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Abstract Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.

Abstract Laryngeal carcinoma (LC) is a common cancer of the respiratory tract. This study aims to investigate the role of RNA-binding motif protein 15 (RBM15) in the cisplatin (DDP) resistance of LC cells. LC-DDP-resistant cells were constructed. RBM15, lysine-specific demethylase 5B (KDM5B), lncRNA Fer-1 like family member 4 (FER1L4), lncRNA KCNQ1 overlapping transcript 1 (KCNQ1OT1), glutathione peroxidase 4 (GPX4), and Acyl-CoA synthetase long-chain family (ACSL4) was examined. Cell viability, IC50, and proliferation were assessed after RBM15 downregulation. The enrichment of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and N6-methyladenosine (m6A) on KDM5B was analyzed. KDM5B mRNA stability was measured after actinomycin D treatment. A tumor xenograft assay was conducted to verify the role of RBM15 in LC. Results showed that RBM15 was upregulated in LC and its knockdown decreased IC50, cell viability, proliferation, glutathione, and upregulated iron ion content, ROS, malondialdehyde, ACSL4, and ferroptosis. Mechanistically, RBM15 improved KDM5B stability in an IGF2BP3-dependent manner, resulting in FER1L4 downregulation and GPX4 upregulation. KDM5B increased KCNQ1OT1 and inhibited ACSL4. KDM5B/KCNQ1OT1 overexpression or FER1L4 knockdown promoted DDP resistance in LC by inhibiting ferroptosis. In conclusion, RBM15 promoted KDM5B expression, and KDM5B upregulation inhibited ferroptosis and promoted DDP resistance in LC by downregulating FER1L4 and upregulating GPX4, as well as by upregulating KCNQ1OT1 and inhibiting ACSL4. Silencing RBM15 inhibited tumor growth in vivo.

Abstract Background The aberrant expression of phosphofructokinase-platelet (PFKP) plays a crucial role in the development of various human cancers by modifying diverse biological functions. However, the precise molecular mechanisms underlying the role of PFKP in head and neck squamous cell carcinoma (HNSCC) are not fully elucidated. Methods We assessed the expression levels of PFKP and c-Myc in tumor and adjacent normal tissues from 120 HNSCC patients. A series of in vitro and in vivo experiments were performed to explore the impact of the feedback loop between PFKP and c-Myc on HNSCC progression. Additionally, we explored the therapeutic effects of targeting PFKP and c-Myc in HNSCC using Patient-Derived Organoids (PDO), Cell Line-Derived Xenografts, and Patients-Derived Xenografts. Results Our findings indicated that PFKP is frequently upregulated in HNSCC tissues and cell lines, correlating with poor prognosis. Our in vitro and in vivo experiments demonstrate that elevated PFKP facilitates cell proliferation, angiogenesis, and metastasis in HNSCC. Mechanistically, PFKP increases the ERK-mediated stability of c-Myc, thereby driving progression of HNSCC. Moreover, c-Myc stimulates PFKP expression at the transcriptional level, thus forming a positive feedback loop between PFKP and c-Myc. Additionally, our multiple models demonstrate that co-targeting PFKP and c-Myc triggers synergistic anti-tumor effects in HNSCC. Conclusion Our study demonstrates the critical role of the PFKP/c-Myc positive feedback loop in driving HNSCC progression and suggests that simultaneously targeting PFKP and c-Myc may be a novel and effective therapeutic strategy for HNSCC.

Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects. The primary challenge is to integrate diverse pharmacophores within a single-molecule framework. To address this, we introduced DeepSA, a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine, a well-known local anesthetic. DeepSA integrates deep neural networks into metaheuristics, effectively constraining molecular space during compound generation. This framework employs a sophisticated objective function that accounts for scaffold preservation, anti-inflammatory properties, and covalent constraints. Through a sequence of local editing to navigate the molecular space, DeepSA successfully identified AT-17, a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models. Mechanistic insights into AT-17 revealed its dual mode of action: selective inhibition of NaV1.7 and 1.8 channels, contributing to its prolonged local anesthetic effects, and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway. These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery, particularly within stringent chemical constraints.

High-performance dielectric tunable materials with both high dielectric tunability and low dielectric loss are urgently needed for new-generation electronic tunable devices. In the present study, a new system, (Ba0.675Sr0.325)1−xLaxTi1−xMnxO3 (x = 0.25%, 0.5%, 0.75%, and 1.0%), was designed. The acceptor dopant Mn was added to lower dielectric loss, while the donor dopant La was introduced to enhance dielectric tunability. The samples were prepared using the conventional solid-state (CS) reaction method and the semi-solution (SS) method. The experimental results showed that the morphology of the ceramics was optimized by further improving the processing procedure. Dense microstructures, homogeneous grains, and uniform dopant distributions could be achieved successfully by the semi-solution method. Moreover, a significant enhancement in the tunable properties was realized owing to the improved microstructure mentioned above. The optimum tunable properties occurred in the samples prepared by the semi-solution method at x = 0.75%, with a high dielectric tunability of 85.0%, a low dielectric loss of 0.0011, and an excellent figure of merit (FOM) of 773. The tunable properties of (Ba,Sr)TiO3 (BST) ceramics were even superior to those of lead-based materials, with an FOM of approximately 700. All the results suggested that the semi-solution method rendered BST ceramics more promising for applications in tunable devices.

Abstract Background Carney syndrome is an uncommon autosomal disorder closely linked to mutations in the PRKAR1A gene. Skin lesions are the most pronounced feature of Carney syndrome, affecting over 80% of individuals with this condition. This syndrome is characterized by a triad of myxomas, skin pigmentation, and endocrine hyperfunction, featuring multiple endocrine neoplasms with skin and cardiac involvement. Dilated cardiomyopathy, a primary cardiomyopathy, is defined as the dilation and impaired systolic function of the left or both ventricles. Its clinical presentation varies from being asymptomatic to heart failure or sudden cardiac death, making it a leading global cause of heart failure. Currently, Dilated cardiomyopathy has an estimated prevalence of 1/2500–1/250 individuals, predominantly affecting those aged 30–40 years, with a male-to-female ratio of 3:1. This case report describes a heart failure patient with cardiac myxoma caused by Carney syndrome combined with dilated cardiomyopathy. The patient was successfully treated for heart failure by heart transplantation. Case presentation Herein, we report a case of heart failure due to Carney syndrome that resulted in cardiac myxoma combined with dilated cardiomyopathy. A 35-year-old male was admitted to the hospital three years ago because of sudden chest tightness and shortness of breath. Echocardiography indicated myxoma, and a combination of genetic screening and physical examination confirmed Carney syndrome with cardiac myxoma. Following symptomatic management, he was discharged. Surgical interventions were not considered at the time. However, the patient’s chest tightness and shortness of breath symptoms worsened, and he returned to the hospital. A New York Heart Association grade IV heart function was confirmed, and echocardiography indicated the presence of dilated cardiomyopathy accompanied by cardiac myxoma. Ultimately, the patient’s heart failure was successfully treated with heart transplantation. Conclusions Cardiac myxoma caused by Carney syndrome combined with heart failure caused by dilated cardiomyopathy can be resolved by heart transplantation.

