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Abstract Chimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCT04835519) with safety and efficacy as primary and secondary endpoints, respectively. Of the four patients treated, one has grade 4 (dose-limiting toxicity) and three have grade 1–2 cytokine release syndrome. Two patients have no detectable bone marrow blasts and one patient has blast reduction after treatment. Thus, overexpressing C-JUN endows CAR-T efficacy in AML.

Abstract Organelles do not act as autonomous discrete units but rather as interconnected hubs that engage in extensive communication by forming close contacts called “membrane contact sites (MCSs)”. And many proteins have been identified as residing in MCS and playing important roles in maintaining and fulfilling specific functions within these microdomains. However, a comprehensive compilation of these MCS proteins is still lacking. Therefore, we developed MCSdb, a manually curated resource of MCS proteins and complexes from publications. MCSdb documents 7010 MCS protein entries and 263 complexes, involving 24 organelles and 44 MCSs across 11 species. Additionally, MCSdb orchestrates all data into different categories with multitudinous information for presenting MCS proteins. In summary, MCSdb provides a valuable resource for accelerating MCS functional interpretation and interorganelle communication deciphering.

Dry eye disease (DED) represents a prevalent ocular surface disease. The development of effective nutritional management strategies for DED is crucial due to its association with various factors such as inflammation, oxidative stress, deficiencies in polyunsaturated fatty acids (PUFAs), imbalanced PUFA ratios, and vitamin insufficiencies. Extensive research has explored the impact of oral nutritional supplements, varying in composition and dosage, on the symptoms of DED. The main components of these supplements include fish oils (Omega-3 fatty acids), vitamins, trace elements, and phytochemical extracts. Beyond these well-known nutrients, it is necessary to explore whether novel nutrients might contribute to more effective DED management. This review provides a comprehensive update on the therapeutic potential of nutrients and presents new perspectives for combination supplements in DED treatment.

Abstract Background Primary hepatocellular carcinoma (HCC) is a malignancy with high morbidity and mortality. KH domain-containing, RNA-binding signal transduction-associated protein 3 (KHDRBS3) is an RNA-binding protein that is aberrantly expressed in multiple tumors; however, its expression and biological function in HCC have not been reported. Methods KHDRBS3 knockdown and overexpression were performed using the lentiviral vector system to investigate the effects of KHDRBS3 on cell proliferation, apoptosis, chemoresistance, and glycolysis. Murine xenograft tumor models were constructed to study the role of KHDRBS3 on tumor growth in vivo. Furthermore, RNA-Pull Down and RNA immunoprecipitation were utilized to explore the interaction between KHDRBS3 and 14-3-3ζ, a phosphopeptide-binding molecule encoded by YWHAZ. Results KHDRBS3 was highly expressed in human HCC tissues and predicted the poor prognosis of patients with HCC. Knockdown of KHDRBS3 exhibited a carcinostatic effect in HCC and impeded proliferation and tumor growth, reduced glycolysis, enhanced cell sensitivity to doxorubicin, and induced apoptosis. On the contrary, forced expression of KHDRBS3 expedited the malignant biological behaviors of HCC cells. The expression of KHDRBS3 was positively correlated with the expression of 14-3-3ζ. RNA immunoprecipitation and RNA pull-down assays demonstrated that KHDRBS3 bound to YWHAZ. We further confirmed that 14-3-3ζ silencing significantly reversed the promotion of proliferation and glycolysis and the inhibition of apoptosis caused by KHDRBS3 overexpression. Conclusions Our findings suggest that KHDRBS3 promotes glycolysis and malignant progression of HCC through upregulating 14-3-3ζ expression, providing a possible target for HCC therapy.

This work is aimed to investigate the relationship between the texture and tensile properties of the AZ31 Mg alloy by the machine learning method. The texture characteristics parameters, namely the maximum pole intensity (Imax), texture dispersion (D), and texture directivities along the longitudinal direction (PLD) and transverse direction (PTD), are extracted from the (0002) pole figures of the AZ31 Mg alloy. An artificial neural networks (ANN) model to describe the relationship between the texture characteristic parameters and tensile properties is constructed and trained by the data collected from the literature. To validate the reliability and generalization performance of the ANN, 6 samples with different texture characteristics are prepared, and their textures and tensile properties are evaluated through electron backscattered diffraction (EBSD) measurement and uniaxial tensile test, respectively. The results indicate that the ANN model exhibits good prediction performance in yield strength and elongation of the AZ31 Mg alloy when it is applied to the new cases. The correlations between the texture characteristics and tensile properties are analyzed according to the ANN-predicted results. The maximum pole intensity and texture dispersion significantly influence the tensile properties of the AZ31 Mg alloy. With increasing the Imax or decreasing the D, the strength is increased but the elongation is reduced. As increasing the texture directivity along the LD, the tensile properties of the AZ31 Mg alloy show non-monotonic changes. This research presents a correlation model between the texture and mechanical properties of the Mg alloy, which contributes to the development of high-performance Mg alloys.

