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Abstract Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy that accounts for approximately 1–2% of all thyroid cancers (TCs). MTC include hereditary and sporadic cases, the former derived from a germline mutation of rearrangement during transfection (RET) proto-oncogene, whereas somatic RET mutations are frequently present in the latter. Surgery is the standard treatment for early stage MTC, and the 10-year survival rate of early MTC is over 80%. While for metastatic MTC, chemotherapy showing low response rate, and there was a lack of effective systemic therapies in the past. Due to the high risk (ca. 15–20%) of distant metastasis and limited systemic therapies, the 10-year survival rate of patients with advanced MTC was only 10–40% from the time of first metastasis. Over the past decade, targeted therapy for RET has developed rapidly, bringing hopes to patients with advanced and progressive MTC. Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment. However, these MKIs have not prolonged overall survival (OS) and their utility is limited due to high rates of off-target toxicities. Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options. Despite the ongoing development of RET inhibitors, the management of advanced and progressive MTC remains challenging, drug resistance remains the main reason for treatment failure, and the mechanisms are still unclear. Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects.

Abstract Background Failure to restore missing teeth in time can easily lead to the mesial tilting of the distal abutment teeth. However, a fixed partial denture (FPD) can improve stress conduction and distribution and prevent periodontal injuries. In these more complex cases, it is necessary to consider various factors comprehensively to improve conventional treatment planning and achieve better results. Methods We selected a patient with a missing first molar and a mesial inclination of the second molar, leaving inadequate space or bone mass for implant denture restoration, necessitating an FPD for restoration. Three-dimensional finite element analysis (3D-FEA) combined with photoelastic analysis were used to explore how the inclination angle (0 ‒ 30°) and different dental restoration materials (zirconia, lithium disilicate, polymer-infiltrated ceramic network, and resin composite) affect the biomechanical behaviour of FPD‒abutments‒periodontal tissue complex. Results The stress was easily concentrated in the FPD connectors, enamel shoulder collar, periapical area, and root bifurcation. The stress on FPD and the periodontal ligament (PDL) of the second premolar increased with an increase in the elastic modulus of FPD, with an opposite trend in the abutments, the alveolar bone, and the PDL of the second molar. The stress on the FPD and alveolar bone increased with increased inclination angle of the distal abutment. The stress on two abutments and their PDL were positively correlated with the inclination angle in two stages; however, when the inclination angle > 12°, the second premolar and its PDL showed a negative correlation. Conclusions FPDs can be used for restoration within 24° of distal abutment inclination, but protecting the abutments ( 12° especially) must be taken seriously. For this purpose, an FPD material with higher strength is recommended.

Abstract Epithelial ovarian cancer (EOC) presents considerable difficulties in prognostication and treatment strategy development. Bevacizumab, an anti-angiogenic medication, has demonstrated potential in enhancing progression-free survival (PFS) in EOC patients. Nevertheless, the identification of individuals at elevated risk of disease progression following treatment remains a challenging task. This study was to develop and validate a deep learning (DL) model using retrospectively collected computed tomography (CT) plain scans of inoperable and recurrent EOC patients receiving bevacizumab treatment diagnosed between January 2013 and January 2024. A total of 525 patients from three different institutions were retrospectively included in the study and divided into training set (N = 400), internal test set (N = 97) and external test set (N = 28). The model’s performance was evaluated using Harrell’s C-index. Patients were categorized into high-risk and low-risk group based on a predetermined cutoff in the training set. Additionally, a multimodal model was evaluated, incorporating the risk score generated by the DL model and the pretreatment level of carbohydrate antigen 125 as input variables. The Net Reclassification Improvement (NRI) metric quantified the reclassification performance of our optimal model in comparison to the International Federation of Gynecology and Obstetrics (FIGO) staging model. The results indicated that DL model achieved a PFS predictive C-index of 0.73 in the internal test set and a C-index of 0.61 in the external test set, along with hazard ratios of 34.24 in the training set (95% CI: 21.7, 54.1; P

With the manufacturing process by vacuum induction， electroslag remelting， vacuum self consumption， homogenization heat treatment， forging， hot extrusion， cold rolling， and heat treatment. we can get two types of GH4169 alloy pipes with Nb content of 4.90% and 5.30% respectively. The effect of Nb content on the microstructure and properties of GH4169 alloy pipes was studied while other components remained basically the same. The results show that under the same heat treatment process， with the increase of Nb element content， the Nb content becomes higher and the grain size becomes smaller； At 200 ℃ and room temperature with the tensile strength and yield strength both increase with the increasing of Nb content， And the content of precipitates in GH4169 alloy pipes also increases. Under different solid solution heat treatments and the same aging heat treatment process， the grain size of GH4169 alloy pipes is in the range of 4.0-7.0. The smaller the grain size， the higher the tensile strength and yield strength of the pipes； At the same grain size， the higher the Nb content， the higher the tensile strength and yield strength of the pipe.

