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Virtual Reality (VR) is increasingly recognized as a promising tool to enhance learning, yet research on the use of VR instructional approaches for online learning remains limited. The present study aims to address this research gap by examining the effects of VR instructional approaches and textual cues on learning. We conducted an educational VR study using a 2 x 2 + 1 between-subjects design involving 67 secondary vocational students. Participants learned computer assembly online and were exposed to either vicarious experience or direct manipulation instructional approaches, with or without textual cues. A control group received traditional online instruction using slides. We collected retention, transfer learning outcomes, cognitive load, and learning experience of students. The findings indicated that while vicarious VR had no effects on long-term retention, transfer, and learning experience, there were significant positive effects on the immediate acquisition of knowledge. Textual cues did not affect learning in general. However, for immediate knowledge gain, they did provide a positive boost to learning in VR involving direct manipulation, while they were unnecessary in vicarious VR experiences. This study contributes to how the cueing principle can be extended to educational VR contexts and expands the knowledge of vicarious VR learning.

The COVID-19 pandemic has popularized online learning as a mode of teaching and learning in universities, thereby exacerbating college students' stress levels in multiple ways. To enhance the quality of college student training, it is crucial to investigate the impact of perceived stress on their online self-directed learning. Using questionnaire data from 969 college students across China, this study performed an empirical analysis of the influence of perceived stress on their online self-directed learning, while also exploring the mediating role of phone dependence and the moderating role of self-management ability. The findings indicate that, firstly, perceived stress has a significant and positive effect on college students' online self-directed learning. Secondly, phone dependence masks the positive impact of perceived stress on students' self-directed learning, thereby weakening the effects of employment and learning stress on their online self-directed learning. Thirdly, self-management ability positively moderates the relationship between employment, social, interpersonal, and learning stress and college students' online self-directed learning. Fourthly, rural college students' online self-directed learning is more susceptible to employment, social, and interpersonal stress; vocational college students' self-directed learning is more influenced by employment, social, and learning stress; and students in the "Double First-Class" initiative universities are more likely to develop phone dependence. Therefore, this paper asserts that using stress reasonably, controlling stress appropriately, channeling stress properly, and enhancing self-management abilities can aid college students in learning autonomous online.

In present work, non-isothermal crystallization behavior for novel Cr50Fe6Co7Mo14C15B6Y2 metallic glass (MG) with super high content of Cr and excellent merits was investigated by differential scanning calorimeter and X-ray diffraction. Both of the Kissinger and Ozawa methods show that the present glass transition is much harder than other transitions for a much larger apparent activation energy (E). While, the growth process of present second crystallization event is the easiest process, since it possesses the smallest E. Meanwhile, the local activation energy established by Kissinger-Akahira-Sunose and Ozawa-Flynn-Wall methods both exhibit a trend of increasing to the maximum value at first and then gradual decrease until the finish of the crystallization, indicating that the difficulty increases until to the maximum at first and then gradually decreases during crystallization. Moreover, all the local Avrami exponent n(x) possesses a value of about 0 < n(x)

Abstract Background Intervertebral disc degeneration (IVDD) is a common spine disease with inflammation as its main pathogenesis. Mulberroside A (MA), isolated from herbal medicine, possesses anti-inflammatory characteristics in many diseases. Whereas, there is little exploration of the therapeutic potential of MA on IVDD. This study aimed at the therapeutic potential of MA on IVDD in vivo and in vitro and the mechanism involved. Methods In vitro, western blotting, RT-qPCR, and immunofluorescence analysis were implemented to explore the bioactivity of MA on interleukin-1 beta (IL-1β)-induced inflammation nucleus pulposus cells (NPCs) isolated from Sprague-Dawley male rats. In vivo, X-ray and MRI were applied to measure the morphological changes, and histological staining and immunohistochemistry were employed to investigate the histological changes of intervertebral disc sections on puncture-induced IVDD rat models. Results In vitro, MA up-regulated the expression level of anabolic-related proteins (Aggrecan and Collagen II) and decreased catabolic-related proteins (Mmp2, Mmp3, Mmp9, and Mmp13) in IL-1β-induced NPCs. Furthermore, MA inhibits the production of pro-inflammatory factors (Inos, Cox-2, and Il-6) stimulated by IL-1β. Mechanistically, MA inhibited the signal transduction of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) pathways in IL-1β-induced NPCs. Moreover, MA might bind to Ppar-γ and then suppress the NF-kB pathway. In vivo experiment illustrated that MA mitigates the IVDD progression in puncture-induced IVDD model. X-ray and MRI images showed MA restore the disc height and T2-weighted signal intensity after puncturing. H&E and Safranin O/Fast Green also showed MA also alleviated morphological changes caused by acupuncture. In addition, MA reversed the expression level of Mmp13, Aggrecan, Collagen II, and Ppar-γ induced in IVDD models. Conclusions MA inhibited degenerative phenotypes in NPCs and alleviated IVDD progression via inhibiting the MAPK and NF-κB pathways; besides, MA suppressed the NF-κB pathway was attributed to activating Ppar-γ, those supported that MA or Ppar-γ might be a potential drug or target for IVDD.

Abstract Background Data on long-term cancer survivors treated with apatinib are lacking. This study aimed to describe the characteristics of long-term cancer survivors after apatinib-based therapy, and to know about their satisfaction degree with apatinib and severity of depression and insomnia. Methods Patients with solid tumors who had received apatinib-based therapy for at least 5 years were invited to complete an online questionnaire. Characteristics of patients and treatment, knowledge of apatinib, satisfaction degree, and severity of depression and insomnia assessed by Patient Health Questionnaire-9 and Insomnia Severity Index were collected. Results Between December 8, 2023 and March 1, 2024, a total of 436 patients completed the online questionnaire. Most patients were satisfied with the efficacy (96.6%) and safety (93.1%) of apatinib, were willing to continue apatinib treatment (99.5%), and would recommend apatinib to other patients (93.3%). Continuous apatinib treatment resulted in significant negative impact on daily life, work, or study in only two (0.5%) patients. Almost all patients currently had no or mild depression (97.0%) and insomnia (97.9%) problems. The most common patient-reported adverse events were hand-foot syndrome (21.3%) and hypertension (18.3%). Conclusions Our survey showed a high satisfaction degree with apatinib in long-term cancer survivors. Long-term apatinib treatment resulted in almost no negative impact on patient’s quality of life.

