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Abstract Background Alport Syndrome (AS) is a progressive hereditary glomerular disease. It is often accompanied by sensorineural hearing loss and ocular abnormalities and can sometimes develop into end stage renal disease (ESRD), which is caused by mutations in the genes encoding the collagen type IV family of proteins. Methods This study analyzed the association between the clinical data of seven AS families and genes and the disease progression of different mutation types, including COL4A3 (OMIM 120070)，COL4A4 (OMIM 120131), and COL4A5 (OMIM303630). Results A total of six new pathogenic mutation sites, one complex heterozygous mutation at COL4A3, and a combined mutation of COL4A5 and INF2 (OMIM 610982) were identified in this study. It was revealed that the clinical manifestations of X‐linked AS caused by mutations in the COL4A5 gene were more severe in males than in females. In addition, the difference in patient phenotype can be attributed to the location of gene mutations affecting the protein domain or functional domain. Our data suggested that the gene deletion and nonsense mutations had a high risk for progression to ESRD. Conclusion Our results revealed the spectrum of type IV collagen genes, which contribute to the enrichment of database resources and has important implications in the diagnosis, prognosis, and guiding treatment of AS.

Abstract Objective This retrospective longitudinal cohort study aimed to explore the best therapeutic regimen and treatment duration of cough variant asthma (CVA) in children. Methods A total of 314 children with CVA were divided into receive inhaled corticosteroids (ICS) combined with long‐acting beta2‐agonist (LABA) group, ICS combined with leukotriene receptor antagonists (LTRA) group, ICS monotherapy group and LTRA monotherapy group. All clinical data were statistically analyzed. Logistic regression model was used to compare the advantages and disadvantages of different treatment schemes at each follow‐up time point and the best treatment scheme. The Cox proportional hazard regression model based on inverse probability weighting was used to compare the effects of different medication regimens on adverse outcomes with asthma recurrence or progression as the end point. Results (1) After comprehensive analysis, ICS + LABA group was the preferred control regimen for CVA within 8 weeks. After 8 weeks of diagnosis, the efficacy of ICS group or LTRA group was comparable to that of ICS + LABA group and ICS + LTRA group. (2) The ICS + LABA group showed a significant improvement in cough at an early stage, particularly at 4 weeks; the symptoms of ICS + LTRA and ICS groups were significantly improved at 36 weeks. The LTRA group alone showed significant improvement at 20 weeks. Conclusion ICS + LABA, ICS + LTRA, ICS alone and LTRA alone can effectively treat CVA. ICS + LABA could improve the symptoms most quickly within 8 weeks after CVA diagnosis, followed by ICS + LATR group. After 8 weeks, it can be reduced to ICS alone to control CVA for at least 36 weeks based on the remission of symptoms in children.

Abstract Regarding the issue of intense mining pressure appearing in the underlying gateway below the remaining coal pillar in the close‐distance coal seam (the remaining coal pillar is perpendicular to the underlying section coal pillar), 401 working face is used as the engineering background. Field measurements, laboratory experiments, numerical simulations, and engineering verification techniques are used to study the abutment pressure's evolution properties and the plastic zone's propagation laws before and after the underlying coal seam roadway experienced the mining impact. The conclusions are as follows: ① The maximum plastic area on the two sides and the roof of the roadway underlying the gob are up to 2 and 1.5 m, whereas the maximum plastic area on the two sides and the roof of the roadway underlying the remaining coal pillar are up to 5 and 4.5 m, respectively. Moreover, the plastic area extends along the two sides, and the section coal pillar is completely broken when the working face is mined below the remaining coal pillar. ② The stress increase coefficient K in the overlap area of the remaining coal pillar and the underlying section coal pillar reaches 3.4 when the mining face penetrates the underlying remaining coal pillar and the advance abutment pressure is overlaid with the concentrated stress of the coal pillar. ③ When the underlying working face is mined to 4, −2, −8, and −14 m away from the remaining coal pillar, the damage range of the roadway 5–10 m ahead increases in turn. At the same time, the maximum plastic area of the roof passes through the plastic area of the upper coal seam floor. Therefore, the underlying and transition areas on both sides of the remaining coal pillar are divided into Area I (15 m) → Area II (the most complicated area to control under the remaining coal pillar, 20 m) → Area III (25 m) according to the width. Furthermore, the divisional differentiated combined control technology of channel steel truss anchor cable with joint double‐way locking control function of roof and coal pillar in Areas I and III, while channel steel truss anchor cable with joint double‐way locking control function of roof and side + high resistance integral door‐type support is proposed in Area II. Field engineering practice shows that the deformation of the roadway surrounding rock can be controlled within 210 mm after adopting the above divisional combined control technology. Finally, the mining operation can safely and efficiently pass through the remaining coal pillar. The research results have important reference values for surrounding rock control of mining roadways in the overlapping area of similar “+”‐type cross‐working face.