Low back pain is among the most grave public health concerns worldwide and the major clinical manifestation of intervertebral disc degeneration (IVDD). The destruction of annulus fibrosus (AF) is the primary cause of IVDD. A sustainable and stable treatment system for IVDD is lacking because of the special organizational structure and low nutrient supply of AF. We here found that IVDD results in the impaired mitochondrial function of AF tissue, and mitochondrial autophagy (mitophagy) plays a protective role in this process. We therefore reported a thread-structural microneedle (T-MN) matching the ring structure of AF. Based on the adsorption effect of laminin, our T-MN could load with bone marrow mesenchymal stem cell-derived exosomes to envelope the regulating mitophagy microRNA (miRNA 378), named as T-MN@EXO@miR−378. In general, we offered in situ locking in the defect site of AF to prevent nucleus pulposus leakage and promoted AF repair. The design of the thread structure was aimed at bionically matching the layered AF structure, thereby providing stronger adhesion. The T-MN@EXO@miR−378 effectively attached to AF and slowly released therapeutic engineered exosomes, and prevented IVDD progression by restoring mitophagy, promoting AF cell proliferation and migration, and inhibiting the pathological remodeling of the extracellular matrix. This functional system can be used as an excellent tool for sustained drug release and has a certain prospect in substituting the conventional treatment of IVDD.

Abstract Intrinsic breast cancer molecular subtyping (IBCMS) provides significant prognostic information for patients with breast cancer and helps determine treatment. This study compared IBCMS methods on various gene-expression platforms in PALOMA-2 and PALLET trials. PALOMA-2 tumor samples were profiled using EdgeSeq and nanostring and subtyped with AIMS, PAM50, and research-use-only (ruo)Prosigna. PALLET tumor biopsies were profiled using mRNA sequencing and subtyped with AIMS and PAM50. In PALOMA-2 (n = 222), a 54% agreement was observed between results from AIMS and gold-standard ruoProsigna, with AIMS assigning 67% basal-like to HER2-enriched. In PALLET (n = 224), a 69% agreement was observed between results from PAM50 and AIMS. Different IBCMS methods may lead to different results and could misguide treatment selection; hence, a standardized clinical PAM50 assay and computational approach should be used. Trial number: NCT01740427

Abstract Background Scedosporium apiospermum (S. apiospermum) is a rare fungal pathogen that causes disseminated infections. It rarely affects immunocompetent individuals and has a poor prognosis. Case presentation A 37-year-old woman presented with multiple lesions in the lungs, brain, and eyes, shortly after near drowning in a car accident. The primary symptoms were chest tightness, limb weakness, headache, and poor vision in the left eye. S. apiospermum infection was confirmed by metagenomic next-generation sequencing (mNGS) of intracranial abscess drainage fluid, although intracranial metastases were initially considered. After systemic treatment with voriconazole, her symptoms improved significantly; however, she lost vision in her left eye due to delayed diagnosis. Conclusion While S. apiospermum infection is rare, it should be considered even in immunocompetent patients. Prompt diagnosis and treatment are essential. Voriconazole may be an effective treatment option.

Abstract Mine slope stability and mining sustainability are related to the local geological structures, which could change the rock mass structure in deep mining. After 20 years mining in a mudstone mine, western China, the slope structure transforms from anti-dipping structure into a bedding structure by a recently discovered fault (F1), further inducing the two landslides (Landslide #I and Landslide #II). Landslide investigation suggested the residual deposits in Landslide #I first slid over 100 m and overburdened the rear of Landslide #II. The bedding rock with weak interlayers at footwall is separated from the anti-dipping rock at the hanging wall by F1. After excavation, a weak interlayer was exposed and softened by rainfall, resulting in the slip of footwall rock mass and further inducing large scale toppling deformation. The fragmented rock mass sliding along a weak interlayer triggers consequent deformation of adjacent slope, reducing safety reserve of the open mine. The discrete element analysis reveals that the bedding rock mass of footwall slid once the weak interlayer was exposed by mining. And retrogressive deformation transmitted to the hanging wall and induced bending and toppling deformation of anti-dipping rock mass. Mine feasibility assessment should recognize the potential deep geological structures as important in the future.