Abstract It is important to study the effect of hydrate production on the physical and mechanical properties of low‐permeability clayey–silty reservoirs for the large‐scale exploitation of hydrate reservoirs in the South China Sea. In this study, a multiphysical‐field coupling model, combined with actual exploration drilling data and the mechanical experimental data of hydrate cores in the laboratory, was established to investigate the physical and mechanical properties of low‐permeability reservoirs with different slope angles during 5‐year hydrate production by the depressurization method via a horizontal well. The result shows that the permeability of reservoirs severely affects gas production rate, and the maximum gas production amount of a 20‐m‐long horizontal well can reach 186.8 m3/day during the 5‐year hydrate production. Reservoirs with smaller slope angles show higher gas production rates. The depressurization propagation and hydrate dissociation mainly develop along the direction parallel to the slope. Besides, the mean effective stress of reservoirs is concentrated in the near‐wellbore area with the on‐going hydrate production, and gradually decreases with the increase of the slope angle. Different from the effective stress distribution law, the total reservoir settlement amount first decreases and then increases with the increase of the slope angle. The maximum settlement of reservoirs with a 0° slope angle is up to 3.4 m, and the displacement in the near‐wellbore area is as high as 2.2 m after 5 years of hydrate production. It is concluded that the pore pressure drop region of low‐permeability reservoirs in the South China Sea is limited, and various slope angles further lead to differences in effective stress and strain of reservoirs during hydrate production, resulting in severe uneven settlement of reservoirs.

Abstract Background Forests play a crucial role in absorbing CO2 from the atmosphere. 55% of the carbon in terrestrial ecosystems is stored in forests, with the majority of forest carbon stored in soil. To better understand soil organic carbon (SOC) of forests and to access interventions that affect their SOC concentration, we conducted a comparative analysis between natural and planted forests. Forest interventions refer to the actions taken by humans to manage, protect, or transform forests, and can be divided into two main categories: environmental intervention and anthropogenic intervention. This study focused on the effects of different interventions on SOC in natural and planted forests by reviewing a total of 75 randomized controlled trials in the global literature and extracting a total of 15 different interventions. Results Through network meta-analysis, we found that natural forests have 22.3% higher SOC than planted forests, indicating their stronger carbon storage function. In natural forests, environmental interventions have a stronger impact. SOC is significantly influenced by forest age, fertilization, and elevation. In planted forests, however, anthropogenic interventions have a stronger impact. Pruning branches and fertilization are effective interventions for planted forests. Furthermore, forest degradation has a significantly negative impact on SOC in planted forests. Conclusion Overall, interventions to enhance soil carbon storage function differ between natural and planted forests. To address global climate change, protect biodiversity, and achieve sustainable development, it is imperative to globally protect forests and employ scientifically sound forest management practices. Regarding natural forests, the emphasis should be on comprehending the effects of environmental interventions on SOC. Conversely, concerning planted forests, the emphasis should be on comprehending the effects of anthropogenic interventions.

Abstract. Background:. There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients. Methods:. In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12. Results:. At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P

Abstract Purpose The purpose of this study was to compare the learning in the implant dentistry hands-on course to that of the flipped classroom (FC) and the traditional lecture cohorts (control). Materials and methods In this study,80 students were enrolled for the first time in an implant dentistry program. Subsequently, they were divided into two groups. The first, the FC group, which had free access to a video with a PowerPoint presentation on the Chaoxing-WHU-MOOC platform about the implant placement on first molar sites before class. The second, the control group, which attended a didactic lecture describing implant practice on the first molar site via a bidirectional multimedia interactive teaching demonstration and then operated on a simulation model. Cone beam computed tomography (CBCT) and the deviation gauge were utilized to analyze the accuracy of the implant placement in the students’ models. An online satisfaction questionnaire was distributed to both groups one week after the class. Results The linear deviation of the CBCT examination did not show any statistical difference between the two groups concerning cervical, apex, and angular. A significant buccal deviation was observed in the control group compared with the FC group (mean: 0.7436 mm vs. 0.2875 mm, p = 0.0035), according to the restoration-level deviation gauge. A total of 74.36% of students in the FC group placed implant within 0.5 mm buccal-to-lingual deviations, but only 41.03% of students in the control group reached within 0.5 mm buccal-to-lingual deviation ranges. Additionally, 91.67% of the students in the FC group and 97.5% of the students in the control group were satisfied with the practical implant class. Conclusion FC was more effective than a didactic lecture for implant dentistry practical skill acquisition.

Abstract Rheumatoid arthritis (RA) is a progressive autoimmune disease accompanied by joint swelling, cartilage erosion and bone damage. Drug therapy for RA has been restricted due to poor therapeutic effect, recurrence and adverse effects. Macrophages and synovial fibroblasts both play important roles in the pathology of RA. Macrophages secrete large amount of pro-inflammatory cytokines, while synovial fibroblasts are tightly correlated with hypoxia synovium microenvironment, cytokine release, recruitment of pro-inflammatory cells, bone and cartilage erosion. Therefore, in this timely research, an injectable and pH-sensitive peptide hydrogel loading methotrexate (MTX) and bismuthene nanosheet/polyethyleneimine (BiNS/PEI) has been developed to reduce the activity of macrophages and eliminate over-proliferated synovial fibroblasts simultaneously. MTX can reduce the cytokine secretion of macrophages/anti-apoptosis property of synovial fibroblasts and BiNS/PEI can eliminate synovial fibroblasts via photodynamic therapy (PDT) and photothermal therapy (PTT) routes. The hydrogel was injected into the acidic inflammatory synovium for precise targeting and served as a drug reservoir for pH responsive and sustained drug release, while improving the bioavailability and reducing the toxicity of MTX. Excellent therapeutic efficacy has been achieved in both in vivo and in vitro studies, and this unique drug delivery system provides a new and robust strategy to eliminate synovial fibroblasts and modulate immune system for RA treatment in clinical. Graphic Abstract

Abstract Background Triple-negative breast cancer (TNBC) is a life-threatening subtype of breast cancer with limited treatment options. Therefore, this network meta-analysis (NMA) aimed to evaluate and compare the effect of various neoadjuvant chemotherapy (NCT) options on the long-term survival of patients with TNBC. Methods PubMed, Embase, Medline, Cochrane Library, Web of Science, and major international conference databases were systematically searched for randomized controlled trials (RCTs) on the efficacy of various NCT options in patients with TNBC. Searches were performed from January 2000 to June 2023. Study heterogeneity was assessed using the I2 statistic. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate disease-free survival (DFS) and overall survival (OS). Odds ratios (ORs) and 95% CIs were used to evaluate the pathologic complete response (pCR). The primary outcome was DFS. Results We conducted an NMA of 21 RCTs involving 8873 patients with TNBC. Our study defined the combination of anthracyclines and taxanes as the preferred treatment option. On this basis, the addition of any of the following new drugs is considered a new treatment option: bevacizumab (B), platinum (P), poly-ADP-ribose polymerase inhibitors (PARPi), and immune checkpoint inhibitor (ICI). Based on the surface under the cumulative ranking curve (SUCRA) values, the top three SUCRA area values of DFS were taxanes, anthracycline, and cyclophosphamide (TAC; 89.23%); CT (84.53%); and B (81.06%). The top three SUCRA area values of OS were CT (83.70%), TAC (62.02%), and B-containing regimens (60.06%). The top three SUCRA area values of pCR were B + P-containing regimens (82.7%), ICI + P-containing regimens (80.2%), and ICI-containing regimens (61.8%). Conclusions This NMA showed that standard chemotherapy is a good choice with respect to long-term survival. Moreover, B associated with P-containing regimens is likely to be the optimal treatment option for neoadjuvant TNBC in terms of pCR.

