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Abstract Objective The study aims to investigate the associations of triglyceride glucose (TyG), TyG combined with body mass index (TyG-BMI), metabolic score for insulin resistance (METS-IR), the triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C), and the risk of mild cognitive impairment (MCI) in individuals without diabetes aged 45 and above. Methods The most recent data in this study were from a cohort study, which sourced samples from the China Health and Retirement Longitudinal Study, spanning 2011 to 2018. The four indices’ associations with MCI risk were analyzed using logistic regression. The predictive capacity was measured using the receiver operating characteristic (ROC) curve. Results Over a 7-year follow-up, 1,261 individuals (31.34%) of the 4,027 participants developed MCI. Logistic regression analysis revealed significant associations between these surrogate indices and MCI. The findings for the highest quartile compared with the lowest quartile were as follows: TyG: 1.24 (95% CI: 1.02, 1.49); TyG-BMI: 1.38 (95% CI: 1.13, 1.68); METS-IR: 1.50 (95% CI: 1.09, 2.06); TG/HDL-C: 1.34 (95% CI: 1.10, 1.64). ROC analysis revealed that TyG, TyG-BMI, TG/HDL-C, and METS-IR demonstrated excellent discriminatory power for MCI, with area under the curve (AUC) values of 0.82 (95% CI: 0.80, 0.83), 0.82 (95% CI: 0.80, 0.83), 0.83 (95% CI: 0.80, 0.84), and 0.83 (95% CI: 0.80, 0.84), respectively. The four indices showed stronger ability to predict MCI risk in females compared to males. Conclusion Elevated levels of four indices are positively correlated with MCI risk. TyG-BMI and METS-IR demonstrate stronger capabilities in identifying MCI across both male and female populations. This suggests that early intervention in patients with elevated IR surrogate indices may help reduce the MCI.

Abstract Plant tissue culture is extensively employed in plant functional genomics research and crop genetic improvement breeding. The callus induction ability is critical for utilizing Agrobacterium-mediated genetic transformation. In this study, we conducted a genome-wide association study (GWAS) utilizing 368 rice accessions to identify traits associated with callus induction rate (CIR), resulting in the identification of a total of 104 significant SNP loci. Integrated with gene function annotation and transcriptome analysis, 13 high-confidence candidate genes involved in auxin-related, CYC cyclins, and histone H3K9-specific methyltransferase were identified in significant loci. Furthermore, we also verified a candidate gene, Os05g0493500 (OsCycB1;5), and employed the CRISPR/Cas9 system to generate OsCycB1;5 knockout mutants in rice (Oryza sativa L.). The OscycB1;5 mutant displays significantly reduced callus induction and proliferation capacity, this result indicating OsCycB1;5 is required for the callus formation in rice. Overall, this study provides several reliable loci and high-confidence candidate genes that may significantly affect callus formation in rice. This information will offer valuable insights into the mechanisms underlying callus formation not only in rice but also in other plants.

Abstract Heavy Meiyu-Baiu rainfall can pose threat to the dense population in East Asia by catastrophic flooding. Although previous studies have identified Indian Ocean (IO) warming as the major cause of heavy Meiyu-Baiu rainfall, it failed to predict the record-breaking rainfall in July 2020. Synthesizing observational analysis, large-ensemble climate simulations, and atmospheric simulations, we show that sea-ice loss in the Kara Sea in May can intensify the IO warming-induced heavy Meiyu-Baiu rainfall and well explains the record-breaking rainfall in July 2020. In the precondition of IO warming, sea-ice loss tends to prolong Meiyu-Baiu season and strengthen convective activity over the Meiyu-Baiu region, thereby enhancing the IO warming-induced heavy Meiyu-Baiu rainfall by ~50% and doubling the risk of extreme events comparable to or greater than the one in 2020. A statistical model is further constructed to demonstrate that taking Arctic sea ice into consideration can significantly improve the seasonal prediction of extreme Meiyu-Baiu rainfall.

The effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection persist months and years after recovery. We conducted an online survey to assess the health condition of convalescents approximately 5 months following the primary infection of SARS-CoV-2. The study recruited 5,510 individuals who were primary infected, 626 participants who had experienced reinfection, and 521 participants who were without infective history. The most common disorders after the primary infection group were fatigue (15.18 %), memory issue (13.13 %), post-exertional malaise (PEM, 11.68 %), and brain fog (11.29 %) at the time of survey. In addition, SARS-CoV-2 infection had an impact on the reproductive systems. In stepwise logistic regression analysis, smoking currently, with background diseases, and outpatient visits in the acute phase could be associated with moderate / severe disorders. Further analysis of different background diseases showed that allergic rhinitis, hyperlipidemia, cardiovascular disease, autoimmune diseases, neurological diseases, and asthma likely increased the risk of moderate/severe disorders. The probability of developing disorders of individuals with SARS-CoV-2 reinfection was higher before the secondary infection than uninfected people. Fatigue, PEM, muscle pain/spasms, chills, joint pain, excessive sweating at rest, headache / dizziness, sore throat or foreign body sensation in the throat, cough, expectoration, dry / painful / watery eyes, loss of appetite and constipation were associated with an increased risk of reinfection. It was essential to undertake further research with enhanced randomization in a larger sample in the community, and to strengthen the validation of the research conclusions. The findings of this study contribute to a deeper understanding of the health recovery process among coronavirus disease 2019 (COVID-19) convalescents. Moreover, the findings help identify characteristic health risk factors associated with convalescents and highlight the risk of moderate / severe disorders and reinfection. Furthermore, the findings also provide valuable guidance and reference for SARS-CoV-2 rehabilitation strategies and the prevention of reinfection, offering insights for scientific recommendations.

SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1+-granulocytic myeloid-derived suppressor cells (G-MDSCs) are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models, respectively. The excessive TGF-β, secreted by tumor-infiltrated CCR1+-G-MDSCs, suppresses the immune response of cytotoxic T lymphocytes (CTLs), thus facilitating metastasis. Hereby, we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules (C/T-NVs) to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF-β through TGF-β-TGFBR2 specific binding. Chemotactic C/T-NVs counteract CCR1+-G-MDSC infiltration through competitive responding CCL9/CCR1 axis. C/T-NVs-induced intratumoral TGF-β exhaustion alleviates the TGF-β-suppressed immune response of CTLs. Collectively, C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC. In further exploration, high expression of programmed cell death ligand-1 (PD-L1) is observed in clinical specimens of SMAD4-deficient CRC. Combining C/T-NVs with anti-PD-L1 antibody (aPD-L1) induces tertiary lymphoid structure formation with sustained activation of CTLs, CXCL13+-CD4+ T, CXCR5+-CD20+ B cells, and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN-γ around tumors, thus eradicating metastatic foci. Our strategy elicits pleiotropic antimetastatic immunity, paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.

This work elucidates the interactions between Re and hydrogen at γ/γ′ interfaces, enhancing the hydrogen-embrittlement resistance of nickel-based single-crystal superalloy (Ni-SX). The H-charged Ni-SX exhibits severe embrittlement characterized by the appearance of parallel dislocation slip bands and micro-cracks, which could be effectively mitigated through improving the Re content. The segregation behaviors of hydrogen at γ/γ′ interfaces, as captured by hydrogen microprint technique, significantly diminish interfacial cohesion strength by reducing the local atomic bonding strength. Detailed characterizations of bonding charge density highlight that Re plays a crucial role in reducing hydrogen embrittlement susceptibility by suppressing the hydrogen-induced degradation of bonding strength.

Abstract Background This study aimed to explore the causal relationship between age at first birth (AFB) and depression. Methods Using the univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) methods to examine the potential correlation between age at first birth (AFB) and major depressive disorder and postpartum depression. A public database was used to obtain the genome-wide association studies (GWAS) summary data. We put inverse-variance-weighted (IVW) as the primary method in Mendelian randomization (MR) analysis and used sensitivity analysis to confirm the robustness of our result. Results We found a significant causal association between AFB and major depressive disorder by using the IVW algorithm (odd ratio [OR] 0.826; 95% confidence interval [CI] 0.793 − 0.861; P = 4.51 × 10− 20). MR-Egger, weighted median, simple mode and weighted mode method concluded the same result (P

Abstract Solid-state infrared-to-visible photon up-conversion is important for spectral-tailoring applications. However, existing up-conversion systems not only suffer from low efficiencies and a need for high excitation intensity, but also exhibit a limited selection of materials and complex fabrication processes. Herein, we propose a sensitizer with a bulk-heterojunction structure, comprising both an energy donor and an energy acceptor, for triplet-triplet annihilation up-conversion devices. The up-conversion occurs through charge separation at the donor-acceptor interface, followed by the formation of charge transfer state between the energy donor and annihilator following the spin statistics. The bulk-heterojunction sensitizer ensures efficient charge generation and low charge recombination. Hence, we achieve a highly efficient solid-state up-conversion device with 2.20% efficiency and low excitation intensity (10 mW cm−2) through a one-step solution method. We also demonstrate bright up-conversion devices on highly-flexible large-area substrates. This study introduces a simple and scalable platform strategy for fabricating efficient up-conversion devices.

Selective activation of Pt(IV) prodrugs within tumors has emerged as a promising strategy in tumor treatment. Although progress has been made with photo- and ultrasound-activated Pt(IV) prodrugs, concerns remain over the non-specific activation of photosensitizers (PS) and the potential for phototoxicity and chemical toxicity. In this study, a sequential dual-locked Pt(IV) nano-prodrug that can be activated by both the acidic tumor microenvironment and light was developed. The Pt(IV) prodrug was prepared by conjugating PS-locked Pt(IV) to a polymeric core, which was then chelated with metallo iron to lock its photoactivity and form a metallo-nano prodrug. Under acidic tumor microenvironment conditions, the metallo-nano prodrug undergoes dissociation of iron, triggering a reduction process in oxaliplatin under light irradiation, resulting in the activation of both chemotherapy and photodynamic therapy (PDT). Additionally, the prodrug could induce metallo-triggered ferroptosis and polarization of tumor-associated macrophages (TAM), thereby enhancing tumor inhibition. The dual-lock strategy employed in a nanoparticle delivery system represents an expansion in the application of platinum-based anticancer drugs, making it a promising new direction in cancer treatment.

