Water quality evaluation and ecological-health risk assessment on trace elements in surface water of the northeastern Qinghai-Tibet Plateau.

The Qinghai-Tibet Plateau is a unique area with water sources for approximately 40 % of the population in the world. Water resources and water quality are closely associated with ecological security and human health. Fifty-one trace elements in surface water samples (n = 40) were measured, and water quality, health and ecological risks were assessed. Trace elements showed significant variations in different surface water bodies in the study area. Concentrations of minor elements were relatively high in saline and salt lakes while those of REEs varied from 0.05 to 33.62 µg/L with an average value of 3.80 µg/L. The Nemerow pollution index (NP) values of trace elements ranged from 0.08 to 3.48, with an average value of 0.36 in rivers, fresh lakes and reservoir water samples; The heavy metal pollution index (HPI) values ranged from 3.70 to 21.18, indicating that most samples were within the critical limit; The heavy metal evaluation index (HEI) values and degree of contamination (DC) values indicated a free pollution status. The water quality index (WQI) values showed that 96 % of the samples belonged to excellent status in rivers, fresh lakes and reservoir water samples. More attention should be given to the Cr, Zn and Hg in the study area according to potential ecological risk assessment. Hazard quotients for residential children in 30 sites exceed 1.0 with maximal value of 10.97, suggesting the high non-carcinogenic risks for children in the study area. U, Zr and Cr for the ingestion pathway, Cr and U for the dermal pathway were primary contributors to the total health risk. Carcinogenic risk values of trace elements for residential and recreational receptors were in the range of 3.20 × 10-5-7.38 × 10-3 and 8.62 × 10-6-3.63 × 10-3, respectively. The carcinogenic risk values of Cr in surface water were higher than the target risk of 1 × 10-4, while the carcinogenic risk values of As were below the target risk. The results of this study provided information on trace elements for human health protection and water management in the northeastern Qinghai-Tibet Plateau.

MicroRNA-204-GSDMD interaction regulates pyroptosis of fibroblast-like synoviocytes in ankylosing spondylitis.

OBJECTIVE: Ankylosing spondylitis (AS) is a disease characterized by inflammation of the sacroiliac joint and the attachment point of the spine. This study aimed to investigate the effect of microRNA (miR)-204-targeted GSDMD on fibroblast-like synoviocytes (FLSs) in AS. METHODS: miR-204, GSDMD, pyrolysis-related genes (Caspase-1, Caspase-11 and NLRP3) in synovial tissues from AS patients were tested by RT-qPCR. Online website prediction and dual luciferase reporter gene assay were conducted to verify the binding relationship between miR-204 and GSDMD. FLSs were isolated from AS patients and transfected with miR-204- or GSDMD-related oligonucleotides, siRNA and plasmids to explore their roles in pyroptosis of FLSs. Intracellular [Ca2+] was detected by laser scanning confocal microscopy, reactive oxygen species (ROS) by DCFH-DA and pyrolysis by AO/EB staining and flow cytometry. RESULTS: Decreased miR-204 and elevated GSDMD were found in synovial tissue of patients with AS. miR-204 could directly target GSDMD and inhibit GSDMD protein expression. FLSs treated with miR-204 mimic inhibited the pyroptosis rate and Caspase-1/PI double-positive cells and reduced [Ca2+], ROS, NLRP3, Caspase-1 and Caspase-11 levels in FLSs. Up-regulating GSDMD blocked the effect of miR-204 overexpression on FLSs. CONCLUSION: Altogether, up-regulated miR-204 suppresses pyroptosis of FLSs in AS via suppressing GSDMD, which may help us to understand the mechanism of AS deeply.

Backers investment behavior on explicit and implicit factors in reward-based crowdfunding based on ELM theory.

The aim of this study is to identify the dynamic explicit and implicit information factors which displayed on the webpage of platforms that influence backers' investment decision-making behavior. We analyze the connections among these factors by collecting the longitudinal dataset from reward-based crowdfunding platform. Based on ELM model, we establish Fixed Estimation Panel Data Model respectively according to explicit and implicit factors and take Funding Status (crowdfunding results) as the moderating variable to observe the goal gradient effect. Results indicate that most variables in the central route affect backers' investment behavior positively, while most variables in the periphery route have a negative impact on backers' investment behavior. The Funding Status has a significant negative moderating effect on the explicit variables, and has no significant moderating effect on the implicit information variables of the project. In addition, we upgrade the econometric method used by previous scholars, which could improve the accuracy of the FE model. Furthermore, we find strong support for the herding effect in reward-based crowdfunding and the intensity tends to decrease before the funding goal draws near.