【Objective】 Drip fertigation is an irrigation technique increasingly used to simultaneously irrigate and fertilize crops grown in different environments. However, calcium and magnesium in the water could react chemically to precipitate, clogging the irrigator as a result. In this paper, we experimentally study the impact of calcium and magnesium concentration on irrigator clogging in drip fertigation using brackish water and humic acid fertilizer. 【Method】 In this experiment, four types of irrigators (FE1, FE2, FE3, FE4) with different rated flow rates (1.6, 1.1, 1.4, 1.75 L/h) were selected, in which three groups of brackish water treatments with calcium ion mass concentration, with ion mass concentrations of 100, 150 and 200 mg/L (G1, G2, G3), and three groups of brackish water treatments with magnesium ion mass concentration, with ion mass concentrations of 100, 150 and 200 mg/L (M1, M2, M3). In each treatment, fertigation using local groundwater was taken as the control (CK), we measured the average flow rate in the irrigator (Dra), clogging distribution in the irrigator, the dry mass of clogging materials (DW), and mineral fraction of the clogging materials in the irrigator. 【Result】 Compared to CK, fertigation using water with elaborated Ca2+ and Mg2+ concentration and humic acid fertilizer increased Dra by 21.58% to 56.75%, and DW by 67.14% to 270.09%, respectively, with the increase depending on dripping rate and Ca2+ and Mg2+ concentration. When Ca2+ and Mg2+concentration was the same, increasing dripping rate reduced DW by 4.77% to 27.26%, with the reduction depending on Ca2+ and Mg2+ concentration. 【Conclusion】 Increasing calcium and magnesium concentration in the fertigation water significantly increased irrigator clogging. When calcium and magnesium concentration was the same, an increase in magnesium concentration significantly reduced the mass of clogged materials due to the reduced carbonate. Thus, increasing magnesium ion can ameliorate irrigator clogging and reduce the risk of irrigator blockage.

Ferritic-martensitic steel is a kind of steel with excellent anti-radiation properties， which is one of superior candidate materials for structural components of the new generation of nuclear reactors with high radiation doses. The harsh service environment requires that ferritic-martensitic steel has good comprehensive mechanical properties， suitable grain size and few internal defects. In this paper， the effects of normalizing and tempering heat treatment on mechanical properties and microstructure evolution of new composition ferritic-martensitic steel were studied. At the same time， the ThermoCalc software is used to calculate the volume proportion of different phase states and compare it with the experimental results， it finds that the calculated results of the two-phase ratio change are highly consistent with the experimental results.After normalizing treatment， the tensile strength and yield strength of the material are mainly affected by the ratio of two phases. The results show high-martensitic steel treated with 1 080 ℃ normalizing + 670 ℃ tempering heat has a tensile strength of 903 MPa and yield strength of 732 MPa， showing the best comprehensive performance of the materials.

[Objective] To compensate for the preset turnout safety gap between track beam and switch beam of the mobile turnout in the suspended monorail transit system, ensure reliable locking when turnout is in place, and improve the safety and passenger comfort when train passing through turnout area, an integrated mechanism for locking and compensation is proposed, where the locking and compensating functions share a common power source, meeting the sequential requirements for locking before compensation after the turnout is in place. [Method] The current application status of suspended monorail turnouts and the main existing problems are introduced, and the application scenarios are analyzed. The design composition of the locking and compensation mechanism between the suspended track beam and the turnout beam is presented, along with an analysis of the motion working principle of the mechanism. [Result & Conclusion] The proposed locking and compensation mechanism has a compact overall external structure, meeting the installation space constraints between the suspended monorail mobile turnout beam and the track beam. Through the spatial layout design of the integrated linkage rod, the mechanism achieves reliable locking between beams, seam compensation between the turnout beam and the track beam, and fulfills the sequential requirements for locking before compensation.

Abstract Background The incidence of refractive surgery-related dry eye disease (DED) is rising due to the increasing popularity of corneal refractive surgery. The moisture chamber goggles (MCGs) have been shown to tear evaporation by increasing local humidity and minimizing airflow. The current study aims to evaluate the efficacy of moisture chamber goggles for refractive surgery-related DED. Methods In this nonrandomized open-label controlled study, 78 participants (156 eyes) receiving refractive surgery were enrolled between July 2021 and April 2022, and sequentially allocated to MGC and control groups. 39 participants were allocated to the MGC groups, of which 53.8% received small-incision lenticule extraction (SMILE) and 46.2% received femtosecond laser-assisted in situ keratomileusis (FS-LASIK), and were instructed to wear MCGs for the duration of 1 month postoperatively, in addition to the standard postoperative treatment received by the control groups (56.4% SMILE, 43.6% FS-LASIK). Participants underwent full ophthalmic examinations, including visual acuity, manifest refraction, DED evaluations, and higher-order aberrations (HOAs), both preoperatively and at routine follow-ups 1 day, 1 week, and 1 month after surgery. DED parameters included non-invasive tear film break-up time (NIBUT), tear meniscus height (TMH), conjunctival congestion, lipid layer thickness (LLT), and ocular surface disease index (OSDI) questionnaires. Student’s t-test was used for comparisons between control and MCG groups, and between preoperative and postoperative parameters within groups. Results Postoperative NIBUT decreased in both SMILE and FS-LASIK control groups 1 day after the surgery (SMILE, P = 0.001; FS-LASIK, P = 0.008), but not in the corresponding MCG groups (SMILE, P = 0.097; FS-LASIK, P = 0.331). TMH in the MCG group was significantly higher at 1 week (P = 0.039) and 1 month (P = 0.015) in SMILE, and 1 day (P = 0.003) in FS-LASIK groups. In FS-LASIK participants, significantly lower HOAs and coma levels in the MCG group were observed 1 day (total HOAs, P = 0.023; coma, P = 0.004) and 1 week (total HOAs, P = 0.010, coma, P = 0.004) after surgery. No consistent statistically significant intergroup difference was observed between MCG and control groups in conjunctival congestion, LLT, and OSDI. Conclusions MCGs effectively slowed tear evaporation, increased tear film stability, and improved HOAs in patients receiving SMILE and FS-LASIK surgeries. MCG is an effective adjuvant therapy in the comprehensive management of refractive surgery-related DED.

