Search Results (9,569)

Our understanding of Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor 1a (GHSR1a), has expanded from considering it to be a “hunger hormone” to a pleiotropic regulator of whole-body physiology. This review synthesizes the current advances spanning ghrelin biogenesis, signaling, and systems biology. Physiologically, preproghrelin processing and O-acylation by ghrelin O-acyltransferase (GOAT) generate acyl-ghrelin, a high-potency GHSR1a agonist; des-acyl ghrelin predominates in circulation and exerts context-dependent, GHSR1a-independent, or low-potency effects, while truncated “mini-ghrelins” can act as competitive antagonists. The emergence of synthetic ligands, agonists, antagonists, and reverse-agonists has provided the necessary tools to decipher GHSR1a activity. Recent cryo-EM structures of GHSR1a with peptide and small-molecule ligands reveal a bipartite binding pocket and provide a framework for biased signaling, constitutive activity, and receptor partner selectivity. Beyond the regulation of feeding and growth-hormone release, ghrelin modulates glucose homeostasis, gastric secretion and motility, cardiovascular tone, bone remodeling, renal hemodynamics, and innate immunity. Ghrelin broadly dampens pro-inflammatory responses and promotes reparative macrophage phenotypes. In the emerging scholarship on ghrelin’s activity in the central nervous system, ghrelin has been found to influence neuroprotection, stress reactivity, and sleep architecture, and has also been implicated in depression, Alzheimer’s disease, and substance-abuse disorders. Practical and transitional aspects are also highlighted in the literature: approaches for ghrelin stabilization; recent GHSR1a agonists/antagonists and inverse agonists findings; LEAP-2-based strategies; and emerging GOAT inhibitors. Together, structural insights and pathway selectivity position the ghrelin system as a druggable axis for the management of inflammatory diseases, neuropsychiatric and addiction conditions, and for obesity treatment in the post-GLP-1 receptor agonist era. Full article

In this study, for the first time, the genes encoding the mammalian steroidogenesis system—cytochrome P450scc (CYP11A1), and its native redox partners adrenodoxin and adrenodoxin reductase—were successfully expressed in the methylobacterium Methylorubrum extorquens. The advantage of using methylobacteria as an expression chassis is that they grow on inexpensive mineral media, use methanol as a carbon and energy source, and do not possess their own sterol catabolism systems. Using recombinant methylobacteria, the valuable steroid pregnenolone was obtained as a sole metabolite from cholesterol. The effect of media composition, bioconversion conditions such as methanol and N-sources content, modes of substrate addition, detergents, methyl-β-cyclodextrin, biomass, and aeration on pregnenolone accumulation was investigated. Under optimized conditions, its yield exceeded 100 mg/L. The results demonstrate a proof of concept relating to the use of bacteria lacking their own steroid degradation systems as microbial chassis for heterologous steroidogenesis systems, including mammalian cytochrome CYP11A1. Full article

Background/Objectives: Pre-analytical variation is a major challenge in metabolomics, yet most stability studies have focused on healthy volunteers and have overlooked the impact of disease and medication. To address this gap, we conducted a pilot study in systemic lupus erythematosus (SLE) to assess serum metabolite stability under delayed centrifugation. Methods: Peripheral blood from 10 SLE patients and 5 healthy controls (HC) was stored at room temperature for 1–24 h before processing and analyzed by untargeted LC-MS-based metabolomics. This design enabled direct evaluation of the effect of pre-analytical delay within the context of clinical heterogeneity. Results: Principal component trajectories showed reproducible temporal shifts in HC but dispersed patterns in SLE, indicating disease- and treatment-related influences. Linear mixed-effects models identified metabolites with condition-specific kinetics, including glucose, choline, glycerophosphocholine, and pyroglutamic acid. Mycophenolate intake was further associated with distinct AMP dynamics. Conclusions: These findings demonstrate that both disease state and medication reshape apparent metabolite stability, highlighting the need for strictly controlled sample handling and well-characterized clinical cohorts in metabolomics studies. Full article

