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William Jeon,1 Graham E Trope,1,2 Yvonne M Buys,2 Richard Wedge,3 Sherif El-Defrawy,2 Qi-Sheng Chen,4 Ya-Ping Jin1,2,5 1Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; 2Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada; 3Health Prince Edward Island, Charlottetown, Prince Edward Island, Canada; 4University of Waterloo, Waterloo, Ontario, Canada; 5Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, CanadaCorrespondence: Ya-Ping JinDepartment of Ophthalmology and Vision Sciences, University of Toronto, 340 College Street, Suite 400, Toronto, M5T 1S8, Ontario, CanadaTel +416-978-7938Email Yaping.Jin@utoronto.caIntroduction: Eye care in many countries is provided by optometrists, ophthalmologists, primary care providers (PCPs, including family physicians and pediatricians) and emergency department (ED) physicians. In the province of Prince Edward Island (PEI), Canada, optometric services are not government-insured, while services provided by other eye care providers are government-insured. Clinics of optometrists, PCPs and ED physicians are widely distributed across the island. Clinics of ophthalmologists however are concentrated in the capital city Charlottetown.Purpose: To investigate if more patients visited government-insured PCPs and EDs for eye care when local optometric services are government-uninsured and government-insured ophthalmologists are potentially distant.Methods: From PEI physician billing database, we identified all patients with an ocular diagnosis from 2010– 2012 using International Classification of Diseases, 9th Revision (ICD-9) codes. The utilization of government-insured PCPs and EDs in five geographical regions was assessed utilizing patients’ residential postal code. Of the five regions, Prince was the region farthest from the capital Charlottetown.Results: Compared to utilization of government-insured PCPs for ocular diagnoses in Charlottetown (13.5% in 2010, 95% confidence interval [CI] 12.9– 14.0%), the utilization in Prince (22.4% in 2010, 95% CI 21.7– 23.1%) was nearly double (p< 0.05). The utilization of ED physicians for ocular diagnoses was similarly double in Prince (8.8%, 95% CI 8.3– 9.3%) versus Charlottetown (4.1%, 95% CI 3.8– 4.5%). The utilization of ophthalmologists however was significantly lower in Prince (43%, 95% CI 41.4– 42.9%) versus Charlottetown (56.3%, 95% CI 55.6– 57.1%). Similar trends remained throughout 2010– 2012.Conclusion: When optometric services are government-uninsured and government-insured ophthalmologist services are geographically distant, ocular patients utilized PCPs and ED physicians more frequently. Due to different levels of training and available equipment for eye examinations among PCPs, ED physicians and optometrists, the quality of eye care and cost-effectiveness of increased use of PCPs and ED physicians for ocular management warrant further investigation.Trial Registration: Not applicable.Keywords: primary care providers, ocular diagnoses, government insurance, emergency physicians, optometrists

Qingshan Chen,1,* Hai Zhang,2,* Yan Cao,3 Ying Li,1 Sen Sun,1 Junping Zhang,4 Guoqing Zhang1 1Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China, 2Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China, 3Department of Biochemical Pharmacy, College of Pharmacy, Second Military Medical University, Shanghai, China; 4Department of Biochemical Pharmacy, College of Pharmacy, Second Military Medical University, Shanghai, China *These authors contributed equally to this work Abstract: Liver fibrosis is a major pathological feature of chronic liver diseases and there is no effective therapy program at present. Schisandrin B (Sch B) is the major bioactive ingredient of Schisandra chinensis, with antioxidative, anti-inflammatory, antitumor, and hepatoprotective properties. This study aimed to investigate the protective effect and related molecular mechanism of Sch B against carbon tetrachloride (CCl4)-induced liver fibrosis in rats. The in vivo therapeutic effect of Sch B on liver fibrosis induced by CCl4 was examined in rats. In vitro, rat hepatic stellate cells (HSC-T6) were used to assess the effect of Sch B on the activation of HSCs. Sch B effectively attenuated liver damage and progression of liver fibrosis in rats, as evidenced by improved liver function and decreased collagen deposition. The effects of Sch B were associated with attenuating oxidative stress by activating nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated antioxidant signaling and suppressing HSC activation by inhibiting the transforming growth factor-β (TGF-β)/Smad signaling pathway. In an in vitro study, it was shown that Sch B inhibited TGF-β-induced HSC activation. Finally, Sch B significantly inhibited TGF-β1-stimulated phosphorylation of Smad and signaling of mitogen-activated protein kinases. This study demonstrates that Sch B prevents the progression of liver fibrosis by the regulation of Nrf2-ARE and TGF-β/Smad signaling pathways, and indicates that Sch B can be used for the treatment of liver fibrosis. Keywords: schisandrin B, liver fibrosis, hepatic stellate cell activation, Nrf2, TGF-β/Smad

We report the demonstration of a composite right/left-handed (CRLH) metamaterial waveguide for terahertz quantum-cascade (QC) lasers. By incorporating gap capacitors (∼ 250 nm) in the top metallization of a metal-metal waveguide operating in a higher order lateral mode, we have realized a CRLH transmission line that supports traveling modes with negative effective phase indices (i.e., left-handed or backward-wave propagation). The CRLH metamaterial waveguide is employed as an active leaky-wave antenna for a terahertz QC-laser. Directional single-lobed beams launched in the backwards direction at angles of - 4 ° and - 63 ° were experimentally observed at excitation frequencies 2.59 and 2.48 THz, respectively. © 2013 American Institute of Physics.

Endocrine-resistant ER+HER2- breast cancer (BC) is particularly aggressive and leads to poor clinical outcomes. Effective therapeutic strategies against endocrine-resistant BC remain elusive. Here, analysis of the RNA-sequencing data from ER+HER2- BC patients receiving neoadjuvant endocrine therapy and spatial transcriptomics analysis both show the downregulation of innate immune signaling sensing cytosolic DNA, which primarily occurs in endocrine-resistant BC cells, not immune cells. Indeed, compared with endocrine-sensitive BC cells, the activity of sensing cytosolic DNA through the cGAS-STING pathway is attenuated in endocrine-resistant BC cells. Screening of kinase inhibitor library show that this effect is mainly mediated by hyperactivation of AKT1 kinase, which binds to kinase domain of TBK1, preventing the formation of a trimeric complex TBK1/STING/IRF3. Notably, inactivation of cGAS-STING signaling forms a positive feedback loop with hyperactivated AKT1 to promote endocrine resistance, which is physiologically important and clinically relevant in patients with ER+HER2- BC. Blocking the positive feedback loop using the combination of an AKT1 inhibitor with a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of endocrine-resistant tumors in humanized mice models, providing a potential strategy for treating patients with endocrine-resistant BC., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Metastasis remains a major challenge in the successful management of malignant diseases. The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon, stomach, and pancreatic cancers, as well as melanoma, breast cancer, and sarcoma. As an important factor that influences the development of metastatic liver cancer, alternative splicing drives the diversity of RNA transcripts and protein subtypes, which may provide potential to broaden the target space. In particular, the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence, progression, aggressiveness, and drug resistance of cancers caused by the selective splicing of specific genes. This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer. It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes, abnormal splicing, and the contribution of hypoxia to these changes during metastasis., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aim: To evaluate the effectiveness and safety of early lens extraction during pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) compared to those of PPV with subsequent cataract surgery., Methods: This multicenter randomized controlled trial was conducted in three Chinese hospitals on patients with PDR, aged >45y, with mild cataracts. The participants were randomly assigned to the combined (PPV combined with simultaneously cataract surgery, i.e. , phacovitrectomy) or subsequent (PPV with subsequent cataract surgery 6mo later) group and followed up for 12mo. The primary outcome was the change in best-corrected visual acuity (BCVA) from baseline to 6mo, and the secondary outcomes included complication rates and medical expenses., Results: In total, 129 patients with PDR were recruited and equally randomized (66 and 63 in the combined and subsequent groups respectively). The change in BCVA in the combined group [mean, 36.90 letters; 95% confidence interval (CI), 30.35-43.45] was significantly better (adjusted difference, 16.43; 95%CI, 8.77-24.08; P <0.001) than in the subsequent group (mean, 22.40 letters; 95%CI, 15.55-29.24) 6mo after the PPV, with no significant difference between the two groups at 12mo. The overall surgical risk of two sequential surgeries was significantly higher than that of the combined surgery for neovascular glaucoma (17.65% vs 3.77%, P =0.005). No significant differences were found in the photocoagulation spots, surgical time, and economic expenses between two groups. In the subsequent group, the duration of work incapacity (22.54±9.11d) was significantly longer ( P <0.001) than that of the combined group (12.44±6.48d)., Conclusion: PDR patients aged over 45y with mild cataract can also benefit from early lens extraction during PPV with gratifying effectiveness, safety and convenience, compared to sequential surgeries., Competing Interests: Conflicts of Interest: Feng WB, None; Zheng L, None; Li YQ, None; Li YH, None; Zhang GM, None; Wang X, None; Liu BQ, None; Jin L, None; Huang YN, None; Yang YF, None; Chen ZD, None; Ma DH, None; Chen QS, None; Qin CJ, None; Feng BM, None; Yang ZM, None; Huang X, None; Yang CJ, None; Liu SH, None; Wu MX, None., (International Journal of Ophthalmology Press.)

