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Abstract. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.

ObjectiveTo investigate the potential significance of FOXP3 expression in BRCA1/2-mutant breast cancer. MethodsA total of 48 BRCA mutation carriers (16 with BRCA1 and 32 with BRCA2) and 78 age-matched non-carriers were included in this study. Immunohistochemistry was used to detect the expression of FOXP3 in breast cancer tissues. The FOXP3 RNA expression in 39 BRCA1, 36 BRCA2, and 948 non-carrier breast cancer patients from TCGA-BRCA and the correlation with homologous recombination deficiency scores were evaluated to validate the immunohistochemistry results. ResultsThe FOXP3 positive rate was 43.8% (7/16) in BRCA1 mutation carriers, 59.4% (19/32) in BRCA2 mutation carriers, and 9.0% (7/78) in non-carriers. The FOXP3 positive rates in patients with BRCA1/2 mutant breast cancer were significantly higher than those in non-carriers (P=0.002; P

Background and aim: Type-2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance (IR) induced by hyperglycaemia and insufficient insulin secretion. We employed a diabetic fly model to examine the effect and molecular mechanism of Atractylodes macrocephala Koidz. and Cuscuta chinensis Lam. (AMK–CCL) extract as traditional Chinese medicine in treating IR and T2DM. Experimental procedure: The contents of the active ingredients (rhamnose, xylose, mannose, and hyperoside) in AMK–CCL extract were determined by high-performance liquid chromatography. Wild-type (Cg-GAL4/+) or diabetic (Cg > InRK1409A) Drosophila flies were divided into the control group or metformin group and AMK–CCL (0.0125, 0.025, 0.05, 0.1 g/ml) groups. Food intake, haemolymph glucose and trehalose, protein, weight, triglycerides (TAG), and glycogen were measured to assess glycolipid metabolism. Phosphatidylinositol-3-kinase (PI3K)/Akt signalling was detected using fluorescent reporters [tGPH, Drosophila forkhead box O (dFoxO)–green fluorescent protein (GFP), Glut1–GFP, 2-NBDG] in vivo. Glut1/3 mRNA levels and Akt phosphorylation levels were detected by quantitative polymerase chain reaction and western blotting, respectively, in vitro. Results: AMK–CCL extract contained 0.038 % rhamnose, 0.017 % xylose, 0.69 % mannose, and 0.039 % hyperoside. AMK–CCL at 0.0125 g/mL significantly suppressed the increase in circulating glucose, and the decrease in body weight, TAG, and glycogen contents of diabetic flies. AMK–CCL improved PI3K activity, Akt phosphorylation, Glut1/3 expression, and glucose uptake in diabetic flies, and also rescued diabetes-induced dFoxO nuclear localisation. Conclusions: These findings indicate that AMK–CCL extract ameliorates IR-induced diabetes via the PI3K/Akt signalling pathway, providing an experimental basis for clinical treatment.

Malignant melanoma (MM) is an extremely aggressive and fatal form of skin cancer that primarily affects the bottom layer of the epidermis and is associated with poor clinical outcomes. Early-stage MM is typically treated through surgical removal, while chemotherapy and radiotherapy are common conventional treatment options that come with harmful side effects. Emerging therapies such as immunotherapy, photodynamic therapy, biologic therapy, and photothermal therapy present hopeful options for treatment due to their effective and secure drug delivery methods. To address the limitations of current treatment options, advanced methods of drug delivery for subcutaneous MM are being developed, with hydrogels emerging as a promising alternative. To date, significant advancements have been made in the treatment of MM through the use of hydrogels-based drug delivery systems through focal plastering, injection, implantation, and microneedles. Recent research on hydrogel-based drug delivery systems that integrate multiple therapies for the treatment of subcutaneous MM is discussed in this review.

The leafhopper genus Smyga Dworakowska (Typhlocybinae, Empoascini) is reviewed and a new species, S. brevipenis Webb & Xu, sp. nov. from Brunei and Malaysia, is described based on specimens previously identified as “aberrant specimens” of Smyga distincta Dworakowska. Images of the types of S. brevipenis and S. distincta are given for the first time. A checklist and key to known species of Smyga are also provided.

Abstract Aim To investigate the correlation of angles α and κ with the refractive and biological parameters in children. Methods This case-series study included 438 eyes of 219 children (males/females = 105/114, age: 3–15 years). Ocular biometric parameters, including axial length, corneal radius of curvature (CR), white-to-white distance (WTW), angle κ and angle α, were measured using IOL Master 700; auto-refraction were assessed under cycloplegia. The eyes were assigned to different groups based on CR, WTW, and gender to compare the angles α and κ, and analyze the correlations between the differences of biological parameters on angles α and κ. Results The means of axial length, CR, WTW, angle α, and angle κ were 23.24 ± 1.14 mm, 7.79 ± 0.27 mm, 11.68 ± 0.41 mm, 0.45 ± 0.25 mm, and 0.27 ± 0.22 mm, respectively. Angle α was correlated with CR and WTW (fixed effect coefficient [FEC] = 0.237, p = 0.015; FEC = -0.109, p = 0.003; respectively), and angle κ also correlated with CR and WTW (FEC = 0.271, p = 0.003; FEC = -0.147, p

Neuroinflammation and mitochondrial dysfunction are closely intertwined with the pathophysiology of neurological disorders. Recent studies have elucidated profound alterations in mitochondrial dynamics across a spectrum of neurological disorders. Dynamin-related protein 1 (DRP1) emerges as a pivotal regulator of mitochondrial fission, with its dysregulation disrupting mitochondrial homeostasis and fueling neuroinflammation, thereby exacerbating disease severity. In addition to its role in mitochondrial dynamics, DRP1 plays a crucial role in modulating inflammation-related pathways. This review synthesizes important functions of DRP1 in the central nervous system (CNS) and the impact of epigenetic modification on the progression of neurodegenerative diseases. The intricate interplay between neuroinflammation and DRP1 in microglia and astrocytes, central contributors to neuroinflammation, is expounded upon. Furthermore, the use of DRP1 inhibitors to influence the activation of microglia and astrocytes, as well as their involvement in processes such as mitophagy, mitochondrial oxidative stress, and calcium ion transport in CNS-mediated neuroinflammation, is scrutinized. The modulation of microglia to astrocyte crosstalk by DRP1 and its role in inflammatory neurodegeneration is also highlighted. Overall, targeting DRP1 presents a promising avenue for ameliorating neuroinflammation and enhancing the therapeutic management of neurological disorders.

