Search Results (379)

Background/Objectives: Prolonged fasting—defined as voluntary abstinence from caloric intake for periods exceeding 24 h—is increasingly recognized not only as a metabolic intervention but also as a psycho-behavioral modulator. According to the 2024 international consensus, intermittent fasting encompasses diverse temporal patterns including time-restricted feeding, alternate-day fasting, and periodic fasting of multi-day duration. While metabolic benefits are well documented, the psychoneurobiological and psychiatric consequences remain incompletely characterized. This review critically appraises current evidence on the psychological and psychiatric effects of prolonged and intermittent fasting, including both secular and religious practices. Methods: A narrative synthesis was conducted on clinical trials, observational studies, and translational research published between January 2010 and June 2025 in PubMed, Scopus, and PsycINFO. Search terms included combinations of “prolonged fasting,” “intermittent fasting,” “psychological,” “psychiatric,” “religious fasting,” “Ramadan,” and “Orthodox Church.” Eligible studies required explicit evaluation of mood, cognition, stress physiology, or psychiatric symptoms. Data were analyzed qualitatively, with particular attention to study quality, fasting regimen characteristics, and participant vulnerability. This is a non-registered narrative synthesis drawing on clinical trials, observational studies, and preclinical evidence published between January 2010 and June 2025. Results: Eighty-seven studies met inclusion criteria (39 human; 48 preclinical). In metabolically healthy adults, short-term time-restricted eating and supervised prolonged fasting were associated with modest reductions in depressive symptoms and perceived stress, with small improvements in executive functioning—typically observed in small samples and with limited follow-up. Religious fasting during Ramadan and the Orthodox Christian fasting periods demonstrated similar neuropsychological effects, including greater perceived spiritual meaning and affective modulation, though cultural context played a moderating role. Potential adverse mental-health impacts included mood destabilization, anxiety exacerbation, and rare psychotic or manic decompensations in vulnerable individuals. Randomized trials reported few adverse events and no signal for severe psychiatric harm, whereas observational studies more often noted symptom exacerbations in at-risk groups. Patients with eating disorder phenotypes exhibited increased cognitive preoccupation with food and a heightened risk of behavioral relapse. Methodological heterogeneity across studies—including variation in fasting protocols, psychological assessments, and follow-up duration—limited cross-study comparability. Conclusions: Evidence indicates a bidirectional relationship wherein fasting may foster psychological resilience in select populations while posing significant psychiatric risks in others. Inclusion of religious fasting traditions enriches understanding of culturally mediated outcomes. To enhance rigor and safety, future studies should incorporate clinician-rated outcomes (e.g., HDRS-17, CGI-S/CGI-I), standardized adverse-event tracking using validated psychiatric terminology, and prospective safety monitoring protocols, with ≥6–12-month follow-up. Full article

Cellular memory, or epigenetic memory, represents the capacity for cells to retain information beyond the underlying DNA sequence. This heritable characteristic is primarily governed by epigenetic mechanisms which enable cells to maintain specialized characteristics across divisions. This persistent cellular state is essential for fundamental biological processes, such as maintaining tissue identity and facilitating cell differentiation, especially embryonic cells. Early-stage perturbations such as assisted reproductive technologies (ART) and nutritional stress links embryonic exposures to adult health and disease within the Developmental Origins of Health and Disease (DOHaD) framework. Crucially, memory established during early embryogenesis links these epigenetic modifications to adult long-term phenotypes related to metabolic disorders. These modifications—including DNA methylation, histone modifications, and non-coding RNAs—support cellular memory transmission across cell divisions, and in certain organisms, can be transmitted across generations without alterations to the DNA sequence. This review synthesizes recent advances in epigenetic pathways that mediate cellular memory, highlights critical preimplantation windows of vulnerability and outlines gaps necessary for mammalian developing interventions that safeguard future generations. Full article

