FMNL2 regulates actin for endoplasmic reticulum and mitochondria distribution in oocyte meiosis.

During mammalian oocyte meiosis, spindle migration and asymmetric cytokinesis are unique steps for the successful polar body extrusion. The asymmetry defects of oocytes will lead to the failure of fertilization and embryo implantation. In present study, we reported that an actin nucleating factor Formin-like 2 (FMNL2) played critical roles in the regulation of spindle migration and organelle distribution in mouse and porcine oocytes. Our results showed that FMNL2 mainly localized at the oocyte cortex and periphery of spindle. Depletion of FMNL2 led to the failure of polar body extrusion and large polar bodies in oocytes. Live-cell imaging revealed that the spindle failed to migrate to the oocyte cortex, which caused polar body formation defects, and this might be due to the decreased polymerization of cytoplasmic actin by FMNL2 depletion in the oocytes of both mice and pigs. Furthermore, mass spectrometry analysis indicated that FMNL2 was associated with mitochondria and endoplasmic reticulum (ER)-related proteins, and FMNL2 depletion disrupted the function and distribution of mitochondria and ER, showing with decreased mitochondrial membrane potential and the occurrence of ER stress. Microinjecting Fmnl2-EGFP mRNA into FMNL2-depleted oocytes significantly rescued these defects. Thus, our results indicate that FMNL2 is essential for the actin assembly, which further involves into meiotic spindle migration and ER/mitochondria functions in mammalian oocytes.

Outcomes of Heart Transplantation From Donation After Circulatory Death: An Up-to-Date Systematic Meta-analysis.

BACKGROUND: Donation after circulatory death (DCD) heart transplantation (HTx) significantly expands the donor pool and reduces waitlist mortality. However, high-level evidence-based data on its safety and effectiveness are lacking. This meta-analysis aimed to compare the outcomes between DCD and donation after brain death (DBD) HTxs. METHODS: Databases, including MEDLINE, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, were systematically searched for randomized controlled trials and observational studies reporting the outcomes of DCD and DBD HTxs published from 2014 onward. The data were pooled using random-effects models. Risk ratios (RRs) with 95% confidence intervals (CIs) were used as the summary measures for categorical outcomes and mean differences were used for continuous outcomes. RESULTS: Twelve eligible studies were included in the meta-analysis. DCD HTx was associated with lower 1-y mortality rate (DCD 8.13% versus DBD 10.24%; RR = 0.75; 95% CI, 0.59-0.96; P = 0.02) and 5-y mortality rate (DCD 14.61% versus DBD 20.57%; RR = 0.72; 95% CI, 0.54-0.97; P = 0.03) compared with DBD HTx. CONCLUSIONS: Using the current DCD criteria, HTx emerges as a promising alternative to DBD transplantation. The safety and feasibility of DCD hearts deserve further exploration and investigation.

Probability-Distribution-Configurable True Random Number Generators Based on Spin-Orbit Torque Magnetic Tunnel Junctions.

The incorporation of randomness into stochastic computing can provide ample opportunities for applications such as simulated annealing, non-polynomial hard problem solving, and Bayesian neuron networks. In these cases, a considerable number of random numbers with an accurate and configurable probability distribution function (PDF) are indispensable. Preferably, these random numbers are provided at the hardware level to improve speed, efficiency, and parallelism. In this paper, how spin-orbit torque magnetic tunnel junctions (SOT-MTJs) with high barriers are suitable candidates for the desired true random number generators is demonstrated. Not only do these SOT-MTJs perform excellently in speed and endurance, but their randomness can also be conveniently and precisely controlled by a writing voltage, which makes them a well-performed Bernoulli bit. By utilizing these SOT-MTJ-based Bernoulli bits, any PDF, including Gaussian, uniform, exponential, Chi-square, and even arbitrarily defined distributions can be realized. These PDF-configurable true random number generators can then promise to advance the development of stochastic computing and broaden the applications of the SOT-MTJs.

Lysimachia capillipes Hemsl. saponins ameliorate colorectal cancer in mice via regulating gut microbiota and restoring metabolic profiles.

