Search

Abstract Eltrombopag has been previously shown to be effective in reversing azacitidine‐mediated thrombocytopenia. This was further investigated in the SUPPORT trial, a phase III study assessing the efficacy/safety of eltrombopag plus azacitidine in patients with intermediate‐ to high‐risk myelodysplastic syndromes and thrombocytopenia. The results did not support a clinical benefit for the addition of eltrombopag to azacitidine. We investigated if the somatic mutational profiles in the patient cohort were associated with treatment outcomes. Based on the available data, we observed no imbalance in the mutational profiles between treatment arms or a clear association between identified somatic mutations and clinical outcomes.

Summary: Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months’ follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4–15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0–not evaluable) and 1.8 months (95% CI 1.8–2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Funding: Bayer/Bristol Myers Squibb.

Abstract Background TGF-β1 is the most abundant cytokine in bone, in which it serves as a vital factor to interdict adipogenesis and osteogenesis of bone marrow-derived mesenchymal stem cells (BM-MSCs). However, how TGF-β1 concurrently manipulates differentiation into these two distinct lineages remains elusive. Methods Treatments with ligands or inhibitors followed by biochemical characterization, reporter assay, quantitative PCR and induced differentiation were applied to MSC line or primary BM-MSCs for signaling dissection. In vivo adipogenesis and ex vivo culture of bone explants were used to verify the functions of different SMAD complexes. Ingenuity Pathway Analysis, and analysis of transcriptomic datasets from human BM-MSCs in combination with hierarchical clustering and STRING assay were used to decipher the interplaying co-repressors. Mouse models of chronic and acute bone loss followed by biochemical assays and micro-computed tomography demonstrated the bone effects when functionally blocking the critical co-repressor HDAC1. Results Distinct from the TGF-β1 inhibition on adipogenesis through canonical SMAD2/3 signaling, we clarified that TGF-β1 suppresses osteogenesis by inducing the formation of previously unidentified mixed SMADs mainly composed of SMAD1 and SMAD2, in which SMAD2 recruits more TGF-β1-induced co-repressors including HDAC1, TGIF1 and ATF3, whereas SMAD1 allows directing the whole transcriptional suppression complex to the cis-elements of osteogenic genes. Depletion of the cross-activation to the mixed SMADs dismantled specifically the TGF-β1 suppression on osteogenesis without affecting its inhibition on adipogenesis. Such phenomena can be reproduced via knockdown of co-repressors such as Hdac1 or addition of HDAC1 inhibitors in TGF-β1-treated MSCs. In either the chronic or the acute bone loss model, we demonstrated that the TGF-β signaling was augmented in the bone niche during osteolysis, whereas administration of HDAC1 inhibitors significantly improved bone quality. Conclusion This study identifies a new signal valve through which TGF-β1 can inhibit osteogenesis specifically. Functional interruption of this valve can tilt the seesaw balance of BM-MSC differentiation towards osteogenesis, highlighting the interplaying co-repressors, such as HDAC1, as promising therapeutic targets to combat diverse degenerative orthopedic diseases.

Abstract Forest cover in Guangdong Province, southern China, has doubled over the last four decades. A large proportion of these forests consists of young planted forests (PFs), which have significant potential as carbon sinks. Yet given the declining carbon accumulation rates as forests mature and limited land for further planting, how best to manage these forests to maximize their future carbon uptake remains poorly studied. Here we employed fine-resolution satellite data, forest growth models, and machine learning to identify key drivers of carbon accumulation. Terrain variables were identified as the most important drivers, followed by climate conditions and soil nutrients. We further assessed the carbon sink potential under five forest management scenarios, each involving different harvest and regeneration strategies. Our results indicate that under the optimal scenario with the highest carbon sink potential, harvesting PFs over a 20-year period and progressively replanting each year could yield a potential carbon stock of 0.53 ± 0.01 PgC by 2060, without expanding forest cover. This represents 2.5 times greater than the baseline scenario, where all PFs and are simply preserved. Our findings suggest that a progressive management approach with a well-planned rotation period could significantly enhance carbon sequestration in planted forests.

Myeloproliferative neoplasms (MPNs) are blood cancers caused by mutations that originate from hematopoietic stem cells. More than 50%–90% of MPN patients had a dominant negative valine (V) to phenylalanine (F) mutation at the Janus kinase 617 codon (JAK2V617F) within the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway; however, this mutation was also found in a high percentage of the general population, its penetrance varied, and its onset was shown to be polygenic. Consequently, it is still unknown what molecular mechanism underlies the MPN transformation produced by JAK2V617F. Patients with MPN have been shown to have dysregulation of noncoding RNAs, such as microRNA (miRNA) and PIWI-interacting RNA (piRNA), although there is not any concrete proof that JAK2V617F alone is responsible for the aberrant regulation of miRNA and piRNA. Human wild type versus V617F-mutated JAK2 are expressed in mouse Ba/F3 cells, and the expressed small and total RNAs were subjected to next generation sequencing analysis to determine the direct induction. Differentially expressed miRNAs, gene expression, and transcript and gene variations were found between exogenously expressed JAK2 and JAK2V617F in Ba/F3 cells. The differently expressed variations contained enriched transposable elements and piRNAs, indicating a rearranged epigenome. The results of the pathway analysis show that the transformation that self-validated the chosen sequencing target genes is impacted by the JAK-STAT pathway. The induction route is functionally conserved, according to exogenously produced miRNA and gene expression. These results may clarify how the JAK2V617F induces transformation.

Abstract Background/aims Research has indicated that treatment with rosuvastatin can improve liver pathology in metabolic-associated fatty liver disease (MAFLD) patients and that treatment with Bifidobacterium can improve MAFLD. Therefore, the effects of Bifidobacterium, rosuvastatin, and their combination on related indices in a rat model of diet-induced MAFLD need to be investigated. Methods Forty rats were divided into five groups: the normal diet group (N), high-fat diet (HFD) model group (M), HFD + probiotic group (P), HFD + statin group (S), and HFD + probiotic + statin group (P-S). To establish the MAFLD model, the rats in Groups M, P, S, and P-S were fed a HFD for 8 weeks. The treatments included saline in Group N and either Bifidobacterium, rosuvastatin, or their combination in Groups P, S, and P-S by intragastrical gavage. After 4 weeks of intervention, the rats were euthanized, and samples were harvested to analyze gastrointestinal motility and liver function, pathological changes, inflammatory cytokine production, and the expression of proteins in key signaling pathways. Results HFD feeding significantly increased the body weight, liver index, and insulin resistance (IR) index of the rats, indicating that the MAFLD model was successfully induced. Bifidobacterium reduced the liver of MAFLD rats, while Bifidobacterium with Rosuvastatin decreased the liver index, IR index, and levels of aspartate aminotransferase and alanine aminotransferase in MAFLD rats. The MAFLD model showed altered expression of proteins in signaling pathways that regulate inflammation, increased production of inflammatory cytokines, an elevated MAFLD activity score (MAS), and pathological changes in the liver. The MAFLD model also showed reduced relative counts of intestinal neurons and enteric glial cells (EGCs), altered secretion of gastrointestinal hormones, and slowed gastrointestinal emptying. Bifidobacterium, rosuvastatin, or their combination inhibited these various changes. HFD feeding changed the rats’ gut microbiota, and the tested treatments inhibited these changes. These results suggest that the gastrointestinal motility disorder and abnormal liver function in MAFLD rats may be related to a reduction in Escherichia-Shigella bacteria and an increase in Asticcacaulis bacteria in the gut microbiota and that the improvement in liver function induced by Bifidobacterium plus rosuvastatin may be related to increases in Sphingomonas and Odoribacter bacteria and a decrease in Turicibacter bacteria in the gut microbiota. Conclusions The combined use of Bifidobacterium and rosuvastatin could better regulate the gut microbiota of MAFLD model rats, promote gastrointestinal emptying, and improve liver pathology and function than single treatment with Bifidobacterium or rosuvastatin. This provides a better strategy for the treatment of MAFLD.

