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Abstract Breast cancer is one of the tumors with the highest prevalence rate among women in the world, and its BRCA1/2 gene is a common mutation site. Talazoparib, as a targeted PARP inhibitor, can effectively control the occurrence and development of breast cancer with BRCA1/2 gene mutation, and play a therapeutic role. Based on the findings from the Phase III EMBRACE trial (NCT01945775 clinical trial), our analysis reveals that the talazoparib group demonstrated a significant extension in progression-free survival, along with improved response markers and patient-reported outcomes when compared to conventional therapies. This study aims to assess the cost-effectiveness of talazoparib for treating advanced breast cancer with germline BRCA1/2 mutations and HER2 negativity, considering the perspectives of health services in China and the United States. The results obtained will serve as a valuable reference for promoting rational drug utilization and enhancing medical resource efficiency. To evaluate the cost-effectiveness of Talazoparib more scientifically and provide clinicians with chemotherapy options, this paper developed a Markov model based on the EMBRACA clinical trial (clinical Trails.gov No., NCT01945775) to simulate the survival events of breast cancer patients in the Talazoparib group and the standard treatment group. The state transition probability and clinical data of breast cancer patients during treatment were extracted from the phase III EMBRACA clinical trial. The cost data generated during the treatment process comes from local hospital pricing, other references, and expert consultation. This article uses US dollars to calculate the treatment cost and incremental cost-effectiveness ratio. Health outcomes are expressed in Quality Adjusted Life Years (QALYs). In addition, Outcomes were measured in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio, which robustness was evaluated by deterministic and probabilistic sensitivity analyses. This article establishes a Markov model for single-item sensitivity analysis. The results show that the economic benefits of using Talazoparib as a new treatment strategy in both China and the United States are higher than other drugs, and it is cost-effective. Compared to the control group, the incremental cost incurred by the Talazoparib treatment group in China was $2484.48/QALY, with an incremental QALY of 1.5. However, Talazoparib in the United States holds a dominant position, saving costs of $10,223.43 and increasing QALYs by 1.5. The clinical treatment effect of Talazoparib group in BRCA1/2 mutant advanced breast cancer patients is better than that of the standard treatment group, and the progression free survival period is significantly prolonged. From the perspective of medical and health services in China and the United States, the Talazoparib group is more economical than the standard treatment group in treating patients with BRCA1/2 mutant advanced breast cancer.

Abstract Sleep deprivation (SD) has emerged as a critical concern impacting human health, leading to significant damage to the cardiovascular system. However, the underlying mechanisms are still unclear, and the development of targeted drugs is lagging. Here, we used mice to explore the effects of prolonged SD on cardiac structure and function. Echocardiography analysis revealed that cardiac function was significantly decreased in mice after five weeks of SD. Real-time quantitative PCR (RT-q-PCR) and Masson staining analysis showed that cardiac remodeling marker gene Anp (atrial natriuretic peptide) and fibrosis were increased, Elisa assay of serum showed that the levels of creatine kinase (CK), creatine kinase-MB (CK-MB), ANP, brain natriuretic peptide (BNP) and cardiac troponin T (cTn-T) were increased after SD, suggesting that cardiac remodeling and injury occurred. Transcript sequencing analysis indicated that genes involved in the regulation of calcium signaling pathway, dilated cardiomyopathy, and cardiac muscle contraction were changed after SD. Accordingly, Western blotting analysis demonstrated that the cardiac-contraction associated CaMKK2/AMPK/cTNI pathway was inhibited. Since our preliminary research has confirmed the vital role of Casein Kinase-2 -Interacting Protein-1 (CKIP-1, also known as PLEKHO1) in cardiac remodeling regulation. Here, we found the levels of the 3’ untranslated region of Ckip-1 (Ckip-1 3’UTR) decreased, while the coding sequence of Ckip-1 (Ckip-1 CDS) remained unchanged after SD. Significantly, adenovirus-mediated overexpression of Ckip-1 3’UTR alleviated SD-induced cardiac dysfunction and remodeling by activating CaMKK2/AMPK/cTNI pathway, which proposed the therapeutic potential of Ckip-1 3’UTR in treating SD-induced heart disease.

Abstract BackgroundObesity is a rapidly increasing health problem in China, causing massive economic and health losses annually. Many techniques have emerged to help people with obesity better adhere to intervention programs and achieve their weight loss goals, including food replacement and internet-delivered weight loss consultations. Most studies on weight loss interventions mainly focused on the change in body weight or BMI; however, body fat, especially visceral fat mass, is considered the main pathogenic factor in obesity. In China, more reliable evidence is required on this topic. Moreover, it is unclear whether an integrated weight loss program combining food replacement products, mobile app-based platforms, and daily body composition monitoring using a wireless scale is useful and practical in China. ObjectiveIn this 2-arm, parallel-designed, randomized study, we explored the effectiveness and safety of the Metawell (Weijian Technologies Inc) weight loss program in China, which combines prepackaged biscuits, a wireless scale, and a mobile app. MethodsParticipants in the intervention group were guided to use food replacement products and a scale for weight loss and monitoring, whereas participants in the control group received printed material with a sample diet and face-to-face education on weight loss at enrollment. The intervention lasted for 3 months, and follow-up visits were conducted at months 3 and 6 after enrollment. Dual-energy x-ray absorptiometry and quantitative computed tomography were used to assess body fat. A multilevel model for repeated measurements was used to compare differences between the 2 groups. ResultsIn total, 220 patients were randomly assigned to intervention (n=110) and control (n=110) groups. Participants in the intervention group had significantly greater decreases in BMI, total body fat, visceral adipose area, and subcutaneous adipose area (all PP ConclusionsThe Metawell program was effective for weight loss. After the intervention, participants in the intervention group lost more body weight and body fat while retaining muscle mass than those in the control group.