Lysimachia capillipes Hemsl., a traditional Chinese medicine (TCM), is commonly prescribed for its anti-inflammatory and anti-tumor properties. Pharmacological studies have demonstrated that Lysimachia capillipes Hemsl. saponins (LCS) are the primary bioactive component. However, its mechanism for treating colorectal cancer (CRC) is still unknown. Increasing evidence suggests a close relationship between CRC, intestinal flora, and host metabolism. Thus, this study aims to investigate the mechanism of LCS amelioration of CRC from the perspective of the gut microbiome and metabolome. As a result, seven gut microbiotas and fourteen plasma metabolites were significantly altered between the control and model groups. Among them, one gut microbiota genera (Monoglobus) and six metabolites (Ureidopropionic acid, Cytosine, L-Proline, 3-hydroxyanthranilic acid, Cyclic AMP and Suberic acid) showed the most pronounced callback trend after LCS administration. Subsequently, the correlation analysis revealed significant associations between 68 pairs of associated metabolites and gut microbes, with 13 pairs of strongly associated metabolites regulated by the LCS. Taken together, these findings indicate that the amelioration of CRC by LCS is connected to the regulation of intestinal flora and the recasting of metabolic abnormalities. These insights highlight the potential of LCS as a candidate drug for the treatment of CRC.

The Therapeutic Potential of Four Main Compounds of Zanthoxylum nitidum (Roxb.) DC: A Comprehensive Study on Biological Processes, Anti-Inflammatory Effects, and Myocardial Toxicity.

Zanthoxylum nitidum (Roxb.) DC. (Z. nitidum) is a traditional Chinese medicinal plant that is indigenous to the southern regions of China. Previous research has provided evidence of the significant anti-inflammatory, antibacterial, and anticancer properties exhibited by Z. nitidum. The potential therapeutic effects and cardiac toxicity of Z. nitidum remain uncertain. The aim of this research was to investigate the potential therapeutic properties of the four main compounds of Z. nitidum in cardiovascular diseases, their impact on the electrical activity of cardiomyocytes, and the underlying mechanism of their anti-inflammatory effects. We selected the four compounds from Z. nitidum with a high concentration and specific biological activity: nitidine chloride (NC), chelerythrine chloride (CHE), magnoflorine chloride (MAG), and hesperidin (HE). A proteomic analysis was conducted on the myocardial tissues of beagle dogs following the administration of NC to investigate the role of NC in vivo and the associated biological processes. A bioinformatic analysis was used to predict the in vivo biological processes that MAG, CHE, and HE were involved in. Molecular docking was used to simulate the binding between compounds and their targets. The effect of the compounds on ion channels in cardiomyocytes was evaluated through a patch clamp experiment. Organ-on-a-chip (OOC) technology was developed to mimic the physiological conditions of the heart in vivo. Proteomic and bioinformatic analyses demonstrated that the four compounds of Z. nitidum are extensively involved in various cardiovascular-related biological pathways. The findings from the patch clamp experiments indicate that NC, CHE, MAG, and HE elicit a distinct activation or inhibition of the IK1 and ICa-L in cardiomyocytes. Finally, the anti-inflammatory effects of the compounds on cardiomyocytes were verified using OOC technology. NC, CHE, MAG, and HE demonstrate anti-inflammatory effects through their specific interactions with prostaglandin-endoperoxide synthase 2 (PTGS2) and significantly influence ion channels in cardiomyocytes. Our study provides a foundation for utilizing NC, CHE, MAG, and HE in the treatment of cardiovascular diseases.

Mechanisms underlying aryl hydrocarbon receptor-driven divergent macrophage function.

Macrophages play an essential role in the innate immune system by differentiating into functionally diverse subsets in order to fight infection, repair damaged tissues, and regulate inappropriate immune responses. This functional diversity stems from their ability to adapt and respond to signals in the environment, which is in part mediated through aryl hydrocarbon receptor (AHR)-signaling. AHR, an environmental sensor, can be activated by various ligands, ranging from environmental contaminants to microbially derived tryptophan metabolites. This review discusses what is currently known about how AHR-signaling influences macrophage differentiation, polarization, and function. By discussing studies that are both consistent and divergent, our goal is to highlight the need for future research on the mechanisms by which AHR acts as an immunological switch in macrophages. Ultimately, understanding the contexts in which AHR-signaling promotes and/or inhibits differentiation, proinflammatory functions, and immunoregulatory functions, will help uncover functional predictions of immunotoxicity following exposure to environmental chemicals as well as better design AHR-targeted immunotherapies.