Effects of surgical approaches and morphological characteristics on the follow up outcomes of patients with posterolateral tibial plateau fractures.

This study aimed to study the effects of surgical approaches and identify the morphological characteristics associated with the 1-year follow-up outcome of patients with posterolateral tibial plateau fractures after successful surgery.We followed 200 postoperative patients for 1 year. The modified Hospital for Special Knee Surgery score (HSS score) was used to evaluate the functional recovery of the knee. We supposed 4 morphological characteristics in CT images acting as possible risk factors, including the anteroposterior diameters of posterolateral broken bone fragments (fragment-diameter), the damage to the posterolateral cortex of the tibial head (cortex-damage), the combinational fracture of the proximal fibula (fibula-fracture) or fracture of the medial tibial condyle (medial-condyle-fracture). Multivariate regression models were used to analyze the effect of these factors on the HSS score after adjusting the 2 surgical approaches and other confounders.The average HSS score was 85.1 ±â€Š5.8 for all the patients. We treated 155 patients with the anterolateral approach and 45 patients with the posterolateral approach. The surgical approach, fragment-diameter, fibula-fracture, and medial-condyle-fracture were correlated with the HSS scores (P < .05). After adjusting for the above factors, the Schatzker type, age and gender, compared with anterolateral approach, the posterolateral approach could improve the HSS scores by an average of 3.7 points. The fragment-diameter <20 mm and posterolateral approach interacted on the HSS scores. Comparing posterolateral and anterolateral approaches, we found that the HSS scores of patients with fragment-diameter <20 mm increased by 6.1 points (95% CI: 4.1-8.2) in the posterolateral approach, while those with fragment-diameter ≥20 mm did not significantly improve the HSS scores.The surgical approach, fragment-diameter, fibula-fracture, and medial-condyle-fracture were independent risk factors associated with the follow-up outcome of patients with posterolateral tibial plateau fractures after successful surgery. The posterolateral approach could significantly improve the HSS score in the studied hospital.

Essential role of the Crk family-dosage in DiGeorge-like anomaly and metabolic homeostasis.

CRK and CRKL (CRK-like) encode adapter proteins with similar biochemical properties. Here, we show that a 50% reduction of the family-combined dosage generates developmental defects, including aspects of DiGeorge/del22q11 syndrome in mice. Like the mouse homologs of two 22q11.21 genes CRKL and TBX1, Crk and Tbx1 also genetically interact, thus suggesting that pathways shared by the three genes participate in organogenesis affected in the syndrome. We also show that Crk and Crkl are required during mesoderm development, and Crk/Crkl deficiency results in small cell size and abnormal mesenchyme behavior in primary embryonic fibroblasts. Our systems-wide analyses reveal impaired glycolysis, associated with low Hif1a protein levels as well as reduced histone H3K27 acetylation in several key glycolysis genes. Furthermore, Crk/Crkl deficiency sensitizes MEFs to 2-deoxy-D-glucose, a competitive inhibitor of glycolysis, to induce cell blebbing. Activated Rapgef1, a Crk/Crkl-downstream effector, rescues several aspects of the cell phenotype, including proliferation, cell size, focal adhesions, and phosphorylation of p70 S6k1 and ribosomal protein S6. Our investigations demonstrate that Crk/Crkl-shared pathways orchestrate metabolic homeostasis and cell behavior through widespread epigenetic controls.

Distribution of Black Carbon in Topsoils of the Northeastern Qinghai-Tibet Plateau Under Natural and Anthropogenic Influences.