Abstract Background Previous studies have demonstrated the relationship between adipocyte factors, insulin resistance, and other indicators with telomere length. However, these studies did not consider the influence of changes in different indicators on telomere length over time. Therefore, the aim of this study is to elucidate the impact of changes in adipocyte factors, HOMA-IR, and other indicators on the dynamic variation of telomere length. Methods The data were from a cohort study conducted in Ningxia, China. A total of 1624 subjects were analyzed. Adipokines and relative leukocyte telomere length (RLTL) were measured, and changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), Homeostatic Model Assessment for β-Cell Function (HOMA-β), and Quantitative Insulin Sensitivity Check Index (QUICKI) were calculated. Generalized linear models evaluated associations between changes in adipokines and RLTL changes. Furthermore, univariate analyses examined the effects of changes in adipokines and insulin resistance indicators on ΔRLTL. Results The research findings indicate that females generally have shorter telomeres compared to males. In comparison to the low-level group of Δleptin (LEP), the high-level group of ΔLEP shows a negative correlation with ΔRLTL (B=-1.32, 95% CI (-2.38, -0.27)). Even after multivariable adjustments, this relationship persists (B=-1.31, 95% CI (-2.24, -0.23)). Further analysis reveals that after adjusting for ΔHOMA-IR, ΔHOMA-β, and ΔQUICKI, the high-level group of ΔLEP still exhibits a significant negative correlation with ΔRLTL (B=-1.37, 95% CI (-2.43, -0.31)). However, the interaction effects between ΔHOMA-IR, ΔHOMA-β, ΔQUICKI, and ΔLEP do not affect ΔRLTL. Conclusions Elevated levels of leptin were significantly correlated with shortened telomere length. This suggests that increased leptin levels may impact overall individual health by affecting telomere length, underscoring the importance of measures to reduce leptin levels to mitigate the onset and progression of related diseases.

BackgroundLong-term exposure to ambient fine particulate matter (PM2.5) may increase the risk of diabetes, and a healthy diet can effectively control fasting blood glucose levels. However, it is unclear whether dietary factors have a moderating effect on the risk of diabetes associated with atmospheric PM2.5 exposure. ObjectiveTo investigate the association between long-term exposure to PM2.5 and diabetes in rural areas of Ningxia, and potential interaction of long-term exposure to atmospheric PM2.5 and diet on diabetes.MethodsThe study subjects were selected from the baseline survey data of the China Northwest Cohort-Ningxia (CNC-NX) , a natural population cohort. A total of 13917 subjects were included, excluding participants with missing covariate information. We utilized the annual average ambient PM2.5 concentration from 2014 to 2018 as the long-term exposure level. Logistic regression and multiple linear regression were employed to analyze the associations of long-term atmospheric PM2.5 exposure with diabetes and fasting blood glucose levels. Stratification by frequency of vegetable consumption, frequency of fruit consumption, and salty taste was used to examine moderating effects on the diabetes risk associated with atmospheric PM2.5 exposure.ResultsThe mean age of the 13917 subjects was (56.8±10.0) years, and the prevalence of diabetes was 9.8%. Between 2014 and 2018, the average annual concentration of PM2.5 was (38.10±4.67) μg·m−3. The risk (OR) of diabetes was 1.018 (95%CI: 1.005, 1.032) and the fasting blood glucose was increased by 0.011 (95%CI: 0.004, 0.017) mmol·L−1 for each 1 μg·m−3 increase in PM2.5 concentration. Compared to those who consumed vegetables < 1 time per week, individuals who consume vegetables 1-3 times per week and ≥4 times per week had a reduced risk of developing diabetes by 27.1% (OR=0.729, 95%CI: 0.594, 0.893) and 16.8% (OR=0.832, 95%CI: 0.715, 0.971) respectively. Similarly, when compared to those who consumed fruits

Abstract Background Higher intakes of dietary antioxidants have been linked to a lower type 2 diabetes mellitus (T2DM) risk. However, few studies have comprehensively examined the overall dietary antioxidant capacity, assessed by dietary antioxidant quality scores (DAQS) and dietary total antioxidant capacity (DTAC), related to T2DM risk, especially in populations consuming relatively monotonous diets. This study aimed to evaluate the associations of DAQS, DTAC, and T2DM among rural Chinese adults. Methods Data from 12,467 participants from the Natural Population Cohort of Northwest China: Ningxia Project was analyzed. Dietary intake was assessed using a validated semi-quantitative food frequency questionnaire. DAQS were calculated based on vitamins A, C, and E, zinc (Zn), and selenium (Se) intake. DTAC was estimated using the ferric-reducing ability of plasma assay. Logistic regression models were used to evaluate the associations of DAQS and DTAC with T2DM risk. Restricted cubic splines were used to assess potential non-linear relationships between DTAC and T2DM. Results T2DM was observed in 1,238 (9.9%) participants. After adjusting for confounders, compared to the lowest tertiles (T1) of DAQS, the odds ratios (ORs) for T2DM were 1.03 (95% CI 0.82–1.30) in T2 and 0.85 (95% CI 0.68–1.06) in T3 (P = 0.010). Compared to T1, the ORs for T2DM in the highest T3 were 0.78 (95% CI 0.67–0.91, P-trend = 0.008) for vitamin A, 1.34 (95% CI 1.15–1.56, P-trend

Abstract The deployment of imaging examinations has evolved into a robust approach for the diagnosis of lymph node metastasis (LNM). The advancement of technology, coupled with the introduction of innovative imaging drugs, has led to the incorporation of an increasingly diverse array of imaging techniques into clinical practice. Nonetheless, conventional methods of administering imaging agents persist in presenting certain drawbacks and side effects. The employment of controlled drug delivery systems (DDSs) as a conduit for transporting imaging agents offers a promising solution to ameliorate these limitations intrinsic to metastatic lymph node (LN) imaging, thereby augmenting diagnostic precision. Within the scope of this review, we elucidate the historical context of LN imaging and encapsulate the frequently employed DDSs in conjunction with a variety of imaging techniques, specifically for metastatic LN imaging. Moreover, we engage in a discourse on the conceptualization and practical application of fusing diagnosis and treatment by employing DDSs. Finally, we venture into prospective applications of DDSs in the realm of LNM imaging and share our perspective on the potential trajectory of DDS development. Graphical Abstract

To investigate the presence of metal elements and assess their health risk for the populace in the Nandong Underground River Basin (NURB), we conducted an analysis of eleven common heavy metals in the water body. A Health risk assessment (HRA) model was employed to analyze 84 water samples from the NURB. The detection results revealed the following order of heavy metals concentrations: Fe > Al > Mn > Zn > As > Cd > Pb > Cr > Ni > Cu > Hg. Correlation analysis indicated a certain similarity in material source and migration transformation among these eleven metal elements. Our study identified that the health risks for local residents exposed to metal elements in the water of NURB primarily stem from carcinogenic risk (10−6–10−4 a−1) through the drinking water pathway. Moreover, the health risk of heavy metal exposure for children through drinking water was notably higher than for adults. The maximum health risks of Cr in both underground and surface water exceeded the recommendation standard (5.0×10−5 a−1) from ICRP, surpassing the values recommended by the Swedish Environmental Protection Agency, the Dutch Ministry of Construction and Environment and the British Royal Society (5.0×10−6 a−1). The results of the health risk assessment indicate that Cr in the water of NURB is the primary source of carcinogenic risk for local residents, followed by Cd and As. Consequently, it is imperative to control these three carcinogenic metals when the water was used as drinking water resource.

