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Fluoride (F) and cadmium (Cd) as well known environmental pollutants can cause nephrotoxicity to damage human health, while the joint toxicity of F and Cd to the renal tubular epithelial cells remains still elusive. The interactive influence between F and Cd in oxidative stress, apoptosis, and mitochondrial autophagy of renal tubular epithelial cells was explored. Cells were submitted to varying concentrations with of NaF (1, 5, 10, and 15 μg/mL) combined with CdCl 2 ·2.5H 2 O (1 μg/mL) for 12 h. Following this, the combined cytotoxicity was assessed. Our results show that different doses of F had varying effects on Cd-mediated nephrotoxicity, with a synergistic effect observed in the high F (15 μg/mL) co-treated with Cd. In response to the Cd induction, the high F treatment resulted in the formation of multiple autophagosomes and notably increased the levels of LDH, ROS, and MMP. It also elevated the MDA contents while decreasing the activities of SOD, GSH-Px, and CAT. Additionally, it yielded a higher Bax/Bcl-2 ratio, which further promotes the apoptotic process. The treatment also disturbed energy metabolism, resulting in a reduction of both ATP and ADP. Furthermore, autophagy-related genes and proteins, including PINK1, Parkin, LC3A, LC3B, and SQSTM1, were significantly improved. In brief, high F of 15 μg/mL aggravated Cd-mediated nephrotoxicity of renal tubular epithelial cells via the ROS-PINK1/Parkin pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purposes: Whether patients with early-onset colorectal cancer (EOCRC) receive chemotherapy has been controversial, so our study aimed to screen patients with EOCRC who benefit from chemotherapy., Methods: A total of 2166 EOCRC patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were divided into chemotherapy and non-chemotherapy groups, propensity score matching (PSM) was performed to balance the differences between the groups, and the Kaplan-Meier method was used to calculate the cancer-specific survival (CSS) of EOCRC patients. Multifactorial COX regression analysis was used to identify independent prognostic factors for CSS and to construct a nomogram for predicting CSS in EOCRC patients. The overall risk score was calculated based on Nomogram, and EOCRC patients were classified into high-risk and low-risk groups to assess further chemotherapy's therapeutic effect on patients with different risk stratification., Results: Before PSM, patients in the chemotherapy group had poorer CSS (p < 0.001). After PSM, there was no significant difference in patient CSS between the two groups (p = 0.057). Independent prognostic factors (Race, Grade, Pathology, AJCC.N, AJCC.M, CEA, Marital. Status) were screened according to multifactorial COX regression analyses and included in the Nomogram predicting CSS in EOCRC patients. A risk stratification system for EOCRC patients was further developed, and the results showed that chemotherapy had no significant effect on CSS in the low-risk group of patients, but in the high-risk group, chemotherapy significantly improved CSS in EOCRC patients., Conclusions: We developed a clinical risk model by combining different risk factors, which can accurately screen those with high-risk EOCRC for benefit from chemotherapy. For low-risk EOCRC patients, our results did not observe a better survival benefit from chemotherapy, and more prospective studies are needed in the future to prove our conclusions., (© 2024. The Author(s).)

High-performance fiber-reinforced composite materials demonstrate great potential for manufacturing diaphragms in human-engineered acoustic loudspeakers. However, the notable scarcity of high-quality fibers and the uncontrollable nature of the diaphragm structure limit the production of high-quality sound that conforms to human hearing. In this study, a novel composite diaphragm material is devloped by integrating the swelling carboxymethyl cellulose microfiber (CMF) with the hot-melted sheath-core fiber (SCF) based on the "interpenetrating polymeric network" ("IPN") strategy. Simulation methods and Flory-Huggins theory are applied to explain the mechanism of fiber-structure-property interaction in composite diaphragm materials. Owing to the distinct microstructure, this bio-based diaphragm material shows superior mechanical characteristics, including low density (≈0.92 g cm - 3 ), high tensile strength (≈235 MPa), and high modulus (≈9.73 GPa). Moreover, the loudspeaker mounted with bio-based diaphragm material exhibits enhanced sensitivity (≈82.6 dB) and stable performance across a broad frequency spectrum. This study not only elucidates the multiphysics working principles of loudspeakers but also establishes a crucial connection between the physical properties of diaphragms and loudspeaker performance. It opens up new avenues for the design of high-performance bio-based loudspeaker diaphragms in high-fidelity (Hi-Fi) acoustic devices., (© 2024 Wiley‐VCH GmbH.)

Ultrasensitive detection of low-abundance biomarkers by modern single-molecule technologies is critical for better diagnosis of severe diseases, but inevitable nonspecific bindings often cause fluctuations in the single-molecule counting results. Here we present an approach to improve the specificity in a single-molecule immunoassay by translating molecular binding signals into periodic nanomotion of magnetic particles. The sandwiched immunoassay is modified by using a long linker to tether one antibody onto a gold-covered substrate and a magnetic particle with another antibody coated as the reporter. By actively oscillating the particles with alternating magnetic fields, we could reliably identify specific binding through intensity fluctuation in plasmonic images of single particles. As a proof of concept, we demonstrate the detection of IFN-γ at the femtomolar level by the digital counting of specifically bound molecules. This active strategy outperforms existing passive motion-based approaches in sensitivity and speed, paving the way for disease diagnosis with low-abundance biomarkers.

Cadmium (Cd) represents a hazardous heavy metal, prevalent in agricultural soil due to industrial and agricultural expansion. Its propensity for being absorbed by edible plants, even at minimal concentrations, and subsequently transferred along the food chain poses significant risks to human health. Accordingly, it is imperative to investigate novel genes and mechanisms that govern Cd tolerance and detoxification in plants. Here, we discovered that the transcription factor MYC2 directly binds to the promoters of HMA2 and HMA4 to repress their expression, thereby altering the distribution of Cd in plant tissues and negatively regulating Cd stress tolerance. Additionally, molecular, biochemical, and genetic analyses revealed that MYC2 interacts and cooperates with MYB43 to negatively regulate the expression of HMA2 and HMA4 and Cd stress tolerance. Notably, under Cd stress conditions, MYC2 undergoes degradation, thereby alleviating its inhibitory effect on HMA2 and HMA4 expression and plant tolerance to Cd stress. Thus, our study highlights the dynamic regulatory role of MYC2, in concert with MYB43, in regulating the expression of HMA2 and HMA4 under both normal and Cd stress conditions. These findings present MYC2 as a promising target for directed breeding efforts aimed at mitigating Cd accumulation in edible plant roots., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: There is limited study that illuminates the relationship between obesity indices and prognosis in patients with heart failure with preserved ejection fraction, nor has it been examined whether the obesity paradox persists when using these metrics., Methods and Results: This study is a post hoc analysis of data from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. A total of 3114 individuals were included in our final analysis, and a total of 481 (15.4%) all-cause deaths, and 389 (12.5%) heart failure hospitalizations were recorded. In a multivariable Cox regression model, compared with patients with a body mass index (BMI) <24.9 kg/m 2 , those with a BMI of 25.0-29.9, 30.0-34.9, and 35-39.9 kg/m 2 were associated with a decreased risk of all-cause death, with hazard ratio (95% CI) of 0.59 (0.45-0.78), 0.61 (0.46-0.82), and 0.66 (0.47-0.92), respectively. Conversely, patients with a BMI ≥40 kg/m 2 showed an increased risk of heart failure hospitalization, compared with BMI <24.9 kg/m 2 . Furthermore, patients in the highest quintile of obesity indices exhibited a significantly elevated hazard ratio for both all-cause death and heart failure hospitalization, compared with the lowest quintile., Conclusions: An elevated BMI over a certain range was associated with a reduced risk of all-cause death in heart failure with preserved ejection fraction, displaying a U-shaped relationship, with no mortality reduction observed in cases of extreme obesity. In contrast, higher values of novel obesity indices were positively correlated with all-cause death and heart failure hospitalization without the obesity paradox.

The present study investigated the Zinc finger BED-type containing 3 (ZBED3) mRNA expression levels, diagnostic and prognostic values, co-expressed and differentially expressed genes, immune infiltration, and functional enrichment analysis in patients with kidney renal clear cell carcinoma (KIRC) using various public databases such as The Cancer Genome Atlas, Genotype-Tissue Expression Project, LinkedOmics, Gene Set Enrichment Analysis databases, and the Xiantao academic tool. Through extensive data mining, our study revealed differential expression of ZBED3 in various tumor and paired normal tissues. Specifically, ZBED3 expression was found to be significantly decreased in KIRC, particularly in advanced pathologic stages and histologic grades, when compared to corresponding control tissues. Our analysis revealed that the overexpression of ZBED3 is associated with a favorable overall survival outcome in KIRC patients. Moreover, functional enrichment analysis identified key pathways related to inflammation response and DNA methylation of ZBED3 in KIRC. Additionally, our findings suggest that the upregulation of ZBED3 leads to the inhibition of cell proliferation by modulating cell-cycle progression in KIRC cell lines. Taken together, these results suggest that ZBED3 may serve as a promising biomarker and prognostic indicator for individuals diagnosed with KIRC., (© 2024. The Author(s).)

