Ethylene regulates auxin-mediated root gravitropic machinery and controls root angle in cereal crops.

Root angle is a critical factor in optimizing the acquisition of essential resources from different soil depths. The regulation of root angle relies on the auxin-mediated root gravitropism machinery. While the influence of ethylene on auxin levels is known, its specific role in governing root gravitropism and angle remains uncertain, particularly when Arabidopsis (Arabidopsis thaliana) core ethylene signaling mutants show no gravitropic defects. Our research, focusing on rice (Oryza sativa L.) and maize (Zea mays), clearly reveals the involvement of ethylene in root angle regulation in cereal crops through the modulation of auxin biosynthesis and the root gravitropism machinery. We elucidated the molecular components by which ethylene exerts its regulatory effect on auxin biosynthesis to control root gravitropism machinery. The ethylene-insensitive mutants ethylene insensitive2 (osein2) and ethylene insensitive like1 (oseil1), exhibited substantially shallower crown root angle compared to the wild type. Gravitropism assays revealed reduced root gravitropic response in these mutants. Hormone profiling analysis confirmed decreased auxin levels in the root tips of the osein2 mutant, and exogenous auxin (NAA) application rescued root gravitropism in both ethylene-insensitive mutants. Additionally, the auxin biosynthetic mutant mao hu zi10 (mhz10)/tryptophan aminotransferase2 (ostar2) showed impaired gravitropic response and shallow crown root angle phenotypes. Similarly, maize ethylene-insensitive mutants (zmein2) exhibited defective gravitropism and root angle phenotypes. In conclusion, our study highlights that ethylene controls the auxin-dependent root gravitropism machinery to regulate root angle in rice and maize, revealing a functional divergence in ethylene signaling between Arabidopsis and cereal crops. These findings contribute to a better understanding of root angle regulation and have implications for improving resource acquisition in agricultural systems.

Ethylene inhibits rice root elongation in compacted soil via ABA- and auxin-mediated mechanisms.

Soil compaction represents a major agronomic challenge, inhibiting root elongation and impacting crop yields. Roots use ethylene to sense soil compaction as the restricted air space causes this gaseous signal to accumulate around root tips. Ethylene inhibits root elongation and promotes radial expansion in compacted soil, but its mechanistic basis remains unclear. Here, we report that ethylene promotes abscisic acid (ABA) biosynthesis and cortical cell radial expansion. Rice mutants of ABA biosynthetic genes had attenuated cortical cell radial expansion in compacted soil, leading to better penetration. Soil compaction-induced ethylene also up-regulates the auxin biosynthesis gene OsYUC8. Mutants lacking OsYUC8 are better able to penetrate compacted soil. The auxin influx transporter OsAUX1 is also required to mobilize auxin from the root tip to the elongation zone during a root compaction response. Moreover, osaux1 mutants penetrate compacted soil better than the wild-type roots and do not exhibit cortical cell radial expansion. We conclude that ethylene uses auxin and ABA as downstream signals to modify rice root cell elongation and radial expansion, causing root tips to swell and reducing their ability to penetrate compacted soil.

Enhancement of Catalytic Activity via Inevitable Reconstruction of the Ni-Mo Interface for Alkaline Hydrogen Oxidation.

The inevitable oxidation of nickel-metal-based catalysts exposed to the air will lead to instability and poor reproducibility of a catalytic interface, which is usually ignored and greatly hinders their application for the catalysis of alkaline hydrogen oxidation. The details on the formation of a world-class nickel-based HOR catalyst Ni3-MoOx/C-500 are reported via an interfacial reconstruction triggered by passive oxidation upon air exposure. Interfacial reconstruction, initiated with various Ni-Mo metal ratios and annealing temperature, can fine-tune the Ni-Mo interface with an increased work function and a reduced d-band center. The optimized Ni3-MoOx/C exhibits a record high mass activity of 102.8 mA mgNi -1, a top-level exchange current density of 76.5 µA cmNi -2, and exceptional resistance to CO poisoning at 1000 ppm CO for hours. The catalyzed alkaline exchange membrane fuel cell exhibits a maximum power output of 600 mW cm-2 and excellent stability, ranking it as one of the most active non-precious metals HOR catalysts to date.

