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Abstract Ovarian granulosa cells are essential to gonadotrophin-regulated estrogen production, female cycle maintenance and fertility. The epithelial Na+ channel (ENaC) is associated with female fertility; however, whether and how it plays a role in ovarian cell function(s) remained unexplored. Here, we report patch-clamp and Na+ imaging detection of ENaC expression and channel activity in both human and mouse ovarian granulosa cells, which are promoted by pituitary gonadotrophins, follicle stimulating hormone (FSH) or luteinizing hormone (LH). Cre-recombinase- and CRISPR-Cas9-based granulosa-specific knockout of ENaC α subunit (Scnn1a) in mice resulted in failed estrogen elevation at early estrus, reduced number of corpus luteum, abnormally extended estrus phase, reduced litter size and subfertility in adult female mice. Further analysis using technologies including RNA sequencing and Ca2+ imaging revealed that pharmacological inhibition, shRNA-based knockdown or the knockout of ENaC diminished spontaneous or stimulated Ca2+ oscillations, lowered the capacity of intracellular Ca2+ stores and impaired FSH/LH-stimulated transcriptome changes for estrogen production in mouse and/or human granulosa cells. Together, these results have revealed a previously undefined role of ENaC in modulating gonadotrophin signaling in granulosa cells for estrogen homeostasis and thus female fertility.

Magnesium metal and its alloys are being developed as effective orthopedic implants; however, the mechanisms underlying the actions of magnesium on bones remain unclear. Cystic fibrosis, the most common genetic disease in Caucasians caused by the mutation of CFTR, has shown bone disorder as a key clinical manifestation, which currently lacks effective therapeutic options. Here we report that implantation of magnesium-containing implant stimulates bone formation and improves bone fracture healing in CFTR-mutant mice. Wnt/β-catenin signaling in the bone is enhanced by the magnesium implant, and inhibition of Wnt/β-catenin by iCRT14 blocks the magnesium implant to improve fracture healing in CFTR-mutant mice. We further demonstrate that magnesium ion enters osteocytes, increases intracellular cAMP level and activates ATF4, a key transcription factor known to regulate Wnt/β-catenin signaling. In vivo knockdown of ATF4 abolishes the magnesium implant-activated β-catenin in bones and reverses the improved-fracture healing in CFTR-mutant mice. In addition, oral supplementation of magnesium activates ATF4 and β-catenin as well as enhances bone volume and density in CFTR-mutant mice. Together, these results show that magnesium implantation or supplementation may serve as a potential anabolic therapy for cystic fibrosis-related bone disease. Activation of ATF4-dependent Wnt/β-catenin signaling in osteocytes is identified as a previously undefined mechanism underlying the beneficial effect of magnesium on bone formation.

Visceral adipose tissue secretes cytokines to regulate the homeostasis of organs. Here, the authors show that epididymal white adipose tissue-secreted osteopontin induces lipophagocytic mobilization of macrophages and promotes bone matrix degradation via activating osteoclasts.

Objective: The beneficial effect of angiotensin(1–7) (Ang(1–7)), via the ac tivation of its receptor, MAS-1, has been noted in diabetes treatment; however, how Ang(1–7) or MAS-1 affects insulin secretion remains elusive and whether the endoge nous level of Ang(1–7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of cystic fibrosis transmembrane conductance regu lator (CFTR), a cAMP-activated Cl− channel, in the regulation of insulin secretion. Here, we tested the possible involvement of CFTR in mediating Ang(1–7)’s effect on insulin se cretion and measured the level of Ang(1–7), MAS-1 as well as CFTR in the blood of in dividuals with or without type 2 diabetes. Methods: Ang(1–7)/MAS-1/CFTR pathway was determined by specific inhibito rs, gene manipulation, Western blotting as well as insulin ELISA in a pancreatic β-cell line, RINm5F. Human blood samples were collected from 333 individuals with (n = 197) and without (n = 136) type 2 diabetes. Ang(1–7), MAS-1 and CFTR levels in the human blood were determined by ELISA. Results: In RINm5F cells, Ang(1–7) induced intracellular cAMP increase, cAMP-response element binding protein (CREB) activation, enhanced CFTR expres sion and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not Ang(1–7), were significantly higher in i ndividuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in ty pe-2 diabetic but not non-diabetic subjects. Conclusion: These results suggested that MAS-1 and CFTR as key players in mediating Ang(1–7)-promoted insulin secretion in pancreatic β-cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.

