Exploring a specialized programmed-cell death patterns to predict the prognosis and sensitivity of immunotherapy in cutaneous melanoma via machine learning.

The mortality and therapeutic failure in cutaneous melanoma (CM) are mainly caused by wide metastasis and chemotherapy resistance. Meanwhile, immunotherapy is considered a crucial therapy strategy for CM patients. However, the efficiency of currently available methods and biomarkers in predicting the response of immunotherapy and prognosis of CM is limited. Programmed cell death (PCD) plays a significant role in the occurrence, development, and therapy of various malignant tumors. In this research, we integrated fourteen types of PCD, multi-omics data from TCGA-SKCM and other cohorts in GEO, and clinical CM patients to develop our analysis. Based on significant PCD patterns, two PCD-related CM clusters with different prognosis, tumor microenvironment (TME), and response to immunotherapy were identified. Subsequently, seven PCD-related features, especially CD28, CYP1B1, JAK3, LAMP3, SFN, STAT4, and TRAF1, were utilized to establish the prognostic signature, namely cell death index (CDI). CDI accurately predicted the response to immunotherapy in both CM and other cancers. A nomogram with potential superior predictive ability was constructed, and potential drugs targeting CM patients with specific CDI have also been identified. Given all the above, a novel CDI gene signature was indicated to predict the prognosis and exploit precision therapeutic strategies of CM patients, providing unique opportunities for clinical intelligence and new management methods for the therapy of CM.

Age at menarche and metabolic dysfunction-associated fatty liver disease: Evidence from a large population-based epidemiological study in Southwest China.

BACKGROUND: The relationship between age at menarche and metabolic dysfunction-associated fatty liver disease remains largely not clear. The objective of this study was to examine the association between age at menarche (AAM) and metabolic dysfunction-associated fatty liver disease (MAFLD) in Chinese women and whether any observed associations were mediated by early adulthood adiposity. METHODS: The cross-sectional study included 46,873 Chinese women, aged 30-79 from baseline data of the China Multi-Ethnic Cohort study. Logistic regression models were used to evaluate the association between AAM and MAFLD. Mediation analysis was adopted to examine whether early adulthood adiposity (around 25 years) mediated the association between AAM and MAFLD. RESULTS: AAM was linearly and inversely associated with the risk of MAFLD (P for nonlinearity =0.743). In a multivariable-adjusted model, the odds ratios and 95% confidence interval (ORs (95% CI)) for MAFLD comparing menarche at <12, 12, 13, 15, 16, 17, ≥18 years to menarche at 14 years were 1.290 (1.082-1.537), 1.172 (1.068-1.285), 1.042 (0.960-1.131), 0.937 (0.861-1.020), 0.911(0.835-0.994), 0.868 (0.786-0.959), and 0.738 (0.670-0.814), respectively (P for trend <0.001). The 6.4% increased MAFLD risk was associated with each preceding year in AAM. The association between AAM and MAFLD was modified by age, ethnicity, and menopause. Early adulthood adiposity partially mediated this association. CONCLUSION: The findings of this study suggest that obesity prevention strategies are needed from young adulthood in women who undergo early menarche to reduce the risk of MAFLD.

Association of major dietary patterns and different obesity phenotypes in Southwest China: the China Multi-Ethnic Cohort (CMEC) Study.