Aim: To identify a maculopathy patient caused by new recessive compound heterozygous variants in RP1L1 ., Methods: Comprehensive retinal morphological and functional examinations were evaluated for the patient with RP1L1 maculopathy. Targeted sequence capture array technique was used to screen potential pathologic variants. Polymerase chain reaction and Sanger sequencing were used to confirm the screening results., Results: Fundus examination showed round macular lesions appeared in both eyes. Optical coherence tomography showed that the inner segment/outer segment continuity was disorganized and disruptive in the left eye, but it was uneven and slightly elevated in the right eye. Fundus autofluorescence showed patchy hyper-autofluorescence in the macula. Visual field examination indicates central defects in both eyes. Electroretinogram (ERG) and multifocal ERG showed no obvious abnormalities. Fundus fluorescein angiography in the macula showed obviously irregular hyper-fluorescence in the right eye and slightly hyper-fluorescence in the left eye. We found that the proband carried a missense variant (c.1972C>T) and a deletion variant (c.4717&#95;4718del) of RP1L1 , which were originated from the parents and formed compound heterozygous variants. Both variants are likely pathogenic according to the ACMG criteria. Multimodal imaging, ERG and detailed medical history are important diagnostic tools for differentiating between acquired and inherited retinal disorders., Conclusion: A maculopathy case with detailed retinal phenotype and new recessive compound heterozygous variants of RP1L1 is identified in a Chinese family, which expands the understanding of phenotype and genotype in RP1L1 maculopathy., (International Journal of Ophthalmology Press.)

Aims: To define endotypes of carotid subclinical atherosclerosis., Methods and Results: We integrated demographic, clinical, and molecular data (n = 124) with ultrasonographic carotid measurements from study participants in the IMPROVE cohort (n = 3340). We applied a neural network algorithm and hierarchical clustering to identify carotid atherosclerosis endotypes. A measure of carotid subclinical atherosclerosis, the c-IMTmean-max, was used to extract atherosclerosis-related features and SHapley Additive exPlanations (SHAP) to reveal endotypes. The association of endotypes with carotid ultrasonographic measurements at baseline, after 30 months, and with the 3-year atherosclerotic cardiovascular disease (ASCVD) risk was estimated by linear (β, SE) and Cox [hazard ratio (HR), 95% confidence interval (CI)] regression models. Crude estimates were adjusted by common cardiovascular risk factors, and baseline ultrasonographic measures. Improvement in ASCVD risk prediction was evaluated by C-statistic and by net reclassification improvement with reference to SCORE2, c-IMTmean-max, and presence of carotid plaques. An ensemble stacking model was used to predict endotypes in an independent validation cohort, the PIVUS (n = 1061). We identified four endotypes able to differentiate carotid atherosclerosis risk profiles from mild (endotype 1) to severe (endotype 4). SHAP identified endotype-shared variables (age, biological sex, and systolic blood pressure) and endotype-specific biomarkers. In the IMPROVE, as compared to endotype 1, endotype 4 associated with the thickest c-IMT at baseline (β, SE) 0.36 (0.014), the highest number of plaques 1.65 (0.075), the fastest c-IMT progression 0.06 (0.013), and the highest ASCVD risk (HR, 95% CI) (1.95, 1.18-3.23). Baseline and progression measures of carotid subclinical atherosclerosis and ASCVD risk were associated with the predicted endotypes in the PIVUS. Endotypes consistently improved measures of ASCVD risk discrimination and reclassification in both study populations., Conclusions: We report four replicable subclinical carotid atherosclerosis-endotypes associated with progression of atherosclerosis and ASCVD risk in two independent populations. Our approach based on endotypes can be applied for precision medicine in ASCVD prevention., Competing Interests: Conflict of interest: The authors disclose no conflicts of interest related to the present work., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Glutathione plays a critical role in plant growth, development and response to stress. It is a major cellular antioxidant and is involved in the detoxification of xenobiotics in many organisms, including plants. However, the role of glutathione-dependent redox homeostasis and associated molecular mechanisms regulating the antioxidant system and pesticide metabolism remains unclear. In this study, endogenous glutathione levels were manipulated by pharmacological treatments with glutathione synthesis inhibitors and oxidized glutathione. The application of oxidized glutathione enriched the cellular oxidation state, reduced the activity and transcript levels of antioxidant enzymes, upregulated the expression level of nitric oxide and Ca 2+ related genes and the content, and increased the residue of chlorothalonil in tomato leaves. Further experiments confirmed that glutathione-induced redox homeostasis is critical for the reduction of pesticide residues. RNA sequencing analysis revealed that miRNA156 and miRNA169 that target transcription factor SQUAMOSA-Promoter Binding Proteins (SBP) and NUCLEAR FACTOR Y (NFY) potentially participate in glutathione-mediated pesticide degradation in tomato plants. Our study provides important clues for further dissection of pesticide degradation mechanisms via miRNAs in plants., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Instant teas are particularly rich in tea polyphenols and caffeine and have great potential as food ingredients or additives to improve the quality of food and enhance their nutritional and commercial value., Methods: To determine the relationships between raw material, drying method, and sensory and other quality attributes, instant teas were prepared from three tea varieties, namely black, green and jasmine tea, using two drying methods, namely spray-drying (SD) and freeze-drying (FD)., Results: Both the raw tea material and drying method influenced the quality of the finished instant teas. Black tea was quality stable under two drying, while green tea taste deteriorated much after SD. Jasmine tea must be produced from FD due to huge aroma deterioration after SD. FD produced instant tea with higher sensory quality, which was attributed to the lower processing temperature. Chemical compositional analysis and widely targeted metabolomics revealed that SD caused greater degradation of tea biochemical components. The flavonoids content changed markedly after drying, and metabolomics, combined with OPLS-DA, was able to differentiate the three varieties of tea. Instant tea preparations via SD often lost a large proportion of the original tea aroma compounds, but FD minimized the loss of floral and fruity aroma compounds. Changes in the tea flavonoids composition, especially during drying, contributed to the flavor development of instant tea., Discussion: These results will provide an practicle method for high-quality instant tea production through choosing proper raw tea material and lowering down drying temperature with non-thermal technologies like FD., Competing Interests: S-XQ was employed by Eastsign Foods (Quzhou) Co., Ltd. Y-FC was employed by Unibioche Food Tech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jin, Liang, Qi, Tang, Chen, Chen, Chen, Yin and Xu.)

Background: Osteoporosis (OP) is considered as one of the major comorbidities of rheumatoid arthritis (RA), and is responsible for fragility fracture. However, there is currently no effective treatment for RA complicated with OP. Tubson-2 decoction (TBD), a Mongolian medicine also known as Erwei Duzhong Decoction, has been shown to exert a preventive effect on post-menopausal osteoporosis (PMOP). The preventive effects of TBD on RA-induced OP, as well as the bioactive compound responsible and the underlying mechanisms, remain to be elucidated., Objective: To explore the effects of TBD on RA-induced OP in vivo, and to elucidate the mechanism of isochlorogenic acid A (ICA), the effective component of TBD, in vitro., Methods: To evaluate the anti-arthritic and anti-osteoporotic effects of TBD, we conducted H&E straining and safranine O/fast green, TEM, immunohistochemistry (IHC), bone histomorphometry, micro-CT imaging, and biomechanical testing in collagen induced arthritis (CIA) rats. The active ingredient in TBD was identified using network pharmacology and molecular docking. The identification was supported by in vivo IHC assay, and further confirmed using qRT-PCR, Western blot, and SEM analysis in TNF-α-treated MH7A cells and/or in LPS-exposed RAW264.7 cells., Results: Oral administration of TBD attenuated the severity of arthritis and osteopenia as well as poor bone quality, in CIA rats. Additionally, TBD and the positive control, tripterygium glycosides (TG), exhibited similar effects in reducing inflammation in both the synovium and ankle joint. They also were both effective in improving bone loss, microarchitecture, and overall bone quality. TBD reduced the expression of MMP13, IL-17, and p-JNK protein in the synovium of CIA rats. ICA, which was screened, suppressed TNF-α or LPS-triggered inflammatory responses via down-regulating IL-17 signaling, involving in MMP13, IL-1β, IL-23, and IL-17, and the MAPK pathway including p-ERK, p-JNK, and p-P38, both in MH7A cells and in RAW264.7 cells. Furthermore, ICA prevented osteoclasts from differentiating and bone resoprtion in a dose-dependent manner in vitro., Conclusion: This study provides the first evidence that TBD exerts intervening effects on RA-induced OP, possibly through the downregulation of the IL-17/MAPK signaling pathway by ICA. The findings of our study provides valuable insights for further research in this area., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier GmbH.)

