Discovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53.

Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation.

Contribution of serum elements to blood pressure during pregnancy by impacting gut microbiota: A prospective cohort study.

Exposure to environmental elements can alter gut microbiota, further affecting host health. Exploring the interrelationships among element exposure, gut microbiota and blood pressure (BP) during pregnancy, as well as the mediating roles of gut microbiota, is warranted, which holds implications for maternal and offspring health. In a prospective cohort study between 2017-2018, 733 pregnant women were included. The serum elements and gut microbiota during the second trimester were assessed, and BP was collected during the second and third trimester and before delivery. Fourteen associations were identified between serum elements and BP, including positive associations of zinc (Zn) and thallium (Tl) with systolic BP during the second trimester. Rubidium (Rb) showed a positive association with Pielou's evenness. Serum elements, such as Tl and Rb, were significantly associated with the relative abundance of bacteria and co-abundance groups (CAGs). Alpha diversity was negatively associated with BP levels and trajectories. Moreover, 15 associations between gut microbiota and BP were shown. Finally, mediation analysis confirmed that CAG2 and Pielou's evenness mediated the associations of Tl and Rb with BP, respectively. We concluded that serum elements can contribute to BP changes during pregnancy through gut microbiota, suggesting gut microbiota-targeted approach as a potential intervention.

An Improved Grain Growth Model and Its Application in Gradient Heat Treatment of Aero-Engine Turbine Discs.

A new grain growth model was developed by introducing the ultimate grain size to the traditional model. The grain growth behavior and its ultimate size under the Zenner pinning force are also discussed. This model was applied to the nickel-based superalloy and integrated into an FEM code. The grain evolution of a forged third-generation powder superalloy heat treated at different temperatures and holding times was studied. A gradient heat treatment setup was designed and implemented for a full-size turbine disc based on the model prediction to meet the accurate dual-microstructure requirements of an advanced aero-engine turbine disc design. The predicted temperature was validated by thermal couple measurements. The relative error between the prediction and the measurements is less than 2%. The metallographic examination of the whole turbine disk through sectioning showed that the grain size was ASTM 7-8 at the rim area and ASTM 11-12 at the bore region, which agrees well with the prediction. The predicted values of the three measurement areas are ASTM 12.1, ASTM 9.1, and ASTM 7.1, respectively, with a maximum error of 5% compared to the measured values. The proposed model was validated and successfully applied to help manufacture a dual-microstructure aero-engine turbine disc.

Escin avoids hemorrhagic transformation in ischemic stroke by protecting BBB through the AMPK/Cav-1/MMP-9 pathway.

BACKGROUND: Hemorrhagic transformation (HT) seriously affects the clinical application of recombinant tissue plasminogen activator (rt-PA). The main strategy for combating HT is to keep the blood-brain barrier (BBB) stable. Escin is the active ingredient of Aesculus hippocastanum and a natural mixture of triterpene saponins, and may play a part in mitigation of HT. PURPOSE: This study sought to investigate the effect of Escin in improving rt-PA-induced HT, explore possible mechanisms, and provide new ideas for the treatment of clinical HT. STUDY DESIGN AND METHODS: In in vivo experiments, transient middle cerebral artery occlusion (tMCAO) was undertaken in 6-week-old and 12-month-old mice, and rt-PA was administered to induce HT injury. The inhibitory effect of Escin on HT and its protective effect on neurobehavior, the BBB, and cerebrovascular endothelial cells was determined. In in vitro experiments, bEnd.3 cells were injured by oxygen-glucose deprivation/reperfusion (OGD/R) and rt-PA. The protective effect of Escin was measured by the CCK8 assay, release of lactate dehydrogenase (LDH), and expression of tight junction (TJ) proteins. In mechanistic studies, the effect of Escin on the adenosine monophosphate-activated kinase / caveolin-1 / matrix metalloprotease-9 (AMPK/Cav-1/MMP-9) pathway was investigated by employing AMPK inhibitor and Cav-1 siRNA. RESULTS: In mice suffering from ischemia, rt-PA caused HT as well as damage to the BBB and cerebrovascular endothelial cells. Escin reduced the infarct volume, cerebral hemorrhage, improved neurobehavioral deficits, and maintained BBB integrity in rt-PA-treated tMCAO mice while attenuating bEnd.3 cells damage caused by rt-PA and OGD/R injury. Under physiological and pathological conditions, Escin increased the expression of p-AMPK and Cav-1, leading to decreased expression of MMP-9, which further attenuated damage to cerebrovascular endothelial cells, and these effects were verified with AMPK inhibitor and Cav-1 siRNA. CONCLUSION: We revealed important details of how Escin protects cerebrovascular endothelial cells from HT, these effects were associated with the AMPK/Cav-1/MMP-9 pathway. This study provides experimental foundation for the development of new drugs to mitigate rt-PA-induced HT and the discovery of new clinical application for Escin.

