Search Results (6,941)

Mouse models of genetic diseases are important research tools. However, the genetic background of the mouse strain can significantly influence how a genetic mutation is expressed. Studies on preclinical models of phenylketonuria (PKU), an inherited metabolic disorder, have used two strains, BTBR and C57Bl/6, created via a chemically induced point mutation in the gene encoding the enzyme phenylalanine hydroxylase (BTBR^enu2 and C57^enu2, respectively). Despite having the same levels of hyperphenylalaninemia (HPA), published results indicate differences in neural and behavioral phenotypes between the two backgrounds. To explore this difference further, the current study examines the genome-wide transcriptome of the prefrontal cortex (pFC), the brain region which is the most vulnerable to the negative effects of HPA. Regardless of the strain, the enu2 mutation upregulated the expression of several aminoacyl-tRNA synthetases and eukaryotic translation initiation factors, suggesting an essential modification in the protein translation process and supporting the downregulation of gene programs related to myelination. Accordingly, we deepened the exploration of cognitive dysfunctions in C57^enu2− mice, showing a previously unreported working memory impairment under increasing information load. These findings identify convergent pFC molecular and cognitive alterations induced by HPA across distinct genetic backgrounds, providing clinically relevant insights into mechanisms that may contribute to executive dysfunctions in PKU. Full article

Background/Objectives: Maternal immune activation (MIA) increases the risk of Autism Spectrum Disorders (ASD). Experimental models demonstrate that maternal exposure to bacterial endotoxin or the viral mimic polyinosinic:polycytidylic acid [poly (I:C)] reliably recapitulates ASD-like behavioral abnormalities in offspring, yet the underlying neurobiological mechanisms linking MIA to altered neurodevelopment remain incompletely understood. Increasing evidence highlights the placenta as a critical mediator in shaping fetal brain development through immunological and hormonal regulation. Likewise, disruption of placental regulatory functions upon MIA may therefore represent a mechanistic pathway. Here, we investigated how alterations in placental cytokine profiles, innate immune cell composition, and endocrine outputs relate to neuroinflammation and neurogenesis in the offspring. Methods: Pregnant mice at gestational day 12.5 received a single intraperitoneal injection of poly (I:C). Placental macrophages, neutrophils, inflammatory cytokines, and nerve growth factor (NGF) expression were examined 72 h later. Neurodevelopmental outcomes, including microglial activity and neurogenic markers, were evaluated in mouse offspring at postnatal day (P) 1 and 6. Results: MIA induced a significant accumulation of monocytes and neutrophils in the placenta, which was associated with elevated levels of a broad spectrum of inflammatory mediators, including Th17-biased proinflammatory cytokines, chemokines, and adhesion proteins, in the placenta and amniotic fluid. In contrast, the placenta-derived NGF levels were significantly reduced. MIA induced strong and sustained microglial activation in the fetal and neonatal brain. This inflammatory milieu was accompanied by disrupted cortical neurogenesis, characterized by a marked increase in Ki67+ neuronal progenitor cells (NPCs) in the subventricular zone (SVZ), overproduction of early-born Tbr1+ neurons at P1, later-born Satb2+ neurons at P6. Conclusions: Collectively, these findings suggest that heightened Th17 inflammatory signaling, coupled with impaired placental endocrine function, contributes to dysregulated cortical neurogenesis in the offspring. Full article