Abstract Background It was reported that either shorter programmed intermittent epidural bolus (PIEB) intervals or high-speed bolus can produce more extensive epidural spread. We hypothesized that a combination of shortened time interval and increased speed of epidural bolus might further improve analgesic effect and therefore reduce the hourly volume for epidural labour analgesia. Methods This double-blind dose-finding study used a biased coin up-and-down sequential allocation method to determine the 90% effective bolus volume of ropivacaine combined with sufentanil while using the push pump at a rate of 400 mL/hr and interval of 30 min to provide effective analgesia without breakthrough pain. We used 0.1% ropivacaine with 0.4 µg/mL sufentanil, with bolus volumes ranging from 3 to 6 mL. The first patient was assigned a volume of 3 mL, and the remaining volumes were assigned according to the biased coin-up-and-down method. Results The estimated 90% effective volume (EV90) of ropivacaine combined with sufentanil for epidural labour analgesia at a time interval of 30 min was 4.88 mL (95% confidence interval 4.83–5.38). Conclusions The optimum bolus volume of ropivacaine with sufentanil while using push pump at a time interval of 30 min is approximately 5 mL. It could probably further reduce the hourly bolus volume for epidural labour analgesia.

Abstract The glymphatic-lymphatic system is increasingly recognized as fundamental for the homeostasis of the brain milieu since it defines cerebral spinal fluid flow in the brain parenchyma and eliminates metabolic waste. Animal and human studies have uncovered several important physiological factors regulating the glymphatic system including sleep, aquaporin-4, and hemodynamic factors. Yet, our understanding of the modulation of the glymphatic system is limited, which has hindered the development of glymphatic-based treatment for aging and neurodegenerative disorders. Here, we present the evidence from fluorescence tracing, two-photon recording, and dynamic contrast-enhanced magnetic resonance imaging analyses that 40 Hz light flickering enhanced glymphatic influx and efflux independently of anesthesia and sleep, an effect attributed to increased astrocytic aquaporin-4 polarization and enhanced vasomotion. Adenosine-A2A receptor (A2AR) signaling emerged as the neurochemical underpinning of 40 Hz flickering-induced enhancement of glymphatic flow, based on increased cerebrofluid adenosine levels, the abolishment of enhanced glymphatic flow by pharmacological or genetic inactivation of equilibrative nucleotide transporters-2 or of A2AR, and by the physical and functional A2AR–aquaporin-4 interaction in astrocytes. These findings establish 40 Hz light flickering as a novel non-invasive strategy of enhanced glymphatic flow, with translational potential to relieve brain disorders.

Abstract Tensor networks are emerging architectures for implementing quantum classification models. The branching multi-scale entanglement renormalization ansatz (BMERA) is a tensor network known for its enhanced entanglement properties. This paper introduces a hybrid quantum-classical classification model based on BMERA and explores the correlation between circuit layout, expressiveness, and classification accuracy. Additionally, we present an autodifferentiation method for computing the cost function gradient, which serves as a viable option for other hybrid quantum-classical models. Through numerical experiments, we demonstrate the accuracy and robustness of our classification model in tasks such as image recognition and cluster excitation discrimination, offering a novel approach for designing quantum classification models.

Abstract Background At present, no studies explored whether dietary fiber intake was associated with the risk of peripheral artery disease (PAD) in hypertensive patients. This study assessed the association between dietary fiber intake and PAD in hypertensive patients. Methods This cross-sectional study collected the data of 4628 participants with the measurement of ankle-brachial pressure index in the National Health and Nutrition Examination Surveys database. Univariate logistic regression analysis was applied to identify variables associated with PAD as confounding factors. Univariate and multivariable logistic regression analyses were used to explore the association between dietary fiber intake and PAD in hypertensive patients. Subgroup analysis was stratified by age, cardiovascular disease, dyslipidemia, diabetes, smoking, and physical activity. Results After adjusting for confounding factors, decreased risk of PAD was observed in hypertensive patients with dietary fiber intake > 21 g [odds ratio (OR) = 0.67, 95% confidence interval (CI) 0.46–0.99]. Compared with people with dietary fiber intake ≤ 21 g, those with dietary fiber intake > 21 g were associated with decreased risk of PAD in hypertensive patients 21 g were associated with reduced risk of PAD (OR = 0.33, 95%CI 0.12–0.95). Decreased risk of PAD was also found in hypertensive patients without diabetes in dietary fiber intake > 21 g group (OR = 0.50, 95%CI 0.31–0.78). Dietary fiber intake > 21 g was linked with reduced risk of PAD in hypertensive patients in never smoke group (OR = 0.46, 95%CI 0.24–0.86). Conclusion Higher dietary fiber intake was associated with reduced risk of PAD in hypertensive patients, suggesting the importance of increase the daily dietary quality especially fiber intake in hypertensive people.

