High altitude may adversely affect patients with pulmonary vascular disease (PVD), but acute cardiopulmonary effects remain unclear. How does two-day high-altitude exposure affect pulmonary hemodynamics and oxygen delivery in patients with PVD defined as pulmonary arterial or chronic thromboembolic pulmonary hypertension? In this randomized, controlled crossover trial, stable, low-risk patients with PVD without resting hypoxemia at 470 m were transported by cable car to 2500 m, where they stayed for two days. Systolic pulmonary arterial pressure (sPAP), total pulmonary resistance (TPR), right ventricular (RV) -arterial coupling, pulmonary arterial elastance (EA) and compliance (PAC) were assessed by echocardiography, while oxygen content was measured in arterial blood gases. Twenty-seven patients with PVD (44% women, 61±14 years) were included. Altitude exposure was associated with an increase in sPAP of 18 mmHg (40%, 95%CI: 9 to 28 mmHg, p<0.001) and TPR of 2.8 WU (32%, 0.7 to 4.9 WU, p=0.007). RV-arterial coupling, assessed by TAPSE/sPAP ratio, decreased from 0.55±0.04 to 0.38±0.04 mm/mmHg (-31%, -0.27 to -0.07 mm/mmHg, p<0.001). EA increased by 0.2 mmHg/mL (33%, 0.07 to 0.33 mmHg/mL, p<0.001) and PAC decreased by 1.6 mL/mmHg (38%, -2.7 to -0.6 mL/mmHg, p=0.002). Although oxygen content was lower at high altitude, oxygen delivery was similar at both altitudes. Two-day exposure to 2500 m in stable, low-risk patients with PVD increases RV resistive and pulsatile afterload and decreases TAPSE/sPAP, indicating reduced RV-arterial coupling. Despite attenuated cardiac adaptation, overall function appears sufficient to maintain oxygen delivery and partially compensate for hypoxemia. Clinicaltrials.gov (NCT05107700).
BackgroundSonodynamic therapy (SDT) has emerged as a promising strategy for cancer treatment; however, its therapeutic efficacy is significantly limited by the hypoxic tumor microenvironment, particularly in breast cancer. To address this limitation, we developed a biomimetic nanoplatform capable of generating oxygen within the tumor microenvironment to enhance SDT performance.MethodsPoly (lactic-co-glycolic acid) (PLGA) nanoparticles were co-loaded with catalase and the sonosensitizer IR780 and subsequently coated with 4T1 cancer cell membranes (CIP@4T1m NPs). A series of in vitro and in vivo experiments were conducted to evaluate tumor-targeting capability, hypoxia alleviation, singlet oxygen (1O2) generation, antitumor efficacy, induction of immunogenic cell death (ICD), and activation of antitumor immune responses.ResultsThe resulting CIP@4T1m NPs were successfully fabricated and exhibited preferential accumulation in 4T1 tumor cells and orthotopic 4T1 tumor-bearing mice. Both in vitro and in vivo studies demonstrated that the nanoplatform partially relieved tumor hypoxia and significantly enhanced SDT-mediated 1O2 production and antitumor effects. Moreover, CIP@4T1m NPs combined with ultrasound induced ICD-associated changes, promoted dendritic cell maturation, facilitated the polarization of tumor-associated macrophages from the M2 to M1 phenotype, reduced regulatory T cell populations, and increased intratumoral CD8+T-cell infiltration.ConclusionThis work describes a biomimetic nanoplatform that integrates homologous targeting with enzymatic oxygen generation to enhance SDT efficacy and promote antitumor immune responses in an orthotopic 4T1 breast cancer model. The proposed strategy offers a potential approach to mitigate hypoxia-associated limitations in cancer therapy.
Management of venoarterial-extracorporeal membrane oxygenation for cardiogenic shock requires prompt diagnosis, rapid intervention with individualized cannulation, adherence to clear device and anticoagulation management protocols, and close hemodynamic and end-organ monitoring. Assessment of left ventricular unloading and oxygen delivery is essential to prevent complications such as malperfusion of end organs, limb ischemia, pulmonary edema, and Harlequin (North-South) syndrome. Daily evaluation guides weaning for myocardial recovery and transition to durable support, transplant, or palliative care. Multidisciplinary coordination with critical care clinicians, early involvement of advanced heart failure and transplant teams, and clear communication with families are crucial to align therapy with patient.
