Positional cloning and characterization reveal the role of TaSRN-3D and TaBSR1 in the regulation of seminal root number in wheat.

Seminal roots play a critical role in water and nutrient absorption, particularly in the early developmental stages of wheat. However, the genes responsible for controlling SRN in wheat remain largely unknown. Genetic mapping and functional analyses identified a candidate gene (TraesCS3D01G137200, TaSRN-3D) encoding a Ser/Thr kinase glycogen synthase kinase 3 (STKc_GSK3) that regulated SRN in wheat. Additionally, experiments involving hormone treatment, nitrate absorption and protein interaction were conducted to explore the regulatory mechanism of TaSRN-3D. Results showed that the TaSRN-3D4332 allele inhibited seminal roots initiation and development, while loss-of-function mutants showed significantly higher seminal root number (SRN). Exogenous application of epi-brassinolide could increase the SRN in a HS2-allelic background. Furthermore, chlorate sensitivity and 15N uptake assays revealed that a higher number of seminal roots promoted nitrate accumulation. TaBSR1 (BIN2-related SRN Regulator 1, orthologous to OsGRF4/GL2 in rice) acts as an interactor of TaSRN-3D and promotes TaBSR1 degradation to reduce SRN. This study provides valuable insights into understanding the genetic basis and regulatory network of SRN in wheat, highlighting their roles as potential targets for root-based improvement in wheat breeding.

Natural variation of STKc_GSK3 kinase TaSG-D1 contributes to heat stress tolerance in Indian dwarf wheat.

Heat stress threatens global wheat (Triticum aestivum) production, causing dramatic yield losses worldwide. Identifying heat tolerance genes and comprehending molecular mechanisms are essential. Here, we identify a heat tolerance gene, TaSG-D1E286K, in Indian dwarf wheat (Triticum sphaerococcum), which encodes an STKc_GSK3 kinase. TaSG-D1E286K improves heat tolerance compared to TaSG-D1 by enhancing phosphorylation and stability of downstream target TaPIF4 under heat stress condition. Additionally, we reveal evolutionary footprints of TaPIF4 during wheat selective breeding in China, that is, InDels predominantly occur in the TaPIF4 promoter of Chinese modern wheat cultivars and result in decreased expression level of TaPIF4 in response to heat stress. These sequence variations with negative effect on heat tolerance are mainly introduced from European germplasm. Our study provides insight into heat stress response mechanisms and proposes a potential strategy to improve wheat heat tolerance in future.

Machine learning-based prediction of in-hospital mortality for critically ill patients with sepsis-associated acute kidney injury.

OBJECTIVES: This study aims to develop and validate a prediction model in-hospital mortality in critically ill patients with sepsis-associated acute kidney injury (SA-AKI) based on machine learning algorithms. METHODS: Patients who met the criteria for inclusion were identified in the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and divided according to the validation (n = 2440) and development (n = 9756, 80%) queues. Ensemble stepwise feature selection method was used to screen for effective features. The prediction models of short-term mortality were developed by seven machine learning algorithms. Ten-fold cross-validation was used to verify the performance of the algorithm in the development queue. The area under the receiver operating characteristic curve (ROC-AUC) was used to evaluate the differentiation accuracy and performance of the prediction model in the validation queue. The best-performing model was interpreted by Shapley additive explanations (SHAP). RESULTS: A total of 12,196 patients were enrolled in this study. Eleven variables were finally chosen to develop the prediction model. The AUC of the random forest (RF) model was the highest value both in the Ten-fold cross-validation and evaluation (AUC: 0.798, 95% CI: 0.774-0.821). According to the SHAP plots, old age, low Glasgow Coma Scale (GCS) score, high AKI stage, reduced urine output, high Simplified Acute Physiology Score (SAPS II), high respiratory rate, low temperature, low absolute lymphocyte count, high creatinine level, dysnatremia, and low body mass index (BMI) increased the risk of poor prognosis. CONCLUSIONS: The RF model developed in this study is a good predictor of in-hospital mortality for patients with SA-AKI in the intensive care unit (ICU), which may have potential applications in mortality prediction.

Natural variations of HvSRN1 modulate the spike rachis node number in barley.