X-ray scintillators are widely used in medical imaging, industrial flaw detection, security inspection, and space exploration. However, traditional commercial scintillators are usually associated with a high use cost because of their substantial toxicity and easy deliquescence. In this work, an atomically precise Au-Cu cluster scintillator ( 1 ) with a thermally activated delayed fluorescence (TADF) property was facilely synthesized, which is environmentally friendly and highly stable to water and oxygen. The TADF property of 1 endows it with an ultrahigh exciton utilization rate. Combined with the effective absorption of X-ray caused by the heavy-atom effect and a limited nonradiative transition caused by close packing in the crystal state, 1 exhibits an excellent radioluminescence property. Moreover, 1 has good processability for fabricating a large, flexible thin-film device (10 cm × 10 cm) for high-resolution X-ray imaging, which can reach 40 μm (12.5 LP mm -1 ). The properties mentioned earlier make the coinage metal cluster promising for use as a substitute for traditional commercial scintillators., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

So far, over 20 causative genes of monogenic Parkinson's disease (PD) have been identified. Some causative genes of non-parkinsonian entities may also manifest with parkinsonism mimicking PD. This study aimed to investigate the genetic characteristics of clinically diagnosed PD with early onset age or family history. A total of 832 patients initially diagnosed with PD were enrolled, of which, 636 were classified into the early-onset group and 196 were classified into the familial late-onset group. The genetic testing included the multiplex ligation-dependent probe amplification and next generation sequencing (target sequencing or whole-exome sequencing). The dynamic variants of spinocerebellar ataxia were tested in probands with family history. In the early-onset group, 30.03% of patients (191/636) harbored pathogenic/likely pathogenic (P/LP) variants in known PD-related genes (CHCHD2, DJ-1, GBA (heterozygous), LRRK2, PINK1, PRKN, PLA2G6, SNCA and VPS35). Variants in PRKN were the most prevalent, accounting for 15.72% of the early-onset patients, followed by GBA (10.22%), and PLA2G6 (1.89%). And 2.52% (16/636) had P/LP variants in causative genes of other diseases (ATXN3, ATXN2, GCH1, TH, MAPT, GBA (homozygous)). In the familial late-onset group, 8.67% of patients (17/196) carried P/LP variants in known PD-related genes (GBA (heterozygous), HTRA2, SNCA) and 2.04% (4/196) had P/LP variants in other genes (ATXN2, PSEN1, DCTN1). Heterozygous GBA variants (7.14%) were the most common genetic cause found in familial late-onset patients. Genetic testing is of vital importance in differential diagnosis especially in early-onset and familial PD. Our findings may also provide some clues to the nomenclature of genetic movement disorders., (© 2023. The Author(s).)

In recent years, homologous recombination deficiency (HRD) has not achieved the expected substantial promotion of immunotherapeutic efficacy in ovarian cancer. This study aims to explore the role of HRD functional phenotype as a powerful biomarker in identifying HRD patients who may benefit from immunotherapy. HRD functional phenotype, namely HRD-EXCUTE, was defined as the average level of the 15 hub genes upregulated in HRD ovarian cancer. A decision tree was plotted to evaluate the critical role of HRD-EXCUTE in HRD patients. Agents inducing HRD-EXCUTE were identified by CMAP web (Connectivity Map). The mechanisms and immunotherapeutic effect of PARPi and HDACi in promoting HRD-EXCUTE was examined in vitro and in vivo . The decision tree plotted on the basis of HRD and HRD-EXCUTE indicated the HRD patients without the HRD functional phenotype were largely unresponsive to immunotherapy, which was validated by the immunotherapeutic cohorts. Furthermore, loss of HRD-EXCUTE in the HRD patients attenuated immunogenicity and inhibited immune cells in tumor microenvironment. Moreover, Niraparib combined with Entinostat induced HRD-EXCUTE by activating the cGAS-STING pathway and increasing the histone acetylation. The combination therapy could enhance the cytotoxicity of immune cells, and promote pro-immune cells infiltrating into ascites, resulting in inhibited ovarian cancer growth. The HRD functional phenotype HRD-EXCUTE was set up as a potent biomarker to identify whether HRD patients can benefit from immunotherapy. Loss of HRD-EXCUTE in HRD patients were largely insensitive to immunotherapy. The combination of PARPi with HDACi could improve the efficacy of the PARPi-based immunotherapy in ovarian cancer by augmenting the HRD functional phenotype., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: To determine the efficacy of eltrombopag for primary immune thrombocytopenia (ITP) in adults and the predictive factors for treatment-free response (TFR) . Methods: Clinical data of adults with ITP who received eltrombopag from June 14, 2013 to May 31, 2021 in the Hematology Department of Ruijin Hospital affiliated with Shanghai Jiao Tong University Medical College were retrospectively analyzed. The initial dose of eltrombopag was 25 mg/d, and the maximum dose was 75 mg/d; the dose was adjusted to maintain the platelet count to within 50-150×10(9)/L. Treatment was discontinued according either to the protocol, on the patient's wishes or doctor's judgment (prescription medication), or based on clinical trials. The efficacy of eltrombopag and factors for TFR among patients who achieved complete response and those who discontinued treatment were analyzed. Results: Overall, 106 patients with ITP (33 men and 73 women) were included in the study. The median age of patients was 50 (18-89) years. There were 2, 10, and 94 cases of newly diagnosed, persistent, and chronic ITP, respectively. The complete response rate was 44.3% (47/106), the response rate was 34.0% (36/106), and the overall response rate was 78.3% (83/106). Meanwhile, 83 patients who responded to treatment discontinued eltrombopag; of these, 81 patients were evaluated. Additionally, 17 patients (21.0%) achieved TFR. The median follow-up duration of patients who achieved TFR was 126 (30-170) weeks. The recurrence rate was 17.6% (3/17), and the relapse-free survival rate was 76.5%. The results of univariate analysis revealed that non-recurrence after discontinuation of other treatments for ITP ( P =0.001), and platelet count and eltrombopag dose of ≥100×10(9)/L ( P =0.007) and ≤25 mg/d ( P =0.031), respectively, upon discontinuation of eltrombopag were predictors of TFR; these effects were attributed to prolonged effective duration of eltrombopag. Multivariate analysis showed that there was a correlation between non-recurrence and prolonged effective duration after discontinuation of other treatments for ITP ( P =0.002) . Conclusion: Eltrombopag is effective for patients with ITP as it can result in TFR. Predictors for TFR include non-recurrence after discontinuation of concomitant ITP treatment, and platelet count and eltrombopag dose of ≥100 × 10(9)/L and ≤25 mg/d upon discontinuation of treatment, respectively.

Purpose: To assess the causes of death (COD) and long-term survival after nasopharyngeal carcinoma (NPC) diagnosis., Methods: Using linked data from the Surveillance, Epidemiology, and End Results program, patients with NPC diagnosed from 1990 to 2010 and followed up >5 years were identified. Chi-squared test, the Kaplan-Meier method, and the Cox proportional hazard model were used for analyses., Results: Among the 3,036 long-term NPC survivors, 1,432 survived for >5-10 years and 1,604 survived for >10 years. The most common COD was primary NPC (36.9%), followed by other causes (28.7%), other cancers (15.3%), cardiac disease (12.9%), and non-malignant pulmonary disease (6.2%). With a median follow-up of 125 months, deaths from NPC decreased with increasing time from diagnosis, while death because of cardiac disease and other causes increased. In those aged <50 years, death due to NPC remained the main COD over time, while cardiopulmonary disease-related death was the leading COD in patients aged ≥50 years. In White patients, death due to NPC decreased, and death due to cardiac disease increased over time. Death from NPC remained significant in Black and Asian patients even 15 years after the diagnosis of NPC, while death due to cardiac disease significantly increased after 9 years of diagnosis in Black patients. Multivariate analyses showed that the independent factors associated with inferior NPC-specific survival were older age, Asians, American Indian/Alaska Native, regional stage, distant stage, and diagnosis in the early years., Conclusions: The probability of death from primary NPC remains significant even 15 years after the NPC diagnosis. Our study advocates continued surveillance for NPC survivors beyond the traditional 5 years. Individualized follow-up strategies are required for patients with NPC of different ages and races., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Rao, Chen, Zhou, Lian and Wu.)

