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Abstract Breast cancer remains a significant global health challenge, and its mechanisms of progression and metastasis are still not fully understood. In this study, analysis of TCGA and GEO datasets revealed a significant increase in CCT2 expression in breast cancer tissues, which was associated with poor prognosis in breast cancer patients. Functional analysis revealed that CCT2 promoted breast cancer growth and metastasis through activation of the JAK2/STAT3 signaling pathway. Additionally, the E3 ubiquitin ligase Trim21 facilitated CCT2 ubiquitination and degradation, significantly reversing the protumor effects of CCT2. Most interestingly, we discovered that exosomal CCT2 derived from breast cancer cells suppressed the activation and proinflammatory cytokine secretion of CD4+ T cell. Mechanistically, exosomal CCT2 constrained Ca2+-NFAT1 signaling, thereby reducing CD40L expression on CD4+ T cell. These findings highlight CCT2 upregulation as a potential driver of breast cancer progression and immune evasion. Our study provides new insights into the molecular mechanisms underlying breast cancer progression, suggesting that CCT2 is a promising therapeutic target and prognostic predictor for breast cancer.

Abstract [11C]Carfentanil ([11C]CFN) is the only selective carbon-11 labeled radiotracer currently available for positron emission tomography (PET) imaging of mu opioid receptors (MORs). Though used extensively in clinical research, [11C]CFN has not been thoroughly characterized as a tool for preclinical PET imaging. As we were occasionally observing severe vital sign instability in rat [11C]CFN studies, we set out to investigate physiological effects of CFN mass and to explore its influence on MOR quantification. In anesthetized rats (n = 15), significant dose-dependent PCO2 increases and heart rate decreases were observed at a conventional tracer dose range (IV, > 100 ng/kg). Next, we conducted baseline and retest [11C]CFN PET scans over a wide range of molar activities. Baseline [11C]CFN PET studies (n = 27) found that nondisplaceable binding potential (BPND) in the thalamus was positively correlated to CFN injected mass, demonstrating increase of MOR availability at higher injected CFN mass. Consistently, when CFN injected mass was constrained

Abstract Background Cellular senescence is essential to TME development, progression, and remodeling. Few studies have examined cellular senescence in HCC after TACE. Investigating the relationship between cellular senescence, post-TACE prognosis, the TME, and immune treatment responses is crucial. Methods We analyzed the GSE104580 dataset to identify DEGs. A cellular senescence-related signature was developed using LASSO Cox regression in the GSE14520 dataset and validated in the ICGC dataset. High- and low-risk subgroups were compared using GSVA and GSEA. Correlation studies were conducted to explore the relationship between the prognostic model, immune infiltration, immunotherapy response, and drug sensitivity. Results A cellular senescence-related signature comprising FOXM1, CDK1, CHEK1, and SERPINE1 was created and validated. High-risk patients showed significantly lower OS than low-risk patients. High-risk patients had carcinogenetic pathways activated, immunosuppressive cells infiltrated, and immunomodulatory genes overexpressed. They also showed higher sensitivity to EPZ004777_1237 and MK-2206_1053 and potential benefits from GSK-3 inhibitor IX, nortriptyline, lestaurtinib, and JNK-9L. Conclusions This study constructed a cellular senescence-related signature that could be used to predict HCC patients’ responses to and prognosis after TACE treatment, aiding in the development of personalized treatment plans.

Abstract Background Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated. Methods RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3. Results Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients. Conclusions Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.

Abstract Peptides and proteins encoded by noncanonical open reading frames (ORFs) of circRNAs have recently been recognized to play important roles in disease progression, but the biological functions and mechanisms of these peptides and proteins are largely unknown. Here, we identified a potential coding circular RNA, circTRIM1, that was upregulated in doxorubicin-resistant TNBC cells by intersecting transcriptome and translatome RNA-seq data, and its expression was correlated with clinicopathological characteristics and poor prognosis in patients with TNBC. CircTRIM1 possesses a functional IRES element along with an 810 nt ORF that can be translated into a novel endogenously expressed protein termed TRIM1-269aa. Functionally, we demonstrated that TRIM1-269aa, which is involved in the biological functions of circTRIM1, promoted chemoresistance and metastasis in TNBC cells both in vitro and in vivo. In addition, we found that TRIM1-269aa can be packaged into exosomes and transmitted between TNBC cells. Mechanistically, TRIM1-269aa enhanced the interaction between MARCKS and calmodulin, thus promoting the calmodulin-dependent translocation of MARCKS, which further initiated the activation of the PI3K/AKT/mTOR pathway. Overall, circTRIM1, which encodes TRIM1-269aa, promoted TNBC chemoresistance and metastasis by enhancing MARCKS translocation and PI3K/AKT/mTOR activation. Our investigation has yielded novel insights into the roles of protein-coding circRNAs and supported circTRIM1/TRIM1-269aa as a novel promising prognostic and therapeutic target for patients with TNBC.

Abstract Pain is a common symptom of many diseases with a high incidence rate. Clinically, drug treatment, as the main method to relieve pain at present, is often accompanied by different degrees of adverse reactions. Therefore, it is urgent to gain a profound understanding of the pain mechanisms in order to develop advantageous analgesic targets. The PD-L1/PD-1 pathway, an important inhibitory molecule in the immune system, has taken part in regulating neuroinflammation and immune response. Accumulating evidence indicates that the PD-L1/PD-1 pathway is aberrantly activated in various pain models. And blocking PD-L1/PD-1 pathway will aggravate pain behaviors. This review aims to summarize the emerging evidence on the role of the PD-L1/PD-1 pathway in alleviating pain and provide an overview of the mechanisms involved in pain resolution, including the regulation of macrophages, microglia, T cells, as well as nociceptor neurons. However, its underlying mechanism still needs to be further elucidated in the future. In conclusion, despite more deep researches are needed, these pioneering studies indicate that PD-L1/PD-1 may be a potential neuroimmune target for pain relief.

PurposeTo investigate the prevalence and characteristics of late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) and its prognostic value in patients with Takayasu arteritis (TA).Materials and methodsSixty TA patients with a CMR examination were retrospectively included. All TA patients were divided into with LGE-positive and LGE-negative groups. Bi-ventricular function and location, distribution, and pattern of left ventricular (LV) LGE were evaluated in both LGE-positive and LGE-negative groups. Primary outcome was defined as a composite of cardiovascular death, hospitalization for heart failure, coronary artery revascularization, and stroke. Univariate and multivariate Cox proportional hazard regression analyses were used to evaluate the association between variables and primary outcomes.ResultsSixty consecutive TA patients were enrolled in this study. The mean age was 38.2 ± 13.8 years and 54 patients (54/60, 90.0%) were female. LGE-positive was observed in twenty-one (21/60, 35%) patients in the total patients with TA. LGE was predominantly distributed in the middle wall and subendocardial. The patchy and infarcted LGE patterns were the most common. Compared with the LGE-negative group, the LGE-positive group had reduced LV ejection fraction (P = 0.033), elevated LV end-diastolic volume index (P = 0.008), LV end-systolic volume index (P = 0.012), and LV mass (P = 0.008). During a median follow-up period of 1,892 days (interquartile range: 1,764–1,988 days), the primary outcomes occurred in thirteen patients. In the univariate analysis, LGE-positive (hazard ratio [HR] = 4.478, 95% confidence interval [CI]: 1.376–14.570; P = 0.013) were independently associated with the primary outcomes. However, LGE-positive did not retain its value as an independent predictor of primary outcomes in the multivariate analysis. Instead, LVMI (HR = 1.030, 95%CI: 1.013–1.048; P = 0.001) was the strongest independent predictor of primary outcomes in patients with TA. The Kaplan-Meier plot revealed that patients with LVMI ≥ 57.5 g/m2 have a worse prognosis.ConclusionLGE-positive detected by CMR was observed in 35% of total TA patients with different distributions and patterns. LGE is associated with adverse LV remodeling and worsen cardiac function. However, LVMI rather than LGE can provide independent prognostic information in patients with TA.

