Disruption Of Function Research Articles

Prolonged immune response to tick-borne Ehrlichia chaffeensis infection using a genetically modified live vaccine.

Ehrlichia chaffeensis, a tick transmitted rickettsial bacterium, causes monocytic ehrlichiosis in humans and dogs. Earlier, we demonstrated that dogs immunized with a mutant strain of E. chaffeensis having a functional disruption in the gene encoding the phage head-to-tail connector protein serves as a modified live vaccine (MLAV) capable of inducing immunity against intravenous and tick-transmitted infection challenges within one month of vaccination. In this follow-up investigation, we assessed the duration of MLAV-induced immunity for one-year period against tick-transmission infection challenge. Dogs vaccinated with the MLAV were subsequently exposed to wild-type E. chaffeensis via tick transmission at 4-, 8-, and 12-months post-vaccination. Unvaccinated controls showed higher infection rates during the one-month assessment following infection. In contrast, MLAV-immunized dogs rapidly cleared infections and exhibited significantly fewer systemic bacterial infections compared to unvaccinated controls. Robust E. chaffeensis-specific IgG and CD4 T-cell responses persisted throughout the assessment period. Our findings underscore the efficacy of MLAV in providing natural hosts with protection against E. chaffeensis infection for up to one year following infected tick exposure.

The Zika virus NS5 protein binds HSP90 to suppress EGF-induced Akt signaling and trophoblast cell migration.

Zika virus (ZIKV) infection during pregnancy can cause congenital Zika virus syndrome (CZV), including fetal growth restriction and death. In the developing placenta, trophoblast cells respond to epidermal growth factor (EGF) to migrate into the decidua to facilitate implantation and fetal development. EGF activates the Akt protein kinase, a master regulator of trophoblast cell migration. Akt signaling and stability are dependent on heat shock protein 90 (HSP90), which mediates the maturation of proteins necessary for EGF/Akt signaling. Here we show that ZIKV infection inhibits EGF-mediated Akt activation and downstream signaling to suppress trophoblast migration. The ZIKV non-structural protein 5 (NS5) is sufficient to inhibit trophoblast migration through its binding interaction with HSP90, leading to suppression of Akt phosphorylation and inhibition of EGF-induced trophoblast migration. Thus, ZIKV NS5/HSP90 interactions play a key role in disruption of trophoblast function, revealing an underlying cause of improper placental development and fetal disease.

Shared Molecular Signature in Alzheimer's Disease and Schizophrenia: A Systematic Review of the Reelin Signaling Pathway.

The Reelin signaling pathway, particularly the RELN-APOER2-DAB1 complex, has emerged as a key contributor to the neuropathology of Alzheimer's disease (AD) and Schizophrenia (SZ). Despite being distinct clinical conditions, these disorders exhibit similar patterns of cognitive decline, including early disruptions in synaptic function and memory impairments. Notably, individuals with SZ have a 2-4 fold increased risk of developing AD or other dementias, highlighting potential shared molecular mechanisms, and positioning Reelin as a pivotal link between them. This systematic review explores the role of Reelin and its signaling components across these disorders. In AD, Reelin disruption correlates with hallmark features such as Tau hyperphosphorylation, amyloid-beta accumulation, and cognitive deficits. In SZ, alterations in Reelin signaling, including epigenetic modifications affecting RELN expression, are linked to disruptions in neuronal development and synaptic plasticity, particularly in the parietal and prefrontal cortices. Additionally, genomic studies reveal specific RELN variants and allelic imbalances that may influence disease severity and treatment response in SZ, suggesting RELN's role as a potential biomarker for therapeutic outcomes. Region-specific Reelin alterations in both AD and SZ suggest differing impacts yet underscore a potential common molecular origin. Our findings highlight the Reelin pathway as a molecular convergence point, warranting further investigation as a therapeutic and diagnostic target for AD, SZ, and potentially other neuropsychiatric disorders. The interplay between genetic and epigenetic regulation of RELN may provide novel insights into neurodegeneration, with implications for personalized intervention strategies in AD and SZ.

