RESUMO
Flowering plants have evolved numerous intraspecific and interspecific prezygotic reproductive barriers to prevent production of unfavourable offspring1. Within a species, self-incompatibility (SI) is a widely utilized mechanism that rejects self-pollen2,3 to avoid inbreeding depression. Interspecific barriers restrain breeding between species and often follow the SI × self-compatible (SC) rule, that is, interspecific pollen is unilaterally incompatible (UI) on SI pistils but unilaterally compatible (UC) on SC pistils1,4-6. The molecular mechanisms underlying SI, UI, SC and UC and their interconnections in the Brassicaceae remain unclear. Here we demonstrate that the SI pollen determinant S-locus cysteine-rich protein/S-locus protein 11 (SCR/SP11)2,3 or a signal from UI pollen binds to the SI female determinant S-locus receptor kinase (SRK)2,3, recruits FERONIA (FER)7-9 and activates FER-mediated reactive oxygen species production in SI stigmas10,11 to reject incompatible pollen. For compatible responses, diverged pollen coat protein B-class12-14 from SC and UC pollen differentially trigger nitric oxide, nitrosate FER to suppress reactive oxygen species in SC stigmas to facilitate pollen growth in an intraspecies-preferential manner, maintaining species integrity. Our results show that SRK and FER integrate mechanisms underlying intraspecific and interspecific barriers and offer paths to achieve distant breeding in Brassicaceae crops.
Assuntos
Brassicaceae , Flores , Hibridização Genética , Proteínas de Plantas , Polinização , Brassicaceae/genética , Brassicaceae/metabolismo , Depressão por Endogamia , Óxido Nítrico/metabolismo , Fosfotransferases/metabolismo , Melhoramento Vegetal , Proteínas de Plantas/metabolismo , Pólen/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Especificidade da Espécie , Flores/metabolismo , AutofertilizaçãoRESUMO
Schizosaccharomyces pombe Php4 is the regulatory subunit of the CCAAT-binding complexes and plays an important role in the regulation of iron homeostasis and iron-dependent metabolism. Here, we show that Php4 undergoes ubiquitin-dependent degradation in the late logarithmic and stationary phases. The degradation and ubiquitination of Php4 could be attenuated by deletion of hul6, a gene encoding a putative HECT-type E3 ubiquitin ligase. The expression levels of Hul6 and Php4 are oppositely regulated during cell growth. Hul6 interacts with the C-terminal region of Php4. Two lysine residues (K217 and K274) located in the C-terminal region of Php4 are required for its polyubiquitination. Increasing the levels of Php4 by deletion of hul6 or overexpression of php4 decreased expression of Php4 target proteins involved in iron-dependent metabolic pathways such as the tricarboxylic cycle and mitochondrial oxidative phosphorylation, thus causing increased sensitivity to high-iron and reductions in succinate dehydrogenase and mitochondrial complex II activities. Hul6 is located primarily in the mitochondrial outer membrane and most likely targets cytosolic Php4 for ubiquitination and degradation. Taken together, our data suggest that Hul6 regulates iron-dependent metabolism through degradation of Php4 under normal growth conditions. Our results also suggest that Hul6 promotes iron-dependent metabolism to help the cell to adapt to a nutrient-starved growth phase.
Assuntos
Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Citosol/metabolismo , Ferro/metabolismo , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Ubiquitina/metabolismoRESUMO
CTNNB1, encoding ß-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated ß-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection-mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in ß-catenin mutant cell lines and livers. Oncogenic ß-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of ß-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed ß-catenin mutant cell proliferation and tumor formation. Therefore, ß-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of ß-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for ß-catenin mutant liver cancer.
