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Abstract Colonizing in the gastrointestinal tract, Escherichia coli confronts diverse acidic challenges and evolves intricate acid resistance strategies for its survival. The lysine-mediated decarboxylation (Cad) system, featuring lysine decarboxylase CadA, lysine/cadaverine antiporter CadB, and transcriptional activator CadC, plays a crucial role in E. coli’s adaptation to moderate acidic stress. While the activation of the one-component system CadC and subsequent upregulation of cadBA operon in response to acid and lysine presence have been proposed, the molecular mechanisms governing the transition of CadC from an inactive to an active state remain elusive. Under neutral conditions, CadC is inhibited by forming a complex with lysine-specific permease LysP, stabilized in this inactive state by a disulfide bond. Our study unveils that, in an acidic environment, the disulfide bond in CadC is reduced by the disulfide bond isomerase DsbC, exposing R184 to periplasmic proteases, namely DegQ and DegP. Cleavage at R184 by DegQ and DegP generates an active N-terminal DNA-binding domain of CadC, which binds to the cadBA promoter, resulting in the upregulated transcription of the cadA and cadB genes. Upon activation, CadA decarboxylates lysine, producing cadaverine, subsequently transported extracellularly by CadB. We propose that accumulating cadaverine gradually binds to the CadC pH-sensing domain, preventing cleavage and activation of CadC as a feedback mechanism. The identification of DegP, DegQ, and DsbC completes a comprehensive roadmap for the activation and regulation of the Cad system in response to moderate acidic stress in E. coli.

Valeriana jatamansi Jones (V. jatamansi) is an ethnomedicinal herb widely used worldwide for its excellent anti-inflammatory activity. However, the quality markers that were correlated with the anti-inflammatory activity in V. jatamansi remained unclear. This study aimed to identify combinatorial quality markers based on the anti-inflammatory effects of V. jatamansi for enhancing its quality control. The chemical constituents of V. jatamansi were identify by UPLC-Q-TOF-MS, and 36 compounds were identified. The anti-inflammatory mechanism was predicted by network pharmacology, STAT3 and JAK1 were selected as key targets. The anti-inflammatory activity and predicted targets were validated by using lipopolysaccharide (LPS)-stimulated RAW264.7 cells in vitro. A combination of bivariate correlation analysis (BCA) and grey correlation analysis (GCA) was applied to evaluate the correlation between the chemical spectrum and the anti-inflammatory activities. Hesperidin, acevaltrate and valtrate were screened as potential quality markers. These three compounds exhibited anti-inflammatory effects by inhibiting the production of inflammatory mediators (NO, IL-6, IL-1β and TNF-α) and suppressing the expression of the two key targets (JAK1 and STAT3). The quantitative analysis results showed that the contents of the combinatorial quality markers were positively correlated with the anti-inflammatory activity of V. jatamansi. The contribution rate of the combinatorial quality markers reached 45.0 %. This study provides a comprehensive strategy for the quality control of V. jatamansi based on combinatorial quality markers.

Suxiao Jiuxin pill (SX) was a commonly used traditional Chinese medical preparation for treating acute myocardial infarction. However, fewer studies have been reported for comprehensively investigating the pharmacokinetic of the non-volatile and volatile chemical constituents in SX. For current study, a comprehensive and sensitive quantitation of twenty-one compounds in rat plasma was developed and validated by integrating UPLC-QQQ-MS/MS with GC-MS after oral administration of SX. The pharmacokinetic study was performed under acceptable specificity, linearity, sensitivity, precision and accuracy, recovery, matrix effect and stability. Ultimately, borneol, isoborneol, senkyunolide A, senkyunolide Ⅰ, ligustilide, ferulic acid, neocnidilide, senkyunolide H and levistolide A were detected. Their ranges of Tmax, Cmax, T1/2z and AUC (0-∞) were 0.07 ∼ 0.33 h, 5.24 ∼ 683.35 μg/L, 0.29 ∼ 1.08 h and 6.55 ∼ 474.62 μg/L*h, respectively. This study would be meaningful in better revealing the therapeutic material basis of SX. Furthermore, it could provide reference on pharmacological effect of SX against acute myocardial infarction.

For wild natural medicine, unanticipated biodiversity as species or varieties with similar morphological characteristics and sympatric distribution may co-exist in a single batch of medical materials, which affects the efficacy and safety of clinical medication. DNA barcoding as an effective species identification tool is limited by its low sample throughput nature. In this study, combining DNA mini-barcode, DNA metabarcoding and species delimitation method, a novel biological sources consistency evaluation strategy was proposed, and high level of interspecific and intraspecific variations were observed and validated among 5376 Amynthas samples from 19 sampling points regarded as “Guang Dilong” and 25 batches of proprietary Chinese medicines. Besides Amynthas aspergillum as the authentic source, 8 other Molecular Operational Taxonomic Units (MOTUs) were elucidated. Significantly, even the subgroups within A. aspergillum revealed here differ significantly on chemical compositions and biological activity. Fortunately, this biodiversity could be controlled when the collection was limited to designated areas, as proved by 2796 “decoction pieces” samples. This batch biological identification method should be introduced as a novel concept regarding natural medicine quality control, and to offer guidelines for in-situ conservation and breeding bases construction of wild natural medicine.

