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Verbascoside treatment ameliorated cognitive and memory deficits in db/db mice by reshaping the gut microbiome composition, alleviating diabetic metabolic disturbances, enhancing insulin sensitivity, and protecting the synaptic ultrastructure.

A convenient strategy for the diastereoselective synthesis of α,β-diamino diacid derivatives bearing congested vicinal acyclic tetrasubstituted stereocenters via catalytic Mannich-type reactions of azlactones and 2-aminoacrylates was established. A diverse set of α,β-diamino diacid derivatives were synthesized in good to excellent yields and diastereoselectivities. Good enantioselectivity (up to 98:2 er) was achieved by employing the catalyst (DHQD)

Circular RNAs (circRNAs) play an important role in regulating the mammalian reproductive system, especially testicular development and spermatogenesis. However, their functions in testicular development and spermatogenesis in the Qianbei Ma goat, the Guizhou endemic breed are still unclear. In this study, tissue sectioning and circRNAs transcriptome analysis were conducted to compare the changes of morphology and circular RNAs gene expression profile at four different developmental stages (0Y, 0-month-old; 6Y, 6-month-old; 12Y, 12-month-old; 18Y, 18-month-old). The results showed that the circumferences and area of the seminiferous tubule gradually increased with age, and the lumen of the seminiferous tubule in the testis differentiated significantly. 12,784 circRNAs were detected from testicular tissues at four different developmental stages by RNA sequencing, and 8,140 DEcircRNAs (differentially expressed circRNAs) were found in 0Y vs. 6Y, 6Y vs. 12Y, 12Y vs. 18Y and 0Y vs. 18Y, 0Y vs. 12Y, 6Y vs. 18Y Functional enrichment analysis of the source genes showed that they were mainly enriched in testicular development and spermatogenesis. In addition, the miRNAs and mRNAs associated with DECircRNAs in 6 control groups were predicted by bioinformatics, and 81 highly expressed DECircRNAs and their associated miRNAs and mRNAs were selected to construct the ceRNA network. Through functional enrichment analysis of the target genes of circRNAs in the network, some candidate circRNAs related to testicular development and spermatogenesis were obtained. Such as circRNA_07172, circRNA_04859, circRNA_07832, circRNA_00032 and circRNA_07510. These results will help to reveal the mechanism of circRNAs in testicular development and spermatogenesis, and also provide some guidance for goat reproduction.

Background Nicotine dependence is a significant public health issue, and understanding the factors associated with nicotine dependence in this population is crucial for developing effective interventions. This study examined the association between family functioning and nicotine dependence levels of smoking fathers based on the McMaster model of family functioning (MMFF), providing evidence for future interventions. Methods In this study, we selected fathers of first- to fifth-grade students from 10 pilot elementary schools in Qingdao whose families smoked. We used the Fagerstrom test to assess nicotine dependence and the Family Assessment Device to evaluate family functioning. We performed univariate analysis to compare differences among those with different levels of nicotine dependence, and we used an ordinal logistic regression analysis to investigate the influences related to nicotine dependence. Results This study included 874 smokers, with 78.5% having mild nicotine dependence, 11.7% having moderate dependence, and 9.84% having severe dependence. Univariate analysis showed that smokers with severe dependence had lower education levels, higher prevalence of chronic diseases, more frequent alcohol consumption, and poorer family functioning compared to those with mild to moderate dependence. Ordinal logistic regression analysis showed that poorer general functioning scores (OR = 1.087, 95% CI: 1.008–1.173, P = 0.030), poorer behavioral control (OR = 1.124, 95% CI: 1.026–1.232, P = 0.012), more quit attempts, frequent alcohol consumption, and longer smoking duration may be associated with a higher likelihood of developing severe nicotine dependence. The older age of starting smoking and higher education level may be associated with a lower likelihood of developing severe nicotine dependence. However, it is important to note that the cross-sectional nature of this study precludes the determination of causal relationships. Conclusions This study finds that heavy nicotine dependence in smoking fathers is associated with risky behaviors and demographics such as longer smoking duration and frequent alcohol consumption. Targeted smoking cessation interventions are crucial for this group, taking these specific factors into consideration. Family functioning, particularly general functioning and behavioral control, may also be linked to nicotine dependence, indicating the need for further research in this area.

Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and phosphodiesterase 4 (PDE4) is an effective target for the treatment of inflammatory diseases such as psoriasis. Toddacoumalone is a natural PDE4 inhibitor with moderate potency and imperfect drug-like properties. To discover novel and potent PDE4 inhibitors with considerable druggability, a series of toddacoumalone derivatives were designed and synthesized, leading to the compound (2

DNA G4-structures from human c-MYC promoter and telomere are considered as important drug targets; however, the developing of small-molecule-based fluorescent binding ligands that are highly selective in targeting these G4-structures over other types of nucleic acids is challenging. We herein report a new approach of designing small molecules based on a non-selective thiazole orange scaffold to provide two-directional and multi-site interactions with flanking residues and loops of the G4-motif for better selectivity. The ligands are designed to establish multi-site interactions in the G4-binding pocket. This structural feature may render the molecules higher selectivity toward c-MYC G4s than other structures. The ligand–G4 interaction studied with 1H NMR may suggest a stacking interaction with the terminal G-tetrad. Moreover, the intracellular co-localization study with BG4 and cellular competition experiments with BRACO-19 may suggest that the binding targets of the ligands in cells are most probably G4-structures. Furthermore, the ligands that either preferentially bind to c-MYC promoter or telomeric G4s are able to downregulate markedly the c-MYC and hTERT gene expression in MCF-7 cells, and induce senescence and DNA damage to cancer cells. The in vivo antitumor activity of the ligands in MCF-7 tumor-bearing mice is also demonstrated.

