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Polyploidy is a major factor in the evolution of plants, yet we know little about the origin and evolution of polyploidy in intertidal species. This study aimed to identify the evolutionary transitions in three true-mangrove species of the genus Acanthus distributed in the Indo–West Pacific region. For this purpose, we took an integrative approach that combined data on morphology, cytology, climatic niche, phylogeny, and biogeography of 493 samples from 42 geographic sites. Our results show that the Acanthus ilicifolius lineage distributed east of the Thai–Malay Peninsula possesses a tetraploid karyotype, which is morphologically distinct from that of the lineage on the west side. The haplotype networks and phylogenetic trees for the chloroplast genome and eight nuclear genes reveal that the tetraploid species has two sub-genomes, one each from A. ilicifolius and A. ebracteatus, the paternal and maternal parents, respectively. Population structure analysis also supports the hybrid speciation history of the new tetraploid species. The two sub-genomes of the tetraploid species diverged from their diploid progenitors during the Pleistocene. Environmental niche models revealed that the tetraploid species not only occupied the near-entire niche space of the diploids, but also expanded into novel environments. Our findings suggest that A. ilicifolius species distributed on the east side of the Thai–Malay Peninsula should be regarded as a new species, A. tetraploideus, which originated from hybridization between A. ilicifolius and A. ebracteatus, followed by chromosome doubling. This is the first report of a true-mangrove allopolyploid species that can reproduce sexually and clonally reproduction, which explains the long-term adaptive potential of the species.

Abstract Sugars will be eventually effluxed transporters (SWEETs) have been confirmed to play diverse physiological roles in plant growth, development and stress response. However, the characteristics and functions of the SWEET genes in Hemerocallis citrina remain unclear and poorly elucidated. In this study, the whole genome of Hemerocallis citrina was utilized to conduct bioinformatics analysis and a total of 19 HcSWEET genes were successfully identified. Analysis of the physicochemical properties indicated dominant differences among these HcSWEETs. A phylogenetic analysis revealed that HcSWEET proteins can be divided into 4 clades ranging from Clade I to IV, where proteins within the same clade exhibited shared conserved motifs and gene structures. Five to six exons were contained in the majority of HcSWEET genes, which were unevenly distributed across 11 chromosomes. The gene duplication analysis showed the presence of 4 gene pairs. Comparative syntenic maps revealed that the HcSWEET gene family might present more closed homology in monocotyledons than dicotyledons. Cis-acting element analysis of HcSWEET genes indicated key responsiveness to various hormones, light, and stresses. Additionally, transcriptome sequencing analysis suggested that most HcSWEET genes had a relatively higher expression in roots, and HcSWEET4a was significantly up-regulated under salt stress. Overexpression further verified the possibility that HcSWEET4a was involved in response to salt stress, which provides novel insights and facilitates in-depth studies of the functional analysis of HcSWEETs in resistance to abiotic stress.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in therapy of ischemic heart disease. However, there are still remaining issues that limit the therapeutic efficacy, such as immune rejection and low retention of hiPSC-CMs. Human adipose mesenchymal stromal cells (hADSCs) have been reported to be able to regulate the immune response, promote angiogenesis and promote the maturation of hiPSC-CMs. In this study, we co-cultured these two types of cells on fiber scaffold made of biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) polymer for several days to develop a composited 3D cardiac tissue sheet. As expected, the cells formed 231.00 ± 15.14 μm thickness tissue, with improved organization, alignment, ECM condition, contractile ability, and paracrine function compared to culture hiPSC-CMs only on PLGA fiber. Furthermore, the composited 3D cardiac tissue sheet significantly promoted the engraftment and survival after transplantation. The composited 3D cardiac tissue sheet also increased cardiac function, attenuated ventricular remodeling, decreased fibrosis, and enhanced angiogenesis in rat myocardial infarction model, indicating that this strategy wound be a promising therapeutic option in the clinical scenario.

Abstract Objective This study aimed to develop and apply a nomogram with good accuracy to predict the risk of CRAB infections in neuro-critically ill patients. In addition, the difficulties and expectations of application such a tool in clinical practice was investigated. Methods A mixed methods sequential explanatory study design was utilized. We first conducted a retrospective study to identify the risk factors for the development of CRAB infections in neuro-critically ill patients; and further develop and validate a nomogram predictive model. Then, based on the developed predictive tool, medical staff in the neuro-ICU were received an in-depth interview to investigate their opinions and barriers in using the prediction tool during clinical practice. The model development and validation is carried out by R. The transcripts of the interviews were analyzed by Maxqda. Results In our cohort, the occurrence of CRAB infections was 8.63% (47/544). Multivariate regression analysis showed that the length of neuro-ICU stay, male, diabetes, low red blood cell (RBC) count, high levels of procalcitonin (PCT), and number of antibiotics ≥ 2 were independent risk factors for CRAB infections in neuro-ICU patients. Our nomogram model demonstrated a good calibration and discrimination in both training and validation sets, with AUC values of 0.816 and 0.875. Additionally, the model demonstrated good clinical utility. The significant barriers identified in the interview include “skepticism about the accuracy of the model”, “delay in early prediction by the indicator of length of neuro-ICU stay”, and “lack of a proper protocol for clinical application”. Conclusions We established and validated a nomogram incorporating six easily accessed indicators during clinical practice (the length of neuro-ICU stay, male, diabetes, RBC, PCT level, and the number of antibiotics used) to predict the risk of CRAB infections in neuro-ICU patients. Medical staff are generally interested in using the tool to predict the risk of CRAB, however delivering clinical prediction tools in routine clinical practice remains challenging.

Doxorubicin (DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients, but related pharmacotherapeutic measures are relatively limited. Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity. Idebenone, a novel ferroptosis inhibitor, is a well-described clinical drug widely used. However, its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear. In this study, we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism. A single intraperitoneal injection of DOX (15 mg/kg) was administrated to establish DOX-induced cardiotoxicity. The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe2+ and ROS overload, which resulted in ferroptosis. CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1. Interestingly, idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX. Idebenone could form stable hydrogen bonds with FSP1 protein at K355, which may influence its association with ubiquitin. The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation. In conclusion, this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1, making it a potential clinical drug for patients receiving DOX treatment.

Abstract Mesial temporal lobe epilepsy (MTLE) is one of the most intractable epilepsies. Previously, we reported that mitochondrial DNA deletions were associated with epileptogenesis. While the underlying mechanism of mitochondrial DNA deletions during epileptogenesis remain unknown. In this study, a novel somatic mutation of DNA2 gene was identified in the hippocampal tissue of two MTLE patients carrying mitochondrial DNA deletions, and this mutation decreased the full-length expression of DNA2 protein significantly, aborting its normal functions. Then, we knocked down the DNA2 protein in zebrafish, and we demonstrated that zebrafish with DNA2 deficiency showed decreased expression of mitochondrial complex II–IV, and exhibited hallmarks of epileptic seizures, including abnormal development of the zebrafish and epileptiform discharge signals in brain, compared to the Cas9-control group. Moreover, our cell-based assays showed that DNA2 deletion resulted in accumulated mitochondrial DNA damage, abnormal oxidative phosphorylation and decreased ATP production in cells. Inadequate ATP generation in cells lead to declined Na+, K+-ATPase activity and change of cell membrane potential. Together, these disorders caused by DNA2 depletion increased cell apoptosis and inhibited the differentiation of SH-SY5Y into branched neuronal phenotype. In conclusion, DNA2 deficiency regulated the cell membrane potential via affecting ATP production by mitochondria and Na+, K+-ATPase activity, and also affected neuronal cell growth and differentiation. These disorders caused by DNA2 dysfunction are important causes of epilepsy. In summary, we are the first to report the pathogenic somatic mutation of DNA2 gene in the patients with MTLE disease, and we uncovered the mechanism of DNA2 regulating the epilepsy. This study provides new insight into the pathogenesis of epilepsy and underscore the value of DNA2 in epilepsy.

