Post-translational modification localizes MYC to the nuclear pore basket to regulate a subset of target genes involved in cellular responses to environmental signals.

The transcription factor MYC (also c-Myc) induces histone modification, chromatin remodeling, and the release of paused RNA polymerase to broadly regulate transcription. MYC is subject to a series of post-translational modifications that affect its stability and oncogenic activity, but how these control MYC's function on the genome is largely unknown. Recent work demonstrates an intimate connection between nuclear compartmentalization and gene regulation. Here, we report that Ser62 phosphorylation and PIN1-mediated isomerization of MYC dynamically regulate the spatial distribution of MYC in the nucleus, promoting its association with the inner basket of the nuclear pore in response to proliferative signals, where it recruits the histone acetyltransferase GCN5 to bind and regulate local gene acetylation and expression. We demonstrate that PIN1-mediated localization of MYC to the nuclear pore regulates MYC target genes responsive to mitogen stimulation that are involved in proliferation and migration pathways. These changes are also present at the chromatin level, with an increase in open regulatory elements in response to stimulation that is PIN1-dependent and associated with MYC chromatin binding. Taken together, our study indicates that post-translational modification of MYC controls its spatial activity to optimally regulate gene expression in response to extrinsic signals in normal and diseased states.

A Programmable Peptidic Hydrogel Adjuvant for Personalized Immunotherapy in Resected Stage Tumors.

Adjuvant treatment after surgical resection usually plays an important role in delaying disease recurrence. Immunotherapy displays encouraging results in increasing patients' chances of staying cancer-free after surgery, as reported by recent clinical trials. However, the clinical outcomes of current immunotherapy need to be improved due to the limited responses, patient heterogeneity, nontargeted distribution, and immune-related adverse effects. This work describes a programmable hydrogel adjuvant for personalized immunotherapy after surgical resection. By filling the hydrogel in the cavity, this system aims to address the limited secretion of granzyme B (GrB) during immunotherapy and improve the low immunotherapy responses typically observed, while minimizing immune-related side effects. The TLR7/8 agonist imidazoquinoline (IMDQ) is linked to the self-assembling peptide backbone through a GrB-responsive linkage. Its release could enhance the activation and function of immune cells, which will lead to increased secretion of GrB and enhance the effectiveness of immunotherapy together. The hydrogel adjuvant recruits immune cells, initiates dendritic cell maturation, and induces M1 polarized macrophages to reverse the immunosuppressive tumor microenvironment in situ. In multiple murine tumor models, the hydrogel adjuvant suppresses tumor growth, increases animal survival and long-term immunological memory, and protects mice against tumor rechallenge, leading to effective prophylactic and therapeutic responses. This work provides a potential chemical strategy to overcome the limitations associated with immunotherapy.

Reciprocal natural hybridization between Lycoris aurea and Lycoris radiata (Amaryllidaceae) identified by morphological, karyotypic and chloroplast genomic data.

BACKGROUND: Hybridization is considered as an important model of speciation, but the evolutionary process of natural hybridization is still poorly characterized in Lycoris. To reveal the phylogenetic relationship of two new putative natural hybrids in Lycoris, morphological, karyotypic and chloroplast genomic data of four Lycoris species were analyzed in this study. RESULTS: Two putative natural hybrids (2n = 18 = 4 m + 5t + 6st + 3 T) possessed obvious heterozygosity features of L. radiata (2n = 22 = 10t + 12st) and L. aurea (2n = 14 = 8 m + 6 T) in morphology (e.g. leaf shape and flower color), karyotype (e.g. chromosome numbers, CPD/DAPI bands, 45S rDNA-FISH signals etc.) and chloroplast genomes. Among four Lycoris species, the composition and structure features of chloroplast genomes between L. radiata and the putative natural hybrid 1 (L. hunanensis), while L. aurea and the hybrid 2, were completely the same or highly similar, respectively. However, the features of the cp genomes between L. radiata and the hybrid 2, while L. aurea and the hybrid 1, including IR-LSC/SSC boundaries, SSRs, SNPs, and SNVs etc., were significantly different, respectively. Combining the karyotypes and cp genomes analysis, we affirmed that the natural hybrid 1 originated from the natural hybridization of L. radiata (♀) × L. aurea (♂), while the natural hybrid 2 from the hybridization of L. radiata (♂) × L. aurea (♀). CONCLUSION: The strong evidences for natural hybridization between L. radiata (2n = 22) and L. aurea (2n = 14) were found based on morphological, karyotypic and chloroplast genomic data. Their reciprocal hybridization gave rise to two new taxa (2n = 18) of Lycoris. This study revealed the origin of two new species of Lycoris and strongly supported the role of natural hybridization that facilitated lineage diversification in this genus.