Artificial intelligence (AI) is profoundly transforming medicine and healthcare, evolving from analytical tools aimed at automating specific tasks to integrated components of complex socio-technical systems. This work presents a conceptual and theoretical review proposing the Model–Context–Relation (M–C–R) framework to interpret how the effectiveness of Artificial Intelligence (AI) in medicine and healthcare emerges from the dynamic alignment among algorithmic, contextual, and relational dimensions. No new patient-level data were generated or analyzed. Through a qualitative conceptual framework analysis, the study integrates theoretical, regulatory, and applicative perspectives, drawing on the Revision of the Semiological Paradigm developed by the Palermo School, as well as on major international guidelines (WHO, European AI Act, FDA). The results indicate that AI-supported processes have been reported in the literature to improve clinical accuracy and workflow efficiency when appropriately integrated, yet its value depends on contextual adaptation and human supervision rather than on algorithmic performance alone. When properly integrated, AI functions as a digital semiotic extension of clinical reasoning and may enhance the physician’s interpretative capacity without replacing it. The M–C–R framework enables understanding of how performance, ethical reliability, and organizational sustainability emerge from the alignment between the technical model, the context of use, and relational trust. In this perspective, AI is conceptualized not as a decision-maker but as an adaptive cognitive partner, fostering a reflective, transparent, and person-centered medicine. The proposed approach supports the design of sustainable and ethically responsible AI systems within a Medicine of Complexity, in which human and artificial intelligence co-evolve to strengthen knowledge, accountability, and equity in healthcare systems. Full article

Contract manufacturing is a pivotal strategy for brand owners, yet small-to-medium enterprises (SMEs) in emerging economies struggle to evolve beyond transactional roles into sustainable strategic partners. This study addresses this gap by empirically validating and refining the Mahove–Matope Sustainable Contract Manufacturing Company Maturity Model (SCMC-MM), a novel framework designed to guide SMEs through a holistic transformation. Through a seven-month longitudinal case study grounded in design science research approach within a South African food manufacturing SME, the model was implemented and evaluated using structured assessments, in-depth interviews, and longitudinal operational data. The application catalysed a system-wide transformation, yielding significant results, including a 133% increase in revenue, ISO 22000 certification, and perfect delivery reliability. Furthermore, the study theoretically refines the framework by identifying and incorporating novel critical success factors for contract manufacturing companies, such as industrial clustering and transformational leadership. The results demonstrate that the SCMC-MM offers a practical, actionable, and scalable tool for building resilient supply chain partnerships. It provides a structured pathway for SMEs to achieve simultaneous gains in economic performance, social equity through enhanced workforce capability and ethical practices, and environmental stewardship via formalised safety, health, and environmental and risk management systems, thereby contributing directly to the United Nations Sustainable Development Goals (SDGs) 8 and 9 in emerging markets. Full article

Background: Parents’ dietary strategies shape children’s eating habits. This study investigated socio-demographic determinants of maternal feeding practices among school-aged children in the Pomeranian province of Poland. Using a cross-sectional survey conducted in July 2025, we compared feeding strategies based on family structure, maternal employment, and number of children, and identified distinct parenting profiles through cluster analysis. Methods: A cross-sectional survey was conducted in July 2025 among 719 mothers of elementary school children in Pomeranian Voivodeship, using a convenience sampling design. An abbreviated version of the Comprehensive Feeding Practices Questionnaire (CFPQ) with 16 items across eight subscales was used. ANOVA compared feeding strategies between groups, Spearman correlations examined associations, and k-means cluster analysis identified maternal parenting profiles. Results: Encouragement and modeling were the most frequent strategies, while monitoring was least common. Mothers raising children with a partner and those employed used monitoring, modeling, and encouragement more often. Single or non-working mothers relied more on food as a reward and for emotion regulation. Mothers of only children applied control and monitoring less intensively than mothers with multiple children. All strategies were positively correlated. Cluster analysis identified three parenting profiles: intensely directive, moderate, and emotional-supportive. Conclusions: Maternal feeding strategies vary with socio-demographic factors. Educational interventions promoting healthy eating should be tailored to family structure and mothers’ employment status. Full article