Distribution of daily protein intake and appendicular skeletal muscle mass in healthy free-living Chinese older adults.

AIMS: Evidence regarding impact of protein intake distribution on skeletal muscle mass in older adults is limited and inconsistent. This study aims to investigate the relationship of evenness of dietary protein distribution and number of meals exceeding a threshold with appendicular skeletal muscle mass (ASM) in healthy and free-living Chinese older adults. METHODS: Repeated measured data of 5689 adult participants aged ≥ 60 years from the China Health and Nutrition Survey (CHNS) 2015 and 2018 waves were analyzed. Mixed-effects linear regression model was performed to examine the relationship between coefficient of variance (CV) of protein intake across meals, number of meals ≥ 0.4 g protein/kg BW and ASM, respectively. Analyses were conducted separately for male and female. RESULTS: The average CV of protein intake in each wave was in the range of 0.34-0.35. More than 40% male and female participants in each wave had no meal reaching 0.4 g protein/kg BW. Female participants in the highest quartile of protein intake CV had significantly lower ASM (ß = -0.18, 95%CI = -0.32, -0.04) compared with those in the lowest quartile, after adjustment for multiple confounders. Significant negative trends were observed across dietary protein CV quartiles with ASM both in male (P trend = 0.043) and female (P trend = 0.007). Significant positive association between number of meals exceeding 0.4 g protein /kg BW and relative ASM were observed in females (2 meals vs. 0 meal: ß = 0.003, 95%CI = 0.0007,0.006;≥3 meals vs. 0 meal: ß = 0.008, 95%CI = 0.003,0.013), after adjusting for multiple covariates. CONCLUSIONS: A more even-distributed protein intake pattern and more meals reaching protein intake threshold were respectively associated with higher appendicular skeletal muscle mass in healthy and free-living older Chinese adults. Prospective studies and intervention trials are needed to confirm these cross-sectional findings.

Roles of auxin response factors in rice development and stress responses.

Auxin signalling plays a key role in various developmental processes ranging from embryogenesis to senescence in plants. Auxin response factor (ARF), a key component of auxin signalling, functions by binding to auxin response element within promoter of auxin response genes, activating or repressing the target genes. Increasing evidences show that ARFs are crucial for plant response to stresses. This review summarises the recent advance on the functions and their regulatory pathways of rice ARFs in development and responding to stresses. The importance of OsARFs is demonstrated by their roles in triggering various physiological, biochemical and molecular reactions to resist adverse environmental conditions. We also describe the transcriptional and post-transcriptional regulation of OsARFs, and discuss the major challenges in this area.

Neferine mitigates cisplatin-induced acute kidney injury in mice by regulating autophagy and apoptosis.

PURPOSE: The nephrotoxicity caused by cisplatin severely limits the application and affects related platinum-based therapeutics. Neferine is a dibenzylisoquinoline alkaloid extracted from a Chinese medicinal herb (Nelumbo nucifera Gaertn), which can decrease cisplatin-induced apoptosis of NRK-52E cells by activating autophagy in vitro in our previous study. In this article, we aimed to further investigate the protective effect of neferine, against to the cispltain-induced kidney damage in mice. METHODS: Six groups were designed in our study. Renal index, mice serum creatinine and blood urea nitrogen levels were detected after the mice were killed. HE staining was used to observe the pathological changes of each group. The apoptosis of mouse kidney tissue was detected by TUNEL. Immunofluorescence and Western blot were used to detect the expression of cleaved-caspase3 and LC3. The transmission electron microscope was used to reveal the changes of apoptosis and autophagy of renal tubular epithelial cells in different groups. RESULTS: In our findings, the pathological changes of acute kidney injury were easily observed in cisplatin-treated mice while those in the neferine-pretreated groups were significantly alleviated. The apoptosis induced by cisplatin in mice increased evidently compared with the control group, which was decreased in the mice with neferine pretreatment. What' more, we found that autophagy increased obviously in mice pretreated by neferine contrast to the cisplatin-treated mice. CONCLUSION: In our study, neferine can effectively alleviate cisplatin-induced renal injury in mice, as well act as an autophagy-regulator in kidney protection.