Distinct disruptions in CA1 and CA3 place cell function in Alzheimer’s disease mice

Distinct disruptions in CA1 and CA3 place cell function in Alzheimer’s disease mice

KAI2-dependent signaling controls vegetative reproduction in Marchantia polymorpha through activation of LOG-mediated cytokinin synthesis (14)

Marchantia polymorpha reproduces vegetatively (asexually) by producing propagules known as gemmae within gemma cups and sexually through spores. We previously reported that KARRIKIN INSENSITIVE2 (KAI2)-dependent signaling promotes gemma cup and gemma formation. KAI2A perceives unidentified endogenous ligand(s), tentatively referred to as KAI2 ligands (KL). Perception of KL by KAI2 triggers MORE AXILLARY GROWTH2 (MAX2)-dependent proteolysis of MpSUPPRESSOR of MORE AXILLALRY GROWTH2 1-LIKE (MpSMXL). In this study, we identify genes working downstream of KAI2-dependent signaling in M. polymorpha. We find that KAI2-dependent signaling positively controls the expression of MpLONELY GUY (MpLOG), encoding a cytokinin biosynthesis enzyme. Disruption of the MpLOG function decreases endogenous cytokinin levels and causes defects similar to KAI2-dependent signaling mutants. Moreover, supplying exogenous cytokinins rescues the defects of Mplog and KAI2-dependent signaling mutants, implying that cytokinins work downstream of KAI2-dependent signaling. Activation of MpLOG by KAI2-dependent signaling occurs in a highly cell-type-specific manner, leading to cell-specific induction of GEMMA CUP-ASSOCIATED MYB1 (GCAM1), the master regulator of vegetative reproduction of M. polymorpha. We propose a genetic cascade, starting from KAI2-dependent signaling, that promotes vegetative reproduction through the induction of MpLOG and GCAM1. The interaction between KAI2-dependent signaling and cytokinin in M. polymorpha provides insights into the function and evolution of KAI2-dependent signaling.

Novel De Novo Intronic Variant of SYNGAP1 Associated With the Neurodevelopmental Disorders.

SYNGAP1 encodes a Ras/Rap GTPase-activating protein that is predominantly expressed in the brain with the functional roles in regulating synaptic plasticity, spine morphogenesis, and cognition function. Pathogenic variants in SYNGAP1 have been associated with a spectrum of neurodevelopmental disorders characterized by developmental delays, intellectual disabilities, epilepsy, hypotonia, and the features of autism spectrum disorder. The aim of this study was to identify a novel SYNGAP1 gene variant linked to neurodevelopmental disorders and to evaluate the pathogenicity of the detected variant. A novel de novo intronic variant in SYNGAP1 was identified by Whole exome sequencing (WES) and confirmed by Sanger sequencing. Minigene assays were conducted to assess whether the intronic variant in SYNGAP1 influenced the normal splicing of mRNA. A novel de novo intronic variant in SYNGAP1 (c.3582+2T>G) was indentified with clinical features suggestive of neurodevelopmental related disorders. Minigene splicing analysis demonstrated that this noncanonical splice site variant led to the activation of a cryptic acceptor splice site. Consequently, 101 base pairs of intron 16 were aberrantly retained in the mRNA, leading to a frameshift. This frameshift resulted in the introduction of a premature stop codon (TGA) in the coding sequence and the production of a truncated SYNGAP1 protein, potentially leding to loss of function and subsequent disruption of its biological roles. Our findings highlight the significance of de novo pathogenic SYNGAP1 variants at the intron 16/exon 17 junction in the SYNGAP1-related neurodevelopmental disorders, providing novel insights into the genetic basis and diagnosis of these disabilities.

Proposing Bromo-epi-androsterone (BEA) for perioperative neurocognitive disorders with Interleukin-6 as a druggable target.