Glutathione (GSH) biosynthesis and regeneration play a significant role in the metabolism of chlorothalonil (CHT) in tomatoes. However, the specific regulatory mechanism of GSH in the degradation of CHT remains uncertain. To address this, we investigate the critical regulatory pathways in the degradation of residual CHT in tomatoes. The results revealed that the detoxification of CHT residue in tomatoes was inhibited by buthionine sulfoximine and oxidized glutathione pretreatment, which increased by 26% and 46.12% compared with control, respectively. Gene silencing of γECS, GS, and GR also compromised the CHT detoxification potential of plants, which could be alleviated by GSH application and decreased the CHT accumulation by 33%, 25%, and 21%, respectively. Notably, it was found that the jasmonic acid (JA) pathway participated in the degradation of CHT regulated by GSH. CHT residues reduced by 28% after application of JA. JA played a role downstream of the glutathione pathway by promoting the degradation of CHT residue in tomatoes via nitric oxide signaling and improving the gene expression of antioxidant and detoxification-related enzymes. This study unveiled a crucial regulatory mechanism of GSH via the JA pathway in CHT degradation in tomatoes and offered new insights for understanding residual pesticide degradation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The efficient asymmetric bio-synthesis of chiral β-hydroxy esters is of great importance for industrial production. In this work, a simple and productive engineered E.coli cell-immobilized strategy was applied for the asymmetric reduction of MAA to (R)-HBME with high enantioselectivity. Compared with the corresponding inactivated free cells, the alginate-immobilized cells remained 45% of initial activity at 50 ℃ and 65% after reuse of 10 times. After 60 days of storage at 4 ℃, the immobilized cells maintained more than 80% relative activity. Immobilization contributed significantly to the improvement of thermal stability, pH tolerance, storage stability and operation stability without affecting the yield of product. The immobilized recombinant E. coli cell had absolute enantioselectivity for the asymmetric reduction of MAA to (R)-HBME with e.e. > 99.9%. Therefore, microbial cell immobilization is a perspective approach in asymmetric synthesis of chiral β-hydroxy esters for industrial applications., (© 2022. The Author(s).)

Innovations in genomics have enabled the development of low-cost, high-resolution, single nucleotide polymorphism (SNP) genotyping arrays that accelerate breeding progress and support basic research in crop science. Here, we developed and validated the SoySNP618K array (618,888 SNPs) for the important crop soybean. The SNPs were selected from whole-genome resequencing data containing 2,214 diverse soybean accessions; 29.34% of the SNPs mapped to genic regions representing 86.85% of the 56,044 annotated high-confidence genes. Identity-by-state analyses of 318 soybeans revealed 17 redundant accessions, highlighting the potential of the SoySNP618K array in supporting gene bank management. The patterns of population stratification and genomic regions enriched through domestication were highly consistent with previous findings based on resequencing data, suggesting that the ascertainment bias in the SoySNP618K array was largely compensated for. Genome-wide association mapping in combination with reported quantitative trait loci enabled fine-mapping of genes known to influence flowering time, E2 and GmPRR3b, and of a new candidate gene, GmVIP5. Moreover, genomic prediction of flowering and maturity time in 502 recombinant inbred lines was highly accurate (>0.65). Thus, the SoySNP618K array is a valuable genomic tool that can be used to address many questions in applied breeding, germplasm management, and basic crop research., (© 2021 Institute of Botany, Chinese Academy of Sciences.)

Environmental exposure to cadmium (Cd) contributes to a decline in the quality of human semen. Although the testis is sensitive to Cd exposure, the mechanism underlying how cadmium affects the testis remains to be defined. In this study, male mice were treated with intraperitoneal injections of 0, 0.5, 1.5 and 2.5 mg CdCl 2 /kg/day for 10 days, respectively. Both the testicular weight and the 3β-HSD activity of Leydig cells were significantly reduced with the administration of 2.5 mg CdCl 2 /kg/day. The height of endothelial cells in the interstitial blood vessels significantly increased with the use of 2.5 mg CdCl 2 /kg/day compared with the control. Western blot data showed that the protein levels of CD31, αSMA, caveolin and Ng2 increased with cadmium exposure, and this increase was particularly significant with the administration of 2.5 mg CdCl 2 /kg/day. CD31, αSMA, caveolin and Ng2 are related to angiogenesis. Based on our data, cadmium exposure may stimulate the proliferation of the mural cells and endothelial cells of blood vessels, which may lead to abnormal function of the testis.

Background: Cognitive dysfunctions have been reported in multiple system atrophy (MSA). However the underlying mechanisms remain to be elucidated. This study aimed to explore the possible cerebral metabolism associated with domain-specific cognitive performances in MSA., Methods: A total of 84 patients were diagnosed as probable or possible MSA, comprised of 27 patients as MSA with predominant parkinsonism (MSA-P) and 57 patients as MSA with predominant cerebellar ataxia (MSA-C). The comprehensive neuropsychological tests and 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) imaging were performed. Z -score was calculated to non-dimensionalize and unify indicators of different tests in the domains of executive function, attention, language, memory, and visuospatial function. Correlations between specific Z -score and cerebral 18 F-FDG uptake were analyzed using statistical parametric mapping. The cognition-related metabolic differences between patients with MSA-P and MSA-C were analyzed using the post-hoc test., Results: Z -scores of the domains including attention, executive function, and language correlated positively with the metabolism in the superior/inferior frontal gyrus and cerebellum, but negatively with that in the insula and fusiform gyrus ( p < 0.001). No significant differences in neuropsychological performances and frontal metabolism were found between patients with MSA-P and MSA-C. Only lower metabolism in the cerebellum was observed in MSA-C., Conclusion: Metabolic changes in the frontal lobe and cerebellum may participate in the cognitive impairments of patients with MSA. Nevertheless, cognitive and corresponding metabolic differences between the two subtypes of MSA still need more exploration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shen, Chen, Zuo, Liu and Wang.)

Exposure to extended periods of darkness is a common source of abiotic stress that significantly affects plant growth and development. To understand how Nicotiana benthamiana responds to dark stress, the proteomes and metabolomes of leaves treated with darkness were studied. In total, 5763 proteins and 165 primary metabolites were identified following dark treatment. Additionally, the expression of autophagy-related gene (ATG) proteins was transiently upregulated. Weighted gene coexpression network analysis (WGCNA) was utilized to find the protein modules associated with the response to dark stress. A total of four coexpression modules were obtained. The results indicated that heat-shock protein (HSP70), SnRK1-interacting protein 1, 2A phosphatase-associated protein of 46 kDa (Tap46), and glutamate dehydrogenase (GDH) might play crucial roles in N. benthamiana's response to dark stress. Furthermore, a protein-protein interaction (PPI) network was constructed and top-degreed proteins were predicted to identify potential key factors in the response to dark stress. These proteins include isopropylmalate isomerase (IPMI), eukaryotic elongation factor 5A (ELF5A), and ribosomal protein 5A (RPS5A). Finally, metabolic analysis suggested that some amino acids and sugars were involved in the dark-responsive pathways. Thus, these results provide a new avenue for understanding the defensive mechanism against dark stress at the protein and metabolic levels in N. benthamiana., (© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objective: To analyze the incidence and risk factors for postoperative venous thromboembolism(VTE) in patients with stage Ⅰa non-small-cell lung cancer(NSCLC), so as to find evidence for further research of prophylactic anticoagulation. Methods: A total of 132 patients with stage Ⅰa NSCLC, 42 males and 90 females aged from 26 to 79 years with an average of (57±10) years, were retrospectively included in this study. All of them underwent surgical treatment at the Department of Thoracic Surgery of Beijing Chaoyang Hospital Affiliated with Capital Medical University from January 2017 to October 2020. A lower extremity venous ultrasound was performed before and after the operation. Participants were divided into VTE group ( n =11) or non-VTE group ( n =121) according to whether or not VTE occurred after operation. The surgical conditions, test indicators, imaging information, pathology information were compared between the two groups. Logistic regression analysis was performed to test the associations of VET with putative risks factors in which significant differences were observed. The independent risk factors of VET were determined by this way. Results: Postoperative VTE occurred in 11 cases (8.3%), including 10 cases (90.9%) of deep vein thrombosis (DVT) of lower limbs and 1 case (9.1%) of DVT complicated with pulmonary embolism (PE). The mean age of Patients in the VTE group was older than that in non-VTE Group ((65±9) years vs (57±10) years, P =0.009). On the fifth day after operation, patients in both groups had significantly higher D-dimer level compared with that before operation (3.18(1.55, 5.15) vs 1.54(1.09, 2.57); 2.66(1.17, 4.65) vs 1.34(0.78, 2.04))(both P <0.05). The value of neuron-specific enolase (NSE) and the number of lymph nodes removed during the operation in the VTE group were significantly higher than those in the non-VTE group ((21.54±12.37) vs (14.72±5.75); (19.7±8.2) vs (13.0±7.9)) (both P <0.05). There was no statistically significant difference in the approach of surgery, imaging features (tumor location, vascular cluster signs, etc.), and pathological information (pathological types, etc.) (all P >0.05). The logistic regression analysis showed that the number of lymph nodes removed during the operation was an independent risk factor related to the occurrence of VTE ( OR =1.306, 95% CI: 1.000-1.600, P <0.05). Conclusions: The incidence of postoperative VTE in patients with stage Ⅰa NSCLC is approximately 8.3%. The number of lymph nodes removed during the operation may be an independent risk factor for postoperative VTE in patients with stage Ⅰa NSCLC.