Voltage-controlled ion insertion provides a powerful strategy for the analog tuning of material properties, enabling adaptive devices such as neuromorphic transistors and smart displays. Among tunable materials, mixed ionic-electronic conducting oxides undergoing topotactic phase transitions are particularly compelling due to their dramatic property changes between fully oxidized and fully reduced states. However, intermediate oxidation states remain largely underexplored because of significant control limitations. In this work, we investigate the topotactic phase transition in strontium ferrite (SrFeO3-δ) thin films by progressively and precisely modulating and quantifying oxygen non-stoichiometry via solid-state electrochemical pumping. This fine-tuning approach unveils the co-existence of multiple stable phases in equilibrium configurations across a broad range of oxidation states. A crystallographic mixing model that captures the structural-electronic coupling underlying this phenomenon is proposed, complemented by a defect chemistry framework that quantitatively describes the oxidation mechanism under applied voltage. These findings highlight the critical role of intermediate states in governing functional properties and open new pathways for designing advanced ionotronic oxygen-responsive devices.
Androgenetic Alopecia (AGA) is a chronic disease characterized by follicular degenerative changes and the continuous deterioration of the follicular microenvironment. Excessive accumulation of reactive oxygen species (ROS) and insufficient local microcirculation are both critical factors contributing to the onset and progression of this disease. However, existing clinical treatment approaches are mostly confined to single-target interventions for AGA. Herein, a multifunctional hydrogel system that integrates multi-active nanozymes with melanin nano photothermal agents was designed for efficient multimodal synergistic treatment of AGA. Owing to the existence of dynamic covalent bonds, such multifunctional hydrogel exhibits favorable injectability and tissue adhesion capability, facilitating the precise and sustained release of nanodrugs. Among them, multi-active nanozymes can mimic the activities of superoxide dismutase (SOD) and catalase (CAT), enabling efficient cascade clearance of reactive oxygen species such as superoxide anions (·O2-) and hydrogen peroxide (H2O2) at the lesion site, thereby restoring the redox homeostasis of hair follicles. Additionally, the low-temperature photothermal effect exerted by melanin nano photothermal agents under infrared laser irradiation can effectively stimulate hair follicle cells, enhance follicular metabolic activity, and improve local microcirculation in the hair area. Through the synergistic effects of ROS scavenging, low-level photothermal stimulation, and microcirculation regulation, this multifunctional hydrogel system holds promise for fundamentally improving the follicular microenvironment, promoting healthy hair growth, and thus achieving multi-target precision therapy for AGA.
A novel process was employed to produce ferric coagulants using iron recovered from the coarse and fine fractions of basic oxygen furnace (BOF) sludge. The FeSO4 obtained as an intermediate product was converted to Fe2(SO4)3 (final product), which was used as a coagulant in water treatment. The iron contents of the coarse and fine BOF sludge fractions were 82.51 ± 0.02% and 45.6 ± 0.5% (dry basis), respectively. Iron was recovered from the sludge fractions by acid leaching with H2SO4 solution, followed by the addition of ethanol to the leachate to crystallize FeSO4, from which ferric coagulants were obtained by oxidation reaction with H2O2. The performance of the coagulants was evaluated using the jar test method. The optimum condition for the production of FeSO4 from the fine fraction of the BOF sludge was established using a desirability function. This resulted in the formation of 13.1 ± 0.2 g of FeSO4‧7H2O from 7.00 g of waste, with a high yield of 91 ± 1%, using 13% (v/v) H2SO4 solution, a leaching time of 140 min, and 120 mL of ethanol. The phase composition of the FeSO4 was investigated by X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDX). The Fe2(SO4)3 produced from the coarse and fine fractions of BOF sludge achieved high turbidity removals (95 ± 1% and 94.1 ± 0.9%, respectively), demonstrating its potential as a coagulant. Performance was compared with a commercial coagulant (polyaluminum chloride), confirming competitive efficiency (97 ± 1%). In addition, bench-scale production costs of ferric coagulants were estimated, and a sensitivity analysis was conducted to assess economic feasibility.