Grain number, one of the major determinants of yield in Triticeae crops, is largely determined by spikelet number and spike rachis node number (SRN). Here, we identified three quantitative trait loci (QTLs) for SRN using 145 recombinant inbred lines derived from a barley R90/1815D cross. qSRN1, the major-effect QTL, was mapped to chromosome 2H and explained up to 38.77% of SRN variation. Map-based cloning revealed that qSRN1 encodes the RAWUL domain-containing protein HvSRN1. Further analysis revealed that two key SNPs in the HvSRN1 promoter region (∼2 kb upstream of the transcription start site) affect the transcript level of HvSRN1 and contribute to variation in SRN. Similar to its orthologous proteins OsLAX2 and ZmBA2, HvSRN1 showed protein-protein interactions with HvLAX1, suggesting that the LAX2-LAX1 model for spike morphology regulation may be conserved in Poaceae crops. CRISPR-Cas9-induced HvSRN1 mutants showed reduced SRN but increased grain size and weight, demonstrating a trade-off effect. Our results shed light on the role of HvSRN1 variation in regulating the balance between grain number and weight in barley.

Evaluation of oral small molecule drugs for the treatment of COVID-19 patients: a systematic review and network meta-analysis.

INTRODUCTION: At present, there are some randomized controlled trials (RCTs) of oral small molecule drugs. The purpose of this study was to evaluate the efficacy and safety of oral small molecule drug treatment for COVID-19. METHODS: RCTs were identified through systematic searches of PubMed, Embase, and Cochrane Central Register of Controlled Trials through 1 April 2023. A total of nine RCTs were included, including 30,970 COVID-19 patients comparing five treatments (azvudine, molnupiravir, paxlovid, VV116, and placebo). The Cochrane risk of bias tool for randomized trials (RoB) was used to assess the bias risk of the included studies. The direct and indirect evidence were combined using a Bayesian network meta-analysis (PROSPERO Code No: CRD42023397837). RESULTS: Direct analysis showed that paxlovid was associated with a reduced risk of mortality (odds ratio [OR] 0.12, 95% confidence interval [CI] 0.06-0.25) and hospitalization (OR = 0.04, 95% CI: 0.00-0.67) compared with placebo. Network meta-analysis showed that paxlovid had the highest probability of being the best management strategy in patients with COVID-19, reducing mortality (OR = 0.11, 95% CI: 0.01-1.99; surface under the cumulative ranking curve [SUCRA]: 0.77) and hospitalization (OR = 0.06, 95% CI: 0.00-1.03; SUCRA: 0.95). For prespecified safety outcomes, SUCRA values ranked VV116 (OR = 0.09, 95% CI: 0.00-2.07: SUCRA 0.86) as the most beneficial intervention for the prevention of serious adverse events. CONCLUSIONS: When compared to other antiviral medications, paxlovid can reduce the mortality and hospitalization of COVID-19 patients.

Polypharmacy, potentially inappropriate medications, and drug-drug interactions in older COVID-19 inpatients.

OBJECTIVES: The purpose of this study was to assess the impact of polypharmacy, potentially inappropriate medications, and drug-drug interactions on in-hospital mortality in older COVID-19 inpatients. METHODS: A cross-sectional study was conducted using electronic medical data from a tertiary hospital in Chengdu from December 2022 to January 2023. The 2019 AGS/Beers criteria was used to evaluate the potentially inappropriate mediation (PIM) status of older COVID-19 inpatients (age ≥ 65 years), the drug-drug interactions were evaluated on Medscape, and multivariate logistic regression was used to identify the risk factors associated with in-hospital mortality. RESULTS: A total of 206 older COVID-19 inpatients were included in the study. The mean number of drugs per day was 13.04. The prevalence of PIM use based on the 2019 AGS Beers Criteria was 66.99%. The prevalence of drug-drug interactions was 61.65%. Logistic regression demonstrated that age ≥ 80 (OR: 10.321, 95% CI: 1.649, 64.579, P = 0.013), renal insufficiency (OR: 4.740, 95% CI: 1.366, 16.447, P = 0.014), long-term hospitalization (OR: 6.637, 95% CI: 1.030, 42.779, P = 0.046), severe pneumonia (OR: 50.230, 95% CI: 5.180, 487.041, P = 0.001) were influencing factors associated with in-hospital mortality in older COVID-19 inpatients. CONCLUSIONS: The polypharmacy, potentially inappropriate medications, and drug-drug interactions were seen in many older COVID-19 inpatients.