Parameters of foam penetration in earth pressure balance (EPB) shield tunnelling, such as permeability coefficients and penetration distances, significantly impact tunnel face stability. However, existing studies have faced inaccuracies in analysing these parameters due to imitations in experimental methods. This study addresses this issue by employing enhanced methods for a more precise analysis of foam penetration. Experiments involving three distinct sand types (coarse, medium, and fine) and three foam expansion ratios (FER) (10, 15, and 20) are conducted using a modified model test setup. Benefiting from a novel computer vision-based method, the model test outcomes unveil two distinct foam penetration paths: liquid migration (Lw) and bubble migration (Lf). Three penetration phases — namely, injection, blockage & drainage, and breakage — are identified based on Lw and Lf variations. The initial “injection” phase conforms to Darcy's law and is amenable to mathematical description. The foam with FER of 15 has the maximum viscosity and, hence the Lf and permeability in the penetration tests with FER of 15 are the lowest in the same sand. The bubble size distribution of foam with different FER shows minor differences. Nevertheless, the characteristics of foam penetration vary due to the distinct particle size distribution (PSD) of different sands. Foam penetration creates low-permeability layers in both medium and fine sands due to the larger bubble size of the foam compared to the estimated pore sizes of medium and fine sands. While the coarse sand results in a different situation due to its large pore size. The distinctive characteristics of foam penetration in different sand strata are notably shaped by FER, PSD, and pore size distributions. These insights shed light on the complex interactions during foam penetration at the tunnel face, contributing valuable knowledge to EPB shield tunnelling practices.

The activation of spinal astrocytes accounts for opioid-induced hyperalgesia (OIH), but the underlying mechanisms remain elusive. The presence of astrocyte-neuron lactate shuttle (ANLS) makes astrocytes necessary for some neural function and communication. The aim of this study was to explore the role of ANLS in the occurrence and maintenance of OIH. After 7 days consecutive morphine injection, a mice OIH model was established and astrocytic pyruvate dehydrogenase kinase 4 (PDK4), phosphorylated pyruvate dehydrogenase (p-PDH) and accumulation of L-lactate was elevated in the spinal dorsal horn. Intrathecally administration of inhibitors of PDK, lactate dehydrogenase 5 and monocarboxylate transporters to decrease the supply of L-lactate on neurons was observed to attenuate hypersensitivity behaviors induced by repeated morphine administration and downregulate the expression of markers of central sensitization in the spinal dorsal horns. The astrocyte line and the neuronal line were co-cultured to investigate the mechanisms in vitro. In this study, we demonstrated that morphine-induced hyperalgesia was sustained by lactate overload consequent upon aberrant function of spinal ANLS. In this process, PDK-p-PDH-lactate axis serves a pivotal role, which might therefore be a new target to improve long-term opioid treatment strategy in clinical practice.

Abstract Dysfunction of pancreatic δ cells contributes to the etiology of diabetes. Despite their important role, human δ cells are scarce, limiting physiological studies and drug discovery targeting δ cells. To date, no directed δ-cell differentiation method has been established. Here, we demonstrate that fibroblast growth factor (FGF) 7 promotes pancreatic endoderm/progenitor differentiation, whereas FGF2 biases cells towards the pancreatic δ-cell lineage via FGF receptor 1. We develop a differentiation method to generate δ cells from human stem cells by combining FGF2 with FGF7, which synergistically directs pancreatic lineage differentiation and modulates the expression of transcription factors and SST activators during endoderm/endocrine precursor induction. These δ cells display mature RNA profiles and fine secretory granules, secrete somatostatin in response to various stimuli, and suppress insulin secretion from in vitro co-cultured β cells and mouse β cells upon transplantation. The generation of human pancreatic δ cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation studies in diabetes.

Abstract Brain metastases (BMs) and high-grade gliomas (HGGs) are the most common and aggressive types of malignant brain tumors in adults, with often poor prognosis and short survival. As their clinical symptoms and image appearances on conventional magnetic resonance imaging (MRI) can be astonishingly similar, their accurate differentiation based solely on clinical and radiological information can be very challenging, particularly for “cancer of unknown primary”, where no systemic malignancy is known or found. Non-invasive multiparametric MRI and radiomics offer the potential to identify these distinct biological properties, aiding in the characterization and differentiation of HGGs and BMs. However, there is a scarcity of publicly available multi-origin brain tumor imaging data for tumor characterization. In this paper, we introduce a multi-center, multi-origin brain tumor MRI (MOTUM) imaging dataset obtained from 67 patients: 29 with high-grade gliomas, 20 with lung metastases, 10 with breast metastases, 2 with gastric metastasis, 4 with ovarian metastasis, and 2 with melanoma metastasis. This dataset includes anonymized DICOM files alongside processed FLAIR, T1-weighted, contrast-enhanced T1-weighted, T2-weighted sequences images, segmentation masks of two tumor regions, and clinical data. Our data-sharing initiative is to support the benchmarking of automated tumor segmentation, multi-modal machine learning, and disease differentiation of multi-origin brain tumors in a multi-center setting.

Abstract Tuning the properties of a pair of entangled electron and hole in a light-induced exciton is a fundamentally intriguing inquiry for quantum science. Here, using semiconducting hybrid perovskite as an exploratory platform, we discover that Nd2+-doped CH3NH3PbI3 (MAPbI3) perovskite exhibits a Kondo-like exciton-spin interaction under cryogenic and photoexcitation conditions. The feedback to such interaction between excitons in perovskite and the localized spins in Nd2+ is observed as notably prolonged carrier lifetimes measured by time-resolved photoluminescence, ~10 times to that of pristine MAPbI3 without Nd2+ dopant. From a mechanistic standpoint, such extended charge separation states are the consequence of the trap state enabled by the antiferromagnetic exchange interaction between the light-induced exciton and the localized 4 f spins of the Nd2+ in the proximity. Importantly, this Kondo-like exciton-spin interaction can be modulated by either increasing Nd2+ doping concentration that enhances the coupling between the exciton and Nd2+ 4 f spins as evidenced by elongated carrier lifetime, or by using an external magnetic field that can nullify the spin-dependent exchange interaction therein due to the unified orientations of Nd2+ spin angular momentum, thereby leading to exciton recombination at the dynamics comparable to pristine MAPbI3.