Summary: Background: Mesenteric adipose tissue (mAT) hyperplasia, known as creeping fat, is a pathologic characteristic of Crohn’s disease (CD). In our previously reported cohort, we observed that Achromobacter pulmonis was the most abundant and prevalent bacteria cultivated from creeping fat. Methods: A whole genomic sequencing and identification of T3SS orthologs of mAT-derived A. pulmonis were used. A functional type III secretion system (T3SS) mediated the pathogenic potential of A. pulmonis in vitro and in mouse colitis model. Furthermore, a T3SS Finder pipeline was introduced to evaluate gut bacterial T3SS orthologs in the feces of CD patients, ulcerative colitis and colorectal cancer patients. Findings: Here, we reveal that mAT-derived A. pulmonis possesses a functional T3SS, aggravates colitis in mice via T3SS, and exhibits T3SS-dependent cytotoxicity via a caspase-independent mechanism in macrophages and epithelial cells, which demonstrated the pathogenic potential of the T3SS-harboring A. pulmonis. Metagenomic analyses demonstrate an increased abundance of Achromobacter in the fecal of Crohn's disease patients compared to healthy controls. A comprehensive comparison of total microbial vT3SS abundance in various intestine diseases demonstrated that the specific enrichment of vT3SS genes was shown in fecal samples of CD, neither ulcerative colitis nor colorectal cancer patients, and ten T3SS gene-based biomarkers for CD were discovered and validated in a newly recruited CD cohort. Furthermore, treatment with exclusive enteral nutrition (EEN), an intervention that improves CD patient symptomatology, was found associated with a significant reduction in the prevalence of T3SS genes in fecal samples. Interpretation: These findings highlight the pathogenic significance of T3SSs in the context of CD and identify specific T3SS genes that could potentially function as biomarkers for diagnosing and monitoring the clinical status of CD patients. Funding: This work is supported by the National Key Research and Development Program of China (2020YFA0907800), the China Postdoctoral Science Foundation (2023M744089), the National Natural Science Foundation of China (32000096), the Shenzhen Science and Technology Programs (KQTD20200820145822023, RCIC20231211085944057, and ZDSYS20220606100803007), National Key Clinical Discipline, Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004), Qingfeng Scientific Research Fund of the China Crohn’s & Colitis Foundation (CCCF) (CCCF-QF-2022B71-1), and the Sixth Affiliated Hospital, Sun Yat-sen University Clinical Research 1010 Program 1010CG(2023)-08. These funding provided well support for this research work, which involved data collection, analysis, interpretation, patient recruitment and so on.

The steady increase in the prevalence of inflammatory bowel disease (IBD) is regarded as a worldwide health issue. Gut microorganisms could modulate host immune and metabolic status and are associated with health effects. Probiotics, Lactobacillus rhamnosus GG (LGG), are beneficial microorganisms that ameliorate disease and exert advantageous effects on intestinal homeostasis. However, the viability of probiotics will suffer from various risk factors in the digestive tract. In this view, we developed a probiotic coating with nanocomposite using tannic acid (TA) and casein phosphopeptide (CPP) through layer-by-layer technology to overcome the challenges after oral administration. LGG showed an improved survival rate in simulated gastrointestinal conditions after coated. The coating (LGG/TA-Mg2+/CPP) had potent reactive oxygen species (ROS) scavenging ability and improved the survival rate of colorectal epithelial cells after H2O2 stimulation. In DSS-induced colitis, administration of LGG/TA-Mg2+/CPP ameliorated intestinal inflammation and reduced the disruption of barrier function. Furthermore, LGG/TA-Mg2+/CPP increased the abundance and diversity of the gut microbiota. In the mouse model of DSS colitis, LGG/TA-Mg2+/CPP can better activate the EGFR/AKT signaling pathway, thereby protecting the epithelial barrier function of the colon epithelium. In conclusion, the probiotic coating with nanocomposite may become a delivery platform for probiotics applied to IBD.

ABSTRACT Companion animals such as cats and dogs harbor diverse microbial communities that can potentially impact human health due to close and frequent contact. To better characterize their total infectomes and assess zoonotic risks, we characterized the overall infectomes of companion animals (cats and dogs) and evaluated their potential zoonotic risks. Meta-transcriptomic analyses were performed on 239 samples from cats and dogs collected across China, identifying 24 viral species, 270 bacterial genera, and two fungal genera. Differences in the overall microbiome and infectome composition were compared across different animal species (cats or dogs), sampling sites (rectal or oropharyngeal), and health status (healthy or diseased). Diversity analyses revealed that viral abundance was generally higher in diseased animals compared to healthy ones, while differences in microbial composition were mainly driven by sampling site, followed by animal species and health status. Disease association analyses validated the pathogenicity of known pathogens and suggested potential pathogenic roles of previously undescribed bacteria and newly discovered viruses. Cross-species transmission analyses identified seven pathogens shared between cats and dogs, such as alphacoronavirus 1, which was detected in both oropharyngeal and rectal swabs albeit with differential pathogenicity. Further analyses showed that some viruses, like alphacoronavirus 1, harbored multiple lineages exhibiting distinct pathogenicity, tissue, or host preferences. Ultimately, a systematic evolutionary screening identified 27 potential zoonotic pathogens in this sample set, with far more bacterial than viral species, implying potential health threats to humans. Overall, our meta-transcriptomic analysis reveals a landscape of actively transcribing microorganisms in major companion animals, highlighting key pathogens, those with the potential for cross-species transmission, and possible zoonotic threats.IMPORTANCEThis study provides a comprehensive characterization of the entire community of infectious microbes (viruses, bacteria, and fungi) in companion animals like cats and dogs, termed the “infectome.” By analyzing hundreds of samples from across China, the researchers identified numerous known and novel pathogens, including 27 potential zoonotic agents that could pose health risks to both animals and humans. Notably, some of these zoonotic pathogens were detected even in apparently healthy pets, highlighting the importance of surveillance. The study also revealed key microbial factors associated with respiratory and gastrointestinal diseases in pets, as well as potential cross-species transmission events between cats and dogs. Overall, this work sheds light on the complex microbial landscapes of companion animals and their potential impacts on animal and human health, underscoring the need for monitoring and management of these infectious agents.

Abstract Wound infections pose a major healthcare issue, affecting the well‐being of millions of patients worldwide. Effective intervention and on‐site detection are important in wound management. However, current approaches are hindered by time‐consuming analysis and a lack of technology for real‐time monitoring and prompt therapy delivery. In this study, a smart wound patch system (SWPS) designed for wireless closed‐loop and in‐situ wound management is presented. The SWPS integrates a microfluidic structure, an organic electrochemical transistor (OECT) based sensor, an electrical stimulation module, and a miniaturized flexible printed circuit board (FPCB). The OECT incorporates a bacteria‐responsive DNA hydrogel‐coated gate for continuous monitoring of bacterial virulence at wound sites. Real‐time detection of OECT readings and on‐demand delivery of electrical cues to accelerate wound healing is facilitated by a mobile phone application linked with an FPCB containing low‐power electronics equipped with parallel sensing and stimulation circuitry. In this proof‐of‐concept study, the functionality of the SWPS is validated and its application both in vitro and in vivo is demonstrated. This proposed system expands the arsenal of tools available for effective wound management and enables personalized treatment.

