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To investigate the molecular etiology of low sperm quality in patients with intractable spermatocystitis, spermatozoa samples from patients with persistent hematospermia undergoing transurethral seminal vesiculoscopy and healthy volunteers were utilized. Spermatozoa samples were collected from the seminal vesicles through transurethral seminal vesiculoscopy or by masturbation ejaculation. Sperm quality was analyzed by a WLJY-9000 color semen analysis system. Measurement of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) in the seminal plasma was performed using enzyme-linked immunosorbent assay (ELISA). Measurement of H2O2 in the seminal plasma was performed with a hydrogen peroxide kit. The protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and phosphorylated-Nrf2 (p-Nrf2) were measured by western blot analysis and immunofluorescence assays. Low sperm quality parameters and increased levels of inflammatory cytokines (TNFα, IL-6, and H2O2) in the seminal plasma were detected among the semen samples from the patients with persistent hematospermia. Nrf2 and p-Nrf2 were strongly expressed in the nucleus and periphery of human sperm cells, according to the results of the immunofluorescence assays. The protein levels of Nrf2 and p-Nrf2 were significantly lower in the spermatozoa samples from patients with persistent hematospermia than in those from healthy volunteers with normal sperm motility. The results suggested that Nrf2 signaling might play a role in the low sperm quality of patients with intractable spermatocystitis.

Abstract Information regarding regional arterial stiffness assessment in osteoarthritis (OA) was scarce and sometimes contradictory. We aimed to investigate the aortic, lower limb peripheral arterial stiffness and their associations with knee OA. Patients with primary knee OA and matched non-OA controls were prospectively enrolled from two medical centers in China. The carotid-femoral pulse wave velocity (cfPWV) and femoral-ankle pulse wave velocity (faPWV) were measured using a novel ultrasound technique. A total of 238 participants (including 128 patients with knee OA and 110 controls) were included. In OA patients, cfPWV was significantly higher than that of non-OA controls (9.40 ± 1.92 vs 8.25 ± 1.26 m/s, P

Abstract Large machine learning models are revolutionary technologies of artificial intelligence whose bottlenecks include huge computational expenses, power, and time used both in the pre-training and fine-tuning process. In this work, we show that fault-tolerant quantum computing could possibly provide provably efficient resolutions for generic (stochastic) gradient descent algorithms, scaling as $${{{{{{{\mathcal{O}}}}}}}}({T}^{2}\times {{{{{{{\rm{polylog}}}}}}}}(n))$$ O ( T 2 × polylog ( n ) ) , where n is the size of the models and T is the number of iterations in the training, as long as the models are both sufficiently dissipative and sparse, with small learning rates. Based on earlier efficient quantum algorithms for dissipative differential equations, we find and prove that similar algorithms work for (stochastic) gradient descent, the primary algorithm for machine learning. In practice, we benchmark instances of large machine learning models from 7 million to 103 million parameters. We find that, in the context of sparse training, a quantum enhancement is possible at the early stage of learning after model pruning, motivating a sparse parameter download and re-upload scheme. Our work shows solidly that fault-tolerant quantum algorithms could potentially contribute to most state-of-the-art, large-scale machine-learning problems.

Abstract Emerging evidence indicates that the activation of ferroptosis by glutathione peroxidase 4 (GPX4) inhibitors may be a prominent therapeutic strategy for tumor suppression. However, the wide application of GPX4 inhibitors in tumor therapy is hampered due to poor tumor delivery efficacy and the nonspecific activation of ferroptosis. Taking advantage of in vivo self-assembly, we develop a peptide-ferriporphyrin conjugate with tumor microenvironment specific activation to improve tumor penetration, endocytosis and GPX4 inhibition, ultimately enhancing its anticancer activity via ferroptosis. Briefly, a GPX4 inhibitory peptide is conjugated with an assembled peptide linker decorated with a pH-sensitive moiety and ferriporphyrin to produce the peptide-ferriporphyrin conjugate (Gi-F-CAA). Under the acidic microenvironment of the tumor, the Gi-F-CAA self-assembles into large nanoparticles (Gi-F) due to enhanced hydrophobic interaction after hydrolysis of CAA, improving tumor endocytosis efficiency. Importantly, Gi-F exhibits substantial inhibition of GPX4 activity by assembly enhanced binding (AEB) effect, augmenting the oxidative stress of ferriporphyrin-based Fenton reaction, ultimately enabling antitumor properties in multiple tumor models. Our findings suggest that this peptide-ferriporphyrin conjugate design with AEB effect can improve the therapeutic effect via induction of ferroptosis, providing an alternative strategy for overcoming chemoresistance.