Abstract The herd immunity against SARS-CoV-2 is continuously consolidated across the world during the ongoing pandemic. However, the potential function of the nonconserved epitopes in the reverse preexisting cross-reactivity induced by SARS-CoV-2 to other human coronaviruses is not well explored. In our research, we assessed T cell responses to both conserved and nonconserved peptides shared by SARS-CoV-2 and SARS-CoV, identifying cross-reactive CD8+ T cell epitopes using enzyme-linked immunospot and intracellular cytokine staining assays. Then, in vitro refolding and circular dichroism were performed to evaluate the thermal stability of the HLA/peptide complexes. Lastly, single-cell T cell receptor reservoir was analyzed based on tetramer staining. Here, we discovered that cross-reactive T cells targeting SARS-CoV were present in individuals who had recovered from COVID-19, and identified SARS-CoV-2 CD8+ T cell epitopes spanning the major structural antigens. T cell responses induced by the nonconserved peptides between SARS-CoV-2 and SARS-CoV were higher and played a dominant role in the cross-reactivity in COVID-19 convalescents. Cross-T cell reactivity was also observed within the identified series of CD8+ T cell epitopes. For representative immunodominant peptide pairs, although the HLA binding capacities for peptides from SARS-CoV-2 and SARS-CoV were similar, the TCR repertoires recognizing these peptides were distinct. Our results could provide beneficial information for the development of peptide-based universal vaccines against coronaviruses.

Multiple myeloma (MM) is the second most prevalent hematological malignancy. Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy. This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy, which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes, termed T-PB@M. The results from our investigations highlight the considerable bone affinity of T-PB@M, both in vitro and in vivo. Additionally, this material demonstrated a capability for drug release triggered by low pH conditions. Moreover, T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose) polymerase 1 (PARP1)–Caspase-3–B-cell lymphoma-2 (Bcl-2) pathway in MM cells. Notably, T-PB@M preferentially targeted bone-involved sites, thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice. Therefore, this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

Immunogenic dying tumor cells hold promising prospects as cancer vaccines to activate systemic immunity against both primary and metastatic tumors. Especially, X-ray- induced dying tumor cells are rich in highly immunogenic tumor-associated antigens and self-generated dsDNA as potent adjuvants. However, we found that the X-ray induction process can result in the excessive exposure of phosphatidylserine in cancer vaccines, which can specifically bind with the MerTK receptor on macrophages, acting as a “checkpoint” to facilitate immune silence in the tumor microenvironment. Therefore, we developed a novel strategy combining X-ray-induced cancer vaccines with UNC2250, a macrophage MerTK “checkpoint inhibitor,” for treating peritoneal carcinomatosis in colon cancer. By incorporating UNC2250 into the treatment regimen, immunosuppressive efferocytosis of macrophages, which relies on MerTK-directed recognition of phosphatidylserine on vaccines, was effectively blocked. Consequently, the immune analysis revealed that this combination strategy promoted the maturation of dendritic cells and M1-like repolarization of macrophages, thereby simultaneously eliciting robust adaptive and innate immunity. This innovative approach utilizing X-ray-induced vaccines combined with a checkpoint inhibitor may provide valuable insights for developing effective cancer vaccines and immunotherapies targeting colon cancer.

Polymer matrix syntactic foams made of hollow glass microspheres (HGMs) and epoxy resin are widely used in underwater vehicles providing buoyancy due to their advantages of low density and high mechanical strength. When HGMs is strong enough, surface modification of HGMs is an effective method to improve the compressive strength of syntactic foams. However, the effects of different surface modifiers on the physical properties of HGMs and the compressive strength of syntactic foams have rarely been systematically studied. It is of great significance to enhance the interfacial strength of syntactic foams. Herein, the T40 HGMs was treated by different modifiers (HCl, NaOH, Li2SiO3, Me3SiONa, KH550, KH560, KH570, and Volan), physical properties of modified HGMs were studied, including true density, angle of repose, isostatic compressive strength, specific surface area, and contact angle. Furthermore, the effects of modified HGMs on the compressive strength of syntactic foams were also studied. The results showed that the compressive strength depend largely on the interface bonding between HGMs and resin matrix. This work can provide some references for mechanical property reinforcement of syntactic foams with high filling ratio and plenty of interface zones.

With the development of microelectronics technology, hafnium oxide (HfO2) has become the research focus of new ferroelectric materials because of its compatibility with Si-based semiconductor technology, suitable relative dielectric constant, good thermal and chemical stabilities, and a large band gap. HfO2 is a typical material that “phase structure determines properties, and properties determine applications.” The ferroelectric property is confirmed by the fact that the phase structure of thin films is stable in a noncentrosymmetric Pca21 orthorhombic phase. Therefore, the prerequisite for stabilizing and improving the ferroelectric properties of HfO2 thin films is to regulate HfO2 in the metastable orthorhombic phase. In general, HfO2 films can be composed of multiple phases, such as the monoclinic, orthorhombic, and tetragonal (or cubic) phases. Among these, the tetragonal phase is the parent phase of the orthogonal and monoclinic phases, and there is no possibility of phase transformation between the orthogonal and monoclinic phases. Therefore, a consensus is reached in the actual phase structure regulation of HfO2 thin films, that is, inhibiting the monoclinic phase formation can also improve the ferroelectric properties of thin films. Considering the orthogonal phase regulation mechanism, the stability factors of the orthogonal phase in HfO2 thin films are reviewed and summarized based on aspects such as film thickness, doping elements, grain orientation, annealing process, and electrode materials. For instance, the orthogonal phase content of HfO2 thin films decreases with the increase of film thickness; appropriate content of element doping can stabilize the orthogonal phase of HfO2 thin films. Both the high heating rate and short annealing time during the heat treatment are important factors in ensuring the orthogonal stability of HfO2 films. Especially, strain also affects the phase structure regulation. First, top electrode clamping can stabilize thin HfO2 films in the orthogonal phase by applying force on the films. Second, thin HfO2 films with a single orientation can be obtained through epitaxial growth, and it can be well observed how the strain regulates the thin film phase structure; that is, applying the tensile strain to the thin film is an effective means to stabilize the orthogonal phase. Simultaneously, with successful HfO2 film preparation with several atomic layers, it is revealed that the rhombohedral phase has out-of-plane spontaneous polarization and ferroelectric properties with compressive strain generation. Finally, the future prospects of thin HfO2 film development are discussed in this paper.