Abstract Background The prognostic significance of myelofibrosis (MF) grade in patients with myelodysplastic syndrome (MDS) following an allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains elusive. Methods We retrospectively analyzed data from 153 patients with MDS who underwent allo-HSCT and divided the patients into the MF-0/1 (N = 119) and MF-2/3 (N = 34) cohorts to explore the impact of MF on outcomes of allo-HSCT. Results The 2-year rates of relapse, non-relapse mortality (NRM), overall survival (OS), and progression-free survival (PFS) were 10.9% (95% confidence interval [CI] 5.9%–17.7%), 16.3% (95% CI 10.2%–23.6%), 76.6% (95% CI 69.0%–85.1%), and 72.8% (95% CI 65.0%–81.5%) in the MF-0/1 cohort, and 16.9% (95% CI 5.8%–32.9%), 14.7% (95% CI 5.3%–28.7%), 71.8% (95% CI 57.6%–89.6%), and 68.4% (95% CI 53.6%–87.2%) in the MF-2/3 cohort, respectively. No significant difference in the outcomes of allo-HSCT was observed between the two cohorts. Both univariate and multivariate analyses confirmed that MF-2/3 in patients with MDS had no effect on the prognosis of transplantation. In addition, major/bidirectional ABO blood type between donors and recipients was an independent risk factor for OS (hazard ratio [HR], 2.55; 95% CI 1.25–5.21; P = 0.010) and PFS (HR, 2.21; 95% CI 1.10–4.42; P = 0.025) in the multivariate analysis. In the subgroup of patients diagnosed with MDS with increased blasts (MDS-IB), it was consistently demonstrated that the clinical outcomes of the MF-2/3 cohort were comparable with those of the MF-0/1 cohort. The risk factors for OS and PFS in patients with MDS-IB were non-complete remission at transplantation and major/bidirectional ABO blood type. Conclusions In conclusion, MF grade had no significant effect on prognosis of allo-HSCT in patients diagnosed with MDS. Major/bidirectional ABO blood type should be carefully considered in the context of more than one available donor.

The current strategy of co-delivering copper ions and disulfiram (DSF) to generate cytotoxic CuET faces limitations in achieving rapid and substantial CuET production, specifically in tumor lesions. To overcome this challenge, we introduce a novel burst-release cascade reactor composed of phase change materials (PCMs) encapsulating ultrasmall Cu2-xSe nanoparticles (NPs) and DSF (DSF/Cu2-xSe@PCM). Once triggered by second near-infrared (NIR-II) light irradiation, the reactor swiftly releases Cu2-xSe NPs and DSF, enabling catalytic reactions that lead to the rapid and massive production of Cu2-xSe-ET complexes, thereby achieving in situ chemotherapy. The mechanism of the burst reaction is due to the unique properties of ultrasmall Cu2-xSe NPs, including their small size, multiple defects, and high surface activity. These characteristics allow DSF to be directly reduced and chelated on the surface defect sites of Cu2-xSe, forming Cu2-xSe-ET complexes without the need for copper ion release. Additionally, Cu2-xSe-ET has demonstrated a similar (to CuET) anti-tumor activity through increased autophagy, but with even greater potency due to its unique two-dimensional-like structure. The light-triggered cascade of interlocking reactions, coupled with in situ explosive generation of tumor-suppressive substances mediated by the size and valence of Cu2-xSe, presents a promising approach for the development of innovative nanoplatforms in the field of precise tumor chemotherapy.

Carbon dots (CDs) are carbon-based zero-dimensional nanomaterials with characteristic sizes of less than 10 ​nm. Recently, bioactive CDs have made remarkable achievements in wound healing, bone and cartilage repair, neural regeneration, and myocardium regeneration owing to their unique physicochemical properties and excellent biocompatibility, which have significantly promoted the advancement of tissue engineering. Herein, we summarize the applications of bioactive CDs in tissue engineering. First, we briefly introduce the characteristics and synthesis methods of bioactive CDs. Subsequently, we review the applications of bioactive CDs in wound healing, bone and cartilage tissue engineering, neural tissue engineering, and cardiac tissue engineering in detail. Finally, we discuss the challenges and prospects of bioactive CDs in tissue engineering.

Introduction: Obesity, a global epidemic, is caused by an imbalance between energy intake and expenditure. The induction of white adipose browning to increase heat production has emerged as a potential effective strategy to address obesity. Ling-gui-zhu-gan (LGZG), a traditional Chinese medicine formula, has been proved to achieve promising results to combat obesity and related metabolic diseases, yet the mechanisms remain largely unexplored. This study aimed to elucidate the anti-obesity properties and the mechanisms of LGZG by investigating its browning effect on 3T3-L1 adipocytes.Methods: LGZG-containing serum obtained by oral administration of LGZG to animals was added to 3T3-L1 adipocytes to simulate in vivo conditions.Results: The results showed that 49 compounds were identified in LGZG-containing serum by UHPLC-Q-Orbitrap HRMS, including compounds such as atractylenolides and polyporenic acid C, etc. LGZG-containing serum alleviated the lipid accumulation and decreased both intracellular and extracellular triglyceride contents in a dose-dependent manner. This reduction is accompanied by enhanced mitochondrial respiratory and heat production function. Mechanistically, LGZG-containing serum led to a decrease in miR-27b expression and an increase in the mRNA and protein levels of browning-related markers, including UCP1, PRDM16, PGC-1α, PPARγ, CTBP1, and CTBP2. Further investigation using miR-27b mimic transfection confirmed that miR-27b/PRDM16 pathway might be a potential mechanism by which LGZG-containing serum promotes browning of 3T3-L1 adipocytes.Discussion: These results underscore the therapeutic potential of LGZG in addressing obesity and its associated metabolic disorders through the promotion of adipose browning.

IntroductionHepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Traditional Chinese Medicine (TCM) is widely utilized as an adjunct therapy, improving patient survival and quality of life. TCM categorizes HCC into five distinct syndromes, each treated with specific herbal formulae. However, the molecular mechanisms underlying these treatments remain unclear.MethodsWe employed a network medicine approach to explore the therapeutic mechanisms of TCM in HCC. By constructing a protein-protein interaction (PPI) network, we integrated genes associated with TCM syndromes and their corresponding herbal formulae. This allowed for a quantitative analysis of the topological and functional relationships between TCM syndromes, HCC, and the specific formulae used for treatment.ResultsOur findings revealed that genes related to the five TCM syndromes were closely associated with HCC-related genes within the PPI network. The gene sets corresponding to the five TCM formulae exhibited significant proximity to HCC and its related syndromes, suggesting the efficacy of TCM syndrome differentiation and treatment. Additionally, through a random walk algorithm applied to a heterogeneous network, we prioritized active herbal ingredients, with results confirmed by literature.DiscussionThe identification of these key compounds underscores the potential of network medicine to unravel the complex pharmacological actions of TCM. This study provides a molecular basis for TCM’s therapeutic strategies in HCC and highlights specific herbal ingredients as potential leads for drug development and precision medicine.

An optimized Affinity Selection-Mass Spectrometry (AS-MS) workflow has been developed for the efficient identification of potent USP1 inhibitors. USP1 was immobilized on agarose beads, ensuring low small molecule retention, efficient protein capture, and protein stability. The binding affinity of 49 compounds to USP1 was evaluated using the optimized AS-MS method, calculating binding index (BI) values for each compound. Biochemical inhibition assays validated the AS-MS results, revealing a potential correlation between higher BI values and lower IC50 values. This optimized workflow enables rapid identification of high-quality USP1 inhibitor hits, facilitating structure-activity relationship studies and accelerating the discovery of potential cancer therapeutics.