Introduction: We previously demonstrated that magnesium ions (Mg2+) was a novel therapeutic alternative for osteoarthritis (OA) through promoting the hypoxia inducible factor-1α (HIF-1α)-mediated cartilage matrix synthesis. However, oxidative stress can inhibit the expression of HIF-1α, amplify the inflammation that potentially impairs the therapeutic efficacy of Mg2+ in OA. Vitamin (VC), a potent antioxidant, may enhance the efficacy of Mg2+ in OA treatment. This study aims to investigate the efficacy of combination of Mg2+ and VC on alleviating joint destruction and pain in OA. Material and methods: Anterior cruciate ligament transection with partial medial meniscectomy induced mice OA model were randomly received intra-articular injection of either saline, MgCl2 (0.5 mol/L), VC (3 mg/ml) or MgCl2 (0.5 mol/L) plus VC (3 mg/ml) at week 2 post-operation, twice weekly, for 2 weeks. Joint pain and pathological changes were assessed by gait analysis, histology, western blotting and micro-CT. Results: Mg2+ and VC showed additive effects to significantly alleviate the joint destruction and pain. The efficacy of this combined therapy could sustain for 3 months after the last injection. We demonstrated that VC enhanced the promotive effect of Mg2+ on HIF-1α expression in cartilage. Additionally, combination of Mg2+ and VC markedly promoted the M2 polarization of macrophages in synovium. Furthermore, combination of Mg2+ and VC inhibited osteophyte formation and expressions of pain-related neuropeptides. Conclusions: Intra-articular administration of Mg2+ and VC additively alleviates joint destruction and pain in OA. Our current formulation may be a cost-effective alternative treatment for OA.

Background: To evaluate the effect of recombinant human thrombopoietin (rhTPO) on clinical prognosis by exploring changes in endothelial cell injury markers and inflammatory factors in patients with sepsis after treatment with rhTPO. Methods: This retrospective observational study involved patients with sepsis (diagnosed according to Sepsis 3.0) admitted to Shanghai General Hospital intensive care unit from January 1, 2019 to December 31, 2022. Patients were divided into two groups (control and rhTPO) according to whether they received rhTPO. Baseline information, clinical data, prognosis, and survival status of the patients, as well as inflammatory factors and immune function indicators were collected. The main monitoring indicators were endothelial cell-specific molecule (ESM-1), human heparin-binding protein (HBP), and CD31; secondary monitoring indicators were interleukin (IL)-6, tumor necrosis factor (TNF)-α, extravascular lung water index, platelet, antithrombin III, fibrinogen, and international normalized ratio. We used intraperitoneal injection of lipopolysaccharide (LPS) to establish a mouse model of sepsis. Mice were randomly divided into four groups: normal saline, LPS, LPS + rhTPO, and LPS + rhTPO + LY294002. Plasma indicators in mice were measured by enzyme-linked immunosorbent assay. Results: A total of 84 patients were included in the study. After 7 days of treatment, ESM-1 decreased more significantly in the rhTPO group than in the control group compared with day 1 (median=38.6 [interquartile range, IQR: 7.2 to 67.8] pg/mL vs. median=23.0 [IQR: −15.7 to 51.5] pg/mL, P=0.008). HBP and CD31 also decreased significantly in the rhTPO group compared with the control group (median=59.6 [IQR: −1.9 to 91.9] pg/mL vs. median=2.4 [IQR: −23.2 to 43.2] pg/mL; median=2.4 [IQR: 0.4 to 3.5] pg/mL vs. median=−0.6 [IQR: −2.2 to 0.8] pg/mL, P

Background: Sepsis-induced myocardial injury (SIMI) is a prevalent form of organ dysfunction with a significant impact on the mortality rate among sepsis patients. This study aims to develop a predictive model for SIMI using plasma CD36 levels. Methods: A prospective study was conducted from January 1, 2023, to December 1, 2023, involving sepsis patients admitted to the Department of Intensive Care Medicine at Shanghai General Hospital. Plasma CD36 levels were measured within 48 h of ICU admission, prior to the diagnosis of sepsis-associated myocardial injury. Myocardial damage was assessed using troponin levels. Results: Two significant risk factors for SIMI were identified: age and elevated CD36 levels. CD36, THBS1, and BNP were determined to be independent mortality risk factors. The myocardial injury group exhibited higher plasma CD36 levels compared to the non-injury group. Additionally, the deceased group had higher plasma CD36 levels than the survivors. No significant differences in CD36 levels were observed between groups with lung and stomach infections or between Gram-positive and Gram-negative infection groups. Similarly, there was no statistically significant difference in CD36 levels between surgical and medical patients. A predictive model for SIMI was formulated as follows: ln [P/(1-P)] = -0.000818age + 0.4975756CD36 − 5.400293. The model’s quality of fit was tested with a P-value of 0.4682, indicating a good degree of discrimination and calibration, as evidenced by the area under the ROC curve (0.7724). Conclusion: The prognosis of individuals with sepsis is closely associated with elevated CD36 levels. Elevated CD36 is identified as an independent risk factor for both SIMI and mortality in sepsis patients. The predictive model suggests that high CD36 levels are indicative of SIMI and are associated with a poor prognosis.

