Search

Introduction: Excessive inflammation and the pyroptosis of vascular endothelial cells caused by estrogen deficiency is one cause of atherosclerosis in post-menopausal women. The autophagy is highly regulated by estrogen, however whether estrogen can reduce vascular endothelial cell pyroptosis through estrogen receptor-mediated activation of autophagy to improve atherosclerosis in post-menopausal stage is still unknown. Objectives: To explore whether estrogen can prevent atherosclerosis by regulating estrogen receptor and subsequently activating autophagy to reduce inflammation and pyroptosis. Methods: Aortic samples from pro-menopausal and post-menopausal women with ascending aortic arteriosclerosis were analyzed, and bilateral ovariectomized (OVX) female ApoE-/- mice and homocysteine (Hcy)-treated HUVECs were used to analyze the effect of estrogen supplementation therapy. Results: The aortic endothelium showed a decrease in ERα expression and autophagy, but presented an increase in inflammation and pyroptosis in female post-menopausal patients. Estrogen treatment accelerated autophagy and ameliorated cell pyroptosis in the cardiac aortas of OVX ApoE-/- mice and Hcy-treated HUVECs. Estrogen had therapeutic effect on atherosclerosis and improved the symptoms associated with lipid metabolism disorders in OVX ApoE-/- mice. Inhibition and silencing of ERα led to a reduction in the autophagy promoting ability of estrogen and aggravated pyroptosis. Moreover, the inhibition of autophagy promoted pyroptosis and abolished the protective effect of estrogen, but had no influence on ERα expression. Conclusion: The results of the present study demonstrated that post-menopausal women present decreased autophagy and ERα expression and excessive damage to the ascending aorta. In addition, in vitro and in vivo assay results demonstrated that estrogen prevents atherosclerosis by upregulating ERα expression and subsequently induces autophagy to reduce inflammation and pyroptosis.

In the field of autonomous driving, the accuracy and real-time requirements for 3D object detection technology continue to improve, which is directly related to the commercialization process and market popularity of autonomous vehicles. Despite the efficiency of pillar-based coding for onboard systems, it falls short in terms of accuracy and the reduction of incorrect positives. In this paper, we will examine how to solve the problem of high incorrect rate and low accuracy of existing methods. Firstly, a MAP coding module is introduced to optimize previous point cloud feature coding modules, allowing for the efficient extraction of fine-grained features from point cloud data. Then, we introduce an innovative sparse dual attention (SDA) to efficiently filter out irrelevant details in feature extraction, thereby improving the pertinence and efficiency of information extraction. Finally, to address the potential loss of information from single local feature extraction, a local and global fusion module (CTGC) is introduced. Our method has proactively demonstrated its efficiency and accuracy through rigorous experimentation across diverse datasets. Analysis of the results leads to the conclusion that our solutions provide accurate and robust detection results. Code will be available at https://github.com/lcy199905/MyOpenPCDet.git.

The vaginal microbiota is proposed to be associated with reproductive health. Exposure to metals during pregnancy is a risk factor for premature rupture of membranes (PROM). PROM can lead to serious maternal complications, thus, identifying the cause and therapeutic targets for it is crucial. However, the role of vaginal microbiota in the association between metals exposure and the risk of PROM are not clear. Based on a prospective birth cohort study including 668 pregnant women, maternal blood levels of 15 metals in the first trimester (n=668) and microbiota of vaginal secretions in the third trimester (n=244) were assessed. The metals that significantly associated with the risk of PROM were screened out via four statistical models, the top three were barium (Ba), chromium (Cr) and thallium (Tl) according to their weight indices. The results from the BKMR model showed a positive association of the mixture (Ba, Cr and Tl) with the risk of PROM. PROM and non-PROM were characterised by different beta diversities, moreover, the relative abundances of Bifidobacterium, Corynebacterium and Collinsella were statistically and negatively related to the risk of PROM [the adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were 0.06 (0.00, 0.82), 0.32 (0.14, 0.74) and 0.50 (0.30, 0.84), respectively]. On the other hand, women with different levels of Ba exposure were also characterised by different beta diversities (p value = 0.047); and blood Ba levels were also negatively associated with the relative abundances of Collinsella; additionally, Cr levels were positively associated with alpha diversity indices [Shannon index: β (95 % CI) = 0.25 (0.01, 0.50); Simpson index: β (95 % CI) = 0.08 (0.00, 0.17), respectively]. The results from mediation analysis showed the proportion of the relationship between Ba exposure and PROM risk mediated by the relative abundance of Collinsella was 26.4 %. Further verification analysis exploring the potential cause of the above phenomenon indicated that the neutrophil count, one of blood inflammation indicators for PROM, was higher in women with the absence of Collinsella (p value = 0.039), moreover, the cumulative hazard of PROM for women with the presence of Collinsella was also significantly lower than that of those without Collinsella (p value = 0.007). Collectively, the changes in the diversity and composition of the bacterial community, especially the reduction in Collinsella abundance caused by metal exposure, may be related to the occurrence of PROM, which provides a new microbiota-based perspective for intervention in metal exposure-related PROM. Confirming these relationships and determining the possible processes at play will require more investigation.