As a Traditional Chinese Medicine prescription, Qingjin Yiqi Granules (QJYQ) provides an effective treatment for patients recovering from COVID-19. However, the pharmacokinetics characteristics of the main components of QJYQ in vivo are still unknown. An efficacious ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was developed and validated for the simultaneous determination of 33 components in rat plasma after oral administration of QJYQ. The plasma samples were precipitated with 400 µL methanol/acetonitrile (1/1, v/v) and analyzed in scheduled multiple reaction monitoring mode. The linear relationship of the 33 components was good (r > 0.9928). The lower limit of quantification for 33 components ranged from 0.4–60.5 ng/mL. The average recoveries and matrix effects of the analytes ranged from 72.9% to 115.0% with RSD of 1.4%–15.0%. All inter-day and intra-day RSDs were within 15.0%. After oral administration (3.15 g/kg), the validated approach was effectively applied to the pharmacokinetics of main components of QJYQ. Finally, fifteen main constituents of QJYQ with large plasma exposure were obtained, including baicalin, wogonoside, wogonin, apigenin-7-O-glucuronide, verbenalin, isoferulic acid, hesperidin, liquiritin, harpagide, protocatechuic acid, p-Coumaric acid, ferulic acid, sinapic acid, liquiritin apioside and glycyrrhizic acid. The present research lays a foundation for clarifying the therapeutic material basis of QJYQ and provides a reference for further scientific research and clinical application of QJYQ.

A simple and sensitive strategy using cyclodextrin-modified micellar electrokinetic chromatography with diode array detector was developed and applied for the simultaneous separation and determination of nine components in Sanyetangzhiqing (SYTZQ), a hypoglycemic and hypolipidemic agent. Several important parameters affecting separation performance were evaluated and optimized using single variable methods. Under the optimal conditions, baseline separation of the nine components, including four flavonoids (hyperoside, isoquercitrin, quercetin-3-O-glucuronoside, and astragalin), four phenolic acids (chlorogenic acid, rosmarinic acid, salvianolic acid B, and lithospermic acid), and a monoterpenoids (paeoniflorin), were achieved in less than 16 min. The correlation coefficients of the calibration curves were over 0.9996 for all the analytes. Intraday and interday precisions ranged from 0.4% to 4.8% and 1.7% to 5.0%, respectively. Recoveries of analytes varied from 95.3% to 105%. Validation results as well as the application to analyse SYTZQ samples demonstrated the applicability of the proposed method and thus provided an effective tool for the quality control of SYTZQ. Moreover, with the advantages of short time consuming, low energy consumption, high efficiency, and low cost, this method has laid a foundation for the determination and quality evaluation of multicomponents in Chinese herbal compounds.

Anthocyanins are important components in the peel of red pears and contribute to the appearance of the fruit. Melatonin application is known to affect anthocyanin biosynthesis, but the effect of preharvest melatonin application on fruit coloration remains largely unknown. The objective of this study was to determine the effects of preharvest melatonin application on pigmentation, phenolic compounds, and the expression of related genes in Nanhong pear (Pyrus ussuriensis). The applications were performed during the pre-color-change period by spraying 50 or 200 µmol L−1 of melatonin on fruits. We found that treatment with melatonin had a significant effect on color development. The concentrations of anthocyanins and flavonols were enhanced by melatonin treatment, whereas hydroxycinnamate and flavanol concentrations were reduced. Quantitative real-time PCR analyses indicated that the transcription levels for most anthocyanin biosynthetic genes and anthocyanin-related transcription factors were induced by melatonin. Melatonin application also stimulated the expression of melatonin biosynthesis-related genes and consequently caused an increase in endogenous melatonin concentration. These results provide insights into melatonin-induced fruit coloration and will facilitate the application of exogenous melatonin in agriculture.

Diabetic neuropathy (DN) is a common complication of diabetes, affecting over 50% of patients, leading to significant pain and a burden. Currently, there are no effective treatments available. Cell death is considered a key factor in promoting the progression of DN. This article reviews how cell death is initiated in DN, emphasizing the critical roles of oxidative stress, mitochondrial dysfunction, inflammation, endoplasmic reticulum stress, and autophagy. Additionally, we thoroughly summarize the mechanisms of cell death that may be involved in the pathogenesis of DN, including apoptosis, autophagy, pyroptosis, and ferroptosis, among others, as well as potential therapeutic targets offered by these death mechanisms. This provides potential pathways for the prevention and treatment of diabetic neuropathy in the future. [ABSTRACT FROM AUTHOR]