We aimed to clarify the changes in sevoflurane blood concentrations in cardiovascular surgeries with cardiopulmonary bypass (CPB) under mild to moderate hypothermia. In this single-center, prospective observational study, we included patients undergoing elective cardiac surgery with CPB under mild and moderate hypothermia using four types of oxygenators. Radial artery blood samples were collected at repeated time points, both before and during CPB. Simultaneously, bladder temperature was recorded. Sevoflurane blood concentration was measured using gas chromatography. Sevoflurane blood concentrations gradually increased during general anesthesia induction via native lung ventilation. When using CPB under mild hypothermia, the concentration dropped sharply after switching to an oxygenator but then gradually increased and reached equilibrium. These changes were observed in all four oxygenators, with no significant differences among them. In moderate hypothermic surgeries, the bladder temperature gradually decreased during the pre-circulatory-arrest phase, and the sevoflurane blood concentration increased accordingly. As rewarming began after the distal aortic anastomosis, the bladder temperature gradually increased, and the sevoflurane blood concentration returned to levels observed during native lung ventilation. In total, 85 patients undergoing mild hypothermic cardiac surgery (SE, n = 21; LI, n = 21; TE, n = 22; ME, n = 21) and 25 patients undergoing moderate hypothermic cardiac surgery were analyzed. Using a linear mixed-effects model, bladder temperature was significantly associated with sevoflurane blood concentration in both mild hypothermia (β = - 5.90 μg/mL per °C; n = 73 patients, 1,123 observations; p < 0.001) and moderate hypothermia (β = - 2.11 μg/mL per °C; n = 25 patients, 378 observations; p < 0.001) cardiac surgery. No significant differences in sevoflurane blood concentrations were observed among the four oxygenator types. We demonstrated chronological changes in sevoflurane blood concentrations during mild and moderate hypothermic cardiac surgery, showing an inverse correlation with bladder temperature.
Multiple VA-ECMO studies have recently reported that early hyperoxia is associated with increased mortality, yet the underlying mechanism is unclear. As prior analyses did not account for native cardiac output or fraction of delivered oxygen, it remains unknown whether hyperoxia is directly injurious or primarily a surrogate of poor intrinsic cardiac function and proximal mixing. This study aims to evaluate whether hyperoxia is an independent predictor of mortality in VA-ECMO patients or whether it primarily reflects impaired native cardiac function. We conducted a single-center retrospective cohort study of 227 VA-ECMO patients to evaluate the relationship between hyperoxia and ICU mortality, accounting for native cardiac index using multivariable regression and principal component analysis. Average PaO2 and cardiac index were analyzed as continuous variables. Decreased cardiac index was the strongest independent predictor of ICU mortality in a multivariable regression (OR 0.22; 95% CI 0.06-0.70; p = 0.018). After adjusting for native cardiac index and utilization of advanced therapies (i.e., heart transplant or LVAD), the association between hyperoxia and mortality became insignificant. Average PaO2 and cardiac index were strongly inversely collinear (Variance Inflation Factor (VIF) = 7.2 and 11.5, respectively), with their interaction term yielding a VIF of 20.3. Non-survivors and survivors who received advanced therapies share similar PC1 score distributions (a weighted composite of average PaO2 and cardiac index) and impaired hemodynamic profiles, including reduced ejection fraction, pulse pressures, and oxygen delivery indices. The association between early hyperoxia and mortality in VA-ECMO is primarily driven by underlying cardiac failure rather than direct oxygen toxicity. The availability of advanced therapies further modifies this relationship, underscoring the need to account for both native cardiac output and heart replacement strategies when evaluating optimal PaO2 targets and the independent effect of hyperoxia on VA-ECMO outcomes.
