As the primary living environment for disabled older adults, families play a crucial role in disease prevention and maintaining their health. However, research has found that both disabled older adults and their family members experience numerous physiological, psychological, and social adaptation problems when adjusting to the changes brought by disability, severely impacting the overall health status of the family. Therefore, guided by the ERG (Existence-Relatedness-Growth) theory, this study aims to understand the family health needs of families with disabled older adults in the community, providing a basis for improving the health level of these families and developing targeted intervention programs. From December 2024 to February 2025, this study employed purposive and snowball sampling to select 12 pairs of disabled older adults and their primary caregivers from communities under the jurisdiction of Zhengzhou City, Henan Province for semi-structured interviews. Thematic analysis was applied to organize and analyze the interview data. Deductive analysis indicated that the famliy health needs of families with disabled older adults in the community can be summarized into the following three themes: existence needs (daily living needs, economic support needs, environmental modification needs), relatedness needs (family communication needs, social resource connection needs, social participation needs), and growth needs (autonomy and dignity maintenance needs, family development needs, demand for technology-enabled solutions). The results show that the family health needs of families with disabled older adults in the community are unique and diverse. Community health workers and social workers can develop and implement effective strategies based on the different levels of family needs to promote the health level of families with disabled older adults and improve the overall quality of life of these families.
Home environments shape children's dietary habits, but which factors are most influential is unclear. The study purpose was to identify factors in the home environment associated with child intake of fruit and vegetables (FV) and sugar-sweetened beverages (SSBs) using a national dataset collected in 2013-2015 in the U.S. Data from 5,138 school-aged children (4-15 years old) from 130 U.S. communities were collected in 2013-2015. Parents and/or children completed a dietary screener and additional survey questions to assess household socioeconomic status (SES), grocery shopping sources, home food availability, social support for healthy eating, eating out frequency, and other home eating and related behaviors. Other child characteristics included breastfeeding history, intake of school foods, and participation in other nutrition programs. Community variables included predominant race/ethnicity and SES. Classification and regression trees (CART) identified key predictors of intake. The FV and SSB CARTS had 14 and 12 terminal groups, respectively. Children with the highest FV intake (0.54 SD from mean cups/day; 13% of sample) had fruit more often available at home, dark green vegetables more often available at home, ate dinner with family more often, had SSBs less often available at home, and were breastfed longer. Conversely, children in the two groups with the lowest FV intake either had fruit less often available at home, and family never complimented their eating (-0.86; 2%), or they had family that rarely or sometimes complimented their eating, and perceived school lunches as unhealthy (-0.87; 1%). For SSB intake, the lowest consumers (-0.63 SD from mean tsp/day sugar; 17%) never or rarely had SSBs available at home, and lived in higher SES communities. Children in the two groups with the highest SSB intakes had SSBs available at home more often, and lived in a SNAP-participating household and either ate out less often, used a phone/computer for social networking, and had SSBs available at home very often (1.3; 1%), or they ate out more often, and were breastfed for a shorter duration (1.1; 5%). Home availability of FV and SSBs were the most salient predictors of intake of both FV and SSBs, while other predictors differed between FV and SSB intake. Study findings highlight several actionable home-environment strategies to test in future studies to improve school-aged children's diets.
Caring for a family member with Alzheimer’s disease can be physically, emotionally, and mentally challenging, affecting a caregiver’s overall well-being and daily life. We looked at two tools—the Adult Social Care Outcomes Toolkit for Carers (ASCOT-Carer) and the EQ-5D-5L—to see how well they measure the impact of caregiving on a caregiver’s quality of life and to expand the available tools for properly evaluating caregiver quality of life in health economic evaluations in Japan. We also examined how these tools related to caregivers’ feelings of stress and burden using the eight-item short Japanese version of the Zarit Burden Interview. We surveyed 705 family caregivers of people with Alzheimer’s disease through an online questionnaire. Our results showed that both tools provide helpful information but focus on different areas of a caregiver’s quality of life. The EQ-5D-5L mainly looks at general health issues like mobility, self-care, and anxiety, but it doesn’t fully capture the social and emotional challenges of caregiving. Alternatively, the ASCOT-Carer offers a clearer picture of a caregiver’s well-being, especially regarding social connections and emotional health. Moreover, the ASCOT-Carer was better than the EQ-5D-5L at showing the stress and burden that caregivers experience. This highlights that the ASCOT-Carer is more sensitive to the specific challenges that caregivers face. While both tools are helpful, the ASCOT-Carer may be a more suitable tool for evaluating the impact of caregivers’ real-life struggles on their quality of life, making it a valuable resource for health economic evaluations.
