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Cell therapy units are facing persistent saturation of their liquid nitrogen storage capacity for cell therapy products (CTPs). This situation compromises the safety of CTPs due to the ageing and increasing number of storage containers, leading to a higher risk of equipment failure. It also results in a significant rise in costs, mainly related to liquid nitrogen consumption. It is therefore essential to control overstocking for both economic and environmental reasons. This work represents an update of the 2014 recommendations, notably introducing a recommended maximum storage duration of 5 years for CTPs, which account for 64% of the stock despite a very low probability of clinical use. In addition, recommendations concerning the criteria for destruction of intrafamilial cord blood units and associated cell banks have been added.
Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of chronic kidney disease in children. Although prenatal ultrasound enables early detection, its ability to predict postnatal renal outcome, particularly in bilateral cases, remains limited due to substantial phenotypic variability and the inability of imaging to capture ongoing disease processes. Genetic testing improves etiological classification but shows weak genotype-phenotype correlations and limited prognostic value, reflecting the multifactorial nature of CAKUT and prompting investigation of molecular biomarkers in prenatal body fluids. This review summarizes current prenatal prognostic strategies in CAKUT, including imaging, genetics, and downstream molecular approaches such as transcriptomics, metabolomics, and proteomics, with particular emphasis on peptide-based profiling. Among these, prenatal peptide signatures derived from fetal urine or amniotic fluid have demonstrated strong prognostic performance for predicting postnatal renal outcome and may capture early molecular processes related to tissue remodeling and inflammation. However, translation into clinical practice remains challenging. Validation requires large prospective multicenter studies that are difficult to conduct in rare diseases and often lack sustained funding. In addition, implementation will likely rely on mass spectrometry-based assays in clinical laboratories. Despite these hurdles, integrating molecular peptide profiling with improved and standardized imaging approaches may enhance prenatal counselling and clinical decision-making in CAKUT.
Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and poor prognosis. Understanding the underlying molecular mechanisms, particularly immune-related gene networks, is critical for identifying novel therapeutic targets. This study aimed to identify immune-related hub genes involved in TNBC progression by integrating microarray and RNA sequencing data. We integrated microarray and RNA sequencing datasets from five Gene Expression Omnibus (GEO) studies (GSE36295, GSE37751, GSE61724, GSE38959, and GSE58135) to identify differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks were constructed using the STRING database. Key modules and hub genes were identified through network analysis. Functional enrichment was performed to elucidate biological pathways, while immune infiltration analysis assessed associations with the tumor microenvironment. Drug-gene interaction databases were queried for FDA-approved compounds targeting hub genes. The PPI network revealed 179 nodes and 781 edges, indicating high connectivity. Module analysis highlighted a significant cluster with the identified key genes such as CDK1, BUB1B, CCNA2, BUB1, CCNB1, KIF20A, CENPF, TOP2A, KIF11 and MELK validated at both mRNA and protein levels. Functional enrichment revealed pathways related to cell cycle control, chromosome segregation, and kinase activity. Immune infiltration analysis indicated involvement of B cells, macrophages, and neutrophils in the TNBC microenvironment. Drug-gene mapping revealed a lack of FDA-approved drugs targeting certain key hub genes. This integrative study identified key immune-related hub genes driving TNBC progression, with KIF20A emerging as a promising yet underexplored target. Drug repurposing strategies focusing on KIF20A and other identified hub genes may accelerate the development of effective treatments, offering valuable insights for future therapeutic and prognostic evaluations in TNBC.
Male infertility accounts for nearly half of global infertility cases and is often linked to poor sperm quality, such as oligospermia, asthenospermia, and teratospermia. Although the exact mechanisms remain unclear, mitochondria, which are critical for ATP production and reactive oxygen species generation during fertilization, are increasingly recognized as key players in male infertility but remain underexplored. ATP synthesis relies on respiratory chain complexes that establish a proton gradient across the inner mitochondrial membrane, powering the F0F1-ATP synthase. Proper stoichiometry of these complexes, encoded by both nuclear and mitochondrial DNA, is essential for efficient energy production. However, no previous studies have directly correlated mitochondrial protein expression with sperm quality. Due to the small size and helical structure of sperm mitochondria, imaging them is challenging, yet crucial for understanding sperm function. This study investigates the role of mitochondrial oxidative phosphorylation proteins in sperm quality using single-cell immunolabeling and high-resolution microscopy. It compares spermatozoa from oligoasthenospermic (OA) patients to normospermic controls. OA sperm show increased levels of mitochondrial genome encoded cytochrome c oxidase subunit 1 and significantly reduced F0F1-ATP synthase subunits. This imbalance may contribute to mitochondrial dysfunction and underscores the need for deeper exploration of the pathophysiological mechanisms involved, which could affect sperm function and fertility. These initial results suggest a potential pathway toward the identification of novel biomarkers of male infertility.
