Microenvironment-dependent growth of Sezary cells in humanized IL-15 mice.

Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small-animal models. Here, we demonstrate that IL-15 is a critical CTCL growth factor. Importantly, an immunodeficient knock-in mouse model genetically engineered to express human IL-15 uniquely supported the growth of SS patient samples relative to conventional immunodeficient mouse strains. SS patient-derived xenograft (PDX) models recapacitated key pathological features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single-cell transcriptomic analysis revealed congruent neoplastic gene expression signatures but distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of immunodeficient humanized IL-15 mice as hosts for SS - and potentially other T and NK cell-derived hematologic malignancies - PDX model generation. Furthermore, these studies advocate the thorough molecular understanding of the resultant PDX models to maximize their translational impact.

Effects of fertilizer and biochar applications on the relationship among soil moisture, temperature, and N2O emissions in farmland.

BACKGROUND: Di-nitrogen oxide (N2O) emissions from soil may lead to nonpoint-source pollution in farmland. Improving the C and N content in the soil is an excellent strategy to reduce N2O emission and mitigate soil N loss. However, this method lacks a unified mathematical index or standard to evaluate its effect. METHODS: To quantify the impact of soil improvement (C and N) on N2O emissions, we conducted a 2-year field experiment using biochar as carbon source and fertilizer as nitrogen source, setting three treatments (fertilization (300 kg N ha-1), fertilization + biochar (30 t ha-1), control). RESULTS: Results indicate that after biochar application, the average soil water content above 20 cm increased by ∼26% and 26.92% in 2019, and ∼10% and 12.49% in 2020. The average soil temperature above 20 cm also increased by ∼2% and 3.41% in 2019. Fertigation significantly promotes the soil N2O emissions, and biochar application indeed inhibited the cumulation by approximately 52.4% in 2019 and 33.9% in 2020, respectively. N2O emissions strongly depend on the deep soil moisture and temperature (20-80 cm), in addition to the surface soil moisture and temperature (0-20 cm). Therefore, we established an exponential model between the soil moisture and N2O emissions based on theoretical analysis. We find that the N2O emissions exponentially increase with increasing soil moisture regardless of fertilization or biochar application. Furthermore, the coefficient a < 0 means that N2O emissions initially increase and then decrease. The aRU < aCK indicates that fertilization does promote the rate of N2O emissions, and the aBRU > aRU indicates that biochar application mitigates this rate induced by fertilization. This conclusion can be verified by the sensitivity coefficient (SCB of 1.02 and 14.74; SCU of 19.18 and 20.83). Thus, we believe the model can quantify the impact of soil C and N changes on N2O emissions. We can conclude that biochar does significantly reduce N2O emissions from farmland.

Effects of irrigation methods and salinity on CO2 emissions from farmland soil during growth and fallow periods.

Drip irrigation and brackish water irrigation are considered to be the two main ways to alleviate the current shortage of agricultural freshwater resources and have been widely used in countries around the world. Our purpose is to evaluate the effects of different irrigation methods (flood irrigation and drip irrigation) and irrigation water salinities (1.1 g·L-1, 2.0 g·L-1, 3.5 g·L-1, and 5.0 g·L-1) on the soil CO2 emissions during the growth and fallow periods of spring maize. Therefore, a two-year field experiment was conducted in Hetao Irrigation District in China from 2017 to 2019. The results showed that compared with flood irrigation, drip irrigation significantly decreased the soil CO2 emissions in the growth period. After irrigation with a salinity of 5.0 g·L-1, the soil moisture was the highest because the plant water absorption was inhabited by soil salt, and the soil CO2 emissions were also promoted during the growth period. Irrigation method and irrigation water salinity had no effect on the soil CO2 emissions in the fallow period. Soil temperature, moisture and inorganic nitrogen content were the main factors affecting the daily CO2 emission flux. The soil CO2 emissions during the growth period accounted for more than 83.93% of the annual soil emissions. Based on the goal of saving freshwater resources, ensuring soil safety, reducing soil CO2 emissions and increasing the size of the carbon pool, adoption of drip irrigation with 2.0 g·L-1 brackish water could be adopted to ensure the sustainable development of local agriculture.