Choline is an essential nutrient required for the synthesis of key molecules, such as phosphatidylcholine, sphingomyelin, acetylcholine, and S-adenosylmethionine. Choline metabolism encompasses two phases, namely the postprandial and postabsorptive states. The former enables the digestion, absorption, distribution, and storage of choline derivatives after a meal, while the latter allows the cellular utilization of choline and the mobilization of stored choline-containing molecules during fasting. Understanding choline metabolism is fundamental to the study of lipid disorders such as steatohepatitis or atherosclerosis, as well as neurodegenerative diseases, including Alzheimer's disease, and inflammatory signaling pathways. Members of the alkaline phosphatase (AP) superfamily are prominent contributors to extracellular choline metabolism. Within this family, several APs and ectonucleotide pyrophosphatases/phosphodiesterases (ENPP) members are required for physiological choline metabolism. While intestinal alkaline phosphatase (IAP) and alkaline sphingomyelinase/ENPP7 both participate in the digestion of choline-containing derivatives in the gut during the postprandial phase, circulating ENPP2, ENPP6, and tissue-nonspecific alkaline phosphatase (TNAP) act during the postabsorptive phase to generate choline. In this review we first provide a comprehensive overview of choline metabolism and then describe how APs and ENPPs have functionally and structurally co-evolved to catalyze sequential reactions within this metabolic pathway.
Metaphyseal anadysplasia 1, which includes Spondyloepimetaphyseal dysplasia Missouri type, is a rare autosomal dominant skeletal dysplasia characterized by short stature, mild limb deformities, and transient metaphyseal irregularities that typically resolve with age. The condition is caused by heterozygous missense variants in the MMP13 gene, encoding matrix metalloproteinase 13, a key enzyme in endochondral ossification and extracellular matrix remodeling. Pathogenic variants in MMP13 are exceedingly rare, with only a few families reported. We report two siblings, aged 3 and 1 years, in Sweden, presenting with clinical and radiological features consistent with Metaphyseal anadysplasia 1. Their father, of Syrian origin, exhibited short stature and mild femoral bowing. Genetic analysis revealed a novel heterozygous missense variant c.217T>C, p.(Ser73Pro) in MMP13, inherited from the affected father, and located within the same MMP13 domain as previously reported patients. The family pedigree demonstrates multiple affected individuals with short stature and bowed femurs, consistent with autosomal dominant inheritance. Radiographic imaging of father confirmed persistent but mild skeletal abnormalities. This report expands the genotypic spectrum of Metaphyseal anadysplasia 1 and suggests a putative mutational hotspot in exon 2. It further emphasizes the importance of thorough clinical, radiological, and genetic evaluation in families with short stature and metaphyseal irregularities and a clinical long-term follow-up is proposed with regular radiographic monitoring.
