AttnPep: A Self-Attention-Based Deep Learning Method for Peptide Identification in Shotgun Proteomics.

In shotgun proteomics, the proteome search engine analyzes mass spectra obtained by experiments, and then a peptide-spectra match (PSM) is reported for each spectrum. However, most of the PSMs identified are incorrect, and therefore various postprocessing software have been developed for reranking the peptide identifications. Yet these methods suffer from issues such as dependency on distribution, reliance on shallow models, and limited effectiveness. In this work, we propose AttnPep, a deep learning model for rescoring PSM scores that utilizes the Self-Attention module. This module helps the neural network focus on features relevant to the classification of PSMs and ignore irrelevant features. This allows AttnPep to analyze the output of different search engines and improve PSM discrimination accuracy. We considered a PSM to be correct if it achieves a q-value <0.01 and compared AttnPep with existing mainstream software PeptideProphet, Percolator, and proteoTorch. The results indicated that AttnPep found an average increase in correct PSMs of 9.29% relative to the other methods. Additionally, AttnPep was able to better distinguish between correct and incorrect PSMs and found more synthetic peptides in the complex SWATH data set.

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.

BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.

The interaction effects of zinc and polygenic risk score with benzo[a]pyrene exposure on lung cancer risk: A prospective case-cohort study among Chinese populations.

The relationship of exposure to benzo[a]pyrene (BaP) with lung cancer risk has been firmly established, but whether this association could be modified by other environmental or genetic factors remains to be explored. To investigate whether and how zinc (Zn) and genetic predisposition modify the association between BaP and lung cancer, we performed a case-cohort study with a 5.4-year median follow-up duration, comprising a representative subcohort of 1399 participants and 359 incident lung cancer cases. The baseline concentrations of benzo[a]pyrene diol epoxide-albumin adduct (BPDE-Alb) and Zn were quantified. We also genotyped the participants and computed the polygenic risk score (PRS) for lung cancer. Our findings indicated that elevated BPDE-Alb and PRS were linked to increased lung cancer risk, with the HR (95%CI) of 1.54 (1.36, 1.74) per SD increment in ln-transformed BPDE-Alb and 1.27 (1.14, 1.41) per SD increment in PRS, but high plasma Zn level was linked to a lower lung cancer risk [HR (95%CI)=0.77 (0.66, 0.91) per SD increment in ln-transformed Zn]. There was evidence of effect modification by Zn on BaP-lung cancer association (P for multiplicative interaction = 0.008). As Zn concentrations increased from the lowest to the highest tertile, the lung cancer risk per SD increment in ln-transformed BPDE-Alb decreased from 2.07 (1.48, 2.89) to 1.33 (0.90, 1.95). Additionally, we observed a significant synergistic interaction of BPDE-Alb and PRS [RERI (95%CI) = 0.85 (0.03, 1.67)], with 42% of the incident lung cancer cases among individuals with high BPDE-Alb and high PRS attributable to their additive effect [AP (95%CI) = 0.42 (0.14, 0.69)]. This study provided the first prospective epidemiological evidence that Zn has protective effect against BaP-induced lung tumorigenesis, whereas high genetic risk can enhance the harmful effect of BaP. These findings may provide novel insight into the environment-environment and environment-gene interaction underlying lung cancer development, which may help to develop prevention and intervention strategies to manage BaP-induced lung cancer.

Distribution and Drug Resistance of Common Pathogens Causing Lower Respiratory Tract Infection in Xinjiang Region.

