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Zn is an important trace element involved in various biochemical processes in aquatic species. An 8-week rearing trial was thus conducted to investigate the effects of Zn on juvenile largemouth bass (Micropterus salmoides) by feeding seven diets, respectively, supplemented with no Zn (Con), 60 and 120 mg/kg inorganic Zn (Sul60 and Sul120), and 30, 60, 90 and 120 mg/kg organic Zn (Bio30, Bio60, Bio90 and Bio120). Sul120 and Bio120 groups showed significantly higher weight gain and specific growth rate than Con group, with Bio60 group obtaining the lowest viscerosomatic index and hepatosomatic index. 60 or 90 mg/kg organic Zn significantly facilitated whole body Zn retention. Up-regulation of hepatic superoxide dismutase, glutathione peroxidase and catalase activities and decline of malondialdehyde contents indicated augmented antioxidant capacities by organic Zn. Zn treatment also lowered plasma aminotransferase levels while promoting acid phosphatase activity and hepatic transcription levels of alp1, acp1 and lyz-c than deprivation of Zn. The alterations in whole body and liver crude lipid and plasma TAG contents illustrated the regulatory effect of Zn on lipid metabolism, which could be possibly attributed to the changes in hepatic expressions of acc1, pparγ, atgl and cpt1. These findings demonstrated the capabilities of Zn in potentiating growth and morphological performance, antioxidant capacity, immunity as well as regulating lipid metabolism in M. salmoides. Organic Zn could perform comparable effects at same or lower supplementation levels than inorganic Zn, suggesting its higher efficiency. 60 mg/kg supplementation of organic Zn could effectively cover the requirements of M. salmoides.

Chiral α-substituted ethylphosphonate and ethylphosphine oxide compounds are widely used in drugs, pesticides, and ligands. However, their catalytic asymmetric synthesis is still rare. Of the only asymmetric hydrogenation methods available at present, all cases use rare metal catalysts. Herein, we report an efficient earth-abundant transition-metal nickel catalyzed asymmetric hydrogenation affording the corresponding chiral ethylphosphine products with up to 99% yield, 96% ee (enantiomeric excess) (99% ee, after recrystallization) and 1000 S/C (substrate/catalyst); this is also the first study on the asymmetric hydrogenation of terminal olefins using a nickel catalyst under a hydrogen atmosphere. The catalytic mechanism was investigated via deuterium-labelling experiments and calculations which indicate that the two added hydrogen atoms of the products come from hydrogen gas. Additionally, it is believed that the reaction involves a Ni(II) rather than Ni(0) cyclic process based on the weak attractive interactions between the Ni catalyst and terminal olefin substrate.

The transcription factor FOXM1 that regulates multiple proliferation-related genes through selective protein-DNA and protein-protein interactions is now considered an attractive oncotarget. There are several small-molecule inhibitors that indirectly suppress the expression of FOXM1 or block its DNA binding domain (FOXM1-DBD). However, insufficient specificity or/and efficacy are two potential drawbacks. Here, we employed in silico modeling of FOXM1-DBD with inhibitors to enable the design of an effective CRBN-recruiting molecule that induced significant FOXM1 protein degradation and exerted promising in vivo antitumor activity against TNBC xenograft models. This study is the first of its kind showcasing the use of an approach described in the literature as protein-targeting chimeras to degrade the elusive FOXM1, providing an alternative strategy to counter the pathological effects resulting from the increased transcriptional activity of FOXM1 observed in cancer cells.

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (21c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells (DC50 = 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21b reveled favorable plasma exposures referring to both the parent 21b and the conversed acid 21c. Further in vivo studies of 21b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases., Graphical abstract The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. A potent and orally active VHL-recruiting PROTAC was developed, displaying robust HMGCR degradation and potent hypolipidemic activity in diet-induced mice.Image 1

The application of lightweight soil for changing and filling is an effective foundation treatment method for the construction of sponge cities in collapsible loess areas. In this paper, the L25(54) orthogonal test targeting on the strength, permeability and density characteristics was first used to optimize the mixture ratio design of proposed lightweight soil with cotton stalk fibres (LSCF). The corresponding effects of each mixed content on the performance of LSCF were analysed. The soil water characteristic curves (SWCCs) of LSCF with different cement and cotton stalk fibre contents were then measured using the quick centrifuge method. In comparison with undisturbed loess, the volumetric moisture content of LSCF (for the same matrix suction) was larger, and LSCF had a better water-holding capacity. Based on the Van Genuchten model, an improved fitting model for matrix suction SWCC of LSCF was proposed by considering the influence of cement. Qualitative agreement with the test results indicates that the proposed model could be potentially used to obtain the SWCC curve without conducting any experiments, which is especially useful for the sponge city constructions in loess areas.