Background and Objectives: Grade 4 adult-type diffuse gliomas remain the most aggressive primary central nervous system malignancies, with limited prognostic tools beyond molecular classification. This study introduces the HALLMOUNT score, a multidimensional prognostic index integrating hematologic, biochemical, and clinical parameters to capture the interplay between tumor biology and systemic host response. Materials and Methods: A total of 227 patients with histologically confirmed grade 4 adult-type diffuse glioma were retrospectively analyzed. The HALLMOUNT score incorporated nine pretreatment variables: hemoglobin, albumin, lactate dehydrogenase (LDH), lymphocyte, monocyte, Eastern Cooperative Oncology Group (ECOG) performance status, uric acid, neutrophil, and thrombocyte counts. Receiver operating characteristic (ROC) analyses determined optimal cut-offs, and Cox regression models evaluated prognostic performance for overall (OS) and progression-free survival (PFS). Results: High HALLMOUNT scores (≥2.5) were significantly associated with older age, comorbidities, poor ECOG status, isocitrate dehydrogenase (IDH)-wild phenotype, lower resection rates, and reduced treatment responses. ROC analysis showed predictive accuracy comparable to CAR and PIV (AUC = 0.650). High scores independently predicted inferior OS (HR = 2.78, p < 0.001) and PFS (HR = 2.76, p < 0.001). Conclusions: The HALLMOUNT score provides a simple, cost-effective, and biologically grounded biomarker reflecting both tumor aggressiveness and host vulnerability. It enables refined risk stratification, supports individualized therapeutic planning, and warrants prospective validation in molecularly defined and multicenter cohorts. Full article

Chronic lymphocytic leukemia (CLL) is an indolent malignancy with modest proliferation in the lymph nodes and accumulation of quiescent B cells in the peripheral blood. Targeted agents, including BTK inhibitors such as ibrutinib and the BCL2 antagonist venetoclax, have transformed therapy by disrupting proliferation, survival, and lymph node retention of CLL cells, yet CLL remains incurable. Recent studies reveal that CLL cells exist along a spectrum of proliferating, activated, and quiescent states, with dynamic transitions that shape intraclonal behavior. Whilst proliferation occurs mainly in lymph nodes, most emigrant cells in the peripheral blood become quiescent, with only a minority remaining activated. Quiescent, activated, and proliferating fractions display distinct phenotypes and CXCR4 and CD5 levels can be used to distinguish these states in the CLL life cycle. While proliferating and activated cells are more susceptible to BTK inhibition, quiescent subsets show greater sensitivity to BCL2 blockade. These functional differences, together with emerging evidence that phenotypic markers may correlate with residual disease activity, point to potential translational significance. Understanding how CLL cells switch between proliferative, activated and quiescent states will be important to uncover novel vulnerabilities and inform rational treatment strategies. Full article

People who use crack cocaine (PWUCC) constitute a key population due to vulnerability and marginalization, especially in a socio-ecologically diverse, relatively isolated region with limited public health infrastructure. This study aimed to perform a genetic characterization of circulating HCV among PWUCC in the municipality of Bragança, situated on the Brazilian Amazon coast, identifying viral genotypes, subtypes, resistance-associated substitutions (RAS)—naturally occurring mutations in the viral genome that can reduce the efficacy of direct-acting antiviral (DAA) agents—and predictions of phenotypic resistance. Methods: Between 2016 and 2018, biological samples and epidemiological data were obtained from 165 PWUCC. Viral detection was performed using RT-PCR, while genotyping, subtyping, and RAS profiling were conducted through nucleotide sequencing and fragment analysis. Results: In 165 PWUCC, 22 (13.3%) tested positive for HCV RNA. Most of them had not had access to public health services (91.5%), and more than half (57.0%) reported living in unstable housing conditions. HCV subtypes 1a (27.3%), 1b (40.9%), and 3a (31.8%) were detected. Evidence of resistance associated with DAAs, such as daclatasvir and dasabuvir, was detected in five PWUCC with HCV (22.7%). Conclusions: The high prevalence of HCV infection, predominantly subtype 1b, and significant levels of resistance are very concerning. This demonstrates the urgent need for targeted public health interventions to expand access to testing, treatment, and effective antiviral therapy in this vulnerable population of the Brazilian Amazon. Full article