Objective: This study aims to analyze the composition and distribution of pathogenic bacteria in lower respiratory tract infections (LRTI) and their antimicrobial resistance patterns in a hospital in Xinjiang, to guide more effective antibiotic selection and inform clinical management. Methods: We retrospectively analyzed 545 strains isolated from various clinical specimens like sputum and blood, collected between June 2020 and June 2023, using the LIST system. The strains were subjected to drug resistance testing, and statistical analyses included t tests and Chi-square tests. Results: Among gram-negative bacilli, Acinetobacter baumannii dominated, accounting for 32.11%, followed by Pseudomonas aeruginosa, accounting for 18.35%. Among gram-positive bacteria, thrombin-negative staphylococcus was at the top of the list, followed by Staphylococcus aureus. Among Acinetobacter baumannii (AB), carbapenem-resistant Acinetobacter baumannii plays a dominant role. The sensitivity rate of these strains to tigecycline and amikacin could reach more than 80%. The sensitivity of Pseudomonas aeruginosa (PA) to piperacillin, gentamicin, imipenem, meropenem, ciprofloxacin and levofloxacin ranged from 50% to 80%. It is worth mentioning that the sensitivity rate of PA to amikacin, cefoperazone, and tobramycin exceeded 80%. Amikacin was more than 60% sensitive to carbapenem, ß-lactam inhibitors, tigecycline, quinolones, and aminoglycosides of ESBL producing Klebsiella pneumoniae. Among gram-positive coccus, methicillin-resistant coagulase-negative staphylococcus was 100% sensitive to duration, e, tigecycline, and vancomycin. In addition, the susceptibility rate of these strains to rifampicin and linezolid was greater than 70%. Conclusions: In patients with lower respiratory tract infection (LRTI) in a hospital in Xinjiang, the most common pathogenic bacteria are gram-negative bacilli, mainly Acinetobacter baumannii and Pseudomonas aeruginosa. Both resistant and non-resistant strains showed sensitivity to amikacin and tigecycline. Additionally, staphylococcus accounted for half of the total number of gram-positive bacteria, among which methicillin-resistant strains were more sensitive to vancomycin and linezolid.

Mediation of association between benzo[a]pyrene exposure and lung cancer risk by plasma microRNAs: A Chinese case-control study.

Epidemiologic studies have reported the positive relationship of benzo[a]pyrene (BaP) exposure with the risk of lung cancer. However, the mechanisms underlying the relationship is still unclear. Plasma microRNA (miRNA) is a typical epigenetic biomarker that was linked to environment exposure and lung cancer development. We aimed to reveal the mediation effect of plasma miRNAs on BaP-related lung cancer. We designed a lung cancer case-control study including 136 lung cancer patients and 136 controls, and measured the adducts of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) and sequenced miRNA profiles in plasma. The relationships between BPDE-Alb adducts, normalized miRNA levels and the risk of lung cancer were assessed by linear regression models. The mediation effects of miRNAs on BaP-related lung cancer were investigated. A total of 190 plasma miRNAs were significantly related to lung cancer status at Bonferroni adjusted P < 0.05, among which 57 miRNAs showed different levels with |fold change| > 2 between plasma samples before and after tumor resection surgery at Bonferroni adjusted P < 0.05. Especially, among the 57 lung cancer-associated miRNAs, BPDE-Alb adducts were significantly related to miR-17-3p, miR-20a-3p, miR-135a-5p, miR-374a-5p, miR-374b-5p, miR-423-5p and miR-664a-5p, which could in turn mediate a separate 42.2%, 33.0%, 57.5%, 36.4%, 48.8%, 32.5% and 38.2% of the relationship of BPDE-Alb adducts with the risk of lung cancer. Our results provide non-invasion biomarker candidates for lung cancer, and highlight miRNAs dysregulation as a potential intermediate mechanism by which BaP exposure lead to lung tumorigenesis.

Associations of mitochondrial DNA copy number with incident risks of gastrointestinal cancers: A prospective case-cohort study.

Epidemiological investigations implied that mitochondrial DNA copy number (mtDNAcn) variations could trigger predisposition to multiple cancers, but evidence regarding gastrointestinal cancers (GICs) was still uncertain. We conducted a case-cohort study within the prospective Dongfeng-Tongji cohort, including incident cases of colorectal cancer (CRC, n = 278), gastric cancer (GC, n = 138), and esophageal cancer (EC, n = 72) as well as a random subcohort (n = 1173), who were followed up from baseline to the end of 2018. We determined baseline blood mtDNAcn and associations of mtDNAcn with the GICs risks were estimated by using weighted Cox proportional hazards models. Significant U-shaped associations were observed between mtDNAcn and GICs risks. Compared to subjects within the second quartile (Q2) mtDNAcn subgroup, those within the 1st (Q1), 3rd (Q3), and 4th (Q4) quartile subgroups showed increased risks of CRC (hazard ratio [HR] [95% confidence interval, CI] = 2.27 [1.47-3.52], 1.65 [1.04-2.62], and 2.81 [1.85-4.28], respectively) and total GICs (HR [95%CI] = 1.84 [1.30-2.60], 1.47 [1.03-2.10], and 2.51 [1.82-3.47], respectively], and those within Q4 subgroup presented elevated GC and EC risks (HR [95% CI] = 2.16 [1.31-3.54] and 2.38 [1.13-5.02], respectively). Similar associations of mtDNAcn with CRC and total GICs risks remained in stratified analyzes by age, gender, smoking, and drinking status. This prospective case-cohort study showed U-shaped associations between mtDNAcn and GICs risks, but further research works are needed to uncover underlying biological mechanisms.