The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent Mpro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent Mpro inhibitors with desirable properties have been developed based on available crystal structures of Mpro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent Mpro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent Mpro inhibitors are also discussed.

The effect of pre-stretching on solid-liquid interaction, microstructure and brazing performance of AA4343/AA3xxx/AA4343 layered aluminum sheet during brazing at the atomic level (solid solution), nanoscale (dislocation) and micron level (grain boundary) are studied by glow discharge optical emission spectrometry (GDOES), scanning electron microscope (SEM), electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM). The microstructure after brazing largely depends on the forming condition. The driving force of liquid film migration (LFM) is the reduction of stored deformation energy. The interaction between the liquid clad and solid core layers changes the elemental distribution and microstructure, which in turn affects the brazing performance of the sheet. The results reveal the mechanism of solid-liquid interaction of layered aluminum sheet during brazing and clarify the driving force of LFM of layered aluminum sheet during brazing. Consequently, these results provide important insights for the design and theoretical research of functional layered aluminum sheet.

As an effective means of structural vibration suppression, piezoelectric actuator vibration suppression system(PAVSS) has been gradually applied in structural vibration control. However, the performance degradation or failure of piezoelectric actuator under long service life will lead to the degradation of service reliability of PAVSS, so the scheme obtained by deterministic optimization method is difficult to ensure the service reliability. Aiming at the reliability evaluation and optimal design of PAVSS in service, the failure mechanism considering of the performance degradation or failure of piezoelectric actuator is analyzed, and the reliability evaluation method based on nested sampling and weighted statistics is constructed, which solves the reliability evaluation problem of PAVSS with the characteristics of load-sharing and redundancy. A reliability-based optimization method based on master-slave parallel genetic algorithm is proposed to optimize the position and angle of the actuators. At last, the feasibility and effectiveness of the proposed method are proved by an example, which not only provides a theoretical basis for the high reliability design of PAVSS in service, but also provides a new solution for the engineering problem of structural vibration control.

Abstract The drilling cuttings weight index fails to reflect coal’s stress conditions under water-rich environments, potentially undermining the drilling cutting method’s reliability for monitoring and early warning of rockburst risks. We integrated theoretical analysis with triaxial drilling tests to investigate the mechanical evolution, the spatio-temporal dynamics of absolute energy, and the failure modes during the drilling of water-bearing coal specimens. Moreover, we established the critical drilling cuttings weight index for these specimens by analyzing test outcomes and associated weakening coefficients. Results show that: (1) as the moisture content increases, the damage and rupture mode of coal changes from punctate frictional damage between microstructures to interlayer slip, dislocation, and friction of weak structural planes; macroscopically, it is shown as the increasing number of cracks in the horizontal and vertical directions in specimens; (2) The dynamic response frequency of rockburst-prone coal has a positive correlation with the moisture content. The elastic energy storage capacity of water-bearing coal is reduced, dynamic events develop in a shorter period while their frequency increases. In addition, the level of single energy release decreases; (3) With increasing moisture content, damage to boreholes in coal can be divided into two stages: convergence and crack initiation; (4) The deformation and damage range of boreholes is positively correlated with the moisture content. When the moisture contents are 1.4%, 2.3%, and 3.7%, the damage radii of specimens along the center of the boreholes are 2.03, 2.98, and 3.36 times the drilling radius; (5) The weight of drilling cuttings for coal with the moisture content of 3.70% is 2.78–3.48 times that of natural coal; for coal containing 5.60% of water, the weight of drilling cuttings is 1.50–3.20 times that of natural coal. The research conclusions provide reference for optimization of the index for the weight of drilling cuttings and effective rockburst monitoring of rockburst-prone coal under water-rich conditions.