To examine the association between blood urea nitrogen (BUN) and risk of type 2 diabetes (T2DM) among Chinese adults, we performed an ongoing cohort study of 38578 Chinese adults (56.3% males; average age, 41.6 y) who underwent repeated health check-up examinations between 2009 and 2016 and without T2DM at baseline. During follow-up, incident T2DM cases were identified based on self-report, medication use, measurements of fasting plasma glucose, 2 h post oral glucose, or haemoglobinA1c. 2009 (5.2%) cases confirmed with incident T2DM were identified during median follow-up of 3.1 years. With increasing quartiles of BUN levels, the incidences of T2DM gradually increased with 0.69%, 1.11%, 1.53%, and 1.87% for quartile 1 to quartile 4 (p trend <0.001). Compared with quartile 1, the multivariate-adjusted hazard ratios (HRs) and its 95% confidence intervals (95% CIs) for T2DM risk were 1.16 (0.97-1.38) for quartile 2, 1.28 (1.07-1.51) for quartile 3, and 1.28 (1.08-1.52) for quartile 4 (p trend = 0.005). HR for per each standard deviation increase in BUN level was 1.10 (1.04-1.16) (p trend <0.001). This association tended to be more pronounced in those with a lower body mass index at baseline (p-interaction <0.001). Our results suggested that BUN levels were positively associated with incident T2DM risk among Chinese adults. Future prospective investigations in other populations are necessary to confirm our findings.

Background: To explore the potential biological function of XPA (Xeroderma pigmentosum group A) in hepatic neoplasms and the underlying molecular mechanisms., Methods: Liver cells were used as experimental models to establish HCC (hepatocellular carcinoma) in vitro. Protein extractions were subjected to Western blotting to detect the proteins expression. The lentivirus transfection efficiency was confirmed by Western blot and RT-qPCR, Tunnel staining was used to detect apoptosis, and Transwell assays were used to observe cell migration and invasion. Cell proliferation was detected with colony formation and CCK-8 (cell counting kit-8) assays., Results: XPA expression was obviously lower in HCC tissue and liver cancer cell lines. XPA overexpression induced autophagy and apoptosis by increasing LC3B II/I, Beclin1, cleaved-caspase-3, and Bax expression and decreasing p62 and Bcl2 protein levels. XPA also suppressed HCC EMT (Epithelial-Mesenchymal Transition) by increasing E-cadherin and decreasing N-cadherin and vimentin protein expression. Cell proliferation, migration and invasion in vivo were significantly inhibited by the overexpression of XPA, and p-PI3K, p-Akt, and p-mTOR expression were decreased in LV-XPA cells. In general, XPA inhibited HCC by inducing autophagy and apoptosis and by modulating the expression of PI3K/Akt/mTOR proteins., Conclusions: XPA overexpression was found to suppress HCC by inducing autophagy and apoptosis and repressing EMT and proliferation. Each of these effects may be involved in modulating the PI3K/Akt/mTOR signaling pathway., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jgo-21-310). The authors have no conflicts of interest to declare., (2021 Journal of Gastrointestinal Oncology. All rights reserved.)

Objective: To assess and compare the performance of fluorine-18-labeled fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET/ CT) and gallium-68-labeled tetraazacyclododecanetetraacetic acid-DPhe1-Tyr3-octreotate ( 68 Ga- DOTATATE) PET/CT in the targeted imaging of culprit tumors causing osteomalacia., Methods: This was a clinical retrospective analysis. We analyzed 13 patients (five men, eight women; mean age, 49 years; range, 19-55 years) with suspicion of tumor-induced osteomalacia (TIO) between March 2017 and October 2019. All patients underwent two functional imaging methods to locate the culprittumors. Studies were performed on a PET/CT scanner. The injection doses of 18 F- FDG and 68 Ga-DOTATATE were 0.5mCi/kg and approximately 5.0mCi, respectively. In the two scans, the whole body was captured from head to toe 45 to 60 min after intravenous tracer injection. 68 Ga-DOTATATE PET/CT and 18 F-FDG PET/CT imaging results locate culprit tumors according to the following criteria: (i) abnormal foci uptake concentration was observed locally, and the uptake level was higher than the background level of the right lobe of the liver; (ii) combined CT showed or did not have obvious abnormal density changes; and (iii) non-specific ingestion lesions due to fracture, arthritis, necrosis of femoral head are excluded. Compared with the results of pathological examination and clinical follow-up, the sensitivity, specificity and accuracy of 68 Ga-DOTATATE PET/CT imaging and 18 F-FDG PET/CT imaging for TIO were analyzed., Results: All patients had symptoms of osteomalacia and hypophosphatemia. The lag time (symptoms to PET diagnosis) ranged from 2 to 12 years. There were eight cases of TIO patients and five cases of non-TIO patients confirmed by surgery, pathology and follow-up. Among the eight TIO patients, there were six cases (75.0%) of PMTs, one case (12.5%) of giant cell tumor, one case (12.5%) of hemangiopericutoma. Most (n = 6, 75.0%) of the confirmed tumors in our patient population were in the lower extremities, followed by craniofacial regions (n = 1, 12.5%), and torso (n = 1, 12.5%), respectively. Among the five non-TIO patients, there were two cases of Fanconi syndrome, one case of rickets, and two cases of sporadic osteomalacia hypophosphorus. The culprit tumors could be located either in the bone (n = 5, 62.5%) or the soft tissue (n = 3, 37.5%). 18 F-FDG PET/CT was able to localize the tumor in six (6/13, 46.1%) patients. 68 Ga-DOTATATE PET/CT detected tumor in 8 (83.3%) of 13 patients. The sensitivity of 68 Ga-DOTATATE PET/CT imaging and 18 F-FDG PET/CT imaging in the evaluation of TIO in our patient population were 100% (8/8) vs 75% (6/8). The specificity of the two different methods was 80% (4/5). The overall accuracy was 92.3% (12/13) vs 76.9% (10/13)., Conclusions: 68 Ga-DOTATATE PET/CT is very effective in assessing hypophosphatemia patients with TIO typical symptoms compared with 18 F-FDG. Therefore, in clinically suspected cases of hypophosphatemic osteomalacia, 68 Ga-DOTATATE PET/CT should be preferred as an imaging modality investigation to avoid delay in the treatment of this disease., (© 2021 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Objective: We aimed to characterize the cognitive profiles in multiple system atrophy (MSA) and explore the cerebral metabolism related to the cognitive decline in MSA using 18 F-fluorodeoxyglucose ( 18 F-FDG) Positron Emission Tomography (PET). Methods: In this study, 105 MSA patients were included for cognitive assessment and 84 of them were enrolled for 18 F-FDG PET analysis. The comprehensive neuropsychological tests covered five main domains including execution, attention, memory, language, and visuospatial function. The cognitive statuses were classified to MSA with normal cognition (MSA-NC) and MSA with cognitive impairment (MSA-CI), including dementia (MSA-D), and mild cognitive impairment (MSA-MCI). With 18 F-FDG PET imaging, the cerebral metabolism differences among different cognitive statuses were analyzed using statistical parametric mapping and post-hoc analysis. Results: Among 84 MSA patients, 52 patients were found with MSA-CI, including 36 patients as MSA-MCI and 16 patients as MSA-D. In detail, the cognitive impairments were observed in all the five domains, primarily in attention, executive function and memory. In 18 F-FDG PET imaging, MSA-D and MSA-MCI patients exhibited hypometabolism in left middle and superior frontal lobe compared with MSA-NC ( p < 0.001). The normalized regional cerebral metabolic rate of glucose (rCMRglc) in left middle frontal lobe showed relative accuracy in discriminating MSA-CI and MSA-NC [areas under the curve (AUC) = 0.750; 95%CI = 0.6391-0.8609]. Conclusions: Cognitive impairments were not rare in MSA, and the hypometabolism in frontal lobe may contribute to such impairments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shen, Chen, Ge, Lu, Chen, He, Li, Zhao, Sun, Wu, Wu, Liu and Wang.)