Tidal heating is often used to interpret ‘radius anomaly’ of hot Jupiters (i.e. radii of a large fraction of hot Jupiters are in excess of 1.2 Jupiter radius which cannot be interpreted by the standard theory of planetary evolution). In this paper, we find that tidal heating induces another phenomenon ‘runaway inflation’ (i.e. planet inflation becomes unstable and out of control when tidal heating rate is above its critical value). With sufficiently strong tidal heating, luminosity initially increases with inflation, but across its peak it decreases with inflation such that heating is stronger than cooling and runaway inflation occurs. In this mechanism, the opacity near radiative-convective boundary (RCB) scales approximately as temperature to the fourth power and heat cannot efficiently radiate away from planet interior, which induces runaway inflation (similar to a tight lid on a boiling pot). Based on this mechanism, we find that radii of hot Jupiters cannot exceed 2.2RJ, which is in good agreement with the observations. We also give an upper limit for orbital eccentricity of hot Jupiters. Moreover, by comparison to the observations we infer that tidal heating locates near RCB.

Testing-culling is a very effective measure for the prevention and control of animal diseases. In this paper, based on sheep brucellosis control policies and animal testing characteristics and considering the limitation of culling resources, a dynamic model is established to study the impact of testing-culling measure. Theoretical analysis reveals that the model may have one or three positive equilibria. The equilibrium in the middle is always unstable, and the model shows saddle-node bifurcation, generalized Hopf bifurcation and Bogdanov-Takens bifurcation. Moreover, the theoretical results are verified via numerical analysis. These results reveal that testing and culling strategies can induce complex transmission dynamics that can help us develop appropriate prevention and control measures for animal brucellosis.

Epithelial–mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a hallmark of the pathogenesis of proliferative vitreoretinopathy (PVR) that can lead to severe vision loss. Nevertheless, the precise regulatory mechanisms underlying the pathogenesis of PVR remain largely unknown. Here, we show that the expression of death-associated protein-like 1 (DAPL1) is downregulated in PVR membranes and that DAPL1 deficiency promotes EMT in RPE cells in mice. In fact, adeno-associated virus (AAV)-mediated DAPL1 overexpression in RPE cells of Dapl1-deficient mice inhibited EMT in physiological and retinal-detachment states. In a rabbit model of PVR, ARPE-19 cells overexpressing DAPL1 showed reduced ability to induce experimental PVR, and AAV-mediated DAPL1 delivery attenuated the severity of experimental PVR. Furthermore, a mechanistic study revealed that DAPL1 promotes P21 phosphorylation and its stabilization partially through NFκB (RelA) in RPE cells, whereas the knockdown of P21 led to neutralizing effects on DAPL1-dependent EMT inhibition and enhanced the severity of experimental PVR. These results suggest that DAPL1 acts as a novel suppressor of RPE-EMT and has an important role in antagonizing the pathogenesis of experimental PVR. Hence, this finding has implications for understanding the mechanism of and potential therapeutic applications for PVR.

A 3D printed conformal polarization converter, based on a novel dielectric unit cell, is proposed for linear-to-circular polarization conversion. The designed dielectric unit cell comprises a cuboid-shaped dielectric block and a thin square dielectric substrate layer for ease of fabrication with 3D printing technology. Meanwhile, the unit cell can achieve linear-to-circular polarization conversion performance from 14.2 GHz to 20.1 GHz with 3-dB axial ratios (ARs) of 34% and good angular stability within 40°. Then, the unit cell is applied to design the conformal dielectric linear-to-circular polarization converters (LCPCs) for cylindrical and spherical surfaces, respectively. To verify the feasibility, three kinds of dielectric converters including planar, cylindrical, and spherical shapes are fabricated and measured. The measured results demonstrate that the proposed dielectric polarization converters with different shapes can produce almost similar linear-to-circular polarization performances with low loss, high conversion efficiency, and angular stability within 40°.

Background: Smoking cessation is not only good for the health of the quitters themselves but also helps reduce the exposure of their families to secondhand smoke. However, nicotine dependence can make smoking cessation very difficult, and studying the relationship between nicotine dependence and family functioning may better help smoking fathers quit. This study examined the association between family functioning and nicotine dependence levels of smoking fathers based on the McMaster model of family functioning (MMFF), providing evidence for future interventions. Methods: In this study, fathers of second to fifth-grade students whose families smoked in 10 pilot elementary schools in Qingdao were selected. The Fagerstrom test for nicotine dependence(FTND) consists of six questions. The70-item Family Assessment Device developed by Epstein and others was used to assess family functioning. One-way ANOVA was used to analyze differences in family functioning among those with different levels of tobacco dependence, and a binary logistic regression analysis was used to examine the influences associated with tobacco dependence. Results: A total of 874 study subjects were included. Most respondents had mild to moderate tobacco dependence (90.16%), and a tiny percentage had heavy tobacco dependence (9.84%). The average age of first smoking was 27.77 years, and the average number of years of smoking was 12.06 years. Family Functioning Scale scores showed that respondents with mild to moderate tobacco dependence had lower total FAD scores and scores on five dimensions than those with heavy tobacco dependence（PPPPPPPConclusions: The better the family functioning, the lower the level of tobacco dependence, while poor general functioning, weak behavioral control, long years of smoking, and quitting more than or equal to 2 times are all risk factors for tobacco dependence.