Work status among middle-aged and older individuals in China: the effects on physical and mental health.

Objective: China's middle-aged and older population is a rich source of human capital. Therefore, considering the health of this group is important when creating and using human resources. Methods: Using data from the nationwide China Health and Retirement Longitudinal Study (CHARLS) 2018 baseline survey of 19,000 adults ages 45 years and older, this study was an objective investigation of the effects of work on the physical and mental health of middle-aged and older adults. We conducted several types of analyses using details of participants' lifestyles and demographic characteristics (living environment, education, financial level, and access to medical services) with work (i.e., employment or volunteer work) as a primary input component of health production to examine their effects on the health status of middle-aged and older individuals. Results: Six primary outcomes were identified: (1) Employment positively affects both the physical and mental health of middle-aged and older people; (2) Employment can influence the physical and mental health of middle-aged and older people through income, cognitive level, and social support networks; (3) Compared to non-self-employment, self-employment dramatically worsens physical health but has no apparent detrimental effects on mental health. Compared to non-agricultural employment, agricultural labor affects both physical and mental health. (4) Employment has more positive physical and mental health effects in Individuals with higher rather than lower levels of education. (5) Employment opportunities in the eastern region are more likely to promote better physical health than those in the central and western regions of China, although the effects on mental health are negative. (6) When considering groups at different ages of the lifespan, the 60-65-year-old group, who are just entering retirement probably benefit more from continuing work. Conclusion: We provide some recommendations to encourage middle-aged and older people to work and utilize their experience, which will enhance their physical and mental well-being and help them in realize their own value and social integration.

Self-controlled in silico gene knockdown strategies to enhance the sustainable production of heterologous terpenoid by Saccharomyces cerevisiae.

Microbial bioengineering is a growing field for producing plant natural products (PNPs) in recent decades, using heterologous metabolic pathways in host cells. Once heterologous metabolic pathways have been introduced into host cells, traditional metabolic engineering techniques are employed to enhance the productivity and yield of PNP biosynthetic routes, as well as to manage competing pathways. The advent of computational biology has marked the beginning of a novel epoch in strain design through in silico methods. These methods utilize genome-scale metabolic models (GEMs) and flux optimization algorithms to facilitate rational design across the entire cellular metabolic network. However, the implementation of in silico strategies can often result in an uneven distribution of metabolic fluxes due to the rigid knocking out of endogenous genes, which can impede cell growth and ultimately impact the accumulation of target products. In this study, we creatively utilized synthetic biology to refine in silico strain design for efficient PNPs production. OptKnock simulation was performed on the GEM of Saccharomyces cerevisiae OA07, an engineered strain for oleanolic acid (OA) bioproduction that has been reported previously. The simulation predicted that the single deletion of fol1, fol2, fol3, abz1, and abz2, or a combined knockout of hfd1, ald2 and ald3 could improve its OA production. Consequently, strains EK1∼EK7 were constructed and cultivated. EK3 (OA07△fol3), EK5 (OA07△abz1), and EK6 (OA07△abz2) had significantly higher OA titers in a batch cultivation compared to the original strain OA07. However, these increases were less pronounced in the fed-batch mode, indicating that gene deletion did not support sustainable OA production. To address this, we designed a negative feedback circuit regulated by malonyl-CoA, a growth-associated intermediate whose synthesis served as a bypass to OA synthesis, at fol3, abz1, abz2, and at acetyl-CoA carboxylase-encoding gene acc1, to dynamically and autonomously regulate the expression of these genes in OA07. The constructed strains R_3A, R_5A and R_6A had significantly higher OA titers than the initial strain and the responding gene-knockout mutants in either batch or fed-batch culture modes. Among them, strain R_3A stand out with the highest OA titer reported to date. Its OA titer doubled that of the initial strain in the flask-level fed-batch cultivation, and achieved at 1.23 ± 0.04 g L-1 in 96 h in the fermenter-level fed-batch mode. This indicated that the integration of optimization algorithm and synthetic biology approaches was efficiently rational for PNP-producing strain design.

Restricted Boltzmann Machines Implemented by Spin-Orbit Torque Magnetic Tunnel Junctions.