Abstract Background Donor-derived CD7-directed chimeric antigen receptor (CAR) T cells showed feasibility and early efficacy in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (r/r T-ALL), in a previous phase I trial report, at a median follow-up of 6.3 months. Here we report long-term safety and activity of the therapy after a 2-year follow-up. Methods Participants received CD7-directed CAR T cells derived from prior stem cell transplantation (SCT) donors or from HLA-matched new donors after lymphodepletion. The target dose was 1 × 106 (± 30%) CAR T cells per kg of patient weight. The primary endpoint was safety with efficacy secondary. This report focuses on the long-term follow-up and discusses them in the context of previously reported early outcomes. Results Twenty participants were enrolled and received infusion with CD7 CAR T cells. After a median follow-up time of 27.0 (range, 24.0–29.3) months, the overall response rate and complete response rate were 95% (19/20 patients) and 85% (17/20 patients), respectively, and 35% (7/20) of patients proceeded to SCT. Six patients experienced disease relapse with a median time-to-relapse of 6 (range, 4.0–10.9) months, and 4 of these 6 patients were found to have lost CD7 expression on tumor cells. Progression-free survival (PFS) and overall survival (OS) rates 24 months after treatment were respectively 36.8% (95% CI, 13.8–59.8%) and 42.3% (95% CI, 18.8–65.8%), with median PFS and OS of respectively 11.0 (95% CI, 6.7–12.5) months and 18.3 (95% CI, 12.5–20.8) months. Previously reported short-term adverse events ( 30 days after treatment included five infections and one grade 4 intestinal GVHD. Despite good CD7 CAR T-cell persistence, non-CAR T and natural killer cells were predominantly CD7-negative and eventually returned to normal levels in about half of the participants. Conclusions In this 2-year follow-up analysis, donor-derived CD7 CAR T-cell treatment demonstrated durable efficacy in a subset of patients with r/r T-ALL. Disease relapse was the main cause of treatment failure, and severe infection was a noteworthy late-onset adverse event. Trial registration ChiCTR2000034762.

X-ray luminescence computed tomography (XLCT) is a hybrid molecular imaging modality having the high spatial resolution of x-ray imaging and high measurement sensitivity of optical imaging. Narrow x-ray beam based XLCT imaging has shown promise for high spatial resolution imaging of luminescent targets in deep tissues, but the slow acquisition speed limits its applications. In this work, we have introduced a superfast XLCT scan scheme based on the photon counter detector and a fly-scanning method. The new scan scheme is compared with three other scan methods. We have also designed and built a single-pixel x-ray detector to detect object boundaries automatically. With the detector, we can perform the parallel beam CT imaging with the XLCT imaging simultaneously. We have built the prototype XLCT imaging system to verify the proposed scan scheme. A phantom embedded with a set of four side-by-side cylindrical targets was scanned. With the proposed superfast scan scheme, we have achieved 43 seconds per transverse scan, which is 28.6 times faster than before with slightly better XLCT image quality. The superfast scan allows us to perform 3D pencil beam XLCT imaging in the future.

Abstract Objective Postoperative pancreatic fistula (POPF) following distal pancreatectomy (DP) is a serious complication. In the present study, we aimed to identify the risk factors associated with clinically relevant postoperative pancreatic fistula (CR-POPF) and establish a nomogram model for predicting CR-POPF after DP. Methods In total, 115 patients who underwent DP at the General Hospital of Northern Theater Command between January 2005 and December 2020 were retrospectively studied. Univariate and multivariable logistic regression analyses were used to identify the independent risk factors associated with CR-POPF. Then, a nomogram was formulated based on the results of multivariable logistic regression analysis. The predictive performance was evaluated with receiver operating characteristic (ROC) curves. Decision curve and clinical impact curve analyses were used to validate the clinical application value of the model. Results The incidence of CR-POPF was 33.0% (38/115) in the present study. Multivariate logistic regression analysis identified the following variables as independent risk factors for POPF: body mass index (BMI) (OR 4.658, P = 0.004), preoperative albumin level (OR 7.934, P = 0.001), pancreatic thickness (OR 1.256, P = 0.003) and pancreatic texture (OR 3.143, P = 0.021). We created a nomogram by incorporating the above mentioned risk factors. The nomogram model showed better predictive value, with a concordance index of 0.842, sensitivity of 0.710, and specificity of 0.870 when compared to each risk factor. Decision curve and clinical impact curve analyses also indicated that the nomogram conferred a high clinical net benefit. Conclusion Our nomogram could accurately and objectively predict the risk of postoperative CR-POPF in individuals who underwent DP, which could help clinicians with early identification of patients who might develop CR-POPF and early development of a suitable fistula mitigation strategy and postoperative management.