Objective: This study aimed to induce the machine vision technology into the appearance detection of Pleurotus eryngii. Methods: A bilateral filter was proposed to replace Gaussian filter as image smoothing filter, and Ostu maximum inter-class variance method was proposed to replace the improved Canny operator, based on fixed double threshold segmentation, and used as edge detection algorithm. HALCON operator and color space conversion were used to extract the length, diameter, curvature, evenness, color and cap defects of P. erynii, and the development and design of visual software function modules were completed, under the VS 2017 development environment with HALCON 18.05 and C#. Results: 200 pieces of P. eryngii were randomly obtained to test the accuracy of the algorithm and the performance of the visual software. The diameter grading accuracy of the Pleurotus eryngii was 83%, and the remaining characteristic elements could reach more than 95%, with the overall classification accuracy of all specifications more than 90%. Conclusion: The classification of appearance quality of P. eryngii can be completed through the improvement of algorithm and the design of visual software.

Objective: Gemcitabine plus nab-paclitaxel (GnP) is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC). S-1, an oral fluoropyrimidine derivative, as compared with gemcitabine, is non-inferior in terms of overall survival (OS) and is associated with lower hematologic toxicity. Accordingly, S-1 is a convenient oral alternative treatment for advanced PDAC. This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1 (GS) vs. GnP as first-line chemotherapy for advanced PDAC. Methods: Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated. Results: A total of 300 patients were assessed, of whom 84 received GS and 216 received GnP. The chemotherapy completion rate was higher with GS than GnP (50.0% vs. 30.3%, P = 0.0028). The objective response rate (ORR) was slightly higher (14.3% vs. 9.7%, P = 0.35), and the median OS was significantly longer (17.9 months vs. 13.3 months, P = 0.0078), in the GS group than the GnP group. However, the median progression-free survival (PFS) did not significantly differ between groups. Leukopenia risk was significantly lower in the GS group than the GnP group (14.9% vs. 28.1%, P = 0.049). Conclusions: As first-line chemotherapy for advanced PDAC, the GS regimen led to a significantly longer OS than the GnP regimen. The PFS, ORR, and incidence of severe adverse events were comparable between the GS and GnP groups.

SIVA-1 has been shown to affect apoptotic processes in various different cell lines, and SIVA-1 significantly contributes to the decreased responsiveness of cancer cells to some chemotherapy agents. However, whether SIVA-1 has potential application in gastric cancer remains unknown. Therefore, the objective of this investigation was to clarify the distinct function of SIVA-1 in chemotherapeutic drug resistance within a living murine model with gastric malignancy, and initially elucidate the underlying mechanisms. In an established multidrug-resistant gastric cancer xenograft mouse model, lentivirus, named Lv-SIVA-1, was injected into xenograft tumors, and increased the mRNA and protein expression of endogenous SIVA-1 in tumors. Immunohistochemical assays of xenograft tumor showed that SIVA-1 was significantly upregulated, and the protein expression levels of SIVA-1 were highly increased, as detected by Western blotting. In addition, we detected the role of SIVA-1 in cell proliferation and cell apoptosis in gastric cancer cells by TUNEL and found that SIVA-1 decreased tumor cell apoptosis and promoted tumor growth in vivo. Using a TMT assay between tumor tissues of experimental and control groups, differentially expressed proteins were examined and three potential biomarkers of multidrug resistance (ARF, MDM2, and p53) were screened. We further investigated the molecular mechanism by which SIVA-1 played an efficient role against chemotherapies and found that overexpressed SIVA-1 leads to increased ARF and MDM2 expression and suppressed expression of p53 in tumor tissue. In conclusion, SIVA-1 plays a significant role in the multidrug resistance of gastric tumors. In addition, overexpressed SIVA-1 positively regulates cell proliferation, adjusts cycle progression, and reduces the response to drug treatment for gastric cancer in an ARF/MDM2/p53-dependent manner. This novel research provides a basis for chemical management of gastric cancer through regulation of SIVA-1 expression.

Objective: In order to effectively solve the problems of low efficiency, quality fluctuation and increasing labor cost of artificial sorting. Methods: A mechanical system based on differential separation principle was designed to complete the classification and separation device of Pleurotus eryngii, and the differential separation principle was introduced and modeled. Results: The test prototype was built and the principle verification test was completed. The success rate of separation of special mushroom was 99.5%, and that of other varieties was 100%. Conclusion: The test device can achieve good differential separation effect.