Two-dimensional layered structure of rGO@Bi2O2CO3@NiCo-LDHs as positive material of supercapacitor is fabricated using the simple hydrothermal reaction, freeze-drying technology, and heat treatment process. The corresponding electrode exhibits a maximum specific capacity of 1147 F/g at 0.5 A/g and 82.2% capacity retention after 1000 times charging and discharging at 10 A/g. Additionally, negative material of rGO film is also prepared, which has a higher specific capacity of 354 F/g than that of other carbon materials. To obtain a high performance of supercapacitor device, an asymmetric supercapacitor of rGO//rGO@Bi2O2CO3@NiCo-LDHs is assembled based on rGO@Bi2O2CO3@NiCo-LDHs, rGO film, and 2 M KOH electrolyte. The testing data show that the maximum specific capacitance and energy density of asymmetric supercapacitor are 85 F/g and 23.14 Wh/kg, respectively. Simultaneously, it also shows the good electrochemical stability, remaining 80% capacity after 3000 cycles. This means that rGO@Bi2O2CO3@NiCo-LDHs could be regarded as a promising electrode material for energy storage devices.

Objectives: Sunlight exposure is an important environmental factor in the pathogenesis of skin cutaneous melanoma (SKCM). Ultraviolet (UV) from sunlight can cause excessive intracellular production of reactive oxygen species (ROS), resulting in damage from oxidative stress to cells. As a major iron-rich and ROS-producing organelle, mitochondria are considered as an important place for cell ferroptosis. Thus, the pathology and potential biological process of UV exposure-induced ferroptosis in the development of SKCM has aroused our strong interest.Methods: Gene expression profile datasets of melanoma cell line datasets (GSE31909) and UV-irradiated mitochondria dataset (GSE3632) were downloaded from the Gene Expression Omnibus (GEO) database, and ferroptosis-related genes were obtained from the FerrDb v2 database. After identifying the common differentially expressed genes (DEGs), comprehensive analyzes were performed, including functional annotation, protein-protein interaction (PPI) network construction, hub gene identification, and gene and tissue protein expression levels, survival analysis, and immune cell infiltration analysis.Results: A total of 14 common DEGs was identified for subsequent analyses. Seven DEGs, including PSMB4, CRELD2, CDKN2A, TIMP1, NDRG1, ATF3 and JUND, have consistent performance in mRNA and protein expression in normal skin and SKCM tissues can be regarded as a good biomarker with SKCM diagnostic effectiveness. Functional enrichment analysis results indicate that HIF-1 signaling pathway and angiogenesis involved in the pathogenesis and development of SKCM. Induction of ferroptosis in tumor cells by enhancing the function of CD8+ T cells is expected to be an effective intervention to promote tumor therapy.Conclusion: Our study reveals the pathogenesis and potential biological processes of UV exposure-induced ferroptosis in the development of SKCM, which may provide potential immunotherapy targets for SKCM treatment via tumor cell ferroptosis mechanisms.

Background Patients with large hemispheric infarction (LHI) are at risk of cerebral edema (CED). This study analyzed health resource use, costs, and outcomes during and after acute hospitalization for LHI in US patients with and without CED. Methods Using IBM® MarketScan® Commercial, Medicaid, and Medicare databases, patients with incident hospitalization for LHI (International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes of I63.03x, I63.13x, I63.23x, I63.31x, I63.41x, I63.51x) from 31 March 2016 through 31 December 2018 were identified and further categorized by the presence or absence of CED based on related diagnosis codes or a procedure code of craniectomy. Health resource use, costs, and outcomes were compared in patients with and without CED during hospitalization and after discharge. Results Of 7336 Commercial, 1946 Medicaid, and 5015 Medicare patients with LHI, 7.8%, 6.9%, and 4.3% had CED, respectively. After adjusting for age, sex, and baseline comorbidities, differences (95% confidence intervals) in mean total costs of the index hospitalization in patients with CED versus without CED were $65,572 ($56,506–$76,335), $44,395 ($26,442–$63,495), and $31,417 ($18,982–$48,543) in the Commercial, Medicaid, and Medicare groups, respectively. Similarly, the adjusted differences (95% confidence intervals) in mean lengths of stay between patients with CED and without CED were 11.75 (10.17–13.48), 10.84 (7.59–14.17), and 3.69 (2.40–5.19) days, respectively. Mortality during index hospitalization was 10–20 times greater in patients with CED versus without CED (p