Black carbon (BC), ubiquitous in soils, plays an important role in global carbon cycles, the radiative heat balance of the Earth, pollutant fate, emissions of greenhouse gas, soil fertility, soil microbial community, and ecosystem stability. However, information on BC in topsoils of the northeastern Qinghai-Tibet Plateau is limited. Therefore, this study performed field sampling and analyzed contents of total BC and soot BC in topsoils. The results indicated that the contents of total BC in all soil samples ranged from 0.504 to 74.381 g kg-1 with an average value of 5.152 g kg-1, whereas those of soot BC were in the range of 0.400-15.200 g kg-1 with a mean value of 1.719 g kg-1. Contents of BC were significantly correlated with those of total carbon and total organic carbon. Soil types affected the distribution of soil BC. The contents of total BC in the loam soils were larger than those in the clay soils, whereas soot BC was more easily enriched in the clay soils. Total BC was negatively correlated with Ca, and soot BC was negatively correlated with Ti. The contents of soil BC in functional areas, such as agricultural and pastoral areas, industrial areas, and mining areas, were significantly higher than those in other areas, illustrating that anthropogenic activities drastically affected the distribution of soil BC. This study exhibits the fundamental information on soil BC in the northeastern Qinghai-Tibet Plateau to provide important knowledge on global soil carbon sink.

Distribution, pollution, bioaccumulation, and ecological risks of trace elements in soils of the northeastern Qinghai-Tibet Plateau.

Environmental quality of the northeastern Qinghai-Tibet Plateau has attracted more attention due to increasing anthropogenic disturbance. Therefore, this study investigated the distribution, pollution, ecological risks, and bioaccumulation of 12 target heavy metals and 16 rare earth elements (REEs) in soils of this area. The average concentrations of target trace elements in soils ranged from 0.16 (Hg) to 500.46 (Cr) mg/kg. Pb caused more serious pollution than the other elements based on geo-accumulation index evaluation. Hg exhibited the strongest enrichment feature with the average enrichment factor of 8.41. Compare with modified contamination degree and pollution load index, Nemerow pollution index method obtained the most serious evaluation results that 45.67% and 16.54% of sampling sites possessed high and moderate pollution. Evaluation results of potential ecological risk index showed that trace elements in soils posed very high and considerable ecological risks in 34.65% and 7.09% of sampling sites, respectively. Mining area was the region with the most serious pollution and ecological risks. Average bioaccumulation factor (BCF) values of target trace elements ranged from 0.05 (REEs) to 2.67 (Cr). Cr was the element that was easier to bio-accumulate in plants of the study area than the other target elements. It is in urgent need to take effective measures for controlling current pollution and potential ecological risks of trace elements in soils of the northeastern Qinghai-Tibet Plateau.

Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain - A fragment based approach.

The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays. A co-crystal structure of KDM4A TUDOR domain in complex with 1a shows that the fragment binds stereo-specifically to the methyl lysine binding pocket forming a network of strong hydrogen bonds and hydrophobic interactions. We anticipate that the fragment 1a can be further developed into a novel allosteric inhibitor of the KDM4 family of enzymes through targeting their C-terminal tandem TUDOR domain.

Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors.

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.

Pollution, ecological-health risks, and sources of heavy metals in soil of the northeastern Qinghai-Tibet Plateau.

The Qinghai-Tibet Plateau, especially the northeastern region, is not a pure land any more due to recently increasing anthropogenic activities. This study collected soil samples from 70 sites of the northeastern Qinghai-Tibet Plateau to evaluate pollution, ecological-health risks, and possible pollution sources of heavy metals. The concentrations of heavy metals in soil were relatively high. Values of geo-accumulation index exhibited that Hg pollution was the most serious meanwhile Hg possessed the strongest enrichment feature based on enrichment factor values. The modified degrees of contamination showed that about 54.3% and 17.1% of sampling sites were at moderate and high contamination degree while pollution load indexes illustrated that 72.9% and 27.1% of sampling sites possessed moderate and high contamination level, respectively. Ecological risk indexes of heavy metals in soil ranged from 234.6 to 3759.0, suggesting that most of sites were under considerable/very high risks. Cancer risks for adults and children were determined as high and high-very high levels while non-cancer risks for children were high although those for adults were low. Industrial source contributed to the main fraction of ecological and health risks. Summarily speaking, heavy metals in soil of the study area has caused significantly serious pollution and exerted high potential ecological and health risks, especially for children who are more susceptible to hurt from pollutants. Therefore, more efficient and strict pollution control and management in study area should be put out as soon as possible.

Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor.

The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9-19-fold. Additional structure-activity relationship (SAR) efforts aimed both at increasing potency and improving pharmacokinetic properties led to the discovery of the clinical candidate 63 (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation.

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors.

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, Ki = 160 µM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.

Preclinical Characterization of BET Family Bromodomain Inhibitor ABBV-075 Suggests Combination Therapeutic Strategies.

ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models, representing a variety of hematologic malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell-cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin lymphoma, and multiple myeloma cells. Apoptosis induced by ABBV-075 was mediated in part by modulation of the intrinsic apoptotic pathway, exhibiting synergy with the BCL-2 inhibitor venetoclax in preclinical models of AML. In germinal center diffuse large B-cell lymphoma, BCL-2 levels or venetoclax sensitivity predicted the apoptotic response to ABBV-075 treatment. In vivo combination studies uncovered surprising benefits of low doses of ABBV-075 coupled with bortezomib and azacitidine treatment, despite the lack of in vitro synergy between ABBV-075 and these agents. The in vitro/in vivo activities of ABBV-075 described here may serve as a useful reference to guide the development of ABBV-075 and other BET family inhibitors for cancer therapy. Cancer Res; 77(11); 2976-89. ©2017 AACR.

Methylpyrrole inhibitors of BET bromodomains.

An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.

CX-5461 induces autophagy and inhibits tumor growth via mammalian target of rapamycin-related signaling pathways in osteosarcoma.

Osteosarcoma (OS) is the most common primary bone tumor, but molecular mechanisms of the disease have not been well understood, and treatment of metastatic OS remains a challenge. Rapid ribosomal RNA synthesis in cancer is transcribed by RNA polymerase I, which results in unbridled cell growth. The recent discovery of CX-5461, a selective RNA polymerase I inhibitor, exerted its inhibitory effect of ribosomal RNA synthesis and antiproliferative potency. Here, we demonstrate that CX-5461 induces G2 arrest in the cell cycle and expression of microtubule-associated protein 1 light chain 3 II isoform in OS cell lines. Autophagic vacuoles could be observed in electron microscopy and 3-methyladenine prevented cell death mediated by CX-5461. Moreover, it significantly augmented phosphorylated AMP-Activated Protein Kinases α (p-AMPK α). (Thr172) expression in U2-OS cells and decreased p-Akt (Ser473) expression in MNNG cells, respectively, which repressed their downstream effector, mammalian target of rapamycin. On the other hand, CX-5461 increased p53 accumulation and messenger RNA level of its target genes, p21, MDM2, and Sestrin1/2 in U2-OS cells. Knockdown of p53 expression markedly impaired cell death as well as the expression of light chain 3-II and p21 induced by CX-5461. It also significantly enhanced doxorubicin-mediated cytotoxic effect in vitro and in vivo together with additive expression of p53, p21, and light chain 3-II in U2-OS cells. Our data indicate that CX-5461 might induce autophagy via mammalian target of rapamycin-associated signaling pathways dependent on p53 status and exert p53-dependent synergistic antitumor effect combined with doxorubicin in OS. These results suggest that CX-5461 might be promising in clinical therapy for OS, especially cases harboring wild-type p53.

Silencing of carboxypeptidase E inhibits cell proliferation, tumorigenicity, and metastasis of osteosarcoma cells.

Carboxypeptidase E (CPE), a prohormone processing enzyme, has been implicated in the progression of multiple malignancies. However, the biological role and molecular mechanisms of CPE in osteosarcoma remain elusive. In this study, we assessed the effects of CPE on cell proliferation, tumorigenicity, migration, and invasion in osteosarcoma. Our results showed that silencing of CPE significantly inhibited cell proliferation, caused cell cycle arrest at G0/G1 phase, decreased the expression levels of cell cycle protein, cyclin D1, and inhibited tumorigenicity in vivo. Additionally, CPE downregulation repressed the migratory and invasive capacities of osteosarcoma cells in vitro. Furthermore, overexpression of CPE-ΔN (a splice variant of CPE) enhanced the cell growth, migration, and invasion of osteosarcoma cells. It is possible that both CPE forms are involved in the tumorigenesis and development of osteosarcoma, and therefore CPE may provide a promising biological target for osteosarcoma therapy.