PURPOSE: Dietary behavior is an important part of lifestyle interventions for obesity and its cardiovascular comorbidities. However, little is known about associations between dietary patterns and obesity phenotypes in Southwest China, a region with unique dietary patterns and significant heterogeneity in obesity. METHODS: Data from the baseline survey of the China Multi-Ethnic Cohort in Southwest China were analyzed (n = 64,448). Dietary intakes during the past year were measured with the semi-quantitative Food Frequency Questionnaire (s-FFQ). Principal component factor analysis (PCFA) was used to identify dietary patterns. Multinomial logistic regressions were used to examine the associations between dietary patterns and obesity phenotypes and stratified analyses were performed to assess whether the associations differed across demographic variables. RESULTS: Three dietary patterns were identified and then named according to their apparent regional gathering characteristics: the Sichuan Basin dietary pattern (characterized by high intakes of various foods), the Yunnan-Guizhou Plateau dietary pattern (characterized by agricultural lifestyles), and the Qinghai-Tibet Plateau dietary pattern (characterized by animal husbandry lifestyles), respectively. Higher adherence to the Sichuan Basin dietary pattern was positively associated with metabolically healthy overweight/obesity (MHO, OR 1.13, 95% CI 1.05-1.21) but negatively associated with metabolically unhealthy normal weight (MUNW, OR 0.78, 95% CI 0.65-0.95). Higher adherence to the other two dietary patterns was positively associated with MHO and metabolically unhealthy overweight/obesity (MUO). Besides, differences in socioeconomic status also affected the relationship between dietary patterns and obesity phenotypes. CONCLUSIONS: Adherence to the more diverse Sichuan basin dietary pattern performed a mixed picture, while the other two may increase the risk of obesity phenotypes, which indicates nutritional interventions are urgently needed.

Influences of microRNA-451 on the expression of HMGB1 in myocardial cells and its mechanism in ischemia-reperfusion injury.

This work aimed to understand the underlying mechanism of micro-ribonucleic acid (MicroRNA) (miR)-451 in ischemia-reperfusion injury (IRI) and the influences of miR-451 on high mobility group box 1 protein (HMGB1) in myocardial cells, 30 specific pathogen-free (SPF) male rats were selected and randomly rolled into 5 groups, which were a sham operation control (Control), an ischemia-reperfusion (I/R), aI/R+Ad-GFP, amiR-451 up-regulation (I/R+Ad-miR-451), and a miR-451 down-regulation groups (I/R+Ad-asmiR-451). There were 6 cases in each group. Myocardial cell apoptosis, the contents of serum lactic acid dehydrogenase (LDH), creatine kinase (CK), and malondialdehyde (MDA), the activity of superoxide dismutase (SOD), and the expressions of miR-451 and HMGB1mRNA were detected. Relative to those in I/R and I/R+Ad-GFP groups, the expressions of CD3+, CD4+, and CD4+/ CD8+ in I/R+Ad-miR-451 group reduced (P<0.05). The expressions of serum LDH and CK decreased (P<0.05). In contrast, MDA content and SOD activity enhanced (P<0.05). HMGB1 and Cleaved-caspase3 declined (P<0.05). Besides, miR-451 improved while the expression of HMGB1mRNA significantly reduced (P<0.05). miR-451 can regulate the expressions of HMGB1mRNA and its protein at the transcriptional level. miR-451 up-regulation can inhibit HMGB1 expression, relieve IRI, and protect myocardial cells, which may be achieved by improving oxidative stress injury and inhibiting cell apoptosis.

The metabolomic landscape of rice heterosis highlights pathway biomarkers for predicting complex phenotypes.

Understanding the molecular mechanisms underlying complex phenotypes requires systematic analyses of complicated metabolic networks and contributes to improvements in the breeding efficiency of staple cereal crops and diagnostic accuracy for human diseases. Here, we selected rice (Oryza sativa) heterosis as a complex phenotype and investigated the mechanisms of both vegetative and reproductive traits using an untargeted metabolomics strategy. Heterosis-associated analytes were identified, and the overlapping analytes were shown to underlie the association patterns for six agronomic traits. The heterosis-associated analytes of four yield components and plant height collectively contributed to yield heterosis, and the degree of contribution differed among the five traits. We performed dysregulated network analyses of the high- and low-better parent heterosis hybrids and found multiple types of metabolic pathways involved in heterosis. The metabolite levels of the significantly enriched pathways (especially those from amino acid and carbohydrate metabolism) were predictive of yield heterosis (area under the curve = 0.907 with 10 features), and the predictability of these pathway biomarkers was validated with hybrids across environments and populations. Our findings elucidate the metabolomic landscape of rice heterosis and highlight the potential application of pathway biomarkers in achieving accurate predictions of complex phenotypes.

Association of Daytime Napping with chronic diseases among Tibetan people in China: a cross-sectional study.