Abstract Background Patient safety is paramount for all healthcare agencies. Health professionals' lack of patient safety competencies threaten patients’ lives, and increase patients, families, hospitals, and social burdens. The new nurse-related patient safety issues have particularly attracted much attention. The aim of this study was to examine the impacts of practice environment and job stress on new nurses' patient safety attitudes by employing the job demands–resources model. Methods The study used a cross-sectional structural equation modeling (SEM). A convenience sample of 370 new nurses was recruited from seven tertiary hospitals in Anhui province, China, from April 2022 to August 2022. Data were collected using self-report questionnaires including the Chinese version of the Nurse Job Stressors Scale, the Practice Environment Scale, and the Safety Attitudes Questionnaire. Results New nurses' patient safety attitudes scores were moderate (126.99 ± 14.39). Practice environment had a significant direct effect on job stress (β = -0.337, t = 6.120), patient safety attitudes (β = 0.604, t = 13.766), practice environment had an indirect effect on patient safety attitudes through job stress (β = 0.066, t = 3.690), and the indirect effect accounted for 9.9% of the total effect. This model was able to explain 48.3% of patient safety attitudes with moderate prediction accuracy. Conclusions This study emphasizes the importance of improving new nurses' attitudes toward patient safety. Hospital administrators should develop policies and strategies to address job characteristics, and establish a favorable work environment to reduce new nurses' job stress as well as to improve patient safety.

Machine learning combined with traditional experimental methods can promote the efficient research and development of materials. In this work, five kinds of algorithm models combined with a genetic algorithm (GA) were used to optimize the compositions of the alloyed high manganese steel. And then the effect of solid solution temperatures on the microstructure, mechanical properties, and impact wear properties of the steel were systematically investigated. The results showed that Categorical Boosting (CB) model exhibited the high validation accuracy (R2 > 0.95, RMSE

Renal unilateral ischemia-reperfusion injury (UIRI) constitutes a significant global health challenge, with poor recovery leading to chronic kidney disease and subsequent renal fibrosis. Extracellular vesicles (EVs) present substantial potential benefits for renal diseases. However, the limited yield and efficacy of EVs produced through traditional methodologies (2D-EVs) severely restrict their widespread application. Moreover, the efficient and effective strategies for using EVs in UIRI treatment and their mechanisms remain largely unexplored. In this study, we propose an innovative approach by integrating bioprinted mesenchymal stem cell microfiber extracellular vesicles production technology (3D-EVs) with a tail vein injection method, introducing a novel treatment strategy for UIRI. Our comparison of the biological functions of 2D-EVs and 3D-EVs, both in vitro and in vivo, reveals that 3D-EVs significantly outperform 2D-EVs. Specifically, in vitro, 3D-EVs demonstrate a superior capacity to enhance the proliferation and migration of NRK-52E cells and mitigate hypoxia/reoxygenation (H/R)-induced injuries by reducing epithelial-mesenchymal transformation, extracellular matrix deposition, and ferroptosis. In vivo, 3D-EVs exhibit enhanced therapeutic effects, as evidenced by improved renal function and decreased collagen deposition in UIRI mouse kidneys. We further elucidate the mechanism by which 3D-EVs derived from KLF15 ameliorate UIRI-induced tubular epithelial cells (TECs) ferroptosis through the modulation of SLC7A11 and GPX4 expression. Our findings suggest that bioprinted mesenchymal stem cells microfiber-derived EVs significantly ameliorate renal UIRI, opening new avenues for effective and efficient EV-based therapies in UIRI treatment.

Abstract Objective Incontinence seriously affects the lives of middle‐aged and older people. Pelvic floor muscle assessment is very important for incontinence, and handgrip strength can be used as an auxiliary diagnostic tool. Our study aims to find new cutoff points of handgrip strength as early indicators of incontinence and analyze the association between low handgrip strength and incontinence among Chinese middle‐aged and older people. Methods Participants were recruited from the 2015 China Health and Retirement Longevity Study. Receiver operating characteristic (ROC) curves were used to find the handgrip strength cutoff point. Logistic regression analysis was performed to explore other incontinence‐related risk factors. Results The study included 10,229 middle‐aged and older people. Compared with normal handgrip strength participants, medium strength participants had 1.510 [men, 95% confidence interval (CI) = 1.017–2.243] and 1.792 (women, 95% CI = 1.294–2.480) times greater risk of incontinence, and low strength participants had 2.420 (men, 95% CI = 1.787–3.277) and 1.516 (women, 95% CI = 1.130–2.032) times greater risk of incontinence. Trend test results showed that the risk of incontinence increased with decreasing handgrip strength in middle‐aged and older people. Conclusions Our study suggests that handgrip strength

Objective To investigate the effect of indoxyl sulfate (IS) on myocardial remodeling in a mouse model of myocardial infarction (MI). Methods A total of 50 adult male C57BL/6J mice were randomly divided into sham-operation group (Sham group) with 10 mice, sham operation+indoxyl sulfate group (Sham+IS group) with 10 mice, myocardial infarction group (MI group) with 15 mice, and myocardial infarction+indoxyl sulfate group (MI+IS group) with 15 mice. Left anterior descending coronary artery ligation was performed to establish a mouse model of MI, and at 24 hours after surgery, the mice in the Sham+IS group and the MI+IS group were given intraperitoneal injection of IS (100 mg/kg), while those in the Sham group and the MI group were given intraperitoneal injection of an equal volume of PBS, once a day for 28 consecutive days. The survival status of the mice in each group was recorded during this period of time. On day 30 of the experiment, echocardiography was performed to evaluate the cardiac function of mice in each group. Ultra-performance liquid chromatography was used to measure the serum concentration of IS. Masson staining was used to assess the degree of myocardial fibrosis in the infarct zone. RT-qPCR was used to measure the mRNA expression levels of α-sma and Collagen Ⅰ in myocardial tissue. Western blot was used to measure the protein expression levels of the TGF-β signaling pathway marker proteins TGF-β, p-Smad2, and p-Smad3 in myocardial tissue. Results On day 30 of the experiment, the MI+IS group had a significant reduction in the survival rate of mice compared with the MI group (χ2=5.02,P0.05). Compared with the MI group, the MI+IS group had significant increases in LVIDd and LVIDs (t=3.96,4.31,P