Abstract Background Although students were removed from patient-facing settings at the beginning of the COVID-19 pandemic due to concerns of burdening teaching physicians and depleting personal protective equipment, some leaders suggest students can be effectively utilized when personnel resources may be scarce. There have been narrative discussions surrounding medical student involvement, but no studies exploring the attitudes of these students. The authors aim to quantify the degree to which factors influenced a medical student’s decision to or to not volunteer during the pandemic and to characterize medical students’ attitudes towards medical professionals’ duty to serve in a pandemic. Methods The authors developed and tested a secure web-based survey before distribution to students at 23 different US allopathic medical schools that did not graduate medical students early to aid in pandemic efforts between April and June 2020. Of the 599 students who completed the survey, 65.5% self-identified as female and were on average 25.94 years old (SD = 2.5). Multiple comparisons were made based on volunteer status. Ordinal scale questions were compared with the Mann Whitney U test, and the Chi-Squared test was used for categorical variables using R version 3.62. Results 67.6% of students volunteered in pandemic relief activities and a majority of those students volunteered in non-patient-facing roles. Community service, new skills, and time commitment were top 3 influencing factors for students who volunteered, while risk to other, time commitment, and risk to self were top 3 influencing factors for students who chose not to volunteer. Compared to other specialties, students interested in primary care specialties agreed to a greater degree that physicians have a duty to serve in pandemic relief efforts. Conclusions Medical students who volunteered cited self-serving factors and altruistic values as significant motivators. Students who did not volunteer were significantly more concerned with risks of COVID-19 exposure. However, medical students in general agreed that students should be allowed to volunteer in COVID-19 related relief efforts. As large areas of the United States continue to experience increases in COVID-19 cases, institutions should involve medical students in balancing the level of acceptable risk with the educational benefits.

The color of urban streets plays a crucial role in shaping a city’s image, enhancing street appeal, and optimizing the experience of citizens. Nevertheless, the relationship between street color environment and residents’ perceptions has rarely been deeply discussed, and most of the existing studies adopt qualitative methods. To accurately and effectively assess the connection between street color environment and residents’ emotional perceptions, this paper introduces a quantitative research framework based on multi-source data called “Color Emotion Perception with K-Means, Adversarial Strategy, SegNet, and SVM (CEP-KASS)”. By combining K-Means unsupervised machine learning and SegNet computer vision techniques, it captures and analyzes visual elements and color data from Baidu Street View Images (BSVI). It then employs a human–machine adversarial scoring model to quantify residents’ perceptions of BSVI and uses the support vector machine regression model to predict the final perception scores. Based on these data, a Pearson correlation analysis and visual analysis were conducted on the elements and color in the urban environment. Subsequently, the streets were classified based on perception frequency and perception scores by integrating multi-source data, and areas within the third ring of Xuzhou City were selected for validating the research framework. The results demonstrate that utilizing street-view images and the CEP-KASS framework can quantitatively analyze urban color perception and establish a connection with residents’ emotions. In terms of color perception, red, orange, and blue all have a strong positive correlation with the interesting score, whereas black is positively correlated with a sense of safety. Regarding color attributes, low-saturation bright colors result in higher fun perception scores in urban spaces; too low saturation and brightness can affect their attractiveness to residents; brightness has an inverse relationship with the perception of safety, and adjusting brightness inversely can improve the perceived safety experience in certain urban external spaces. The street classification criteria based on perception frequency and perception scores proposed herein can provide references for planners to prioritize color transformation decisions, with a priority on emulating HSHF streets and transforming LSHF streets. When formulating color planning, suggestions for color adjustment can be given based on the correlation study of color with visual elements and perception scores, optimizing urban residents’ spatial perception and their emotional experiences. These findings provide robust theoretical support for further enhancing the visual quality of streets and refining urban color planning.

The oncoprotein c-Myc is often overexpressed in triple negative breast cancer and has a role in tumor progression and resistance to therapy. Here the authors show that elevated MYC expression is correlated with low immune infiltration, diminished MHC-I pathway expression and that CpG/aOX40 treatment could overcome resistance to PD-L1 blockade in MYC-high breast tumors.

Objective. Our study aimed to develop and validate a nomogram to predict severe hypocalcemia (SH) before total parathyroidectomy (TPTX) without auto-transplantation in patients with secondary hyperparathyroidism. Methods. A total of 299 consecutive patients who underwent TPTX without transplantation for secondary hyperparathyroidism were selected from the General Hospital of Northern Theater Command between January 2013 and December 2021. Of these, patients who underwent surgery between January 2013 and December 2020 formed the training cohort (n = 208) to develop a nomogram, and those who underwent surgery thereafter formed the validation cohort (n = 91) to validate the performance of this nomogram. Univariate and multivariate logistic regression analyses were used to identify the risk factors associated with SH, and then, a nomogram was constructed. Results. The incidence of postoperative SH was 27.9% and 35.2% in the training and validation cohorts, respectively. The preoperative factors associated with SH were younger age, lower serum calcium (Ca) level, higher intact parathyroid hormone (iPTH) level, and higher serum alkaline phosphatase (ALP) level. Incorporating these 4 factors, the nomogram achieved good concordance indexes of 0.866 (95%CI, 0.816–0.916) and 0.867 (95% CI, 0.793–0.941) in predicting SH in the training and validation cohorts, respectively, and had well-fitted calibration curves. The positive predictive values of the nomogram were 64.7% (54.1%–78.4%) and 75.0% (58.6%–88.5%), and negative predictive values of the nomogram were 90.0% (82.9%–93.6%) and 86.4% (73.5%–94.0%) for the training and validation cohorts, respectively. Conclusions. We developed and validated a nomogram for the prediction of SH in patients who underwent TPTX without auto-transplantation for secondary hyperparathyroidism. Our nomogram may facilitate the identification of high-risk SH in patients after TPTX and optimization of preoperative decision-making.