Peripheral inflammation is increasingly recognized as a critical driver of sustained neuroinflammation and cognitive dysfunction in neurodegenerative and inflammation-associated disorders. Systemic inflammatory mediators can compromise blood–brain barrier integrity, activate glial cells, and initiate maladaptive neuroimmune cascades that disrupt hippocampal–prefrontal circuits underlying learning and memory. Here, we investigated whether early systemic administration of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) mitigates inflammation-driven cognitive deficits in a chronic lipopolysaccharide (LPS) mouse model. Adult mice received daily LPS injections for seven days to induce persistent systemic and central inflammation, which was confirmed by serum and hippocampal cytokine analyses in a separate cohort at the time of MSC administration, followed by intravenous MSC treatment immediately after cessation of the inflammatory insult. Behavioral testing revealed significant impairments in spatial working memory, recognition memory, and associative learning. These deficits were accompanied by pronounced microglial activation, immune cell accumulation, astrocytosis, and a shift toward a pro-inflammatory cytokine milieu with suppression of IL-10 in the hippocampal CA1 region and medial prefrontal cortex. Early MSC treatment attenuated glial reactivity, reduced pro-inflammatory cytokines, restored IL-10 expression, and partially rescued cognitive performance. Collectively, these findings identify a post-inflammatory therapeutic window in which early MSC-based immunomodulation can rebalance neuroimmune signaling and limit inflammation-induced hippocampal–prefrontal circuit dysfunction, highlighting a clinically relevant strategy for targeting cognitive impairment associated with chronic systemic inflammation. Full article

22q11.2 deletion syndrome (22q11.2DS) is the most common recurrent microdeletion in humans and a prototypical high-risk neurogenetic copy number variant (CNV) associated with a broad spectrum of neurodevelopmental and psychiatric disorders, including intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), anxiety, and psychotic symptoms. This hemizygous deletion encompasses multiple genes involved in brain development and neural circuit function, contributing to marked phenotypic variability and multisystem involvement. In pediatric populations, deficits in adaptive functioning are frequently reported and may occur independently of global intellectual impairment, reflecting broader behavioral vulnerabilities within this genetic risk architecture. Background/Objectives: This study aimed to characterize the sociodemographic, clinical, and intellectual profiles of children and adolescents with 22q11.2DS and to examine adaptive functioning and its associations with behavioral difficulties. Methods: Thirty-four patients aged 1–17 years with a confirmed molecular diagnosis of 22q11.2DS were assessed. Standardized instruments were used to evaluate cognitive performance, adaptive functioning, and behavioral outcomes. Results: Intellectual disability was highly prevalent, with most participants showing combined cognitive and adaptive impairments. Adaptive functioning was compromised across domains, with relatively higher socialization scores compared to other areas, such as daily living skills. Multivariate analyses indicated associations between sociodemographic factors and behavioral difficulties, as well as between social problems and lower global adaptive functioning. Conclusions: Together, these findings contribute to the characterization of the adaptive and behavioral phenotype associated with a high-risk neurogenetic CNV and highlight the relevance of adaptive functioning as a key outcome for early evaluation and intervention in pediatric 22q11.2DS. Full article

The placenta is often described as the “window to the brain” due to its crucial role in fetal neurological development. In this study, we investigated a family where the older male offspring exhibited severe neurodevelopmental and mild motor coordination disorders. His brother displayed emotional and behavioral dysregulation along with mild motor coordination disorders. The father was asymptomatic, while the mother and daughter showed mild learning disabilities. Whole exome sequencing (WES) identified a disruptive X-linked pathogenic variant, c.1088_1089del p.Asp363GlyfsTer2, within the calpain-6 (CAPN6) gene. We have submitted this variant to the ClinVar database (RCV005234146.2). The variant was found in hemizygous condition in the affected male offspring and in heterozygous condition in both the mother and daughter. As predicted, the variant undergoes nonsense-mediated mRNA decay (NMD), preventing the translation of the CAPN6 gene into a functional protein. CAPN6 is a critical gene predominantly expressed in placental and trophoblast tissues. Although its function is not well characterized, CAPN6 is also expressed in several regions of the developing brain. Recent studies have shown that genetic variants in CAPN6 significantly influence vascular endothelial growth factor (VEGF) activity, thereby affecting angiogenesis and the blood supply essential for fetal growth and development. Although CAPN6 lacks an MIM phenotype code, we hypothesize that it might be enumerated as a novel candidate gene contributing to neurodevelopmental disorders. Functional studies are imperative to elucidate the role of CAPN6 in placental function and its potential implications for neurodevelopmental processes. This work aims to inspire further research into the role of CAPN6 in placental biology and its relevance to neurodevelopmental disorders. Full article