Depression is closely linked to neuroinflammation, and in chronic kidney disease, the accumulation of uremic toxins (UTs) may promote neuroinflammatory processes through the activation of inflammatory pathways. The objective of this longitudinal study was to evaluate the association between UTs and depressive symptoms in a large, well-characterised cohort of non-dialysed adults with chronic kidney disease, a population in which this relationship had not yet been investigated. The Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort comprised 3033 CKD stage 2-5 patients with 5 years of follow-up. Changes over time in depressive symptoms were assessed on the Center for Epidemiologic Studies Depression (CESD) scale. Mixed models were used to examine associations between the change in the CESD score and baseline levels of the UTs phenylacetylglutamine (PAG), indoxyl sulphate (IS), indole-3-acetic acid (IAA), p-cresyl sulphate, kynurenine, kynurenic acid and trimethylamine N-oxide. 2165 patients were included (median age: 68 years; mean estimated glomerular filtration rate (eGFR): 35 mL/min/1.73 m²; median baseline CESD score: 7; mean follow-up time: 4.0 years). After adjustment for confounders, the CESD score was found to have increased by 0.11 (0.04 to 0.18) points per year. A doubling in PAG level was associated with an additional increase of 0.06 (0.01 to 0.18) points per year in the CESD. A doubling in IS and IAA levels was associated with a higher mean CESD score (0.20 (0.01 to 0.39) for IS and 0.28 (0.05 to 0.50) for IAA) but not with the score's change over time. PAG was significantly associated with changes in CESD score over time. Higher IS and IAA levels were linked to higher mean scores. Further studies are needed to confirm these results and to determine whether lowering serum UT levels would help to manage depressive symptoms in patients with CKD. Further research is needed to clarify the role of UTs; a better understanding could uncover novel metabolic pathways and inform new therapeutic strategies to complement the management of depressive symptoms.
The pharmaco-epidemiological research program in kidney transplantation (PERP-KT) aims to evaluate, for the principal maintenance immunosuppressive drugs (MISDs): the influence of model-informed precision dosing on graft and patient survival; long-term exposure-effects relationships; and the benefit-harm balance of their combinations and time sequences in patient groups or clinical settings not adequately evaluated in comparative randomized clinical trials. It also aims to develop a hybrid, dynamic, deep learning model capable of predicting the rate of renal graft function decline, thereby providing a platform for individualized prediction of the benefits and risks associated with MISDs. After obtaining all regulatory andd ethical approvals, de-identified extracts of three national databases were linked to create the nationwide PERP-KT dataset, which is hosted within the highly secure environment of the French Health Data Hub. CRISTAL (the exhaustive registry of the French Agence de la Biomédecine) comprises data from 49 886 kidney donors and the corresponding 47 842 transplant recipients between 2005 and 2020. Following iterative deterministic matching and extensive quality control procedures, CRISTAL data were successfully linked to: the French national Health Data System (SNDS), which records reimbursed healthcare utilization, for 30 782 kidney transplant recipients; and to ISBA, a web-based platform for Bayesian dose adjustment of MISDs that contains pharmacological data, for 17 700 kidney grafts and 17 576 recipients. More than 20 pharmaco-epidemiological studies will leverage the database's extensive follow-up, large population size and richness of clinical, healtcare-utilization, and pharmacological data. This research program on kidney transplantation (PERP‐KT) intends to evaluate: the efficacy of fine‐tuned, individual dose adjustment of the main maintenance immunosuppressive drugs (MISDs) on the longevity of the graft and on patient survival; the long term effects of different blood levels of the main MISDs; the efficacy and adverse effects of the different combinations and time sequences of MISDs in patient groups or clinical conditions not previously evaluated; and to develop an artificial intelligence tool able to predict the speed at which each kidney graft will deteriorate after transplantation. PERP‐KT leverages the CRISTAL registry (managed by the French Agence de la Biomédecine) exhaustively listing kidney transplant procedures in France (49 886 donors and 47 842 recipients between 2005 and 2020), combined with the SNDS (Système National des Données de Santé) that contains all drugs delivered and healthcare activities for 30 782 of them, and ISBA (ImmunoSuppressive Bayesian dose Adjustment website) a database about the dose and blood levels of the main MISDs for 17 700 kidney grafts and 17 576 patients. This unprecedented database will support more than 20 studies on the efficacy and adverse events of MISDs and will foster personalized medicine in kidney transplantation.