Cognitive impairment following surgery is a significant complication, affecting multiple neurocognitive domains. The term "perioperative neurocognitive disorders" (PND) is recommended to encompass this entity. Individuals who develop PND are typically older and have increases in serum and brain pro-inflammatory cytokines notwithstanding the type of surgery undergone. Surgical trauma induces production of small biomolecules, damage-associated molecular patterns (DAMP), particularly the DAMP known as high molecular group box 1 protein (HMGB1). Mechanistically, peripheral surgical trauma promotes pro-inflammatory cytokines that stimulate central nervous system (CNS) inflammation by disrupting the blood-brain barrier (BBB) causing functional neuronal disruption that leads to PND. PND is strongly linked to elevations in serum and CNS pro-inflammatory cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα); these cytokines cause further release of HMGB1 creating a positive feedback loop that amplifies the inflammatory response. The cytokine IL-6 is necessary and sufficient for PND. Dehydroepiandrosterone (DHEA) is a principal component of the steroid metabolome and is involved in immune homeostasis. DHEA has been shown to suppress expression of several pro-inflammatory cytokines by regulation of the NF-kB pathway. Bromo-epi-androsterone (BEA) is a potent synthetic analog of DHEA; unlike DHEA, it is non-androgenic, non-anabolic and is an effective modulator of immune dysregulation. In a randomized, placebo-controlled clinical trial, BEA effected significant and sustained decreases in IL-1β, TNFα and IL-6. This article presents BEA as a potential candidate for clinical trials targeting PND and further suggests the use of BEA in elective total hip arthroplasty as a well-documented surgical entity relevant to the management of PND.

Nursing Assistance For Traumatic Brain Injury Patients With Intracranial Adaptive Capacity Decrease Using 30o Head Up Position Intervention At Jendral Ahmad Yani Hospital Metro City

Background & Objective: A head injury is a traumatic disruption of brain function with or without interstitial hemorrhage in the brain substance without a break in brain continuity. The purpose of this study was to determine Nursing Care for Traumatic Brain Injury Patients with Decreased Intracranial Adaptive Capacity Using the 30⁰ Head Up Position Intervention. Method: The method in this scientific work with a descriptive approach to nursing care involving 2 head injury patients, the instrument used is an assessment sheet, the application of the 30⁰ Head Up position is carried out for 4 days in patients 1 and 2, with the intensity of giving the 30⁰ Head Up position 3 times a day for 30 minutes. Result: The results of this study found that the main problem that arose in both patients was a decrease in intracranial adaptive capacity, the intervention that was arranged was intracranial management combined with giving the Head Up 30⁰ position, implementation was carried out for 4 days, nursing evaluation of intracranial decline improved to 2 in the first patient and day 3 in the second patient. Conclusion: The recommendation that the author can give is that the application of the Head Up 30⁰ position can restore intracranial decline quickly.

Quercetin triggers cell apoptosis-associated ROS-mediated cell death and induces S and G2/M-phase cell cycle arrest in KON oral cancer cells