The association between dietary fat intake during pregnancy and the risk of developing preeclampsia has been examined in many epidemiological studies, but the results remain inconsistent. The aim of this study was to clarify this association in pregnant Chinese women. After conducting 1:1 matching, 440 pairs consisting of pregnant women with preeclampsia and hospital-based, healthy pregnant women matched by gestational week (± 1 week) and age (± 3 years) were recruited. A 79-item semi-quantitative food frequency questionnaire administered during face-to-face interviews was used to estimate the participants' dietary intake of fatty acids. We found that the intakes of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were inversely associated with the risk of developing preeclampsia. Compared with the lowest quartile intake, the multivariate-adjusted odds ratios (95% confidence interval) of the highest quartile intake were 0.42 (0.26-0.68, p-trend < 0.001) for EPA, 0.52 (0.3-0.83, p-trend = 0.005) for DHA, and 0.41 (0.19-0.88, p-trend = 0.007) for AA. However, we did not observe any significant associations between the intake of total fatty acids, saturated fatty acids, and mono-unsaturated fatty acids and the risk of developing preeclampsia. Our results showed that the dietary intake of long-chain polyunsaturated fatty acids (i.e., EPA, DHA, and AA) may protect pregnant Chinese women against the development of preeclampsia.

As all- trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority ( P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups ( P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297)., Competing Interests: The authors declare no competing interest.

Findings for the roles of dairy products, Ca and vitamin D on ovarian cancer risk remain controversial. We aimed to assess these associations by using an updated meta-analysis. Five electronic databases (e.g. PubMed and Embase) were searched from inception to 24 December 2019. Pooled relative risks (RR) with 95 % CI were calculated. A total of twenty-nine case-control or cohort studies were included. For comparisons of the highest v. lowest intakes, higher whole milk intake was associated with increased ovarian cancer risk (RR 1·35; 95 % CI 1·15, 1·59), whereas decreased risks were observed for higher intakes of low-fat milk (RR 0·84; 95 % CI 0·73, 0·96), dietary Ca (RR 0·71; 95 % CI 0·60, 0·84) and dietary vitamin D (RR 0·80; 95 % CI 0·67, 0·95). Additionally, for every 100 g/d increment, increased ovarian cancer risks were found for total dairy products (RR 1·03; 95 % CI 1·01, 1·04) and for whole milk (RR 1·07; 95 % CI 1·03, 1·11); however, decreased risks were found for 100 g/d increased intakes of low-fat milk (RR 0·95; 95 % CI 0·91, 0·99), cheese (RR 0·87; 95 % CI 0·76, 0·98), dietary Ca (RR 0·96; 95 % CI 0·95, 0·98), total Ca (RR 0·98; 95 % CI 0·97, 0·99), dietary vitamin D (RR 0·92; 95 % CI 0·87, 0·97) and increased levels of circulating vitamin D (RR 0·84; 95 % CI 0·72, 0·97). These results show that whole milk intake might contribute to a higher ovarian cancer risk, whereas low-fat milk, dietary Ca and dietary vitamin D might reduce the risk.

Background: The association between free triiodothyronine (FT3) and long-term prognosis in dilated cardiomyopathy (DCM) patients has not been evaluated. The purpose of this study was to determine whether the level of FT3 could provide prognostic value in patients with DCM., Methods: Data of consecutive patients diagnosed with DCM were collected from October 2009 to December 2014. FT3 was measured by fluoroimmunoassay. Other biochemical markers, such as free thyroxin (FT4), thyroid-stimulating hormone, red blood cell, hemoglobin, blood urea nitrogen, and serum creatinine, were tested at the same time. Follow-up was performed every 3 months. The primary endpoint was all-cause mortality. Pearson analysis was used to evaluate the correlation of FT3 and other lab metrics with DCM patients' prognosis. The association of long-term mortality in DCM and FT3 was compared using Cox hazards model., Results: Data of 176 patients diagnosed with DCM were collected. Of them, 24 patients missed FT3 values and six patients were lost to follow-up. Altogether, data of 146 patients were analyzed. During the median follow-up time of 79.9 (53.5-159.6) months, nine patients lost, 61 patients died (non-survival group), and 85 patients survived (survival group). FT3 was significantly lower in non-survival group than that in survival group (3.65 ± 0.83 pmol/L vs. 4.36 ± 1.91 pmol/L; P = 0.003). FT3 also showed a significantly positive correlation with red blood cell and hemoglobin, negatively correlated with age, blood urea nitrogen and serum creatinine (P < 0.05), respectively. Patients in the group of lower FT3 levels (FT3 ≤3.49 pmol/L) suffered from a higher risk of all-cause mortality (P for log-rank = 0.001). In multivariate Cox regression analysis, FT3 level was significantly associated with all-cause mortality (hazard ratio: 0.70, 95% confidence interval 0.52-0.95, P for trend = 0.021)., Conclusion: Low levels of FT3 were associated with increased all-cause mortality in patients with DCM.

Objective: To evaluate the clinical outcomes of on-pump total arterial revascularization with bilateral radial artery (BRA) and left internal mammary artery (LIMA) as conduits in coronary artery bypass grafting (CABG) patients with left ventricular dysfunction (LVD). Methods: All the perioperative medical records and follow-up results of coronary artery disease patients with left ventricular ejection fraction (LVEF) ≤ 40% undergoing CABG from 24 heart centers of 15 provinces and autonomous regions in China between July 2015 and December 2019 were retrospectively analyzed. Results: A total of 87 consecutive patients (55 males and 32 females) underwent on-pump CABG with BRA and LIMA, with a mean age of (57.5±9.1) years old. There were 22 patients complicated with primary hypertension, 12 with diabetes mellitus, 8 with peripheral vascular disease, 7 with chronic obstructive lung disease, 12 with mild renal injury and 3 with partial aortic calcification. There were 43 cases with in-stent stenosis, and 21 had left main disease. The mean LVEF and left ventricular end-diastolic diameter (LVEDD) was (35.5±7.3)% and (65.5±2.6) mm, respectively. The mean graft number, aortic cross-clamp time and cardiopulmonary bypass duration was 3.2±0.9, (90.5±22.7) min and (113.4±19.2) min, respectively. There were 32 mitral and 9 aortic valve replacements, and 5 tricuspid annuloplasties. Prophylactic intra-aortic balloon pumps were implanted in 27 patients. There were 2 operative deaths from acute heart failure. After surgery, there were 15 cases of atrial fibrillation, 1 case of acute kidney injury, 1 case of acute myocardial infarction, and 1 cases of stroke. All the patients fulfilled the follow-up, with a mean time of (39.5±7.7) months. At 3 months after surgery, LVEDD was decreased and LVEF was improved significantly compared with pre-operative indicators [(53.0±1.5) mm vs (65.5±2.6) mm, t= 9.51 P= 0.02; (45.2±3.3)% vs (35.5±7.3)%, t= 13.79, P= 0.001]. No major cardiac events were reported during the follow-up. At (30.5±7.4) months after surgery, 62.4% of patients (53/85) underwent coronary CT angiography examination, and the results indicated that the graft patency was 98.8%, with only one case of RA occlusion occurred. Conclusion: In selected patients of LVD, on-pump total arterial revascularization with BRA and LIMA conduits was proved to be safe and effective.