Abstract Background To describe the clinical features, visual outcomes, management, and complications of ocular injury in badminton and investigate risk factors associated with visual impairment. Methods Data on patients injured while playing badminton admitted to Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital, Fudan University between January 2018 to December 2020.The relationship between visual acuity (VA) and demographic and clinical variables was also analyzed. Patients were managed medically or surgically as per their needs, followed up for at least 18 months. The visual outcomes were predicted using ocular trauma score (OTS), predicted outcomes were compared with actual outcomes using statistical tests. Results This study involved 102 patients (78 men, 24 women) with a mean age of 43.8 ± 16.1 years (7–71 years). Of these, 93 patients had closed-globe injuries and 9 had open-globe injuries. Vision-threatening findings included lens subluxation(31.4%),retinal detachment(13.7%),hyphema(12.7%). Open-globe injury had significantly lower presenting VA and final VA (P= 0.0164, 0.0053).Final VA was found to be correlated with presenting VA, maculopathy, retinal detachment, and OTS (P=0.0000, 0.0494, 0.0001, 0.0000 respectively), it was worse in patients who were under 20 years of age and were female. OTS prediction was not significantly different when compared with actual visual outcomes postoperatively in OTS3, OTS4, and OTS5 (P > 0.05),while the prognosis of patients with OTS1 and OTS2 was better than OTS study (P=0.001, 0.007, respectively). Conclusion Badminton-related closed-globe injuries were more frequent; open-globe injuries were usually more serious. Younger and female patients have poorer visual recovery prognoses. OTS was found to be a reliable tool for predicting visual outcomes.

The herbicide paraquat is an agonist of Stromal Interaction Molecule 1 (STIM1), leading to extracellular calcium entry observed in epithelial-mesenchymal transition in alveolar cells during pulmonary fibrosis.

Background: Sepsis is typically associated with poor outcomes. There are various risk factors and predictive models for sepsis based on clinical indicators. However, these models are usually predictive of all critical patients. This study explored the risk factors for 28-day outcomes of patients with sepsis and developed a prognosis prediction model. Methods: This was a multicenter retrospective analysis of sepsis patients hospitalized in three intensive care units (ICUs) from September 1st 2015, to June 30th 2020. Demographic, clinical history, and laboratory test data were extracted from patient records. Investigators explored the risk factors affecting 28-day sepsis prognosis by univariate analysis. The effects of confounding factors were excluded by multivariate logistic regression analysis, and new joint predictive factors were calculated. A model predicting 28-day sepsis prognosis was constructed through data processing analysis. Results: A total of 545 patients with sepsis were included. The 28-day mortality rate was 32.3%. Risk factors including age, D-dimer, albumin, creatinine, and prothrombin time (PT) were predictive of death from sepsis. The goodness-of-fit value for this prediction model was 0.534, and the area under the receiver operating characteristic curve was 0.7207. Further analysis of the immune subgroups (n=140) revealed a significant decrease in CD3+, CD4+CD8-, and CD4+CD29+ memory effector T lymphocytes and an increase in CD56+ natural killer (NK) cells in the hypoalbuminemia group compared with the normal albumin group (65.5 vs. 58.3, P=0.005; 41.2 vs. 32.4, P=0.005; 21.8 vs. 17.1, P=0.029; 12.6 vs. 17.6, P=0.004). Conclusions: Risk factors for 28-day sepsis mortality include age, D-dimer, creatinine, PT, and albumin. A decrease in albumin level may exacerbate immunosuppression in patients with sepsis. This study establishes a prediction model based on these indicators, which shows a good degree of calibration and differentiation. This model may provide good predictive value for clinical sepsis prognosis.

In this paper, 8 loading strain rates were configured to carry out experimental research on the compressive dynamic behaviors of plain concrete (PC) and lightweight aggregate concrete (LWAC) by utilizing a hydraulic servo machine. The compressive failure modes and stress-strain curves of PC and LWAC under various loading states were generated from the experiments. The peak stress and peak strain values extracted from the stress-strain curves, as well as the elastic modulus, were comparatively analyzed between the two types of concrete. The experimental findings indicate that the failure mode of PC under the static strain rate mainly manifest as the damage to bonding materials, while the failure under dynamic strain rates involves part of coarse aggregates. For LWAC, the failure modes under both static and dynamic loading mainly manifest as the damage to shale ceramisite. As the strain rate increases, the peak stress and elastic modulus of both PC and LWAC increase significantly. Compared with PC, the strain rate effect on LWAC is more obvious. The peak strain of both PC and LWAC varies insignificantly across different strain rates, even though the changing trend shows a discrete pattern. In addition, on the basis of the experimental results, the relationship equations between the strain rate and the related mechanical parameters were established for both PC and LWAC. It is found that the values of peak stress and elastic modulus and the logarithmic value of the corresponding strain rate after non-dimensional treatment fit a linear relationship. The findings provide theoretical insights into the research and engineering application of LWAC.