Objective: Due to the initiation of the priority review program in China, many antitumor drugs have been approved for marketing based on phase II clinical trials and short-term surrogate endpoint indicators. This study used approved targeted drugs for the treatment of non-small-cell lung cancer (NSCLC) in China as an example to evaluate the association between short-term surrogate endpoints [objective response rate (ORR) and disease control rate (DCR)] and median progression-free survival (mPFS) and median overall survival (mOS).Methods: Five databases, i.e., MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Data were searched, for phase II or phase III clinical trials of all molecular targeted drugs that have been marketed in China for the treatment of NSCLC. After screening the literature and extracting information, both univariate and multivariate linear regression were performed on the short-term surrogate indicators and mPFS and mOS to explore the relationship.Results: A total of 63 studies were included (25 studies with only ORR, DCR, and mPFS and 39 studies with ORR, DCR, mPFS, and mOS). In terms of the targeted drugs for the treatment of NSCLC, in addition to the good but not excellent linear relationship between DCR and mOS (0.4 < R2adj = 0.5653 < 0.6), all other short-term surrogate endpoint indicators had excellent linear relationships with mPFS and mOS (R2adj≥0.6), while mPFS and mOS had the most excellent linear relationships (R2adj = 0.8036).Conclusion: For targeted drugs for the treatment of NSCLC, short-term surrogate endpoint indicators such as ORR and DCR may be reliable surrogate indicators for mPFS and mOS. However, whether short-term surrogate endpoint indicators can be used to predict final endpoints remains to be verified.

Pheretima, one of the animal-derived traditional Chinese medicines, has been wildly used in various cardiovascular and cerebrovascular diseases, including stroke, coronary heart disease, hyperlipidemia, and hyperglycemia. However, it was still a big challenge to select the quality markers for Pheretima quality control. The fingerprint and network pharmacology-based strategy was proposed to screen the efficiency related quality markers (Q-Markers) of Pheretima. The ratio of sample to liquid, ultrasonic-extraction time, temperature, and power were optimized by orthogonal design, respectively. The chemical fingerprint of forty batches of Pheretima was established, and six common peaks were screened. The network pharmacology was used to construct the Pheretima-Components-Targets-Pathways-Stroke network. It was found that six potential efficacy Q-markers in Pheretima could exert the relaxing meridians effect to treat stroke through acting on multiple targets and regulating various pathways. A simple HPLC-DAD method was developed and validated to determine the efficacy Q-markers. Grey relational analysis was used to further verify the relation of potential efficiency related quality markers with the anticoagulation activity of Pheretima, which indicated that the contents of these markers exhibited high relationship with the anticoagulation activity. It was concluded that hypoxanthine, uridine, phenylalanine, inosine, guanosine, and tryptophan were selected as quality markers related to relaxing meridians to evaluate the quality of Pheretima. The fingerprint and network pharmacology-based strategy was proved to be a powerful strategy for the discovery of efficiency related Q-markers of Pheretima.

Abstract Cardiac hypertrophy is a pivotal pathophysiological step of various cardiovascular diseases, which eventually leads to heart failure and death. Extracts of Rhodiola species (Ext.R), a class of commonly used medicinal herbs in Europe and East Asia, can attenuate cardiac hypertrophy both in vitro and in vivo. Serum/glucocorticoid regulated kinase 1 (SGK1) is identified as a potential target of Ext. R. By mass spectrometry‐based kinase inhibitory assay, herbacetin (HBT) from Ext.R is identified as a novel SGK1 inhibitor with IC50 of 752 nmol. Thermal shift assay, KINOMEscan in vitro assay combined with molecular docking proves a direct binding between HBT and SGK1. Site‐specific mutation of Asp177 in SGK1 completely ablates the inhibitory activity of HBT. The presence of OH groups at the C‐3, C‐8, C‐4’ positions of flavonoids is suggested to be favorable for the inhibition of SGK1 activity. Finally, HBT significantly suppresses cardiomyocyte hypertrophy in vitro and in vivo, reduces reactive oxygen species (ROS) synthesis and calcium accumulation. HBT decreases phosphorylation of SGK1 and regulates its downstream forkhead box protein O1 (FoxO1) signaling pathway. Taken together, the findings suggest that a panel of flavonoids structurally related to HBT may be novel leads for developing new therapeutics against cardiac hypertrophy.

Background: Several drugs currently are available for the treatment of Crohn's disease, including non-biological agents such as anti-inflammatory agents, steroids, immunosuppressive agents, and biologic agents such as anti-tumor necrosis factor (TNF), anti-α4β7 integrin, anti-alpha-4 integrin and anti-interleukin 12/23. However, the choice of treatments for induction and maintenance is still a challenge. The relevant comparison between non-biologic agents and biologic agents is few. In our research, we aimed to help making decisions, as well as providing clinicians and patients with medication references.Methods: We searched MEDLINE, Embase, and the Cochrane Central Register of controlled trials for relevant randomized controlled trials published through to July 2020 and systematic reviews published from January 2011 to December 2020. Search results were screened by 2 independent reviewers first by title and abstract and then by full text. Disagreements were resolved through discussion with a third reviewer.Results: 54 randomized controlled trials were included in our analysis. For induction of remission, azathioprine (OR, 3.5; 95% Crl, 1.4–8.9), infliximab (OR, 4.1; 95% Crl, 1.2–16.0), infliximab + azathioprine (OR, 7.0; 95% Crl, 1.2–41.0) and infliximab+ methotrexate (OR, 7.8; 95% Crl, 1.2–65.0) were more effective in first-line therapy than placebo. Adalimumab showed superiority to placebo in second-line therapy, but the range of SD was wide. For maintenance of remission, adalimumab (OR,2.24;95% Crl,1.17–4.76) and azathioprine (OR,2.05; 95% Crl,1.14–3.96) were more effective than placebo. Adalimumab (OR,0.56; 95%Crl,0.27–1.2), budesonide (OR,0.63; 95%Crl,0.26–1.6) and natalizumab (OR,0.65; 95%Crl,0.30–1.4) was associated with less risk of withdrawals when compared with placebo.Conclusion: For induction of remission, azathioprine, infliximab, and infliximab + azathioprine were more effective in first-line therapy. In second-line therapy, adalimumab was more effective but should be interpreted carefully. For maintenance of remission, adalimumab and azathioprine were more effective. Besides, adalimumab, budesonide, natalizumab had lower withdrawals. Therefore, biological agents were not always better than non-biological agents and they have their own advantages in different treatment methods of Crohn's disease.