Rescue therapy with an albuvirtide-based antiretroviral regimen in an HIV-infected child with multidrug resistance and multiple opportunistic infections: a case report.

BACKGROUND: Managing multidrug-resistant (MDR) HIV infections in children is particularly challenging due to the lack of experience with new drugs in the pediatric setting. Second-line albuvirtide (ABT) with an optimized antiretroviral background therapy was approved for adults and adolescents after first-line treatment failure. This paper describes the treatment outcomes and adverse effects of an ABT-based dual-active antiretroviral treatment regimen in a child with MDR HIV strains. CASE PRESENTATION: A 13 year-old Chinese female patient infected with MDR HIV strains showed a decrease in viral load (from 4.48 log10 to 1.73 log10) and an increase in CD4 + T cells (from 15 to 308 cells/µl) after 12 months of treatment with an ABT-based antiretroviral regimen. The child showed no relevant drug-related adverse reactions. CONCLUSIONS: The case reported here could suggest that an ABT-based antiretroviral therapy might be beneficial and without relevant toxicity in children with MDR HIV. Infectiologists specializing in managing HIV should be prepared to manage an increasing number of children with MDR HIV. ABT might be a new treatment option for MDR HIV infection in children.

Enhanced microwave metrology using an optical grating in Rydberg atoms.

An enhanced measurement of the microwave (MW) electric (E) field is proposed using an optical grating in Rydberg atoms. Electromagnetically induced transparency (EIT) of Rydberg atoms appears driven by a probe field and a control field. The EIT transmission spectrum is modulated by an optical grating. When a MW field drives the Rydberg transition, the central principal maximum of the grating spectrum splits. It is interesting to find that the magnitude of the sharp grating spectrum changes linearly with the MW E-field strength, which can be used to measure the MW E-field. The simulation result shows that the minimum detectable E-field strength is nearly 1/8 of that without gratings, and its measurement accuracy could be enhanced by about 60 times. Other discussion of MW metrology based on a grating spectrum is also presented.

Microwave Electrometry with Multi-Photon Coherence in Rydberg Atoms.

A scheme for the measurement of a microwave (MW) electric field is proposed via multi-photon coherence in Rydberg atoms. It is based on the three-photon electromagnetically induced absorption (TPEIA) spectrum. In this process, the multi-photon produces a narrow absorption peak, which has a larger magnitude than the electromagnetically induced transparency (EIT) peak under the same conditions. The TPEIA peak is sensitive to MW fields, and can be used to measure MW electric field strength. We found that the magnitude of TPEIA peaks shows a linear relationship with the MW field strength. The simulation results show that the minimum detectable strength of the MW fields is about 1/10 of that based on an common EIT effect, and the probe sensitivity could be improved by about four times. Furthermore, the MW sensing based on three-photon coherence seems to be robust against the changes in the control field and shows a broad tunability, and the scheme may be useful for designing novel MW sensing devices.

[Trajectories of body mass index and risk of hypertension and blood pressure among Chinese adults].