Diffusion-weighted imaging (DWI) is widely utilized for evaluating uterine diseases. However, the prevalent technique, single-shot echo planar imaging (ssEPI), is hindered by notable image distortion and low spatial resolution. Therefore, optimizing uterine DWI sequences is vital for improving image quality. To investigate the efficacy of multiplexed sensitivity encoding (MUSE) combined with reverse polarity gradient (RPG) in enhancing uterine DWI quality and assessing local invasion in endometrial and cervical cancer, we included 149 patients. Each patient underwent DWI of the uterus using ssEPI, MUSE, and RPG-MUSE techniques. We compared these three sequences regarding image quality, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), geometric distortion rate (GDR), ADC values, accuracy in determining the extent of cancer invasion, and the Area Under the Curve (AUC) for identifying endometrial cancer and benign endometrial lesions using ADC values. The results indicated that RPG-MUSE DWI had less artifacts than MUSE and ssEPI (P 0.05). Furthermore, the AUC of the ROC for detecting endometrial cancer and benign endometrial lesions using ADC values showed no significant differences across the sequences (P = 0.7609, 0.7186, and 0.8706, respectively). When combining each DWI sequence with T2WI for FIGO staging, RPG-MUSE and MUSE exhibited better alignment with pathology findings compared to ssEPI (P

Abstract Acute kidney injury (AKI) represents a significant challenge to global public health problem and is associated with poor outcomes. There is still considerable debate about the effect of mean blood glucose (MBG) and coefficient of variation (CV) of blood glucose on the short-term mortality of AKI patients. This retrospective cohort study aimed to explore the association between glycemic variability and short-term mortality in patients with AKI. Data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database were analyzed, including 6,777 adult AKI patients. MBG and CV on the first day of ICU admission were calculated to represent the overall glycemic status and variability during the ICU stay in AKI patients. The primary outcome indicator was ICU 30-day mortality of AKI patients. Multivariate Cox regression analysis and smoothed curve fitting were used to assess the relationship between blood glucose levels and mortality. Eventually, the ICU 30-day mortality rate of AKI patients was 23.5%. The increased MBG and CV were significantly correlated with ICU 30-day mortality (hazards ratio (HR) = 1.20, 95% confidence interval (CI) 1.14–1.27; HR = 1.08, 95% CI 1.03–1.13). The smoothed curve fitting showed a U-shaped relationship between MBG on the first day of ICU admission and ICU 30-day mortality (inflection point = 111.3 mg/dl), while CV had a linear relationship with 30-day ICU mortality. Thus, we conclude that MBG and CV were significantly associated with short-term mortality in intensive care patients with AKI. Tighter glycemic control may be an effective measure to improve the prognosis of patients with AKI.

Considering tag sensitivity and in-phase and quadrature-phase imbalance (IQI), this paper investigates the reliability and security of a cognitive radio (CR)-aided ambient backscatter communication (AmBC) non-orthogonal multiple access (NOMA) system. Herein, the source communicates with its NOMA users in the presence of an eavesdropper, and to bolster security, artificial noise (AN) injection is introduced. The effects of non-ideal successive interference cancellation (SIC) and AN removal on system performance are also examined. Subsequently, outage probabilities (OPs) and interception probabilities (IPs) of the tag and NOMA signals are derived, with asymptotic results for further insights. Finally, simulation results are provided to validate the theoretical analysis. It is observed that both reliability and security remain stable even as interference or maximum transmission power increases up to a certain threshold. Furthermore, the reliability under NOMA mechanism outperforms that of orthogonal multiple access. Notably, IQI can consistently enhance the confidentiality of NOMA but selectively strengthen backscatter transmission, albeit at the expense of reliability. This paper comprehensively underscores the potential for real-world implementation by incorporating sensitivity constraints, IQI, AN, and imperfect SIC into the system model.

Abstract Acute respiratory failure (ARF) is a prevalent and serious condition in intensive care unit (ICU), often associated with high mortality rates. High-flow nasal oxygen (HFNO) therapy has gained popularity for treating ARF in recent years. However, there is a limited understanding of the factors that predict HFNO failure in ARF patients. This study aimed to explore early indicators of HFNO failure in ARF patients, utilizing machine learning (ML) algorithms to more accurately pinpoint individuals at elevated risk of HFNO failure. Utilizing ML algorithms, we developed seven predictive models. Their performance was evaluated using various metrics, including the area under the receiver operating characteristic curve, calibration curve, and precision recall curve. The study enrolled 700 patients, with 490 in the training group and 210 in the validation group. The overall HFNO failure rate was 14.1% among the 700 patients. The ML algorithms demonstrated robust performance in our study. This research underscores the potential of ML techniques in creating clinically relevant models for predicting HFNO outcomes in ARF patients. These models could play a pivotal role in enhancing the risk management of HFNO, leading to more patient-centered and personalized care approaches.

Gut microbiota of centenarians has garnered significant attention in recent years, with most studies concentrating on the analysis of microbial composition. However, there is still limited knowledge regarding the consistent signatures of specific species and their biological functions, as well as the potential causal relationship between gut microbiota and longevity. To address this, we performed the fecal metagenomic analysis of eight longevous populations at the species and functional level, and employed the Mendelian randomization (MR) analysis to infer the causal associations between microbial taxa and longevity-related traits. We observed that several species including Eisenbergiella tayi, Methanobrevibacter smithii, Hungatella hathewayi, and Desulfovibrio fairfieldensis were consistently enriched in the gut microbiota of long-lived individuals compared to younger elderly and young adults across multiple cohorts. Analysis of microbial pathways and enzymes indicated that E. tayi plays a role in the protein N-glycosylation, while M. smithii is involved in the 3-dehydroquinate and chorismate biosynthesis. Furthermore, H. hathewayi makes a distinct contribution to the purine nucleobase degradation I pathway, potentially assisting the elderly in maintaining purine homeostasis. D. fairfieldensis contributes to the menaquinone (vitamin K2) biosynthesis, which may help prevent age-related diseases such as osteoporosis-induced fractures. According to MR results, Hungatella was significantly positively correlated with parental longevity, and Desulfovibrio also exhibited positive associations with lifespan and multiple traits related to parental longevity. Additionally, Alistipes and Akkermansia muciniphila were consistently enriched in the gut microbiota of the three largest cohorts of long-lived individuals, and MR analysis also suggests their potential causal relationships with longevity. Our findings reveal longevity-associated gut microbial signatures, which are informative for understanding the role of microbiota in regulating longevity and aging.

This systematic review and meta-analysis were conducted to evaluate the cardiac and kidney-related adverse effects of roxadustat for the treatment of anemia in CKD patients. 18 trials with a total of 8806 participants were identified for analysis. We employed a fixed-effects model for analysis. The pooled result revealed no significant difference in the risk of occurrence of cardiac disorders when comparing CKD patients receiving roxadustat with the placebo (RR = 1.049; CI [0.918 to 1.200]) or ESA (RR = 1.066; CI [0.919 to 1.235]), in both dialysis-dependent (DD) (RR = 1.094; CI [0.925 to 1.293]) or non-dialysis-dependent (NDD) (RR = 1.036; CI [0.916 to 1.171]) CKD patients. No significant difference was observed in the risk of kidney-related adverse events when comparing roxadustat with the placebo (RR = 1.088; CI [0.980 to 1.209]) or ESA (RR = 0.968; CI [0.831 to 1.152]), in DD (RR = 2.649; CI [0.201 to 34.981]) or NDD (RR = 1.053; CI [0.965 to 1.149]) CKD patients. A high risk of hyperkalemia was observed in the roxadustat group in DD (RR = 0.939; CI [0.898 to 0.981]). Incidence of hypertension was higher in the roxadustat for NDD patients (RR = 1.198; CI [1.042 to 1.377]), or compared to the placebo (RR = 1.374; CI [1.153 to 1.638]). In summary, the risk of cardiac or kidney-related events observed in the roxadustat was not significantly increase whether in DD or NDD patients. However, attention must be paid to the occurrence of hyperkalemia for DD patients and hypertension in NDD patients using roxadustat.

Arteriosclerotic cerebral small vessel disease (aCSVD) is a major cause of stroke and dementia. Although its underlying pathogenesis remains poorly understood, both inflammaging and gut microbiota dysbiosis have been hypothesized to play significant roles. This study investigated the role of gut microbiota in the pathogenesis of aCSVD through a comparative analysis of the gut microbiome and metabolome between CSVD patients and healthy controls. The results showed that patients with aCSVD exhibited a marked reduction in potentially beneficial bacterial species, such as Faecalibacterium prausnitzli and Roseburia intestinalis, alongside an increase in taxa from Bacteroides and Proteobacteria. Integrated metagenomic and metabolomic analyses revealed that alterations in microbial metabolic pathways, including LPS biosynthesis and phenylalanine-tyrosine metabolism, were associated with the status of aCSVD. Our findings indicated that microbial LPS biosynthesis and phenylalanine-tyrosine metabolism potentially influenced the symptoms and progression of aCSVD via pro-inflammatory effect and modulation of systemic neurotransmitters, respectively. These results imply that gut microbiota characteristics may serve as indicators for early detection of aCSVD and as potential gut-directed therapeutic intervention target.