BACKGROUND: Obesity, diabetes, and hypertension, as three of the most prevalent chronic diseases, remain a daunting health challenge. However, to our knowledge, no study has made a thorough examination of the association between the three chronic diseases and daytime napping, a widely accepted behavior in many countries. This is especially necessary among Tibetan populations, whose lifestyles and health outcomes may be unique, yet patterns of chronic diseases and napping are under-examined. Thus, we sought to explore the aforementioned association in the Tibetan population of China. METHODS: A total of 2902 participants aged 45-79 in 2019 were included. Multivariate logistic regressions were conducted in 2020. The sex disparity was examined through interaction and stratified analyses. RESULTS: Hypertension (40.7%) was more prevalent than obesity (20.2%) and diabetes (21.6%). Comparing to non-nappers, those who napped were more likely to have any conditions (OR = 1.30, 95% CI = 1.04-1.62 for 1-59 min/day group and OR = 1.40, 95% CI = 1.10-1.80 for ≥60 min/day group). Participants who had 1-59 min/day of napping were more likely to develop obesity (OR = 1.37, 95% CI = 1.07-1.75), and ≥ 60 min/day of napping was associated with diabetes (OR = 1.33, 95% CI = 1.01-1.74). The interactions between napping and sex were not statistically significant in the models. CONCLUSIONS: The study revealed napping was unfavorably associated with obesity, diabetes, and any conditions in Tibetan people living on the Tibetan Plateau. Future interventions regarding the three chronic diseases may pay more attention to napping. TRIAL REGISTRATION: Not applicable.

Determinants of self-rated health among an older Tibetan population in a Chinese plateau area: analysis based on the conceptual framework for determinants of health.

BACKGROUND: Self-rated health (SRH) has been frequently used in population health surveys. However, most of these studies only focus on specific factors that might directly affect SRH, so only partial or confounding information about the determinants of SRH is potentially obtained. Conducted in an older Tibetan population in a Chinese plateau area, the aim of our study is to assess interrelationships between various factors affecting SRH based on the conceptual framework for determinants of health. METHODS: Between May 2018 and September 2019, 2707 Tibetans aged 50 years or older were recruited as part of the China Multi-Ethnic Cohort Study (CMEC) from the Chengguan District of Lhasa city in Tibet. The information included SRH and variables based on the conceptual framework for determinants of health (i.e., socioeconomic status, health behaviors, physical health, mental health, and chronic diseases). Structural equation modeling (SEM) was used to estimate the direct and indirect effects of multiple factors in the conceptual framework. RESULTS: Among all participants, 5.54% rated their health excellent, 51.16% very good, 33.58% good, 9.12% fairly poor and 0.59% poor. Physical health (ß = - 0.23, P <  0.001), health behaviors (ß = - 0.44, P <  0.001), socioeconomic status (ß = - 0.29, P <  0.001), chronic diseases (ß = - 0.32, P <  0.001) and gender (ß = 0.19, P <  0.001) were directly associated with SRH. Socioeconomic status, physical health and gender affected SRH both directly and indirectly. In addition, there are potential complete mediator effects in which age and mental health affect SRH through mediators, such as physical health, health behaviors and chronic diseases. CONCLUSIONS: The findings suggested that interventions targeting behavioral changes, health and chronic disease management should be attached to improve SRH among older populations in plateau areas without ignoring gender and socioeconomic disparities.

Extracellular ATP Shapes a Defense-Related Transcriptome Both Independently and along with Other Defense Signaling Pathways.