Cornelia de Lange syndrome is a rare congenital disorder marked by considerable clinical variability, including intellectual disability, growth retardation, distinctive facial features, limb abnormalities, and multisystem involvement. The condition is primarily linked to mutations in genes encoding components of the cohesin complex that are essential for chromosomal stability and gene regulation. We report a case of a mild type of Cornelia de Lange syndrome caused by a de novo mutation in an Iranian family. We investigated a 19-year-old Iranian male individual presenting with developmental delay, borderline intellectual disability, dysmorphic facial features, and multisystem involvement. Whole-exome sequencing was performed to identify causative variants. A de novo heterozygous variant affecting the start codon of NIPBL (NM_133433.4:c.2T>A; NP_597677.2:p.Met1Lys) was identified. This variant was absent from population databases and predicted to disrupt normal translation initiation. Sanger sequencing and co-segregation analysis confirmed the genetic findings. In silico tools and population databases were utilized to assess variant pathogenicity. Clinically, the patient exhibited classical Cornelia de Lange syndrome features with relatively mild intellectual impairment compared with typical loss-of-function cases, consistent with the hypothesis of potential use of alternative start sites. This case shows a known NIPBL start-loss variant's correlation with a relatively mild clinical presentation and offers more genotype-phenotype evidence for it. This finding suggests a possible role for downstream translation initiation as a modifier of disease severity, although further functional validation is required. Comprehensive genetic analysis remains essential for accurate diagnosis, prognosis, and counseling in patients with Cornelia de Lange syndrome.
School belonging is a key protective factor for socioemotional functioning during the preschool period. Counsellors working in preschool institutions play an important role in developing sense of school belonging by meeting their emotional and social needs and fostering a positive school environment. This study examined the views of school counsellors working in preschool education institutions in Türkiye regarding sense of school belonging and, to support these views and to reveal their reflection at the level of institutional practice, analysed routine guidance and counselling documents to identify how belonging-supportive practices are formally planned, implemented, and recorded over the school year. A phenomenological qualitative design was employed. Data were collected through structured interviews with school counsellors and complemented by document analysis of counselling artefacts to examine how belonging practices are formally planned, implemented, and documented across the school year. The document corpus comprised 186 written artefacts from 10 kindergartens. Data were analysed using computer-aided content analysis, and a hierarchical code-subcode model was utilised in MAXQDA 2020. Findings indicated that counsellors conceptualised school belonging as children's feelings of acceptance and security within the school community and described belonging-related differences in children's emotions, participation, and peer interactions. Counsellors also highlighted multi-level strategies targeting emotional safety, peer relationships, teacher practices, and family involvement. Complementing these findings, the document analysis yielded five practice-oriented domains through which counselling services may support school belonging: (1) emotional safety and adjustment to school routines, (2) support for peer relationships and social problem-solving, (3) cultivation of a positive classroom/school climate through teacher collaboration, (4) systematic family involvement and parent education, and (5) developmental monitoring and evaluation. Document analysis corroborated counsellors' reported perspectives by providing practice-level evidence of how belonging-supportive strategies were formally embedded in institutional plans and documented in artefacts. Preschool children's school belonging is supported through a year-long programme of practice spanning children, teachers, and families. Strengthening preventive counselling services that promote emotional safety, peer-inclusion, and family-school collaboration may improve school belonging in early childhood, as this phenomenon has far-reaching implications for children's educational trajectories, working lives, and broader societal and democratic engagement.