Abstract Objectives To evaluate gender differences in optical biometry measurements and lens power calculations. Methods Eight thousand four hundred thirty-one eyes of five thousand five hundred nineteen patients who underwent cataract surgery at University of Michigan’s Kellogg Eye Center were included in this retrospective study. Data including age, gender, optical biometry, postoperative refraction, implanted intraocular lens (IOL) power, and IOL formula refraction predictions were gathered and/or calculated utilizing the Sight Outcomes Research Collaborative (SOURCE) database and analyzed. Results There was a statistical difference between every optical biometry measure between genders. Despite lens constant optimization, mean signed prediction errors (SPEs) of modern IOL formulas differed significantly between genders, with predictions skewed more hyperopic for males and myopic for females for all 5 of the modern IOL formulas tested. Optimization of lens constants by gender significantly decreased prediction error for 2 of the 5 modern IOL formulas tested. Conclusions Gender was found to be an independent predictor of refraction prediction error for all 5 formulas studied. Optimization of lens constants by gender can decrease refraction prediction error for certain modern IOL formulas.

On the basis of hazard analysis critical control point(HACCP) principle, SARS-CoV-2 is analyzed and studied as a non-traditional food safety risk, and the activities of employees in food production enterprises are included in the whole process of cold chain food production. The key control points of employees under the epidemic prevention and control situation were determined and controlled, the HACCP system reshaped to help cold chain food manufacturers to establish a food safety management system based on HACCP principles, including COVID-19 epidemic prevention and control.

Flower color is one of the most important qualitative characteristics of ornamental horticultural plants, which mainly depends on anthocyanins and carotenoids. Modification of flower color in ornamental plants involves many aspects, including complicated structural gens, transcription factors and metabolic pathways. Anthocyanins are important secondary metabolites in the flavonoid biosynthesis pathway, which mainly derive from six anthocyanidins. Anthocyanin has antioxidant activity, protects plants and performs some other functions. Studying the genes and regulatory factors in the biosynthesis pathway will contribute to cultivating novel flower color plants and to improving plants’ resistance. To date, a series of structural and regulatory genes that are involved in anthocyanin synthesis and color formation have been reported, whose functions have also been revealed. Some color-related transgenic flowers have been successfully obtained. Carotenoids are the source of the yellow pigments in the petals of many flowers. The carotenoid biosynthesis pathway as well as its major enzymes and genes are conducive to regulate its biosynthesis via genetic engineering methods and thereby changing the color of flowers. In this paper, we review the plant flower color in terms of mechanisms of plant pigment formation, classification of flower color, biosynthesis pathway, and genes related to anthocyanin formation. Subsequently, we analyze the regulating mechanism of the expression of these genes, including transcription regulation and post-transcription regulation. The methods and achievements in flower color improvement in recent years are summarized. Finally, analyzing the molecular regulatory network in flower color formation provides a theoretical basis for the improvement and modification of flower color.

Flower color is the decisive factor that affects the commercial value of ornamental flowers. Therefore, it is important to study the regulation of flower color formation in lily to discover the positive and negative factors that regulate this important trait. In this study, MYB transcription factors (TFs) were characterized to understand the regulatory mechanism of anthocyanin biosynthesis in lily. Two R2R3-MYB TFs, LvMYB5, and LvMYB1, were found to regulate anthocyanin biosynthesis in lily flowers. LvMYB5, which has an activation motif, belongs to the SG6 MYB protein subgroup of Arabidopsis thaliana. Transient expression of LvMYB5 indicated that LvMYB5 can promote coloration in Nicotiana benthamiana leaves, and that expression of LvMYB5 increases the expression levels of NbCHS, NbDFR, and NbANS. VIGS experiments in lily petals showed that the accumulation of anthocyanins was reduced when LvMYB5 was silenced. Luciferase assays showed that LvMYB5 can promote anthocyanin synthesis by activating the ANS gene promoter. Therefore, LvMYB5 plays an important role in flower coloration in lily. In addition, the transient expression experiment provided preliminary evidence that LvMYB1 (an R2R3-MYB TF) inhibits anthocyanin synthesis in lily flowers. The discovery of activating and inhibitory factors related to anthocyanin biosynthesis in lily provides a theoretical basis for improving flower color through genetic engineering. The results of our study provide a new direction for the further study of the mechanisms of flower color formation in lilies.