It is valuable that graphene-like porous carbon materials are prepared from the biomass resources due to theirs porous structure, heteroatom, and high specific surface area. Herein, we use egg white and graphene oxides as precursor and employ post-hydrothermal carbonization approach, freeze-drying technique, carbonization, and activation methods by KOH to prepare the graphite carbon nanoflakes with Fe7C3@graphite carbon nanoflakes hybrid materials. Morphology tests imply that the formation of graphite carbon nanoflakes are mainly depended by activation step, it implies that carbon flakes are exfoliated via introducing K+ into carbon layers and further destroying the van der Waals force (VDWF). As a result, this hybrid materials exhibit a attractive capacitance (528 mF·cm-2@1 mA·cm-2) and durability (91@10 mA·cm-2, 4000 cycles). For hydrogen evolution reaction (HER), the as-collected samples also deliver a low overpotential and remarkable stability. We believes that the as-obtained hybrid materials have a greatly application value in energy storage devices.

Long non-coding RNAs (lncRNAs) play critical roles in gastric cancer (GC) initiation progression. However, the biological function of theThe expression levels of theThe results demonstrated that theIn conclusion, the findings of this study suggested that the

In this work, a series of FeS1-xTex (0 ≤ x ≤ 0.15) single crystals were successfully synthesized by a hydrothermal method for the first time. According to the measurement of in-plane resistivity, Hall effect, and magnetoresistance (MR), we find that the superconducting transition temperature Tc is rapidly suppressed with the increasing Te substitution, and finally the superconductivity disappears when x > 0.05. With the substitution of Te for S, the residual resistivity ρ0 increases while the residual resistivity ratio (RRR) decreases monotonously. Meanwhile, the MR of FeS1-xTex is also reduced by Te doping. All these results reveal that the Te substitution introduces more impurity scattering. In consequence, the non-linear field-dependent of Hall resistivity ρxy at low temperature region is suppressed and a linear behavior is restored upon Te doping. The negative Hall coefficients RH for all the FeS1-xTex samples suggest that the electron-type carrier dominates the electrical conduction. Moreover, the MR of FeS1-xTex obviously follows Kohler’s law, indicating the isotropic scattering rates in the Fermi surface.

In this study, we introduce the concept of high-entropy into high-temperature superconductors and report the successful synthesis of a series of high-entropy oxides, REBa2Cu3O7-δ (REBCO), with superconducting critical temperature (Tc) around 92 K. The superconductivity transition temperatures of these compounds are very close to that of the parent superconductor, YBa2Cu3O7-δ (YBCO). The temperatures of the zero-resistance appearing (Tczero), the critical current density (Jc) calculated from the hysteresis loop, and the irreversible fields (Hirr) of REBCO are not improved compared to that of YBCO. Our results indicate that the introduction of high-entropy elements with strong magnetic moments at RE site does not affect Tc, but may decrease other superconducting properties such as Jc, Tczero, and Hirr.

The service-oriented digital transformation of the construction industry is a development trend of cross-border industrial integration and transformation and upgrading in the digital economy environment, and collaborative value creation among stakeholders is seen as a strategic imperative to promote this process. This study aims to achieve efficient collaborative value co-creation and accelerate the digital transformation process of the construction industry by exploring the collaborative strategies and evolution laws of value co-creators in the digital service ecosystem of the construction industry. Based on evolutionary game theory and methods, this paper analyzes the evolutionary stability strategies and conditions of each participant in the service-oriented value chain at different stages of the digital transformation of the construction industry. It is found that with the improvement of the level of digitalization, the degree of cooperation among game players continues to increase until a stable state of full cooperation is achieved. The initial willingness of the game players to cooperate accelerates the speed of the system’s evolution to the stable state of full cooperation in the middle stage of digital transformation. Additionally, the improvement of the construction process digitalization level can subvert the evolution result of full non-coordination caused by a low initial willingness to cooperate. The research conclusions and corresponding countermeasures and suggestions can provide a strategic reference for the service-oriented digital transformation of the construction industry.

Due to excessive greenhouse gas emissions, carbon emission-reducing measures are urgently needed. Important emission-reduction measures mainly include carbon trading and low-carbon cost subsidies. Comprehensive consideration of these two policies is a research hotspot in the field of low-carbon technology investment. Based on this background, this paper considers the impact of consumer low-carbon preferences on market demand and the impact of uncertainty in carbon emission-reduction behaviour. We construct a stochastic differential game model with upstream and downstream enterprises based on cost-sharing coordination under a cost subsidy. From a dynamic perspective, this paper researches the optimal equilibrium strategy and evolution characteristics of the joint emission-reduction mechanism in a supply chain. This paper discusses the sensitivity of the parameters and uses numerical simulation to verify the impact of each parameter on the emission-reduction decision-making activities of stakeholders after introducing the cost subsidy. The results show that a cost subsidy policy can promote carbon emission-reduction investment and supply chain profit. Thus, it is important to strengthen technical cooperation and exchange among enterprises.