Abstract Octacosanol is a plant natural product with the potential to ameliorate alcoholic liver injury. However, its poor solubility limits its application in the food industry. This study first verified that octacosanol has a favorable effect on acute and subchronic alcoholic liver injury in mice by protecting the gastric mucosa and ameliorating disease levels. Additionally, octacosanol microcapsules were prepared under the optimal drying conditions of the feed flow rate of 400 mL/h and drying temperature of 180°C to improve the ameliorative effects of octacosanol, with moisture content, water activity, dispersibility, and solubility of 1.53%, 0.16%, 89.84%, and 95.30%, respectively. The microcapsules had a spherical structure, and the droplet sizes after redissolution ranged from 0.061 to 4.63 µm. Instrumental measurements and simulated digestion experiments have shown that microencapsulation enhanced the solubility and thermal stability of octacosanol, with 90.88% of the octacosanol being continuously released. As expected, microencapsulation significantly enhanced the effect of octacosanol in ameliorating alcoholic liver injury by determining the disease index in the mice model. This study demonstrated the beneficial effects of octacosanol on alcoholic liver injury and explored a viable method to improve its solubility and bioaccessibility, thereby enhancing its therapeutic efficacy for the treatment of alcoholic liver injury.

Abstract Background Monoterpenes are among the most important volatile aromatic compounds contributing to the flavor and aroma of grapes and wine. However, the molecular basis of monoterpene biosynthesis has not yet been fully elucidated. Results In our study, transcriptomics and gas chromatography-mass spectrometry (GC-MS) were used to mine candidate genes and transcription factors involved in monoterpene biosynthesis between high-monoterpene and zero-monoterpene table grape cultivars. We found that monoterpene biosynthesis was positively correlated by the expression of five genes encoding 1-deoxy-D-xylulose-5-phosphate synthase (VvDXSs), one encoding 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (VvHDR), three hydroxy-3-methylglutaryl-CoA synthases (VvHMGSs) and one mevalonate kinase (VvMVK), whereas the expression of one isopentenyl diphosphate isomerase (VvIDI) and one 3-hydroxy-3-methylglutaryl-CoA reductase (VvHMGR) negatively correlated monoterpene biosynthesis. Of these genes, VvIDI was selected to validate its function in monoterpene accumulation through a transient overexpression experiment, and was shown to inhibit the biosynthesis of grape linalool and α-terpineol. Meanwhile, we found that a 64-amino acid extension sequence at the N-terminus can guide the VvIDI protein to target the chloroplast. Conclusions The findings of this study should help to guide future functional analysis of key genes as well as mining the potential regulatory mechanism of monoterpene biosynthesis in grapes and grape products.

Offshore wind farms are becoming increasingly distant from onshore centralized control centers, and the communication delays between them inevitably introduce time delays in the measurement signal of the primary frequency control. This causes a deterioration in the performance of the primary frequency control and, in some cases, may even result in frequency instability within the power system. Therefore, a frequency response model that incorporates communication delays was established for power systems that integrate offshore wind power. The Padé approximation was used to model the time delays, and a linearized frequency response model of the power system was derived to investigate the frequency stability under different time delays. The influences of the wind power proportion and frequency control parameters on the system frequency stability were explored. In addition, a Smith delay compensation control strategy was devised to mitigate the effects of communication delays on the system frequency dynamics. Finally, a power system incorporating offshore wind power was constructed using the MATLAB/Simulink platform. The simulation results demonstrate the effectiveness and robustness of the proposed delay compensation control strategy.

Abstract The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal cancer development and decreased five-year survival rate in patients with colorectal cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.

Abstract. Background:. Cardiovascular disease (CVD) has emerged as the leading cause of death from prostate cancer (PCa) in recent decades, bringing a great disease burden worldwide. Men with preexisting CVD have an increased risk for major adverse cardiovascular events when treated with androgen deprivation therapy (ADT). The present study aimed to explore the prevalence and risk evaluation of CVD among people with newly diagnosed PCa in China. Methods:. Clinical data of newly diagnosed PCa patients were retrospectively collected from 34 centers in China from 2010 to 2022 through convenience sampling. CVD was defined as myocardial infarction, arrhythmia, heart failure, stroke, ischemic heart disease, and others. CVD risk was estimated by calculating Framingham risk scores (FRS). Patients were accordingly divided into low-, medium-, and high-risk groups. χ2 or Fisher’s exact test was used for comparison of categorical variables. Results:. A total of 4253 patients were enrolled in the present study. A total of 27.0% (1147/4253) of patients had comorbid PCa and CVD, and 7.2% (307/4253) had two or more CVDs. The enrolled population was distributed in six regions of China, and approximately 71.0% (3019/4253) of patients lived in urban areas. With imaging and pathological evaluation, most PCa patients were diagnosed at an advanced stage, with 20.5% (871/4253) locally progressing and 20.5% (871/4253) showing metastasis. Most of them initiated prostatectomy (46.6%, 1983/4253) or regimens involving ADT therapy (45.7%, 1944/4253) for prostate cancer. In the present PCa cohort, 43.1% (1832/4253) of patients had hypertension, and half of them had poorly controlled blood pressure. With FRS stratification, as expected, a higher risk of CVD was related to aging and metabolic disturbance. However, we also found that patients with treatment involving ADT presented an originally higher risk of CVD than those without ADT. This was in accordance with clinical practice, i.e., aged patients or patients at advanced oncological stages were inclined to accept systematic integrative therapy instead of surgery. Among patients who underwent medical castration, only 4.0% (45/1118) received gonadotropin releasing hormone antagonists, in stark contrast to the grim situation of CVD prevalence and risk. Conclusions:. PCa patients in China are diagnosed at an advanced stage. A heavy CVD burden was present at the initiation of treatment. Patients who accepted ADT-related therapy showed an original higher risk of CVD, but the awareness of cardiovascular protection was far from sufficient.

