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Summary: Metastatic prostate cancer (PCa) in bone induces bone-forming lesions. We have previously shown that PCa-induced bone originates from endothelial cells (ECs) that have undergone EC-to-osteoblast (OSB) transition. Here, we investigated whether EC-to-OSB transition also occurs during normal bone formation. We developed an EC and OSB dual-color reporter mouse (DRM) model that marks EC-OSB hybrid cells with red and green fluorescent proteins. We observed EC-to-OSB transition (RFP and GFP co-expression) in both endochondral and intramembranous bone formation during embryonic development and in adults. Co-expression was confirmed in cells isolated from DRM. Bone marrow– and lung-derived ECs underwent transition to OSBs and mineralization in osteogenic medium. RNA-sequencing revealed GATA family transcription factors were upregulated in EC-OSB hybrid cells and knockdown of GATA3 inhibited BMP4-induced mineralization. Our findings support that EC-to-OSB transition occurs during normal bone development and suggest a new paradigm regarding the endothelial origin of OSBs.

The metabotropic γ-aminobutyric acid type B receptor (GABABR) remains a hotspot in the recent research area. Being an idiosyncratic G-protein coupled receptor family member, the GABABR manifests adaptively tailored functionality under multifarious modulations by a constellation of agents, pointing to cross-talk between receptors and effectors that converge on the domains of mood and memory. This review systematically summarizes the latest achievements in signal transduction mechanisms of the GABABR-effector-regulator complex and probes how the up-and down-regulation of membrane-delimited GABABRs are associated with manifold intrinsic and extrinsic agents in synaptic strength and plasticity. Neuropsychiatric conditions depression and addiction share the similar pathophysiology of synapse inadaptability underlying negative mood-related processes, memory formations, and impairments. In the attempt to emphasize all convergent discoveries, we hope the insights gained on the GABABR system mechanisms of action are conducive to designing more therapeutic candidates so as to refine the prognosis rate of diseases and minimize side effects.

Background and Aims: We aimed to determine the utility of coronary artery calcium (CAC) for atherosclerotic cardiovascular disease (ASCVD) risk stratification in women with and without early menopause (EM). Methods: To examine the association between CAC and incident ASCVD, we performed Kaplan-Meier survival analysis and multivariable Cox proportional hazards modeling using data from 2,456 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis (MESA) with or without EM, defined as occurring at 50% of middle-aged postmenopausal women with EM had CAC = 0, similar to those without EM. Among women with CAC = 0, those with EM had a low to borderline 10-year risk of ASCVD, but the 15-year risk was significantly higher for women with EM versus those without EM. When CAC ≥ 1, the incidence of ASCVD was similar for women with and without EM. These findings support the use of CAC to help improve ASCVD risk stratification in women with EM. Condensed abstract: This study investigated the association between coronary artery calcium (CAC) and incident atherosclerotic cardiovascular disease (ASCVD) in postmenopausal women with and without early menopause (EM). We found that >50% of women had CAC = 0 and an associated low-to-borderline 10-year cumulative incidence of ASCVD. However, the risk for ASCVD was significantly higher for women with EM after 15-years follow-up. Additional research is needed to better understand the differences in long-term ASCVD risk between women with and without EM who have CAC = 0.

Summary: Cell type transition occurs during normal development and under pathological conditions. In prostate cancer bone metastasis, prostate cancer-secreted BMP4 induces endothelial cell-to-osteoblast (EC-to-OSB) transition. Such tumor-induced stromal reprogramming supports prostate cancer progression. We delineate signaling pathways mediating EC-to-OSB transition using EC lines 2H11 and SVR. We found that BMP4-activated pSmad1-Notch-Hey1 pathway inhibits EC migration and tube formation. BMP4-activated GSK3β-βcatenin-Slug pathway stimulates Osx expression. In addition, pSmad1-regulated Dlx2 converges with the Smad1 and β-catenin pathways to stimulate osteocalcin expression. By co-expressing Osx, Dlx2, Slug and Hey1, we were able to achieve EC-to-OSB transition, leading to bone matrix mineralization in the absence of BMP4. In human prostate cancer bone metastasis specimens and MDA-PCa-118b and C4-2b-BMP4 osteogenic xenografts, immunohistochemical analysis showed that β-catenin and pSmad1 are detected in activated osteoblasts rimming the tumor-induced bone. Our results elucidated the pathways and key molecules coordinating prostate cancer-induced stromal programming and provide potential targets for therapeutic intervention.

BACKGROUND: Bone metastasis is common in renal cell carcinoma (RCC), and the lesions are mainly osteolytic. The mechanism of bone destruction in RCC bone metastasis is unknown. METHODS: We used a direct intrafemur injection of mice with bone-derived 786-O RCC cells (Bo-786) as an in vivo model to study if inhibition of osteoblast differentiation is involved in osteolytic bone lesions in RCC bone metastasis. RESULTS: We showed that bone-derived Bo-786 cells induced osteolytic bone lesions in the femur of mice. We examined the effect of conditioned medium of Bo-786 cells (Bo-786 CM) on both primary mouse osteoblasts and MC3T3-E1 preosteoblasts and found that Bo-786 CM inhibited osteoblast differentiation. Secretome analysis of Bo-786 CM revealed that BIGH3 (Beta ig h3 protein), also known as TGFBI (transforming growth factor beta-induced protein), is highly expressed. We generated recombinant BIGH3 and found that BIGH3 inhibited osteoblast differentiation in vitro. In addition, CM from Bo-786 BIGH3 knockdown cells (786-BIGH3 KD) reduced the inhibition of osteoblast differentiation compared to CM from vector control. Intrafemural injection of mice with 786-BIGH3 KD cells showed a reduction in osteolytic bone lesions compared to vector control. Immunohistochemical staining of 18 bone metastasis specimens from human RCC showed strong BIGH3 expression in 11/18 (61%) and moderate BIGH3 expression in 7/18 (39%) of the specimens. CONCLUSIONS: These results suggest that suppression of osteoblast differentiation by BIGH3 is one of the mechanisms that enhance osteolytic lesions in RCC bone metastasis, and raise the possibilty that treatments that increase bone formation may improve therapy outcomes.

Cell division cycle 6 (CDC6), an androgen receptor (AR) target gene, is implicated in regulating DNA replication and checkpoint mechanisms. CDC6 expression is increased during prostate cancer (PCa) progression and positively correlates with AR in PCa tissues. AR or CDC6 knockdown, together with AZD7762, a Chk1/2 inhibitor, results in decreased TopBP1-ATR-Chk1 signaling and markedly increased ataxia-telangiectasia-mutated (ATM) phosphorylation, a biomarker of DNA damage, and synergistically increases treatment efficacy. Combination treatment with the AR signaling inhibitor enzalutamide (ENZ) and the Chk1/2 inhibitor AZD7762 demonstrates synergy with regard to inhibition of AR-CDC6-ATR-Chk1 signaling, ATM phosphorylation induction, and apoptosis in VCaP (mutant p53) and LNCaP-C4-2b (wild-type p53) cells. CDC6 overexpression significantly reduced ENZ- and AZD7762-induced apoptosis. Additive or synergistic therapeutic activities are demonstrated in AR-positive animal xenograft models. These findings have important clinical implications, since they introduce a therapeutic strategy for AR-positive, metastatic, castration-resistant PCa, regardless of p53 status, through targeting AR-CDC6-ATR-Chk1 signaling.