Background: Wolfram syndrome (WS) is an ultrarare neuroendocrine disorder caused by pathogenic variants in WFS1, frequently leading to progressive neurological, autonomic, and cognitive impairment. Anticipating neurological trajectories remains challenging due to marked phenotypic variability and limited genotype–phenotype data. Methods: Forty-five genetically confirmed patients with WS were evaluated between 1998 and 2024 in Spain. All WFS1 variants were systematically classified by exon, zygosity, protein-level functional impact, and predicted wolframin production (Classes 0–3). Machine learning models (Random Forests with engineered gene–gene interaction terms) were applied to predict neurological manifestations and identify the strongest genetic determinants of symptom severity. Results: Neurological involvement was present in 93% of patients. The most prevalent manifestations were absence of gag reflex (67%), gait instability (64%), dysphagia (60%), and sialorrhea (60%), followed by dysmetria (56%), impaired tandem gait (53%), anosmia (44%), dysarthria (44%), and adiadochokinesia (42%). Most symptoms emerged in early adulthood (23–26 years), whereas cognitive decline occurred later (29.9 ± 12.2 years). Homozygosity for truncating variants—particularly c.409_424dup16 (Val142fsX110)—and complete loss of wolframin production (Class 0; 67–83% across symptoms) were the strongest predictors of early and severe neurological involvement. Machine learning models achieved high discrimination for ataxia, gait instability, and absent gag reflex (AUC 0.63–0.86; calibrated AUC up to 0.97), identifying Mut1_Protein_Class and Mut2_Protein_Class as dominant predictors across all phenotypes, followed by coherent secondary effects from zygosity × exon interaction terms (Prod_mgm). Conclusions: Integrating detailed genetic classification with machine learning methods enables accurate prediction of neurological outcomes in WS. Protein-level dysfunction and allele interaction structure are the principal drivers of neurological vulnerability. This framework enhances precision diagnosis and offers a foundation for individualized surveillance, clinical risk stratification, and future therapeutic trial design in WFS1-related disorders. Full article

Human life expectancy has risen dramatically in the last century, but this demographic triumph has come at the cost of an explosion of non-communicable diseases (NCDs), threatening the sustainability of healthcare systems in aging, low-fertility societies. Evolutionary medicine provides a framework to understand, at least in part, this paradox. Many vulnerabilities to disease are not failures of design but the predictable outcomes of evolutionary trade-offs, constraints, and mismatches. Evolutionary mismatch theory explains how traits once advantageous in ancestral environments become maladaptive in modern contexts of abundance, sedentarism, and urbanization. The developmental origins of health and disease (DOHaD) concept describes how epigenetic plasticity in early life can buffer or amplify these mismatches, depending on whether adult environments align with developmental forecasts. Transgenerational epigenetic inheritance, even if still debated in humans, may further influence phenotypic plasticity, increasing or mitigating the mismatch. In evolutionary terms, the theories of mutation accumulation, antagonistic pleiotropy, and the disposable soma explain why longer lifespans, and ecological and social conditions profoundly different from those in which we developed, increase the likelihood that these costs are expressed clinically. Because most NCDs can be prevented and effectively controlled but not cured, efforts should prioritize quality of life for people, families, and communities. At the individual level, aligning lifestyles with evolved biology can mitigate risk, but the greatest leverage lies in population-level interventions. Urban health strategies represent a forward-looking attempt to realign modern environments with human biology. In this way, the concept of the evolutionary misfit becomes not just a diagnosis of maladaptation, but a guide for building healthier, more sustainable societies. Full article