Abstract To identify different patterns of neurogenic lower urinary tract dysfunction management among Chinese community-dwelling individuals with spinal cord injury and explore the factors associated with latent classes. This was a cross-sectional study conducted in communities throughout China Mainland. Participants were recruited through the China Association of Persons with Physical Disability and a total of 2582 participants was included in the analysis. The data were collected by a questionnaire consisting of socio-demographic factors, disease-related factors, and a list of 8 bladder management methods. Latent class analysis was used to identify different latent classes of neurogenic lower urinary tract dysfunction management. Then the multinomial logistic regression was applied to analyze the relationship between neurogenic lower urinary tract dysfunction management patterns and socio-demographic and disease-related factors. Neurogenic lower urinary tract dysfunction management pattern among community-dwelling individuals with spinal cord injury was divided into four latent classes: “urinal collecting apparatus dominated pattern” (40.3%), “bladder compression dominated pattern” (30.7%), “intermittent catheterization dominated pattern” (19.3%) and “urethral indwelling catheterization dominated pattern” (9.6%). Multinomial logistic regression analysis found that the employment status, residential region, nursing need, payment method for catheterization products, hand function, time since spinal cord injury, urinary incontinence and concerns about social interaction affected by urination problems were significantly associated with latent classes. Only 19.3% of people used the intermittent catheterization as their main neurogenic lower urinary tract dysfunction management method. More attention needs to be paid to the promotion of the standardization process of intermittent catheterization in community-dwelling individuals with spinal cord injury. The associated factors of the four classes can be used for tailored and targeted interventions to increase the use of intermittent catheterization.

Abstract Background Mycobacterium tuberculosis heat-resistant antigen (Mtb-HAg) is a peptide antigen released from the mycobacterial cytoplasm into the supernatant of Mycobacterium tuberculosis (Mtb) attenuated H37Ra strain after autoclaving at 121 °C for 20 min. Mtb-HAg can specifically induce γδ T-cell proliferation in vitro. However, the exact composition of Mtb-HAg and the protein antigens that are responsible for its function are currently unknown. Methods Mtb-HAg extracted from the Mtb H37Ra strain was subjected to LC‒MS mass spectrometry. Twelve of the identified protein fractions were recombinantly expressed in Escherichia coli by genetic engineering technology using pET-28a as a plasmid and purified by Ni–NTA agarose resin to stimulate peripheral blood mononuclear cells (PBMCs) from different healthy individuals. The proliferation of γδ T cells and major γδ T-cell subset types as well as the production of TNF-α and IFN-γ were determined by flow cytometry. Their proliferating γδ T cells were isolated and purified using MACS separation columns, and Mtb H37Ra-infected THP-1 was co-cultured with isolated and purified γδ T cells to quantify Mycobacterium viability by counting CFUs. Results In this study, Mtb-HAg from the attenuated Mtb H37Ra strain was analysed by LC‒MS mass spectrometry, and a total of 564 proteins were identified. Analysis of the identified protein fractions revealed that the major protein components included heat shock proteins and Mtb-specific antigenic proteins. Recombinant expression of 10 of these proteins in by Escherichia coli genetic engineering technology was used to successfully stimulate PBMCs from different healthy individuals, but 2 of the proteins, EsxJ and EsxA, were not expressed. Flow cytometry results showed that, compared with the IL-2 control, HspX, GroEL1, and GroES specifically induced γδ T-cell expansion, with Vγ2δ2 T cells as the main subset, and the secretion of the antimicrobial cytokines TNF-α and IFN-γ. In contrast, HtpG, DnaK, GroEL2, HbhA, Mpt63, EsxB, and EsxN were unable to promote γδ T-cell proliferation and the secretion of TNF-α and IFN-γ. None of the above recombinant proteins were able to induce the secretion of TNF-α and IFN-γ by αβ T cells. In addition, TNF-α, IFN-γ-producing γδ T cells inhibit the growth of intracellular Mtb. Conclusion Activated γδ T cells induced by Mtb-HAg components HspX, GroES, GroEL1 to produce TNF-α, IFN-γ modulate macrophages to inhibit intracellular Mtb growth. These data lay the foundation for subsequent studies on the mechanism by which Mtb-HAg induces γδ T-cell proliferation in vitro, as well as the development of preventive and therapeutic vaccines and rapid diagnostic reagents.

Abstract The engineered clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein (Cas) system is currently widely applied in genetic editing and transcriptional regulation. The catalytically inactivated CasRx (dCasRx) has the ability to selectively focus on the mRNA coding region without disrupting transcription and translation, opening up new avenues for research on RNA modification and protein translation control. This research utilized dCasRx to create a translation-enhancement system for mammals called dCasRx-eIF4GI, which combined eukaryotic translation initiation factor 4G (eIF4GI) to boost translation levels of the target gene by recruiting ribosomes, without affecting mRNA levels, ultimately increasing translation levels of different endogenous proteins. Due to the small size of dCasRx, the dCasRx-eIF4GI translation enhancement system was integrated into a single viral vector, thus optimizing the delivery and transfection efficiency in subsequent applications. Previous studies reported that ferroptosis, mediated by calcium oxalate (CaOx) crystals, significantly promotes stone formation. In order to further validate its developmental potential, it was applied to a kidney stone model in vitro and in vivo. The manipulation of the ferroptosis regulatory gene FTH1 through single-guide RNA (sgRNA) resulted in a notable increase in FTH1 protein levels without affecting its mRNA levels. This ultimately prevented intracellular ferroptosis and protected against cell damage and renal impairment caused by CaOx crystals. Taken together, this study preliminarily validated the effectiveness and application prospects of the dCasRx-eIF4GI translation enhancement system in mammalian cell-based disease models, providing novel insights and a universal tool platform for protein translation research and future therapeutic approaches for nephrolithiasis.