High-fat diet (HFD) has long been recognized as risk factors for the development and progression of ulcerative colitis (UC), but the exact mechanism remained elusive. Here, HFD increased intestinal deoxycholic acid (DCA) levels, and DCA further exacerbated colonic inflammation. Transcriptome analysis revealed that DCA triggered ferroptosis pathway in colitis mice. Mechanistically, DCA upregulated hypoxia-inducible factor-2α (HIF-2α) and divalent metal transporter-1 (DMT1) expression, causing the ferrous ions accumulation and ferroptosis in intestinal epithelial cells, which was reversed by ferroptosis inhibitor ferrostatin-1. DCA failed to promote colitis and ferroptosis in intestine-specific HIF-2α-null mice. Notably, byak-angelicin inhibited DCA-induced pro-inflammatory and pro-ferroptotic effects through blocking the up-regulation of HIF-2α by DCA. Moreover, fat intake was positively correlated with disease activity in UC patients consuming HFD, with ferroptosis being more pronounced. Collectively, our findings demonstrated that HFD exacerbated colonic inflammation by promoting DCA-mediated ferroptosis, providing new insights into diet-related bile acid dysregulation in UC.

Background: Several studies have shown that bedside lung ultrasound findings in postanaesthesia care units (PACUs) and intensive care units (ICUs) correlate with postoperative pulmonary complications(PPCs) after noncardiac major surgery. However, it remains unclear whether lung ultrasound findings can be used as early predictors of PPCs in patients undergoing cardiac surgery. The main aim of our study was to evaluate the relationship between early postoperative point-of-care lung ultrasound findings and PPCs after cardiac surgery. Methods: Two board-certified physicians performed a point-of-care pulmonary ultrasound on cardiac surgery patients approximately 2 h after the patient was admitted to the ICU. Pulmonary complications occurring within 30 days postoperatively were recorded. Logistic regression modeling was used to analyze the relationship between lung ultrasound findings and PPCs. Results: PPCs occurred in 61 (30.9 %) of the 197 patients. Lung ultrasound scores(LUS), number of lung consolidation(NLC), and depth of pleural effusion(DPE) were more significant in patients who developed PPCs (P 0.95(aOR 3.79,95%CI 1.60–8.99; p = 0.002) were found to be independently associated with PPCs during this study. Conclusions: Our study demonstrated that DPE >0.95 and NLC ≥3 were associated with PPCs after cardiac surgery based on bedside lung ultrasound findings in the ICU. When these signs manifest perioperatively, the surgeon should be alerted and the necessary steps should be taken, especially if they present simultaneously.

IntroductionChronic kidney disease (CKD) is worldwide healthcare burden with growing incidence and death rate. Emerging evidence demonstrated the compositional and functional differences of gut microbiota in patients with CKD. As such, gut microbial features can be developed as diagnostic biomarkers and potential therapeutic target for CKD.MethodsTo eliminate the outcome bias arising from factors such as geographical distribution, sequencing platform, and data analysis techniques, we conducted a comprehensive analysis of the microbial differences between patients with CKD and healthy individuals based on multiple samples worldwide. A total of 980 samples from six references across three nations were incorporated from the PubMed, Web of Science, and GMrepo databases. The obtained 16S rRNA microbiome data were subjected to DADA2 processing, QIIME2 and PICRUSt2 analyses.ResultsThe gut microbiota of patients with CKD differs significantly from that of healthy controls (HC), with a substantial decrease in the microbial diversity among the CKD group. Moreover, a significantly reduced abundance of bacteria Faecalibacterium prausnitzii (F. prausnitzii) was detected in the CKD group through linear discriminant analysis effect size (LEfSe) analysis, which may be associated with the alleviating effects against CKD. Notably, we identified CKD-depleted F. prausnitzii demonstrated a significant negative correlation with three pathways based on predictive functional analysis, suggesting its potential role in regulating systemic acidbase disturbance and pro-oxidant metabolism.DiscussionOur findings demonstrated notable alterations of gut microbiota in CKD patients. Specific gut-beneficial microbiota, especially F. prausnitzii, may be developed as a preventive and therapeutic tool for CKD clinical management.

Background: Irinotecan is widely used in the treatment of various solid tumors, but the adverse effects from it, especially diarrhea, limit its use. Several clinical trials of prophylactic treatment of irinotecan-induced diarrhea (IID) have been ongoing, and some of the data are controversial. This encouraged us to conduct a meta-analysis of the effects of interventions on preventing IID. Method: This systematic review was conducted based on the PRISMA statement. We performed literature searches from PubMed, Web of Science, Embase, and Cochrane Library. The number registered in PROSPERO is CRD42022368633. After searching 1034 articles in the database and references, 8 studies were included in this meta-analysis. Result: The RR of high-grade diarrhea and all-grade diarrhea were 0.31 ( I 2 = 51%, 95% CI: 0.14-0.69; P = .004) and .76 ( I 2 = 65%, 95% CI: 0.62-0.93; P

Peptostreptococcus anaerobius is an anaerobic bacterium, which has been found selectively en-riched in the fecal and mucosal microbiota of colorectal cancer (CRC) patients. Emerging evidence suggest P. anaerobius may contribute to the development of CRC in human. In this study, we designed a multi-epitope chimeric vaccine against P. anaerobius PCWBR2, a recently identified adhesin that interacts directly with colon cell lines by binding α2/β1 integrin frequently overexpressed in human CRC tumors and cell lines. Immunoinformatics tools predicted six cytotoxic T lymphocyte epitopes, five helper T lymphocyte epitopes, and six linear B lymphocyte epitopes. The predicted epitopes were joined with AAY or GPGPG linkers and a previously reported TLR4 agonist was added to the vaccine construct's N terminal as an adjuvant using EAAAK linkers and the order of epitopes was optimized. Further in silico analysis revealed that the vaccine construct possesses satisfactory antigenicity, allergenicity, solubility, physicochemical properties, adjuvant-TLR4 molecular docking, and immune profile characteristics. Our study provided a promising design for vaccines against P. anaerobius.

Green macroalgae bloom (GMB), with the dominant species of Ulva prolifera, has regularly occurred since 2007 along the China coast. Although disaster prevention and control achieved favorable results in 2020, the satellite-observed GMB annual maximum coverage (AMC) rebounded sharply in 2021 to an unprecedented level. The reasons for this rebound and the significant interannual variability over past 15 years are still open questions. Here, by using long-term time-series (2007–2022) optical and Synthetic Aperture Radar satellite observations (1000+ scenes), meteorological data and water quality statistics, the mechanism analysis was performed by exploring effects from natural factors and human activities. Two key determinants for AMC are successfully identified from numerous potential factors which are the macroalgae distribution in a key area (the Subei Shoal) during a critical period (from April to May 20) and the nutrient availability. Furthermore, by using these two parameters, a novel model for AMC prediction (R2 = 0.87, p

Rapidly changing climate issues and increasingly severe carbon emissions are great challenges to the carbon peaking and carbon neutrality strategy. Analyzing the impact of future land use changes on carbon emissions can provide an important basis and reference for scientifically constructing a low-carbon and sustainable territorial spatial planning, as well as realizing the goal of the dual-carbon strategy. Based on land use data, agricultural production activity data, and energy consumption statistics, this study simulated the land use changes of the Yangtze River Delta region (YRDR) from 2030 to 2060 under the natural development (ND) scenario and sustainable development (SD) scenario by using the Patch-generating Land Use Simulation (PLUS) model and analyzed the impacts of future land use changes on carbon emissions. The results showed that: (1) The land use simulation results obtained by using the PLUS model under the sustainable development scenario were highly consistent with the actual land use with an OA value of 97.0%, a Kappa coefficient of 0.952, and a FoM coefficient of 0.403; (2) Based on the simulated land use under the SD scenario from 2030 to 2060, the quantity of construction land was effectively controlled, and the spatial distributions of cropland and forests were found to dominate in the north and south of the Yangtze River, respectively; (3) Anhui Province was the major contributor (accounted for 49.5%) to the net carbon absorption by cropland while Zhejiang Province was the major contributor (accounted for 63.3%) to the net carbon absorption by forest in the YRDR during the period 2020–2060 under the SD scenario; (4) Carbon emissions from construction land were the main source of carbon emissions from land use in the YRDR during the period 2020–2060 with proportions higher than 99% under both the ND and SD development scenarios. These findings underscore the urgent need for the government to take measures to balance the relationships between cropland and ecological protection and economic development, which provides a reference for the optimization of land use structure and policy formulation in the future.