BackgroundLing-gui-zhu-gan (LGZG) formula has been demonstrated to effectively ameliorate the clinical symptoms of patients with obesity or metabolic syndrome. This study aimed to explore both the effect and the underlying mechanisms of LGZG against obesity.MethodsMale C57BL/6N mice were randomized into four groups (n = 8): normal control (NC), obese (OB), metformin (Met), and LGZG. After 8 weeks of gavage administration, the pharmacological effects of LGZG on obesity and metabolism were investigated using biochemical parameters, histomorphological examination, and lipidomics techniques. Pivotal factors associated with white adipose tissue browning were evaluated using quantitative real-time polymerase chain reaction and western blotting.ResultsThe results revealed that LGZG reduced the levels of obesity markers, including body weights, body fat mass and food intake in obese mice. Further evaluations highlighted that LGZG restored glucose homeostasis and significantly improved insulin sensitivity in obese mice. Importantly, LGZG could adjust serum lipid profiles and regulate the lipidomic spectrum of intestinal contents, with noticeable shifts in the levels of certain lipids, particularly diacylglycerols and monoacylglycerols. Histopathological examinations of LGZG-treated mice also revealed more favorable adipose tissue structures than their obese counterparts. Furthermore, we found that LGZG upregulated the expression of several key thermogenesis-related factors, such as UCP1, PRDM16, PGC-1α, PPARα, PPARγ, CTBP1, and CTBP2 in white adipose tissues.ConclusionOur findings position LGZG as a novel strategy for preventing obesity and improving metabolic health.

Brain development is a highly complex process regulated by numerous genes at the molecular and cellular levels. Brain tissue exhibits serial microstructural changes during the development process. High-resolution diffusion magnetic resonance imaging (dMRI) affords a unique opportunity to probe these changes in the developing brain non-destructively. In this study, we acquired multi-shell dMRI datasets at 32 µm isotropic resolution to investigate the tissue microstructure alterations, which we believe to be the highest spatial resolution dMRI datasets obtained for postnatal mouse brains. We adapted the Allen Developing Mouse Brain Atlas (ADMBA) to integrate quantitative MRI metrics and spatial transcriptomics. Diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and neurite orientation dispersion and density imaging (NODDI) metrics were used to quantify brain development at different postnatal days. We demonstrated that the differential evolutions of fiber orientation distributions contribute to the distinct development patterns in white matter (WM) and gray matter (GM). Furthermore, the genes enriched in the nervous system that regulate brain structure and function were expressed in spatial correlation with age-matched dMRI. This study is the first one providing high-resolution dMRI, including DTI, DKI, and NODDI models, to trace mouse brain microstructural changes in WM and GM during postnatal development. This study also highlighted the genotype-phenotype correlation of spatial transcriptomics and dMRI, which may improve our understanding of brain microstructure changes at the molecular level.

Natural environments play a crucial role in transmission of antimicrobial resistance (AMR). Development of methods to manage antibiotic resistance genes (ARGs) in natural environments are usually limited to the laboratory or field scale, partially due to the complex dynamics of transmission between different environmental compartments. Here, we conducted a nine-year longitudinal profiling of ARGs at a watershed scale, and provide evidence that restrictions on livestock farms near water bodies significantly reduced riverine ARG abundance. Substantial reductions were revealed in the relative abundance of genes conferring resistance to aminoglycosides (42%), MLSB (36%), multidrug (55%), tetracyclines (53%), and other gene categories (59%). Additionally, improvements in water quality were observed, with distinct changes in concentrations of dissolved reactive phosphorus, ammonium, nitrite, pH, and dissolved oxygen. Antibiotic residues and other pharmaceuticals and personal care products (PPCPs) maintain at a similarly low level. Microbial source tracking demonstrates a significant decrease in swine fecal indicators, while human fecal pollution remains unchanged. These results suggest that the reduction in ARGs was due to a substantial reduction in input of antibiotic resistant bacteria and genes from animal excreta. Our findings highlight the watershed as a living laboratory for understanding the dynamics of AMR, and for evaluating the efficacy of environmental regulations, with implications for reducing environmental risks associated with AMR on a global scale.

Abstract There are limited studies on mutation profiling for Peripheral T‐cell lymphomas (PTCL) in the Chinese population. We retrospectively analyzed the clinical and genetic landscape of 66 newly diagnosed Chinese patients. Targeted next‐generation sequencing (NGS) was performed for tissues from these patients. At least one mutation was detected in 60 (90.9%) patients, with a median number of 3 (0–7) mutations, and 32 (48.5%) cases detected with more than 4 mutations. The genes with higher mutation frequencies were TET2, RHOA, DNMT3A, IDH2, TP53, STAT3, and KMT2D respectively. When mutant genes are classified by functional group, the most prevalent mutations are related to epigenetics and signal transduction. IPI ≥2, PIT ≥2, and failure to achieve partial remission (PR) were factors for inferior progression‐free survival (PFS) and overall survival (OS). Multivariate analysis showed TP53 was an adverse factor for PFS (HR, 3.523; 95% CI, 1.262–9.835; p = 0.016), and KMT2D was an adverse factor for OS (HR, 10.097; 95% CI, 1.000–101.953; p = 0.048). Mutation profiling could help differentiate distinct types of PTCL and serve as a useful tool for determining treatment options and prognoses.

Efficiency, safety and cost are three major evaluation indexes of warehouse operation. However, the uncertainty of efficiency, safety and cost factors will lead to economic losses and waste of resources. The purpose of this study is to propose a novel parameterized neutrosophic objective–proportionate genetic algorithm model (PNO–PGA) to optimize the above three objectives. There are three main contributions of this study. Firstly, a novel score function of neutrosophic sets (NSs) is proposed to effectively integrate the fuzziness of efficiency, safety and cost to avoid the evaluation result being too idealized. Secondly, a novel proportionate genetic algorithm is applied to adaptively realize the iteration and inheritance processes. Finally, two parameters are proposed to make the algorithm model flexibly adapt to different types of environments and problems. Then, an example is used to compare the new method with genetic algorithm (GA). The result shows that PNO-PGA has better problem-solving ability in warehouse operation than GA.

Abstract Deep penetration and downregulation of heat shock protein (HSP) expression in multimodal synergistic therapy are promising approaches for curing cancer in clinical trials. However, free small‐molecule drugs and most drug vehicles have a low delivery efficiency deep into the tumor owing to poor drug penetration and hypoxic conditions at the tumor site. In this study, the objective is to use reactive oxygen species (ROS)‐responsive supramolecular gels co‐loaded with the photosensitizer Zn(II) phthalocyanine tetrasulfonic acid (ZnPCS4) and functionalized tetrahedral DNA (TGSAs) (G@P/TGSAs) to enhance deep tissue and cell penetration and block the HSP90 pathway for chemo‐ photodynamic therapy (PDT) ‐ photothermal therapy (PTT) trimodal synergistic therapy. The (G@P/TGSAs) are injected in situ into the tumor to release ZnPCS4 and TGSAs under high ROS concentrations originating from both the tumor and PDT. TGSAs penetrate deeply into tumor tissues and augment photothermal therapy by inhibiting the HSP90 pathway. Proteomics show that HSP‐related proteins and molecular chaperones are inhibited/activated, inhibiting the HSP90 pathway. Simultaneously, the TGSA‐regulated apoptotic pathway is activated. In vivo study demonstrates efficient tumor penetration and excellent trimodal synergistic therapy (45% tumor growth inhibition).