Assuntos
Neoplasias Hepáticas , Pirimidinas , beta Catenina , Animais , Ácido Aspártico , Carcinogênese , Di-Hidro-Orotase/genética , Di-Hidro-Orotase/metabolismo , Sistemas de Liberação de Medicamentos , Ligases , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/fisiopatologia , Camundongos , Nucleotídeos , Fosfatos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/biossíntese , beta Catenina/metabolismoRESUMO
Cattle-yak is a hybrid offspring resulting from the crossbreeding of yak and cattle, and it exhibits substantial heterosis in production performance. However, male sterility in cattle-yak remains a concern. Reports suggest that noncoding RNAs are involved in the regulation of spermatogenesis. Therefore, in this study, we comprehensively compared testicular transcription profiles among cattle, yak, and cattle-yak. Numerous differentially expressed genes (DEGs), differentially expressed circRNAs (DECs), and differentially expressed miRNAs (DEMs) were identified in the intersection of two comparison groups, namely cattle versus cattle-yak and yak versus cattle-yak, with the number of DEGs, DECs, and DEMs being 4968, 360, and 59, respectively. The DEGs in cattle-yaks, cattle, and yaks were mainly associated with spermatogenesis, male gamete generation, and sexual reproduction. Concurrently, GO and KEGG analyses indicated that DEC host genes and DEM source genes were involved in the regulation of spermatogenesis. The construction of a potential competing endogenous RNA network revealed that some differentially expressed noncoding RNAs may be involved in regulating the expression of genes related to testicular spermatogenesis, including miR-423-5p, miR-449b, miR-34b/c, and miR-15b, as well as previously unreported miR-6123 and miR-1306, along with various miRNA-circRNA interaction pairs. This study serves as a valuable reference for further investigations into the mechanisms underlying male sterility in cattle-yaks.
Assuntos
Redes Reguladoras de Genes , MicroRNAs , RNA Circular , RNA Mensageiro , Testículo , Bovinos/genética , Bovinos/metabolismo , Animais , Masculino , Testículo/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espermatogênese/genética , Transcriptoma , RNA Endógeno CompetitivoRESUMO
Electrochemical energy conversion and storage are playing an increasingly important role in shaping the sustainable future. Differential electrochemical mass spectrometry (DEMS) offers an operando and cost-effective tool to monitor the evolution of gaseous/volatile intermediates and products during these processes. It can deliver potential-, time-, mass- and space-resolved signals which facilitate the understanding of reaction kinetics. In this review, we show the latest developments and applications of DEMS in various energy-related electrochemical reactions from three distinct perspectives. (I) What is DEMS addresses the working principles and key components of DEMS, highlighting the new and distinct instrumental configurations for different applications. (II) How to use DEMS tackles practical matters including the electrochemical test protocols, quantification of both potential and mass signals, and error analysis. (III) Where to apply DEMS is the focus of this review, dealing with concrete examples and unique values of DEMS studies in both energy conversion applications (CO2 reduction, water electrolysis, carbon corrosion, N-related catalysis, electrosynthesis, fuel cells, photo-electrocatalysis and beyond) and energy storage applications (Li-ion batteries and beyond, metal-air batteries, supercapacitors and flow batteries). The recent development of DEMS-hyphenated techniques and the outlook of the DEMS technique are discussed at the end. As DEMS celebrates its 40th anniversary in 2024, we hope this review can offer electrochemistry researchers a comprehensive understanding of the latest developments of DEMS and will inspire them to tackle emerging scientific questions using DEMS.
RESUMO
Understanding how life's essential homochiral biopolymers arose from racemic precursors is a challenging quest. Herein, we present a groundbreaking approach involving hierarchical chiral assembly-driven stereoselective ring-opening polymerization of ε-benzyloxycarbonyl-l/d-lysine N-carboxyanhydrides assisted by ultrasonication in an aqueous medium. This method enabled a narrow dispersity within a few minutes and the achievement of high molecular weight for polypeptides, employing a living polymerization mechanism. The polymerization of l and d enantiomers yielded predominantly right- and left-handed superhelical assemblies in a one-pot preparation, respectively. Notably, stereoselective polypeptide segments were efficiently prepared through hierarchical assembly-driven polymerization of racemic monomers in the absence of a catalyst. This research offers an innovative strategy for the convenient preparations of stereoenriched polypeptides and, more importantly, sheds light on the plausible emergence of homochiral peptides in the origin of life.
