated with a higher odds of suicidal thoughts and behaviors, regular use of cigarettes, and drug use. When compared to same-sex attracted adolescents, the harmful relationship between gender-variant-based victimization and each of these outcomes was similar in nature. These findings suggest that gender-variant-based victimization has potentially serious implications for the psychological wellbeing and substance use of other-sex attracted adolescents, not just same-sex attracted adolescents, supporting the need to address gender expression as a basis for victimization separate from sexuality- or gender-minority status. The impact that gender-variant-based victimization has on all adolescents should not be overlooked in research and interventions aimed at addressing sexual orientation-based and gender-variant-based victimization, substance use, and suicide prevention.

One hundred eighty four strains belonging to the species Lactobacillus casei, L. paracasei and L. rhamnosus were screened for their ability to grow under aerobic conditions, in media containing heme and menaquinone and/or compounds generating reactive oxygen species (ROS), in order to identify respiratory and oxygen-tolerant phenotypes. Most strains were able to cope with aerobic conditions and for many strains aerobic growth and heme or heme/menaquinone supplementation increased biomass production compared to anaerobic cultivation. Only four L. casei strains showed a catalase-like activity under anaerobic, aerobic and respiratory conditions and were able to survive in presence of H2O2 (1 mM). Almost all L. casei and L. paracasei strains tolerated menadione (0.2 mM) and most tolerated pyrogallol (50 mM), while L. rhamnosus was usually resistant only to the latter compound. This is the first study in which an extensive screening of oxygen and oxidative stress tolerance of members of the L. casei group has been carried out. Results allowed the selection of strains showing the typical traits of aerobic and respiratory metabolism (increased pH and biomass under aerobic or respiratory conditions) and unique oxidative stress response properties. Aerobic growth and respiration may confer technological and physiological advantages in the L. casei group and oxygen-tolerant phenotypes could be exploited in several food industry applications.

Abundant research supports the benefits of participating in mindfulness meditation training programs including Mindfulness-Based Stress Reduction and Mindfulness-Based Cognitive Therapy. However, these well researched programs include a narrow range of meditation practices and research to date has minimally examined how home practice associates with favorable outcomes. The present study evaluated the 3 Doors Compassion Project (3DCP), a structured 9-months meditation program that teaches Tibetan Mind-Body practices and examined how frequency and duration of home practice associated with favorable outcomes. Twenty-seven medical and mental healthcare professionals completed assessments prior to, during, and following participation in the 3DCP program and recorded daily meditation practices. Study aims were to test general effectiveness of the 3DCP program and to test the hypotheses that frequency and duration of meditation home-practice would associate with improvements on mindfulness, stress, and depression. General linear mixed modeling demonstrated significant improvements throughout the duration of the 3DCP program for mindfulness, depression (p < .001) and stress (p < .05), with each variable evidencing incremental monthly improvements. Frequency of meditation (i.e., days practiced per month), but not time (i.e., minutes per month) was significantly associated with improvements throughout the 3DCP program. Results provide support for the benefits of the 3DCP while offering clinically useful information that can inform current guidelines for meditation home practice. As predicted, the 3DCP was associated with significant improvements on all outcomes. Favorable outcomes were linked to frequency, but not total time of meditation practice, which suggests that consistent meditation may be more helpful than extended meditation., Author(s): M. Gawrysiak [sup.1] [sup.2] , R. T. Pohlig [sup.3] , A. Chaoul [sup.4] , M. Vaughn [sup.5] , G. Rocco [sup.5] , C. Clark [sup.6] , S. Grassetti [sup.1] [...]