Abstract Background Chronic obstructive pulmonary disease (COPD) is a significant global health issue, suspected to elevate the risk for various cancers. This study sought to discern whether COPD serves as a risk marker or a causative factor for prevalent cancers. Methods We employed univariable MR (UVMR) analyses to investigate the causal relationship between COPD and the top ten common cancers. Sensitivity analyses were performed to validate the main findings. Multivariable MR (MVMR) and two-step MR analyses were also conducted. False-discovery-rate (FDR) was used to correct multiple testing bias. Results The UVMR analysis demonstrated notable associations between COPD and lung cancer (odds ratio [OR] = 1.42, 95%CI 1.15–1.77, FDR = 6.37 × 10–3). This relationship extends to lung cancer subtypes such as squamous cell carcinoma (LUSC), adenocarcinoma (LUAD), and small cell lung cancer (SCLC). A tentative link was also identified between COPD and bladder cancer (OR = 1.53, 95%CI 1.03–2.28, FDR = 0.125). No significant associations were found between COPD and other types of cancer. The MVMR analysis that adjusted for smoking, alcohol drinking, and body mass index did not identify any significant causal relationships between COPD and either lung or bladder cancer. However, the two-step MR analysis indicates that COPD mediated 19.2% (95% CI 12.7–26.1%), 36.1% (24.9–33.2%), 35.9% (25.7–34.9%), and 35.5% (26.2–34.8%) of the association between smoking and overall lung cancer, as well as LUAD, LUSC, and SCLC, respectively. Conclusions COPD appears to act more as a risk marker than a direct cause of prevalent cancers. Importantly, it partially mediates the connection between smoking and lung cancer, underscoring its role in lung cancer prevention strategies.

Abstract Background Circulating tumor cells (CTCs) hold immense promise in guiding treatment strategies for advanced gastric cancer (GC). However, their clinical impact has been limited due to challenges in identifying epithelial-mesenchymal transition (EMT)-CTCs using conventional methods. Methods To bridge this knowledge gap, we established a detection platform for CTCs based on the distinctive biomarker cell surface vimentin (CSV). A prospective study involving 127 GC patients was conducted, comparing CTCs enumeration using both EpCAM and CSV. This approach enabled the detection of both regular and EMT-CTCs, providing a comprehensive analysis. Spiking assays and WES were employed to verify the reliability of this marker and technique. To explore the potential inducer of CSV+CTCs formation, a combination of Tandem Mass Tag (TMT) quantitative proteomics, m6A RNA immunoprecipitation–qPCR (MeRIP–qPCR), single-base elongation- and ligation-based qPCR amplification method (SELECT) and RNA sequencing (RNA-seq) were utilized to screen and confirm the potential target gene. Both in vitro and in vivo experiments were performed to explore the molecular mechanism of CSV expression regulation and its role in GC metastasis. Results Our findings revealed the potential of CSV in predicting therapeutic responses and long-term prognosis for advanced GC patients. Additionally, compared to the conventional EpCAM-based CTCs detection method, the CSV-specific positive selection CTCs assay was significantly better for evaluating the therapeutic response and prognosis in advanced GC patients and successfully predicted disease progression 14.25 months earlier than radiology evaluation. Apart from its excellent role as a detection marker, CSV emerges as a promising therapeutic target for attenuating GC metastasis. It was found that fat mass and obesity associated protein (FTO) could act as a potential catalyst for CSV+CTCs formation, and its impact on the insulin-like growth factor-I receptor (IGF-IR) mRNA decay through m6A modification. The activation of IGF-I/IGF-IR signaling enhanced the translocation of vimentin from the cytoplasm to the cell surface through phosphorylation of vimentin at serine 39 (S39). In a GC mouse model, the simultaneous inhibition of CSV and blockade of the IGF-IR pathway yielded promising outcomes. Conclusion In summary, leveraging CSV as a universal CTCs marker represents a significant breakthrough in advancing personalized medicine for patients with advanced GC. This research not only paves the way for tailored therapeutic strategies but also underscores the pivotal role of CSV in enhancing GC management, opening new frontiers for precision medicine.

Abstract Background Mesenchymal stem cells (MSCs) are attracting attention as a promising cell-based therapy for the treatment of liver fibrosis or cirrhosis. However, the strategies and potential mechanisms of MSCs therapy need further investigation. The CXCL12/CXCR4/CXCR7 chemokine axis is well known to regulate cell migration and is involved in the regulation of liver fibrosis. This study aims to treat MSCs with a CXCR7-specific agonist to evaluate its therapeutic effects on hepatic fibrosis and potential mechanisms. Methods TC14012, a potent agonist of CXCR7, has been used to pretreat human umbilical cord-derived MSCs (UC-MSCs) and assess its effect on proliferation, apoptosis, migration, immunoregulation, and gene regulatory network. Then, CCl4-induced liver fibrosis mice models were used to evaluate the therapeutic effect and mechanism of TC14012-treated UC-MSCs for treating hepatic fibrosis. Results TC14012 increased CXCR7 expression in UC-MSCs. Notably, co-culture of liver sinusoidal endothelial cells (LSEC) with TC14012-pretreated UC-MSCs increased CXCR7 expression in LSEC. Additionally, TC14012 promoted cell migration and mediated the immunoregulation of UC-MSCs. Compared to UC-MSCs without TC14012 pretreatment, UC-MSCs treated with TC14012 ameliorated live fibrosis by restoring CXCR7 expression, reducing collagen fibril accumulation, inhibiting hepatic stellate cells activation, and attenuating the inflammatory response. Conclusion This study suggests that TC14012 pretreatment can enhance the therapeutic effects of UC-MSCs on liver fibrosis, mainly by promoting the migration and immunoregulation of MSCs.

Abstract An increasing number of studies have focused on the role of NEDD4-2 in regulating neuronal excitability and the mechanism of epilepsy. However, the exact mechanism has not yet been elucidated. Here, we explored the roles of NEDD4-2 and the CLC-2 channel in regulating neuronal excitability and mesial temporal lobe epilepsy (MTLE) pathogenesis. First, chronic MTLE models were induced by lithium-pilocarpine in developmental rats. Coimmunoprecipitation analysis revealed that the interaction between CLC-2 and NEDD4-2. Western blot analyses indicated that NEDD4-2 expression was downregulated, while phosphorylated (P-) NEDD4-2 and CLC-2 expression was upregulated in adult MTLE rats. Then, the primary hippocampal neuronal cells were isolated and cultured, and the NEDD4-2 was knocked down by shRNA vector, resulting in decreased protein levels of CLC-2. While CLC-2 absence caused increased NEDD4-2 in cells. Next, in an epileptic cell model induced by a Mg2+-free culture, whole-cell current-clamp recording demonstrated that NEDD4-2 deficiency inhibited the spontaneous action potentials of cells, and CLC-2 absence caused more significant decrease in the spontaneous action potentials of cells. In conclusion, we herein revealed that NEDD4-2 regulates the expression of CLC-2, which is involved in neuronal excitability, and participates in the pathogenesis of MTLE.

Abstract Purpose To construct a radiomics-clinical nomogram model for predicting the risk of local and metastatic recurrence within 3 years after radical cystectomy (RC) of bladder cancer (BCa) based on the radiomics features and important clinical risk factors for arterial computed tomography (CT) images and to evaluate its efficacy. Methods Preoperative CT datasets of 134 BCa patients (24 recurrent) who underwent RC were collected and divided into training (n = 93) and validation sets (n = 41). Radiomics features were extracted from a 1.5 mm CT layer thickness image in the arterial phase. A radiomics score (Rad-Score) model was constructed using the feature dimension reduction method and a logistic regression model. Combined with important clinical factors, including gender, age, tumor size, tumor number and grade, pathologic T stage, lymph node stage and histology type of the archived lesion, and CT image signs, a radiomics-clinical nomogram was developed, and its performance was evaluated in the training and validation sets. Decision curve analyses (DCA) the potential clinical usefulness. Results The radiomics model is finally linear combined by 8 features screened by LASSO regression, and after coefficient weighting, achieved good predictive results. The radiomics nomogram developed by combining two independent predictors, Rad-Score and pathologic T stage, was developed in the training set [AUC, 0.840; 95% confidence interval (CI) 0.743–0.937] and validation set (AUC, 0.883; 95% CI 0.777–0.989). The calibration curve showed good agreement between the predicted probability of the radiomics-clinical model and the actual recurrence rate within 3 years after RC for BCa. DCA show the clinical application value of the radiomics-clinical model. Conclusion The radiomics-clinical nomogram model constructed based on the radiomics features of arterial CT images and important clinical risk factors is potentially feasible for predicting the risk of recurrence within 3 years after RC for BCa.