Background/Objectives: The 10-session How to Eat intervention was developed to institute Eating Competence (EatC) and repair distorted eating attitudes and behaviors growing out of chronically restrained eating and/or repeated weight reduction dieting. How to Eat was conducted over a 12-year period as an employee wellness option at two locations in the midwestern United States. Methods: Participants in How to Eat were adult employees of their respective hospital or university who voluntarily enrolled after screening and assessment by each site facilitator. Pre- and post-measures were the 16-item EatC measure, the 26-item Eating Attitudes Test (EAT-26), and body weight. Results: In the hospital setting, a total of 43 adults participated, with a mean (±SD) age of 47.5 ± 10.7 years, primarily female (95.3%) and white (90.7%). How to Eat was associated with a significant increase in EatC total scores (22.8 ± 6.5 to 34.3 ± 4.9) and a decrease in EAT-26 scores (10.7 ± 8.1 to 3.7 ± 2.9), both p < 0.001. In the university setting, a total of 52 adults participated, 89.4% female, with a mean (±SD) age of 39.3 ± 11.4 years. University participants were significantly younger, p < 0.001. How to Eat was also associated with a significant increase in EatC total scores (24.1 ± 7.0 to 36.6 ± 6.9) and EAT-26 scores (13.9 ± 8.8 to 3.2 ± 4.2), both p < 0.001. At both sites, changes in total EatC, Contextual skills, and EAT-26 scores had strong effect sizes. Mean body weight was ±5% pre/post-intervention at either site. Conclusions: How to Eat is associated with clinically significant improvements in measures of EatC and a decrease in eating disturbances among repeat dieters without significantly impacting body weight. Positive results from employee wellness settings support future experimental studies with more diverse samples and additional outcome measures. Full article

Background: Autism Spectrum Disorder (ASD) involves social, emotional, and behavioral challenges, and conventional therapies show limited effectiveness. Aims: To evaluate the effect of Yoga Therapy (YT) on neurophysiological regulation and behavioral functioning in individuals with ASD. Methods: Thirty-six autistic individuals, aged 6 to 25 years and with Childhood Autism Rating Scale (CARS) scores above 15, were randomly assigned to yoga (YG) and control (CG) groups. YG received 60 min YT sessions twice weekly for six months alongside a regular school routine, while CG followed only a regular school routine. Handgrip strength (HGS), visual reaction time (VRT), systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR), and CARS scores were assessed at pre-, mid-, and post-intervention. Repeated measures ANOVA and Pearson’s correlation were used for statistical analysis. Results: The study showed an increase in HGS (Δ = 3.27 kg) and a reduction in VRT (Δ = −523.86 ms) with a marked decrease in total CARS score (Δ = −5.67), p < 0.01 in YG. There was a mild, non-significant reduction in cardiovascular (CV) dysfunction in YG, while CG showed no significant changes across all measures. Conclusion: Biweekly YT sessions over six months enhanced neurophysiological regulation, improving sensorimotor integration and accelerating cognitive, emotional, and behavioral outcomes in individuals with ASD. Full article

The treatment of depression is an uphill battle due to the low efficiency and delayed clinical response of antidepressants and the fact that most of them cause numerous side effects. Psychobiotics, probiotics that affect brain function and confer mental health benefits, emerged as a promising ally showing protective effects against depressive- and anxiety-like behaviors in various animal models of depression. There is rapidly accumulating evidence that psychobiotics show protective effects at the molecular level as well, affecting several pathophysiological processes implicated in depression. This narrative review summarizes preclinical insights into molecular changes related to the hypothalamic-pituitary-adrenal (HPA) axis, peripheral inflammation, neuroinflammation, neurotransmission and tryptophan metabolism underlying psychobiotic-driven mitigation of depressive and anxiety symptoms in stress-based, corticosterone-induced and inflammation-induced animal models of depression. Research evidence indicates that psychobiotics normalize the activity of the HPA axis, decrease levels of inflammatory mediators in the intestine, circulation, and brain, normalize the levels of neurotransmitters and their receptors, and regulate tryptophan metabolism in various animal models of depression. The main setbacks in this field are the extensive diversity of studied probiotic strains, which are often insufficiently characterized, and the lack of mechanistic studies in animal models. However, despite these challenges, further study of psychobiotics in the pursuit of supportive therapies for depressive disorders is firmly grounded. Full article