BackgroundPlant flavonoids such as quercetin are useful for both the therapeutic and preventive care of a variety of illnesses. Nevertheless, their antitumor efficacy against KON oral cancer is still unknown. Therefore, the aim of this investigation was to examine quercetin’s anti-growth, anti-migrative, and anti-invasive characteristics. The cell cycle arrest property and mitochondrial function disruption of quercetin were also investigated. Additionally, the cellular mechanism responsible for inducing apoptosis and the anti-metastasis mechanism were identified.MethodsKON cells were treated with quercetin in order to test the anticancer activity of this compound. The MTT colorimetric assay was used to examine the cell viability of the treated cells in comparison to MRC-5 fibroblast cells. After being exposed to the detrimental effects of quercetin, the morphology of the KON cells was examined using DAPI and FDA double staining, as well as Hoechst 33,258 and AO double staining. Annexin V-FITC with a flow cytometer and DCFDA labeling were used to detect apoptosis induction and the ROS production associated with cell death. Quercetin’s ability to stop the cell cycle was evaluated via PI staining and the flow cytometer. The examination included anti-proliferative, anti-migration, and anti-invasion activities. Values for the transepithelial electrical resistance, or TEER, were measured. Ultimately, the mechanisms of action of the apoptotic markers and genes implicated in the metastatic process were clarified.ResultsQuercetin treatment reduced the vitality of KON cells and had minimal effect on MRC cells. Following quercetin treatment, the characterization of apoptosis and cell death in KON cells was observed. When quercetin was applied to KON cells, the generation of ROS increased. Furthermore, it was discovered that quercetin increased the percentage of dead cells and cell cycle arrests in the S and G2/M phases. Moreover, quercetin inhibited KON cells’ capacity for migration and invasion in addition to their effects on cell stability and structure. As a result of identifying the mechanism responsible for inducing apoptosis and preventing metastasis, quercetin was found to downregulate the expression of BCL-2/BCL-XL while increasing the expression of BAX. TIMP-1 expression was upregulated while MMP-2 and MMP-9 were downregulated. Quercetin’s anticancer properties and specific mechanisms of action in relation to KON cells were clarified.ConclusionQuercetin is greatly cytotoxic in oral cancer cells, triggering cells undergoing apoptosis and ROS-mediated cell death, possessing S and G2/M cell cycle arrest properties, and exhibiting anti-metastatic activities. Finally, this discovery opens up a wide range of possibilities for developing an anti-oral cancer drug and further investigating its effectiveness in vivo and in clinical trials as an alternative cancer treatment.

Sphingolipid metabolism orchestrates establishment of the hair follicle stem cell compartment.

Sphingolipids serve as building blocks of membranes to ensure subcellular compartmentalization and facilitate intercellular communication. How cell type-specific lipid compositions are achieved and what is their functional significance in tissue morphogenesis and maintenance has remained unclear. Here, we identify a stem cell-specific role for ceramide synthase 4 (CerS4) in orchestrating fate decisions in skin epidermis. Deletion of CerS4 prevents the proper development of the adult hair follicle bulge stem cell (HFSC) compartment due to altered differentiation trajectories. Mechanistically, HFSC differentiation defects arise from an imbalance of key ceramides and their derivate sphingolipids, resulting in hyperactivation of noncanonical Wnt signaling. This impaired HFSC compartment establishment leads to disruption of hair follicle architecture and skin barrier function, ultimately triggering a T helper cell 2-dominated immune infiltration resembling human atopic dermatitis. This work uncovers a fundamental role for a cell state-specific sphingolipid profile in stem cell homeostasis and in maintaining an intact skin barrier.

Porphyromonas gingivalis affects neutrophil pro-inflammatory activities

Porphyromonas gingivalis is the primary pathogen responsible for the development of periodontal inflammatory disease. Although gingipains are the major virulence factor of the pathogen, their role in impairing apoptosis and immune cell function is not fully understood. To investigate the impact of gingipains on neutrophil viability and function, we conducted studies using murine HoxB8 neutrophils and primary human neutrophils infected with wild-type strains of Porphyromonas gingivalis (W83 and ATCC 33277), or a gingipains-null mutant with deleted gingipains encoding genes, or wild-type bacteria preincubated with specific gingipain inhibitors. Flow cytometry revealed that wild-type Porphyromonas gingivalis had a marked effect on neutrophil viability regulated by anti-apoptotic proteins belonging to the Bcl-2 family; however, these effects were independent of gingipain expression or activity. Importantly, experiments using primary human neutrophils and macrophages revealed that gingipains play a significant role in the disruption of immune cell functions via the induction of reactive oxygen species and inactivation of neutrophil elastase activity. Additionally, although gingipains played a role in modulating the IL-8-dependent inflammatory response of human neutrophils, they did not affect the expression levels of pro-inflammatory cytokines TNF-α and IL-6.

The role of mitochondrial dysfunction in Huntington's disease: Implications for therapeutic targeting.

