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Background In bladder cancer, up to 70% of patients will relapse after resection within 5 years, in which the mechanism underlying the recurrence remains largely unclear. Methods Quantitative real-time PCR, western blot and immunohistochemistry were conducted. The assays of tumor sphere formation and tumor xenograft were further performed to assess the potential biological roles of ATF5 (activating transcription factor 5). Chromatin immunoprecipitation-qPCR and luciferase activity assays were carried out to explore the potential molecular mechanism. A two-tailed paired Student's t-test, χ2 test, Kaplan Meier and Cox regression analyses, and Spearman's rank correlation coefficients were used for statistical analyses. Results ATF5 is elevated in bladder urothelial cancer (BLCA) tissues, especially in recurrent BLCA, which confers a poor prognosis. Overexpressing ATF5 significantly enhanced, whereas silencing ATF5 inhibited, the capability of tumor sphere formation in bladder cancer cells. Mechanically, ATF5 could directly bind to and stimulate the promoter of DVL1 gene, resulting in activation of Wnt/β-catenin pathway. Conclusions This study provides a novel insight into a portion of the mechanism underlying high recurrence potential of BLCA, presenting ATF5 as a prognostic factor or potential therapeutic target for preventing recurrence in BLCA.

In order to cut the costs and overcome the leakage current of batteries caused in traditional method, this study introduces an improved voltage transfer method for lithium battery string management chip. This proposed circuit based on the improved voltage transfer method is fabricated in 180‐nm Bipolar‐CMOS‐DMOS is correct technology, and has been successfully applied to a three lithium batteries string management chip. These measurements indicate that this circuit transfers each cell’s voltage reliably and adopt protection against abnormal conditions. Furthermore, analysis of 50 samples shows that the improved method can greatly eliminate the battery leakage. The circuit reduces the leakage current to nanoampere scale and is integrated into the lithium battery string management chip, which is helpful for battery voltage balance and low cost.

Ketoreductases have shown considerable potential as biocatalysts in the asymmetric synthesis of chiral alcohols. However, compared to the widely studied ketoreductases for chiral alcohols, limited knowledge is available about ketoreductases for efficient dynamic reductive kinetic resolution (DYRKR) of bulky α-amino β-keto esters. In this study, structure-guided rational direct evolution was applied to a ketoreductase (WTEA) from Exiguobacterium sp. F42 for the asymmetric reduction of bulky α-amino β-keto esters. A number of mutants were then obtained with remarkably improved activity toward various bulky α-amino β-keto esters with excellent stereoselectivity by performing structure-guided rational design. In particular, mutant M30 (W82L/F88V/V121A/A138L/R142M/A190V/S193A/Y201F/N204A) exhibited excellent stereoselectivity (>99% dr, >99% de) and high conversion (>99%) for six α-amino β-keto esters. Furthermore, novel and practical chemoenzymatic routes were developed for the synthesis of chloramphenicol and florfenicol, which featured the application of enzymatic DYRKR to establish the two stereocenters of amino alcohols 4-NO2-substituted (2S, 3R)-5b and 4-SO2Me-substituted (2S, 3R)-8b with > 99% dr, > 99% de and >99% conversion from 100 g L−1 α-amino β-keto esters 5a and 8a (highest substrate loading reported), respectively. Crystal structure and molecular dynamics studies revealed the potential molecular basis for activity improvement and the stereoselectivity control mechanism at the atomic level. These results provide important insights into the evolution of ketoreductases for the asymmetric synthesis of chiral vicinal amino alcohols and establish a solid foundation for further large-scale industrial applications in the future.

We first developed a novel and efficient chemoenzymatic process to prepare (S)-1-(pyridin-4-yl)-1,3-propanediol, a vital HepDirect prodrug intermediate, from inexpensive and commercially available ...

(S)-2-Chloro-1-(2,4-dichlorophenyl) ethanol (3) is a chiral intermediate in the synthesis of luliconazole ((R)-E-1). Here, we report a novel biopreparation of 3 by bioreduction of 2-chloro-1-(2,4-d...