Predictive Impact of Prognostic Nutritional Index in Patients with Cancer Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

A few previous studies have investigated the prognostic value of the prognostic nutritional index (PNI) in patients treated with immune checkpoint inhibitors (ICIs); however, the results are inconsistent. Therefore, this study aimed to clarify the prognostic significance of PNI. The PubMed, Embase, and Cochrane Library databases were searched. A meta-analysis of the impact of PNI on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and rate of adverse events (AEs) in patients treated with ICIs was performed. Twenty-three studies involving 2,386 patients were included. Low PNI was associated with significantly poor OS (hazard ratio [HR] = 2.26, 95% confidence interval [CI]: 1.81-2.82, P < .001) and short PFS (HR = 1.75, 95% CI: 1.54-1.99, P < .001). Patients with low PNI tended to have a low ORR (odds ratio [OR] = 0.47, 95% CI: 0.34-0.65, P < .001) and DCR (OR = 0.43, 95% CI: 0.34-0.56, P < .001). However, the subgroup analysis demonstrated no significant association between PNI and survival time in patients receiving a programmed death ligand-1 inhibitor. PNI was significantly associated with survival time and treatment efficacy in patients treated with ICIs.

Current extraction, purification, and identification techniques of tea polyphenols: An updated review.

Tea, as a beverage, has been reputed for its health benefits and gained worldwide popularity. Tea polyphenols, especially catechins, as the main bioactive compounds in tea, exhibit diverse health benefits and have wide applications in the food industry. The development of tea polyphenol-incorporated products is dependent on the extraction, purification, and identification of tea polyphenols. Recent years, many green and novel extraction, purification, and identification techniques have been developed for the preparation of tea polyphenols. This review, therefore, introduces the classification of tea and summarizes the main conventional and novel techniques for the extraction of polyphenols from various tea products. The advantages and disadvantages of these techniques are also intensively discussed and compared. In addition, the purification and identification techniques are summarized. It is hoped that this updated review can provide a research basis for the green and efficient extraction, purification, and identification of tea polyphenols, which can facilitate their utilization in the production of various functional food products and nutraceuticals.

Wheat authentication：An overview on different techniques and chemometric methods.

Wheat (Triticum aestivum L.) is one of the most important cereal crops and is consumed as a staple food around the globe. Wheat authentication has become a crucial issue over the last decades. Recently, many techniques have been applied in wheat authentication including the authentication of wheat geographical origin, wheat variety, organic wheat, and wheat flour from other cereals. This paper collected related literature in the last ten years, and attempted to highlight the recent studies on the discrimination and authentication of wheat using different determination techniques and chemometric methods. The stable isotope analysis and elemental profile of wheat are promising tools to obtain information regarding the origin, and variety, and to differentiate organic from conventional farming of wheat. Image analysis, genetic parameters, and omics analysis can provide solutions for wheat variety, organic wheat, and wheat adulteration. Vibrational spectroscopy analyses, such as NIR, FTIR, and HIS, in combination with multivariate data analysis methods, such as PCA, LDA, and PLS-DA, show great potential in wheat authenticity and offer many advantages such as user-friendly, cost-effective, time-saving, and environment friendly. In conclusion, analytical techniques combining with appropriate multivariate analysis are very effective to discriminate geographical origin, cultivar classification, and adulterant detection of wheat.

Recent advances in the influences of drying technologies on physicochemical properties and biological activities of plant polysaccharides.