Children with autism spectrum disorder (ASD) frequently exhibit selective eating behaviors characterized by food refusal and limited dietary variety, which can lead to nutritional deficiencies and impaired family functioning. This study evaluated the effectiveness of the Schmetterling Nutritional Behavior Intervention (NBI) Program, a creative behavioral intervention integrating established behavioral strategies with innovative components, including imitation chaining, shaping, and therapist-guided exoskeleton modeling. Three children (YW, RA, and JK) diagnosed with autism spectrum disorder (ASD) participated in a single-case experimental design. The study employed the Childhood Autism Rating Scale, 2nd Edition (CARS-2) assessing autism symptom severity, while the Child Eating Behavior Questionnaire (CEBQ) measured changes in eating behavior. Substantial increases in food acceptance were observed across all participants, with the highest improvements in food responsiveness, enjoyment of food, and food fussiness. Tau-U analysis revealed large and significant intervention effects for both therapist-implemented and parent-implemented sessions. Although CARS-2 scores remained within the 'severe' classification range, notable percentage reductions suggested clinically relevant improvements in core autism symptoms. These findings support the Schmetterling NBI Program as an individualized, evidence-based approach to enhancing dietary diversity and reducing maladaptive feeding behaviors in children with ASD. Children with autism spectrum disorder (ASD) commonly demonstrate selective eating patterns, including food refusal and restricted dietary repertoire, which may contribute to nutritional deficits and compromised family dynamics. This investigation examined the efficacy of the Schmetterling Nutritional Behavior Intervention (NBI) Program, a novel behavioral intervention that synthesizes established behavioral methodologies with innovative components such as imitation, shaping procedures, and therapist-guided training. Utilizing a single-case experimental design, three children diagnosed with ASD (YW, RA, and JK) were assessed with the Childhood Autism Rating Scale, Second Edition (CARS-2) to evaluate autism symptom severity, and the Child Eating Behavior Questionnaire (CEBQ) to measure alterations in feeding behavior. Results indicated substantial improvements in food acceptance across all participants, with pronounced enhancements in food responsiveness, enjoyment of food, and reductions in food fussiness. Tau-U statistical analysis demonstrated large and significant intervention effects for both therapist-administered and parent-implemented sessions. Although CARS-2 scores remained within the severe classification range, notable percentage reductions indicated clinically meaningful improvements in core autism symptomatology. These findings support the Schmetterling NBI Program as an individualized, evidence-based intervention for promoting dietary diversity and reducing maladaptive feeding behavior among children with ASD. Replicating our preliminary findings in a larger sample and finding evidence-based tailored interventions for children with ASD pose important challenges for future research.
Executive function is an essential cognitive domain for typical human behavior which is disrupted in neurodevelopmental and neurodegenerative disorders, but little is known about its underlying molecular basis. To address this, we perform genome-wide association studies (GWAS) using three different measures of executive function in UK Biobank (N = 84,238) and NIHR BioResource's Genes and Cognition (N = 9932) study participants, followed by a meta-analysis. The trail-making alphanumeric (TMA) measure is the most heritable phenotype (h²=7-26%), associated with 18 independent loci that exhibit a similar direction of effect in both cohorts. Across these loci, in-silico follow-up implicates 178 genes, of which NT5DC2 and RP11-579E24.2 are independently replicated prior to meta-analysis. TMA is linked to pan-cerebral differences in brain structure, with brain-enriched genes showing a biphasic expression profile from early development through to later life. Our data implicate specific cell types, histone modifications and butyrophilin immunoglobulin family proteins as potential targets for promoting cognitive resilience.
The PE_PGRS gene family in Mycobacterium tuberculosis exhibits extensive sequence variability across genotypes, which is consistent with antigenic divergence. Here we investigate how Mtb-despite lacking horizontal gene transfer-balances genomic stability with adaptive plasticity. Comparative analysis of 88 bacterial genomes reveals that PE_PGRS genes exhibit features facilitating mutability, including a significantly elevated CGGC tetramer density (mean 4.97 per 100 nt; range 1.7-7.4) compared with the genome-wide average (1.62 per 100 nt; p = 0.011) and depleted in out-of-frame stop codons, potentially conferring robustness to 1-nt and 2-nt frameshifts. Computational predictions suggest that CGGC motifs may promote secondary DNA structures, potentially destabilizing replication and contributing to replication errors, while the scarcity of out-of-frame stop codons allows continued translation beyond frameshifts, leading to changes in protein sequence and length. This dual organization may contribute to the observed adaptability of M. tuberculosis and could highlight a broader principle by which some pathogens evolve under strong constraints on horizontal gene transfer. We propose that CGGC-rich regions may function as programmed mutational hotspots across a wide range of microorganisms.