Intramedullary nail versus plate treatments for distal tibial fractures: a meta-analysis.

INTRODUCTION: Controversy remained on whether the optimal treatment for distal tibial fractures is intramedullary nail (IMN) or plate. METHODS: Databases including PubMed, Embase, Cochrane library, Wanfang and CNKI were retrieved up to May 31, 2014 for eligible studies. Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used to evaluate literature qualities. Q and I(2) test were applied to estimate heterogeneities. Moreover, subgroup analyses were performed and publication bias was detected. Mean difference (MD) and relative risk (RR), with their corresponding 95% confidence interval (CI) were used to calculate the pooled results. RESULTS: Sixteen studies were included involving 1140 participants (IMN: 599; plate: 541). There were no significant differences between IMN and plate treatments in operation time (OT), hospital time (HT), union time (UT), and incidence of deep infection (DI) and union complications (UC). However, IMN achieved a significant lower superficial infection (SI) incidence (RR, 0.41; 95% CI, 0.23 to 0.71; P = 0.001) and a significant higher malunion incidence (RR, 2.27; 95% CI, 1.56 to 3.31; P < 0.001). In subgroup analyses, IMN had significant shorter OT than plate in randomized controlled trials (RCTs) (MD, -19.04; 95% CI, -24.86 to -13.21; P < 0.0001), but comparable incidence of SI to plate in non-Asia countries. No obvious publication bias was indicated in UT and malunion. CONCLUSION: For distal tibial fractures treatment, IMN might be advantageous over plate with lower SI incidence, and comparable UT, OT and HT. Meanwhile, IMN was related to higher risk of malunion. However, more RCTs are warranted.

Developing lipid nanoparticle-based siRNA therapeutics for hepatocellular carcinoma using an integrated approach.

Successful siRNA therapeutics requires the optimal integration of multiple components, including an efficient delivery system, a disease indication that is appropriate for siRNA-based therapy, and a potent and nontoxic siRNA against a robust therapeutic target. Although all currently available delivery systems have limitations, it is important to recognize that a careful selection of the disease indication, therapeutic target, and siRNA molecule could partially compensate for deficiencies associated with the delivery system and makes it possible to advance a therapeutic siRNA regimen. In this study, we present the development of siRNA therapeutics for hepatocellular carcinoma using an integrated approach, including the development of an efficient lipid nanoparticle delivery system, the identification of a robust therapeutic target that does not trigger liver toxicity upon target knockdown, and the selection of potent and nonimmunogenic siRNA molecules against the target. The resulting siRNA-containing lipid nanoparticles produced significant antitumor efficacy in orthotopic hepatocellular carcinoma models, and, thus, represent a promising starting point for the development of siRNA therapeutics for hepatocellular carcinoma.

RNA interference-mediated knockdown of Livin suppresses cell proliferation and invasion and enhances the chemosensitivity to cisplatin in human osteosarcoma cells.

Livin is a novel member of the inhibitor of apoptosis protein (IAP) family that has been reported to be overexpressed in a variety of human malignancies, including osteosarcoma. However, the potential roles of Livin in tumorigenesis have not been elucidated. In the present study, we employed RNA interference (RNAi) technology to suppress endogenous Livin expression in osteosarcoma cells and successfully generated a U2-OS cell line with stably knockdown of Livin. Functional analysis showed that knockdown of Livin significantly reduced cell proliferation, colony formation, and invasion and migration capacities of U2-OS cells in vitro. Moreover, specific downregulation of Livin led to cell cycle arrest at the G0/G1 phase and eventual apoptosis. Meanwhile, western blot analysis revealed that cells with stably knockdown of Livin showed decreased expression levels of Cyclin D1, Bcl-2, matrix metalloproteinase (MMP)-2 and MMP-9, but increased expression levels of activated Caspase-3, Bax and cleaved poly (ADP-ribose) polymerase (PARP) compared to those transfected with a control vector. We also observed that suppression of Livin expression in osteosarcoma cells increased their chemosensitivity to cisplatin. Taken together, our data suggest that Livin is involved in tumorigenesis of human osteosarcoma and may serve as a promising therapeutic target for osteosarcoma.