CoreSNP: an efficient pipeline for core marker profile selection from genome-wide SNP datasets in crops.

BACKGROUND: DNA marker profiles play a crucial role in the identification and registration of germplasm, as well as in the distinctness, uniformity, and stability (DUS) testing of new plant variety protection. However, selecting minimal marker sets from large-scale SNP dataset can be challenging to distinguish a maximum number of samples. RESULTS: Here, we developed the CoreSNP pipeline using a "divide and conquer" strategy and a "greedy" algorithm. The pipeline offers adjustable parameters to guarantee the distinction of each sample pair with at least two markers. Additionally, it allows datasets with missing loci as input. The pipeline was tested in barley, soybean, wheat, rice and maize. A few dozen of core SNPs were efficiently selected in different crops with SNP array, GBS, and WGS dataset, which can differentiate thousands of individual samples. The core SNPs were distributed across all chromosomes, exhibiting lower pairwise linkage disequilibrium (LD) and higher polymorphism information content (PIC) and minor allele frequencies (MAF). It was shown that both the genetic diversity of the population and the characteristics of the original dataset can significantly influence the number of core markers. In addition, the core SNPs capture a certain level of the original population structure. CONCLUSIONS: CoreSNP is an efficiency way of core marker sets selection based on Genome-wide SNP datasets of crops. Combined with low-density SNP chip or genotyping technologies, it can be a cost-effective way to simplify and expedite the evaluation of genetic resources and differentiate different crop varieties. This tool is expected to have great application prospects in the rapid comparison of germplasm and intellectual property protection of new varieties.

Efficacy and safety of azvudine in patients with COVID-19: A systematic review and meta-analysis.

Introduction: Azivudine has undergone a few randomized controlled trials (RCTs) as of late. This study aimed to assess the COVID-19 treatment with azvudine's efficacy and safety. Methods: Through January 20, 2023, systematic searches of PubMed, Embase, ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), Cochrane Central Register of Controlled Trials (CENTRAL), and MedRxiv were conducted to find the RCTs. The included studies' bias risk was evaluated using the Cochrane Handbook for Systematic Reviews of Interventions. Meta-analysis was performed using Revman 5.4 (PROSPERO Code: CRD42023395022). Results: A total of five RCTs with 1142 COVID-19 patients, 575 of whom received azvudine, were included. Additionally, seven RCTs are currently being conducted. In terms of clinical improvement and PT-PCR (reverse transcription polymerase chain reaction) negativity, the azvudine group had a greater patient percentage than the usual treatment or placebo group. It also took less time for the PT-PCR to become negative. In comparison to the placebo or standard treatment groups, the frequency of adverse events was reduced in the azvudine group (risk ratio [RR] = 0.89, 95% confidence interval [CI]: 0.80 to 0.99) and major adverse events (RR = 0.63, 95% CI: 0.22 to 1.79) groups. Conclusions: Without the burden of side effects, azvudine can hasten the clinical symptoms of COVID-19 patients and PT-PCR negative. It will take more extensive research to confirm these conclusions.

Global prevalence of polypharmacy and potentially inappropriate medication in older patients with dementia: a systematic review and meta-analysis.

Background: Older patients with dementia always need multiple drugs due to comorbidities and cognitive impairment, further complicating drug treatment and increasing the risk of potentially inappropriate medication. The objective of our study is to estimate the global prevalence of polypharmacy and potentially inappropriate medication (PIM) and explore the factors of PIM for older patients with dementia. Methods: We searched PubMed, Embase (Ovid), and Web of Science databases to identify eligible studies from inception to 16 June 2023. We conducted a meta-analysis for observational studies reporting the prevalence of potentially inappropriate medication and polypharmacy in older patients with dementia using a random-effect model. The factors associated with PIM were meta-analyzed. Results: Overall, 62 eligible studies were included, of which 53 studies reported the prevalence of PIM and 28 studies reported the prevalence of polypharmacy. The pooled estimate of PIM and polypharmacy was 43% (95% CI 38-48) and 62% (95% CI 52-71), respectively. Sixteen studies referred to factors associated with PIM use, and 15 factors were further pooled. Polypharmacy (2.83, 95% CI 1.80-4.44), diabetes (1.31, 95% CI 1.04-1.65), heart failure (1.17, 95% CI 1.00-1.37), depression (1.45, 95% CI 1.14-1.88), history of cancer (1.20, 95% CI 1.09-1.32), hypertension (1.46, 95% CI 1.05-2.03), ischemic heart disease (1.55, 95% CI 0.77-3.12), any cardiovascular disease (1.11, 95% CI 1.06-1.17), vascular dementia (1.09, 95% CI 1.03-1.16), chronic obstructive pulmonary disease (1.39, 95% CI 1.13-1.72), and psychosis (1.91, 95% CI 1.04-3.53) are positively associated with PIM use. Conclusion: PIM and polypharmacy were highly prevalent in older patients with dementia. Among different regions, the pooled estimate of PIM use and polypharmacy varied widely. Increasing PIM in older patients with dementia was closely associated with polypharmacy. For other comorbidities such as heart failure and diabetes, prescribing should be cautioned.