Abstract We investigate invisible decays of the third neutrino mass eigenstate in future accelerator neutrino experiments using muon-decay beams such as MuOn-decay MEdium baseline NeuTrino beam experiment (MOMENT). MOMENT has outstanding potential to measure the deficit or excess in the spectra caused by neutrino decays, especially in ν μ and ν ¯ μ $$ {\overline{\nu}}_{\mu } $$ disappearance channels. Such an experiment will improve the constraints of the neutrino lifetime τ 3. Compared with exclusion limits in the current accelerator neutrino experiments T2K and NOvA under the stable ν assumption, we expect that MOMENT gives the bound of τ 3 /m 3 ≥ 10−11 s/eV at 3σ, which is better than their recent limits: τ 3 /m 3 ≥ 7 × 10−13 s/eV in NOvA and τ 3 /m 3 ≥ 1.41 × 10−12 s/eV in T2K. The non-decay scenario is expected to be excluded by MOMENT at a confidence level > 3σ, if the best fit results in T2K and NOvA are confirmed. We further find that reducing systematic uncertainties is more important than the running time. Finally, we find some impact of τ 3 /m 3 on the precision measurement of other oscillation parameters.

Abstract 14‐3‐3ζ, a phosphopeptide‐binding molecule, is reportedly overexpressed in the cancerous tissues of patients with hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) protein X (HBx) draws intensive attention in HBV‐related HCC because it not only regulates HBV replication, but also promotes carcinogenesis by interacting with various tumor or antitumor molecules. This study is performed to investigate whether and how 14‐3‐3ζ interacts with HBx. The coimmunoprecipitation (Co‐IP) results showed that 14‐3‐3ζ bond to HBx in HBV‐infected Hep3B HCC cells and CSQT‐2 portal vein tumor thrombosis (PVTT) cells. By performing Co‐IP assay in HBV‐free Huh7 cells expressing wild‐type HBx, mutant HBx‐S31A, or HBx‐S31D (serine31 was mutated into alanine31 or aspartic acid31), we found that the phosphorylated serine31 with its near amino acid residues constituted a RPLphosphoS31GP (R, arginine; P, proline; L, leucine; S, serine; G, glycine) motif in HBx for 14‐3‐3ζ docking. This 14‐3‐3ζ‐HBx interaction was partly impaired when Akt signaling transduction was blocked by LY294002. Furthermore, 14‐3‐3ζ silencing augmented HBx ubiquitination and decreased its expression in cancer cells and xenograft tumor. The migratory and invasive abilities of CSQT‐2 cells were inhibited upon 14‐3‐3ζ silencing, whereas partly restored by HBx overexpression. Additionally, 14‐3‐3ζ positively correlated with HBx to be overexpressed in the primary HCC tissues (r = 0.344) and metastatic PVTT (r = 0.348). In summary, findings of this study reveal a novel 14‐3‐3ζ‐HBx interaction in HCC cells and suggest 14‐3‐3ζ as a candidate target for treating HBV‐related HCC.

The maximum temperature difference of Tianshan Road can reach 77.4°C in a year. Under such complex mechanical environment, the mechanical properties of rock mass and structural planes will change significantly as the increase of freeze-thaw cycles (FTC). Consequently, the FTC has become a key factor in the instability and failure of rocky slopes along the Tianshan Road. In this paper, the progressive deformation of rocky slopes and sudden failure process after critical instability were studied through the FTC tests of rock mass and structural planes, discrete element method, and theoretical analysis. The results show that the structural planes and internal microcracks of the rock mass expand under the action of the FTC, causing a gradual decrease in the stability of the slope. The dynamic collapse of the rocky slope has a certain degree of randomness caused by the spatial distribution of structural planes and the interaction between the rock fragments. Due to the limitation of the slipping space and the tilt angle of the trailing edge of the slope, long-distance migration did not occur, and the in situ accumulation of the slope was obvious after failure. The analysis method in this paper can provide an important reference for guiding the catastrophe mechanism analysis and protection of engineering slopes in cold regions.