Abstract Extra‐thick coal seams are widely distributed in the Datong mine area in China. The rapid stopping of mining and the support withdrawal technology for extra‐thick coal seams need to be developed urgently. The reasonable stopping top coal caving distance, main roof's fracture line position, and large section roadway during the stopping period (LSRSP) support method of the header face of 15 m extra‐thick coal seam are systematically studied by using field measurement, experiment, numerical simulation, and similar material simulation methods. With the increase in stopping coal caving distance, the range of the medium and low displacement zone of the LSRSP overburden gradually expands. In contrast, the depth of the plastic zone decreases. The scope and intensity of the high‐stress area of the overlying rock in front gradually decrease and shift from deep to the outside, while the peak stress area shifts from the top coal area to the coal rib of the retracement channel. Comparing the stopping of medium‐thick and thick coal seam working face, the interaction between “main roof−unmined top coal−supports” is analyzed. The unique characteristics of the extra‐thick coal seam working face are derived: when the stopping coal caving distance is shorter than the length of the key block, the dropped coal body cannot effectively restrict the movement of key blocks. Mutual compression and subsidence occur between key blocks, making the broken coal rock block squeeze into the supports. By the simulation study of each index, the stopping coal caving distance of the extra‐thick coal seam is optimal when it is slightly larger than the length of the key block (i.e., the periodic weighting step), simultaneously, the main roof fracture line behind the supports is most favorable for stopping mining. After ensuring the stability of the LSRSP's overburden structure, the differentiated support scheme of “controlled zoning−strength grading” was proposed, and the scheme was modified and verified by simulating the support prestress field. After field practice, the roof of the retracement channel is better controlled in deformation under the joint horizontal and vertical support, the robust control effect of the combined anchor cable is noticeable, the integrity of the polyurethane network is more substantial, and the working face supports have successfully achieved a safe and rapid evacuation.

Abstract Background The global spread of coronavirus disease 2019 (COVID‐19) has resulted in a significant disease burden, yet asthma patients do not have the expected high morbidity and mortality rates in the pandemics of COVID‐19. Objective To find the difference of angiotensin‐converting enzyme 2 (ACE2) in asthma and nonasthma children and evaluate the effect of inhaled corticosteroids (ICS) on its expression. Methods The ACE2, immunoglobulin E (IgE), and eosinophils were tested in different children. Results A total of 157 children aged 3–16 years were enrolled. The expression of ACE2 in asthma children were lower than nonasthma children (T = −2.512, p = .013). Allergic nonasthma children had a significant higher ACE2 expression than children with allergic asthma (p = .013) and nonallergic asthma (p = .029). The expression of ACE2 had no significant difference between first‐diagnosed asthma children and that had been treated with ICS for ≥6 months (F = 0.028, p = .598). The allergic asthma children showed a significantly higher eosinophils cells (EC) count than the allergic nonasthma (W = 200, p

Abstract Aiming at the occluded real‐world face images across illumination, pose, expression, and resolution variations, a robust face recognition for occluded real‐world images using constrained probabilistic sparse network is presented. A constrained probabilistic sparse representation network is constructed to obtain the features of all the training images from a global perspective, and the new network nodes are generated through the random combination of the training images. In the probabilistic sparse representation network, the probabilities of each class of the sparse subspace that the occluded test images individually belong to are defined and calculated. The final classifications of the test images are determined by the joint maximum probability of the network nodes. Meanwhile the second‐order gradient constraint is the first introduced in the probabilistic sparse representation network. It is found that the constraint uses the adjacent pixels of the face images to obtain the local texture similarity, and further use the local texture similarity to distinguish the occlusion and non‐occlusion parts. Thus the constraint can reduce the influence of the occlusion part on face recognition. Extensive experiments with the 12 existing methods on the five face databases demonstrate that the recognition rate of the proposed method is the best than the non‐deep learning methods compared, and the proposed method can obtain nearly the same recognition rate with an advantage of a very less time consumption compared to the state‐of‐the‐art deep learning methods.

Abstract Cancer is a genetic disease caused by alterations in genome and epigenome and is one of the leading causes for death worldwide. The exploration of disease development and therapeutic strategies at the genetic level have become the key to the treatment of cancer and other genetic diseases. The functional analysis of genes and mutations has been slow and laborious. Therefore, there is an urgent need for alternative approaches to improve the current status of cancer research. Gene editing technologies provide technical support for efficient gene disruption and modification in vivo and in vitro, in particular the use of clustered regularly interspaced short palindromic repeats (CRISPR)–Cas systems. Currently, the applications of CRISPR–Cas systems in cancer rely on different Cas effector proteins and the design of guide RNAs. Furthermore, effective vector delivery must be met for the CRISPR–Cas systems to enter human clinical trials. In this review article, we describe the mechanism of the CRISPR–Cas systems and highlight the applications of class II Cas effector proteins. We also propose a synthetic biology approach to modify the CRISPR–Cas systems, and summarize various delivery approaches facilitating the clinical application of the CRISPR–Cas systems. By modifying the CRISPR–Cas system and optimizing its in vivo delivery, promising and effective treatments for cancers using the CRISPR–Cas system are emerging.