As conversational artificial intelligence (CAI), including smart speakers, social robots, and dialogic learning apps, becomes increasingly present in children’s lives, its potential to support early mathematical thinking warrants closer attention. While existing research largely concentrates on literacy and language development, the role of CAI in early numeracy remains underexplored. This paper examines how voice-based CAI might contribute to informal mathematical thinking in early childhood. Adopting a conceptual lens, this paper synthesises existing theory and research to examine the potential roles of CAI in early mathematical learning. Grounded in sociocultural theory and dialogic pedagogy, this paper positions CAI as a potential mediator of early mathematical thinking through responsive dialogue. Four interrelated dimensions (child agency, cognitive scaffolding, mathematical language quality, and responsiveness and timing) are identified as a conceptual lens for evaluating how dialogue-based interactions with CAI may support or constrain young children’s mathematical thinking. Rather than framing CAI as a direct teaching tool, this paper explores its potential role as a dialogic partner in play-based numeracy and inquiry. The framework contributes to early mathematics education by highlighting both the promise and the limitations of CAI, offering guidance for research, technology design, and educational practice. It underscores the need for intentional, ethically informed integration of CAI that approximates the qualities of human dialogue while acknowledging current constraints in real-world use. Full article

This research explores gender differences in long- and short-term relationships and sexual satisfaction among older adults. Socioemotional Selectivity Theory posits that as people age, they prioritize immediate emotional satisfaction due to perceptions of limited time. This shift influences older adults’ romantic relationships, increasing the likelihood of seeking meaningful connections and reducing the prevalence of negative emotions. With healthy relationships linked to physical, psychological, and financial benefits, research is needed to further understand older adult romantic relationships. Older adults (n = 155) from the Seniors Together in Aging Research (STAR) completed a survey assessing relationship preferences and current and predicted sexual satisfaction. T-tests were used to determine gender differences. Several gender differences were noted. Men reported greater levels of sexual satisfaction and predicted more positive future sex as compared to women. Men placed greater importance on long-term relationships. There was no gender difference in short-term relationship importance. Women may have shorter-term relationship desires to avoid taking on caregiving. This aligns with previous research indicating that when seeking new relationships, women are cautious about the potential of providing care to a partner. Greater sexual satisfaction reported by men aligns with previous research noting that men tend to be more sexually satisfied throughout the lifespan. Full article

We previously described an increased incidence of HIV among individuals infected with Wuchereria bancrofti (WB). However, no host, parasite, or viral factors were reported as directly associated with the increase in HIV incidence in this group. To investigate this, we compared T cell phenotypes between WB+ and WB− women. Flow cytometry analysis of activation and differentiation markers on CD4 T cells, as well as HIV entry receptor CCR5 was performed on cervical and peripheral blood samples from 54 women living without HIV (WLWoH). Additionally, HPV testing was performed on their specimens and for 13 WLWH. WB infection was associated with a significantly increased frequency of CD3⁺γδ2⁺ T cells in the cervical mucosa (median 4.0% vs. 1.4%, p = 0.012). Contrary to our expectations, we found lower frequencies of CCR5 on total, memory and activated memory CD4 T cells in the WB+ group. However, differences diminished after accounting for age and site of recruitment. WB and HIV infections were associated with an increased likelihood of high-risk human papillomavirus (HR HPV) positivity. (WB status: odds ratio (OR) 4.1, p = 0.066; HIV status: OR 5.5, p = 0.068). Our findings suggest immunological mechanisms by which WB increases the risk for other infections, e.g., HIV and HR HPV, albeit independent of the CCR5 receptor. Full article

Alcohol use disorder (AUD) is associated with widespread epigenetic alterations, including changes in DNA methylation (DNAm). This multi-cohort study validated and extended previous findings on DNAm of HECW2 and GDAP1 in AUD, assessed sex differences, and explored DNAm in blood and brain tissue in humans and rats. DNAm was measured via pyrosequencing in human blood (N_Ctrl = 341, N_AUD = 258), postmortem frontal cortex (Brodmann area 9; discovery cohort: N_Ctrl = 10, N_AUD = 13, replication cohort: N_Ctrl = 64, N_AUD = 55) and rat blood and medial prefrontal cortex (N_Ctrl = 16, N_AUD = 15). Gene expression was assessed in human postmortem brain by quantitative real-time PCR. AUD-associated DNAm differences in HECW2 and GDAP1 were replicated in human blood. While decreased GDAP1 DNAm was only observed in men, HECW2 hypomethylation was present in both sexes. In brain tissue, initial DNAm increases in AUD and HECW2 gene expression decreases were not validated in the replication cohort. In rats, HECW2 hypomethylation appeared in the prelimbic cortex but not in blood. Our findings support the involvement of HECW2 and GDAP1 DNAm in AUD, revealing sex-specific and tissue-dependent epigenetic patterns. The opposing DNAm directionality in blood and brain underscores the complexity of alcohol-related epigenetic modifications and suggests the need for multi-tissue, cross-species, and longitudinal studies to clarify causal mechanisms. Full article

