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Abstract Background Isthmin-1 (ISM1) plays an important role in maintaining glucose homeostasis and lipid metabolism. However, the relationship between circulating ISM1 and hypertension remains unclear. This study was aimed to investigate the association between serum ISM1 levels and blood pressure and evaluate value of circulating ISM1 for predicting abnormal Na+ excretion and insulin resistance. Methods Four hundred sixty-eight individuals newly diagnosed with primary hypertension and 582 healthy individuals were initially screened. 84 participants were eligible for this case–control study. Serum ISM1 levels were assessed using ELISA. Spearman correlation analysis and partial correlation analysis were conducted to confirm the correlation. Multiple linear regression analysis was used to assess the independent association of serum ISM1 concentration with blood pressure. The receiver operating characteristic (ROC) curve was employed to evaluate the sensitivity of ISM1 in predicting abnormal Na+ excretion and insulin resistance in hypertensive subjects. Results The serum ISM1 levels of hypertensive individuals were higher than that of healthy individuals. ISM1 levels were positively associated with systolic blood pressure (SBP), diastolic blood pressure (DBP) and brachial-ankle pulse wave velocity, but negatively associated with nocturnal urine Na+ concentration and excretion. These associations remained significant even after adjusting for age, body mass index, sex, heart rate, glucose, total cholesterol and estimated glomerular filtration rate. Multiple linear regression analysis revealed that SBP was an independent factor associated with serum ISM1 levels. The area under receiver operating characteristic curve (AUROC) for predicting low urine Na+ excretion and insulin resistance were 0.873 and 0.740, respectively. Conclusions Serum ISM1 levels were positively associated with SBP and DBP. ISM1 may serve as a potential biomarker of abnormal urine Na+ excretion and insulin resistance in primary hypertensive individuals. Trial registration Registered on chictr.org.cn 18/04/2024 (Registration number: ChiCTR2400083204).

Extracellular vesicles from skin-derived precursor Schwann cells (SKP-SC-EVs) promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats. This study aimed at expanding the application of SKP-SC-EVs in nerve grafting by creating a chitosan/PLGA-based, SKP-SC-EVs-containing tissue engineered nerve graft (TENG) to bridge a 40-mm long sciatic nerve defect in dogs. SKP-SC-EVs contained in TENGs significantly accelerated the recovery of hind limb motor and electrophysiological functions, supported the outgrowth and myelination of regenerated axons, and alleviated the denervation-induced atrophy of target muscles in dogs. To clarify the underlying molecular mechanism, we observed that SKP-SC-EVs were rich in a variety of miRNAs linked to the axon growth of neurons, and miR-30b-5p was the most important among others. We further noted that miR-30b-5p contained within SKP-SC-EVs exerted nerve regeneration-promoting effects by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK, STAT3 or CREB. Our findings suggested that SKP-SC-EVs-incorporating TENGs represent a novel type of bioactive material with potential application for peripheral nerve repair in the clinic.

Abstract Background Placenta previa accreta (PPA) is a severe obstetric condition that can cause massive postpartum hemorrhage and transfusion. Cesarean hysterectomy is necessary in some severe cases of PPA to stop the life-threatening bleeding, but cesarean hysterectomy can be associated with significant surgical blood loss and major complications. The current study is conducted to investigate the potential risk factors of excessive blood loss during cesarean hysterectomy in women with PPA. Methods This is a retrospective study including singleton pregnancies after 28 weeks of gestation in women with placenta previa and pathologically confirmed placenta accreta spectrum who received hysterectomy during cesarean sections. A total of 199 women from January 2012 to August 2023 were included in this study and were divided into Group 1 (estimated surgical blood loss (EBL) ≤ 3500 mL, n = 103) and Group 2 (EBL > 3500 mL, n = 96). The primary outcome was defined as an EBL over 3500 mL. Baseline characteristics and surgical outcomes were compared between the two groups. A multivariate logistic regression model was applied to find potential risk factors of the primary outcome. Results Massive surgical blood loss was prevalent in our study group, with a median EBL of 3500 mL. The multivariate logistic analysis showed that emergency surgery (OR 2.18, 95% CI 1.08–4.41, p = 0.029), cervical invasion of the placenta (OR 2.70, 95% CI 1.43–5.10, p = 0.002), and intraoperative bladder injury (OR 5.18, 95% CI 2.02–13.28, p = 0.001) were all associated with the primary outcome. Bilateral internal iliac arteries balloon occlusion (OR 0.57, 95% CI 0.34–0.97) and abdominal aortic balloon occlusion (OR 0.33, 95% CI 0.19–0.56) were negatively associated with the primary outcome. Conclusions Emergency surgery, cervical invasion of the placenta, and intraoperative bladder injury were potential risk factors for additional EBL during cesarean hysterectomy in women with PPA. Future prospective studies are needed to confirm the effect of intra-arterial balloon occlusion in cesarean hysterectomy of PPA.