Few studies have described physiological and cardiac rhythm responses to maximal voluntary breath-holding in elite freedivers. This case study presents minute ventilation, PETO2, PETCO2, involuntary breathing movements (IBMs; surface electromyography), SpO2, muscle and cerebral oxygenation (near-infrared spectroscopy), and cardiac rhythm changes (electrocardiogram) before, during, and after a maximal dry static voluntary breath-hold in a world champion freediver. Glossopharyngeal insufflation prior to the breath-hold increased forced vital capacity from 6.92L (138% predicted) to 9.04L (180% predicted). Compared to resting end-tidal gas pressures, the breathe-up in preparation of the breath-hold increased PETO2 (108mmHg to 135mmHg) and decreased PETCO2 (36mmHg to 21mmHg). The breath-hold was 06'07" in duration, of which 02'20" was spent in the easy-going phase and 03'47" in the struggle phase - the latter encompassing a total of 48 IBMs. Throughout the breath-hold, PETO2 decreased to 38mmHg and PETCO2 increased to 65mmHg. SpO2 decreased from 97% to 73%. Muscle oxygenation decreased from 50% to 22%, whereas cerebral oxygenation remained relatively stable until the final ∼20s of the breath-hold (∼68% to ∼62%). Heart rate variability-based markers of autonomic cardiac activity decreased during the easy-going phase, increased during the struggle phase, and normalized after. Asymptomatic bradycardia with competition between sinus bradycardia and junctional rhythm and (supra)ventricular extrasystoles manifested throughout the struggle phase and resolved after breath-hold cessation. This report of a world champion freediver shows that a long voluntary breath-hold induced transient asymptomatic cardiac arrhythmias, likely linked to the physiological stress of extreme voluntary breath-holding.
Ureaplasma spp. colonization/infection has been implicated in the inflammatory pathogenesis of bronchopulmonary dysplasia (BPD) in very low birth weight (VLBW) infants, but the benefit of targeted macrolide therapy remains uncertain. We evaluated respiratory outcomes associated with early Ureaplasma positivity in VLBW infants and assessed feasibility and preliminary efficacy of a standardized intravenous azithromycin regimen in a nested pilot randomized trial. This single-center study comprised (1) a retrospective cohort of inborn VLBW infants (< 1,500 g) born between July 2017 and December 2021 who underwent Ureaplasma screening within 24 h after birth, and (2) a prospective, double-blind, randomized, placebo-controlled pilot trial nested among Ureaplasma-positive infants requiring significant respiratory support. In the cohort, outcomes included moderate-to-severe and severe BPD at 36 weeks' postmenstrual age and home oxygen therapy. Multivariable logistic regression adjusted for gestational age, sex, preterm premature rupture of membranes, histologic chorioamnionitis, antenatal steroid exposure, patent ductus arteriosus treatment, and sepsis. In the trial, infants were randomized 1:1 to intravenous azithromycin for 14 days (10 mg/kg/day for 7 days, then 5 mg/kg/day for 7 days) or placebo. Microbiologic response at 2 weeks and safety, including QTc, were assessed. Among 536 VLBW infants, 34 (6.3%) were Ureaplasma positive. Ureaplasma-positive infants had higher rates of moderate-to-severe BPD (76.5% vs. 41.0%), severe BPD (67.6% vs. 36.0%), and home oxygen therapy (46.2% vs. 19.1%). After adjustment, Ureaplasma positivity remained associated with moderate-to-severe BPD (adjusted odds ratio [aOR] 3.86, 95% confidence interval [CI] 1.44-10.35) and severe BPD (aOR 2.93, CI 1.21-7.10). In the pilot trial (n = 26; 13 per group), moderate-to-severe BPD occurred in 61.5% (8/13) with azithromycin versus 84.6% (11/13) with placebo, and severe BPD in 46.2% (6/13) versus 76.9% (10/13). Loss of detectable Ureaplasma by culture at 2 weeks occurred in 13/13 azithromycin-treated infants, while 5/13 placebo infants remained positive. No QTc prolongation or clinically significant safety concerns attributable to azithromycin were observed. Early Ureaplasma positivity in VLBW infants was associated with substantially worse respiratory outcomes. A two-week intravenous azithromycin regimen was feasible, microbiologically active, and showed directionally favorable estimates for BPD without an observed safety signal. Larger microbiology-guided trials are warranted. KCT0002373 (registered 7 July 2017).