Plant polysaccharides, as significant functional macromolecules with diverse biological properties, are currently receiving increasing attention. Drying technologies play a pivotal role in the research, development, and application of various foods and plant polysaccharides. The chemical composition, structure, and function of extracted polysaccharides are significantly influenced by different drying technologies (e.g., microwave, infrared, and radio frequency) and conditions (e.g., temperature). This study discusses and compares the principles, advantages, disadvantages, and effects of different drying processes on the chemical composition as well as structural and biological properties of plant polysaccharides. In most plant-based raw materials, molecular degradation, molecular aggregation phenomena along with intermolecular interactions occurring within cell wall components and cell contents during drying represent primary mechanisms leading to variations in chemical composition and structures of polysaccharides. These differences further impact their biological properties. The biological properties of polysaccharides are determined by a combination of multiple relevant factors rather than a single factor alone. This review not only provides insights into selecting appropriate drying processes to obtaining highly bioactive plant polysaccharides but also offers a fundamental theoretical basis for the structure-function relationship of these compounds.

Multiple metals exposure and blood mitochondrial DNA copy number: A cross-sectional study from the Dongfeng-Tongji cohort.

OBJECTIVE: Mitochondria are essential organelles that execute fundamental biological processes, while mitochondrial DNA is vulnerable to environmental insults. The aim of this study was to investigate the individual and mixture effect of plasma metals on blood mitochondria DNA copy number (mtDNAcn). METHODS: This study involved 1399 randomly selected subcohort participants from the Dongfeng-Tongji cohort. The blood mtDNAcn and plasma levels of 23 metals were determined by using quantitative real-time polymerase chain reaction (qPCR) and inductively coupled plasma mass spectrometer (ICP-MS), respectively. The multiple linear regression was used to explore the association between each metal and mtDNAcn, and the LASSO penalized regression was performed to select the most significant metals. We also used the quantile g-computation analysis to assess the mixture effect of multiple metals. RESULTS: Based on multiple linear regression models, each 1% increase in plasma concentration of copper (Cu), rubidium (Rb), and titanium (Ti) was associated with a separate 0.16% [ß(95% CI) = 0.158 (0.066, 0.249), P = 0.001], 0.20% [ß(95% CI) = 0.196 (0.073, 0.318), P = 0.002], and 0.25% [ß(95% CI) = 0.245 (0.081, 0.409), P = 0.003] increase in blood mtDNAcn. The LASSO regression also confirmed Cu, Rb, and Ti as significant predictors for mtDNAcn. There was a significant mixture effect of multiple metals on increasing mtDNAcn among the elder participants (aged ≥65), with an approximately 11% increase in mtDNAcn for each quartile increase in all metal concentrations [ß(95% CI) = 0.146 (0.048, 0.243), P = 0.004]. CONCLUSIONS: Our results show that plasma Cu, Rb and Ti were associated with increased blood mtDNA, and we further revealed a significant mixture effect of all metals on mtDNAcn among elder population. These findings may provide a novel perspective on the effect of metals on mitochondrial dysfunction.

Frailty and its combined effects with lifestyle factors on cognitive function: a cross-sectional study.

BACKGROUND: Frailty describes an age-related state of deterioration in biological function. This study aimed to investigate the association between frailty and cognitive function and its combined effects with lifestyles. METHODS: A total of 3,279 participants from the Dongfeng-Tongji (DFTJ) cohort were tested the cognitive function by using the Chinese version of Mini-mental State Examination (MMSE). Frailty was evaluated based on a 35-item frailty index (FI). Frailty status was dichotomized into robust (FI < 0.15) and frail (FI ≥ 0.15). Multivariate generalized linear regression models and logistic regression models were used to estimate the associations of frailty with MMSE score and cognitive impairment. We also analysed the modification and combined effects of lifestyle factors, including smoking status, drinking status, and regular physical exercise, on the above associations. RESULTS: FI was significantly associated with lower MMSE score [ß (95%Cl) = -0.28 (-0.43, -0.13)] and cognitive impairment [OR (95%Cl) = 1.19 (1.04, 1.35)]. The association of frailty status with MMSE were found to be stronger among ever smokers [ß(95%Cl) = -1.08 (-1.64, -0.51)] and physical inactive individuals [ß(95%Cl) = -1.59 (-2.63, -0.54)] while weaker or not significant among never smokers [ß(95%Cl) = -0.30 (-0.62, 0.01)] and physical active individuals [ß(95%Cl) = -0.37 (-0.65, -0.08))]. There were significant combined effects of frailty status with unhealthy lifestyles including smoking, alcohol drinking, and physical inactive on cognitive impairment. CONCLUSIONS: Frailty was associated with cognitive impairment among Chinese middle-aged and elderly people, while smoking cessation and regular physical exercise could attenuate the above associations, which highlight the potential preventive interventions.