Background/Objectives: Cytochrome P450 (CYP) enzymes are crucial for drug metabolism, yet inter-individual variability in their activity remains a significant clinical challenge. Current phenotyping methods are often impractical or even impossible, particularly in forensic toxicology and vulnerable populations. This proof-of-concept study investigated the feasibility of using in vitro assays with human liver microsomes (HLM) and recombinant CYP enzymes (isoenzymes), combined with untargeted metabolomics, to identify potential endogenous biomarker candidates indicative of CYP phenotype. Methods: This study uses in vitro incubations of HLM and isoenzymes in tandem with targeted and untargeted LC-(HR)MS and metabolomics techniques as well as statistical processing. Results: We demonstrate that HLM and isoenzymes maintain activity in the presence of complex biological matrices (blood/plasma), enabling metabolomic profiling. Untargeted analysis of assays in plasma revealed numerous potential biomarkers, with several showing significant correlations to enzyme activity. Conclusions: While identification remains the major challenge, this approach offers a promising avenue for developing accessible and efficient methods for indirect CYP phenotyping, potentially facilitating investigations in scenarios where traditional approaches are limited. This work provides a foundation for future studies focused on further developing in vitro assays and validating the proposed biomarkers, as well as establishing their utility in clinical and forensic settings. Full article

This narrative review aims to summarize, synthesize, and organize current knowledge on the adaptation of sheep and goats to stressful environments and to discuss how these adaptations contribute to food security in vulnerable communities. A structured search of Web of Science, Scopus, PubMed, and Google Scholar was conducted using combinations of terms related to sheep and goats, harsh environments (e.g., arid and semi-arid regions, heat stress, water restriction, poor-quality forage), and adaptation or resilience, combined with Boolean operators. A total of 1718 research publications were found, of which 86 were retained as the most relevant because they provided direct and detailed evidence on anatomical, physiological, digestive–microbiome, behavioral, and genomic adaptations of sheep and goats to stressful environments. The selected studies describe a wide range of phenotypic and integumentary traits, thermoregulatory and endocrine responses, digestive and microbial adjustments, behavioral strategies, and genomic signatures that, together, allow small ruminants to maintain basic functions, reproduction, and production under conditions of climatic and nutritional stress. Evidence from these studies also highlights how adaptive traits support herd productivity, economic stability of households, and the sustainable use of natural resources in regions where climatic variability and resource scarcity are common. Overall, the synthesis presented here underscores the importance of conserving and strategically using locally adapted sheep and goat breeds, incorporating resilience-related traits into breeding and management programs, and prioritizing further research on genomic, microbiome, and epigenetic mechanisms that underpin adaptation to harsh environments. Full article

Head-and-neck squamous cell carcinoma (HNSCC) remains a lethal malignancy with stagnant survival despite advances in surgery, radiotherapy, and systemic therapy. Beyond cetuximab and PD-1 inhibitors, there are only a few targeted options, which benefit only a minority of patients, underscoring the need for new biomarkers and druggable dependencies. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) Cas9 screening now enables systematic, high-specificity investigation of gene function to reveal determinants of tumor proliferation, survival, and therapy response. Compared with RNA interference, CRISPR provides cleaner on-target knockout and more interpretable phenotypes, allowing efficient discovery of essential genes and synthetic-lethal interactions. Although the Cancer Dependency Map profiled 89 OSCC/HNSCC lines to nominate baseline dependencies, drug-perturbed states critical for understanding platinum resistance remain underexplored. Only a handful of HNSCC studies have applied genome-wide CRISPR cas9 screening: two mapped core essential genes; two mapped cisplatin resistance and radiation resistance; and others uncovered synthetic-lethal targets, including vulnerabilities to mTOR inhibition, EGFR inhibition, glutamine metabolism inhibition, and host determinants of oncolytic HSV-1 efficacy. This review synthesizes these findings, highlights methodological considerations (library design, coverage, and treatment duration), and integrates complementary functional data to prioritize targets for rational combinations. This review also provides information on the TCGA database and in vivo CRISPR screening that can accelerate precision therapeutics for patients with HNSCC. Full article