Chemotherapy-induced peripheral neuropathy (CIPN) and its related pain are common challenges for patients receiving oxaliplatin chemotherapy. Oxaliplatin accumulation in dorsal root ganglion (DRGs) is known to impair gene transcription by epigenetic dysregulation. We hypothesized that sodium butyrate, a pro-resolution short-chain fatty acid, inhibited histone acetylation in DRGs and abolished K+ channel dysregulation-induced neuronal hyperexcitability after oxaliplatin treatment. Mechanical allodynia and cold hyperalgesia of mice receiving an accumulation of 15 ​mg/kg oxaliplatin, with or without intraperitoneal sodium butyrate supplementation, were assessed using von Frey test and acetone evaporation test. Differential expressions of histone deacetylases (HDACs) and pain-related K+ channels were quantified with rt-qPCR and protein assays. Immunofluorescence assays of histone acetylation at H3K9/14 were performed in primary DRG cultures treated with sodium butyrate. Current clamp recording of action potentials and persistent outward current of Twik-related-spinal cord K+ (TRESK) channel were recorded in DRG neurons with small diameters extract. Accompanied by mechanical allodynia and cold hyperalgesia, HDAC1 was upregulated in mice receiving oxaliplatin treatment. Sodium butyrate enhanced global histone acetylation at H3K9/14 in DRG neurons. In vivo sodium butyrate supplementation restored oxaliplatin-induced Kcnj9 and Kcnk18 expression and pain-related behaviors in mice for at least 14 days. Oxaliplatin-induced increase in action potentials frequencies and decrease in magnitudes of KCNK18-related current were reversed in mice receiving sodium butyrate supplementation. This study suggests that sodium butyrate was a useful agent to relieve oxaliplatin-mediated neuropathic pain.

The tea moth pest, Agriophara rhombata is an economically important and highly damaging pest that drastically affects tea plant leaves. The chemical composition of its pheromone glands metabolites before and during calling period has not been reported yet. Therefore, the present study aimed at the metabolomic profiling of female moths’ sex pheromones glands before and during calling period using gas chromatography time-of-flight mass spectrometry. A total of 114 significant differentially expressed metabolites were identified including 54 up- and 70 down-regulated metabolites in pheromone glands of the female moth. Two of the important previously recognized moth pheromones were identified including E,Z-5,7-dodecadien-1-ol acetate and Z-12-Octadecen-1-ol acetate, which were downregulated. The top ten up-regulated metabolites were “dodecanamide”, “tetradecanamide”, “2-propyn-1-amine, N,N-dimethyl”, “cyclohexane, (1-methylethyl)”, “tetradecane, 2-methyl”, “1-cyclopentyleicosane”, “cyclohexane, octyl”, “1-decan-3-one”, “cyclopentane, decyl” and “cyclopentadecane”. In conclusion, while most of the identified compounds have not previously been identified as primary pheromones in moths, their differential expression in A. rhombata's pheromone glands during the calling period strongly suggests their supporting roles in the synthesis, stabilization, or release of the active pheromone components.

To explore the impact of ursodeoxycholic acid (UDCA) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and clinical outcomes in patients with autoimmune liver disease (AILD). Patients diagnosed with AILD were enrolled and divided into a UDCA group and a non-UDCA group based on whether they received UDCA treatment. Relevant data were collected regarding AILD diagnosis, treatment, biochemical indicators, and imaging examination. The incidence of SARS-CoV-2 infection and the prognosis of AILD patients were observed. A total of 1,138 patients completed follow-up. The usage rate of hormone (P = 0.003) and immunosuppressant (P = 0.001) used for treating AILD in the non-UDCA group was markedly lower than in the UDCA group. The UDCA usage rate was markedly lower in SARS-CoV-2 infected patients than in uninfected patients (P = 0.003). The rate of SARS-CoV-2 infection in the non-UDCA group was significantly higher than in the UDCA group (P = 0.018). Logistic regression analysis showed that UDCA use (P = 0.003) was correlated to a lower incidence of SARS-CoV-2, while immunosuppressant use (P = 0.017) increased the incidence. Recovery time from SARS-CoV-2 infection was markedly longer for those receiving UDCA treatment than those in the non-UDCA group (P = 0.018). UDCA is associated with low SARS-CoV-2 incidence in AILD patients, while immunosuppressant increases its incidence instead. Patients receiving UDCA treatment have a longer recovery time after being infected.