Osteoporosis (OP) is a systemic metabolic bone disorder. The excessive activation of osteoclasts (OCs) leads to a decrease in bone mass and damage to the bone microstructure, which plays a crucial role in OP. β-Hydroxybutyrate (BHB), the main component of ketone bodies, not only serves as an ancillary fuel substituting for glucose but also induces anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone β-hydroxybutyrylation (Kbhb). Recent research has found that BHB has a positive therapeutic effect on OP, but the underlying molecular mechanism remains unclear. In this study, we established osteoporosis (OP) animal models induced by estrogen deficiency and type 2 diabetes using ovariectomized (OVX) and db/db mice, respectively, and administered BHB to OP mice via free drinking in vivo. Our results indicated that BHB increased bone mineral density (BMD), improved bone microstructure, and inhibited the OC formation. Additionally, BHB upregulated the levels of PanKbhb, H3K9bhb, and H3K27bhb modifications in the bone tissue of OP mice. In vitro, we found that BHB or β-hydroxybutyryl-CoA (BHB-CoA) could inhibit RANKL-induced OC differentiation and bone resorption, and upregulate histone Kbhb levels in a concentration-dependent manner. Furthermore, the effects of BHB or BHB-CoA-induced histone Kbhb were reversed by inhibiting the activity of Acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300. In summary, our data reveal that BHB may alleviate bone loss caused by estrogen deficiency and type 2 diabetes through ACSS2/P300-induced histone Kbhb.
In this review we comprehensively discuss organic cation transporter novel 1 (OCTN1), encoded by the SLC22A4 gene as a member in the solute carrier 22 (SLC22) family, which facilitates the cellular transport of diverse cationic and zwitterionic substrates. OCTN1 is highly expressed in many vital organs in humans, where it facilitates absorption and distribution of both endogenous compounds and therapeutic drugs. Among its substrates, ergothioneine (EGT) serves as the primary antioxidant and anti-inflammatory molecule, underscoring the essential role of OCTN1 in cellular defense and inflammation control. Genetic polymorphisms in SLC22A4 significantly alter OCTN1 expression, substrate affinity, and drug pharmacokinetics, with strong associations to susceptibility and treatment outcomes in human diseases. Insights from knockout models revealed that OCTN1 deficiency leads to reduced EGT availability, heightened oxidative stress, and aggravated inflammation, particularly in the tissues such as intestine, liver and lung. Moreover, OCTN1 activity is dynamically regulated by epigenetic modifications, cytokines, and hormones, linking it to immune modulation and disease progression. Put together, OCTN1 plays a defined role via high-affinity EGT transport, while its broader transport capacity and pharmacological relevance remain under investigation, with possible - though not yet established - implications for inflammation-associated biomarker development.
The plastic pollution crisis urges innovative recycling solutions. Promising approaches especially for polyester-containing wastes include enzymatic hydrolysis and microbial upcycling. For efficient enzymatic hydrolysis of polyesters, elevated temperatures (70-80 °C) are required, necessitating thermophilic microbial chassis for consolidated bioprocessing (CBP). In this study, we engineered Geobacillus thermoleovorans through adaptive laboratory evolution (ALE) for robust growth on adipic acid (AA) and 1,4-butanediol (BDO), two relevant monomers for example derived from poly(butylene adipate-co-terephthalate) (PBAT), enabling growth rates of up to 0.10 h-1 on AA and 0.13 h-1 on BDO. Based on a high-quality annotated genome sequence of the wild type, genomic mutations and gene expression levels were characterized in mutants grown on the respective substrates compared to glucose. For BDO, an alcohol dehydrogenase (Gth_001044) and an aldehyde dehydrogenase (Gth_001082) were identified to be likely responsible for its oxidative degradation. AA uptake appears to be mediated by a dicarboxylate transporter (Gth_003270), followed by CoA activation and β-oxidation involving a CoA transferase (Gth_003192) and several upregulated CoA-family dehydrogenases. To demonstrate applicability of these strains in plastic upcycling, they were co-cultivated with PBAT as the sole carbon source in combination with the cutinase HiC for PBAT hydrolysis. This resulted in growth on the released AA and BDO. Given the potential to purify the remaining terephthalate (TA), this approach highlights the feasibility of selective monomer valorization in bioprocesses. Additional ALE enabled co-utilization of AA and BDO by a single strain and improved AA consumption at lower concentrations, underscoring the strains' adaptability and high potential for plastic upcycling applications. KEY POINTS: • G. thermoleovorans evolved for robust growth on adipate and 1,4-butanediol at 60 °C. • Genome and transcriptome analyses revealed underlying pathways and enzymes involved. • Co-cultivation of the evolved strains on PBAT with HiC as the sole carbon source.
