Search

AbstractZeta chain-associated protein kinase 70 (ZAP-70) is a non-receptor tyrosine kinase that interacts with the activated T-cell receptor to transduce downstream signals, and thus plays an important role in the adaptive immune system. The biphosphorylated immunotyrosine-based activation motifs (ITAM-Y2P) binds to the N-SH2 and C-SH2 domains of ZAP-70 to promote the activation of ZAP-70. The present study explores molecular mechanisms of allosteric inactivation of ZAP-70 induced by the hot spot W165C mutation through atomically detailed molecular dynamics simulation approaches. We report microsecond-length simulations of two states of the tandem SH2 domains of ZAP-70 in complex with the ITAM-Y2P motif, including the wild-type and W165C mutant. Extensive analysis of local flexibility and dynamical correlated motions show that W165C mutation changes coupled motions of protein domains and community networks. The binding affinities of the ITAM-Y2P motif to the wild-type and W165C mutant of ZAP-70 are predicted using binding free energy calculations. The results suggest that the driving force to decrease the binding affinity in the W165C mutant derives from the difference in the protein-protein electrostatic interactions. Moreover, the per-residue free energy decomposition unravels that the contributions from residues in the phosphorylated Tyr315 (pY315) binding site, in particular pY315 of ITAM-Y2P, and Arg43, Tyr240 of ZAP-70, are the key determinants for the loss of binding affinity. This study may insights into our understanding of the pathological mechanism of ZAP-70.Communicated by Ramaswamy H. Sarma

Highly efficient kinetic resolution of P-chiral phosphindole oxides via rhodium-catalyzed asymmetric arylation under mild conditions is described. Selectivity factors of up to 569 were achieved by employing chiral diene*as a ligand. The transformation of the enantiopure benzophosphole derivative into a useful P-chiral bisphosphine ligand is also demonstrated.

The reaction of 4/5-carbonyl-cycloalkenone 1or its achiral isomer 1′with organoboronic acid 2in the presence of a chiral diene (S,S)-Fc-tfb-rhodium catalyst gave disubstituted trans-cycloalkanone 3with high diastereo- and enantioselectivity. This highly efficient dynamic kinetic resolution is achieved by fast racemization of 1through the formation of a dienolate followed by kinetic resolution with the chiral catalyst. The utility is demonstrated by the synthesis of key intermediates en route to (−)-cannabidiol.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that suddenly emerged at the end of December 2019 and caused coronavirus disease 2019 (COVID-19) continues to afflict humanity, not only seriously affecting healthcare systems but also leading to global social and economic imbalances. As of August 2022, there were approximately 580 million confirmed cases of COVID-19 and approximately 6.4 million confirmed deaths due to this disease. The data are sufficient to highlight the seriousness of SARS-CoV-2 infection. Although most patients with COVID-19 present primarily with respiratory symptoms, an increasing number of extrapulmonary systemic symptoms and manifestations have been associated with COVID-19. Since the outbreak of COVID-19, much has been learned about the disease and its causative agent. Therefore, great effort has been aimed at developing treatments and drug interventions to treat and reduce the incidence of COVID-19. In this narrative review, we provide a brief overview of the epidemiology, mechanisms, clinical manifestations, diagnosis, and therapeutics of COVID-19.

The extrusion direction (ED) and transverse direction (TD) samples were cut from Mg−2.6Nd− 0.55Zn−0.5Zr alloy sheet, and the effects of bimodal basal texture on the bending stress and microstructure evolution were investigated. Results showed that the ED sample with weak basal texture possessed much lower bending stress than the TD sample. This anisotropy is attributed to the role of different textures on the evolution of deformation mechanisms and microstructures. For the ED sample with weak basal texture, the dominant deformation mechanisms were basal slip in the majority with minor supplement of tension twin in the inner region while basal slip and prismatic slip in the outer region. In comparison, the TD sample with strong basal texture activated more tension twin in the inner region and more prismatic slip in the outer region. The activation of tension twin promoted the development of 〈0002〉//compression direction type texture with the confined ±30° angle range in the inner region and reduced the emergence propensity of high dislocation density and low angle grain boundaries. The massive activation of tension twin allowed the TD sample to maintain a high strain-hardening capacity, which was the fundamental reason for the high bending stress in this sample.