Abstract Background and purpose Esophageal and gastric varices hemorrhage (EGVH) is a life-threatening condition with the 6-week mortality rate of 15–25%. Up to 60% of patients with EGVH may experience rebleeding with a mortality rate of 33%. The existing scoring systems, such as RS scoring system (Rockall score, RS) and GBS scoring system (Glasgow-Blatchford score, GBS), have limitations in predicting the risk of rebleeding. Our study was to construct and validate a novel predictive model for the risk of rebleeding in patients with EGVH and to compare the predictive power of the predictive model with GBS and pRS. Methods Data of patients with EGVH was collected in the First Affiliated Hospital of Dalian Medical University from January 2016 to June 2020. Binary logistic and stepwise regression was performed to construct a predictive model. We compared the predictive power of the new predictive model to the GBS and pRS scoring systems. Results Clinical data from a total of 265 patients with EGVH was collected. Six factors including systolic blood pressure, transfusion requirement, CA199, platelet count, upper esophageal varices and severity of esophageal varices were included in our new predictive model. The AUCs of the specificity of the predictive model, GBS and pRS are 0.82, 0.60 and 0.56. Conclusion This study successfully constructed a predictive model for the risk of rebleeding in patients with EGVH. This predictive model demonstrated higher predictive ability than pRS and GBS scoring systems for assessing rebleeding risk in EGVH patients.

Introduction: Light-harvesting chlorophyll a/b-binding (LHCB) protein complexes of photosystem II are integral to the formation of thylakoid structure and the photosynthetic process. They play an important role in photoprotection, a crucial process in leaf development under low-temperature stress. Nonetheless, potential key genes directly related to low-temperature response and albino phenotype have not been precisely identified in tea plant. Moreover, there are no studies simultaneously investigating multiple albino tea cultivars with different temperature sensitivity. Objectives: The study aimed to clarify the basic characteristics of CsLHCB gene family members, and identify critical CsLHCB genes potentially influential in leaf color phenotypic variation and low-temperature stress response by contrasting green and albino tea cultivars. Concurrently, exploring the differential expression of the CsLHCB gene family across diverse temperature-sensitive albino tea cultivars. Methods: We identified 20 putative CsLHCB genes according to phylogenetic analysis. Evolutionary relationships, gene duplication, chromosomal localization, and structures were analyzed by TBtools; the physiological and biochemical characteristics were analyzed by protein analysis websites; the differences in coding sequences and protein accumulation in green and albino tea cultivars, gene expression with maturity were tested by molecular biology technology; and protein interaction was analyzed in the STRING database. Results: All genes were categorized into seven groups, mapping onto 7 chromosomes, including three tandem and one segmental duplications. They all own a conserved chlorophyll A/B binding protein domain. The expression of CsLHCB genes was tissue-specific, predominantly in leaves. CsLHCB5 may play a key role in the process of leaf maturation and senescence. In contrast to CsLHCB5, CsLHCB1.1, CsLHCB2, and CsLHCB3.2 were highly conserved in amino acid sequence between green and albino tea cultivars. In albino tea cultivars, unlike in green cultivars, the expression of CsLHCB1.1, CsLHCB1.2, and CsLHCB2 was down-regulated under low-temperature stress. The accumulation of CsLHCB1 and CsLHCB5 proteins was lower in albino tea cultivars. Greater accumulation of CsLHCB2 protein was detected in RX1 and RX2 compared to other albino cultivars. Conclusions: CsLHCB1.1, CsLHCB1.2, and CsLHCB2 played a role in the response to low-temperature stress. The amino acid sequence site mutation of CsLHCB5 would distinguish the green and albino tea cultivars. The less accumulation of CsLHCB1 and CsLHCB5 had a Chl influence on albino leaves. Albino cultivars more sensitive to temperature exhibited lower CsLHCB gene expression. CsLHCB2 may serve as an indicator of temperature sensitivity differences in albino tea cultivars. This study could provide a reference for further studies of the functions of the CsLHCB family and contribute to research on the mechanism of the albino in tea plant.

Abstract Background To investigate the clinical significance of high intensity signals in interspinous ligaments at the affected segment in degenerative lumbar spondylolisthesis (DLS), as well as to determine the most effective diagnostic modalities for evaluating segmental instability. Methods This study reviewed a consecutive series of patients with L4/5 DLS between July 2023 and December 2023. The enrolled patients were divided into two groups based on the presence or absence of high-intensity signals in interspinous ligaments: the higher group (Group H), and the non-higher group (Group NH). Translational and angular motion was determined using flexion and extension (FE) radiographs or a sitting lumbar lateral radiograph with a supine sagittal MR image (combined, S-MR). The five-repetition sit-to-stand test (5R-STS) was employed to evaluate patients’ objective functional impairment (OFI). Results Overall, 73 patients were enrolled in this study, and there were 22 (30.1%) patients in group H and 51(69.9%) patients in group NH, with an average age of 60.3 ± 8.1 years. The patients in Group H exhibited significantly longer 5R-STS times and serious OFI compared to those in Group NH. Compared to Group NH, Group H exhibited significantly higher SP in the sitting position (21.8% vs 16.7%; P 0.05). In Group H, “instability” was recognized in 77.3% of patients using S-MR versus 40.9% patients using FE (P

Abstract To evaluate the levels of YKL40, IL-6(interleukin-6), IL-8(interleukin-8), IL-10(interleukin-10), TNF-α (tumor necrosis factor-α) in OSAS (obstructive sleep apnea syndrome)children and explore the mechanism of YKL40 promoting inflammatory factors overexpression in tonsils. qPCR and ELISA were used to identify the expression of YKL40, IL-6, IL-8, IL-10, and TNF-α in the tonsils of OSAS children. Primary tonsil lymphocytes (PTLCs) were cultured and recombinant human YKL40(rhYKL40)was used to stimulate PTLCs in different concentrations and at different time points. The activation of NF-κB in PTLCs was screened by western blotting. Relative mRNA of YKL40, IL-6, IL-8, TNF-α was over expressed in OSAS-derived tonsil tissue and the levels of YKL40, IL-6, IL-8, and TNF-α was increased in OSAS-derived protein supernatant of tonsil tissue.The relative mRNA expression of IL-6, IL-8 and TNF-α increased under the treatment of YKL40 (100 ng/mmol for 24 h). The phosphorylation of p65 in NF-κB pathway was stimulated in the process. The levels of YKL40, IL-6, IL-8, and TNF-α increases in OSAS children, and YKL40 promotes the overexpression of IL-6, IL-8 and TNF-α in PTLCs via NF-κB pathway. The result implements that inflammation may play an important role in the pathogenesis of OSAS in children.

Abstract Background Recent magnetic resonance imaging (MRI) studies have established that brain iron accumulation might accelerate cognitive decline in Alzheimer’s disease (AD) patients. Both normal aging and AD are associated with cerebral atrophy in specific regions. However, no studies have investigated aging- and AD-selective iron deposition-related cognitive changes during normal aging. Here, we applied quantitative susceptibility mapping (QSM) to detect iron levels in cortical signature regions and assessed the relationships among iron, atrophy, and cognitive changes in older adults. Methods In this Taizhou Imaging Study, 770 older adults (mean age 62.0 ± 4.93 years, 57.5% women) underwent brain MRI to measure brain iron and atrophy, of whom 219 underwent neuropsychological tests nearly every 12 months for up to a mean follow-up of 2.68 years. Global cognition was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Domain-specific cognitive scores were obtained from MoCA subscore components. Regional analyses were performed for cortical regions and 2 signature regions where atrophy affected by aging and AD only: Aging (AG) -specific and AD signature meta-ROIs. The QSM and cortical morphometry means of the above ROIs were also computed. Results Significant associations were found between QSM levels and cognitive scores. In particular, after adjusting for cortical thickness of regions of interest (ROIs), participants in the upper tertile of the cortical and AG-specific signature QSM exhibited worse ZMMSE than did those in the lower tertile [ $$\:\beta\:$$ β = -0.104, p = 0.026; $$\:\beta\:$$ β = -0.118, p = 0.021, respectively]. Longitudinal analysis suggested that QSM values in all ROIs might predict decline in ZMoCA and key domains such as attention and visuospatial function (all p

Abstract Microbial carbon use efficiency (CUE) affects the fate and storage of carbon in terrestrial ecosystems, but its global importance remains uncertain. Accurately modeling and predicting CUE on a global scale is challenging due to inconsistencies in measurement techniques and the complex interactions of climatic, edaphic, and biological factors across scales. The link between microbial CUE and soil organic carbon relies on the stabilization of microbial necromass within soil aggregates or its association with minerals, necessitating an integration of microbial and stabilization processes in modeling approaches. In this perspective, we propose a comprehensive framework that integrates diverse data sources, ranging from genomic information to traditional soil carbon assessments, to refine carbon cycle models by incorporating variations in CUE, thereby enhancing our understanding of the microbial contribution to carbon cycling.