Sanye Tablet (SYT) is a patent prescription widely used in treating T2D and pre-diabetes, especially T2D comorbid with hypertriglyceridemia, for many years in China. However, the underlying mechanism that accounts for the anti-diabetic potential of SYT by regulating lipid-related intermediates remains to be elucidated. This study aimed to investigate the mechanism of SYT on lipid metabolism and insulin sensitivity in high-fat diet (HFD)-induced obese mice by means of combining lipidomics and proteomics. The obese mice models were developed via HFD feeding for 20 consecutive weeks. Mice in the treatment group were given metformin and SYT respectively, and the effects of SYT on body weight, blood glucose, insulin sensitivity, fat accumulation in the organs, and pathological changes in the liver were monitored. Lipid metabolism was examined by lipidomics. Further determination of signaling pathways was detected by proteomics. The biological contributions of the compounds detected in SYT’s chemical fingerprint were predicted by network pharmacology. SYT treatment reduced body weight, inhibited viscera and hepatic steatosis lipid accumulation, and prevented insulin resistance. Furthermore, it was found that circulatory inflammatory cytokines were reduced by SYT treatment. In addition, lipidomics analysis indicated that SYT targets lipid intermediates, including diacylglycerol (DAG) and Ceramide (Cer). Mechanistically, SYT positively affected these lipid intermediates by suppressing liver lipogenesis via downregulation of SREBP1/ACC and the JAK/STAT signaling pathway. Our results predicted that astragalin and rosmarinic acid might regulate the JAK-STAT pathway by targeting PIM2 and STAT1, respectively, while paeoniflorin and rosmarinic acid were likely to regulate inflammatory responses by targeting TNFα, IL-6, and IL-4 during T2D. Overall, our study provides supportive evidence for the mechanism of SYT’s therapeutic effect on dysregulated lipid metabolism in diabesity.

Pancreatic fibrosis is a pathological characteristic of chronic pancreatitis (CP) and pancreatic cancer. Chaihu Guizhi Ganjiang Decoction (CGGD) is a traditional Chinese medicine, which is widely used in the clinical treatment of digestive diseases. However, the potential anti-fibrosis mechanism of CGGD in treating CP remains unclear. Here, we conducted a series of experiments to examine the effect of CGGD on the CP rat model and primary isolated pancreatic stellate cells (PSCs). The results revealed that CGGD attenuated pancreatic damage, decreased collagen deposition, and inhibited PSC activation in the pancreas of CP rats. However, compared with the CP group, CGGD had no effect on body weight and serum amylase and lipase. In addition, CGGD suppressed autophagy by downregulating Atg5, Beclin-1, and LC3B and facilitated phosphorylation of mTOR and JNK in pancreatic tissues and PSCs. Moreover, the CGGD-containing serum also decreased LC3B or collagen I expression after rapamycin (mTOR inhibitor) or SP600125 (JNK inhibitor) treatment in PSCs. In conclusion, CGGD attenuated pancreatic fibrosis and PSC activation, possibly by suppressing autophagy of PSCs through the JNK/mTOR signaling pathway.

Abstract Background Echinococcosis caused by Echinococcus is one of the most major infectious diseases in north-west highland of China. E. granulosus sensu strict, E. multilocularis, and E. canadensis are known to be the only three species related to human health transmitting in the areas. To achieve targeted treatment and control of echinococcosis, the accurate identification and discrimination of the species are important. However, currently the available diagnostic approaches do not present ideal results either in accuracy or efficiency. Methods In the study, a set of primers were designed to aim at the three human-pathogenic Echinococcus species in China. The one-step multiplex PCR assay was developed and evaluated for the specificity and sensitivity. A total of 73 parasitic lesions and 41 fecal materials obtained from human and various animals collected in the clinic and the field were tested to assess the applicability of this method. Results The multiplex PCR effectively detected the individual DNA from the targeted species and their random mixtures generating with distinguishable expected size of products. The detection limit of the assay for each of the three species was 5 pg/μl when they were tested separately. When DNA mixtures of the targeted species containing the same concentration were used as templates, the lowest amount of DNA which can be detected was 50 pg/μl, 10 pg/μl and 5 pg/μl for E. granulosus s. s., E. multilocularis, and E. canadensis respectively. No cross-reactivity was observed when DNA from eight genetically close species was used as control templates. The multiplex PCR identifications of all samples were in line with the original sequencing results except for those infected with E. shiquicus, which showed negative signals in the developed assay. Of all the tested stool materials, 16 were previously found positive for Echinococcus by visual and microscopic examination. Among these 16 samples, 13 were confirmed by the multiplex PCR, and the other three tested negative. Additionally, the multiplex PCR identified another 14 positive feces from the remained 25 stool samples which absence of worms. Conclusions The developed multiplex PCR shows advantages in fast diagnosis and large-scale epidemiological investigation, which proven to be a promising tool utilized in clinic and surveillance system.