The design of stable formulations remains a major challenge for protein therapeutics, particularly the need to minimize aggregation. Experimental formulation screens are typically based on thermal transition midpoints ( T m ), and forced degradation studies at elevated temperatures. Both approaches give limited predictions of long-term storage stability, particularly at low temperatures. Better understanding of the mechanisms of action for formulation of excipients and buffers could lead to improved strategies for formulation design. Here, we identified a complex impact of glycine concentration on the experimentally determined stability of an antibody Fab fragment and then used molecular dynamics simulations to reveal mechanisms that underpin these complex behaviors. T m values increased monotonically with glycine concentration, but associated Δ S vh measurements revealed more complex changes in the native ensemble dynamics, which reached a maximum at 30 mg/mL. The aggregation kinetics at 65 °C were similar at 0 and 20 mg/mL glycine, but then significantly slower at 50 mg/mL. These complex behaviors indicated changes in the dominant stabilizing mechanisms as the glycine concentration was increased. MD revealed a complex balance of glycine self-interaction, and differentially preferred interactions of glycine with the Fab as it displaced hydration-shell water, and surface-bound water and citrate buffer molecules. As a result, glycine binding to the Fab surface had different effects at different concentrations, and led from preferential interactions at low concentrations to preferential exclusion at higher concentrations. During preferential interaction, glycine displaced water from the Fab hydration shell, and a small number of water and citrate molecules from the Fab surface, which reduced the protein dynamics as measured by root-mean-square fluctuation (RMSF) on the short time scales of MD. By contrast, the native ensemble dynamics increased according to Δ S vh , suggesting increased conformational changes on longer time scales. The aggregation kinetics did not change at low glycine concentrations, and so the opposing dynamics effects either canceled out or were not directly relevant to aggregation. During preferential exclusion at higher glycine concentrations, glycine could only bind to the Fab surface through the displacement of citrate buffer molecules already favorably bound on the Fab surface. Displacement of citrate increased the flexibility (RMSF) of the Fab, as glycine formed fewer bridging hydrogen bonds to the Fab surface. Overall, the slowing of aggregation kinetics coincided with reduced flexibility in the Fab ensemble at the very highest glycine concentrations, as determined by both RMSF and Δ S vh , and occurred at a point where glycine binding displaced neither water nor citrate. These final interactions with the Fab surface were driven by mass action and were the least favorable, leading to a macromolecular crowding effect under the regime of preferential exclusion that stabilized the dynamics of Fab.

Mechanically interlocked molecules, such as rotaxanes, have drawn significant attention within supramolecular chemistry. Although a variety of macrocycles have been thoroughly explored in rotaxane synthesis, metal-organic macrocycles remain relatively under-investigated. Aluminum molecular rings, with their inner cavities and numerous binding sites, present a promising option for constructing rotaxanes. Here, we introduce an innovative "ring-donor⋅⋅⋅axle-acceptor" motif utilizing Al 8 molecular rings, enabling the stepwise assembly of molecules, complexes, and polymers through tailored coordination chemistry. This novel approach can not only be applied to macrocycle-based systems like catenanes but also enhance specific functionalities progressively., (© 2024 Wiley-VCH GmbH.)

Background: Artificial intelligence has been proposed for brain metastasis (BM) segmentation but it has not been fully clinically validated. The aim of this study was to develop and evaluate a system for BM segmentation., Methods: A deep-learning-based BM segmentation system (BMSS) was developed using contrast-enhanced MR images from 488 patients with 10338 brain metastases. A randomized crossover, multi-reader study was then conducted to evaluate the performance of the BMSS for BM segmentation using data prospectively collected from 50 patients with 203 metastases at 5 centers. Five radiology residents and 5 attending radiologists were randomly assigned to contour the same prospective set in assisted and unassisted modes. Aided and unaided Dice similarity coefficients (DSCs) and contouring times per lesion were compared., Results: The BMSS alone yielded a median DSC of 0.91 (95% confidence interval, 0.90-0.92) in the multi-center set and showed comparable performance between the internal and external sets (P = .67). With BMSS assistance, the readers increased the median DSC from 0.87 (0.87-0.88) to 0.92 (0.92-0.92) (P < .001) with a median time saving of 42% (40-45%) per lesion. Resident readers showed a greater improvement than attending readers in contouring accuracy (improved median DSC, 0.05 [0.05-0.05] vs 0.03 [0.03-0.03]; P < .001), but a similar time reduction (reduced median time, 44% [40-47%] vs 40% [37-44%]; P = .92) with BMSS assistance., Conclusions: The BMSS can be optimally applied to improve the efficiency of brain metastasis delineation in clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Colored leaves, a notable horticultural trait, have high research and ornamental value. The evergreen sweet olive (Osmanthus fragrans), one of the top ten traditional flowers in China, has been cultivated for more than two thousand years. However, in recent years, an increasing number of O. fragrans cultivars with colored leaves have been cultivated for their ornamental value. To study the molecular mechanism underlying the observed changes in leaf color, we selected O. fragrans 'Yinbi Shuanghui' (Y), which has yellow-white leaves, and O. fragrans 'Sijigui' (S), which has green leaves, as materials. Pigment content measurement showed that the chlorophyll, carotenoid and anthocyanin contents in Y were lower than in S. According to the SWATH-MS sequencing results, a total of 3,959 proteins were quantitatively identified, 1,300 of which were differentially expressed proteins (DEPs), including 782 up-regulated and 518 down-regulated proteins in Y compared to S. Functional enrichment analysis of DEPs revealed that down-regulated expression of photosynthesis related proteins may lead to the inhibition of chlorophyll synthesis in Y, this may be the main cause of leaf color change. Moreover, a protein interaction prediction model also showed that proteins such as PetC, PsbO, PsbP, and PsbQ were key proteins in the interaction network, and the up-regulated proteins participating in the anthocyanin and carotenoid pathways may be related to the formation of yellow-white leaves. Taken together, our findings represent the first SWATH-MS-based proteomic report on colored leaf O. fragrans and reveal that chlorophyll synthesis and secondary metabolism pathways contribute to the changes in leaf color., (© 2024. The Author(s).)

Objective: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which activated CD4 + T cells participate in the disease process by inducing inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) on CD4 + T cells in RA patients, and to elucidate the underlying mechanisms by which TLR2 contributes to the pathogenesis of RA., Methods: Serum samples were collected from RA patients and healthy controls. Soluble TLR2 levels were quantified using an enzyme-linked immunosorbent assay (ELISA). Flow cytometry was employed to assess the TLR2 expression level, activation status, cytokine production, reactive oxygen species (ROS) levels, and glucose uptake capacity of CD4 + T cells. Quantitative polymerase chain reaction (qPCR) was used to measure the expression of enzymes associated with glucose and lipid metabolism. The concentration of lactic acid in the culture supernatant was determined using a dedicated detection kit., Results: RA patients had higher levels of TLR2 in their serum, which positively correlated with C-reactive protein and rheumatoid factor. The expression level of TLR2 in CD4 + T cells of RA patients was increased, and TLR2 + cells showed higher activation levels than TLR2- cells. Activation of TLR2 in CD4 + T cells of RA patients promoted their activation, TNF-α secretion, and increased production of ROS. Furthermore, TLR2 activation led to changes in enzymes related to glucose metabolism, causing a shift in glucose metabolism towards the pentose phosphate pathway. Blocking oxidative phosphorylation and the pentose phosphate pathway had varying effects on CD4 + T cell function., Conclusion: TLR2 reprograms the glucose metabolism of CD4 + T cells in RA patients, contributing to the development of RA through ROS-mediated cell hyperactivation and TNF-α secretion. Key Points • TLR2 is upregulated in CD4 + T cells of RA patients and correlates with disease severity markers such as CRP and RF. • Activation of TLR2 in CD4 + T cells promotes cell activation, TNF-α secretion, and increased ROS production, contributing to the pathogenesis of RA. • TLR2 activates glucose metabolism in CD4 + T cells, shifting towards the pentose phosphate pathway, which may be a novel therapeutic target for RA treatment. • Blocking glucose metabolism and ROS production can reduce CD4 + T cell hyperactivation and TNF-α secretion, indicating potential therapeutic strategies for RA management., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