The future intelligent devices requires ultra-low communication delay and high QoS requirement for the following beyond-5G network. Space-air-ground Integrated Network (SAGIN) integrated with satellite networks in space, aerial networks, and terrestrial networks is an advanced network framework to expand the networking overage and improve connectivity for intelligent applications. However, due to the heterogeneous structure and high dynamic of SAGIN, the resource management and transmission strategy should be carefully designed to adjust to the unbalanced resources and varying environments. Federated learning is an innovative distributed learning method to intelligently manage the resource scheduling problem in SAGIN with security and guarantee of user privacy. In this article, we introduce the advantages and potential usage directions of using federated learning in SAGIN in terms of different optimization objectives. To better illustrate the potential deployment of federated learning in SAGIN, we further provide a case study of a federated reinforcement learning-based traffic offloading approach in SAGIN.

In this paper, we study the quantum geometric effects near the locations where classical black hole horizons used to appear in Einstein’s classical theory, within the framework of an improved dynamic approach, in which the internal region of a black hole is modeled by the Kantowski-Sachs (KS) spacetime and the two polymerization parameters are functions of the phase space variables. Our detailed analysis shows that the effects are so strong that black and white hole horizons of the effective quantum theory do not exist at all and instead are replaced by transition surfaces, across which the metric coefficients and their inverses are smooth and remain finite, as are the corresponding curvatures, including the Kretschmann scalar. These surfaces always separate trapped regions from anti-trapped regions. The number of such surfaces is infinite, so the corresponding KS spacetimes become geodesically complete, and no black and white hole-like structures exist in this scheme.

Asymmetric lowered-temperature rolling was applied to the fabrication of fine-grained ZK60 magnesium alloy sheet with weak basal texture along the rolling direction (RD). The results showed that multi-pass lowered- temperature rolling could significantly improve the microstructure homogeneity and refine the grain size. Meanwhile, a fiber texture along the transverse direction (TD) gradually developed during rolling process. Importantly, the shear deformation along the RD made the c-axis of basal plane rotate to the RD, weakening the basal texture along this direction. Influenced by such microstructure variation, the yield strength along the TD continuously increased due to the successive grain refinement and the increased activation of prismatic slips, whereas the uniform elongation decreased owing to the decline of strain hardening ability. In contrast, the continuous weakening of basal texture along the RD increased the activation of soft basal slips, greatly offsetting the strengthening effect contributed by grain refinement and thereby causing the slight decrease of yield strength.

Immunoglobulin detection is essential for diagnosing progression of SARS-CoV-2 infection, for which SARS-CoV-2 IgG is one of the most important indexes. In this paper, Ag nanoparticles with ultrathin Au shells (∼2 nm) embedded with 4-mercaptobenzoic acid (MBA) (AgMBA@Au) were manufactured via a ligand-assisted epitaxial growth method and integrated into lateral flow immunoassay (LFIA) for colorimetric and SERS dual-mode detection of SARS-CoV-2 IgG. AgMBA@Au possessed not only the surface chemistry advantages of Au but also the superior optical characteristics of Ag. Moreover, the nanogap between the Ag core and the Au shell also greatly enhanced the Raman signal. After being modified with anti-human antibodies, AgMBA@Au recognized and combined with SARS-CoV-2 IgG, which was captured by the SARS-CoV-2 spike protein on the T line. Qualitative analysis was achieved by visually observing the color of the T line, and quantitative analysis was conducted by measuring the SERS signal with a sensitivity four orders of magnitude higher (detection limit: 0.22 pg/mL). The intra-assay and inter-assay variation coefficients were 7.7 and 10.3%, respectively, and other proteins at concentrations of 10 to 20 times higher than those of SARS-CoV-2 IgG could hardly produce distinguishable signals, confirming good reproducibility and specificity. Finally, this method was used to detect 107 clinical serum samples. The results agreed well with those obtained from enzyme-linked immunosorbent assay kits and were significantly better than those of the colloidal gold test strips. Therefore, this dual-mode LFIA has great potential in clinical practical applications and can be used to screen and trace the early immune response of SARS-CoV-2.