Artificial intelligence has surged forward with the advent of generative models, which rely heavily on stochastic computing architectures enhanced by true random number generators with adjustable sampling probabilities. In this study, we develop spin-orbit torque magnetic tunnel junctions (SOT-MTJs), investigating their sigmoid-style switching probability as a function of the driving voltage. This feature proves to be ideally suited for stochastic computing algorithms such as the restricted Boltzmann machines (RBM) prevalent in pretraining processes. We exploit SOT-MTJs as both stochastic samplers and network nodes for RBMs, enabling the implementation of RBM-based neural networks to achieve recognition tasks for both handwritten and spoken digits. Moreover, we further harness the weights derived from the preceding image and speech training processes to facilitate cross-modal learning from speech to image generation. Our results clearly demonstrate that these SOT-MTJs are promising candidates for the development of hardware accelerators tailored for Boltzmann neural networks and other stochastic computing architectures.

Professional values education for undergraduate nursing students: developing a framework based on the professional values growth theory.

BACKGROUND: Education has been recognised as necessary in forming and internalising professional values. The system and instructors' content in existing educational institutions focus on developing students' knowledge, skills and practices. Still, the development of values has yet to achieve significant effects, leading to a crisis in students' professional identity. AIMS: To construct a professional values growth theory for undergraduate nursing students and develop a corresponding education framework. METHODS: Through the review, some databases(PubMed、CINAHL、Web of Science、Wiley and Google Scholars)were searched using a systematic search strategy to collect relevant literature on professional values education. Based on the nursing professional values growth theory (Li and Li, Nursing Ethics In press, 2022), a theory of professional values growth of nursing undergraduates was developed using the method of theory derivation. Two rounds of expert meetings were conducted to review and revise an education framework of professional values of nursing undergraduates derived from that theory. FINDINGS: A total of 10 studies were included. The contents of two themes were analysed: theories and models and the current status of the professional values development of nursing students. The resulting professional values growth theory for undergraduate nursing students consists of five parts: key aspects, decisive opportunities, drivers, embodiment (humanistic sentiments, moral emotions), and outcomes. A total of five experts in the relevant fields were invited to this study. After two rounds of expert meetings, an education framework for undergraduate nursing students was finally developed, which consists of four parts: education objectives, education process and content, environment and conditions, and evaluation. CONCLUSION: The education framework developed in this study has practical implications for the development of professional values of undergraduate nursing students, providing educational strategies and methods for the growth and internalisation of professional values of undergraduate nursing students.

In-depth LC-MS and in-vitro studies of a triterpenoid saponin capilliposide-A metabolism modulation in gut microbiota of mice.

Introduction: Some herbal ingredients can reshape the composition of the gut microbiome as well as its metabolites. At the same time, the gut microbiota can also affect drug metabolism. A large number of studies have reported that saponins are biotransformed under the action of intestinal microorganisms to improve drug efficacy and bioavailability. Capilliposide A is a triterpenoid saponin, which is derived from Lysimachia capillipes Hemsl. CPS-A has anti-inflammatory pharmacological activity, but the substance basis in vivo is unknown at present, so studies on the interaction between intestinal microorganisms and CPS-A may clarify the pharmacodynamic substance basis of CPS-A. Methods: This study established a colitis mouse model, collected sterile feces from normal mice and colitis mice, and incubated CPS-A with two different intestinal flora in vitro. Based on LC-MS, the metabolic process of CPS-A mediated by intestinal microbes and the intervention effect of CPS-A on intestinal microbiome derived metabolites were studied. Results: The results of experiments indicate that intestinal microorganisms can mediate the biotransformation of CPS-A and metabolize it into corresponding deglycosylation products, thereby promoting its drug effect. Not only that, CPS-A can also promote metabolites such as Deoxycholic acid, Histamine, 3-Hydroxytridecanoic acid, and Indole-3-acetic acid in the intestinal microbiota of mice with colitis. This may result in anti-colitis effects. CPS-A mainly involved in metabolic pathways such as azathioprine and mercaptopurine, which may also have beneficial or adverse effects. Discussion: This study on the interaction between CPS-A and microbiota provides a new idea for the study of traditional Chinese medicine with poor oral bioavailability. The regulatory effect of CPS-A on the metabolites of intestinal flora in colitis mice was also found. It laid a foundation for exploring the mechanism of action of saponins on colitis mice.