ABSTRACT Objective Chronic kidney disease (CKD) is increasingly recognized as a risk factor for alterations in brain function. However, detecting early‐stage symptoms and structural changes remains challenging, potentially leading to delayed treatment. In our study, we aimed to investigate spontaneous brain activity changes in CKD patients using resting‐state functional magnetic resonance imaging (fMRI). Additionally, we explored the correlation between common biomarkers reflecting CKD severity and brain activity. Methods We recruited a cohort of 22 non–dialysis‐dependent CKD patients and 22 controls for resting‐state fMRI scans. Amplitude of low‐frequency fluctuations (ALFFs) and regional homogeneity (ReHo) were calculated to evaluate brain activity. Regression analysis was conducted to explore the correlations between biomarkers reflecting the severity of CKD and brain activity. Results CKD patients exhibited reduced z‐scored ALFF (zALFF) and mean ALFF (mALFF) in the bilateral putamen, right caudate nucleus, left anterior cingulate, and right precuneus. Changes in bilateral putamen were also found in smCohe‐ReHo and szCohe‐ReHo analyses. Urine albumin‐to‐creatinine ratio (UACR), urine protein‐to‐creatinine ratio (UPCR), and serum albumin levels were associated with attenuated putamen activity. Conclusion Non–dialysis‐dependent CKD patients had changes in zALFF, mALFF, smCohe‐ReHo, and szCohe‐ReHo values in specific brain regions, especially bilateral putamen. UACR, UPCR, and serum albumin levels are associated with putamen activity attenuation in rs‐fMRI.

Abstract Background The implementation of antibiotic intravenous-to-oral switch (IVOS) therapy in hospitals can slow down the development of drug resistance, reduce the occurrence of adverse reactions, and bring significant economic benefits. The aim of this study is to investigate the understanding of physicians at the Second Affiliated Hospital of Soochow University in Suzhou, China towards the antibiotic IVOS therapy. Methods 15 physicians working in 9 different departments of the Second Affiliated Hospital of Soochow University participated in this study. A semi-structured face-to-face interview was conducted to collect interview information about the antibiotic IVOS therapy. NVivo12 software was used to organize the entire interview content, and the interview data was analyzed and summarized using the Colaizzi seven step method. Results 60% of participants were not familiar with antibiotic IVOS therapy. Barriers of antibiotic IVOS therapy were included by three key issues: (i) Physicians’ potential cognition: ‘Iv is always better than oral’; (ii) Subjective infusion intention of patients; and (iii) Limitations of drug selection. 60% of participants expressed welcome for pharmacists to help them perform antibiotic IVOS treatment. And electronic recognition technology may be a feasible method for prompting IVOS conversion that recognized by all participants in the interview. Participants also provided some suggestions for pharmacists and IVOS computer reminders. Conclusion Physicians’ in China still have insufficient understanding of antibiotic IVOS therapy. The promotion of antibiotic IVOS therapy in China faces many challenges and obstacles. Strategies such as IVOS therapy computer reminders and clinical pharmacists’ medication guidance were worth studying to help physicians develop antibiotic IVOS treatment.

Background Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy.Methods We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene Gsk3a as a candidate for further investigation. Flow cytometry was used to analyze the impact of Gsk3a on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by Gsk3a and alterations in downstream molecules. The therapeutic value of the combination of Gsk3a inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored.Results Gsk3a, as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. Gsk3a inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. Gsk3a promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when Gsk3a inhibitor was in combination with anti-PD-1 antibody.Conclusions We identified a potential HCC immune evasion target, Gsk3a, through CRISPR screening. Gsk3a induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting Gsk3a can enhance CTLs function and improve the efficacy of ICIs.

Abstract Liver cancer is one of the most common cancers in the world and a primary cause of cancer-related death. In recent years, despite the great development of diagnostic methods and targeted therapies for liver cancer, the incidence and mortality of liver cancer are still on the rise. As a universal post-transcriptional modification, N6-methyladenosine (m6A) modification accomplishes a dynamic and reversible m6A modification process, which is executed by three types of regulators, methyltransferases (called writers), demethylases (called erasers) and m6A-binding proteins (called readers). Many studies have shown that m6A RNA methylation has an important impact on RNA metabolism, whereas its regulation exception is bound up with the occurrence of human malignant tumors. Aberrant methylation of m6A RNA and the expression of related regulatory factors may be of the essence in the pathogenesis and progression of liver cancer, yet the precise molecular mechanism remains unclear. In this paper, we review the current research situations of m6A methylation in liver cancer. Among the rest, we detail the mechanism by which methyltransferases, demethylases and m6A binding proteins regulate the occurrence and development of liver cancer by modifying mRNA. As well as the potential effect of m6A regulators in hepatocarcinogenesis and progression. New ideas and approaches will be given to the prevention and treatment of liver cancer through the following relevant research results.

This study presents an in-depth exploration of the impact of online learning interactions on student learning outcomes. Drawing from the Stimulus-Organism-Response (SOR) paradigm, our study focuses on the effects of online learning interactions on learners' perception usefulness and ease of use, subsequently impacting their learning outcomes. The study employs a quantitative research methodology, gathering data from a sample of 397 students enrolled in various higher education institutions across China. Data collection involved administering structured questionnaires that were designed to quantitatively assess the three components of the SOR model: stimulus (online learning interactions), organism (students' perceptions), and response (learning outcomes). The measurement model assessment and structural model assessment were conducted. Our findings reveal that online learning interactions can effectively enhance learners' perception of online learning (usefulness and ease of use), thereby influencing their learning outcomes. Notably, perceived usefulness negatively mediates the relationship between online learning interactions and learning outcomes, while perceived ease of use positively mediates this relationship. These findings offer both theoretical and practical implications.