Abstract Methods Single-cell transcriptomics and high-throughput transcriptomics were used to screen factors significantly correlated with intervertebral disc degeneration (IDD). Expression changes of CFIm25 were determined via RT-qPCR and Western blot. NP cells were isolated from mouse intervertebral discs and induced to degrade with TNF-α and IL-1β. CFIm25 was knocked out using CRISPR-Cas9, and CFIm25 knockout and overexpressing nucleus pulposus (NP) cell lines were generated through lentiviral transfection. Proteoglycan expression, protein expression, inflammatory factor expression, cell viability, proliferation, migration, gene expression, and protein expression were analyzed using various assays (alcian blue staining, immunofluorescence, ELISA, CCK-8, EDU labeling, transwell migration, scratch assay, RT-qPCR, Western blot). The GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA was designed, and its effects on NP regeneration were assessed through in vitro and mouse model experiments. The progression of IDD in mice was evaluated using X-ray, H&E staining, and Safranin O-Fast Green staining. Immunohistochemistry was performed to determine protein expression in NP tissue. Proteomic analysis combined with in vitro and in vivo experiments was conducted to elucidate the mechanisms of hydrogel action. Results CFIm25 was upregulated in IDD NP tissue and significantly correlated with disease progression. Inhibition of CFIm25 improved NP cell degeneration, enhanced cell proliferation, and migration. The hydrogel effectively knocked down CFIm25 expression, improved NP cell degeneration, promoted cell proliferation and migration, and mitigated IDD progression in a mouse model. The hydrogel inhibited inflammatory factor expression (IL-6, iNOS, IL-1β, TNF-α) by targeting the p38/NF-κB signaling pathway, increased collagen COLII and proteoglycan Aggrecan expression, and suppressed NP degeneration-related factors (COX-2, MMP-3). Conclusion The study highlighted the crucial role of CFIm25 in IDD and introduced a promising therapeutic strategy using a porous spherical GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA. This innovative approach offers new possibilities for treating degenerated intervertebral discs. Graphical Abstract Molecular mechanism of GCA targeting CFIm25 in NP cells to promote regeneration of degenerated intervertebral disc NP

Abstract Background The syncytiotrophoblast (SCT) layer in the placenta serves as a crucial physical barrier separating maternal-fetal circulation, facilitating essential signal and substance exchange between the mother and fetus. Any abnormalities in its formation or function can result in various maternal syndromes, such as preeclampsia. The transition of proliferative villous cytotrophoblasts (VCT) from the mitotic cell cycle to the G0 phase is a prerequisite for VCT differentiation and their fusion into SCT. The imprinting gene P57Kip2, specifically expressed in intermediate VCT capable of fusion, plays a pivotal role in driving this key event. Moreover, aberrant expression of P57Kip2 has been linked to pathological placental conditions and adverse fetal outcomes. Methods Validation of STK40 interaction with P57Kip2 using rigid molecular simulation docking and co-immunoprecipitation. STK40 expression was modulated by lentivirus in BeWo cells, and the effect of STK40 on trophoblast fusion was assessed by real-time quantitative PCR, western blot, immunofluorescence, and cell viability and proliferation assays. Co-immunoprecipitation, transcriptome sequencing, and western blot were used to determine the potential mechanisms by which STK40 regulates P57Kip2. Results In this study, STK40 has been identified as a novel interacting protein with P57Kip2, and its expression is down-regulated during the fusion process of trophoblast cells. Overexpressing STK40 inhibited cell fusion in BeWo cells while stimulating mitotic cell cycle activity. Further experiments indicated that this effect is attributed to its specific binding to the CDK-binding and the Cyclin-binding domains of P57Kip2, mediating the E3 ubiquitin ligase COP1-mediated ubiquitination and degradation of P57Kip2. Moreover, abnormally high expression of STK40 might significantly contribute to the occurrence of preeclampsia. Conclusions This study offers new insights into the role of STK40 in regulating the protein-level homeostasis of P57Kip2 during placental development.

Abstract According to management by objectives (MBO) theory, the significance of management objectives must be considered as a reference point in a performance evaluation. Cross efficiency evaluation has always been considered to be one of the important performance evaluation methods. However, few studies to date have considered the impact of management objectives on cross efficiency. According to prospect theory, the choice of reference point will cause irrational psychology in decision makers. A management objective is a natural reference point, which will cause a ‘gain and loss’ psychology in enterprises and may create irrational psychology. Performance level is an important index by which to evaluate resource allocation, which in turn can be regarded as an important enterprise management objective. This paper proposes a cross efficiency evaluation method based on performance level. Cross efficiency evaluation models are constructed, based on the irrational psychology that occurs under organization objectives, personal objectives and composite objectives. This method not only considers the bounded rational behavior of enterprises, but is also more flexible. A numerical example is given to illustrate the application of the bounded rational cross efficiency evaluation method in data envelopment analysis (DEA) ranking.

Abstract Background Doxorubicin (DOX) is a first-line chemotherapeutic drug for various malignancies that causes cardiotoxicity. Plant-derived exosome-like nanovesicles (P-ELNs) are growing as novel therapeutic agents. Here, we investigated the protective effects in DOX cardiotoxicity of ELNs from Momordica charantia L. (MC-ELNs), a medicinal plant with antioxidant activity. Results We isolated MC-ELNs using ultracentrifugation and characterized them with canonical mammalian extracellular vesicles features. In vivo studies proved that MC-ELNs ameliorated DOX cardiotoxicity with enhanced cardiac function and myocardial structure. In vitro assays revealed that MC-ELNs promoted cell survival, diminished reactive oxygen species, and protected mitochondrial integrity in DOX-treated H9c2 cells. We found that DOX treatment decreased the protein level of p62 through ubiquitin-dependent degradation pathway in H9c2 and NRVM cells. However, MC-ELNs suppressed DOX-induced p62 ubiquitination degradation, and the recovered p62 bound with Keap1 promoting Nrf2 nuclear translocation and the expressions of downstream gene HO-1. Furthermore, both the knockdown of Nrf2 and the inhibition of p62-Keap1 interaction abrogated the cardioprotective effect of MC-ELNs. Conclusions Our findings demonstrated the therapeutic beneficials of MC-ELNs via increasing p62 protein stability, shedding light on preventive approaches for DOX cardiotoxicity.

This article explores the nexus of cultural appropriateness, arts-based care, and well-being in sensitive research on sexual violence, with a focus on New Zealand’s Asian community. Drawing on the author’s background as an Asian immigrant arts-based researcher, this study underscores the pivotal role of care, both culturally and through arts-based approaches, in facilitating understanding and expression. Emphasizing the importance of caring for both research participants and the researcher’s own well-being, the article advocates for culturally sensitive practices throughout the research process. It demonstrates how arts-based research methods enable creative expression and deeper cultural comprehension, enhancing care provision for participants. Moreover, the article highlights the need for culturally sensitive self-care strategies for researchers, acknowledging the emotional toll of engaging with sensitive topics. Ultimately, it calls for a more compassionate, culturally attuned, and ethically grounded approach to sensitive research within diverse cultural contexts.