OBJECTIVE: To explore the relationship between trajectories of body mass index(BMI) and the risk of hypertension and blood pressure among Chinese adults. METHODS: The current study was based on data from 10 waves of the China Health and Nutrition Survey from 1991 to 2018. A multistage stratified random sample was used in this study.11885 adults whose BMI had been measured at least three times were included in the study. Group-based trajectory modeling(GBTM) was used to identify the BMI trajectories in different genders, Cox regression model was used to analyze the association between BMI trajectories and the risk of incident hypertension. Generalized linear model was used to analyze the association between BMI trajectories and the blood pressure level. RESULTS: Three distinct BMI trajectories were determined for both genders: normal-stable group, normal-overweight group, obesity-stable group. The numbers of each group among males were 3595(63.23%), 1412(24.83%) and 679(11.94%), and the numbers of each group among females were 4566(73.66%), 1214(19.58%) and 419(6.76%). Taking the normal-stable group as a reference, after adjusting for confounding factors, the normal-overweight group, obesity-stable group had 1.14(1.03-1.25), P=0.01 and 1.42(1.24-1.63), P<0.01 increased risk(HR(95% CI)) of developing hypertension in male. The normal-overweight group, obesity-stable group had 1.29(1.13-1.46), P<0.01 and 1.58(1.23-2.03), P<0.01 increased risk of developing hypertension in female. Taking the normal-stable group as a reference, after adjusting for confounding factors, the systolic blood pressure[ß(95% CI)] in the male normal-overweight group and obesity-stable group increased by 3.01(1.88-4.14)mmHg, P<0.01 and 5.44(3.85-7.03)mmHg, P<0.01 respectively. The diastolic blood-pressure level was increased by 2.20(1.48-2.91)mmHg, P<0.01 and 4.04(3.04-5.04)mmHg, P<0.01 respectively. The systolic blood pressure in the female normal-overweight group and obesity-stable group were increased by 3.65(2.44-4.85)mmHg, P<0.01 and 2.96(0.97-4.94)mmHg, P<0.01 respectively. The diastolic blood pressure level was increased by 3.11(2.38-3.86)mmHg, P<0.01 and 1.25(0.03-2.47)mmHg, P=0.05 respectively. CONCLUSION: Both the trajectory of BMI increasing with age and the trajectory of maintaining a high BMI level increased the risk of hypertension, and blood pressure also increased significantly compared with those who maintained normal BMI.

CALMODULIN-LIKE-38 and PEP1 RECEPTOR 2 integrate nitrate and brassinosteroid signals to regulate root growth.

Plants exhibit remarkable developmental plasticity, enabling them to adapt to adverse environmental conditions such as low nitrogen (N) in the soil. Brassinosteroids (BRs) promote root foraging for nutrients under mild N deficiency, but the crosstalk between the BR- and N-signaling pathways in the regulation of root growth remains largely unknown. Here, we show that CALMODULIN-LIKE-38 (CML38), a calmodulin-like protein, specifically interacts with the PEP1 RECEPTOR 2 (PEPR2), and negatively regulates root elongation in Arabidopsis (Arabidopsis thaliana) in response to low nitrate (LN). CML38 and PEPR2 are transcriptionally induced by treatments of exogenous nitrate and BR. Compared with Col-0, the single mutants cml38 and pepr2 and the double mutant cml38 pepr2 displayed enhanced primary root growth and produced more lateral roots under LN. This is consistent with their higher nitrate absorption abilities, and their stronger expression of nitrate assimilation genes. Furthermore, CML38 and PEPR2 regulate common downstream genes related to BR signaling, and they have positive roles in BR signaling. Low N facilitated BR signal transmission in Col-0 and CML38- or PEPR2-overexpressing plants, but not in the cml38 and pepr2 mutants. Taken together, our results illustrate a mechanism by which CML38 interacts with PEPR2 to integrate LN and BR signals for coordinating root development to prevent quick depletion of N resources in Arabidopsis.

Trajectories of energy intake distribution and subsequent risk of hyperglycemia among Chinese adults: findings from the China Health and Nutrition Survey (1997-2018).