Tilletia horrida glycoside hydrolase family 128 protein, designated ThGhd_7, modulates plant immunity by blocking reactive oxygen species production.

Tilletia horrida is an important soilborne fungal pathogen that causes rice kernel smut worldwide. We found a glycoside hydrolase family 128 protein, designated ThGhd_7, caused cell death in Nicotiana benthamiana leaves. The predicted signal peptide (SP) of ThGhd_7 targets it for secretion. However, loss of the SP did not affect its ability to induce cell death. The 23-201 amino acid sequence of ThGhd_7 was sufficient to trigger cell death in N. benthamiana. ThGhd_7 expression was induced and upregulated during T. horrida infection. ThGhd_7 localised to both the cytoplasm and nucleus of plant cells, and nuclear localisation was required to induce cell death. The ability of ThGhd_7 to trigger cell death in N. benthamiana depends on RAR1 (required for Mla12 resistance), SGT1 (suppressor of G2 allele of Skp1), and BAK1/SERK3 (somatic embryogenesis receptor-like kinase 3). Heterologous overexpression of ThGhd_7 in rice reduced reactive oxygen species (ROS) production and enhanced susceptibility to T. horrida. Further research revealed that ThGhd_7 interacted with and destabilised OsSGT1, which is required for ROS production and is a positive regulator of rice resistance to T. horrida. Taken together, these findings suggest that T. horrida employs ThGhd_7 to disrupt ROS production and thereby promote infection.

MRI Diagnosis of Coronary Artery Lesions in Children With Kawasaki Disease and Their Correlation With Inflammatory Factors.

BACKGROUND: Ultrasonography (US), as a routine examination for evaluating coronary artery lesions (CAL) in children with Kawasaki disease (KD), has strong subjectivity and limitations. Non-contrast enhanced coronary magnetic resonance angiography (NCE-CMRA) is sensitive and reliable in displaying the segments of coronary arteries (CA). PURPOSE: To evaluate the CA using NCE-CMRA, to compare NCE-CMRA with US, and to assess the correlation between KD-related inflammatory factors and the occurrence of CAL. STUDY TYPE: Retrospective. POPULATION: 61 children with KD who had undergone NCE-CMRA. Ultimately, 52 cases were included (32 males and 20 females), with an average of 5.9 ± 0.3 years old. FIELD STRENGTH/SEQUENCE: 3-T, 3D balanced turbo field echo sequence. ASSESSMENT: NCE-CMRA and US coronary visualization rates were compared in 41 children who were imaged with both techniques. Inflammatory factors were compared between CAL and normal coronary artery (NCA) subgroups. In the CAL group, correlations of these inflammatory factors with CAL parameters were investigated. STATISTICAL TESTS: Comparison between groups was performed by the two independent samples t-test; the comparison of enumeration data between groups was performed by chi-square test. Receiver operating characteristic (ROC) curve analysis was performed to determine the sensitivity of inflammatory factors for detecting CAL. The correlation between CAL and inflammatory indexes was analyzed by multiple linear regression. A P value <0.05 was considered statistically significant. RESULTS: NCE-CMRA visualized significantly more segments than US (76% vs. 46%). There were significant differences in PLT, CRP, ESR, and D-dimer between the CAL and NCA groups. ROC curve analysis showed that the sensitivities of these four indicators in diagnosing CAL were 39%, 44%, 72%, and 61%, respectively, at cut-off points of 562.5 × 109 /L, 48.93 mg/L, 45.5 mm/h, and 0.5 mg/L, respectively. DATA CONCLUSION: The combination of NCE-CMRA and inflammatory factors is helpful for the early diagnosis and disease severity of CAL in children with KD. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Reprogramming Macrophages toward Pro-inflammatory Polarization by Peptide Hydrogel.