Classical swine fever virus non-structural protein 5B hijacks host METTL14-mediated m6A modification to counteract host antiviral immune response.

Classical Swine Fever (CSF), caused by the Classical Swine Fever Virus (CSFV), inflicts significant economic losses on the global pig industry. A key factor in the challenge of eradicating this virus is its ability to evade the host's innate immune response, leading to persistent infections. In our study, we elucidate the molecular mechanism through which CSFV exploits m6A modifications to circumvent host immune surveillance, thus facilitating its proliferation. We initially discovered that m6A modifications were elevated both in vivo and in vitro upon CSFV infection, particularly noting an increase in the expression of the methyltransferase METTL14. CSFV non-structural protein 5B was found to hijack HRD1, the E3 ubiquitin ligase for METTL14, preventing METTL14 degradation. MeRIP-seq analysis further revealed that METTL14 specifically targeted and methylated TLRs, notably TLR4. METTL14-mediated regulation of TLR4 degradation, facilitated by YTHDF2, led to the accelerated mRNA decay of TLR4. Consequently, TLR4-mediated NF-κB signaling, a crucial component of the innate immune response, is suppressed by CSFV. Collectively, these data effectively highlight the viral evasion tactics, shedding light on potential antiviral strategies targeting METTL14 to curb CSFV infection.

Development and validity of an intermediate conceptual measurement (ICM) -based measurement tool for the nursing professional values of undergraduate students.

BACKGROUND: Nursing professional values are the foundation of nursing practice. There has been no research to develop an instrument to measure professional values in nursing based on intermediate conceptual measurement theory. OBJECTIVES: To develop an ICM-based measurement tool for the nursing professional values of undergraduate students. DESIGN: A cross-sectional study. METHODS: The Nursing Professional Values-Intermediate Conceptual Measurement (NPV-ICM) was developed using the steps of Cunningham's process to generate questionnaire items. The tool was devised in three stages: identifying the intermediate concepts, developing stories reflecting the intermediate concepts and setting up options for action and justification in the stories and setting up scoring criteria for the measurement tool. The tool was tested through internal consistency reliability, content validity and calibration correlation validity. RESULTS: This study resulted in five nursing professional values situational stories containing five themes (care, altruism, responsibility, respect and justice) respectively. Each situational story contained a varying number of action options and justification options, totalling 72 Richter 5 level options and 20 ranked items. Reliability and validity were found to be good, with a total Cronbach's α of 0.93 and Cronbach's α of 0.75-0.80 for each situational story and calibrated correlational validity was found to correlate significantly between the total Nursing Professional Values Scale Revised (NPVS-R) scores and the NPV-ICM. CONCLUSIONS: The NPV-ICM created in this study possesses high reliability and validity. It alters the values perception research, moving from abstract conceptual measurements to measurements of particular values actions and justifications for participation in activities. And the study presents preliminary evidence supporting the reliability of the NVP-ICM as a measure of professional values.

Synthesis and antifungal activity of hexahydropyrrolidoindole alkaloids.

Twenty-one hexahydropyrrolidoindole alkaloids were designed and synthesised via acylation reaction at the 3-N position from the commercially available indole-3-acetonitrile as the starting material in excellent yields. The effects of all target compounds against Verticillium dahlia, Fusarium oxysperium sp., Cytospora juglandis, Aspergillu sflavu, Aspergillus niger and Fusarium oxysporum were determined. The results of bioassays indicated that the majority of tested compounds displayed comparable or better in vitro bioactivity than the positive control. Notably, compounds 8 and 17 revealed potent activity against C. juglandis and A. sflavu, both with the same minimum inhibitory concentration value of 1.9 µg mL-1, which has fungicidal activity far exceeded that of amphotericin B and chlorothalonil.

Role of artificial intelligence in digital pathology for gynecological cancers.

The diagnosis of cancer is typically based on histopathological sections or biopsies on glass slides. Artificial intelligence (AI) approaches have greatly enhanced our ability to extract quantitative information from digital histopathology images as a rapid growth in oncology data. Gynecological cancers are major diseases affecting women's health worldwide. They are characterized by high mortality and poor prognosis, underscoring the critical importance of early detection, treatment, and identification of prognostic factors. This review highlights the various clinical applications of AI in gynecological cancers using digitized histopathology slides. Particularly, deep learning models have shown promise in accurately diagnosing, classifying histopathological subtypes, and predicting treatment response and prognosis. Furthermore, the integration with transcriptomics, proteomics, and other multi-omics techniques can provide valuable insights into the molecular features of diseases. Despite the considerable potential of AI, substantial challenges remain. Further improvements in data acquisition and model optimization are required, and the exploration of broader clinical applications, such as the biomarker discovery, need to be explored.