Lithium-ion battery as an efficient, sustainable, and clean energy for electric vehicles (EVs) and smart devices becomes more popular with the worldwide demand for reduction of greenhouse gas emission. In all kinds of applications, an accurate real-time estimation for state of charge (SOC) of battery is necessary. Some conventional methods usually need to sample both battery currents and voltages. This article presents a novel SOC estimation algorithm without current detection. This algorithm just acquires the port voltages of cell to calculate the open-circuit voltage (OCV) which is related to SOC. By extracting a large number of battery voltages based on a step response, some important parameters that can track battery working process are determined. In order to verify the algorithm feasibility and accuracy, it has been tested on a commercial common field-programmable gate array (FPGA) in different application conditions. The algorithm accuracy is mainly limited by model accuracy and sampling sensor accuracy. The maximum error between ideal SOC and calculated SOC by this algorithm is within 4%, and the mean error is about 0.99%. So, this high-feasibility, accredited accuracy, easy integration, and low-cost solution has bright potential in smarter future.

Increasing availability of reactive nitrogen (N) threatens plant diversity in diverse ecosystems. While there is mounting evidence for the negative impacts of N deposition on one component of diversity, species richness, we know little about its effects on another one, species evenness. It is suspected that ecosystem management practice that removes nitrogen from the ecosystem, such as hay-harvesting by mowing in grasslands, would mitigate the negative impacts of N deposition on plant diversity. However, empirical evidence is scarce. Here, we reported the main and interactive effects of N deposition and mowing on plant diversity in a temperate meadow steppe with 4-year data from a field experiment within which multi-level N addition rates and multiple N compounds are considered. Across all the types of N compounds, species richness and evenness significantly decreased with the increases of N addition rate, which was mainly caused by the growth of a tall rhizomatous grass, Leymus chinensis. Such negative impacts of N addition were accumulating with time. Mowing significantly reduced the dominance of L. chinensis, and mitigated the negative impacts of N deposition on species evenness. We present robust evidence that N deposition threatened biodiversity by reducing both species richness and evenness, a process which could be alleviated by mowing. Our results highlight the changes of species evenness in driving the negative impacts of N deposition on plant diversity and the role of mowing in mediating such negative impacts of N deposition.

Nitrogen (N) enrichment has great consequences on several fundamental ecological processes through its impacts on plant nutrition traits (i.e. nutrient concentration and stoichiometric ratios); however, the extent to which the effects of N enrichment depend on phosphorus (P) availability are less well understood. While there is mounting evidence for the species-specific responses of plant nutrition traits to nutrient enrichment, we know little about the changes at the community-level. Here, we measured community-level biomass weighted (CWM) and non-weighted (CM) plant N and P concentrations and N:P ratio in a temperate meadow steppe after four years factorial N and P addition, with biomass and nutrition traits of each species in each plot being recorded. Nitrogen addition significantly increased community-level N concentration, decreased P concentration, and enhanced community N:P ratio. Phosphorus addition had no impacts on community-level N concentration, significantly increased P concentration, and reduced community N:P ratio. The impacts of N addition on community nutrition traits were not dependent on P addition and the community-level nutrition trait responses to N and P additions were primarily driven by intraspecific trait variation (ITV) rather than by species turnover. Community-level nutrition traits in the temperate meadow steppe were sensitive to the projected N and P enrichment. While nutrient enrichment had substantially changed community composition, its impacts on community nutrition traits were driven by ITV. Nitrogen deposition would result in imbalance of N and P in plant community, as indicated by the substantial increase in community-level N:P, which was not affected by increased P availability.