Abstract Background Thyroid eye disease (TED) is highly correlated with dysregulated immunoendocrine status. The insular cortex was found to regulate peripheral inflammation and immunomodulation in mice. This study aimed to explore whether the insular cortex in patients with TED played a modulatory role including the aberrant brain functional alteration and its association with immunoendocrine status. Methods This study included 34 active patients (AP), 30 inactive patients (IP) with TED, and 45 healthy controls (HC) matched for age, sex, and educational level. Comprehensive clinical details (especially immunoendocrine markers) and resting-state functional magnetic resonance imaging data were collected from each participant. The amplitude of low-frequency fluctuation (ALFF) was used to probe the aberrant alterations of local neural activity. The seed-based functional connectivity (FC) analysis was used to explore the relationship between the insular cortex and each voxel throughout the whole brain. The correlation analysis was conducted to assess the association between insular neurobiomarkers and immunoendocrine parameters. Results When compared with the IP and HC groups, the AP group displayed significantly higher ALFF values in the right insular cortex (INS.R) and lower FC values between the INS.R and the bilateral cerebellum. None of the neurobiomarkers differed between the IP and HC groups. Besides, correlations between insular neurobiomarkers and immunoendocrine markers (free thyroxine, the proportion of T cells, and natural killer cells) were identified in both AP and IP groups. Conclusions This study was novel in reporting that the dysregulation of the insular cortex activity in TED was associated with abnormal peripheral immunoendocrine status. The insular cortex might play a key role in central–peripheral system interaction in TED. Further research is crucial to enhance our understanding of the central–peripheral system interaction mechanisms involved in autoimmune diseases.

BackgroundThe associations of neutrophil-percentage-to-albumin ratio (NPAR) level with all-cause and cardiovascular disease (CVD)-cause mortality among patients with hypertension remain unclear. This study aims to investigate the associations of NPAR level with all-cause and CVD-cause mortality among patients with hypertension.MethodsThis prospective cohort study included 8,990 patients with hypertension who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010. Multivariable Cox proportional hazards regression models were used to compute hazard ratios and 95% CIs for the associations of NPAR level with all-cause mortality and CVD-cause mortality. Restricted cubic spline analyses were used to examine the nonlinear association of NPAR level with all-cause mortality and CVD-cause mortality.ResultsThis cohort study included data from 8,990 participants in analysis. During 104,474 person-years of follow-up, 3,069 all-cause deaths and 1,449 CVD-cause deaths were documented. Nonlinear associations were observed for NPAR levels with risk of all-cause mortality and CVD-cause mortality among patients with hypertension. Compared with participants in T1 of NPAR, there was a significantly increased risk of all-cause mortality and CVD-cause mortality for participants in both T2 and T3 in the fully adjusted model (model 3). The corresponding HRs for all-cause mortality were 1.10 (95% CI, 0.98–1.22) and 1.63 (95% CI, 1.45–1.82). The corresponding HRs for CVD-cause mortality were 1.10 (95% CI, 0.99–1.23) and 1.63 (95% CI, 1.46–1.81).ConclusionsElevated NPAR level was significantly associated with an increased risk of all-cause and CVD-cause mortality in adults with hypertension. NPAR may be clinically useful for predicting long-term health outcomes and mortality in hypertensive population.

ObjectiveThe aim of this systematic review and meta-analysis is to assess the clinical efficacy of intramedullary fixation (IF) vs. plate fixation (PF) in the treatment of midshaft clavicle fractures.MethodsWe conducted a computerized search of the electronic databases (PubMed, EMBASE, Cochrane Library, Medlineand Chinese Journal Full-text Database) from the establishment of the database to the end of November 2022. The quality of the included studies was assessed according to the Cochrane Collaboration's “Risk of bias”. Comparisons between the two groups were based on 8 variables, including Constant score, disabilities of the arm, shoulder and hand (DASH) score, surgery time, length of incision, hospital stay; time to union, blood loss and infection.ResultsThirteen randomized controlled trials (RCTs) comprising a total of 928 patients were included in our meta-analysis. The pooled results showed that IF can benefit midshaft clavicle fractures with a reduced surgery time and hospital stay, a smaller incision, a better shoulder function (DASH score), shorter time to union and lower rate of infection compared with PF. However, there was no significant difference between the two groups in terms of Constant score at 12-month follow-up.ConclusionIF is superior to PF for the treatment of midshaft clavicle fractures.

Because of its enhanced antitumor efficacy, lapatinib (LAP) is commonly used clinically in combination with the anthracycline drug doxorubicin (DOX) to treat metastatic breast cancer. While it is well recognized that this combination chemotherapy can lead to an increased risk of cardiotoxicity in adult women, its potential cardiotoxicity in the fetus during pregnancy remains understudied. Here, we aimed to examine the combination of LAP chemotherapy and DOX-induced cardiotoxicity in the fetus using a zebrafish embryonic system and investigate the underlying pathologic mechanisms. First, we examined the dose-dependent cardiotoxicity of combined LAP and DOX exposure in zebrafish embryos, which mostly manifested as pericardial edema, bradycardia, cardiac function decline and reduced survival. Second, we revealed that a significant increase in oxidative stress concurrent with activated MAPK signaling, as indicated by increased protein expression of phosphorylated p38 and Jnk, was a notable pathophysiological event after combined LAP and DOX exposure. Third, we showed that inhibiting MAPK signaling by pharmacological treatment with the p38MAPK inhibitor SB203580 or genetic ablation of the map2k6 gene could significantly alleviate combined LAP and DOX exposure-induced cardiotoxicity. Thus, we provided both pharmacologic and genetic evidence to suggest that inhibiting MAPK signaling could exert cardioprotective effects. These findings have implications for understanding the potential cardiotoxicity induced by LAP and DOX combinational chemotherapy in the fetus during pregnancy, which could be leveraged for the development of new therapeutic strategies.

PurposeThe optimal resuscitative fluid for patients with diabetic ketoacidosis (DKA) remains controversial. Therefore, our objective was to assess the effect of balanced crystalloids in contrast to normal saline on clinical outcomes among patients with DKA.MethodsWe searched electronic databases for randomized controlled trials comparing balanced crystalloids versus normal saline in patients with DKA, the search period was from inception through October 20th, 2023. The outcomes were the time to resolution of DKA, major adverse kidney events, post-resuscitation chloride, and incidence of hypokalemia.ResultsOur meta-analysis encompassed 11 trials, incorporating a total of 753 patients with DKA. There was no significant difference between balanced crystalloids and normal saline group for the time to resolution of DKA (MD -1.49, 95%CI -4.29 to 1.31, P=0.30, I2 = 65%), major adverse kidney events (RR 0.88, 95%CI 0.58 to 1.34, P=0.56, I2 = 0%), and incidence of hypokalemia (RR 0.80, 95%CI 0.43 to 1.46, P=0.46, I2 = 56%). However, there was a significant reduction in the post-resuscitation chloride (MD -3.16, 95%CI -5.82 to -0.49, P=0.02, I2 = 73%) among patients received balanced crystalloids.ConclusionAmong patients with DKA, the use of balanced crystalloids as compared to normal saline has no effect on the time to resolution of DKA, major adverse kidney events, and incidence of hypokalemia. However, the use of balanced crystalloids could reduce the post-resuscitation chloride.Systematic review registrationhttps://osf.io, identifier c8f3d.

Distributed Optical Fiber Sensing Technology, with advantages such as long detection distance, resistance to electromagnetic interference, and easy maintenance, is widely applied in various fields including security monitoring, electrical safety, and aerospace. However, the current Distributed Optical Fiber Sensing Technology faces challenges such as short localization distance, limited range for stress measurement, low accuracy, and time-consuming processes. This study proposes a novel approach for extracting Brillouin frequency shift signals using an adaptive gradient descent algorithm (Adam Algorithm). A Brillouin strain testing system based on heterodyne coherent detection is also constructed. Experimental results show that the distributed strain testing system using the Adam Algorithm can achieve accurate and fast measurement of maximum strain up to 9500 µϵ within a range of 10 kilometers. The average strain measurement deviation is 32.88 µϵ, and the time required for frequency shift extraction is less than 18.5 ms. This method provides a theoretical and experimental basis for the application of BOTDR Distributed Optical Fiber Sensing Technology.