Peritoneal recurrence remains a major concern in colorectal cancer surgery. We aimed to evaluate the safety and preliminary efficacy of a novel poloxamer-based thermogel delivering Mitomycin C (TGel-MMC) as a simple prophylactic approach to reduce peritoneal carcinomatosis risk. The cytotoxicity effect of the MMC within the thermogel was assessed over time on CT26 cells using the alamar blue assay. TGel biocompatibility and cytoreductive effect was evaluated on a murine model. Finally, TGel-MMC safety was tested in a porcine model with laparotomy and anastomoses to assess tissue reaction, adhesions, and anastomotic integrity. Prolonged exposure of CT26 to TGel-MMC enhanced MMC cytotoxicity at low doses in vitro. In mice, TGel alone did not cause significant adhesions or diffuse inflammation up to 63 days. The TGel-MMC group showed effective prophylactic cytoreduction comparable to MMC alone. In pigs, no anastomotic fistulae and no chemical peritonitis were observed up to day 15. Pharmacokinetic profiles showed MMC absorption highly comparable to standard HIPEC, with peak levels at 1 h and gradual decline over 6 h. This study shows the sustained release of MMC in thermogel in-vitro. It demonstrates for the first time the feasibility and short-term safety of intraperitoneal TGel-MMC administration in a large animal model with digestive sutures. These results support further investigation on TG-MMC as a prophylactic strategy to reduce peritoneal metastases in high-risk colorectal surgery.
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FUS is an RNA-binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show in this work that a heterozygous knock-in mutation in the mouse Fus gene leads to cell-autonomous ultrastructural defects in skeletal muscle, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionarily conserved cell-autonomous function of FUS in muscle development. Mechanistically, FUS is required for the transcription of MEF2 target genes, binds to the promoter of genes bound by ETS transcription factors, in particular ETV5, and co-activates the transcription of MEF2-dependent genes with ETV5. FUS phase-separates with ETV5 and MEF2A, and stimulation of MEF2-dependent transcription by FUS is dependent upon its phase separation properties. Finally, Etv5 haploinsufficiency exacerbates muscle weakness and atrophy in Fus knock-in mice. Our findings establish a key role for FUS in skeletal muscle differentiation through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.
Clozapine remains the gold-standard antipsychotic for treatment-resistant schizophrenia, but its use is hindered by rare but serious adverse effects, such as hematologic abnormalities and myocarditis. This study investigated the adverse impacts of clozapine on blood markers and electrocardiographic (ECG) findings among patients with schizophrenia, emphasizing in early detection of life-threatening complications. All patients initiated on clozapine at a psychiatric hospital in Athens, Greece, between January 2022 and June 2024 were considered for inclusion. Thirty-one patients with complete clinical and laboratory data were monitored for hematological, biochemical, and ECG changes at baseline, days 5-10, and after 1-2 months. Parameters evaluated included white blood cell (WBC) counts, differential counts, C-reactive protein (CRP), hepatic enzymes, creatine phosphokinase (CPK), troponin, and ECG changes. Of the 31 patients, two (6.5%) developed clozapine-induced myocarditis within the first three weeks, confirmed by clinical symptoms, ECG abnormalities, and elevated troponin levels, necessitating immediate clozapine discontinuation. Four patients exhibited prolonged QTc, two overlapping with myocarditis cases. Eleven experienced elevated CRP, while eosinophilia and transient hepatic or muscular enzyme elevations were also common, especially during rapid titration phases; indicating inflammatory responses or mild organ involvement. No cases of agranulocytosis or severe eosinophilic complications occurred. Clozapine can induce significant hematologic, inflammatory, hepatic, muscular, and cardiac adverse effects, particularly during rapid titration. Systematic monitoring of blood markers and ECGs was vital in early detection and management of these complications, especially myocarditis. The findings underscore the importance of cautious titration protocols and tailored surveillance strategies to enhance clozapine safety in clinical practice.