AIMS: Few studies have examined the secular trend of the energy intake distribution, and its effect on future risk of hyperglycemia. This study aims to describe trajectories of energy intake distribution over 12 years and relate them to subsequent risk of hyperglycemia over 9 years of follow-up. METHODS: Our study used ten waves of data from the CHNS survey, a population-based longitudinal survey in China, ongoing since 1989. We examined a cohort of adult participants who were free from diabetes but had at least three waves of dietary data from 1997 to 2009. We assessed energy intake using three consecutive 24 h recalls. We used these data to identify trajectory groups of energy intake distribution by multi-trajectory model based on energy intake proportions of breakfast, lunch, and dinner. We followed up participants for hyperglycemia, diabetes, and impaired fasting glucose for 9 years from 2009 to 2018. Outcomes were ascertained with fasting glucose, serum HbA1c, and self-report of diabetes and/or glucose-lowering medication. We estimated relative risk (RR) for hyperglycemia, diabetes, and impaired fasting glucose by identified trajectory groups using multilevel mixed-effects modified Poisson regression with robust (sandwich) estimation of variance. Gender difference was additionally examined. RESULTS: A total of 4417 participants were included. Four trajectory groups were identified, characterized and labeled by "Energy evenly distributed with steady trend group" (Group 1), "Dinner and lunch energy dominant with relatively steady trend group" (Group 2), "Dinner energy dominant with increasing trend and breakfast energy with declining trend group" (Group 3), and "breakfast and dinner energy dominant with increasing trend group" (Group 4). During 48,091 person-years, 1053 cases of incident hyperglycemia occurred, 537 cases of incident diabetes occurred, and 516 cases of impaired fasting glucose occurred. Compared with Group 1, Group 3 was associated with higher subsequent risk of incident hyperglycemia in 9 years of follow-up (RR = 1.28, 95% CI = 1.02, 1.61). No association was found for incident diabetes and impaired fasting glucose. Among males, Group 3 was associated with higher risk of incident hyperglycemia in 9 years of follow-up (RR = 1.44, 95% CI = 1.07, 1.94). No relationship was found in females. CONCLUSIONS: Energy intake distribution characterized by over 40% of energy intake from dinner with a rising trend over years was associated with higher long-term risk of hyperglycemia in Chinese adults.

[Agreement analysis and result calibration by ordinary least product regression between bioelectrical impedance analysis and dual energy X-ray absorptiometry].

OBJECTIVE: To analyze agreement of body fat percentage measured by bioelectrical impedance analysis(BIA) and dual energy X-ray absorptiometry(DXA) in Chinese adults, and to calibrate BIA measurement by ordinary least product regression(OLP). METHODS: Volunteers aged 18-65 were recruited to measure total body fat percentage and trunk fat percentage by BIA(Tanita BC-601 F) and DXA(Hologic Discovery QDR), respectively. Agreement between the two methods was compared by OLP. Bootstrap method was used to do the internal validation of the calibration equation. The calibration effect was verified by the agreement analysis of the calibrated BIA result and the DXA result. RESULTS: Before calibration, all 95%CIs of the intercepts of the OLP regression lines did not include 0, and all 95%CIs of the slopes of the OLP regression lines did not include 1. 00. After calibration, all 95% CIs of the intercepts of the OLP regression lines included 0, and all 95% CIs of the slopes included 1. 00. CONCLUSION: There are fixed bias and proportion bias between BIA and DXA in measuring total body fat percentage and trunk fat percentage in Chinese men and women. Calibration should be considered when body fat percentage is measured by BIA.

Arabidopsis NRT1.2 interacts with the PHOSPHOLIPASE Dα1 (PLDα1) to positively regulate seed germination and seedling development in response to ABA treatment.