Abstract Microglia are the resident immune cells in the brain that play a key role in driving neuroinflammation, a hallmark of neurodegenerative disorders. Inducible microglia-like cells have been developed as an in vitro platform for molecular and therapeutic hypothesis generation and testing. However, there has been no systematic assessment of similarity of these cells to primary human microglia along with their responsiveness to external cues expected of primary cells in the brain. In this study, we performed transcriptional characterization of commercially available human inducible pluripotent stem cell (iPSC)-derived microglia-like (iMGL) cells by bulk and single cell RNA sequencing to assess their similarity with primary human microglia. To evaluate their stimulation responsiveness, iMGL cells were treated with Liver X Receptor (LXR) pathway agonists and their transcriptional responses characterized by bulk and single cell RNA sequencing. Bulk transcriptome analyses demonstrate that iMGL cells have a similar overall expression profile to freshly isolated human primary microglia and express many key microglial transcription factors and functional and disease-associated genes. Notably, at the single-cell level, iMGL cells exhibit distinct transcriptional subpopulations, representing both homeostatic and activated states present in normal and diseased primary microglia. Treatment of iMGL cells with LXR pathway agonists induces robust transcriptional changes in lipid metabolism and cell cycle at the bulk level. At the single cell level, we observe heterogeneity in responses between cell subpopulations in homeostatic and activated states and deconvolute bulk expression changes into their corresponding single cell states. In summary, our results demonstrate that iMGL cells exhibit a complex transcriptional profile and responsiveness, reminiscent of in vivo microglia, and thus represent a promising model system for therapeutic development in neurodegeneration.

Abstract Background Radiomics analysis of orbital magnetic resonance imaging (MRI) shows preliminary potential for intravenous glucocorticoid (IVGC) response prediction of thyroid eye disease (TED). The current region of interest segmentation contains only a single organ as extraocular muscles (EOMs). It would be of great value to consider all orbital soft tissues and construct a better prediction model. Methods In this retrospective study, we enrolled 127 patients with TED that received 4·5 g IVGC therapy and had complete follow-up examinations. Pre-treatment orbital T2-weighted imaging (T2WI) was acquired for all subjects. Using multi-organ segmentation (MOS) strategy, we contoured the EOMs, lacrimal gland (LG), orbital fat (OF), and optic nerve (ON), respectively. By fused-organ segmentation (FOS), we contoured the aforementioned structures as a cohesive unit. Whole-orbit radiomics (WOR) models consisting of a multi-regional radiomics (MRR) model and a fused-regional radiomics (FRR) model were further constructed using six machine learning (ML) algorithms. Results The support vector machine (SVM) classifier had the best performance on the MRR model (AUC = 0·961). The MRR model outperformed the single-regional radiomics (SRR) models (highest AUC = 0·766, XGBoost on EOMs, or LR on OF) and conventional semiquantitative imaging model (highest AUC = 0·760, NaiveBayes). The application of different ML algorithms for the comparison between the MRR model and the FRR model (highest AUC = 0·916, LR) led to different conclusions. Conclusions The WOR models achieved a satisfactory result in IVGC response prediction of TED. It would be beneficial to include more orbital structures and implement ML algorithms while constructing radiomics models. The selection of separate or overall segmentation of orbital soft tissues has not yet attained its final optimal result.

Abstract Background Heart failure (HF) is a major cause of death worldwide. The most effective treatment for HF is heart transplantation, but its use is limited by the scarcity of donor hearts. Recently, stem cell-based therapy has emerged as a promising approach for treating myocardial infarction. Our research group has been investigating the use of human induced pluripotent stem cell-derived cardiomyocyte patches as a potential therapeutic candidate. We have successfully conducted eight cases of clinical trials and demonstrated the safety and effectiveness of this approach. However, further advancements are necessary to overcome immune rejection and enhance therapeutic efficacy. In this study, we propose a novel and efficient technique for constructing mesenchymal stem cell (MSC) tissue sheets, which can be transplanted effectively for treating myocardial infarction repair. Methods We applied a one-step method to construct the human adipose-derived mesenchymal stem cell (hADSC) tissue sheet on a poly(lactic-co-glycolic acid) fiber scaffold. Histology, immunofluorescence, and paracrine profile assessment were used to determine the organization and function of the hADSC tissue sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, fibrosis area, angiogenesis, and left ventricular remodeling. Results In vitro, the hADSC tissue sheet showed great organization, abundant ECM expression, and increased paracrine secretion than single cells. In vivo, the hADSC tissue sheet group demonstrated improved cardiac functional recovery, less ventricular remodeling, decreased fibrosis, and enhanced angiogenesis than the MI group. Conclusions We developed thick and functional hADSC tissue sheets via the one-step strategy. The hADSC tissue sheet showed excellent performance in treating myocardial infarction in the rat model. Graphical Abstract

Abstract Lightweight block ciphers are the essential encryption algorithm for devices with limited resources. Its goal is to ensure the security of data transmission through resource-constrained devices. Impossible differential cryptanalysis is one of the most effective cryptanalysis on block ciphers, and assessing the ability of resisting this attack is a basic design criterion. Shadow is a lightweight block cipher proposed by Guo et al. (IEEE Internet Things J 8(16):13014–13023, 2021). It utilizes a combination of ARX operations and generalized Feistel structure to overcome the weakness of the traditional Feistel structure that only diffuses half in one round. In this paper, we focus on the differential property of Shadow and its security against impossible differential cryptanalysis. First, we use the SAT method to automatically search for a full-round impossible differential distinguisher of Shadow-32. Then, based on the experimental results, we prove that Shadow has a differential property with probability 1 based on the propagation of the state. Further, we can obtain an impossible differential distinguisher for an arbitrary number of rounds of Shadow. Finally, we perform a full key recovery attack on the full-round Shadow-32 and Shadow-64. Both experimentally and theoretically, our results indicate that Shadow is critically flawed, and regardless of the security strength of the internal components and the number of rounds applied, the overall cipher remains vulnerable to impossible differential cryptanalysis.

BackgroundThe success rate of periprosthetic joint infection (PJI) treatment is still low. Early diagnosis is the key to successful treatment. Therefore, it is necessary to find a biomarker with high sensitivity and specificity. The diagnostic value of serum procalcitonin (PCT) for PJI was systematically evaluated to provide the theoretical basis for clinical diagnosis and treatment in this study.MethodsWe searched the Web of Science, Embase, Cochrane Library, and PubMed for studies that evaluated the diagnostic value of serum PCT for PJI (from the inception of each database until September 2020). Two authors independently screened the literature according to the inclusion and exclusion criteria. The quality of each selected literature was evaluated by using the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) tool. RevMan 5.3 software was used for the quality evaluation. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were merged by using Meta-DiSc 1.4 software. The area under the curve (AUC) and Q index were calculated after the summary receiver operating characteristic (SROC) was generated. We also performed subgroup analysis.ResultsA total of 621 patients were enrolled in the nine studies. The pooled sensitivity of serum PCT for PJI diagnosis was 0.441 [95% confidence interval (CI), 0.384–0.500], the pooled specificity was 0.852 (95% CI, 0.811–0.888), the pooled PLR was 2.271 (95% CI, 1.808–2.853), the pooled NLR was 0.713 (95% CI, 0.646–0.786), and the pooled DOR was 5.756 (95% CI, 3.673–9.026). The area under SROC (the pooled AUC) was 0.76 (0.72–0.79). Q index was 0.6948.ConclusionThis study showed that PCT detection of PJI had poor diagnostic accuracy. Hence, the serum PCT is not suitable as a serum marker for PJI diagnosis.