This study investigates the direct and indirect influences of behavioral quality, social support, perceived system, emotional perception, and public expectation on user favorability regarding government chatbots in both government service and policy consultation contexts. The findings reveal that while behavioral quality, social support, and perceived system directly affect user favorability in both scenarios, public expectation uniquely impacts user favorability in policy consultation settings, but not in government service scenarios. Furthermore, the analysis indicates that social support, emotional perception, and public expectation all indirectly influence user favorability through their mediating effect on behavioral quality in both contexts. Notably, the significant distinction between the two scenarios is the presence of an indirect impact of perceived system on user favorability within policy consultation scenarios, which is absent in government service scenarios. This study sheds light on the intricate interplay of factors shaping user favorability with government chatbots, and provides valuable insights for improving user experiences and user favorability in different governmental service contexts.

Abstract Osteoporosis is a highly prevalent metabolic disease characterized by low systemic bone mass and deterioration of bone microarchitecture, resulting in reduced bone strength and increased fracture risk. Current treatment options for osteoporosis are limited by factors such as efficacy, cost, availability, side effects, and acceptability to patients. Gold nanoparticles show promise as an emerging osteoporosis therapy due to their osteogenic effects and ability to allow therapeutic delivery but have inherent constraints, such as low specificity and the potential for heavy metal accumulation in the body. This study reports the synthesis of ultrasmall gold particles almost reaching the Ångstrom (Ång) dimension. The antioxidant alpha-lipoic acid (LA) is used as a dispersant and stabilizer to coat Ångstrom-scale gold particles (AuÅPs). Alendronate (AL), an amino-bisphosphonate commonly used in drug therapy for osteoporosis, is conjugated through LA to the surface of AuÅPs, allowing targeted delivery to bone and enhancing antiresorptive therapeutic effects. In this study, alendronate-loaded Ångstrom-scale gold particles (AuÅPs-AL) were used for the first time to promote osteogenesis and alleviate bone loss through regulation of the WNT signaling pathway, as shown through in vitro tests. The in vivo therapeutic effects of AuÅPs-AL were demonstrated in an established osteoporosis mouse model. The results of Micro-computed Tomography, histology, and tartrate-resistant acid phosphatase staining indicated that AuÅPs-AL significantly improved bone density and prevented bone loss, with no evidence of nanoparticle-associated toxicity. These findings suggest the possible future application of AuÅPs-AL in osteoporosis therapy and point to the potential of developing new approaches for treating metabolic bone diseases using Ångstrom-scale gold particles.

BackgroundPatients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis often experience severe symptoms. Resting-state functional MRI (rs-fMRI) has revealed widespread impairment of functional networks in patients. However, the changes in information flow remain unclear. This study aims to investigate the intrinsic functional connectivity (FC) both within and between resting-state networks (RSNs), as well as the alterations in effective connectivity (EC) between these networks.MethodsResting-state functional MRI (rs-fMRI) data were collected from 25 patients with anti-NMDAR encephalitis and 30 healthy controls (HCs) matched for age, sex, and educational level. Changes in the intrinsic functional connectivity (FC) within and between RSNs were analyzed using independent component analysis (ICA). The functional interaction between RSNs was identified by granger causality analysis (GCA).ResultsCompared to HCs, patients with anti-NMDAR encephalitis exhibited lower performance on the Wisconsin Card Sorting Test (WCST), both in terms of correct numbers and correct categories. Additionally, these patients demonstrated decreased scores on the Montreal Cognitive Assessment (MoCA). Neuroimaging studies revealed abnormal intra-FC within the default mode network (DMN), increased intra-FC within the visual network (VN) and dorsal attention network (DAN), as well as increased inter-FC between VN and the frontoparietal network (FPN). Furthermore, aberrant effective connectivity (EC) was observed among the DMN, DAN, FPN, VN, and somatomotor network (SMN).ConclusionPatients with anti-NMDAR encephalitis displayed noticeable deficits in both memory and executive function. Notably, these patients exhibited widespread impairments in intra-FC, inter-FC, and EC. These results may help to explain the pathophysiological mechanism of anti-NMDAR encephalitis.