Abstract Detecting pancreatic duct adenocarcinoma (PDAC) in its early stages and predicting late‐stage patient prognosis undergoing chemotherapy is challenging. This work shows that the activation of specific oncogenes leads to elevated expression of mRNAs and their corresponding proteins in extracellular vesicles (EVs) circulating in blood. Utilizing an immune lipoplex nanoparticle (ILN) biochip assay, these findings demonstrate that glypican 1 (GPC1) mRNA expression in the exosomes‐rich (Exo) EV subpopulation and GPC1 membrane protein (mProtein) expression in the microvesicles‐rich (MV) EV subpopulation, particularly the tumor associated microvesicles (tMV), served as a viable biomarker for PDAC. A combined analysis effectively discriminated early‐stage PDAC patients from benign pancreatic diseases and healthy donors in sizable clinical from multiple hospitals. Furthermore, among late‐stage PDAC patients undergoing chemotherapy, lower GPC1 tMV‐mProtein and Exo‐mRNA expression before treatment correlated significantly with prolonged overall survival. These findings underscore the potential of vesicular GPC1 expression for early PDAC screenings and chemotherapy prognosis.

Abstract Bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and osteoblast function play critical roles in bone formation, which is a highly regulated process. Long noncoding RNAs (lncRNAs) perform diverse functions in a variety of biological processes, including BMSC osteogenic differentiation. Although several studies have reported that HOX transcript antisense RNA (HOTAIR) is involved in BMSC osteogenic differentiation, its effect on bone formation in vivo remains unclear. Here, by constructing transgenic mice with BMSC (Prx1-HOTAIR)- and osteoblast (Bglap-HOTAIR)-specific overexpression of HOTAIR, we found that Prx1-HOTAIR and Bglap-HOTAIR transgenic mice show different bone phenotypes in vivo. Specifically, Prx1-HOTAIR mice showed delayed bone formation, while Bglap-HOTAIR mice showed increased bone formation. HOTAIR inhibits BMSC osteogenic differentiation but promotes osteoblast function in vitro. Furthermore, we identified that HOTAIR is mainly located in the nucleus of BMSCs and in the cytoplasm of osteoblasts. HOTAIR displays a nucleocytoplasmic translocation pattern during BMSC osteogenic differentiation. We first identified that the RNA-binding protein human antigen R (HuR) is responsible for HOTAIR nucleocytoplasmic translocation. HOTAIR is essential for osteoblast function, and cytoplasmic HOTAIR binds to miR-214 and acts as a ceRNA to increase Atf4 protein levels and osteoblast function. Bglap-HOTAIR mice, but not Prx1-HOTAIR mice, showed alleviation of bone loss induced by unloading. This study reveals the importance of temporal and spatial regulation of HOTAIR in BMSC osteogenic differentiation and bone formation, which provides new insights into precise regulation as a target for bone loss.

Abstract Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted EVs with high RNA loading. Together with a low dose chemotherapy drug, Gemcitabine, dtEVs suppress large orthotopic PANC-1 and patient derived xenograft tumours and metastasis in mice and extended animal survival. Our work presents a clinically accessible and scalable way to produce abundant EVs for delivering multiple gene cargoes to large solid tumours.

As an important part of the digital reactor, the pin-by-pin wise fine coupling calculation is a research hotspot in the field of nuclear engineering in recent years. It provides more precise and realistic simulation results for reactor design, operation and safety evaluation. CORCA-K a nodal code is redeveloped as a robust pin-by-pin wise neutronics and thermal-hydraulic coupled calculation code for pressurized water reactor (PWR) core. The nodal green's function method (NGFM) is used to solve the three-dimensional space-time neutron dynamics equation, and the single-phase single channel model and one-dimensional heat conduction model are used to solve the fluid field and fuel temperature field. The mesh scale of reactor core simulation is raised from the nodal-wise to the pin-wise. It is verified by two benchmarks: NEACRP 3D PWR and PWR MOX/UO2. The results show that: 1) the pin-by-pin wise coupling calculation system has good accuracy and can accurately simulate the key parameters in steady-state and transient coupling conditions, which is in good agreement with the reference results; 2) Compared with the nodal-wise coupling calculation, the pin-by-pin wise coupling calculation improves the fuel peak temperature, the range of power distribution is expanded, and the lower limit is reduced more.

Metal-organic frameworks (MOFs), with biocompatible and bio-friendly properties, exhibit intriguing potential for the drug delivery system and imaging-guided synergistic cancer theranostics. Even though tremendous attention has been attracted on MOFs-based therapeutics, which play a crucial role in therapeutic drugs, gene, and biomedical agents delivery of cancer therapy, they are often explored as simple nanocarriers without further “intelligent” functions. Herein, Fe-doped MOFs with CoP nanoparticles loading were rationally designed and synthesized for photothermal enhanced reactive oxygen species (ROS)-mediated treatment. Fe-ZIFs@CoP could generate efficient ROS through the Fenton reaction while depleting glutathione for amplifying oxidative stress. Particularly, due to the photothermal effect of Fe-ZIFs@CoP, the hyperthermia generated by as-synthesized Fe-ZIFs@CoP facilitated the advanced performance of the Fenton effect for a high amount of ROS generation. The promising “all-in-one” synergistic MOFs platform herein reported provides some prospects for future directions in this area.