Summary: Cleaner heating policies aim to reduce air pollution and may bring about health benefits to individuals. Based on a fixed-effect model focusing on Beijing, this study found that after the onset of air pollution, daily clinic visits, hospitalization days, and hospitalization expenses increased several days after the occurrence of air pollution. These hospitalization changes were observed in males and females and three different age groups. A difference-in-differences (DID) model was constructed to identify the influences of cleaner heating policies on health consequences. The study revealed that the policy positively affects health outcomes, with an average decrease of 3.28 thousand clinic visits for all diseases. The total hospitalization days and expenses tend to decrease by 0.22 thousand days and 0.34 million CNY (Chinese Yuan), respectively. Furthermore, implementing the policy significantly reduced the number of daily clinic visits for respiratory diseases, asthma, stroke, diabetes, and chronic obstructive pulmonary diseases (COPDs).

Rapid evolution of porcine reproductive and respiratory syndrome virus (PRRSV) is the bottleneck for effective prevention and control of PRRS. Thus, understanding the prevalence and genetic background of PRRSV strains in swine-producing regions is important for disease prevention and control. However, there is only limited information about the epizootiological situation of PRRS in the Xinjiang Uygur Autonomous Region, China. In this study, blood or lung tissue samples were collected from 1,411 PRRS-suspected weaned pigs from 9 pig farms in Changji, Shihezi, and Wujiaqu cities between 2020 and 2022. The samples were first tested by RT-quantitative PCR, yielding a PRRSV-2 positive rate of 53.6%. Subsequently, 36 PRRSV strains were isolated through initial adaptation in bone marrow-derived macrophages followed by propagation in grivet monkey Marc-145 cells. Furthermore, 28 PRRSV-positive samples and 20 cell-adapted viruses were selected for high-throughput sequencing (HTS) to obtain the entire PRRSV genome sequences. Phylogenetic analysis based on the nucleotide sequences of the ORF5 gene of the PRRSV strains identified in this study grouped into sub-lineages 1.8 and 8.7 the former being the dominant strain currently circulating in Xinjiang. However, the NSP2 proteins of the Xinjiang PRRSV strains shared the same deletion patterns as sub-lineage 1.8 prototype strain NADC30 with the exception of 4 strains carrying 2-3 additional amino acid deletions. Further analysis confirmed that recombination events had occurred in 27 of 37 PRRSVs obtained here with the parental strains belonging to sub-lineages 1.8 and 8.7, lineages 3 and 5, with the recombination events having occurred most frequently in the 5' and 3' termini of ORF1a and 5' terminus of ORF1b.

Abstract Layered SnAs‐based Zintl compounds exhibit a distinctive electronic structure, igniting extensive research efforts in areas of superconductivity, topological insulators, and quantum magnetism. In this paper, the crystal structures and electronic properties of the Zintl compound SrSn2As2 upon compression are systematically investigated. Pressure‐induced superconductivity is observed in SrSn2As2 with a nonmonotonic evolution of superconducting transition temperature Tc. Theoretical calculations together with high‐pressure synchrotron X‐ray diffraction and Raman spectroscopy have identified that SrSn2As2 undergoes a structural transformation from a rhombohedral R3¯m phase to the monoclinic C2/m phase. Beyond 28.3 GPa, Tc is suppressed due to a reduction of the density of state (DOS) at the Fermi level. The discovery of pressure‐induced superconductivity, accompanied by structural transitions in SrSn2As2, greatly expands the physical properties of layered SnAs‐based compounds and provides new ground states upon compression.

Background A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9, as an add‐on treatment to optimized lipid‐lowering therapy in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia. Methods and Results A total of 806 patients who were receiving stable and optimized lipid‐lowering therapy but did not achieve their low‐density lipoprotein cholesterol (LDL‐C) targets were enrolled and randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks, or ongericimab 300 mg or matching placebo every 4 weeks for 52 weeks. Efficacy and safety were evaluated in 802 patients who received at least 1 dose of ongericimab or placebo. The primary end point was the percentage change in LDL‐C from baseline to week 24. Our findings demonstrated that the least‐squares mean difference of percentage change in LDL‐C from baseline to week 24 was −67.7% (95% CI, −72.5% to −63.0%; P

Abstract With the rapid development of white LEDs, the research of new and efficient white light emitting materials has attracted increasing attention. Zero dimensional (0D) organic–inorganic hybrid metal halide perovskites with superior luminescent property are promising candidates for LED application, due to their abundant and tailorable structure. Herein, [(CH3)3S]2SnCl6·H2O is synthesized as a host for dopant ions Bi3+ and Sb3+. The Sb3+ doped, or Bi3+/Sb3+ co-doped, [(CH3)3S]2SnCl6·H2O has a tunable optical emission spectrum by means of varying dopant ratio and excitation wavelength. As a result, we can achieve single-phase materials suitable for emission ranging from cold white light to warm white light. The intrinsic mechanism is examined in this work, to clarify the dopant effect on the optical properties. The high stability of title crystalline material, against water, oxygen and heat, makes it promising for further application. Graphical Abstract

Abstract Background Circular RNAs are highly stable regulatory RNAs that have been increasingly associated with tumorigenesis and progression. However, the role of many circRNAs in triple-negative breast cancer (TNBC) and the related mechanisms have not been elucidated. Methods In this study, we screened circRNAs with significant expression differences in the RNA sequencing datasets of TNBC and normal breast tissues and then detected the expression level of circRPPH1 by qRT‒PCR. The biological role of circRPPH1 in TNBC was then verified by in vivo and in vitro experiments. Mechanistically, we verified the regulatory effects between circRPPH1 and ZNF460 and between circRPPH1 and miR-326 by chromatin immunoprecipitation (ChIP), fluorescence in situ hybridization assay, dual luciferase reporter gene assay and RNA pull-down assay. In addition, to determine the expression of associated proteins, we performed immunohistochemistry, immunofluorescence, and western blotting. Results The upregulation of circRPPH1 in TNBC was positively linked with a poor prognosis. Additionally, both in vivo and in vitro, circRPPH1 promoted the biologically malignant behavior of TNBC cells. Additionally, circRPPH1 may function as a molecular sponge for miR-326 to control integrin subunit alpha 5 (ITGA5) expression and activate the focal adhesion kinase (FAK)/PI3K/AKT pathway. Conclusion Our research showed that ZNF460 could promote circRPPH1 expression and that the circRPPH1/miR-326/ITGA5 axis could activate the FAK/PI3K/AKT pathway to promote the progression of TNBC. Therefore, circRPPH1 can be used as a therapeutic or diagnostic target for TNBC.