Herein, we revealed the factors that affect the emission in mixed-ligand metal–organic frameworks (MOFs) with the combination of terephthalic acid (BDC), 2-aminoterephthalic acid (BDC-NH2), and 2,5-dihydroxylterephthalic acid [BDC-(OH)2] as models. The −NH2and −(OH)2groups change the π-conjugation and luminescence behaviors than BDC, so the ligands show different optical behaviors. The Zn2+ion with a 3d10full electronic structure shows little effect on the emission of the ligand and is selected as the metal node. We found that the emission of BDC is weak and incompatible to that of BDC-NH2, so only the emission of BDC-NH2was observed in the BDC/BDC-NH2-MOF. Crosstalk occurs between the emissions from BDC and BDC-(OH)2for the single emission from BDC/BDC-(OH)2-MOFs, even different ratios are selected. The MOFs prepared with BDC-NH2and BDC-(OH)2show dual emission at 450 and 550 nm, while the relative intensity was easily tuned with the ligand ratio and excitation wavelength. Thus, abundant optical behaviors and extensive applications were realized, including but not limited to (1) dual emission from single MOFs, (2) tunable color from blue to yellow with the excitation from 290 to 370 nm for information encryption and decryption, (3) white emission obtained under an excitation of 330 nm, and (4) response of −NH2groups to HCHO and Fe3+ions for ratiometric fluorescence sensing and visual detection. This work revealed the factors that affect the emission in mixed-ligand MOFs, studied their optical behaviors, and realized different applications with single MOFs.

Mechanisms controlling phosphorus (P) availability and the roles of microorganisms in the efficient utilization of soil P in the wheat–maize double cropping system are poorly understood. In the present study, we conducted a pot experiment for four consecutive wheat–maize seasons (2016–2018) using calcareous soils with high (30.36 mg kg−1) and low (9.78 mg kg−1) initial Olsen-P content to evaluate the effects of conventional P fertilizer application to both wheat and maize (Pwm) along with a reduced P fertilizer application only to wheat (Pw). The microbial community structure along with soil P availability parameters and crop yield were determined. The results showed that the Pw treatment reduces the annual P input by 33.3% without affecting the total yield for at least two consecutive years as compared with the Pwm treatment in the high Olsen-P soil. Soil water-soluble P concentrations in the Pw treatment were similar to those in the Pwm treatment at the 12-leaf collar stage when maize requires the most P. Furthermore, the soil P content significantly affected soil microbial communities, especially fungal communities. Meanwhile, the relative abundances of Proteobacteria and alkaline phosphatase (ALP) activity of Pw were significantly higher (by 11.4 and 13.3%) than those of Pwm in soil with high Olsen-P. The microfloral contribution to yield was greater than that of soil P content in soil with high Olsen-P. Relative abundances of Bacillusand Rhizobiumwere enriched in the Pw treatment compared with the Pwm treatment. Bacillusshowed a significant positive correlation with acid phosphatase (ACP) activity, and Rhizobiumdisplayed significant positive correlations with ACP and ALP in soil with high Olsen-P, which may enhance P availability. Our findings suggested that the application of P fertilization only to wheat is practical in high P soils to ensure optimal production in the wheat and maize double cropping system and that the soil P availability and microbial community may collaborate to maintain optimal yield in a wheat–maize double cropping system.

The aim of the present study was to determine the neuroimaging predictors of poor participation after acute ischemic stroke. A total of 443 patients who had acute ischemic stroke were assessed. At 1-year recovery, the Reintegration to Normal Living Index was used to assess participation restriction. We also assessed the Activities of Daily Living Scale and modified Rankin Scale (mRS) score. Brain MRI measurement included acute infarcts and pre-existing abnormalities such as enlarged perivascular spaces, white matter lesions, ventricular-brain ratio, and medial temporal lobe atrophy (MTLA). The study included 324 men (73.1%) and 119?women (26.9%). In the univariate analysis, patients with poor participation after 1?year were older, more likely to be men, had higher National Institutes of Health Stroke Scale (NIHSS) score on admission, with more histories of hypertension and atrial fibrillation, larger infarct volume, more severely enlarged perivascular spaces and MTLA, and more severe periventricular hyperintensities and deep white matter hyperintensities. Patients with participation restriction also had poor activities of daily living (ADL) and mRS score. Multiple logistic regression showed that, in model 1, age, male gender, NIHSS score on admission, and ADL on follow-up were significant predictors of poor participation, accounting for 60.2% of the variance. In model 2, which included both clinical and MRI variables, male gender, NIHSS score on admission, ADL on follow-up, and MTLA were significant predictors of poor participation, accounting for 61.2% of the variance. Participation restriction was common after acute ischemic stroke despite good mRS score. Male gender, stroke severity, severity of ADL on follow-up, and MTLA may be predictors of poor participation.Trial registration numberChiCTR1800016665.