ATP is not only an essential metabolite of cellular biochemistry but also acts as a signal in the extracellular milieu. In plants, extracellular ATP is monitored by the purinergic receptor P2K1. Recent studies have revealed that extracellular ATP acts as a damage-associated molecular pattern in plants, and its signaling through P2K1 is important for mounting an effective defense response against various pathogenic microorganisms. Biotrophic and necrotrophic pathogens attack plants using different strategies, to which plants respond accordingly with salicylate-based or jasmonate/ethylene-based defensive signaling, respectively. Interestingly, defense mediated by P2K1 is effective against pathogens of both lifestyles, raising the question of the level of interplay between extracellular ATP signaling and that of jasmonate, ethylene, and salicylate. To address this issue, we analyzed ATP-induced transcriptomes in wild-type Arabidopsis (Arabidopsis thaliana) seedlings and mutant seedlings defective in essential components in the signaling pathways of jasmonate, ethylene, and salicylate (classic defense hormones) as well as a mutant and an overexpression line of the P2K1 receptor. We found that P2K1 function is crucial for faithful ATP-induced transcriptional changes and that a subset of genes is more responsive in the P2K1 overexpression line. We also found that more than half of the ATP-responsive genes required signaling by one or more of the pathways for the classical defense hormones, with the jasmonate-based signaling being more critical than others. By contrast, the other ATP-responsive genes were unaffected by deficiencies in signaling for any of the classical defense hormones. These ATP-responsive genes were highly enriched for defense-related Gene Ontology terms. We further tested the ATP-induced genes in knockout mutants of transcription factors, demonstrating that MYCs acting downstream of the jasmonate receptor complex and calmodulin-binding transcription activators are nuclear transducers of P2K1-mediated extracellular ATP signaling.

Knowledge, attitudes and practices regarding echinococcosis in Xizang Autonomous Region, China.

BACKGROUND: Echinococcosis is a neglected zoonotic parasitic disease caused echinococcus parasitizes, poseing a significant economic burden on both humans and animals. There are limited studies on echinococcosis in China, especially Xizang Autonomous Region, although the area is endemic area for echinococcosis. The study aimed to provide information for strategic prevention against this disease. METHODS: A cross-sectional survey was conducted among the residents in Xizang Autonomous Region, China to evaluate their knowledge, attitudes and practices on endemicity of echinococcosis. A face-to-face survey was conducted to collect the data using a well-designed questionnaire. The contents included basic personal information, knowledge, attitudes and practices about echinococcosis, personal hygiene and behavior habits, dog feeding and whether they had received the information on echinococcosis, and so on. We surveyed 840 persons in practice. All data analysis was performed using Epi Info 7.2. RESULTS: Of the total particpants, 86.8% had a primary education level or below (including primary and illiterate), and even 45.0% were illiterate. Farmers and herdsmen represent the main occupations in this study. People who know all the echinococcosis-related knowledge in the questionnaire only accounted for 8.7% of the participants. However, none of the participants was aware of routes of echinococcosis infection in human or dogs. The data showed participants with higher educational background had the high awareness rate of echinococcosis-related knowledge or attitudes (chi-square for trend, χ2 = 21.23, p<0.05 & χ2 = 48.43, p<0.05). In addition, The percentage of the participant with awareness of echinococcosis-related practices was associated with their age and principle occupation (χ2 = 52.72, p<0.05 & χ2 = 20.63, p<0.05). CONCLUSIONS: Xizang Autonomous Region is an epidemic area of Echinococcosis. The prevalence of the disease has been largely due to the lack of knowledge, awareness, and poor hygiene practice in local residences. Therefore, effective disease prevention education and awareness campaigns in community will be significantly helpful in prevention and control of echinococcosis.

Comparative proteomic analysis of developing rhizomes of the ancient vascular plant Equisetum hyemale and different monocot species.

The rhizome is responsible for the invasiveness and competitiveness of many plants with great economic and agricultural impact worldwide. Besides its value as an invasive organ, the rhizome plays a role in the establishment and massive growth of forage, providing biomass for biofuel production. Despite these features, little is known about the molecular mechanisms that contribute to rhizome growth, development, and function in plants. In this work, we characterized the proteome of rhizome apical tips and elongation zones from different species using a GeLC-MS/MS (one-dimensional electrophoresis in combination with liquid chromatography coupled online with tandem mass spectrometry) spectral-counting proteomics strategy. Five rhizomatous grasses and an ancient species were compared to study the protein regulation in rhizomes. An average of 2200 rhizome proteins per species were confidently identified and quantified. Rhizome-characteristic proteins showed similar functional distributions across all species analyzed. The over-representation of proteins associated with central roles in cellular, metabolic, and developmental processes indicated accelerated metabolism in growing rhizomes. Moreover, 61 rhizome-characteristic proteins appeared to be regulated similarly among analyzed plants. In addition, 36 showed conserved regulation between rhizome apical tips and elongation zones across species. These proteins were preferentially expressed in rhizome tissues regardless of the species analyzed, making them interesting candidates for more detailed investigative studies about their roles in rhizome development.