Abstract Identifying high-risk regions and turning points of influenza with a precise spatiotemporal scale may provide effective prevention strategies. In this study, epidemiological characteristics and spatiotemporal clustering analysis at the township level were performed. A descriptive study and a Joinpoint regression analysis were used to explore the epidemiological characteristics and the time trend of influenza. Spatiotemporal autocorrelation and clustering analyses were carried out to explore the spatiotemporal distribution characteristics and aggregation. Furthermore, the hotspot regions were analyzed by spatiotemporal scan analysis. A total of 4025 influenza cases were reported in Yinchuan showing an overall increasing trend. The tendency of influenza in Yinchuan consisted of three stages: increased from 2012 to the first peak in 2019 (32.62/100,000) with a slight decrease in 2016; during 2019 and 2020, the trend was downwards; then it increased sharply again and reached another peak in 2022. The Joinpoint regression analysis found that there were three turning points from January 2012 to December 2022, namely January 2020, April 2020, and February 2022. The children under ten displayed an upward trend and were statistically significant. The trend surface analysis indicated that there was a shifting trend from northern to central and southern. A significant positive spatial auto-correlation was observed at the township level and four high-incidence clusters of influenza were detected. These results suggested that children under 10 years old deserve more attention and the spatiotemporal distribution of high-risk regions of influenza in Yinchuan varies every year at the township level. Thus, more monitoring and resource allocation should be prone to the four high-incidence clusters, which may benefit the public health authorities to carry out the vaccination and health promotion timely.

Abstract Background This study aimed to uncover the changing prevalence of obesity and its association with hypertension across socioeconomic gradients in rural southwest China. Methods Data were collected from two cross-sectional health interviews and surveys from 2011 to 2021 among individuals aged ≥ 35 years in rural China. Each participant’s height, weight, waist circumference, and blood pressure were measured. The overall prevalence of obesity, central obesity, and hypertension was directly standardized by age based on the total population of the two surveys. Multivariate logistic regression was used to analyze the association between obesity and prevalence of hypertension and an individual socioeconomic position (SEP) index was constructed using principal component analysis. Results From 2011 to 2021, the prevalence of obesity, central obesity, and hypertension increased substantially, from 5.9%, 50.2%, and 26.1–12.1%, 58.0%, and 40.4% (P

Abstract There lacks real‐world study with a large sample size assessing olmesartan medoxomil‐amlodipine besylate (OM‐AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM‐AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM‐AML (20/5 mg) tablet were analyzed in the current prospective, single‐arm, multi‐center, real‐world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was ‐10.8 ± 0.4/‐6.6 ± 0.3 mmHg at W4 and ‐12.7 ± 0.5/‐7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home‐measured SeSBP and SeDBP decreased from W1 to W8 (both p

Abstract Background Adiposity and insulin resistance (IR) are closely associated with hypertension; however, the role of interactions between obesity phenotypes and IR in hypertension is unclear. This study aimed to evaluate the interactions of body mass index (BMI), waist circumference (WC), and body fat percentage (BF%) with IR on hypertension risk. Methods We analyzed data from 4888 participants (mean age 57 years, 41.2% men) in the China Northwest Natural Population Cohort, Ningxia Project. BMI, WC, and BF% were determined using bioelectrical impedance analysis devices. IR was estimated using a homeostasis model assessment index (HOMA-IR). Multivariable-adjusted logistic regression was used to evaluate the association between HOMA-IR and hypertension risk. We calculated the relative excess risk and attributable proportion with their 95% confidence intervals (CIs) to assess whether adiposity phenotypes modified the effect of HOMA-IR on hypertension risk. Results The crude prevalence of hypertension was 52.2%. The multivariable-adjusted odds ratio of HOMA-IR was 1.80 (95% CI: 1.23–2.65) for the risk of hypertension in the highest versus the lowest quartiles, but this association became marginal in models further adjusting for BMI, WC, and BF% (P for trend = 0.056). Relative excess risk and attributable proportion for interaction between high HOMA-IR and high BF% were 0.32 (0.04–0.59) and 0.33 (0.06–0.60), respectively. Additionally, high truncal and leg BF% and high HOMA-IR accounted for the hypertension risk in women, but not in men. We did not observe any significant interactions between BMI or WC and HOMA-IR on hypertension. Conclusion BF% modified the association between IR and increased risk of hypertension in women with high truncal and leg BF%, but not in men.

Abstract Transformer winding turns often consist of multiple parallel strands. The spatial position variation of each strand affects the leakage inductance of each branch, resulting in an uneven distribution of short‐circuit currents within the winding turns. And this unevenness persists even when transposition structures are implemented. Traditional methods in transformer analysis frequently overlooked the distribution characteristics of short‐circuit currents when calculating electromagnetic forces. A frequency‐domain calculation method for analysing the current distribution in winding turns was proposed, with a deviation of less than 3% compared to existing analysis methods. Two typical 110 kV transformer models were utilised to investigate the influence of uneven current distribution on the spatial distribution of electromagnetic forces. The spatial distribution of short‐circuit electromagnetic forces in low‐voltage (LV) windings exhibited significant changes, with maximum change rates of 10% and 61.2% for axial and radial electromagnetic force, respectively, in a LV winding with 4 parallel strands. The research also analysed how strand radial width and axial height affect current distribution unevenness and proposed specific design principles to mitigate these disparities in winding design. The findings offer valuable insights for selecting structural parameters and assessing short‐circuit stability during transformer design.

Abstract Accurately calculating axial electromagnetic force is essential to analyse transformer winding axial stability. Prior research has mainly focused on the effect of winding structure on static axial electromagnetic force and studying vibration by substituting the static force in a time‐varying function. However, the coupling effect between axial electromagnetic force and winding vibration has not been addressed, and no calculation method for the axial electromagnetic force that considers both winding meso‐structures and vibration coupling effects has been proposed. Previously the authors presented an electromagnetic force calculation model that considers winding structure characteristics, and an iterative algorithm for magnetic‐structure coupling calculation. Currently, the winding vibration model was first proposed and the dynamic calculation method was formulated. By applying the method to a typical 110kV transformer, the spatial‐temporal distribution of winding axial short‐circuit electromagnetic force was obtained. It was found that the peak value of the axial short‐circuit electromagnetic force of some windings appears at the second or third peak moment of the short‐circuit current, which is called as peak time shift phenomenon. Further stress analysis indicates that existing evaluation methods may overestimate the short‐circuit resistance of windings by only considering short‐circuit electromagnetic force under maximum peak of short‐circuit current.

ABSTRACTRoof vertex information is vital for 3D roof structures. Reconstructing 3D roof structures from point cloud data using traditional methods remains a challenge because their extracted roof vertices are affected by uncertainty and additional errors from roof plane segmentation and supplementary sub-steps for extracting primitives. In this study, instead of segmenting roof planes and then extracting primitives based on them, a flexible rule-based method is proposed to directly detect the vertices of building roofs from point cloud data without the requirement of training data. The point cloud data is first voxelized with a dominant direction-based rotation. Based on the different features of the interior roof points and vertices, rules for voxel filtering and structure line determination are defined to extract the roof vertices. The experimental results on a custom dataset in Trondheim, Norway demonstrate that the proposed method can effectively and accurately extract roof vertices from point cloud data. The comparative experimental results with an unfine-tuned deep learning-based method on custom and benchmark datasets with different point densities further show that the proposed method has good generalization and can adapt to changes of datasets.

AbstractBrain tumor accounts for about 1.6% of incidence and 2.5% of mortality of all tumors, and the median survival for brain tumor patients is only about 20 months. The treatment for brain tumor still faces many challenges, such as the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), the overexpressed efflux pumps, the infiltration, invasion, high heterogeneity of tumor cells, drug resistance and immune escape caused by tumor microenvironment (TME) and cancer stem cells (CSC). This review attempts to clarify the challenges for multi-functional nano drug delivery systems (NDDS) to cross the BBB and target the cancer cells or organelles, and also provides a brief description of the different types of targeted multi-functional NDDS that have shown potential for success in delivering drugs to the brain. Further, this review also summarizes the research progress of multi-functional NDDS in the combination therapy of brain tumors from the following sections, the combination of chemotherapy drugs, chemotherapy-chemodynamic combination therapy, chemotherapy-immunization combination therapy, and chemotherapy-gene combination therapy. We also provide an insight into the recent advances in designing multi-functional NDDS for combination therapy.