Innovations in mental health are desperately needed in Healthy China with increasing benefits of a growth mindset on mental health among Chinese. Currently, empirical research in China reveals significant discrepancies in the correlation between growth mindset and mental health. To elucidate this discrepancy, we conducted a meta-analysis on 59 studies utilizing a random-effects model, with 68 effect sizes and 54,302 participants included. The main effects revealed a significantly positive correlation between growth mindset and positive indicators of mental health (r = 0.36, [0.27, 0.45]), as well as a significantly negative correlation between growth mindset and negative indicators of mental health (r = −0.25, [−0.31, −0.20]). Subgroup test and meta-regression results indicated that age, economic region, and measurement instruments moderated the growth mindset and positive indicators of mental health. In contrast, negative indicators were moderated by gender and measurement instruments. The above findings suggest that a growth mindset significantly correlates with mental health. Consequently, it can be developed into an effective psychological service strategy in Healthy China. Future empirical studies should continue to examine this relationship and explore additional potential moderating variables. Furthermore, the clinical effects of growth mindset interventions in mental health should be tested.

Summary: The live attenuated yellow fever vaccine (YF17D) has caused controversial safety issues in history with low-yield problems, which has led to a large population being unable to be vaccinated and vaccine shortage in facing recent outbreaks. Here, we report a safer live attenuated vaccine candidate, YF17D-Δ77, which contains 77 nucleotides deletion in the 3′ untranslated region (3′ UTR) of the YF17D genome. YF17D-Δ77 exhibited no neurotropism and decreased viscerotropism and caused significantly lower lethality in mice compared to YF17D. Mechanistically, the deletion enhanced the sensitivity of the virus to type I and type II interferon responses, which hindered viral replication. Encouragingly, YF17D-Δ77 provided comparable immune protection in mice as did YF17D. Even 10 PFU of YF17D-Δ77 completely protected mice against YFV-Asibi challenge. In addition, the Δ77 mutation showed excellent stability after successive passages in Vero cells. Collectively, the data suggest that further development of YF17D-Δ77 as vaccine candidate is warranted.

The red blood cell (RBC) lifespan is a crucial indicator used in clinical diagnostics, treatment, and disease monitoring. This biomarker quantifies the duration that red blood cells (RBCs) circulate within the bloodstream after being released from the bone marrow, serving as a sensitive and direct indicator of red blood cell turnover. Conventional techniques for RBC lifespan measurement, including differential agglutination, 51Cr labeling, and 15N glycine labeling, each present their own set of challenges, such as complexity, radioactive exposure, and potential allergic reaction. The carbon monoxide (CO) breath test has emerged as an advanced and non-invasive alternative, indirectly assessing RBC lifespan through hemoglobin (Hb) renewal rates. This method is convenient, rapid, and lacks the drawbacks of traditional approaches. The CO breath test for RBC lifespan is widely utilized in benign anemia, malignant hematological disorders, neonatal hyperbilirubinemia, and diabetes mellitus, offering valuable insights into disease mechanisms, progression, and treatment outcomes.

Objectives: This study aimed to evaluate the measurement properties and methodological quality of assessment tools for Kinesophobia among patients with cardiovascular disease and provide a reference for healthcare professionals in selecting high-quality assessment tools. Methods: A systematic search was performed on specific databases: Embase, the Cochrane Library, PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang database, China Biological Medicine disc, CINAHL, and China Science and Technology Journal Database, from inception to April 1, 2023. The researchers retrieved studies on the measurement attributes of the exercise fear scale in patients with cardiovascular diseases. They also traced back the references of the included studies to supplement relevant literature. According to the inclusion and exclusion criteria, screening and data extraction were independently undertaken by two reviewers. Two researchers individually used the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) Risk of Bias Checklist to assess the methodological quality of the scale, applied the COSMIN criteria to evaluate the measurement properties of the scale, and used a modified Grading, Recommendations, Assessment, Development, and Evaluation system to assess the certainty of evidence. Results: Seventeen studies were identified that reported the psychometric properties of six patient reported outcome measurement tools (included different languages version) The methodological quality of content validity was adequate in only two studies, the remaining patient-reported outcome measures demonstrated doubtful content validity. Limited information on cross-cultural validity/measurement invariance, measurement error, and responsiveness was retrieved. The Swedish version and the Chinese version of the Tampa Scale for Kinesiophobia Heart were graded “A.” The remaining instruments were graded “B.” Conclusions: The methodological and measurement attributes of the Swedish and Chinese versions of the Tampa Scale for Kinesiophobia Heart are relatively high quality and can be tentatively recommended. The measurement properties of the remaining scales remain to be verified.