ABSTRACT: Follicle selection in chicken refers to the process of selecting a follicle to enter hierarchy from a cohort of small yellow follicles (SY) with a diameter of 6 to 8 mm. The follicle being selected will develop rapidly and ovulate. Follicle selection is a key stage affecting chicken egg-laying performance. Our previous study showed that the phosphorylation level of lysine (K)-specific demethylase 1A (LSD1) at serine 54 (LSD1Ser54p) was significantly increased in F6 follicles compared to prehierarchal SY follicles, but its function was unclear. Here, the mechanism of this modification, the effect of LSD1Ser54p dephosphorylation on gene expression profile of chicken hierarchal granulosa cells and the function of fibroblast growth factor 9 (FGF9) that is regulated by LSD1Ser54p were further investigated. The modification of LSD1Ser54p was predicted to be mediated by cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK3). Treatment of chicken hierarchal granulosa cells with CDK5 inhibitor significantly decreased LSD1Ser54p level (P < 0.05) and LSD1Ser54p interacted with CDK5, suggesting that, in the granulosa cells of chicken hierarchal follicles, LSD1Ser54p modification was carried out by CDK5. When the LSD1Ser54p level decreased in the granulosa cells of chicken hierarchal follicles, both the mRNA expression of FGF9 and α-actinin 2 (ACTN2) and the H3K4me2 level in their promoter regions significantly increased (P < 0.05), indicating that this phosphorylation modification enhanced the demethylation activity of LSD1. Moreover, in chicken hierarchal granulosa cells, overexpression of chicken FGF9 stimulated their proliferation and increased the mRNA expression of hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 (Hsd3b) and steroidogenic acute regulatory protein (StAR). This study collectively revealed that phosphorylation of LSD1 at serine 54 by CDK5 enhanced its demethylation activity in chicken ovarian granulosa cells and regulated genes including FGF9 that is engaged in chicken follicle selection.

Summary: Aging-related cardiac fibrosis represents the principal pathological progression in cardiovascular aging. The Muscleblind-like splicing regulator 2 (MBNL2) has been unequivocally established as being associated with cardiovascular diseases. Nevertheless, its role in aging-related cardiac fibrosis remains unexplored. This investigation revealed an elevation of MBNL2 levels in the aged heart and senescent cardiac fibroblasts. Notably, the inhibition of MBNL2 demonstrated a capacity to mitigate H2O2-induced myofibroblast transformation and aging-related cardiac fibrosis. Further mechanistic exploration unveiled that aging heightened the expression of SENP1 and impeded the SUMO1 binding with KLF4, and SUMOylation of KLF4 effectively increased by the inhibition of MBNL2. Additionally, the inhibition of TGF-β1/SMAD3 signaling attenuated the impact of over-expression of MBNL2 in inducing senescence and cardiac fibrosis. MBNL2, by orchestrating SUMOylation of KLF4, upregulating the TGF-β1/SMAD3 signaling pathway, emerges as a significant promoter of aging-related cardiac fibrosis. This discovery identifies a novel regulatory target for managing aging-related cardiac fibrosis.

Summary: Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. Methods: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan–Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. Findings: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48–1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41–0.66, p

The applications and researches of the aerogel in the field of building materials and building energy conservation had been widely concerned due to its excellent thermal insulation properties. However, it has not been paid attention that the potential application values for excellent CO2 adsorption properties of aerogel in building materials. The CO2 adsorption properties of aerogel and the research progress on utilizing SiO2 aerogel in building materials had been reviewed. And the application prospect of the technologies that exploit the CO2 adsorption properties of aerogel and the carbonization technology to prepare SiO2 aerogel-based low-carbon building materials was discussed. It was shown that the type, morphology, and pore structure of aerogel significantly affect the resulting carbon adsorption performance. Amino modification was an effective method for improving the carbon adsorption capacity of aerogel. The performance of aerogel-incorporated cement-based composites could be optimized by improving the performance of binder materials, modifying the aerogel, or preparing new aggregates by loading aerogel into porous materials with higher strength. In addition, it was feasible to prepare new green low-carbon building materials by using aerogel as thermal insulating aggregate and carbon adsorption material, industrial solid wastes rich in alkali metal ions as cementitious materials, and carbonation curing technology. The purpose of this review was to promote the application of CO2 adsorption properties of aerogel in building materials, and enhance the development of low-carbon (or zero-carbon, or negative-carbon) building materials. This is of great significance for reducing carbon emissions in the construction sector and promoting the ''carbon neutrality'' of global.

This study proposes a novel colorimetric method based on the ultraviolet/visible spectrophotometry-colorimetric method (UV/Vis-CM) for detecting and quantifying total triterpenoids in traditional Chinese medicine. By incorporating the colourants 2-hydroxy-5-methylbenzaldehyde and concentrated sulfuric acid, triterpenoid compounds colour development became more sensitive, and the detection accuracy was significantly improved. 2-hydroxy-5-methylbenzaldehyde and concentrated sulfuric acid were incorporated in a 1:3 vol ratio at room temperature to react with the total triterpenes for 25 min, incorporated to an ice bath for 5 min, and then detected at the optimal absorption wavelength. The accuracy and reliability of this method were verified by comparison with high-performance liquid chromatography and four other colorimetric methods. Additionally, this approach has the advantages of not requiring heating during operation, high sensitivity, short usage time, low solvent usage, and low equipment costs. This study not only offers a reliable method for detecting total triterpenes in traditional Chinese medicine but also offers a rapid detection tool for on-site testing and large-scale screening, laying a foundation for the modernization of traditional Chinese medicine research, quality control, and drug development.

