APC/C prevents a noncanonical order of cyclin/CDK activity to maintain CDK4/6 inhibitor-induced arrest.

Regulated cell cycle progression ensures homeostasis and prevents cancer. In proliferating cells, premature S phase entry is avoided by the E3 ubiquitin ligase anaphasepromoting complex/cyclosome (APC/C), although the APC/C substrates whose degradation restrains G1-S progression are not fully known. The APC/C is also active in arrested cells that exited the cell cycle, but it is not clear whether APC/C maintains all types of arrest. Here, by expressing the APC/C inhibitor, EMI1, we show that APC/C activity is essential to prevent S phase entry in cells arrested by pharmacological cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition (Palbociclib). Thus, active protein degradation is required for arrest alongside repressed cell cycle gene expression. The mechanism of rapid and robust arrest bypass from inhibiting APC/C involves CDKs acting in an atypical order to inactivate retinoblastoma-mediated E2F repression. Inactivating APC/C first causes mitotic cyclin B accumulation which then promotes cyclin A expression. We propose that cyclin A is the key substrate for maintaining arrest because APC/C-resistant cyclin A, but not cyclin B, is sufficient to induce S phase entry. Cells bypassing arrest from CDK4/6 inhibition initiate DNA replication with severely reduced origin licensing. The simultaneous accumulation of S phase licensing inhibitors, such as cyclin A and geminin, with G1 licensing activators disrupts the normal order of G1-S progression. As a result, DNA synthesis and cell proliferation are profoundly impaired. Our findings predict that cancers with elevated EMI1 expression will tend to escape CDK4/6 inhibition into a premature, underlicensed S phase and suffer enhanced genome instability.

Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1.

BACKGROUND: Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. METHODS: We screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo CHD4 (chromodomain helicase DNA-binding protein 4) proband, CHD4M202I, with congenital heart defects. We engineered a humanized mouse model of CHD4M202I (mouse CHD4M195I). Histological analysis, immunohistochemistry, flow cytometry, transmission electron microscopy, and echocardiography were used to analyze cardiac anatomy and function. Ex vivo culture, immunopurification coupled with mass spectrometry, transcriptional profiling, and chromatin immunoprecipitation were performed to deduce the mechanism of CHD4M195I-mediated ventricular wall defects. RESULTS: CHD4M195I/M195I mice developed biventricular hypertrabeculation and noncompaction and died at birth. Proliferation of cardiomyocytes was significantly increased in CHD4M195I hearts, and the excessive trabeculation was associated with accumulation of ECM (extracellular matrix) proteins and a reduction of ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif 1), an ECM protease. We rescued the hyperproliferation and hypertrabeculation defects in CHD4M195I hearts by administration of ADAMTS1. Mechanistically, the CHD4M195I protein showed augmented affinity to endocardial BRG1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4). This enhanced affinity resulted in the failure of derepression of Adamts1 transcription such that ADAMTS1-mediated trabeculation termination was impaired. CONCLUSIONS: Our study reveals how a single mutation in the chromatin remodeler CHD4, in mice or humans, modulates ventricular chamber maturation and that cardiac defects associated with the missense mutation CHD4M195I can be attenuated by the administration of ADAMTS1.

The consequences of differential origin licensing dynamics in distinct chromatin environments.

Eukaryotic chromosomes contain regions of varying accessibility, yet DNA replication factors must access all regions. The first replication step is loading MCM complexes to license replication origins during the G1 cell cycle phase. It is not yet known how mammalian MCM complexes are adequately distributed to both accessible euchromatin regions and less accessible heterochromatin regions. To address this question, we combined time-lapse live-cell imaging with immunofluorescence imaging of single human cells to quantify the relative rates of MCM loading in euchromatin and heterochromatin throughout G1. We report here that MCM loading in euchromatin is faster than that in heterochromatin in early G1, but surprisingly, heterochromatin loading accelerates relative to euchromatin loading in middle and late G1. This differential acceleration allows both chromatin types to begin S phase with similar concentrations of loaded MCM. The different loading dynamics require ORCA-dependent differences in origin recognition complex distribution. A consequence of heterochromatin licensing dynamics is that cells experiencing a truncated G1 phase from premature cyclin E expression enter S phase with underlicensed heterochromatin, and DNA damage accumulates preferentially in heterochromatin in the subsequent S/G2 phase. Thus, G1 length is critical for sufficient MCM loading, particularly in heterochromatin, to ensure complete genome duplication and to maintain genome stability.