TaACTIN7-D regulates plant height and grain shape in bread wheat.

Exploitation of new gene resources and genetic networks contributing to the control of crop yield-related traits, such as plant height, grain size, and shape, may enable us to breed modern high-yielding wheat varieties through molecular methods. In this study, via ethylmethanesulfonate mutagenesis, we identify a wheat mutant plant, mu-597, that shows semi-dwarf plant architecture and round grain shape. Through bulked segregant RNA-seq and map-based cloning, the causal gene for the semi-dwarf phenotype of mu-597 is located. We find that a single-base mutation in the coding region of TaACTIN7-D (TaACT7-D), leading to a Gly-to-Ser (G65S) amino acid mutation at the 65th residue of the deduced TaACT7-D protein, can explain the semi-dwarfism and round grain shape of mu-597. Further evidence shows that the G65S mutation in TaACT7-D hinders the polymerization of actin from monomeric (G-actin) to filamentous (F-actin) status while attenuates wheat responses to multiple phytohormones, including brassinosteroids, auxin, and gibberellin. Together, these findings not only define a new semi-dwarfing gene resource that can be potentially used to design plant height and grain shape of bread wheat but also establish a direct link between actin structure modulation and phytohormone signal transduction.

CpxR promotes the carbapenem antibiotic resistance of Klebsiella pneumoniae by directly regulating the expression and the dissemination of blaKPC on the IncFII conjugative plasmid.

Klebsiella pneumoniae is an important human pathogen known for its resistance to carbapenem antibiotics, especially the increasing carbapenem-resistant hypervirulent variants. The carbapenem resistance is mainly caused by the carbapenemase gene blaKPC which was commonly found on the IncFII transferable plasmids in K. pneumoniae ST11 isolates in regions of China. However, the mechanisms of the plasmid-carrying blaKPC regulation by the host strain are not clear. To investigate the chromosome-encoded two-component system (TCS) that regulates the carbapenem resistance of K. pneumoniae caused by blaKPC, twenty-four TCSs of a carbapenem-resistant classical K. pneumoniae ST11 clinical isolate were knocked out. The deletion mutation of the TCS regulator cpxR exhibited increased sensitivity to carbapenem, which could be restored by complementation with cpxR in trans. Electrophoretic mobility shift, isothermal titration calorimetry and DNase I footprinting results revealed that CpxR directly bound to the promoter DNA of blaKPC and the binding was abolished by disrupting the DNA-binding domain in CpxR. The subsequent in vivo assays using the lacZ reporter system and qPCR showed that CpxR upregulates the transcription of blaKPC. Notably, CpxR was also found to activate the transfer of the blaKPC-carrying IncFII plasmid between the hypervirulent K. pneumoniae and E. coli isolates, in which CpxR promoted the transcription of the tra operon via binding to its promoter region. These results provide an important insight into the regulation of the host factor CpxR in the plasmid-carrying carbapenemase gene in the classical and hypervirulent K. pneumoniae.

Prevalence of Use of Potentially Inappropriate Medications Among Older Adults Worldwide: A Systematic Review and Meta-Analysis.