Abstract An important research direction in applying wearable devices in sports is motion recognition and segmentation. The authors propose an end‐to‐end motion recognition–segmentation method in basketball. First, data are collected using an arm guard with an inertial measurement unit (IMU) module. Next, a sliding window is used to extract the data features. The feature extraction method is a multi‐model long short‐term memory (LSTM) network. After feature extraction, a label vector is obtained and a result vector is formed after temporal matrix processing. The results of the experiment on the accuracy, precision and recall were 97.1% ± 1.6%, 94.4% ± 0.7% and 96.4% ± 1.1%, respectively, showing better performance among similar studies.

Abstract Oral squamous cell carcinoma (OSCC), the eighth most prevalent cancer in the world, arises from the interaction of multiple factors including tobacco, alcohol consumption, and betel quid. Chemotherapeutic agents such as cisplatin, 5‐fluorouracil, and paclitaxel have now become the first‐line options for OSCC patients. Nevertheless, most OSCC patients eventually acquire drug resistance, leading to poor prognosis. With the discovery and identification of non‐coding RNAs (ncRNAs), the functions of dysregulated ncRNAs in OSCC development and drug resistance are gradually being widely recognized. The mechanisms of drug resistance of OSCC are intricate and involve drug efflux, epithelial‐mesenchymal transition, DNA damage repair, and autophagy. At present, strategies to explore the reversal of drug resistance of OSCC need to be urgently developed. Nano‐delivery and self‐cellular drug delivery platforms are considered as effective strategies to overcome drug resistance due to their tumor targeting, controlled release, and consistent pharmacokinetic profiles. In particular, the combined application of new technologies (including CRISPR systems) opened up new horizons for the treatment of drug resistance of OSCC. Hence, this review explored emerging regulatory functions of ncRNAs in drug resistance of OSCC, elucidated multiple ncRNA‐meditated mechanisms of drug resistance of OSCC, and discussed the potential value of drug delivery platforms using nanoparticles and self‐cells as carriers in drug resistance of OSCC.

Abstract Microsatellite markers were isolated and characterized for Hopea hainanensis Merrill & Chun, an endangered tree species with scattered distribution in Hainan Island and northern Vietnam. Twenty‐six microsatellite markers were developed based on next‐generation sequencing data and were genotyped by capillary electrophoresis on an ABI 3730xl DNA Analyzer. Twelve markers were found to be polymorphic in H. hainanensis. GENODIVE analyses indicated that the number of alleles ranged from 2 to 6 per locus, and the observed and expected heterozygosity varied from 0 to 0.755 and from 0.259 to 0.779, respectively. Primer transferability was tested with Hopea chinensis Hand.‐Mazz. and Hopea reticulata Tardieu, in which 3 and 7 microsatellite markers were found to be polymorphic, separately. The results showed that H. reticulata and H. hainanensis had similar levels of genetic diversity. A neighbor joining dendrogram clustered all individuals into two major groups, one of which was exclusively constituted by H. hainanensis, while the other consisted of two subgroups, corresponding to H. reticulata and H. chinensis, respectively. The 12 polymorphic microsatellite markers could be applied to study genetic diversity, population differentiation, mating system, and fine‐scale spatial genetic structures of H. hainanensis as well as its close relatives, facilitating the conservation and restoration of these endangered but valuable Hopea species.

An asynchronous heterogeneous decomposition (async‐HGD) algorithm for integrated transmission and distribution networks coordinated optimisation considering communication conditions is proposed. Compared with traditional synchronous HGD (sync‐HGD), a partial synchronisation mechanism is introduced instead of the full synchronisation to alleviate the influence of communication delays. Under this mechanism, the transmission system operator does not need to wait for the slowest distribution system operator to complete its subproblem and update boundary parameters before the next iteration can proceed. Also, a bounded delay is introduced under this mechanism to ensure sufficient freshness of all the updates. Further, the previous value strategy (PVS) and linear regression strategy (LVS) are applied to handle non‐instantaneous interruptions in the communication networks as an improvement of the async‐HGD. Numerical experiments show that considering communication delays in the actual operation; the async‐HGD takes less time to converge compared with the sync‐HGD under appropriate settings. In addition, PVS and LVS can both enhance the robustness of the overall algorithm by achieving approximate solutions, and the LVS can achieve more accurate results compared with the PVS.