Standard chemotherapy regimens for patients with breast cancer are based on epirubicin-cyclophosphamide (EC) and paclitaxel (TAX) administrations. While it has been shown that first EC administration impairs mitochondrial homeostasis, the isolated effects of TAX have not been studied without previous chemotherapy exposure. We conducted a prospective clinical study including five patients with breast cancer who underwent two vastus lateralis muscle biopsies before and 4 days after the first TAX administration, without any prior chemotherapy exposure. Mitochondrial respiratory capacity, reactive oxygen species production, mitochondrial dynamics and ultrastructure, and apoptosis were assessed using high-resolution respirometry, western blotting, transmission electron microscopy, and TUNEL assay, respectively. Post-TAX, the number of intermyofibrillar mitochondria decreased (-18%; P = 0.049), while the proportion of damaged mitochondria increased (+34%; P = 0.012). Mitochondrial area, perimeter and major/minor axis lengths increased (P < 0.05) while intermyofibrillar cristae area decreased (4.29% pre-TAX vs. 2.60% post-TAX; P = 0.044). Despite these morphological changes, oxidative phosphorylation capacity and respiratory control ratio remained unchanged, whereas complex I-linked substrate respiration decreased (-29%; P = 0.046). MFN2 (-43%; P = 0.040) and Fis1 (-46%; P = 0.046) protein levels decreased post-TAX while mitophagy markers were unchanged. Apoptosis was increased, as documented by increased Bax (+58%; P = 0.045) and TUNEL-positive nuclei (+395%; P = 0.041). In only 4 days, the first TAX administration induced severe skeletal muscle mitochondrial remodelling in patients with breast cancer, characterized by impaired mitochondrial dynamics that resulted in swollen and damaged organelles. These findings demonstrate that mitochondrial toxicity, classically documented at the end of treatment, occurs acutely and after only one chemotherapy administration.
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Pain modulation relies on complex molecular interactions among ion channels, G protein-coupled receptors, and intracellular signaling cascades. The Transient Receptor Potential Vanilloid 1 (TRPV1) channel serves as a polymodal detector and integrator of noxious stimuli, linking sensory transduction with broader neuromodulatory systems. This review delineates the mechanistic crosstalk between TRPV1, endocannabinoid, and opioid pathways in nociceptive regulation. TRPV1 activation by heat, protons, or endogenous lipids induces calcium influx and engages protein kinase C (PKC), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) pathways that modulate channel phosphorylation and neuronal excitability. Endocannabinoids such as anandamide act as dual CB1 and TRPV1 agonists, establishing feedback loops that adjust nociceptive thresholds, while μ-opioid receptor activation inhibits adenylate cyclase and TRPV1 sensitization through Gi/o-mediated signaling. Given the recent progress in cryo-electron microscopy and molecular modeling, simulation studies have been possible, revealing key structural determinants underlying key receptor interactions. Integrating pharmacophore modeling, molecular docking, and artificial intelligence-based screening enables rational design of multi-target ligands that exploit TRPV1-endocannabinoid-opioid synergy. This mechanistic framework supports the development of next-generation analgesics that achieve potent, sustained, and safe modulation of nociceptive signaling.
Patients with obesity have a reduced access to kidney transplantation due to the higher risk of surgical and medical complications. Our aim was to provide clinical guidelines in this population focused on: (i) the main anthropometric parameter that contraindicates open kidney transplantation; (ii) other clinical factors to consider before transplantation; (iii) contraindications to robot-assisted transplantation; (iv) efficient and safe weight loss methods for kidney transplantation candidates with obesity. After a systematic review of studies published between January 2010 and June 2025 performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria, these guidelines were developed by a multidisciplinary task force and reviewed by independent experts. In total, 153/962 publications met the inclusion criteria. The decision to allow kidney transplantation should not be based solely on Body Mass Index (BMI), but also on skin-to-vessel distance and pelvis angle. Robot-assisted kidney transplantation may be considered in highly selected patients with obesity and limited vascular disease, even those with grade 3 obesity. Patients with frailty should receive appropriate care before weight loss therapies. After appropriate nutritional preparation, bariatric surgery should be considered fairly quickly in patients with kidney failure and grade ≥ 2 obesity (grade B), or grade 1 obesity and poorly controlled type 2 diabetes. While Roux-en-Y gastric bypass achieves superior long-term weight loss than sleeve gastrectomy, it is associated with an increased mortality and morbidity. Pharmacological treatment (mainly GLP-1 agonists) is currently evaluated for weight loss in this population. These guidelines allow personalizing the management in kidney transplantation candidates with obesity.