BackgroundStudies have shown that work readiness is closely related to nurses’ role adaptation, career development, and patient safety. However, we know little about the nursing students’ work readiness and its influencing factors before participating in a nurse residency program, and whether factors have changed from before.Aim(1) To investigate the work readiness of nursing students ready to engage in a nurse residency program; (2) to identify the factors affecting the nursing students’ work readiness and the associations between emotional intelligence and work readiness; and (3) to discuss the changes of factors affecting nursing students’ work readiness.DesignAn online, multicenter cross-sectional study.Methods878 nursing students from eight tertiary hospitals in Chongqing, China were recruited. The online investigation used the General Information Questionnaire, the Nursing Students’ Work Readiness Scale, and the Emotional Intelligence scale. The data were analyzed using IBM SPSS V23.0.Results768 valid questionnaires were included in this study. The nurses obtained a work readiness score of 277.08 ± 44.39 and an emotional intelligence score of 89.57 ± 13.89. Univariate analysis revealed that the following factors affected work readiness: age, sex, family support for becoming a nurse, voluntary choice of nursing major, previous experience as a student cadre, scholarship recipient status, willingness to engage in nursing work during the COVID-19 pandemic and confidence in clinical nursing practice. Frequent incidents of violence, poor salary for nurses for the nurse residency program, and low social acceptance were the top three reasons for decreased confidence in clinical nursing among nursing students. Furthermore, multiple linear regression analysis indicated that age, voluntary choice of nursing major, student leadership experience, confidence in clinical nursing work, self-emotion, and emotional application significantly influenced nurses’ work readiness.ConclusionClinical instructors and administrators should dynamically assess nurses’ work readiness, prioritize individuals aged ≤23, who have chosen the nursing profession involuntarily, lack prior experience as student cadres, and exhibit low confidence in clinical nursing work. This focus will enhance their emotional self-management skills and ability to apply emotions effectively, improving their work readiness and training efficacy.

Summary: Identifying the atlas of immune cells from coronary sinus circulation (CSC) of patients with persistent atrial fibrillation (PerAF) may provide new insights into the role of immune cells in the progression of AF. Single-cell sequencing revealed substantial alterations in immune cells from CSCs of patients with PerAF, especially a markedly elevated abundance of T cells, after which we identified a T cell subset: FGFBP2(+)TRDC(−)CD4(−) T cells (Ftc-T cells), which can promote the proliferation of cardiac fibroblasts (CFs),and the proportion of Ftc-T had a positive linear with AF recurrence post catheter ablation (CA). Moreover, IFI27 was found to be highly enriched in Ftc-T cells and promoted CFs proliferation and collagen expression. Altogether, our findings represent a unique resource providing in-depth insights into the heterogeneity of the immune cell from CSC of patients with PerAF and highlight the potential role of Ftc-T cells and IFI27 for AF progression.

Abstract Background The liver ranks as the sixth most prevalent site of primary cancer in humans, and it frequently experiences metastases from cancers originating in other organs. To facilitate the development of effective treatments and improve survival rates, it is crucial to comprehend the intricate and diverse transcriptome landscape of primary and metastatic liver cancers. Methods We conducted long-read isoform sequencing and short-read RNA sequencing using a cohort of 95 patients with primary and secondary liver cancer who underwent hepatic resection. We compared the transcriptome landscapes of primary and metastatic liver cancers and systematically investigated hepatocellular carcinoma (HCC), paired primary tumours and liver metastases, and matched nontumour liver tissues. Results We elucidated the full-length isoform-level transcriptome of primary and metastatic liver cancers in humans. Our analysis revealed isoform-level diversity in HCC and identified transcriptome variations associated with liver metastatis. Specific RNA transcripts and isoform switching events with clinical implications were profound in liver cancer. Moreover, we defined metastasis-specific transcripts that may serve as predictors of risk of metastasis. Additionally, we observed abnormalities in adjacent paracancerous liver tissues and characterized the immunological and metabolic alterations occurring in the liver. Conclusions Our findings underscore the power of full-length transcriptome profiling in providing novel biological insights into the molecular mechanisms underlying tumourigenesis. These insights will further contribute to improving treatment strategies for primary and metastatic liver cancers.

Accurate and reliable segmentation of rectal cancer in Magnetic Resonance Imaging holds crucial significance in preoperative prediction, tumor staging, and neoadjuvant therapy. Currently, the automated segmentation methods for rectal tumor have predominantly relied on Convolutional Neural Networks (CNNs), which lean heavily on discerning the contrast disparities among locally neighboring MRI voxels. However, these methods tend to exhibit segmentation inaccuracies when confronted with rectal cancer instances characterized by indistinct contrasts and markedly diverse shapes. Here, we propose a FCTformer who Fuses Convolutional operations and Transformer modules for accurate rectal tumor segmentation in 3D MRI. Specifically, first, FCTformer integrates a transformer-based global feature extraction mechanism and a CNN-based local feature extraction approach to obtain a dual-faceted multiscale feature representation. This representation enhances the model’s capability to capture both the comprehensive semantic features and intricate details of rectal cancer instances, especially in challenging situations such as low-contrast imaging and substantial shape variations. Second, to capitalize on features captured across different scales, thereby enhancing segmentation accuracy, we have incorporated a Dual-Attention decoder. Third, to enhance the tumor’s edges and contours, the Prediction Aggregation Unit is designed to capture sharper tumor boundaries and retain fine details that could be lost during repetitive down-sampling stages. Experimental results involving 362 instances of rectal tumor segmentation demonstrate that our proposed method achieves a Dice Similarity Coefficient of 0.827, surpassing existing methods. The satisfactory results obtained from evaluating our approach on a publicly available prostate dataset validate its generalizability.

Adenosine-to-inosine (A-to-I) RNA editing, mediated by metazoan ADAR enzymes, is a prevalent post-transcriptional modification that diversifies the proteome and promotes adaptive evolution of organisms. The Drosophila Adar gene has an auto-recoding site (termed S>G site) that forms a negative-feedback loop and stabilizes the global editing activity. However, the evolutionary trajectory of Adar S>G site in many other insects remains largely unknown, preventing us from a deeper understanding on the significance of this auto-editing mechanism. In this study, we retrieved the well-annotated genomes of 375 arthropod species including the five major insect orders (Lepidoptera, Diptera, Coleoptera, Hymenoptera and Hemiptera) and several outgroup species. We performed comparative genomic analysis on the Adar auto-recoding S>G site. We found that the ancestral state of insect S>G site was an uneditable serine codon (unSer) and that this state was largely maintained in Hymenoptera. The editable serine codon (edSer) appeared in the common ancestor of Lepidoptera, Diptera and Coleoptera and was almost fixed in the three orders. Interestingly, Hemiptera species possessed comparable numbers of unSer and edSer codons, and a few ‘intermediate codons’, demonstrating a multi-step evolutionary trace from unSer-to-edSer with non-synchronized mutations at three codon positions. We argue that the evolution of Adar S>G site is the best genomic evidence supporting the ‘proteomic diversifying hypothesis’ of RNA editing. Our work deepens our understanding on the evolutionary significance of Adar auto-recoding site which stabilizes the global editing activity and controls transcriptomic diversity.