Barriers and facilitators of adherence to evidence-based pressure injury prevention clinical practice guideline among intensive care nurses: A cross-sectional survey.

OBJECTIVE: To explore intensive care unit (ICU) nurses' perceptions of their adherence to pressure injury prevention clinical practice guideline and identify the perceived barriers and facilitators that influence evidence-based pressure injury prevention practices in Chinese tertiary hospitals. RESEARCH METHODOLOGY/DESIGN: This was a multi-site, quantitative, cross-sectional study. Data were collected using a self-report questionnaire with three sections: participant demographic information, adherence to pressure injury prevention clinical practice guideline, and barriers to and facilitators of pressure injury prevention clinical practice guideline implementation. SETTING: Thirty-three adult ICUs in 16 tertiary general hospitals in 5 major cities in Liaoning Province, China. RESULTS: In total, 473 nurses responded to the survey. The mean score for adherence to pressure injury prevention clinical practice guideline was 159.06 ± 20.65, with 65.3 % reporting good adherence. Multiple stepwise regression analysis indicated that smaller ICU size (ß = -0.114, p = 0.012) and having participated in training on pressure injury prevention clinical practice guideline (ß = 0.149, p = 0.001) were statistically significantly associated with better adherence. ICU nurses identified the low priority given to pressure injury prevention as the top barrier. The top three facilitators were awareness of evidence-based practice, the current documentation format for pressure injury risk/nursing interventions, and leadership support. CONCLUSION: ICU nurses' adherence to pressure injury prevention clinical practice guideline was satisfactory, and they reported low-to-moderate barriers and moderate facilitators. IMPLICATIONS FOR CLINICAL PRACTICE: Participating in training on pressure injury prevention clinical practice guideline was a predictor of ICU nurses' adherence. Therefore, it is highly recommended that healthcare organisations consider providing training to nurses and address the barriers identified to improve nurses' adherence to evidence-based pressure injury prevention guidelines.

Integrative physiological, metabolomic, and transcriptomic analysis reveals the drought responses of two apple rootstock cultivars.

BACKGROUND: Drought is considered the main environmental factor restricting apple production and thus the development of the apple industry. Rootstocks play an important role in enhancing the drought tolerance of apple plants. Studies of the physiology have demonstrated that 'ZC9-3' is a strong drought-resistant rootstock, whereas 'Jizhen-2' is a weak drought-resistant rootstock. However, the metabolites in these two apple rootstock varieties that respond to drought stress have not yet been characterized, and the molecular mechanisms underlying their responses to drought stress remain unclear. RESULTS: In this study, the physiological and molecular mechanisms underlying differences in the drought resistance of 'Jizhen-2' (drought-sensitive) and 'ZC9-3' (drought-resistant) apple rootstocks were explored. Under drought stress, the relative water content of the leaves was maintained at higher levels in 'ZC9-3' than in 'Jizhen-2', and the photosynthetic, antioxidant, and osmoregulatory capacities of 'ZC9-3' were stronger than those of 'Jizhen-2'. Metabolome analysis revealed a total of 95 and 156 differentially accumulated metabolites in 'Jizhen-2' and 'ZC9-3' under drought stress, respectively. The up-regulated metabolites in the two cultivars were mainly amino acids and derivatives. Transcriptome analysis revealed that there were more differentially expressed genes and transcription factors in 'ZC9-3' than in 'Jizhen-2' throughout the drought treatment. Metabolomic and transcriptomic analysis revealed that amino acid biosynthesis pathways play key roles in mediating drought resistance in apple rootstocks. A total of 13 metabolites, including L-α-aminoadipate, L-homoserine, L-threonine, L-isoleucine, L-valine, L-leucine, (2S)-2-isopropylmalate, anthranilate, L-tryptophan, L-phenylalanine, L-tyrosine, L-glutamate, and L-proline, play an important role in the difference in drought resistance between 'ZC9-3' and 'Jizhen-2'. In addition, 13 genes encoding O-acetylserine-(thiol)-lyase, S-adenosylmethionine synthetase, ketol-acid isomeroreductase, dihydroxyacid dehydratase, isopropylmalate isomerase, branched-chain aminotransferase, pyruvate kinase, 3-dehydroquinate dehydratase/shikimate 5-dehydrogenase, N-acetylglutamate-5-P-reductase, and pyrroline-5-carboxylate synthetase positively regulate the response of 'ZC9-3' to drought stress. CONCLUSIONS: This study enhances our understanding of the response of apple rootstocks to drought stress at the physiological, metabolic, and transcriptional levels and provides key insights that will aid the cultivation of drought-resistant apple rootstock cultivars. Especially, it identifies key metabolites and genes underlying the drought resistance of apple rootstocks.