Nonalcoholic steatohepatitis (NASH) may soon become the leading cause of end-stage liver disease worldwide with limited treatment options. Liver fibrosis, which is driven by chronic inflammation and hepatic stellate cell (HSC) activation, critically determines morbidity and mortality in patients with NASH. Pyruvate kinase M2 (PKM2) is involved in immune activation and inflammatory liver diseases; however, its role and therapeutic potential in NASH-related fibrosis remain largely unexplored. Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells (NPCs), especially macrophages, in the livers of patients with fibrotic NASH. Macrophage-specific PKM2 knockout (PKM2FL/FLLysM-Cre) significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine- and choline-deficient (MCD) diet, a high-fat high-cholesterol (HFHC) diet, and a western diet plus weekly carbon tetrachloride injection (WD/CCl4). Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6Chigh macrophage infiltration. Mechanistically, PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3 (NLRP3) activation in proinflammatory macrophages, which induced HSC activation and fibrogenesis. A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo. Translationally, ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides, a novel oligonucleotide drug that preferentially accumulates in the liver, dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity. The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis. Thus, therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.

The bio-corrosion behavior and bio-compatibility of TiNbZrTa and TiNbZrTaMo high entropy alloys (HEAs) are crucial for their efficient maintenance during biological implantation. In this work, TiNbZrTa and TiNbZrTaMo HEAs were successfully prepared via vacuum melting, with a β-type titanium alloy Ti35Nb7Zr5Ta, exhibiting good biocompatibility used as a comparison. Due to the high entropy effect of equal atomic ratios, both TiNbZrTa and TiNbZrTaMo HEAs exhibit body-centered cubic (BCC) structure and lattice distortion compared to the β titanium alloy Ti35Nb7Zr5Ta. Mo elements contribute to the formation of a new BCC phase, resulting in a white matrix rich in Ta and Mo, and a dark second phase rich in Ti, Zr, and Nb. Electrochemical test results at 37 °C shown that TiNbZrTa has a wider and more stable passivation area than TiNbZrTaMo. The XPS results shown that formation of the passive film is related to the main elements added. Ti, Nb, Ta and Mo formed oxides via the solid-liquid interface and migrate inward, while Zr is formed at the passivation film/metal substrate interface and migrates outward, finally forming the layered structure of the passivation film. Additionally, the cytotoxicity test of mouse fiber cells was carried out to evaluate the biocompatibility of the HEAs. The results shown that the cell proliferation rate of TiNbZrTa and TiNbZrTaMo HEAs reached 0 and 1, respectively, with TiNbZrTa exhibiting better biocompatibility, as adding Mo reduced the cell proliferation rate. These findings may provide a method for predicting the bio-corrosion behavior and bio-compatibility of HEAs used for biological implantation.

Peptides, as small molecular compounds, exhibit prominent advantages in the inhibition of coronaviruses due to their safety, efficacy, and specificity, holding great promise as drugs against coronaviruses. The rapid and efficient determination of the activity of anti-coronavirus peptides (ACovPs) can greatly accelerate the development of drugs for treating coronavirus-related diseases. Hence, we present ACVPICPred, a computational model designed to predict the inhibitory activity of ACovPs based on their sequences and structural information. By leveraging bioinformatics tools AlphaFold3 for structural predictions and several feature extraction methods, the model integrates both sequence and structural features to enhance prediction accuracy. To address the limitations of existing datasets, we employed data augmentation techniques, including the introduction of noise and the SMOGN, to improve the model robustness. The model’s performance was evaluated through five-fold cross-validation, achieving a Pearson correlation coefficient of 0.7668 (p

Cliffside carving images are often affected by various types of noise, such as uneven lighting, shadows, dust, and weathering, which impair the clarity and detail of the images. These noise factors significantly impact image quality, making effective denoising crucial. Denoising can enhance the clarity and quality of cliffside carving images, facilitating the study of their artistic style, historical background, and cultural significance. Therefore, this paper proposes the Complementary Transformer Network (CoTrNet), which utilizes an encoding-decoding framework to denoise cliffside carving images. The Diverse Feature Complementary Module (DFCM) is employed for feature extraction and image reconstruction, while the Skip Connection Cross Transformer (SCCT) enhances the transfer of low-level features to higher levels, improving the overall denoising effect. CoTrNet accurately captures the details and features in the images, significantly reducing noise. Using images from Tongtian Rock in Ganzhou, China, experiments show that CoTrNet outperforms existing techniques, achieving Peak Signal-to-Noise Ratios (PSNR) of 27.5706 and 24.9113 at noise levels of 15% and 25%, respectively. This research provides a powerful tool for the preservation, restoration, and conservation of cliffside carving cultural heritage.

Lung cancer is the main cause of cancer-related deaths worldwide. Due to lack of obvious clinical symptoms in the early stage of the lung cancer, it is hard to distinguish between malignancy and pulmonary nodules. Understanding the immune responses in the early stage of malignant lung cancer patients may provide new insights for diagnosis. Here, using high-through-put sequencing, we obtained the TCRβ repertoires in the peripheral blood of 100 patients with Stage I lung cancer and 99 patients with benign pulmonary nodules. Our analysis revealed that the usage frequencies of TRBV, TRBJ genes, and V-J pairs and TCR diversities indicated by D50s, Shannon indexes, Simpson indexes, and the frequencies of the largest TCR clone in the malignant samples were significantly different from those in the benign samples. Furthermore, reduced TCR diversities were correlated with the size of pulmonary nodules. Moreover, we built a backpropagation neural network model with no clinical information to identify lung cancer cases from patients with pulmonary nodules using 15 characteristic TCR clones. Based on the model, we have created a web server named “Lung Cancer Prediction” (LCP), which can be accessed at http://i.uestc.edu.cn/LCP/index.html.

Myocardial ischemia is a serious threat to human health, and vascular dysfunction is its main cause. Buxu Tongyu (BXTY) Granule is an effective traditional Chinese medicine (TCM) for treating myocardial ischemia. However, the underlying mechanism of BXTY is still unclear. In this study, we demonstrate that BXTY ameliorates myocardial ischemia by activating the soluble guanylate cyclase (sGC)–3′,5′-cyclic guanosine monophosphate (cGMP)–protein kinase G (PKG) signaling pathway in vascular smooth muscle cells (VSMCs) to dilate the arteries. BXTY was given by gavage for ten consecutive days before establishing an animal model of acute myocardial ischemia in mice via the intraperitoneal injection of pituitrin. The results showed that BXTY alleviated the symptoms of myocardial ischemia induced by pituitrin in mice, including electrocardiogram abnormalities and changes in plasma enzymes. In addition, BXTY dilated pre-constricted blood vessels and inhibited the vasoconstriction of the superior mesenteric artery in a dose-dependent but endothelial-independent manner. These effects were eliminated by pre-incubating vascular rings with the sGC inhibitors NS 2028 or ODQ, or with the PKG inhibitor KT 5823. Moreover, BXTY increased the protein expression of sGC-β1 and the intracellular second messenger cGMP level in mouse aortic vascular smooth muscle cells (MOVAs). NS 2028 or ODQ reversed these effects of BXTY. The expression level of the cGMP downstream effector protein PKG-1 increased after treating MOVAs with BXTY. NS 2028, ODQ, or KT 5823 also reversed this effect of BXTY. In conclusion, BXTY can improve the symptoms of acute myocardial ischemia in mice, and activating the sGC–cGMP–PKG pathway in VSMCs to induce vasodilation is its key pharmacodynamic mechanism.