NRT1.2 has been characterized as a low-affinity nitrate transporter and an abscisic acid (ABA) transporter in Arabidopsis. In this study, we demonstrate that NRT1.2 positively regulated the ABA response during germination and seedling development. The transgenic Arabidopsis NRT1.2-over-expressionors showed increased sensitivity to ABA during these processes. qRT-PCR assays indicated that NRT1.2 over-production in 7-days-old seedlings up-regulated the expression of ABA-responsive genes: ABI1, ABI2, ABI3, ABI4, ABI5, RAB18, RD29A, and RD29B and PHOSPHOLIPASE Dα1 (PLDα1). The expression of these genes was suppressed in the nrt1.2 mutant in comparison with the wild type following ABA treatment. Importantly, bimolecular fluorescence complementation assays indicated that NRT1.2 interacts with PLDα1 at the plasma membrane. Their interaction was further confirmed by using yeast two hybrid (Y2H) experiments with the mating-based split ubiquitin system (MbSUS). Moreover, genetic assays indicated that PLDα1 acts epistatically on NRT1.2 to affect ABA signaling. Taken together, our results provide detailed mechanisms of NRT1.2 in ABA-mediated seed germination and seedling development.

Association between dairy consumption and prevalence of obesity in adult population of northeast China: An internet-based cross-sectional study.

BACKGROUND AND OBJECTIVES: Dairy has been shown to reduce the risk of obesity in many epidemiological studies. However, few studies have been fully conducted in China in this respect. We aimed to investigate the association between dairy consumption and prevalence of obesity in an adult Chinese population. METHODS AND STUDY DESIGN: A cross-sectional study was performed in an adult population of 5598 in northeast China, aged ≥18. Intakes of dairy products were obtained by internet-based dietary questionnaire for the Chinese (IDQC). The associations between total and individual dairy consumption and prevalence of overall and abdominal obesity were examined by logistic regression. Sex stratification was performed. RESULTS: A total of 3871 participants, including 1700 men and 2171 women, were eligible for analysis. Men who consumed ≥100 g/day of yogurt had lower risks of abdominal obesity (multivariate-adjusted OR=0.41; 95% CI: 0.24-0.70) than men who did not consume yogurt. Women who consumed ≥200 g/day of milk had lower risks of overall obesity (multivariate-adjusted OR=0.47; 95% CI: 0.24-0.91) than women who did not consume milk. CONCLUSIONS: Increased dairy consumption was associated with lower risk of obesity in adult population in northeast China. Further studies are needed to confirm these observational findings and explain the observed gender-specific difference.

IBR5 Regulates Leaf Serrations Development via Modulation of the Expression of PIN1.

Biodiversity in plant shape is mainly attributable to the diversity of leaf shape, which is largely determined by the transient morphogenetic activity of the leaf margin that creates leaf serrations. However, the precise mechanism underlying the establishment of this morphogenetic capacity remains poorly understood. We report here that INDOLE-3-BUTYRIC ACID RESPONSE 5 (IBR5), a dual-specificity phosphatase, is a key component of leaf-serration regulatory machinery. Loss-of-function mutants of IBR5 exhibited pronounced serrations due to increased cell area. IBR5 was localized in the nucleus of leaf epidermis and petiole cells. Introducing a C129S mutation within the highly conserved VxVHCx2GxSRSx5AYLM motif of IBR5 rendered it unable to rescue the leaf-serration defects of the ibr5-3 mutant. In addition, auxin reporters revealed that the distribution of auxin maxima was expanded ectopically in ibr5-3. Furthermore, we found that the distribution of PIN1 on the plasma membrane of the epidermal and cells around the leaf vein was compromised in ibr5-3. We concluded that IBR5 is essential for the establishment of PIN-FORMED 1 (PIN1)-directed auxin maxima at the tips of leaf serration, which is vital for the elaborated regulation during its formation.

CiRS-7 targeting miR-7 modulates the progression of non-small cell lung cancer in a manner dependent on NF-κB signalling.