Background/Objectives: Hydroxyurea (HU), a cornerstone treatment for sickle cell disease (SCD), exhibits marked interindividual pharmacokinetic/pharmacodynamic (PK/PD) variability that remains poorly understood. This study aimed to establish a population PK model using OPTIMDREP randomized trial data (NCT06464458), quantify parameter variability, and identify covariates influencing HU PK and hematological response. Methods: Plasma sampling data from 22 SCD patients (20 pediatric and 2 adult patients; median age: 11.2 years [range: 2.5-35.7]) on once-daily oral HU underwent a non-compartmental analysis (NCA) followed by nonlinear mixed-effects modeling (MonolixSuite®). PK variability covariates and PK/PD correlations with the mean corpuscular volume (MCV), reticulocytes, fetal hemoglobin percentage (HbF%) and neutrophils were investigated. Results: NCA identified two absorption phenotypes (rapid/slow), with higher maximum concentration values observed for rapid (36.5 ± 18.8 mg/L) compared to slow (22.3 ± 8.4 mg/L) (p = 0.0013) profiles but not statistically different total exposures, apparent clearances (Cl/F) or volumes of distribution (Vd/F). The population approach identified the one-compartment model (first-order absorption and linear elimination) and confirmed the absorption phenotype as the key absorption rate (ka) covariate (9.93 vs. 1.36 h-1), explaining half of the ka interindividual variability (IIV). The median-normalized body weight was retained for both the Cl/F and Vd/F, as it significantly reduced the objective function value. No hematological parameter was correlated to PK parameters. However, rapid absorbers showed a superior response on the MCV (Δ = 9.1 fL, p < 0.0001), reticulocytes (Δ = -42.2 G/L, p < 0.01), and HbF% trend (Δ = 2.8%, p = 0.0835) but not on neutrophil counts (p = 0.8757). Conclusions: The absorption phenotype, a novel covariate explaining half of the ka IIV, predicts a superior erythropoietic response without toxicity in SCD patients. These findings support absorption phenotype integration into PK-guided dosing algorithms to optimize early-response biomarkers and personalize HU therapy.
Weight loss, partially caused by hypermetabolism, represents a well-documented and therapeutically relevant feature of the amyotrophic lateral sclerosis phenotype worldwide. In this study, we retrospectively analysed the association between thyroid function and clinical, prognostic and metabolic parameters in a cohort of patients with amyotrophic lateral sclerosis in an experienced centre in Germany (n = 1754). Specifically, we examined the relationship between thyroid stimulating hormone levels, age, glucose and body mass index and-in subgroups-phosphorylated neurofilament heavy chain levels in CSF. There was no association between thyroid stimulating hormone levels and body mass index in patients with amyotrophic lateral sclerosis (n = 954). In contrast with other cohorts, thyroid stimulating hormone levels decreased with age in patients with amyotrophic lateral sclerosis indicating hypothalamic deficiency in the ageing patients. There was no association between thyroid stimulating hormone and phosphorylated neurofilament heavy chain (prognostic marker) in CSF of a subcohort (n = 646). Thyroid stimulating hormone levels correlated with glucose levels, an effect more pronounced in male patients. In conclusion, our results suggest that thyroid metabolism does not significantly contribute to amyotrophic lateral sclerosis-related weight loss or disease prognosis as estimated by phosphorylated neurofilament heavy chain; thyroid dysfunction is unlikely to be a primary driver of the metabolic dysregulation observed in amyotrophic lateral sclerosis. Most interestingly, thyroid stimulating hormone levels show an unexpected negative relation to age in patients with amyotrophic lateral sclerosis.
Tobacco smoke inhalation disrupts the integrity of the alveolar-capillary barrier (ACB) and contributes to the pathogenesis of multiple chronic pulmonary diseases as chronic obstructive pulmonary disease (COPD). Nicotine, a major component of both cigarette smoke and electronic cigarette (e-cigarette) aerosol, is predominantly deposited on the alveolar surface, where it is rapidly absorbed, yet its specific contribution to ACB dysfunction remains insufficiently characterized. Our objective was to decipher the effects of nicotine across a wide concentration range (2.5 µM to 250 mM) on the modulation of the ACB in vitro. To this end, the following endpoints were investigated: cell viability (MTS and BrdU assays), cytotoxicity (LDH assay), mitochondrial oxidative stress (MitoSOX assay) and barrier integrity using Trans-Epithelial/Endothelial Electric Resistance (TEER) following exposure to increasing nicotine concentrations. Autophagic flux (LC3B-II, p62 and LAMP2 protein expression and localization) and occludin modulation and trafficking were also examined and compared with the effects of bafilomycin A1. Nicotine exposure slowed cell proliferation and enhanced mitochondrial reactive oxygen species (ROS) production, effects that were partially reversed by N-acetyl-cysteine (NAC). Nicotine inhibited autophagic flux through a mechanism distinct from that of bafilomycin A1, and this inhibition was partially reversed by NAC. In parallel, nicotine compromised barrier integrity, inducing a TEER decrease associated with occludin internalization and defective lysosomal degradation and recycling. These findings identify nicotine as an independent disruptor of ACB integrity, acting through oxidative stress, impaired autophagy and junctional remodeling, mechanisms relevant to smoking-related pulmonary diseases beyond COPD, including those associated with e-cigarette use.