The cGAS-STING pathway is essential in innate immunity, especially in antiviral responses and cellular stress management. cGAS acts as a cytoplasmic DNA sensor by initiating the synthesis of the second messenger cyclic GMP-AMP synthase (cGAMP), which subsequently activates the STING pathway, leading to the production of type I interferons and other cytokines, as well as the activation of inflammatory mediators. Recent studies have demonstrated that ubiquitination changes closely regulate the function of the cGAS-STING pathway. Ubiquitination modifications influence the stability and activity of cGAS and STING, while also influencing the accuracy of the immune response by adjusting their degradation and signal intensity. E3 ubiquitin ligase specifically facilitates the degradation or modulates the signaling of cGAS-STING-associated proteins via ubiquitination alterations. Furthermore, the ubiquitination of the cGAS-STING pathway serves distinct functions in various cell types and engages with NF-κB, IRF3/7, autophagy, and endoplasmic reticulum stress. This ubiquitin-mediated regulation is crucial for sustaining the balance of innate immunity, while excessive or inadequate ubiquitination can result in autoimmune disorders, cancers, and viral infections. An extensive examination of the ubiquitination process within the cGAS-STING pathway elucidates its specific regulatory mechanisms in innate immunity and identifies novel targets for the intervention of associated diseases.

IntroductionBrodifacoum is a highly potent superwarfarin rodenticide that leads to coagulopathy. Although the effect of warfarin during pregnancy is well understood, reports on superwarfarin poisoning, like brodifacoum, during pregnancy are scarce.Case PresentationWe report a case involving a woman with a singleton pregnancy who experienced sudden nasal hemorrhage accompanied by hematuria at 34 weeks and 3 days of gestation, with no apparent etiology. It was ultimately diagnosed as acquired coagulopathy resulting from brodifacoum poisoning. Fetal ultrasonography revealed significant intracranial hemorrhage, leading to intrauterine fetal demise and subsequent pregnancy termination. Following the correction of the patient’s coagulation profile through intravenous and oral administration of vitamin K1, tailored to the serum levels of brodifacoum, diligent monitoring confirmed that the patient was in stable condition.ConclusionThe primary hazard associated with the ingestion of brodifacoum is hemorrhage, with clinical presentations varying from asymptomatic cases to overt bleeding, which may present as hematuria, epistaxis, menometrorrhagia, and intracranial hemorrhage. Therefore, the diagnosis and management of this type of poisoning pose significant challenges. Prompt recognition and ongoing care for pregnant individuals affected by rodenticide toxicity are crucial for optimizing maternal health outcomes.

In response to the repeated occurrence of loosening in the fixed structure of the ring leads at the end of generator, as well as issues such as bolt loosening and lead wear, during the recent major overhauls of a large steam turbine generator, this paper conducts an analysis of the causes of loosening and proposes corresponding improvement measures. Taking the generator end ring leads fixed structure as the research object, this paper employs comparative analysis and finite element simulation methods to analyze the causes of loosening. It identifies factors such as bolt fixing methods and cleat support methods contributing to loosening, and proposes improvement solutions including increasing the wrapping angle of the cleat and enhancing pretightening force of the bolts. According to the actual component size of the unit, a sample test platform is designed and built, and the correctness of the loosening cause and the effectiveness of the improvement plan are verified by the sample test. The experimental results confirm that the cleat support form and bolt fixing method significantly contribute to fixing structural loosening, while the proposed improvements effectively delay bolt loosening. Increasing the cleat wrapping angle and pre-tightening force of the bolts are both feasible on-site and offer practical engineering value, laying the foundation for solving the technical challenges associated with securing the generator’s end ring lead structure and ensuring safe and stable generator operation.

Taking a type of test centrifuge as the research object, the finite element model of the test centrifuge was established, the vibration characteristics and aerodynamic performance of the test centrifuge were analyzed, and a structural optimization design of the test centrifuge was carried out. In this paper, the load was applied according to the actual working condition of a type of test centrifuge. The vibration of the mounting seat of the test centrifuge was analyzed, and the structure of the mounting seat was improved. After improvement, the vibration of the mounting seat was 77.38% lower than that of the original mounting seat. Then, the aerodynamic analysis of the test centrifuge was carried out. The analysis results show that the test centrifuge moved more smoothly under the whole-package shell and the fairing, the resistance decreased, and the shaft load decreased. Finally, the fairing of the test centrifuge was optimized. The analysis shows that an increase in the width of the fairing can reduce the resistance coefficient, which is helpful to the stability of the test centrifuge during operation and reduces the unbalanced response of the system caused by air resistance.