The formation of sheep (Ovis aries) breeds is influenced by different ecological environments and populations with different living habits, resulting in the development of germplasm resources with stable genetic key agronomic traits. Thus, investigating the genetic mechanisms behind various agronomic traits can enhance the conservation and utilization of diverse sheep breeds. Here, we explored the sheep variome and selection signatures using the Ovine Infinium HD SNP BeadChip (600 K SNPs) from 23 sheep breeds, comprising a total of 1215 sheep. The genetic mechanisms of wool quality and tail morphology were analyzed by selective sweep and genome-wide association study. Based on the results of within-population selective sweep analysis, we performed gene network analysis and divided them into 6 gene communities. We identified genetic regions containing genes linked to sheep wool and tail, which have been and may continue to be important targets for breeding and selection. Furthermore, our results revealed the expression profiles of genes in these regions across different biological systems. Our study provides insights into categorizing sheep breeds into distinct gene communities, as well as references for constructing genetic network pathways related to key agronomic traits in sheep and other domestic animals., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, author- ship, and/or publication of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

High Epidermal growth factor receptor (EGFR) in Cutaneous Squamous Cell Carcinoma (cSCC) is associated with poor prognosis and advanced metastatic stages, severely impeding the efficacy of EGFR-targeting immunotherapy. This is commonly attributed to the combinatory outcomes of hypoxic tumor microenvironment (TME) and immunosuppressive effector cells together. Herein, a novel paradigm of EGFR-targeting oxygen-saturated nanophotosensitizers, designated as CHPFN-O 2 , has been specifically tailored to mitigate tumor hypoxia in EGFR-positive cSCC and achieve Cetuximab (CTX)-mediated immunotherapy (CIT). The conjugated CTX in CHPFN-O 2 serves to initiate immune responses by recruiting Fc receptor (FcR)-expressing immune effector cells towards tumor cells, thereby eliciting antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular trogocytosis (ADCT) and antibody-dependent cellular cytotoxicity (ADCC). Besides, CHPFN-O 2 can engender a shift from a tumor-friendly to a tumor-hostile one through improved tumor oxygenation, contributing to oxygen-elevated photodynamic therapy (oxPDT). Notably, the combination of oxPDT and CIT eventually promotes T-cell-mediated antitumor activity and successfully inhibits the growth of EGFR-expressing cSCC with good safety profiles. This comprehensive oxPDT/CIT integration aims not only to enhance therapeutic efficacy against EGFR high cSCC but also to extend its applicability to other EGFR high malignancies, thus delineating a new avenue for the highly efficient synergistic treatment of EGFR-expressing malignancies., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: To extract anthocyanins with high efficiency, a hypothesis for high-speed shear homogenization extraction (HSHE) method was established through a combination of solvent and ultrasonic-assisted extractions. The efficacy of this hypothesis was demonstrated by performing qualitative and quantitative analyses of 16 anthocyanins extracted from five northern vegetables, and five berry fruits using ultra-high-performance Q-Exactive Orbitrap tandem mass spectrometry. Single-factor experiments were conducted by varying ethanol concentration, temperature, pH and extraction cycles to determine the optimal conditions for this method., Results: Optimal extraction conditions (ethanol 70-80%, 40-50 °C, pH 3-4, performed twice) were determined using an HSHE (5 min, 10 000 rpm, 25 °C) assisted shaker (60 min) and ultrasonication (40 kHz, 160 W cm -2 , 30 min, 25 °C) procedure. Compared to the traditional non-HSHE method, the total anthocyanin content obtained through HSHE extraction showed a significant increase, ranging from 1.0 to 3.9 times higher, with purple cabbage exhibiting the most pronounced enhancement in content. More types of anthocyanins were detected in blueberry (9), black bean (7) and raspberry (5), of which malvidin was the major anthocyanin (0.426 g kg -1 ) in blueberry, having an amount five times than previously obtained., Conclusion: The established HSHE method has been proven to be a superior technique for anthocyanin extraction, with higher extraction efficiency and concentrations. This technique also provides a new avenue for extracting bioactive compounds from diverse food sources, with potential applications in improving the functional properties of food products. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Glycogen synthase kinase 3β (GSK-3β) is a potential therapeutic target for the treatment of a variety of human diseases. Here, we report the design and synthesis of a series of thieno[3,2-c]pyrazol-urea derivatives and evaluation of their GSK-3β inhibitory activity. Among these analogues, the compound without substitution on terminal phenyl ring (3a) was found to be the most potent GSK-3β inhibitor with an IC 50 of 74.4 nM, while substitution on the terminal phenyl (3b-3p) led to decreased potency, independent of the position, size, or electronic properties of the substituents. Kinase selectivity assay revealed that 3a showed good selectivity over a panel of kinases, but was less selective over CDK1, CDK2 and CDK5. Additionally, the pharmacological properties of the synthesized compounds were investigated computationally by the SwissADME and the results showed that most of the compounds have good ADME profiles., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

As vulnerable road users, pedestrians and cyclists are facing a growing number of injuries and fatalities, which has raised increasing safety concerns globally. Based on the crash records collected in the Australian Capital Territory (ACT) in Australia from 2012 to 2021, this research firstly establishes an extended crash dataset by integrating road network features, land use features, and other features. With the extended dataset, we further explore pedestrian and cyclist crashes at macro- and micro-levels. At the macro-level, random parameters negative binomial (RPNB) model is applied to evaluate the effects of Suburbs and Localities Zones (SLZs) based variables on the frequency of pedestrian and cyclist crashes. At the micro-level, binary logit model is adopted to evaluate the effects of event-based variables on the severity of pedestrian and cyclist crashes. The research findings show that multiple factors are associated with high frequency of pedestrian total crashes and fatal/injury crashes, including high population density, high percentage of urban arterial road, low on-road cycleway density, high number of traffic signals and high number of schools. Meanwhile, many factors have positive relations with high frequency of cyclist total crashes and fatal/injury crashes, including high population density, high percentage of residents cycling to work, high median household income, high percentage of households with no motor vehicle, high percentage of urban arterial road and rural road, high number of bus stops and high number of schools. Additionally, it is found that more severe pedestrian crashes occur: (i) at non-signal intersections, (ii) in suburb areas, (iii) in early morning, and (iv) on weekdays. More severe cyclist crashes are observed when the crash type is overturned or struck object/pedestrian/animal; when more than one cyclist is involved; and when crash occurs at park/green space/nature reserve areas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The high-energy (H 2 dabco)[NH 4 (ClO 4 ) 3 ] (DAP-4) with excellent energetic performance attracts wide attention from researchers. The investigation of its interaction with the Aluminum (Al) is of great importance. However, the higher ignition threshold of DAP-4 and the dense oxide layer (Al 2 O 3 ) of Al severely limit the energy release efficiency of Al/DAP-4. In this study, a new idea to is first proposed to improve and adjust the thermal decomposition and combustion performance of Al/DAP-4 by constructing a highly dispersed iron (Fe) nanoparticle interfacial layer. It acts as a gradient catalyst to promote the thermal decomposition and combustion of DAP-4 and Al, and it also act as an oxygen transport channel to promote the contact and reaction of oxidizing gases with the internal reactive Al powder. It reduces the thermal decomposition temperature of Al@Fe-3/DAP-4 from 386.30 °C (Al/DAP-4) to 349.48 °C and leads to the vigorous combustion. Theoretical calculations show that Fe nanoparticle interfacial layer can facilitate the transport of oxygen through the established oxygen transport channels, and it can also significantly improve the energetic properties of Al@Fe-3/DAP-4 composites. In conclusion, the new approach is proposed to improve the performance of metal fuel/oxidizer composites by constructing interfacial layers, which is expected to promote their practical applications., (© 2024 Wiley‐VCH GmbH.)

Increasing the number of teats in sheep helps to improve the survival rate of sheep lambs after birth. In order to analyze the candidate genes related to the formation of multiple teats in Hu sheep, the present study was conducted to investigate the genetic pattern of multiple teats in Hu sheep. In this study, based on genome-wide data from 157 Hu sheep, Fst, xp-EHH, Pi and iHS signaling were performed, and the top 5% signal regions of each analyzed result were annotated based on the Oar&#95;v4.0 for sheep. The results show that a total of 142 SNP loci were selected. We found that PTPRG, TMEM117 and LRP1B genes were closely associated with polypodium formation in Hu sheep, in addition, among the candidate genes related to polypodium we found genes such as TMEM117, SLC25A21 and NCKAP5 related to milk traits. The present study screened out candidate genes for the formation of multiple teats at the genomic level in Hu sheep.