Abstract Background Understanding of the early immune response in severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) breakthrough infections is limited. Methods Ninety‐eight patients with coronavirus disease 2019 (COVID‐19) breakthrough infections were divided into two groups, with intervals from receiving the second dose of inactivated vaccine to the onset of illness

Background As the most common clinical manifestation and a major complication in chronic kidney disease, anemia affects the patients' quality of life, increases the risk of renal disease progression and death. Hence, it is important to improve anemia, and monitor and evaluate drug efficacy and safety in the treatment of renal anemia. Objective To compare the efficacy and safety between roxadustat and erythropoiesis stimulating agents (ESAs) in treating renal anemia in patients with dialysis-dependent chronic kidney disease. Methods We searched PubMed, FMRS, Wanfang Data and ClinicalTrials.gov from inception to January 19, 2022 for randomized controlled trials (RCTs) about maintenance hemodialysis patients with dialysis duraion≥3 months treated with oral roxadustat (experimental group), versus injection of ESAs (control group). Two researchers independently conducted literature screening, data extraction and quality evaluation. Meta-analysis was performed using Review Manager 5.3. Results A total of 5 studies with 6 RCTs were included, involving 901 patients (549 in the experimental group and 352 in the control group). Meta-analysis showed that roxadustat was superior to ESAs in improving the levels of serum iron〔MD=2.49, 95%CI (0.82, 4.16), P=0.004〕, transferrin〔MD=0.31, 95%CI (0.17, 0.44), P

Abstract Background Post-stroke depression (PSD) can be conceptualized as a complex network where PSD symptoms (PSDS) interact with each other. The neural mechanism of PSD and interactions among PSDS remain to be elucidated. This study aimed to investigate the neuroanatomical substrates of, as well as the interactions between, individual PSDS to better understand the pathogenesis of early-onset PSD. Methods A total of 861 first-ever stroke patients admitted within 7 days poststroke were consecutively recruited from three independent hospitals in China. Sociodemographic, clinical and neuroimaging data were collected upon admission. PSDS assessment with Hamilton Depression Rating Scale was performed at 2 weeks after stroke. Thirteen PSDS were included to develop a psychopathological network in which central symptoms (i.e. symptoms most strongly correlated with other PSDS) were identified. Voxel-based lesion-symptom mapping (VLSM) was performed to uncover the lesion locations associated with overall PSDS severity and severities of individual PSDS, in order to test the hypothesis that strategic lesion locations for central symptoms could significantly contribute to higher overall PSDS severity. Results Depressed mood, Psychiatric anxiety and Loss of interest in work and activities were identified as central PSDS at the early stage of stroke in our relatively stable PSDS network. Lesions in bilateral (especially the right) basal ganglia and capsular regions were found significantly associated with higher overall PSDS severity. Most of the above regions were also correlated with higher severities of 3 central PSDS. The other 10 PSDS could not be mapped to any certain brain region. Conclusions There are stable interactions among early-onset PSDS with Depressed mood, Psychiatric anxiety and Loss of interest as central symptoms. The strategic lesion locations for central symptoms may indirectly induce other PSDS via the symptom network, resulting in higher overall PSDS severity. Trial registration URL: http://www.chictr.org.cn/enIndex.aspx ; Unique identifier: ChiCTR-ROC-17013993.

Abstract Background Post-stroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. The occurrence, development and prognosis of PSD have long been different between males and females. The main purpose of this study was to explore the influencing factors of PSD at 3 months in males and females, and construct random forest (RF) models to rank the influencing factors. Methods This is a prospective multicenter cohort study (Registration number: ChiCTR-ROC-17013993). Stroke patients hospitalized in the department of Neurology of three hospitals in Wuhan were enrolled from May 2018 to August 2019. Scale assessments were performed 24 hours after admission and 3 months after stroke onset. Binary logistic regression analysis was used for univariate and multivariate (stepwise backward method) analysis, when p was less than 0.05, the difference between groups was considered statistically significant. Lastly, the RF models were constructed according to the results of multivariate regression analysis. Results This study found that several baseline variables were associated with PSD at 3 months in males and females. RF model ranked them as stroke severity (OR [odds ratio] =1.17, p

The BERT pre-trained language model removes the tones of the syllables when segmenting Vietnamese words,which leads to the loss of some semantic information during the training process of grammatical error detection model.To address this problem,an approach combining part of speech and tonal features is proposed to complete the semantic information of the input syllables.Grammatical error detection task confronts the problem of insufficient training data due to the scarcity of labeled Vietnamese data.To address this problem,a data augmentation algorithm is designed to generate a large number of error texts from the correct corpus.Experimental results on Vietnamese Wikipedia and news corpus show that the proposed method achieves the highest F0.5 and F1 score on the test set,which proves it improves the detection performance.Both the proposed method and the baseline model method have a gradual improvement with the increasing scales of the generated data,which proves that the proposed data augmentation algorithm is effective.