Differentially regulated genes in the salivary glands of brown planthopper after feeding in resistant versus susceptible rice varieties.

Brown planthopper (BPH) is a damaging insect pest of rice. We used suppression subtractive hybridization (SSH) and mirror orientation selection to identify differentially regulated genes in salivary glands of BPH after feeding on resistant and susceptible varieties. The forward SSH library included 768 clones with insertions ranging from 250 to 1000 bp. After differential screening, a total of 112 transcripts were identified, which included 27 upregulated genes and seven downregulated genes. Several of these transcripts showed sequence homology to known proteins such as trehalase, mucin-like protein, vitellogenin, calcium ion binding protein, and eukaryotic initiation factor-like protein. About half of the transcripts, however, did not match to any sequences in the protein databases currently available. Functional annotation of the transcripts showed gene ontology association with metabolism, signal transduction, and regulatory responses. Notably, many known functional genes were predicted to be secreted proteins. Also, gene expression profiles of the salivary glands of BPH feeding on resistant rice (B5) and susceptible rice (TN1) varieties were compared. Our data provide a molecular resource for future functional studies on salivary glands and will be useful for elucidating the molecular mechanisms between BPH feeding and rice varieties with BPH resistance differences.

A systems-wide comparison of red rice (Oryza longistaminata) tissues identifies rhizome specific genes and proteins that are targets for cultivated rice improvement.

BACKGROUND: The rhizome, the original stem of land plants, enables species to invade new territory and is a critical component of perenniality, especially in grasses. Red rice (Oryza longistaminata) is a perennial wild rice species with many valuable traits that could be used to improve cultivated rice cultivars, including rhizomatousness, disease resistance and drought tolerance. Despite these features, little is known about the molecular mechanisms that contribute to rhizome growth, development and function in this plant. RESULTS: We used an integrated approach to compare the transcriptome, proteome and metabolome of the rhizome to other tissues of red rice. 116 Gb of transcriptome sequence was obtained from various tissues and used to identify rhizome-specific and preferentially expressed genes, including transcription factors and hormone metabolism and stress response-related genes. Proteomics and metabolomics approaches identified 41 proteins and more than 100 primary metabolites and plant hormones with rhizome preferential accumulation. Of particular interest was the identification of a large number of gene transcripts from Magnaportha oryzae, the fungus that causes rice blast disease in cultivated rice, even though the red rice plants showed no sign of disease. CONCLUSIONS: A significant set of genes, proteins and metabolites appear to be specifically or preferentially expressed in the rhizome of O. longistaminata. The presence of M. oryzae gene transcripts at a high level in apparently healthy plants suggests that red rice is resistant to this pathogen, and may be able to provide genes to cultivated rice that will enable resistance to rice blast disease.

Development and implementation of nested single-nucleotide polymorphism (SNP) assays for breeding and genetic research applications.

SoySNP50K and SoySNP6K are commonly used for soybean (Glycine max) genotyping. The SoySNP50K assay has been used to genetically analyze the entire USDA Soybean Germplasm Collection, while the SoySNP6K assay, containing a subset of 6000 single-nucleotide polymorphisms (SNPs) from SoySNP50K, has been used for quantitative trait loci mapping of different traits. To meet the needs for genomic selection, selection of parents for crosses, and characterization of breeding populations, especially early selection of ideal offspring from thousands of lines, we developed two assays, SoySNP3K and SoySNP1K, containing 3072 and 1252 SNPs, respectively, based on SoySNP50K and SoySNP6K mark sets. These two assays also contained the trait markers reported or contributed by soybean breeders. The SNPs in the SoySNP3K are a subset from SoySNP6K, while the SNPs in the SoySNP1K are a subset from SoySNP3K. These SNPs were chosen to reduce the SNP number in the large linkage blocks while capturing as much of the haplotype diversity as possible. They are highly polymorphic and of high quality. The mean minor allele frequencies of the SNPs in the southern and northern US elites were 0.25 and 0.27 for SoySNP3K, respectively, and 0.29 and 0.33 for SoySNP1K. The selected SNPs are a valuable source for developing targeted amplicon sequencing assay or beadchip assay in soybean. SoySNP3K and SoySNP1K assays are commercialized by Illumina Inc. and AgriPlex Genomics, respectively. Together with SoySNP50K and SoySNP6K, a series of nested assays with different marker densities will serve as additional low-cost genomic tools for genetic, genomic, and breeding research.