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by cognitive decline, motor dysfunction, and psychiatric disturbances. A common feature of neurodegenerative disorders is mitochondrial dysfunction, which affects the brain's sensitivity to oxidative damage and its high oxygen demand. This dysfunction may plays a significant role in the pathogenesis of Huntington's disease. HD is caused by a CAG repeat expansion in the huntingtin gene, which leads to the production of a toxic mutant huntingtin (mHTT) protein. This disruption in mitochondrial function compromises energy metabolism and increases oxidative stress, resulting in mitochondrial DNA abnormalities, impaired calcium homeostasis, and altered mitochondrial dynamics. These effects ultimately may contribute to neuronal dysfunction and cell death, underscoring the importance of targeting mitochondrial function in developing therapeutic strategies for HD. This review discusses the mechanistic role of mitochondrial dysfunction in Huntington's disease. Mitochondrial dysfunction is a crucial factor in HD, making mitochondrial-targeted therapies a promising approach for treatment. We explore therapies that address bioenergy deficits, antioxidants that reduce reactive oxygen species, calcium modulators that restore calcium homeostasis, and treatments that enhance mitochondrial dynamics to rejuvenate mitochondrial function. We also highlight innovative treatment approaches such as gene editing and stem cell therapy, which offer hope for more personalized strategies. In conclusion, understanding mitochondrial dysfunction in Huntington's disease may guide potential treatment strategies. Targeting this dysfunction may help to slow disease progression and enhance the quality of life for individuals affected by Huntington's disease.

Intracerebral Hemorrhage-Associated Iron Release Leads to Pericyte-Dependent Cerebral Capillary Function Disruption

Intracerebral hemorrhage leads to immediate brain injury due to local mechanical damage, on which current treatment approaches are focused, but it also induces secondary brain injury. The purpose of this study is to characterize blood components, degradation products and their effects in secondary brain injury. Immunocyto- and immunohistochemistry, Fluorescence-Activated Cell Sorting, WST-1 assays and RNA sequencing were applied using human cell cultures and human ex vivo brain tissue slices. Brain tissue was immediately collected, cooled and sliced during neurosurgical operations to perform experiments on living tissue slices of the human brain. Among the blood degradation products, free iron (Fe2+ and Fe3+), but not hemoglobin, induced detrimental effects on pericyte function and survival (78.5% vs. 94.3%; p-value < 0.001). RNA sequencing revealed ferroptosis as the underlining cellular mechanism, mediated via GPX-4 (log2 fold change > 1.0, p-value < 1.08 × 10−30) in pathway analysis and eventually resulting in oxidative cell death. Pericytes located at cerebral capillary branching sites were specifically affected by ferroptosis, leading to capillary disruption and vasoconstriction, which were partially prevented by ferrostatin-1. Free iron induces the pericyte-dependent disruption of cerebral capillary function and represents a therapeutic target to attenuate secondary injury after intracerebral hemorrhage.

OP29 Young Researcher Award: Breaking New Ground in IBD Research: Organoid Models as the Vanguard for Personalized Therapies