Feature selection (FS) is a significant dimensionality reduction technique in machine learning and data mining that is adept at managing high-dimensional data efficiently and enhancing model performance. Metaheuristic algorithms have become one of the most promising solutions in FS owing to their powerful search capabilities as well as their performance. In this paper, the novel improved binary walrus optimizer (WO) algorithm utilizing the golden sine strategy, elite opposition-based learning (EOBL), and population regeneration mechanism (BGEPWO) is proposed for FS. First, the population is initialized using an iterative chaotic map with infinite collapses (ICMIC) chaotic map to improve the diversity. Second, a safe signal is obtained by introducing an adaptive operator to enhance the stability of the WO and optimize the trade-off between exploration and exploitation of the algorithm. Third, BGEPWO innovatively designs a population regeneration mechanism to continuously eliminate hopeless individuals and generate new promising ones, which keeps the population moving toward the optimal solution and accelerates the convergence process. Fourth, EOBL is used to guide the escape behavior of the walrus to expand the search range. Finally, the golden sine strategy is utilized for perturbing the population in the late iteration to improve the algorithm’s capacity to evade local optima. The BGEPWO algorithm underwent evaluation on 21 datasets of different sizes and was compared with the BWO algorithm and 10 other representative optimization algorithms. The experimental results demonstrate that BGEPWO outperforms these competing algorithms in terms of fitness value, number of selected features, and F1-score in most datasets. The proposed algorithm achieves higher accuracy, better feature reduction ability, and stronger convergence by increasing population diversity, continuously balancing exploration and exploitation processes and effectively escaping local optimal traps.

Aim: Diabetic sarcopenia leads to disability and seriously affects the quality of life. Currently, there are no effective therapeutic strategies for diabetic sarcopenia. Our previous studies have shown that inflammation plays a critical role in skeletal muscle atrophy. Interestingly, the connection between chronic inflammation and diabetic complications has been revealed. However, the effects of non-steroidal anti-inflammatory drug celecoxib on diabetic sarcopenia remains unclear.Materials and Methods: The streptozotocin (streptozotocin)-induced diabetic sarcopenia model was established. Rotarod test and grip strength test were used to assess skeletal muscle function. Hematoxylin and eosin and immunofluorescence staining were performed to evaluate inflammatory infiltration and the morphology of motor endplates in skeletal muscles. Succinate dehydrogenase (SDH) staining was used to determine the number of succinate dehydrogenase-positive muscle fibers. Dihydroethidium staining was performed to assess the levels of reactive oxygen species (ROS). Western blot was used to measure the levels of proteins involved in inflammation, oxidative stress, endoplasmic reticulum stress, ubiquitination, and autophagic-lysosomal pathway. Transmission electron microscopy was used to evaluate mitophagy.Results: Celecoxib significantly ameliorated skeletal muscle atrophy, improving skeletal muscle function and preserving motor endplates in diabetic mice. Celecoxib also decreased infiltration of inflammatory cell, reduced the levels of IL-6 and TNF-α, and suppressed the activation of NF-κB, Stat3, and NLRP3 inflammasome pathways in diabetic skeletal muscles. Celecoxib decreased reactive oxygen species levels, downregulated the levels of Nox2 and Nox4, upregulated the levels of GPX1 and Nrf2, and further suppressed endoplasmic reticulum stress by inhibiting the activation of the Perk-EIF-2α-ATF4-Chop in diabetic skeletal muscles. Celecoxib also inhibited the levels of Foxo3a, Fbx32 and MuRF1 in the ubiquitin-proteasome system, as well as the levels of BNIP3, Beclin1, ATG7, and LC3Ⅱ in the autophagic-lysosomal system, and celecoxib protected mitochondria and promoted mitochondrial biogenesis by elevating the levels of SIRT1 and PGC1-α, increased the number of SDH-positive fibers in diabetic skeletal muscles.Conclusion: Celecoxib improved diabetic sarcopenia by inhibiting inflammation, oxidative stress, endoplasmic reticulum stress, and protecting mitochondria, and subsequently suppressing proteolytic systems. Our study provides evidences for the molecular mechanism and treatment of diabetic sarcopenia, and broaden the way for the new use of celecoxib in diabetic sarcopenia.