Abstract So far, pure organic room temperature phosphorescence (RTP) materials are developing rapidly and have become a research hotspot in the scientific community. They are regarded as valuable resources with great potential for development in many fields, such as biomedicine, information multi‐level encryption, smart anti‐counterfeiting, and so on. Among them, a series of pure organic RTP polymer systems emerged at the right moment based on the excellent properties of polymers such as easy processing, low cost, and good biocompatibility. Furthermore, the huge molecular weight, long‐chain intertwined structure, and potential interactions with phosphors of polymers make them a focus for RTP emission. Herein, we describe the development history of this system in detail, explore the necessary factors for highly efficient emission from the phosphorescence emission process, and based on the dual effects of enhancing phosphorescence emission and shortening luminescence lifetime brought by heavy atoms, we summarize the internal mechanism and achievements of various researches from the perspective of heavy atom–containing and non‐heavy atom systems.

Studying the high-temperature mechanical properties of rocks is of great significance to engineering disasters caused by deep rock mining and underground protection projects. In view of insufficient research on the high-temperature mechanical properties of deep rocks in southwestern China, we used high-temperature heating devices and statics equipment to conduct static tests on Skarn. XW7L-12 box-type resistance furnace was adopted to heat Skarn (25°C, 200°C, 400°C, 600°C, and 800°C), and the temperature effect of its basic physical parameters (density and wave velocity) was measured and analyzed. Uniaxial compression experiments were performed on two cooling methods of Skarn (natural cooling and water cooling) by a constant stress pressure testing machine to obtain a stress-strain curve and analyze its statics index (peak strength, tensile strength, elastic modulus, and peak strain) and the change rule of failure mode with temperature rise and different cooling methods. With the temperature increasing, various static mechanical indexes of Skarn will be greatly affected. Meanwhile, the different cooling methods are not related to the change trend of the mechanical properties of Skarn under high temperature.

The loss of auditory sensory hair cells (HCs) is the most common cause of sensorineural hearing loss (SNHL). As the main sound transmission structure in the cochlea, it is necessary to maintain the normal shape and survival of HCs. In this review, we described and summarized the signaling pathways that regulate the development and survival of auditory HCs in SNHL. The role of the mitogen-activated protein kinase (MAPK), phosphoinositide-3 kinase/protein kinase B (PI3K/Akt), Notch/Wnt/Atoh1, calcium channels, and oxidative stress/reactive oxygen species (ROS) signaling pathways are the most relevant. The molecular interactions of these signaling pathways play an important role in the survival of HCs, which may provide a theoretical basis and possible therapeutic interventions for the treatment of hearing loss.

Aiming at the voltage rise due to the photovoltaic generation system (PVGS) at the point of common coupling (PCC), the cause is analysed with power transmission theory. Here, the principle and strategies of voltage regulation based on active and reactive power in PVGS are proposed. In this control strategy, the voltage of PCC is tracked by PV system in real time. When the voltage of PCC is normal, inverter will output in the way of maximum power point tracking (MPPT).When the voltage of PCC exceeds the upper limit, the inverter will regulate the voltage using the remaining capacity preferentially. If the remaining capacity is insufficient, the inverter will adjust active output and dynamically calculate the active and reactive best out values. In this way, the voltage of PCC is adjusted in an appropriate range to achieve the active output minimisation and reactive output optimisation of inverter. The experimental results validate the effectiveness of the proposed control scheme for voltage regulation.

To develop new slabs with light weight and high rigidity as well as meet the requirements of use and facilitate construction, a large-span multi-ribbed composite slab (R-CS) with filled lightweight blocks is proposed based on systematic research. Static tests of the bending behaviour of the four pieces of the R-CS specimens and one ordinary concrete cast-in-place slab were carried out. The fracture distribution, bearing capacity, deflection, and load-strain curves of the tensile steel bars were analysed. The difference in the bending behaviour between the R-CS specimens and the cast-in-place slab and the influence of different structural forms on the bending behaviour of the R-CS samples were studied. By calculating the bearing capacity of the fully composite state, their composite performance was evaluated. The research shows that the bending failure process of the R-CS specimens is similar to that of the cast-in-place slab and the crack and deflection development as well as ductility are relatively good. The measured bearing capacity of the specimen can reach more than 70% of the theoretical calculation strength under the fully composite state. The composite performance is satisfactory.