Abstract BackgroundOpenAI released versions ChatGPT-3.5 and GPT-4 between 2022 and 2023. GPT-3.5 has demonstrated proficiency in various examinations, particularly the United States Medical Licensing Examination. However, GPT-4 has more advanced capabilities. ObjectiveThis study aims to examine the efficacy of GPT-3.5 and GPT-4 within the Taiwan National Pharmacist Licensing Examination and to ascertain their utility and potential application in clinical pharmacy and education. MethodsThe pharmacist examination in Taiwan consists of 2 stages: basic subjects and clinical subjects. In this study, exam questions were manually fed into the GPT-3.5 and GPT-4 models, and their responses were recorded; graphic-based questions were excluded. This study encompassed three steps: (1) determining the answering accuracy of GPT-3.5 and GPT-4, (2) categorizing question types and observing differences in model performance across these categories, and (3) comparing model performance on calculation and situational questions. Microsoft Excel and R software were used for statistical analyses. ResultsGPT-4 achieved an accuracy rate of 72.9%, overshadowing GPT-3.5, which achieved 59.1% (PP ConclusionsThis study demonstrates that GPT-4 outperforms GPT-3.5 in the Taiwan National Pharmacist Licensing Examination, particularly in basic subjects. While GPT-4 shows potential for use in clinical practice and pharmacy education, its limitations warrant caution. Future research should focus on refining prompts, improving model stability, integrating medical databases, and designing questions that better assess student competence and minimize guessing.

Abstract Prediction of surface freshwater flux (precipitation or evaporation) in a CO2‐enriched climate is highly uncertain, primarily depending on the hydrological responses to physiological and radiative forcings of CO2 increase. Using the 1pctCO2 (a 1% per year CO2 increase scenario) experiments of 12 CMIP6 models, we first decouple and quantify the magnitude of global hydrological sensitivity to CO2 physiological and radiative forcings. Results show that the direct global hydrological sensitivity (for land plus ocean precipitation) to CO2 increase only is −0.09 ± 0.07% (100 ppm) −1 and to CO2‐induced warming alone is 1.54 ± 0.24% K−1. The latter is about 10% larger than the global apparent hydrological sensitivity (i.e., including all effects, not only direct responses to warming, ηa = 1.39 ± 0.22% K−1). These hydrological sensitivities are relatively stable over transient 2× to 4 × CO2 scenario. The intensification of the global water cycle are dominated by the CO2 radiative effect (79 ± 12%) with a smaller positive contribution from the interaction between the two effects (6 ± 12%), but are reduced by the CO2 physiological effect (−10 ± 8%). This finding underlines the importance of CO2 vegetation physiology in global water cycle projections under a CO2‐enriched and warming climate.

Fibroblast growth factor 7 (FGF7) is involved in lipid metabolism, which is considered as a candidate gene with close relation with muscle development by eGWAs and RNA-Seq analyses. To date, limited research has been conducted on the relationship between FGF7 gene and growth traits. The main objective of this work was to further investigate the association between novel InDel within FGF7 gene and growth traits in goat. Herein, FGF7 mRNA expression levels were investigated in various Fuqing goat tissues. We found that FGF7 gene was expressed in six adult goat tissues with the highest mRNA levels in adipose tissue. This result suggested that FGF7 gene might play a critical role in fat deposition. We also detected potential polymorphisms in Fuqing, Nubian and Jianyang Daer breeds. A 22-bp InDel polymorphism in FGF7 gene was detected in 396 goats and the three genotypes were designated as II, ID, and DD. Correlation analysis revealed that InDel polymorphism was significantly associated with growth traits (P

Biochar, a carbon-rich material that has attracted considerable interest in interdisciplinary research, is produced through a process known as pyrolysis, which involves the thermal decomposition of organic material in the absence of oxygen. Bamboo biochar is a specific type of biochar, manufactured from bamboo straw through carbonisation at 800 °C and subsequent filtration through a 100-mesh sieve. There is currently a lack of research into the potential benefits of bamboo biochar in improving soil quality in tea gardens. The aim of this study was to investigate the effect of bamboo biochar on the physicochemical properties, enzymatic activity, and microbial community structure of tea garden soils. The results demonstrate that the integration of bamboo biochar into the soil significantly enhanced the soil pH, total nitrogen, available nitrogen, total phosphorus, available phosphorus, available potassium, and slowly available potassium by 15.3%, 52.0%, 91.5%, 91%, 48.4%, 94.2%, and 107.7%, respectively. In addition, soil acid phosphatase activity decreased significantly by 52.5%. In contrast, the activities of sucrase, catalase, and β-glucosidase increased substantially by 54.0%, 68.7%, and 68.4%, respectively, when organic fertilizer and bamboo biochar were applied concurrently. Additionally, the Shannon, Simpson, and Pielou diversity indices of the microbial communities were significantly enhanced. Following the incorporation of bamboo biochar in the soil samples, the relative abundance of Proteobacteria increased significantly, whereas that of Acidobacteria decreased. Various concentrations of bamboo biochar markedly influenced microbial markers in the soil. The results of this study suggest that the application of bamboo biochar to soil may modestly improve its physicochemical properties, enzyme activity, and microbial community structure. These findings provide a foundation for future investigations on soil ecological restoration.

BackgroundChronic comorbidities are often associated with higher risks of depression and mortality. This study aims to explore the relationships between the Charlson Comorbidity Index (CCI) and depression, and their combined effect on mortality.MethodsThis study made use of data gathered in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018, including a collective of 23,927 adult participants. According to CCI score distribution, CCI was categorized into three groups (T1 with CCI = 0; T2 with CCI = 1; T3 with CCI ≥ 2). In the CCI ≥ 2 group, patients may have two or more chronic diseases. Multivariable logistic regression models were employed to explore the relationship between CCI and depression. The study utilized the Cox proportional hazards model to investigate the association between CCI, the combination of CCI and depression, and all-cause mortality.ResultsOur analysis revealed that after adjusting for potential confounders, a positive association was found between CCI and depression (OR = 1.25, 95% CI: 1.21, 1.29). Moreover, a greater CCI was found to be closely linked to higher mortality in individuals with depression (HR = 1.14, 95% CI 1.11, 1.18). Stratifying CCI into tertiles, higher tertiles of CCI (T2, T3 vs T1) also showed positive associations with depression and all-cause mortality. For patients with CCI ≥2 (T3) combined with depression, the risk of mortality was significantly elevated compared to those with CCI = 0 (T1) and non-depressed participants (HR = 2.01, 95% CI: 1.60, 2.52).ConclusionThe study findings demonstrate a positive correlation between CCI and the risk of depression, along with an association with increased all-cause mortality among depression patients. Hence, it is important to prioritize the clinical care of patients with a high CCI (≥2) and depression in order to lower the chances of mortality.