Abstract Background Minimally invasive modifications of inguinal lymphadenectomy (IL), including laparoscopic IL (LIL) and robotic-assisted IL (RAIL), have been utilized for penile cancer. Comparative study is necessary to guide the decision about which minimally invasive technique to select for IL. Therefore we compared RAIL with LIL performed via an antegrade approach in terms of perioperative outcomes. Methods We conducted a retrospective study of 43 patients who underwent RAIL (n = 20) or LIL (n = 23) for penile cancer from 2016 to 2020. The key surgical procedures and techniques are described. Complications were graded by the Clavien-Dindo classification, and operative time, estimated blood loss (EBL), lymph nodal yield, nodal positivity, postoperative drain duration, and disease recurrence during follow-up were assessed. Categorical variables were compared using chi-squared whereas continuous variables were compared by t-tests. Results The operative time for RAIL was significantly shorter than that of LIL (median 83 vs 95 min). Significantly less blood loss was reported with RAIL than with LIL (median 10 vs 35 ml). Lymph node yield, pathological positive nodes, the hospital stay, postoperative drain duration, postoperative complications and recurrence were similar for RAIL and LIL. Conclusions For patients with penile cancer, perioperative outcomes of RAIL and LIL were similar, but there was less blood loss, a shorter operative time for robotic cases.

ABSTRACTBackground Thrombospondins (TSPs) play important roles in several cardiovascular diseases. However, the association between circulating (plasma) thrombospondin 2 (TSP2) and essential hypertension remains unclear. The present study was aimed to investigate the association of circulating TSP2 with blood pressure and nocturnal urine Na+ excretion and evaluate the predictive value of circulating TSP2 in subjects with hypertension.Methods and Results 603 newly diagnosed essential hypertensive subjects and 508 healthy subjects were preliminarily screened, 47 healthy subjects and 40 newly diagnosed essential hypertensive subjects without any chronic diseases were recruited. The results showed that the levels of circulating TSP2 were elevated in essential hypertensive subjects. The levels of TSP2 positively associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and other clinical parameters, including homeostasis model assessment of insulin resistance (HOMA-IR), brachial-ankle pulse wave velocity, and serum triglycerides, but negatively associated with nocturnal urine Na+ concentration and excretion and high-density lipoprotein cholesterol. Results of multiple linear regressions showed that HOMA-IR and nocturnal Na+ excretion were independent factors related to circulating TSP2. Mantel–Haenszel chi-square test displayed linear relationships between TSP2 and SBP (χ2 = 35.737) and DBP (χ2 = 26.652). The area under receiver operating characteristic curve (AUROC) of hypertension prediction was 0.901.Conclusion Our study suggests for the first time that the circulating levels of TSP2 may be a novel potential biomarker for essential hypertension. The association between TSP2 and blood pressure may be, at least in part, related to the regulation of renal Na+ excretion, insulin resistance, and/or endothelial function.

Abstract Background Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse perinatal outcomes leading to high perinatal morbidity and mortality. However, few studies have examined twin pregnancies complicated by ICP. To assess the perinatal outcomes of twin pregnancies with ICP, a retrospective cohort study was conducted. Methods A total of 633 twin pregnancies and 1267 singleton pregnancies with ICP were included. In addition, a correlation study was performed on the matched total bile acid (TBA) levels from maternal serum, fetal umbilical venous blood, and amniotic fluid of 33 twin pregnancies from twin groups. Results When compared to singletons, twin pregnancies with ICP had a higher risk of cesarean section (CS) (96.4% vs. 76.1%), preterm birth (PTB) (82.6% vs. 19.7%), fetal distress (2.0% vs. 1.3%), and neonatal intensive care unit (NICU) admission (23.6% vs. 5.1%), which was significantly related to increasing TBA levels (P

Abstract Background Cervical cerclage has been proposed as an effective treatment for cervical insufficiency, but there has been controversy regarding the surgical options of cervical cerclage in singleton and twin pregnancies. This study aimed to compare the pregnancy outcomes between transvaginal cervical cerclage (TVC) and laparoscopic abdominal cervical cerclage (LAC) in patients with cervical insufficiency. We also aimed to evaluate the efficacy and safety, and provide more evidence to support the application of cervical cerclage in twin pregnancies. Methods A retrospective study was carried out from January 2015 to December 2021. The primary outcomes were the incidence of spontaneous preterm birth (sPTB)