The purpose of this study was to figure out the effect of ciRS-7/miR-7/NF-κB axis on the development of non-small cell lung cancer (NSCLC). In response, the expressions of ciRS-7, miR-7 and NF-κB subunit (ie RELA) within NSCLC tissues and cell lines were determined with real-time polymerase chain reaction (RT-PCR) and Western blot. Moreover, the NSCLC cells were transfected with pcDNA3-ciRS-7-ir, pcDNA3-ciRS-7, miR-NC and miR-7 mimic. Furthermore, the targeted relationships between ciRS-7 and miR-7, as well as between miR-7 and RELA, were confirmed by luciferase reporter assay. The proliferation, migration and apoptosis of NSCLC cells were, successively, measured using CCK-8 assay, wound-healing assay and flow cytometry test. Consequently, ciRS-7, miR-7, histopathological grade, lymph node metastasis and histopathological stage could independently predict the prognosis of patients with NSCLC (all P < .05). Moreover, remarkably up-regulated ciRS-7 and RELA expressions, as along with down-regulated miR-7 expressions, were found within NSCLC tissues and cells in comparison with normal ones (P < .05). Besides, overexpressed ciRS-7 and underexpressed miR-7 were correlated with increased proliferation, migration and invasion, yet reduced apoptosis rate of NSCLC cells (P < .05). More than that, ciRS-7 specifically targeted miR-7 to reduce its expressions (P < .05). Ultimately, the NSCLC cells within miR-7 + RELA group were observed with superior proliferative, migratory and invasive capabilities than those within miR-7 group (P < .05), and RELA expression was also significantly modified by both ciRS-7 and miR-7 (P < .05). In conclusion, the ciRS-7/miR-7/NF-kB axis could exert pronounced impacts on the proliferation, migration, invasion and apoptosis of NSCLC cells.

ß-Arrestin 1 has an essential role in neurokinin-1 receptor-mediated glioblastoma cell proliferation and G2/M phase transition.

Glioblastoma is the most common malignant brain tumor and has a poor prognosis. Tachykinin receptor neurokinin-1 (NK1R) is a promising target in glioblastoma therapy because of its overexpression in human glioblastoma. NK1R agonists promote glioblastoma cell growth, whereas NK1R antagonists efficiently inhibit cell growth both in vitro and in vivo However, the molecular mechanisms involved in these effects are incompletely understood. ß-Arrestins (ARRBs) serve as scaffold proteins and adapters to mediate intracellular signal transduction. Here we show that the ARRB1-mediated signaling pathway is essential for NK1-mediated glioblastoma cell proliferation. ARRB1 knockdown significantly inhibited NK1-mediated glioblastoma cell proliferation and induced G2/M phase cell cycle arrest. ARRB1 knockdown cells showed remarkable down-regulation of CDC25C/CDK1/cyclin B1 activity. We also demonstrated that ARRB1 mediated prolonged phosphorylation of ERK1/2 and Akt in glioblastoma cells induced by NK1R activation. ERK1/2 and Akt phosphorylation are involved in regulating CDC25C/CDK1/cyclin B1 activity. The lack of long-term ERK1/2 and Akt activation in ARRB1 knockdown cells was at least partly responsible for the delayed cell cycle progression and proliferation. Moreover, we found that ARRB1-mediated ERK1/2 and Akt phosphorylation regulated the transcriptional activity of both NF-κB and AP-1, which were involved in cyclin B1 expression. ARRB1 deficiency increased the sensitivity of glioblastoma cells to the treatment of NK1R antagonists. Taken together, our results suggest that ARRB1 plays an essential role in NK1R-mediated cell proliferation and G2/M transition in glioblastoma cells. Interference with ARRB1-mediated signaling via NK1R may have potential significance for therapeutic strategies targeting glioblastoma.

Staurosporine scaffold-based rational discovery of the wild-type sparing reversible inhibitors of EGFR T790M gatekeeper mutant in lung cancer with analog-sensitive kinase technology.