Macrophages play crucial roles in the innate immune response, exhibiting context-dependent behaviors. Within the tumor microenvironment, macrophages exist as tumor-associated or M2-like macrophages, presenting reprogramming challenges. In this study, we develop a peptide hydrogel that is able to polarize M0 macrophages into pro-inflammatory M1 macrophages through the activation of NF-κB signaling pathways. Importantly, this system is also found to be capable of reprogramming M2 macrophages into pro-inflammatory M1-like macrophages by activating CD206 receptors. The nanofibrous hydrogel self-assembles from a short peptide that contains an innate defense regulator peptide and a self-assembly promoting motif, presenting densely arrayed regulators that multivalently engage with macrophage membrane receptors to not only polarize M0 macrophages but also repolarize M2 macrophages into M1-like macrophages. Overall, this work offers a promising strategy for reprogramming macrophages, holding the potential to enhance immunotherapy by remodeling immune-resistant microenvironments.

Inverse association between maternal serum concentrations of trace elements and risk of spontaneous preterm birth: a nested case-control study in China.

Few studies have evaluated the joint effect of trace elements on spontaneous preterm birth (SPTB). This study aimed to examine the relationships between the individual or mixed maternal serum concentrations of Fe, Cu, Zn, Se, Sr and Mo during pregnancy, and risk of SPTB. Inductively coupled plasma MS was employed to determine maternal serum concentrations of the six trace elements in 192 cases with SPTB and 282 controls with full-term delivery. Multivariate logistic regression, weighted quantile sum regression (WQSR) and Bayesian kernel machine regression (BKMR) were used to evaluate the individual and joint effects of trace elements on SPTB. The median concentrations of Sr and Mo were significantly higher in controls than in SPTB group (P < 0·05). In multivariate logistic regression analysis, compared with the lowest quartile levels of individual trace elements, the third- and fourth-quartile Sr or Mo concentrations were significantly associated with reduced risk of SPTB with adjusted OR (aOR) of 0·432 (95 CI < 0·05). In multivariate logistic regression analysis, compared with the lowest quartile levels of individual trace elements, the third- and fourth-quartile Sr or Mo concentrations were significantly associated with reduced risk of SPTB with adjusted aOR of 0·432 (95 % CI 0·247, 0·756), 0·386 (95 % CI 0·213, 0·701), 0·512 (95 % CI 0·297, 0·883) and 0·559 (95 % CI 0·321, 0·972), respectively. WQSR revealed the inverse combined effect of the trace elements mixture on SPTB (aOR = 0·368, 95 % CI 0·228, 0·593). BKMR analysis confirmed the overall mixture of the trace elements was inversely associated with the risk of SPTB, and the independent effect of Sr and Mo was significant. Our findings suggest that the risk of SPTB decreased with concentrations of the six trace elements, with Sr and Mo being the major contributors.

Combined Use of Emapalumab With Ruxolitinib and Dexamethasone as an Effective Treatment for Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis Complicated With Multiorgan Damage and Severe Infection.

Anti-interferon-γ monoclonal antibody emapalumab and JAK1/2 inhibitors ruxolitinib have been widely reported for the treatment of hemophagocytic lymphohistiocytosis (HLH) recently. These targeted drugs have fewer side effects and may provide new options for patients with HLH who are refractory to previous treatment or intolerant to chemotherapy. Herein, we reported a case of Epstein-Barr virus-related HLH, which did not respond well to HLH-94 plus ruxolitinib and developed severe fungal infection. The disease was successfully controlled after a combination therapy of emapalumab, ruxolitinib, and dexamethasone.

Identification and Analysis of Potential Biomarkers Associated with Neutrophil Extracellular Traps in Cervicitis.