Abstract Background Right ventricle failure (RVF) is a progressive heart disease that has yet to be fully understood at the molecular level. Elevated M-type pyruvate kinase 2 (PKM2) tetramerization alleviates heart failure, but detailed molecular mechanisms remain unclear. Objective We observed changes in PKM2 tetramerization levels during the progression of right heart failure and in vitro cardiomyocyte hypertrophy and explored the causal relationship between altered PKM2 tetramerization and the imbalance of redox homeostasis in cardiomyocytes, as well as its underlying mechanisms. Ultimately, our goal was to propose rational intervention strategies for the treatment of RVF. Method We established RVF in Sprague Dawley (SD) rats by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right heart function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. TEPP-46 was used both in vivo and in vitro to promote PKM2 tetramerization. Results We observed that oxidative stress and mitochondrial disorganization were associated with increased apoptosis in the right ventricular tissue of RVF rats. Quantitative proteomics revealed that PKM2 was upregulated during RVF and negatively correlated with the cardiac function. Facilitating PKM2 tetramerization promoted mitochondrial network formation and alleviated oxidative stress and apoptosis during cardiomyocyte hypertrophy. Moreover, enhancing PKM2 tetramer formation improved cardiac mitochondrial morphology, mitigated oxidative stress and alleviated heart failure. Conclusion Disruption of PKM2 tetramerization contributed to RVF by inducing mitochondrial fragmentation, accumulating ROS, and finally promoted the progression of cardiomyocyte apoptosis. Facilitating PKM2 tetramerization holds potential as a promising therapeutic approach for RVF.

AIM: To investigate the effect of electroacupuncture (EA) on the mitochondria-dependent apoptotic signaling pathway in the ciliary muscle of guinea pigs with negative lens-induced myopia (LIM). METHODS: Guinea pigs were randomly divided into normal control (NC) group, LIM group, LIM+SHAM acupoint (LIM+SHAM) group, and LIM+EA group. Animals in the NC group received no intervention, while those in other three groups were covered with -6.0 diopter (D) lenses on right eyes. Meanwhile, animals in the LIM+EA group received EA at Hegu (LI4) combined with Taiyang (EX-HN5) acupoints, while those in the LIM+SHAM group were treated at sham points. After treatments for 1, 2, and 4wk, morphological changes in ciliary muscles were observed with hematoxylin and eosin (H&E) staining and nick end labeling (TUNEL), and the expression of the mitochondrial apoptotic signaling pathway-related molecules in ciliary muscles was measured by real-time quantitative polymerase chain reaction (qPCR) and Western blot. Additionally, the adenosine triphosphate (ATP) contents were also determined in ciliary muscles. RESULTS: Axial length increased significantly in the LIM and LIM+SHAM groups and decreased in the LIM+EA group. The ciliary muscle fibers were broken and destroyed in both LIM and LIM+SHAM groups, whereas those in the LIM+EA group improved significantly. TUNEL assay showed the number of apoptotic cells increased in the LIM and LIM+SHAM groups, whereas reduced in the LIM+EA group. ATP contents showed a significant decrease in the LIM and LIM+SHAM groups, whereas increased after EA treatment. Compared with the NC group, the dynamin-related protein 1 (DRP1), Caspase3, and apoptotic protease activator 1 (APAF1) levels were significantly increased in the LIM group and decreased in the LIM+EA group. CONCLUSION: The results provide evidence of EA inhibiting the development of myopia by regulating the mitochondrial apoptotic signaling pathway.