Evolution of insulin at the edge of foldability and its medical implications.

Proteins have evolved to be foldable, and yet determinants of foldability may be inapparent once the native state is reached. Insight has emerged from studies of diseases of protein misfolding, exemplified by monogenic diabetes mellitus due to mutations in proinsulin leading to endoplasmic reticulum stress and ß-cell death. Cellular foldability of human proinsulin requires an invariant Phe within a conserved crevice at the receptor-binding surface (position B24). Any substitution, even related aromatic residue TyrB24, impairs insulin biosynthesis and secretion. As a seeming paradox, a monomeric TyrB24 insulin analog exhibits a native-like structure in solution with only a modest decrement in stability. Packing of TyrB24 is similar to that of PheB24, adjoining core cystine B19-A20 to seal the core; the analog also exhibits native self-assembly. Although affinity for the insulin receptor is decreased ∼20-fold, biological activities in cells and rats were within the range of natural variation. Together, our findings suggest that the invariance of PheB24 among vertebrate insulins and insulin-like growth factors reflects an essential role in enabling efficient protein folding, trafficking, and secretion, a function that is inapparent in native structures. In particular, we envision that the para-hydroxyl group of TyrB24 hinders pairing of cystine B19-A20 in an obligatory on-pathway folding intermediate. The absence of genetic variation at B24 and other conserved sites near this disulfide bridge-excluded due to ß-cell dysfunction-suggests that insulin has evolved to the edge of foldability. Nonrobustness of a protein's fitness landscape underlies both a rare monogenic syndrome and "diabesity" as a pandemic disease of civilization.

Genome-wide identification and expression pattern analysis of novel chemosensory genes in the German cockroach Blattella germanica.

The German cockroach Blattella germanica is an important urban insect pest worldwide. In many insects, chemosensation is essential for guiding their behaviors for survival. Although a large number of chemosensory-related genes have been identified in B. germanica, little information on tissue-specific and developmental expression patterns has not been uncovered yet. In this study, we performed transcriptome analysis of different B. germanica tissues to reveal novel chemosensory proteins (CSPs) and sensory neuron membrane proteins (SNMPs). In addition, a phylogenetic tree and gender-specific expression of multiple chemosensory gene families have been analyzed. We identified three CSPs genes (BgerCSP11, BgerCSP12, and BgerCSP13) and five SNMP genes in B. germanica. Tissue-specific expression profiling showed that CSP1, 8, and 9 exhibited significant expression levels in both adult and 5th instar nymph antennae. The results have paved the way for further functional study of the chemosensory mechanism in B. germanica and provided potential insecticide targets.

Physiological and Transcriptional Analyses Provide Insight into Maintaining Ion Homeostasis of Sweet Sorghum under Salt Stress.

Sweet sorghum is an important bioenergy grass and valuable forage with a strong adaptability to saline environments. However, little is known about the mechanisms of sweet sorghum coping with ion toxicity under salt stresses. Here, we first evaluated the salt tolerance of a sweet sorghum cultivar "Lvjuren" and determined its ion accumulation traits under NaCl treatments; then, we explored key genes involved in Na+, Cl-, K+ and NO3- transport using transcriptome profiling and the qRT-PCR method. The results showed that growth and photosynthesis of sweet sorghum were unaffected by 50 and 100 mM NaCl treatments, indicative of a strong salt tolerance of this species. Under NaCl treatments, sweet sorghum could efficiently exclude Na+ from shoots and accumulate Cl- in leaf sheaths to avoid their overaccumulation in leaf blades; meanwhile, it possessed a prominent ability to sustain NO3- homeostasis in leaf blades. Transcriptome profiling identified several differentially expressed genes associated with Na+, Cl-, K+ and NO3- transport in roots, leaf sheaths and leaf blades after 200 mM NaCl treatment for 6 and 48 h. Moreover, transcriptome data and qRT-PCR results indicated that HKT1;5, CLCc and NPF7.3-1 should be key genes involved in Na+ retention in roots, Cl- accumulation in leaf sheaths and maintenance of NO3- homeostasis in leaf blades, respectively. Many TFs were also identified after NaCl treatment, which should play important regulatory roles in salt tolerance of sweet sorghum. In addition, GO analysis identified candidate genes involved in maintaining membrane stability and photosynthetic capacity under salt stresses. This work lays a preliminary foundation for clarifying the molecular basis underlying the adaptation of sweet sorghum to adverse environments.