Introduction: The toxicity of fine particulate matter (PM2.5) is determined by its components, while the evidence regarding associations of PM2.5 components with blood pressure (BP) is limited, especially in rural areas. Objectives: This study aimed to explore the associations of PM2.5 and its chemical components with systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), mean artery pressure (MAP) levels and hypertension prevalence, and to identify key components in Chinese rural areas. Methods: 39,211 adults from the Henan Rural Cohort were included during 2015–2017. Different periods of PM2.5 and chemical components were estimated by hybrid satellite model. The single-pollutant, component-PM2.5 model, component-residual model and component-proportion model were applied to explore the associations of pollutants with BP levels and hypertension prevalence. Exposure-response (E-R) relationships, stratified analyses and sensitivity analyses were used to explore these associations further. Results: 12,826 (32.71%) were identified with hypertension. For each 1 μg/m3 increase of pollutants, the adjusted odds ratio (OR) for hypertension prevalence was 1.03 for PM2.5 mass, 1.40 for BC, 1.16 for NH4+, 1.08 for NO3–, 1.17 for OM, 1.12 for SO42− and 1.25 for SOIL in the single-pollutant model. BC and SOIL were statistically significant in the component-PM2.5 model, component-residual model and component-proportion model. Similarly, associations of these pollutants with elevated BP levels were also found in aforementioned four models. These pollutants produced a stronger association with SBP than DBP, PP and MAP. Most of associations were non-linear in E-R relationships. The groups of older, the men, with lower per capita monthly income, lower educational level and higher BMI were more vulnerable to these pollutants in stratified analyses. The results remained stable in sensitivity analyses. Conclusion: Long-term exposure to PM2.5 and its components, especially BC and SOIL, was associated with elevated BP and hypertension prevalence in rural adults, and decreasing pollutants may provide additional benefits.

Background and objective: Robot-assisted radical prostatectomy (RARP) is widely used because of the many advantages of a robotic approach. The da Vinci Si robot is one of the most commonly used surgical robot systems, but it may be associated with higher costs owing to the use of consumable surgical supplies. Our aim was to conduct a preliminary investigation of the capability of the MP1000 system for RARP. Methods: In this prospective, multicentre, single-blinded study, we randomly assigned 42 patients scheduled to undergo RARP between April and September 2021 to a da Vinci Si group (control) or an MP1000 group (intervention). Patients underwent RARP performed using the assigned robotic system and were followed up at 3-mo intervals. The primary outcome was the rate of conversion to open/laparoscopic surgery. Secondary outcomes were installation and operation times, intraoperative blood loss, postoperative surgical margin status, hospital stay, incontinence, complications, safety indicators, and surgeon ergonomics. Key findings and limitations: All procedures were successfully completed without conversion to open/laparascopic surgery or major complications. Secondary outcomes, including oncological and ergonomic indicators, did not differ significantly between the groups over the study period. One patient in the control group experienced dysuria (Clavien-Dindo grade 3). No patients had incontinence at 3 mo. A limitation of the study is the small sample size. Conclusions and clinical implications: RARP with the MP1000 system is feasible, safe, and effective in the management of localised prostate cancer. Patient summary: We assessed the effectiveness and safety of the new MP1000 robot system for robot-assisted removal of the prostate in comparison to the da Vinci Si robot. We found no difference in effectiveness or safety among 42 patients with prostate cancer who were assigned randomly to one of the two systems. We conclude that the MP1000 is a suitable robot for this surgery.

ABSTRACT: Various types of dietary fats undergo distinct fermentation processes by gut microbes, potentially leading to the production of neurotransmitters that can influence the gut. Serotonin and dopamine are recognized neurotransmitters with positive effects on gut function. A broiler chicken trial was conducted to evaluate the influence of dietary fat types on protein expression of 2 neurotransmitter transporters, dopamine (DAT) and serotonin (5-HTT). A total of 560 day-old (Ross 708) male broiler chicks were randomly assigned to 7 dietary treatments. The experimental treatments included a basal diet of corn-soybean meal (SBM), supplemented with 3% of various fats: poultry fat (CON), olive oil (OLIV), fish oil (FISH), canola oil (CANO), lard (LARD), coconut oil (COCO), or flaxseed oil (FLAX). Bodyweight (BW) and feed conversion ratio (FCR) were recorded. Ileal tissues were aseptically collected to determine the expression levels of DAT and 5-HTT through western blot analysis. In addition, plasma samples were analyzed for reactive oxygen metabolites (d-ROM) tests on d 55. Results showed that dietary fat type inclusion did not have any detrimental effect on growth performance parameters. The expression levels of DAT were higher (P < 0.05) in FLAX treatments compared to CON treatments on d 20 and d 55, respectively. Similarly, with 5-HTT levels, FLAX, CANO, and LARD treatments were higher (P < 0.05) than CON treatments on d 20 and d 55. However, higher levels of oxidative stress (d-ROM values) were recorded in COCO (32.75 Carr U), CANO (29 Carr U), and CON treatments (25.5 Carr U) compared to FLAX (18.5 Carr U; P < 0.05) treatment. These findings suggest that incorporating dietary flaxseed oil at a 3% level in the diet has significant potential to elevate the expression levels of intestinal DAT and 5-HTT without inducing oxidative stress.

ABSTRACT: Trimethyltin chloride (TMT) is widespread in the environment and is harmful to both humans and animals. In order to investigate the toxicity mechanism of TMT exposure on chicken liver, We established an in vivo experimental model by giving chickens oral administration of different concentrations of TMT dilution solution and vitro experiments of treating leghorn male hepatoma (LMH) cells for 12 h. The results showed that Albumin (ALB), total protein (TP) and alanine aminotransferase (ALT) in the blood of TMT-treated chickens, as well as ALT and aspartate aminotransferase (AST) in the liver, were dose-dependently increased, and different degrees of necrosis of hepatocytes were observed in histology. Meanwhile, TMT exposure led to a significant decrease in glutathione (GSH) content in chicken liver tissues and LMH cells, what's more a significant increase in malondialdehyde (MDA) content in cell supernatants. The expression of apoptosis-related genes Caspase8, Caspase3 and Caspase9 were increased in chicken liver tissues and LMH cells after treated by TMT, and an increased in the percentage of late apoptosis in LMH cells. This suggests that TMT can cause oxidative stress and apoptosis in chicken livers and cells, resulting in liver injury.

Background and aims: There is no evidence on the longitudinal and causal associations between multiple pesticides and the incidence of type 2 diabetes mellitus (T2DM) in the Chinese rural population, and whether physical activity (PA) modified these associations remains unclear. Here, we aimed to investigate the longitudinal and causal associations between pesticides mixture and T2DM, and determine whether PA modified these associations. Methods: A total of 925 subjects with normal glucose and 925 subjects with impaired fasting glucose (IFG) were enrolled in this case-cohort study. A total of 51 targeted pesticides were quantified at baseline. Logistic regression, quantile g-computation, and Bayesian kernel machine regression (BKMR) were used to assess the individual and combined effects of pesticides on IFG and T2DM. Mendelian randomization (MR) analysis was employed to obtain the causal association between pesticides and T2DM. Results: After 3-year follow-up, one-unit increment in ln-isofenphos, ln-malathion, and ln-deltamethrin were associated with an increase conversion of IFG to T2DM (FDR-P

Molten salt from the service environment leaches Y2O3 from yttria-stabilized zirconia (YSZ), threatening the security of thermal barrier coatings (TBCs). In this study, we compared the molten salt corrosion resistances of YSZ coatings prepared via plasma-spraying physical vapor deposition (PS-PVD) before and after laser remelting. At 1000 °C, the molten salt reacted with YSZ particulates in the PS-PVD YSZ coating and infiltrated the gaps between quasi-columnar crystals, resulting in phase transition of the coating and column breakage. A dense glazed layer was formed on the YSZ coating surface after remelting by the low-energy-density laser, which prohibited the penetration of molten salt and improved the hot corrosion resistance of the YSZ coating. By contrast, the failure of the high-energy-density laser-treated YSZ coating was accelerated due to the significant interfacial stress from the thick glazed layer and volume expansion caused by the corrosion products. Our investigation revealed the structural evolution of the PS-PVD YSZ coating under hot corrosion conditions, emphasized the role of laser remelting, and could serve as a guideline for TBCs modification.