Background. The relationship between heart rate in CAD patients who underwent percutaneous coronary intervention (PCI) and had long-term outcomes over up to 10 years of follow-up has not been investigated. Methods. All patients were from the CORFCHD-PCI, a retrospective cohort study that included a total of 6050 CAD patients who underwent PCI from January 2008 to December 2016. One patient was excluded due to a lack of heart rate data. Ultimately, 6049 patients were enrolled. The primary outcome was long-term mortality after PCI. Results. Patients were divided into 5 groups according to heart rate quintiles: 1st quintile (heart rate

On the basis of liquid-phase reduction mechanism, a novel synthesis method to prepare silver nanoparticles (AgNPs) is proposed, which uses piezoelectric-actuated three-phase flow pulsating mixing microfluidic chip. In order to study and explore the influence of different factors on the synthesis of AgNPs, a series of related synthesis experiments were carried out. The corresponding experimental conditions include the concentration of sodium hydroxide and reducing agent solution, polyvinylpyrrolidone (PVP) dosage, inlet flow rate, and synthesis temperature. The synthesized AgNPs were characterized by the UV-Vis absorption spectrophotometer and transmission electron microscopy. The effects of different experimental conditions on the controllable synthesis of AgNPs were analyzed, and the optimum synthesis conditions of AgNPs were obtained. Experimental results show that the spherical AgNPs with an average particle diameter of about 29 nm, high yield, fine morphology, and good monodispersity were synthesized using the microfluidic chip under the conditions of the working frequency (200 Hz), the initial concentration of silver nitrate (1 mM), the synthesis temperature (80°C), the concentration ratio of sodium hydroxide to silver nitrate (2 : 1), the concentration ratio of glucose to silver nitrate (4 : 1), the inlet flow rate (3.5 ml/min), and the quality ratio of PVP to silver (more than 1 : 1). The related research shows that it is an efficient synthesis method to develop the controllable synthesis experiments of AgNPs under multifactors using the three-phase pulsating mixing microfluidic chip.

In China, Gaomiaozi (GMZ) bentonite serves as a feasible buffer material in the high-level radioactive waste (HLW) repository, while its thermal conductivity is seen as a crucial parameter for the safety running of the HLW disposal. Due to the tremendous amount of heat released by such waste, the thermal conductivity of the buffer material is a crucial parameter for the safety running of the high-level radioactive waste disposal. For the purpose of improving its thermal conductivity, this research used the graphene oxide (GO) to modify the pure bentonite and then the nanocarbon-based bentonite (GO-GMZ) was obtained chemically. The thermal conductivity of this modified soil has been measured and investigated under various conditions in this study: the GO content, dry density, and water content. Researches confirm that the thermal conductivity of the modified bentonite is codetermined by the three conditions mentioned above, namely, the value of GO content, dry density, and water content. Besides, the study proposes an improved geometric mean model based on the special condition to predict the thermal conductivity of the compacted specimen; moreover, the calculated values are also compared with the experimental data.

BackgroundIt has been reported that sleep deprivation is associated with cardiac autonomic disorder, inflammation, and oxidative stress. Statins have significant cardiovascular protective effects in patients with cardiovascular disease. This study aimed to investigate the protective effect of statins on arrhythmia and heart rate variability in young healthy persons after 48‐hour sleep deprivation. Methods and ResultsThis study enrolled 72 young healthy participants aged 26.5±3.5 years. All participants received 48‐hour continuous ambulatory electrocardiogram monitoring. Arrhythmia, time, and frequency domain parameters were analyzed for all participants. The primary end point, low/high frequency ratio, was significantly lower in the statin group than in the control group (2.48±1.12 versus 3.02±1.23, P

Background. We previously found that expression of SET gene was up-regulated in polycystic ovaries by using microarray. It suggested that SET may be an attractive candidate regulator involved in the pathophysiology of polycystic ovary syndrome (PCOS). In this study, expression and cellular localization of SET protein were investigated in human polycystic and normal ovaries. Method. Ovarian tissues, six normal ovaries and six polycystic ovaries, were collected during transsexual operation and surgical treatment with the signed consent form. The cellular localization of SET protein was observed by immunohistochemistry. The expression levels of SET protein were analyzed by Western Blot. Result. SET protein was expressed predominantly in the theca cells and oocytes of human ovarian follicles in both PCOS ovarian tissues and normal ovarian tissues. The level of SET protein expression in polycystic ovaries was triple higher than that in normal ovaries (P