The energy balance approach is one of the design approaches approved in fall protection standards Z359.6, Z259.16 and SS 607 to ensure that horizontal lifeline systems (HLLSs) are adequately designed. However, this study found that theoretical calculations predicting the total fall distance (hTFD) and maximum arrest load (MAL) using an energy balance approach need to be corrected before they can be used safely. Based on the data from 48 drop tests, the authors determined that energy balance calculations differ significantly from the empirical hTFDand MAL values of HLLSs. As a result, further correction factors are introduced into the theoretical calculations to estimate hTFDand MAL conservatively. These correction factors are estimated from a regression equation derived based on experimental results and theoretical calculations.

The aim of the present study was to determine the neuroimaging predictors of poor participation after acute ischemic stroke. A total of 443 patients who had acute ischemic stroke were assessed. At 1-year recovery, the Reintegration to Normal Living Index was used to assess participation restriction. We also assessed the Activities of Daily Living Scale and modified Rankin Scale (mRS) score. Brain MRI measurement included acute infarcts and pre-existing abnormalities such as enlarged perivascular spaces, white matter lesions, ventricular-brain ratio, and medial temporal lobe atrophy (MTLA). The study included 324 men (73.1%) and 119 women (26.9%). In the univariate analysis, patients with poor participation after 1 year were older, more likely to be men, had higher National Institutes of Health Stroke Scale (NIHSS) score on admission, with more histories of hypertension and atrial fibrillation, larger infarct volume, more severely enlarged perivascular spaces and MTLA, and more severe periventricular hyperintensities and deep white matter hyperintensities. Patients with participation restriction also had poor activities of daily living (ADL) and mRS score. Multiple logistic regression showed that, in model 1, age, male gender, NIHSS score on admission, and ADL on follow-up were significant predictors of poor participation, accounting for 60.2% of the variance. In model 2, which included both clinical and MRI variables, male gender, NIHSS score on admission, ADL on follow-up, and MTLA were significant predictors of poor participation, accounting for 61.2% of the variance. Participation restriction was common after acute ischemic stroke despite good mRS score. Male gender, stroke severity, severity of ADL on follow-up, and MTLA may be predictors of poor participation.Trial registration numberChiCTR1800016665.

Intrahepatic cholangiocarcinoma (ICC) is the second most common liver cancer. Chemotherapy remains the main therapeutic strategy for advanced ICC patients, but chemosensitivity varies individually. Here, we applied cytometry by time-of-flight (CyTOF) to establish the immune profile of peripheral blood mononuclear cells (PBMCs) on the single-cell level at indicated time points before, during, and after chemotherapy. Multiplex immunofluorescence staining was applied to examine the spatial distribution of certain immune clusters. Tissue microarrays (TMAs) were used for prognostic evaluation. A total of 20 ICC patients treated with gemcitabine (GEM) were enrolled in our study, including eight cases with good response (R) and 12 cases with non-response (NR). Tremendous changes in PBMC composition, including an increased level of CD4/CD8 double-positive T cells (DPT), were observed after chemotherapy. Patients with higher level of CD4+CD45RO+CXCR3+T cells before treatment had a favorable response to chemotherapy. Our study identified a positive correlation between the percentage of T cell subpopulations and clinical response after chemotherapy, which suggests that it is practical to predict the potential response before treatment by evaluating the proportions of the cell population in PBMCs.

Effective mixing is crucial for enhancing the kinetics of chemical and biochemical processes. The synergistic effect on the properties of fabricated Fe3O4@MIL-100(Fe)-Au makes it conducive for the magnetic property to be harnessed as a nanostirrer to significantly enhance the kinetics of pathogen sequestration, colorimetric detection of H2O2, and the reduction of organic pollutants.

To ensure that vertical lifeline systems (VLLSs) are well designed, calculation methods are required to estimate the extension of a personal energy absorber (PEA) (xPEA) and the total fall distance (hTFD). Thus, the authors conducted 28 tests to validate the accuracy of the energy balance approach for estimating xPEAand hTFDof VLLSs and propose suitable correction factors to improve the accuracy and safety of the estimated xPEAand hTFD. For 9 out of 19 tests with a PEA, the difference between the theorical xPEAand empirical xPEAwas 25% or higher, indicating that the energy balance approach is not accurate for estimation of xPEA. In contrast, theoretical values of hTFDare more accurate. Linear regression equations for estimating xPEA(R2 = 0.81) and hTFD(R2 = 0.99) were developed. The regression equations can be used to improve the accuracy and conservativeness of estimations of xPEAand hTFDduring the design of VLLSs.

