Gate-Tunable Quantum Acoustoelectric Transport in Graphene.

Transport probes the motion of quasi-particles in response to external excitations. Apart from the well-known electric and thermoelectric transport, acoustoelectric transport induced by traveling acoustic waves has rarely been explored. Here, by adopting hybrid nanodevices integrated with piezoelectric substrates, we establish a simple design of acoustoelectric transport with gate tunability. We fabricate dual-gated acoustoelectric devices based on hBN-encapsulated graphene on LiNbO3. Longitudinal and transverse acoustoelectric voltages are generated by launching a pulsed surface acoustic wave. The gate dependence of zero-field longitudinal acoustoelectric signal presents strikingly similar profiles to that of Hall resistivity, providing a valid approach for extracting carrier density without magnetic field. In magnetic fields, acoustoelectric quantum oscillations appear due to Landau quantization, which are more robust and pronounced than Shubnikov-de Haas oscillations. Our work demonstrates a feasible acoustoelectric setup with gate tunability, which can be extended to the broad scope of various van der Waals materials.

RGA1 regulates grain size, rice quality and seed germination in the small and round grain mutant srg5.

BACKGROUND: Generating elite rice varieties with high yield and superior quality is the main goal of rice breeding programs. Key agronomic traits, including grain size and seed germination characteristics, affect the final yield and quality of rice. The RGA1 gene, which encodes the α-subunit of rice G-protein, plays an important role in regulating rice architecture, seed size and abiotic stress responses. However, whether RGA1 is involved in the regulation of rice quality and seed germination traits is still unclear. RESULTS: In this study, a rice mutant small and round grain 5 (srg5), was identified in an EMS-induced rice mutant library. Systematic analysis of its major agronomic traits revealed that the srg5 mutant exhibited a semi-dwarf plant height with small and round grain and reduced panicle length. Analysis of the physicochemical properties of rice showed that the difference in rice eating and cooking quality (ECQ) between the srg5 mutant and its wild-type control was small, but the appearance quality was significantly improved. Interestingly, a significant suppression of rice seed germination and shoot growth was observed in the srg5 mutant, which was mainly related to the regulation of ABA metabolism. RGA1 was identified as the candidate gene for the srg5 mutant by BSA analysis. A SNP at the splice site of the first intron disrupted the normal splicing of the RGA1 transcript precursor, resulting in a premature stop codon. Additional linkage analysis confirmed that the target gene causing the srg5 mutant phenotype was RGA1. Finally, the introduction of the RGA1 mutant allele into two indica rice varieties also resulted in small and round rice grains with less chalkiness. CONCLUSIONS: These results indicate that RGA1 is not only involved in the control of rice architecture and grain size, but also in the regulation of rice quality and seed germination. This study sheds new light on the biological functions of RGA1, thereby providing valuable information for future systematic analysis of the G-protein pathway and its potential application in rice breeding programs.

Turbidity-tolerant underwater wireless optical communications using dense blue-green wavelength division multiplexing.

Underwater wireless optical communication (UWOC) has demonstrated high-speed and low-latency properties in clear and coastal ocean water because of the relatively low attenuation 'window' for blue-green wavelengths from 450 nm to 550 nm. However, there are different attenuation coefficients for transmission in ocean water at different wavelengths, and the light transmission more seriously deteriorates with fluctuations in the water turbidity. Therefore, traditional UWOC using a single wavelength or coarse blue-green wavelengths has difficulty tolerating variations in water turbidity. Dense wavelength division multiplexing (WDM) technology provides sufficient communication channels with a narrow wavelength spacing and minimal channel crosstalk. Here, we improve the UWOC in clear and coastal ocean water using dense blue-green WDM. A cost-effective WDM emitter is proposed with directly modulated blue-green laser diodes. Dense wavelength beam combination and collimation are demonstrated in a 20-metre underwater channel from 490 nm to 520 nm. Demultiplexing with a minimum channel spacing of 2 nm is realized by an optical grating. Remarkably, our WDM results demonstrate an aggregate data rate exceeding 10 Gbit/s under diverse water turbidity conditions, with negligible crosstalk observed for each channel. This is the densest WDM implementation with a record channel spacing of 2 nm and the highest channel count for underwater blue-green light communications, providing turbidity-tolerant signal transmission in clear and coastal ocean water.