Background: Serum creatinine (Scr) may be not suited to timely and accurately reflect kidney injury related to chronic liver disease. Currently, the ability of arterial spin labeling (ASL) and blood oxygen level-dependent (BOLD) sequences to evaluate renal blood flow (RBF) and blood oxygen in chronic liver disease remains to be verified., Purpose: To investigate the value of ASL and BOLD imaging in evaluating hemodynamics and oxygenation changes during kidney injury in an animal model of chronic liver disease., Study Type: Prospective., Animal Model: Chronic liver disease model was established by subcutaneous injection of carbon tetrachloride. Forty-three male Sprague-Dawley rats (8 weeks) were divided into a pathological group (0, 2, 4, 6, 8, 12 weeks, each group: N = 6) and a continuous-scanning group (N = 7)., Field Strength/sequence: 3-T, ASL, BOLD, and T2W., Assessment: Regions of interest in the cortex (CO), outer stripe of the outer medulla (OSOM), and inner stripe of the outer medulla (ISOM) are manually delineated. The RBF and T2* values at each time point (0, 2, 4, 6, 8, 12 weeks) are measured and compared. Hematoxylin-eosin score (HE Score, damage area scoring method), alpha-smooth muscle actin (α-SMA), hypoxia-inducible factor-1alpha (HIF-1α), peritubular capillar (PTC) density, Scr, and neutrophil gelatinase-associated lipocalin were harvested., Statistical Tests: Analysis of variance, Spearman correlation analysis, Kruskal-Wallis tests, and receiver operating characteristic analysis with the area under the curve (AUC). A P-value <0.05 was considered statistically significant., Results: Renal RBF and T2* values of CO, OSOM, and ISOM were significantly different from baseline. Both RBF and T2* were significantly correlated with HE Score, α-SMA, HIF-1α, and PTC density (|r| = 0.406-0.853). RBF demonstrated superior diagnostic capability in identifying severe kidney injury in this model of chronic liver disease (AUC = 0.964)., Data Conclusion: Imaging by ASL and BOLD may detect renal hemodynamics and oxygenation changes related to chronic liver disease early., Evidence Level: 5 TECHNICAL EFFICACY: Stage 2., (© 2024 International Society for Magnetic Resonance in Medicine.)

Secondary lymphedema (LE) following breast cancer-related surgery is a life-long complication, which currently has no cure. LE induces significant regional adipose tissue deposition, requiring liposuction as a treatment. Here, we aimed to elucidate the transcriptional, metabolomic, and lipidomic signature of the adipose tissue developed due to the surgery-induced LE in short- and long-term LE patients and compared the transcriptomic landscape of LE adipose tissue to the obesity-induced adipose tissue. Adipose tissue biopsies were obtained from breast cancer-operated females with LE from the affected and non-affected arms (n = 20 patients). To decipher the molecular properties of the LE adipose tissue, we performed RNA sequencing, metabolomics, and lipidomics combined with bioinformatics analyses. Differential gene expression data from a cohort of lean and obese patients without LE was used for comparisons. Integrative analysis of functional genomics revealed that inflammatory response, cell chemotaxis, and angiogenesis were upregulated biological processes in the LE arm, indicating a sustained inflammation in the edematous adipose tissue; whereas, epidermal differentiation, cell-cell junction organization, water homeostasis, and neurogenesis were downregulated in the LE arm. Surprisingly, only a few genes were found to be the same in the LE-induced and the obesity-induced adipose tissue expansion, indicating a different type of adipose tissue development in these two conditions. In metabolomics analysis, we found reduced levels of a branched-chain amino acid valine in the LE arm and downregulation of the mRNA levels of its transporter SLC6A15. Lipidomics analyses did not show any significant differences between the LE and non-LE arms, suggesting that other factors affect the lipid composition of the adipose tissue more than the LE in these patients. Our results provide a detailed molecular characterization of adipose tissue in secondary LE after breast cancer-related surgery. We also show distinct differences in transcriptomic signatures between LE-induced adipose tissue and obesity-induced adipose tissue, but only minor differences in metabolome and lipidome between the LE and the non-LE arm., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Ubiquitination, a multifaceted post-translational modification, regulates protein function, degradation, and gene expression. The pivotal role of ubiquitination in the pathogenesis and progression of cancer, including colorectal, breast, and liver cancer, is well-established. Osteosarcoma, an aggressive bone tumor predominantly affecting adolescents, also exhibits dysregulation of the ubiquitination system, encompassing both ubiquitination and deubiquitination processes. This dysregulation is now recognized as a key driver of osteosarcoma development, progression, and chemoresistance. This review highlights recent progress in elucidating how ubiquitination modulates tumor behavior across signaling pathways. We then focus on the mechanisms by which ubiquitination influences osteosarcoma cell function. Finally, we discuss the potential for targeting the ubiquitin-proteasome system in osteosarcoma therapy. By unraveling the impact of ubiquitination on osteosarcoma cell physiology, we aim to facilitate the development of novel strategies for prognosis, staging, treatment, and overcoming chemoresistance., Competing Interests: No potential conflicts of interest are disclosed., (Copyright © 2024 The Authors.)

Extrahepatic cholangiocarcinoma (ECC), a highly malignant type of cancer with increasing incidence, has a poor prognosis due to limited treatment options. Based on genomic analysis of ECC patient samples, here we report that aldo-keto reductase family 1 member C1 (AKR1C1) is highly expressed in human ECC tissues and closely associated with ECC progression and poor prognosis. Intriguingly, we show that inducible AKR1C1 knockdown triggers ECC cells to undergo ferroptosis. Mechanistically, AKR1C1 degrades the protein stability of the cytochrome P450 family member CYP1B1, a newly discovered mediator of ferroptosis, via ubiquitin-proteasomal degradation. Additionally, AKR1C1 decreases CYP1B1 mRNA level through the transcriptional factor aryl-hydrocarbon receptor (AHR). Furthermore, the AKR1C1-CYP1B1 axis modulates ferroptosis in ECC cells via the cAMP-PKA signaling pathway. Finally, in a xenograft mouse model of ECC, AKR1C1 depletion sensitizes cancer cells to ferroptosis and synergizes with ferroptosis inducers to suppress tumor growth. Therefore, the AKR1C1-CYP1B1-cAMP signaling axis is a promising therapeutic target for ECC treatment, especially in combination with ferroptosis inducers., (© 2024. The Author(s).)

Two-dimensional noble transition metal chalcogenide (NTMC) semiconductors represent compelling building blocks for fabricating flexible electronic and optoelectronic devices. While binary and ternary compounds have been reported, the existence of quaternary NTMCs with a greater elemental degree of freedom remains largely unexplored. This study presents the pioneering experimental realization of a novel semiconducting quaternary NTMC material, AuPdNaS 2 , synthesized directly on Au foils through chemical vapor deposition. The ribbon-shaped morphology of the AuPdNaS 2 crystal can be finely tuned to a thickness as low as 9.2 nm. Scanning transmission electron microscopy reveals the atomic arrangement, showcasing robust anisotropic features; thus, AuPdNaS 2 exhibits distinct anisotropic phonon vibrations and electrical properties. The field-effect transistor constructed from AuPdNaS 2 crystal demonstrates a pronounced anisotropic conductance (σ max /σ min  = 3.20) under gate voltage control. This investigation significantly expands the repertoire of NTMC materials and underscores the potential applications of AuPdNaS 2 in nano-electronic devices., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