Skin damage resulting from burns, injuries, or diseases can lead to significant functional and esthetic deficits. However, traditional treatments, such as skin grafting, have limitations including limited donor skin availability, poor aesthetics, and functional impairment. Skin tissue engineering provides a promising alternative, with engineered artificial skins offering a highly viable avenue. Engineered artificial skin is designed to mimic or replace the functions of natural human skin and find applications in various medical treatments, particularly for severe burns, chronic wounds, and other skin injuries or defects. These artificial skins aim to promote wound healing, provide temporary coverage, permanent skin replacement, and restore the skin's barrier function. Artificial skins have diverse applications in medicine and wound care, addressing burns, chronic wounds, and traumatic injuries. They also serve as valuable tools for research in tissue engineering, offering experimental models for studying wound healing mechanisms, testing new biomaterials, and exploring innovative approaches to skin regeneration. This review provides an overview of current construction strategies for engineered artificial skin, including cell sources, biomaterials, and construction techniques. It further explores the primary application areas and future prospects of artificial skin, highlighting their potential to revolutionize skin reconstruction and advance the field of regenerative medicine.

AbstractThe effect of the combination of 10-Hydroxycamptothecin (HCPT) and crizotinib (CRI) on EGFR- and KRAS-mutant lung cancer cells was investigated and the conjugates of the two drugs were synthesised. HCPT combined with CRI synergistically inhibited the cell growth and proliferation of H1975, HCC827, and H460 without aggravating adverse effect on the normal cells. The combination synergistically enhanced the cell apoptosis rate through releasing Cyto-C by activation of Bcl-2 family-mediated mitochondrial signalling, which was associate with inactivating of EGFR related downstream signalling pathways including AKT, ERK, JNK, and p38 MAPK. Based on this synergy, the conjugates of HCPT and CRI (compounds CH-1 and CH-2) with different chemical bonds were synthesised. Compound CH-1 exhibited stronger cytotoxicity than HCPT and CRI alone or in combination. The combination of HCPT and CRI might be a promising therapeutic regimen and the conjugate CH-1was a potential target drug for the treatment of lung cancer.

Summary: Background: Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. Methods: From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. Findings: In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. Interpretation: This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. Funding: This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).

Anisakiasis is a food-borne parasitic disease mainly caused by the third stage of Anisakis simplex (s. s.) and Anisakis pegreffii. Traditional methods for detecting of Anisakis involve morphology identification such as visual inspection, enzyme digestion, and molecular methods based on PCR, but they have certain limitations. In this study, the internal transcribed spacer 1 (ITS 1) regions of Anisakis were targeted to develop a visual screening method for detecting A. simplex (s. s.) and A. pegreffii in fish meat based on recombinase polymerase amplification (RPA) combined with lateral flow dipstick (LFD). Specific primers and probes were designed and optimized for temperature, reaction time, and detection threshold. LFD produced clear visual results that were easily identifiable after a consistent incubation of 10–20 min at 37 °C. The whole process of DNA amplification by RPA and readout by LFD did not exceed 30 min. In addition, the detection limit is up to 9.5 × 10−4 ng/μL, and the detection of the artificially contaminated samples showed that the developed assay can effectively and specifically detect A. simplex (s. s.) and A. pegreffii, which fully meet the market's requirements for fish food safety supervision.

In the context of the digital economy, empowering firm innovation investment through digital transformation is an important strategy for promoting innovation development in China. This study investigates the effects and mechanisms of digital transformation on firm innovation investment from the perspective of total factor productivity, using a sample of manufacturing companies listed on the A-share market in China from 2012 to 2021. The following three main findings were obtained. First, results of both fixed- and random-effects regression methods revealed that digital transformation significantly promotes firms’ innovation investment. This conclusion remains robust after controlling for endogeneity issues using the instrumental variable method and replacing the explanatory variable measurement methods. Second, stepwise regression analysis revealed a negative mediating mechanism of total factor productivity (TFP) in the impact of digital transformation on the level of firm innovation investment. The main reason for this is that an improvement in TFP intensifies the competition for capital and labor input between the production and innovation departments. Third, the group regression for heterogeneity analysis found that the overall effect of digital transformation on firm innovation investment is significantly positive in groups with low financing constraints and high human capital, but not significant in groups with high financing constraints and low human capital. Moreover, the negative mediating mechanism of TFP is significantly valid in all groups, further validating the competition between the production and innovation departments for capital and labor input. Based on the findings of this study and from the perspective of governance by the Chinese government, three policy recommendations are proposed to empower firm innovation development through digital transformation.

Abstract Background Parkinson's disease (PD) is a common neurodegenerative disorder. Microglia‐mediated neuroinflammation has emerged as an involving mechanism at the initiation and development of PD. Activation of adenosine triphosphate (ATP)‐sensitive potassium (KATP) channels can protect dopaminergic neurons from damage. Sodium butyrate (NaB) shows anti‐inflammatory and neuroprotective effects in some animal models of brain injury and regulates the KATP channels in islet β cells. In this study, we aimed to verify the anti‐inflammatory effect of NaB on PD and further explored potential molecular mechanisms. Methods We established an in vitro PD model in BV2 cells using 1‐methyl‐4‐phenylpyridinium (MPP+). The effects of MPP+ and NaB on BV2 cell viability were detected by cell counting kit‐8 assays. The morphology of BV2 cells with or without MPP+ treatment was imaged via an optical microscope. The expression of Iba‐1 was examined by the immunofluorescence staining. The intracellular ATP content was estimated through the colorimetric method, and Griess assay was conducted to measure the nitric oxide production. The expression levels of pro‐inflammatory cytokines and KATP channel subunits were evaluated by reverse transcription–quantitative polymerase chain reaction and western blot analysis. Results NaB (5 mM) activated the KATP channels through elevating Kir6.1 and Kir6.1 expression in MPP+‐challenged BV2 cells. Both NaB and pinacidil (a KATP opener) suppressed the MPP+‐induced activation of BV2 cells and reduced the production of nitrite and pro‐inflammatory cytokines in MPP+‐challenged BV2 cells. Conclusion NaB treatment alleviates the MPP+‐induced inflammatory responses in microglia via activation of KATP channels.

Abstract Background To investigate the prevalence and risk factors of refractive astigmatism (RA) and corneal astigmatism (CA) in preschool children and school-aged children in Shanghai, China. Methods In this school-based, cross-sectional study, 4–15 years old children across three learning stages of kindergarten, primary school, and junior high school underwent noncycloplegic autorefraction and completed comprehensive questionnaires involving time spent on daily homework and outdoor activities. Data from the right eyes were analysed. Results Overall, 7084 children (mean ± standard deviation (SD) of age: 8.08 ± 3.11 years) were included, and the prevalence rates of RA/CA ( ≤ − 1.0 D) in children were 15.8%/64% in kindergartens, 16.5%/65% in primary schools, and 32.8%/76.9% in junior high schools. The magnitude and prevalence of RA and CA all increased with age or with learning stage (all P

MicroRNAs (miRNAs) are short endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level in a broad range of eukaryotic species. In animals, it is estimated that more than 60% of mammalian genes are targets of miRNAs, with miRNAs regulating cellular processes such as differentiation and proliferation. In plants, miRNAs regulate gene expression and play essential roles in diverse biological processes, including growth, development, and stress responses. Arabidopsis mutants with defective miRNA biogenesis are embryo lethal, and abnormal expression of miRNAs can cause severe developmental phenotypes. It is therefore crucial that the homeostasis of miRNAs is tightly regulated. In this review, we summarize the key mechanisms of plant miRNA biogenesis and stabilization. We provide an update on nuclear proteins with functions in miRNA biogenesis and proteins linking miRNA biogenesis to environmental triggers.