Abstract Driven by their many unique features, perovskite solar cells (PSCs) have become one of the most promising candidates in the photovoltaic field. Two‐step preparation of perovskite film is advantageous for its higher stability and reproducibility compared to the one‐step method, which is more suitable for practical application. However, the incomplete conversion of the dense lead iodide (PbI2) layer during the sequential spin‐coating of formamidinium/methylammonium (FA+/MA+) organic amine salts severely affect the performance of PSCs. Herein, sodium bicarbonate (NaHCO3) is used to induce the formation of porous PbI2, which facilitates the penetration of the FA+/MA+ ions and the formation of a perovskite film with high crystallinity and large grain microstructure. Meanwhile, the introduction of Na+ not only improves the energetic alignment of the PSC, but also increases the conductivity via p‐doping. As a result, the optimized NaHCO3‐modified PSC achieves a champion power conversion efficiency of 24.0% with suppressed hysteresis. Moreover, the significant reduction in defect density and ion migration as well as a mild alkaline environment enhance the stability of device. The unencapsulated NaHCO3‐modified PSCs maintain over 90% of their original efficiency upon storage in ambient air (30%–40% relative humidity) for 2160 h. We have demonstrated an ingenious strategy for controlling the quality of perovskite and improving the performance of device by low‐temperature foaming of simple inorganic molecules of NaHCO3.

Abstract Background Conjoined twins are a rare and serious complication of monochorionic twins. The total incidence is 1.5 per 100,000 births, and about 50% are liveborn. Prenatal screening and diagnosis of conjoined twins is usually performed by ultrasonography. Magnetic resonance imaging can be used to assist in the diagnosis if necessary. Conjoined twins in dichorionic diamniotic triplet pregnancy are extremely rare. Case presentation We reported three cases of dichorionic diamniotic triplet pregnancy with conjoined twins. Due to the poor prognosis of conjoined twins evaluated by multidisciplinary teams, selective termination of conjoined twins was performed in three cases. In case 1, selective reduction of the conjoined twins was performed at 16 gestational weeks, and a healthy female baby weighing 3270 g was delivered at 37 weeks. In case 2, the conjoined twins were selectively terminated at 17 weeks of gestation, and a healthy female baby weighing 2760 g was delivered at 37 weeks and 4 days. In case 3, the conjoined twins were selectively terminated at 15 weeks and 2 days, and a healthy female baby weighing 2450 g was delivered at 33 weeks and 6 days. The babies of all three cases were followed up and are in good health. Conclusion(s) Surgical separation is the only treatment for conjoined twins after birth. Early determination of chorionicity and antenatal diagnosis of conjoined twins in triplet gestations are critical for individualized management options and the prognosis of normal triplets. Expecting parents should be extensively counseled by multidisciplinary teams. If there are limitations in successful separation after birth, early selective termination of the conjoined twins by intrathoracic injection of potassium chloride may be a procedure in dichorionic diamniotic triplet pregnancy to improve perinatal outcomes of the normal triplet.

In recent years, the operation of cascade reservoirs in the upper reaches of the Yangtze River led by the Three Gorges Reservoir has significantly changed the low water level of Dongting Lake, which has had an adverse impact on the water resources and ecological security in the lake area. As a result, the low water level situation of Dongting Lake is drawing more and more attention. Based on the abundant and long-term daily observation data of Dongting Lake and main stream of the Yangtze River, the spatial and temporal evolution characteristics of low water level in the Dongting Lake area since the 1950s were analyzed in this study, especially during the storage period of the Three Gorges Reservoir. In addition, the influence of the jacking effect of the Yangtze River on Dongting Lake was also discussed to analyze the impact of the Three Gorges Reservoir. The results show that the annual minimum water level in the Dongting Lake area over the years generally occurs from January to February and December. Since it is not within the storage period of the Three Gorges Reservoir, it is not affected by the Three Gorges Reservoir. However, the average water level in September and October during the main storage period of the Three Gorges Reservoir has significantly reduced, and the closer it is to the main stream of the Yangtze River, the greater the influence is. In recent years, affected by the advance of the impounding period, the average water level has decreased further in September. In addition, the low water level of Dongting Lake is obviously affected by the jacking effect of the main stream of the Yangtze River. After the impoundment of the Three Gorges Reservoir, the water surface slope of the Dongting Lake area has decreased, while that of the main stream of the Yangtze River has increased. This has strengthened the jacking effect of the main stream. The research results can provide reference for the solution of water resource and ecological crises in the Dongting Lake area.