Background Aberrant proliferation of retinal pigment epithelial (RPE) cells under pathologic condition results in the occurrence of proliferative vitreoretinopathy (PVR). Icariin (ICA)-a flavonol glucoside-has been shown to inhibit proliferation of many cell types, but the effect on RPE cells is unknown. This study aimed to clarify the inhibitory effects of ICA on RPE cells against platelet-derived growth factor (PDGF)-BB-induced cell proliferation, and discuss the regulatory function of H19 in RPE cells. Methods MTS assay was conducted to determine the effects of ICA on cell proliferation. Flow cytometry analysis was performed to detect cell cycle progression. Quantitative real-time PCR and western blot assay were used to measure the expression patterns of genes in RPE cells. Results ICA significantly suppressed PDGF-BB-stimulated RPE cell proliferation in a concentration-dependent manner. Moreover, since administration of ICA induced cell cycle G0/G1 phase arrest, the anti-proliferative activity of ICA may be due to G0/G1 phase arrest in RPE cells. At molecular levels, cell cycle regulators cyclin D1, CDK4, CDK6, p21 and p53 were modulated in response to treatment with ICA. Most importantly, H19 was positively regulated by ICA and H19 depletion could reverse the inhibitory effects of ICA on cell cycle progression and proliferation in PDGF-BB-stimulated RPE cells. Further mechanical explorations showed that H19 knockdown resulted in alternative expressions levels of cyclin D1, CDK4, CDK6, p21 and p53 under ICA treatment. Conclusions Our findings revealed that ICA was an effective inhibitor of PDGF-BB-induced RPE cell proliferation through affecting the expression levels of cell cycle-associated factors, and highlighted the potential application of ICA in PVR therapy. H19 was described as a target regulatory gene of ICA whose disruption may contribute to excessive proliferation of RPE cells, suggesting that modulation of H19 expression may be a novel therapeutic approach to treat PVR.

PKZ is a novel and unique eIF2α protein kinase identified in fish. Although PKZ is most homologous to PKR, particularly in the C-terminal catalytic domain, it contains two N-terminal Z-DNA-binding domains (Zα1 and Zα2) instead of the dsRNA binding domains (dsRBDs) in PKR. As a novel member of eIF2α kinase family, the available data suggest that PKZ has some distinct mechanisms for recognition, binding, and B-Z DNA transition. Functionally, PKZ seems to be activated by the binding of Zα to Z-DNA and participates in innate immune responses. In this review, we summarize the recent progress on fish PKZ.

The spinyhead croaker (Collichthys lucidus) is a commercially important fish species, which is mainly distributed in the coastal regions of China. However, little is known about the molecular regulatory mechanism underlying reproduction in C. lucidus. A de novo transcriptome assembly in brain, liver, ovary and testis tissues of C. lucidus was performed. Illumina sequencing generated 60,322,004, 57,044,284, 60,867,978 and 57,087,688 clean reads from brain, liver, ovary and testis tissues of C. lucidus, respectively. Totally, 131,168 unigenes with an average length of 644 bp and an N50 value of 1033 bp were assembled. In addition, 1288 genes were differentially expressed between ovary and testis, including 442 up-regulated and 846 down-regulated in ovary. Functional analysis revealed that the differentially expressed genes between ovary and testis were mainly involved in the function of sexual reproduction, sex differentiation, development of primary male sexual characteristics, female gamete generation, and male sex differentiation. A number of genes which might be involved in the regulation of reproduction and sex determination were found, including HYAL and SYCP3 and BMP15. Furthermore, 35,476 simple sequence repeats (SSRs) were identified in this transcriptome dataset, which would contribute to further genetic and mechanism researches. De novo transcriptome sequencing analysis of four organs of C. lucidus provides rich resources for understanding the mechanism of reproductive development of C. lucidus and further investigation of the molecular regulation of sex determination and reproduction of C. lucidus.

Background/Aims: Gluconeogenesis, a reverse process of glycolysis, is suppressed in neoplastic livers. Cytoplasmic phosphoenolpyruvate carboxykinase (PEPCK-C/PCK1, encoded by PCK1) is a step limiting enzyme of gluconeogenesis. The induced expression of the factor is reported to initiate gluconeogenesis process and antagonize hepatocellular carcinoma (HCC). In the current study, the effect of the modulation of PCK1 expression on HCC was assessed. Methods: The levels of PCK1 in clinical HCC tissues and different HCC cell lines were investigated with real time quantitative PCR, immunochemistry, and western blotting. Thereafter, the expression of PCK1 gene was induced in two HCC cell lines and the effect of the overexpression on proliferation and migration potentials of HCC cells was detected with CCK-8 assay, flow cytometry, TUNEL staining, and transwell assay. The activities of glycolysis and gluconeogenesis pathways in PCK1-overexpressed HCC cell lines were detected with specific kits to underlie the mechanism by which PCK1 exerted its function. The results of the in vitro experiments were validated with HCC xenograft rat models. Results: The expression levels of PCK1 were suppressed in HCC samples and in cells derived from HCC tissues. According to the results of the in vitro assays, the overexpression of PCK1 decreased viability, induced apoptosis, and inhibited migration in both HCC cell lines. The effect was associated with the suppressed glycolysis and the induced gluconeogenesis pathways, represented by the enhanced production of glucose and the limited production of pyruvic acid, lactate, citrate, and malate. The results of the in vitro assays were confirmed in rat models in that the growth rate of solid HCC tumors was reduced in mice transplanted with PCK1-overexpressed HCC cells. Conclusion: Findings outlined in the current study demonstrated that activating gluconeogenesis process via PCK1 overexpression was a potential treating strategy against HCC.