Therapeutic resistance to chemotherapy or radiotherapy is a significant issue in several cancers, including head and neck squamous cell carcinoma (HNSCC). One pathway associated with therapeutic resistance is the NFκB pathway, which promotes survival in response to the cytokine TNFα, a key mediator of chemotherapy and radiotherapy-induced cytotoxicity. However, direct targeting of the NFκB pathway is associated with significant toxicity and thus targeting the regulation of this pathway is a promising therapeutic target. We recently demonstrated that the USP14/UCHL5 inhibitor b-AP15 inhibits NFκB activity, inhibiting proliferation and inducing apoptosis in HNSCC cells. Furthermore, b-AP15 treatment sensitised HNSCC cells to the cytotoxic effects of TNFα, as well as TNF-inducing radiation treatment. Here, we investigated if b-AP15 sensitised HNSCC cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cancer selective member of the TNF family. b-AP15 treatment sensitised HNSCC cells to TRAIL treatment. Mechanistically, we show that b-AP15 induced expression of the TRAIL receptor Death Receptor 5 (DR5)/TRAIL Receptor 2 (TRAILR2), which was required for b-AP15-mediated TRAIL sensitisation. b-AP15 induced reactive oxygen species (ROS) and activated the JNK signalling pathway and both ROS and JNK signalling were required for the induction of DR5 expression and TRAIL sensitisation. We further show that b-AP15-mediated reduction of the NFκB-dependent gene XIAP induced DR5 expression and TRAIL sensitisation and that combination between b-AP15 and IAP antagonists was synergistic in HNSCC cells in vitro. Our data further define the mechanism of b-AP15-mediated cytotoxicity and highlight potential combination treatments that warrant further exploration in pre-clinical studies in HNSCC.
The c-Jun N-terminal kinase (JNK) pathway is an evolutionarily conserved signaling cascade that regulates development, stress responses, and pathogenesis. While aberrant JNK activation is linked to cancer and neurodegeneration, its regulatory mechanisms are not fully understood. Here, we identify the RNA-binding protein Ataxin-2 (Atx2) as a novel, essential regulator of JNK-mediated cell death and migration in Drosophila. Atx2 deficiency suppressed JNK-dependent apoptosis, tumor growth and invasion, and thorax closure in normal development, while its overexpression activated JNK signaling, promoting cell death, migration, and tissue remodeling. Mechanistically, Atx2 binds the 3' UTR of hipk mRNA, stabilizing it to enhance the expression of Hipk, a core upstream JNK kinase. Strikingly, this mechanism is conserved: human ATXN2L potently activated Hipk-JNK signaling and cell death in Drosophila and HeLa cells. Our findings reveal a conserved post-transcriptional mechanism for JNK pathway regulation and nominate Atx2 family proteins as potential therapeutic targets in JNK-associated pathologies.
Broad-spectrum resistance genes are highly valuable for sustainable crop protection, yet the molecular basis of their activity is often unknown. The Pm3 allelic series in wheat encodes NLR receptors that recognize avirulence (AVR) effectors of wheat powdery mildew. Here, we show that near-identical Pm3 alleles vary greatly in resistance efficacy and broadness against a global mildew isolate collection and subsequently use this model system to study the mechanisms underlying broad-spectrum resistance. We demonstrate that two alleles, Pm3d and Pm3e, provide resistance against most isolates worldwide, by each recognizing two AVR genes, thereby lowering the risk of resistance breakdown. Pm3d recognizes two highly similar RNase-like AVRs, encoded by gene paralogs. In contrast, Pm3e detects two structurally diverse AVRs: one shared with Pm3d, the other originating from a large, uncharacterized protein family with a discrete structural fold. Using chimeric Pm3 NLRs, we identify specificity-defining polymorphisms of Pm3d and Pm3e against their diverse effector targets. Lastly, we demonstrate that Pm3d and Pm3e activities can be combined in engineered Pm3 NLRs, thereby further extending their recognition spectrum. Our findings highlight the potential of Pm3 immune receptors for long-lasting wheat protection by demonstrating their versatility in recognizing structurally diverse effectors and their amenability to NLR engineering.