BackgroundIn recent years, novel therapies targeting specific molecular pathways and immunotherapies have exhibited promising outcomes for treating human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Our work aimed to assess the effectiveness and safety of these emerging treatment regimens for this disease.Material and methodsWe systematically searched databases including PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials their inception to August 2023 to identify relevant randomized controlled trials (RCTs). The quality of eligible RCTs was evaluated with the Cochrane risk-of-bias tool, version 2 (RoB2). Investigated outcomes encompassed progression-free survival (PFS), overall survival (OS), disease-free survival (DFS), pathologic complete remission (pCR), and adverse events (AEs). They were expressed as hazard ratio (HR) with 95% conference intervals (CI) or risk ratio (RR) with 95% CI.ResultsOur analysis identified a total of 28 RCTs suitable for inclusion in the NMA. Regarding the PFS, all these treatment regimens exhibited comparable effectiveness. In terms of OS, Capecitabine+Trastuzumab, Lapatinib+Trastuzumab and Pyrotinib+Capecitabine exhibited better effect compared to other treatments. Regarding pCR and AEs, all these treatment regimens exhibited comparable effectiveness, especially Lapatinib+Trastuzumab and Pyrotinib+Capecitabine.ConclusionOur study highlights the prominent role of targeted therapies and immunotherapies in treating HER2-positive breast cancer. The efficacy of trastuzumab-containing regimens was superior to other treatment options, while maintaining a comparable safety profile. Based on these findings, trastuzumab-containing regimens emerge as a preferable and recommended choice in clinical practice for managing HER2-positive breast cancer.Systematic Review RegistrationPROSPERO, identifier CRD42023414348.

Summary: Neuromodulation is pivotal in modifying neuronal properties and motor states. CKR-1, a homolog of the cholecystokinin receptor, modulates robust escape steering and undulation body bending in C. elegans. Nevertheless, the mechanisms through which CKR-1 governs these motor states remain elusive. We elucidate the head motoneuron SMD as the orchestrator of both motor states. This regulation involves two neuropeptides: NLP-12 from DVA enhances undulation body curvature, while NLP-18 from ASI amplifies Ω-turn head curvature. Moreover, synthetic NLP-12 and NLP-18 peptides elicit CKR-1-dependent currents in Xenopus oocytes and Ca2+ transients in SMD neurons. Notably, CKR-1 shows higher sensitivity to NLP-18 compared to NLP-12. In situ patch-clamp recordings reveal CKR-1, NLP-12, and NLP-18 are not essential for neurotransmission at C. elegans neuromuscular junction, suggesting that SMD independently regulates head and body bending. Our studies illustrate that a single motoneuron SMD utilizes a cholecystokinin receptor CKR-1 to integrate two motor states.

This study aimed to evaluate the usefulness of optical coherence tomography angiography (OCTA) in assessing retinal microvascular structural changes in preterm-born children and compare them with those in term-born children. The Web of Science Library, Cochrane Library, PubMed, Embase, CNKI, Wanfang, VIP, and Sino Med databases were searched systematically to extract studies published till April 25, 2023. Two independent reviewers searched all the literature and completed the data extraction and quality assessment. Mean differences (MDs) with 95% confidence intervals (CIs) were used to assess the continuous estimates. STATA software (v15.1; StataCorp, College Station, TX) was used to analyze the data. Twelve published studies were eligible for inclusion in this study. The meta-analysis revealed that the foveal avascular zone (FAZ) area of preterm-born children was remarkably smaller than that of term-born children, with the laser photocoagulation (LP)-ROP group showing the most pronounced reduction. The foveal superficial capillary plexus vessel density (SCP-VD) and deep capillary plexus vessel density (DCP-VD) were remarkably higher in the preterm-born group than in the control group, with variations in subgroups (LP-ROP, anti-VEGF-ROP, SR-ROP, and Pre-T-ROP). The parafoveal SCP-VD was remarkably lower in preterm-born children compared to that of the controls, while no significant difference was identified in the parafoveal DCP-VD. Preterm-born children had a smaller FAZ area, higher foveal SCP-VD and DCP-VD, and lower parafoveal SCP-VD compared to their term-born counterparts. The parafoveal DCP-VD did not differ substantially between preterm- and term-born children. OCTA is an effective modality for assessing alterations in the retinal microvasculature in preterm children.

The lean resource management and reliable interaction of massive data are important components of a low-carbon-oriented new grid. However, with a high proportion of distributed low-carbon resources connected to a new grid, issues such as data anomalies, data redundancy, and missing data lead to inefficient resource management and unreliable interaction, affecting the accuracy of power grid decision-making, as well as the effectiveness of emission reduction and carbon reduction. Therefore, this paper proposes a lean resource management and reliable interaction framework of a middle platform based on distributed data governance. On this basis, a distributed data governance approach for the lean resource management method of the middle platform in the low-carbon new grid is proposed, which realizes anomalous data cleaning and missing data filling. Then, a data storage and traceability method for reliable interaction is proposed, which prevents important data from being illegally tampered with in the interaction process. The simulation results demonstrate that the proposed algorithm significantly enhances efficiency, reliability, and accuracy in anomalous data cleaning and filling, as well as data traceability.

Abstract The solid wastes such as coal bottom ash and tailings are currently widely used in various building materials, but further research on their application in autoclaved aerated concrete (AAC) is needed. To study the physical and mechanical properties of AAC produced from coal bottom ash and tailings, the pore characteristics of two different density grades of AAC were extracted and analyzed, and wave velocity and uniaxial compressive tests under water‐saturated and dry conditions were carried out. The results show that the AAC produced from solid waste has excellent performance. The specimen is anisotropic, and the pore size distribution of its cross‐section is mainly concentrated in the ranges of

BackgroundUsual-type cervical adenocarcinoma is the most frequent type of adenocarcinoma, and its prevalence is increasing worldwide. Tumor recurrence is the leading cause of mortality; therefore, recognizing the risk factors for cervical cancer recurrence and providing effective therapy for recurrent cervical cancer are critical steps in increasing patient survival rates. This study aimed to retrospectively analyze the clinicopathological data of patients with usual-type cervical adenocarcinoma by combining the diagnosis and treatment records after the initial treatment and recurrence.MethodsWe retrospectively analyzed patients diagnosed with usual-type cervical adenocarcinoma who underwent radical hysterectomy and pelvic lymph node dissection at Shengjing Hospital of China Medical University between June 2013 and June 2022. We constructed a nomogram-based postoperative recurrence prediction model, internally evaluated its efficacy, and performed internal validation.ResultsThis study included 395 participants, including 87 individuals with recurrence. At a 7:3 ratio, the 395 patients were divided into two groups: a training set (n = 276) and a validation set (n = 119). The training set was subjected to univariate analysis, and the risk variables for recurrence included smoking, ovarian metastasis, International Federation of Gynaecology and Obstetrics (FIGO) staging, lymphovascular space invasion, perineural invasion, depth of muscular invasion, tumor size, lymph node metastasis, and postoperative HPV infection months. The aforementioned components were analyzed using logistic regression analysis, and the results showed that the postoperative HPV infection month, tumor size, perineural invasion, and FIGO stage were independent risk factors for postoperative recurrence (p

Summary: Human iPSC-derived cardiomyocytes (hiPSC-CMs) exhibit functional immaturity, potentially impacting their suitability for assessing drug proarrhythmic potential. We previously devised a traveling wave (TW) system to promote maturation in 3D cardiac tissue. To align with current drug assessment paradigms (CiPA and JiCSA), necessitating a 2D monolayer cardiac tissue, we integrated the TW system with a multi-electrode array. This gave rise to a hiPSC-derived closed-loop cardiac tissue (iCT), enabling spontaneous TW initiation and swift pacing of cardiomyocytes from various cell lines. The TW-paced cardiomyocytes demonstrated heightened sarcomeric and functional maturation, exhibiting enhanced response to isoproterenol. Moreover, these cells showcased diminished sensitivity to verapamil and maintained low arrhythmia rates with ranolazine—two drugs associated with a low risk of torsades de pointes (TdP). Notably, the TW group displayed increased arrhythmia rates with high and intermediate risk TdP drugs (quinidine and pimozide), underscoring the potential utility of this system in drug assessment applications.