Asymmetric Synthesis of Tertiary α-Hydroxylation-Cyclopentanones via Synergetic Catalysis of Chiral-at-Metal Rhodium(III) Complexes/Pyrrolidine.

Catalytic and asymmetric domino Michael/aldol reaction of 1,2-dicarbonyl compounds with α,ß-unsaturated ketones under the synergetic catalysis of chiral-at-metal rhodium complexes and pyrrolidine to deliver tertiary α-hydroxylation-cyclopentanones (45-89% yields with 81-99% ee and up to >20:1 dr) bearing three contiguous stereogenic centers had been established. Moreover, the scalability and practical utility of this protocol were well demonstrated by employing a gram-scale reaction and some representative transformations.

The impact of isolated obesity compared with obesity and other risk factors on risk of stillbirth: a retrospective cohort study.

BACKGROUND: Maternal obesity is associated with stillbirth, but uncertainty persists around the effects of higher obesity classes. We sought to compare the risk of stillbirth associated with maternal obesity alone versus maternal obesity and additional or undiagnosed factors contributing to high-risk pregnancy. METHODS: We conducted a retrospective cohort study using the Better Outcomes Registry and Network (BORN) for singleton hospital births in Ontario between 2012 and 2018. We used multivariable Cox proportional hazard regression and logistic regression to evaluate the relationship between prepregnancy maternal body mass index (BMI) class and stillbirth (reference was normal BMI). We treated maternal characteristics and obstetrical complications as independent covariates. We performed mediator analyses to measure the direct and indirect effects of BMI on stillbirth through major common-pathway complications. We used fully adjusted and partially adjusted models, representing the impact of maternal obesity alone and maternal obesity with other risk factors on stillbirth, respectively. RESULTS: We analyzed data on 681 178 births between 2012 and 2018, of which 1956 were stillbirths. Class I obesity was associated with an increased incidence of stillbirth (adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.35-1.78). This association was stronger for class III obesity (adjusted HR 1.80, 95% CI 1.44-2.24), and strongest for class II obesity (adjusted HR 2.17, 95% CI 1.83-2.57). Plotting point estimates for odds ratios, stratified by gestational age, showed a marked increase in the relative odds for stillbirth beyond 37 weeks' gestation for those with obesity with and without other risk factors, compared with those with normal BMI. The impact of potential mediators was minimal. INTERPRETATION: Maternal obesity alone and obesity with other risk factors are associated with an increased risk of stillbirth. This risk increases with gestational age, especially at term.

Discovery of indole-2-one derivatives as BRD4 (BD1) selective inhibitors.

Bromodomain protein 4 (BRD4) is a member of the BET family, and its overexpression is closely associated with the development of many tumors. Inhibition of BRD4 shows great therapeutic potential in anti-tumor, and pan-BRD4 inhibitors show adverse effects of dose limiting toxicity and thrombocytopenia in clinical trials. To improve clinical effects and reduce side effects, more efforts have focused on seeking selective inhibitors of BD1 or BD2. Herein, a series of indole-2-one derivatives were designed and synthesized through docking-guided optimization to find BRD4-BD1 selective inhibitors, and their BRD4 inhibitory and antiproliferation activities were evaluated. Among them, compound 21r had potent BRD4 inhibitory activity (the IC50 values of 41 nM and 313 nM in BD1 and BD2 domain), excellent anti-proliferation (the IC50 values of 4.64 ± 0.30 µM, 0.78 ± 0.03 µM, 5.57 ± 1.03 µM against HL-60, MV-4-11 and HT-29 cells), and displayed low toxicity against normal cell GES-1 cells. Further studies revealed that 21r inhibited proliferation by decreasing the expression of proto-oncogene c-Myc, blocking cell cycle in G0/G1 phase, and inducing apoptosis in MV-4-11 cells in a dose-dependent manner. All the results showed that compound 21r was a potent BRD4 inhibitor with BD1 selectivity, which had potential in treatment of leukemia.

Discovery of novel coumarin-based KRAS-G12C inhibitors from virtual screening and Rational structural optimization.