Objective: Despite N 6 -methyladenosine (m 6 A) being closely involved in various pathophysiological processes, its potential role in liver injury is largely unknown. We designed the current research to study the potential role of fat mass and obesity-associated protein (FTO), an m 6 A demethylase, on hepatic ischemia-reperfusion injury (IRI). Methods: Wild-type mice injected with an adeno-associated virus carrying fat mass and obesity-associated protein (AAV-FTO) or adeno-associated virus carrying green fluorescent protein (GFP) (AAV-GFP) were subjected to a hepatic IRI model in vivo. Hematoxylin-eosin staining was performed to observe IRI. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to observe the cell apoptosis. Reverse transcription polymerase chain reaction (RT-PCR) was used to observe the expression of FTO. The protein levels of FTO, apoptosis, or autophagy-associated signaling proteins were detected by western blot. Reactive oxygen species (ROS) levels were determined by flow cytometry, and immunohistochemistry was used to detect the FTO and LC3-II expression. For in vitro experiments, cultured hepatocytes were subjected to hypoxia/reoxygenation (H/R) stimulation. Monodansylcadaverine (MDC) staining was used to visualize autophagic vesicles. Results: In the present study, we showed that FTO was involved in hepatic IRI, apoptosis, and autophagy. Specifically, the expression level of FTO was significantly reduced in the hepatic IRI. Besides, increasing FTO expression (AAV-FTO) ameliorated the hepatic IRI in animal models, accompanied by decreased apoptosis and autophagy. Furthermore, the FTO inhibitor (FB23-2) aggravated autophagy in hepatocytes upon H/R-induced damage. Conclusion: FTO could act as a protective effector during hepatic IRI, associated with decreased apoptosis and autophagy. FTO-mediated m 6 A demethylation modification may be an important therapeutic target for hepatic IRI., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 Pi-Xiao Wang et al. Gastroenterology Research and Practice published by John Wiley & Sons Ltd.)

Background: Mendelian randomization analysis was applied to elucidate the causal relationship between the basal metabolic rate (BMR) and common cardiovascular diseases., Method: We choose BMR as exposure. BMR is the metabolic rate of the body when the basic physiological activities (blood circulation, breathing and constant body temperature) are maintained. The normal BMR is 1507 kcal/day for men and 1276 kcal/day for women. The dataset was drawn from the public GWAS dataset (GWAS ID: ukb-a-268), collected and analysed by UK biobank, containing 331,307 European males and females. SNPs independently and strongly associated with BMR were used as instrumental variables in the inverse variance weighted analysis. MR-Egger, weighted median, MR pleiotropy residual sum, and outlier methods were also performed, and the sensitivity was evaluated using horizontal pleiotropy and heterogeneity analyses to ensure the stability of the results., Results: An increased BMR is associated with a higher risk of cardiomyopathy (odds ratio [OR] = 2.00, 95% confidence interval [CI], 1.57-2.54, p = 1.87 × 10 -8 ), heart failure (OR = 1.39, 95% CI, 1.27-2.51, p = 8.1 × 10 -13 ), and valvular heart disease (OR = 1.18, 95% CI, 1.10-1.27, p = .00001). However, there was no clear association between BMR and the subtypes of other cardiovascular diseases, such as coronary disease (OR = .96, 95% CI, .85-1.08, p = .48651) and atrial fibrillation (AF) (OR = 1.85, 95% CI, 1.70-2.02, p = 6.28 × 10 -44 )., Conclusion: Our study reveals a possible causal effect of BMR on the risk of cardiomyopathy, heart failure and valvular disease, but not for coronary disease and AF., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Objective: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) commonly coexist and act synergistically to drive adverse clinical outcomes. This study is aimed at investigating the effects of exercise intervention and oral hypoglycaemic drug of metformin (MET) alone or combined on hepatic lipid accumulation. To investigate if oxidative stress and endoplasmic reticulum stress (ERS) are involved in lipotoxicity-induced hepatocyte apoptosis in diabetic mice and whether exercise and/or MET alleviated oxidative stress or ERS-apoptosis by AMPK-Nrf2-HO-1 signaling pathway., Methods: Forty db/db mice with diabetes (random blood glucose ≥ 250 mg/dL) were randomly allocated into four groups: control (CON), exercise training alone (EX), metformin treatment alone (MET), and exercise combined with metformin (EM) groups. Hematoxylin-eosin and oil red O staining were carried out to observe hepatic lipid accumulation. Immunohistochemical and TUNEL methods were used to detect the protein expression of the binding immunoglobulin protein (BiP) and superoxide dismutase-1 (SOD1) and the apoptosis level of hepatocytes. ERS-related gene expression and the AMPK-Nrf2-HO-1 signaling pathway were tested by western blotting., Results: Our data showed that db/db mice exhibited increased liver lipid accumulation, which induced oxidative and ER stress of the PERK-eIF2 α -ATF4 pathway, and hepatocyte apoptosis. MET combined with exercise training significantly alleviated hepatic lipid accumulation by suppressing BiP expression, the central regulator of ER homeostasis, and its downstream PERK-eIF2 α -ATF4 pathway, as well as upregulated the AMPK-Nrf2-HO-1 signaling pathway. Moreover, the combination of exercise and MET displayed protective effects on hepatocyte apoptosis by downregulating Bax expression and TUNEL-positive staining, restoring the balance of cleaved-caspase-3 and caspase-3, and improving the antioxidant defense system to prevent oxidative damage in db/db mice., Conclusion: Compared to MET or exercise intervention alone, the combined exercise and metformin exhibited significant effect on ameliorating hepatic steatosis, inhibiting oxidative and ER stress-induced hepatocyte apoptosis via improving the capacity of the antioxidant defense system and suppression of the PERK-eIF2 α -ATF4 pathway. Furthermore, upregulation of AMPK-Nrf2-HO-1 signaling pathway might be a key crosstalk between MET and exercise, which may have additive effects on alleviating hepatic lipid accumulation., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this study., (Copyright © 2022 Yuan Zhang et al.)