Summary: Obesity and overweight are significant global health issues, and numerous obesity intervention studies have been conducted. Summarizing current knowledge of interventions aims to inform researchers and policymakers to keep up-to-date with the latest scientific advancements and trends. In this review, we comprehensively retrieved and screened 4,541 studies on obesity intervention published between 2018 and 2022 in the Web of Science Core Collection, and objectively presented research frontiers using bibliometric analysis. The research frontiers of intervention are mainly focused on dietary, exercise, pharmacological interventions, bariatric surgery, environmental, and cognitive interventions. Time-restricted eating is the hottest research topic, followed by probiotics and Roux-en-Y gastric bypass. Gut microbiota is located in the “Basic and transversal themes” quadrant with a high centrality and low density, which has great development potentiality. Obesity intervention is becoming increasingly common,and we advocate for researchers to undertake more focused research endeavors that consider the specific characteristics of diverse populations or patients.

Objectives: Nasopharyngeal carcinoma (NPC) is an aggressive epithelial cancer. The expression of miR-186 is decreased in a variety of malignancies and can promote the invasion and metastasis of cancer cells. This study aimed to explore the role and possible mechanism of miR-186 in the metastasis and epithelial–mesenchymal transformation (EMT) of NPC. Methods: The expression of miR-186 in NPC tissues and cells was detected by RT-PCR. Then, miR-186 mimic was used to transfect NPC cell lines C666-1 and CNE-2, and cell activity, invasion and migration were detected by CCK8, transwell and scratch assay, respectively. The expression of EMT-related proteins was analyzed by western blotting analysis. The binding relationship between miR-186 and target gene Zinc Finger E-Box Binding Homeobox 1 (ZEB1) was confirmed by double luciferase assay. Results: The expression of miR-186 in NPC was significantly decreased, and transfection of miR-186 mimic could significantly inhibit the cell activity, invasion, and migration, and regulate the protein expressions of E-cadherin, N-cadherin and vimentin in C666-1 and CNE-2 cells. Further experiments confirmed that miR-186 could directly target ZEB1 and negatively regulate its expression. In addition, ZEB1 has been confirmed to be highly expressed in NPC, and inhibition of ZEB1 could inhibit the activity, invasion, metastasis and EMT of NPC cells. And co-transfection of miR-186 mimic and si-ZEB1 could further inhibit the proliferation and metastasis of NPC. Conclusion: miR-186 may inhibit the proliferation, metastasis and EMT of NPC by targeting ZEB1, and the miR-186/ZEB1 axis plays an important role in NPC.

Objective: To explore the kidney yang deficiency pattern (KYDP) in a chronic kidney disease (CKD) rat model and the mechanisms underlying the effects of Zhenwu decoction (ZWD) by conducting transcriptomic and metabolomic analyses. Methods: Adriamycin (ADR) combined with hydrocortisone (HC) was used to induce CKD with KYDP in rats. ADR was injected into the tail vein twice. HC was injected intramuscularly for 8 weeks. ZWD was administered by gavage for 8 weeks. The general condition was observed, 24-h urine protein was detected, serum corticosterone, triiodothyronine, thyroxine, TSH, testosterone, cAMP, and cGMP levels were determined, and pathological analysis was conducted. Transcriptomic and metabolomic analyses were conducted to screen differentially expressed genes (DEGs), differentially expressed metabolites (DEMs), and differentially expressed pathways (DEPs). The core DEMs and DEGs were input to Metaboanalyst 5.0 to identify the pathways affected by ZWD. Results: In the HC group, KYDP symptoms were observed. Compared with control group, the levels of 24-h urine protein, TSH, and cGMP significantly increased (all P

In the spacer acquisition stage of CRISPR-Cas immunity, spacer orientation and protospacer adjacent motif (PAM) removal are two prerequisites for functional spacer integration. Cas4 has been implicated in both processing the prespacer and determining the spacer orientation. In Cas4-lacking systems, host 3′–5′ DnaQ family exonucleases were recently reported to play a Cas4-like role. However, the molecular details of DnaQ functions remain elusive. Here, we characterized the spacer acquisition of the adaptation module of the Streptococcus thermophilus type I-E system, in which a DnaQ domain naturally fuses with Cas2. We presented X-ray crystal structures and cryo-electron microscopy structures of this adaptation module. Our biochemical data showed that DnaQ trimmed PAM-containing and PAM-deficient overhangs with different efficiencies. Based on these results, we proposed a time-dependent model for DnaQ-mediated spacer acquisition to elucidate PAM removal and spacer orientation determination in Cas4-lacking CRISPR-Cas systems.