Acute fish toxicity (AFT) tests are performed in aquatic risk assessments of chemical compounds globally. However, the specific endpoint of in vivo AFT is based on the lethal concentration 50 (LC50), which is a serious challenge in terms of animal welfare. To support the 3Rs principle of replacing, reducing, and refining use of animals, integrated testing strategies (ITS) have recently been developed for environmental risk assessment. ITS efficiently integrates multiple types of information, especially new approach methodologies (NAMs), and further supports regulatory decision-making. Currently, an effective ITS framework for evaluating aquatic toxicity is lacking. Therefore, we aimed to develop a promising ITS for AFT using in silico, in vitro, and in vivo data. We established the ITS via in silico (OECD QSAR Toolbox 4.6), fish cell line acute toxicity (FCT), and fish embryo acute toxicity (FET) tests and then validated the NAMs with AFT testing. The NAM data were derived from the European Chemicals Agency (ECHA) dossier, toxicology databases, peer-reviewed research articles, and this study. For the first step in the ITS process, we aimed to design a high-throughput screening tool to identify non-toxic and toxic chemicals. We found that results of in silico, FCT, and FET tests alone were strongly correlated with AFT. Among the models, the in silico model was most suitable for identifying toxicants due to its high sensitivity and minimal animal use. Next, considering regulatory purposes and flexibility, we determined the predictive LC50 of toxic chemicals by pursuing a preference-dependent strategy, sequential testing strategy, and sensitivity-dependent strategy. All the strategies demonstrated a predictive power equal to or greater than 73%. In addition, to meet user preferences, our ITS approach has high flexibility and supports animal welfare and environmental protection. We have therefore developed multiple powerful, flexible, and more humane ITS methods for acute fish toxicity assessment by integrating NAMs.

Carbon dioxide (CO2) capture has become a hot topic in recent years because of global warming issues. However, most research has focused primarily on gas capture, with limited methods available for achieving both CO2 capture and conversion within a single material. Here, we synthesized FMU-101, a metal-organic framework (MOF) with metal-open sites, through the self-assembly of [1,1′-Biphenyl]-3,3′,5-tricarboxylic acid and lanthanide ions in a solvothermal environment. FMU-101 features hexagonal one-dimensional pores with a diameter of 1.4 nm. The presence of free dimethylamine cations and metal open sites in the channel contributes to its remarkable capability for selectively enriching CO2 from CO2/CH4 mixtures in dynamic breakthrough experiments. Furthermore, the metal-open sites in FMU-101 play a crucial role in CO2 fixation, serving as effective catalytic sites for converting the adsorbed CO2 into high-value chloropropylene carbonate, a versatile chemical intermediate. The segregation and conversion mechanisms were further elucidated through density-functional theory (DFT) calculations and Grand Canonical Monte Carlo (GCMC) simulations, which highlighted the critical role of metal-open sites in CO2 adsorption and transformation.

AIM: To explore ocular surface manifestations of dry eye disease (DED) and its influencing factors in systemic lupus erythematosus (SLE) patients. METHODS: Ophthalmological examinations were conducted in SLE patients (n=43) and controls (n=41), including Ocular Surface Disease Index (OSDI), objective scatter index (OSI), tear meniscus height (TMH), lipid layer thickness (LLT), non-invasive Keratograph tear breakup time (NIKBUT), corneal fluorescein score (CFS), Schirmer I test. DED was diagnosed according to the Tear Film and Ocular Surface Society Dry Eye Workshop II Criteria. SLE patients were further divided into DED group and non-DED group, the disease activity, clinical manifestations and laboratory investigations were compared between the two groups. The disease activity was evaluated by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Receiver operative characteristic (ROC) curve and multiple-factor binary logistic regression were performed. RESULTS: SLE patients showed higher OSDI [9.1 (2.8-15.9) vs 6.3 (2.2-7.5), P=0.035], higher OSI [1.67 (1.09-2.60) vs 0.96 (0.87-1.60), P=0.001], higher CFS [1 (0-2) vs 0 (0-1), P=0.001], lower LLT [65 (42-100) vs 100 (79.5-100), P=0.010], and lower NIKBUT [8.03 (4.02-9.73) vs 9.67 (5.26-12.71), P=0.030] than controls. The 32.6% of SLE patients had DED, which was higher than 12.2% of healthy controls. DED group showed higher SLEDAI-2K score [9.7±6.1 vs 5.4±3.4, P=0.025], higher anti-cardiolipin antibody (ACL) [8.7 (3.5-13.2) vs 3.6 (2.0-6.9), P=0.035], and higher proportion of patients with cutaneous eruption [42.9% vs 6.9%, P=0.015] than non-DED group. According to multiple-factor binary logistic regression analysis, the SLEDAI-2K score (OR=1.194, P=0.041) and cutaneous eruption (OR=7.094, P=0.045) could be consider as risk factors for DED in SLE patients. The ROC curve of the combined factors including age, disease duration, SLEDAI-2K score, ACL, and cutaneous eruption was analyzed, with a sensitivity of 0.786, a specificity of 0.793, and an area under curve of 0.820. CONCLUSION: Ocular surface affection is frequent in SLE patients, and patients with high disease activity and cutaneous eruption show increased risk of DED.

Vascularization is a key step to achieve pulp tissue regeneration and in vitro pre-vascularized dental pulp tissue could be applied as a graft substitute for dental pulp tissue repair. In this study, human dental pulp stem cells (DPSCs) and human umbilical vein endothelial cells (hUVECs) were co-cultured in 3D Matrigel and 150 mV/mm electric fields (EFs) were used to promote the construction of pre-vascularized dental pulp tissue. After optimizing co-cultured ratio of two cell types, immunofluorescence staining, and live/dead detection were used to investigate the effect of EFs on cell survival, differentiation and vessel formation in 3D engineered dental pulp tissue. RNA sequencing was used to investigate the potential molecular mechanisms by which EF regulates vessel formation in 3D engineered dental pulp tissue. Here we identified that EF-induced pre-vascularized engineered dental pulp tissue not only had odontoblasts, but also had a rich vascular network, and smooth muscle-like cells appeared around the blood vessels. The GO enrichment analysis showed that these genes were significantly enriched in regulation of angiogenesis, cell migration and motility. The most significant term of the KEGG pathway analysis were NOTCH signaling pathway and Calcium signaling pathway etc. The PPI network revealed that NOTCH1 and IL-6 were central hub genes. Our study indicated that EFs significantly promoted the maturation and stable of blood vessel in 3D engineered pulp tissue and provided an experimental basis for the application of EF in dental pulp angiogenesis and regeneration.

Abstract Background Thesium chinense Turcz. (Named as Bai Rui Cao in Chinese) and its preparations (e.g., Bairui Granules) have been used to treat inflammatory diseases, such as acute mastitis, lobar pneumonia, tonsillitis, coronavirus disease 2019 (COVID-19), and upper respiratory tract infection. However, the material basis, pharmacological efficiency, and safety have not been illustrated. Methods Anti-inflammatory activity-guided isolation of constituents has been performed using multiple column chromatography, and their structures were elucidated by NMR spectroscopy and ECD calculations. The inhibitory effects on lung inflammation and safety of the crude ethanol extract (CE), Bairui Granules (BG), and the purified active constituents were evaluated using lipopolysaccharide (LPS)-stimulated acute lung inflammation (ALI) mice model or normal mice. Results Seven new compounds (1–7) and fifty-six known compounds (8–63) were isolated from T. chinense, and fifty-four were reported from this plant for the first time. The new flavonoid glycosides 1–2, new fatty acids 4–5, new alkaloid 7 as well as the known constituents including flavonoid aglycones 8–11, lignans 46–54, alkaloids 34 and 45, coumarins 57, phenylpropionic acids 27, and simple aromatic compounds 39, 44 and 58 exhibited anti-inflammatory activity. Network pharmacology analysis indicated that anti-inflammation of T. chinense was attributed to flavonoids and alkaloids by regulating inflammation-related proteins (e.g., TNF, NF-κB, TGF-β). Furthermore, constituents of T. chinense including kaempferol-3-O-glucorhamnoside (KN, also named as Bairuisu I, 19), astragalin (AG, Bairuisu II, 12), and kaempferol (KF, Bairuisu III, 8), as well as CE and BG could alleviate lung inflammation caused by LPS in mice by preventing neutrophils infiltration and the expression of the genes for pro-inflammatory cytokines NLRP3, caspase-1, IL-1β, and COX-2. After a 28-day subacute toxicity test, BG at doses of 4.875 g/kg and 9.750 g/kg (equivalent to onefold and twofold the clinically recommended dose) and CE at a dose of 11.138 g/kg (equivalent to fourfold the clinical dose of BG) were found to be safe and non-toxic. Conclusions The discovery of sixty-three constituents comprehensively illustrated the material basis of T. chinense. T. chinense and Bairui Granules could alleviate lung inflammation by regulating inflammation-related proteins and no toxicity was observed under the twofold of clinically used doses.