Importance: The use of potentially inappropriate medications (PIMs) is widespread yet continues to receive little attention in outpatient services. Objective: To estimate the overall prevalence of PIM use in outpatient services. Data Sources: PubMed, Embase, and Web of Science were searched to identify relevant studies published from January 1, 1990, to November 21, 2022. Study Selection: Observational studies that reported the prevalence of PIM use among older patients in outpatient services were screened. Data Extraction and Synthesis: Two reviewers independently selected eligible articles, extracted data, and assessed the risk of bias. A random-effects meta-analysis was conducted to pool the prevalence estimates. Main Outcomes and Measures: The global patterns in the prevalence of PIM use among older patients in outpatient services were estimated, and the temporal trends and regional differences in PIM use were investigated. Results: A total of 94 articles with 132 prevalence estimates were analyzed, including nearly 371.2 million older participants from 17 countries. Overall, the pooled prevalence of PIM use was 36.7% (95% CI, 33.4%-40.0%). Africa had the highest prevalence of PIM use (47.0%; 95% CI, 34.7%-59.4%), followed by South America (46.9%; 95% CI, 35.1%-58.9%), Asia (37.2%; 95% CI, 32.4%-42.2%), Europe (35.0%; 95% CI, 28.5%-41.8%), North America (29.0%; 95% CI, 22.1%-36.3%), and Oceania (23.6%; 95% CI, 18.8%-28.8%). In addition, the prevalence of PIM use is highest in low-income areas. Use of PIMs among older patients has become increasingly prevalent in the past 2 decades. Conclusions and Relevance: This study of patterns of PIM use by different groups, such as geographic regions and World Bank countries, suggests noticeable geographic environment and economic income differences in the burden of PIMs in outpatient services. Furthermore, the high prevalence trend in the past 2 decades indicates that the global burden of PIM use continues to be worthy of attention.

Deprescribing Interventions for Older Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: Deprescribing reduces polypharmacy in older adults. A thorough study of the effect of deprescribing interventions on clinical outcomes in older adults is presently lacking. As a result, we evaluated the impact of deprescribing on clinical outcomes in older patients. DESIGN: Meta-analysis and systematic review of randomized controlled trials (RCTs). PubMed, EMBASE, and Cochrane Library were searched from the time of creation to March 2023. SETTING AND PARTICIPANTS: Randomized controlled trial with participants at least 60 years old. MEASURES: Mortality, falls (number of fallers), hospitalization rates, emergency department visits, medication adherence, HRQoL (health-regulated quality of life), incidence of ADR (adverse drug reactions), PIM (potentially inappropriate medication), and PPO (potentially prescription omission) were evaluated in the meta-analysis. RESULTS: A total of 32 RCTs (18,670 patients) were included. Deprescribing interventions significantly reduced proportions of older adults with PIM, PPO, and the incidence of ADRs. The interventions group also improved medication compliance. CONCLUSIONS AND IMPLICATIONS: Compared to routine care, deprescribing interventions significantly improve clinical outcome indicators for older adults.

Prophylactic use amphotericin B use in patients with hematologic disorders complicated by neutropenia: a systematic review and meta-analysis.

The purpose of this study is to evaluate the efficacy of prophylactic use amphotericin B in patients with hematologic disorders complicated by neutropenia. We searched the PubMed, EMBASE, The Cochrane Library, CBM, CNKI, VIP and WanFang Data database and the China Clinical Trials Registry ( www.chictr.org.cn ) to collect randomized controlled trials (RCTs) of amphotericin B for patients with hematologic disorders complicated by neutropenia from inception to May 2023. The Cochrane risk-of-bias tool for RCTs was used to assess the bias risk of the included studies. The meta-analysis was performed using RevMan 5.3 software. A total of 6 studies with a total of 1019 patients were included. The results of the meta-analysis showed that the treatment group was superior to the control group in terms of the fungal infection rate, and the differences were statistically significant [RR = 0.47, 95% CI (0.32, 0.69), P < 0.0001]. There was no significant difference between the two groups in terms of the mortality [RR = 0.87, 95% CI (0.61, 1.23), P = 0.43] and the incidence of colonization [OR = 0.51, 95% CI (0.25, 1.03), P = 0.06]. The evidence shows that amphotericin B prophylactic use for patients with hematologic disorders complicated by neutropenia can decrease the fungal infection rate. However, there was no significant difference in reducing mortality or the incidence of colonization. Due to the limited quality and quantity of the included studies, more high-quality studies are needed to verify the above conclusion.