Introduction: This study evaluated the cost-effectiveness of atezolizumab + chemotherapy vs. chemotherapy as first-line treatment for extensive-stage small-cell lung cancer (SCLC) in the United States (US).Methods: The three health states partitioned survival (PS) model was used over the lifetime. Effectiveness and safety data were derived from the IMpower133 trial. The parametric survival model and mixture cure model were used for the atezolizumab + chemotherapy group to explore the long-term uncertainty of the effect of immunotherapy, and the parametric survival model was used for the chemotherapy group. Costs were derived from the pricing files of Medicare and Medicaid Services, and utility values were derived from previous studies. Sensitivity analyses were performed to observe model stability.Results: If the mixture cure model was considered for the intervention group, compared with chemotherapy alone, atezolizumab + chemotherapy yielded an additional 0.11 quality-adjusted life-years (QALYs), with an incremental cost of US$84,257. The incremental cost-utility ratio (ICUR) was US$785,848/QALY. If the parametric survival model was considered for the intervention group, atezolizumab + chemotherapy yielded an additional 0.10 QALYs, with an incremental cost of US$84,257; the ICUR was US$827,610/QALY. In the one-way sensitivity analysis, progression-free (PF) and postprogression (PP) utilities were the main drivers. In the scenario analysis (PF utility = 0.673, PP utility = 0.473), the results showed that the ICUR was US$910,557/QALY and US$965,607/QALY when the mixture cure model and parametric survival model was considered for the intervention group, respectively. In the PSA, the probabilities that atezolizumab + chemotherapy would not be cost-effective were 100% if the willingness-to-pay threshold was US$100,000/QALY.Conclusions: The findings of the present analysis suggest that atezolizumab + chemotherapy is not cost-effective in patients receiving first-line treatment for extensive-stage SCLC in the US.

Objective: This study aimed to compare the economic evaluation of recombinant human thrombopoietin+rituximab (rhTPO + RTX) vs. RTX as second-line treatment for adult patients with immunologic thrombocytopenic purpura in China.Methods: The Markov model was used in our research. The response rate and relapse rate data were derived from two clinical trials and one retrospective study. Cost and utility values were derived from published literature, a third-party database, and healthcare documents. In addition, one-way sensitivity analysis and probabilistic sensitivity analysis were performed to observe the stability of the model and data source.Results: In the Markov model, compared with RTX, rhTPO+RTX yielded an additional 0.04 QALYs, with an incremental cost of 2,802 USD. The ICER was 69,097 USD/QALY. According to the results from the one-way sensitivity analysis, complete response of rhTPO+RTX, utility of complete response and response of RTX were the main drivers in the model. The results from the probabilistic sensitivity analysis demonstrated that there was a 100% probability that rhTPO+RTX was not cost-effective vs. RTX alone at a threshold of $10,805/QALY and an 84% probability at a threshold of $32,415/QALY.Conclusion: RTX+rhTPO was not more cost-effective than RTX alone as second-line treatment for adult patients with immunologic thrombocytopenic purpura in China.

A green, flexible, and effective strategy was proposed to quantify four target compounds (muscone, ethyl palmitate, ethyl oleate, and ethylparaben) from musk by binary eluent based vortex-assisted matrix solid-phase dispersion (MSPD) extraction coupled with GC/MS. Single-factor tests and orthogonal design were employed to optimize the MSPD parameters. In addition, the binary eluent system, methanol, and ethyl acetate 3 : 7 (v/v) were used to extract the target analytes. Finally, C18 was applied as the easily available dispersant and the sample powder was ground for 2 min. Thereafter, the mixture was rapidly extracted with the binary eluents under whirling for 3 min. Eventually, the analysis of the samples was completed within 12 min by GC/MS. All correlation coefficients (r) of four targets were more than 0.9991. The recoveries of all target compounds ranged from 92.8% to 101% while their RSDs were less than 6.94%. There was no significant matrix interference for the analysis. Thus, the combination of vortex-assisted MSPD with GC/MS was considered as a novel, rapid, and environmentally friendly quantitative approach for musk samples.