In this study the authors have, for the first time, quantified DNA replication origin licensing dynamics and distribution in single cells at subnuclear resolution. The cell cycle and DNA replication fields have long appreciated that origin licensing is both absolutely essential for replication and that licensing is strictly confined to G1 phase. The biochemical process of origin licensing- which is the DNA loading of MCM complexes- is known in considerable detail. What has never been explored in any system, is the dynamics of origin licensing itself. Here the authors define the dynamics of human MCM loading at different times within G1 in both euchromatin and heterochromatin, and explore the consequences of those dynamics for genome stability.

Efficiency and equity in origin licensing to ensure complete DNA replication.

The cell division cycle must be strictly regulated during both development and adult maintenance, and efficient and well-controlled DNA replication is a key event in the cell cycle. DNA replication origins are prepared in G1 phase of the cell cycle in a process known as origin licensing which is essential for DNA replication initiation in the subsequent S phase. Appropriate origin licensing includes: (1) Licensing enough origins at adequate origin licensing speed to complete licensing before G1 phase ends; (2) Licensing origins such that they are well-distributed on all chromosomes. Both aspects of licensing are critical for replication efficiency and accuracy. In this minireview, we will discuss recent advances in defining how origin licensing speed and distribution are critical to ensure DNA replication completion and genome stability.

Drugs affecting renin-angiotensin-aldosterone system and the cancer risk: A meta-analysis of nested case-control studies.

Multiple studies have discussed the associations between drugs affecting the renin-angiotensin-aldosterone system and the cancer risk, but their consequence s were conflicting. A meta-analysis of nested case-control studies published regarding this subject was conducted in our study, aims to estimate the association between ACEI/ARB and the cancer risk. Pubmed database was searched up to February, 1 2016 to identify eligible nested case-control studies, and we used Newcastle-Ottawa Scale (NOS) to assess quality of the studies. Pooled odds ratio (OR) and 95% confidence intervals (CIs) were calculated (with fixed effect model: Mantel-Haenszel). Publication bias and heterogeneity were evaluated before the calculation. Subgroup analysis and sensitivity analysis were also performed. Seven studies contributed to the analysis. Overall, ACEI/ARB use was not associated with the risk of cancer (OR=0.99, 95% CI 0.97-1.01), nor in long-term use patients (OR=0.97, 95% CI 0.92-1.01). ACEI may decrease cancer risk (OR=0.90, 95% CI 0.82-0.99). We observed no significant publication bias. In conclusion, ACEI/ARB use was not associated with cancer risk, nor in long-term use patients, but ACEI use may decrease cancer risk. More researches are needed to confirm these findings.

The 24-Hour Intensivists Staffing Model Improves the Outcome for Nighttime Admitted Patients: A Matched Historical Control Study.

INTRODUCTION: We previously showed that a "10-hour daytime on-site" and "nighttime (NT) on-call" staffing strategy was associated with higher mortality for intensive care unit (ICU) patients admitted during NT than it was for patients admitted during office hours (OH). In here, we evaluated the clinical effects of a 24-hour intensivist staffing model. METHODS: We formed an intervention group of 3034 consecutive ICU patients hospitalized from January 2013 to December 2015, and a control group of 2891 patients from our previous study (2009-2011). We applied propensity score matching (PSM) for whole and subgroup analyses adjusting for confounding factors. We compared clinical outcomes of patients under the 2 staffing models using multivariate logistic regression and survival analyses. RESULTS: After PSM, we balanced the clinical data between the complete cohorts and the subgroups. Comparison of ICU survivals between the intervention and control cohorts yielded no significant differences. However, the intervention was significantly associated with a higher ICU survival in the NT (5:30 pm-07:30 am) admission patients (P = .049) than in those admitted during OH (07:30 am to 5:30 pm; P = .456). Additionally, the intervention shortened the LOSHOS (P = .001) and/or LOSICU (P < .001), reduced the hospital (P = .672) and/or ICU (P = .004) expenses, and resulted in earlier mechanical ventilation extubation (P = .442) as compared to the same variables in the control group, especially for NT admissions. CONCLUSIONS: The 24-hour intensivists staffing could significantly improve ICU outcomes, especially for NT-admission patients in high-acuity, high-volume ICUs with frequent NT admissions.