Biological evaluation and in silico studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment.

Introduction: Schizophrenia is a serious mental illness that requires effective treatment with minimal adverse effects. As preclinical and clinical research progresses, trace amine-associated receptor 1 (TAAR1) is becoming a potential new target for the treatment of schizophrenia. Methods: We used molecular docking and molecular dynamics (MD) simulations to discover TAAR1 agonists. The agonistic or inhibitory effects of compounds on TAAR1, 5-HT1A, 5-HT2A, and dopamine D2-like receptors were determined. We used an MK801-induced schizophrenia-like behavior model to assess the potential antipsychotic effects of compounds. We also performed a catalepsy assay to detect the adverse effects. To evaluate the druggability of the compounds, we conducted evaluations of permeability and transporter substrates, liver microsomal stability in vitro, human ether-à-go-go-related gene (hERG), pharmacokinetics, and tissue distribution. Results: We discovered two TAAR1 agonists: compounds 50A and 50B. The latter had high TAAR1 agonistic activity but no agonistic effect on dopamine D2-like receptors and demonstrated superior inhibition of MK801-induced schizophrenia-like behavior in mice. Interestingly, 50B had favorable druggability and the ability to penetrate the blood-brain barrier (BBB) without causing extrapyramidal symptoms (EPS), such as catalepsy in mice. Conclusion: These results demonstrate the potential beneficial role of TAAR1 agonists in the treatment of schizophrenia. The discovery of a structurally novel TAAR1 agonist (50B) may provide valuable assistance in the development of new treatments for schizophrenia.

Radiative Decay Width of J/ψ→γη_{(2)} from N_{f}=2 Lattice QCD.

The large radiative production rate for pseudoscalar mesons in the J/ψ radiative decay remains elusive. We present the first lattice QCD calculation of partial decay width of J/ψ radiatively decaying into η_{(2)}, the SU(2) flavor singlet pseudoscalar meson, which confirms QCD U_{A}(1) anomaly enhancement to the coupling of gluons with flavor singlet pseudoscalar mesons. The lattice simulation is carried out using N_{f}=2 lattice QCD gauge configurations at the pion mass m_{π}≈350 MeV. In particular, the distillation method has been utilized to calculate light quark loops. The results are reported here with the mass m_{η_{(2)}}=718(8) MeV and the decay width Γ(J/ψ→γη_{(2)})=0.385(45) keV. By assuming the dominance of U_{A}(1) anomaly and flavor singlet-octet mixing angle θ=-24.5°, the production rates for the physical η and η^{'} in J/ψ radiative decay are predicted to be 1.15(14)×10^{-3} and 4.49(53)×10^{-3}, respectively, which agree well with the experimental measurement data. Our study manifests the potential of lattice QCD studies on the light hadron production in J/ψ radiative decays.

The landscape of micron-scale particles including microplastics in human enclosed body fluids.

Exogenous microparticles including microplastics are novel pollutants that could persist in the environment with potential health effects, while crucial data on their exposure in humans are still lacking. To understand the panorama of microparticles including microplastics exposure and distribution characteristics in different kinds of body fluids. A non-targeted microparticle internal exposure landscape analysis was done in thirteen kinds of human enclosed body fluids covering eight body systems. Totally 104 patients aged 24-96 years with an average age of 56 years were included in this study. After sample digestion, non-soluble microparticles were detected and identified with one Raman Microspectroscope under a strict quality control-particle detection system. Totally 702 microparticles with size ranging from 2.15 to 103.27 µm were detected in samples. Microparticles were identified into 84 substances or 66 molecules, most of which were firstly reported inside human body. Nine kinds of microplastics were originally reported in human body fluids with their size ranging from 19.66 to 103.27 µm. Microparticles exposure was unexpectedly high inside the human body despite the protection of biological barriers and membranes, raising awareness of the impact of particle pollution on sustainable development.

Pyridoxal 5'-phosphate alleviates prenatal pyridaben exposure-induced anxiety-like behaviors in offspring.