Background and Purpose: Tacrolimus a first-line medication used after transplantation can induce β-cell dysfunction, causing new-onset diabetes mellitus (NODM). Regenerating islet-derived protein 3 gamma (Reg3g), a member of the pancreatic regenerative gene family, has been reported to improve type 1 diabetes by promoting β-cell regeneration. We aim to investigate the role of Reg3g in reversing tacrolimus-induced β-cell dysfunction and NODM in mice., Experimental Approach: Circulating REG3A (the human homologue of mouse Reg3g) in heart transplantation patients treated with tacrolimus was detected. The glucose-stimulated insulin secretion and mitochondrial functions, including mitochondria membrane potential (MMP), mitochondria calcium, ATP production, oxygen consumption rate and mitochondrial morphology were investigated in β-cells. Additionally, effects of Reg3g on tacrolimus-induced NODM in mice were analysed., Key Results: Circulating REG3A level in heart transplantation patients with NODM significantly decreased compared with those without diabetes. Tacrolimus down-regulated Reg3g via inhibiting STAT3-mediated transcription activation. Moreover, Reg3g restored glucose-stimulated insulin secretion suppressed by tacrolimus in β-cells by improving mitochondrial functions, including increased MMP, mitochondria calcium uptake, ATP production, oxygen consumption rate and contributing to an intact mitochondrial morphology. Mechanistically, Reg3g increased accumulation of pSTAT3(Ser727) in mitochondria by activating ERK1/2-STAT3 signalling pathway, leading to restoration of tacrolimus-induced mitochondrial impairment. Reg3g overexpression also effectively mitigated tacrolimus-induced NODM in mice., Conclusion and Implications: Reg3g can significantly ameliorate tacrolimus-induced β-cell dysfunction by restoring mitochondrial function in a pSTAT3(Ser727)-dependent manner. Our observations identify a novel Reg3g-mediated mechanism that is involved in tacrolimus-induced NODM and establish the novel role of Reg3g in reversing tacrolimus-induced β-cell dysfunction., (© 2022 The British Pharmacological Society.)

Language comprehension is compositional: individual words are combined structurally to form larger meaning representations. The neural basis for compositionality is at the center of a growing body of recent research. Previous work has largely used univariate analysis to investigate the question, a technique that could potentially lead to the loss of fined-grained information due to the procedure of averaging over neural responses. In a functional magnetic resonance imaging experiment, the present study examined different types of composition relations in Chinese phrases, using a 1-back composition relation probe (CRP) task and a 1-back word probe (WP) task. We first analyzed the data using the multivariate representation similarity analysis, which better captures the fine-grained representational differences in the stimuli. The results showed that the left angular gyrus (AG) represents different types of composition relations in the CRP task, but no brain areas were identified in the WP task. We also conducted a traditional univariate analysis and found greater activations in the bilateral inferior frontal gyrus in the CRP task relative to the WP task. We discuss the methodological and theoretical implications of our findings in the context of the larger language neural network identified in previous studies. Our findings highlight the role of left AG in representing and distinguishing fine-grained linguistic composition relations., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Myocardial ischemia is a disease with high morbidity and mortality, for which reperfusion is currently the standard intervention. However, the reperfusion may lead to further myocardial damage, known as myocardial ischemia/reperfusion injury (MI/RI). Oxidative stress is one of the most important pathological mechanisms in reperfusion injury, which causes apoptosis, autophagy, inflammation, and some other damage in cardiomyocytes through multiple pathways, thus causing irreversible cardiomyocyte damage and cardiac dysfunction. This article reviews the pathological mechanisms of oxidative stress involved in reperfusion injury and the interventions for different pathways and targets, so as to form systematic treatments for oxidative stress-induced myocardial reperfusion injury and make up for the lack of monotherapy., Competing Interests: The authors declare that they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2021 Mi Xiang et al.)