TaSYP137 and TaVAMP723, the SNAREs Proteins from Wheat, Reduce Resistance to Blumeria graminis f. sp. tritici.

SNARE protein is an essential factor driving vesicle fusion in eukaryotes. Several SNAREs have been shown to play a crucial role in protecting against powdery mildew and other pathogens. In our previous study, we identified SNARE family members and analyzed their expression pattern in response to powdery mildew infection. Based on quantitative expression and RNA-seq results, we focused on TaSYP137/TaVAMP723 and hypothesized that they play an important role in the interaction between wheat and Blumeria graminis f. sp. Tritici (Bgt). In this study, we measured the expression patterns of TaSYP132/TaVAMP723 genes in wheat post-infection with Bgt and found that the expression pattern of TaSYP137/TaVAMP723 was opposite in resistant and susceptible wheat samples infected by Bgt. The overexpression of TaSYP137/TaVAMP723 disrupted wheat's defense against Bgt infection, while silencing these genes enhanced its resistance to Bgt. Subcellular localization studies revealed that TaSYP137/TaVAMP723 are present in both the plasma membrane and nucleus. The interaction between TaSYP137 and TaVAMP723 was confirmed using the yeast two-hybrid (Y2H) system. This study offers novel insights into the involvement of SNARE proteins in the resistance of wheat against Bgt, thereby enhancing our comprehension of the role of the SNARE family in the pathways related to plant disease resistance.

Expanding the Promiscuity of a Copper-Dependent Oxidase for Enantioselective Cross-Coupling of Indoles.

Herein, we disclose the highly enantioselective oxidative cross-coupling of 3-hydroxyindole esters with various nucleophilic partners as catalyzed by copper efflux oxidase. The biocatalytic transformation delivers functionalized 2,2-disubstituted indolin-3-ones with excellent optical purity (90-99 % ee), which exhibited anticancer activity against MCF-7 cell lines, as shown by preliminary biological evaluation. Mechanistic studies and molecular docking results suggest the formation of a phenoxyl radical and enantiocontrol facilitated by a suited enzyme chiral pocket. This study is significant with regard to expanding the catalytic repertoire of natural multicopper oxidases as well as enlarging the synthetic toolbox for sustainable asymmetric oxidative coupling.

A truncated CC-NB-ARC gene TaRPP13L1-3D positively regulates powdery mildew resistance in wheat via the RanGAP-WPP complex-mediated nucleocytoplasmic shuttle.

MAIN CONCLUSION: A wheat RPP13-like isoform interacting with WPP1 contributes to quantitative and/or basal resistance to powdery mildew (Blumeria graminis f. sp. tritici) by restricting the development of Bgt conidia. Plant disease resistance (R) genes confer an ability to resist infection by pathogens expressing specific avirulence genes. Recognition of Peronospora parasitica 13-like (RPP13-like) genes belong to the nucleotide-binding site and leucine-rich repeat (NBS-LRR) superfamily and play important roles in resistance to various plant diseases. Previously, we detected a TaRPP13-like gene located on chromosome 3D (TaRPP13L1-3D) in the TaSpl1 resided region, which is strongly induced by the cell death phenotype (Zhang et al. 2021). Here, we investigated the expression and functional role of TaRPP13L1-3D in wheat responding to fungal stress. TaRPP13L1-3D encoded a typical NB-ARC structure characterized by Rx-N and P-loop NTPase domains. TaRPP13L1-3D transcripts were strongly upregulated in wheat by powdery mildew (Blumeria graminis f. sp. tritici; Bgt) and stripe rust (Puccinia striiformis f. sp. tritici; Pst) infection although opposing expression patterns were observed in response to wheat-Bgt in incompatible and compatible backgrounds. Overexpression of TaRPP13L1-3D enhanced disease resistance to Bgt, accompanied by upregulation of the defense-related marker genes encoding phytoalexin-deficient4 (PAD4), thaumatin-like protein (TLP) and chitinase 8-like protein (Chi8L), while silencing of TaRPP13L1-3D disrupted the resistance to Bgt infection. Subcellular localization studies showed that TaRPP13L1-3D is located in both the plasma membrane and nucleus, while yeast-two-hybrid (Y2H) assays indicated that TaRPP13L1-3D interacts with WPP domain-containing protein 1 (TaWPP1). This indicates that TaRPP13L1-3D shuttles between the nucleus and cytoplasm membrane via a mechanism that is mediated by the RanGAP-WPP complex in nuclear pores. This insight into TaRPP13L1-3D will be useful in dissecting the mechanism of fungal resistance in wheat, and understanding the interaction between R gene expression and pathogen defense.