Per- and polyfluoroalkyl substances are persistent environmental contaminants increasingly implicated in neurotoxicity. Establishing causality and mechanisms relevant to Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis requires human-relevant systems that capture exposure, barrier function, and brain circuitry. We review advanced cellular platforms—iPSC-derived neuronal and glial cultures, cerebral and midbrain organoids, and chip-based microphysiological systems—that model disease-relevant phenotypes (Aβ/tau pathology, dopaminergic vulnerability, myelination defects) under controlled PFAS exposures and defined genetic risk backgrounds. Modular, fluidically coupled BBB-on-chip → brain-organoid microphysiological systems have been reported, enabling chronic, low-dose PFAS perfusion under physiological shear, real-time barrier integrity readouts such as transepithelial/transendothelial electrical resistance (TEER), quantification of PFAS partitioning and translocation, and downstream neuronal–glial responses assessed by electrophysiology and multi-omics. Across platforms, convergent PFAS-responsive processes emerge—mitochondrial dysfunction and oxidative stress, lipid/ceramide dysregulation, neuroinflammatory signaling, and synaptic/network impairments—providing a mechanistic scaffold for biomarker discovery and gene–environment interrogation with isogenic lines. We outline principles for exposure design (environmentally relevant ranges, longitudinal paradigms), multimodal endpoints (omics, electrophysiology, imaging), and cross-lab standardization to improve comparability. Together, these models advance the quantitative evaluation of PFAS neurotoxicity and support translation into risk assessment and therapeutic strategies. Full article

Background: Down syndrome (DS) is commonly associated with complex respiratory phenotypes due to anatomical, immunological, and vascular factors. Pulmonary sequestration (PS) is a rare congenital malformation of non-functioning lung tissue with anomalous systemic arterial supply, occasionally reported in syndromic individuals. Case presentation: We report the case of a female infant with DS who developed acute respiratory distress secondary to respiratory syncytial virus infection. Chest imaging revealed an intralobar pulmonary pseudosequestration in the right lower lobe, supplied by the celiac trunk and draining into the pulmonary veins, with a communication to the bronchial tree. The patient required pediatric intensive care support and nutritional rehabilitation. Surgical resection was deferred until adequate weight optimization could be achieved. Discussion: This is, to our knowledge, the first description of intralobar pulmonary pseudosequestration in a patient with DS. The association suggests possible overlapping developmental mechanisms involving abnormal angiogenesis and emphasizes the importance of considering congenital pulmonary malformations in DS patients presenting with recurrent or severe respiratory symptoms. Conclusions: Early recognition and tailored management may improve clinical outcomes in this vulnerable population. Full article

Background/Objectives: Frailty is an age-related clinical syndrome characterized by diminished physiological reserves and increased vulnerability to adverse outcomes. Growing evidence suggests that frailty involves shared brain networks that regulate both gait and cognitive functions. This study aimed to examine the relationship between frailty status, spatiotemporal gait parameters, and cognitive functions in community-dwelling older adults. Methods: A cross-sectional study was conducted with 99 adults aged ≥70 years, classified as non-frail, prefrail, or frail according to the Fried phenotype. Gait parameters were measured under usual and fast walking conditions using the OptoGait^® photoelectric system. Cognitive status was assessed with the Montreal Cognitive Assessment (MoCA) and a comprehensive neuropsychological battery. Multivariate logistic regression analyses were performed to identify factors associated with transitions between frailty stages. Results: The prevalence of frailty was 9.1%, with 51.5% prefrail and 39.4% non-frail. The transition from non-frail to prefrail was associated with shorter stride length at fast pace (OR = 0.92, 95% CI: 0.88–0.96), mild cognitive impairment (OR = 3.71, 95% CI: 1.08–12.69), depressive symptoms (OR = 1.82, 95% CI: 1.26–2.62), and female sex (OR = 4.94, 95% CI: 1.20–16.77). The transition from prefrail to frail was linked to increased stride time variability at fast pace (OR = 2.94, 95% CI: 1.34–6.44) and poorer working memory (OR = 0.40, 95% CI: 0.16–0.97). Conclusions: Shorter stride length, mild cognitive impairment, and depressive symptoms emerged as key markers of the transition from non-frailty to prefrailty, whereas increased stride time variability and poorer working memory distinguished prefrail from frail individuals. These findings highlight gait- and executive-function-related markers as sensitive early indicators of vulnerability. Incorporating quantitative gait assessment and brief cognitive screening into routine geriatric evaluations may substantially enhance early detection and support targeted preventive strategies for healthy aging. Full article