Efficient design and preparation of cost-effective and binder-free bifunctional electrocatalysts to accelerate the hydrogen and oxygen evolution reaction (HER and OER) are critical for overall water splitting. In this work, 3D hierarchical NiFe-LDH/FeCoS2/CFC electrodes were synthesized for the first time. The carboxyl groups derived from acid treating promote the homogeneously coated FeCoS2 on CFC, giving rise to the strongly coupled FeCoS2/CFC hybrid. The NiFe-LDH exhibited the vertical growth feature on the FeCoS2/CFC composite, which can efficiently expose the active edges sites. Due to unique structure and synergistic effect between the components, the NiFe-LDH/FeCoS2/CFC exhibits significant electrocatalytic activity and stability under alkaline environments, with overpotentials of 190 and 308 mV to achieve 10 mA cm−2 for OER and HER, respectively, providing it as a promising electrocatalyst for water splitting reaction. In addition, we deeply studied the synergistic catalytic mechanism of NiFe-LDH/FeCoS2/CFC, explaining the reasons leading to the improved catalytic performance of HER and OER.

Various third-party single sign-on (SSO) services (e.g., Facebook Login and Twitter Login) are widely deployed by web applications to facilitate their authentication and authorization processes. Nevertheless, integrating these services in a secure manner remains challenging, such that security issues are continually reported in recent years. In this work, we develop MoScan, a model-based scanner that can be used by software testers and security analysts for detecting and reporting security vulnerabilities in SSO implementations. MoScan takes as input a state machine built based on an SSO standard and our empirical study to represent participants' states and transitions during the login process. In the testing process, it analyzes network traces captured during the execution of SSO services, and increments the state machine which is then used to generate payloads to test the protocol participants. We evaluate MoScan with 23 real-world websites which integrate the Facebook SSO service to test its capability of identifying security vulnerabilities. To show the adaptability of MoScan's state machine, we also test it on Twitter and LinkedIn’s SSO services, and Github's authentication plugin in Jenkins. It detects three known weaknesses and one new logic fault from them, showing a new perspective in testing stateful protocol implementations like SSO services. Our demonstration and the source code of MoScan are available at https://github.com/baigd/moscan.

Neonicotinoid insecticides are widely used in agriculture, including in many California specialty crops. With mounting evidence that these insecticides are harmful to bees, state and national governments have increasingly regulated their use. The European Union, Canada, and United States have imposed use restrictions on several neonicotinoids, such as on the timing of applications. In 2020, California proposed a draft regulation to mitigate harm to managed pollinators from four nitroguanidine-substituted neonicotinoids (NGNs): clothianidin, dinotefuran, imidacloprid, and thiamethoxam. We use data on California pesticide use from 2015 to 2017 to analyze the economic and pest management implications of the 2020 draft proposed regulation for seven crops: almond, cherry, citrus, cotton, grape, strawberry, and tomato. From 2015 to 2017, these crops accounted for approximately 85% of total hectares treated with NGNs and 87% of NGN use by kilograms of active ingredient applied in treatments that would have been affected by the proposed regulation. These insecticides often primarily target Hemipteran insect pests. In most cases there are alternatives; however, these are often more expensive per hectare and do not have the same residual effectiveness as the NGNs, which are systemic insecticides. Overall, we estimate that pest management costs for these crops would have increased an estimated $13.6 million in 2015, $12.8 million in 2016, and $11.1 million in 2017 if the 2020 draft proposed regulation had been in effect, representing a 61% to 72% increase in the cost of managing the target pests.

Greenhouse gas (GHG) trading markets have been widely discussed for climate change mitigation. However in implementation coverage has not been universal. Agriculture, despite being the source of nearly 25% of net emissions, has not commonly been capped. But it has been mentioned as voluntary source of net emission offsets. Such offsets could arise from action reducing GHG emissions, enhancing sequestration, or producing feedstocks for low emitting bioenergy replacements for fossil based energy. This could be harnessed by setting up voluntary carbon markets that producers could join at their discretion. However, such a scheme could have unintended consequences. We conduct theoretical and empirical analyses of a voluntary “carbon” market examining both intended and unintended effects. We find certain participation rules can stimulate rebound effects from emitters and suppress participation from sequestration and bioenergy producing entities. To overcome this we develop and simulate offset participation limitations that could preclude unintended consequences.

A general access to chiral dihydroindole derivatives in high yields is achieved by C–H functionalization in a highly site- and enantioselective cascade reaction of propargyl diazoacetates. Highly site-selective intramolecular C(sp3)–H bond insertions are realized by catalyst control. Sterically demanding dirhodium carboxylates, optimized with Rh2(S-BTPCP)4, favor C–H insertion into 1° C–H bonds with regioselectivities reaching >95:5 (1° > 2° benzylic) and >90% ee. With Rh2(S-TBPTTL)4, preferential 2° and 3° C–H bond insertion occurs due to the configuration of catalyst and electronic effects. The chiral dirhodium catalyst not only promotes carbene/alkyne metathesis (CAM) to generate the donor/donor carbene intermediate, but is also responsible for the observed asymmetric induction in the terminating C–H bond insertion reaction.