Abstract Background The triglyceride-glucose (TyG) index is regarded as a sophisticated surrogate biomarker for insulin resistance, offering a refined means for evaluating cardiovascular diseases (CVDs). However, prospective cohort studies have not simultaneously conducted baseline and multi-timepoint trajectory assessments of the TyG index in relation to CVDs and their subtypes in elderly participants. Methods After excluding data deficiencies and conditions that could influence the research outcomes, this study ultimately incorporated a cohort of 20,185 participants, with data chronicles extending from 2016 to 2022. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Latent Class Trajectory Model (LCTM) was used to assess the change trends of the TyG index over multiple time points. Utilizing the Cox proportional-hazards models, we assessed the relationship between the baseline quartiles of the TyG index and various trajectories with CVDs and subtypes. Results During the mean follow-up time of 4.25 years, 11,099 patients experienced new CVDs in the elderly population. After stratifying by baseline TyG quartiles, the higher TyG level was associated with an increased risk of CVDs; the aHR and 95% CI for the highest quartile group were 1.28 (1.19–1.39). Five trajectory patterns were identified by the LCTM model. The low gradual increase group as the reference, the medium stable group, and the high gradual increase group exhibited an elevated risk of CVDs onset, aHR and 95%CIs were 1.17 (1.10–1.25) and 1.25 (1.15–1.35). Similar results were observed between the trajectories of the TyG index with subtypes of CVDs. Conclusion Participants with high levels of baseline TyG index and medium stable or high gradual increase trajectories were associated with an elevated risk of developing CVDs in elderly populations.

Abstract The development of 3D spiral microfluidics has opened new avenues for leveraging inertial focusing to analyze small fluid volumes, thereby advancing research across chemical, physical, and biological disciplines. While traditional straight microchannels rely solely on inertial lift forces, the novel spiral geometry generates Dean drag forces, eliminating the necessity for external fields in fluid manipulation. Nevertheless, fabricating 3D spiral microfluidics remains a labor-intensive and costly endeavor, hindering its widespread adoption. Moreover, conventional lithographic methods primarily yield 2D planar devices, thereby limiting the selection of materials and geometrical configurations. To address these challenges, this work introduces a streamlined fabrication method for 3D spiral microfluidic devices, employing rotational force within a miniaturized thermal drawing process, termed as mini-rTDP. This innovation allows for rapid prototyping of twisted fiber-based microfluidics featuring versatility in material selection and heightened geometric intricacy. To validate the performance of these devices, we combined computational modeling with microtomographic particle image velocimetry (μTPIV) to comprehensively characterize the 3D flow dynamics. Our results corroborate the presence of a steady secondary flow, underscoring the effectiveness of our approach. Our 3D spiral microfluidics platform paves the way for exploring intricate microflow dynamics, with promising applications in areas such as drug delivery, diagnostics, and lab-on-a-chip systems.

Understanding how human leukocyte antigen (HLA) polymorphism affects both the susceptibility and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will help to identify individuals at higher risk to better manage and prioritize vaccination at the clinical level and explain the differences in epidemic trends in different regions at the epidemiological level. This study compared the frequencies of HLA class I alleles (HLA-A, B) in 214 coronavirus disease 2019 (COVID-19) patients with different disease severity and 35 healthy controls and analyzed the correlations between specific HLA alleles and disease severity and T cell memory. The results showed no significant difference in HLA allele frequencies between COVID-19 patients and healthy controls (P > 0.05). The allele HLA-B*13:02 was significantly correlated with the disease severity of COVID-19 patients (P = 0.006). After adjustment for age and disease severity, the T cell responses of COVID-19 convalescents with the allele HLA-B*40:01 may be lower at six months (P = 0.044) and 12 months (P = 0.069). Moreover, these results may be due to their rare peptide anchors by analyzing the binding peptide motifs of these HLA alleles. The study may be valuable for investigating the potential association of specific HLA alleles with SARS-CoV-2 infection.

Purpose The Bone And MicroBiOme Onset (BAMBOO) study is an ongoing prospective observational cohort study conducted in Tianjin, China, aiming to determine age-appropriate trajectories for microbiome maturation and bone development and to identify the influence of dietary factors in the process.Participants The recruitment started in September 2021 and was completed in February 2023. A total of 1380 subjects were recruited, 690 at birth (group 1) and 690 at 6 months of age (group 2). Groups 1 and 2 will be followed up for 12 months and 36 months, respectively.Findings to date The age of the mothers was 31.1±3.7 (mean±SD), and the birth weight of infants was 3.3±0.5 kg with an incidence of caesarean section 50.4%. Food diary information of the first 100 subjects showed that 64 food items were introduced by 6 months. A pilot microbiome analysis revealed that at the species level, bacterial communities were composed of mostly Bacteroides dorei, Bacteroides vulgatus and Escherichia coli, which were consistent with that of previous reports. Feasibility assessments of breast milk vitamin D and human milk oligosaccharides were validated through certified reference measurements. The early data assessment showed a high reliability of the data generated from this study.Future plans Data collection will be completed in August 2025. Four stage-statistical analyses will be performed as the cohort reaches certain age thresholds before the final report. Analysis of BAMBOO data will be used to develop age-appropriate trajectories for microbiome maturation and bone development for children aged 0–3 years and investigate the contribution of dietary factors in the process.Trial registration number ChiCTR2100049972

Drawing upon Hofstede's cultural model, this study establishes a framework for examining the factors influencing citizens' continuous use of e-government websites. This paper, employing quantile regression, reveals that collectivism, masculinity, long-term orientation, and constraint culture exhibit varying degrees of influence on different levels of continuous use of China's e-government websites. Moreover, it has been observed that masculine culture exerts a limiting effect on the continuous use of e-government websites by the Chinese public, but this restriction diminishes beyond the 50th percentile of continuous usage level. In contrast, constraint-oriented culture consistently influences the Chinese public's continuous usage behavior of e-government websites. Both collectivist culture and long-term orientation culture demonstrate their impact on the continuous use of e-government websites among the Chinese public once a certain threshold of continuous usage level is achieved. In light of these findings, the study suggests that the government should pay attention to the cultural aspects of e-government websites and provide culturally adaptive e-government services to better meet the public's needs and expectations.