Plasma membrane Ca²⁺-ATPases (PMCA) are activated by calmodulin (CaM) via a C-terminal calmodulin-binding domain, CaMBD. Although specific mutations in this domain have been linked to disease, the broader impact of alternative substitutions across the interface remains unexplored. We applied an integrative in silico workflow to test six substitutions within CaMBD positions 1–18, L5R, N6I, I8T, V14E/D, and F18S, across PMCA isoforms 1–4. CaMBD sequences were aligned across isoforms, and candidates for substitutions were selected by conservation and nucleotide feasibility, prioritizing conserved or co-evolutionarily relevant sites, with substitutions possible by single-nucleotide change. PolyPhen-2 screened the impact of the substitutions on the protein functionality, the DisGeNET database was used to contextualize ATP2B genes with clinical phenotypes, and structural models plus binding free energy changes were estimated with AlphaFold3, FoldX, and MutaBind2. Effects were isoform and subregion dependent, with the strongest weakening toward the CaMBD C-terminus. V14E/D and F18S showed the largest and consistent predicted destabilization, consistent with disruption of conserved hydrophobic anchors. I8T and L5R had mixed outcomes depending on isoform, while N6I presented various scenarios with no clear effect. PolyPhen-2 classified most tested substitutions as damaging. Gene-disease evidence linked ATP2B to neurological, endocrine, and oncologic phenotypes, consistent with roles in Ca²⁺ homeostasis. Overall, CaMBD appears highly sensitive to perturbation, with distal positions 14–18 particularly vulnerable to substitutions that can destabilize CaM binding and potentially impair PMCA-mediated Ca²⁺ clearance in susceptible tissues. Full article

Background/Objectives: Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections. Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted. We present a pediatric case from Kazakhstan to broaden the clinical and molecular spectrum of TYK2-related immunodeficiency and accentuate diagnostic challenges. Methods: The proband underwent clinical assessment, immunophenotyping, and biochemical analysis during episodes of active pathology and subsequent follow-up. Whole-exome sequencing (WES) was executed, followed by confirmatory Sanger sequencing and segregation analysis in first-degree kin. Functional assays for phagocyte oxidative burst and phagocytosis were conducted to exclude CGD. Results: WES identified two rare TYK2 variants (c.209_212del, pathogenic; c.2395G>A, previously reported as pathogenic in a Chinese patient with TYK2 deficiency) and a heterozygous MEFV duplication (c.761_764dup). Paternal DNA was unavailable; therefore, allelic phase could not be formally established, but the combined genotype and phenotype are consistent with autosomal recessive TYK2 deficiency. Sanger sequencing confirmed segregation of the frameshift TYK2 variant in the mother, while the clinically healthy brother carried only the wild-type allele. The missense alteration was exclusive to the proband. Conclusions: This case exemplifies the significance of contemplating TYK2 deficiency in pediatric patients with refractory mycobacterial infections, particularly in BCG-endemic locales. Genetic validation provided a definitive diagnosis, differentiating the condition from CGD and informing patient management. To our knowledge, this constitutes one of the inaugural genetically confirmed instances of TYK2 deficiency in Central Asia, enhancing regional epidemiological comprehension and emphasizing the role of molecular diagnostics in directing treatment and vaccination policies. Full article