Pyridaben (PY) is a widely used organochlorine acaricide, which can be detected in the peripheral blood of pregnant women. Available evidence suggests that PY has reproductive toxicity. However, it remains uncertain whether prenatal PY exposure impacts neurobehavioral development in offspring. Here, we administered PY to pregnant mice at a dose of 0.5 and 5 mg kg-1 day-1 via gavage and observed anxiety-like behaviors in PY offspring aged five weeks. We then integrated the metabolome and transcriptome of the offspring's brain to explore the underlying mechanism. Metabolome data indicated that the vitamin B6 metabolism pathway was significantly affected, and the pyridoxal 5'-phosphate (PLP) concentration and the active form of vitamin B6 was significantly reduced. Moreover, the transcriptome data showed that both PLP generation-related Pdxk and anxiety-related Gad1 were significantly down-regulated. Meanwhile, there was a decreasing trend in the concentration of GABA in the hippocampal DG region. Next, we supplemented PLP at a dose of 20 mg kg-1 day-1 to the PY offspring via intraperitoneal injection at three weeks. We found up-regulated expression of Pdxk and Gad1 and restored anxiety-like behaviors. This study suggests that prenatal exposure to PY can disrupt vitamin B6 metabolism, reduce the concentration of PLP, down-regulate the expression levels of Pdxk and Gad1, inhibit the production of GABA, and ultimately lead to anxiety-like behaviors in offspring.

Artificial intelligence: A powerful paradigm for scientific research.

Artificial intelligence (AI) coupled with promising machine learning (ML) techniques well known from computer science is broadly affecting many aspects of various fields including science and technology, industry, and even our day-to-day life. The ML techniques have been developed to analyze high-throughput data with a view to obtaining useful insights, categorizing, predicting, and making evidence-based decisions in novel ways, which will promote the growth of novel applications and fuel the sustainable booming of AI. This paper undertakes a comprehensive survey on the development and application of AI in different aspects of fundamental sciences, including information science, mathematics, medical science, materials science, geoscience, life science, physics, and chemistry. The challenges that each discipline of science meets, and the potentials of AI techniques to handle these challenges, are discussed in detail. Moreover, we shed light on new research trends entailing the integration of AI into each scientific discipline. The aim of this paper is to provide a broad research guideline on fundamental sciences with potential infusion of AI, to help motivate researchers to deeply understand the state-of-the-art applications of AI-based fundamental sciences, and thereby to help promote the continuous development of these fundamental sciences.

Proton Mass Decomposition from the QCD Energy Momentum Tensor.

We report results on the proton mass decomposition and also on related quark and glue momentum fractions. The results are based on overlap valence fermions on four ensembles of N_{f}=2+1 domain wall fermion configurations with three lattice spacings and three volumes, and several pion masses including the physical pion mass. With fully nonperturbative renormalization (and universal normalization on both quark and gluon), we find that the quark energy and glue field energy contribute 32(4)(4)% and 36(5)(4)% respectively in the MS[over ¯] (modified minimal substraction) scheme at µ=2 GeV. A quarter of the trace anomaly gives a 23(1)(1)% contribution to the proton mass based on the sum rule, given 9(2)(1)% contribution from the u, d, and s quark scalar condensates. The u, d, s, and glue momentum fractions in the MS[over ¯] scheme are in good agreement with global analyses at µ=2 GeV.

Enhanced flux performance of polyamide composite membranes prepared via interfacial polymerization assisted with ethyl formate.

A novel thin film composite (TFC) polyamide reverse osmosis membrane was prepared via the interfacial polymerization of m-phenylene diamine (MPD) in aqueous phase and 1,3,5-trimesoyl chloride (TMC) in organic phase on a polysulfone ultrafiltration support by assisting with ethyl formate as a co-solvent added in the organic phase. The ethyl formate added in the organic phase is intended to form a narrow miscibility zone, which leads to the thicker reaction zone. The multi-layered loose polyamide structure with larger pore size was formed due to the thicker reaction zone and lower content of MPD. The enhanced hydrophilicity of the membrane was proved by the decreased water contact angle. Water flux was measured at 1.6 MPa with 2,000 ppm NaCl aqueous solution. Compared to the TFC membrane prepared without ethyl formate, the water flux across the TFC membrane with ethyl formate in the organic phase increased with the increased ethyl formate content (from 23 to 45 L/(m2 h)) and the salt rejection remained at a high level (>90%). The ethyl formate can be used as a co-solvent to effectively enhance the performance of the TFC membrane.