Abstract Background Organoid technology has emerged as a pivotal tool in IBD research, offering unparalleled insights into disease mechanisms, mechanisms-of-action, and host-microbiota interactions. Advances in these models enable the establishment of co-cultures in dynamic and IBD-specific intestinal environments. Methods Intestinal crypts from biopsies of IBD patients were isolated, adult stem cells expanded into 3D organoids and differentiated to reflect epithelial subtypes. To enable easy basolateral and apical access, organoid-derived epithelial cells were cultured in Transwells. For enhanced physiological relevance, organoids were integrated into gut-on-a-chip platforms featuring microfluidic flow and peristalsis, and prolonged co-cultures with stimuli and cell types of interest. Advanced imaging techniques, including high-resolution microscopy, were used to evaluate epithelial dynamics, barrier integrity, and inflammatory responses. These models were utilized to test therapeutic compounds and assess personalized responses based on patient-specific profiles (Figure 1). Results Organoid-based models replicated key features of IBD pathology, including inflammation-induced epithelial dysfunction and barrier loss. Imaging provided critical insights into cell-cell interactions and mucus expression under inflammatory conditions and therapeutic interventions. Barrier integrity was rigorously assessed using transepithelial electrical resistance in Transwells, confirming functional disruptions associated with inflammation or ER-stress. Transcriptomic analyses revealed patient- and disease-specific responses to cytokines, microbial metabolites, and environmental stressors, demonstrating the relevance for personalized therapeutic strategies. Early gut-on-a-chip experiments validated the integration of intact (Papp) organoid-derived epithelial monolayers with stromal components and dynamic flow. Conclusion The convergence of organoid technology and gut-on-a-chip systems heralds a new era in IBD translational research. These platforms provide complementary strengths, enabling researchers to tailor models to specific investigative needs. Gut-on-a-chip models integrate organoid-derived epithelial layers with stromal, vascular, and/or immune components under dynamic flow conditions, offering unparalleled insight into the spatial and functional complexities of the gut environment. Together, these systems support personalized exploration of disease pathways and (preclinical) therapeutic efficacy, bridging the gap between in vitro modeling and clinical application. This convergence establishes a versatile foundation for precision medicine, addressing individual variability and driving transformative advances in patient care.

Deletion of Pyruvate Carboxylase in Tubular Epithelial Cell Promotes Renal Fibrosis by Regulating SQOR/cGAS/STING-Mediated Glycolysis.

Renal fibrosis is a common pathway involved in the progression of various chronic kidney diseases to end-stage renal disease. Recent studies show that mitochondrial injury of renal tubular epithelial cells (RTECs) is a crucial pathological foundation for renal fibrosis. However, the underlying regulatory mechanisms remain unclear. Pyruvate carboxylase (PC) is a catalytic enzyme located within the mitochondria that is intricately linked with mitochondrial damage and metabolism. In the present study, the downregulation of PC in various fibrotic animal and human kidney samples is demonstrated. Renal proximal tubule-specific Pcx gene knockout mice (PcxcKO) has significant interstitial fibrosis compared to control mice, with heightened expression of extracellular matrix molecules. This is further demonstrated in a stable PC knock-out RTEC line. Mechanistically, PC deficiency reduces its interaction with sulfide:quinone oxidoreductase (SQOR), increasing the ubiquitination and degradation of SQOR. This leads to mitochondrial morphological and functional disruption, increased mtDNA release, activation of the cGAS-STING pathway, and elevated glycolysis levels, and ultimately, promotes renal fibrosis. This study investigates the molecular mechanisms through which PC deficiency induces mitochondrial injury and metabolic reprogramming in RTECs. This study provides a novel theoretical foundation and potential therapeutic targets for the pathogenesis and treatment of renal fibrosis.

Oral supplementation of curcumin-encapsulated chitosan nanoconjugates as an innovative strategy for mitigating nickel-mediated hepatorenal toxicity in rats.

Nickel pollution adversely affects human health and causes various disorders, mainly hepatic and renal dysfunction. The present work focused on a comparative evaluation of the pure form of curcumin (CU) with curcumin-encapsulated chitosan nanoconjugates (CS/CU NCs), on mitigation of the delirious effects of Ni on hepatorenal tissue. Forty-two male rats were allocated into 6 groups (n = 7 for each) as follows: (1) control, (2) CU, (3) CS/CU NCs, (4) Ni, (5) Ni + CU, (6) Ni + CS/CU NCs. After 30days, blood and tissue (liver and kidneys) were collected to measure hepatorenal biomarkers, oxidant/antioxidant balance, inflammatory gene expression, liver and kidney histopathology, and immunohistochemistry. Results revealed disruption of hepatorenal functions, oxidative stress, and inflammatory markers at biochemical and molecular levels associated with severe hepatorenal histopathological alterations and abnormal immunohistochemical tissue expression for caspase-3 and cyclooxygenase-2. On the contrary, the treatment of Ni-intoxicated rats with CS/CU NCs markedly mitigated the adverse effect of Ni on hepatorenal tissue via regulation of oxidative stress, inflammatory, and apoptotic markers. The present study provides a novel nanoformulation for curcumin using CS NPs encapsulation that selectively targets the injured cells and improves the beneficial effect of CU via enhancing the antioxidant activity and regulating both inflammatory and apoptotic markers.