As a medicinal fungus, Inonotus obliquus (IO) has been widely used in the treatment of cancer and digestive system diseases. Despite the progress that has been made in the studies of IO and its active compounds, their applications in the treatment of other important clinical diseases, such as cardiovascular diseases, which are major global issues with limited treatment strategies, are seldom reported. This review summarizes the separation and purification methods of chemical components of IO, the advances in their applications, and research progress on the pharmacological effects and related mechanisms of IO in disease prevention. This review will help researchers and clinicians to further understand the pharmacological functions and mechanisms of IO and its active components, which may extend their medical applications in the prevention and treatment of other diseases in addition to tumors and digestive system diseases in the near future.

Reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) hold great promise for tumor treatment. However, hypoxia, insufficient H2O2, and overexpressed glutathione (GSH) in the tumor microenvironment (TME) hinder ROS generation significantly. Herein, we reported CaO2@Cu-TCPP/CUR with O2/H2O2/Ca2+self-supply and GSH depletion for enhanced PDT/CDT and Ca2+overload synergistic therapy. CaO2nanospheres were first prepared and used as templates for guiding the coordination between the carboxyl of tetra-(4-carboxyphenyl)porphine (TCPP) and Cu2+ions as hollow CaO2@Cu-TCPP, which facilitated GSH-activated TCPP-based PDT and Cu+-mediated CDT. The hollow structure was then loaded with curcumin (CUR) to form CaO2@Cu-TCPP/CUR composites. Cu-TCPP prevented degradation of CaO2, while Cu2+ions reacted with GSH to deplete GSH, produce Cu+ions, and release TCPP, CaO2, and CUR. CaO2reacted with H2O to generate O2, H2O2, and Ca2+to achieve O2/H2O2/Ca2+self-supply for TCPP-based PDT, Cu+-mediated CDT, and CUR-enhanced Ca2+overload therapy. Thus, this multilevel ROS amplifier enhances synergistic therapy with fewer side effects and drug resistance.

Lateral flow immunoassay (LFIA) has played a vital role in point-of-care (POC) testing on account of its simplicity, rapidity, and low cost. However, the low sensitivity and difficulty of quantitation limit its further development. Sensitive markers with new detection modes are being developed to dramatically improve LFIA’s performance. Herein, a ligand-complex approach was proposed to uniformly coat a thin layer of Au onto Ag triangular nanoplates (Ag TNPs) without etching the Ag cores, which not only retain the unique optical properties from Ag TNPs but also acquire the surface stability and biocompatibility of gold. The localized surface plasmon resonance absorption of these Ag@Au TNPs could be finely adjusted from visible (550 nm) to the second near-infrared region (NIR-II) (1100 nm), and even longer, by simply adjusting the ratio between edge length and thickness. Utilizing the Ag@Au TNPs as new markers for LFIA, a highly sensitive colorimetric and photothermal dual-mode detection of the SARS-CoV-2 nucleocapsid protein was achieved with a very low background. The Ag@Au TNPs showed an exceedingly high photothermal conversion efficiency of 61.4% (ca. 2 times higher than that of Au nanorods), endowing the LFIA method with a low photothermal detection limit (40 pg/mL), which was 25-fold lower than that of the colorimetric results. The generality of the method was further verified by the sensitive and accurate analysis of cardiac troponin I (cTnI). This method is robust, reproducible, and highly specific and has been successfully applied to SARS-COV-2 detection in 35 clinical samples with satisfactory results, demonstrating its potential for POC applications.