Abstract Eradication of MRSA osteomyelitis requires elimination of distinct biofilms. To overcome this, we developed bisphosphonate-conjugated sitafloxacin (BCS, BV600072) and hydroxybisphosphonate-conjugate sitafloxacin (HBCS, BV63072), which achieve “target-and-release” drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo. Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA (USA300LAC::lux). Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging (BLI) after debridement and implant exchange surgery on day 7, and mice were randomized into seven groups: 1) Baseline (harvested at day 7, no treatment); 2) HPBP (bisphosphonate control for BCS) + vancomycin; 3) HPHBP (hydroxybisphosphonate control for HBCS) + vancomycin; 4) vancomycin; 5) sitafloxacin; 6) BCS + vancomycin; and 7) HBCS + vancomycin. BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS + vancomycin. Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS + vancomycin, which also displayed decreases in peri-implant bone loss, osteoclast numbers, and biofilm. To confirm this, we assessed the efficacy of vancomycin, sitafloxacin, and HBCS monotherapy in a transtibial implant model. The results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control, and some had evidence of osseous integrated septic implants, suggestive of biofilm eradication. Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.

The equilibrium optimizer (EO) algorithm is a newly developed physics-based optimization algorithm, which inspired by a mixed dynamic mass balance equation on a controlled fixed volume. The EO algorithm has a number of strengths, such as simple structure, easy implementation, few parameters and its effectiveness has been demonstrated on numerical optimization problems. However, the canonical EO still presents some drawbacks, such as poor balance between exploration and exploitation operation, tendency to get stuck in local optima and low convergence accuracy. To tackle these limitations, this paper proposes a new EO-based approach with an adaptive gbest-guided search mechanism and a chaos mechanism (called a chaos-based adaptive equilibrium optimizer algorithm (ACEO)). Firstly, an adaptive gbest-guided mechanism is injected to enrich the population diversity and expand the search range. Next, the chaos mechanism is incorporated to enable the algorithm to escape from the local optima. The effectiveness of the developed ACEO is demonstrated on 23 classical benchmark functions, and compared with the canonical EO, EO variants and other frontier metaheuristic approaches. The experimental results reveal that the developed ACEO method remarkably outperforms the canonical EO and other competitors. In addition, ACEO is implemented to solve a mobile robot path planning (MRPP) task, and compared with other typical metaheuristic techniques. The comparison indicates that ACEO beats its competitors, and the ACEO algorithm can provide high-quality feasible solutions for MRPP.

Carbon dioxide (CO2) is a non-toxic, abundant and recoverable source of carbon monoxide. Despite its thermodynamically stable and kinetically inert nature, research on CO2 utilisation is ongoing. CO2-based aryne reactions, crucial for synthesising ortho-substituted benzoic acids and their cyclisation products, have garnered significant attention, and multi-component reactions (MCRs) involving CO2, aryne and nucleophilic reagents have been extensively studied. This review highlights recent advancements in CO2 capture reactions utilising phenylalkyne reactive intermediates. Mechanistic insights into these reactions are provided together with prospects for further development in this field.

ABSTRACT This study aimed to develop and validate a simple-to-use nomogram model to assess the risk of infection caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) in neurocritically ill patients. The clinical data of 544 patients with CRKP infection admitted to a neurointensive care unit (neuro-ICU) were retrospectively analyzed. The demographic data, laboratory test results, and clinical characteristics of patients in the neuro-ICU were collected. Subsequently, multivariate regression analysis was used to construct a nomogram to predict the risk of CRKP infection in these patients. The calibration ability, clinical effectiveness, and discriminative ability of the nomogram were evaluated. The incidence of CRKP infection was estimated to be 6.43%, and a majority of bacterial isolates causing the infection were found in sputum (74.3%). Multivariate regression analysis showed that the number of antibiotics of ≥2 [odds ratio (OR): 9.08, 95% confidence interval (CI): 2.78–29.71], undergoing surgery (OR: 3.84, 95% CI: 1.09–13.54), and long neuro-ICU stay (OR: 1.08, 95% CI: 1.01–1.14) were associated with CRKP infection in neurocritically ill patients. The nomogram model demonstrated good calibration and discrimination in both the training and validation sets, with area under the curve values of 0.860 and 0.907, respectively. This study developed and validated a nomogram that combines three easily accessed variables during clinical practice to predict the risk of nosocomial CRKP infection in neuro-ICU patients. The tool demonstrated a good predictive performance and discrimination, which might serve as a useful tool to facilitate early detection and reduction of the CRKP infection risk in neurocritically ill patients. IMPORTANCE Patients in neuro-ICU are at a high risk of developing nosocomial CRKP infection owing to complex conditions, critical illness, and frequent invasive procedures. However, studies focused on constructing prediction models for assessing the risk of CRKP infection in neurocritically ill patients are lacking at present. Therefore, this study aims to establish a simple-to-use nomogram for predicting the risk of CRKP infection in patients admitted to the neuro-ICU. Three easily accessed variables were included in the model, including the number of antibiotics used, surgery, and the length of neuro-ICU stay. This nomogram might serve as a useful tool to facilitate early detection and reduction of the CRKP infection risk of neurocritically ill patients.

Introduction: Cancer remains a significant health challenge, with chemotherapy being a critical treatment modality. However, traditional chemotherapy faces limitations due to non-specificity and toxicity. Nanogels, as advanced drug carriers, offer potential for targeted and controlled drug release, improving therapeutic efficacy and reducing side effects.Methods: This review summarizes the latest developments in nanogel-based chemotherapy drug delivery systems, focusing on the role of functional groups in drug loading and the design of smart hydrogels with controlled release mechanisms. We discuss the preparation methods of various nanogels based on different functional groups and their application in cancer treatment.Results: Nanogels composed of natural and synthetic polymers, such as chitosan, alginate, and polyacrylic acid, have been developed for chemotherapy drug delivery. Functional groups like carboxyl, disulfide, and hydroxyl groups play crucial roles in drug encapsulation and release. Smart hydrogels have been engineered to respond to tumor microenvironmental cues, such as pH, redox potential, temperature, and external stimuli like light and ultrasound, enabling targeted drug release.Discussion: The use of functional groups in nanogel preparation allows for the creation of multifunctional nanogels with high drug loading capacity, controllable release, and good targeting. These nanogels have shown promising results in preclinical studies, with enhanced antitumor effects and reduced systemic toxicity compared to traditional chemotherapy.Conclusion: The development of smart nanogels with functional group-mediated drug delivery and controlled release strategies represents a promising direction in cancer therapy. These systems offer the potential for improved patient outcomes by enhancing drug targeting and minimizing adverse effects. Further research is needed to optimize nanogel design, evaluate their safety and efficacy in clinical trials, and explore their potential for personalized medicine.

Myeloid-derived suppressor cells (MDSCs) occupy a pivotal role in the intricate pathogenesis of the autoimmune disorder, Type 1 diabetes mellitus (T1DM). Since our previous work demonstrated that trichosanthin (TCS), an active compound of Chinese herb medicine Tian Hua Fen, regulated immune response, we aimed to clarify the efficacy and molecular mechanism of TCS in the treatment of T1DM. To this end, T1DM mouse model was established by streptozotocin (STZ) induction. The mice were randomly divided into normal control group (Ctl), T1DM group (STZ), TCS treated diabetic group (STZ + TCS) and insulin-treated diabetic group (STZ + insulin). Our comprehensive evaluation encompassed variables such as blood glucose, glycosylated hemoglobin, body weight, pertinent biochemical markers, pancreatic histopathology, and the distribution of immune cell populations. Furthermore, we meticulously isolated MDSCs from the bone marrow of T1DM mice, probing into the expressions of genes pertaining to the advanced glycation end product receptor (RAGE)/NF-κB signaling pathway through RT-qPCR. Evidently, TCS exhibited a substantial capacity to effectively counteract the T1DM-induced elevation in random blood glucose, glycosylated hemoglobin, and IL-6 levels in plasma. Pathological scrutiny underscored the ability of TCS to mitigate the damage incurred by islets. Intriguingly, TCS interventions engendered a reduction in the proportion of MDSCs within the bone marrow, particularly within the IL-6+ MDSC subset. In contrast, IL-10+ MDSCs exhibited an elevation following TCS treatment. Moreover, we observed a significant down-regulation of relative mRNA of pro-inflammatory genes, including arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), RAGE and NF-κB, within MDSCs due to the influence of TCS. It decreases total MDSCs and regulates the balance between IL-6+ and IL-10+ MDSCs thus alleviating the symptoms of T1DM. TCS also down-regulates the RAGE/NF-κB signaling pathway, making it a promising alternative therapeutic treatment for T1DM. Collectively, our study offered novel insights into the underlying mechanism by which TCS serves as a promising therapeutic intervention for T1DM.