The aim of the study was to observe the effect of allogeneic acellular dermal matrix (ADM) combined with autologous razor‐thin graft on the appearance and function of hands in patients with extremely large area burns combined with deep hand burns. Sixty‐four patients with severe burn combined with deep burn of the hand in our hospital from August 2015 to August 2019 were selected as the study subjects. All patients were randomly divided into the study group (32 cases, given allogeneic ADM combined with autologous razor‐thin graft) and the control group (32 cases, given autologous scar tissue combined with autologous razor‐thin graft). Hand appearance, wound healing, wound contraction, hand function, and quality of life were compared between the two groups at 3 and 6 months after treatment. The vascular distribution, skin thickness, and flexibility scores of the two groups 6 months post operation were lower than those of the 3 months post operation (P

Cyclic cryogenic treatment, a major cycle accompanied by zero or more subsidiary cycles, was conducted on the hardened 42CrMo steel using orthogonal design method to investigate the effect of different parameters (cryogenic temperature, holding time, and cycles number) of cryogenic treatment on wear resistance and impact toughness of the steel. Range analysis was performed to obtain the influencing order of the three parameters and their optimum values. The results show that after cryogenic treatment, the steel exhibits higher wear resistance and impact toughness, whereas no significant change in hardness. For wear resistance, the influencing order of parameters is cryogenic temperature, holding time, and cycles number, and the optimum values of the parameters are −160°C, 24 h and two cycles, respectively. For impact toughness, the influencing order of parameters is cryogenic temperature, cycles number, and holding time, and the optimum values are −120°C, 24 h and three cycles, respectively. The wear topography and fracture topography were examined using scanning electronic microscopy (SEM) to investigate the wear mechanism and fracture mechanism of the steel after cryogenic treatment, respectively. The results show that after cryogenic treatment, the wear mechanism is the combination of abrasive wear and adhesive wear with oxidative wear, and the fracture mechanism is a quasicleavage fracture. The microstructure was also examined by SEM to investigate the influencing mechanism of cryogenic treatment for improving wear resistance and impact toughness of the steel. It suggests that more precipitation of fine carbides dispersively distributed in the matrix is responsible for the beneficial effect of cryogenic treatment on wear resistance and impact toughness of the steel.

We report the direct asymmetric synthesis of pyrimido[2,1-b]benzothiazoles using a commercially available chiral amine catalyst. A variety of 2-benzothiazolimines and aldehydes were well tolerated under the reaction conditions and generated the corresponding products in 81-99% yields with excellent diastereoselectivities and enantioselectivities (up to >20:1 dr, 99% ee). Furthermore, the products could be easily converted to other useful chiral building blocks.

A one-pot efficient asymmetric domino annulation of 2-isothiocyanato-1-indanones with tert-butyl 2-hydroxybenzylidenecarbamates in situ generated from 2-hydroxyaryl-substituted α-amido sulfones was developed. This reaction firstly provided a powerful tool for the enantioselective construction of functionalized bridged fused ring hererocycles bearing three adjacent stereogenic centers in high yields with excellent diastereo- and enantioselectivities (up to 91% yield, >20 : 1 dr and 99% ee).

A series of copper thiospinels compounds, CuCo₂S_(4‐x)Se_x (x = 0, 0.2, 0.4, 0.6, 0.8), have been successfully synthesized by solid state reaction and their structure and magnetic properties have been studied. The Rietveld refinements of X‐Ray diffractions indicate that both the lattice constants and the nearest neighbor Cu‐Cu distances increase with increasing selenium doping. A weakly antiferromagnetic transition occurring at about 4 K is observed in CuCo₂S₄. Two antiferromagnetic transitions at about 3.5 K and 6 K are observed in selenium‐doped samples, which suggest that the exchange couplings associated with Cu‐S(Se)‐Cu and Cu‐Se(S)‐Cu, respectively, are responsible for the two antiferromagnetic transitions. Detailed analysis of the experimental results further indicate that the nearest‐neighbor molecular field coefficient is comparable to the next‐neighbor molecular field coefficient. We propose a reasonable model to explain this phenomenon.

Background Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Novel drugs for CRC therapy are urgently needed. Digoxin has been in clinical use for treatment of heart failure and atrial arrhythmias for many years. Fragmentary reports suggested that digoxin might have antitumor efficacy on CRC. Here, we aimed to investigate the antitumor effect of digoxin on human CRC cells and the underlying mechanism. Methods Cell viability was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and plate colony formation assay. The effects of digoxin on cell-cycle distribution and apoptosis were analysed by flow cytometry. The anti-metastatic effect on tumor cells was determined by wound-healing assay and transwell assay. Anti-angiogenic effect was examined by determining the inhibition against proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Mechanism study was performed by Western blot, enzyme-linked immunosorbent assay (ELISA), and gelatin-zymography assay. Results Digoxin potently inhibited cell proliferation, induced G1-phase and G2/M-phase arrest in colorectal-cancer HCT8 and SW620 cells, respectively. No obvious apoptosis was observed in the treated cells. Anti-metastatic activities were shown on HCT8 cells by inhibiting the migration and invasion. Meanwhile, the expression of MMP2, MMP9, and phosphorylated Integrinβ1 were decreased. Digoxin inhibited the proliferation, migration, and tube formation of HUVECs and reduced HIF1α expression and vascular endothelial growth factor A (VEGF-A) secretion in HCT8 cells, suggesting anti-angiogenic activity. Furthermore, digoxin significantly reversed ABCB1-mediated multidrug resistance on SW620/Ad300 cells. Conclusion Our findings suggest that digoxin has the potential to be applied as an antitumor drug via inhibiting proliferation and metastasis as well as reversing the ABCB1-mediated multidrug resistance of colorectal cancer.