Abstract The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, an important component of the innate immune system, is involved in the development of several diseases. Ectopic DNA-induced inflammatory responses are involved in several pathological processes. Repeated damage to tissues and metabolic organelles releases a large number of damage-associated molecular patterns (mitochondrial DNA, nuclear DNA, and exogenous DNA). The DNA fragments released into the cytoplasm are sensed by the sensor cGAS to initiate immune responses through the bridging protein STING. Many recent studies have revealed a regulatory role of the cGAS-STING signaling pathway in cardiovascular diseases (CVDs) such as myocardial infarction, heart failure, atherosclerosis, and aortic dissection/aneurysm. Furthermore, increasing evidence suggests that inhibiting the cGAS-STING signaling pathway can significantly inhibit myocardial hypertrophy and inflammatory cell infiltration. Therefore, this review is intended to identify risk factors for activating the cGAS-STING pathway to reduce risks and to simultaneously further elucidate the biological function of this pathway in the cardiovascular field, as well as its potential as a therapeutic target.

Discriminating strong aroma-type Baijiu (SAB) of different origins was significant for product quality control and origin protection. In this study, a 4×3 sensor array was constructed based on the Ag nanoprism (AgNPR) etching mechanism, in which four AgNPRs varying in shape and size were used as sensing materials, and two metal ions and one oxide anion were used as oxidation etchants. With this array, colorimetric reaction was conducted on 41 representative SAB samples from Sichuan, Jianghuai and North China. The obtained colorimetric signal values were subjected to linear discriminant analysis (LDA). Furthermore, some samples of unknown origin were selected to perform external validation on the discrimination model. Based on the results of colorimetric reaction mechanism, the samples could promote the etching effect of AgNPRs, which might be related to various organic acids contained in Baijiu. Sample discrimination showed that single array produced a comparatively low effect on samples of different origins. The combination of three arrays significantly improved the discrimination effect, whose rate of origin discrimination was up to 99% for 41 samples, and was up to 98% for 15 unknown samples. With combined array, the discriminant rates of 21 samples from 5 brands in Sichuan and 13 samples from 3 brands in Jianghuai could reach 99% and 100%, respectively, while all the discriminant rates could reach 100% for different grades of products from various manufacturers in Sichuan with single array. Being simple and fast, the nanocolorimetric sensing method adopted in this study is not only applicable to product identification and anti-counterfeiting, but also be auxiliarily used for quality control in production process, laying a research foundation for intelligent quality monitoring of Baijiu.

Abstract Cellular behavior is regulated by mechanical signals within the cellular microenvironment. Additionally, changes of temperature, blood flow, and muscle contraction also affect cellular state and the development of diseases. In clinical practice, physical therapy techniques such as ultrasound, vibration, exercise, cold therapy, and hyperthermia are commonly employed to alleviate pain and treat diseases. However, the molecular mechanism about how these physiotherapy methods stimulate local tissues and control gene expression remains unknow. Fortunately, the discovery of YAP filled this gap, which has been reported has the ability to sense and convert a wide variety of mechanical signals into cell-specific programs for transcription, thereby offering a fresh perspective on the mechanisms by which physiotherapy treat different diseases. This review examines the involvement of Hippo/YAP signaling pathway in various diseases and its role in different physical therapy approaches on diseases. Furthermore, we explore the potential therapeutic implications of the Hippo/YAP signaling pathway and address the limitations and controversies surrounding its application in physiotherapy.

Abstract Background The repair of peripheral nerve injury poses a clinical challenge, necessitating further investigation into novel therapeutic approaches. In recent years, bone marrow mesenchymal stromal cell (MSC)-derived mitochondrial transfer has emerged as a promising therapy for cellular injury, with reported applications in central nerve injury. However, its potential therapeutic effect on peripheral nerve injury remains unclear. Methods We established a mouse sciatic nerve crush injury model. Mitochondria extracted from MSCs were intraneurally injected into the injured sciatic nerves. Axonal regeneration was observed through whole-mount nerve imaging. The dorsal root ganglions (DRGs) corresponding to the injured nerve were harvested to test the gene expression, reactive oxygen species (ROS) levels, as well as the degree and location of DNA double strand breaks (DSBs). Results The in vivo experiments showed that the mitochondrial injection therapy effectively promoted axon regeneration in injured sciatic nerves. Four days after injection of fluorescently labeled mitochondria into the injured nerves, fluorescently labeled mitochondria were detected in the corresponding DRGs. RNA-seq and qPCR results showed that the mitochondrial injection therapy enhanced the expression of Atf3 and other regeneration-associated genes in DRG neurons. Knocking down of Atf3 in DRGs by siRNA could diminish the therapeutic effect of mitochondrial injection. Subsequent experiments showed that mitochondrial injection therapy could increase the levels of ROS and DSBs in injury-associated DRG neurons, with this increase being correlated with Atf3 expression. ChIP and Co-IP experiments revealed an elevation of DSB levels within the transcription initiation region of the Atf3 gene following mitochondrial injection therapy, while also demonstrating a spatial proximity between mitochondria-induced DSBs and CTCF binding sites. Conclusion These findings suggest that MSC-derived mitochondria injected into the injured nerves can be retrogradely transferred to DRG neuron somas via axoplasmic transport, and increase the DSBs at the transcription initiation regions of the Atf3 gene through ROS accumulation, which rapidly release the CTCF-mediated topological constraints on chromatin interactions. This process may enhance spatial interactions between the Atf3 promoter and enhancer, ultimately promoting Atf3 expression. The up-regulation of Atf3 induced by mitochondria further promotes the expression of downstream regeneration-associated genes and facilitates axon regeneration.