Clinical consequences of psychoemotional stress in adolescence

The problem of stress-induced health disorders has become increasingly important during the military conflict in Ukraine. Adolescence is characterized by significant challenges for the body due to intense anatomical, physiological, neuroendocrine, and psychological changes. Increased sensitivity to the effects of stressors, in particular due to the maturation of stress-sensitive parts of the brain and related changes in hormonal responsiveness, is typical of adolescents. Stress caused by war-related factors is becoming chronic in Ukrainian children and adolescents. It can lead to disruption of body functions and adaptive capacities, formation or exacerbation of organic pathology. The article analyzes the data of modern scientific literature on clinical manifestations of acute and chronic stress in adolescents. Particular attention is paid to somatic changes in children and adolescents that are induced by chronic stress or observed against its background. Disorders of physical development, skin and musculoskeletal system functioning, peculiarities of the course of certain diseases of the bronchopulmonary system are described. Attention is focused on the formation of cardiovascular pathology, including life-threatening conditions, on disorders of various parts of the gastrointestinal tract and the gut microbiome, changes in kidney and urinary system function. The article provides up-to-date information on the manifestations of endocrine diseases, disorders of autonomic regulation and immune homeostasis under the influence of psychoemotional stress. The results of our own research on the frequency and nature of clinical manifestations in adolescents who lived in the war zone or became internally displaced people, as well as the presence of an imbalance of stress-supplying systems in adolescents during the war are presented. The features of the perception of pain and signs of disease in the conditions of chronic stress are determined, in particular, a decrease in the fixation of attention on personal somatic sensations in children who were constantly in the combat zone and witnessed shelling. Psychoemotional stress experienced in adolescence can have long-term significant consequences in the form of persistent changes in the functioning of various organs and systems of the growing organism, as well as diseases in later life.

Mapping Human Uterine Disorders Through Single-Cell Transcriptomics

Disruptions in uterine tissue function contribute to disorders such as endometriosis, adenomyosis, endometrial cancer, and fibroids, which all significantly impact health and fertility. Advances in transcriptomics, particularly single-cell RNA sequencing, have revolutionized uterine biological research by revealing the cellular heterogeneity and molecular mechanisms underlying disease states. Single-cell RNA sequencing and spatial transcriptomics have mapped endometrial and myometrial cellular landscapes, which helped to identify critical cell types, signaling pathways, and phase-specific dynamics. Said transcriptomic technologies also identified stromal and immune cell dysfunctions, such as fibroblast-to-myofibroblast transitions and impaired macrophage activity, which drive fibrosis, chronic inflammation, and lesion persistence in endometriosis. For endometrial cancer, scRNA-seq uncovered tumor microenvironmental complexities, identifying cancer-associated fibroblast subtypes and immune cell profiles contributing to progression and therapeutic resistance. Similarly, studies on adenomyosis highlighted disrupted signaling pathways, including Wnt and VEGF, and novel progenitor cell populations linked to tissue invasion and neuroinflammation, while single-cell approaches characterized smooth muscle and fibroblast subpopulations in uterine fibroids, elucidating their roles in extracellular matrix remodeling and signaling pathways like ERK and mTOR. Despite challenges such as scalability and reproducibility, single-cell transcriptomic approaches may have potential applications in biomarker discovery, therapeutic target identification, and personalized medicine in gynecological disorders.

Maternal exposure to chronic, low-dose nonylphenol in zebrafish: Disruption of ovarian health, reproductive function, and embryogenesis.