Pre-column dilution large volume injection ultra-high performance liquid chromatography-tandem mass spectrometry for the analysis of multi-class pesticides in cabbages.

Pre-column dilution large volume injection (PD-LVI), a novel sample injection technique for reverse phase ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), was developed in this study. The PD-LVI UHPLC-MS/MS system was designed by slightly modifying the commercial UHPLC-MS/MS equipment with a mixer chamber. During the procedure of PD-LVI, sample solution of 200µL was directly carried by the organic mobile phase to the mixer and diluted with the aqueous mobile phase. After the mixture was introduced to the UHPLC column in a mobile phase of acetonitrile-water (15/85, v/v), the target analytes were stacked on the head of the column until following separation. Using QuEChERS extraction, no additional steps such as solvent evaporation or residue redissolution were needed before injection. The features of PD-LVI UHPLC-MS/MS system were systematically investigated, including the injection volume, the mixer volume, the precondition time and the gradient elution. The efficiency of this approach was demonstrated by direct analysis of 24 pesticides in cabbages. Under the optimized conditions, low limits of detection (0.00074-0.8 ng/kg) were obtained. The recoveries were in the range of 63.3-109% with relative standard deviations less than 8.1%. Compared with common UHPLC-MS/MS technique, PD-LVI UHPLC-MS/MS showed significant advantages such as excellent sensitivity and reliability. The mechanism of PD-LVI was demonstrated to be based on the column-head stacking effect with pre-column dilution. Based on the results, PD-LVI as a simple and effective sample injection technique of reverse phase UHPLC-MS/MS for the analysis of trace analytes in complex samples showed a great promising prospect.

CR1 retroposons provide a new insight into the phylogeny of Phasianidae species (Aves: Galliformes).

Chicken repeat 1 (CR1) elements, a class of retroposons belonging to non-long-terminal repeats, have been recognized as powerful tools for phylogenetic studies. Here we examine the phylogenetic relationships of 11 Phasianidae species based on CR1 retroposons. Together with 19 loci reported previously, a total of 99 CR1 loci were identified from chicken genome and turkey BAC clone sequences. 75 insertion events were used to address the branching order of 11 species in Phasianidae. The topology of our tree suggests that: 1) Gallus gallus possessed a basal phylogenetic position within Phasianidae and was related to Bambusicola thoracica (BSP=100%); 2) After the split of G. gallus and B. thoracica, Arborophila rufipectus diverged from Phasianidae (BSP=100%). Nine unambiguous insertion events supported a phylogenetic position of A. rufipectus different to previous mitochondrial data suggesting a hybrid origin or an ancient introgression of A. rufipectus; and 3) 22 CR1 insertion events strongly supported the eight phasianids under investigation sharing a common ancestor. Our study has revisited the phylogenetic position of G. gallus and A. rufipectus and provided a new insight into the phylogeny of Phasianidae birds. It showed that a CR1-based methodology has a great potential to be informative within Phasianidae in resolving relationships of closely related species whose radiation and speciation have occurred very recently.

Dynamic rheological studies of poly(p-phenyleneterephthalamide) and carbon nanotube blends in sulfuric acid.

We have studied the dynamic scanning of liquid-crystalline (LC) poly(p-phenyleneterephthalamide) sulfuric acid (PPTA-H(2)SO(4)) solution, and its blend with single-walled carbon nanotubes (SWNTs), by using a flat plate rotational rheometer. The effects of weight concentration and molecular weight of PPTA, as well as operating temperature, on dynamic viscoelasticity of the PPTA-H(2)SO(4) LC solution system are discussed. The transition from a biphasic system to a single-phase LC occurs in the weight concentration range of SWNTs from 0.1% to 0.2%, in which complex viscosity reaches the maximum at 0.2 wt% and the minimum at 0.1 wt%, respectively, of SWNTs. With increasing SWNT weight concentration, the endothermic peak temperature increases from 73.6 to 79.9 degrees C. The PPTA/SWNT/H(2)SO(4) solution is in its plateau zone and storage modulus (G') is a dominant factor within the frequency (omega) range of 0.1-10 rad/s. As omega increases, the G' rises slightly, in direct proportion to the omega. The loss modulus (G'') does not rise as a function of omega when omega < 1 s(-1), then when omega > 1 s(-1) G'' increases faster than G', yet not in any proportion to the omega.