Background & Aims: Current antiviral drugs, including nucleoside analogs and interferon, fail to eliminate the HBV covalently closed circular DNA (cccDNA), which serves as a transcript template in infected hepatocytes. Silencing the HBV X protein, which plays a crucial role in cccDNA transcription, is a promising approach to inhibit HBV replication. Therefore, the identification of novel compounds that can inhibit HBx-mediated cccDNA transcription is critical. Methods: Initially, a compound library consisting of 715 monomers derived from traditional Chinese medicines known for their liver-protecting properties was established. Then, MTT assays were used to determine the cytotoxicity of each compound. The effect of candidates on Flag-HBx expression was examined by real-time PCR and western blotting in Flag-HBx transfected HepG2-NTCP cells. Ultimately, the antiviral effect of gambogic acid (GA) on HBV was observed in HBV-infected HepG2-NTCP cells. Mechanistically, the functional role of DTX1 in GA-induced HBV inhibition was examined using RNA-seq. Finally, the antiviral effect of GA was estimated in vivo. Results: Gambogic acid (GA), a natural bioactive compound with a myriad of biological activities, markedly reduced Flag-HBx expression. Potent and dose-dependent reductions in extracellular HBV RNAs, HBV DNA, HBsAg, HBeAg and HBc protein were discovered three days after GA treatment in HBV-infected cells, accompanied by the absence of significant cytotoxicity. Furthermore, our research revealed that GA exhibited a dose-dependent inhibition of HBx expression, which is a pleiotropic protein required for HBV infection in vivo. We explored the mechanisms underlying GA-mediated inhibition of HBV and confirmed that this inhibition is accomplished by upregulating the expression of the DTX1 gene and boosting the Notch signaling pathway. Finally, the inhibitory effect of GA on HBV replication was tested in vivo using a mouse model of hepatitis B virus recombinant cccDNA. Conclusions: Herein, we discovered GA, which is a natural bioactive compound that targets HBx to inhibit hepatitis B virus replication by activating the DTX1-Notch signaling pathway.

BackgroundThe relative prognostic importance of handgrip strength (HGS) in comparison with other risk factors for mortality remains to be further clarified, and thresholds used for best identify high-risk individuals in health screening are not yet established. Using machine learning and nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS), the study aimed to investigate the prognostic importance of HGS and establish sex-specific thresholds for health screening.MethodsA total of 6,762 participants from CHARLS were enrolled. A random forest model was built using 30 variables with all-cause mortality as outcome. SHapley Additive exPlanation values were applied to explain the model. Cox proportional hazard models and Harrell’s C index change were used to validate the clinical importance of the thresholds.ResultsAmong the participants, 3,102 (45.9%) were men, and 622 (9.1%) case of death were documented follow-up period of 6.78 years. The random forest model identified HGS as the fifth important prognostic variable, with thresholds for identifying high-risk individuals were

In this study, we explored the impact of ionic liquid gating on YBa2Cu3O7−x superconductivity. We observed that direct contact of YBa2Cu3O7−x and the ionic liquid N-diethyl-N-methyl-N-(2methoxyethyl)ammonium bis(trifluoromethanesulfonyl)imide (DEME-TFSI) results in irreversible electrochemical reactions, despite the application of a relatively low gate voltage at 220 K. Capping a thin layer of boron nitride (BN) on YBa2Cu3O7−x enabled a reversible modulation of carrier density at 300 K. Benefiting from the higher ion mobility of ionic liquid at 300 K, this modification led to more than a one-time increase in carrier density, a 3-time improvement in voltage modulation efficiency, and a reversible tuning of the superconducting temperature. These findings suggest that using a BN capping layer holds promise for enhancing the stability and efficiency of devices using ionic liquid gating.

ABSTRACTSepsis is a leading cause of fatality in invasive candidiasis. The magnitude of the inflammatory response is a determinant of sepsis outcomes, and inflammatory cytokine imbalances are central to the pathophysiological processes. We previously demonstrated that a Candida albicans F1Fo-ATP synthase α subunit deletion mutant was nonlethal to mice. Here, the potential effects of the F1Fo-ATP synthase α subunit on host inflammatory responses and the mechanism were studied. Compared with wild-type strain, the F1Fo-ATP synthase α subunit deletion mutant failed to induce inflammatory responses in Galleria mellonella and murine systemic candidiasis models and significantly decreased the mRNA levels of the proinflammatory cytokines IL-1β, IL-6 and increased those of the anti-inflammatory cytokine IL-4 in the kidney. During C. albicans-macrophage co-culture, the F1Fo-ATP synthase α subunit deletion mutant was trapped inside macrophages in yeast form, and its filamentation, a key factor in inducing inflammatory responses, was inhibited. In the macrophage-mimicking microenvironment, the F1Fo-ATP synthase α subunit deletion mutant blocked the cAMP/PKA pathway, the core filamentation-regulating pathway, because it failed to alkalinize environment by catabolizing amino acids, an important alternative carbon source inside macrophages. The mutant downregulated Put1 and Put2, two essential amino acid catabolic enzymes, possibly due to severely impaired oxidative phosphorylation. Our findings reveal that the C. albicans F1Fo-ATP synthase α subunit induces host inflammatory responses by controlling its own amino acid catabolism and it is significant to find drugs that inhibit F1Fo-ATP synthase α subunit activity to control the induction of host inflammatory responses.

BackgroundCurrently, there is no “gold standard” for early diagnosing PJI. The diagnosis of periprosthetic joint infection (PJI) is a challenging problem in the clinic. As we know, many serum markers have been used in the early diagnosis of PJI. The aim of this study was to validate the value of PCT in the diagnosis of PJI.MethodsA retrospective review of 77 patients with revision arthroplasties from January 2013 to July 2020 was conducted. PJI was defined using the modified Musculoskeletal Infection Society (MSIS) criteria combined with follow-up results. Besides medical history, clinical and laboratory data was gathered. Preoperative blood was taken for serum PCT and other biomarkers measurement. Receiver operating characteristic (ROC) curves were generated to evaluate the biomarkers’ diagnostic performance and optimal cut-off value.ResultsForty-one patients were identified as the PJI group (27 hips and 14 knees), while thirty-six patients were identified as the aseptic loosening (AL) group (33 hips and 3 knees). The AUCs for C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Platelets (PLT), Fibrinogen (FIB), and Procalcitonin (PCT) were 0.845 (95% CI 0.755–0.936, p

Objective: To evaluate the relationship between periodontitis and postmenopausal osteoporosis. Methods: This research was carried out according to the principles laid down by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline statement. We searched the Web of Science, Embase, PubMed, The Cochrane Library, CNKI, VIP, and WanFang databases from inception to July 1, 2023 to collect all relevant publications, with no restrictions on publication date or Languages. Cochrane's tool for assessing RoB was used to evaluate the RoB for RCTs. The Newcastle-Ottawa Scale was used to assess the RoB for cohort studies and case-control studies. Mean differences (MD) with 95 % confidence intervals (CI) were used for analysis of continuous data. Heterogeneity was measured using the I2 statistic. Revman 5.4 software was used for the meta-analysis. Results: 28 observational studies with 19611 patients, including 5813 cases in the postmenopausal osteoporosis group and 13798 cases in the non-osteoporosis group. The studies showed that the degrees of clinical attachment loss (CAL), probing depth (PD), gingival recession (GR), simplified oral hygiene index (OHIS), and percentage of sites with bleeding on probing (BOP) in the postmenopausal osteoporosis group were higher than those in the non-osteoporosis group[CAL(MD = 0.89(mm), 95 % CI [0.48,1.30], p

The feasibility of chemobiocatalytic production of furfuryl alcohol from biomass-derived D-xylose was investigated using a tandem catalysis with deep eutectic solvent betaine:benzenesulfonic acid (DES BE:BA) and recombinant Escherichia coli DCF cell. The DES BE:BA (2.5 wt%) was applied to catalyze D-xylose under 170 °C for 0.5 h, resulting in a furfural yield of 51.1%. Consequently, recombinant Escherichia coli DCF fully transformed D-xylose-derived furfural to furfuryl alcohol in DES BE:BA-water under pH 7.5 and 40 °C using HCOONa as cosubstrate. This eco-friendly chemobiocatalytic strategy was successfully applied for transforming D-xylose to furfuryl alcohol in DES BE:BA-water.