Oxidative stress has been identified as a major factor in the development and progression of pain and psychiatric disorders, but the underlying biomarkers and molecular signaling pathways remain unclear. This study aims to identify oxidative stress-related biomarkers and signaling pathways in pain–depression comorbidity. Integrated bioinformatics analyses were applied to identify key genes by comparing pain–depression comorbidity-related genes and oxidative stress-related genes. A total of 580 differentially expressed genes and 35 differentially expressed oxidative stress-related genes (DEOSGs) were identified. By using a weighted gene co-expression network analysis and a protein–protein interaction network, 43 key genes and 5 hub genes were screened out, respectively. DEOSGs were enriched in biological processes and signaling pathways related to oxidative stress and inflammation. The five hub genes, RNF24, MGAM, FOS, and TKT, were deemed potential diagnostic and prognostic markers for patients with pain–depression comorbidity. These genes may serve as valuable targets for further research and may aid in the development of early diagnosis, prevention strategies, and pharmacotherapy tools for this particular patient population.

IntroductionCongenital tracheal stenosis (CTS) is a rare but life-threatening disease that can lead to respiratory dysfunction in children. Obstructive sleep apnea syndrome (OSAS) in children is characterized by prolonged partial upper airway obstruction and/or intermittent complete obstruction. Both of the diseases require surgical intervention. Although respective treatments of these two diseases are clear, there is a lack of literature discussing the surgical treatment of patients with CTS complicated by OSAS.MethodsWe conducted a patient-specific study of patient with CTS complicated by OSAS. Computer-aided design was used to simulate surgical correction under different surgical sequences. Computational fluid dynamics was used to compare the outcomes of different sequences.ResultsAerodynamic parameters, pressure drop, velocity streamlines, wall shear stress (WSS), and the ratio of airflow distribution and energy loss rate were evaluated. An obvious interaction was found between the two diseases in different surgical sequences. The order of correction for CTS or OSAS greatly affected the aerodynamic parameters and turbulence flows downstream of tracheal stenosis and upstream of epiglottis. The CTS and OSAS had mutual influences on each other on the aerodynamic parameters, such as pressure drops and WSS.DiscussionWhen evaluating the priority of surgical urgency of CTS and OSAS, surgeons need to pay attention to the state of both CTS and OSAS and the physiological conditions of patients. The aerodynamic performance of the uneven airflow distribution and the potential impact caused by the correction of CTS should be considered in surgical planning and clinical management.

IntroductionIgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally. While nephrotic syndrome (NS) is uncommon in IgAN, its significance remains unclear.MethodsWe conducted a retrospective analysis of 170 IgAN patients, classifying them into NS (n = 85) and non-NS (n = 85) groups. Our study aims to compare their clinical characteristics, treatment responses, and prognoses. Patients were selected based on renal biopsy from 2003 to 2020. Propensity score matching ensured comparability. Clinical, pathological, and immunological data were analyzed. Composite endpoints were defined as end-stage kidney disease (ESKD) or a 30% decline in estimated glomerular filtration rate (eGFR).ResultsNS patients showed higher eGFR (74.3 ± 36.8 vs. 61.5 ± 33.6 mL/min.1.73 m2, p = 0.02), severe hematuria (35.0 (4.7,147.5) vs. 4.0 (1.8,45,0) cells/μl, p

Objective: The aim of this study is to construct a curated bibliographic dataset for a landscape analysis on Health Artificial Intelligence (HAI) research. Data Source: We integrated HAI-related bibliographic records, including publications, open research datasets, patents, research grants, and clinical trials from Medline and Dimensions. Methods: Searching: Relevant documents were identified using Medical Subject Headings (MeSH) and Field of Research (FoR) indexed by 2 bibliographic databases, Medline and Dimensions. Extracting: MeSH terms annotated from the aforementioned bibliographic databases served as the primary information for our processing. For document records lacking MeSH terms, we re-extracted them using the Medical Text Indexer (MTI). Mapping: In order to enhance interoperability, HAI multi-documents were organized using a mapping system incorporating MeSH, FoR, The International Classification of Diseases (ICD-10), and Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT). Integrating: All documents were curated based on a pre-defined ontology of health problems and AI technologies from the MeSH hierarchy. Results: We collected 96,332 HAI documents (publications: 75,820, open research datasets: 638, patents: 11,226, grants: 6,113, and clinical trials: 2,535) during 2009 to 2021. On average, 75.12% of the documents were tagged with at least one label related to either health problems or AI technologies (with 92.9% of publications tagged). Summary: This study presents a comprehensive pipeline for processing and curating HAI bibliographic documents following the FAIR (Findable, Accessible, Interoperable, Reusable) standard, offering a valuable multidimensional collection for the community. This dataset serves as a crucial resource for horizontally scanning the funding, research, clinical assessments, and innovations within the HAI field.

Objective: To compare MUSE-DWI with conventional DWI in assessing lesions of invasive breast cancer and evaluating the ADC values for preoperative histological grading. Methods: A retrospective analysis was conducted on 63 lesions confirmed as invasive breast cancer by surgical or biopsy pathology. Preoperatively, all patients underwent MUSE-DWI, conventional DWI, and dynamic contrast-enhanced (DCE) scans. Two radiologists with over 5 years of experience (intermediate and senior levels, respectively) subjectively evaluated the images for clarity, image artifacts, and distortion. Objective evaluation included signal-to-noise ratio (SNR) of lesions and fibrous tissue, as well as the ADC values of both imaging techniques. Due to the limited number of cases classified as grade I and the insignificant difference in disease-specific survival and recurrence scores between grades I and II tumors, grades I and II were grouped as low-grade, while grade III was classified as high-grade. Receiver operating characteristic (ROC) curves were used to evaluate the efficacy of ADC values in preoperatively predicting the grading of invasive breast cancer. Results: The SNR and subjective quality scores of MUSE-DWI images were significantly higher than those of conventional DWI (p

Abstract Background Human epidermal growth factor receptor 2‐positive (HER2+) metastatic breast cancer (MBC) is a subtype of breast cancer with a worse prognosis. Little is known about the relationship between histology and prognosis among different distant metastasis sites (DMS). Our aims were to explore the prognostic value of histologic subtypes in different DMS and screen out specific subtypes with particular DMS that need more attention in HER2+ MBC. Methods HER2+ MBC patient data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2014. Chi‐squared tests were utilized to compare histologic subtypes in four DMS. The logistic regression analyses were used to control confounding factors. The log‐rank tests were used to analyze the correlation of histologic subtype with disease‐specific survival and overall survival. The survival data was analyzed using Kaplan–Meier methods. Results A total of 1174 HER2+ MBC patients were involved. First, the distribution of histological subtypes varied across metastatic sites, and the proportions of metastatic sites in different histological subtypes were also different. Furthermore, different histological subtypes within specific DMS showed divergent prognoses, and the different outcomes were shown by distinct DMS for specific histological subtypes. Among them, lobular carcinoma (ILC) subtypes showed the worst prognosis in bone metastasis, and lung metastasis predicted the worst prognosis in infiltration duct and lobular carcinoma (IDC‐ILC) subtypes. After further consideration of hormone receptor (HR) status, the IDC‐ILC subtype with liver metastasis in HR+/HER2+ MBC patients and the ILC subtype with bone metastasis in HR−/HER2+ MBC patients proved to be noteworthy. Conclusions Histological subtypes are involved in determining the heterogeneity of HER2+ MBC patient prognosis, which is helpful to guide the prognosis prediction and monitoring of HER2+ breast cancer patients in clinics.