Based upon density functional theory (DFT) calculations, we present the basic electronic structure of CuPb₉(PO₄)₆O (Cu-doped lead apatite, aka LK-99), in two scenarios: (1) where the structure is constrained to the P3 symmetry and (2) where no symmetry is imposed. At the DFT level, the former is predicted to be metallic while the latter is found to be a charge-transfer insulator. In both cases the filling of these states is nominally $d^9$, consistent with the standard Cu²⁺ valence state, and Cu with a local magnetic moment of order 0.7 μ_B. In the metallic case we find these states to be unusually flat (∼0.2 eV dispersion), giving a very high density of electronic states (DOS) at the Fermi level that we argue can be a host for novel electronic physics. The flatness of the bands is the likely origin of symmetry-lowering gapping possibilities that would remove the spectral weight from $E_F$. Motivated by some initial experimental observations of metallic or semiconducting behavior, we propose that disorder (likely structural) is responsible for closing the gap. Here, we consider a variety of possibilities that could possibly close the charge-transfer gap but limit consideration to kinds of disorder that preserve electron count. Of the possible kinds we considered (spin disorder, O populating vacancy sites, and Cu on less energetically favorable Pb sites), the local Cu moment, and consequently the charge-transfer gap, remains robust. We conclude that disorder responsible for metallic behavior entails some kind of doping where the electron count changes. Further, we claim that the emergence of the flat bands should be due to weak wave function overlap between the orbitals on Cu and O sites, owing to the directional character of the constituent orbitals. Therefore, finding an appropriate host structure for minimizing hybridization between Cu and O while allowing them to still weakly interact should be a promising route for generating flat bands at $E_F$ which can lead to interesting electronic phenomena, regardless of whether LK-99 is a superconductor. Full article

Background: Childhood obesity represents the most common nutritional and metabolic disorder in industrialized countries and constitutes a major public health concern. In Italy, 20–25% of school-aged children are overweight and 10–14% are obese, with marked regional variability. Excess adiposity in childhood is frequently associated with hypertension, dyslipidemia, insulin resistance, and non-alcoholic fatty liver disease (NAFLD), predisposing to future cardiovascular disease (CVD). Objective: To investigate anthropometric indicators of cardiometabolic risk in 810 children and adolescents aged 7–17 years who underwent assessment for competitive sports eligibility at the Sports Medicine Unit of Modena, evaluate baseline knowledge of cardiovascular health aligned with ESC, AAP (2023), and EASO guidelines. Methods: 810 children and adolescents aged 7–17 years undergoing competitive sports eligibility assessment at the Sports Medicine Unit of Modena underwent evaluation of BMI percentile, waist circumference (WC), waist-to-height ratio (WHtR), and blood pressure. Cardiovascular knowledge and lifestyle habits were assessed via a previously used questionnaire. Anthropometric parameters, blood pressure (BP), and lifestyle-related knowledge and behaviors were assessed using standardized procedures. Overweight and obesity were defined according to WHO BMI-for-age percentiles. Elevated BP was classified based on the 2017 American Academy of Pediatrics age-, sex-, and height-specific percentiles. Statistical analyses included descriptive statistics, group comparisons, chi-square tests with effect size estimation, correlation analyses, and multivariable logistic regression models. Results: Overall, 22% of participants were overweight and 14% obese. WHtR > 0.5 was observed in 28% of the sample and was more frequent among overweight/obese children (p < 0.001). Elevated BP was detected in 12% of participants with available measurements (n = 769) and was significantly associated with excess adiposity (χ² = 7.21, p < 0.01; Cramér’s V = 0.27). In multivariable logistic regression analyses adjusted for age and sex, WHtR > 0.5 (OR 2.14, 95% CI 1.32–3.47, p = 0.002) and higher sedentary time (OR 1.41 per additional daily hour, 95% CI 1.10–1.82, p = 0.006) were independently associated with elevated BP, whereas BMI percentile lost significance when WHtR was included in the model. Lifestyle knowledge scores were significantly lower among overweight and obese participants compared with normal-weight peers (p < 0.01). Conclusions: WHtR is a sensitive early marker of cardiometabolic risk, often identifying at-risk children missed by BMI alone. Baseline cardiovascular knowledge was suboptimal. The observed gaps in cardiovascular knowledge underscore the importance of integrating anthropometric screening with structured educational interventions to promote healthy lifestyles and long-term cardiovascular prevention. Full article