Abstract Background A variety of apoptosis genes have been confirmed to be related to the occurrence and development of bladder cancer patients, but few studies have paid attention to their significance in the prognosis of bladder cancer. Therefore, this study explored the value of apoptosis-related genes in the prognosis of BLCA by using the data in TCGA database. Methods We downloaded the mRNA expression profiles and corresponding clinical data of bladder cancer patients from TCGA database, and obtained 2411 apoptosis-related genes from Deathbase database. Screening out differentially expressed apoptosis-related genes. Cox regression was used to determine the prognostic value of apoptosis-related genes, and then a prognostic risk model was developed. A nomogram based on risk model was constructed to predict the prognosis of bladder cancer patients. At the same time, immune infiltration correlation analysis of genes in the prognosis model. Results A prognostic model composed of 12 apoptosis-related genes was constructed. According to the risk score calculated by the model, patients were divided into high-risk group and low-risk group. There are significant differences in the expression of immune cells, immune function and immune checkpoint molecules between high-risk group and low-risk group. P4HB may promote bladder cancer progression. Conclusion Based on the differential expression of apoptosis-related genes, we established a risk model to predict the prognosis of bladder cancer patients, in which P4HB promotes BLCA progression.

ADP-ribosylation factor 6 (Arf6), a small G-protein of the Ras superfamily, plays pivotal roles in multiple cellular events, including exocytosis, endocytosis, actin remodeling, plasma membrane reorganization and vesicular transport. Arf6 regulates the progression of cancer through the activation of cell motility and invasion. Aberrant Arf6 activation is a potential therapeutic target. This review aims to understand the comprehensive function of Arf6 for future cancer therapy. The Arf6 GEFs, protein structure, and roles in cancer have been summarized. Comprehending the mechanism underlying Arf6-mediated cancer cell growth and survival is essential. The structural features of Arf6 and its efforts are discussed and may be contributed to the discovery of future novel protein-protein interaction inhibitors. In addition, Arf6 inhibitors and mechanism of action are listed in the table. This review further emphasizes the crucial roles in drug resistance and attempts to offer an outlook of Arf6 in cancer therapy.

Globally, dockless bike-sharing (DBS) systems are acclaimed for their convenience and seamless integration with public transportation, such as buses and metros. While much research has focused on the connection between the built environment and the metro–DBS integration, the influence of urban road characteristics on DBS and bus integration remains underexplored. This study defined the parking area of DBS around bus stops by a rectangular buffer so as to extract the DBS–bus integration, followed by measuring the access and egress integration using real-time data on dockless bike locations. This indicated that the average trip distance for DBS–bus access and egress integration corresponded to 1028.47 m and 1052.33 m, respectively. A zero-inflated negative binomial (ZINB) regression model assessed how urban roads and other transportation facilities correlate with DBS–bus integration across various scenarios. The findings revealed that certain street patterns strongly correlate with frequent connection hotspots. Furthermore, high-grade roads and ‘dense loops on a stick’ street types may negatively influence DBS–bus integration. The increase in the proportion of three-legged intersections and culs-de-sac in the catchment makes it difficult for bus passengers to transfer by DBS. These insights offer valuable guidance for enhancing feeder services in public transit systems.

The accelerated growth of urban areas has resulted in substantial alterations to the spatial structure of these settlements. The accurate identification of the multi-centre spatial structure is a fundamental prerequisite for the assessment of urban spatial development and the optimisation of urban space. Accordingly, this study aimed to identify the multi-centre spatial structure of cities through a novel approach of data fusion based on night-time lighting data, LandScan data, and population heat data. Furthermore, this study compared the differential effects of population distribution and population mobility in identifying urban spatial structures. The empirical research results for Zhengzhou City demonstrate that the accuracy of using LandScan data fusion to identify multi-centre spatial structures was 0.7463, while the accuracy of using night-time light data fusion to identify urban spatial structures through population mobility reached 0.8235. This suggests that, in the context of increasing population mobility and economic activity, the integration of population mobility data may have a significant impact on the accuracy of urban spatial research. Moreover, this study places a dual focus on population distribution and population mobility and a new method of data integration for urban spatial research. These are of considerable practical value in facilitating spatial optimisation and the coordinated development of cities.

The melanoma-associated antigen (MAGE) family found in eukaryotes plays a crucial role in cell proliferation and differentiation, spermatogenesis, neural development, etc. This study explored the validation and evolution of MAGE genes in eukaryotic genomes and their distribution and expression patterns in pigs. In total, 249 MAGE genes were found on 13 eukaryotic species. In total, 33, 25, and 18 genes were located on human, mouse, and pig genomes, respectively. We found eight, four, and three tandemly duplicated gene clusters on the human, mouse, and pig genomes, respectively. The majority of MAGE genes in mammals are located on the X chromosome. According to the phylogenetic analysis, the MAGE family genes were classified into 11 subfamilies. The NDN gene in zebrafish (DreNDN) was the root of this evolutionary tree. In total, 10 and 11 MAGE genes on human and mouse genomes, respectively, exhibited a collinearity relationship with the MAGE genes on pig genomes. Taking the MAGE family genes in pigs, the MAGE subfamilies had similar gene structures, protein motifs, and biochemical attributes. Using the RNA-seq data of Duroc pigs and Rongchang pigs, we detected that the expression of type I MAGE genes was higher in reproductive tissues, but type II MAGE genes were predominantly expressed in the brain tissue. These findings are a valuable resource for gaining insight into the evolution and expression of the MAGE family genes.