Abstract Mechanical force loading is essential for maintaining bone homeostasis, and unloading exposure can lead to bone loss. Osteoclasts are the only bone resorbing cells and play a crucial role in bone remodeling. The molecular mechanisms underlying mechanical stimulation-induced changes in osteoclast function remain to be fully elucidated. Our previous research found Ca2+-activated Cl− channel Anoctamin 1 (Ano1) was an essential regulator for osteoclast function. Here, we report that Ano1 mediates osteoclast responses to mechanical stimulation. In vitro, osteoclast activities are obviously affected by mechanical stress, which is accompanied by the changes of Ano1 levels, intracellular Cl− concentration and Ca2+ downstream signaling. Ano1 knockout or calcium binding mutants blunts the response of osteoclast to mechanical stimulation. In vivo, Ano1 knockout in osteoclast blunts loading induced osteoclast inhibition and unloading induced bone loss and. These results demonstrate that Ano1 plays an important role in mechanical stimulation induced osteoclast activity changes.

Highlights Hyperelastic and superlight multifunctional MXene/nanocellulose composite aerogels with high conductivity are designed by constructing biomimetic texture. The MXene/nanocellulose aerogels as flexible pressure sensors exhibit appealing linear sensitivity performance (817.3 kPa−1). The as-prepared compressible supercapacitor with MXene/nanocellulose electrodes reveals superior electrochemical performance (849.2 mF cm−2 at 0.8 mA cm−2).

This study investigated combustion characteristics of composite fuel grains designed based on a modular fuel unit strategy. The modular fuel unit comprised a periodical helical structure with nine acrylonitrile–butadiene–styrene helical blades. A paraffin-based fuel was embedded between adjacent blades. Two modifications of the helical structure framework were researched. One mirrored the helical blades, and the other periodically extended the helical blades by perforation. A laboratory-scale hybrid rocket engine was used to investigate combustion characteristics of the fuel grains at an oxygen mass flux of 2.1–6.0 g/(s·cm2). Compared with the composite fuel grain with periodically extended helical blades, the modified composite fuel grains exhibited higher regression rates and a faster rise of regression rates as the oxygen mass flux increased. At an oxygen mass flux of 6.0 g/(s·cm2), the regression rate of the composite fuel grains with perforation and mirrored helical blades increased by 8.0% and 14.1%, respectively. The oxygen-to-fuel distribution of the composite fuel grain with mirrored helical blades was more concentrated, and its combustion efficiency was stable. Flame structure characteristics in the combustion chamber were visualized using a radiation imaging technique. A rapid increase in flame thickness of the composite fuel grains based on the modular unit was observed, which was consistent with their high regression rates. A simplified numerical simulation was carried out to elucidate the mechanism of the modified modular units on performance enhancement of the composite hybrid rocket grains.

Abstract Regenerative medicine in tissue engineering often relies on stem cells and specific growth factors at a supraphysiological dose. These approaches are costly and may cause severe side effects. Herein, therapeutic small extracellular vesicles (t‐sEVs) endogenously loaded with a cocktail of human vascular endothelial growth factor A (VEGF‐A) and human bone morphogenetic protein 2 (BMP‐2) mRNAs within a customized injectable PEGylated poly (glycerol sebacate) acrylate (PEGS‐A) hydrogel for bone regeneration in rats with challenging femur critical‐size defects are introduced. Abundant t‐sEVs are produced by a facile cellular nanoelectroporation system based on a commercially available track‐etched membrane (TM‐nanoEP) to deliver plasmid DNAs to human adipose‐derived mesenchymal stem cells (hAdMSCs). Upregulated microRNAs associated with the therapeutic mRNAs are enriched in t‐sEVs for enhanced angiogenic–osteogenic regeneration. Localized and controlled release of t‐sEVs within the PEGS‐A hydrogel leads to the retention of therapeutics in the defect site for highly efficient bone regeneration with minimal low accumulation in other organs.

Aflatoxin is one of the most toxic mycotoxins and causes server threaten to human health and food safety issues. It is crucial to develop efficient materials to remove and degrade aflatoxins. In this work, we adopted PVP modified ZIF-8 as precursor to prepare novel ZnO@NPC core–shell heterostructures (NPC is N-doped porous carbon) via “pyrolysis-in situ transformation-pyrolysis” strategy and used it as catalyst for degradation of aflatoxin B1 (AFB1). Various technologies were adopted to characterize to the structures and properties of the catalyst, such as XRD, SEM, BET, and TEM. The results show that the coating of N-doped porous carbon on ZnO can extend its light absorption wavelength to 800 nm, enhancing its photocatalytic activity for degradation of AFB1 (94.8%). The synergetic effect of high absorption capacity on N-doped porous carbon and excellent photocatalytic activity on ZnO was proven to contribute high degradation performance of ZnO@NPC. ZnO@NPC also shows excellent reparation and reusability. The photocatalytic activity of ZnO@NPC reduces only 1.71% after five repeated cycles. The developed ZnO@NPC may bring a promising solution for toxin degradation.