Background/Aims: 14-3-3ζ is involved in the regulation of PI3K/Akt pathway which is closely associated with carcinogenesis. However, the clinical significance of combined detection of 14-3-3ζ and p-Akt in hepatocellular carcinoma (HCC) remains unclear. Methods: Two-hundred pairs of HCC and adjacent liver specimens were subjected to tissue microarray. The association of 14-3-3ζ and p-Akt levels with the postoperative survival and recurrence in HCC patients was analyzed with univariate and multivariate methods. Moreover, the effects of 14-3-3ζ overexpression on the growth of HCC and the expressions of p-Akt and HIF-1α were assessed in a xenograft mouse model. Results: Elevated levels of 14-3-3ζ and p-Akt were detected in HCC and a positive correlation between the levels of 14-3-3ζ and p-Akt was verified. HCC patients with satellite nodules, microvascular invasion, portal vein tumor thrombosis, poor tumor differentiation and an advanced tumor stage tended to have higher levels of 14-3-3ζ and p-Akt. In addition, the postoperative 3-, 5-, and 7-year overall survival rates in HCC patients with 14-3-3ζhigh and p-Akthigh were significantly lower compared with those with 14-3-3ζlow and p-Aktlow, and the cumulative recurrence rate in HCC patients with 14-3-3ζhigh and p-Akthigh was significantly higher than that in those with 14-3-3ζlow and p-Aktlow. The multivariate Cox proportional hazard analysis indicated that concomitant upregulation of 14-3-3ζ and p-Akt was an independent factor that predicted poor survival and high recurrence in HCC patients. Furthermore, animal experiment showed that overexpression of 14-3-3ζ accelerated the growth of HCC xenograft tumors and induced the expressions of p-Akt and HIF-1α in vivo. Conclusion: Co-upregulation of 14-3-3ζ and p-Akt predicts poor prognosis in patients with HCC, and 14-3-3ζ-induced activation of the Akt signaling pathway contributes to HCC progression.

The possible existence of light and heavy sterile neutrinos may give rise to direct and indirect unitarity violation of the 3×3 lepton mixing matrix respectively. In the current work we study the potential of future accelerator neutrino facilities in probing the unitarity violation effects. Taking DUNE, T2HK and a low-energy Neutrino Factory (LENF) as working examples of future accelerator neutrino facilities, we study the distinct effects of direct and indirect unitarity violation on the discovery reach of the leptonic CP violation and precision measurements of θ23 in the three neutrino framework. In addition, constraints on the additional mixing parameters of direct and indirect unitarity violation are also discussed. Finally, we stress that the combination of experiments with different oscillation channels, different neutrino beams and different detector techniques will be an effective solution to the parameter degeneracy problem and give the robust measurement of leptonic CP violation even if the direct and indirect unitarity violation are taken into account.

In this study, we investigate a low-grade oxidized lead ore containing noble metal silver, with complex mineralogy. The sulfurization behaviors of different types of lead-silver minerals at different pH values were analyzed using the chemical phase analysis method. The interactions between different types of lead-silver minerals and different types of collectors were investigated. An effective laboratory process was developed, and closed-circuit tests were carried out at industrial sites. We found that the order of difficulty for sulfidizing various lead minerals and silver minerals was (PbFe6(OH)12SO4)4 < PbCO3 < PbSO4 < Pb5(P/As/VO4)3Cl; Ag2AsS2 < AgCl < natural-Ag. Aerophine 3418A had the best selectivity and capture capacity of the silver minerals. In the laboratory, the total recovery of lead and silver was 65.16% and 87.81%, respectively. In industrial closed-circuit testing, flotation alone was used, which produced a total lead recovery yield of 67.71%, and a total silver recovery yield of 87.64%.

Background: Several studies have attempted to relate the bioactive alkaloid with atherosclerotic cardiovascular diseases prevention in animal models, providing inconsistent results. Moreover, the direct anti-atherosclerotic effects of alkaloid have hardly been studied in patients. Therefore, the aim of this systematic review was to assess the reported effects of alkaloids on aortic atherosclerosis in ApoE−/− mouse models.Methods: Pubmed and Embase were searched to identify studies which estimated the effect of isolated alkaloids on atherosclerosis in apolipoprotein E deficient mice. Study quality was assessed using SYRCLE's risk of bias tool. We conducted a meta-analysis across 14 studies using a random-effect model to determine the overall effect of the alkaloids, and performed subgroup analyses to compare the effects of the isoquinolone alkaloids and indole alkaloids.Results: The quality of the included studies was low in the majority of included studies. We clarified that alkaloid administration was significantly associated with reduced aortic atherosclerotic lesion area (SMD −3.19, 95% CI −3.88, −2.51). It is important to remark that the experimental characteristics of studies were quite diverse, and the methodological variability could also contribute to heterogeneity. Subgroup analyses suggested that the isoquinoline alkaloids (SMD −4.19, 95% CI −5.18, −3.20), and the indole alkaloids (SMD −2.73, 95% CI −3.56, −1.90) obviously decreased atherosclerotic burden.Conclusion: Isoquinoline alkaloids and indole alkaloids appear to have a direct anti-atherosclerotic effect in ApoE−/− mice. Besides the limitations of animal modal studies, this systematic review could provide an important reference for future preclinical animal trials of good quality and clinical development.