Abstract Colorectal cancer (CRC) has become a global health problem which has almost highest morbidity and mortality in all types of cancers. This study aimed to uncover the biological functions and underlying mechanism of MCM8 in the development and progression of CRC. The expression level of MCM8 was found to be upregulated in CRC tissues and significantly associated with tumor grade and patients’ survival. Knocking down MCM8 expression in CRC cells could restrain cell growth and cell motility while promoting cell apoptosis in vitro, as well as inhibit tumor growth in xenograft mice model. Based on the RNA screening performing on CRC cells with or without MCM8 knockdown and the following IPA analysis, CHSY1 was identified as a potential target of MCM8 in CRC, whose expression was also found to be higher in tumor tissues than in normal tissues. Moreover, it was demonstrated that MCM8 may regulate the expression of CHSY1 through affecting its NEDD4-mediated ubiquitination, both of which synergistically execute tumor promotion effects on CRC. In conclusion, the outcomes of our study showed the first evidence that MCM8 act as a tumor promotor in CRC, and may be a promising therapeutic target of CRC treatment.

Red mud (RM), a hazardous solid waste generated in the alumina production process, of which the mineral composition is mainly hematite, is unable to be applied directly in the cement industry due to its high alkalinity. With the rise of geopolymers, RM-based grouting materials play an essential role in disaster prevention and underground engineering. To adequately reduce the land-based stockpiling of solid wastes, ultrafine calcium oxide, red mud, and slag were utilized as the main raw materials to prepare geopolymers, the C-R-S (calcium oxide–red mud–slag) grouting cementitious materials. The direct impact of red mud addition on the setting time, fluidity, water secretion, mechanical properties, and rheological properties of C-R-S were also investigated. In addition, a scanning electron microscope (SEM), X-ray diffraction (XRD), three-dimensional CT (3D-CT), Fourier transform infrared spectroscopy (FT-IR), and other characterization techniques were used to analyze the microstructure and polymerization mechanism. The related results reveal that the increase in red mud addition leads to an enhanced setting time, and the C-R-S-40 grouting cementitious material (40% red mud addition) exhibits the best fluidity of 27.5 cm, the lowest water secretion rate of 5.7%, and a high mechanical strength of 57.7 MPa. The C-R-S polymer grout conforms to the Herschel–Bulkley model, and the fitted value of R2 is above 0.99. All analyses confirm that the preparation process of C-R-S grouting cementitious material not only substantially improves the utilization rate of red mud, but also provides a theoretical basis for the high-volume application of red mud in the field of grouting.

BackgroundThere is currently a lack of studies examining the long-term therapeutic effectiveness of the third-generation anti-sezure medication, perampanel (PER), for focal-onset seizures (FOS), particularly in Chinese patients with sleep-related epilepsy (SRE). Additionally, the appropriate dosage, plasma concentration, and the relationship between dose and plasma concentration of PER in Chinese patients are still uncertain.MethodsA prospective, single-center, 24-month observational study was conducted in patients diagnosed with FOS, with a focus on patients with SRE. Changes in seizure frequency from baseline, adverse events, and retention rates were analyzed at 12 and 24 months following the start of the treatment. Tolerability was evaluated based on adverse events and discontinuation profiles. PER plasma concentrations were used to assess dose-concentration-response relationships.ResultsA total of 175 patients were included (median age: 25 years; range: 4–72 years; 53. 1% males and 46.9% females), with the SRE population accounting for 49. 1% (n = 86). The patients diagnosed with SRE showed considerably higher response rates than those who did not have this diagnosis (p = 0.025, odds ratio = 3.8). Additionally, the SRE group adhered better to PER treatment (r = 0.0009). Patients with a shorter duration of epilepsy (median: 3 years; range:2–7 years) demonstrated a more favorable therapeutic response to PER (p = 0.032). Throughout the administration of maintenance doses, among the entire FOS population, the concentration of PER (C0) ranged between 101.5 and 917.4 ng/mL (median, 232.0 ng/mL), and the mean plasma concentration of PER in the responders was 292.8 ng/mL. We revealed a linear relationship between PER dose and plasma concentration, regardless of whether PER was used as monotherapy or add-on therapy. The retention rates were 77.7% and 65. 1% at 12 and 24 months, respectively. Drug-related adverse events occurred in 45.0% of the patients and were mostly manageable.ConclusionPER effectively reduced seizure frequency in Chinese patients with FOS, particularly in those with SRE, over a 24-month period. The treatment was well-tolerated and had a clear linear dose-plasma concentration relationship.

BackgroundMyopia poses a global health concern and is influenced by both genetic and environmental factors. The incidence of myopia tends to increase during infectious outbreaks, such as the COVID-19 pandemic. This study examined the screen-time behaviors among Chinese children and adolescents and investigated the efficacy of artificial intelligence (AI)-based alerts in modifying screen-time practices.MethodsA cross-sectional analysis was performed using data from 6,716 children and adolescents with AI-enhanced tablets that monitored and recorded their behavior and environmental light during screen time.ResultsThe median daily screen time of all participants was 58.82 min. Among all age groups, elementary-school students had the longest median daily screen time, which was 87.25 min and exceeded 4 h per week. Children younger than 2 years engaged with tablets for a median of 41.84 min per day. Learning accounted for 54.88% of participants’ screen time, and 51.03% (3,390/6,643) of the participants used tablets for 1 h at an average distance

This article investigates whether higher classification accuracy can always be achieved by utilizing a pre-trained deep learning model as the feature extractor in the Bag-of-Deep-Visual-Words (BoDVW) classification model, as opposed to directly using the new classification layer of the pre-trained model for classification. Considering the multiple factors related to the feature extractor -such as model architecture, fine-tuning strategy, number of training samples, feature extraction method, and feature encoding method-we investigate these factors through experiments and then provide detailed answers to the question. In our experiments, we use five feature encoding methods: hard-voting, soft-voting, locally constrained linear coding, super vector coding, and fisher vector (FV). We also employ two popular feature extraction methods: one (denoted as Ext-DFs(CP)) uses a convolutional or non-global pooling layer, and another (denoted as Ext-DFs(FC)) uses a fully-connected or global pooling layer. Three pre-trained models-VGGNet-16, ResNext-50(32×4d), and Swin-B-are utilized as feature extractors. Experimental results on six datasets (15-Scenes, TF-Flowers, MIT Indoor-67, COVID-19 CXR, NWPU-RESISC45, and Caltech-101) reveal that compared to using the pre-trained model with only the new classification layer re-trained for classification, employing it as the feature extractor in the BoDVW model improves the accuracy in 35 out of 36 experiments when using FV. With Ext-DFs(CP), the accuracy increases by 0.13% to 8.43% (averaged at 3.11%), and with Ext-DFs(FC), it increases by 1.06% to 14.63% (averaged at 5.66%). Furthermore, when all layers of the pre-trained model are fine-tuned and used as the feature extractor, the results vary depending on the methods used. If FV and Ext-DFs(FC) are used, the accuracy increases by 0.21% to 5.65% (averaged at 1.58%) in 14 out of 18 experiments. Our results suggest that while using a pre-trained deep learning model as the feature extractor does not always improve classification accuracy, it holds great potential as an accuracy improvement technique.