The extracellular matrix (ECM) is a dynamic, tissue-specific network that integrates biochemical and mechanical cues to regulate cell behavior and organ homeostasis. Increasing evidence indicates that dysregulated ECM remodeling is an upstream driver of chronic human diseases rather than a passive consequence of injury. This review summarizes principles of ECM organization, mechanotransduction, and pathological remodeling and highlights translational opportunities for ECM-targeted therapies, biomaterial platforms, and precision diagnostics. We conducted a narrative synthesis of foundational and recent literature covering ECM composition and turnover, stiffness-dependent signaling, and disease-associated remodeling across fibrosis/cardiovascular disease, cancer, and metabolic disorders, together with advances in ECM-based biomaterials, drug delivery, and ECMderived biomarkers and imaging. Across organs, a self-reinforcing cycle of altered matrix composition, excessive crosslinking, and stiffness-dependent mechanotransduction (including integrin–FAK and YAP/TAZ pathways) sustains fibroinflammation, myofibroblast persistence, and progressive tissue dysfunction. In tumors, aligned and crosslinked ECM promotes invasion, immune evasion, and therapy resistance while also shaping perfusion and drug penetration. Translational strategies increasingly focus on modulating ECM synthesis and crosslinking, normalizing rather than ablating matrix architecture, and targeting ECM–cell signaling axes in combination with anti-fibrotic, cytotoxic, or immunotherapeutic regimens. ECM biology provides a unifying framework linking pathogenesis, therapy, and precision diagnostics across chronic diseases. Clinical translation will benefit from standardized quantitative measures of matrix remodeling, mechanism-based biomarkers of ECM turnover, and integrative imaging–omics approaches for patient stratification and treatment monitoring. Full article

This review highlights the anti-inflammatory and antioxidant effects of probiotics and their complex health-related impacts. The main health areas targeted are gastrointestinal inflammation, neuroinflammation, systemic metabolic disorders, and liver conditions. Probiotics work mechanistically to regulate key inflammatory pathways by suppressing nuclear factor (NF-κb) and mitogen-activated protein kinase (MAPK) pathways and activating antioxidant defenses through nuclear erythroid 2-related factor (Nrf2). They stimulate anti-inflammatory cytokines (including interleukin 10 (IL-10) and inhibit pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), partly through the regulation of T cells. Probiotics also produce antioxidant metabolites (e.g., exopolysaccharides and short-chain fatty acids), which enhance the host’s resistance to oxidative stress. Supplementation with probiotics improves intestinal inflammation and oxidative injury in gut disorders. Clinical trials suggest that probiotic supplements may reduce neuroinflammation and oxidative stress, while improving cognitive or behavioral outcomes in neurodegenerative disorders. Overall, this review underscores that probiotics have potent anti-inflammatory and antioxidant effects within the gut–brain axis and across various organ systems, supporting their use as valuable adjunctive therapies for inflammatory and oxidative stress-related conditions. It further emphasizes that additional mechanistic research and controlled clinical trials are essential to translate these findings into the most effective therapeutic strategies. Full article