Ambient Effect Filtering Using NLPCA-SVR in High-Rise Buildings.

The modal frequencies of a structure are affected by continuous changes in ambient factors, such as temperature, wind speed etc. This study incorporates nonlinear principal component analysis (NLPCA) with support vector regression (SVR) to build a mathematical model to reflect the correlation between ambient factors and modal frequencies. NLPCA is first used to eliminate the high correlation among different ambient factors and extract the nonlinear principal components. The extracted nonlinear principal components are input into the SVR model for training and predicting. The proposed method is verified by the measured data provided in the Guangzhou New TV Tower (GNTVT) Benchmark. The grid search method (GSM), genetic algorithm (GA) and fruit fly optimization algorithm (FOA) are applied to determine the optimal hyperparameters for the SVR model. The optimized result of FOA is most suitable for the NLPCA-SVR model. As evaluated by the hypothesis test and goodness-of-fit test, the results show that the proposed method has a high generalization performance and the correlation between the ambient factor and modal frequency can be strongly reflected. The proposed method can effectively eliminate the effects of ambient factors on modal frequencies.

Output-Only Damage Detection of Shear Building Structures Using an Autoregressive Model-Enhanced Optimal Subpattern Assignment Metric.

This paper proposes a novel output-only structural damage indicator by incorporating the pole-based optimal subpattern assignment distance with autoregressive models to localize and relatively assess the severity of damages for sheared structures. Autoregressive models can model dynamic systems well, while their model poles can represent the state of the dynamic systems. Structural damage generally causes changes in the dynamic characteristics (especially the natural frequency, mode shapes and damping ratio) of structures. Since the poles of the autoregressive models can solve the modal parameters of the structure, the poles have a close relationship with the modal parameters so that the changes in the poles of its autoregressive model reflect structural damages. Therefore, we can identify the damage by tracking the shifts in the dynamic system poles. The optimal subpattern assignment distance, which is the performance evaluator in multi-target tracking algorithms to measure the metric between true and estimated tracks, enables the construction of damage sensitive indicator from system poles using the Hungarian algorithm. The proposed approach has been validated with a five-story shear-building using numerical simulations and experimental verifications, which are subjected to excitations of white noise, El Centro earthquake and sinusoidal wave with frequencies sweeping, respectively; the results indicate that this approach can localize and quantify structural damages effectively in an output-only and data-driven way.

[Study on chemical bibenzyls in Dendrobium gratiosissimum].

Nineteen compounds were isolated and structurally characterized from an ethanol extract of Dendrobium gratiossimum, including dendrogratiol A(1), DDB-1(2), 3,4-dihydroxyl-5,3',4'-trimethoxybibenzyl(3), amoenylin(4), chrysotoxine(5), DTB(6), 3,4,4'-trihydroxyl-5,3'-dimethoxybenzyl(7), 3-methylgiga(8), aloifol(9), gigantol tetramethyl ether(10), batatasin Ⅲ(11), moscatilin(12), moniliformine(13), gigantol(14), DMB(15), flavanthrinin(16), cannithrene-2(17), 3,4-dihydroxyl-5,4'-dimethoxystilbene(18) and 4-hydroxy-3,5,4'-trimethoxystilbene(19). 1 was a new compound, and 2-10, 16, 18 and 19 were obtained from this plant species for the first time. In vitro cytotoxic and antiviral activities of these isolates were evaluated, which displayed that 4 showed moderate cytotoxicity against human hepatoma cell line HepG2 with the IC_(50) of 10.15 µmol·L~(-1); 7 and 12 exhibited moderate inhibitory activity towards HIV virus with the IC_(50) of 9.35 and 9.15 µmol·L~(-1), respectively; and 10 displayed inhibitory activity against IAV virus with the IC_(50) of 8.90 µmol·L~(-1).