Complete genome sequence of Mycobacterium Mya-zh01, an endophytic bacterium, promotes plant growth and seed germination isolated from flower stalk of Doritaenopsis.

No genomic sequence of Mycobacterium isolated from orchids has been reported yet; therefore, this study intends to analyze the complete genomic sequence of a growth-promoting Mycobacterium from orchid Doritaenopsis. Mycobacterium strain Mya-zh01 was isolated from the flower stalk of Doritaenopsis Jiuhbao Red Rose. Our results show that Mya-zh01 can effectively produce and secrete the plant growth hormone indole-3-acetic acid (IAA). Inoculation of Mya-zh01 increased root number and length, plant height, leaf number, and leaf length in Doritaenopsis. Furthermore, inoculation of Mya-zh01 promotes seed germination in Doritaenopsis. We sequenced and assembled chromosome for Mya-zh01 (5,027,704 bp with 68.48% GC content), which was predicted to encode 4968 proteins with functions in oxidation reduction, growth, plasma membrane, ATP and DNA binding, carbon metabolism and biosynthesis of amino acids pathways. Mya-zh01 may trap iron from nature or host cells to facilitate the growth of the orchids by producing two siderophores (Mycobactin and Nocobactin NA). Four pathways (tryptamine, indole-3-acetamide, indole-3-pyruvate, and flavin monooxygenase) and seven enzymes [tryptophan synthase alpha chain, tryptophan synthase beta chain, amidase, monoamine oxidase, indole-3-pyruvate monooxygenase, indole-3-pyruvate decarboxylase and aldehyde dehydrogenase (NAD +)] involved in IAA biosynthesis were predicted in Mya-zh01 genome. In conclusion, this study demonstrated the significance of Mya-zh01 in facilitating plant growth and seed germination in Doritaenopsis by IAA biosynthesis, which provides a new insight into the mechanism of plant-bacteria interaction in Doritaenopsis.

Finding the optimal fertilizer type and rate to balance yield and soil GHG emissions under reclaimed water irrigation.

Water and inorganic nitrogen fertilizer have a notable impact on crop yield and greenhouse gas (GHG) emissions from soil. Reclaimed water (RW) is widely used for irrigation when there are shortages of water resources. It is very important to control yield and greenhouse gas emissions by fertilization under reclaimed water irrigation (RWI). The study consisted of a continuous test that evaluated three types of fertilizer treatments (urea, amine, and slow-release fertilizer) and a no-fertilizer treatment under three-year RWI and four fertilizer levels (150, 200, 250 and 300 kg.N.ha-1) under one-year RWI to determine the best fertilizer to support maize production and reduce GHG (CO2 and N2O) emissions from soil; further, the applicability of RWI in the DNDC model was verified. For many years, GHG emissions under RWI showed an increasing trend, but the effect was not significant. A strong correlation was found between the GHG emissions flux and fertilizer amount, and a threshold fertilization amount existed between 220 and 260 kg.N.ha-1 that minimized yield-scaled N2O emissions and the ratio of GHG cumulative emission to yield (GHG/Y). The results indicated that the optimal amounts of SF and UF under RWI were 240 and 225 kg.N.ha-1 by second-order equation and the DNDC model, respectively, and the rate better balanced the yield and GHG emissions.

Effects of fertilizer types and water quality on carbon dioxide emissions from soil in wheat-maize rotations.

The use of fertilizers as addition inputs in agricultural systems can increase the yield of wheat and maize, while also stimulating the emission of carbon dioxide from soil that the main man-made greenhouse gas. Our objectives focused on the impact of different types of synthetic fertilizers and water quality. The purposes were to determine the feasibility of using wasted water for irrigation and to relate CO2 fluxes to the yield of maize and wheat, as well as to select the best fertilizer type with low CO2 emission and high yield. The experiment consisted of a double factors test focusing on four forms of fertilizer (urea, amine and slow release fertilizer) and the quality of water (reclaimed water and underground water). The results showed that the reclaimed water was not significant on the CO2 discharge rate, the maize-wheat yield or the soil properties in 2014 or 2015; however, the CO2 emission increased slightly in 2015. Focusing on fertilizer treatments, the reclaimed water & amine fertilizer treatment (CAF) that had higher cumulative CO2 emissions was 32.75 t·ha-1 in 2014 and 33.86 t·ha-1 in 2015. According to the ratio CO2/Y, the slow released fertilizer that reduces CO2 emissions and keeps the yield high is the preferred choice.