BackgroundImmune-checkpoint inhibitors(ICIs) combined with chemotherapy are emerging as an effective first-line treatment in advanced non-small cell lung cancer (NSCLC); however, reports on the magnitude of effectiveness and safety are conflicting.MethodsRelevant articles published before February 2022 were searched in PubMed, Embase, and the Cochrane Library. The study included all randomized controlled trials that evaluated ICIs with chemotherapy versus chemotherapy for the treatment of NSCLC. Among the outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs).ResultsOur meta-analysis included a total of 12 studies. Overall analysis indicated that ICIs plus chemotherapy could significantly improve OS (HR = 0.79; 95% CI: 0.74-0.84; I2 = 44.4%, P = 0.055), PFS (HR = 0.62; 95% CI: 0.59-0.67; I2 = 75.3%, P = 0.000), and ORR (RR = 1.48; 95% CI: 1.27-1.73; I2 = 79.0%, P = 0.000) when compared to chemotherapy treatments. Subgroup analysis showed that PD-1/PD-L1 inhibitors combined with chemotherapy significantly improved OS, PFS, and ORR when compared with chemotherapy with decreased grade 1-2 TRAEs. In addition, female patients with nonsquamous histology might receive more OS benefit from ICIs plus chemotherapy when compared to chemotherapy alone. Despite the fact that CTLA-4 inhibitors combined with chemotherapy increased PFS, there were no benefits gained in OS nor ORR. When PD-L1/CTLA-4 inhibitors were added to chemotherapy, the risk of grade 3-5 adverse events increased whereas PD-1 inhibitors did not.ConclusionsICIs plus chemotherapy, compared with chemotherapy, were associated with significantly improved PFS, ORR, and OS in NSCLC therapy. However, PD-L1/CTLA-4 inhibitors plus chemotherapy could increase the risk of grade 3-5 adverse events, but not PD-1 inhibitors plus chemotherapy.

Abstract Rapid identification of pathogens is critical for early and appropriate treatment of bloodstream infections. The various culture‐independent assays that have been developed often have long turnaround times, low sensitivity and narrow pathogen coverage. Here, we propose a new multiplex PCR assay, MeltArray, which uses intact microbial cells as the source of genomic DNA (gDNA). The successive steps of the MeltArray assay, including selective lysis of human cells, microbial cell sedimentation, microbial cellular DNA extraction, target‐specific pre‐amplification and multiplex PCR detection, allowed the detection of 35 major bloodstream infectious pathogens in whole blood within 5.5 h. The limits of detection varied depending on the pathogen and ranged from 1 to 5 CFU/mL. Of 443 blood culture samples, including 373 positive blood culture samples and 70 negative blood culture samples, the MeltArray assay showed a sensitivity of 93.8% (350/373, 95% confidence interval [CI] = 90.7%–96.0%), specificity of 98.6% (69/70, 95% CI = 91.2%–99.9%), positive predictive value of 99.7% (95% CI = 98.1%–99.9%), and negative predictive value of 75.0% (95% CI = 64.7%–83.2%). The MeltArray detection results of 16 samples differed from MALDI–TOF and were confirmed by Sanger sequencing. Further testing of 110 whole blood samples from patients with suspected bloodstream infections using blood culture results revealed that the MeltArray assay had a clinical sensitivity of 100% (9/9, 95% CI = 62.8%–100.0%), clinical specificity of 74.5% (70/94, 95% CI = 64.2%–82.7%), positive predictive value of 27.3% (95% CI = 13.9%–45.8%), and negative predictive value of 100.0% (95% CI = 93.5%–100.0%). Compared with metagenomic next‐generation sequencing, the MeltArray assay displayed a positive agreement of 85.7% (6/7, 95% CI = 42.0%–99.2%) and negative agreement of 100.0% (4/4, 95% CI = 39.6%–100.0%). We conclude that the MeltArray assay can be used as a rapid and reliable tool for direct identification of pathogens in bloodstream infections.

Background: Protection against ischemic stroke may be most effective when multiple components of the neurovascular unit are protected, yet current treatments target mainly neurons. Here we explored whether the PSD-95 inhibitor Tat-NR2B9c (NA-1) can protect not only neurons but also the blood-brain barrier. Methods: Adult male Sprague-Dawley rats were randomly divided into three groups, which were subjected to either sham surgery or transient cerebral ischemia-reperfusion, after which some animals were treated with Tat-NR2B9c. The therapeutic efficacy of Tat-NR2B9c was assessed in terms of the degree of neurological deficit and cerebral infarction, integrity of the blood-brain barrier, cerebral water content, as well as expression of PSD-95, nitric oxide synthase, and matrix metalloprotease-9. Results: Tat-NR2B9c (NA-1) ameliorated neurofunctional deficit, reduced cerebral infarction, mitigated blood-brain barrier injury and improved its integrity following ischemia-reperfusion, leading to less cerebral edema. These improvements were associated with upregulation of tight junction proteins in the blood-brain barrier. At the same time, Tat-NR2B9c (NA-1) downregulated neuronal nitric oxide synthase and matrix metalloprotease-9, while reversing the ischemia-induced downregulation of endothelial nitric oxide synthase in brain. We report here the first evidence that PSD-95 is expressed in vascular endothelial cells in the brain. Conclusion: Our experiments in a rat model of transient occlusion of the middle cerebral artery suggest that Tat-NR2B9c (NA-1) can mitigate ischemic injury to the blood-brain barrier, and that it may do so by downregulating matrix metalloprotease-9 and upregulating endothelial nitric oxide synthase.