RESUMO
In this comprehensive review, we examine the intricate interplay between inflammation, ferroptosis, and atrial fibrillation (AF), highlighting their significant roles in AF pathophysiology and pathogenesis. Augmented inflammatory responses are pivotal to AF, potentially leading to atrial remodeling and reentry phenomena by impacting calcium channels and atrial tissue fibrosis. A strong correlation exists between inflammatory cytokines and AF, underscoring the importance of inflammatory signaling pathways, such as NOD-like receptor thermal protien domain associated protein 3 (NLRP3) inflammasome, Nuclear Factor kappa B (NF- κ B) signaling, and Tumor necrosis factor- α (TNF- α ) signaling in AF development. Ferroptosis, a non-apoptotic regulated mode of cell death, has been widely studied in relation to cardiovascular diseases including heart failure, myocardial infarction, cardiomyopathy, and reperfusion injury. The interaction between ferroptosis and inflammation is complex and mutually influential. While significant progress has been made in understanding the inflammation-AF relationship, the role of inflammation as a conduit linking ferroptosis and AF remains underexplored. The specific pathogenesis and key molecules of atrial fibrosis caused by ferroptosis are still not fully understood. Here we review the role of inflammatory signaling in ferroptosis and AF. We elucidated the association between ferroptosis and AF, aiming to unveil mechanisms for targeted inhibition of atrial cell fibrosis and to propose novel therapeutic strategies for AF. This exploration is vital for advancing our knowledge and developing more effective interventions for AF, a condition deeply intertwined with inflammatory processes and ferroptotic pathways.
RESUMO
OBJECTIVE: To investigate the prognostic value of preoperative body composition and serum tumor markers (STM) in patients undergoing surgical treatment for colorectal cancer (CRC) and to establish the prognostic score for patients with CRC. METHODS: This study enrolled 365 patients (training set 245, validation set 120) with CRC who underwent surgical resection. The predictive value of various body composition features and STM for determining CRC prognosis were compared. A novel index score based on the independent risk factors from Cox regression for CRC patients was established and evaluated for its usefulness. RESULTS: Multivariate Cox regression showed that low skeletal muscle radiodensity (SMD) (p = 0.020), low subcutaneous fat area (SFA) (p = 0.029), high carcinoembryonic antigen (CEA) (p = 0.008), and high alpha-fetoprotein (AFP) (p = 0.039) were all independent prognostic factors for poor overall survival (OS). The multifactorial analysis indicated that high intermuscular fat area (IMFA) (p = 0.033) and high CEA (p = 0.009) were independent prognostic factors for poor disease-free survival (DFS). Based on these findings, two scoring systems for OS and DFS were established in the training datasets. CRC patients who scored higher on the new scoring systems had lower OS and DFS (both p < 0.001) as shown in the Kaplan-Meier survival curves in the training and validation datasets. CONCLUSION: In predicting the prognosis of CRC patients, SFA and SMD are superior to other body composition measurements. A scoring system based on body composition and STM can have prognostic value and clinical applicability. CLINICAL RELEVANCE STATEMENT: This scoring system, combining body composition and serum tumor markers, may help predict postoperative survival of CRC patients and help clinicians make well-informed decisions regarding the treatment of patients. KEY POINTS: Colorectal cancer prognosis can be related to body composition. High intermuscular fat area and CEA were independent prognostic factors for poor disease-free survival. This scoring system, based on body composition and tumor markers, can prognosticate for colorectal cancer patients.
RESUMO
A 60-year-old male patient suffered from frequent episodes of atrial tachycardia (AT), after the index procedure of catheter ablation for paroxysmal atrial fibrillation. During the repeat procedure, the activation map showed that the earliest activation site was located at the roof of left atrium. Multiple ablations at the earliest activation site on the roof failed to terminate the AT; however, ablation within the pulmonary artery at an adjacent anatomical site successfully eliminated the AT, even without recording distinct near-field potential.