Therapeutic targeting of Notch signaling and immune checkpoint blockade in a spontaneous, genetically heterogeneous mouse model of T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer derived from the malignant transformation of T-cell progenitors. Outcomes remain poor for T-ALL patients who have either primary resistance to standard-of-care chemotherapy or disease relapse. Notably, there are currently no targeted therapies available in T-ALL. This lack of next-generation therapies highlights the need for relevant preclinical disease modeling to identify and validate new targets and treatment approaches. Here, we adapted a spontaneously arising, genetically heterogeneous, thymic transplantation-based murine model of T-ALL, recapitulating key histopathological and genetic features of the human disease, to the preclinical testing of targeted and immune-directed therapies. Genetic engineering of the murine Notch1 locus aligned the spectrum of Notch1 mutations in the mouse model to that of human T-ALL and confirmed aberrant, recombination-activating gene (RAG)-mediated 5' Notch1 recombination events as the preferred pathway in murine T-ALL development. Testing of Notch1-targeting therapeutic antibodies demonstrated T-ALL sensitivity to different classes of Notch1 blockers based on Notch1 mutational status. In contrast, genetic ablation of Notch3 did not impact T-ALL development. The T-ALL model was further applied to the testing of immunotherapeutic agents in fully immunocompetent, syngeneic mice. In line with recent clinical experience in T-cell malignancies, programmed cell death 1 (PD-1) blockade alone lacked anti-tumor activity against murine T-ALL tumors. Overall, the unique features of the spontaneous T-ALL model coupled with genetic manipulations and the application to therapeutic testing in immunocompetent backgrounds will be of great utility for the preclinical evaluation of novel therapies against T-ALL.

CO2 and N2O Emissions from Spring Maize Soil under Alternate Irrigation between Saline Water and Groundwater in Hetao Irrigation District of Inner Mongolia, China.

Alternative irrigation between saline water and groundwater can alleviate shortages of available agricultural water while effectively slowing the adverse effects of saline water on the soil-crop system when compared with continuous irrigation with saline water and blending irrigation between saline water and groundwater. In 2018, we tested the effect on soil CO2 and N2O emissions by two types of irrigation regimes (alternating groundwater and saline water (GW-SW), and alternating groundwater, followed by two cycles of saline water (GW-SW-SW)) between groundwater and three levels of salinity of irrigation water (mineralization of 2 g/L, 3.5 g/L, and 5 g/L), analyzed the correlation between gas emissions and soil properties, calculated comprehensive global warming potential (GWP), and investigated the maize yield. The results show that, with the same alternate irrigation regime, cumulative CO2 emissions decreased with increasing irrigation water salinity, and cumulative N2O emissions increased. Cumulative CO2 emissions were higher in the GW-SW regime for the same irrigation water salinity, and cumulative N2O emissions were higher in the GW-SW-SW regime. The GW-SW-SW regime had less comprehensive GWP and maize yield as compared to the GW-SW regime. The 2 g/L salinity in both regimes showed larger comprehensive GWP and maize yield. The 3.5 g/L salinity under the GW-SW regime will be the best choice while considering that the smaller comprehensive GWP and the larger maize yield are appropriate for agricultural implication. Fertilizer type and irrigation amount can be taken into consideration in future research direction.

Mathematical model of ammonium nitrogen transport with overland flow on a slope after polyacrylamide application.