Selective mutism (SM) is an anxiety disorder that prevents speech in certain situations. Increasingly, it is reported that a proportion of those with SM may also be autistic and that physical freezing may be an important feature of SM. Information on speech and freezing behavior in children with a diagnosis of autism only (n = 20), SM only (n = 61), both autism and SM (n = 19), or neither diagnosis (n = 131) was collected via a self-selected cross-sectional online parent survey with an embedded child survey completed by a small subsection of the children (total n = 27: autism only n = 1, SM only n = 13, both autism and SM n = 3, neither diagnosis n = 10). Throat and body freezing were reported by children with SM, whether they were also autistic or not. The most common reasons given by the children that increased their difficulty in speaking were pressure to talk, worries about how they would be perceived, and fear of making mistakes. The Selective Mutism Questionnaire (SMQ) gave the lowest median score for children with both autism and SM, with median scores increasing in the order SM only, autism only, and neither diagnosis. Children who reported more freezing tended to have lower SMQ scores. Full article

In the study of disordered hyperuniformity, which bridges ordered and disordered states and has broad implications in physics and biology, active matter systems offer a rich platform for spontaneous pattern formation. This work investigates frustrated Vicsek–Kuramoto systems, where frustration induces complex collective behaviors, to explore how hyperuniform states arise. We numerically analyze the phase diagram via the structure factor $S\left(q\right)$ and the density variance $⟨\delta {\rho }^2\left(R\right)⟩$. Results show that recessive lattice states exhibit Class I hyperuniformity under high coupling strength and intermediate frustration, emerging from the interplay of frustration-induced periodicity and active motion, characterized by dynamic, drifting rotation centers rather than static order. Notably, global hyperuniformity emerges from the spatial complementarity of orientation subgroups that are individually non-hyperuniform, a phenomenon termed “orientation-modulated hyperuniformity”. This work establishes frustration as a novel mechanism for generating hyperuniform states in active matter, highlighting how anisotropic interactions can yield global order from disordered components, with potential relevance to biological systems and material science. Full article

Major depressive disorder (MDD) is a leading cause of global morbidity and mortality. Although pharmacological treatments are widely used, their effects are often limited, and nearly half of patients show resistance to current antidepressants, including those unresponsive to all available therapies. These challenges highlight the need to better understand the neurobiological mechanisms driving MDD and to develop novel therapeutic strategies, especially those involving natural compounds with multitarget actions. Baicalin, a bioactive flavonoid from Scutellaria baicalensis, exhibits antioxidant, anti-inflammatory, and neuroprotective properties and has recently gained attention for its potential to improve cognitive deficits and mood disorders. In this study, we investigated baicalin’s antidepressant potential and its underlying mechanisms across multiple experimental levels. We found that oral administration of baicalin produced antidepressant-like effects in both naïve mice and those subjected to chronic restraint stress (CRS). CRS impaired hippocampal long-term potentiation (LTP), whereas baicalin restored these synaptic deficits. Importantly, intra-dorsal hippocampal microinjection of the TrkB receptor antagonist ANA-12 abolished baicalin’s antidepressant effects, indicating the involvement of BDNF–TrkB signaling. Baicalin also reduced reactive oxygen species (ROS)/H₂O₂ production in a BDNF-associated manner, demonstrating clear antioxidant activity. Molecular docking further suggested that baicalin binds more effectively to the TrkB receptor than ANA-12, supporting its capacity to activate TrkB-mediated signaling. By integrating in vivo, ex vivo, in vitro, and in silico approaches, our study shows that baicalin exerts robust antioxidant in vitro and antidepressant effects in vivo. These benefits are primarily mediated through activation of BDNF–TrkB signaling, leading to reduced ROS/H₂O₂ accumulation and alleviation of CRS-induced depression-like behaviors. Full article