Background To primarily evaluate the effects and safety of a selective angiotensin II type 1 (AT1) receptor blocker (ARB) allisartan isoproxil combined with amlodipine or indapamide in the treatment of patients with essential hypertension who failed allisartan monotherapy. Methods Patients aged 18–75 years with mild-to-moderate essential hypertension [office systolic blood pressure (SBP) 140 to Results A total of 2,212 patients were enrolled, among them 2,126 patients were included in the efficacy analysis, with an average age of 55.1 ± 10.2 years. A total of 1,463 cases (68.8%) were effective after 4 weeks allisartan treatment, and the mean SBP and DBP were significantly decreased by 14.7 ± 12.2 and 8.0 ± 8.4 mm Hg compared with the baseline levels (all P < 0.001). In nonachievers, allisartan combined with indapamide for 8 weeks significantly lowered the sitting BP (SBP/DBP) by 14.0 ± 12.2/8.3 ± 9.2 mm Hg, respectively, compared with 4 weeks monotherapy with allisartan with a BP targeting rate of 57.7% (169/293). In the allisartan + amlodipine group, the SBP/DBP were significantly decreased by (14.4 ± 12.1/8.2 ± 8.2) mm Hg, respectively, with a BP targeting rate of 62.8% (181/288). There was no statistical significance in BP reduction, targeting rate, or adverse reactions between the 2 combined therapies. Conclusions Allisartan isoproxil combined with indapamide or amlodipine can further improve the BP targeting rate when allisartan monotherapy failed in essential hypertension. The 2 combined therapies have similar efficacy and safety.

Two new hybrid compounds with chemical formulas [Co(L1)2(H2O)2]2[SiW12O40]·6H2O (1) and [Cu2(C9H22 N)2(L2)2][SiW12O40]·2H2O (2) (L1 = 3,3′-diamino-5,5′-bis(1H-1,2,4-triazole), L2 = 1,2-bis(3-(2-pyridyl)pyrazole-1-ylmethyl)benzene, C9H22 N = tripropylamine) were prepared in a hydrothermal reaction system containing Keggin-type polyoxometalates (POMs), transition metal (TM) salts (cobalt salts and copper salts), and chelate L1/L2 ligands. X-ray structural analysis reveals that 1 and 2 possess 3-D supramolecular host frameworks with large cavities and the polyoxoanions SiW12 reside in these cavities as the guest templates. The photocatalytic activities of 1 and 2 were investigated. Both compounds show efficient catalytic activity for degradation of RhB with 1 > 2. The loading amount of the POM units and the structural features of these POM-based organic-inorganic hybrid compounds may be necessary factors that affect the activity of catalysts in the photocatalytic degradation.

In this paper, a new high-voltage level shifter (HVLS) structure is proposed, which has a significantly improved transient response over existing structures. To overcome signal transfer delay of the conventional HVLS caused by parasitic capacitance due to high-voltage MOSFETs, this structure employs a novel circuit module "inverse Schmitt trigger" to drive the pull-up transistors of conventional HVLS. As a result, the "Miller Plateau" caused by parasitic capacitance can be minimized. Hence, the overall transfer delay of the structure is significantly reduced. The simulation results based on SPECTRE and 0.5 $$\upmu $$μm high-voltage CMOS process show that compared to other currently available structures whose transfer delays are several nanoseconds on average, the proposed structure is able to provide a nanosecond transfer delay without using large boost capacitors which are impractical to be integrated or using complex logic units which decrease reliability of circuit. Also, the typical transfer delay of the proposed structure is a constant 1.3 ns, which is irrelevant to parasitic capacitance and insensitive to transfer voltage level.

Two new polyoxometalate(POM)-based entangled coordination networks with chemical formula of [Mn2(H2O)2(BBPTZ)5][SiW12O40] (1) and [Ni2(H2O)2(BBPTZ)5][SiMo12O40]·6H2O (2) (BBPTZ = 4.4′-bis(1,2,4-triazol-1-ylmethyl)biphenyl), were prepared in a hydrothermal reaction system. Compounds 1–2 were characterized by elemental analyses, IR spectroscopy, thermogravimetric analysis, powder X-ray diffraction and single-crystal X-ray diffraction. In compound 1, dangling arms thread in quadrangular window of the adjacent 2-D layers, thus resulting in a rare 2-D → 3-D polythreading motif. Compound 2 exhibits a rare 2-D → 3-D zipper-closing motif. Using the degradation of methylene blue (MB) as the model, the photocatalytic activities of compounds 1–2 were investigated. Both compounds show efficient catalytic activity for the degradation of MB with the order of 2 > 1. It is found that the POM species of compounds 1–2 play the main role in the photocatalytic degradation process.