KRAS-G12C inhibitors has been made significant progress in the treatment of KRAS-G12C mutant cancers, but their clinical application is limited due to the adaptive resistance, motivating development of novel structural inhibitors. Herein, series of coumarin derivatives as KRAS-G12C inhibitors were found through virtual screening and rational structural optimization. Especially, K45 exhibited strong antiproliferative potency on NCI-H23 and NCI-H358 cancer cells harboring KRAS-G12C with the IC50 values of 0.77 µM and 1.50 µM, which was 15 and 11 times as potent as positive drug ARS1620, respectively. Furthermore, K45 reduced the phosphorylation of KRAS downstream effectors ERK and AKT by reducing the active form of KRAS (KRAS GTP) in NCI-H23 cells. In addition, K45 induced cell apoptosis by increasing the expression of anti-apoptotic protein BAD and BAX in NCI-H23 cells. Docking studies displayed that the 3-naphthylmethoxy moiety of K45 extended into the cryptic pocket formed by the residues Gln99 and Val9, which enhanced the interaction with the KRAS-G12C protein. These results indicated that K45 was a potent KRAS-G12C inhibitor worthy of further study.

Associations of neighborhood greenspace, and active living environments with autism spectrum disorders: A matched case-control study in Ontario, Canada.

BACKGROUND: Increasing evidence links early life residential exposure to natural urban environmental attributes and positive health outcomes in children. However, few studies have focused on their protective effects on the risk of autism spectrum disorder (ASD). The aim of this study was to investigate the associations of neighborhood greenspace, and active living environments during pregnancy with ASD in young children (≤6 years). METHODS: We conducted a population-based matched case-control study of singleton term births in Ontario, Canada for 2012-2016. The ASD and environmental data was generated using the Ontario Autism Spectrum Profile, the Better Outcomes Registry & Network Ontario, and Canadian Urban Environmental Health Research Consortium. We employed conditional logistic regressions to estimate the odds ratio (OR) between ASD and environmental factors characterizing selected greenspace metrics and neighborhoods conducive to active living (i.e., green view index (GVI), normalized difference vegetation index (NDVI), tree canopy, park proximity and active living environments index (ALE)). RESULTS: We linked 8643 mother-child pairs, including 1554 cases (18%). NDVI (OR 1.034, 0.944-1.024, per Inter Quartile Range [IQR] = 0.08), GVI (OR 1.025, 95% CI 0.953-1.087, per IQR = 9.45%), tree canopy (OR 0.992, 95% CI 0.903-1.089, per IQR = 6.24%) and the different categories of ALE were not associated with ASD in adjusted models for air pollution. In contrast, living closer to a park was protective (OR 0.888, 0.833-0.948, per 0.06 increase in park proximity index), when adjusted for air pollution. CONCLUSIONS: This study reported mixed findings showing both null and beneficial effects of green spaces and active living environments on ASD. Further investigations are warranted to elucidate the role of exposure to greenspaces and active living environments on the development of ASD.

Temporal Trends in Gestational Diabetes Mellitus and Associated Risk Factors in Ontario, Canada, 2012-2020: A Population-Based Cohort Study.

OBJECTIVES: The prevalence of gestational diabetes mellitus (GDM) has been increasing globally over recent decades; however, underlying reasons for the increase remain unclear. We analyzed trends in GDM rates and evaluated risk factors associated with the observed trends in Ontario, Canada. METHODS: We conducted a retrospective population-based cohort study using the Better Outcomes Registry and Network Ontario, linked with the Canadian Institute for Health Information Discharge Abstract Database. All pregnant individuals who had a singleton hospital delivery from 1 April 2012 to 31 March 2020 were included. We calculated rates and 95% CIs for GDM by year of delivery and contrasted fiscal year 2019/20 with 2012/13. Temporal trends in GDM were quantified using crude and adjusted risk ratios by modified Poisson regression. We further quantified the temporal increase attributable to changes in maternal characteristics by decomposition analysis. RESULTS: Among 1 044 258 pregnant individuals, 82 896 (7.9%) were diagnosed with GDM over the 8 years. GDM rate rose from 6.1 to 10.4 per 100 deliveries between fiscal years 2012/13 and 2019/20. The risk of GDM in 2019/20 was 1.53 times (95% CI 1.50-1.56) higher compared with 2012/13. 27% of the increase in GDM was due to changes in maternal age, 8 BMI, and Asian ethnicity. CONCLUSIONS: The GDM rate has been consistently increasing in Ontario, Canada. The contribution of increasing maternal age, pre-pregnancy obesity, and Asian ethnicity to the recent increase in GDM is notable. Further investigation is required to better understand the contributors to increasing GDM.