Nirmatrelvir-ritonavir compared with other antiviral drugs for the treatment of COVID-19 patients: A systematic review and meta-analysis.

At present, there are some differences in the research results of nirmatrelvir-ritonavir compared with other antiviral drugs for the treatment of COVID-19 patients. We aimed to evaluate the efficacy and safety of nirmatrelvir-ritonavir compared with other antiviral drugs and the impact of different antiviral drugs on the short- and long-term effects of COVID-19. PubMed, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, Google Scholar, and MedRxiv were searched to identify relevant studies from inception to March 30, 2023. We conducted a meta-analysis to estimate the effects of nirmatrelvir-ritonavir compared with other antiviral drugs for the treatment of COVID-19 patients and safety outcomes. The RoB1 and ROBINS-I were used to assess the bias risk of the included studies. Revman 5.4 software was used for meta-analysis (PROSPERO Code No: CRD42023397816). Twelve studies were included, including 30 588 COVID-19 patients, of whom 13 402 received nirmatrelvir-ritonavir. The meta-analysis results showed that the nirmatrelvir-ritonavir group had a lower proportion of patients than the control group in terms of long-term mortality (odds ratio [OR] = 0.29, 95% confidence interval [CI]: 0.13-0.66), hospitalization (OR = 0.44, 95% CI: 0.37-0.53, short term; OR = 0.52, 95% CI: 0.36-0.77, long term), and disease progression (OR = 0.56, 95% CI: 0.38-0.83, short term; OR = 0.60, 95% CI: 0.48-0.74, long term), and nirmatrelvir ritonavir showed little difference in safety compared to the control group. Nirmatrelvir-ritonavir can reduce the mortality and hospitalization of COVID-19 patients compared with other antiviral drugs. Further large-scale studies remain to validate these findings.

Efficacy and Safety of Molnupiravir Treatment for COVID-19: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: There are currently some differences in the research results of molnupiravir. This study aimed to evaluate the efficacy and safety of molnupiravir in the treatment of COVID-19. METHODS: PubMed, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), ClinicalTrials.gov, ICTRP (International Clinical Trials Registry Platform) and medRxiv were searched to identify relevant randomised controlled trials (RCTs) from inception to 1 January 2023. The Cochrane risk of bias tool for randomised trials was used to assess the bias risk of the included studies. Revman 5.4 software was used for meta-analysis. RESULTS: Nine RCTs were included, including 31 573 COVID-19 patients, of whom 15 846 received molnupiravir. The meta-analysis results showed that the molnupiravir group had a higher proportion in terms of clinical improvement (Day 5 RR 2.41, 95% CI 1.18-4.92; Day 10 RR 1.45, 95% CI 1.04-2.01) and real-time polymerase chain reaction negativity (Day 5 RR 2.78, 95% CI 1.38-5.62; Day 10 RR 1.18, 95% CI 1.07-1.31). However, no significant difference was observed between the two groups in terms of mortality, hospitalisation, adverse events and serious adverse events. CONCLUSIONS: Molnupiravir can accelerate the rehabilitation of COVID-19 patients, but it does not significantly reduce mortality and hospitalisation.

Model for predicting prognosis and immunotherapy based on CD+8 T cells infiltration in neuroblastoma.

BACKGROUND: Neuroblastoma (NBL) is an extracranial malignant tumor in children deriving from the neural crest in the sympathetic nervous system. Although various immunotherapy interventions have made significant breakthroughs in many adult cancers, the efficacy of these immunotherapies was still limited in NBL. NBL has low immunogenicity which results in a lack of tumor-infiltrating T lymphocytes in the tumor microenvironment (TME). Moreover, tumor cells can wield many immune evasion strategies both in the TME and systemically to impede lymphocyte infiltration and activation. All these factors hamper the anti-tumor effects of CD8+ T cells during immunotherapy and the levels of infiltrating CD8+ T cells correlate with therapy response. MATERIALS AND METHODS: In this study, we utilized multidimensional bioinformatic methods to establish a risk model based on CD8+ T cells -related genes (CD8+ TRGs). RESULTS: We obtained 33 CD8+ TRGs with well-predictive ability for prognosis in both GSE49711 and E-MTAB-8248 cohorts. Then, 12 CD8+ TRGs including HK2, RP2, HPSE, ELL2, GFI1, SLC22A16, FCGR3A, CTSS, SH2D1A, RBP5, ATF5, and ADAM9 were finally identified for risk model construction and validation. This model revealed a stable performance in prognostic prediction of the overall survival (OS) and event-free survival (EFS) in patients with NBL. Additionally, our research indicated that the immune and stromal scores, immune-related pathways, immune cell infiltration, the expression of major histocompatibility complex (MHC) and immune checkpoint molecules, immunotherapy response, and drug susceptibility revealed significant differences between high and low-risk groups. CONCLUSIONS: According to our analyses, the constructed CD8+ TRGs-based risk model may be promising for the clinical prediction of anti-tumor therapy responses and prognoses in NBL.