Differential gene expression of Asian citrus psyllids infected with 'Ca. Liberibacter asiaticus' reveals hyper-susceptibility to invasion by instar fourth-fifth and teneral adult stages.

The bacterial pathogen Candidatus Liberibacter asiaticus (CLas) is the causal agent of citrus greening disease. This unusual plant pathogenic bacterium also infects its psyllid host, the Asian citrus psyllid (ACP). To investigate gene expression profiles with a focus on genes involved in infection and circulation within the psyllid host of CLas, RNA-seq libraries were constructed from CLas-infected and CLas-free ACP representing the five different developmental stages, namely, nymphal instars 1-2, 3, and 4-5, and teneral and mature adults. The Gbp paired-end reads (296) representing the transcriptional landscape of ACP across all life stages and the official gene set (OGSv3) were annotated based on the chromosomal-length v3 reference genome and used for de novo transcript discovery resulting in 25,410 genes with 124,177 isoforms. Differential expression analysis across all ACP developmental stages revealed instar-specific responses to CLas infection, with greater overall responses by nymphal instars, compared to mature adults. More genes were over-or under-expressed in the 4-5th nymphal instars and young (teneral) adults than in instars 1-3, or mature adults, indicating that late immature instars and young maturing adults were highly responsive to CLas infection. Genes identified with potential for direct or indirect involvement in the ACP-CLas circulative, propagative transmission pathway were predominantly responsive during early invasion and infection processes and included canonical cytoskeletal remodeling and endo-exocytosis pathway genes. Genes with predicted functions in defense, development, and immunity exhibited the greatest responsiveness to CLas infection. These results shed new light on ACP-CLas interactions essential for pathogenesis of the psyllid host, some that share striking similarities with effector protein-animal host mechanisms reported for other culturable and/or fastidious bacterial- or viral- host pathosystems.

Altitude and metabolic syndrome in China: Beneficial effects of healthy diet and physical activity.

Background: The correlation between altitude and metabolic syndrome has not been extensively studied, and the mediation effects of diet and physical activity remain unclear. We evaluated the cross-sectional correlations between altitude and metabolic syndrome and the possible mediation effects of diet and physical activity in China. Methods: We included 89 485 participants from the China Multi-Ethnic Cohort. We extracted their altitude information from their residential addresses and determined if they had metabolic syndrome by the presence of three or more of the following components: abdominal obesity, reduced high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, elevated glucose, and high blood pressure at recruitment. We conducted multivariable logistic regression and mediation analyses for all and separately for Han ethnic participants. Results: The participants had a mean age of 51.67 years and 60.56% were female. The risk difference of metabolic syndrome was -3.54% (95% confidence interval (CI) = -4.24, -2.86) between middle and low altitudes, -1.53% (95%CI = -2.53, -0.46) between high and low altitudes, and 2.01% (95% CI = 0.92, 3.09) between high and middle altitudes. Of the total estimated effect between middle and low altitude, the effect mediated by increased physical activity was -0.94% (95% CI = -1.04, -0.86). Compared to low altitude, the effects mediated by a healthier diet were -0.40% (95% CI = -0.47, -0.32) for middle altitude and -0.72% (95% CI = -0.87, -0.58) for high altitude. Estimates were similar in the Han ethnic group. Conclusions: Living at middle and high altitudes was significantly associated with lower risk of metabolic syndrome compared to low altitude, with middle altitude having the lowest risk. We found mediation effects of diet and physical activity.

Identification of necroptosis-related features in diabetic nephropathy and analysis of their immune microenvironent and inflammatory response.