Objective: To explore the protective effect and potential mechanisms of danshen root (Salvia miltiorrhiza Bge., S. miltiorrhiza) and its extracts for the treatment of diabetic nephropathy (DN). Methods: Preclinical studies of S. miltiorrhiza and its extracts on DN were systematically searched in nine databases. The primary outcomes were blood glucose, kidney function, proteinuria, and renal histopathology. The secondary outcomes included the related mechanisms. The methodological quality of animal studies was assessed based on the risk of bias tool of the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) for animal studies. Meta-analysis was performed using R software (version 4.1.2). Results: Twenty-nine animal experimental studies that met the eligibility criteria were included in this study. Compared to the control group, S. miltiorrhiza reduced the serum creatinine, blood urea nitrogen, 24-h urine protein, 24-h urine albumin, blood glucose, and kidney index (kidney weight/body weight), and alleviated renal pathological damage. In terms of the mechanism of action, compared to the control group, S. miltiorrhiza reduced the levels of transforming growth factor β1, collagen IV, malondialdehyde, tumor necrosis factor α, interleukin-6, and monocyte/macrophage (ED-1), and increased the levels of superoxide dismutase, glutathione peroxidase, nuclear factor E2–related factor 2, and heme oxygenase-1. Conclusion: The existing evidence shows that S. miltiorrhiza has beneficial effects on the animal model of DN, and its mechanism is mainly related to improving kidney fibrosis, oxidative stress, and inflammatory response.

ABSTRACT: Objectives: Linezolid-dependent growth has contributed to wide dissemination of Staphylococcus epidermidis in hospitals. This study aimed to characterise linezolid-resistant coagulase-negative staphylococci (CoNS) isolates and the possibility of linezolid dependence in China. Methods: Phenotypic and genotypic resistance of 13 CoNS isolates were investigated by antimicrobial susceptibility testing and PCR. Similarity of isolates was determined by pulsed-field gel electrophoresis (PFGE). Characterisation of the cfr-carrying plasmid was performed by S1 nuclease PFGE, Southern blotting and whole-genome sequencing (WGS). A maximum likelihood phylogenetic tree was constructed for phylogenetic analysis. Growth curve analysis was performed with and without linezolid to determinate the possible contribution of linezolid dependence to linezolid-resistant CoNS dissemination. Results: Thirteen CoNS isolates showed linezolid MICs of 8 mg/L to >256 mg/L, typed into three PFGE profiles. Southern blotting and WGS indicated that the cfr gene was located on a 39.5-kb plasmid with 99% identity to cfr-harbouring plasmids pSR01, pLRSA417 and pH29-46. The cfr gene was flanked by two copies of an IS256-like element ISEnfa4 family transposase, indicating the transferability of linezolid resistance conferred by the cfr gene. Comparative phylogenetic analysis revealed that Staphylococcus capitis XZ03 shared high similarity with linezolid-resistant S. capitis isolates in Huashan Hospital, Shanghai. Thirteen CoNS isolates did not exhibit linezolid dependence on exposure from 8–32 mg/L. Conclusion: The endemic CoNS clone carrying the cfr gene in our hospital showed high-level linezolid resistance, threatening linezolid use. Linezolid-dependent growth under linezolid selective pressure was not observed, indicating that it may not yet be a common phenotype in Staphylococcus spp.

Background: Postoperative gastrointestinal dysfunction (PGD) is a common complication in patients undergoing gastrointestinal surgery. Several studies have evaluated the effect of transcutaneous electrical acupoint stimulation (TEAS) on PGD, so we conducted a systematic review and meta-analysis to better understand these studies methodologic limitations and summarize clinical effects. Methods: Articles (published from January 2010 to April 2022) were searched from the following databases: Wanfang Database, China National Knowledge Infrastructure (CNKI), Cochrane Library, PubMed, Web of Science and Embase. Two authors conducted literature selection, data extraction and statistical analysis independently. This meta-analysis used RevMan 5.4 software to implement statistical analysis and applied Cochrane bias risk tool to assess methodologic weaknesses of included articles. We assessed the effect of TEAS on time to first flatus, first defecation and bowel sound recovery through meta-analyses using a random-effects model. Results: The meta-analysis included 10 articles including 1497 patients. This study showed that TEAS could effectively promote postoperative gastrointestinal function recovery by analyzing the time to first flatus (MD−14.81 h, 95% CI −15.88 to −13.75 h), time to first defecation (MD−14.68 h, 95% CI −20.59 to −8.76 h), time to bowel sound recovery (MD−5.79 h, 95% CI −10.87 to −0.71 h), length of hospital stay (MD−1.48d, 95% CI −1.86 to −1.11d), and the incidence of postoperative nausea and vomiting (PONV) (OR 0.41, 95% CI 0.29–0.58). In addition, we assessed the quality of the articles and found small sample sizes and lower methodological quality in some articles. Conclusion: Our meta-analysis revealed that TEAS could be a nonpharmacological treatment for PGD in patients after gastrointestinal surgery. However, positive findings should be treated carefully and future studies with high quality and large samples are needed to support this results.