An Improved Step-Type Liquid Level Sensing System for Bridge Structural Dynamic Deflection Monitoring.

Real-time and accurate monitoring of dynamic deflection is of great significance for health monitoring and condition assessment of bridge structures. This paper proposes an improved step-type liquid level sensing system (LLSS) for dynamic deflection monitoring. Layout of straight-line-type pipeline is replaced by step-type pipeline in this improved deflection monitoring system, which can remove the interference of the inclination angle on the measurement accuracy and is applicable for dynamic deflection monitoring. Fluid dynamics are first analyzed to demonstrate that measurement accuracy is interfered with by the fluid velocity induced by structural vibration, and ANSYS-FLOTRAN is applied for analyzing the influence range caused by the turbulent flow. Finally, a step-type LLSS model is designed and experimented with to verify the influence of the three key parameters (initial displacement excitation, step height, and distance from the measurement point to the elbow) on the measurement accuracy, and the reasonable placement scheme for the measurement point is determined. The results show that the measurement accuracy mainly depends on the turbulent flow caused by step height. The measurement error gets smaller after about 1.0 m distance from the elbow. To ensure that the measurement error is less than 6%, the distance between the measurement point and the elbow should be larger than 1.0 m.

Cable Interlayer Slip Damage Identification Based on the Derivatives of Eigenparameters.

Cables are the main load-bearing structural components of long-span bridges, such as suspension bridges and cable-stayed bridges. When relative slip occurs among the wires in a cable, the local bending stiffness of the cable will significantly decrease, and the cable enters a local interlayer slip damage state. The decrease in the local bending stiffness caused by the local interlayer slip damage to the cable is symmetric or approximately symmetric for multiple elements at both the fixed end and the external load position. An eigenpair sensitivity identification method is introduced in this study to identify the interlayer slip damage to the cable. First, an eigenparameter sensitivity calculation formula is deduced. Second, the cable is discretized as a mass-spring-damping structural system considering stiffness and damping, and the magnitude of the cable interlayer slip damage is simulated based on the degree of stiffness reduction. The Tikhonov regularization method is introduced to solve the damage identification equation of the inverse problem, and artificial white noise is introduced to evaluate the robustness of the method to noise. Numerical examples of stayed cables are investigated to illustrate the efficiency and accuracy of the method proposed in this study.

An Integrated Machine Learning Algorithm for Separating the Long-Term Deflection Data of Prestressed Concrete Bridges.

Deflection is one of the key indexes for the safety evaluation of bridge structures. In reality, due to the changing operational and environmental conditions, the deflection signals measured by structural health monitoring systems are greatly affected. These ambient changes in the system often cover subtle changes in the vibration signals caused by damage to the system. The deflection signals of prestressed concrete (PC) bridges are regarded as the superposition of different effects, including concrete shrinkage, creep, prestress loss, material deterioration, temperature effects, and live load effects. According to multiscale analysis theory of the long-term deflection signal, in this paper, an integrated machine learning algorithm that combines a Butterworth filter, ensemble empirical mode decomposition (EEMD), principle component analysis (PCA), and fast independent component analysis (FastICA) is proposed for separating the individual deflection components from a measured single channel deflection signal. The proposed algorithm consists of four stages: (1) the live load effect, which is a high-frequency signal, is separated from the raw signal by a Butterworth filter; (2) the EEMD algorithm is used to extract the intrinsic mode function (IMF) components; (3) these IMFs are utilized as input in the PCA model and some uncorrelated and dominant basis components are extracted; and (4) FastICA is applied to derive the independent deflection component. The simulated results show that each individual deflection component can be successfully separated when the noise level is under 10%. Verified by a practical application, the algorithm is feasible for extracting the structural deflection (including concrete shrinkage, creep, and prestress loss) only caused by structural damage or material deterioration.

H. pylori modifies methylation of global genomic DNA and the gastrin gene promoter in gastric mucosal cells and gastric cancer cells.