An exploration of antibacterial components from the whole plant of Euphorbia humifusa led to the isolation of 14 new triterpenoids, euphohumifusoids A-N (1-7 and 9-15), as well as four known analogues (8 and 16-18). Their structures were elucidated by extensively analysis of the spectroscopic data and X-ray crystallography using Cu Kα radiation. Among them, euphohumifusoid A (1) bears an unique 6(7 → 8)abeo scaffold originated from a D:C-friedo-oleanane skeleton for the first time, euphohumifusoids H and I (9 and 10) possess a rare α,β-unsaturated-γ-lactone chain originated from 25,26,27-trinordammaranes, and euphohumifusoid L (13) is a highly modified 3,4-seco-25,26,27-trinorcycloartane. Notably, in antibacterial bioassay, compound 1 displayed excellent antibacterial activities against Bacillus cereus, Staphylococcus aureus, and S.epidermidis with MIC of 12.5, 25, and 25 μg/mL, comparable to the positive controls. Upon exposure to 1 and 2 MIC of 1, B.cereus underwent drastic morphological changes, resulting in complete disruption of the cells. Meanwhile, compound 1 also exhibited remarkable antibiofilm activity against B.cereus at 1 MIC and 2 MIC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is the most aggressive form of glioma, characterized by high mortality and poor prognosis. Dysregulation of microRNAs (miRNAs) plays a critical role in the progression and metastasis of GBM. This study aimed to investigate the role and molecular mechanism of miR-124-3p in GBM. Levels of miR-124-3p, EPHA2, and ALKBH5 were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, migration, invasion, and stemness were assessed using the Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and sphere formation assays, respectively. Bioinformatics prediction, dual-luciferase reporter assays, and RNA pull-down experiments were employed to validate the target of miR-124-3p. RNA binding protein immunoprecipitation (RIP) and methylated RNA immunoprecipitation (Me-RIP) were utilized to evaluate the regulation of miR-124-3p maturation by ALKBH5. The results indicated that overexpression of miR-124-3p inhibited the proliferation, migration, invasion, and stemness of GBM cells. EPHA2 was identified as a direct downstream target of miR-124-3p, and its overexpression reversed the inhibitory effects of miR-124-3p on cellular functions. Furthermore, miR-124-3p targeted EPHA2 to inactivate the Wnt/β-catenin pathway. Additionally, ALKBH5 negatively regulated miR-124-3p by impeding its processing. In conclusion, knockdown of ALKBH5 promoted the processing of pri-miR-124-3p, increasing mature miR-124-3p levels, which inhibited the malignant behaviors of GBM cells by targeting EPHA2. These findings highlight the importance of the ALKBH5/miR-124-3p/EPHA2 axis in GBM., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Breast cancer is a malignancy caused by the abnormal proliferation of breast epithelial cells, predominantly affecting female patients, and it is commonly diagnosed using histopathological images. Currently, deep learning techniques have made significant breakthroughs in medical image processing, outperforming traditional detection methods in breast cancer pathology classification tasks. This paper first reviewed the advances in applying deep learning to breast pathology images, focusing on three key areas: multi-scale feature extraction, cellular feature analysis, and classification. Next, it summarized the advantages of multimodal data fusion methods for breast pathology images. Finally, the study discussed the challenges and future prospects of deep learning in breast cancer pathology image diagnosis, providing important guidance for advancing the use of deep learning in breast diagnosis.

Transcranial direct current stimulation (tDCS) is an important method for treating mental illnesses and neurodegenerative diseases. This paper reconstructed two ex vivo brain slice models based on rat brain slice staining images and magnetic resonance imaging (MRI) data respectively, and the current densities of hippocampus after cortical tDCS were obtained through finite element calculation. Subsequently, a neuron model was used to calculate the response of rat hippocampal pyramidal neuron under these current densities, and the neuronal responses of the two models under different stimulation parameters were compared. The results show that a minimum stimulation voltage of 17 V can excite hippocampal pyramidal neuron in the model based on brain slice staining images, while 24 V is required in the MRI-based model. The results indicate that the model based on brain slice staining images has advantages in precision and electric field propagation simulation, and its results are closer to real measurements, which can provide guidance for the selection of tDCS parameters and scientific basis for precise stimulation.

Hydrogels, known for their mechanical and chemical similarity to biological tissues, are widely used in biotechnologies, whereas semiconductors provide advanced electronic and optoelectronic functionalities such as signal amplification, sensing, and photomodulation. Combining semiconducting properties with hydrogel designs can enhance biointeractive functions and intimacy at biointerfaces, but this is challenging owing to the low hydrophilicity of polymer semiconductors. We developed a solvent affinity-induced assembly method that incorporates water-insoluble polymer semiconductors into double-network hydrogels. These semiconductors exhibited tissue-level moduli as soft as 81 kilopascals, stretchability of 150% strain, and charge-carrier mobility up to 1.4 square centimeters per volt per second. When they are interfaced with biological tissues, their tissue-level modulus enables alleviated immune reactions. The hydrogel's high porosity enhances molecular interactions at semiconductor-biofluid interfaces, resulting in photomodulation with higher response and volumetric biosensing with higher sensitivity.

Background: Elevated hepatic glucose production (HGP) is a prominent manifestation of impaired hepatic glucose metabolism in individuals with diabetes. Increased hepatic gluconeogenesis plays a pivotal role in the dysregulation of hepatic glucose metabolism and contributes significantly to fasting hyperglycemia in diabetes. Previous studies have identified zinc-finger BED domain-containing 3 (ZBED3) as a risk gene for type 2 diabetes (T2DM), and its single nucleotide polymorphism (SNPs) is closely associated with the fasting blood glucose level, suggesting a potential correlation between ZBED3 and the onset of diabetes. This study primarily explores the effect of ZBED3 on hepatic gluconeogenesis and analyzes the relevant signaling pathways that regulate hepatic gluconeogenesis., Methods: The expression level of ZBED3 was assessed in the liver of insulin-resistant (IR)-related disease. RNA-seq and bioinformatics analyses were employed to examine the ZBED3-related pathway that modulated HGP. To investigate the role of ZBED3 in hepatic gluconeogenesis, the expression of ZBED3 was manipulated by upregulation or silencing using adeno-associated virus (AAV) in mouse primary hepatocytes (MPHs) and HHL-5 cells. In vivo, hepatocyte-specific ZBED3 knockout mice were generated. Moreover, AAV8 was employed to achieve hepatocyte-specific overexpression and knockdown of ZBED3 in C57BL/6 and db/db mice. Immunoprecipitation and mass spectrometry (IP-MS) analyses were employed to identify proteins that interacted with ZBED3. Co-immunoprecipitation (co-IP), glutathione S-transferase (GST) - pulldown, and dual-luciferase reporter assays were conducted to further elucidate the underlying mechanism of ZBED3 in regulating hepatic gluconeogenesis., Results: The expression of ZBED3 in the liver of IR-related disease models was found to be increased. Under the stimulation of glucagon, ZBED3 promoted the expression of hepatic gluconeogenesis-related genes PGC1A, PCK1, G6PC, thereby increasing HGP. Consistently, the rate of hepatic gluconeogenesis was found to be elevated in mice with hepatocyte-specific overexpression of ZBED3 and decreased in those with ZBED3 knockout. Additionally, the knockdown of ZBED3 in the liver of db/db mice resulted in a reduction in hepatic gluconeogenesis. Moreover, the study revealed that ZBED3 facilitated the nuclear translocation of protein arginine methyltransferases 5 (PRMT5) to influence the regulation of PRMT5-mediated symmetrical dimethylation of arginine (s-DMA) of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), which in turn affects the phosphorylation of CREB and ultimately promotes HGP., Conclusions: This study indicates that ZBED3 promotes hepatic gluconeogenesis and serves as a critical regulator of the progression of diabetes., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Intramolecular noncovalent interaction (INCI), a crucial strategy for effectively enhancing molecular planarity and extending π-electron delocalization in organic semiconductors (OSCs), has played an increasingly important role in optoelectronic applications. However, though the INCI formation is regularly considered to improve the device performance by literature, there is no feasible approach to directly and reliably characterizing its formation in practical-OSC films thus far. Here in this study, by theoretical analysis and calculation, the generation of INCIs in OSCs is found, normally consisting of relatively heavy elements, such as O···Se, O···S, N···S interactions, etc., can induce enhanced strength of spin-orbit coupling, the primary factor dominating spin lifetime in OSCs. Based on this newly discovered theory, spin lifetime is creatively employed as a probe for sensitively detecting INCIs in OSC films via spin valves or field-induced electron paramagnetic resonance, respectively. This study will highly promote academic and applicable developments of the cross-cutting frontier research field between organic spintronics and electronics., (© 2024 Wiley‐VCH GmbH.)