Early diagnosis of cervicitis is important. Previous studies have found that neutrophil extracellular traps (NETs) play pro-inflammatory and anti-inflammatory roles in many diseases, suggesting that they may be involved in the inflammation of the uterine cervix and NETs-related genes may serve as biomarkers of cervicitis. However, what NETs-related genes are associated with cervicitis remains to be determined. Transcriptome analysis was performed using samples of exfoliated cervical cells from 15 patients with cervicitis and 15 patients without cervicitis as the control group. First, the intersection of differentially expressed genes (DEGs) and neutrophil extracellular trap-related genes (NETRGs) were taken to obtain genes, followed by functional enrichment analysis. We obtained hub genes through two machine learning algorithms. We then performed Artificial Neural Network (ANN) and nomogram construction, confusion matrix, receiver operating characteristic (ROC), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Moreover, we constructed ceRNA network, mRNA-transcription factor (TF) network, and hub genes-drug network. We obtained 19 intersecting genes by intersecting 1398 DEGs and 136 NETRGs. 5 hub genes were obtained through 2 machine learning algorithms, namely PKM, ATG7, CTSG, RIPK3, and ENO1. Confusion matrix and ROC curve evaluation ANN model showed high accuracy and stability. A nomogram containing the 5 hub genes was established to assess the disease rate in patients. The correlation analysis revealed that the expression of ATG7 was synergistic with RIPK3. The GSEA showed that most of the hub genes were related to ECM receptor interactions. It was predicted that the ceRNA network contained 2 hub genes, 3 targeted miRNAs, and 27 targeted lnRNAs, and that 5 mRNAs were regulated by 28 TFs. In addition, 36 small molecule drugs that target hub genes may improve the treatment of cervicitis. In this study, five hub genes (PKM, ATG7, CTSG, RIPK3, ENO1) provided new directions for the diagnosis and treatment of patients with cervicitis.

Efficacy and safety of immune checkpoint inhibitors combined with chemotherapy or tyrosine kinase inhibitors in advanced endometrial cancer: A systematic review and meta-analysis.

OBJECTIVE: The objective of this meta-analysis was to conduct a comprehensive assessment of the therapeutic effectiveness and safety profile of the combination of immune checkpoint inhibitors (ICIs) with either chemotherapy or tyrosine kinase inhibitors (TKIs) in the treatment of advanced-stage endometrial cancer (EC). METHODS: This meta-analysis conducted a thorough literature search across PubMed, Cochrane Library, Embase, and Web of Science databases from their earliest records up to November 18th, 2023, identifying qualified randomized controlled trials (RCTs), cohort studies, and single-arm trials for inclusion in the analysis. The meta-analysis were performed to quantify and analyzed the evidence from the existing literature, focusing on outcomes including the objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), progression-free survival (PFS), and adverse events (AE). RESULTS: A total of 13 studies were included. In terms of ICI combined with chemotherapy, the single-arm trials showed that ICI combined with chemotherapy was effective in improving the ORR, but the overall rate of AE was higher. The results based on RCT suggested that ICI combined with chemotherapy resulted in a longer PFS of 12-24 months and OS of 18-month compared to the control group in advanced EC. In terms of ICI combined with TKI, the pooled ORR was 39.0%, the pooled DCR was 79.9%, the pooled OS rate was 50.4%, and the pooled overall AE rate was 95.8%, the pooled grade ≥3 AE rate was 73.8%, the pooled median progression-free survival (mPFS) was 6.126 months, and pooled OS was 15.099 months in advanced EC. CONCLUSIONS: The integrative therapeutic approach combining (ICIs) with chemotherapy or (TKIs demonstrates notable clinical efficacy in advanced EC, which can prolong the survival and help to disease control. Nevertheless, it is imperative for clinicians to be vigilant regarding the potential for adverse reactions to emerge. In addition, more RCTs are needed to solidify this study's efficacy and safety further.

The predictive utility of cytokines, procalcitonin and C-reactive protein among febrile pediatric hematology and oncology patients with severe sepsis or septic shock.