Abstract Background A novel form of cell death termed cuproptosis was proposed recently. miRNAs play important roles in colorectal cancer (CRC). However, their relationships have not been reported. Methods miRNAs that negatively regulate 16 cuproptosis regulators were predicted using Targetscan database. The univariate Cox, LASSO, and multivariate Cox regression analyses were performed to select cuproptosis‐related miRNAs. GSEA and ssGSEA analysis was carried out for functional enrichment analysis. The immune cell proportion score (IPS) and the efficiencies of multiple chemotherapy drugs were compared between different risk groups. The CCK8, cell colony, edu, and flow cytometry assays were performed to validate the roles of miRNA. Luciferase reporter assay confirmed the regulatory mechanism of miRNA on cuproptosis. Results Six cuproptosis‐related miRNAs (hsa‐miR‐653, hsa‐miR‐216a, hsa‐miR‐3684, hsa‐miR‐4437, hsa‐miR‐641, and hsa‐miR‐552) were screened out for model construction. The risk score could act as an independent prognostic indicator in CRC (p

Abstract Parabramis pekinensis was treated as research object in order to investigate the correlation between morphological traits and body weight. We measured 9 morphological indexes including total length (X 1 ), body length (X 2 ), body height (X 3 ), head length (X 4 ), snout length (X 5 ), eye diameter (X 6 ), eye distance (X 7 ), caudal stalk length (X 8 ) and caudal stalk height (X 9 ). The principal morphological traits affecting body weight were screened out and the regression equation was established. The regression equation of Y1 (age 1 group) shape character (X) and weight (Y) was Y = − 169.183 + 32.544 × 3 + 10.263 × 4 + 15.655 × 7. The regression equation of Y2 (age 2 group) shape character (X) and weight (Y) was Y = − 694.082 + 7.725 × 1 + 72.822 × 3 + 77.023 × 6, the regression equation of Y3 (age 3 group) shape character (X) and weight (Y) was Y = − 1161.512 + 26.062 × 1 + 22.319 × 2- 107.218 × 5 + 83.901 × 7. Gene expression was consistent with these conclusions. TOR signaling pathway expression raised in Y1 then width increased. And GH-IGF-1 signaling pathway expression raised in Y2 then the length increased. In conclusion, the paper could prove that P. pekinensis showed a growth trend, which was increasing width first and length later. In some sense, the study not only enriched the basic biological data of P. pekinensis, but also provided waiting morphological traits for selective breeding of P. pekinensis artificial breeding in future.

Abstract Background C-to-U RNA editing in plants is believed to confer its evolutionary adaptiveness by reversing unfavorable DNA mutations. This “restorative hypothesis” has not yet been tested genome-wide. In contrast, A-to-I RNA editing in insects like Drosophila and honeybee is already known to benefit the host by increasing proteomic diversity in a spatial-temporal manner (namely “diversifying hypothesis”). Methods We profiled the RNA editomes of multiple tissues of Arabidopsis thaliana, Drosophila melanogaster, and Apis melifera. We unprecedentedly defined the haplotype diversity (HD) of RNA molecules based on nonsynonymous editing events (recoding sites). Results Signals of adaptation is confirmed in Arabidopsis by observing higher frequencies and levels at nonsynonymous editing sites over synonymous sites. Compared to A-to-I recoding sites in Drosophila, the C-to-U recoding sites in Arabidopsis show significantly lower HD, presumably due to the stronger linkage between C-to-U events. Conclusions C-to-U RNA editing in Arabidopsis is adaptive but it is not designed for diversifying the proteome like A-to-I editing in Drosophila. Instead, C-to-U recoding sites resemble DNA mutations. Our observation supports the restorative hypothesis of plant C-to-U editing which claims that editing is used for fixing unfavorable genomic sequences.

Stem cell therapies have made great progress in the treatment of diabetic wounds during recent decades, while their short in vivo residence, alloimmune reactions, undesired behaviors, and dramatic losses of cell functions still hinder the translation of them into clinic. Here, inspired by the natural components of stem cell niches, we presented novel microfluidic hydrogel microcarriers with extracellular matrix (ECM)-like composition and adipose-derived stem cells (ADSCs) encapsulation for diabetic wound healing. As the hydrogel was synthesized by conjugating hyaluronic acid methacryloyl (HAMA) onto the Fibronectin (FN) molecule chain (FN-HAMA), the laden ADSCs in the microcarriers showed improved bioactivities and pro-regenerative capabilities. Based on these features, we have demonstrated that these ADSCs microcarriers exhibited significant promotion of neovascularization, follicular rejuvenation, and collagen deposition in a mouse diabetic wound model. These results indicated that the stem cell niche-inspired FN-HAMA microcarriers with ADSCs encapsulation have great clinical potential for diabetic wound treatment.

Abstract Hepatocellular carcinoma (HCC) is a malignant tumor, frequently causing both intrahepatic and extrahepatic metastases. The overall prognosis of patients with metastatic HCC is poor. Recently, single-cell (sc) polarity is proved to be an innate feature of some tumor cells in liquid phase, and directly involved in the cell adhesion to blood vessel and tumor metastasis. Here, we characterize the maintained sc polarity of HCC cells in a suspension culture, and investigate its roles and regulatory mechanisms during metastasis. We demonstrate that transient receptor potential vanilloid 4 (TRPV4) is a promoting regulator of sc polarity via activating Ca2+-dependent AMPK/MLC/ERM pathway. This attenuates the adhesion of metastatic HCC cells to vascular endothelial cells. The reduction of cancer metastases can result from TRPV4 inhibition, which not only impacts the migration and invasion of tumor cells, but also prevents the adhesion to vascular endothelial cells. Additionally, we discover a brand-new TRPV4 inhibitor called GL-V9 that modifies the degree of sc polarization and significantly decreases the metastatic capacity of HCC cells. Taken together, our data shows that TRPV4 and calcium signal are significant sc polarity regulators in metastatic HCC, and that the pharmacological intervention that results in HCC cells becoming depolarized suggests a promising treatment for cancer metastasis.

This study used Dutch potatoes at the end of dormancy as a material to explore the impact of menthol (0.2 and 0.5 g/kg based on potato mass) treatment on sprouting inhibition and potato quality. The findings revealed that a menthol concentration of 0.5 g/kg effectively inhibited potato tuber sprouting and significantly reduced glucoside alkaloid production. After a storage period of 15 days, the sprouting percentage and glucoside alkaloid content of potatoes treated with 0.5 g/kg menthol were observed to be significantly lower at 4.17% and 68.63 mg/kg, respectively, compared to the control group which exhibited values of 100% and 282.01 mg/kg, respectively (p < 0.05). Throughout the storage period, 0.5 g/kg of menthol promoted respiration, reduced malondialdehyde production in potatoes, inhibited polyphenol oxidase activity, and slowed down tissue browning. Additionally, it mitigated the decline in starch and soluble protein content, inhibiting the accumulation of reducing sugars.

Abstract Background Hepatic failure induced by immune checkpoint inhibitors (ICIs) has been reported in only a few case series and case reports. Objective We aimed to explore the association between ICIs and hepatic failure and characterize the clinical features of ICI‐associated hepatic failure in the pharmacovigilance database. Methods Data from the first quarter (Q1) of 2015 to the fourth quarter (Q4) of 2021 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database were retrieved for disproportionality and Bayesian analysis. Reporting odds ratios (ROR) and information component (IC) were used to evaluate correlations between ICIs and hepatic failure. Results Hepatic failure occurred in 0.19% (18,454/9,647,655) of all cases in the FAERS database, of which 654 cases were associated with ICIs. The overall median time from ICIs initiation to hepatic failure onset was 38 days, 72.3% of the adverse events occurred within the first 3 months, and 68.65% of the cases died after developing hepatic failure. In general, a strong signal was shown between ICIs and hepatic failure (ROR025 = 2.70, IC025 = 1.39). For the three categories of ICIs, programmed cell death 1 ligand 1 inhibitors (ROR025 = 3.09, IC025 = 1.57) had a higher risk signal than programmed cell death protein 1 inhibitors and cytotoxic T lymphocyte‐associated protein 4 inhibitors. For monotherapy, atezolizumab showed the strongest risk signal (ROR025 = 4.07, IC025 = 1.90). The combination of nivolumab and ipilimumab showed stronger signals of hepatic failure compared with nivolumab or ipilimumab alone (nivolumab + ipilimumab vs. ipilimumab: ROR025 = 1.40, IC025 = 0.16; nivolumab + ipilimumab vs. nivolumab: ROR025 = 1.24, IC025 = 0.34). Considering the concomitant agents used with ICIs, the majority of these regimens showed stronger signals than ICI monotherapy, such as acetaminophen (ICIs + acetaminophen vs. ICIs: ROR025 = 1.06, IC025 = 0.32). Conclusions ICIs had possible strong signals associated with hepatic failure, and most cases of hepatic failure occurred within the first 3 months and had poor outcomes, which should attract clinical attention.