This letter presents a fixed-frequency beam-steering leaky-wave antenna (LWA) with switchable beam number. The proposed LWA consists of an impedance modulation surface (IMS) and dc bias circuit. A three-strip structure is designed as the unit cell of the IMS. In this design, varactor diodes are inserted in the unit cell and the impedance characteristics of every unit cell can be controlled independently. Both average reactance and modulation periodicity of the IMS can be tuned for leaky-wave radiation with different beam angle. The proposed LWA can be configured to work in single-beam mode or dual-beam mode. A prototype of the proposed LWA operating at 8 GHz is fabricated and measured. By controlling the dc voltages of varactor diodes, a scanning range of 118° can be achieved.

Anti-angiogenesis drug therapy is ineffective in treating uveal melanoma since it only targets angiogenesis leaving vasculogenic mimicry aside. There is no effective clinical strategy targeting vasculogenic mimicry, yet. We show here that CD146 is a novel target to inhibit uveal melanoma progression since it regulates both uveal melanoma angiogenesis and vasculogenic mimicry activity.CD146 inhibition was achieved with its specific siRNAs or antibody AA98. Tube formation and migration of primary human retinal microvascular endothelial cells and tube-like structure formation, migration, invasion of uveal melanoma cells were evaluated after CD146 inhibition. The underlying mechanisms were investigated by Western blot and immunofluorescence. Finally, uveal melanoma cells were injected subretinally into the eyes of nude mice and AA98 was administrated. Tumor size was revealed by HE staining, and angiogenesis and vasculogenic mimicry were evaluated with CD31-PAS staining.CD146 inhibition induced declines in tube formation and migration of primary human retinal microvascular endothelial cells and tube-like structure formation of uveal melanoma cells. CD146 mediated VEGFR/AKT/p38/NF-κB and FAK/VE-cadherin signal cascades were partially responsible for these biological effects. CD146 blockade by siRNA or AA98 also resulted in inhibition of migration and invasion as well as EMT process of uveal melanoma cells. The physiological relevance of such declines was confirmed by showing that AA98 treatment markedly suppressed the tumor growth, angiogenesis and vasculogenic mimicry induced by implantation of uveal melanoma cells into the eyes of nude mice.CD146 is a novel mediator of both angiogenesis and vasculogenic mimicry in uveal melanoma. Its antibody AA98 has the potency to be developed as a new antibody drug for treating uveal melanoma. Our results warrant further assessment of CD146 as a potential target to improve therapeutic management of uveal melanoma in a clinical setting.

To explore the effect of CXCR4 on the treatment response and prognosis of Carfilzomib (CFZ) in multiple myeloma.Dataset GSE69078 based on microarray data from two CFZ-resistant MM cell lines and their corresponding parental cell lines (KMS11-KMS11/CFZ and KMS34-KMS34/CFZ) were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified, and Protein-protein interaction (PPI) network was established to identify the key genes involved in CFZ resistance acquisition. Finally, the prognostic roles of the CFZ risistance key genes in MM using MMRF-CoMMpass data study was verified.44 up-regulated and 46 down-regulated DEGs were identified. Top 10 hub genes (CCND1, CXCR4, HGF, PECAM1, ID1, HEY1, TCF4, HIST1H4J, HIST1H2BD and HIST1H2BH) were identified via Protein-protein interaction (PPI) network analysis. The CoMMpass data showed that high CXCR4 expression showed correlation to relative higher relapse and progress rates and the overall survival was significant decreased in high CXCR4 patients (P=0.013).CXCR4 perhaps plays a crucial role in CFZ acquired resistance, which might help identifying potential CFZ-sensitive patients before treatment and providing a new therapeutic target in CFZ-resistant MM.CXCR4在多发性骨髓瘤中对卡菲佐米疗效及预后的影响.探讨CXCR4对卡菲佐米（CFZ）治疗多发性骨髓瘤(MM)患者的效果及预后的影响.下载在线数据库Gene Expression Omnibus（GEO）中含两种耐CFZ的MM细胞株（KMS11/CFZ及KMS34/CFZ）以及相对应的亲本株KMS11和KMS34基因表达谱数据的数据集GSE69078。分析差异表达基因（DEGs）并构建蛋白-蛋白互作（PPI）网络，获得CFZ耐药关键基因。最终，以MMRF-CoMMpass研究数据作为验证数据集探讨CFZ耐药关键基因的临床意义.共鉴定出44个上调DEGs和46个下调DEGs，通过PPI网络分析筛选出前10位关键基因（CCND1、CXCR4、HGF、PECAM1、ID1、HEY1、TCF4、HIST1H4J、HIST1H2BD及HIST1H2BH）。MMRF-CoMMpass数据显示，C-X-C基序趋化因子受体4（CXCR4）高表达与较高的复发/进展率相关，且CXCR4高表达患者的总生存（OS）率显著降低（P=0.013）.CXCR4高表达可能与MM患者CFZ获得性耐药相关，有助于在治疗前筛选潜在的CFZ敏感患者，并有望为CFZ耐药MM提供新的治疗靶点.