Abstract MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules encoded by endogenous genes, which play a vital role in cell generation, metabolism, apoptosis and stem cell differentiation. C3H10T1/2, a mesenchymal cell extracted from mouse embryos, is capable of osteogenic differentiation, adipogenic differentiation and chondrogenic differentiation. Extensive studies have shown that not only miRNAs can directly trigger targeted genes to regulate the tri-lineage differentiation of C3H10T1/2, but it also can indirectly regulate the differentiation by triggering different signaling pathways or various downstream molecules. This paper aims to clarify the regulatory roles of different miRNAs on C3H10T1/2 differentiation, and discussing their balance effect among osteogenic differentiation, adipogenic differentiation and chondrogenic differentiation of C3H10T1/2. We also review the biogenesis of miRNAs, Wnt signaling pathways, MAPK signaling pathways and BMP signaling pathways and provide some specific examples of how these signaling pathways act on C3H10T1/2 tri-lineage differentiation. On this basis, we hope that a deeper understanding of the differentiation and regulation mechanism of miRNAs in C3H10T1/2 can provide a promising therapeutic method for the clinical treatment of bone defects, osteoporosis, osteoarthritis and other diseases.

Abstract Poststroke depression (PSD) is a common complication of stroke. Brain network disruptions caused by stroke are potential biological determinants of PSD but their conclusive roles are unavailable. Our study aimed to identify the strategic structural disconnection (SDC) pattern for PSD at three months poststroke and assess the predictive value of SDC information. Our prospective cohort of 697 first-ever acute ischemic stroke patients were recruited from three hospitals in central China. Sociodemographic, clinical, psychological and neuroimaging data were collected at baseline and depression status was assessed at three months poststroke. Voxel-based disconnection-symptom mapping found that SDCs involving bilateral temporal white matter and posterior corpus callosum, as well as white matter next to bilateral prefrontal cortex and posterior parietal cortex, were associated with PSD. This PSD-specific SDC pattern was used to derive SDC scores for all participants. SDC score was an independent predictor of PSD after adjusting for all imaging and clinical-sociodemographic-psychological covariates (odds ratio, 1.25; 95% confidence interval, 1.07, 1.48; P = 0.006). Split-half replication showed the stability and generalizability of above results. When added to the clinical-sociodemographic-psychological prediction model, SDC score significantly improved the model performance and ranked the highest in terms of predictor importance. In conclusion, a strategic SDC pattern involving multiple lobes bilaterally is identified for PSD at 3 months poststroke. The SDC score is an independent predictor of PSD and may improve the predictive performance of the clinical-sociodemographic-psychological prediction model, providing new evidence for the brain-behavior mechanism and biopsychosocial theory of PSD.

Abstract Background Tauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor functions and has been observed in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The aetiology of tauopathy remains mysterious; however, recent studies suggest that the autophagic-endolysosomal function plays an essential role in the degradation and transmission of pathological tau. We previously demonstrated that tetrandrine could ameliorate memory functions and clear amyloid plaques in transgenic AD mice by restoring autophagic-endolysosomal function. However, the efficacy of tetrandrine and the associated therapeutic mechanism in tauopathies have not been evaluated and elucidated. Methods Novel object recognition, fear conditioning and electrophysiology were used to evaluate the effects of tetrandrine on memory functions in transgenic tau mice. Western blotting and immunofluorescence staining were employed to determine the effect of tetrandrine on autophagy and tau clearance in vivo. Calcium (Ca2+) imaging and flow cytometry were used to delineate the role of pathological tau and tetrandrine in lysosomal Ca2+ and pH homeostasis. Biochemical BiFC fluorescence, Western blotting and immunofluorescence staining were used to evaluate degradation of hyperphosphorylated tau in vitro, whereas coculture of brain slices with isolated microglia was used to evaluate tau clearance ex vivo. Results We observed that tetrandrine treatment mitigated tau tangle development and corrected memory impairment in Thy1-hTau.P301S transgenic mice. Mechanistically, we showed that mutant tau expression disrupts lysosome pH by increasing two-pore channel 2 (TPC2)-mediated Ca2+ release, thereby contributing to lysosome alkalinization. Tetrandrine inhibits TPC2, thereby restoring the lysosomal pH, promotes tau degradation via autophagy, and ameliorates tau aggregation. Furthermore, in an ex vivo assay, we demonstrated that tetrandrine treatment promotes pathological tau clearance by microglia. Conclusions Together, these findings suggest that pathological tau disturbs endolysosomal homeostasis to impair tau clearance. This impairment results in a vicious cycle that accelerates disease pathogenesis. The success of tetrandrine in reducing tau aggregation suggests first, that tetrandrine could be an effective drug for tauopathies and second, that rescuing lysosomal Ca2+ homeostasis, thereby restoring ALP function, could be an effective general strategy for the development of novel therapies for tauopathies.

Abstract Tough hydrogel has attracted considerable interest in various fields, however, due to poor biocompatibility, nondegradation, and pronounced compositional differences from natural tissues, it is difficult to be used for tissue regeneration. Here, a gelatin‐based tough hydrogel (GBTH) is proposed to fill this gap. Inspired by human exercise to improve muscle strength, the synergistic effect is utilized to generate highly functional crystalline domains for resisting crack propagation. The GBTH exhibits excellent tensile strength of 6.67 MPa (145‐fold that after untreated gelation). Furthermore, it is directly sutured to a ruptured tendon of adult rabbits due to its pronounced toughness and biocompatibility, self‐degradability in vivo, and similarity to natural tissue components. Ruptured tendons can compensate for mechanotransduction by GBTH and stimulate tendon differentiation to quickly return to the initial state, that is, within eight weeks. This strategy provides a new avenue for preparation of highly biocompatible tough hydrogel for tissue regeneration.