Background: The most common disease caused by biallelic AFG3L2 mutations is spastic ataxia type 5 (SPAX5). Identification of complex phenotypes resulting from biallelic AFG3L2 mutations has been increasing in recent years. Methods: A retrospective analysis was performed on a child with microcephaly and recurrent seizures. The child underwent physical and neurological examinations, laboratory tests, electroencephalography (EEG), and brain magnetic resonance imaging (MRI). Trio-whole-exome sequencing (trio-WES) was performed to identify possible causative mutations. Results: We described a child who exhibited early-onset and intractable epilepsy, developmental regression, microcephaly, and premature death. Neuroimaging revealed global cerebral atrophy (GCA) involving the cerebrum, cerebellum, corpus callosum, brainstem, cerebellar vermis, and basal ganglia. On trio-WES, two novel compound heterozygous mutations, c.1834G > T (p.E612*) and c.2176-6T > A in the AFG3L2 gene, were identified in this patient. Conclusions: Our findings have expanded the mutation spectrum of the AFG3L2 gene and identified a severe neurodegenerative phenotype of global cerebral atrophy caused by biallelic AFG3L2 mutations.

Background: Docetaxel (DCT) is widely used in clinical practice, but the drug resistance of breast cancer patients has become an important reason to limit its clinical efficacy. Chan’su is a commonly used traditional Chinese medicine for the treatment of breast cancer. Bufalin (BUF) is a bioactive polyhydroxy steroid extracted from chan’su and has strong antitumor activity, but there are few studies on reversing drug resistance in breast cancer. The aim of this study is to determine whether BUF can reverse the drug resistance to DCT and restore efficacy in breast cancer. Methodology: The reversal index of BUF was detected by Cell Counting Kit-8 (CCK-8) assays. The effects of BUF on enhancing the apoptosis of DCT were detected by flow cytometry and Western Blot (WB), and the main differential expression levels of sensitive and resistant strains were detected by high-throughput sequencing. Rhodamine 123 assay, WB and ATP Binding Cassette Subfamily B Member 1 (ABCB1) ATPase activity experiments were used to detect the effect of BUF on ABCB1. The nude mouse orthotopic model was constructed to investigate the reversal effect of BUF on DCT resistance in vivo. Results: With BUF intervention, the sensitivity of drug-resistant cell lines to DCT was increased. BUF can inhibit the expression of ABCB1 protein, increase the drug accumulation of DCT in drug-resistant strains, and reduce the ATPase activity of ABCB1. Animal experiments show that BUF can inhibit the growth of drug-resistant tumors in an orthotopic model of breast cancer and decrease the expression of ABCB1. Conclusion: BUF can reverse ABCB1-mediated docetaxel resistance in breast cancer.

Smoking is an independent risk factor for the cardiovascular diseases. Nicotine, a major component of tobacco, is responsible for the impaired endothelial-dependent vasorelaxation in smokers. Procyanidin B2 (PCB2), a natural flavonoid, has been reported to possess several potential beneficial effects on the cardiovascular system. However, whether PCB2 prevents nicotine-induced endothelial dysfunction remains unknown. In this study, we demonstrated that PCB2 improved nicotine-impaired endothelium-dependent vasorelaxation in mouse thoracic aortas. Mechanistically, PCB2 increased the expression levels of dihydrofolate reductase (DHFR) and GTP cyclohydrolase 1 (GCH1), two important enzymes in the synthesis of tetrahydrobiopterin (BH4), in mouse aortas and cultured ECs. GSK0660, a selective antagonist of peroxisome proliferator-activated receptor δ (PPARδ), abolished the PCB2-induced effects on BH4 synthesis, nitric oxide (NO) production and vasodilation. Collectively, we demonstrated that PCB2 mitigates nicotine-induced endothelial dysfunction through a PPARδ-BH4 dependent manner, thereby suggesting a novel role of PCB2 in preventing vascular dysfunction caused by nicotine exposure.

Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERRα, C-Abelson, and as well as their relevant small-molecule compounds in PD models, which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.

Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 (NTRK1, NTRK2 and NTRK3) genes, respectively. TRKs can regulate cell proliferation, differentiation and even apoptosis through the RAS/MAPKs, PI3K/AKT and PLCγ pathways. Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors, and TRKs have become promising antitumor targets. Therefore, achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications. This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins, the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity, and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.

Purpose: This study explored the mediating effect of career calling in the relationship between family-supportive supervisor behaviors and turnover intention among nurses. Methods: Data were gathered from 563 nurses enrolled in eight public hospitals in China. They were required to complete measures of family-supportive supervisor behaviors, career calling, and turnover intention. Hierarchical multiple regression analysis and the bootstrapping procedure were used to examine the mediating role of career calling. Results: Family-supportive supervisor behaviors were positively associated with career calling, but negatively associated with turnover intention. Furthermore, career calling partially mediated the relationship between family-supportive supervisor behaviors and turnover intention. Conclusion: This study provides strong evidence for an increasing body of work that emphasizes the importance of nursing leaders engaging in family-supportive behaviors for increasing employee career calling and reducing turnover intention.

Objective: Fever with thrombocytopenia syndrome virus (SFTS) is a tick-borne infection now known to spread among humans as an aerosol, which has resulted in several outbreaks across Asia over the past decade. As mortality is substantial, it is vital to establish a rapid, on-site nucleic acid detection method for diagnosis. Here we describe such a method for SFTSV (Dabie bandavirus) based on CRISPR-Cas13a. Methods: Specific recombinase-aided amplification (RAA) primers and CRISPR (cr)RNA nucleic acid detection targets were designed and synthesized for the conserved sequence of the SFTSV genome, and fluorescent CRISPR detection was used to screen for high-sensitivity crRNAs. Colloidal immunochromatography test paper was used to read CRISPR detection results. Sensitivity and specificity were evaluated by running tests on gradient dilutions of SFTSV nucleic acid and the nucleic acids of other pathogens with similar transmission routes or clinical manifestations. Results: One crRNA with high detection sensitivity was screened out of 5 crRNAs with conserved sequences from the SFTSV genome. This CRISPR nucleic acid-based detection method was able to detect a single crRNA copy per microliter but not the nucleic acids of similar pathogens. Conclusion: This CRISPR test strip detection method permits rapid, sensitive, and specific diagnosis of SFTS without the need for advanced nucleic acid detection equipment, thus allowing for on-site application.

Background: Toxic and essential trace elements are reported to have impact on female fertility. However, studies on the potential synergistic or antagonistic effects of metal mixtures on IVF outcomes remain limited. Objective: To evaluate whether serum concentrations of metals, individually and as mixtures, are associated with pregnancy outcomes in women undergoing IVF. Methods: In a prospective birth cohort study about IVF from the First Affiliated Hospital of Anhui Medical University (n = 1184), we measured the concentrations of serum metals by ICP-MS according to a previously established method. Oocyte/embryo development indicators and follow-up results were also collected. The individual and joint effects of metals were estimated using logistic regressions and Bayesian kernel machine regressions (BKMR). Results: At embryonic stage, we found negative associations between the serum lead (Pb) (β = −0.14, 95%CI: −0.32, −0.04) and cadmium (Cd) (β = −0.24, 95%CI: −0.39, −0.09) concentrations and the high-quality embryos rate; and positive associations between the serum cobalt (Co) (β = 0.18, 95%CI: 0.05, 0.31) and selenium (Se) (β = 0.17, 95%CI: 0.06, 0.41) concentrations and the MII rate. Regarding to the pregnancy outcomes, the serum Pb was negatively related with successful implantation (OR=0.85, 95%CI: 0.77, 0.94) and clinical pregnancy (OR=0.95, 95%CI: 0.91, 0.99); and positively associated with spontaneous abortion (OR=1.39, 95% CI: 1.02, 1.91). The BKMR analysis showed linear or parabolic associations between the metal mixtures and pregnancy outcomes, with Pb showing the highest posterior inclusion probabilities. Conclusions: The toxic (Pb, Cd) and essential (Co, Se) metals could be incorporated as simultaneous predictors of IVF outcomes including potential antagonistic effects, in which Pb exhibits major contributions.

p-Aramid is an ideal building block for forward osmosis (FO) membranes due to its extraordinary thermal resistance, chemical stability, and mechanical properties. However, existing aramid membranes have certain limitations such as large pore diameters and low salt rejection rates. In this work, we describe a facile solvent exchange-delay phase inversion strategy to prepare p-aramid nanofibrous membranes that would be suitable for FO applications. In this strategy, p-aramid nanofibers with an average diameter of 16 ± 4 nm and an average length of 382 ± 89 nm were employed as membrane matrices. Prior to the immersion of the cast film into a coagulation bath, a pre-evaporation protocol was carefully designed and introduced to provide a slower exchange rate between the good solvent and the non-solvent, which delayed the demixing process between p-aramid nanofibers and thus yielded an asymmetric membrane with a denser active layer as well as a loose substrate layer. The resultant membrane showed excellent FO water flux, NaCl rejection ratios, tensile strength, thermal properties, and solvent resistance. The membrane reported in this work may provide a promising candidate for separation applications and the results reported herein will facilitate the development of high-performance nanofibrous membranes.