ABSTRACTMetal-organic framework materials (MOFs) have been widely studied because of their adjustable composition and controllable structure in the field of microwave absorption (MA). Therein, Prussian blue analogs (PBA) have attracted the attention of researchers with ultra-high metal content. However, the attenuation ability of microwave for PBA-based composites is still unsatisfactory up to now. Therefore, the NiFe/CoFe@C composites were prepared by carbonizing polymetallic PBA (NiCoFe PBA) materials in this work, and the influence of different metal alloy components on MA was explored by adjusting the ratio of metal ions (Ni2+/Co2+). Moreover, the NiFe/CoFe@C composites have rich interfaces and enhance the polarization loss due to the introduction of Ni and it has an optimal performance at 2.7 mm that is the reflection loss (RL) is −41.49 dB and an effective absorption bandwidth (EAB) is 7.12 GHz with 1/1 (Ni2+/Co2+). The above data provides a research idea for obtaining light and efficient absorbers.

IntroductionExcessive calorie intake and physical inactivity have dramatically increased nutrient overload-associated disease, becoming a global public health issue. Chimonanthus salicifolius S. Y. Hu (CHI) is a homology plant of food and medicine in China and shows several health benefits.MethodsThis work investigated the antioxidant activity, the alleviating effects, and the mechanism of action on diabetes and hyperlipidemia of CHI leaves.Results and discussionResults showed that CHI leaves infusion displayed in vitro antioxidant activity measured by ABTS and ferric reducing antioxidant power methods. In wild-type Kunming mice, CHI leaves infusion consumption activated the hepatic antioxidant enzymes, including glutathione reductase, glutathione S-transferase, glutathione peroxidase and thioredoxin reductase as well as thioredoxin reductase 1. In alloxan-induced type 1 diabetic mice, CHI leaves infusion ameliorated diabetic symptoms, including polyuria, polydipsia, polyphagia and hyperglycemia, in a dose-dependent and time-course manners. The mechanism involved CHI leaves up-regulating renal water reabsorption associated protein – urine transporter A1–and promoting the trafficking of urine transporter A1 and aquaporin 2 to the apical plasma membrane. Despite this, in high-fat diet-induced hyperlipidemic golden hamsters, CHI leaves powder did not significantly effect on hyperlipidemia and body weight gain. This might be attributed to CHI leaves powder increasing the calorie intake. Interestingly, we found that CHI leaves extract containing a lower dose of total flavonoid than CHI leaves powder pronouncedly reduced the levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol in serum in golden hamsters fed a high-fat diet. Furthermore, CHI leaves extract elevated the diversity of gut microbiota and the abundance of Bifidobacterium and Ruminococcaceae_UCG-014. It also decreased the abundance of Lactobacillus at the genus level in golden hamsters fed a high-fat diet. Overall, CHI leaves benefit oxidative stress prevention and metabolic syndrome amelioration in vivo.

Bortezomib (BTZ), a boronic acid-derived proteasome inhibitor, is commonly employed in treating multiple myeloma (MM). However, the applications of BTZ are limited due to its poor stability and low bioavailability. Herein, we develop an optimized liposomal formulation of BTZ (L-BTZ) by employing a remote-loading strategy. This formulation uses Tiron, a divalent anionic catechol derivative, as the internal complexing agent. Compared to earlier BTZ-related formulations, this alternative formulation showed significantly greater stability due to the Tiron–BTZ complex’s higher pH stability and negative charges, compared to the meglumine–BTZ complex. Significantly, the plasma AUC of L-BTZ was found to be 30 times greater than that of free BTZ, suggesting an extended blood circulation duration. In subsequent therapeutic evaluations using two murine xenograft tumor models of MM, the NCI-H929 and OPM2 models showed tumor growth inhibition (TGI) values of 37% and 57%, respectively. In contrast, free BTZ demonstrated TGI values of 17% and 11% in these models. Further, L-BTZ presented enhanced antitumor efficacy in the Hepa1-6 HCC syngeneic model, indicating its potential broader applicability as an antineoplastic agent. These findings suggest that the optimized L-BTZ formulation offers a significant advancement in BTZ delivery, holding substantial promise for clinical investigation in not merely MM, but other cancer types.

Abstract Mechanical stimulation plays an important role in bone remodeling. Exercise-induced mechanical loading enhances bone strength, whereas mechanical unloading leads to bone loss. Increasing evidence has demonstrated that long noncoding RNAs (lncRNAs) play key roles in diverse biological, physiological and pathological contexts. However, the roles of lncRNAs in mechanotransduction and their relationships with bone formation remain unknown. In this study, we screened mechanosensing lncRNAs in osteoblasts and identified Neat1, the most clearly decreased lncRNA under simulated microgravity. Of note, not only Neat1 expression but also the specific paraspeckle structure formed by Neat1 was sensitive to different mechanical stimulations, which were closely associated with osteoblast function. Paraspeckles exhibited small punctate aggregates under simulated microgravity and elongated prolate or larger irregular structures under mechanical loading. Neat1 knockout mice displayed disrupted bone formation, impaired bone structure and strength, and reduced bone mass. Neat1 deficiency in osteoblasts reduced the response of osteoblasts to mechanical stimulation. In vivo, Neat1 knockout in mice weakened the bone phenotypes in response to mechanical loading and hindlimb unloading stimulation. Mechanistically, paraspeckles promoted nuclear retention of E3 ubiquitin ligase Smurf1 mRNA and downregulation of their translation, thus inhibiting ubiquitination-mediated degradation of the osteoblast master transcription factor Runx2, a Smurf1 target. Our study revealed that Neat1 plays an essential role in osteoblast function under mechanical stimulation, which provides a paradigm for the function of the lncRNA-assembled structure in response to mechanical stimulation and offers a therapeutic strategy for long-term spaceflight- or bedrest-induced bone loss and age-related osteoporosis.