Anti-Müllerian hormone (AMH) actions during ovarian follicular development appear to be stage-dependent. AMH expression increases during preantral follicle growth, which regulates granulosa cell proliferation. Preantral follicles are located in the ovarian cortex, an avascular region with limited oxygen supply. Therefore, experiments were performed to determine the mechanism of AMH in promoting cell cycle progression and cellular energy production of granulosa cells under hypoxia in preantral follicles. Ovaries were collected from macaques. Paraffin sections were obtained for immunohistochemistry to detect carbonic anhydrase IX. Preantral follicles were isolated for culture at 5% oxygen in two groups: (a) control media and (b) recombinant human AMH supplementation. Follicle diameters were measured on days 2 and 8. Control media samples were collected on day 2 for no-grow and growing follicles and analyzed using enzyme-linked immunosorbent assay and liquid chromatography tandem mass spectrometry. Selected control follicles were stained with Image-iT Hypoxia Reagent. Follicles from the control and AMH-treatment groups were pooled for each animal on day 8. RNA was extracted for RNA sequencing and RT-PCR. Culture media samples from these follicles were pooled accordingly for liquid chromatography tandem mass spectrometry. Data were analyzed using mixed models. Carbonic anhydrase IX immunostaining was identified in granulosa cells of preantral follicles developed in vivo. Granulosa cells of cultured preantral follicles were positive for Hypoxia Reagent staining. Although diameters of no-grow and growing follicles were comparable on day 2, growing follicles secreted higher levels of AMH, guanidinoacetate, and creatine. When cultured with AMH supplementation, follicle diameters were larger than those of the control group on day 8. The mRNA levels of minichromosome maintenance proteins 2, 3, 5, and 7, but not hypoxia-inducible factor-1 A, increased in AMH-treated follicles. AMH supplementation increased follicular secretion of guanidinoacetate, creatine, and creatinine. Granulosa cells of preantral follicles experience physiological hypoxia which can be mimicked using 5% oxygen culture. AMH may inhibit hypoxia-inducible factor-1 protein action via elevating minichromosome maintenance protein expression which stimulates cell cycle progression of granulosa cells under hypoxia. Granulosa cell proliferation is also supported by creatine-mediated adenosine triphosphate production which is promoted by AMH. Not applicable.
The aim of this study was to compare cardiorespiratory responses during high-intensity land-based exercise between free-breathing and breath-holding conditions in swimmers. Twenty varsity swimmers (20 ± 2 years, 10 females) performed 20 s bouts of simultaneous arm and leg ergometry exercise at high intensity (total power output = 606 ± 76 W). Heart rate (HR), muscle deoxygenation ([HHb]) and total hemoglobin ([THb]) at the triceps and vastus lateralis, and gas exchange and ventilatory variables were recorded continuously. Blood pressure and lactate were measured pre- and post-exercise. Exercise HR was higher under the breath-holding condition (free-breathing [FB] = 118 ± 14 bpm, breath-holding [BH] = 131 ± 17 bpm; p = 0.001) as were post-exercise blood pressures (systolic: FB = 141 ± 14 mmHg, BH = 156 ± 16 mmHg, p = 0.002; diastolic: FB = 71 ± 14 mmHg, BH = 79 ± 9 mmHg; p = 0.01, respectively). During exercise, muscle [THb] was higher under the breath-holding condition (FB = -1.6 ± 2.7 μM, BH = -0.3 ± 1.6 μM; p = 0.01). No between-condition differences in post-exercise blood lactate (FB = 8.8 ± 1.8 mmol.L-1, BH = 9.2 ± 3.9 mmol.L-1; p = 0.63) or [HHb] (FB = 2.9 ± 2.6 μM, BH = 3.4 ± 2.2 μM; p = 0.39) were observed. These data suggest that the exercise response prevailed over the breath-holding response during high-intensity land-based exercise in swimmers and that intrinsic oxygen stores may have been sufficient to sustain the aerobic energy contribution during 20 s high-intensity exercise while breath holding.
The association of erythrocytosis, splenomegaly, and iron overload represents a complex diagnostic situation that may reveal hereditary stomatocytosis related to a PIEZO1 mutation. We report the case of a 76-year-old patient presenting with erythrocytosis, iron overload, and splenomegaly. The initial etiological workup was unremarkable. The identification of chronic hemolysis, associated with a decreased oxygen partial pressure at which 50% of haemoglobin is saturated with oxygen (venous P50) and abnormalities in erythrocyte deformability, guided further molecular investigations. Next-generation sequencing (NGS) identified a heterozygous pathogenic PIEZO1 mutation, confirming the diagnosis of stomatocytosis. This case highlights a misleading presentation of chronic hemolysis masked by polycythemia. Venous P50 appears to be a key discriminating marker. An integrated approach combining biological and molecular analyses is essential to avoid diagnostic delay.