Secondary choledocholithiasis occurs when stones leave the gallbladder. After therapeutic endoscopic retrograde cholangiopancreatography (ERCP) with stone removal, cholecystectomy should be performed to prevent recurrence. However, the optimal timing for cholecystectomy in secondary choledocholithiasis patients is unclear. The aim of this study was to determine the optimal timing for laparoscopic cholecystectomy in patients with secondary choledocholithiasis. In total, 22,996 patients in the Taiwan National Health Insurance Research Database (NHIRD) who underwent laparoscopic cholecystectomy for acute cholecystitis from 1998–2015 were divided into three groups according to whether they underwent surgery as an inpatient (early cholecystectomy (ELC)), within 2 months of admission (intermediate cholecystectomy (ILC)), or 2 months after admission (delayed cholecystectomy (DLC)). The primary outcomes included the recurrence, complication, and mortality rates. After adjusting for confounders, according to the 2013 Tokyo guidelines (cut-off at 2013), a subgroup analysis showed that, compared to the ELC group, the ILC group had lower recurrence, complication, and mortality rates, whereas the DLC group exhibited statistically significantly higher recurrence and mortality rates. In conclusion, the optimal timing of cholecystectomy in secondary choledocholithiasis patients after preoperative ERCP is within 2 months (ILC) after hospital admission. Moreover, ELC is associated with a measurable risk of complications. [ABSTRACT FROM AUTHOR]

Acute nociception is essential for survival by warning organisms against potential dangers, whereas tissue injury results in a nociceptive hypersensitivity state that is closely associated with debilitating disease conditions, such as chronic pain. Transient receptor potential (Trp) ion channels expressed in nociceptors detect noxious thermal and chemical stimuli to initiate acute nociception. The existing hypersensitivity model suggests that under tissue injury and inflammation, the same Trp channels in nociceptors are sensitized through transcriptional and posttranslational modulation, leading to nociceptive hypersensitivity. Unexpectedly and different from this model, we find that in Drosophila larvae, acute heat nociception and tissue injury-induced hypersensitivity involve distinct cellular and molecular mechanisms. Specifically, TrpA1-D in peripheral sensory neurons mediates acute heat nociception, whereas TrpA1-C in a cluster of larval brain neurons transduces the heat stimulus under the allodynia state. As a result, interfering with synaptic transmission of these brain neurons or genetic targeting of TrpA1-C blocks heat allodynia but not acute heat nociception. TrpA1-C and TrpA1-D are two splicing variants of TrpA1 channels and are coexpressed in these brain neurons. We further show that Gq-phospholipase C signaling, downstream of the proalgesic neuropeptide Tachykinin, differentially modulates these two TrpA1 isoforms in the brain neurons by selectively sensitizing heat responses of TrpA1-C but not TrpA1-D. Together, our studies provide evidence that nociception and noncaptive sensitization could be mediated by distinct sensory neurons and molecular sensors. [ABSTRACT FROM AUTHOR]

Considering the basic concepts of P‐type and N‐type originated from inorganic semiconductors, it has been deduced in this report that the non‐doped polymer semiconductors should be ambipolar materials. Thus, the carrier dynamics of hole‐only and electron‐only devices of poly(N‐vinylcarbazole) (PVK) are researched through impedance spectroscopy. The results show that the hole and electron transports both possess high dispersion with parameter of 0.1–0.2 and 0.1, respectively. In addition, the hole and electron mobilities under different electric field are basically in the same order of magnitude, which shows that PVK is one intrinsically ambipolar polymer semiconductor although it is traditionally thought to "P‐type." Finally, the abnormal negative slope phenomenon of transferring curve is analyzed, which is ascribed to the energy relaxation through vibration in polymer segment. [ABSTRACT FROM AUTHOR]

Context: We previously reported a novel tumour associated antigen (TTA) with molecular weight around 48 kDa and identified the novel TTA as a fragment derived from human DNA-topoiomerase I (TOP1). We termed the novel TAA as TOPO48 and termed autoantibody against the TAA as anti-TOPO48 autoantibody. Objective: To explore the clinical significance of anti-TOPO48 autoantibody in patients with colorectal carcinoma (CRC). Materials and methods: Serum levels of the autoantibody in patients with CRC or benign tumours and healthy volunteers were measured with a specific ELISA. Results: CRC patients at early stage had higher frequency of positive levels of the autoantibody and CRC patients with positive autoantibody levels had higher overall survival rate than those with negative autoantibody levels. Conclusion: The autoantibody is a potential biomarker for early diagnosis and favourable prognosis of CRC. [ABSTRACT FROM AUTHOR]

A series of charge-neutral cyclometalated iridium(III) complexes (1–3 and 5–7) containing triptycene-substituted ligands (tbt and tpbi) and two parent complexes (4 and 8) were synthesized and characterized. The crystal structures indicated that π–π stacking interactions existed in ligand tbtH, but not in complex 6. However, a large intramolecular repulsion was found in complex 6. These triptycene-based complexes exhibited good thermal stability, which was higher compared with that of the parent complexes. These complexes showed green to yellow emission with peaks that ranged from 503 to 563 nm. The introduction of the rigid non-conjugate triptycene skeleton caused a slight emission red shift (<25 nm), but a significant increase in the PLQYs (>47%) was observed. The electroluminescent devices employing 2 and 6 as phosphors displayed impressive performance improvements and low efficiency roll-off because of the higher PLQYs and HOMO levels of these triptycene-based complexes. The maximum current and external quantum efficiencies of the devices based on complexes 2 and 6 were 41.7 cd A−1, 11.9% and 41.2 cd A−1, 12.6%, respectively, which were about 31% higher than that of the devices based on the parent complexes 4 and 8. This work provides a novel approach to develop highly efficient phosphors with a triptycene skeleton. [ABSTRACT FROM AUTHOR]