Point defect pinning centers are the key factors responsible for the flux pinning and critical current density in type II superconductors. The introduction of the point defects and increasing their density without any changes to the superconducting transition temperature Tc, irreversibility field Hirr, and upper critical field Hc2, would be ideal to gain insight into the intrinsic point-defect-induced pinning mechanism. In this work, we present our investigations on the critical current density Jc, Hc2, Hirr, the activation energy U0, and the flux pinning mechanism in Fe1-xCoxSe0.5Te0.5 (x = 0, 0.03 and 0.05) single crystals. Remarkably, we observe that the Jc and U0 are significantly enhanced by up to 12 times and 4 times for the 3at.% Co-doped sample, whereas, there is little change in Tc, Hirr, and Hc2. Furthermore, charge-carrier mean free path fluctuation, δl pinning, is responsible for the pinning mechanism in Fe1-xCoxSe0.5Te0.5.

OBJECTIVE:To evaluate the relationship between subclinical hypothyroidism (SCH) and the risk of miscarriage before 20 weeks of pregnancy. METHODS:Literature databases were searched, including the PubMed, Web of Science, Embase and Cochrane databases, from January 1, 1980, to December 31, 2015. The following search terms were used: subclinical hypothyroidism, hypothyroidism, thyroid dysfunction, thyroid hypofunction, subclinical thyroid disease, thyroid dysfunction, pregnancy loss, abortion and miscarriage. Studies comparing the prevalence of miscarriage in pregnant women with SCH with those who were euthyroid were selected. From the studies matched, the relative risk (RR) and corresponding 95% confidence interval (95% CI) were calculated to yield outcomes. All the statistical analyses were performed using Review Manager (Revman) Version 5.3 and Stata Version 12.0 software. The publication bias of the studies was assessed by forest plot and Begg's test, while the stability of the results was evaluated by sensitivity analysis. RESULTS:Nine articles satisfying the inclusion criteria were analysed. Compared to euthyroid pregnant women, patients with non-treated SCH had a higher prevalence of miscarriage (RR = 1.90, 95% CI1.59-2.27, P

First-principle calculations were used to investigate the surface structure and electronic properties of sulfide (pyrite, galena, and sphalerite) and oxide minerals (hematite, cerussite, and smithsonite). Surface relaxation and Femi energy, as well as projected DOS, are considered. Results show that the surface atoms of the sulfide minerals are more susceptible and more easily affected by the fracture bonds. The sulfide surfaces possess higher chemical potential than the corresponding oxide surfaces, and are more likely to be electron donors in reactions. The S 3p states are the mainly contributing states in the sulfide surface, while that in the oxide surface are O 2p states. The bonds of the sulfide surface have more covalent features and that of the oxide surface are ionic interactions. The O–M (M represents Fe, Pb or Zn) bonds are more stable, as the DOS of the oxide surfaces distribute in the lower energy range.

This article presented a hybrid cryocooler which combines the room temperature displacers and the pulse tube in one system. Compared with a traditional pulse tube cryocooler, the system uses the rod-less ambient displacer to recover the expansion work from the pulse tube cold end to improve the efficiency while still keeps the advantage of the pulse tube cryocooler with no moving parts at the cold region. In the meantime, dual-opposed configurations for both the compression pistons and displacers reduce the cooler vibration to a very low level. In the experiments, a lowest no-load temperature of 38.5 K has been obtained and the cooling power at 80K was 26.4 W with an input electric power of 290 W. This leads to an efficiency of 24.2% of Carnot, marginally higher than that of an ordinary pulse tube cryocooler. The hybrid configuration herein provides a very competitive option when a high efficiency, high-reliability and robust cryocooler is desired.

Optical sensors have been investigated and widely deployed in industrial andscientific measurement and control processes, mainly due to their accuracy, high sensitivityand immunity to electromagnetic interference and other unique characteristics. They areespecially suited for harsh environments applications, where no commercial electricalsensors are available for long-term stable operations. This paper reports a novel contactoptical high temperature sensor targeting at harsh environments. Utilizing birefringentsingle crystal sapphire as the sensing element and white light interferometric signalprocessing techniques, an optical birefringence based temperature sensor was developed.With a simple mechanically structured sensing probe, and an optical spectrum-codedinterferometric signal processor, it has been tested to measure temperature up to 1600 °Cwith high accuracy, high resolution, and long-term measurement stability.