In this study, a novel colorimetric sensor array based on chemo dyes including porphyrins and pH indicators were developed to analyse the volatile organic compounds of Chinese Baijiu with different grades. Ethyl acetate, ethyl butyrate and ethyl caproate appeared by significantly different concentration in different Baijiu grades measuring by gas chromatography and mass spectrometry and they were chosen as characteristic volatile organic components. The olfactory visualization system based on colorimetric sensor arrays was used to identify different Baijiu grades. The data were processed by building the principle components analysis, linear discriminant analysis and K-nearest neighbor classification models with the results of sensory evaluation and olfactory visualization system. This work presents a new-style colorimetric sensor using sensitive chemo dyes which has significant potential in quantitative analysis of volatile organic compounds, afterwards identifying different grades of Baijiu., (© The Korean Society of Food Science and Technology 2020.)

Introduction: Previous studies have found that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was involved in the progression of pulmonary hypertension (PH), and TRAIL knocking (KO) has an inhibitory effect on PH, but its mechanism is not completely clear. Methods: The effects of TRAIL on the accumulation of extracelluar matrix (ECM), which is one of the most important processes of vascular remodeling, were observed in mice and isolated pulmonary artery smooth muscle cells (PASMCs). In vivo, mice were divided into four groups: Control group (n = 5), hypoxia-induced PH mice group (n = 8), anti-TRAIL antibody (TRAIL-Ab) treatment group (n = 8) and IgG antibody (IgG) group (n = 8). The effects of TRAIL-Ab on ECM expression in hypoxic induced PH were researched; in vivo, PASMCs were divided into three groups: Control group, hypoxia-induced group, TRAIL-Ab group. Expressions of p-Smad2/3 and p-Smad1/5/8 were compared among the three groups. Results: Hypoxia-induced PH mice had significant increases in right ventricle systolic pressure (RVSP) (P < 0.001), right ventricular hypertrophy (RVH) (P = 0.007), vascular stenosis (P < 0.001) compared with controls. Mice with anti-TRAIL antibody had lower levels in RVSP (P < 0.001), RVH (P < 0.001), vascular stenosis (P < 0.001) than PH mice. Besides, the TRAIL-Ab significantly inhibited the phosphorylation of Smad2/3 compared with hypoxia-induced group. Conclusion: TRAIL regulates the accumulation of ECM in pulmonary artery by activating pSmad2/3.

Background: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a contributing factor for non-alcoholic fatty liver disease (NAFLD). Non-invasive algorithms including fatty liver index (FLI) and hepatic steatosis index (HSI) have been used as a screening test for NAFLD in epidemiologic studies. The aim of this study is to compare the diagnostic accuracy of FLI and HSI for NAFLD detection in adults with OSAHS., Methods: We enrolled consecutive adult subjects who were newly diagnosed with OSAHS from March 2016 to January 2018. NAFLD was diagnosed by ultrasonography. The accuracy and cut-off point of the FLI and HSI to detect NAFLD were assessed by analyzing the area under the receiver operating characteristic (AUROC) curve and the maximum Youden index analysis, respectively., Results: The 326 subjects were diagnosed as NAFLD according to ultrasound findings, while 105 subjects who had normal abdominal ultrasonography were grouped as controls. Both FLI and HSI values were significantly higher in patients with NAFLD compared with controls. The AUROC of FLI and HSI for predicting NAFLD was 0.802 (95% confidence interval [CI] 0.762-0.839) and 0.753 (95% CI 0.710-0.793), respectively. The AUROC of FLI was significantly higher than that of HSI (P = 0.0383). The optimal cut-off value of FLI and HSI was 60 (sensitivity 66% and specificity 80%) and 35 (sensitivity 81% and specificity 60%), respectively., Conclusions: Both FLI and HSI can serve as screening tools for NAFLD in OSAHS adults. The FLI shows better performance in diagnosing NAFLD than HSI., Trial Registration: Chinese Clinical Trial Registry (No. ChiCTR-OOB-15007253), http://www.chictr.org.cn/showproj.aspx?proj=11606.

Soybean is an important cash crop that is widely used as a source of vegetable protein and edible oil. The regeneration ability of soybean directly affects the application of biotechnology. In this study, we used the exogenous hormone 2,4-D to treat immature embryos. Different levels of somatic incidence were selected from the chromosome segment substitution lines (CSSLs) constructed by SN14 and ZYD00006. Transcriptome sequencing of extreme materials was performed, and 2666 differentially expressed genes were obtained. At the same time, a difference table was generated by combining the data on CSSL rearrangement. In the extreme materials, a total of 93 differentially expressed genes were predicted and were then analyzed by cluster analysis and Gene Ontology (GO) annotation. After screening and annotating the target genes, three differentially expressed genes with hormone pathways were identified. The expression patterns of the target genes were verified by real-time quantitative PCR (qRT-PCR). Haplotype polymorphism detection and linkage disequilibrium analysis were performed on the candidate gene Glyma.09g248200 . This study provided more information on the regulation network of soybean somatic embryogenesis and regeneration processes, and further identified important genes in the soybean regeneration process and provided a theoretical basis for accelerating the application of biotechnology to soybean for improving its breeding efficiency.

Background: Patients suffering from acute kidney injury (AKI) were associated with impaired sodium and potassium homeostasis. We aimed to investigate how admission serum sodium and potassium independently and jointly modified adverse clinical outcomes among AKI patients., Methods: Patient data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care Database III. Participants were categorized into three groups according to admission serum sodium and potassium, and the cut-off values were determined using smooth curve fitting. The primary outcome was 90-day mortality in the intensive care unit (ICU). Cox proportional hazards models were used to evaluate the prognostic effects of admission serum sodium and potassium levels., Results: We included 13,621 ICU patients with AKI (mean age: 65.3 years; males: 55.4%). The middle category of admission serum sodium and potassium levels were 136.0-144.9 mmol/L and 3.7-4.7 mmol/L through fitting smooth curve. In multivariable Cox models, compared with the middle category, patients with hyponatremia or hypernatremia were associated with excess mortality and the HRs and its 95%CIs were 1.38 (1.27, 1.50) and 1.56 (1.36, 1.79), and patients with either hypokalemia or hyperkalemia were associated with excess mortality and the hazard ratios (HRs) and its 95% confidential intervals (95% CIs) were 1.12 (1.02, 1.24) and 1.25 (1.14, 1.36), respectively. Significant interactions were observed between admission serum sodium and potassium levels (P interaction = 0.001), with a higher serum potassium level associated with increased risk of 90-day mortality among patients with hyponatremia, whereas the effects of higher sodium level on prognostic effects of potassium were subtle., Conclusions: Admission serum sodium and potassium were associated with survival in a U-shaped pattern among patients with AKI, and hyperkalemia predict a worse clinical outcome among patients with hyponatremia.

Soybeans are an important cash crop and are widely used as a source of vegetable protein and edible oil. MicroRNAs (miRNA) are endogenous small RNA that play an important regulatory role in the evolutionarily conserved system of gene expression. In this study, we selected four lines with extreme phenotypes, as well as high or low protein and oil content, from the chromosome segment substitution line (CSSL) constructed from suinong (SN14) and ZYD00006, and planted and sampled at three stages of grain development for small RNA sequencing and expression analysis. The sequencing results revealed the expression pattern of miRNA in the materials, and predicted miRNA-targeted regulatory genes, including 1967 pairs of corresponding relationships between known-miRNA and their target genes, as well as 597 pairs of corresponding relationships between novel-miRNA and their target genes. After screening and annotating genes that were targeted for regulation, five specific genes were identified to be differentially expressed during seed development and subsequently analyzed for their regulatory relationship with miRNAs. The expression pattern of the targeted gene was verified by Real-time Quantitative PCR (RT-qPCR). Our research provides more information about the miRNA regulatory network in soybeans and further identifies useful genes that regulate storage during soy grain development, providing a theoretical basis for the regulation of soybean quality traits., Competing Interests: The authors declare no conflict of interest.

Based on the leukemia-associated immunophenotypes (LAIPs), minimal residual disease (MRD) related to the outcome can be detected by multiparameter flow cytometry in acute myeloid leukemia (AML) patients. Although 0.1% was commonly used as a cutoff value, measurable MRD or MRD level below 0.1% has also been associated with prognostic significance and more sensitive thresholds (<0.1%) are required for improving AML prognosis prediction. In this study, 292 adult patients diagnosed with AML (non-M3) were enrolled, 36 kinds of LAIPs were identified, and the baseline expression levels in normal or regenerating bone marrows of each kind of LAIP were established, which ranged from <2.00 × 10 -5 to 5.71 × 10 -4 . The baseline level of each LAIP was considered as the individual threshold for MRD assessment. MRD statuses stratified by 0.1% and individual threshold were termed as 0.1%-MRD and individual-MRD, respectively. The patients of individual-MRD neg showed significantly better survival compared with those of 0.1%-MRD neg /individual-MRD pos or 0.1%-MRD pos . Multivariate analysis showed that when time points of complete remission, post the first and second consolidation courses, were considered, only individual-MRD post second consolidation presented independent prognostic value. Notably, in patients of cytogenetic/molecular low-risk (LR) or intermediate-risk (IR), the individual-MRD status could identify the patients with significantly different outcomes, while 0.1%-MRD status could not. Furthermore, among the patients of the LR or IR group which received chemotherapy only, those with individual-MRD neg status presented favorable survival, which was comparable with that of the patients accepted allogeneic hematopoietic stem cell transplantation (ASCT). This approach is useful in the selection of an ASCT strategy for clinical practice., (© 2019 Wiley Periodicals, Inc.)

