Estimating selection models without instrument with Stata

Ministry of Education, Singapore under its Academic Research Funding Tier

Targeting p53 via JNK Pathway: A Novel Role of RITA for Apoptotic Signaling in Multiple Myeloma

The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK) signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP) analysis showed that activated c-Jun binds to the activator protein-1 (AP-1) binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA) against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with JNK activators in the treatment of MM

Interactions of arsenic, copper, and zinc in soil-plant system:Partition, uptake and phytotoxicity

Arsenic, copper, and zinc are common elements found in contaminated soils but little is known about their combined effects on plants when presented simultaneously. Here, we systematically investigated the phytotoxicity and uptake of binary and ternary mixtures of As, Cu, and Zn in a soil-plant system, using wheat (Triticum aestivum) as model species. The reference models of concentration addition (CA) and response addition (RA) coupled with different expressions of exposure (total concentrations in soil ([M]tot, mg/kg), free ion activities in soil solution ({M}, μM), and internal concentrations in plant roots ([M]int, μg/g)), were selected to assess the interaction mechanisms of binary mixtures of As–Cu, As–Zn, and Cu–Zn. Metal(loid) interactions in soil were estimated in terms of solution-solid partitioning, root uptake, and root elongation effects. The partitioning of one metal(loid) between the soil solution and solid phase was most often inhibited by the presence of the other metal(loid). In terms of uptake, inhibitory effects and no effects were observed in the mixtures of As, Cu, and Zn, depending on the mixture combinations and the dose metrics used. In terms of toxicity, simple (antagonistic or synergistic) and more complex (dose ratio-dependent or dose level-dependent) interaction patterns of binary mixtures occurred, depending on the dose metrics selected and the reference models used. For ternary mixtures (As-Cu-Zn), nearly additive effects were observed irrespective of dose descriptors and reference models. The observed interactions in this study may help to understand and predict the joint toxicity of metal(loid)s mixtures in soil-plant system. Mixture interactions and bioavailability should be incorporated into the regulatory framework for accurate risk assessment of multimetal-contaminated sites

Sweetpotato bZIP Transcription Factor IbABF4 Confers Tolerance to Multiple Abiotic Stresses

The abscisic acid (ABA)-responsive element binding factors (ABFs) play important regulatory roles in multiple abiotic stresses responses. However, information on the stress tolerance functions of ABF genes in sweetpotato (Ipomoea batatas [L.] Lam) remains limited. In the present study, we isolated and functionally characterized the sweetpotato IbABF4 gene, which encodes an abiotic stress-inducible basic leucine zipper (bZIP) transcription factor. Sequence analysis showed that the IbABF4 protein contains a typical bZIP domain and five conserved Ser/Thr kinase phosphorylation sites (RXXS/T). The IbABF4 gene was constitutively expressed in leaf, petiole, stem, and root, with the highest expression in storage root body. Expression of IbABF4 was induced by ABA and several environmental stresses including drought, salt, and heat shock. The IbABF4 protein localized to the nucleus, exhibited transcriptional activation activity, and showed binding to the cis-acting ABA-responsive element (ABRE) in vitro. Overexpression of IbABF4 in Arabidopsis thaliana not only increased ABA sensitivity but also enhanced drought and salt stress tolerance. Furthermore, transgenic sweetpotato plants (hereafter referred to as SA plants) overexpressing IbABF4, generated in this study, exhibited increased tolerance to drought, salt, and oxidative stresses on the whole plant level. This phenotype was associated with higher photosynthetic efficiency and lower malondialdehyde and hydrogen peroxide content. Levels of endogenous ABA content and ABA/stress-responsive gene expression were significantly upregulated in transgenic Arabidopsis and sweetpotato plants compared with wild-type plants under drought stress. Our results suggest that the expression of IbABF4 in Arabidopsis and sweetpotato enhances tolerance to multiple abiotic stresses through the ABA signaling pathway

Efficacy and safety of olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a systematic review and meta-analysis of randomized controlled trials

BackgroundOlaparib has been proven for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This meta-analysis aims to comprehensively evaluate the efficacy and safety of the combination of olaparib and abiraterone in patients with mCRPC.MethodsThe literature in PubMed, Embase, and Cochrane Library up until April 27, 2023, was systematically searched. In the studies included in this meta-analysis, olaparib combined with abiraterone was compared with abiraterone combined with placebo.ResultsTwo randomized controlled trials involving a total of 938 patients were included. Analysis indicated that olaparib combined with abiraterone significantly prolonged radiographic progression-free survival (rPFS: relative risk [RR] 0.66, 95% confidence interval [CI] 0.55–0.79), time to secondary progression or death (PFS2: hazard ratio [HR] 0.72, 95% CI 0.56–0.93), time to first subsequent therapy or death (TFST: HR 0.75, 95% CI 0.63–0.89), time to second subsequent therapy or death (TSST: HR 0.73, 95% CI 0.58–0.93), and confirmed prostate-specific antigen (PSA) response (RR 1.14, 95% CI 1.05–1.24). However, no statistically significant differences were found in the overall survival (OS: HR 0.87 95% CI 0.70–1.09), objective response rate (ORR: RR 0.97, 95% CI 0.70–1.33), and incidence of total adverse events (RR 1.07, 95% CI 0.94–1.22). A notable detail that the combination of olaparib and abiraterone was associated with an increased incidence of high-grade anemia (RR 7.47, 95% CI 1.36–40.88).ConclusionOlaparib combined with abiraterone is effective for patients with mCRPC. However, combination therapy has treatment-related adverse events compared with monotherapy, and this could be improved in future treatment management.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023432287