Background: Diabetic nephropathy (DN) was considered a severe microvascular complication of diabetes, which was recognized as the second leading cause of end-stage renal diseases. Therefore, identifying several effective biomarkers and models to diagnosis and subtype DN is imminent. Necroptosis, a distinct form of programmed cell death, has been established to play a critical role in various inflammatory diseases. Herein, we described the novel landscape of necroptosis in DN and exploit a powerful necroptosis-mediated model for the diagnosis of DN. Methods: We obtained three datasets (GSE96804, GSE30122, and GSE30528) from the Gene Expression Omnibus (GEO) database and necroptosis-related genes (NRGs) from the GeneCards website. Via differential expression analysis and machine learning, significant NRGs were identified. And different necroptosis-related DN subtypes were divided using consensus cluster analysis. The principal component analysis (PCA) algorithm was utilized to calculate the necroptosis score. Finally, the logistic multivariate analysis were performed to construct the necroptosis-mediated diagnostic model for DN. Results: According to several public transcriptomic datasets in GEO, we obtained eight significant necroptosis-related regulators in the occurrence and progress of DN, including CFLAR, FMR1, GSDMD, IKBKB, MAP3K7, NFKBIA, PTGES3, and SFTPA1 via diversified machine learning methods. Subsequently, employing consensus cluster analysis and PCA algorithm, the DN samples in our training set were stratified into two diverse necroptosis-related subtypes based on our eight regulators' expression levels. These subtypes exhibited varying necroptosis scores. Then, we used various functional enrichment analysis and immune infiltration analysis to explore the biological background, immune landscape and inflammatory status of the above subtypes. Finally, a necroptosis-mediated diagnostic model was exploited based on the two subtypes and validated in several external verification datasets. Moreover, the expression level of our eight regulators were verified in the singe-cell level and glomerulus samples. And we further explored the relationship between the expression of eight regulators and the kidney function of DN. Conclusion: In summary, our necroptosis scoring model and necroptosis-mediated diagnostic model fill in the blank of the relationship between necroptosis and DN in the field of bioinformatics, which may provide novel diagnostic insights and therapy strategies for DN.

A multicenter, randomized, double-blind, duloxetine-controlled, non-inferiority trial of desvenlafaxine succinate extended-release in patients with major depressive disorder.

BACKGROUND: Desvenlafaxine and duloxetine are selective serotonin and norepinephrine reuptake inhibitors. Their efficacy has not been directly compared using statistical hypotheses. This study evaluated the non-inferiority of desvenlafaxine extended-release (XL) to duloxetine in patients with major depressive disorder (MDD). METHODS: In this study, 420 adult patients with moderate-to-severe MDD were enrolled and randomly assigned (1:1) to receive 50 mg (once daily [QD]) of desvenlafaxine XL (n = 212) or 60 mg QD of duloxetine (n = 208). The primary endpoint was evaluated using a non-inferiority comparison based on the change from baseline to 8 weeks in the 17-item Hamilton Depression Rating Scale (HAMD17) total score. Secondary endpoints and safety were evaluated. RESULTS: Least-squares mean change in HAM-D17 total score from baseline to 8 weeks was -15.3 (95% confidence interval [CI]: -17.73, -12.89) in the desvenlafaxine XL group and - 15.9 (95% CI, -18.44, -13.39) in the duloxetine group. The least-squares mean difference was 0.6 (95% CI: -0.48, 1.69), and the upper boundary of 95% CI was less than the non-inferiority margin (2.2). No significant between-treatment differences were found in most secondary efficacy endpoints. The incidence of the most common treatment-emergent adverse events (TEAEs) was lower for desvenlafaxine XL than for duloxetine for nausea (27.2% versus 48.8%) and dizziness (18.0% versus 28.8%). LIMITATIONS: A short-term non-inferiority study without a placebo arm. CONCLUSIONS: This study demonstrated that desvenlafaxine XL 50 mg QD was non-inferior to duloxetine 60 mg QD in efficacy in patients with MDD. Desvenlafaxine had a lower incidence of TEAEs than duloxetine did.