Objective: We aim at investigating the molecular mechanisms through which the Qingfei Jiedu decoction (QFJDD) regulates PD-L1 expression in lung adenocarcinoma (LUAD).Methods: Bioactive compounds and targets of QFJDD were screened from TCMSP, BATMAN-TCM, and literature. Then, GeneCard, OMIM, PharmGKB, Therapeutic Target, and DrugBank databases were used to identify LUAD-related genes. The protein-protein interaction (PPI) network was constructed using overlapping targets of bioactive compounds in LUAD with the Cytoscape software and STRING database. The potential functions and pathways in which the hub genes were enriched by GO, KEGG, and DAVID pathway analyses. Molecular docking of bioactive compounds and key genes was executed via AutoDock Vina. Qualitative and quantitative analyses of QFJDD were performed using UPLC-Q-TOF-MS and UPLC. Expressions of key genes were determined by qRT-PCR, immunoreactivity score (IRS) of PD-L1 was assessed by immunohistochemistry (IHC), while the CD8+PD-1+T% derived from spleen tissues of Lewis lung cancer (LLC) bearing-mice was calculated using flow cytometry (FCM).Results: A total of 53 bioactive compounds and 288 targets of QFJDD as well as 8151 LUAD associated genes were obtained. Further, six bioactive compounds, including quercetin, luteolin, kaempferol, wogonin, baicalein, and acacetin, and 22 hub genes were identified. The GO analysis showed that the hub genes were mainly enriched in DNA or RNA transcription. KEGG and DAVID pathway analyses revealed that 20 hub genes were primarily enriched in virus, cancer, immune, endocrine, and cardiovascular pathways. The EGFR, JUN, RELA, HIF1A, NFKBIA, AKT1, MAPK1, and MAPK14 hub genes were identified as key genes in PD-L1 expression and PD-1 checkpoint pathway. Moreover, ideal affinity and regions were identified between core compounds and key genes. Notably, QFJDD downregulated EGFR, JUN, RELA, HIF1A, NFKBIA, and CD274 expressions (p < 0.05), while it upregulated AKT1 and MAPK1 (p < 0.05) levels in A549 cells. The PD-L1 IRS of LLC tissue in the QFJDD high dose (Hd) group was lower than model group (p < 0.01). CD8+PD-1+T% was higher in the QFJDD Hd group than in normal and model groups (p < 0.05).Conclusion: QFJDD downregulates PD-L1 expression and increases CD8+PD-1+T% via regulating HIF-1, EGFR, JUN and NFκB signaling pathways. Therefore, QFJDD is a potential treatment option for LUAD.

The poor resistance to cold stress conditions has become the bottleneck problem in Tetrastigma hemsleyanum (T. hemsleyanum) planting industry. Exogenous hydrogen (H2) plays an important role in improving stress resistance in plants. However, the key factors and regulatory network of plants in response to hydrogen-rich water (HRW) treatment under environmental stress are not clear. Here, we conducted integrative analyses of metabolome and transcriptome profiles to reveal the defense mechanism involved in the HRW-regulated cold stress response of T. hemsleyanum. The application of 75% HRW could alleviate stress damage by decreasing stomatal apparatus density and significantly increasing photosynthetic efficiency and mitigating physiological indexes of resistance, such as Pn, Cond, MDA, SOD, etc., which were changed by cold stress conditions. A total of 7,883 DEGs and 439 DEMs were identified. DEGs were the most relevant to phenylpropanoid, isoflavonoid, monoterpenoid, and flavonoid biosynthesis pathways. Using gene co-expression analysis (WGCNA), we identified one gene module that showed a strong correlation between total antioxidant capacity and transpiration rate. Trend analysis indicated that the phenylpropanoid biosynthesis pathway played a major role in the transcription and metabolism process of HRW treatment under cold stress. Based on the integrated analysis of genes and metabolites, the results showed cold stress upregulated the expression of PAL, CHS, COMT, CCR, AtBG1, etc., resulting in the accumulation of coniferyl alcohol and eriodictyol contents in T. hemsleyanum under cold stress, but the 75% HRW treatment could attenuate the enhancement. The study not only identified the main strategy of HRW protection against cold stress but also provided candidate genes for flavonoid biosynthesis, so as to better improve cold tolerance through molecular breeding techniques.

Photocatalytic degradation method has been recognized as an effective way to eliminate the contamination of environment. However, developing photocatalysts with excellent photocatalytic properties are still a big challenge. In this paper, Ag doped ZnO coating with a layer of N doped porous carbon (Ag/ZnO@N-carbon) was successfully synthesized by using polyvinyl pyrrolidone (PVP) modified ZIF-8 as precursor via adsorption, hydrothermal treatment, in situ growth and carbonization processes. The physical and chemical properties of all samples were characterized by X-ray powder diffraction (XRD), scanning electron microscope (SEM), electron transmission microscopy (TEM) and so on. The results show that Ag doping does not change the crystallinity of ZnO, but broaden its photo-response property. The coating of N doped carbon can improve the specific surface area of photocatalyst. The photocatalytic activity of all samples was evaluated by degradation of rhodamine B (RhB) solution under UV light irradiation for 25 min. Ag/ZnO@N-carbon exhibits the highest photocatalytic activity for degradation of RhB with a degradation of 98.65%. Furthermore, Ag/ZnO@N-carbon also has high stability. Based on the characterization, possible mechanism for degradation of RhB by Ag/ZnO@N-carbon under UV light irradiation was proposed.