A pseudo-type-III compensation circuit integrated in a 2.25-MHz voltage-mode dc–dc buck regulator is presented. By summing high- and low-frequency signal paths at the outputs of an error amplifier, two zeros are generated to counteract the pair of complex $LC$ poles. Comparing with traditional and various reported type-III compensation, the proposed scheme is compact, and the area of the compensation capacitor is reduced by about 37%. The addition of a high-frequency path also helps to improve the transient response. Experimental results show that the fabricated regulator with the proposed scheme achieves good stability and fast load-step response. The output is settled within 10 $\mu \hbox{s}$ for a load current step of 400 mA. In addition, the measured load regulation and line regulation is 0.2%/A and 0.2%/V, respectively. The current consumption of the compensator is 120 $\mu \hbox{A}$ , and the measured maximum efficiency is up to 96%.

Considering the tradeoff between efficiency and output ripple over a wide load range, a monolithic dc-dc buck converter with switch-on-demand modulation (SODM) and switch size control (SSC) is presented in this paper. SODM achieves a hybrid mode of pulse skip and pulse width modulation (PWM) without mode detection circuit. The converter's on time is adaptively adjusted with the load demand, achieving low output voltage ripple. Detecting the output of the error amplifier by a comparator, the SSC circuit can select appropriate switch size according to load current for reducing switching loss in a light load. The threshold level of the comparator varies with respect to the amount of slope compensation, which maintains a substantially constant switch size changing point. Experimental results show that the fabricated converter with the proposed scheme achieves high efficiency from 83% to 96% over a wide load range from 10 mA to 5 A. The switch size is 1/4 of the maximum value when load current is below 1 A with 0.5-A hysteresis. Also, the measured maximum output ripple is less than 10 mV.

Procontarinia robusta Li, Bu & Zhang (Diptera: Cecidomyiidae) induces distinctive brown conical galls on the upper side of mango leaves. Here, we describe the larva and pupa and illustrate the gall of P. robusta collected at type locality in China and use gall morphology to identify galls reported previously from India and Indonesia. Analyses of the cytochrome oxidase unit I mitochondrial gene segment showed significant differ- ences between P. robusta and two other pests of mango, P. mangicola (Shi) and P. pustulata Kolesik, and confirmed the identification of P. robusta specimens from East Timor.Asummary of the biology of P. robusta is provided.

Anaplastic lymphoma kinase (ALK), physiologically expressed only by certain neural cells, becomes highly oncogenic, when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin (NPM) and other partners. The reason why NPM-ALK succeeds in transforming specifically CD4 + T lymphocytes remains unknown. The IL-2R common γ-chain (IL-2Rγ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal CD4 + T lymphocytes and other immune cells. We show that IL-2Rγ expression is inhibited in T-cell lymphoma cells expressing NPM-ALK kinase as a result of DNA methylation of the IL-2Rγ gene promoter. IL-2Rγ promoter methylation is induced in malignant T cells by NPM-ALK. NPM-ALK acts through STAT3, a transcription factor that binds to the IL-2Rγ gene promoter and enhances binding of DNA methyltransferases (DNMTs) to the promoter. In addition, STAT3 suppresses expression of miR-21, which selectively inhibits DNMT1 mRNA expression. Reconstitution of IL-2Rγ expression leads to loss of the NPM-ALK protein and, consequently, apoptotic cell death of the lymphoma cells. These results demonstrate that the oncogenic tyrosine kinase NPM-ALK induces epigenetic silencing of the IL-2Rγ gene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.

The physiological indices of Chinese cabbage(Brassica chinensis L.) grown under different intercropping systems used for this study included total soluble protein content, soluble sugar content, reducing sugar content, nitrate content, and pigment concentration. The objective of the present study is to discover the physiological level changes in Chinese cabbage in intercropping systems. The intercropping systems studied involved Chinese cabbage- garlic (Allium sativum L.) (CG), and Chinese cabbage-lettuce (Lactuca sativa L.) (CL). Chinese cabbage monoculture served as control (CK). Overall, higher mean soluble protein content and nitrate content were found in Chinese cabbage grown in the intercropping systems than those in CK. Significantly higher chlorophyll a content was found in cabbages from CL than CK during the latter half of the growing season. No significant difference in soluble sugar concentrations was found in CG and CL, as compared with CK. Reducing sugar content varied over the growing period of the Chinese cabbage in CG and CL. These results suggest that Chinese cabbage intercropped with noncrucifer plants increase the plant nutrient content.