To assess in neonates with hypoxic-ischemic encephalopathy (HIE) whether multimodal neuromonitoring, using near-infrared spectroscopy and amplitude-integrated electroencephalography (aEEG), correlates with cerebral injury observed on brain magnetic resonance imaging (MRI) as well as neurodevelopmental outcome. Neonates born at >35 weeks and >1800 gram undergoing therapeutic hypothermia were included in this prospective-retrospective, multicenter study. The aEEG pattern, cerebral tissue oxygenation (rScO2), burden of rScO2≥95%, arterial blood pressure, heart rate, and cerebrovascular autoregulation were monitored during therapeutic hypothermia and rewarming from 0-24, 24-48, 48-72, and 72-96 hours. Early cerebral MRI was assessed using a validated quali-quantitative score. Neurodevelopmental outcome was assessed using Bayley Scales of Infant Development (BSID-III) cognitive and motor scores at 24 months. In 128 neonates with a median Thompson score of 9, greater seizure burden (beta coefficient, B24-48h=3.21, 95% confidence interval limits, 95%CI [2.01, 4.41]), absent sleep-wake-cycling (B24-48h=-5.53, 95%CI [-8.29, -2.77]), and a higher burden of rScO2≥95% (B0-24h=0.34, 95%CI [0.07, 0.61]) were associated with worse cerebral injury on MRI. Cognitive and motor scores inversely correlated with aEEG abnormalities, rScO2, burden of rScO2≥95%, and absent sleep-wake-cycling, whereas higher arterial blood pressures between 0-24 hours were associated with higher neurodevelopmental outcome scores. Combined abnormal aEEG characteristics and rScO2, but not cerebrovascular autoregulation assessed as cerebral oximetry index or tissue oxygenation heart rate-reactivity index, correlated significantly with brain injury on MRI and neurodevelopmental outcome after HIE. These findings provide valuable clinical information and, in future studies, may support identification of infants who might benefit from adjuvant therapies.
Standard semen analysis has little prognostic value in distinguishing fertile from infertile men. Furthermore, in men with semen parameters within the reference ranges, it cannot distinguish fertile men from infertile men, i.e. partners of couples with idiopathic infertility. Oxidative stress, mitochondrial dysfunction, sperm telomere shortening, and DNA fragmentation have been proposed as contributors to impaired male fertility. However, these biomarkers have not been evaluated as a whole in subjects with normal semen parameters, partners of fertile and infertile couples. To characterise a multidimensional panel of sperm biomarkers-including sperm telomere length (STL), mitochondrial DNA copy number (mtDNAcn), reactive oxygen species (ROS), lipid peroxidation (LP), sperm chromatin dispersion (SCD), and respiratory control ratio (RCR)-and to identify whether these parameters might discriminate, in men with normal semen parameters, infertile men from fertile controls. A total of 150 men with semen parameters within the normal ranges were enrolled: 47 male partners of couples with idiopathic infertility and 103 fertile controls. STL and mtDNAcn were quantified by qPCR; ROS were assessed using OxiSperm®II with semiquantitative imaging; LP was measured spectrophotometrically in seminal plasma; SCD was used to determine DNA fragmentation; and mitochondrial function was evaluated by oxygen consumption and RCR. Correlations between biomarkers and semen parameters were analysed using Pearson or Spearman coefficients, and intergroup comparisons were adjusted for age. Semen parameters did not differ significantly between male partners of fertile and infertile couples. compared to men of fertile couples, men of infertile couples exhibited significantly shorter STL (0.57 ± 0.59 vs 1.21 ± 1.13, p_adj = 0.001) and higher oxidative stress, with both ROS (8300.9 ± 4214.8 vs 6555.3 ± 3394.3, p_adj = 0.027) and LP (88.33 ± 55.50 vs 40.29 ± 46.98, p_adj < 0.001) markedly elevated. mtDNAcn, SCD, and RCR showed no difference between the groups. Across the entire cohort, STL correlated negatively with ROS and LP and positively with RCR. ROS correlated negatively with total sperm count, motility and RCR, and positively with LP. LP displayed the strongest pattern of associations, correlating negatively with concentration, total count, motility, STL and RCR, and positively with age and volume. Among men with normal semen analysis, partners of couples with idiopathic infertility exhibit a distinct sperm molecular profile characterised by telomere shortening and oxidative imbalance. STL, ROS and LP emerged as age-independent biomarkers associated with infertility status and showed promising discriminatory ability in this cohort, supporting their integration as second-level tests to complement routine semen analysis in cases of normozoospermia.