Nonylphenol (NP), a non-ionic surfactant and potent endocrine disruptor, is known for its environmental persistence, biotic accumulation potential and toxicity. Nonetheless, mechanisms underlying NP modulation of female fertility with potential impact on embryogenesis in the unexposed offspring remain elusive. This study investigates the effects and toxic mechanisms of maternal exposure to NP at varying concentrations (50 and 100μg/L) on zebrafish (Danio rerio), specifically focusing on ovarian health, reproductive parameters, and early developmental potential in the F1 generation. Our findings indicate a higher accumulation of NP in the ovaries compared to muscle tissue. Further, chronic (28 days) NP exposure promotes ovarian reactive oxygen species (ROS) accumulation, activates the MAPK (JNK, p38 MAPK, ERK1/2) pathways, AP-1 induction, and elevated expression of pro-inflammatory cytokines (Tnf-α, Il-1β, Il-6) triggering inflammation. Besides, heightened follicular atresia in NP-treated ovaries relates to increased Bax/Bcl2 ratio, cleaved caspase 3 and Parp1 activation prompting apoptosis. While it showed higher affinity to zebrafish ERα (in silico analysis), NP exposure in vivo promotes a robust increase in ovarian ERα but abrogated ERβ expression and a significant alteration in fshr and lhcgr transcripts. While attenuated StAR and P450 aromatase expression at both mRNA and protein levels and reduced igf3 expression reveal impaired ovarian microenvironment, NP-induced dysregulated NO/NOS/cyclooxygenase signaling and attenuation of hCG-induced p34cdc2 activation and oocyte maturation correspond well with decreased fecundity and fertilization efficiency. Intriguingly, maternal exposure to NP resulted in delayed embryogenesis, developmental aberrations, and reduced hatching rates in the unexposed offspring, risking F1 generation. Collectively, this study provides mechanistic insights into the detrimental influence of maternal exposure to NP on ovarian dysfunction, reproductive insufficiency and embryotoxicity.

Iron deposition is associated with motor and non-motor network breakdown in parkinsonism.

Iron deposition has been observed in Parkinsonism and is emerging as a diagnostic marker for movement disorders. Brain functional network disruption has also been detected in parkinsonism, and is believed to be accountable for specific symptoms in parkinsonism. However, how iron deposition influences brain network remains to be elucidated. We recruited 16 Parkinson's disease (PD), 8 multiple system atrophy (MSA) and 7 progressive supranuclear palsy (PSP) patients. T1-weighted, susceptibility weighted images and resting-state functional MRI (rs-fMRI) were acquired. Quantitative susceptibility mapping (QSM) analysis was performed to quantify iron deposition in substantia nigra, putamen and dentate nucleus. Cerebellar network, sensorimotor network, default mode network and language networks were segregated using independent analysis. Network and iron deposition status were evaluated in relation to diagnostic groups, motor and non-motor symptoms. The relationship between quantitative iron deposition and brain network status was further interrogated. To further validate the findings, 13 healthy controls and 37 PD patients who had available T1 and rs-fMRI scans were selected from Parkinson's progression markers initiative (PPMI) database, and network analysis was performed. In local cohort, compared to PD, MSA patients showed greater iron deposition in putamen, while PSP patients had greater iron deposition in caudate nucleus and thalamus. Cerebellar and language networks showed significant difference across diagnostic groups, while default mode network and sensorimotor network did not. MSA patients had significantly impaired cerebellar network and language networks compared to PD patients. Cerebellar network was positively associated with motor symptom scores while language network was positively associated with MoCA scores in the patients. Iron deposition was negatively associated with both networks' activity in the patients. In PPMI cohort, impairment was found in both cerebellar and language networks in PD. Cerebellar and language networks correlated with motor and cognitive impairment, respectively. Cerebellar network and language networks are differently influenced in MSA, PD and PSP, which can serve as potential diagnostic marker. Impairment of cerebellar network and language network are associated with motor symptoms and cognitive impairment, respectively. Moreover, dysfunction of the networks is associated with iron deposition in deep nuclei (SN, DN, Putamen).