Infant Infections Following Cesarean Delivery on Maternal Request: A Population-Based Cohort Study.

OBJECTIVES: Investigations about cesarean delivery (CD) on maternal request (CDMR) and infant infection risk frequently rely on administrative data with poorly defined indications for CD. We sought to determine the association between CDMR and infant infection using an intent-to-treat approach. METHODS: This was a population-based cohort study of low-risk singleton pregnancies with a term live birth in Ontario, Canada between April 2012 and March 2018. Subjects with prior CD were excluded. Outcomes included upper and lower respiratory tract infections, gastrointestinal infections, otitis media, and a composite of these 4. Relative risk and 95% CI were calculated for component and composite outcomes up to 1 year following planned CDMR versus planned vaginal deliveries (VDs). Subgroup and sensitivity analyses included age at infection (≤28 vs. >28 days), type of care (ambulatory vs. hospitalisation), restricting the cohort to nulliparous pregnancies, and including individuals with previous CD. Last, we re-examined outcome risk on an as-treated basis (actual CD vs. actual VD). RESULTS: Of 422 134 pregnancies, 0.4% (1827) resulted in a planned CDMR. After adjusting for covariates, planned CDMR was not associated with a risk of composite infant infections (adjusted relative risk 1.02; 95% CI 0.92-1.11). Findings for component infection outcomes, subgroup, and sensitivity analyses were similar. However, the as-treated analysis of the role of delivery mode on infant risk for infection demonstrated that actual CD (planned and unplanned) was associated with an increased risk for infant infections compared to actual VD. CONCLUSIONS: Planned CDMR is not associated with increased risk for neonatal or infant infections compared with planned VD. Study design must be carefully considered when investigating the impact of CDMR on infant infection outcomes.

Relationship Between Gestational Weight Gain and Health Service Utilization in Early Childhood: A Retrospective Cohort Study.

OBJECTIVE: Gestational weight gain (GWG) outside recommended ranges can negatively impact both the woman and child. The long-term effects of below-recommended or above-recommended GWG on the child are unclear. METHODS: This retrospective cohort study used a population-based birth registry of 258,005 live births to evaluate the relationship between maternal GWG and paediatric health service use. RESULTS: The results suggest below recommended GWG in underweight women in particular is associated with an increased rate of hospitalizations and specialist visits for the child in the first 24 months. CONCLUSION: Findings indicate that GWG may impact paediatric outcomes in ways that depend on pre-pregnancy body mass index, as derived from maternal height and weight measures.

Identification of a psychiatric risk gene NISCH at 3p21.1 GWAS locus mediating dendritic spine morphogenesis and cognitive function.