The nutrient loss caused by soil erosion is the main reason for soil degradation and environmental pollution, and polyacrylamide (PAM) as a common soil amendment has a great influence on runoff and erosion processes at the slope. In order to investigate the mechanism of nutrient transport with runoff, a field experiment was conducted and a simple mathematical model was developed in this study. Four PAM application rates (0, 1, 2, and 4 g·m-2) and two rainfall intensities (50 and 80 mm·h-1) were applied in the field experiment. The results revealed that runoff rate of 2 g·m-2 PAM application treatments decreased by 5.3%-10.6% compared with the control groups, but it increased by10.9%-18.7% at 4 g·m-2 PAM application treatments. Polyacrylamide application reduced ammonium nitrogen concentrations of runoff by 10.0% to 44.3% relative to the control groups. The best performance with correlation coefficient (R2) and Nash-Sutcliffe efficiency (NSE) showed that the ammonium transport with runoff could be well described by the proposed model. Furthermore, the model parameter of the depth of the mixing layer (hm) linearly increased with an increase in flow velocity, but exponentially decreased with an increase in PAM application rate.

An Inverse Method to Estimate the Root Water Uptake Source-Sink Term in Soil Water Transport Equation under the Effect of Superabsorbent Polymer.

The widespread use of superabsorbent polymers (SAPs) in arid regions improves the efficiency of local land and water use. However, SAPs' repeated absorption and release of water has periodic and unstable effects on both soil's physical and chemical properties and on the growth of plant roots, which complicates modeling of water movement in SAP-treated soils. In this paper, we proposea model of soil water movement for SAP-treated soils. The residence time of SAP in the soil and the duration of the experiment were considered as the same parameter t. This simplifies previously proposed models in which the residence time of SAP in the soil and the experiment's duration were considered as two independent parameters. Numerical testing was carried out on the inverse method of estimating the source/sink term of root water uptake in the model of soil water movement under the effect of SAP. The test results show that time interval, hydraulic parameters, test error, and instrument precision had a significant influence on the stability of the inverse method, while time step, layering of soil, and boundary conditions had relatively smaller effects. A comprehensive analysis of the method's stability, calculation, and accuracy suggests that the proposed inverse method applies if the following conditions are satisfied: the time interval is between 5 d and 17 d; the time step is between 1000 and 10000; the test error is ≥ 0.9; the instrument precision is ≤ 0.03; and the rate of soil surface evaporation is ≤ 0.6 mm/d.

New frontiers in fibrotic disease therapies: The focus of the Joan and Joel Rosenbloom Center for Fibrotic Diseases at Thomas Jefferson University.

Fibrotic diseases constitute a world-wide major health problem, but research support remains inadequate in comparison to the need. Although considerable understanding of the pathogenesis of fibrotic reactions has been attained, no completely effective therapies exist. Although fibrotic disorders are diverse, it is universally appreciated that a particular cell type with unique characteristics, the myofibroblast, is responsible for replacement of functioning tissue with non-functional scar tissue. Understanding the cellular and molecular mechanisms responsible for the creation of myofibroblasts and their activities is central to the development of therapies. Critical signaling cascades, initiated primarily by TGF-ß, but also involving other cytokines which stimulate pro-fibrotic reactions in the myofibroblast, offer potential therapeutic targets. However, because of the multiplicity and complex interactions of these signaling pathways, it is very unlikely that any single drug will be successful in modifying a major fibrotic disease. Therefore, we have chosen to examine the effectiveness of administration of several drug combinations in a mouse pneumoconiosis model. Such treatment proved to be effective. Because fibrotic diseases that tend to be chronic, are difficult to monitor, and are patient variable, implementation of clinical trials is difficult and expensive. Therefore, we have made efforts to identify and validate non-invasive biomarkers found in urine and blood. We describe the potential utility of five such markers: (i) the EDA form of fibronectin (Fn(EDA)), (ii) lysyl oxidase (LOX), (iii) lysyl oxidase-like protein 2 (LoxL2), (iv) connective tissue growth factor (CTGF, CCNII), and (v) the N-terminal propeptide of type III procollagen (PIIINP).

Pathobiological mechanisms of peritoneal adhesions: The mesenchymal transition of rat peritoneal mesothelial cells induced by TGF-ß1 and IL-6 requires activation of Erk1/2 and Smad2 linker region phosphorylation.