Pretreatment Body Mass Index (BMI) as an Independent Prognostic Factor in Nasopharyngeal Carcinoma Survival: A Systematic Review and Meta-Analysis.

We performed a meta-analysis to investigate the association between pretreatment body mass index (BMI) and prognosis of nasopharyngeal carcinoma (NPC). Case-control and cohort studies were searched from PubMed, Web of Science, EMBASE, and CNKI databases. Pooled hazard ratios (HR) with 95% confidence intervals (CI) for overall survival (OS) or distant metastasis-free survival (DMSF) were used to estimate the prognostic value. Bias in the included studies was evaluated using funnel plots. The results showed that compared with normal weight patients, the estimated HR of OS was 1.54 (95% CI: 1.25-1.90; P < 0.05) for underweight, 0.63 (95% CI: 0.48-0.83; P < 0.05) for overweight, and 0.67 (95% CI: 0.41-1.08; P = 0.102) obese patients. We also found that compared with normal-weight patients, the estimated HR of DMFS was 1.63 (95% CI: 1.38-1.92; P < 0.05) for underweight, 0.83 (95% CI: 0.61-1.13; P = 0.244) for overweight, and 0.60 (95% CI: 0.39-0.92; P < 0.05) for patients with obesity. BMI is an independent prognostic factor for NPC survival. Being underweight before treatment was associated with poorer OS and DMFS in patients with NPC. Neither overweight nor obesity before treatment has an unfavorable effect on NPC survival.

Are High- or Low-dose SGLT2 Inhibitors Associated With Cardiovascular and Respiratory Adverse Events? A Meta-analysis.

ABSTRACT: The association between high-dose or low-dose sodium-glucose cotransporter 2 (SGLT2) inhibitors and various cardiovascular and respiratory serious adverse events (SAE) is unclear. Our meta-analysis aimed to define the association between high-dose or low-dose SGLT2 inhibitors and 86 kinds of cardiovascular SAE and 58 kinds of respiratory SAE. We included large cardiorenal outcome trials of SGLT2 inhibitors. Meta-analysis was conducted and stratified by the dose of SGLT2 inhibitors (high dose or low dose) to synthesize risk ratio (RR) and 95% confidence interval (CI). We included 9 trials. Compared with placebo, SGLT2 inhibitors used at high dose or low dose were associated with the decreased risks of 6 kinds of cardiovascular SAE [eg, bradycardia (RR, 0.60; 95% CI, 0.41-0.89), atrial fibrillation (RR, 0.79; 95% CI, 0.69-0.92), and hypertensive emergency (RR, 0.34; 95% CI, 0.15-0.78)] and 6 kinds of respiratory SAE [eg, asthma (RR, 0.59; 95% CI, 0.37-0.93), chronic obstructive pulmonary disease (RR 0.77, 95% CI 0.62-0.96), and sleep apnea syndrome (RR 0.37, 95% CI 0.17-0.81)]. SGLT2 inhibitors used at high dose or low dose did not show significant associations with 132 other cardiopulmonary SAE. For any outcome of interest, the subgroup difference according to the dose of SGLT2 inhibitors was not significant (Psubgroup > 0.05). SGLT2 inhibitors used at whether high dose or low dose are associated with the decreased risks of 12 cardiopulmonary disorders (eg, bradycardia, atrial fibrillation, hypertensive emergency, asthma, chronic obstructive pulmonary disease, and sleep apnea syndrome). These findings may suggest the potential efficacy of high- or low-dose SGLT2 inhibitors for the prevention and treatment of these cardiopulmonary disorders.