Reversible data hiding (RDH) algorithms have been extensively employed in the field of copyright protection and information dissemination. Among various RDH algorithms, the multiple histogram modification (MHM) algorithm has attracted significant attention because of its capability to generate high-quality marked images. In previous MHM methods, the prediction error histograms were mostly generated in a fixed way. Recently, clustering algorithms automatically classify prediction errors into multiple classes, which enhances the similarity among prediction errors within the same class. However, the design of features and the determination of clustering numbers are crucial in clustering algorithms. Traditional algorithms utilize the same features and fix the number of clusters (e.g., empirically generate 16 classes), which may limit the performance due to the lack of adaptivity. To address these limitations, an adaptive initial feature selection scheme and a clustering number optimization scheme based on the Fuzzy C-Means (FCM) clustering algorithm are proposed in this paper. The superiority of the proposed scheme over other state-of-the-art schemes is verified by experimental results.

ABSTRACT: The freezability of chicken spermatozoa is low, therefore, effective cryoprotectants is desiderated. Antifreeze proteins (AFPs) are widely found in cold-tolerant species and help them to survive in freezing environments. This study was the first to evaluate the effects of different concentrations of plant-originated antifreeze glycoprotein (AFGP) (0, 0.1, 1, and 5 μg/mL) on post-thawed sperm motion characteristics, morphology, mitochondrial function, antioxidant activity, and fertilizing potential in chickens. Results showed that the total motility of 0.1 to 1 μg/mL AFGP groups were significantly higher than those of the 5 μg/mL AFGP group (P < 0.05). The post-thawed sperm viability of 0.1 μg/mL AFGP group was significantly higher than any of test groups (P < 0.05). Higher abnormal morphology rate of post-thawed sperm was observed in the control group (0 μg/mL AFGP) than in the 0.1, 1, and 5 μg/mL AFGP groups (P < 0.05). The concentrations of malondialdehyde (MDA) decreased gradually with the increase of AFGP concentration. ATP was significantly higher in the 0.1 and 1 μg/mL AFGP groups than those of control and any of test groups (P < 0.05). The 0.1 to 1 μg/mL AFGP groups had increased mitochondrial membrane potential (MMP) level (P > 0.05). The 0.1 μg/mL AFGP group had the highest average fertility (61.36%) compared with control group (57.02%) and any of test groups of chickens at 31 wk of age, and the 1 μg/mL AFGP group had the highest average fertility (37.72%) compared with control group (21.73%) and any of test groups of chickens at 65 wk of age. In conclusion, the results from this study suggest lower concentration of AFGP (0.1–1 μg/mL) showed positive effect for sperm function. This study inspires the continuous evaluation and seeking right way of adopting different kinds of AFPs in rooster semen cryopreservation.

Programmed cell death 2 (PDCD2) is related to cancer progression and chemotherapy sensitivity. The role of PDCD2 in solid cancers (excluding hematopoietic malignancies) and their diagnosis and prognosis remains unclear. The TCGA, CGGA, GEPIA, cBioPortal, and GTEx databases were analyzed for expression, prognostic value, and genetic modifications of PDCD2 in cancer patients. Functional enrichment analysis, CCK8, colony formation assay, transwell assay, and xenograft tumor model were undertaken to study the PDCD2's biological function in glioma (GBMLGG). The PDCD2 gene was associated with solid cancer progression. In the functional enrichment analysis results, PDCD2 was shown to participate in several important GBMLGG biological processes. GBMLGG cells may be inhibited in their proliferation, migration, invasion, and xenograft tumor growth by knocking down PDCD2. Our research can provide new insights into solid cancer prognostic biomarkers of PDCD2.

Antibiotic resistance is an escalating global health concern, exacerbated by the pervasive presence of antibiotic resistance genes (ARGs) in natural environments. The Yangtze River, the world's third-longest river, traversing areas with intense human activities, presents a unique ecosystem for studying the impact of these genes on human health. Here, we explored ARGs in the Yangtze River, examining 204 samples from six distinct habitats of approximately 6000 km of the river, including free-living and particle-associated settings, surface and bottom sediments, and surface and bottom bank soils. Employing shotgun sequencing, we generated an average of 13.69 Gb reads per sample. Our findings revealed a significantly higher abundance and diversity of ARGs in water-borne bacteria compared to other habitats. A notable pattern of resistome coalescence was observed within similar habitat types. In addition, we developed a framework for ranking the risk of ARG and a corresponding method for calculating the risk index. Applying them, we identified water-borne bacteria as the highest contributors to health risks, and noted an increase in ARG risks in particle-associated bacteria correlating with heightened anthropogenic activities. Further analysis using a weighted ARG risk index pinpointed the Chengdu–Chongqing and Yangtze River Delta urban agglomerations as regions of elevated health risk. These insights provide a critical new perspective on ARG health risk assessment, highlighting the urgent need for strategies to mitigate the impact of ARGs on human health and to preserve the ecological and economic sustainability of the Yangtze River for future human use.

Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimer’s disease (AD; n=61,212). Among 1738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits related to intelligence and education showed strong and independent associations with AD. Furthermore, we identified 41 significant associations for a variety of AD endophenotypes. While family history and high cholesterol were strongly associated with AD subgroups and pathologies, only intelligence and education-related traits predicted pre-clinical cognitive phenotypes. These results provide novel insights into the distinct biological processes underlying various risk factors for AD.

Abstract Background Comparative investigations evaluating the efficacy of pomalidomide‐based (Pom‐based) versus daratumumab‐based (Dara‐based) therapies in patients with relapsed/refractory multiple myeloma (RRMM) remain scarce, both in randomized controlled trials and real‐world studies. Methods This retrospective cohort study included 140 RRMM patients treated with Pom‐based or Dara‐based or a combination of pomalidomide and daratumumab (DPd) regimens in a Chinese tertiary hospital between December 2018 and July 2023. Results The overall response rates (ORR) for Pom‐based (n = 48), Dara‐based (n = 68), and DPd (n = 24) groups were 57.8%, 84.6%, and 75.0%, respectively (p = 0.007). At data cutoff on August 1, 2023, the median progression‐free survival (PFS) was 5.7 months (95% CI: 5.0–6.5) for the Pom‐based group, 10.5 months (5.2–15.8) for the Dara‐based group, and 6.7 months (4.0–9.3) for the DPd group (p = 0.056). Multivariate analysis identified treatment regimens (Dara‐based vs. Pom‐based, DPd vs. Pom‐based) and Eastern Cooperative Oncology Group performance status (ECOG PS) as independent prognostic factors for PFS. In the subgroups of patients aged >65 years, with ECOG PS ≥2, lines of therapy ≥2, extramedullary disease or double‐refractory disease (refractory to both lenalidomide and proteasome inhibitors), the superiority of Dara‐based regimens over Pom‐based regimens was not evident. A higher incidence of infections was observed in patients receiving Dara‐based and DPd regimens (Pom‐based 39.6% vs. Dara‐based 64.7% vs. DPd 70.8%, p = 0.009). Conclusions In real‐world settings, Pom‐based, Dara‐based, and DPd therapies exhibited favorable efficacy in patients with RRMM. Dara‐based therapy yielded superior clinical response and PFS compared to Pom‐based therapy.