Tumor necrosis factor-α-stimulated gene-6(TSG-6), a secreted protein with anti-inflammatory and tissue-protective properties, mediates a cascade of proinflammatory cytokines and ameliorates tissue fibrosis. Previous studies have found that TSG-6 can attenuate the degree of fibrosis, inhibit the inflammatory response, and reduce adipogenesis in orbital tissues in a Thyroid Eye Disease (TED) mouse model of thyroid-eye disease; however, the exact mechanism has not been elucidated. In the present study, we investigated the mechanism by which TSG-6 exerts its anti-inflammatory and antifibrotic effects in an in vitro cellular model of TED. Human orbital connective tissue was collected from primary and passaged cultures and 3-5 passages-cells were used in subsequent experiments. The expression of relevant inflammatory markers, including tumor necrosis factor-α(TNF-α), Interleukin-6(IL-6), monocyte chemoattractant protein-1(MCP-1), Cyclooxygenase-2(COX-2), and intercellular cell adhesion molecule-1(ICAM-1), was detected by western blotting with 5, 10, and 15 ng/ml TSG-6 pretreatment in the presence or absence of 10 ng/ml Interleukin-1beta (IL-1β) and H2DCFDA (DCFH-DA) fluorescent staining, and flow cytometry was used to detect reactive oxygen species(ROS) indices. Orbital fibroblasts (OF) were treated with TSG-6 in the presence or absence of transforming growth factor-beta 1(TGF-β1) agonist (SRI-011381:MCE, HY-100347) and the expression of TGF-β1/Smad pathway-associated fibrosis factors, including α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and collagen type 1 (COL1A1). TSG-6 inhibited IL-1β-induced production of the inflammatory mediators TNF-α, IL-6, MCP-1, COX-2, and ICAM-1, and the release of ROS in a dose-dependent manner in an in vitro cell model of TED. TSG-6 downregulated the expression of TGF-β1, Smad2/3, p-smad2/3, α-SMA, CTGF, and COL1A1 in a dose-dependent manner after TGF-β1 pretreatment and reduced the phosphorylation of Smad2/3, suggesting that TSG-6 inhibits the TGF-β1 signaling cascade response in orbital fibroblasts. TSG-6 inhibited the production of inflammatory mediators and the release of ROS, and suppressed fibrosis of human orbital fibroblasts by downregulating the TGF-β1/Smad pathway. These data suggest a potential application of TSG-6 in the treatment of TED and provide a novel target for the treatment of TED.
Pediatric lung transplantation remains a life-saving option for selected children and adolescents with end-stage lung disease. We aimed to describe clinical characteristics, survival, post-transplant morbidity, and exploratory factors associated with mortality in a single-center Saudi cohort. We retrospectively reviewed all pediatric patients who underwent lung transplantation between January 2010 and December 2023. Demographic, anthropometric, perioperative, and post-transplant data were extracted. Survival was assessed with Kaplan-Meier analysis, and Cox regression was used to explore associations with mortality. Twenty-eight recipients underwent transplantation, predominantly bilateral sequential procedures, at a median age of 16 years. All recipients were adolescents, and cystic fibrosis (CF) was the most common indication. Severe undernutrition was common, with 64.3% meeting failure-to-thrive criteria (< 1st centile for weight) and 71.4% below the 3rd centile. Intraoperative extracorporeal membrane oxygenation replaced cardiopulmonary bypass after 2016. One-year survival was 96.4%, and median post-transplant survival was 6.8 years. Survival did not differ significantly by intraoperative extracorporeal support, but median survival was shorter in CF than in non-CF recipients (2.9 vs. 8.9 years). Hypertension developed in 53.5% of patients, diabetes in 28.5%, and acute kidney injury in 46.4%. In age- and sex-adjusted Cox models, CF, longer waiting time, Pseudomonas aeruginosa colonization, and diabetes at 1 year were associated with mortality. Pediatric lung transplantation in this cohort achieved excellent short-term survival but substantial long-term morbidity. Mortality associations should be interpreted cautiously, given the small sample size and event count. The shorter survival observed in CF recipients warrants further study, particularly in the context of severe undernutrition and chronic airway colonization.