Reducing brassinosteroid signalling enhances grain yield in semi-dwarf wheat.

Modern green revolution varieties of wheat (Triticum aestivum L.) confer semi-dwarf and lodging-resistant plant architecture owing to the Reduced height-B1b (Rht-B1b) and Rht-D1b alleles1. However, both Rht-B1b and Rht-D1b are gain-of-function mutant alleles encoding gibberellin signalling repressors that stably repress plant growth and negatively affect nitrogen-use efficiency and grain filling2-5. Therefore, the green revolution varieties of wheat harbouring Rht-B1b or Rht-D1b usually produce smaller grain and require higher nitrogen fertilizer inputs to maintain their grain yields. Here we describe a strategy to design semi-dwarf wheat varieties without the need for Rht-B1b or Rht-D1b alleles. We discovered that absence of Rht-B1 and ZnF-B (encoding a RING-type E3 ligase) through a natural deletion of a haploblock of about 500 kilobases shaped semi-dwarf plants with more compact plant architecture and substantially improved grain yield (up to 15.2%) in field trials. Further genetic analysis confirmed that the deletion of ZnF-B induced the semi-dwarf trait in the absence of the Rht-B1b and Rht-D1b alleles through attenuating brassinosteroid (BR) perception. ZnF acts as a BR signalling activator to facilitate proteasomal destruction of the BR signalling repressor BRI1 kinase inhibitor 1 (TaBKI1), and loss of ZnF stabilizes TaBKI1 to block BR signalling transduction. Our findings not only identified a pivotal BR signalling modulator but also provided a creative strategy to design high-yield semi-dwarf wheat varieties by manipulating the BR signal pathway to sustain wheat production.

Antibiotic-induced degradation of antitoxin enhances the transcription of acetyltransferase-type toxin-antitoxin operon.

BACKGROUND: Bacterial toxin-antitoxin (TA) modules respond to various stressful conditions. The Gcn5-related N-acetyltransferase-type toxin (GNAT) protein encoded by the GNAT-RHH TA locus is involved in the antibiotic tolerance of Klebsiella pneumoniae. OBJECTIVES: To investigate the transcriptional mechanism of the GNAT-RHH operon kacAT under antibiotic stress. METHODS: The transcriptional level of the kacAT operon of K. pneumoniae was measured by quantitative real-time (qRT) PCR assay. The degradation of antitoxin KacA was examined by western blot and fluorescent protein. The ratio of [KacA]:[KacT] was calculated by the fluorescence intensity of KacA-eGFP and mCherry-KacT. Mathematical modelling predicted protein and transcript synthesis dynamics. RESULTS: A meropenem-induced increase in transcript levels of kacA and kacT resulted from the relief from transcriptional autoregulation of the kacAT operon. Meropenem induces the degradation of KacA through Lon protease, resulting in a reduction in the ratio of [KacA]:[KacT]. The decreased ratio causes the dissociation of the KacAT complex from its promoter region, which eliminates the repression of kacAT transcription. In addition, our dynamic model of kacAT expression regulation quantitatively reproduced the experimentally observed reduction of the [KacA]:[KacT] ratio and a large increase in kacAT transcript levels under the condition of strong promoter autorepression by the KacAT complex. CONCLUSIONS: Meropenem promotes the degradation of antitoxin by enhancing the expression of Lon protease. Degradation of antitoxin reduces the ratio of intracellular [antitoxin]:[toxin], leading to detachment of the TA complex from its promoter, and releasing repression of TA operon transcription. These results may provide an important insight into the transcriptional mechanism of GNAT-RHH TA modules under antibiotic stress.