BACKGROUND: Schizophrenia and bipolar disorder (BD) are believed to share clinical symptoms, genetic risk, etiological factors, and pathogenic mechanisms. We previously reported that single nucleotide polymorphisms spanning chromosome 3p21.1 showed significant associations with both schizophrenia and BD, and a risk SNP rs2251219 was in linkage disequilibrium with a human specific Alu polymorphism rs71052682, which showed enhancer effects on transcriptional activities using luciferase reporter assays in U251 and U87MG cells. METHODS: CRISPR/Cas9-directed genome editing, real-time quantitative PCR, and public Hi-C data were utilized to investigate the correlation between the Alu polymorphism rs71052682 and NISCH. Primary neuronal culture, immunofluorescence staining, co-immunoprecipitation, lentiviral vector production, intracranial stereotaxic injection, behavioral assessment, and drug treatment were used to examine the physiological impacts of Nischarin (encoded by NISCH). RESULTS: Deleting the Alu sequence in U251 and U87MG cells reduced mRNA expression of NISCH, the gene locates 180 kb from rs71052682, and Hi-C data in brain tissues confirmed the extensive chromatin contacts. These data suggested that the genetic risk of schizophrenia and BD predicted elevated NISCH expression, which was also consistent with the observed higher NISCH mRNA levels in the brain tissues from psychiatric patients compared with controls. We then found that overexpression of NISCH resulted in a significantly decreased density of mushroom dendritic spines with a simultaneously increased density of thin dendritic spines in primary cultured neurons. Intriguingly, elevated expression of this gene in mice also led to impaired spatial working memory in the Y-maze. Given that Nischarin is the target of anti-hypertensive agents clonidine and tizanidine, which have shown therapeutic effects in patients with schizophrenia and patients with BD in preliminary clinical trials, we demonstrated that treatment with those antihypertensive drugs could reduce NISCH mRNA expression and rescue the impaired working memory in mice. CONCLUSIONS: We identify a psychiatric risk gene NISCH at 3p21.1 GWAS locus influencing dendritic spine morphogenesis and cognitive function, and Nischarin may have potentials for future therapeutic development.

Reduced Vrk2 expression is associated with higher risk of depression in humans and mediates depressive-like behaviors in mice.

BACKGROUND: Genome-wide association studies (GWAS) have reported single-nucleotide polymorphisms (SNPs) in the VRK serine/threonine kinase 2 gene (VRK2) showing genome-wide significant associations with major depression, but the regulation effect of the risk SNPs on VRK2 as well as their roles in the illness are yet to be elucidated. METHODS: Based on the summary statistics of major depression GWAS, we conducted population genetic analyses, epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to identify the functional SNPs regulating VRK2; we also carried out behavioral assessments, dendritic spine morphological analyses, and phosphorylated 4D-label-free quantitative proteomics analyses in mice with Vrk2 repression. RESULTS: We identified a SNP rs2678907 located in the 5' upstream of VRK2 gene exhibiting large spatial overlap with enhancer regulatory marks in human neural cells and brain tissues. Using luciferase reporter gene assays and eQTL analyses, the depression risk allele of rs2678907 decreased enhancer activities and predicted lower VRK2 mRNA expression, which is consistent with the observations of reduced VRK2 level in the patients with major depression compared with controls. Notably, Vrk2-/- mice exhibited depressive-like behaviors compared to Vrk2+/+ mice and specifically repressing Vrk2 in the ventral hippocampus using adeno-associated virus (AAV) lead to consistent and even stronger depressive-like behaviors in mice. Compared with Vrk2+/+ mice, the density of mushroom and thin spines in the ventral hippocampus was significantly altered in Vrk2-/- mice, which is in line with the phosphoproteomic analyses showing dysregulated synapse-associated proteins and pathways in Vrk2-/- mice. CONCLUSIONS: Vrk2 deficiency mice showed behavioral abnormalities that mimic human depressive phenotypes, which may serve as a useful murine model for studying the pathophysiology of depression.

Gestational weight loss and fetal growth in uncomplicated pregnancies among women with obesity: a population-based retrospective cohort study.

OBJECTIVE: The impact of gestational weight loss (GWL) on fetal growth among women with obesity remains unclear. This study aimed to examine the association between weight loss during pregnancy among women with body mass index (BMI) ≥ 30 kg/m2 and the risk of small-for-gestational-age (SGA) and large-for-gestational-age (LGA) neonates. METHODS: We conducted a retrospective, population-based cohort study of women with pre-pregnancy obesity that resulted in a singleton live birth in 2012-2017, using birth registry data in Ontario, Canada. Women with pregnancy complications or health conditions which could cause weight loss were excluded. GWL is defined as negative gestational weight change (≤0 kg). The association between GWL and fetal growth was estimated using generalized estimating equation models and restricted cubic spline regression analysis. Stratified analysis was conducted by obesity class (I:30-34.9 kg/m2, II:35-39.9 kg/m2, and III + : ≥40 kg/m2). RESULTS: Of the 52,153 eligible women who entered pregnancy with a BMI ≥ 30 kg/m2, 5.3% had GWL. Compared to adequate gestational weight gain, GWL was associated with an increased risk of SGA neonates (aRR:1.45, 95% CI: 1.30-1.60) and a decreased risk of LGA neonates (aRR: 0.81, 95% CI:0.73-0.93). Non-linear L-shaped associations were observed between gestational weight change and SGA neonates, with an increased risk of SGA observed with increased GWL. On the contrary, non-linear S-shaped associations were observed between gestational weight change and LGA neonates, with a decreased risk of LGA observed with increased GWL. Similar findings were observed from the stratified analysis by obesity class. CONCLUSION: These findings highlight that GWL in women with obesity may increase the risk of SGA neonates but reduce the risk of LGA neonates. Recommendations of GWL for women with obesity should be interpreted with caution.