ABSTRACT: Constipation is directly related to the intestinal microenvironment, in which the promotion of gastrointestinal (GI) motility and improvement of gut microbiota distribution are important for alleviating symptoms. Herein, after the intervention of probiotic fermented milk (FMMIX) containing Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 for 14 d in Kunming mice with loperamide-induced constipation, the results indicated that FMMIX significantly increased the secretion of serum motilin, gastrin and 5-hydroxytryptamine, as well as decreased the secretion of peptide YY, vasoactive intestinal peptide, and nitric oxide in mice. As determined by immunohistochemical analysis, FMMIX promoted an augmentation in the quantity of Cajal interstitial cells. In addition, the mRNA and protein expression of c-kit and stem cell factor (SCF) were upregulated to facilitate intestinal motility. High-throughput sequencing and gas chromatography techniques revealed that FMMIX led to an increase in the relative abundance of beneficial bacteria (Lactobacillus, Oscillospira, Ruminococcus, Coprococcus, and Akkermansia), reduced the presence of harmful bacteria (Prevotella), and resulted in elevated levels of short-chain fatty acids (SCFA) with a superior improvement compared with unfermented milk. Untargeted metabolomics revealed significant upregulation of functional metabolites such as l-pipecolinic acid, dl-phenylalanine, and naringenin in FMMIX, presumably playing a potential role in constipation relief. Overall, our results showed that FMMIX had the potential to alleviate constipation symptoms in mice by improving the secretion of serum GI regulatory peptides and neurotransmitters, increasing the expression of c-kit and SCF proteins, and modulating the gut microbiota structure and SCFA levels, and may be associated with an increase in these functional metabolites. This suggested that FMMIX could be a promising adjunctive strategy for managing constipation symptoms and could contribute to the development of functional foods aimed at improving gut health.

Anaplastic lymphoma kinase (ALK) is an attractive therapeutic target for the treatment of anaplastic large cell lymphoma (ALCL). We identified novel deuterated 2,4-diarylamino pyrimidine compounds as potent ALK inhibitors. The compound 9 (AMX6001) showed better in vitro activity against ALK and NPM-ALK kinase and significantly inhibited proliferation of Karpas299 and SU-DHL-1 cell lines. In vivo efficacy of compound 9 was better than reference standard ceritinib in ALCL Karpas299 mice models. Daily oral treatment of compound 9 (25 mg/kg) induced tumor suppression TGI up to 95.8 % in ALCL models.

Atrial fibrillation (AF) is a common cardiac arrhythmia that seriously affects the quality of life of patients. Effective treatment and prevention are important to control the morbidity and mortality of AF. It has been found that cardiac fibrosis promotes the onset and progression of AF. It is now known that transforming growth factor β (TGF-β), an important fibrotic cytokine, plays an important role in cardiac fibrosis by inducing myofibroblast activation via the activation of classical (SMAD-based) and non-classical (non-SMAD-based) signaling pathways. In addition, specific activation of the Wnt/β-catenin pathway has been shown to promote the transformation of fibroblasts into myofibroblasts. In recent years, a new family of proteins, namely Disheveled-associated antagonist of beta-catenin (DACT) 2, can affect the Wnt/β-catenin and TGF-β signaling pathways by regulating the phosphorylation levels of these target proteins, which in turn affects the progression of fibrosis. The present study focuses on the effect of DACT2-guided β-catenin on atrial fibrosis. It is expected that the summarized information can be helpful in the treatment of AF.

ABSTRACT: Ultrasound-induced egg white fluidic gels (UEFG) were prepared through ultrasonic pretreatment followed by subsequent heating. The optimal preparation parameters for UEFG were: ultrasonic power density between 0.2 to 0.8 W/mL, ultrasonic treatment time surpassing 150 s, heating temperature within 70 to 76°C, and heating time under 16 min. The prepared UEFG is a milky white solution with a viscosity lower than that of fresh egg white, and displayed a particle size distribution primarily between 100 and 1,200 nm. Stability assessments conducted over 28 d at 4°C revealed that UEFG remained stable at pH 6-10, with exceptional stability from pH 8 to 10, while it is less stable in highly acidic (pH 2-4) or basic environments (pH 12). The UEFG also showed commendable stability in the presence of salt and sucrose solutions. We report a simple and novel method for preparing UEFG with good flowability after heating treatment. The UEFG has broad applications in the food industry, such as precooked egg white powder, high protein beverages, composite dairy products, etc.

Mitotic kinesin-like protein 2 (MKLP2/KIF20A) is a key mitotic regulator frequently overexpressed in human malignancies and its abundance is positively correlated with poor outcomes of the disease. Despite extensive research on MKLP2 as a potential target for oncology, the development of small-molecule inhibitors specific to MKLP2 remains limited. We have previously identified a benzoazipinone compound, HJ81 as a potent disruptor of Aurora kinase B (AURKB) localization during late mitosis. This study reveals that such disruption results from a failure of AURKB relocation at the onset of anaphase and this phenomenon can be specifically attributed to the disablement of MKLP2, a recognized facilitator of the relocation process. Further optimization of HJ81 leads to identifying compounds such as 12a as promising lead inhibitors of MKLP2-mediated processes, with improved pharmacokinetic properties. 12a inhibits the microtubule-stimulated ATPase activity of the recombinant MKLP2 in vitro. Significant suppression of tumor growth was observed in mice bearing the Calu-6 lung cancer cell line when treated with 12a at a well-tolerated dose. Overall, our findings suggest that benzoazipinone derivatives represent a novel chemical scaffold with the potential to be developed to mimic MKLP2 inhibition for cancer treatment.

Summary: The oxidative-stress-related protein Kelch-like ECH-associated protein 1 (KEAP1) is a substrate articulator of E3 ubiquitin ligase, which plays an important role in the ubiquitination modification of proteins. However, the function of KEAP1 in breast cancer and its impact on the survival of patients with breast cancer remain unclear. Our study demonstrates that KEAP1, a positive prognostic factor, plays a crucial role in regulating cell proliferation, apoptosis, and cell cycle transition in breast cancer. We investigate the underlying mechanism using human tumor tissues, high-throughput detection technology, and a mouse xenograft tumor model. KEAP1 serves as a key regulator of cellular metabolism, the reprogramming of which is one of the hallmarks of tumorigenesis. KEAP1 has a significant effect on mitochondrial biogenesis and oxidative phosphorylation by regulating HSPA9 ubiquitination and degradation. These results suggest that KEAP1 could serve as a potential biomarker and therapeutic target in the treatment of breast cancer.

Summary: ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion.