Diabetes mellitus (DM) is a typical chronic disease that can be divided into 2 types, dependent on insulin deficiency or insulin resistance. Incidences of diabetic complications gradually increase as the disease progresses. Studies in diabetes complications have mostly focused on kidney and cardiovascular diseases, as well as neuropathy. However, DM can also cause skeletal muscle atrophy. Diabetic muscular atrophy is an unrecognized diabetic complication that can lead to quadriplegia in severe cases, seriously impacting patients’ quality of life. In this review, we first identify the main molecular mechanisms of muscle atrophy from the aspects of protein degradation and synthesis signaling pathways. Then, we discuss the molecular regulatory mechanisms of diabetic muscular atrophy, and outline potential drugs and treatments in terms of insulin resistance, insulin deficiency, inflammation, oxidative stress, glucocorticoids, and other factors. It is worth noting that inflammation and oxidative stress are closely related to insulin resistance and insulin deficiency in diabetic muscular atrophy. Regulating inflammation and oxidative stress may represent another very important way to treat diabetic muscular atrophy, in addition to controlling insulin signaling. Understanding the molecular regulatory mechanism of diabetic muscular atrophy could help to reveal new treatment strategies.

The maintenance of muscle homeostasis is vital for life and health. Skeletal muscle atrophy not only seriously reduces people’s quality of life and increases morbidity and mortality, but also causes a huge socioeconomic burden. To date, no effective treatment has been developed for skeletal muscle atrophy owing to an incomplete understanding of its molecular mechanisms. Exercise therapy is the most effective treatment for skeletal muscle atrophy. Unfortunately, it is not suitable for all patients, such as fractured patients and bedridden patients with nerve damage. Therefore, understanding the molecular mechanism of skeletal muscle atrophy is crucial for developing new therapies for skeletal muscle atrophy. In this review, PubMed was systematically screened for articles that appeared in the past 5 years about potential therapeutic strategies for skeletal muscle atrophy. Herein, we summarize the roles of inflammation, oxidative stress, ubiquitin-proteasome system, autophagic-lysosomal pathway, caspases, and calpains in skeletal muscle atrophy and systematically expound the potential drug targets and therapeutic progress against skeletal muscle atrophy. This review focuses on current treatments and strategies for skeletal muscle atrophy, including drug treatment (active substances of traditional Chinese medicine, chemical drugs, antioxidants, enzyme and enzyme inhibitors, hormone drugs, etc.), gene therapy, stem cell and exosome therapy (muscle-derived stem cells, non-myogenic stem cells, and exosomes), cytokine therapy, physical therapy (electroacupuncture, electrical stimulation, optogenetic technology, heat therapy, and low-level laser therapy), nutrition support (protein, essential amino acids, creatine, β-hydroxy-β-methylbutyrate, and vitamin D), and other therapies (biomaterial adjuvant therapy, intestinal microbial regulation, and oxygen supplementation). Considering many treatments have been developed for skeletal muscle atrophy, we propose a combination of proper treatments for individual needs, which may yield better treatment outcomes.

Various diseases can cause skeletal muscle atrophy, usually accompanied by inflammation, mitochondrial dysfunction, apoptosis, decreased protein synthesis, and enhanced proteolysis. The underlying mechanism of inflammation in skeletal muscle atrophy is extremely complex and has not been fully elucidated, thus hindering the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy. In this review, we elaborate on protein degradation pathways, including the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), the calpain and caspase pathways, the insulin growth factor 1/Akt protein synthesis pathway, myostatin, and muscle satellite cells, in the process of muscle atrophy. Under an inflammatory environment, various pro-inflammatory cytokines directly act on nuclear factor-κB, p38MAPK, and JAK/STAT pathways through the corresponding receptors, and then are involved in muscle atrophy. Inflammation can also indirectly trigger skeletal muscle atrophy by changing the metabolic state of other tissues or cells. This paper explores the changes in the hypothalamic-pituitary-adrenal axis and fat metabolism under inflammatory conditions as well as their effects on skeletal muscle. Moreover, this paper also reviews various signaling pathways related to muscle atrophy under inflammatory conditions, such as cachexia, sepsis, type 2 diabetes mellitus, obesity, chronic obstructive pulmonary disease, chronic kidney disease, and nerve injury. Finally, this paper summarizes anti-amyotrophic drugs and their therapeutic targets for inflammation in recent years. Overall, inflammation is a key factor causing skeletal muscle atrophy, and anti-inflammation might be an effective strategy for the treatment of skeletal muscle atrophy. Various inflammatory factors and their downstream pathways are considered promising targets for the treatment and prevention of skeletal muscle atrophy.