Background: Dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI) can reflect the angiogenesis of ischemic stroke., Purpose: To investigate the value of DSC-MRI with ultrasmall superparamagnetic particles of iron oxides (USPIO) in evaluating angiogenesis in the peri-infarction zones in subacute ischemic stroke in a permanent middle cerebral artery occlusion (pMCAO) rat model., Material and Methods: A total of 21 Sprague-Dawley rats were randomly divided into the pMCAO and sham operation groups. Every rat in each group underwent DSC-MRI with USPIO at 3, 5, and 7 days. DSC-MRI parameters of the relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), relative mean transit time (rMTT), and relative time to peak (rTTP) were measured, calculated, and compared among the different times. Sequential correlations were analyzed among the histopathological indexes with the microvascular density (MVD) and percentage of vascular area (%VA), the serum factors with vascular endothelial growth factor (VEGF), vascular cell adhesion molecule 1 (VCAM-1), and perfusion parameters, respectively., Results: The rCBV and rCBF in the peri-infarction area of pMCAO rats were significantly higher on day 7 than on day 3, whereas no significant changes in rMTT and rTTP were observed at 3, 5, and 7 days. Significantly positive correlations were found between rCBV and MVD, %VA, VEGF, VCAM-1, between rCBF and MVD, %VA, VEGF, and VCAM-1 at 3, 5, and 7 days in the pMCAO group., Conclusion: The rCBV and rCBF deriving from USPIO-DSC may be potentially useful for evaluating the angiogenesis of the peri-infarction zones in the subacute phase of ischemic stroke., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Gemcitabine is widely used in the treatment of various cancers. This study aims to evaluate gemcitabine-associated adverse events (AEs) using the Food and Drug Administration Adverse Event Reporting System (FAERS) database., Research Design and Methods: We analyzed data spanning from January 2004 to June 2023. Employing reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN) algorithms, we identified AEs with positive signals in patients administered gemcitabine., Results: Out of 16,623,939 reports, 23,645 involved gemcitabine as the 'primary suspected (PS)' resulting in 74,306 AEs. Consistent with the reports in the specification and clinical trials, thrombocytopenia, pyrexia, neutropenia, and anemia were the most common AEs. Notably, our study identified some unexpected AEs such as abdominal pain, pleural effusion, ascites, and gastrointestinal hemorrhage, among others. The most significant SOC was 'Blood and lymphatic system disorders'. The median onset time for gemcitabine-related AEs was 24 days (interquartile range [IQR] 6-82 days), with most cases occurring within the initial 30 days following gemcitabine administration., Conclusion: Gemcitabine is associated with a broad spectrum of AEs affecting multiple organ systems, with a notable incidence of hospitalization. The study highlights both expected and unexpected AEs, which could enhance future clinical applications and safety of gemcitabine.

E1A binding protein (p300) is a promising therapeutic target for the treatment of cancer. Herein, we report the discovery of a series of novel inhibitors with an ( S )-3-fluoropyrrolidin-2-one scaffold targeting p300 bromodomain. The best compound 29 (CZL-046) shows potent inhibitory activity of p300 bromodomain (IC 50 = 3.3 nM) and antiproliferative activity in the multiple myeloma (MM) cell line (OPM-2 IC 50 = 51.5 nM). 29 suppressed the mRNA levels of c-Myc and IRF4 and downregulated the expression of c-Myc and H3K27Ac. Compared to the lead compound 5 , 29 exhibits significantly improved in vitro and in vivo metabolic properties. Oral administration of 29 with 30 mg/kg achieved a TGI value of 44% in the OPM-2 xenograft model, accompanied by good tolerability. The cocrystal structure of CREB binding protein bromodomain with 29 provides an insight into the precise binding mode. The results demonstrate that 29 is a promising p300 bromodomain inhibitor for the treatment of MM.

The quality of the electrocardiography (ECG) signals depends on the effectiveness of the electrode-skin connection. However, current electrocardiogram electrodes (ECGE) often face challenges such as high contact impedance and unstable conductive networks, which hinder accurate measurement during movement and long-term wearability. Herein, in this work, a bionic 3D pile textile as an ECGE with high electrical conductivity and flexibility is prepared by a facile, continuous, and high-efficiency electrostatic self-assembly process. Integrating pile textiles with conductive materials creates a full textile electrode for bioelectrical signal detection that can retain both the inherent characteristics of textiles and high conductivity. Moreover, the dense piles on the textile surface make full contact with the skin, mitigating motion artifacts caused by the sliding between the textile and the skin. The continuous conductive network formed by the interconnected piles allows the pile textile ECGE (PT-ECGE) to function effectively under both static and dynamic conditions. Leveraging the unique pile structure, the PT-ECGE achieves superior flexibility, improved conductivity, low contact impedance, and high adaptivity, washability, and durability. The textile electrode, as a promising candidate for wearable devices, offers enormous application possibilities for the unconscious and comfortable detection of physiological signals.

Background: The causal relationship between familial hypercholesterolemia (FH) and various vitamin deficiencies has not yet been elucidated. Therefore, this study investigated the cause-and-effect relationship between FH and the risk of multiple vitamin deficiencies in humans., Methods: Mendelian randomization (MR) analysis was performed by extracting six datasets for FH, FH with ischemic heart disease (IHD), and vitamin deficiency (vitamin A, thiamine, other B-group vitamins, and vitamin D) from the FinnGen study, covering a total of 329,115; 316,290; 354,932; 354,949; 355,411 and 355,238 individuals, respectively., Results: FH was suggestively associated with higher odds of thiamine deficiency [inverse variance weighted odds ratio (OR IVW ) 95% confidence interval (CI): 1.62 (1.03, 2.55), P = 0.036] and vitamin D deficiencies [OR IVW CI: 1.35 (1.04, 1.75), P = 0.024], low-density lipoprotein receptor ( LDLR ) rs112898275 variant, rs11591147 and rs499883 in proprotein convertase subtilisin/kexin 9 ( PCSK9 ), rs9644862 in cyclin-dependent kinase inhibitor 2 B antisense RNA1 ( CDKN2B-AS1 ), and rs142834163 in dedicator of cytokinesis 6 ( DOCK6 ) and rs115478735 in ABO blood group ( ABO ) strongly influenced the risk of thiamine deficiency, while the rs7412 variant in apolipoprotein E ( APOE ) mostly influenced the risk of vitamin D deficiency. FH with IHD was suggestively associated with higher odds of vitamin D deficiency (OR IVW, weighted median [WM][95%CI]: 1.31 [1.05, 1.64]; 1.47 [1.10, 1.97]) ( P = 0.018; 0.010) without any single significant SNPs observed., Conclusion: FH was positively associated with increased risks of thiamine and vitamin D deficiencies, revealing a prospective and unfortunate complication of FH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Wei, Zhou and Liu.)