Background: The comparative risks of a second cancer diagnosis are uncertain after primary cancer treatment with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), or proton beam radiotherapy (PBRT)., Methods: Pediatric and adult patients with a first cancer diagnosis between 2004 and 2015 who received 3DCRT, IMRT, or PBRT were identified in the National Cancer Database from 9 tumor types: head and neck, gastrointestinal, gynecologic, lymphoma, lung, prostate, breast, bone/soft tissue, and brain/central nervous system. The diagnosis of second cancer was modeled using multivariable logistic regression adjusting for age, follow-up duration, radiotherapy (RT) dose, chemotherapy, sociodemographic variables, and other factors. Propensity score matching also was used to balance baseline characteristics., Results: In total, 450,373 patients were identified (33.5% received 3DCRT, 65.2% received IMRT, and 1.3% received PBRT) with median follow-up of 5.1 years after RT completion and a cumulative follow-up period of 2.54 million person-years. Overall, the incidence of second cancer diagnosis was 1.55 per 100 patient-years. In a comparison between IMRT versus 3DCRT, there was no overall difference in the risk of second cancer (adjusted odds ratio [OR], 1.00; 95% CI, 0.97-1.02; P = .75). By comparison, PBRT had an overall lower risk of second cancer versus IMRT (adjusted OR, 0.31; 95% CI, 0.26-0.36; P < .0001). Results within each tumor type generally were consistent in the pooled analyses and also were maintained in propensity score-matched analyses., Conclusions: The risk of a second cancer diagnosis was similar after IMRT versus 3DCRT, whereas PBRT was associated with a lower risk of second cancer risk. Future work is warranted to determine the cost-effectiveness of PBRT and to identify the population best suited for this treatment., (© 2020 American Cancer Society.)

Aims: Treatment for acute kidney injury (AKI) is challenging. Induced pluripotent stem cells (iPSCs) have great therapeutic potential. This study sought to determine whether iPSCs attenuate AKI and the role of reactive oxygen species (ROS)., Results: We intravenously injected isogenic iPSCs into mice 2 h after renal ischemia-reperfusion injury (IRI). The cells were selectively trafficked to ischemia/reperfusion-injured kidney where they decreased kidney ROS and inflammatory cytokines and improved kidney function and morphology. Pretreating the cells with ROS inhibitors before administration decreased iPSC engraftment and abolished the protective effect of iPSCs. In contrast, pretreating iPSCs with hydrogen peroxide increased iPSC engraftment and therapeutic effect. Although the intravenously administered iPSCs trafficked to the IRI kidney, the cells did not differentiate into proximal or distal tubular epithelial cells. In vitro , the capabilities of the iPSC-released substances to promote proliferation and decrease apoptosis of renal epithelial cells were increased by ROS pretreatment of iPSCs. Moreover, pretreatment of the iPSCs with ROS inhibitor had the opposite effect. Similarly, moderate concentrations of ROS increased while ROS inhibitors decreased iPSC mobility, adhesion to the extracellular matrix, and mitochondrial metabolism. Innovation and Conclusion . iPSCs decreased renal ischemia/reperfusion injury mainly through iPSC-released substances. The therapeutic effect, mitochondrial metabolism, mobility, and kidney trafficking of iPSCs were ROS dependent., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Shun Wang et al.)

Objectives: Type 2 diabetes mellitus (T2DM) is associated with coronary artery calcification (CAC) which is an independent risk factor for cardiovascular events. Metformin is the first-line antidiabetic medication. We aimed to investigate the association between metformin use and CAC., Methods: We included 369 patients with T2DM in this cross-sectional study. CAC scores, clinical characteristics, and antidiabetic drug prescription information of the patients were acquired. Baseline parameters were balanced for metformin and nonmetformin users using the propensity score matching (PSM) strategy., Results: Among the 369 subjects who met our inclusion criteria, 288 subjects were included for further analysis after PSM. Metformin prescription rather than other antidiabetic medications was related to lower CAC scores (OR [95% CI] = 0.55 [0.34-0.90]; P = 0.018). Further multivariable logistic regression analysis demonstrated that metformin was negatively associated with CAC severity (OR [95% CI] = 0.58 [0.34-0.99]; P = 0.048), which was independent of age, BMI, eGFR, gender, cigarette smoking, duration of diabetes, hypertension, statin prescription, and number of nonmetformin antidiabetic agents. A subgroup analysis revealed a significant association between metformin and CAC scores in smokers (OR [95% CI] = 0.38 [0.16-0.93]; P = 0.035), but the association was not observed in never-smokers (OR [95% CI] = 0.72 [0.34-1.51]; P = 0.383)., Conclusions: Metformin usage was independently associated with lower CAC scores in T2DM patients. The negative correlation between CAC scores and metformin was most prominent in patients with a history of cigarette smoking.

Patients with triple negative breast cancer were identified using the Surveillance, Epidemiology, and End Results database. Competing risks analysis was used to assess the cumulative incidence of breast cancer-specific mortality (BCSM). Multivariable Fine-Gray regression was used to identify predictors of BCSM. Women age 70+ (n = 4221) were less likely to receive chemotherapy and radiation treatment (P < 0.0001) and had higher BCSM compared to younger women (P < 0.0001). There were no differences in BCSM in patients who received adjuvant treatment (P = 0.10). Stage II patients derived the greatest relative and absolute benefit from adjuvant treatment. Age was not a significant predictor of BCSM., (© 2019 Wiley Periodicals, Inc.)