Severe sepsis and septic shock are life-threatening for pediatric hematology and oncology patient receiving chemotherapy. Th1/Th2 cytokines, C-reactive protein (CRP), and procalcitonin (PCT) are all thought to be associated with disease severity. The aim of this study was to prospectively verify the utility of Th1/Th2 cytokines and compare them with PCT and CRP in the prediction of adverse outcomes. Data on patients were collected from January 1, 2011, to December 31, 2020. Blood samples were taken for Th1/Th2 cytokine, CRP, and PCT measurements at the initial onset of infection. Severe infection (SI) was defined as severe sepsis or septic shock. Th1/Th2 cytokine levels were determined by using flow cytometric bead array technology. In total, 7,735 febrile episodes were included in this study. For SI prediction, the AUCs of IL-6, IL-10 and TNF-α were 0.814, 0.805 and 0.624, respectively, while IL-6 and IL-10 had high sensitivity and specificity. IL-6 > 220.85 pg/ml and IL-10 > 29.95 pg/ml had high odds ratio (OR) values of approximately 3.5 in the logistic regression. Within the subgroup analysis, for bloodstream infection (BSI) prediction, the AUCs of IL-10 and TNF-α were 0.757 and 0.694, respectively. For multiorgan dysfunction syndrome (MODS) prediction, the AUC of CRP was 0.606. The AUC of PCT for mortality prediction was 0.620. In conclusion, IL-6 and IL-10 provide good predictive value for the diagnosis of SI. For children with SI, IL-10 and TNF-α are associated with BSI, while CRP and PCT are associated with MODS and death, respectively.

O-Fucosylation of BMP1 promotes endometrial decidualization by activating BMP/Smad signaling pathway.

Endometrial decidualization is critical to successful uterine receptivity and embryo implantation. Dysfunction of decidualization is associated with some pregnancy-related disorders, including miscarriage. Protein glycosylation is involved in many physiological and pathological processes. Protein O-fucosyltransferase 1 (poFUT1) is a key enzyme responsible for O-fucosylation biosynthesis on glycoproteins. Bone morphogenetic protein 1 (BMP1) is an essential glycoprotein in reproduction. However, the role and molecular mechanism of fucosylated BMP1 in endometrial stromal cell decidualization are still unknown. In the current study, we found that BMP1 contains a potential O-fucosylation site. Moreover, poFUT1 and BMP1 levels in the secretory phase are higher than those in the proliferative phase, and the highest level was observed in the human uterine tissues of early pregnancy, while a decrease of poFUT1 and BMP1 in the decidua was observed in miscarriage patients. Using human endometrial stromal cells (hESCs), we demonstrated that O-fucosylation of BMP1 was elevated after induced decidualization. Moreover, the increase of BMP1 O-fucosylation by poFUT1 promoted BMP1 secretion to the extracellular matrix, and more actively binds to CHRD. The binding of BMP1 and CHRD further released BMP4 originally bound to CHRD, and activated BMP/Smad signaling pathway, thereby accelerating the decidualization of human endometrial stromal cells. In summary, these results suggest that BMP1 O-fucosylation by poFUT1 could be a potential diagnostic and therapeutic target to predict miscarriage in early pregnancy examinations.

Controlling Supramolecular Fiber Formation of Nucleopeptide by Guanosine Triphosphate.

Cells use dynamic self-assembly to construct functional structures for maintaining cellular homeostasis. However, using a natural biological small molecule to mimic this phenomenon remains challenging. This work reports the dynamic microfiber formation of nucleopeptide driven by guanosine triphosphate, the small molecule that controls microtubule polymerization in living cells. Deactivation of GTP by enzyme dissociates the fibers, which could be reactivated by adding GTP. Molecular dynamic simulation unveils the mystery of microfiber formation of GBM-1 and GTP. Moreover, the microfiber formation can also be controlled by diffusion-driven GTP gradients across a semipermeable membrane in bulk conditions and the microfluidic method in the defined droplets. This study provides a new platform to construct dynamic self-assembly materials of molecular building blocks driven by GTP.