Abstract Nao-an Dropping Pill (NADP) is a Chinese patent medicine which commonly used in clinic for ischemic stroke (IS). However, the material basis and mechanism of its prevention or treatment of IS are unclear, then we carried out this study. 52 incoming blood components were resolved by UHPLC-MS/MS from rat serum, including 45 prototype components. The potential active prototype components hydroxysafflor yellow A, ginsenoside F1, quercetin, ferulic acid and caffeic acid screened by network pharmacology showed strongly binding ability with PIK3CA, AKT1, NOS3, NFE2L2 and HMOX1 by molecular docking. In vitro oxygen–glucose deprivation/reperfusion (OGD/R) experimental results showed that NADP protected HA1800 cells from OGD/R-induced apoptosis by affecting the release of LDH, production of NO, and content of SOD and MDA. Meanwhile, NADP could improve behavioral of middle cerebral artery occlusion/reperfusion (MCAO/R) rats, reduce ischemic area of cerebral cortex, decrease brain water and glutamate (Glu) content, and improve oxidative stress response. Immunohistochemical results showed that NADP significantly regulated the expression of PI3K, Akt, p-Akt, eNOS, p-eNOS, Nrf2 and HO-1 in cerebral ischemic tissues. The results suggested that NADP protects brain tissues and ameliorates oxidative stress damage to brain tissues from IS by regulating PI3K/Akt/eNOS and Nrf2/HO-1 signaling pathways.

Abstract In order to cope with the complexity and variability of the terrestrial environment, amphibians have developed a wide range of reproductive and parental behaviors. Nest building occurs in some anuran species as parental care. Species of the Music frog genus Nidirana are known for their unique courtship behavior and mud nesting in several congeners. However, the evolution of these frogs and their nidification behavior has yet to be studied. With phylogenomic and phylogeographic analyses based on a wide sampling of the genus, we find that Nidirana originated from central-southwestern China and the nidification behavior initially evolved at ca 19.3 Ma but subsequently lost in several descendants. Further population genomic analyses suggest that the nidification species have an older diversification and colonization history, while N. adenopleura complex congeners that do not exhibit nidification behavior have experienced a recent rapid radiation. The presence and loss of the nidification behavior in the Music frogs may be associated with paleoclimatic factors such as temperature and precipitation. This study highlights the nidification behavior as a key evolutionary innovation that has contributed to the diversification of an amphibian group under past climate changes.

Abstract Orthopedic conditions have emerged as global health concerns, impacting approximately 1.7 billion individuals worldwide. However, the limited understanding of the underlying pathological processes at the cellular and molecular level has hindered the development of comprehensive treatment options for these disorders. The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized biomedical research by enabling detailed examination of cellular and molecular diversity. Nevertheless, investigating mechanisms at the single-cell level in highly mineralized skeletal tissue poses technical challenges. In this comprehensive review, we present a streamlined approach to obtaining high-quality single cells from skeletal tissue and provide an overview of existing scRNA-seq technologies employed in skeletal studies along with practical bioinformatic analysis pipelines. By utilizing these methodologies, crucial insights into the developmental dynamics, maintenance of homeostasis, and pathological processes involved in spine, joint, bone, muscle, and tendon disorders have been uncovered. Specifically focusing on the joint diseases of degenerative disc disease, osteoarthritis, and rheumatoid arthritis using scRNA-seq has provided novel insights and a more nuanced comprehension. These findings have paved the way for discovering novel therapeutic targets that offer potential benefits to patients suffering from diverse skeletal disorders.

Abstract Background Advanced hepatocellular carcinoma (HCC) can be treated with sorafenib, which is the primary choice for targeted therapy. Nevertheless, the effectiveness of sorafenib is greatly restricted due to resistance. Research has shown that exosomes and circular RNAs play a vital role in the cancer’s malignant advancement. However, the significance of exosomal circular RNAs in the development of resistance to sorafenib in HCC remains uncertain. Methods Ultracentrifugation was utilized to isolate exosomes (Exo-SR) from the sorafenib-resistant HCC cells’ culture medium. Transcriptome sequencing and differential expression gene analysis were used to identify the targets of Exo-SR action in HCC cells. To identify the targets of Exo-SR action in HCC cells, transcriptome sequencing and analysis of differential expression genes were employed. To evaluate the impact of exosomal circUPF2 on resistance to sorafenib in HCC, experiments involving gain-of-function and loss-of-function were conducted. RNA pull-down assays and mass spectrometry analysis were performed to identify the RNA-binding proteins interacting with circUPF2. RNA immunoprecipitation (RIP), RNA pull-down, electrophoretic mobility shift assay (EMSA), immunofluorescence (IF) -fluorescence in situ hybridization (FISH), and rescue assays were used to validate the interactions among circUPF2, IGF2BP2 and SLC7A11. Finally, a tumor xenograft assay was used to examine the biological functions and underlying mechanisms of Exo-SR and circUPF2 in vivo. Results A novel exosomal circRNA, circUPF2, was identified and revealed to be significantly enriched in Exo-SR. Exosomes with enriched circUPF2 enhanced sorafenib resistance by promoting SLC7A11 expression and suppressing ferroptosis in HCC cells. Mechanistically, circUPF2 acts as a framework to enhance the creation of the circUPF2-IGF2BP2-SLC7A11 ternary complex contributing to the stabilization of SLC7A11 mRNA. Consequently, exosomal circUPF2 promotes SLC7A11 expression and enhances the function of system Xc- in HCC cells, leading to decreased sensitivity to ferroptosis and resistance to sorafenib. Conclusions The resistance to sorafenib in HCC is facilitated by the exosomal circUPF2, which promotes the formation of the circUPF2-IGF2BP2-SLC7A11 ternary complex and increases the stability of SLC7A11 mRNA. Focusing on exosomal circUPF2 could potentially be an innovative approach for HCC treatment. Graphical Abstract

Avian pathogen Escherichia coli (APEC) poses a significant threat to poultry farming, causing colibacillosis in various hosts, including chickens, ducks, geese, and pigeons. This study aimed to investigate the molecular epidemiology of APEC in Jiangxi Province, China, to inform prevention and control strategies. Between 2020 and 2024, 186 APEC strains were isolated and identified, with 88.7 % from liver samples and 5.4 % from brain tissues. Whole-genome sequencing and analysis revealed that serotypes O145, O78, O8, and O111 comprised 32.9 %, 9.3 %, 7.9 %, and 4.3 % of the isolates, respectively. The dominant H serotypes included H21 (23.8 %), H9 (22.7 %), and H4 (18.2 %), with ST23 being the most prevalent sequence type at 24.2 %, followed by ST117 (10.1 %) and ST2505 (7.3 %). Virulence-associated genes in the strains O145, O78, O8, and O111 were further analyzed for quantity and pattern. Eight strains were selected for in vivo pathogenicity testing in ducks, four highly pathogenic strains were then identified, which were used to develop inactivated vaccines with the novel aqueous adjuvant MONTANIDE™ GEL P PR and the traditional adjuvant alumVax hydroxide. Compared with existing vaccines, those formulated in this study showed superior protection, with the MONTANIDE™ GEL P PR adjuvant achieving the highest protection rate (90.0 %, 36/40) and lower lesion scores. This research enhances the understanding of APEC epidemiology and offers promising strategies for effective vaccine development against prevalent APEC.