Study on the preparation process of quinoa anti-hypertensive peptide and its stability

Quinoa seeds are a food resource rich in protein, vitamins, minerals, and other functional components such as polyphenols, polysaccharides, and saponins. The seeds have become favored by modern consumers due to being gluten-free and featuring a high protein content. This study focused on the preparation of quinoa peptides by short-time enzymatic-assisted fermentation. Quinoa flour (QF) was mixed with water in a certain ratio before being enzymatically digested with 0.5% amylase and 0.1% lipase for 6 h. Then, 16 bacterial taxa were used for fermentation, respectively. The peptide content in the resulting fermentation broths were determined by the biuret method. The dominant taxon was then identified and the peptide content, amino acid distribution, and molecular weight distribution of the prepared quinoa peptides were analyzed. Further, the temperature, pH, metal ions, organic solvents, ion concentration, and anti-enzyme stability of the quinoa anti-hypertensive peptides of different molecular weights after fermentation with the dominant taxon were investigated. Finally, the inhibitory activity of fermented quinoa peptides on bacteria was studied. The results show that the peptide content of the fermentation broth reached 58.72 ± 1.3% at 40 h of fermentation with Lactobacillus paracasei and the molecular weights of the hydrolyzed quinoa peptides were mainly distributed below 2 kDa by polyacrylamide gel. The Angiotensin Converting Enzyme (ACE) inhibition and peptide retention of the 0–3 kDa quinoa peptides were screened to be high and stable. At the same time, the inhibitory activity of quinoa peptide after fermentation on E. coli was obvious. This study provides a theoretical basis for further research on quinoa peptide and its application in industrial production, and also lays a foundation for the later application of polypeptides in new food and chemical products

Evolutionary origin of genomic structural variations in domestic yaks

Yak has been subject to natural selection, human domestication and interspecific introgression during its evolution. However, genetic variants favored by each of these processes have not been distinguished previously. We constructed a graph-genome for 47 genomes of 7 cross-fertile bovine species. This allowed detection of 57,432 high-resolution structural variants (SVs) within and across the species, which were genotyped in 386 individuals. We distinguished the evolutionary origins of diverse SVs in domestic yaks by phylogenetic analyses. We further identified 334 genes overlapping with SVs in domestic yaks that bore potential signals of selection from wild yaks, plus an additional 686 genes introgressed from cattle. Nearly 90% of the domestic yaks were introgressed by cattle. Introgression of an SV spanning the KIT gene triggered the breeding of white domestic yaks. We validated a significant association of the selected stratified SVs with gene expression, which contributes to phenotypic variations. Our results highlight that SVs of different origins contribute to the phenotypic diversity of domestic yaks

A Myb Transcription Factor of Phytophthora sojae, Regulated by MAP Kinase PsSAK1, Is Required for Zoospore Development

PsSAK1, a mitogen-activated protein (MAP) kinase from Phytophthora sojae, plays an important role in host infection and zoospore viability. However, the downstream mechanism of PsSAK1 remains unclear. In this study, the 3'-tag digital gene expression (DGE) profiling method was applied to sequence the global transcriptional sequence of PsSAK1-silenced mutants during the cysts stage and 1.5 h after inoculation onto susceptible soybean leaf tissues. Compared with the gene expression levels of the recipient P. sojae strain, several candidates of Myb family were differentially expressed (up or down) in response to the loss of PsSAK1, including of a R2R3-type Myb transcription factor, PsMYB1. qRT-PCR indicated that the transcriptional level of PsMYB1 decreased due to PsSAK1 silencing. The transcriptional level of PsMYB1 increased during sporulating hyphae, in germinated cysts, and early infection. Silencing of PsMYB1 results in three phenotypes: a) no cleavage of the cytoplasm into uninucleate zoospores or release of normal zoospores, b) direct germination of sporangia, and c) afunction in zoospore-mediated plant infection. Our data indicate that the PsMYB1 transcription factor functions downstream of MAP kinase PsSAK1 and is required for zoospore development of P. sojae