Asgard is a recently discovered superphylum of archaea that appears to include the closest archaeal relatives of eukaryotes1–5. Debate continues as to whether the archaeal ancestor of eukaryotes belongs within the Asgard superphylum or whether this ancestor is a sister group to all other archaea (that is, a two-domain versus a three-domain tree of life)6–8. Here we present a comparative analysis of 162 complete or nearly complete genomes of Asgard archaea, including 75 metagenome-assembled genomes that—to our knowledge—have not previously been reported. Our results substantially expand the phylogenetic diversity of Asgard and lead us to propose six additional phyla that include a deep branch that we have provisionally named Wukongarchaeota. Our phylogenomic analysis does not resolve unequivocally the evolutionary relationship between eukaryotes and Asgard archaea, but instead—depending on the choice of species and conserved genes used to build the phylogeny—supports either the origin of eukaryotes from within Asgard (as a sister group to the expanded Heimdallarchaeota–Wukongarchaeota branch) or a deeper branch for the eukaryote ancestor within archaea. Our comprehensive protein domain analysis using the 162 Asgard genomes results in a major expansion of the set of eukaryotic signature proteins. The Asgard eukaryotic signature proteins show variable phyletic distributions and domain architectures, which is suggestive of dynamic evolution through horizontal gene transfer, gene loss, gene duplication and domain shuffling. The phylogenomics of the Asgard archaea points to the accumulation of the components of the mobile archaeal ‘eukaryome’ in the archaeal ancestor of eukaryotes (within or outside Asgard) through extensive horizontal gene transfer.

The root of Paris polyphyllavar. yunnanensis, a famous and endangered traditional Chinese herb, has a significant medicinal value. The aim of this study was to analyze the composition and functional characteristics of bacterial endophytes in roots, stems, and leaves of P. polyphyllavar. yunnanensis. The 16S rRNA gene sequencing and functional prediction of bacterial endophytes in roots, stems, and leaves of P. polyphyllavar. yunnanensiswere conducted. The Chao and Shannon indices of the bacteria in roots were significantly higher than those in stems and leaves. The dominant endophyte phyla were Cyanobacteria, Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria. The main genera detected in roots were unclassified Cyanobacteria, Rhizobium, Flavobacterium, and Sphingobium; the main genera in stems were norank_c__Cyanobacteria, Bacillus, and Pseudomonas; the main genera in leaves were norank_c__Cyanobacteriaand Rhizobium. The microbiota in roots was particularly enriched in functional categories “extracellular structures” and “cytoskeleton” compared with stems and leaves (p< 0.05). Our study reveals the structural and functional characteristics of the endophytic bacteria in roots, stems, and leaves of P. polyphyllavar. yunnanensis, which aids in the scientific understanding of this plant.

ABSTRACTA new isoflavone derivative compound 1(psoralenone) was isolated from soybean inoculated with a marine fungus Aspergillus terreusC23-3, together with seven known compounds including isoflavones 2–6, butyrolactone I (7) and blumenol A (8). Their structures were elucidated by MS, NMR, and ECD. Psoralenone displayed moderate in vitroanti-inflammatory activity in the LPS-induced RAW264.7 cell model. Compound 2(genistein) showed moderate acetylcholinesterase (AChE) inhibitory activity whereas compounds 2, 5(biochanin A), 6(psoralenol), and 7exhibited potent larvicidal activity against brine shrimp. Compounds 3(daidzein), 4(4ʹ-hydroxy-6,7-dimethoxyisoflavone), and 5–7showed broad-spectrum anti-microbial activity, and compound 7also showed moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity.

Colorectal cancer (CRC) is the third most common type of cancer. In recent decades, genomic analysis has played an increasingly important role in understanding the molecular mechanisms of CRC. However, its pathogenesis has not been fully uncovered. Identification of genes related to CRC as complete as possible is an important way to investigate its pathogenesis. Therefore, we proposed a new computational method for the identification of novel CRC-associated genes. The proposed method is based on existing proven CRC-associated genes, human protein–protein interaction networks, and random walk with restart algorithm. The utility of the method is indicated by comparing it to the methods based on Guilt-by-association or shortest path algorithm. Using the proposed method, we successfully identified 298 novel CRC-associated genes. Previous studies have validated the involvement of the majority of these 298 novel genes in CRC-associated biological processes, thus suggesting the efficacy and accuracy of our method.