Litter distribution significantly affects nutrient cycling, energy transfer, and various ecosystem services. However, little is known about how microtopography affects litter accumulation and distribution on the forest floor. Distribution characteristics of litter stocks at the slope-scale and their relationship with topography and rock exposure rate (RER) in a typical subtropical karst forest in China were determined by measuring the litter stock and RER of 300 grids of1 × 1 m in a 10 × 120 m square on a limestone hill. The results showed that (1) the average litter stock of karst forest was 691.54 ± 332.60 g∙m-2, among which 65.81% was undecomposed litter; (2) the spatial distribution of litter stocks was uneven with moderate variation, presenting five aggregated areas and four sparse areas on the entire slope; (3) there was a significant negative correlation between RER and litter stock (R = −0.37, P

Lift-off velocity, the wind speed at which a diaspore starts moving during secondary wind dispersal, representing diaspore mobile capacity, may greatly depend on vegetation where dispersal takes place. However, how vegetation structure influences lift-off velocity and which is the most important vegetation attribute remain unknown. The vegetation with various attributes (four coverages-0, 10 %, 20 % and 30 %, three life-form compositions-herb, shrub and herb + shrub, two vertical patterns-one and two layers, and two horizontal patterns-uniform and aggregated) were set up for the wind tunnel experiment. Diaspores of 30 species varied in wing loading, terminal velocity, mass, projected area, length, width, height, and shape index were selected to measure their lift-off velocity within various vegetation structures. Lift-off velocity significantly increased with the increasing vegetation coverage, in the case of any life-form composition, vertical pattern and horizontal pattern of vegetation. For the vertical pattern of vegetation, the lift-off velocity in one-layer vegetation was significantly higher than that in two-layer vegetation, but only for 10 % vegetation coverage. Both the life-form composition and the horizontal pattern of vegetation had no influences on lift-off velocity. The correlation between lift-off velocity and diaspore attributes (length, width, height, projected area, mass and wing loading) increased with vegetation coverage and the correlation in two-layer vegetation was larger than that in one-layer vegetation. Our results indicate that vegetation coverage is the key vegetation attribute determining lift-off velocity during secondary wind dispersal. Lift-off velocity is also influenced by diaspore traits, but their relationships tend to be regulated by vegetation attributes, especially the coverage and vertical pattern of vegetation. Our study demonstrates the important role of vegetation coverage in determining the second dispersal capacity, which is helpful to understand the dispersal strategies of plants in response to vegetation structure and succession.

Abstract Purpose Humeral shaft fractures (HSFs) can be treated non-operatively (Non-OP), with open reduction and plate osteosynthesis (ORPO), minimally invasive plate osteosynthesis (MIPO), or with intramedullary nails (IMN). However, the best treatment for HSFs still remains controversial.We performed a network meta-analysis to explore which should be the best method for HSFs. Methods The computerized search had been conducted on electronic databases PubMed, EMBASE, Cochrane Library, and Medline from the establishment of the database to the end of December 2022. The quality evaluation of the included literature had been completed by Review Manager (version 5.4.1). Stata 17.0 software (Stata Corporation, College Station, Texas, USA)was used for network meta-analysis.We included randomized controlled trials (RCTs) comparing different treatments to treating HSFs. Results The pairwise comparison results demonstrated that there was no statistical difference between IMN, MIPO, Non-OP, and ORPO in terms of radial nerve injury and infection, and Non-OP presented significantly more nonunion than ORPO, IMN, and MIPO. However, no statistically significant difference between ORPO, IMN, and MIPO was discovered. The results of the network meta-analysis displayed that surface under the cumulative ranking curve (SUCRA) probabilities of IMN, MIPO, Non-OP, and ORPO in radial nerve injury were 46.5%, 66.9%, 77.3%, and 9.3%, respectively, in contrast, that in infection were 68.6%, 53.3%, 62.4%, and 15.4%, respectively, and that in nonunion were 51.7%, 93.1%, 0.7%, and 54.5%, respectively. Conclusion We came to the conclusion that MIPO is currently the most effective way to treat HSFs. Trial registration Name of the registry: Prospero, 2. Unique Identifying number or registration ID: CRD42023411293.

In recent years, with the continuous improvement of medical level, people pay more attention to their own health, pulmonary nodules and other space-occupying lesions can be detected earlier, but on a global scale, the number of deaths caused by malignant lung lesions Still rising and remaining high. Radiomics is an emerging field that aims to derive automated quantitative imaging features from medical images to noninvasively predict nodular and tumor behavior. Compared with traditional visual image features, radiomics can extract more nodular features with better reproducibility. The scientific and systematic use of radiomics can not only prevent excessive medical behaviors and reduce the economic burden of patients, but also enable patients with lung lesions to receive early treatment for the best prognosis.

Abstract The accumulation of foam cells in arterial intima and the accompanied chronic inflammation are considered major causes of neoatherosclerosis and restenosis. However, both the underlying mechanism and effective treatment for the disease are yet to be uncovered. In this study, we combined transcriptome profiling of restenosis artery tissue and bioinformatic analysis to reveal that NLRP3 inflammasome is markedly upregulated in restenosis and that several restenosis‐related DEGs are also targets of mulberry extract, a natural dietary supplement used in traditional Chinese medicine. We demonstrated that mulberry extract suppresses the formation of ox‐LDL‐induced foam cells, possibly by upregulating the cholesterol efflux genes ABCA1 and ABCG1 to inhibit intracellular lipid accumulation. In addition, mulberry extract dampens NLRP3 inflammasome activation by stressing the MAPK signaling pathway. These findings unveil the therapeutic value of mulberry extract in neoatherosclerosis and restenosis treatment by regulating lipid metabolism and inflammatory response of foam cells.

Abstract Dysregulated lineage commitment of mesenchymal stem cells (MSCs) contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis. The intrinsic cellular mechanism that regulates MSC commitment remains unclear. Here, we identified Cullin 4B (CUL4B) as a critical regulator of MSC commitment. CUL4B is expressed in bone marrow MSCs (BMSCs) and downregulated with aging in mice and humans. Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation. Moreover, depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy. In addition, CUL4B deficiency in MSCs reduced bone strength. Mechanistically, CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδ expression, respectively. The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription. Collectively, this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs, which has therapeutic implications in osteoporosis.

Abstract Neutrophil extracellular traps (NETs) play an important role in abdominal aortic aneurysm (AAA) formation; however, the underlying molecular mechanisms remain unclear. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) may exert therapeutic effects on AAA through their immunomodulatory and regenerative abilities. This study aimed to examine the role and mechanism of MSC-EVs in regulating the development of NET-mediated AAA. Excessive release of NETs was observed in patients with AAA, and the levels of NET components were associated with the clinical outcomes of the patients. Datasets from the Gene Expression Omnibus database were analyzed and revealed that the PI3K/AKT pathway and ferroptosis were strongly associated with NETosis during AAA formation. Further experiments verified that NETs promoted AAA formation by inducing ferroptosis in smooth muscle cells (SMCs) by inhibiting the PI3K/AKT pathway. The PI3K agonist 740 Y-P, the ferroptosis inhibitor ferrostatin-1, and Padi4 deficiency significantly prevented AAA formation. MSC-EVs attenuated AAA formation by reducing NET release in an angiotensin II-induced AAA mouse model. In vitro experiments revealed that MSC-EVs reduced the release of NETs by shifting NETosis to apoptosis. Our study indicates an important role for NET-induced SMC ferroptosis in AAA formation and provides several potential targets for AAA treatment.