Background: Perianal fistulizing Crohn's disease (pfCD) poses significant healing challenges, closely associated with neutrophil extracellular traps (NETs). This study aimed to investigate the microbe-host interactions influencing NETs in pfCD., Methods: From January 2019 to July 2022, patients with pfCD were screened at Ren Ji Hospital. Patients in remission following comprehensive treatment were recruited. We documented clinical characteristics, medication regimens, healing outcomes, and infliximab levels in fistula tissues. NET positivity was confirmed by positive results in citrullinated histone H3 (CitH3) enzyme-linked immunosorbent assay (ELISA) and dual immunofluorescence staining for myeloperoxidase and CitH3. Microbial and transcriptomic profiles from fistula tissues, obtained during surgery, were analyzed using 16S rRNA gene sequencing and RNA sequencing. Differences in microbiome and transcriptomic profiles were evaluated, and their relationships were assessed using Mantel's and Spearman's coefficients., Results: Significant differences in microbial communities were found between groups (P = .007). Representatively differential microbes such as Prevotella bivia, Streptococcus gordonii, and Bacteroides dorei were enriched in NETs-positive fistulas (P < .05). Functional analysis of microbes revealed reduced ubiquinol biosynthesis and butanoate production in NETs-negative fistulas (P < .05). Transcriptomic analysis indicated increased neutrophil and monocyte infiltration in NETs-positive fistulas, associated with pathways involving bacterial response, neutrophil chemotaxis, secretory processes, and peptidase activity (P < .05). Species prevalent in NETs-positive fistulas correlated positively with immune responses and wound healing pathways, whereas bacteria in NETs-negative fistulas correlated negatively. NETs were negatively associated with tissue infliximab levels (P = .001) and healing outcomes (P = .025)., Conclusions: Our findings reveal unique microbial and transcriptomic signatures associated with NETs in pfCD, highlighting their profound influence on clinical outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Among patients with aortic stenosis, ventricular remodeling by hypertrophy can limit the augmentation of flow with exertion, even after valve intervention. However, the effect of hypertrophy on quality of life (QoL) improvement has not been studied. We aimed to determine the effect of ventricular hypertrophy on QoL outcomes after transcatheter aortic valve replacement (TAVR)., Methods: All patients undergoing TAVR from 2011 to 2021 at our institution were included. Groups were divided into none/mild ventricular hypertrophy (non-remodeled, NR) and moderate/severe left ventricular hypertrophy (VH) according to guideline-recommended cut-offs for left ventricular (LV) wall thickness. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was utilized to assess QoL; primary outcome was KCCQ change <5 from baseline to 30 days and 1 year., Results: We analyzed 679 patients (NR: N = 389, VH: N = 290). Groups differed by septal thickness (1.12 cm vs. 1.44 cm, p < 0.001), posterior wall thickness (1.08 cm vs. 1.33 cm, p < 0.001), and LV internal diastolic diameter (4.34 cm vs. 4.19 cm, p = 0.006). The primary outcome was similar between NR and VH at 30 days (31.6 % vs. 28.6 %, p = 0.449) and 1 year (27.7 % vs. 21.5 %, p = 0.217). NR and VH experienced similar proportions of worsening, no change, or small, moderate, and large improvements in KCCQ score. Both groups experienced similar domain score changes and New York Heart Association class improvement. A subgroup analysis of VH patients did not reveal interaction with cavity size or stroke volume., Conclusion: Patients with significant ventricular remodeling by hypertrophy and aortic stenosis have similar QoL changes after intervention compared to patients without significant remodeling., Competing Interests: Declaration of competing interest Toby Rogers – Consultant: Edwards Lifesciences, Medtronic, Boston Scientific; Advisory board: Medtronic, Boston Scientific; Equity: Transmural Systems; Intellectual property: co-inventor on patents, assigned to NIH. William S. Weintraub – Research Support: Amarin Corporation, Lexicon Pharmaceuticals, National Institutes of Health; Consultant: Amarin Corporation, AstraZeneca, Janssen, Lexicon Pharmaceuticals, SC Pharma, The Medicines Company. Ron Waksman – Advisory Board: Abbott Vascular, Boston Scientific, Medtronic, Philips IGT, Pi-Cardia Ltd.; Consultant: Abbott Vascular, Append Medical, Biotronik, Boston Scientific, J Valve, MedAlliance/Cordis, Medtronic, Philips IGT, Pi-Cardia Ltd., Swiss Interventional/SIS Medical AG, Transmural Systems Inc.; Institutional Grant Support: Biotronik, Medtronic, Philips IGT; Investor: Transmural Systems Inc. All other authors – None., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Social engagement is closely related to well-being among older adults. However, studies on the changing trajectory and influencing factors (especially time-varying factors) of social engagement are limited. This study aimed to examine the social engagement trajectory of older Chinese adults and explore its time-fixed and time-varying factors, thus providing evidence for the development of strategies to promote a rational implementation for healthy aging., Methods: This study included 2,195 participants from a subset of four surveys from the Chinese Longitudinal Healthy Longevity Survey conducted from 2008 to 2018 (with the latest survey completed in 2018), with follow-ups conducted approximately every three years. Growth mixture modeling was used to explore the social engagement trajectory of older adults and the effects of time-varying variables. In addition, multinomial logistic regression was employed to analyze the association between time-fixed variables and latent classes., Results: Three distinct trajectories of social engagement among older adults in China were identified: slow declining (n = 204; 9.3%), which meant social engagement score decreased continuously, but social engagement level improved; slow rising (n = 1,039; 47.3%), marked by an increased score of social engagement, but with an depressed engagement level; and middle stabilizing (n = 952; 43.4%), which meant social engagement score and engagement level remained quite stable. A time-fixed analysis indicated that age, marital status, educational level, and annual family income had a significant impact on social engagement (P < 0.05). In contrast, the time-varying analysis showed that a decline in functional ability, insufficient exercise (means no exercise at present), deteriorating self-reported health and quality of life, negative mood, monotonous diet, and reduced community services were closely related to the reduction in social engagement levels (P < 0.05)., Conclusion: Three trends were observed at the social engagement level. Older adults with initially high levels of social engagement exhibited a continuous upward trend, whereas those with initially low levels experienced a decline in their social engagement, and those with initially intermediate levels remained quite stable. Considering the primary heterogeneous factors, it is imperative for governments to enhance basic services and prioritize the well-being of older adults. Additionally, families should diligently monitor the emotional well-being of older adults and make appropriate arrangements for meals., (© 2024. The Author(s).)

The intricate interplay between the gut microbiome and colorectal cancer (CRC) presents novel avenues for early diagnosis and prognosis, crucial for improving patient outcomes. This comprehensive review synthesizes current findings on the gut microbiome's contribution to CRC pathogenesis, highlighting its potential as a biomarker for non-invasive CRC screening strategies. We explore the mechanisms through which the microbiome influences CRC, including its roles in inflammation, metabolism, and immune response modulation. Furthermore, we assess the viability of microbial signatures as predictive tools for CRC prognosis, offering insights into personalized treatment approaches. Our analysis underscores the necessity for advanced metagenomic studies to elucidate the complex microbiome-CRC nexus, aiming to refine diagnostic accuracy and prognostic assessment in clinical settings. This review propels forward the understanding of the microbiome's diagnostic and prognostic capabilities, paving the way for microbiome-based interventions in CRC management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Ren, Zhong, Li, Huang, Zhang, Yuan, Feng, Chen, Wang and Feng.)

Background: The genetic links between heart disease and psychiatric disorders are complex and not well understood. This study uses genome-wide association studies (GWAS) and advanced multilevel analyses to explore these connections., Methods: We analyzed GWAS data from seven psychiatric disorders and five types of heart disease. Genetic correlations and overlaps were examined using linkage disequilibrium score regression (LDSC), high-definition likelihood (HDL), and Genetic analysis incorporating Pleiotropy and Annotation (GPA). Pleiotropic single-nucleotide variations (SNVs) were identified with pleiotropic analysis under the composite null hypothesis (PLACO) and annotated via Functional mapping and annotation of genetic associations (FUMA). Potential pleiotropic genes were identified using Multi-marker Analysis of GenoMic Annotation (MAGMA) and Summary data-based Mendelian Randomization (SMR)., Results: Among 35 trait pairs, 32 showed significant genetic correlations or overlaps. PLACO identified 15,077 SNVs, with 287 recognized as pleiotropic loci and 20 colocalization sites. MAGMA and SMR revealed 75 potential pleiotropic genes involved in diverse pathways, including cancer, neurodevelopment, and cellular organization. Mouse Genome Informatics (MGI) queries provided evidence linking multiple genes to heart or psychiatric disorders., Conclusions: This analysis reveals loci and genes with pleiotropic effects between heart disease and psychiatric disorders, highlighting shared biological pathways. These findings illuminate the genetic mechanisms underlying the brain-heart axis and suggest shared biological foundations for these conditions, offering potential targets for future prevention and treatment strategies., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Due to the seamless interfaces between solid polymer electrolytes (SPEs) and electrode materials, SPEs-based all-solid-state sodium-ion batteries (ASSSIBs) are considered promising energy storage systems. However, the sluggish Na + transport and uncontrollable Na dendrite propagation still hinder the practical application of SPEs-based ASSSIBs. Herein, Ca-doped CeO 2 (Ca-CeO 2 ) nanotube framework is synthesized and integrated with poly (ethylene oxide) methyl ether acrylate-perfluoropolyether copolymer (PEOA-PFPE), resulting in multifunctional solid nanocomposite electrolytes (namely SNEs, i.e., PEOA-PFPE/Ca-CeO 2 ). Our investigations demonstrate that the fluorous effect incurred by the fluorine-containing PEOA-PFPE and the oxygen vacancy effect induced by the Ca-CeO 2 framework could synergistically promote the dissociation of sodium salt, ultimately enhancing the Na + mobility in SNEs. Besides, the resultant SNEs construct rapid Na + transport channels and homogenize the Na deposition in SNEs/Na interface, which effectively prevents the Na dendrite growth. Furthermore, the assembled carbon-coated sodium vanadium phosphate (NVP@C)||PEOA-PFPE/Ca-CeO 2 ||Na coin cell delivers impressive rate capability of 97.9 mAh g -1 at 2 C and outstanding cycling stability with capacity retention of 84.3 % after 300 cycles at 1 C. This work illustrates that constructing multifunctional SNEs via incorporating functional inorganic frameworks into fluorine-containing SPEs could be a promising strategy for the commercialization of robust and high-performance ASSSIBs., (© 2024 Wiley-VCH GmbH.)