Objective: To evaluate the efficacy and safety of recombinant human thrombopoietin (rhTPO) treatment for primary immune thrombocytopenia (ITP) patients during the perioperative period. Methods: Adult ITP patients who were refractory to first-line glucocorticoid therapy and underwent selective surgery were enrolled to be treated with rhTPO at the dosage of 1.5×10(4)U/d subcutaneously during the perioperative period. rhTPO treatment would not be terminated until one of the following conditions occurred: ①Platelet counts met the requirement of surgery; ②Platelet counts were ≥100×10(9)/L; ③Completed the 14 days of therapy. End points of the study were surgery rate, rhTPO therapy response rate, rescue therapy rate and adverse responses. Results: 42 patients were enrolled from Jan. 1, 2016 to Jun. 30, 2018. 14 were male and 28 were female. The median age was 60 (25-73) years old. There were no newly diagnosed patients. 5 patients were persistent and 37 were chronic. 27 patients completed selective surgery. The surgery rate was 64.3% (27/42) . Among them, 13 patients were under local anesthesia and 14 under general anesthesia. Of 42 cases receiving rhTPO therapy. 31 patients achieved responses, The overall response rate was of 73.8%. Among them, 24 patients achieved CR. The CR ratio was 77.4% (24/31) . 7 achieved response. The response ratio was 22.6% (7/31) . 11 patients did not respond to rhTPO therapy. The non-response rate was 26.2% (11/42) . The median time to reach CR was 7 (3-16) days. The median time to reach the peak of platelet counts were 10 (3-21) days. rhTPO was used for a median of 7 (3-14) days. The median platelet counts of patients undergoing surgery before rhTPO therapy, before surgery and at day 7 after surgery were 33 (20-89) ×10(9)/L, 125 (78-245) ×10(9)/L and 72 (30-250) ×10(9)/L, respectively. The median peak of platelet counts was 149 (101-466) ×10(9)/L. No infection, bleeding, thromboembolism and therapy-related adverse responses occurred in the patients. Conclusion: rhTPO for ITP patients during the perioperative period is safe and effective.

In nature, microbes use extracellular electron transfer (EET) to recover noble metals. Most attention has been paid to the biorecovery process occurring intracellularly and on the cell surface. In this work, we report that Pd nanorods could be biosynthesized by Enterobacter cloacae SgZ-5T in the extracellular space. This bacterium possesses both a direct EET pathway through membrane redox systems and an indirect EET pathway via the self-secreted electron carrier hydroquinone (HQ). When exposed to Pd(II), the bacteria adjusted their metabolic pathway and membrane-bound proteins to secrete riboflavin (RF). However, no HQ was detected in the supernatant in presence of Pd(II). No significant change was observed through metabolomic analysis regarding the abundance of HQ in presence of Pd(II) compared to Pd(II)-free supernatant. Similar results were also obtained through transcriptomic analysis of YqjG gene encoding glutathionyl-HQ reductase synthase. X-ray photoelectron spectroscopic evidence indicated that HQ may adsorb to the surface of Pd nanorods. Moreover, the gene encoding RF synthase (ribE) was up-regulated in the present of Pd(II), suggesting that this bioreduction process induced RF synthase, which had been shown in previous results. The UV-vis spectroscopy data demonstrated that the Pd(II) reduction rate was enhanced by 5%, 5.5% and 30% by the addition of 3.33 μM HQ, 3.33 μM RF and the both, respectively. All these results revealed that the bi-mediators secreted by bacteria were beneficial for biorecovery of Pd. This work is of significance for understanding metal biorecovery processes and natural biogeochemical processes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Tobacco mosaic virus (TMV) is a common source of biological stress that significantly affects plant growth and development. It is also useful as a model in studies designed to clarify the mechanisms involved in plant viral disease. Plant responses to abiotic stress were recently reported to be regulated by complex mechanisms at the post-translational modification (PTM) level. Protein phosphorylation is one of the most widespread and major PTMs in organisms. Using immobilized metal ion affinity chromatography (IMAC) enrichment, high-pH C18 chromatography fraction, and high-accuracy mass spectrometry (MS), a set of proteins and phosphopeptides in both TMV-infected tobacco and control tobacco were identified. A total of 4905 proteins and 3998 phosphopeptides with 3063 phosphorylation sites were identified. These 3998 phosphopeptides were assigned to 1311 phosphoproteins, as some proteins carried multiple phosphorylation sites. Among them, 530 proteins and 337 phosphopeptides corresponding to 277 phosphoproteins differed between the two groups. There were 43 upregulated phosphoproteins, including phosphoglycerate kinase, pyruvate phosphate dikinase, protein phosphatase 2C, and serine/threonine protein kinase. To the best of our knowledge, this is the first phosphoproteomic analysis of leaves from a tobacco cultivar, K326. The results of this study advance our understanding of tobacco development and TMV action at the protein phosphorylation level., Competing Interests: The authors declare no conflicts of interest

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. An Expression of Concern for this article was previously published while an investigation was conducted (see related editorial: https://doi.org/10.1016/j.biopha.2022.113812). This retraction notice supersedes the Expression of Concern published earlier. Concern was raised about the reliability of the Western blot data in Figure 4A, which appear to represent a distinct phenotype as found in many other publications, as detailed here: https://pubpeer.com/publications/029A84E50BD071A2088140723E3CF0; and here: https://docs.google.com/spreadsheets/d/1r0MyIYpagBc58BRF9c3luWNlCX8VUvUuPyYYXzxWvgY/edit#gid=262337249. Independent analysis confirmed the presence of suspected image duplications between the Western blots in Figure 4A and those contained in Yan et al (2017). The journal requested the corresponding author comment on these concerns and provide the associated raw data. The authors did not respond to this request and therefore the Editor-in-Chief decided to retract the article., (Copyright © 2018. Published by Elsevier Masson SAS.)

Backgroud: Cationic liposomes (CLs) can be used as non-viral vectors in gene transfer and drug delivery. However, the underlying molecular mechanism of its cytotoxicity has not been well elucidated yet., Methods: We herein report a systems biology approach based on whole-transcriptome sequencing coupled with computational method to identify the predominant genes and pathways involved in the cytotoxicity of CLs in HepG2 cell line., Results: Firstly, we validated the concentration-dependent cytotoxicity of CLs with an IC 50 of 120 μg/ml in HepG2 exposed for 24 h. Subsequently, we used whole-transcriptome sequencing to identify 220 (77 up- and 143 down-regulated) differentially expressed genes (DEGs). Gene ontology (GO) and pathway analysis showed that these DEGs were mainly related to cholesterol, steroid, lipid biosynthetic and metabolic processes. Additionally, "key regulatory" genes were identified using gene act, pathway act and co-expression network analysis, and expression levels of 11 interested altered genes were confirmed by quantitative real time PCR. Interestingly, no cell cycle arrest was observed through flow cytometry., Conclusions: These data are expected to provide deep insights into the molecular mechanism of CLs cytotoxicity.

The microanatomy of the intestinal epithelium in the Chinese soft-shelled turtle (CST) was studied by light and transmission electron microscopy (TEM). The small intestinal epithelium (SIE) was single layered or pseudostratified. The enterocytes contained mitochondria or mitochondria and lipid droplets. The enterocytes were arranged tightly in the apical parts of epithelium and connected by desmosomes and interdigitations. The large intestinal epithelium (LIE) was pseudostratified and the enterocytes did not contain lipid droplets. Enterocytes were arranged compactly in the apical part, forming spaces in the middle and basal parts of epithelium. Numerous mucous cells were scattered in the epithelium and there were intraepithelial lymphocytes (IELs) with their pseudopodia extended into the intestinal lumen. This study provides detailed features of intestinal epithelium in the Pelodiscus sinensis that could be related to function. In addition, these findings are discussed in relation to other vertebrates., Competing Interests: We declare that there is no conflict of interest.