Based on the model of multiple random phase screens of atmospheric turbulence, the optical fields of a ring Airyprime vortex beam (RAPVB) and an Airyprime vortex beam array (APVBA) propagating in atmospheric turbulence are expressed in the form of operators. The effect of the refractive index structure constant on normalized light intensity and vortex phase for a RAPVB and an APVBA propagating in atmospheric turbulence is examined. The influences of the atmospheric propagation distance, the refractive index structure constant, and the topological charge on the target orbital angular momentum (OAM) power proportion of a RAPVB and an APVBA are analyzed. Anyway, the topological charge initially carried by a RAPVB and an APVBA can be successfully detected on the observation plane. This study indicates that a RAPVB and an APVBA with the saturated beam number are equivalent when used for analysis of target OAM power proportion. Further, this study is beneficial to the optimal design of atmospheric optical communication (AOC) systems. A RAPVB is more suitable for short distance AOC, while an APVBA is more suitable for long distance AOC.

Analytical expressions of the electric field, the centriod, the beam half width, and the linear momentum of the fractional Fourier transform (FrFT) of an Airyprime beam are derived, respectively. The relation between the centriods or the beam half widths of an Airyprime beam in the exit and the input planes of a FrFT system is also presented. The effect of the fractional order p on the FrFT of an Airyprime beam is investigated in detail and graphically presented. The cycle of the light intensity, the centriod, and the linear momentum of an Airyprime beam in the exit plane of a FrFT system versus p is 4, while the cycle of the beam half width versus p is 2. This research in the FrFT of an Airyprime beam has potential applications. First, special laser beams with different shapes can be generated by controlling p. Then, the FrFT of an Airyprime beam can be used as an optical switch due to the reversal of the positive and the negative signs of the linear momentum in the first and the last half cycle. Finally, the mirror transformation of the spatial orientation of the beam spot for the FrFT of an Airyprime can be used in optical micro-manipulation.

Summary: Biofilm formation plays a significant role in antibiotic resistance, necessitating the search for alternative therapies against biofilm-associated infections. This study demonstrates that 20 μg/mL tryptanthrin can hinder biofilm formation above 50% in various A. baumannii strains. Tryptanthrin impacts various stages of biofilm formation, including the inhibition of surface motility and eDNA release in A. baumannii, as well as an increase in its sensitivity to H202. RT-qPCR analysis reveals that tryptanthrin significantly decreases the expression of the following genes: abaI (19.07%), abaR (33.47%), bfmR (43.41%), csuA/B (64.16%), csuE (50.20%), ompA (67.93%), and katE (72.53%), which are related to biofilm formation and quorum sensing. Furthermore, tryptanthrin is relatively safe and can reduce the virulence of A. baumannii in a Galleria mellonella infection model. Overall, our study demonstrates the potential of tryptanthrin in controlling biofilm formation and virulence of A. baumannii by disrupting different stages of biofilm formation and intercellular signaling communication.

Nanoplastic contamination has been of intense concern by virtue of the potential threat to human and ecosystem health. Animal experiments have indicated that exposure to nanoplastics (NPs) can deposit in the liver and contribute to hepatic injury. To explore the mechanisms of hepatotoxicity induced by polystyrene-NPs (PS-NPs), mice and AML-12 hepatocytes were exposed to different dosages of 20 nm PS-NPs in this study. The results illustrated that in vitro and in vivo exposure to PS-NPs triggered excessive production of reactive oxygen species and repressed nuclear factor erythroid-derived 2-like 2 (NRF2) antioxidant pathway and its downstream antioxidase expression, thus leading to hepatic oxidative stress. Moreover, PS-NPs elevated the levels of NLRP3, IL-1β and caspase-1 expression, along with an activation of NF-κB, suggesting that PS-NPs induced hepatocellular inflammatory injury. Nevertheless, the activaton of NRF2 signaling by tert-butylhydroquinone mitigated PS-NPs-caused oxidative stress and inflammation, and inbihited NLRP3 and caspase-1 expression. Conversely, the rescuing effect of NRF2 signal activation was dramatically supressed by treatment with NRF2 inhibitor brusatol. In summary, our results demonstrated that NRF2-NLRP3 pathway is involved in PS-NPs-aroused hepatotoxicity, and the activation of NRF2 signaling can protect against PS-NPs-evoked liver injury. These results provide novel insights into the hepatotoxicity elicited by NPs exposure.

Summary: Background: The tumour stroma is associated with unfavourable prognosis in diverse solid tumours, but its prognostic and predictive value in bladder cancer (BCa) is unclear. Methods: In this multicentre, retrospective study, we included 830 patients with BCa from six independent cohorts. Differences in overall survival (OS) and cancer-specific survival (CSS) were investigated between high-tumour stroma ratio (TSR) and low-TSR groups. Multi-omics analyses, including RNA sequencing, immunohistochemistry, and single-cell RNA sequencing, were performed to study stroma-immune interactions. TSR prediction models were developed based on pelvic CT scans, and the best performing model was selected based on receiver operator characteristic analysis. Findings: Compared to low-TSR tumours, high-TSR tumours were significantly associated with worse OS (HR = 1.193, 95% CI: 1.046–1.361, P = 0.008) and CSS (HR = 1.337, 95% CI: 1.139–1.569, P

Landslides are a prevalent natural hazard in West Bengal, India, particularly in Darjeeling and Kurseong, resulting in substantial socio-economic and physical consequences. This study aims to develop a hybrid model, integrating a Genetic-based Random Forest (GA-RF) and a novel Self-Attention based Convolutional Neural Network and Long Short-term Memory (SA-CNN-LSTM), for accurate landslide susceptibility mapping (LSM) and generate landslide vulnerability-building map in these regions. To achieve this, we compiled a database with 1830 historical data points, incorporating a landslide inventory as the dependent variable and 32 geo-environmental parameters from Remote Sensing (RS) and Geographic Information Systems (GIS) layers as independent variables. These parameters include features like topography, climate, hydrology, soil properties, terrain distribution, radar features, and anthropogenic influences. Our hybrid model exhibited superior performance with an AUC of 0.92 and RMSE of 0.28, outperforming standalone SA-CNN-LSTM, GA-RF, RF, MLP, and TreeBagger models. Notably, slope, Global Human Modification (gHM), Combined Polarization Index (CPI), distances to streams and roads, and soil erosion emerged as key layers for LSM in the region. Our findings identified around 30% of the study area as having high to very high landslide susceptibility, 20% as moderate, and 50% as low to very low. The vulnerability-building map for 244,552 building footprints indicated varying landslide risk levels, with a significant proportion (27.74%) at high to very high risk. Our model highlighted high-risk zones along roads in the northeastern and southern areas. These insights can enhance landslide risk management in Darjeeling and Kurseong, guiding sustainable strategies for future damage qualification.

Infertility is a growing health concern among many couples worldwide. Men account for half of infertility cases. CatSper, a sperm-specific Ca2+ channel, is expressed on the cell membrane of mammalian sperm. CatSper plays an important role in male fertility because it facilitates the entry of Ca2+ necessary for the rapid change in sperm motility, thereby allowing it to navigate the hurdles of the female reproductive tract and successfully locate the egg. Many pollutants present in the environment have been shown to affect the functions of CatSper and sperm, which is a matter of capital importance to understanding and solving male infertility issues. Environmental pollutants can act as partial agonists or inhibitors of CatSper or exhibit a synergistic effect. In this article, we briefly describe the structure, functions, and regulatory mechanisms of CatSper, and discuss the body of literature covering the effects of environmental pollutants on CatSper.