RESUMO
OBJECTIVE: Large cohort studies provided evidence that elevated remnant cholesterol (RC) was an important risk factor for ischemic stroke. However, the association between high RC and clinical outcomes in acute ischemic stroke (AIS) individuals was still undetermined. METHODS: This retrospective study enrolled 165 AIS patients undergoing mechanical thrombectomy in one tertiary stroke center. We divided patients into two groups based on the median of their RC levels (0.49 mmol/L). The modified Rankin Scale (mRS) was used to evaluate the primary outcome 90 days after the onset of symptoms. The mRS scores ≤ 2 and ≤ 1 at 90 days were deemed as favorable and excellent outcomes, respectively. RESULTS: In the overall AIS patients undergoing mechanical thrombectomy, there was no obvious distinction between the high and low RC group at 90-day favorable outcome (41.0% vs. 47.1%, P = 0.431) or excellent outcome (23.1% vs. 31.0%, P = 0.252). In the subgroup analysis stratified by stroke etiology, non-large artery atherosclerosis (non-LAA) stroke patients yielded with less favorable or excellent prognosis in the high RC group (26.8% vs. 46.8%, adjusted OR = 0.31, 95%CI: 0.11-0.85, P = 0.023; or 12.2% vs. 29.0%, adjusted OR = 0.18, 95%CI: 0.04-0.80, P = 0.024, respectively.). Post hoc power analyses indicated that the power was sufficient for favorable outcome (80.38%) and excellent outcome (88.72%) in non-LAA stroke patients. Additionally, RC can enhance the risk prediction value of a poor outcome (mRS scores 3-6) based on traditional risk indicators (including age, initial NIHSS score, operative duration, and neutrophil-to-lymphocyte ratio) for non-LAA stroke patients (AUC = 0.86, 95%CI: 0.79-0.94, P < 0.001). CONCLUSION: In AIS patients undergoing mechanical thrombectomy, elevated RC was independently related to poor outcome for non-LAA stroke patients, but not to short-term prognosis of LAA stroke patients.
Assuntos
Aterosclerose , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/etiologia , Resultado do Tratamento , Estudos Retrospectivos , Trombectomia/efeitos adversos , Acidente Vascular Cerebral/etiologia , Aterosclerose/etiologia , Colesterol , Isquemia Encefálica/etiologiaRESUMO
Receptor-interacting protein kinase-3 (RIP-3) is a key component for inducing necroptosis following acute brain injury. Purpose of this study is to unveil whether serum RIP-3 levels are related to severity and clinical outcomes after human severe traumatic brain injury (sTBI). In this two-center prospective cohort study, serum RIP-3 levels were detected in 127 healthy controls coupled with 127 sTBI patients. The prognostic indicators encompassed posttraumatic 180-day mortality, overall survival and poor prognosis (defined as extended Glasgow outcome scale scores of 1-4). The prognosis associations were verified via multivariate analysis. There was a significant incremental serum RIP-3 levels in patients with sTBI, relative to the controls. RIP-3 levels of patients were independently correlated with Rotterdam Computed Tomography (CT) scores and Glasgow coma scale (GCS) scores, as well as were independently predictive of mortality, overall survival and poor prognosis. Mortality and poor prognosis were effectively predicted by serum RIP-3 levels under the receiver operating characteristic curve. Linear relationships between RIP-3 levels and their risks were verified. Mortality and poor prognosis models of serum RIP-3 levels combined with GCS and Rotterdam CT scores displayed efficient predictive abilities. The two models were graphically represented, which were of clinical stability and value by employing the calibration and decision curves. Increased serum RIP-3 levels after sTBI are closely linked to heightened trauma severity and poor prognosis, signifying that serum RIP-3 may be an encouraging biomarker for evaluating severity and predicting clinical outcome of sTBI.
Assuntos
Biomarcadores , Lesões Encefálicas Traumáticas , Proteína Serina-Treonina Quinases de Interação com Receptores , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Adulto , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/mortalidade , Lesões Encefálicas Traumáticas/diagnóstico , Biomarcadores/sangue , Estudos Prospectivos , Proteína Serina-Treonina Quinases de Interação com Receptores/sangue , Idoso , Escala de Coma de Glasgow , Estudos de Coortes , Adulto JovemRESUMO
Li and Zn metal batteries are the most promising candidates to replace conventional Li-ion batteries. However, a series of issues, especially dendrites caused by uneven deposition of cations during charge-discharge cycles, hinder their practical application. Here, we proposed a facile separator modification method which combines physical and chemical forces to regulate uniform and rapid deposition of both Li+ and Zn2+. Physically, the electronegativity of modified separators drives rapid transport of metal ions via a surface diffusion mode. Chemically, the polar surface functional groups on coated separators induce uniform deposition of metal ions so that the dendrite growth is effectively inhibited. As a result, the Li and Zn metal anodes employing modified separators can cycle stably for over 1000 h under a large current density of 10 mA cm-2.