Background We previously reported a novel tumor-associated antigen with a molecular weight of approximately 48 kDa that was a fragment derived from human DNA-topoisomerase I. The aim of this study is to further investigate the clinical significance of the autoantibody in patients with non-small cell lung cancer (NSCLC). Methods We determined serum levels of the autoantibody in 127 NSCLC patients, 127 age-, sex-, and smoking history–matched healthy control subjects, and 38 patients with pulmonary benign tumors by using a specific enzyme linked immunosorbent assay for the autoantibody. We then statistically evaluated its clinical application value. Results Serum levels of the autoantibody in NSCLC patients were significantly higher than in healthy control subjects and patients with benign tumors ( p = 0.001). The percentage of sera with a positive level of the autoantibody was 71.8%, 65.6%, 41.9%, and 48.0% in stages I, II, III, and IV of the cancer, respectively ( p = 0.049). The area under the receiver-operating characteristics curve was 0.971 (95% confidence interval: 0.953 to 0988) for healthy controls and patients with benign tumors versus early stage NSCLC patients. Moreover, the overall survival rate of the patients in stages I, II, and IV with negative levels of the autoantibody was significantly lower than that of patients with positive levels of the autoantibody ( p = 0.013, 0.023, and 0.047 for stages I, II, and IV, respectively). Conclusions Our results indicate that the autoantibody can be used as a novel biomarker for the early diagnosis and prognosis of NSCLC. [ABSTRACT FROM AUTHOR]

Herein, a new series of ambipolar host materials is synthesized, which features a pyridine core and triphenylamine or carbazole arm combined in a non-conjugated configuration. Theoretical calculation results show that their HOMO/LUMO distribution is adjusted from an overlapped state to partially and thoroughly separated states, and their hole/electron transportation ability and energy levels are also tuned, in addition to their triplet energy level varying from 2.38 to 2.87 eV. Thermogravimetric analysis and DSC measurement results display a high thermal decomposition temperature of 420–490 °C and a wide glass transition temperature range of 160–173 °C, along with excellent reversible redox behavior in electrochemical processes. Utilizing the pure host of 4′,4′′′-(pyridine-2,6-diylbis(9H-fluorene-9,9-diyl))bis(N,N-diphenyl-[1,1′-biphenyl]-4-amine), blue organic light-emitting diodes (OLEDs) show a high efficiency of 18.5 cd A−1 and 13.6 lm W−1 compared with 16.3 cd A−1 and 11.6 lm W−1 for the cohost diodes, respectively. Additionally, orange phosphorescent device from the N,N′-((pyridine-2,6-diylbis(9H-fluorene-9,9-diyl))bis(4,1-phenylene))bis(N-phenylnaphthalen-1-amine) cohost shows higher efficiency than the single host devices with a maximum luminous efficiency of 37.3 cd A−1 in a high brightness region of around 12 680 cd m−2, which makes it one of the most efficient orange OLEDs containing a solution processed single emissive layer structure. Significantly, their efficiency roll-off is greatly suppressed at high luminance, particularly for the orange device with a 3.21% decrease in efficiency from the maximum to a high brightness of 10 000 cd m−2. This work provides a useful guide for molecular design toward solution processed OLEDs. [ABSTRACT FROM AUTHOR]

Background: The production of autoantibodies against tumour-associated antigens (TAAs) is believed to reflect greater immunologic reactivity in cancer patients and enhanced immune surveillance for cancer cells. Over the past few decades, a number of different TAAs and their corresponding autoantibodies have been investigated. However, positive frequency of autoantibody detection in cancer patients has been relatively low. Here we describe a novel TAA that was a fragment derived from human DNA-topoiomerase I and an autoantibody against the novel TAA with relatively high positive frequency in the sera of early-stage non-small-cell lung cancer (NSCLC), gastric cancer (GC), colorectal cancer (CRC) and oesophageal squamous cell carcinoma (ESCC).Methods: Serologic enzyme-linked immunosorbent assay (ELISA) and western blot were used to discover a novel TAA with a molecular weight of 48 kDa separated by ion exchange chromatography. Autoantibody ELISA, immnohistochemistry and immunofluorescent staining, recombinant protein cloning/expression and western blot were used to identify the novel TAA. The association of the autoantibody against the novel TAA with early-stage carcinoma was explored by screening 203 stage I/II patients and 170 stage III/IV patients with NSCLC, GC, CRC or ESCC.Results: We identified the novel TAA as a fragment derived from human DNA-topoiomerase I (TOP1). We found that the novel TAA induced specific autoantibodies with a high prevalence that ranged from 58 to 72% in some of the most common types of cancer. We observed that the immune response against the novel TAA was associated with early stage ESCC, GC, CRC and NSCLC.Conclusions: The findings in this study suggest that the autoantibody against the novel TAA may be a potential biomarker for use in the early detection and diagnosis of cancer. [ABSTRACT FROM AUTHOR]