Early corrosion behavior of 35CrMo low-alloy steel for high-strength bolt in the simulated shallow seawater and deep-sea environment was studied using mass loss measurement, electrochemical impedance spectroscopy (EIS), scanning electron microscope (SEM), energy dispersive spectrometer (EDS), Raman spectrometer, X-ray photoelectron spectrometer (XPS) and 3D microscope. The results show that the corrosion of 35CrMo steel initiates mainly at the steel matrix around the inclusions of CaO–MgO–Al2O3, (Ca, Mn)S and their mixed composite. The corrosion rate in the simulated deep-sea environment is lower than that in the shallow seawater, which is declined with immersion time. The corrosion products formed in the two environments are composed of γ-FeOOH, α-FeOOH, Fe3O4 and little Cr(III) oxide or/and hydroxide, but the rust layer produced in the deep-sea environment is thin and uniform. The steel has pits in a shallow dish shape and tends to develop uniform corrosion in the deep-sea environment.

Geothermal reservoir rocks have the characteristics of high stress, high hardness and high abrasiveness, which makes the drilling rate low and the drilling cost high, and hinders the application of geothermal energy. Improving drilling efficiency in hard rock strata is the prerequisite for large-scale application of geothermal energy. Impact drilling is considered to be the most effective drilling method in hard formations. PDC (Polycrystalline diamond Compact) bit compound impact drilling is one of the impact drilling methods, which has been widely concerned in recent years. In order to further improve the drilling efficiency of this method, the mechanism of PDC bit compound impact rock breaking is studied. Drucker–Prager criterion was used as rock constitutive relation, equivalent plastic strain was used as rock failure criterion, MSE (mechanical special energy) was used as evaluation method of rock-breaking efficiency, and a three-dimensional simulation model of full-size PDC bit for compound impact rock-breaking was built. The rock breaking law in PDC bit compound rock breaking process and the impact vector angle and impact duration on rock breaking efficiency are analyzed. The results show that the compound impact drilling can effectively alleviate the stick–slip vibration phenomenon, and improve drilling efficiency. In the compound impact mode, compressive stress failure and tensile stress failure occur at the same time, and the tensile stress failure is the main failure mode. The peak stress of the rock is 5.49% larger, and the residual plastic deformation is about 4.28% smaller than that of non-impact mode. With the increase of impact angle, the MSE decreases first and then increases a little. The optimal impact vector angle is in the range of 30°–50°. With the increase of the impact time, the MSE decreases in a wavy manner. In the range of 0.2 ms–1.0 ms, the optimal impact time is 0.8 ms–1.0 ms.

Diabetic nephropathy (DN) is a common microvascular complication with limited effective interventions in diabetic patients. Linderae Radix is a traditional herbal tonic used to treat various kidney and metabolic diseases. In this study, we evaluated the efficacy and mechanism of the main bioactive components, sesquiterpene lactones in L. Radix (SLR), on DN. The results showed that treatment with SLR reduced the levels of apoptotic rates, ROS, TNF-α, IL-6, and IL-1β, but increased the activities of SOD and GSH-Px in high glucose-treated HK2 cells. Furthermore, SLR improved renal dysfunction but increased the activities of SOD and GSH-Px in the renal tissues of DN mice. Mechanistically, SLR upregulated the expressions of Nrf2 and HO-1 but downregulated NF-κB in high glucose-treated HK2 cells by targeting PPAR, which could be reversed by the PPARγ inhibitor SR202. Therefore, SLR improved DN by reducing oxidative stress, cell apoptosis, and inflammatory response through activating PPARγ/Nrf2 pathway.

Alzheimer’s disease (AD) is a progressive neurological disorder, with two main pathological hallmarks of senile plaques and neurofibrillary tangles accumulated of abnormally phosphorylated Tau. Ginkgolic acid (GA), as an inhibitor of SUMO-1, exhibits many biological activities, including neuroprotective effects. However, the efficacy of GA in AD treatment has not been sufficiently investigated. Therefore, the current study aimed to explore the function and the underlying molecular mechanisms of GA related to AD. Our study revealed that GA exerted protective effects on cognitive impairment of an Aβ-induced AD rat model, and suppressed the neuronal apoptosis and oxidative stress induced by Aβ1-42 both in vivo and in vitro. Of crucial importance, GA significantly inhibited Tau phosphorylation, and blocked the activation of the SUMO-1/GSK3β signaling pathway. Taken together, these observations demonstrated that GA improved cognitive ability and inhibited Tau phosphorylation through SUMO1/GSK3β pathway, indicating that GA is a potential drug for the preventing and treatment of AD.

Summary: Background: Urine cytology is an important non-invasive examination for urothelial carcinoma (UC) diagnosis and follow-up. We aimed to explore whether artificial intelligence (AI) can enhance the sensitivity of urine cytology and help avoid unnecessary endoscopy. Methods: In this multicentre diagnostic study, consecutive patients who underwent liquid-based urine cytology examinations at four hospitals in China were included for model development and validation. Patients who declined surgery and lacked associated histopathology results, those diagnosed with rare subtype tumours of the urinary tract, or had low-quality images were excluded from the study. All liquid-based cytology slides were scanned into whole-slide images (WSIs) at 40 × magnification and the WSI-labels were derived from the corresponding histopathology results. The Precision Urine Cytology AI Solution (PUCAS) was composed of three distinct stages (patch extraction, features extraction, and classification diagnosis) and was trained to identify important WSI features associated with UC diagnosis. The diagnostic sensitivity was mainly used to validate the performance of PUCAS in retrospective and prospective validation cohorts. This study is registered with the ChiCTR, ChiCTR2300073192. Findings: Between January 1, 2018 and October 31, 2022, 2641 patients were retrospectively recruited in the training cohort, and 2335 in retrospective validation cohorts; 400 eligible patients were enrolled in the prospective validation cohort between July 7, 2023 and September 15, 2023. The sensitivity of PUCAS ranged from 0.922 (95% CI: 0.811–0.978) to 1.000 (0.782–1.000) in retrospective validation cohorts, and was 0.896 (0.837–0.939) in prospective validation cohort. The PUCAS model also exhibited a good performance in detecting malignancy within atypical urothelial cells cases, with a sensitivity of over 0.84. In the recurrence detection scenario, PUCAS could reduce 57.5% of endoscopy use with a negative predictive value of 96.4%. Interpretation: PUCAS may help to improve the sensitivity of urine cytology, reduce misdiagnoses of UC, avoid unnecessary endoscopy, and reduce the clinical burden in resource-limited areas. The further validation in other countries is needed. Funding: National Natural Science Foundation of China; Key Program of the National Natural Science Foundation of China; the National Science Foundation for Distinguished Young Scholars; the Science and Technology Planning Project of Guangdong Province; the National Key Research and Development Programme of China; Guangdong Provincial Clinical Research Centre for Urological Diseases.

ABSTRACT: Chicken egg chalaza (CLZ) is a natural colloidal structure in eggs that exists as an egg yolk stabilizer and is similar in composition to egg white. In this study, the proteome, phosphoproteome, and N-glycoproteome of CLZ were characterized in depth. We hydrolyzed the CLZ proteins and enriched the phosphopeptides and glycopeptides. We identified 45 phosphoproteins and 80 N-glycoproteins, containing 59 phosphosites and 203 N-glycosylation sites, respectively. Typically, the ovalbumin in CLZ was both phosphorylated and N-glycosylated, with 4 phosphosites and 4 N-glycosylation sites. Moreover, we identified 2 N-glycosylated subunits of ovomucin, mucin-5B and mucin-6, with 32 and nine N- glycosylation sites, respectively. Analysis of the phosphorylation and N-glycosylation status of CLZ proteins could provide novel insights into the structural and functional characteristics of CLZ.