RESUMO
Li and Zn metal batteries using organic and aqueous electrolytes, respectively, are desirable next-generation energy storage systems to replace the traditional Li-ion batteries. However, their cycle life and safety performance are severely constrained by a series of issues that are attributed to dendrite growth. To solve these issues, a nanothick ZnO-oleic acid (ZnO-OA) composite protective layer is developed by a facile ionic layer epitaxy method. The ZnO-OA layer provides strong lithophilic and zincophilic properties, which can effectively induce uniform ion deposition. As a result, the ZnO-OA protected Li and Zn metal anodes can cycle stably for over 600 and 1000 h under a large current density of 10 mA cm-2. Employing the ZnO-OA protected anodes, the Li||LiFePO4 cell can maintain a capacity retention of 99.5% after 600 cycles at a 1 C rate and the Zn||MnO2 cell can operate stably for 1000 cycles at 1 A g-1 current density.
RESUMO
Guanine nucleotide-exchange factors (GEFs) genes play key roles in plant root and pollen tube growth, phytohormone responses, and abiotic stress responses. RopGEF genes in Brassica rapa have not yet been explored. Here, GEF genes were found to be distributed across eight chromosomes in B. rapa and were classified into three subfamilies. Promoter sequence analysis of BrRopGEFs revealed the presence of cis-elements characteristic of BrRopGEF promoters, and these cis-elements play a role in regulating abiotic stress tolerance and stress-related hormone responses. Organ-specific expression profiling demonstrated that BrRopGEFs were ubiquitously expressed in all organs, especially the roots, suggesting that they play a role in diverse biological processes. Gene expression analysis revealed that the expression of BrRopGEF13 was significantly up-regulated under osmotic stress and salt stress. RT-qPCR analysis revealed that the expression of BrRopGEF13 was significantly down-regulated under various types of abiotic stress. Protein-protein interaction (PPI) network analysis revealed interactions between RopGEF11, the homolog of BrRopGEF9, and the VPS34 protein in Arabidopsis thaliana, as well as interactions between AtRopGEF1, the homolog of BrRopGEF13 in Arabidopsis, and the ABI1, HAB1, PP2CA, and CPK4 proteins. VPS34, ABI1, HAB1, PP2CA, and CPK4 have previously been shown to confer resistance to unfavorable environments. Overall, our findings suggest that BrRopGEF9 and BrRopGEF13 play significant roles in regulating abiotic stress tolerance. These findings will aid future studies aimed at clarifying the functional characteristics of BrRopGEFs.
Assuntos
Brassica rapa , Brassica rapa/metabolismo , Estresse Fisiológico/genética , Estresse Salino , Família Multigênica , Perfilação da Expressão Gênica , Filogenia , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
OBJECTIVES: To investigate the oral anticoagulants (OACs) use after acute ischemic stroke (AIS) and prognosis of patients with atrial fibrillation (AF). METHODS: This was a real-world follow-up research of AIS patients with AF admitted to 5 hospitals in northwestern China. We visited these individuals every 6 months to check the type, dosage of OACs, and to record IS recurrence, bleeding, and death events and modified Rankin Scale (mRS) scores until December 2022. When one of the following occurring first was endpoint: IS recurrence, death or study end. Patients were divided into continuous anticoagulation group and non-continuous anticoagulation group based on whether they continued to take OACs from the moment they were discharged until the endpoint. We further analyzed the association between anticoagulation persistence and outcomes. RESULTS: Among all 250 patients with OACs indication, 147 patients (58.8 %) received OACs at discharge. Only 37.9 % of patients (39/103) started OACs after discharge. Of the 147 patients treated with OACs, 21.8 % (32/147) discontinued anticoagulation after discharge. 239 of the 250 patients had completed the median 40-month follow-up with 91 patients in continuous anticoagulation group and 148 patients in non-continuous anticoagulation group. In the multivariate COX regression, non-continuous anticoagulation was an independent risk factor for poor prognosis (mRS>2) in AIS patients with AF (1.452[1.011, 2.086], p = 0.043). CONCLUSIONS: This study revealed an upward trend in the use rate of OACs, but low OACs rates that meet guideline-based criteria and low anticoagulation persistence in AF patients after AIS in the northwestern China. Discontinuous anticoagulation was associated with an increased risk of poor prognosis in these patients.