AIMS: The aim of this study was to evaluate the correlation between H. pylori infection and global DNA methylation, as well as the methylation levels of the gastrin promoters. MATERIALS AND METHODS: We constructed a eukaryotic expression vector, pcDNA3.1::cagA, and transfected it into GES-1 gastric mucosal cells and SGC-7901 gastric cancer cells. Both cell lines were infected with the H. pylori/CagA+ strain NCTC11637. Then, we detected global DNA methylation by capture and detection antibodies, followed by colorimetric quantification. The methylation levels of the gastrin promoter were evaluated by base-specific cleavage and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: In H. pylori/CagA+-infected GES-1 and SGC-7901 cells, the methylation levels of genomic DNA decreased by 49.4% and 18.8%, and in GES-1 and SGC-7901 cells transfected with pcDNA3.1::cagA, the methylation levels of genomic DNA decreased by 17.05% and 25.6%, respectively. Among 24 methylation sites detected in the gastrin promoter region, the methylation levels of 9 CpG sites were significantly decreased in H. pylori/CagA+-infected and pcDNA3.1:: cagA-transfected cells in comparison to corresponding control cells. CONCLUSION: These results indicate that H. pylori/CagA+ decreases the methylation of the genome and the gastrin promoter at some CpG sites in gastric mucosal and gastric cancer cells.

Vitamin C deficiency exacerbates diabetic glomerular injury through activation of transforming growth factor-ß signaling.

BACKGROUND: The hyperglycemia and hyperoxidation that characterize diabetes lead to reduced vitamin C (VC) in diabetic humans and experimentally diabetic animals. Herein, we access the effects of VC deficiency on the diabetic kidney injury and explore the underlying mechanism. METHODS: l-gulonolactone oxidase conventional knockout (Gulo-/-) mice genetically unable to synthesize VC were subjected to streptozotocin-induced diabetic kidney injury and the role of VC deficiency was evaluated by biochemical and histological approaches. Rat mesangial cells were cultured to investigate the underlying mechanism. RESULTS: Functionally, VC deficiency aggravates the streptozotocin-induced renal insufficiency, exhibiting the increased urine albumin, water intake, and urine volume in Gulo-/- mice. Morphologically, VC deficiency exacerbates the streptozotocin-induced kidney injury, exhibiting the increased glomerular expansion, deposition of Periodic Acid-Schiff- and Masson-positive materials, and expression of α-smooth muscle actin, fibronectin and type 4 collagen in glomeruli of Gulo-/- mice. Mechanistically, VC activates protein kinase B (Akt) to destabilize Ski and thereby induce the expression of Smad7, resulting in suppression of TGF-ß/Smad signaling and extracellular matrix deposition in mesangial cells. CONCLUSIONS: VC is essential for the renal function maintenance in diabetes. GENERAL SIGNIFICANCE: Compensation for the loss of VC could be an effective remedy for diabetic kidney injury.

Hedgehog signaling through GLI1 and GLI2 is required for epithelial-mesenchymal transition in human trophoblasts.

BACKGROUND: Epithelial to mesenchymal transition (EMT) is critical for human placental development, trophoblastic differentiation, and pregnancy-associated diseases. Here, we investigated the effects of hedgehog (HH) signaling on EMT in human trophoblasts, and further explored the underlying mechanism. METHODS: Human primary cytotrophoblasts and trophoblast-like JEG-3 cells were used as in vitro models. Quantitative real-time RT-PCR and Western blot analysis were performed to examine mRNA and protein levels, respectively. Lentiviruses expressing short hairpin RNA were used to knock down the target genes. Reporter assays and chromatin immunoprecipitation were performed to determine the transactivity. Cell migration, invasion and colony formation were accessed by wound healing, Matrigel-coated transwell, and colony formation assays, respectively. RESULTS: Activation of HH signaling induced the transdifferentiation of cytotrophoblasts and trophoblast-like JEG-3 cells from epithelial to mesenchymal phenotypes, exhibiting the decreases in E-Cadherin expression as well as the increases in vimentin expression, invasion, migration and colony formation. Knockdown of GLI1 and GLI2 but not GLI3 attenuated HH-induced transdifferentiation, whereas GLI1 was responsible for the expression of HH-induced key EMT regulators including Snail1, Slug, and Twist, and both GLI1 and GLI2 acted directly as transcriptional repressor of CDH1 gene encoding E-Cadherin. CONCLUSION: HH through GLI1 and GLI2 acts as critical signals in supporting the physiological function of mature placenta. GENERAL SIGNIFICANCE: HH signaling through GLI1 and GLI2 could be required for the maintenance of human pregnancy.