Background: Tumor genetic anomalies and immune dysregulation are pivotal in the progression of multiple myeloma (MM). Accurate patient stratification is essential for effective MM management, yet current models fail to comprehensively incorporate both molecular and immune profiles. Methods: We examined 776 samples from the MMRF CoMMpass database, employing univariate regression with LASSO and CIBERSORT algorithms to identify 15 p53-related genes and six immune cells with prognostic significance in MM. A p53-TIC (tumor-infiltrating immune cells) classifier was constructed by calculating scores using the bootstrap-multicox method, which was further validated externally (GSE136337) and through ten-fold internal cross-validation for its predictive reliability and robustness. Results: The p53-TIC classifier demonstrated excellent performance in predicting the prognosis in MM. Specifically, patients in the p53low/TIChigh subgroup had the most favorable prognosis and the lowest tumor mutational burden (TMB). Conversely, those in the p53high/TIClow subgroup, with the least favorable prognosis and the highest TMB, were predicted to have the best anti-PD1 and anti-CTLA4 response rate (40 %), which can be explained by their higher expression of PD1 and CTLA4. The three-year area under the curve (AUC) was 0.80 in the total sample. Conclusions: Our study highlights the potential of an integrated analysis of p53-associated genes and TIC in predicting prognosis and aiding clinical decision-making in MM patients. This finding underscores the significance of comprehending the intricate interplay between genetic abnormalities and immune dysfunction in MM. Further research into this area may lead to the development of more effective treatment strategies.

Despite extensive research reveal rheumatoid arthritis (RA) is related to atherosclerosis (AS), common pathogenesis between these two diseases still needs to be explored. In current study, we explored the common pathogenesis between rheumatoid arthritis (RA) and atherosclerosis (AS) by identifying 297 Differentially Expressed Genes (DEGs) associated with both diseases. Through KEGG and GO functional analysis, we highlighted the correlation of these DEGs with crucial biological processes such as the vesicle transport, immune system process, signaling receptor binding, chemokine signaling and many others. Employing Protein-Protein Interaction (PPI) network analysis, we elucidated the associations between DEGs, revealing three gene modules enriched in immune system process, vesicle, signaling receptor binding, Pertussis, and among others. Additionally, through CytoHubba analysis, we pinpointed 11 hub genes integral to intergrin-mediated signaling pathway, plasma membrane, phosphotyrosine binding, chemokine signaling pathway and so on. Further investigation via the TRRUST database identified two key Transcription Factors (TFs), SPI1 and RELA, closely linked with these hub genes, shedding light on their regulatory roles. Finally, leveraging the collective insights from hub genes and TFs, we proposed 10 potential drug candidates targeting the molecular mechanisms underlying RA and AS pathogenesis. Further investigation on xCell revealed that 14 types of cells were all different in both AS and RA. This study underscores the shared pathogenic mechanisms, pivotal genes, and potential therapeutic interventions bridging RA and AS, offering valuable insights for future research and clinical management strategies.

Summary: Artificial intelligence (AI) has been found to assist in optical differentiation of hyperplastic and adenomatous colorectal polyps. We investigated whether AI can improve the accuracy of endoscopists’ optical diagnosis of polyps with advanced features. We introduced our AI system distinguishing polyps with advanced features with more than 0.870 of accuracy in the internal and external validation datasets. All 19 endoscopists with different levels showed significantly lower diagnostic accuracy (0.410–0.580) than the AI. Prospective randomized controlled study involving 120 endoscopists into optical diagnosis of polyps with advanced features with or without AI demonstration identified that AI improved endoscopists’ proportion of polyps with advanced features correctly sent for histological examination (0.960 versus 0.840, p

Summary: Background: An intronic GAA repeat expansion in FGF14 was recently identified as a cause of GAA-FGF14 ataxia. We aimed to characterise the frequency and phenotypic profile of GAA-FGF14 ataxia in a large Chinese ataxia cohort. Methods: A total of 1216 patients that included 399 typical late-onset cerebellar ataxia (LOCA), 290 early-onset cerebellar ataxia (EOCA), and 527 multiple system atrophy with predominant cerebellar ataxia (MSA-c) were enrolled. Long-range and repeat-primed PCR were performed to screen for GAA expansions in FGF14. Targeted long-read and whole-genome sequencing were performed to determine repeat size and sequence configuration. A multi-modal study including clinical assessment, MRI, and neurofilament light chain was conducted for disease assessment. Findings: 17 GAA-FGF14 positive patients with a (GAA)≥250 expansion (12 patients with a GAA-pure expansion, five patients with a (GAA)≥250-[(GAA)n (GCA)m]z expansion) and two possible patients with biallelic (GAA)202/222 alleles were identified. The clinical phenotypes of the 19 positive and possible positive cases covered LOCA phenotype, EOCA phenotype and MSA-c phenotype. Five of six patients with EOCA phenotype were found to have another genetic disorder. The NfL levels of patients with EOCA and MSA-c phenotypes were significantly higher than patients with LOCA phenotype and age-matched controls (p

Background: Osteosarcoma, a tumor that originates from bone cells, has a poor prognosis and a high degree of malignancy. Anlotinib, a small-molecule multi-target tyrosine kinase inhibitor (TKI), is the first-line drug in treating osteosarcoma, especially in late-stage osteosarcoma. However, patients often develop resistance after using anlotinib for a certain period, which poses a challenge to its further clinical application. Recently, several TKIs, for instance regorafenib and cabozantinib, have showed clinical interest in treating osteosarcoma and target both vascular endothelial growth factor receptor (VEGFR) and mesenchymal epithelial transition factor (c-MET). Therefore, the identification of new TKI warrants further investigation. Methods: We performed CCK8 aasays to confirm that BMS-794833 sensitization osteosarcoma cells to anlotinib. Bioinformatics analysis and rescue experiments showed that the reduce of resistance were dependent on the VEGFR/Ras/CDK2 pathway. Cell line based xenograft model were used to demonstrate that BMS-794833 and anlotinib could synergistically treat OS. Results: Here, we found that BMS-794833 reduced anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway. CCK8 assay showed that BMS-794833 significantly improved the resistance of osteosarcoma cells to anlotinib. The results of rescue experiments showed that the regulatory effects of BMS-794833 on the proliferation and drug resistance of osteosarcoma cells were dependent on the VEGFR/Ras/CDK2 pathway. In addition, BMS-794833 affected the resistance of osteosarcoma cells to anlotinib through epithelial–mesenchymal transition (EMT) and apoptosis pathways. More importantly, BMS-794833 and anlotinib exerted synergistic therapeutic effects against osteosarcoma in vivo. Conclusion: Altogether, this study reveals a new (VEGFR)-targeting drug that can be combined with anlotinib for the treatment of osteosarcoma, which provides an important theoretical basis for overcoming anlotinib resistance.