Summary: Multi-region sequencing is used to detect intratumor genetic heterogeneity (ITGH) in tumors. To assess whether genuine ITGH can be distinguished from sequencing artifacts, we performed whole-exome sequencing (WES) on three anatomically distinct regions of the same tumor with technical replicates to estimate technical noise. Somatic variants were detected with three different WES pipelines and subsequently validated by high-depth amplicon sequencing. The cancer-only pipeline was unreliable, with about 69% of the identified somatic variants being false positive. Even with matched normal DNA for which 82% of the somatic variants were detected reliably, only 36%–78% were found consistently in technical replicate pairs. Overall, 34%–80% of the discordant somatic variants, which could be interpreted as ITGH, were found to constitute technical noise. Excluding mutations affecting low-mappability regions or occurring in certain mutational contexts was found to reduce artifacts, yet detection of subclonal mutations by WES in the absence of orthogonal validation remains unreliable. : Shi et al. report that standard coverage whole-exome sequencing and bioinformatics pipelines cannot discriminate between genuine intratumor genetic heterogeneity and sequencing artifacts. Although aggressive minimum depth filtering would not improve the false detection rate of subclonal mutations, excluding mutations in low-mappability regions or in certain mutational contexts could help. Keywords: massively parallel sequencing, whole-exome sequencing, somatic mutations, intratumor genetic heterogeneity, multi-region profiling, breast cancer, mutational signatures, mappability, subclonal

Adenoid cystic carcinoma (ACC) is a malignant tumor of the major and minor salivary glands. It is rarely found in the jaw. We described a case of central adenocarcinoma arising from the mandible of a 76-year -old woman. Computed tomography (CT) revealed bone involvement in the right mandible. CT-guided fine needle aspiration biopsy (FNA) was performed, finding a poorly-differentiated adenoid cystic carcinoma (ACC) of the mandible. Due to her poor condition and her refusal of surgery, we performed permanent implantation of I125seeds. After brachytherapy, the tumor went into partial remission and new bone formed in three months. To our knowledge, this is the first case of central ACC of the mandible treated with I125 brachytherapy. We reviewed previous English-language reports on the ACC in the mandible. We can only speculate as to why this patient's ACC responded so quickly and new bone formed in a short period of time after brachytherapy. Keywords: Adenoid cystic carcinoma, I125 brachytherapy, Mandible

Yes-associated protein (YAP) is regulated by mechanical cues via the interaction of the Hippo pathway with cytoskeleton. Previous studies showed that YAP plays a role in regulating the actomyosin network by suppressing Rho GTPase in medaka fish. Here, we identify Rho GTPase activating protein 29 (ARHGAP29) as a transcriptional target of YAP in a human gastric cancer cell line. YAP promotes the expression of ARHGAP29 to suppress the RhoA-LIMK-cofilin pathway, destabilizing F-actin. The overexpression of YAP causes cytoskeletal rearrangement by altering the dynamics of F-actin/G-actin turnover, thus promoting migration. In a mouse model, circulating tumor cells (CTCs) exhibit an increased ARHGAP29 RNA level compared with cells at primary tumor sites, and the metastatic potential of CTCs is positively correlated with ARHGAP29 expression. Moreover, increased ARHGAP29 expression is correlated with shortened survival of human gastric cancer patients. Our study provides a model to understand YAP’s contribution to cancer metastasis via regulation of actin dynamics.

V(D)J recombination relies on the presence of proximal enhancers that activate the antigen receptor (AgR) loci in a lineage- and stage-specific manner. Unexpectedly, we find that both active and inactive AgR enhancers cooperate to disseminate their effects in a localized and long-range manner. Here, we demonstrate the importance of short-range contacts between active enhancers that constitute an Igk super-enhancer in B cells. Deletion of one element reduces the interaction frequency between other enhancers in the hub, which compromises the transcriptional output of each component. Furthermore, we establish that, in T cells, long-range contact and cooperation between the inactive Igk enhancer MiEκ and the active Tcrb enhancer Eβ alters enrichment of CBFβ binding in a manner that impacts Tcrb recombination. These findings underline the complexities of enhancer regulation and point to a role for localized and long-range enhancer-sharing between active and inactive elements in lineage- and stage-specific control.