Peritoneal adhesions, primarily caused by surgical procedures, are the leading cause of pelvic pain, bowel obstruction, and infertility. TGF-ß1 and IL-6 have been found to be elevated in the peritoneal fluid of patients during/after abdominal surgery. However, it remains to be determined whether these cytokines interact and facilitate adhesion formation by promoting mesothelial to mesenchymal transition (MMT). In the present study, isolated rat peritoneal mesothelial cells were treated with TGF-ß1 and/or IL-6 which elicited MMT as determined by morphologic and biochemical techniques. During this transition, cellular morphology changed from that of cobblestone polygonal cells to elongated/spindle-shaped fibroblast-like cells. There was decreased expression of genes characteristic of mesothelial cells, such as E-cadherin, and increased expression of genes characteristic of the myofibroblast phenotype, including α-smooth muscle actin and the EDA form of fibronectin, both of which appear to mediate the transfer of force to the extracellular matrix. Partial characterization of relevant signaling pathways identified Erk1/2 activation, which was enhanced by combined TGF-ß1/IL-6 administration, as a crucial necessary factor in the transition. Erk1/2 activation as well as the phosphorylation of the linker region of Smad2 and MMT could be blocked by the MEK inhibitor, U0126, suggesting that such activation may be a potential pharmaceutical target to prevent MMT. In addition, the phenotypic transition could be prevented by hydrocortisone.

The activating transcription factor 3 protein suppresses the oncogenic function of mutant p53 proteins.

Mutant p53 proteins (mutp53) often acquire oncogenic activities, conferring drug resistance and/or promoting cancer cell migration and invasion. Although it has been well established that such a gain of function is mainly achieved through interaction with transcriptional regulators, thereby modulating cancer-associated gene expression, how the mutp53 function is regulated remains elusive. Here we report that activating transcription factor 3 (ATF3) bound common mutp53 (e.g. R175H and R273H) and, subsequently, suppressed their oncogenic activities. ATF3 repressed mutp53-induced NFKB2 expression and sensitized R175H-expressing cancer cells to cisplatin and etoposide treatments. Moreover, ATF3 appeared to suppress R175H- and R273H-mediated cancer cell migration and invasion as a consequence of preventing the transcription factor p63 from inactivation by mutp53. Accordingly, ATF3 promoted the expression of the metastasis suppressor SHARP1 in mutp53-expressing cells. An ATF3 mutant devoid of the mutp53-binding domain failed to disrupt the mutp53-p63 binding and, thus, lost the activity to suppress mutp53-mediated migration, suggesting that ATF3 binds to mutp53 to suppress its oncogenic function. In line with these results, we found that down-regulation of ATF3 expression correlated with lymph node metastasis in TP53-mutated human lung cancer. We conclude that ATF3 can suppress mutp53 oncogenic function, thereby contributing to tumor suppression in TP53-mutated cancer.

MicroRNA-138 regulates hypoxia-induced endothelial cell dysfunction by targeting S100A1.

The Ca(2+) sensor S100A1 is essential for proper endothelial cell (EC) nitric oxide (NO) synthase (eNOS) activation. S100A1 levels are greatly reduced in primary human microvascular ECs subjected to hypoxia, rendering them dysfunctional. However mechanisms that regulate S100A1 levels in ECs are unknown. Here we show that ECs transfected with a S100A1-3' untranslated region (UTR) luciferase reporter construct display significantly reduced gene expression when subjected to low oxygen levels or chemical hypoxia. Bioinformatic analysis suggested that microRNA -138 (MiR-138) could target the 3'UTR of S100A1. Patients with critical limb ischemia (CLI) or mice subjected to femoral artery resection (FAR) displayed increased MiR-138 levels and decreased S100A1 protein expression. Consistent with this finding, hypoxia greatly increased MiR-138 levels in ECs, but not in skeletal muscle C2C12 myoblasts or differentiated myotubes or primary human vascular smooth muscle cells. Transfection of a MiR-138 mimic into ECs reduced S100A1-3 'UTR reporter gene expression, while transfection of an anti MiR-138 prevented the hypoxia-induced downregulation of the reporter gene. Deletion of the 22 nucleotide putative MiR-138 target site abolished the hypoxia-induced loss of reporter gene expression. Knockdown of Hif1-α mediated by siRNA prevented loss of hypoxia-induced reporter gene expression. Conversely, specific activation of Hif1-α by a selective prolyl-hydroxylase inhibitor (IOX2) reduced reporter gene expression even in the absence of hypoxia. Finally, primary ECs transfected with a MiR-138 mimic displayed reduced tube formation when plated onto Matrigel matrix and expressed less NO when stimulated with VEGF. These effects were reversed by gene transfer of S100A1 using recombinant adenovirus. We conclude that hypoxia-induced MiR-138 is an essential mediator of EC dysfunction via its ability to target the 3'UTR of S100A1.