Grammar-based test generation (GBTG) has seen extensive study and practical use since the 1970s. GBTG was introduced to generate source code for testing compilers from context-free grammars specifying language syntax. More recently, GBTG has been applied to many other testing problems, including the generation of eXtensible Markup Language (XML) documents and the generation of packets for testing communications protocols. Recent research has shown how to integrate covering-array techniques such as pairwise testing into GBTG tools. While the integration offers considerable power to the tester, there are few practical demonstrations in the literature. We present two case studies showing how to use grammars and covering arrays for automated software testing. The first case study exposes HTML injection vulnerabilities in an RSS feed parser. The second case study determines the effectiveness of network firewalls when faced with TCP flag attacks. The case studies illustrate the use of covering arrays in a GBTG context, the use of visualization to understand large test logs, and the issues and tradeoffs in the design of fully automated GBTG test suites.

Surgeons often can contribute failure of sphincter-preserving procedure to a limitation of pelvis anatomy; however, they cannot determine definitely which anatomic diameter or spatial factor actually affected the success of the procedure. Colorectal surgeons, radiologists, and research fellows collaborated closely to establish a three-dimensional digital model of the pelvis with spiral computerized tomography scanning data of patients with rectal cancer. Retrospective analysis on data of 97 patients with low rectal cancer was performed with this model to identify geometric factors that might affect a successful sphincter preservation procedure for low rectal cancer. A digital pelvic model was established. Multivariate analysis demonstrated that distance from the anal verge, body mass index, and pelvic factors affected the success of sphincter preservation. Sphincter preservation was more likely to succeed when the distance from anal verge was ≥5 cm and body mass index was

Human cytokine induced killer cells (CIK) have shown potent non-major histocompatibility (MHC)-restricted antitumor activity in vitro in recent years. Using a similar protocol, we generated murine cytokine activated T lymphocytes (CAT) from splenocytes with the sequential addition of IFN-gamma, IL-1beta, anti-CD3 and IL-2. The NK depleted CATs did not possess significant antitumor activity both in vitro and in vivo. However, after cocultured with dendritic cells (DC) pulsed with whole tumor lysates, significant specific antitumor activity was observed both in vitro and in vivo. Our data demonstrated that the CATs cocultured with dendritic cells pulsed with whole tumor lysates have potent specific antitumor effects and might be useful in the treatment of malignancies.

In this article, we report that cutaneous T cell lymphoma (CTCL) cells and tissues ubiquitously express the immunosuppressive cell surface protein CD80 (B7-1). CD80 expression in CTCL cells is strictly dependent on the expression of both members of the STAT5 family, STAT5a and STAT5b, as well as their joint ability to transcriptionally activate the CD80 gene. In IL-2–dependent CTCL cells, CD80 expression is induced by the cytokine in a Jak1/3- and STAT5a/b-dependent manner, whereas in the CTCL cells with constitutive STAT5 activation, CD80 expression is also STAT5a/b dependent but is independent of Jak activity. Although depletion of CD80 expression does not affect the proliferation rate and viability of CTCL cells, induced expression of the cell-inhibitory receptor of CD80, CD152 (CTLA-4), impairs growth of the cells. Coculture of CTCL cells with normal T lymphocytes consisting of both CD4+ and CD8+ populations or the CD4+ subset alone, transfected with CD152 mRNA, inhibits proliferation of normal T cells in a CD152- and CD80-dependent manner. These data identify a new mechanism of immune evasion in CTCL and suggest that the CD80–CD152 axis may become a therapeutic target in this type of lymphoma.

1-Benzyl-1, 4-dihydronicotinamide (1) and KCN reacted with 2-( o-bromomethyl)-benzylidene-1, 3-indandione (2) to give 7, 12-dihydro-1-oxoindeno[3, 2-c][2]benzooxepine (3) and 1′-cyano-3′-hydro-2, 2′-spirobi[2H-indene]-1, 3-dione (4), respectively, and the selectivity of O-alkylation and C-alkylation is discussed.