The consumption of highly processed, hyperpalatable food in Western societies increases the risk of developing obesity and compulsive eating behaviors, which include food addiction (FA) and eating disorders (EDs), such as bulimia nervosa (BN) and binge eating disorder (BED). These behaviors can lead to a range of health consequences, including cardiovascular and metabolic diseases, cognitive impairments, and mental health disorders, among others. Given the evidence suggesting the involvement of the gut microbiota in regulating eating behavior, in recent years, scientists have sought to identify microbiota signatures associated with EDs and FAs. Multiple pro- and prebiotics, as well as other microbiota-based therapeutic interventions, have been suggested as preventive or treatment strategies for FA and EDs. To provide a comprehensive overview, this review is structured into two main sections. The first section describes compulsive eating behaviors, namely, BN, BED, and FA, recognizing their similarities and differences, and highlighting the importance of the proper distinction for the selection of targeted and effective treatment approaches. The second section provides an extensive summary of the recent research years behind the search for microbiota signatures and potential microbiota-based therapeutic interventions for managing EDs and FA in both humans and animal models.
Chromatin serves as the dynamic carrier of genetic and epigenetic information in eukaryotic cells, playing a pivotal role in maintaining nuclear shape, mechanical stability, and cellular function. Aberrant nuclear morphology, often observed in mechanically stressed environments or diseases such as progeria and muscular dystrophy, correlates with nuclear dysfunction, DNA damage, and disrupted mechanotransduction. Chromatin exists in two main configurations - compacted heterochromatin and decompacted euchromatin - each regulating gene expression and cellular behaviour through epigenetic modifications. Histone acetyltransferases and deacetylases modulate chromatin compaction, while histone methylation introduces further regulatory complexity. Chromatin's viscoelastic properties enable it to store and restore mechanical energy, acting as a mechanosensitive component within the nucleus. External forces propagate from the extracellular matrix through focal adhesions, the cytoskeleton, and the nuclear lamina to chromatin, forming a direct mechanotransduction pathway. However, the reverse pathway - how internal nuclear forces generated during chromatin remodelling influence the nuclear membrane, cytoskeleton, and cell adhesion - remains poorly understood. This review explores the role of chromatin as a tensegrity element, capable of generating mechanical forces through condensate formation. It examines evidence supporting chromatin decompaction as a regulator of reverse mechanotransduction and identifies potential mechanical partners involved in this process. Understanding these mechanisms may elucidate how chromatin dynamics contribute to cellular fate decisions and disease pathogenesis.
To investigate uterine healing at delivery after fetoscopic myelomeningocele (MMC) closure in an ovine model. This descriptive study was conducted in Romane ewes. Fetal MMC lesions were created after hysterotomy at 75 days of gestation. Fetoscopic MMC closure using three trocars was performed at 90 days of gestation and cesarean delivery at 143 days. Subtotal hysterectomy was performed, and each hysterectomy specimen was examined in fresh condition. The areas of interest and the surrounding intact tissue were then sampled en bloc and fixed in 4% buffered formaldehyde solution for 3-6 weeks. Macroscopic appearance of the scars was assessed in fresh condition. Microscopic examinations were conducted in fixed samples. The uteri of six ewes were studied. Macroscopic examination revealed identifiable fetoscopic scars without any scar dehiscence. There was no evidence of a difference in thickness between scarred and healthy adjacent myometrium, although a slightly lower proportion of muscle fibers was observed in scarred areas. Our study demonstrates that myometrial healing of trocar orifices is complete 53 days after fetoscopic MMC closure in an ovine model. Given the limitations of an ovine model, further studies are needed to determine the risk of uterine rupture and the optimal obstetric management of patients after fetoscopic MMC closure.