[Hg Content Characteristics and Safe Planting Zoning of Paddy Soil and Rice in Guizhou Province].

Guizhou Province ranks first in terms of Hg reserves and production in the country, and rice is its largest grain crop. In order to study the characteristics and pollution causes of soil-rice Hg content at the provincial level in Guizhou and to carry out safe planting zoning, 1 564 pairs of soil-rice samples, 470 natural soil samples, and 203 individual paddy soil samples were collected to test their Hg content and basic physical and chemical properties of the soil. The results showed that:① Paddy soil was mainly neutral and acidic, the paddy soil ω (Hg) range was 0.005-93.06 mg·kg-1, and the geometric mean was 0.864 mg·kg-1. The Hg content of paddy soil in Guizhou Province was significantly higher than that in natural soil (0.16 mg·kg-1,P < 0.05). Compared with the filtered value and control value, the soil samples exceeded the standard by 63.25% and 14.71%, respectively. Among them, the soil Hg pollution in Danzhai County of Qiandongnan Prefecture, Wuchuan County of Zunyi City, Zhenfeng County of Qianxinan Prefecture, and Wanshan District of Tongren City was more prominent. ② Rice ω(Hg) ranged from 0.000 5 to 0.52 mg·kg-1, and the geometric mean was 0.010 mg·kg-1, the percentage of rice Hg content exceeding the standard was 25.87%, and the exceeding points were mainly distributed in Suiyang County of Zunyi City, Zhenfeng County of Qianxinan Prefecture, Xixiu District of Anshun City, Bijiang District of Tongren City, and other industrial and mining activity-intensive areas. ③ The majority of the study area was in the priority protection category (74.75%); the safe use category accounted for (24.62%); and the strictly controlled category (0.93%) was scattered in Danzhai County at the border between Qiannan Prefecture and Qiandongnan Prefecture, Zhenfeng County in Qianxinan Prefecture, and Wanshan District in Tongren. It is not recommended to plant rice, which can be used as feed for reproduction.

Andrographolide protects against lipopolysaccharide-induced vascular hyporeactivity by suppressing the expression of inducible nitric oxide in periaortic adipose.

This study investigated the role of perivascular adipose tissue (PVAT) in the beneficial effects of andrographolide on vascular reactivity in endotoxaemic rats. After being challenged by lipopolysaccharide (4 mg/kg intraperitoneally), the rats were treated with andrographolide (1 mg/kg intraperitoneally). The response to phenylephrine of aortic rings with or without PVAT was recorded. Vascular relaxing effect of PVAT was determined by bioassay experiments. Inducible nitric oxide synthase (iNOS) in aortic PVAT was tested by Western blot, immunofluorescence, and quantitative polymerase chain reaction. Lipopolysaccharide injection lowered the contraction force induced by phenylephrine in aortic rings with or without PVAT and andrographolide treatment reversed these effects. In bioassay experiments, transferring bathing solution incubated with a PVAT+ ring to a PVAT- ring induced relaxation in the recipient. This relaxing effect of PVAT from endotoxaemic rats was more potent than the rats treated with vehicles. Andrographolide treatment decreased the relaxing effect of PVAT in endotoxaemic rats. The levels of iNOS protein and messenger RNA in PVAT were significantly higher in endotoxaemic rats than in the rats treated with vehicles. Andrographolide treatment decreased PVAT iNOS protein and messenger RNA levels in endotoxaemic rats. Our results suggest that andrographolide restores vascular reactivity in endotoxaemic rats by downregulation of iNOS in PVAT.

[Low Accumulation Characteristics of Sweet-waxy Maize in Pb and Cd Complex Contaminated Soils Based on Field Trials].