Objectives: Overuse of antibiotics in healthcare remains prevalent and requires urgent attention in China, particularly in primary healthcare (PHC) facilities. This study aimed to describe the patterns of antibiotic prescriptions for acute upper respiratory tract infections (URTIs) in PHC facilities in China and to investigate how PHC physicians’ knowledge influences their antibiotic prescribing behavior. Methods: A cross-sectional survey linking physician questionnaire responses and their prescription data was conducted in Shaanxi Province, China. The proportions of URTI visits that received at least one antibiotic, combined antibiotics, and broad-spectrum antibiotics were the main outcomes reflecting antibiotic prescribing behavior. Multivariate mixed-effects logistic regressions were applied to analyze the relationship between PHC physicians’ knowledge about antibiotics and their antibiotic prescribing behavior. Results: A total of 108 physicians filled out the questionnaires between February 2021 and July 2021, and a sample of 11,217 URTI visits attended by these physicians from 1 January 2020 to 31 December 2020 were included in the analysis. The overall mean score of our respondents on the knowledge questions was 5.2 (total score of 10). Over sixty percent (61.2%; IQR 50.2–72.1) of the URTI visits received antibiotics. The percentages of URTI visits prescribed with combined and broad-spectrum antibiotics were 7.8% (IQR 2.3–10.2) and 48.3% (IQR 36.7–58.7), respectively. Third-generation cephalosporins were the most frequently used antibiotics. Physicians with lower antibiotic knowledge scores were more inclined to prescribe antibiotics (p < 0.001), combined antibiotics (p = 0.001), and broad-spectrum antibiotics (p < 0.001). Conclusions: Physicians’ insufficient knowledge was significantly associated with antibiotic overprescribing. Professional training targeting physicians’ knowledge of antibiotics is urgently needed to improve the rational use of antibiotics in grassroots healthcare facilities in China.

Multi-physical inversion plays a critical role in geophysics. It has been widely used to infer various physical properties (such as velocity and conductivity). Among those inversion problems, some are explicitly governed by partial differential equations (PDEs), while others are not. Without explicit governing equations, conventional multi-physical inversion techniques will not be feasible and data-driven inversion requires expensive full labels. To overcome this issue, we develop a new data-driven multi-physics inversion technique with extremely weak supervision. Our key finding is that the pseudo labels can be constructed by learning the local relationship among geophysical properties at very sparse well-logging locations. We explore a multi-physics inversion problem from two distinct measurements (seismic and EM data) to three geophysical properties (velocity, conductivity, and CO2 saturation). Our results show that we are able to invert for properties without explicit governing equations. Moreover, the label data on three geophysical properties can be significantly reduced by 50 times (from 100 down to only 2 locations).

BackgroundFragile X syndrome is characterized by a myriad of physical features, behavioral features, and medical problems. Commonly found behavioral features are hyperactivity, anxiety, socialization difficulties, and ASD. There is also a higher incidence than in the general population of strabismus, otitis media, and mitral valve prolapse. In addition, one of the most common medical problems associated with FXS is an increased risk of seizures. A subset of individuals carrying the full mutation of the FMR1 gene and diagnosed with fragile X syndrome (FXS) are reported to experience seizures, mostly during the first 10 years of their life span.MethodsAs part of a larger project to identify genetic variants that modify the risk of seizures, we collected clinical information from 49 carriers with FXS who experienced seizures and 46 without seizures. We compared seizure type and comorbid conditions based on the source of data as well as family history of seizures.ResultsWe found that the concordance of seizure types observed by parents and medical specialists varied by type of seizure. The most common comorbid condition among those with seizures was autism spectrum disorder (47% per medical records vs. 33% per parent report compared with 19% among those without seizures per parent report); the frequency of other comorbid conditions did not differ among groups. We found a slightly higher frequency of family members who experienced seizures among the seizure group compared with the nonseizure group.ConclusionThis study confirms previously reported features of seizures in FXS, supports additional genetic factors, and highlights the importance of information sources, altogether contributing to a better understanding of seizures in FXS.