Naringenin nanoparticles targeting cyclin B1 suppress the progression of rheumatoid arthritis-associated lung cancer by inhibiting fibroblast-to-myofibroblast transition.

There is growing evidence of an elevated risk of lung cancer in patients with rheumatoid arthritis. The poor prognosis of rheumatoid arthritis-associated lung cancer and the lack of therapeutic options pose an even greater challenge to the clinical management of patients. This study aimed to identify potential molecular targets associated with the progression of rheumatoid arthritis-associated lung cancer and examine the efficacy of naringenin nanoparticles targeting cyclin B1. Mendelian randomizatio analysis revealed that rheumatoid arthritis has a positive correlation with the risk of lung cancer. Cyclin B1 was significantly upregulated in patients with rheumatoid arthritis-associated lung cancer and was significantly overexpressed in synovial tissue fibroblasts. Furthermore, the overexpression of cyclin B1 in rheumatoid arthritis fibroblast-like synoviocytes, which promotes their proliferation and fibroblast-to-myofibroblast transition, can significantly contribute to the growth and infiltration of lung cancer cells. Importantly, our prepared naringenin nanoparticles targeting cyclin B1 effectively attenuated proliferation and fibroblast-to-myofibroblast transition by blocking cells at the G2/M phase. In vivo experiments, naringenin nanoparticles targeting cyclin B1 significantly alleviated the development of collagen-induced arthritis and lung orthotopic tumors. Collectively, our results reveal that naringenin nanoparticles targeting cyclin B1 can suppress the progression of rheumatoid arthritis-associated lung cancer by inhibiting fibroblast-to-myofibroblast transition. These findings provide new insights into the treatment of rheumatoid arthritis-associated lung cancer therapy.

Nobiletin enhances mitochondrial function by regulating SIRT1/PGC-1α signaling in porcine oocytes during in vitro maturation.

Nobiletin is a natural flavonoid found in citrus fruits with beneficial effects, including anti-inflammatory, anti-cancer and anti-oxidation effects. The aim of this study was to investigate whether nobiletin improves mitochondrial function in porcine oocytes and examine the underlying mechanism. Oocytes enclosed by cumulus cells were cultured in TCM-199 for 44 h with 0.1% dimethyl sulfoxide (control), or supplemented with 5, 10, 25, and 50 µM of nobiletin (Nob5, Nob10, Nob25, and Nob50, respectively). Oocyte maturation rate was significantly enhanced in Nob10 (70.26 ± 0.45%) compared to the other groups (control: 60.12 ± 0.47%; Nob5: 59.44 ± 1.63%; Nob25: 63.15 ± 1.38%; Nob50: 46.57 ± 1.19%). The addition of nobiletin reduced the levels of reactive oxygen species and increased glutathione levels. Moreover, Nob10 promoted mitochondrial biogenesis by upregulating the protein levels of sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α). This resulted in an increase in the number of active mitochondria, mitochondrial DNA copy number, mitochondrial membrane potential, and ATP production, thereby enhancing mitochondrial function. The protein level of p53 decreased, followed by the phosphorylation of B-cell lymphoma 2, suggesting a reduction in mitochondria-mediated apoptosis in the Nob10 group. Additionally, the release of cytochrome c from the mitochondria was significantly diminished along with a decrease in the protein expression of caspase 3. Thus, nobiletin has a great potential to promote the in vitro maturation of porcine oocytes by suppressing oxidative stress and promoting mitochondrial function through the upregulation of the SIRT1/PGC-1α signaling pathway.