Abstract Background Traditional fixed thresholds for oral glucose tolerance test (OGTT) results may inadequately prevent adverse pregnancy outcomes in twin pregnancies. This study explores latent OGTT patterns and their association with adverse outcomes. Methods This study retrospectively analyzed 2644 twin pregnancies using latent mixture models to identify glucose level patterns (high, HG; medium, MG; and low, LG) and their relationship with maternal/neonatal characteristics, gestational age at delivery, and adverse outcomes. Results Three distinct glucose patterns, HG, MG, and LG patterns were identified. Among the participants, 16.3% were categorized in the HG pattern. After adjustment, compared with the LG pattern, the HG pattern was associated with a 1.79‐fold, 1.66‐fold, and 1.32‐fold increased risk of stillbirth, neonatal respiratory distress, and neonatal hyperbilirubinemia, respectively. The risk of neonatal ICU admission for MG and HG patterns increased by 1.22 times and 1.32 times, respectively, compared with the LG pattern. As gestational weeks increase, although there is an overlap in the confidence intervals between the HG pattern and other patterns in the restricted cubic splines analysis, the trend suggests that pregnant women with the HG pattern are more likely to face risks of their newborns requiring neonatal intensive care unit admission, and adverse comprehensive outcomes, compared with other patterns. In addition, with age and body mass index increasing in HG mode, gestation weeks at delivery tend to be later than in other modes. Conclusion Distinct OGTT glucose patterns in twin pregnancies correlate with different risks of adverse perinatal outcomes. The HG pattern warrants closer glucose monitoring and targeted intervention.

Summary: A wide variety of electrophilic derivatives of itaconate, the Kreb’s cycle-derived metabolite, are immunomodulatory, yet these derivatives have overlapping and sometimes contradictory activities. Therefore, we generated a genetic system to interrogate the immunomodulatory functions of endogenously produced itaconate in human macrophages. Endogenous itaconate is driven by multiple innate signals restraining inflammatory cytokine production. Endogenous itaconate directly targets cysteine 13 in IRAK4 (disrupting IRAK4 autophosphorylation and activation), drives the degradation of nuclear factor κB, and modulates global ubiquitination patterns. As a result, cells unable to make itaconate overproduce inflammatory cytokines such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1β in response to these innate activators. In contrast, the production of interferon (IFN)β, downstream of LPS, requires the production of itaconate. These data demonstrate that itaconate is a critical arbiter of inflammatory cytokine production downstream of multiple innate signaling pathways, laying the groundwork for the development of itaconate mimetics for the treatment of autoimmunity.

Abstract Purpose To evaluate the effect of intrahepatic cholestasis of pregnancy (ICP) with gestational diabetes mellitus (GDM) on perinatal outcomes and establish a prediction model of adverse perinatal outcomes in women with ICP. Methods This multicenter retrospective cohort study included the clinical data of 2,178 pregnant women with ICP, including 1,788 women with ICP and 390 co-occurrence ICP and GDM. The data of all subjects were collected from hospital electronic medical records. Univariate and multivariate logistic regression analysis were used to compare the incidence of perinatal outcomes between ICP with GDM group and ICP alone group. Results Baseline characteristics of the population revealed that maternal age (p

Aims: The optimal management of posterior malleolar ankle fractures, a prevalent type of ankle trauma, is essential for improved prognosis. However, there remains a debate over the most effective surgical approach, particularly between screw and plate fixation methods. This study aims to investigate the differences in outcomes associated with these fixation techniques. Methods: We conducted a comprehensive review of clinical trials comparing anteroposterior (A-P) screws, posteroanterior (P-A) screws, and plate fixation. Two investigators validated the data sourced from multiple databases (MEDLINE, EMBASE, and Web of Science). Following PRISMA guidelines, we carried out a network meta-analysis (NMA) using visual analogue scale and American Orthopaedic Foot and Ankle Score (AOFAS) as primary outcomes. Secondary outcomes included range of motion limitations, radiological outcomes, and complication rates. Results: The NMA encompassed 13 studies, consisting of four randomized trials and eight retrospective ones. According to the surface under the cumulative ranking curve-based ranking, the A-P screw was ranked highest for improvements in AOFAS and exhibited lowest in infection and peroneal nerve injury incidence. The P-A screws, on the other hand, excelled in terms of VAS score improvements. Conversely, posterior buttress plate fixation showed the least incidence of osteoarthritis grade progression, postoperative articular step-off ≥ 2 mm, nonunions, and loss of ankle dorsiflexion ≥ 5°, though it underperformed in most other clinical outcomes. Conclusion: The NMA suggests that open plating is more likely to provide better radiological outcomes, while screw fixation may have a greater potential for superior functional and pain results. Nevertheless, clinicians should still consider the fragment size and fracture pattern, weighing the advantages of rigid biomechanical fixation against the possibility of soft-tissue damage, to optimize treatment results. Cite this article: Bone Jt Open 2024;5(3):227–235.

The microwave-derived vegetation optical depth (VOD) products were used to monitor aboveground biomass (AGB) at regional to global scales, but the ability of VOD to monitor AGB in China is uncertain. This study evaluated the sensitivity of four VOD products (e.g. L-VOD, IB-VOD, LPDR-VOD, and Liu-VOD) and optical vegetation indices (VI) (e.g. NDVI, EVI, LAI, and tree cover from MODIS) to the AGB across China. Our results showed tree cover product has the highest spatial agreement with reference AGBs (indicated by the median correlation value of 0.85), followed by L-VOD (with a median correlation value of 0.80), which performs better than other VIs and VODs. Further comparisons between reference and estimated AGB computed using the fitted logistic regression showed that AGB estimations from tree cover and L-VOD outperformed the estimations from other VIs and VODs over most vegetation types (except forest), indicated by the higher median correlation value of 0.86 and 0.83 and lower RMSD of 23.9 and 27.3 Mg/ha, respectively. The good performance of tree cover could be partly due to that tree cover product is not independent from the reference AGBs. The good performance of L-VOD can be explained by its higher sensitivity to the vegetation characteristics of the entire canopy (including woody component), relative to other VODs and VIs. Among the six reference AGB products, Saatchi-WT and Saatchi-RF products were found to have the best correlations with VIs and VODs. This study demonstrates that microwave VODs, particularly L-VOD, are effective proxies for large-scale monitoring of vegetation AGB in China.

Abstract Background Zinc oxide nanoparticles (ZnONPs) are common materials used in skin-related cosmetics and sunscreen products due to their whitening and strong UV light absorption properties. Although the protective effects of ZnONPs against UV light in intact skin have been well demonstrated, the effects of using ZnONPs on damaged or sunburned skin are still unclear. In this study, we aimed to reveal the detailed underlying mechanisms related to keratinocytes and macrophages exposed to UVB and ZnONPs. Results We demonstrated that ZnONPs exacerbated mouse skin damage after UVB exposure, followed by increased transepidermal water loss (TEWL) levels, cell death and epithelial thickness. In addition, ZnONPs could penetrate through the damaged epithelium, gain access to the dermis cells, and lead to severe inflammation by activation of M1 macrophage. Mechanistic studies indicated that co-exposure of keratinocytes to UVB and ZnONPs lysosomal impairment and autophagy dysfunction, which increased cell exosome release. However, these exosomes could be taken up by macrophages, which accelerated M1 macrophage polarization. Furthermore, ZnONPs also induced a lasting inflammatory response in M1 macrophages and affected epithelial cell repair by regulating the autophagy-mediated NLRP3 inflammasome and macrophage exosome secretion. Conclusions Our findings propose a new concept for ZnONP-induced skin toxicity mechanisms and the safety issue of ZnONPs application on vulnerable skin. The process involved an interplay of lysosomal impairment, autophagy-mediated NLRP3 inflammasome and macrophage exosome secretion. The current finding is valuable for evaluating the effects of ZnONPs for cosmetics applications.