Study on the growth and the photosynthetic characteristics of low energy C(+) ion implantation on peanut.

Employing the Nonghua 5 peanut as experimental material, the effects of low energy C(+) ion implantation on caulis height, root length, dry weight, photosynthetic characteristics and leaf water use efficiency (WUE) of Peanut Ml Generation were studied. Four fluences were observed in the experiment. The results showed that ion implantation harmed the peanut seeds because caulis height, root length and dry weight all were lower in the treatments than in CK, and the harm was aggravated with the increase of ion fluence. Both Pn and Tr show a saddle-shape curve due to midday depression of photosynthesis. Low fluence of low energy C(+) ion implantation could increase the diurnal average Pn of peanut. The diurnal variation of Tr did not change as significantly as Pn. The light saturation point (LSP) was restrained by the ions. After low energy C(+) ion implantation, WUE was enhanced. When the fluence increased to a certain level, the WUE began to decrease.

Platelet IκB kinase-ß deficiency increases mouse arterial neointima formation via delayed glycoprotein Ibα shedding.

OBJECTIVE: On the luminal surface of injured arteries, platelet activation and leukocyte-platelet interactions are critical for the initiation and progression of arterial restenosis. The transcription factor nuclear factor-κB is a critical molecule in platelet activation. Here, we investigated the role of the platelet nuclear factor-κB pathway in forming arterial neointima after arterial injury. METHODS AND RESULTS: We performed carotid artery wire injuries in low-density lipoprotein receptor-deficient (LDLR(-/-)) mice with a platelet-specific deletion of IκB kinase-ß (IKKß) (IKKß(fl/fl)/PF4(cre)/LDLR(-/-)) and in control mice (IKKß(fl/fl)/LDLR(-/-)). The size of the arterial neointima was 61% larger in the IKKß(fl/fl)/PF4(cre)/LDLR(-/-) mice compared with the littermate control IKKß(fl/fl)/LDLR(-/-) mice. Compared with the control mice, the IKKß(fl/fl)/PF4(cre)/LDLR(-/-) mice exhibited more leukocyte adhesion at the injured area. The extent of glycoprotein Ibα shedding after platelet activation was compromised in the IKKß-deficient platelets. This effect was associated with a low level of the active form of A Disintegrin And Metalloproteinase 17, the key enzyme involved in mediating glycoprotein Ibα shedding in activated IKKß-deficient platelets. CONCLUSIONS: Platelet IKKß deficiency increases the formation of injury-induced arterial neointima formation. Thus, nuclear factor-κB-related inhibitors should be carefully evaluated for use in patients after an arterial intervention.

[Effects of irrigation with treated wastewater on nutrient distribution in cucumber and tomato plants and their fruit quality].

A field experiment was conducted to investigate the effects of irrigation with treated wastewater on the nutrient distribution in cucumber and tomato plants and their fruit quality. Irrigation with treated wastewater promoted tomato growth significantly, but had definite inhibition effect on cucumber growth. After the irrigation with treated wastewater, the nitrogen in plants had the characteristics of upward translocation, potassium was easily to be accumulated in cucumber leaf but not accumulated in tomato root, and sodium was mostly accumulated in root but less enriched in leaf, not giving damage to the plants. No significant effects were observed on the distribution of calcium, magnesium, and chlorine in plants. Under the irrigation with treated wastewater, the overall quality of cucumber and tomato fruits was less affected. The nitrate concentration in cucumber and tomato fruits was increased by 5.3% and 32.9%, respectively, but still lower than the state food safety standard of China.