Abstract The angiotensin-converting enzyme 2 (ACE2) is a primary cell surface viral binding receptor for SARS-CoV-2, so finding new regulatory molecules to modulate ACE2 expression levels is a promising strategy against COVID-19. In the current study, we utilized islet organoids derived from human embryonic stem cells (hESCs), animal models and COVID-19 patients to discover that fibroblast growth factor 7 (FGF7) enhances ACE2 expression within the islets, facilitating SARS-CoV-2 infection and resulting in impaired insulin secretion. Using hESC-derived islet organoids, we demonstrated that FGF7 interacts with FGF receptor 2 (FGFR2) and FGFR1 to upregulate ACE2 expression predominantly in β cells. This upregulation increases both insulin secretion and susceptibility of β cells to SARS-CoV-2 infection. Inhibiting FGFR counteracts the FGF7-induced ACE2 upregulation, subsequently reducing viral infection and replication in the islets. Furthermore, retrospective clinical data revealed that diabetic patients with severe COVID-19 symptoms exhibited elevated serum FGF7 levels compared to those with mild symptoms. Finally, animal experiments indicated that SARS-CoV-2 infection increased pancreatic FGF7 levels, resulting in a reduction of insulin concentrations in situ. Taken together, our research offers a potential regulatory strategy for ACE2 by controlling FGF7, thereby protecting islets from SARS-CoV-2 infection and preventing the progression of diabetes in the context of COVID-19.

Abstract Post-stroke depression (PSD) is regarded as the consequence of multiple contributors involving the process of cognition, mood and autonomic system, with the specific mechanism unclear yet. As a common type of stroke-heart syndromes, post-stroke arrhythmia shared some common pathogenesis with PSD. We presumed that post-stroke arrhythmia might be an early distinguishable marker for the presence of PSD and aimed to verity their association in this study. Patients with first-ever ischemic stroke were enrolled. The presence of post-stroke ectopic arrhythmia and the symptoms of arrhythmia were recorded with anti-arrhythmia drugs prescribed when necessary. Patients were followed up 3 months later to identify their presence and severity of PSD using Hamilton Depression Scale (HAMD) and also presence and severity of arrhythmia. Characteristics including the prevalence of various types of arrhythmias were compared between PSD and non-PSD groups. The HAMD scores were compared between patients with and without arrhythmia in PSD group. Logistic regression was used to identify the independent predictor of PSD. Patients with PSD had higher prevalence of post-stroke arrhythmia especially newly-detected arrhythmia, symptomatic arrhythmia and poor-controlled arrhythmia. In PSD group, patients of post-stroke arrhythmia had higher scores of HAMD than those without arrhythmia. Presence of newly-detected, symptomatic and poor-controlled arrhythmias were independent predictor of PSD. post-stroke arrhythmia especially newly-detected arrhythmia and symptomatic arrhythmia could be an early predictor of PSD. Successful control of arrhythmia was associated with reduced prevalence and severity of PSD.

The fluctuations in power output from distributed power sources are rapid and dramatic, causing voltage fluctuations in the distribution network that threaten the safety of electricity consumption. Soft open points (SOPs) can replace traditional contact switches and are expected to suppress voltage fluctuations. However, traditional power regulation methods based on the reference values are unable to address rapid and large voltage fluctuations. Therefore, this paper proposes an adaptive power control method for SOPs based on virtual impedance. The SOP is modeled as a series link of adjustable impedance and a voltage source. Then, the voltage difference component is used to calculate the reference for the DQ domain to regulate the power flow in real time automatically. By doing so, the proposed method can smooth the voltage fluctuations in the distribution network. Additionally, the virtual impedance is also optimized to minimize the power loss. Finally, the method is validated through simulation and experiments, demonstrating that this method can automatically regulate power and significantly reduce voltage fluctuations.

Abstract Glioblastoma multiforme (GBM) is the most aggressive and lethal subtype of gliomas of the central nervous system. The efficacy of sonodynamic therapy (SDT) against GBM is significantly reduced by the expression of apoptosis‐inhibitory proteins in GBM cells. In this study, an intelligent nanoplatform (denoted as Aza‐BD@PC NPs) based on the aza‐boron‐dipyrromethene dye and phenyl chlorothionocarbonate‐modified DSPE‐PEG molecules is developed for synergistic ferroptosis‐enabled gas therapy (GT) and SDT of GBM. Once internalized by GBM cells, Aza‐BD@PC NPs showed effective cysteine (Cys) consumption and Cys‐triggered hydrogen sulfide (H2S) release for ferroptosis‐enabled GT, thereby disrupting homeostasis in the intracellular environment, affecting GBM cell metabolism, and inhibiting GBM cell proliferation. Additionally, the released Aza‐BD generated abundant singlet oxygen (1O2) under ultrasound irradiation for favorable SDT. In vivo and in vitro evaluations demonstrated that the combined functions of Cys consumption, H2S production, and 1O2 production induced significant death of GBM cells and markedly inhibited tumor growth, with an impressive inhibition rate of up to 97.5%. Collectively, this study constructed a cascade nanoreactor with satisfactory Cys depletion performance, excellent H2S release capability, and prominent reactive oxygen species production ability under ultrasound irradiation for the synergistic ferroptosis‐enabled GT and SDT of gliomas.

During the Mesozoic, the North China Craton experienced intense tectonic movements that resulted in the formation of numerous gold deposits on the Liaodong and Jiaodong Peninsulas in northeastern China. To investigate the relationship between deep crustal structure and gold mineralization in the Liaodong Peninsula, we deployed 334 dense seismic stations in the Wulong goldfield (WLGF) with the idea of analysing numerous receiver functions at different array stations. The purpose focused on knowing the potential for gold mineralization in the area. The study revealed the following: (1) The WLGF is characterized by a crustal thickness of approximately 32 km and an average Vp/Vs ratio of 1.76. The high value of the Vp/Vs ratio near the Wulong gold deposit suggests that mantle materials have penetrated into the crust and contributed to the mineralization process. (2) A low-velocity layer located at a depth of 10–18 km below the WLGF seems to support the existence of a potentially brittle-ductile transition zone. Also, hydrothermal magma upwelling channels are observed in the upper crust beneath the Wulong gold deposit. (3) The presence of a discontinuous low-velocity layer in the middle crust beneath the Liaodong Peninsula suggests promising prospects for gold ore exploration. The receiver functions method based on a dense seismic array employed in this study can offer valuable references and guidance for the fine exploration and research of ore deposits in other regions globally.