Recently, although ginseng (Panax ginsengC. A. Meyer) and its main component saponins (ginsenosides) have been reported to exert protective effects on cisplatin (CDDP)-induced acute kidney injury (AKI), the beneficial activities of non-saponin on CDDP-induced AKI is little known. This research was designed to explore the protective effect and underlying mechanism of arginyl-fructosyl-glucose (AFG), a major and representative non-saponin component generated during the process of red ginseng, on CDDP-caused AKI. AFG at doses of 40 and 80 mg/kg remarkably reversed CDDP-induced renal dysfunction, accompanied by the decreased levels of serum creatinine and blood urea nitrogen. Interestingly, all of oxidative stress indices were ameliorated after pretreatment with AFG continuously for 10 days. Importantly, AFG relieved CDDP-induced inflammation and apoptosis in part by mitigating the cascade initiation steps of nuclear factor κB signals and regulating the participation of the phosphatidylinositol 3-kinase/protein kinase B signal pathway. In conclusion, these results clearly provide strong rationale for the development of AFG to prevent CDDP-induced AKI.

A tissue engineering model of heart valve calcification induced in a bioreactor was established to evaluate the calcification induced by abnormal mechanical stimulation and explore the underlying molecular mechanisms. Polyethylene glycol (PEG)-modified decellularized porcine aortic leaflets seeded with human valve interstitial cells (huVICs) were mounted on a Ti-Ni alloy frame to fabricate two-leaflet and threeleaflet tissue engineered valves. The two-leaflet model valves were exposed to abnormal pulsatile flow stimulation with null (group A), low (1000 mL/min, group B), medium (2000 mL/min, group C), and high velocity (3000 mL/min, group D) for 14 days. Morphology and calcification were assessed by von Kossa staining, alkaline phosphatase (ALP) content, and Runx2 immunostaining. Leaflet calcification and mRNA and protein expression of transforming growth factor (TGF)-β1, bone morphogenetic protein 2 (BMP2), Smad1, and MSX2 were measured at different time points. ALP content was examined in two-leaflet valves seeded with BMP2 shRNA plasmid-infected huVICs and exposed to the same stimulation conditions. The results showed that during 14 days of flow stimulation, huVICs on the leaflet surface proliferated to generate normal monolayer coverage in groups A, B, and C. Under mechanical stimulation, huVICs showed a parallel growth pattern in the direction of the fluid flow, but huVICs exhibited disordered growth in the high-velocity flow environment. von Kossa staining, ALP measurement, and immunohistochemical staining for Runx2 confirmed the lack of obvious calcification in group A and significant calcification in group D. Expression levels of TGF-β1, BMP2, and MSX2 mRNA and protein were increased under fluid stimulation. ALP production by BMP2 shRNA plasmid-infected huVICs on model leaflets was significantly reduced. In conclusion, abnormal mechanical stimulation in a bioreactor induced calcification in the tissue engineering valve model. The extent of calcification correlated positively with the flow velocity, as did the mRNA and protein levels of TGF-β1, BMP2, and MSX2. These findings indicate that TGF-β1/BMP2 signaling is involved in valve calcification induced by abnormal mechanical stimulation.

Background: Pre-treated patients with first-line treatment can be offered a second treatment with the aim of improving their poor clinical prognosis. The therapy of metastatic colorectal cancer (CRC) patients who did not respond to first-line therapy has limited treatment options. Recently, many studies have paid much attention to the efficacy of bevacizumab as an adjuvant treatment for metastatic colorectal cancer. Objectives: We aimed to evaluate the efficacy and toxicity of bevacizumab plus chemotherapy compared with bevacizumab-naive based chemotherapy as second-line treatment in people with metastatic CRC. Methods: Electronic databases were searched for eligible studies updated to March 2018. Randomized-controlled trials comparing addition of bevacizumab to chemotherapy without bevacizumab in MCRC patients were included, of which, the main interesting results were the efficacy and safety profiles of the addition of bevacizumab in patients with MCRC as second-line therapy. Result: Five trials were eligible in the meta-analysis. Patients who received the combined bevacizumab and chemotherapy treatment in MCRC as second-line therapy showed a longer overall survival (OS) (OR=0.80,95%CI=0.72-0.89, P<0.0001) and progression-free survival (PFS) (OR=0.69,95%CI=0.61-0.77, P<0.00001). In addition, there was no significant difference in objective response rate (ORR) (RR=1.36,95%CI=0.82-2.24, P=0.23) or severe adverse event (SAE) (RR=1.02,95%CI=0.88-1.19, P=0.78) between bevacizumab-based chemotherapy and bevacizumabnaive based chemotherapy. Conclusion: Our results suggest that the addition of bevacizumab to the chemotherapy therapy could be an efficient and safe treatment option for patients with metastatic colorectal cancer as second-line therapy and without increasing the risk of an adverse event.