The impact of contact between two elastic–plastic bodies is highly complex, with no established theoretical contact model currently available. This study investigates the problem of an elastic–plastic sphere impacting an elastic–plastic half-space at low speed and low energy using the finite element method (FEM). Existing linear contact loading laws exhibit significant discrepancies as they fail to consider the impact of elasticity and yield strength on the elastic–plastic sphere. To address this limitation, a novel linear contact loading law is proposed in this research, which utilizes the concept of equivalent contact stiffness rather than the conventional linear contact stiffness. The theoretical expressions of this new linear contact loading law are derived through FEM simulations of 150 sphere and half-space impact cases. The segmental linear characteristics of the equivalent contact stiffness are identified and fitted to establish the segmental expressions of the equivalent contact stiffness. The new linear contact loading law is dependent on various factors, including the yield strain of the half-space, the ratio of elastic moduli between the half-space and sphere, and the ratio of yield strengths between the half-space and sphere. The accuracy of the proposed linear contact loading law is validated through extensive Finite Element Method simulations, which involve an elastic–plastic half-space being struck by elastic–plastic spheres with varying impact energies, sizes, and material combinations.

Methyl jasmonate (MeJA), as a natural endogenous substance and a signal molecule, plays an important role in stress response and development in plant. The effect of MeJA fumigation (100 μmol/L, treatment at 20 ℃ for 20 h) on phenylpropanoid pathway during storage of 'Xizhoumi-17' melon was assayed in this study. Results showed that MeJA treatment significantly increased the total phenolics content, and enhanced the activities of phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxylase (C4H) and 4-coumarate: CoA ligase (4CL) (P

Abstract The advancement of contemporary X-ray imaging heavily depends on discovering scintillators that possess high sensitivity, robust stability, low toxicity, and a uniform size distribution. Despite significant progress in this field, the discovery of a material that satisfies all of these criteria remains a challenge. In this study, we report the synthesis of monodisperse copper(I)-iodide cluster microcubes as a new class of X-ray scintillators. The as-prepared microcubes exhibit remarkable sensitivity to X-rays and exceptional stability under moisture and X-ray exposure. The uniform size distribution and high scintillation performance of the copper(I)-iodide cluster microcubes make them suitable for the fabrication of large-area, flexible scintillating films for X-ray imaging applications in both static and dynamic settings.

Background: Central compartment atopic disease (CCAD) is a subtype of chronic rhinosinusitis (CRS). Research focusing on the endoscopic sinus surgery (ESS) outcomes of CCAD is limited. This study aimed to evaluate the outcomes of ESS in CCAD and compared to 2 following subtypes: chronic rhinosinusitis with nasal polyps (CRSwNP) and concomitant polypoid disease in the central compartment (CRSwNP/CC) and CRSwNP not otherwise specified (CRSwNP NOS). Methods: This case-control study enrolled patients with bilateral CRSwNP who underwent ESS and had at least 1 year of follow-up. Patients were classified into CCAD, CRSwNP/CC, and CRSwNP NOS. The demographic data, preoperative disease severity, and surgery outcomes, including CRS control status, endoscopic score, and symptom scores at 1 year postoperatively, were collected. We defined well controlled and partly controlled as appropriate disease control. Results: This study screened 259 patients and enrolled 138 patients with complete medical records and 1-year follow-up (CCAD N = 51, CRSwNP/CC N = 55, CRSwNP NOS N = 32). Among them, appropriate disease control was achieved in 84.3% of patients (43/51) in the CCAD group, 69.1% (38/55) in the CRSwNP/CC group, and 93.7% (30/32) in the CRSwNP NOS group (P = 0.029). Then we performed post-hoc analysis using appropriate disease control and uncontrolled. There was a significant difference between CRSwNP/CC and CRSwNP NOS (P = 0.007), but no significant difference compared CCAD group to CRSwNP/CC group (P = 0.065) and CRSwNP NOS group (P = 0.199). There were significant differences in endoscopic E-score among groups (P

Understanding the evolution of rural landscapes in metropolises during rapid urbanization is crucial for formulating policies to protect the rural ecological environment. In this study, remote sensing and geographical information system data, as well as applied landscape index analysis, are used to examine the spatiotemporal evolution of rural landscape patterns in the Beijing-Tianjin region of China, which has experienced rapid urbanization. The relationships between land use/land cover changes and changes in rural landscape patterns are explored. The results revealed significant spatial differences in the rural landscapes in the Beijing-Tianjin region; farmland and forestland were the main types of landscapes, creating a "mountain-field-sea" natural landscape pattern. The conversion of rural landscapes in the Beijing-Tianjin region involved mainly the conversion of farmland to urban areas, with few exchanges between other landscape types. The urban areas in the Beijing-Tianjin region increased by 3% per decade; farmland decreased at the same rate. Additionally, the rural landscape patterns in the Beijing-Tianjin region were dominated by fragmentation, dispersion, and heterogeneity and moved from complex to regular. Water bodies displayed the most fragmented natural landscape; their number of patches increased by 36%, though their network characteristics were maintained. Forestland was the most concentrated natural landscape. In this study, theoretical support and a scientific reference for the optimization of rural landscape patterns and the improvement in rural living environments in rapidly urbanizing areas are provided.