Abstract Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a tumor growth-promoting phenotype through activation of the anaplastic lymphoma kinase (ALK) signaling pathway. Targeting the RNase1/ALK axis reprograms the macrophage polarization, with increased CD8+ T- and Th1- cell recruitment. Moreover, simultaneous targeting of the checkpoint protein PD-1 unleashes cytotoxic CD8+ T-cell responses. Treatment utilizing both an ALK inhibitor and an anti-PD-1 antibody exhibits enhanced tumor regression and facilitates long-term immunity. Our study elucidates the role of RNase1 in mediating tumor resistance to immunotherapy and reveals an RNase1-mediated immunosuppressive tumor microenvironment, highlighting the potential of targeting RNase1 as a promising strategy for cancer immunotherapy in HCC.

Objective To analyze the high risk factors of obstetric brachial plexus palsy （OBPP）, and to explore how to evaluate the relationship between fault medical behavior and OBPP in the process of medical damage forensic identification. Methods A retrospective analysis was carried out on 25 cases of medical damage liability disputes related to OBPP from 2017 to 2021 in Beijing Fayuan Judicial Science Evidence Appraisal Center. The shortcomings of hospitals in birth weight assessment, delivery mode selection, labor process observation and shoulder dystocia management, and the causal relationship between them and the damage consequences of the children were summarized. Results Fault medical behavior was assessed as the primary cause in 2 cases, equal cause in 10 cases， secondary cause in 8 cases, minor cause in 1 case, no causal relationship in 1 case, and unclear causal force in 3 cases. Conclusion In the process of forensic identification of OBPP, whether medical behaviors fulfill diagnosis and treatment obligations should be objectively analyzed from the aspects of prenatal evaluation, delivery mode notification, standardized use of oxytocin, standard operation of shoulder dystocia, etc. Meanwhile, it is necessary to fully consider the objective risk of different risk factors and the difficulty of injury prevention, and comprehensively evaluate the causal force of fault medical behavior in the damage consequences.

Biological evidence is relatively common evidence in criminal cases, and it has strong probative power because it carries DNA information for individual identification. At the scene of fire-related cases, the complex thermal environment, the escape of trapped people, the firefighting and rescue operations, and the deliberate destruction of criminal suspects will all affect the biological evidence in the fire scene. Scholars at home and abroad have explored and studied the effectiveness of biological evidence identification in fire scenes, and found that the blood stains, semen stains, bones, etc. are the main biological evidence which can be easily recovered with DNA in fire scenes. In order to analyze the research status and development trend of biological evidence in fire scenes, this paper systematically sorts out the relevant research, mainly including the soot removal technology, appearance method of typical biological evidence, and possibility of identifying other biological evidence. This paper also prospects the next step of research direction, in order to provide reference for the identification of biological evidence and improve the value of biological evidence in fire scenes.

Objective: Understanding the characteristics of alveolar bone resorption in an East Asian population after maxillary incisor extraction and providing a reference for implant treatment plans. Study design: Cone-beam computerized tomography (CBCT) data of 125 East Asian patients with unilateral extraction of maxillary incisors for 3 months were collected. The alveolar bone width and height in the extraction sites were measured and compared with the corresponding contralateral sites. Results: The differences in alveolar bone width between the extraction site and contralateral site were as follows: 4.11 mm, 2.68 mm, and 2.09 mm (3 mm, 5 mm, 7 mm apical from CEJ of the contralateral tooth). Data are expressed as the median. The horizontal resorption ratio of alveolar bone was 49.94 %, 31.5 %, and 24.46 %. The difference in alveolar bone height was 0.78 mm. The vertical resorption ratio was 7.78 %. The resorption did not differ significantly between sexes and was not significantly affected by tooth positions. Conclusions: In the studied East Asian population, significant horizontal and vertical alveolar bone resorption occurs after natural healing of maxillary incisor extraction for 3 months. The closer to the alveolar ridge crest, the more significant the horizontal resorption, resulting in an “inverted triangle” shape residual alveolar bone.

Abstract Background Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve patient survival. We aimed to develop a blood‐based assay to aid in the diagnosis, detection and prognostic evaluation of HCC. Methods A three‐phase multicentre study was conducted to screen, optimise and validate HCC‐specific differentially methylated regions (DMRs) using next‐generation sequencing and quantitative methylation‐specific PCR (qMSP). Results Genome‐wide methylation profiling was conducted to identify DMRs distinguishing HCC tumours from peritumoural tissues and healthy plasmas. The twenty most effective DMRs were verified and incorporated into a multilocus qMSP assay (HepaAiQ). The HepaAiQ model was trained to separate 293 HCC patients (Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 224) from 266 controls including chronic hepatitis B (CHB) or liver cirrhosis (LC) (CHB/LC, 96), benign hepatic lesions (BHL, 23), and healthy controls (HC, 147). The model achieved an area under the curve (AUC) of 0.944 with a sensitivity of 86.0% in HCC and a specificity of 92.1% in controls. Blind validation of the HepaAiQ model in a cohort of 523 participants resulted in an AUC of 0.940 with a sensitivity of 84.4% in 205 HCC cases (BCLC stage 0/A, 167) and a specificity of 90.3% in 318 controls (CHB/LC, 100; BHL, 102; HC, 116). When evaluated in an independent test set, the HepaAiQ model exhibited a sensitivity of 70.8% in 65 HCC patients at BCLC stage 0/A and a specificity of 89.5% in 124 patients with CHB/LC. Moreover, HepaAiQ model was assessed in paired pre‐ and postoperative plasma samples from 103 HCC patients and correlated with 2‐year patient outcomes. Patients with high postoperative HepaAiQ score showed a higher recurrence risk (Hazard ratio, 3.33, p

Abstract Three‐dimensional (3D) echocardiography is an emerging technique for assessing right ventricular (RV) volume and function, but 3D‐RV normal values from a large Chinese population are still lacking. The aim of the present study was to establish normal values of 3D‐RV volume and function in healthy Chinese volunteers. A total of 1117 Han Chinese volunteers from 28 laboratories in 20 provinces of China were enrolled, and 3D‐RV images of 747 volunteers with optimal image quality were ultimately analyzed by a core laboratory. Both vendor‐dependent and vendor‐independent software platforms were used to analyze the 3D‐RV images. We found that men had larger RV volumes than women did in the whole population, even after indexing to body surface area, and older individuals had smaller RV volumes. The normal RV volume was significantly smaller than that recommended by the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines in both sexes. There were significant differences in 3D‐RV measurements between the two vendor ultrasound systems and the different software platforms. The echocardiographic measurements in normal Chinese adults II study revealed normal 3D‐RV volume and function in a large Chinese population, and there were significant differences between the sexes, ages, races, and vendor groups. Thus, normal 3D‐RV values should be stratified by sex, age, race, and vendor.

C20H22N2O4, monoclinic, P21/n (no. 14), a = 11.4033(15) Å, b = 14.2998(16) Å, c = 11.6486(16) Å, β = 91.197(8)°, V = 1899.1(4) Å3, Z = 4, Rgt(F) = 0.0513, wRref(F2) = 0.1542, T = 296.2 K.

Abstract Numerous drivers such as farming practices, erosion, land-use change, and soil biogeochemical background, determine the global spatial distribution of phosphorus (P) in agricultural soils. Here, we revised an approach published earlier (called here GPASOIL-v0), in which several global datasets describing these drivers were combined with a process model for soil P dynamics to reconstruct the past and current distribution of P in cropland and grassland soils. The objective of the present update, called GPASOIL-v1, is to incorporate recent advances in process understanding about soil inorganic P dynamics, in datasets to describe the different drivers, and in regional soil P measurements for benchmarking. We trace the impact of the update on the reconstructed soil P. After the update we estimate a global averaged inorganic labile P of 187 kgP ha−1 for cropland and 91 kgP ha−1 for grassland in 2018 for the top 0–0.3 m soil layer, but these values are sensitive to the mineralization rates chosen for the organic P pools. Uncertainty in the driver estimates lead to coefficients of variation of 0.22 and 0.54 for cropland and grassland, respectively. This work makes the methods for simulating the agricultural soil P maps more transparent and reproducible than previous estimates, and increases the confidence in the new estimates, while the evaluation against regional dataset still suggests rooms for further improvement.