Background/Objectives: People with Alzheimer’s dementia (AD) experience distressing changes in social behaviour. However, little is understood about whether social behaviour is associated with support provided by, or familiarity with, conversation partners. We aimed to explore the association between support provided by, and familiarity with, conversation partners and the social behaviour of people with mild AD during conversation. Method: We designed an exploratory within-subjects study wherein conversations between 19 participants with mild AD and a familiar informant, followed by an unfamiliar researcher, were video-recorded and double-rated using two measures of social behaviour (Social Observation Inventory and Measure of Participation in Conversation—Dementia), and one measure of support from the conversation partner (Measure of Support in Conversation—Dementia). Multilevel linear regression with within-subject clusters was used to explore adjusted associations between support and familiarity and social behaviour. Results: Greater support in conversation was associated with more appropriate participation in social conversation of participants with AD. In fully adjusted models, every 1-point increase in MSC-D score was associated with a 0.29 (95% CI: 0.14 to 0.44) increase in MPC-D score and a 1.59 (95% CI: 0.87 to 2.32) increase in SOI score. Familiarity with the conversation partner was not associated with the social behaviour of the participants with AD. Conclusions: We found evidence for an association between social behaviour in AD and support provided by unimpaired conversation partners, but the numbers were small, and this should be interpreted cautiously. Future research should continue this hypothetical lead to expand our understanding of how support and familiarity influence social behaviour to inform potential interventions. Full article

Through binding to complementary mRNAs, microRNAs (miRNAs) mediate gene silencing. The stability and half-life of microRNAs are controlled by two isoforms of the RNA-binding protein Roquin. This study aimed at identifying the role of Roquin to miRNA-dependent regulation of the transcriptome in the post-ischemic heart. Both Roquin isoforms are highly conserved between rats and humans and constitutively expressed in cardiomyocytes. In both cell species, hypoxia induces a down-regulation of Roquin-1 and Roquin-2. An integrative miRNA-and-mRNA analysis (MMIA) identified miR-23b-5p as a potential interaction partner of Roquins. The open data bank TargetScan8.0 suggests that the transcription factor ZBTB20 is a potential target of miR-23b-5p. The level of expression of ZBTB20 correlated with the functional recovery of rat hearts after myocardial infarction. Moreover, the down-regulation of Roquin-2 in AC16 cells by siRNA under normoxic conditions was associated with an up-regulation of miR-23b-5p and a down-regulation of ZBTB20. Furthermore, in the case of hypoxia-dependent down-regulation of Roquin, the subsequent down-regulation of ZBTB20 was reversed with the help of an antagomir against miR-23b-5p. In conclusion, hypoxia-induced down-regulation of the two Roquin isoforms was associated with an increased stability of miR-23b-5p, a Roquin-2-dependent miRNA, which subsequently led to silencing of the transcription factor ZBTB20. Full article