A series of novel steroidal-chalcone derivates were designed and synthesized based on the molecular hybridization strategy and further evaluated for their growth inhibitory activity against three human cancer cell lines. The MTT results indicated that most compounds were apparently more sensitive to human breast cancer cells MDA-MB-231. Compounds 8 and 18 exerted the best cytotoxic activity against triple-negative MDA-MB-231 cells with the IC50 values of 0.42 μM and 0.52 μM respectively, which were 23-fold increase or more compared with 5-Fu. Further mechanism studies demonstrated that compound 8 could induce cells apoptosis through regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. Moreover, compound 8 could upregulate the cellular ROS levels which accelerated the apoptosis of MDA-MB-231 cells. In addition, interestingly, cell cycle assay showed that compound 8 could arrest MDA-MB-231 cells at S phase but not commonly anticipated G2/M phase. These evidences fully confirmed that compound 8 could be a potential candidate that deserves further development as an antitumor agent against triple-negative breast cancer.

An enantioselective Mannich-type reaction of 3-butynol and nitrones is described, which affords dihydrofuran-3-ones in good yields and with excellent enantioselectivities. The reaction is initiated by gold-catalyzed alkyne oxidation and modification of the resulting gold carbene species with a tethered hydroxy group to form enolate species; the reaction terminates with an enantioselective Mannich-type addition with the assistance of chiral phosphoric acid (CPA) and hydrogen bonding. This novel pattern of alkyne transformation involving chemical bond cleavage, and a fragment modification and reassembly process, provides an atom- and step-economic method, and is the first example of cooperative asymmetric catalysis in gold-catalyzed alkyne oxidations via an α-oxo gold carbene route.

To evaluate the efficacy and safety of Fuzheng Jiedu Huayu Decoction (FJHD) in treating pneumonia in the elderly.Adopting a multi-center, double-blind, parallel, randomized controlled trial, 284 elderly pneumonia patients were enrolled and randomly allocated to the standard treatment with FJHD (treatment group, TG) and the standard treatment with placebo group (control group, CG). Efficacy and safety was evaluated through mortality rate, curative rate, symptom improvement, chest X-ray (CXR) lesion absorption, arterial blood gas (ABG), peripheral blood leukocyte count (PBLC) and adverse events.There was no significant difference in mortality rate between both groups (P 0.05). TG significantly enhanced the curative rate of a 2-week treatment course (P 0.05). Compared with CG, TG significantly decreased the expectoration score during the first and second week of treatment (P 0.05). During the first week, improvement in expectoration was conducive to airway patency. During the second week, wheezing, shortness of breath and other symptoms were also significantly improved. During the third week, body temperature was stable. TG improved lesion absorption with Pneumonia Severity Index (PSI) class II (P 0.05) and SMART-COP score 1 (P 0.05). TG significantly decreased the arterial carbon dioxide partial pressure after a 1-week treatment. There were no serious adverse events in TG.Standard anti-infection treatment with FJHD is a safe and reliable method of treating elderly patients with pneumonia, improving the curative effect after a 2-week treatment course, ameliorating expectoration and promoting the absorption of pneumonia lesions.

The purpose of this study was to assess the efficacy of zishentongluo (ZSTL) for the treatment of diabetic nephropathy (DN) and its related mechanisms. Forty-five patients with DN were randomized to receive either ZSTL (n = 25) or benazepril (n = 20), an angiotensin converting enzyme inhibitor, for 12 weeks. Conventional biochemical tests were performed to determine fasting blood glucose (FBG), glycated hemoglobin (HbA1c), serum creatinine (SCr), endogenous creatinine clearance rate (Ccr), total cholesterol (TC), and triglyceride (TG) levels. The urinary albumin excretion rate (UAER), and endothelin 1 (ET-1), and atrial natriuretic peptide (ANP) levels were determined with a radioimmunoassay, and vascular endothelial growth factor (VEGF) was detected using an enzyme-linked immunosorbent assay. The primary endpoint was change from the baseline to post-treatment in HbA1c. Secondary endpoints were change from baseline to post-treatment in FBG, TC, TG, UAER, SCr, Ccr, VI-C, ANP, ET-1, and VEGF. ZSTL was significantly more effective at improving the primary (i.e., HbA1c) and secondary (i.e., FBG, TC, TG, UAER, SCr, ANP, ET-1, and VEGF) outcomes than benazepril (p < 0.05). These findings suggest that ZSTL is superior to benazepril at improving the metabolic and renal functioning in patients with early-stage DN, in part, by modifying ANP, ET-1, and VEGF.

The calculation of re-entry condition and the analysis of influencing factors based on space tethered-assisted deorbit system are provided. Firstly, the process of space tethered-assisted return is described, then the dynamical model of this system and the backswing model of capsule in elliptic orbit coordinate system are established, according to Pontryagin’s maximum principle the optimal control law is presented, and the calculation of re-entry condition is given. The influence on re-entry conditions from tether mass, eccentricity, true anomaly and the altitude of the orbit are analysed. Based on the above calculation and analysis, the correlation parameters that meet the re-entry condition under the elliptic orbit are obtained. Through the study of this article, we give a reference for choosing the parameters of future tethered-assisted return system and a theoretical reference for the calculation of re-entry condition in future space tether-assisted return technology.