Highly-time-resolved FMCW LiDAR with synchronously-nonlinearity-corrected acquisition for dynamic locomotion.

Highly-time-resolved and precise tracking of position, velocity, and acceleration is urgently required when highly dynamic legged robots are walking, trotting, and jumping. Frequency-modulated continuous-wave (FMCW) laser ranging is able to provide precise measurement in short distance. However, FMCW light detection and ranging (LiDAR) suffers from a low acquisition rate and poor linearity of laser frequency modulation in wide bandwidth. A sub-millisecond-scale acquisition rate and nonlinearity correction in the wide frequency modulation bandwidth have not been reported in previous studies. This study presents the synchronous nonlinearity correction for a highly-time-resolved FMCW LiDAR. The acquisition rate of 20 kHz is obtained by synchronizing the measurement signal and the modulation signal of laser injection current with a symmetrical triangular waveform. The linearization of laser frequency modulation is conducted by resampling of 1000 intervals interpolated in every up-sweep and down-sweep of 25 µs, while measurement signal is stretched or compressed in every period of 50 µs. The acquisition rate is demonstrated to be equal to the repetition frequency of laser injection current for the first time to the best of authors' knowledge. This LiDAR is successfully used to track the foot trajectory of a jumping single-leg robot. The high velocity up to 7.15 m/s and high acceleration of 365 m/s2 are measured during the up-jumping phase, while heavy shock takes place with high acceleration of 302 m/s2 as the foot end strikes the ground. The measured foot acceleration of over 300 m/s2, which is more than 30 times gravity acceleration, is reported on a jumping single-leg robot for the first time.

High-Order Fractal Quantum Oscillations in Graphene/BN Superlattices in the Extreme Doping Limit.

Recent studies of van der Waals (vdW) heterostructures and superlattices have shown intriguing quantum phenomena, but these have been largely explored only in the moderate carrier density regime. Here, we report the probe of high-temperature fractal Brown-Zak (BZ) quantum oscillations through magnetotransport in the extreme doping regimes by applying a newly developed electron beam doping technique. This technique gives access to both ultrahigh electron and hole densities beyond the dielectric breakdown limit in graphene/BN superlattices, enabling the observation of nonmonotonic carrier-density dependence of fractal BZ states and up to fourth-order fractal BZ features despite strong electron-hole asymmetry. Theoretical tight-binding simulations qualitatively reproduce all observed fractal BZ features and attribute the nonmonotonic dependence to the weakening of superlattice effects at high carrier densities.

Design, synthesis, and biological evaluation of quinoxalinone derivatives as potent BRD4 inhibitors.

The bromodomain-containing protein 4 (BRD4) has gained growing interest as an effective drug target for the treatment of hepatocellular carcinoma (HCC). Herein, we designed and synthesized a series of quinoxalinone derivatives as BRD4 inhibitors via scaffold hopping. The representative compound X9 showed potent BRD4 inhibitory activity (with IC50 = 82.3 nM), and preferable antiproliferative activity against HepG2 cells (with IC50 = 1.13 ± 0.07 µM), as well as less toxicity against GES-1 cells (with IC50 = 57.24 ± 5.46 µM). Furthermore, compound X9 dose-dependently inhibited colony formation and blocked the migration of HepG2 cells by down-regulating the expression of Snail and MMP-9 while up-regulating the E-cadherin and Occludin. Besides, compound X9 efficiently down-regulated the expression of c-Myc in HepG2 cells, induced apoptosis, and arrested at G0/G1 phase. In total, quinoxalinone was a potential core as BRD4 inhibitor and compound X9 might be effective for liver cancer therapy.