Background/Objectives: T cell bispecific antibodies (TCBs) result in the activation of T cell receptor signaling upon binding to tumor antigens providing signal 1 to T cells. To enhance and sustain their activity, a co-stimulatory signal 2 is required. Here CEACAM5-targeted 4-1BBL antibody fusion proteins for combination with CEA-TCB (cibisatamab, RG7802) are described in an investigation of the relationship between the CEACAM5 epitope and T cell activity. Methods: CEACAM5-targeted bispecific 4-1BBL antibody fusion proteins (CEA-4-1BBLs) were generated based on different CEACAM5 antibodies and characterized in vitro in Jurkat-4-1BB reporter and PBMC cell assays. The impact of shed CEA on in vitro activity and cynomolgus cross-reactivity was studied. In vivo efficacy was assessed in human stem cell humanized NSG mice xenograft models bearing MKN-45 and HPAFII tumors. Results: MFE23-4-1BBL and Sm9b-4-1BBL showed superior functional activity in Jurkat-4-1BB reporter and primary T cell assays when combined with the CD3 antibody V9, whereas T84.66-LCHA-4-1BBL and A5B7-4-1BBL performed better when combined with CEA-TCB. In humanized NSG mice MKN-45 and HPAFII xenograft models, T84.66-LCHA-4-1BBL mediated the best anti-tumor efficacy. Conclusions: For the assessment of the combination of CEA-TCB with CEA-4-1BBL, co-stimulatory antibody fusion protein in vitro assays are not sufficient to fully capture the complex relationships affecting efficacy. Thus, screening with different cell assays and in vivo efficacy studies in combination with CEA-TCB are essential to select the best candidate. Based on the totality of data on the T84.66-LCHA-4-1BBL antibody fusion protein comprising the CEACAM5 antibody, T84.66-LCHA was selected as the optimal combination partner for CEA-TCB. Full article

The CITED proteins function as transcriptional modulators that are essential for vertebrate development. These proteins interact with numerous partners, notably transcription factors and co-activators. The hallmark of the CITED family is their conserved carboxy-terminal domain, which interacts strongly with the CBP/p300 co-activators. The expression of CITED genes is detected early during embryogenesis within embryonic and foetal regions critical for cardiac morphogenesis, among other developmental processes. Notably, CITED2 loss of function is strongly associated with congenital heart malformations in mice and zebrafish embryos, as well as congenital heart disease (CHD) in humans, whereas other CITED family members are not critical for cardiogenesis. Emerging evidence implicates CITED2 and CITED4 in regulating heart physiological adaptations and protective responses to pathological stress. This review provides a detailed analysis of CITED proteins and their interactors, focusing on CITED-target genes relevant for cardiogenesis and heart disease. We also highlight recent findings indicating that CITED2 and CITED4 may be instrumental for the development of novel therapeutic strategies to mitigate CHD and preserve adult cardiac function. Full article

Background: Research on psychological abuse among patients with breast cancer and survivors of breast cancer in Saudi Arabia is scarce. This study aimed to identify psychological abuse and its associated factors among these individuals. Methods: This cross-sectional study included 146 patients with breast cancer and survivors of breast cancer. Data were collected from December 2024 to April 2025 using a modified survey instrument based on the United Nations Economic Commission for Europe violence against women module. An online questionnaire comprised two parts: the first collected demographic characteristics, including age, education, employment, breast cancer diagnosis, and mastectomy duration, and the second assessed psychological abuse via four items: insults, belittlement/humiliation, intimidation, and undermining of relationship stability. The association between psychological abuse and sociodemographic factors was assessed using the chi-square test. Significant associations in bivariate analyses were subsequently analyzed using exploratory logistic regression. Results: Approximately 20.5% of participants reported experiencing at least one form of psychological abuse. The most commonly reported behaviors were insults and undermining of relationship stability (both 20.5%), followed by belittlement/humiliation (17.8%) and intimidation (15.1%). Bivariate analyses indicated a greater incidence of humiliation among women whose spouses were unemployed or retired, as well as among those with more than six children. Logistic analysis indicated that spouse unemployment or retirement (OR = 5.36, 95% CI 1.62–17.74, p = 0.006) and having more than six children (OR = 5.84, 95% CI 1.33–25.55, p = 0.019) were associated with belittlement/humiliation, even after FDR correction. No significant correlations were identified regarding patient age, education, mastectomy status, or duration since diagnosis. Model diagnostics demonstrated a satisfactory fit (Nagelkerke R² = 0.22; accuracy = 82.2%) and a lack of multicollinearity (VIF = 1.00–1.03). Conclusions: Psychological abuse affects around 20% of women diagnosed with breast cancer, especially those with unemployed spouses and larger families. These results highlight the need for psychological screening and couple-based therapies in cancer care to mitigate marital stresses and enhance survivors’ well-being. Full article