Abstract Aim This study aimed to systematically characterize transplant rejection after immune checkpoint inhibitors (ICIs) initiation in solid organ transplant recipients (SOTRs). Methods Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database and case reports in the literature. Disproportionality analysis including information component and reported odds ratio (ROR) was performed to access potential risk signals. Results A total of 168 patients with transplant rejection after ICIs usage were identified in the FAERS database, and 89 cases were identified in the literature review. ICIs were significantly associated with transplant rejection (ROR025: 2.2). A strong risk signal was found for combination therapy with pembrolizumab and ipilimumab compared to monotherapy. Conclusion Immune checkpoint inhibitors were significantly associated with transplant rejection in SOTRs.

Objectives: This study aimed to elucidate resistance to carbapenems and fluoroquinolones, the transmission mechanism of blaKPC-2, and the virulence characteristics of a Pseudomonas aeruginosa strain (TL3773) isolated in East China. Methods: The virulence and resistance mechanisms of TL3773 were investigated by whole genome sequencing (WGS), comparative genomic analysis, conjugation experiments, and virulence assays. Results: This study isolated carbapenem-resistant P. aeruginosa from blood resistant to carbapenems. The patient's clinical data showed poor prognosis compounded by multiple sites of infection. WGS showed that TL3773 carried aph (3′)-IIb, blaPAO, blaOXA-486, fosA, catB7, and two crpP resistance genes on chromosome, and the carbapenem resistance gene blaKPC-2 on plasmid. We identified a novel crpP gene named TL3773-crpP2. Cloning experiments proved that TL3773-crpP2 was not the primary cause of fluoroquinolone resistance in TL3773. GyrA and ParC mutations may confer fluoroquinolone resistance. The blaKPC-2 genetic environment was IS26-TnpR-ISKpn27-blaKPC-2-ISKpn6-IS26-Tn3-IS26, potentially mediating the transmission of blaKPC-2 in P. aeruginosa. The overall virulence of TL3773 was lower than that of PAO1. However, the pyocyanin and biofilm formation of TL3773 was higher than that of PAO1. WGS further indicated that TL3773 was less virulent than PAO1. Phylogenetic analysis showed that TL3773 was most similar to the P. aeruginosa isolate ZYPA29 from Hangzhou, China. These observations further indicate that ST463 P. aeruginosa is rapidly spreading. Conclusions: The threat of ST463 P. aeruginosa harbouring blaKPC-2 is emergent and may pose a threat to human health. More extensive surveillance and effective actions are urgently needed to control its further spread.

Chronic wounds are characterized by prolonged healing processes and poor prognoses, which have substantially impacted human health and daily life. Traditional treatment strategies have various limitations and drawbacks. Therefore, fully effective therapeutic approaches remain urgently needed. Stem cell (SC)-based therapies have drawn significant attention for their abilities of immunomodulation and pro-regeneration. It has been demonstrated that stem cells (SCs) can improve angiogenesis, collagen deposition, and hair rejuvenation, thus facilitating wound healing. In addition, attempts were performed to facilitate the cell survival, function, retention, and engraftment of the delivered SCs. In this review, we first introduce the pathological process involved in chronic wound healing. Following that, the mechanism of SCs in promoting chronic wound repair is discussed in detail. Then, we highlight recent SC-based therapies for chronic wound repair developments. Finally, we present our views on the remaining challenges and future trends of SC-based therapies for chronic wound treatment.

Abstract Hyaluronic acid (HA) is an attractive extracellular matrix‐derived polymer. The related HA‐based hydrogels are emerging to be the hotspots in the cutting edge of biomaterials. The continuous sights concentrate on exploring modification methods and crosslinking strategies to promote the advancement of HA‐based hydrogels with enhanced physical/chemical properties and enriched biological performance. Here, the advances on modification methods and crosslinking strategies for fabricating HA‐based hydrogels with diverse capacities are summarized. Firstly, the modification reactions that occur on the active hydroxyl, carboxyl and N‐acetyl groups of HA molecule are discussed. Next, the emphasis is put on various crosslinking strategies including physical crosslinking, covalent crosslinking and dynamic covalent crosslinking. Finally, we provide a general summary and give a critical viewpoint on the remaining challenges and the future development of HA‐based hydrogels. It is hoped that this review can provide new proposals for the specific design of functional hydrogel biomaterials.

Metabolic fluxes are at the heart of metabolism and growth in any living system. During tuberculosis (TB) infection, the pathogenic Mycobacterium tuberculosis (Mtb) adapts its nutritional behaviour and metabolic fluxes to survive in human macrophages and cause infection. The infected host cells also undergo metabolic changes. However, our knowledge of the infected host metabolism and identification of the reprogrammed metabolic flux nodes remains limited. In this study, we applied systems-based 13C-metabolic flux analysis (MFA) to measure intracellular carbon metabolic fluxes in Mtb-infected human THP-1 macrophages. We provide a flux map for infected macrophages that quantified significantly increased fluxes through glycolytic fluxes towards pyruvate synthesis and reduced pentose phosphate pathway fluxes when compared to uninfected macrophages. The tri carboxylic acid (TCA) cycle fluxes were relatively low, and amino acid fluxes were reprogrammed upon Mtb infection. The knowledge of host metabolic flux profiles derived from our work expands on how the host cell adapts its carbon metabolism in response to Mtb infection and highlights important nodes that may provide targets for developing new therapeutics to improve TB treatment.