Analysis of the spatial-temporal evolution of Green and low carbon utilization efficiency of agricultural land in China and its influencing factors under the goal of carbon neutralization.

Agricultural land is the most basic input factor for agricultural production and an essential component of terrestrial ecosystems, which plays a vital role in achieving carbon neutrality. Giving full play to the carbon-neutral contribution of agricultural land is a crucial part of China's economic transformation and green development. It incorporates carbon and pollution emissions from agricultural land use into the unexpected outputs of the Green and Low-carbon Utilization Efficiency of Agricultural Land (GLUEAL) evaluation system. The study utilized several advanced analytical tools, including the super-efficient Slacks-Based Measure (SBM) model, Exploratory Spatial-Temporal Data Analysis (ESTDA) method, Geodetector, and Geographically and Temporally Weighted Regression (GTWR) model. The objective was to examine the spatial-temporal evolution of GLUEAL and identify the factors that influenced it in all 31 provinces of China from 2005 to 2020. The results show that: (1) The overall spatial-temporal evolution of GLUEAL showed an increasing trend, but the disparity between provinces and regions became wider. (2) Most provinces have not yet made significant spatial and temporal jumps. They have high spatial cohesion with specific "path-dependent" characteristics. (3) The Geodetector results reveal that the Number of Rural Labor Force with Higher Education (NRLFHE) and Technology Support for Agriculture (TSA) have insufficient explanatory power on average for GLUEAL. Agricultural Economic Development Level (AEDL), Urbanization Level (UL), Multiple Crop Index (MCI), Planting Structure (PS), Degree of Crop Damage (DCD), Financial support for agriculture (FSA), and Agricultural mechanization level (AML) had stronger explanatory power on average for GLUEAL and were important factors influencing GLUEAL levels. (4) The average influence of AEDL, UL, FSA, and AML on GLUEAL changed from negative to positive. The average influence of MCI and DCD on GLUEAL was negative, and the average influence of PS on GLUEAL changed from positive to negative. This study provides a comprehensive description of the spatial and temporal evolution of GLUEAL in China. It reveals the key factors influencing GLUEAL and analyzes their spatial variations and impact patterns. These findings offer robust evidence for government policymakers to formulate policy measures for sustainable agricultural development and optimized resource allocation, promoting the transformation of agricultural land towards green and low-carbon practices and advancing the achievement of sustainable development goals.

The trend of unintentional injury-related mortality among children aged under-five years in China, 2010-2020: a retrospective analysis from a national surveillance system.

BACKGROUND: In this study, we estimated the trend of unintentional injury mortality among children aged under-five years in China during 2010-2020. METHODS: Data were obtained from China's Under 5 Child Mortality Surveillance System (U5CMSS). The total unintentional injury mortality and all specific-causes unintentional injury mortality was calculated, annual numbers of deaths and live births were adjusted by a 3-year moving average under-reporting rate. The Poisson regression model and the Cochran-Mantel-Haenszel method were used to calculate the average annual decline rate (AADR) and the adjusted relative risk (aRR) of the unintentional injury mortality. RESULTS: In 2010-2020, a total of 7,925 unintentional injury-related deaths were reported in U5CMSS, accounting for 18.7% of all reported deaths. The overall proportion of unintentional injury-related deaths to total under-five children deaths has increased from 15.2% to 2010 to 23.8% in 2020 (χ2 = 227.0, p < 0.001), the unintentional injury mortality significantly decreased from 249.3 deaths per 100,000 live births in 2010 to 178.8 deaths per 100,000 live births in 2020, with an AADR 3.7% (95%CI 3.1-4.4). The unintentional injury mortality rate decreased from 2010 to 2020 in both urban (from 68.1 to 59.7 per 100,000 live births) and rural (from 323.1 to 230.0 per 100,000 live births) areas (urban: χ2 = 3.1, p < 0.08; rural: χ2 = 113.5, p < 0.001). The annual rates of decline in rural areas and urban areas were 4.2% (95%CI 3.4-4.9) and 1.5% (95%CI 0.1-3.3), respectively. The leading causes of unintentional injury mortality were suffocation (2,611, 32.9%), drowning (2,398, 30.3%), and traffic injury (1,428, 12.8%) in 2010-2020. The cause-specific of unintentional injury mortality rates decreased with varying AADRs in 2010-2020, except for traffic injury. The composition of unintentional injury-related deaths also varied by age group. Suffocation was the leading cause in infants, drowning and traffic injury were the leading causes in children aged 1-4 years. Suffocation and poisoning has high incidence in October to March and drowning has high in June to August. CONCLUSION: The unintentional injury mortality rate of children aged under-five years decreased significantly from 2010 to 2020 in China, but great inequity exists in unintentional injury mortality in urban and rural areas. Unintentional injuries are still an important public health problem affecting the health of Chinese children. Effective strategies should be strengthened to reduce unintentional injury in children and these policies and programmes should be targeted to more specific populations, such as rural areas and males.