Phosphodiesterase-4 (PDE4) is an important drug target for inflammatory diseases. Previously, we identified a series of novel PDE4 inhibitors derived from the natural Toddacoumalone, among which the hit compound 2 with a naphthyridine scaffold showed moderate potency with the IC

Introduction: Lacking of normal innervation increases the chance of chronic wounds and recurrence of ulceration. Various rodent models are designed to reveal nerve-wound relationship but present many limitations to mimic human wound which heals primarily by re-epithelialization rather than contraction in rodents. This article tested a modified rat model of denervated wound healing to better mimic clinical common denervated wounds. Material and Methods: The wounds formed on right hind paws of 18 SD rats served as the experimental (denervated) group and the left side as contra-lateral control (non-denervated). The denervation was achieved through sciatic and femoral nerve co-transection and the control side underwent sham-surgery 3 days prior to a skin punch wound formation on both sides. Wound closure rate was calculated under digital photographing. Loss of innervation and affected healing process was confirmed by histological analyses. Results: Truncation of the sciatic and femur nerve successfully denervated the skin of the hind paw and resulted in a significantly declined healing rate, prolonged inflammation, weakened dermal contraction, hindered macrophage recruitment, retarded re-epithelialization and collagen deposition, decreased angiogenesis and epidermal proliferation, and persisted epidermal apoptosis compared to the innervated contra-lateral control. Conclusion: Wound on denervated dorsal pedis in rats can be used to study denervated skin healing in multiple histological process. We believe that this model will assist in understanding the underlying mechanism of nerve-wound relationship and identifying new treatment strategies that can be more rapidly translated into clinical practice.

Cisplatin is a widely used chemotherapeutic drug in lung cancer treatment. Most cancer patients eventually develop cisplatin resistance, resulting in a poor prognosis. Previously, we identified a novel marker, family with sequence similarity 60A (FAM60A), that was responsible for resistance in cisplatin-resistant human lung adenocarcinoma A549 (A549/DDP) cells. Here, we investigated the biological effects of FAM60A in A549/DDP cells and explored the underlying molecular mechanisms to understand its functional role in cisplatin resistance. Real-time quantitative PCR and western blot analysis were used to determine the expression levels of FAM60A in A549/DDP cells. FAM60A and SKP2 were knockdown with small-interfering RNA (siRNA). Cancer cell viability was analyzed with flow cytometry. The mRNA and protein expression levels of FAM60A increased significantly and dose-dependently in A549/DDP cells following cisplatin treatment. FAM60A overexpression up-regulated MDR1 expression, inhibited caspase 3, cleaved-caspase 3, and caspase 8 expression, and prevented cancer cell death. Microarray analysis of cells transfected with siRNA against the FAM60A transcript and control samples showed that SKP2 expression was positively regulated by FAM60A. SKP2 knockdown using a short-hairpin RNA reversed the functions induced by FAM60A. These results suggest that overexpression of FAM60A in A549/DDP cells led to SKP2 upregulation and enhanced cisplatin resistance in cancer cells. These provide new insights into chemoresistance and may contribute to reversing cisplatin resistance during lung cancer treatment.

A broadband balanced-to-single-ended (BTSE) four- way power divider (PD) with out-of-phase is designed in this letter. The proposed four-way PD composed of three-series T-junction PDs, a balanced U-type microstrip–slotline transition structure, and multiple cross-junction microstrip–slotline transitions. The series T-junction PD achieves equal amplitude and out-of-phase power distribution at the output ports over a wide frequency band. Meanwhile, the balanced U-type structure as the feed of the BTSE PD can realize a great broadband common-mode (CM) rejection without affecting the differential-mode (DM) responses. In addition, the proposed BTSE PD is employed with four quasi-Yagi antennas to realize a balanced quasi-Yagi antenna array. The proposed antenna array keeps the merits of wide DM transmission and high CM suppression level and achieves low cross-polarization level and high gain in the endfire direction. Finally, a prototype antenna array is fabricated and measured, and the experimental results show that it exhibits 10 dB return loss bandwidth of 5.7–8.9 GHz, peak gain of 12.5 dBi, and maximum cross-polarization levels of −25.6/−34.6 dB in E -/ H -planes at 5.8 GHz, respectively.

In this letter, transmitting metasurface using single dielectric substrate for orbital angular momentum (OAM) generation is presented in Ku -band. A dimension extension method is introduced in designing the unit cell of the proposed transmitting metasurface to achieve required phase shift and transmission magnitude for generating OAM. A prototype of the proposed transmitting metasurface is fabricated and measured. Measured results suggest that the proposed transmitting metasurface can generate OAM vortex wave at 18 GHz. The proposed method can be applied in wireless communication systems requiring low-profile transmitted OAM generator.