Abstract Background Sepsis is still a common critical disease with high morbidity and mortality in intensive care unit. Despite published guidelines for sepsis, development of antibiotic therapy and advanced organ support technologies, the mortality of sepsis patients is still 25% or more. It is necessary to distinguish the subtypes of sepsis, and the targeted therapy for the patients need to be explored. Platelets have various biological functions in hemostasis and thrombosis, host defense, inflammatory/immune responses and tissue repair/regeneration. Moreover, severe thrombocytopenia or sustained thrombocytopenia was closely associated with multiply organ dysfunction and higher mortality in sepsis patients. The clinical therapies for thrombocytopenia are platelet transfusion and platelet-elevating drugs. However, platelet transfusion has many defects in clinical practice in sepsis patients, and the impact of platelet-elevating drugs for sepsis patients is still unclear. RESCUE trial is aim to explore the effect of a platelet-elevating drug, recombinant human thrombopoietin (rhTPO), as an effective rescue therapy on sepsis patients with acute severe thrombocytopenia. Methods It is a randomized, open-label, multi-center, controlled trial in 5 tertiary academic hospitals including medical, surgical or general ICUs. In this study, a total of 200 sepsis patients with severe thrombocytopenia will be randomly assigned in a 1:1 ratio to the control and rhTPO group. The patients will be followed up to 28 days after randomization. All patients in two groups receive the same treatment based on the guideline of Surviving Sepsis Campaign. Primary outcome is 28-day mortality. Secondary outcomes are the changes of PCs, blood transfusion, biomarkers of infection and organ function, days free from advanced organ support, drug-related adverse events, the length of ICU and hospital stay. Discussion RESCUE trial is the first randomized controlled trial to explore the impact of rhTPO for severe thrombocytopenia in sepsis patients diagnosed by sepsis-3.0 standard. Furthermore, RESCUE trial results will be of significant clinical value on the targeted therapy and add clinical evidence that rhTPO is an effective rescue therapy for these sepsis patients. Trial registration ClinicalTrials.gov: NCT02707497. Registered Date: March 3rd, 2016. Protocol Version 3. Protocol Date: January 25th, 2019.

An experimental study was conducted using a hydraulic servo machine to examine the compressive dynamic performance of rubber concrete under freeze-thaw cycles by considering 4 different numbers of freeze-thaw cycles and 8 different strain rates. The compressive stress-strain curves of rubber concrete under different loading conditions were obtained. By comparatively analyzing the mechanical characteristic parameters of the compressive stress-strain curves (i.e., peak stress, elastic modulus, and peak strain), the following conclusions were drawn: at the same loading strain rate, the compressive peak stress of rubber concrete is gradually decreased while the mass loss rate is gradually increased, as the number of freeze-thaw cycles increases. Compared to ordinary concrete, rubber concrete has a better frost resistance property. At the same number of freeze-thaw cycles, the compressive peak stress and elastic modulus of rubber concrete are gradually increased as the loading strain rate increases. The increase in the number of freeze-thaw cycles enlarges the increasing amplitude of the peak stress and elastic modulus under the action of loading strain rate. The compressive peak stress and elastic modulus dynamic increase factors of rubber concrete exhibit a linear relationship with the dimensionless logarithm of the loading strain rate. Meanwhile, a calculation model was proposed for the compressive peak stress dynamic increase factor of rubber concrete under the coupling effect of freeze-thaw cycles and loading strain rate, and the corresponding stress mechanism was discussed in detail. The research findings are of great significance to the application and development of antifreeze concrete in engineering practice.

As tea is an important economic crop in many regions, efficient and accurate methods for remotely identifying tea plantations are essential for the implementation of sustainable tea practices and for periodic monitoring. In this study, we developed and tested a method for tea plantation identification based on multi-temporal Sentinel-2 images and a multi-feature Random Forest (RF) algorithm. We used phenological patterns of tea cultivation in China’s Shihe District (such as the multiple annual growing, harvest, and pruning stages) to extracted multi-temporal Sentinel-2 MSI bands, their derived first spectral derivative, NDVI and textures, and topographic features. We then assessed feature importance using RF analysis; the optimal combination of features was used as the input variable for RF classification to extract tea plantations in the study area. A comparison of our results with those achieved using the Support Vector Machine method and statistical data from local government departments showed that our method had a higher producer’s accuracy (96.57%) and user’s accuracy (96.02%). These results demonstrate that: (1) multi-temporal and multi-feature classification can improve the accuracy of tea plantation recognition, (2) RF classification feature importance analysis can effectively reduce feature dimensions and improve classification efficiency, and (3) the combination of multi-temporal Sentinel-2 images and the RF algorithm improves our ability to identify and monitor tea plantations.