Periodontitis, a chronic inflammatory disease, is increasingly prevalent among young people and impairs their quality of life. Adverse childhood experiences (ACE), depressive symptoms, and suboptimal health status (SHS) are linked to health risks and chronic diseases, but their interrelationships with periodontitis in Chinese young adults remain unclear. This study aimed to explore associations among these factors. From December 2024 to May 2025, 2,888 participants (aged 18-35) from Tongji Hospital completed surveys on demographics, ACE, depressive symptoms, and SHS. Periodontitis was diagnosed according to the 2018 criteria. Simple, parallel, and chain mediation models were used, controlling for age, sex, marital status, and smoking. Periodontitis prevalence was 25.00% and higher in married individuals (P < 0.001) and smokers (P = 0.004). ACE correlated positively with depressive symptoms (r = 0.28, P < 0.001), SHS (r = 0.19, P < 0.001), and periodontitis (r = 0.16, P < 0.001). Mediation analyses showed: Simple model: Depressive symptoms and SHS partially mediated the effect of ACE on periodontitis (indirect effect = 0.011 for both). Parallel model: Only SHS significantly mediated the effect (indirect effect = 0.011). Chain model: ACE was related to periodontitis via "depressive symptoms → SHS" (indirect effect = 0.010), with significant direct and indirect effects. ACE associated with higher periodontitis risk in young people. This association included both a direct link between ACE and periodontitis, and an indirect link through the chain pathway of "depressive symptoms → SHS"; among these pathways, SHS was a key mediator. The study was registered in the Chinese Clinical Trial Registry (ChiCTR) with the registration number ChiCTR2500103464. Childhood trauma can exert long‐term impacts on health, including oral health. This study involving 2,888 Chinese young adults aged 18‐35 found that 25% of the participants had periodontitis. Those who experienced childhood abuse, neglect, or family issues showed a higher association with the disease. The research revealed two pathways linking early trauma to periodontitis: a direct association and an indirect chain of “depressive symptoms → suboptimal health status (e.g., persistent fatigue).” While depressive symptoms played a role, suboptimal health status was the critical mediator. Higher periodontitis rates in married individuals and smokers may relate to stress or lifestyle factors. The findings suggested that early identification of childhood trauma, combined with interventions targeting mental health or overall well‐being (e.g., counseling, health management), could be more effective than oral care alone in prevention. This underscored the association between early‐life experiences and long‐term health and the need for integrated interventions.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping pathology. Mutations in CCNF, encoding the E3 ubiquitin ligase, Cyclin F, can cause ALS, FTD, or both, even within the same family. Most prior studies of CCNFS621G have relied on overexpression systems, potentially confounding outcomes through disruption of endogenous Cyclin F. Here, we generated the first knock-in mouse model of endogenous CcnfS621G using CRISPR/Cas9. Heterozygous and homozygous CcnfS621G mice showed no motor decline or neuronal loss after 18 months, however immunohistochemistry revealed increased hippocampal astrocyte ramification, with sex-, age, and subfield-dependent effects. These data indicate that endogenous CcnfS621G may prime early astrocyte alterations in the absence of overt neurodegeneration. Similar astrocyte morphological changes were observed in canonically affected regions of sporadic ALS and FTD-ALS patients post mortem, as well as in CCNFS621G iPSC-derived astrocytes following inflammatory stimulation. Proteomics on Ccnf mice identified early dysregulation of pathways related to translation, mitochondrial function, cytoskeletal remodelling, synaptic transmission and neuroinflammation. Correspondingly, CCNFS621G iPSC-derived astrocytes displayed impaired mitochondrial membrane potential and altered network morphology under both basal and inflammatory stimuli. As altered neuronal excitability is a hallmark of ALS, we examined astrocyte-driven changes to neuronal excitability. CCNFS621G iPSC-derived motor neurons cultured alone were hyperexcitable, firing more action potentials than isogenic controls. Remarkably, co-culture with CCNFS621G astrocytes, but not isogenic control astrocytes, abolished repetitive firing, increased the proportion of neurons unable to generate action potentials, and reduced voltage-gated sodium currents in CCNFS621G and isogenic control neurons. Together, these findings identify astrocyte alterations as an early feature of CCNFS621G-mediated disease, in the absence of neuronal loss. Moreover, the combination of astrocytic mitochondrial dysfunction and the ability of CCNFS621G astrocytes to suppress repetitive neuronal firing suggests a critical astrocyte-driven non-cell autonomous mechanism that may contribute to an oligogenic role for CCNF in ALS/FTD pathogenesis.