Background: The watch-and-wait (W&W) strategy is a novel treatment option for patients with rectal cancer who have a strong desire for organ preservation. The study aimed to explore the long-term outcomes of the W&W strategy in a large cohort of rectal cancer patients who achieved a clinical complete response (cCR) after consolidation total neoadjuvant therapy (TNT), and to compare with patients who achieved a pathological complete response (pCR) after radical surgery. Methods: The W&W group comprised patients who were assessed as having a cCR after consolidation TNT and adopted the W&W strategy. Patients who underwent standard resection and achieved a pCR were compared as a reference. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan–Meier analysis with log-rank test was used to compare survival outcomes. Results: We included 89 and 171 patients in the W&W and pCR groups, respectively. The median follow-up period was 45 and 58 months for the W&W and pCR groups, respectively. After IPTW adjustment, the 2-year local regrowth/recurrence rate for the W&W and pCR groups were 9.9% and 2.0%, respectively ( p < 0.001). The W&W and pCR groups had similar 5-year outcomes, including overall survival, disease-free survival, and distant metastasis-free survival (all p > 0.05). No significant difference was observed in the rates of distant metastasis between patients in the W&W group with local regrowth and those without local regrowth (25% versus 6.2%, p = 0.119). Conclusion: Patients who were managed with a W&W strategy after consolidation TNT had favorable survival outcomes, which were similar to those of patients with a pCR. The rate of local regrowth in W&W patients was lower in our study than in other studies as a result of the implementation of consolidation TNT.

Objective: The spectrum and risk of cancer in relatives of BRCA1/2 pathogenic variant carriers in the Chinese population have not been established. Methods: A family history of cancer in 9903 unselected breast cancer patients was retrospectively analyzed. BRCA1/2 status was determined for all patients and relative risks (RRs) were calculated to evaluate cancer risk in relatives of the patients. Results: The incidences of breast cancer in female relatives of BRCA1 carriers, BRCA2 carriers, and non-carriers were 33.0%, 32.2%, and 7.7%, respectively. The corresponding incidences of ovarian cancer were 11.5%, 2.4%, and 0.5%, respectively. The incidences of pancreatic cancer in male relatives of BRCA1 carriers, BRCA2 carriers, and non-carriers were 1.4%, 2.7%, and 0.6%, respectively. The corresponding incidences of prostate cancer were 1.0%, 2.1%, and 0.4%, respectively. The risks of breast and ovarian cancers in female relatives of BRCA1 and BRCA2 carriers were significantly higher than female relatives of non-carriers (BRCA1: RR = 4.29, P < 0.001 and RR = 21.95, P < 0.001; BRCA2: RR = 4.19, P < 0.001 and RR = 4.65, P < 0.001, respectively). Additionally, higher risks of pancreatic and prostate cancers were noted in male relatives of BRCA2 carriers than non-carriers (RR = 4.34, P = 0.001 and RR = 4.86, P = 0.001, respectively). Conclusions: Female relatives of BRCA1 and BRCA2 carriers are at increased risk for breast and ovarian cancers, and male relatives of BRCA2 carriers are at increased risk for pancreatic and prostate cancers.

The leafhopper genus Cornicola Ohara & Hayashi, previously recorded from Japan, is recorded from China for the first time and a new species, C. maculatus Xu, Dietrich & Qin, sp. nov., is described and illustrated, including its color polymorphism. This genus has male genitalia and hind wing venation similar to those found in Empoascini but it is more appropriately placed in Dikraneurini. A key to species of Cornicola is given together with a key to the genera of Dikraneurini from China.

Abstract Aims Limited data are available on the outcomes of cryoballoon ablation (CBA)‐based pulmonary vein isolation (PVI) for atrial fibrillation (AF) in patients with heart failure (HF) with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF). The present study aimed to evaluate the safety and effectiveness of CBA in such patients. Methods and results Consecutive patients with AF referred for CBA‐based PVI from two highly experienced electrophysiology centres were included in this retrospective study. Of 651 patients undergoing CBA, 471 cases were divided into four groups: No HF (n = 255), HFpEF (n = 101), HFmrEF (n = 78), and HF with reduced ejection fraction (n = 37). Similar early recurrence of atrial arrhythmia was found among groups (16.2% vs. 15.4% vs. 14.9% vs. 12.2%, P = 0.798), and no significant difference of long‐term sinus rhythm (SR) maintenance was identified among the HFmrEF, HFpEF, and No HF groups (71.8% vs. 75.2% vs. 79.6%, P = 0.334). CBA is safe for patients with HFmrEF and HFpEF with similar complications compared with the No HF group (3.8% vs. 4.0% vs. 3.1%, P = 0.814). The reassessment of cardiac function after CBA showed that patients with HF indicated beneficial outcomes. Left atrial diameter (LAD) and left ventricular ejection fraction were significantly improved in the HFmrEF group. There were 41.6% of patients in the HFpEF group who were completely relieved from HF. LAD and New York Heart Association (NYHA) were associated with recurrence in the HFpEF and HFmrEF groups, and the maintenance of SR was an independent predictor of NYHA improvement for all HF groups. Conclusions Patients with HFmrEF and HFpEF could benefit from CBA with high SR maintenance and significant HF improvement.

Ovarian cancer is one of the leading causes of death in female reproductive system cancers. However, the pathogenesis of ovarian cancer remains elusive. Our aim is to investigate the potential targets for ovarian cancer. Two microarray datasets were obtained from the Gene Expression Omnibus public database. Using R package limma, the differentially expressed genes (DEGs) were identified from the datasets. There were 95 overlapping DEGs in two microarray datasets. GO, KEGG pathway analysis, and protein-protein interaction (PPI) network analysis were carried out based on the DEGs. Wnt signaling pathway and cell cycle were enriched in the KEGG pathway analysis. Moreover, the top 10 hub genes with the most nodes were determined by PPI network analysis. E2F8, one of hub genes was positively linked to a bad outcome in ovarian cancer patients. Furthermore, E2F8 knockdown suppressed cell proliferation and induced cell cycle arrest in ovarian cancer. In addition, we found that silencing E2F8 inhibited the Wnt/β-catenin signaling pathway. In ovarian cancer cells with E2F8 knockdown, overexpressing β-catenin restored both the suppressed capacity of cell proliferation and cell cycle progression. Therefore, our results revealed that E2F8 had an involvement in the development of ovarian cancer which might act as a therapeutic target.

The senescence-associated secretory phenotype (SASP) is closely associated with the tumorigenesis and progression of intrahepatic cholangiocarcinoma (ICC). However, it remains unclear its relation to stemness of ICC. In the study, the stemness indices of ICC were calculated using one-class linear regression (OCLR) and single-sample gene set enrichment analysis (ssGSEA) algorithms. A total of 14 senescence-related stemness genes (SRSGs) were identified using Pearson correlation analysis in ICC. Subsequently, a SRSGs-related classification was established using a consensus clustering for ICC. Different types of ICC exhibit distinct prognosis, immunity, metabolisms, and oncogenic signatures. Additionally, we constructed a risk score model for ICC using principal component analysis (PCA). The risk score was positively correlated with stemness, immune infiltration, metabolisms and oncogenic signatures, but negatively with prognosis in ICC. Patients with a high risk score may respond well to immunotherapy. Furthermore, we employed 3D fibrin gels to select tumor-repopulating cells (TRC) with stemness features. We found that HELLS, belonging to the 14 SRSGs, was up-regulated in ICC-TRC. And silencing HELLS significantly reduced the colony size, inhibited migration and invasion, and attenuated SASP in ICC-TRC. In summary, we provided a novel classification and risk score for ICC and uncovered a molecular mechanism via which CSLCs could obtain an active SASP.