Abstract Background Triple-negative breast cancer (TNBC) is a subtype of breast cancer with higher aggressiveness and poorer outcomes. Recently, long non-coding RNAs (lncRNAs) have become the crucial gene regulators in the progression of human cancers. However, the function and underlying mechanisms of lncRNAs in TNBC remains unclear. Methods Based on public databases and bioinformatics analyses, the low expression of lncRNA MIDEAS-AS1 in breast cancer tissues was detected and further validated in a cohort of TNBC tissues. The effects of MIDEAS-AS1 on proliferation, migration, invasion were determined by in vitro and in vivo experiments. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were carried out to reveal the interaction between MIDEAS-AS1 and MATR3. Luciferase reporter assay, Chromatin immunoprecipitation (ChIP) and qRT-PCR were used to evaluate the regulatory effect of MIDEAS-AS1/MATR3 complex on NCALD. Results LncRNA MIDEAS-AS1 was significantly downregulated in TNBC, which was correlated with poor overall survival (OS) and progression-free survival (PFS) in TNBC patients. MIDEAS-AS1 overexpression remarkably inhibited tumor growth and metastasis in vitro and in vivo. Mechanistically, MIDEAS-AS1 mainly located in the nucleus and interacted with the nuclear protein MATR3. Meanwhile, NCALD was selected as the downstream target, which was transcriptionally regulated by MIDEAS-AS1/MATR3 complex and further inactivated NF-κB signaling pathway. Furthermore, rescue experiment showed that the suppression of cell malignant phenotype caused by MIDEAS-AS1 overexpression could be reversed by inhibition of NCALD. Conclusions Collectively, our results demonstrate that MIDEAS-AS1 serves as a tumor-suppressor in TNBC through modulating MATR3/NCALD axis, and MIDEAS-AS1 may function as a prognostic biomarker for TNBC.

Abstract Background Obesity is a crucial risk factor for obstructive sleep apnea (OSA), but the association between adiposity deposition and OSA risk has not reached a consistent conclusion. This study sought to reveal the association of multiple adiposity indicators with OSA risk. Methods This cross-sectional study included 9,733 participants aged 35–74 years, recruited from an ongoing population-based cohort. OSA was assessed by the Berlin Questionnaire. Six adiposity indicators, including neck circumference (NC), body fat percentage (BF%), waist-to-hip ratio (WHR), visceral adiposity index (VAI), lipid accumulation product (LAP), and resting metabolic rate (RMR), were selected. Multivariate logistic regression models were used to examine the association of adiposity indicators with OSA risk. Results One thousand six hundred twenty-six participants (16.71%) were classified into the OSA group. NC, BF%, WHR, VAI, LAP, and RMR were all positively associated with the risk of OSA after adjusting for confounders, regardless of age, sex, and history of dyslipidemia. Every 1-unit increment of NC, BF%, and VAI was associated with a 13%, 9%, and 14% increased risk of OSA, respectively; every 0.01-unit increment of WHR was associated with a 3% increased risk of OSA; every 10-unit increment of LAP and RMR was associated with 2% and 4% increased risk of OSA, respectively. Conclusions NC, BF%, WHR, VAI, LAP, and RMR were all independently and positively associated with OSA risk, regardless of age, sex, history of dyslipidemia, and menopausal status. Application of these new indicators could help to more comprehensively reflect and predict the risk of OSA in the general population.

Abstract Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease that carries mutations in NOTCH3. The clinical manifestations are influenced by genetic and environmental factors that may include gut microbiome. Results We investigated the fecal metagenome, fecal metabolome, serum metabolome, neurotransmitters, and cytokines in a cohort of 24 CADASIL patients with 28 healthy household controls. The integrated-omics study showed CADASIL patients harbored an altered microbiota composition and functions. The abundance of bacterial coenzyme A, thiamin, and flavin-synthesizing pathways was depleted in patients. Neurotransmitter balance, represented by the glutamate/GABA (4-aminobutanoate) ratio, was disrupted in patients, which was consistent with the increased abundance of two major GABA-consuming bacteria, Megasphaera elsdenii and Eubacterium siraeum. Essential inflammatory cytokines were significantly elevated in patients, accompanied by an increased abundance of bacterial virulence gene homologs. The abundance of patient-enriched Fusobacterium varium positively correlated with the levels of IL-1β and IL-6. Random forest classification based on gut microbial species, serum cytokines, and neurotransmitters showed high predictivity for CADASIL with AUC = 0.89. Targeted culturomics and mechanisms study further showed that patient-derived F. varium infection caused systemic inflammation and behavior disorder in Notch3 R170C/+ mice potentially via induction of caspase-8-dependent noncanonical inflammasome activation in macrophages. Conclusion These findings suggested the potential linkage among the brain-gut-microbe axis in CADASIL. Video Abstract

Abstract Background Oxaliplatin-induced peripheral neurotoxicity (OIPN) limits the dose of chemotherapy and seriously affects the quality of life. Huangqi Guizhi Wuwu Decoction (HGWD) is a classical Traditional Chinese Medicine (TCM) formula for the prevention of OIPN. However, its specific pharmacological mechanism of action remains unknown. Our study found that HGWD can effectively alleviate chronic OIPN and regulate intestinal flora. Therefore, we explored the mechanism of action of HGWD in alleviating chronic OIPN from the perspective of intestinal flora. Methods In this study, we established an OIPN model in C57BL/6 mice treated with different concentrations of HGWD. Mechanical pain and cold pain were assessed at certain time points, and samples of mice colon, dorsal root ganglion (DRG), serum, and feces were collected. Associated inflammation levels in the colon and DRG were detected using immunohistochemical techniques; the serum lipopolysaccharide (LPS) levels and associated inflammation were assessed using the appropriate kits; and 16S rRNA sequencing was used to examine the dynamic changes in gut microorganisms. Finally, established fecal microbiota transplantation (FMT) and antibiotic (ABX) pretreatment models were used to validate flora’s role in HGWD for chronic OIPN by pain scoring and related pathological analysis. Results HGWD treatment significantly alleviated pain sensitivity in chronic OIPN mice. Pathological results showed that HGWD treatment improved intestinal ZO-1 expression and reduced serum LPS levels and associated inflammatory factors in the colon, serum, and DRG. The 16S rRNA results showed that HGWD restored the composition of the intestinal flora in a time-dependent manner to alleviate OIPN. FMT and ABX experiments demonstrated that HGWD can alleviate chronic OIPN by regulating intestinal flora homeostasis. Conclusions HGWD prevents chronic OIPN by dynamically regulating intestinal flora homeostasis, thereby ameliorating intestinal barrier damage and reducing serum LPS and relevant inflammatory factor levels in the colon, serum, and DRG.

Abstract Background Circular RNAs (circRNAs) have been shown to play diverse biological functions in the progression of multiple diseases. However, the impacts of circRNAs on breast cancer (BC) progression remains unclear. Therefore, the objective of this paper is to investigate the role and mechanisms of a functional circRNA in BC metastasis and immune escape. Methods This study used a circRNA microarray and identified a novel circRNA hsa_circ_0067842. The validation and characteristics of hsa_circ_0067842 were investigated using qRT-PCR, sanger sequencing, RNase R treatment, actinomycin D treatment and fluorescence in situ hybridization (FISH). Gain- and loss-of-function assays were performed to evaluate the biological function of hsa_circ_0067842 in BC progression and immune escape. Mechanistically, the interaction between hsa_circ_0067842 and HuR was explored by RNA pull down, mass spectrometry (MS), subcellular component protein extraction and immunofluorescence (IF). The regulatory mechanisms of hsa_circ_0067842/HuR/CMTM6/PD-L1 axis were investigated by qRT-PCR, western blot, FISH, immunoprecipitation and rescue assays. Results The expression of hsa_circ_0067842 was upregulated in BC tissues and cells, which was found to be significantly associated with poor prognosis, regardless of other clinical covariates. Function assays showed that hsa_circ_0067842 promoted the migration and invasion capacities of BC cells. Moreover, co-culture experiment with peripheral blood mononuclear cells (PBMCs) showed that hsa_circ_0067842 played a role in the immune escape of BC cells. Mechanistically, our study showed that hsa_circ_0067842 interacted with HuR, affecting its nuclear translocation, thus enhancing the stability of CMTM6. CMTM6 not only enhances the migration and invasion ability of BC cells, but also affects the ubiquitination of PD-L1 and inhibits its degradation. Conclusion Collectively, our results demonstrated that hsa_circ_0067842 promoted BC progression through the HuR/CMTM6/PD-L1 axis, providing new insight and a potential target for BC prognosis and therapy.