Spectrum and clinical features of gene mutations in Chinese pediatric acute lymphoblastic leukemia.

PURPOSE: The 5-year survival rate of children with acute lymphoblastic leukemia (ALL) is 85-90%, with a 10-15% rate of treatment failure. Next-generation sequencing (NGS) identified recurrent mutated genes in ALL that might alter the diagnosis, classification, prognostic stratification, treatment, and response to ALL. Few studies on gene mutations in Chinese pediatric ALL have been identified. Thus, an in-depth understanding of the biological characteristics of these patients is essential. The present study aimed to characterize the spectrum and clinical features of recurrent driver gene mutations in a single-center cohort of Chinese pediatric ALL. METHODS: We enrolled 219 patients with pediatric ALL in our single center. Targeted sequencing based on NGS was used to detect gene mutations in patients. The correlation was analyzed between gene mutation and clinical features, including patient characteristics, cytogenetics, genetic subtypes, risk stratification and treatment outcomes using χ2-square test or Fisher's exact test for categorical variables. RESULTS: A total of 381 gene mutations were identified in 66 different genes in 152/219 patients. PIK3R1 mutation was more common in infants (P = 0.021). KRAS and FLT3 mutations were both more enriched in patients with hyperdiploidy (both P < 0.001). NRAS, PTPN11, FLT3, and KMT2D mutations were more common in patients who did not carry the fusion genes (all P < 0.050). PTEN mutation was significantly associated with high-risk ALL patients (P = 0.011), while NOTCH1 mutation was common in middle-risk ALL patients (P = 0.039). Patients with ETV6 or PHF6 mutations were less sensitive to steroid treatment (P = 0.033, P = 0.048, respectively). CONCLUSION: This study depicted the specific genomic landscape of Chinese pediatric ALL and revealed the relevance between mutational spectrum and clinical features of Chinese pediatric ALL, which highlights the need for molecular classification, risk stratification, and prognosis evaluation.

Outcomes of COVID-19 patients undergoing extracorporeal membrane oxygenation: A systematic review and meta-Analysis.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has been ongoing for over 3 years, during which numerous clinical and experimental studies have been conducted. The objective of this systematic review and meta-analysis was to assess the survival probability and complications of COVID-19 patients receiving extracorporeal membrane oxygenation (ECMO). METHODS: We searched the databases by using Population-Intervention-Comparison-Outcome-Study Design (PICOS). We conducted a search of the PubMed, Web of Science, and EMBASE databases to retrieve studies published until December 10, 2022. A random-effects meta-analysis, subgroup analysis, and assessed the studies using the Newcastle-Ottawa Scale score. The results were presented as pooled morbidity with 95% confidence intervals. RESULTS: The study was conducted on 19 studies that enrolled a total of 1494 patients, and the results showed a pooled survival probability of 66.0%. The pooled morbidity for intracranial hemorrhage was 8.7%, intracranial thrombosis 7.0%, pneumothorax 9.0%, pulmonary embolism 11.0%, pulmonary hemorrhage 9.0%, heart failure 14.0%, liver failure 13.0%, renal injury 44.0%, gastrointestinal hemorrhage 6.0%, gastrointestinal ischemia 6.0% and venous thrombosis 31.0%. CONCLUSION: This systematic review and meta-analysis of observational studies focused on the survival probability and complications of COVID-19 patients undergoing ECMO, which are significant in evaluating the use of ECMO in COVID-19 patients and provide a basis for further research. TRIAL REGISTRATION: Our study was registered on PROSPERO with registration number CRD42022382555.