More and more evidence has supported the interaction between circadian rhythms and intestinal microbes, which provides new insights into how dietary nutrition can improve host health. Our research showed that Ficus pandurata Hance var. angustifolia Cheng flavonoids (FCF) ameliorated the pathological damage of colon and abnormal intestinal microflora structure in mice with circadian clock disorder and improved their exploration and memory behaviors. Mechanism studies have shown that FCF is involved in regulating metabolic pathways and related metabolites, regulating the expression of related tight junction proteins in the colon and the levels of Aβ and inflammatory factors in the hippocampus. Further analysis found that these metabolites showed a certain correlation with intestinal flora and played a certain role in alleviating intestinal physiological damage and cognitive decline.

Abstract Metastasis is a major contributor to cancer-associated deaths. It involves complex interactions between primary tumorigenic sites and future metastatic sites. Accumulation studies have revealed that tumour metastasis is not a disorderly spontaneous incident but the climax of a series of sequential and dynamic events including the development of a pre-metastatic niche (PMN) suitable for a subpopulation of tumour cells to colonize and develop into metastases. A deep understanding of the formation, characteristics and function of the PMN is required for developing new therapeutic strategies to treat tumour patients. It is rapidly becoming evident that therapies targeting PMN may be successful in averting tumour metastasis at an early stage. This review highlights the key components and main characteristics of the PMN and describes potential therapeutic strategies, providing a promising foundation for future studies.

As hematopoietic stem cells can differentiate into all hematopoietic lineages, mitigating the damage to hematopoietic stem cells is important for recovery from overdose radiation injury. Cells in bone marrow microenvironment are essential for hematopoietic stem cells maintenance and protection, and many of the paracrine mediators have been discovered in shaping hematopoietic function. Several recent reports support exosomes as effective regulators of hematopoietic stem cells, but the role of osteoblast derived exosomes in hematopoietic stem cells protection is less understood. Here, we investigated that osteoblast derived exosomes could alleviate radiation damage to hematopoietic stem cells. We show that intravenous injection of osteoblast derived exosomes promoted WBC, lymphocyte, monocyte and hematopoietic stem cells recovery after irradiation significantly. By sequencing osteoblast derived exosomes derived miRNAs and verified in vitro, we identified miR-21 is involved in hematopoietic stem cells protection via targeting PDCD4. Collectively, our data demonstrate that osteoblast derived exosomes derived miR-21 is a resultful regulator to radio-protection of hematopoietic stem cells and provide a new strategy for reducing radiation induced hematopoietic injury.

There is an increasing interest in understanding how defect chemistry can alter material reactivity. Here, authors tune the electronic structure of RuO2 by introducing W and Er dopants that boost acidic oxygen evolution performances by limiting oxygen vacancy formation during catalysis.

This paper aims to solve the problem of high energy consumption in forging production through energy-saving scheduling. By analyzing the flow shop characteristics of a forging workshop, an energy-efficient hybrid flow shop scheduling problem with forging tempering (EEHFSP-FT) is proposed. An energy-efficient scheduling model is established to simultaneously minimize both the completion time and energy consumption. In the scheduling model, constraints such as heating furnace capacity, required forging temperature, and required quenching temperature are taken into consideration. An energy-saving strategy of heat treatment with residual forging heat is adopted to address the problem of energy underutilization after forging. In order to use multi-objective optimization algorithms to solve the scheduling problems of charging and machine selection in forging production, encoding and decoding rules and evolutionary search strategies are designed. Finally, a case study on the flow shop of an automated forging center is analyzed. The validity of the proposed model is demonstrated by testing cases of different scales in conjunction with three different evolutionary algorithms. By analyzing the performance of the three algorithms, the algorithm suitable for solving the proposed model is determined.

Cardiac muscle is extremely sensitive to changes in loading conditions; the microgravity during space flight can cause cardiac remodeling and function decline. At present, the mechanism of microgravity-induced cardiac remodeling remains to be revealed. WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is an important activator of pressure overload-induced cardiac remodeling by stabilizing disheveled segment polarity proteins 2 (DVL2) and activating the calcium-calmodulin-dependent protein kinase II (CaMKII)/histone deacetylase 4 (HDAC4)/myocyte-specific enhancer factor 2C (MEF2C) axis. However, the role of WWP1 in cardiac remodeling induced by microgravity is unknown. The purpose of this study was to determine whether WWP1 was also involved in the regulation of cardiac remodeling caused by microgravity. Firstly, we detected the expression of WWP1 and DVL2 in the heart from mice and monkeys after simulated microgravity using western blotting and immunohistochemistry. Secondly, WWP1 knockout (KO) and wild-type (WT) mice were subjected to tail suspension (TS) to simulate microgravity effect. We assessed the cardiac remodeling in morphology and function through a histological analysis and echocardiography. Finally, we detected the phosphorylation levels of CaMKII and HDAC4 in the hearts from WT and WWP1 KO mice after TS. The results revealed the increased expression of WWP1 and DVL2 in the hearts both from mice and monkeys after simulated microgravity. WWP1 deficiency alleviated simulated microgravity-induced cardiac atrophy and function decline. The histological analysis demonstrated WWP1 KO inhibited the decreases in the size of individual cardiomyocytes of mice after tail suspension. WWP1 KO can inhibit the activation of the DVL2/CaMKII/HDAC4 pathway in the hearts of mice induced by simulated microgravity. These results demonstrated WWP1 as a potential therapeutic target for cardiac remodeling and function decline induced by simulated microgravity.