Objective: This trial aimed to identify the Minimum Effective Concentration (MEC90, defined as the concentration which can provide successful block in 90% of patients) of 30 mL ropivacaine for single-shot ultrasound-guided transmuscular Quadratus Lumborum Block (QLB) in patients undergoing Total Hip Arthroplasty (THA). Methods: A double-blind, randomized dose-finding study using the biased coin design up-and-down sequential method, where the concentration of local anesthetic administered to each patient depended on the response from the previous one. Block success was defined as a Numeric Rating Scale (NRS) score during motion ≤ 3 at 6 hours after arrival in the ward. If the block was successful, the next subject received either a 0.025% smaller dose (probability of 0.11) or the same dose (probability of 0.89); otherwise, the next subject received a 0.025% higher ropivacaine concentration. MEC90, MEC95 and MEC99 were estimated by isotonic regression, and the corresponding 95% Confidence Intervals (95% CIs) were calculated by the bootstrapping method. Results: Based on the analysis of 52 patients, MEC90, MEC95, and MEC99 of ropivacaine for QLB were estimated to be 0.352% (95% CI 0.334–0.372%), 0.363% (95% CI 0.351–0.383%), and 0.373% (95% CI 0.363–0.386%). The concentration of ropivacaine at 0.352% in a volume of 30 ml can provide a successful block in 90% of patients. Conclusions: For ultrasound-guided transmuscular QLB in patients undergoing THA, 0.352% ropivacaine in a volume of 30 ml can provide a successful block in 90% of patients. Further dose-finding studies and large sample size are required to verify the concentration.

It has been shown that exposure to hexavalent Chromium, Cr (Ⅵ), via nasal cavity can have neurotoxicological effects and induces behavioral impairment due to the fact that blood brain barrier (BBB) does not cover olfactory bulb. But whether Cr (Ⅵ) can cross the BBB and have a toxicological effects in central nervous system (CNS) remains unclear. Therefore, we investigated the effects of Cr (Ⅵ) on mice treated with different concentrations and exposure time (14 days and 28 days) of Cr (Ⅵ) via intraperitoneal injection. Results revealed that Cr accumulated in hypothalamus (HY) in a timely dependent manner. Much more severer neuropathologies was observed in the group of mice exposed to Cr (Ⅵ) for 28 days than that for 14 days. Gliosis, neuronal morphological abnormalities, synaptic degeneration, BBB disruption and neuronal number loss were observed in HY. In terms of mechanism, the Nrf2 related antioxidant stress signaling dysfunction and activated NF-κB related inflammatory pathway were observed in HY of Cr (Ⅵ) intoxication mice. And these neuropathologies and signaling defects appeared in a timely dependent manner. Taking together, we proved that Cr (Ⅵ) can enter HY due to weaker BBB in HY and HY is the most vulnerable CNS region to Cr (Ⅵ) exposure. The concentration of Cr in HY increased along with time. The accumulated Cr in HY can cause BBB disruption, neuronal morphological abnormalities, synaptic degeneration and gliosis through Nrf2 and NF-κB signaling pathway. This finding improves our understanding of the neurological dysfunctions observed in individuals who have occupational exposure to Cr (Ⅵ), and provided potential therapeutic targets to treat neurotoxicological pathologies induced by Cr (Ⅵ).

As the superposition of an even and odd modes constitutes an elegant Laguerre-Gaussian beam (ELGB), Airy transformation of the even mode, the odd mode, and the ELGB is studied. Analytical expressions of the even mode, the odd mode, and the ELGB in the receiver plane of Airy transformation are derived, respectively. Also, the analytical centroid and the analytical beam width for the arbitrary even mode, the arbitrary odd mode, and the arbitrary ELGB in the receiver plane of Airy transformation are concluded by numerical calculations. Moreover, the relationship of the centroids and the beam widths among the even mode, the odd mode, and the ELGB in the receiver plane of Airy transformation are presented. As typical examples, the properties of the even, the odd, and the whole beam for E01, E02, E11, and E12 are demonstrated in the receiver plane of Airy transformation. The above two subscripts correspond to the radial and the angular moduli, respectively. The effects of the transform coefficients on the normalized light intensity, the centroid, and the beam width of the even, the odd, and the whole beam for E01, E02, E11, and E12 in the receiver plane of Airy transformation are analyzed. Furthermore, the effect of the transform coefficients on the orbital angular momentum (OAM) density of E01, E02, E11, and E12 are examined. The OAM of the ELGB in the receiver plane of Airy transformation is conserved, which is not subject to influence of the transform coefficients. This study provides an optional scheme for obtaining peculiar laser beams, and also it expands applications of the even mode, the odd mode, and the ELGB.

Background: The coexistence of autoimmune encephalitis (AE) with multiple neural auto-antibodies is of great clinical significance because overlying antibodies may cause superposition or variation of clinical syndrome, which increases the difficulty of diagnosis and treatment of the disease. To the best of our knowledge, the coexistence of anti-N-methyl d-aspartate Receptor (NMDAR) and anti-IgLON5 antibodies in AE has not been published previously. Case presentation: A 38-year-old female patient presented to our hospital due to headache and abnormal psychiatric behavior. Based on her clinical manifestations (psychiatric and behavioral abnormalities, involuntary limb movements, and sleep disorders) and laboratory assessment results (positive human leukocyte antigen (HLA)-DQB1*05:01 haplotype, anti-NMDAR, and anti-IgLON5 antibodies), she was diagnosed as AE with coexisting anti-NMDAR and anti-IgLON5 antibodies. After treatment with intravenous methylprednisolone and immunoglobulin, as well as plasmapheresis, her symptoms gradually improved with exception for the sleep disorders. Although oral prednisone acetate and mycophenolate mofetil were continued after discharge, her symptoms of sleep disorders did not improve at 6-month follow-up. Conclusion: This is the first case of AE co-existing with anti-NMDAR and anti-IgLON5 antibodies. Co-existence of neural auto-antibodies should be considered when patients present with overlapping or atypical symptoms. Special attention should be paid to the treatment of these patients as some anti-IgLON5 encephalitis patients may not benefit from immunotherapy treatment.

In recent years, nanoplastics (NPs) and triclosan (TCS, a pharmaceutical and personal care product) have emerged as environmental pollution issues, and their combined presence has raised widespread concern regarding potential risks to organisms. However, the combined toxicity and mechanisms of NPs and TCS remain unclear. In this study, we investigated the toxic effects of polystyrene NPs and TCS and their mechanisms on KGN cells, a human ovarian granulosa cell line. We exposed KGN cells to NPs (150 μg/mL) and TCS (15 μM) alone or together for 24 hours. Co-exposure significantly reduced cell viability. Compared with exposure to NPs or TCS alone, co-exposure increased reactive oxygen species (ROS) production. Interestingly, co-exposure to NPs and TCS produced synergistic effects. We examined the activity of superoxide dismutase (SOD) and catalase (CAT), two antioxidant enzymes; it was significantly decreased after co-exposure. We also noted an increase in the lipid oxidation product malondialdehyde (MDA) after co-exposure. Furthermore, co-exposure to NPs and TCS had a more detrimental effect on mitochondrial function than the individual treatments. Co-exposure activated the NRF2–KEAP1–HO-1 antioxidant stress pathway. Surprisingly, the expression of SESTRIN2, an antioxidant protein, was inhibited by co-exposure treatments. Co-exposure to NPs and TCS significantly increased the autophagy-related proteins LC3B-II and LC3B-Ⅰ and decreased P62. Moreover, co-exposure enhanced CASPASE-3 expression and inhibited the BCL-2/BAX ratio. In summary, our study revealed the synergistic toxic effects of NPs and TCS in vitro exposure. Our findings provide insight into the toxic mechanisms associated with co-exposure to NPs and TCS to KGN cells by inducing oxidative stress, activations of the NRF2-KEAP1-HO-1 pathway, autophagy, and apoptosis.