The P-Rex family proteins P-Rex1 and P-Rex2 are Dbl-type guanine-nucleotide exchange factors (GEFs) that activate Rac small GTPases upon synergistic stimulation by PIP3 and Gβγ, acting as coincidence detectors for PI3K and GPCR signalling. P-Rex Rac-GEFs control physiological responses ranging from inflammation, innate and adaptive immunity to GPCR trafficking, glucose homeostasis, and the function of the vascular endothelium, nervous system, and adipose tissue. P-Rex2 also increases PI3K-signalling through its catalysis-independent inhibition of the tumour suppressor PTEN. Deregulated levels of P-Rex1 are linked to fibrotic diseases, asthma, and autism spectrum disorders, and both P-Rex1 and P-Rex2 are deregulated in metabolic diseases. Upregulation of P-Rex1 and P-Rex2 as well as activating P-Rex2 mutations also occur in many types of cancer, including breast, prostate, lung, liver and colorectal cancer, as well as in melanoma and glioma. and contribute to tumour growth or metastasis depending on the P-Rex protein and cancer type. Deregulation of P-Rex1 in cancer typically promotes tumour growth or metastasis, whereas upregulation or mutation of P-Rex2 in cancer is mostly associated with tumour growth. Recently, structural data have increased our understanding of P-Rex regulation, the first P-Rex inhibitors have been developed, and GEF-activity independent functions of P-Rex proteins in GPCR trafficking, neutrophil-responses, innate immunity, and glucose homeostasis have been described. This review summarises the P-Rex literature from the discovery of the P-Rex protein family in 2002 to the present, with a focus on recent advances.
Reptiles often inhabit environments that are in close proximity to humans and livestock, creating opportunities for parasite transmission. They are common in areas where they find shelter, food and warmth. The Bengal monitor lizard (Varanus bengalensis), a member of the family Varanidae, represents one of the largest groups of extant poikilothermic predators. Monitor lizards are known to harbor several tick species that serve as vectors for a variety of pathogens. No prior information is available in the literature regarding ticks infesting V. bengalensis in Pakistan as well as regarding the occurrence of Toxoplasma gondii in these ticks. Therefore, we aimed to determine the molecular prevalence of T. gondii in Amblyomma gervaisi ticks (n = 93) collected from 24 V. bengalensis in Buner District, Khyber Pakhtunkhwa Province, Pakistan, between May and September 2023. Polymerase chain reaction (PCR) amplified a 300 bp fragment specific for the ITS-1 region of T. gondii in 10 of the 93 (11%) A. gervaisi ticks. DNA sequencing and BLAST analysis confirmed the presence of T. gondii. Phylogenetic analysis showed that these sequences clustered with the ITS-1 sequences of T. gondii detected in reptiles and mammals from Pakistan, Brazil, China, Tunisia and Portugal. The prevalence of T. gondii in A. gervaisi was not limited to a specific tick sex, feeding stage or month of sampling. However, among the tick developmental stages, nymphs had the highest rate of T. gondii infection. In conclusion, for the very first time from Pakistan, we are reporting the presence of T. gondii in A. gervaisi that were infesting monitor lizards. We recommend that similar and large scale studies should be conducted in all those areas of Pakistan that are unexplored for the presence of T. gondii in A. gervaisi ticks. Prevalence of this parasite should also be screened in all the animals harboring these as well as other tick species. This will help in better understanding of T. gondii transmission to new hosts that will lead toward its effective control.