Adoptive cell therapy using TCR-engineered T cells (TCR-T cells) represents a promising strategy for treating relapsed and metastatic cancers. We previously established methods to identify neoantigen-specific TCRs based on patients’ PBMCs. However, in clinical practice isolation of PBMCs from advanced-stage cancer patients proves to be difficult. In this study, we substituted blood-derived T cells for tumor-infiltrating lymphocytes (TILs) and used an HLA-matched cell line of antigen-presenting cells (APCs) to replace autologous dendritic cells. Somatic mutations were determined in head and neck squamous cell carcinoma resected from two patients. HLA-A*02:01-restricted neoantigen libraries were constructed and transferred into HLA-matched APCs for stimulation of patient TILs. TCRs were isolated from reactive TIL cultures and functionality was tested using TCR- T cells in vitro and in vivo. To exemplify the screening approach, we identified the targeted neoantigen leading to recognition of the minigene construct that stimulated the strongest TIL response. Neoantigen peptides were used to load MHC-tetramers for T cell isolation and a TCR was identified targeting the KIAA1429D1358E mutation. TCR-T cells were activated, exhibited cytotoxicity, and secreted cytokines in a dose-dependent manner, and only when stimulated with the mutant peptide. Furthermore, comparable to a neoantigen-specific TCR that was isolated from the patient’s PBMCs, KIAA1429D1358E-specific TCR T cells destroyed human tumors in mice. The established protocol provides the required flexibility to methods striving to identify neoantigen-specific TCRs. By using an MHC-matched APC cell line and neoantigen-encoding minigene libraries, autologous TILs can be stimulated and screened when patient PBMCs and/or tumor material are not available anymore. Abbreviations: Head and neck squamous cell carcinoma (HNSCC); adoptive T cell therapy (ACT); T cell receptor (TCR); tumor-infiltrating lymphocytes (TIL); cytotoxic T lymphocyte (CTL); peripheral blood mononuclear cell (PBMC); dendritic cell (DC); antigen-presenting cells (APC)

Background: Pulmonary hypertension (PH) is a life-threatening disease with significant maternal morbidity and mortality. Methods: To assess pregnancy and neonatal outcomes and determine the risk factors for adverse maternal and neonatal outcomes in women with pulmonary hypertension (PH), a retrospective analysis was carried out examining 71 pregnancies in patients with PH who delivered at a tertiary care center in West China between January 2011 and May 2016. Results: One pregnancy resulted in spontaneous abortion and six resulted in terminated abortions. Cardiac complications were encountered in 16.9% including three maternal mortalities. At least one pregnancy complication occurred in 28.2% of all the pregnancies. Diagnosis after the third trimester, severe PH and/or right ventricular systolic dysfunction were predictive of adverse fetal/neonatal events. A history of prior cardiac events and right ventricular systolic dysfunction and/or baseline New York Heart Association (NYHA) class III or IV were the main predictive factors of adverse maternal cardiac events. Conclusions: In our study, we found that PH poses high risks for maternal and fetal morbidity and mortality. A detailed pre-pregnancy baseline assessment is strongly recommended in women with PH to identify those with the highest risk and subsequently guide clinical management.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons, leading to muscle atrophy, paralysis and even death. Immune disorder, redox imbalance, autophagy disorder, and iron homeostasis disorder have been shown to play critical roles in the pathogenesis of ALS. However, the exact pathogenic genes and the underlying mechanism of ALS remain unclear. The purpose of this study was to screen for pathogenic regulatory genes and prognostic markers in ALS using bioinformatics methods. We used Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analysis (GSEA), and expression regulation network analysis to investigate the function of differentially expressed genes in the nerve tissue, lymphoid tissue, and whole blood of patients with ALS. Our results showed that the up-regulated genes were mainly involved in immune regulation and inflammation, and the down-regulated genes were mainly involved in energy metabolism and redox processes. Eleven up-regulated transcription factors (CEBPB, CEBPD, STAT5A, STAT6, RUNX1, REL, SMAD3, GABPB2, FOXO1, PAX6, and FOXJ1) and one down-regulated transcription factor (NOG) in the nerve tissue of patients with ALS likely play important regulatory roles in the pathogenesis of ALS. Based on construction and evaluation of the ALS biomarker screening model, cluster analysis of the identified characteristic genes, univariate Cox proportional hazards regression analysis, and the random survival forest algorithm, we found that MAEA, TPST1, IFNGR2, and ALAS2 may be prognostic markers regarding the survival of ALS patients. High expression of MAEA, TPST1, and IFNGR2 and low expression of ALAS2 in ALS patients may be closely related to short survival of ALS patients. Taken together, our results indicate that immune disorders, inflammation, energy metabolism, and redox imbalance may be the important pathogenic factors of ALS. CEBPB, CEBPD, STAT5A, STAT6, RUNX1, REL, SMAD3, GABPB2, FOXO1, PAX6, FOXJ1, and NOG may be important regulatory factors linked to the pathogenesis of ALS. MAEA, TPST1, IFNGR2, and ALAS2 are potential important ALS prognostic markers. Our findings provide evidence on the pathogenesis of ALS, potential targets for the development of new drugs for ALS, and important markers for predicting ALS prognosis.