[Effects of canal-lining project on groundwater and ecological environment in Hetao Irrigation District of Inner Mongolia].

The canal-lining project in Hetao Irrigation District (HID) for water-saving irrigation has been implemented for many years. By using statistical method, ordinary Kriging, and software ArcGIS 9.0, this paper analyzed the spatiotemporal variation of groundwater table depth and salinity in HID in September, 2001 and 2009. In the meantime, the vegetation distribution on the both shores of the lining part and non-lining part of Yangjiahe channel was also investigated. After the many years implementation of the project, the water diversion amount in HID in 2009 was reduced to 44.5 x 10(8) m3. The region area of groundwater table with a depth of 2.5-3.0 m was increased from 1.2 x 10(4) hm2 in 2001 to 9.11 x 10(4) hm2 in 2009. The region area of groundwater table with a depth of 2.0-2.5 m in 2009 took 80% of the total area of HID. In the northwestern region of HID, the groundwater salinity had reduced from 5000-10000 mg x L(-1) to 3000-5000 mg x L(-1). In Wulate irrigation region, the areas of salt water belt and half-salt water belt were increasing. After the canal-lining of Yangjiahe channel, the plant species and diversity index on both shores reduced, and some herbaceous plants with shallow roots showed degradation signs. The implementation of the project and the reduction of water diversion for irrigation did not exert negative effects on the maintenance of water surface area of Wuliangsuhai Lake.

A small-molecule inhibitor of MDMX activates p53 and induces apoptosis.

The p53 inactivation caused by aberrant expression of its major regulators (e.g., MDM2 and MDMX) contributes to the genesis of a large number of human cancers. Recent studies have shown that restoration of p53 activity by counteracting p53 repressors is a promising anticancer strategy. Although agents (e.g., nutlin-3a) that disrupt MDM2-p53 interaction can inhibit tumor growth, they are less effective in cancer cells that express high levels of MDMX. MDMX binds to p53 and can repress the tumor suppressor function of p53 through inhibiting its trans-activation activity and/or destabilizing the protein. Here we report the identification of a benzofuroxan derivative [7-(4-methylpiperazin-1-yl)-4-nitro-1-oxido-2,1,3-benzoxadiazol-1-ium, NSC207895] that could inhibit MDMX expression in cancer cells through a reporter-based drug screening. Treatments of MCF-7 cells with this small-molecule MDMX inhibitor activated p53, resulting in elevated expression of proapoptotic genes (e.g., PUMA, BAX, and PIG3). Importantly, this novel small-molecule p53 activator caused MCF-7 cells to undergo apoptosis and acted additively with nutlin-3a to activate p53 and decrease the viability of cancer cells. These results thus show that small molecules targeting MDMX expression would be of therapeutic benefits.

S100A1 gene therapy for heart failure: a novel strategy on the verge of clinical trials.

Representing the common endpoint of various cardiovascular disorders, heart failure (HF) shows a dramatically growing prevalence. As currently available therapeutic strategies are not capable of terminating the progress of the disease, HF is still associated with a poor clinical prognosis. Among the underlying molecular mechanisms, the loss of cardiomyocyte Ca(2+) cycling integrity plays a key role in the pathophysiological development and progression of the disease. The cardiomyocyte EF-hand Ca(2+) sensor protein S100A1 emerged as a regulator both of sarcoplasmic reticulum (SR), sarcomere and mitochondrial function implicating a significant role in cardiac physiology and dysfunction. In this review, we aim to recapitulate the translation of S100A1-based investigation from first clinical observations over basic research experiments back to a near-clinical setting on the verge of clinical trials today. We also address needs for further developments towards "second-generation" gene therapy and discuss the therapeutic potential of S100A1 gene therapy for HF as a promising novel strategy for future cardiologists. This article is part of a Special Section entitled "Special Section: Cardiovascular Gene Therapy".