Abstract Dysregulated ERα signaling is responsible for endocrine resistance and eventual relapse in patients with estrogen receptor-positive (ER+) breast cancer. Thus, identifying novel ERα regulators is necessary to fully understand the mechanisms of endocrine resistance. Here, we identified circRNA-SFMBT2 to be highly expressed in ER+ breast cancer cells in comparison to ER− cells and found that high circRNA-SFMBT2 levels were related to larger tumor size and poor prognosis in patients with ER+ breast cancer. In vitro and in vivo experiments confirmed that the circRNA-SFMBT2 level was positively correlated with the ERα protein level, implying a regulatory role for circRNA-SFMBT2 in ERα signaling. Moreover, we found that circRNA-SFMBT2 biogenesis could be facilitated via RNA-binding protein quaking (QKI), and biologically elevated circRNA-SFMBT2 expression promoted cell growth and tamoxifen resistance in ER+ breast cancer. Mechanistically, circRNA-SFMBT2 exhibits a specific tertiary structure that endows it with a high binding affinity for ERα and allows it to interact with the AF2 and DBD domains of ERα, enforcing recruitment of RNF181 to the AF1 domain of ERα. Furthermore, the circRNA-SFMBT2/RNF181 axis differentially regulated K48-linked and K63-linked ubiquitination of ERα to enhance ERα stability, resulting in increased expression of ERα target genes and tumor progression. In summary, circRNA-SFMBT2 is an important regulator of ERα signaling, and antagonizing circRNA-SFMBT2 expression may constitute a potential therapeutic strategy for breast cancer.

Abstract Breast cancer is the major common malignancy worldwide among women. Previous studies reported that cancer-associated fibroblasts (CAFs) showed pivotal roles in regulating tumor progression via exosome-mediated cellular communication. However, the detailed mechanism underlying the exosomal circRNA from CAFs in breast cancer progression remains ambiguous. Here, exosomal circRNA profiling of breast cancer-derived CAFs and normal fibroblasts (NFs) was detected by high-throughput sequencing, and upregulated circTBPL1 expression was identified in CAF exosomes. The exosomal circTBPL1 from CAFs could be transferred to breast cancer cells and promoted cell proliferation, migration, and invasion. Consistently, circTBPL1 knockdown in CAFs attenuated their tumor-promoting ability. Further exploration identified miR-653-5p as an inhibitory target of circTBPL1, and ectopic expression of miR-653-5p could partially reverse the malignant phenotypes induced by circTBPL1 overexpression in breast cancer. Additionally, TPBG was selected as a downstream target gene, and circTBPL1 could protect TPBG from miR-653-5p-mediated degradation, leading to enhanced breast cancer progression. Significantly, the accelerated tumor progression triggered by exosomal circTBPL1 from CAFs was confirmed in xenograft models. Taken together, these results revealed that exosomal circTBPL1 derived from CAFs contributed to cancer progression via miR-653-5p/TPBG pathway, indicating the potential of exosomal circTBPL1 as a biomarker and novel therapeutic target for breast cancer.

Abstract Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients. However, the underlying mechanism remains elusive. Here, we identified novel functional roles of heat shock protein beta-1 (HSPB1), regulating chemoresistance and ferroptotic cell death in breast cancer. Based on TCGA and GEO databases, HSPB1 expression was upregulated in breast cancer tissues and associated with poor prognosis of breast cancer patients, which was considered an independent prognostic factor for breast cancer. Functional assays revealed that HSPB1 could promote cancer growth and metastasis in vitro and in vivo. Furthermore, HSPB1 facilitated doxorubicin (DOX) resistance through protecting breast cancer cells from drug-induced ferroptosis. Mechanistically, HSPB1 could bind with Ikβ-α and promote its ubiquitination-mediated degradation, leading to increased nuclear translocation and activation of NF-κB signaling. In addition, HSPB1 overexpression led to enhanced secretion of IL6, which further facilitated breast cancer progression. These findings revealed that HSPB1 upregulation might be a key driver to progression and chemoresistance through regulating ferroptosis in breast cancer while targeting HSPB1 could be an effective strategy against breast cancer.

The integration of two-dimensional Ti3C2Tx nanosheets and other materials offers broader application options in the antibacterial field. Ti3C2Tx-based composites demonstrate synergistic physical, chemical, and photodynamic antibacterial activity. In this review, we aim to explore the potential of Ti3C2Tx-based composites in the fabrication of an antibiotic-free antibacterial agent with a focus on their systematic classification, manufacturing technology, and application potential. We investigate various components of Ti3C2Tx-based composites, such as metals, metal oxides, metal sulfides, organic frameworks, photosensitizers, etc. We also summarize the fabrication techniques used for preparing Ti3C2Tx-based composites, including solution mixing, chemical synthesis, layer-by-layer self-assembly, electrostatic assembly, and three-dimensional (3D) printing. The most recent developments in antibacterial application are also thoroughly discussed, with special attention to the medical, water treatment, food preservation, flexible textile, and industrial sectors. Ultimately, the future directions and opportunities are delineated, underscoring the focus of further research, such as elucidating microscopic mechanisms, achieving a balance between biocompatibility and antibacterial efficiency, and investigating effective, eco-friendly synthesis techniques combined with intelligent technology. A survey of the literature provides a comprehensive overview of the state-of-the-art developments in Ti3C2Tx-based composites and their potential applications in various fields. This comprehensive review covers the variety, preparation methods, and applications of Ti3C2Tx-based composites, drawing upon a total of 171 English-language references. Notably, 155 of these references are from the past five years, indicating significant recent progress and interest in this research area.

The recent advancements of mobile edge computing (MEC) technologies and unmanned aerial vehicles (UAVs) have provided resilient and flexible computation services for ground users beyond the coverage of terrestrial service. In this paper, we focus on a UAV-assisted MEC system in which the UAV equipped with MEC servers is used to assist user devices in computing their tasks. To minimize the weighted average energy consumption and delay in the UAV-assisted MEC system, a LQR-Lagrange-based DDPG (LLDDPG) algorithm, which jointly optimizes the user task offloading and the UAV trajectory design, is proposed. To be specific, the LLDDPG algorithm consists of three subproblems. The DDPG algorithm is used to address the issue of UAV desired trajectory planning, and subsequently, the LQR-based algorithm is employed to achieve the real-time tracking control of UAV desired trajectory. Finally, the Lagrange duality method is proposed to solve the optimization problem of computational resource allocation. Simulation results indicate that the proposed LLDDPG algorithm can effectively improve the system resource management and realize the real-time UAV trajectory design.

Physiologically based pharmacokinetic/toxicokinetic (PBPK/PBTK) models are designed to elucidate the mechanism of chemical compound action in organisms based on the physiological, biochemical, anatomical, and thermodynamic properties of organisms. After nearly a century of research and practice, good results have been achieved in the fields of medicine, environmental science, and ecology. However, there is currently a lack of a more systematic review of progress in the main research directions of PBPK models, especially a more comprehensive understanding of the application in aquatic environmental research. In this review, a total of 3974 articles related to PBPK models from 1996 to 24 March 2024 were collected. Then, the main research areas of the PBPK model were categorized based on the keyword co-occurrence maps and cluster maps obtained by CiteSpace. The results showed that research related to medicine is the main application area of PBPK. Four major research directions included in the medical field were “drug assessment”, “cross-species prediction”, “drug–drug interactions”, and “pediatrics and pregnancy drug development”, in which “drug assessment” accounted for 55% of the total publication volume. In addition, bibliometric analyses indicated a rapid growth trend in the application in the field of environmental research, especially in predicting the residual levels in organisms and revealing the relationship between internal and external exposure. Despite facing the limitation of insufficient species-specific parameters, the PBPK model is still an effective tool for improving the understanding of chemical–biological effectiveness and will provide a theoretical basis for accurately assessing potential risks to ecosystems and human health. The combination with the quantitative structure–activity relationship model, Bayesian method, and machine learning technology are potential solutions to the previous research gaps.