Molded pulp products can improve the utilization of recycled paper by achieving close to zero waste emission and a 100% recycling rate, while satisfying the national goals for recycled packaging materials of various countries. Molded pulp products are often designed using finite-element simulations to optimize their performance, which requires the input of accurate material properties. However, studies on the constitutive model, an essential factor related to material properties, are still rare. This study investigated the mechanical behavior of the molded pulp material to simplify the parameters and improve the accuracy of the constitutive model. The fiber distribution and connection within the molded pulp material were investigated; treating the pores of the molded pulp as a virtual material enhances the meso-mechanical model and gives a transversely isotropic constitutive model. The elastic modulus in the thickness direction was calculated as 1.5997 MPa, and the experimentally measured value is 1.5368 MPa. The error of proposed model is 4.1%, but significantly smaller than treating molded pulp as an isotropic material, the error of which is ~80 times larger of experimental result.

The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer cells may affect tumor cells’ behavior and resistance to neoadjuvant and adjuvant therapy. Our study aimed to ascertain the relationship between the differential expression of p21 in rectal cancer and patient survival outcomes. Using tissue microarrays, 266 rectal cancer specimens were immunohistochemically stained for p21. The expression patterns were scored separately in cancer cells retrieved from the center and the periphery of the tumor; compared with clinicopathological data, tumor regression grade (TRG), disease-free, and overall survival. Negative p21 expression in tumor periphery cells was significantly associated with longer overall survival upon the univariate (p = 0.001) and multivariable analysis (p = 0.003, HR = 2.068). Negative p21 expression in tumor periphery cells was also associated with longer disease-free survival in the multivariable analysis (p = 0.040, HR = 1.769). Longer overall survival times also correlated with lower tumor grades (p= 0.011), the absence of vascular and perineural invasion (p = 0.001; p < 0.005), the absence of metastases (p < 0.005), and adjuvant treatment (p = 0.009). p21 expression is a potential predictive and prognostic biomarker for clinical outcomes in rectal cancer patients. Negative p21 expression in tumor periphery cells demonstrated significant association with longer overall survival and disease-free survival. Larger prospective studies are warranted to investigate the ability of p21 to identify rectal cancer patients who will benefit from neoadjuvant and adjuvant therapy.

Abstract While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, combined with endocrine therapy (ET), are becoming the standard-of-care for hormone receptor–positive/human epidermal growth factor receptor 2‒negative metastatic breast cancer, further mechanistic insights are needed to maximize benefit from the treatment regimen. Herein, we conducted a systematic comparative analysis of gene expression/progression-free survival relationship from two phase 3 trials (PALOMA-2 [first-line] and PALOMA-3 [≥second-line]). In the ET-only arm, there was no inter-therapy line correlation. However, adding palbociclib resulted in concordant biomarkers independent of initial ET responsiveness, with shared sensitivity genes enriched in estrogen response and resistance genes over-represented by mTORC1 signaling and G2/M checkpoint. Biomarker patterns from the combination arm resembled patterns observed in ET in advanced treatment-naive patients, especially patients likely to be endocrine-responsive. Our findings suggest palbociclib may recondition endocrine-resistant tumors to ET, and may guide optimal therapeutic sequencing by partnering CDK4/6 inhibitors with different ETs. Pfizer (NCT01740427; NCT01942135).

The inverse design method of aerodynamic configuration is hard to give a reasonable pressure distribution, and strongly rely on experience of designers. The method has been difficult to adapt to the needs of modern aircraft design. Aiming at the shortcoming of the method, an efficient and robust aerodynamic configuration inverse design method is developed, employing knowledge of machine learning methods and optimization methods. The present method establishes the mapping between the high dimensional data obtained from aerodynamic shape and pressure distribution and the variables in the latent space. Then, the global optimization is carried out in the latent space by using the genetic algorithm. The optimum pressure distribution and the corresponding shape can be obtained. Through the the GTM model with high precision, there is not necessary for the flow solver in the whole iterative process, thus the design efficiency can be enhanced. Besides, by taking the advantage of optimization method, the target pressure distribution can be given in a very flexible way, and does not need to be physically meaningful. This feature can reduce reliance on the design experience. Airfoils in low speed and transonic flow and a three-dimensional laminar nacelle design cases are carried out. It is shown that the method robustly and efficiently converges to the target pressure, and has good engineering application potential.

Abstract The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.

Chiral emitters with high photoluminescence quantum yield are desirable for use in circularly polarized LEDs. The authors demonstrate the transfer of chirality from nanoscale copper iodide clusters to microscale chiral luminescent polycrystals by non-classical crystallization.

Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs for survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of murine pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors. Here, we develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling us to study PDAC metabolism ex vivo under physiological nutrient conditions. We show that PDAC cells cultured in TIFM adopt a cellular state closer to that of PDAC cells present in tumors compared to standard culture models. Further, using the TIFM model, we found arginine biosynthesis is active in PDAC and allows PDAC cells to maintain levels of this amino acid despite microenvironmental arginine depletion. We also show that myeloid derived arginase activity is largely responsible for the low levels of arginine in PDAC tumors. Altogether, these data indicate that nutrient availability in tumors is an important determinant of cancer cell metabolism and behavior, and cell culture models that incorporate physiological nutrient availability have improved fidelity to in vivo systems and enable the discovery of novel cancer metabolic phenotypes.

Alzheimer's disease (AD), characterized by the accumulation of protein aggregates including phosphorylated Tau aggregates, is the most common neurodegenerative disorder with limited therapeutic agents. Autophagy plays a critical role in the degradation of phosphorylated Tau aggregates, and transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Thus, small-molecule autophagy enhancers targeting TFEB hold promise for AD therapy. Here, we found that celastrol, an active ingredient isolated from the root extracts of Tripterygium wilfordii (Lei Gong Teng in Chinese) enhanced TFEB-mediated autophagy and lysosomal biogenesis in vitro and in mouse brains. Importantly, celastrol reduced phosphorylated Tau aggregates and attenuated memory dysfunction and cognitive deficits in P301S Tau and 3xTg mice, two commonly used AD animal models. Mechanistical studies suggest that TFEB-mediated autophagy-lysosomal pathway is responsible for phosphorylated Tau degradation in response to celastrol. Overall, our findings indicate that Celastrol is a novel TFEB activator that promotes the degradation of phosphorylated Tau aggregates and improves memory in AD animal models. Therefore, Celastrol shows potential as a novel agent for the treatment and/or prevention of AD and other tauopathies.

Abstract Background Post-stroke depression (PSD) is one of the most common neuropsychiatric complications after stroke. Studies on the underlying mechanisms and biological markers of sex differences in PSD are of great significance, but there are still few such studies. Therefore, the main objective of this study was to investigate the association of biomarkers with PSD at 3 months after minor stroke in men and women. Methods This was a prospective multicenter cohort study that enrolled 530 patients with minor stroke (males, 415; females, 115). Demographic information and blood samples of patients were collected within 24 h of admission, and followed up at 3 months after stroke onset. PSD was defined as a depressive disorder due to another medical condition with depressive features, major depressive-like episode, or mixed-mood features according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V). Univariate analysis was performed using the chi-square test, Mann–Whitney U test, or t-test. Partial least-squares discriminant analysis (PLS-DA) was used to distinguish between patients with and without PSD. Factors with variable importance for projection (VIP) > 1.0 were classified as the most important factors in the model segregation. Results The PLS-DA model mainly included component 1 and component 2 for males and females. For males, the model could explain 13% and 16.9% of the variables, respectively, and 29.9% of the variables in total; the most meaningful predictors were exercise habit and fibrinogen level. For females, the model could explain 15.7% and 10.5% of the variables, respectively, and 26.2% of the variables in total; the most meaningful predictors in the model were brain-derived neurotrophic factor (BDNF), magnesium and free T3. Fibrinogen was positively correlated with the Hamilton Depression Scale-17 items (HAMD-17) score. BDNF, magnesium, and free T3 levels were negatively correlated with the HAMD-17 score. Conclusions This was a prospective cohort study. The most important markers found to be affecting PSD at 3 months were fibrinogen in males, and free T3, magnesium, and BDNF in females. Trial registration ChiCTR-ROC-17013993 .

Abstract Background Predicting hospital mortality risk is essential for the care of heart failure patients, especially for those in intensive care units. Methods Using a novel machine learning algorithm, we constructed a risk stratification tool that correlated patients’ clinical features and in-hospital mortality. We used the extreme gradient boosting algorithm to generate a model predicting the mortality risk of heart failure patients in the intensive care unit in the derivation dataset of 5676 patients from the Medical Information Mart for Intensive Care III database. The logistic regression model and a common risk score for mortality were used for comparison. The eICU Collaborative Research Database dataset was used for external validation. Results The performance of the machine learning model was superior to that of conventional risk predictive methods, with the area under curve 0.831 (95% CI 0.820–0.843) and acceptable calibration. In external validation, the model had an area under the curve of 0.809 (95% CI 0.805–0.814). Risk stratification through the model was specific when the hospital mortality was very low, low, moderate, high, and very high (2.0%, 10.2%, 11.5%, 21.2% and 56.2%, respectively). The decision curve analysis verified that the machine learning model is the best clinically valuable in predicting mortality risk. Conclusion Using readily available clinical data in the intensive care unit, we built a machine learning-based mortality risk tool with prediction accuracy superior to that of linear regression model and common risk scores. The risk tool may support clinicians in assessing individual patients and making individualized treatment.