To screen out sweet-waxy maize varieties with low accumulation characteristics suitable for planting in lead (Pb) and cadmium (Cd) complex contaminated soils, 39 maize varieties were selected, and the enrichment characteristics and differences of grains and straws on Pb and Cd were studied through field trials. Maize yield, bioaccumulation factors, and soil Pb and Cd risk thresholds were used as evaluation indicators for screening low accumulation maize varieties. The results showed that there were significant differences between the yield and Pb and Cd contents in grains and straws of different varieties of maize (P<0.05). Bioaccumulation factors of grains for Pb and Cd were in the range of 0.00003-0.00230 and 0.01-0.15, respectively, and those of straws for Pb and Cd were in the range of 0.003-0.065 and 0.64-4.28, respectively. Through the cluster analysis of bioaccumulation factors, the soil Pb and Cd risk thresholds of different varieties of maize were comprehensively obtained:Huitian 5, Xinmeitian 818, and Yunuo 9 could be safely produced in the farmland with Pb and Cd content exceeding the risk control value, and Tianguinuo 937 and Jinwannuo 2000 could be safely produced in the farmland with Cd content exceeding the risk screening value. Huitian 5, Xinmeitian 818, and Yunuo 9, as low Pb and Cd accumulation varieties, were suitable to be popularized on Pb and Cd polluted soil in Guangxi, China. Tianguinuo 937 and Jinwannuo 2000, as low grain and high Cd accumulation varieties, are suggested to be used as phytoremediation resources.

STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity.

STING is an innate immune sensor for immune surveillance of viral/bacterial infection and maintenance of an immune-friendly microenvironment to prevent tumorigenesis. However, if and how STING exerts innate immunity-independent function remains elusive. Here, the authors report that STING expression is increased in renal cell carcinoma (RCC) patients and governs tumor growth through non-canonical innate immune signaling involving mitochondrial ROS maintenance and calcium homeostasis. Mitochondrial voltage-dependent anion channel VDAC2 is identified as a new STING binding partner. STING depletion potentiates VDAC2/GRP75-mediated MERC (mitochondria-ER contact) formation to increase mitochondrial ROS/calcium levels, impairs mitochondria function, and suppresses mTORC1/S6K signaling leading to RCC growth retardation. STING interaction with VDAC2 occurs through STING-C88/C91 palmitoylation and inhibiting STING palmitoyl-transferases ZDHHCs by 2-BP significantly impedes RCC cell growth alone or in combination with sorafenib. Together, these studies reveal an innate immunity-independent function of STING in regulating mitochondrial function and growth in RCC, providing a rationale to target the STING/VDAC2 interaction in treating RCC.

HSP90ß chaperoning SMURF1-mediated LATS proteasomal degradation in the regulation of bone formation.

Heat shock protein 90 (HSP90) molecular chaperone is responsible for the stabilization and biological activity of a diverse set of client proteins. We have previously demonstrated that inhibition of HSP90 by 17-Demethoxy-17-allyaminogeldanmycin (17-AAG) not only reverses the glucocorticoid-induced bone loss but also enhances the basal level of bone mass in mice. Here, we investigate the potential mechanism underlying HSP90-associated osteoblast differentiation and bone formation. Knockdown of HSP90ß but not HSP90α or inhibition of HSP90 by 17-AAG or NVP-BEP800 negates the protein levels of large tumor suppressor (LATS), the core kinases of Hippo signaling, resulting in the inactivation of LATS and activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), in the enhancement of osteoblastic differentiation. In contrast, genetic ablation of Lats1 in mesenchymal stem cells is sufficient to abolish the HSP90 inhibition-induced osteoblastic differentiation and bone formation. Mechanistically, HSP90ß but not HSP90α chaperones and prevents the SMAD specific E3 ubiquitin protein ligase 1 (SMURF1)-mediated and ubiquitination-dependent LATS protein proteasomal degradation, whereas 17-AAG abolishes these effects of HSP90ß. Thus, these results uncover the HSP90ß chaperoning SMURF1-mediated LATS protein proteasomal degradation and the subsequent YAP/TAZ activation as a hitherto uncharacterized mechanism controlling osteoblastic differentiation and bone formation.