Background Microtubule-associated protein 1 light chain 3 (LC3), an autophagic gene, has been reported as a vital marker for many diseases and cancers. However, the role of LC3 in hepatocellular carcinoma (HCC) was not still investigated. Therefore, we conducted a meta-analysis to examine the association of LC3 with its clinicopathological and prognostic in HCC. Methods We consulted the PubMed, Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure and Wan Fang databases for published studies on LC3 in HCC. Newcastle–Ottawa scale was used to screen the quality of the literature. The statistical analysis was calculated by STATA 14.2. Results Of the 1329 titles identified, 10 articles involving 949 patients in HCC were included in this meta-analysis. The results of our study show that increased LC3 expression is related to size of tumor, but not to gender, age, number of tumor, liver cirrhosis, HBsAg, TNM stage, alpha fetoprotein, vascular invasion and histological grade. Positive LC3 expression was associated with overall survival by pooled hazard ratio. Conclusions This meta-analysis indicated that positive LC3 expression was related to size of tumor, and could predict prognosis in human hepatocellular carcinoma.

An efficient asymmetric and enantio-swithchable organocatalytic [3 + 3] annulation reaction using MBH-2-naphthoates of nitroalkenes and 4-hydroxyquinolin-2(1H)-ones has been developed. Densely substituted tetrahydropyrano[3,2-c]quinolinones scaffolds with two adjacent stereogenic centers are obtained with high yield (up to 95% yield) and good stereoselectivities (up to >20:1 dr and 96% ee) in an enantio-switchable manner. Furthermore, gram scale synthesis was achieved and the nitro group could easily transform into an amino group without any appreciable loss in the diastereo- and enantioselectivity.

In this article, the three-phase asynchronous motor is taken as the research object, and the deadbeat predictive control is the control core, and its control performance is studied. Considering the overshoot of flux linkage and speed response in deadbeat predictive control, an improved deadbeat predictive control algorithm based on synergy theory is proposed. Different from deadbeat predictive control, improved deadbeat predictive control can control the flux linkage and speed independently through two adjustment parameters, which are achieved through the manifold of synergy theory. To accurately obtain the feedback flux linkage and load torque in the control, a flux observer and a load torque observer are designed. Based on these, a simulation platform is built, and the control performance of the two control algorithms is compared. The robustness of the two control algorithms is further verified by changing parameters. Finally, the experimental platform of three-phase asynchronous motor is built in this article. The experimental program based on deadbeat predictive control is designed. The no-load experiment and loading experiment are carried out, respectively. The feasibility of the algorithm is verified by experimental data.

Purpose Radiotherapy is one major curative treatment modality for esophageal squamous cell carcinoma (ESCC) patients. This study aimed to find out small-molecular kinase inhibitors, which can significantly enhance the radiosensitivity of ESCC in vitro and in vivo. Materials and methods Ninety-three kinase inhibitors were tested for their radiosensitizing effect in ESCC cells through high-content screening. The radiosensitizing effect of kinase inhibitors was investigated in vitro by detection of DNA double-strand breaks (DSBs) and clonogenic survival assay. By the establishment of xenograft tumor models in BALB/c nude mice, the radiosensitizing effect of kinase inhibitors was investigated in vivo. Results Among the 93 kinase inhibitors tested, we found NVP-BSK805, an inhibitor of JAK2 kinase, significantly radiosensitized ESCC cells through enhancing DSBs, inhibiting DNA damage repair and arresting cell cycle in G2/M or G0/G1 phase. After treatment with NVP-BSK805, ESCC cells showed decreased clonogenic survival and delayed tumor growth in vivo. JAK2 kinase was highly expressed in tumor tissues of ESCC patients, while rarely expressed in matched normal esophageal epithelial tissues. Survival analysis revealed JAK2 kinase as a prognostic factor of ESCC patients treated with chemoradiotherapy. Conclusion Our study discovered JAK2 kinase as an attractive target to enhance the radiosensitivity of ESCC cells in vitro and in vivo.

In order to fully understand and effectively utilize the genetic diversity of Jerusalem artichoke accessions in China. 257 Jerusalem artichoke accessions were analyzed. Among them, 12 quantitative traits had 6%–50% of the coefficient of variation, with a mean of 24.75%, which was the highest in tuber weight per plant (50%) and the smallest in growth period (6%). The diversity index ( H′ ) of these 12 traits was 1.24–1.53, with a mean of 1.44, which was the highest in tuber number per plant (1.53) and the lowest in leaf width (1.24). The diversity index of the eight quality traits was 0.85–1.08, with a mean of 0.98, which was the highest in tuber habit and the lowest in tuber uniformity, showing rich genetic diversity in most traits. The subordinate function of 257 Jerusalem artichoke accessions was 0.12–0.58, in which the highest was in JA1095 (0.58) with the obvious advantages of flower number and tuber weight per plant. The correlation analysis of 12 quantitative traits indicated that stem diameter, leaf length, flower and disk size could be used as the main target traits for high yield Jerusalem artichoke varieties breeding in the future. The results of principal component analysis showed that the cumulative contribution rate of the seven principal component factors was 66.794%. Among them, the number of flowers, the tuber number per plant, the number of tuber hairs and the smoothness of tuber epidermis were the main factors contributing to the phenotypic difference of Jerusalem artichoke. By cluster analysis, 257 accessions materials were divided into five categories based on 20 traits,among them class I and class II accounted for 85% of the total germplasm resources. This results can provide an important reference for the utilization of Jerusalem artichoke accessions and variety breeding.

We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of pyranoquinolinones and 3-methylcrotonaldehyde are well tolerated under the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a' with the best PDE4 inhibitory activity (IC50 = 0.18 μM).