Abstract Background Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia. Inflammation and inflammasome activation have emerged as a potential link between these disparate pathologies. As diet is a key factor in both the development of metabolic disorders and inflammation, we hypothesize that long term changes in dietary factors can influence nervous system function by regulating inflammasome activity and that this phenotype would be sex-dependent, as sex hormones are known to regulate metabolism and immune processes. Methods 5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter underwent cranial window surgeries and were fed control (65% complex carbohydrates, 15% fat), high glycemic index (65% carbohydrates from sucrose, 15% fat), or ketogenic (1% complex carbohydrates, 79% fat) diet from 6 to 26 weeks of age. Glucose regulation was assessed with a glucose tolerance test following a 4-h morning fast. Bioluminescence in the brain was quantified using IVIS in vivo imaging. Blood cytokine levels were measured using cytokine bead array. 16S ribosomal RNA gene amplicon sequencing of mouse feces was performed to assess alterations in the gut microbiome. Behavior associated with these dietary changes was also evaluated. Results The ketogenic diet caused weight gain and glucose intolerance in both male and female mice. In male mice, the high glycemic diet led to increased caspase-1 biosensor activation over the course of the study, while in females the ketogenic diet drove an increase in biosensor activation compared to their respective controls. These changes correlated with an increase in inflammatory cytokines present in the serum of test mice and the emergence of anxiety-like behavior. The microbiome composition differed significantly between diets; however no significant link between diet, glucose tolerance, or caspase-1 signal was established. Conclusions Our findings suggest that diet composition, specifically the source and quantity of carbohydrates, has sex-specific effects on inflammasome activation in the central nervous system and behavior. This phenotype manifested as increased anxiety in male mice, and future studies are needed to determine if this phenotype is linked to alterations in microbiome composition.

IntroductionGastric cancer (GC) is an aggressive and heterogeneous malignancy marked by cellular and molecular diversity. In GC, cancer cells invade locally in the stomach at stage I and can progress to metastasis in distant organs by stage IV, where it often becomes fatal.MethodsWe analyzed gene expression profiles from 719 stage I and stage IV GC patients across seven public datasets, conducting functional enrichment analysis to identify a gene signature linked to disease progression. Additionally, we developed an in vitro model of a simplified extracellular matrix (ECM) for cell-based assays.ResultsOur analysis identified a progression-associated gene signature (APOD, COL1A2, FSTL1, GEM, LUM, and SPARC) that characterizes stage IV GC. This signature is associated with ECM organization and epithelial-to-mesenchymal transition (EMT), both of which influence the tumor microenvironment by promoting cell invasion and triggering EMT.DiscussionThis gene signature may help identify stage I GC patients at higher risk, offering potential utility in early-stage patient management. Furthermore, our experimental ECM model may serve as a platform for investigating molecular mechanisms underlying metastatic spread in gastric cancer.

The Messinian-Zanclean boundary in the Mediterranean basin marks the end of the Messinian salinity crisis (MSC) at approximately 5.33 Ma. The mechanism behind the return to normal marine conditions after the MSC are debated, with two main hypotheses proposed: an instantaneous reflooding of the Mediterranean at the base of the Zanclean, following its near-complete desiccation, or a gradual sea level rise in a non-desiccated basin during the late MSC phase (Lago-Mare). Our objectives are to refine the age model of the Pollenzo section in the Piedmont basin, Italy, and to elucidate environmental variability during this phase. We employ high-resolution biomagnetostratigraphic and cyclostratigraphic analyses, integrated with statistical multivariate and cluster analyses, and tie the results with other Italian Mediterranean reference sections of the basal Zanclean. The proposed age model is based on biostratigraphic markers (planktic foraminifera and calcareous nannofossils), alongside the identification of the base of the Thvera subchron. Although no astrochronological tuning was proposed, the influence of orbital parameters variation on calcareous plankton was noted, especially at tie of eccentricity maxima. Our results indicate a gradual restoration of open marine conditions after the MSC, spanning from 5.33 to 5.23 Ma. We observe a transition from a more marginal environment to more open marine conditions at the termination of MSC. Our findings challenge the notion of an abrupt transition at the end of the MSC, emphasizing the gradual nature of environmental change in the northernmost Mediterranean basin, from the late Messinian to the early Zanclean.