Abstract Background With the rising utilization of cardiovascular implantable electronic devices (CIEDs), infections secondary to device implantation are increasingly encountered. Staphylococcus aureus and coagulase-negative staphylococci are usually the predominant causative organisms. A CIED infection due to non-tuberculous mycobacteria (NTM) is extremely rare. Case presentation A 68-year-old man was admitted to our hospital with a history of pain and swelling at his cardiac resynchronization therapy-defibrillator (CRT-D) pocket site, for 4 days. The CRT-D had been implanted 2 weeks prior. The exudate smear was positive for acid-fast bacilli and culture results revealed rapidly growing nontuberculous mycobacteria (RGM). After an urgent removal of the device followed by 1 year of antibiotic treatment, the patient was completely cured. A new device was finally implanted, 3 years later. Conclusions Infections caused by nontuberculous mycobacteria following the implantation of cardiac devices are very rare. The typical manifestations of post-implantation CIED infections caused by RGMs include an early onset, with local redness, swelling, and spontaneous drainage. Systemic symptoms such as fever, chills, and fatigue are absent. Mycobacterium fortuitum is the most common species of RGM implicated in CIED infections, the manifestations of which usually appear within several weeks of the implantation procedure. An urgent removal of the device and appropriate antibiotic therapy are essential therapeutic measures. This is the first such reported case, in which the patient has been re-implanted with another device at the same site, after achieving a complete cure. We followed-up the patient for an additional 3 years and observed that the patient remained free of infection. Our case report shows that though an RGM infection is rare and difficult to treat, it can be completely cured. In addition, we demonstrated that it is subsequently possible to safely re-implant a CIED for the patient, at the same site.

Lung cancer is the leading cause of cancer-related deaths mainly attributable to metastasis, especially extrathoracic metastasis. This large-cohort research is aimed to explore metastatic profiles in different histological types of lung cancer, as well as to assess clinicopathological and survival significance of diverse metastatic lesions. Lung cancer cases were extracted and enrolled from the Surveillance, Epidemiology, and End Results (SEER) database. χ2-tests were conducted to make comparisons of metastatic distribution among different histological types and odds ratios were calculated to analyze co-occurrence relationships between different metastatic lesions. Kaplan–Meier methods were performed to analyze survival outcomes according to different metastatic sites and Cox regression models were conducted to identify independent prognostic factors. In total, we included 159,241 lung cancer cases with detailed metastatic status and complete follow-up information. In order to understand their metastatic patterns, we elucidated the following points in this research: (1) Comparing the frequencies of different metastatic lesions in different histological types. The frequency of bone metastasis was highest in adenocarcinoma, squamous cell carcinoma, LCLC and NSCLC/NOS, while liver was the most common metastatic site in SCLC. (2) Elaborating the tendency of combined metastases. Bi-site metastases occurred more common than tri-site and tetra-site metastases. And several metastatic sites, such as bone and liver, intended to co-metastasize preferentially. (3) Clarifying the prognostic significance of single-site and bi-site metastases. All single-site metastases were independent prognostic factors and co-metastases ended up with even worse survival outcomes. Thus, our findings would be beneficial for research design and clinical practice.

Abstract Background Foam cells play a key role in the occurrence and pathogenesis of atherosclerosis. Its formation starts with the ingestion of oxidized low-density lipoprotein (oxLDL). The process is associated with Ras related protein in brain 5 (Rab5) which plays a critical role in regulating endocytosis and early endosomal trafficking. Base on this, we presumed that Rab5 might participate in the maturation of foam cell. The aim of this study is to investigate the effect of Rab5 on macrophage cholesterol during the evolvement of macrophage when induced by oxLDL to the formation of foam cell. Methods Immunohistochemistry was performed to analyze the distribution of macrophages and Rab5 in atherosclerotic plaque. RNA inteference study and transfection of inactive mutant (GFP-Rab5-S34N) and active mutant (GFP-Rab5-Q79L) in U937-derived macrophage were utilized to investigate the impact of Rab5 on the process of macrophage cholesterol, which could be detected by oil red O staining, determination of intracellular lipid content, filipin staining, nile red staining and the costaining of early endosome antigen-1 (EEA-1) and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylin dicarbocyanine (Dil)-labelled oxLDL (Dil-oxLDL). Results Rab5 was found abundantly localized in macrophage rich areas of human atherosclerotic lesions. On the foam cell study, the expression of Rab5 was increased after the incubation of oxLDL. The inteference study indicated the depletion of Rab5 led to the decreases of oil red O staining areas, total cholesterol and cholesterol esters in U937-derived marophages. Moreover, the fluorescence intensity of filipin and nile red staining were lower in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L. The confocal study demonstrated less Dil-oxLDL was internalized in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L; the result showed also the decrease in colocalization of internalized Dil-oxLDL and EEA-1 for GFP-Rab5-S34N as compared with GFP-Rab5-Q79L. Conclusions Rab5 plays an important role in modulating the intracellular cholesterol of macrophages and consequently mediating the formation of foam cells.

Conductive cotton fabric was prepared by coating single-wall carbon nanotubes (CNTs) on a knitted cotton fabric surface through a “dip-and-dry” method. The combination of CNTs and cotton fabric was analyzed using scanning electron microscopy (SEM) and Raman scattering spectroscopy. The CNTs coating improved the mechanical properties of the fabric and imparted conductivity to the fabric. The electromechanical performance of the CNT-cotton fabric (CCF) was evaluated. Strain sensors made from the CCF exhibited a large workable strain range (0~100%), fast response and great stability. Furthermore, CCF-based strain sensors was used to monitor the real-time human motions, such as standing, walking, running, squatting and bending of finger and elbow. The CCF also exhibited strong electric heating effect. The flexible strain sensors and electric heaters made from CCF have potential applications in wearable electronic devices and cold weather conditions.