Rice (Oryza sativa L.) cytochrome P450 protein 716A subfamily CYP716A16 regulates disease resistance.

BACKGROUND: The sustainable development of rice production is facing severe threats by a variety of pathogens, such as necrotrophic Rhizoctonia solani and hemibiotrophic Xanthomonas oryzae pv. oryzae (Xoo). Mining and applying resistance genes to increase the durable resistance of rice is an effective method that can be used to control these diseases. RESULTS: In this research, we isolated and characterized CYP716A16, which is a positive regulator of rice to R. solani AG1-IA and Xoo, and belongs to the cytochrome P450 (CYP450) protein 716A subfamily. Overexpression (OE) of CYP716A16 resulted in enhanced resistance to R. solani AG1-IA and Xoo, while RNA interference (RNAi) of CYP716A16 resulted in increased susceptibility compared with wild-type (WT) plants. Additionally, jasmonic acid (JA)-dependent defense responses and reactive oxygen species (ROS) were activated in the CYP716A16-OE lines after R. solani AG1-IA inoculation. The comparative transcriptomic and metabolomics analysis of CYP716A16-OE and the WT lines showed that OE of CYP716A16 activated the biosynthesis of flavonoids and increased the amounts of narcissoside, methylophiopogonanone A, oroxin A, and amentoflavone in plants. CONCLUSION: Based on these results, we suggest that JA-dependent response, ROS level, multiple resistance-related proteins, and flavonoid contents play an important role in CYP716A16-regulated R. solani AG1-IA and Xoo resistance. Our results broaden our knowledge regarding the function of a P450 protein 716A subfamily in disease resistance and provide new insight into the molecular mechanism of rice immune response.

Crystal structure of the cytokinin-producing enzyme "lonely guy" (LOG) from Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) is an extremely successful intracellular pathogen that cause a large number of death worldwide. It is interesting that this non-phytopathogen can synthesize cytokinin by "lonely guy" (LOG) protein. The cytokinin biosynthesis pathway in Mtb is not clear. Here we determined the crystal structure of LOG from Mtb (MtLOG) at a high resolution of 1.8 Å. MtLOG exists as dimer which belongs to type-I LOG and shows a typical α-ß Rossmann fold. Like other LOGs, MtLOG also contains a conserved "PGGXGTXXE" motif that contributes to the formation of an active site. For the first time, we found that the MtLOG binds to Mg2+ in the negative potential pocket. According to the docking result, we found that Arg78, Arg98 and Tyr162 should be the key amino acid involved in substrate binding. Our findings provide a structural basis for cytokinin study in Mtb and will play an important role in design and development of enzyme inhibitors.

The mouse resource at National Resource Center for Mutant Mice.

Mouse models are essential for dissecting disease mechanisms and defining potential drug targets. There are more than 18,500 mouse strains available for research communities in National Resource Center for Mutant Mice (NRCMM) of China, affiliated with Model Animal Research Center of Nanjing University and Gempharmatech Company. In 2019, Gempharmatech launched the Knockout All Project (KOAP) aiming to generate null mutants and gene floxed strains for all protein-coding genes in mouse genome within 5 years. So far, KOAP has generated 8,004 floxed strains and 9,769 KO (knockout) strains (updated to Oct, 2021). NRCMM also created hundreds of Cre transgenic lines, mutant knock-in models, immuno-deficient models, and humanized mouse models. As a member of the international mouse phenotyping consortium (IMPC), NRCMM provides comprehensive phenotyping services for mouse models. In summary, NRCMM will continue to support biomedical community with new mouse models as well as related services.