Next-generation sequencing-based transcriptomic and proteomic analysis of the common reed, Phragmites australis (Poaceae), reveals genes involved in invasiveness and rhizome specificity.

PREMISE OF THE STUDY: The common reed (Phragmites australis), one of the most widely distributed of all angiosperms, uses its rhizomes (underground stems) to invade new territory, making it one of the most successful weedy species worldwide. Characterization of the rhizome transcriptome and proteome is needed to identify candidate genes and proteins involved in rhizome growth, development, metabolism, and invasiveness. METHODS: We employed next-generation sequencing technologies including 454 and Illumina platforms to characterize the reed rhizome transcriptome and used quantitative proteomics techniques to identify the rhizome proteome. KEY RESULTS: Combining 336514 Roche 454 Titanium reads and 103350802 Illumina paired-end reads in a de novo hybrid assembly yielded 124450 unique transcripts with an average length of 549 bp, of which 54317 were annotated. Rhizome-specific and differentially expressed transcripts were identified between rhizome apical tips (apical meristematic region) and rhizome elongation zones. A total of 1280 nonredundant proteins were identified and quantified using GeLC-MS/MS based label-free proteomics, where 174 and 77 proteins were preferentially expressed in the rhizome elongation zone and apical tip tissues, respectively. Genes involved in allelopathy and in controlling development and potentially invasiveness were identified. CONCLUSIONS: In addition to being a valuable sequence and protein data resource for studying plant rhizome species, our results provide useful insights into identifying specific genes and proteins with potential roles in rhizome differentiation, development, and function.

Identification and characterization of Bph14, a gene conferring resistance to brown planthopper in rice.

Planthoppers are highly destructive pests in crop production worldwide. Brown planthopper (BPH) causes the most serious damage of the rice crop globally among all rice pests. Growing resistant varieties is the most effective and environment-friendly strategy for protecting the crop from BPH. More than 19 BPH-resistance genes have been reported and used to various extents in rice breeding and production. In this study, we cloned Bph14, a gene conferring resistance to BPH at seedling and maturity stages of the rice plant, using a map-base cloning approach. We show that Bph14 encodes a coiled-coil, nucleotide-binding, and leucine-rich repeat (CC-NB-LRR) protein. Sequence comparison indicates that Bph14 carries a unique LRR domain that might function in recognition of the BPH insect invasion and activating the defense response. Bph14 is predominantly expressed in vascular bundles, the site of BPH feeding. Expression of Bph14 activates the salicylic acid signaling pathway and induces callose deposition in phloem cells and trypsin inhibitor production after planthopper infestation, thus reducing the feeding, growth rate, and longevity of the BPH insects. Our work provides insights into the molecular mechanisms of rice defense against insects and facilitates the development of resistant varieties to control this devastating insect.

The physical and genetic framework of the maize B73 genome.

Maize is a major cereal crop and an important model system for basic biological research. Knowledge gained from maize research can also be used to genetically improve its grass relatives such as sorghum, wheat, and rice. The primary objective of the Maize Genome Sequencing Consortium (MGSC) was to generate a reference genome sequence that was integrated with both the physical and genetic maps. Using a previously published integrated genetic and physical map, combined with in-coming maize genomic sequence, new sequence-based genetic markers, and an optical map, we dynamically picked a minimum tiling path (MTP) of 16,910 bacterial artificial chromosome (BAC) and fosmid clones that were used by the MGSC to sequence the maize genome. The final MTP resulted in a significantly improved physical map that reduced the number of contigs from 721 to 435, incorporated a total of 8,315 mapped markers, and ordered and oriented the majority of FPC contigs. The new integrated physical and genetic map covered 2,120 Mb (93%) of the 2,300-Mb genome, of which 405 contigs were anchored to the genetic map, totaling 2,103.4 Mb (99.2% of the 2,120 Mb physical map). More importantly, 336 contigs, comprising 94.0% of the physical map ( approximately 1,993 Mb), were ordered and oriented. Finally we used all available physical, sequence, genetic, and optical data to generate a golden path (AGP) of chromosome-based pseudomolecules, herein referred to as the B73 Reference Genome Sequence version 1 (B73 RefGen_v1).