Potential biomarker detection is a crucial area of study for the prediction, diagnosis, and monitoring of Alzheimer's disease (AD). The voxelwise genome-wide association study (vGWAS) is widely used in imaging genomics studies that is usually applied to the detection of AD biomarkers in both imaging and genetic data. However, performing vGWAS remains a challenge because of the computational complexity of the technique and our ignorance of the spatial correlations within the imaging data. In this paper, we propose a novel method based on the exploitation of spatial correlations that may help to detect potential AD biomarkers using a fast vGWAS. To incorporate spatial correlations, we applied a nonlocal method that supposed that a given voxel could be represented by weighting the sum of the other voxels. Three commonly used weighting methods were adopted to calculate the weights among different voxels in this study. Then, a fast vGWAS approach was used to assess the association between the image and the genetic data. The proposed method was estimated using both simulated and real data. In the simulation studies, we designed a set of experiments to evaluate the effectiveness of the nonlocal method for incorporating spatial correlations in vGWAS. The experiments showed that incorporating spatial correlations by the nonlocal method could improve the detecting accuracy of AD biomarkers. For real data, we successfully identified three genes, namely, ANK3, MEIS2, and TLR4, which have significant associations with mental retardation, learning disabilities and age according to previous research. These genes have profound impacts on AD or other neurodegenerative diseases. Our results indicated that our method might be an effective and valuable tool for detecting potential biomarkers of AD. Keywords: AD biomarker, vGWAS, Imaging genomics studies, Spatial correlations, Nonlocal method

Molecular modulators have been demonstrated to be an effectual strategy for reducing the defect at the interface and in bulk of perovskite and ameliorating the performance and stability of perovskite solar cells (PSCs). Herein, 1-aza-15-crown 5-ether (A15C5), with a unique nitrogen heterocyclic structure as a molecular modulator is introduced at the interface between perovskite layer and hole transport layer of PSCs. Multiple supramolecular synergistic interaction between A15C5 and perovskite dramatically suppress and passivate defects, resulting in a 38% decrease in electron trap-state density in perovskite. The formation of two-dimensional/th3D perovskite heterojunctions induced by planar A15C5 releases residual strain of perovskite film, optimizes the match of energy level array and boosts the stability of devices. Consequently, A15C5-modulated PSC achieves an impressing efficiency of 24.13% along with excellent humidity, light and thermal stability. This work provides a typical strategy to utilize supramolecular crown ether in PSCs. [ABSTRACT FROM AUTHOR]

Background: Thrombospondins (TSPs) play important roles in several cardiovascular diseases. However, the association between circulating (plasma) thrombospondin 2 (TSP2) and essential hypertension remains unclear. The present study was aimed to investigate the association of circulating TSP2 with blood pressure and nocturnal urine Na+ excretion and evaluate the predictive value of circulating TSP2 in subjects with hypertension. Methods and Results: 603 newly diagnosed essential hypertensive subjects and 508 healthy subjects were preliminarily screened, 47 healthy subjects and 40 newly diagnosed essential hypertensive subjects without any chronic diseases were recruited. The results showed that the levels of circulating TSP2 were elevated in essential hypertensive subjects. The levels of TSP2 positively associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), and other clinical parameters, including homeostasis model assessment of insulin resistance (HOMA-IR), brachial-ankle pulse wave velocity, and serum triglycerides, but negatively associated with nocturnal urine Na+ concentration and excretion and high-density lipoprotein cholesterol. Results of multiple linear regressions showed that HOMA-IR and nocturnal Na+ excretion were independent factors related to circulating TSP2. Mantel-Haenszel chi-square test displayed linear relationships between TSP2 and SBP (χ2 = 35.737) and DBP (χ2 = 26.652). The area under receiver operating characteristic curve (AUROC) of hypertension prediction was 0.901. Conclusion: Our study suggests for the first time that the circulating levels of TSP2 may be a novel potential biomarker for essential hypertension. The association between TSP2 and blood pressure may be, at least in part, related to the regulation of renal Na+ excretion, insulin resistance, and/or endothelial function. [ABSTRACT FROM AUTHOR]