This research aimed to investigate the effects of dietary fructooligosaccharides (FOS) on attenuating the Aeromonas hydrophila (A. hydrophila)-induced oxidative stress and apoptosis in blunt snout bream Megalobrama amblycephala. Fish were divided into three groups as follows: C1 (Control), T1 (A. hydrophila), and T2 (A. hydrophila + 4 g/kg FOS). The results showed that the activities of antioxidant enzymes increased, the liver morphology had disorderly arrangement, and extensive cell necrosis occurred because of A. hydrophila-infection. While the dietary FOS improved the above-mentioned liver damage. Additionaly, FOS elevated mRNA levels of pro-apoptotic molecules, including caspase-8 and 9, and down-regulated mRNA levels of the anti-apoptotic molecule Bcl-2, which is triggered by A. hydrophila-infection. The transcriptome analysis showed that the oxidative stress-related DEGs pathways were activated in intestine of blunt snout bream by A. hydrophila-infection. The FOS-added group led to the enrichment of more pathways to health. Further WGCNA co-expression network analysis showed that the screened single genes were clustered into 49 modules. The two modules with the highest association to the five traits (10 hub genes) were chosen to build the network by combining the physiological and biochemical characteristic. In summary, this research offers a foundation for the exploring of A. hydrophila-restoration genes in dietary FOS, and also lays a theoretical foundation for aquaculture in the future., (© 2024. The Author(s).)

The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicin-induced cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy. Cardiomyocyte-specific ADAM17-knockout (A17 α-MHCKO ) and ADAM17-overexpressing (AAV9-oeA17) mice were generated. In addition, RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes (NRCMs) receiving different treatment were performed. Mouse tumor models were constructed in A17 fl/fl and A17 α-MHCKO mice. In addition, cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated. ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs. A17 α-MHCKO mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17 fl/fl mice, and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin. In contrast, AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment. Mechanistically, doxorubicin enhanced the expression of transcription factor C/EBPβ, leading to increased expression and activity of ADAM17 in cardiomyocyte, which enhanced TNF-α shedding and upregulated the expression of TRAF3. Increased TRAF3 promoted TAK1 autophosphorylation, resulting in activated MAPKs pathway and cardiomyocyte apoptosis. ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling. Thus, targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity., (© 2024. The Author(s).)

Objective: To investigate the perioperative changes in serum interleukin 6 (IL-6) levels in elderly male patients with intertrochanteric fractures, and provide evidence for inflammatory control in this patient population., Methods: The clinical data of 40 male patients aged more than 60 years with intertrochanteric fractures who met the selection criteria between January 2021 and December 2022 were retrospectively analyzed, including 25 non-osteoporosis patients (T value>-2.5, group A) and 15 osteoporosis patients (T value≤-2.5, group B). In addition, 40 healthy men aged more than 60 years old were included as controls (group C) according to the age matching rule. There was no significant difference in age, smoking history, drinking history, body mass index, complications (hypertension and diabetes), alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, and total protein among the 3 groups ( P >0.05). Serum samples were collected from group C subjects and from groups A and B patients preoperatively and on postoperative days 1, 3, 5, and 7. IL-6 levels were measured using ELISA assay. Pearson correlation analysis was used to assess the relationship between IL-6 levels and T values at various time points in groups A and B. Postoperative complications during hospitalization and 1-year mortality rates were recorded for groups A and B., Results: Preoperative IL-6 levels were significantly higher in groups A and B than in group C ( P <0.05), with group B being significantly higher than group A ( P <0.05). In groups A and B, IL-6 levels increased significantly on postoperative day 1 compared to preoperative levels and then gradually decreased, approaching preoperative levels by postoperative day 7. IL-6 levels in group B were significantly higher than those in group A at all postoperative time points ( P <0.05). Correlation analysis showed that IL-6 levels were negatively correlated with T values at all perioperative time points in all patients from groups A and B ( P <0.05). Complications occurred in 4 patients (16.0%) in group A, including 2 cases of pulmonary infection, 1 case of urinary tract infection, and 1 case of heart failure, and in 3 patients (20.0%) in group B, including 2 cases of pulmonary infection and 1 case of gastrointestinal bleeding. There was no significant difference in the incidence of complications between the two groups ( χ 2 =0.104, P =0.747). There were 2 cases (8.0%) and 4 cases (26.7%) died within 1 year after operation in groups A and B, respectively, and there was no significant difference in 1-year mortality rates between the two groups ( χ 2 =2.562, P =0.109)., Conclusion: Serum IL-6 levels significantly increase in the early postoperative period in elderly male patients with intertrochanteric fractures, especially in those with osteoporosis. Monitoring the inflammatory state and promptly controlling the inflammatory response during the perioperative period, may reduce complications and improve postoperative survival in this patient population.

Ovarian cancer is a common malignant tumor in the female reproductive system, and Granulosa cell tumor (GCT) of the ovary is a rare type of ovarian cancer, which significantly threatens women's reproductive health. It has been reported that dysregulation of thyroid hormones (THs) may be closely related to the progression and prognosis of ovarian cancer. Moreover, THs regulate phosphorylation of signal transducer and activator of transcription (STAT3) and Octamer-binding transcription factor 4 (OCT4) expression. It has been reported that STAT3 and OCT4 play important roles in cellular development and tumorigenesis. However, the mechanisms by which THs affect the development of GCT are still remained unclear. To evaluate the effect of THs on human ovarian granulosa tumor cells (KGN), cells were treated with 3,5,3' -triiodothyronine (T 3 ). Oct4 small interfering (Oct4 siRNA) or STAT3 inhibitor C188-9 was also co-cultured with cells in some experiments, respectively. The cell viability, proliferation, and proteins content were detected by CCK-8, EdU, and Western Blotting, respectively. The results showed that T 3 enhanced cell viability and proliferation. Moreover, T 3 also increased the expression of thyroid hormone receptor (TR), p-STAT3, and OCT4 proteins. The effects of T 3 on both p-STAT3 and OCT4 expression were blocked by TR antagonist 1-850. Meanwhile, C188-9, an inhibitor of STAT3, decreased T 3 -induced cellular viability, proliferation, and OCT4 expression, highlighting that p-STAT3 can regulate the expression of OCT4 and affect cellular viability, and proliferation. Furthermore, T 3 -induced cellular growth was reduced by Oct4 siRNA, which indicates that T 3 regulates cellular development through OCT4. These findings suggest that T 3 increases cellular development via OCT4, which is mediated by phosphorylation of STAT3, and TR is also involved in these processes., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Magnetic particle imaging (MPI) has emerged as a novel technology utilizing superparamagnetic nanoparticles as tracers, essential for disease diagnosis and treatment guidance in preclinical animal models. Unlike other modalities, MPI provides high sensitivity, deep tissue penetration, and no signal attenuation. However, existing MPI tracers suffer from "always-on" signals, which complicate organ-specific imaging and hinder accuracy. To overcome these challenges, we have developed a responsive MPI tracer using pH-responsive PdFe alloy particles coated with a gatekeeper polymer. This tracer exhibits pH-sensitive Fe release and modulation of the MPI signal, enabling selective imaging with a higher signal-to-noise ratio and intratumoral pH quantification. Notably, this responsive tracer facilitates subtraction-enhanced MPI imaging, effectively eliminating interference from liver uptake and expanding the scope of abdominal imaging. Additionally, the tracer employs a dual-function mechanism for adaptive cancer therapy, combining pH-switchable enzyme-like catalysis with dual-key co-activation of ROS generation, and Pd skeleton that scavenges free radicals to minimize Fe-related toxicity. This advancement promises to significantly expand MPI's applicability in diagnostics and therapeutic monitoring, marking a leap forward in imaging technology., (© 2024 Wiley‐VCH GmbH.)

Imbalanced nicotinamide adenine dinucleotide (NAD + ) homeostasis has been reported in multiple autoimmune diseases and supplementation with NAD + precursors has consistently demonstrated positive therapeutic benefits for these conditions. Immune thrombocytopenia (ITP) is an acquired autoimmune disease, in which the decreased number and impaired function of regulatory T cells (Tregs) contribute to the main pathogenesis. Here we found NAD + level was decreased in the plasma and CD4 + T cells of ITP patients. Supplementation with NAD + precursor nicotinamide (NAM), but not nicotinamide mononucleotide (NMN), increased Treg frequency and ameliorated thrombocytopenia in an ITP murine model. Moreover, whilst both NAM and NMN restored cytosolic NAD + level in the CD4 + T cells from ITP patients, only NAM promoted Treg differentiation. Mechanistically, Sirtuin1 (Sirt1), a major consumer of NAD + , was highly expressed in the CD4 + T cells of ITP patients, potentially contributing to the low level of NAD + . NAM, which could act as Sirt1 inhibitor, promoted Foxp3 acetylation and stability in induced Tregs derived from naïve CD4 + T cells of ITP patients. These findings suggest that NAM holds promise as a novel therapeutic strategy for restoring immune balance in ITP., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)