In Hymenoptera, the monophyly of Evaniomorpha has been the focus of debate among different scholars. In this study, we sequenced two mitochondrial genomes of Dendrocerus (Hymenoptera: Megaspilidae) to analyze the mitochondrial genomic features of Dendrocerus and provide new molecular data for phylogenetic studies of Evaniomorpha. The mitogenome sizes of D. bellus and D. anisodontus were 15,445 bp and 15,373 bp, respectively, with the trnG of D. bellus missing. The nucleotide composition was significantly biased toward adenine and thymine, with A + T contents of 81.2% (D. bellus) and 82.4% (D. anisodontus). Using Ceraphron sp. (Ceraphronidae) as reference, the Ka/Ks values of NAD4L and NAD6 in D. anisodontus were both greater than one, indicating that non-synonymous mutations are favored by Darwinian selection, which is rare in other hymenopteran species. Compared with Ceraphon sp. gene order, nine operations were identified in D. anisodontus, including four reversals, four TDRLs (tandem duplication random losses) and one transposition, or four reversals and five TDRLs. Phylogenetic analysis of 40 mitochondrial genomes showed that Evaniomorpha was not a monophyletic group, which was also supported by the PBD values. Ceraphronoidea is a monophyletic group and is a sister to Aulacidae + Gasteruptiidae. Based on the conserved region of the newly sequenced mitochondrial genomes, a pair of specific primers MegaF/MegaR was designed for sequencing the COX1 genes in Megaspilidae and a 60% rate of success was achieved in the genus Dendrocerus.

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

A transparent ceramic glaze with good apparent quality and water wettability was successfully prepared by adjusting the mass fraction ratio of Na₂O/K₂O and R₂O/Al₂O₃ at 1280 °c. The effects of the Na₂O/K₂O and R₂O/Al₂O₃ ratios on the surface energy and glossiness of the ceramic glaze were studied in the present work. The results show that the mass fraction ratio of Na₂O/K₂O and R₂O/Al₂O₃ showed an obvious effect on the high temperature viscosity and melting temperature of the glaze, the density of the glaze network structure and the number of broken bonds on the glaze. When Na₂O/K₂O=0.8-1.6, R₂O/Al₂O₃=0.8-1.2, the glaze showed a glossiness of 88.3-108.3 with a 0.11%-12% increase, and the surface energy of 70.17-78.5 mJ · m-2 with a 5.62%-29.55% increase, being obviously higher than those of the basic glaze. The greater the surface energy of the glaze was, the greater the polarity component was, and the better the wettability of the water on the glaze was, which would be conducive to improving the antifouling and easy cleaning of ceramic products.

China’s rapid development of aquaculture has focused attention on its environmental impacts and the need for a comprehensive method that will enable environmental managers to estimate and evaluate aquaculture pollutant emissions. Few reports have estimated the environmental quality load of aquaculture conducted under different culture modes at the township level, and even fewer have studied the methods used to evaluate pollutant emissions. Here, we present a novel joint method based on an inventory analysis and an improved entropy weight method supplemented by remote sensing and an analysis of emission intensity. The method was applied to estimate and evaluate the environmental mass load of aquaculture in Zhuhai, Guangdong Province, China. The results showed that the main pollutant in areas dominated by freshwater aquaculture was chemical oxygen demand, whereas in areas dominated by mariculture the main pollutant was total nitrogen. Negative emissions occurred in Jinwan and Gaolan Port Districts, whereas the highest environmental quality load under different aquaculture modes was found in Baijiao Town, located in Doumen District. This study identified the excessive aquaculture density in Zhuhai. More generally, it provides a reference method for the environmental management of aquaculture in coastal cities.

Abstract Background HIST1H1E is a member of the H1 gene family. Excess de novo likely gene‐disruptive variants involving the C‐terminal tail of HIST1H1E have been reported in neurodevelopmental disorders. Although clinical phenotypes in some patients have been described in single studies, few studies have reviewed the genotype and phenotype relationships using a relatively large cohort of patients with HIST1H1E variants. Methods Whole‐exome sequencing (WES) was performed on the proband. The variant was validated using Sanger sequencing in both proband and parents. Published HIST1H1E variants in neuropsychiatric disorders were reviewed. Results Herein, we reported a new de novo frameshift mutation in HIST1H1E (NM_005321.2, c.416_419dupAGAA, p.Ala141GlufsTer56) in an individual with Rahman syndrome. To explore the genotype–phenotype correlations for HIST1H1E variants in neurodevelopmental disorders, we comprehensively curated and summarized 23 variants and the clinical features from 52 patients. Our findings revealed that likely gene‐disrupting variants in HIST1H1E contribute to a wide range of neurodevelopmental phenotypes. We observed the common phenotypes including craniofacial features, ID, hypotonia, and autism/behavior problem in patients with HIST1H1E variants. While the different genotypes corresponding to different phenotypes or the same phenotype were also observed. Conclusion These data provide scientific evidence for the genetic diagnosis and precision clinical management.

Allelopathy has been demonstrated to be an environmentally friendly way to control harmful algal blooms. Allelochemicals of submerged plants have attracted extensive research due to their bioavailability. The dose-response of submerged plant extracts on algae growth is worth further study to improve the efficiency of bioremediation. In this study, the ultrasonic-enzymatic assistance method was utilized to extract allelochemicals from Ceratophyllum, Myriophyllum spicatum, and Vallisneria. The effects of low-dosage and high-dosage extracts on the growth of Microcystis aeruginosa were compared based on cell biomass and morphology, photosynthetic parameters, reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels. The results showed that the three submerged plant extracts exhibited hormetic effects at low dosages and inhibitory effects at high dosages on algal growth. Within 48 h of cultivation, the enzymatic activities of Microcystis aeruginosa fluctuated, suggesting that the extracts of the three submerged plants induced different oxidative reactions. After 120 h of cultivation with high-dosage extracts, the physiological and biochemical reactions of Microcystis aeruginosa significantly decreased, indicating the effectiveness of the allelopathy of Ceratophyllum, Myriophyllum spicatum, and Vallisneria extracts in controlling algal blooms. The phenomenon of hormesis and inhibition effect confirmed a significant dose-response relationship between the allelochemicals of submerged plant extracts and Microcystis aeruginosa, which could be attributed to the composition and content of allelochemicals. These findings highlight the importance of the relative concentration of the biological algaecide and will benefit other researchers in determining the safe dosage of plant allelochemicals when used in water.

Abstract Background Mitochondrial dysfunction is considered to be an important contributor in podocyte injury under diabetic conditions. The BaoShenTongLuo (BSTL) formula has been shown to reduce podocyte damage and postpone the progression of diabetic kidney disease (DKD). The potential mechanisms underlying the effects of BSTL, however, have yet to be elucidated. In this study, we aimed to investigate whether the effects of BSTL are related to the regulation of mitochondrial biogenesis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. Methods High-Performance Liquid Chromatography Electrospray Ionization Mass Spectrometer (HPLC–ESI–MS) analysis was performed to investigate the characteristics of pure compounds in BSTL. db/db mice and mouse podocyte clone-5 (MPC5) cells were exposed to high glucose (HG) to induce DKD and podocyte damage. Body weight, random blood glucose, urinary albumin/creatinine ratio (UACR), indicators of renal function and renal histological lesions were measured. Markers of podocyte injury, mitochondrial morphology, mitochondrial deoxyribonucleic acid (mtDNA) content, mitochondrial respiratory chain complexes activities, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) levels were assessed. Protein expressions of AMPK, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), transcription factor A (TFAM), mitochondrial fusion protein 2 (MFN2) and dynamin-related protein 1 (DRP1) were also detected. MPC5 cells were transfected with AMPKα small interfering RNA (AMPKα siRNA) to determine the underlying mechanisms of BSTL improvement of mitochondrial function under diabetic conditions. Results In vivo, treatment with BSTL reduced the UACR levels, reversed the histopathological changes in renal tissues, and alleviated the podocyte injury observed in db/db mice. After BSTL treatment, the decreased mtDNA content and mitochondrial respiratory chain complex I, III, and IV activities were significantly improved, and these effects were accompanied by maintenance of the protein expression of p-AMPKαT172, PGC-1α, TFAM and MFN2. The in vitro experiments also showed that BSTL reduced podocyte apoptosis, suppressed excessive cellular ROS production, and reversed the decreased in MMP that were observed under HG conditions. More importantly, the effects of BSTL in enhancing mitochondrial biogenesis and reducing podocyte apoptosis were inhibited in AMPKα siRNA-treated podocytes. Conclusion BSTL plays a crucial role in protecting against podocyte injury by regulating the AMPK-mediated mitochondrial biogenesis in DKD.