GATOR1 is an evolutionarily-conserved negative regulator of mTORC1-dependent signal transduction with pathogenic mutations linked to epilepsy, infantile spasms, and autism spectrum disorders. While a biochemical role of GATOR1 in amino acid-signaling is established, its cell-type specific contributions within the brain remain poorly defined. Here, we show that loss of GATOR1 function in astrocytic cells disrupts mitochondrial metabolism, with a selective dysfunction of the electron transport chain Complex II leading to elevated reactive oxygen species (ROS) and redox imbalance. These changes are accompanied by compensatory increases in antioxidant regulatory systems including superoxide dismutase, but remain insufficient to ameliorate the increased ROS. GATOR1-deficient astrocytes show metabolic rewiring marked by enhanced expression of glutamate uptake and glutamine synthesis pathways that contribute to the glutamate-glutamine cycle governing neuronal glutamine availability and synaptic homeostasis. In vivo, GATOR1 deficiency results in progressive astrocytic reactivity, seizures, and a reduced lifespan. These findings demonstrate that GATOR1 function is critical to coordinate astrocytic mitochondrial activity and neurotransmitter cycling pathways, establishing a novel link between intracellular amino acid-signaling in astrocytes and excitatory neural network homeostasis.
This study investigates the endocrine-disrupting effects of the fungicide carbendazim (CBZ) on human and murine reproductive health. Mass spectrometry confirmed systemic human exposure, detecting CBZ in the plasma and follicular fluid of 15-18% of the women sampled. In vitro, CBZ did not affect viability in human KGN and primary granulosa cells (hGCs) but significantly inhibited KGN proliferation. Furthermore, CBZ reduced steroidogenesis stimulated by FSH, LH, or IGF-1 in both cell types. This dysfunction correlated with a dose-dependent increase in the Oxidative Stress Index, driven by elevated total oxidant status and reactive oxygen species. Corroborating these findings, in vivo murine models exposed to CBZ (100 μg/kg/day) exhibited a prolonged diestrus phase, alongside reduced numbers of corpora lutea and preovulatory follicles, and decreased gonadotropin and E2  plasma levels. Collectively, these results identify CBZ as a potent reproductive toxicant that impairs ovarian function via oxidative stress-mediated hormonal disruption.
Current understanding of how multiple stressors shape freshwater biodiversity at continental scales relies heavily on evidence from postindustrial temperate regions, potentially misrepresenting the dynamics of ecosystems facing rapid development and extreme environmental heterogeneity. Here, we present a standardized, continental-scale field survey of benthic macroinvertebrates across 502 sites in China to test the universality of established macroecological patterns. Contrary to the expectation that physical habitat and climatic gradients primarily drive community structure, we found that organic pollution, with a focus on oxygen-demand assays (COD and BOD), emerged as the single most influential variable, explaining the largest proportion of variation in taxonomic, functional, and phylogenetic diversity. Together with total nitrogen and total phosphorus loading, this chemical pressure largely overrode the explanatory contribution of land-use and climatic drivers, with stressor interactions characterized by asymmetric dominance rather than the synergistic amplification commonly predicted. Furthermore, despite steep environmental gradients that theoretically favor deterministic sorting, community assembly was overwhelmingly dominated by stochastic processes ( ∼ $$ \sim $$ 86%, based on overall pairwise comparisons across all sites). We suggest this pattern is consistent with a "stochastic trap" hypothesis, potentially arising from high-frequency anthropogenic disturbances that weaken trait-environment matching. These findings indicate that biodiversity frameworks derived from stabilized, temperate systems may not generalize to the compressed modernity of developing regions. We propose that global conservation strategies should consider prioritizing the reduction of chemical bottlenecks, which may act as critical physiological constraints on freshwater resilience in the Anthropocene.