Background: Human cystic echinococcosis (CE) and alveolar echinococcosis (AE) are highly endemic in Tibetan communities of Sichuan Province. Previous research in the region indicated that domestic dog was the major source of human infection, and observations indicated that domestic dog could have more access to intermediate hosts of Echinococcus spp.: both domestic livestock (CE) viscera and small mammals (AE), in early winter and again in spring. We hypothesized that there would therefore be a significant increase in the risk of canine infection with Echinococcus spp. in these two seasons and conducted a reinfection study to investigate this further. Methods: Faecal samples were collected from owned dogs in seven townships in Ganze Tibetan Autonomous Prefecture (Sichuan Province, China), and Echinococcus spp. infection status was determined using copro-antigen ELISA. Dogs were sampled in April (spring), July (early summer), September/October (autumn/early winter) and December (winter) in 2009; and in April (spring) 2010. Dogs were treated with praziquantel following each of the five sample collections to eliminate any tapeworms. Information on dog sex, age and body weight was also collected. The t-test, Fisher's exact test, Poisson regression and logistic regression were used to compare means and prevalences, and to identify factors associated with infection status. Results: The proportion of female dogs was significantly lower than that of male dogs; female dogs had significantly higher (22.78 %) baseline copro-ELISA prevalence than males (11.88 %). Dog body weight, sex, age, county and previous infection status at any sampling point had no influence on the re-infection prevalence in general. Poisson regression did not found a significant influence on the re-infection prevalence due to different deworming/sampling time spans. Dogs exhibited significantly higher re-infection prevalences in spring and early summer of 2009 and in early winter between September/October and December of 2009, suggesting a higher infection pressure in these seasons comparing with other seasons. Conclusion: Following praziquantel treatment, dog body weight, sex, age, county, deworming time span and previous infection status at any sampling point had no influence on the re-infection prevalence in the region in general. The differences between re-infection prevalences were probably due to the seasonality in Echinoccocus spp. infection pressure in the region. Early winter, spring and early summer should be important seasons for optimal dog deworming intervention in these Tibetan communities. [ABSTRACT FROM AUTHOR]

Cost-effective fabrication of white organic light-emitting diodes (WOLED) is meaningful toward commercial application of environment-friendly solid-state lighting sources. Electroluminescent efficiency and color quality are two opposite performance characteristics facing solution processed WOLEDs requiring balanced consideration. Herein, a recently synthesized molecule of 4,4’-(9,9’-(1,3-phenylene)bis(9 H -fluorene-9,9-diyl))bis( N , N -diphenylaniline) (DTPAFB) is introduced as a host material for solution processed all-phosphor WOLEDs, embracing four well-known molecules which are blue iridium (III) bis(2-(4,6-difluorophenyl)pyridinato-N,C 2 )(picolinate) (FIrpic), green iridium (III) bis[2-(2-pyridinyl- N )phenyl-C](2,4-pentanedionato-O 2 ,O 4 ) [Ir(ppy) 2 (acac)], and orange iridium (III) bis(2-phenyl-benzothiazole-C 2 ,N)(acetylacetonate) [Ir(bt) 2 (acac)] plus a home-made red phosphor of iridium (III) tris(1-(2,6-dimethylphenoxy)-4-(4-chlorophenyl)phthalazine) [Ir(MPCPPZ) 3 ]. Illumination quality white light with high brightness, high efficiency, suitable correlated color temperature (CCT), high color-rendering index (CRI), and stable electroluminescent (EL) emission is obtained. A stable white emission with a CRI over 70, Commission Internationale de L'Eclairage (CIE) of (0.37, 0.42), and high EL efficiency of 19.6 lm W −1 at high luminance of 2000 cd m −2 for blue/orange complementary color WOLEDs is demonstrated. The optimized red/green/blue three primary color WOLEDs show improved CRI up to 81, moderate high efficiency of 25.8 cd A −1 , 14.4 lm W −1 , and EQE of 13.9%. Furthermore, the red/green/blue/orange four primary color WOLEDs show the optional balance between color quality and EL efficiency with high CRI of around 81–83 and medium CCT of 3755–3929 K which is warm and soft to human eyes. At an illumination relevant luminance of 1000 cd m −2 , the total power efficiency reaches 33.6 lm W −1 , and still remains 30.2 lm W −1 at 3000 cd m −2 , approaching the efficiency of state-of-the-art fluorescent-tube (40–70 lm W −1 ), potentially suitable as an environment-friendly solid-state lighting source. This work indicates that developing high performance host materials and highly efficient phosphors and carefully combining them with common phosphors is an effective way toward high performance WOLEDs. [ABSTRACT FROM AUTHOR]