1H-Indazoles derivatives targeting PI3K/AKT/mTOR pathway: Synthesis, anti-tumor effect and molecular mechanism.

The PI3K/AKT/mTOR signaling pathway is one of the most common abnormal activation pathways in tumor cells, and has associated with multiple functions such as tumor cell growth, proliferation, migration, invasion, and tumor angiogenesis. Here, a series of 3-amino-1H-indazole derivatives were synthesized, and their antiproliferative activities against HT-29, MCF-7, A-549, HepG2 and HGC-27 cells were evaluated. Among them, W24 exhibited the broad-spectrum antiproliferative activity against four cancer cells with IC50 values of 0.43-3.88 µM. Mechanism studies revealed that W24 inhibited proliferation by affecting the DNA synthesis, induced G2/M cell cycle arrest and apoptosis by regulating Cyclin B1, BAD and Bcl-xL, meanwhile induced the change of intracellular ROS and mitochondrial membrane potential in HGC-27 cells. Moreover, W24 inhibited the migration and invasion of HGC-27 cells by decreasing EMT pathway related proteins and reducing the mRNA expression levels of Snail, Slug and HIF-1α. Furthermore, W24 displayed low tissue toxicity profile and good pharmacokinetic properties in vivo. Therefore, 3-amino-1H-indazole derivatives might serve as a new scaffold for the development of PI3K/AKT/mTOR inhibitor and anti-gastric cancer reagent.

Recent development of multi-target VEGFR-2 inhibitors for the cancer therapy.

Vascular epidermal growth factor receptor-2 (VEGFR-2), as an important tyrosine transmembrane protein, plays an important role in regulating endothelial cell proliferation and migration, regulating angiogenesis and other biological functions. VEGFR-2 is aberrantly expressed in many malignant tumors, and it is also related to the occurrence, development, and growth of tumors and drug resistance. Currently, there are nine VEGFR-2 targeted inhibitors approved by US.FDA for clinical use as anticancer drugs. Due to the limited clinical efficacy and potential toxicity of VEGFR inhibitors, it is necessary to develop new strategies to improve the clinical efficacy of VEGFR inhibitors. The development of multitarget therapy, especially dual-target therapy, has become a hot research field of cancer therapy, which may provide an effective strategy with higher therapeutic efficacy, pharmacokinetic advantages and low toxicity. Many groups have reported that the therapeutic effects could be improved by simultaneously inhibiting VEGFR-2 and other targets, such as EGFR, c-Met, BRAF, HDAC, etc. Therefore, VEGFR-2 inhibitors with multi-targeting capabilities have been considered to be promising and effective anticancer agents for cancer therapy. In this work, we reviewed the structure and biological functions of VEGFR-2, and summarized the drug discovery strategies, and inhibitory activities of VEGFR-2 inhibitors with multi-targeting capabilities reported in recent years. This work might provide the reference for the development of VEGFR-2 inhibitors with multi-targeting capabilities as novel anticancer agents.

Structural phase transition in monolayer MoTe2 driven by electrostatic doping.

Monolayers of transition-metal dichalcogenides (TMDs) exhibit numerous crystal phases with distinct structures, symmetries and physical properties. Exploring the physics of transitions between these different structural phases in two dimensions may provide a means of switching material properties, with implications for potential applications. Structural phase transitions in TMDs have so far been induced by thermal or chemical means; purely electrostatic control over crystal phases through electrostatic doping was recently proposed as a theoretical possibility, but has not yet been realized. Here we report the experimental demonstration of an electrostatic-doping-driven phase transition between the hexagonal and monoclinic phases of monolayer molybdenum ditelluride (MoTe2). We find that the phase transition shows a hysteretic loop in Raman spectra, and can be reversed by increasing or decreasing the gate voltage. We also combine second-harmonic generation spectroscopy with polarization-resolved Raman spectroscopy to show that the induced monoclinic phase preserves the crystal orientation of the original hexagonal phase. Moreover, this structural phase transition occurs simultaneously across the whole sample. This electrostatic-doping control of structural phase transition opens up new possibilities for developing phase-change devices based on atomically thin membranes.