Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia:randomized trials and multiomics analysis

Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).

Banxia xiexin decoction prevents the development of gastric cancer

BACKGROUND In China banxia xiexin decoction(BXD)has been used in treating gastric cancer(GC)for thousands of years and BXD has a good role in reversing GC histopathology,but its chemical composition and action mechanism are still unknown.AIM To investigate the mechanism of action of BXD against GC based on transcriptomics,network pharmacology,in vivo and in vitro experiments.METHODS The transplanted tumor model was prepared,and the nude mouse were pathologically examined after administration,and hematoxylin-eosin staining was performed.The active ingredients of BXD were quality controlled and identified using ultra-performance liquid chromatography tandem quadrupole electrostatic field orbitrap mass spectrometry(UPLC-Q-Orbitrap MS/MS),and traditional Chinese medicines systems pharmacology platform,drug bank and the Swiss target prediction platform to predict the relevant targets,the differentially expressed genes(DEGs)of GC were screened by RNA-seq sequencing,and the overlapping targets were analyzed to obtain the key targets and pathways.Cell Counting Kit-8,apoptosis assay,cell migration and Realtime fluorescence quantitative polymerase chain reaction were used for in vitro experiments.RESULTS All dosing groups inhibited the growth of transplanted tumors in laboratory-bred strain nude,with the capecitabine group and the BXD medium-dose group being the best.A total of 29 compounds and 859 potential targets in BXD were identified by UPLC-Q-Orbitrap MS/MS and network pharmacology,RNA-seq sequencing found 4767 GC DEGs,which were combined with network pharmacology and analyzed 246 potential therapeutic targets were obtained and pathway results showed that BXD may against GC through the Phosphoinositide 3-kinase(PI3K)/protein kinase B(AKt)signaling pathway.In vitro cellular experiments confirmed that BXDcontaining serum and LY294002 could inhibit the proliferation of GC cells,promote apoptosis,and inhibit the migration of GC cells by decreasing the expression of EGFR,PIK3CA,IL6,BCL2 and AKT1 in the PI3K-Akt pathway in MGC-803 expression.CONCLUSION BXD has the effect of inhibiting tumor growth rate and delaying the development of GC.Its mechanism of action may be related to the regulation of PI3K-Akt signaling pathway.

Effect of Ti and Al on microstructure and partitioning behavior of alloying elements in Ni-based powder metallurgy superalloys

The microstructure and partitioning behaviors of alloying elements in the γ and γ′ phases in Ni-based powder metallurgy superalloys with different Ti and Al contents were investigated. The results showed that Ti and Al were mainly enriched in the γ′ phase, partially partitioned in the γ matrix, and slightly distributed in the carbides. Different Ti and Al contents in various alloys influenced the composition and amount of MC carbides but did not influence the MC carbides' morphology. With increasing Ti and Al contents, γ + γ′ fan-type structures formed at the grain boundary, eventually resulting in a coarsened γ′ phase. In addition, the morphology of the secondary γ′ phase transformed from nearly spherical to cuboidal. The saturation degrees of Cr, Co, and Mo in the γ matrix were substantially improved with increasing Ti and Al contents.

Oxidation behavior of Ni-based superalloy GH4738 under tensile stress

Revealing the oxidation behavior of superalloys is crucial for optimizing material properties and extending service life.This study investigated the oxidation behavior of superalloy GH4738 under stress states at 850℃.High-throughput specimens were fabricated to withstand different stresses at the same time.Isothermal oxidation s amples were analyzed using the mass gain method to obtain oxidation kinetic curves.The results show that the external stress below 200 MPa could improve the oxidation resistance of the GH4738.With tensile stress increasing,the oxide layer becomes thinner,denser and more complete,while internal oxidation decreases.The tensile stress alters the structure of the external oxide layer from a two-layer to a threelayer configuration.The Cr_(2)O_(3) oxide layer inhibits the outward diffusion of Ti,leading to Ti enrichment at the oxide-matrix interface and altering the oxidation mechanism of GH4738.

Patterning of Triblock Copolymer Film and Its Application for Surface-enhanced Raman Scattering

In this paper, microphase behavior of an ABC triblock copolymer, polystyrene-block-poly（2-vinylpyridine）-block- poly（ethylene oxide）, namely PS-b-P2VP-b-PEO, was systematically studied during spin-coating and solvent vapor annealing based on various parameters, including the types of the solvent, spin speed and thickness. The morphological features and the microdomain location of the different blocks were characterized by atomic force microscope （AFM） and high resolution transmission electron microscopy （HRTEM）. With increasing thickness, the order-order transition from nanopores array to the pattern of nanostripes was observed due to microdomain coarsening. These processes of pattern transformation were based on the selectivity of toluene for different blocks and on the contact time between solvent molecules and the three blocks. This work provides different templates for preparation of gold nanoparticle array on silicon wafer, which can be adopted as an active surface-enhanced Raman scattering （SERS） substrate for poly（3-hexylthiophene） （P3HT）.

Surface-enhanced Raman Scattering Effect of Ordered Gold Nanoparticle Array for Rhodamine B with Different Morphologies

In this study, well-ordered gold nanoparticle array on silicon substrate was adopted as an active surface-enhanced Raman scattering substrate for detecting rhodamine B （RB）, and the influence of RB morphologies on surface-enhanced Raman scattering （SERS） properties was discussed. The Au nanoparticle array was prepared by using patterned P4VP nanodomains of poly（styrene-b-4-vinylpyridine） （PS-b-P4VP） diblock copolymer thin films as nanoreactors which is a simple and economical approach. The results show that Raman spectra of RB on the Au nanopaticle array have much stronger intensity than those on the bare silicon substrate by detecting same RB solution. It indicates that the prepared Au nanoparticle array on silicon substrate has a significant Raman enhancement for RB. Interestingly, the Raman intensity of RB from its ethanol solution is much stronger than that from its aqueous solution due to the special morphologies of RB formed in their ethanol solutions. This work provides an effective approach to prepare highly sensitive and stable surface-enhanced Raman scattering substrate.

A high-throughput strategy for rapid synthesis and characterization of Ni-based superalloys

This study developed a new high-throughput strategy,designated as hot-isostatic-pres sing-based microsynthesis approach(HIP-MSA),to optimize high-performance nickel-based superalloys in a rapid,efficient,and cost-effective manner.A specific honeycomb-array structure containing 106 discrete cells was designed and optimized using finite element analysis(FEA)and then applied to create a combinatorial library consisting of 106 Ni-based superalloys with various Co,Nb and Ta concentrations.By integration with high-throughput characterization tools,extensive composition and phase structure data were collected quickly and efficiently.In the superalloys with higher amounts of Nb and Ta,the detrimentalηphase displaying needle-like morphology was observed,and its content(wt%)increased drastically with Ta and Nb contents increasing.However,the increase of Co addition in those alloys was confirmed to be surprisingly beneficial by significantly suppressing the formation ofηphase that was induced by high Nb and Ta contents.The zero-phasefraction(ZPF)line ofηphase was established,which is critical to design superalloy chemistry for superior micros tructural stability at high-temperature service conditions.