The human epidermal growth factor receptor (EGFR) has been established as an attractive target for lung cancer therapy. However, an acquired EGFR T790M gatekeeper mutation is frequently observed in patients treated with first-line anticancer agents such as gefitinib and erlotinib to cause drug resistance, largely limiting the application of small-molecule kinase inhibitors in EGFR-targeted chemotherapy. Previously, the reversible pan-kinase inhibitor staurosporine and its several analogs such as Gö6976 and K252a have been reported to selectively inhibit the EGFR T790M mutant (EGFRT790M ) over wild-type kinase (EGFRWT ), suggesting that the staurosporine scaffold is potentially to develop the wild-type sparing reversible inhibitors of EGFRT790M . Here, we systematically evaluated the inhibitor response of 28 staurosporine scaffold-based compounds to EGFR T790M mutation at structural, energetic, and molecular levels by using an integrated in silico-in vitro analog-sensitive (AS) kinase technology. With the strategy, we were able to identify 4 novel wild-type sparing inhibitors UCN-01, UCN-02, AFN941, and SB-218078 with high or moderate selectivity of 30-, 45-, 5-, and 8-fold for EGFRT790M over EGFRWT , respectively, which are comparable with or even better than that of the parent compound staurosporine (24-fold). Molecular modeling and structural analysis revealed that van der Waals contacts and hydrophobic forces can form between the side chain of mutated residue Met790 and the pyrrolidinone moiety of inhibitor ligand UCN-02, which may simultaneously improve the favorable interaction energy between the kinase and inhibitor, and reduce the unfavorable desolvation penalty upon the kinase-inhibitor binding. A hydroxyl group of UCN-02 additional to staurosporine locates at the pyrrolidinone moiety, which can largely alter the electronic distribution of pyrrolidinone moiety and thus promote the intermolecular interaction with Met790 residue. This can well explain the measured higher selectivity of UCN-02 than staurosporine for mutant over wild-type kinase.

[The prevalence of hyperuricemia in Xinjiang Kazaks in Fuhaii].

OBJECTIVE: to investigate the prevalence of hyperuricemia (HUA) in Kazak population in Fuhai county, Xinjiang Aletai area. METHODS: A randomized cross-sectional cluster sampling was performed in Kazaks in Fuhai. A total of 2 006 inhabitants were investigated by household survey. The questionnaires were completed for general performance, past illness history and family history. Height, weight, body mass index (BMI) and blood pressure were measured and recorded. Fasting blood samples were collected for serum uric acid and other biochemical tests. RESULTS: (1) Finally a total of 1 921 Kazaks were enrolled.The serum uric acid level in Kazaks in Fuhai was (234.11 ± 82.56) µmol/L, which was higher in males (287.48 ± 80.27) µmol/L than that in females (201.03 ± 64.74) µmol/L (P<0.001). In HUA group, serum uric acid level also had significant difference between men and women [(498.93 ± 130.24) µmol/L vs (471.20 ± 167.71) µmol/L; P = 0.044]. (2) the prevalence of HUA in Kazak general population was 2.97% (57/1 921). After standardization according to the natural population survey in 2000, the standardized rate in general group was 3.34%, in which the prevalence in males (4.76%, standardized rate was 4.64%) was higher than that in females (1.85%, standardized rate was 1.88%) (P<0.001). There was no gout found in 1 921 Kazaks in Fuhan when the study was taken. (3) Cohorts of different dietary habit ( who preferred vegetable or meat or both of them) who had drunk alcohol had higher prevalence of HUA than those with vegetarian diet without alcohol group (7.69%, 5.66% and 5.62% vs 0.78%; all P<0.05). The cohort who preferred animal food with alcohol had higher prevalence of HUA than those who preferred both vegetable and meat without alcohol (5.66% vs 5.62%; P = 0.009). (4) In men, those who had stable career, higher degree of education, regular income, had higher HUA prevalence than other cohorts. (5) people with HUA had higher plasma TC, TG, LDL, urea nitrogen and creatinine levels, higher blood pressure and higher BMI. CONCLUSION: The prevalence of HUA was lower in Kazaks in Fuhai than that in other areas in China. Males were more susceptible to HUA. diet, occupation, educational background and economic status may partly affect the prevalence of HUA in Kazaks in Fuhai.