Assuntos
Fibrilação Atrial , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/complicações , AVC Isquêmico/diagnóstico , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/induzido quimicamente , Anticoagulantes/uso terapêutico , Prognóstico , Fatores de Risco , Administração OralRESUMO
INTRODUCTION: Migraine, as a complex neurological disease, brings heavy burden to patients and society. Despite the availability of established therapies, existing medications have limited efficacy. Thus, we aimed to find the drug targets that improve the prognosis of migraine. METHOD: We used Mendelian Randomization (MR) and Summary-data-based MR (SMR) analyses to study possible drug targets of migraine by summary statistics from FinnGen cohorts (nCase = 44,616, nControl = 367,565), with further replication in UK Biobank (nCase = 26,052, nControl = 487,214). Genetic instruments were obtained from eQTLGen and UKB-PPP to verify the drug targets at the gene expression and protein levels. The additional analyses including Bayesian co-localization, the heterogeneity in dependent instruments(HEIDI), Linkage Disequilibrium Score(LDSC), bidirectional MR, multivariate MR(MVMR), heterogeneity test, horizontal pleiotropy test, and Steiger filtering were implemented to consolidate the findings further. Lastly, drug prediction analysis and phenome-wide association study(PheWAS) were employed to imply the possibility of drug targets for future clinical applications. RESULT: The MR analysis of eQTL data showed that four drug targets (PROCR, GSTM4, SLC4A1, and TNFRSF10A) were significantly associated with migraine risk in both the FinnGen and UK Biobank cohorts. However, only GSTM4 exhibited consistent effect directions across the two outcomes(Discovery cohort: OR(95%CI) = 0.94(0.93-0.96); p = 2.70e - 10; Replication cohort: OR(95%CI) = 0.93(0.91-0.94); p = 4.21e - 17). Furthermore, GSTM4 passed the SMR at p < 0.05 and HEIDI test at p > 0.05 at both the gene expression and protein levels. The protein-level MR analysis revealed a strong correlation between genetically predicted GSTM4 with a lower incidence of migraine and its subtypes(Overall migraine: OR(95%CI) = 0.91(0.87-0.95); p = 6.98e-05; Migraine with aura(MA): OR(95%CI) = 0.90(0.85-0.96); p = 2.54e-03; Migraine without aura(MO): OR(95%CI) = 0.90(0.83-0.96); p = 2.87e-03), indicating a strong co-localization relationship (PPH4 = 0.86). Further analyses provided additional validation for the possibility of GSTM4 as a migraine treatment target. CONCLUSION: This study identifies GSTM4 as a potential druggable gene and promising therapeutic target for migraine.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Transtornos de Enxaqueca , Humanos , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/tratamento farmacológico , Análise da Randomização Mendeliana/métodos , Locos de Características Quantitativas/genética , Polimorfismo de Nucleotídeo Único/genética , Glutationa Transferase/genética , Predisposição Genética para Doença/genética , MultiômicaRESUMO
Polyethylene oxide (PEO)-based solid-state batteries hold great promise as the next-generation batteries with high energy density and high safety. However, PEO-based electrolytes encounter certain limitations, including inferior ionic conductivity, low Li+ transference number, and poor mechanical strength. Herein, we aim to simultaneously address these issues by utilizing one-dimensional zwitterionic cellulose nanofiber (ZCNF) as fillers for PEO-based electrolytes using a simple aqueous solution casting method. Multiple characterizations and theoretical calculations demonstrate that the unique zwitterionic structure imparts ZCNF with various functions, such as disrupting PEO crystallization, dissociating lithium salts, anchoring anions through cationic groups, accelerating Li+ migration by anionic groups, as well as its inherent reinforcement effect. As a result, the prepared PL-ZCNF electrolyte exhibits remarkable ionic conductivity (5.37×10-4â S cm-1) and Li+ transference number (0.62) at 60 °C without sacrificing mechanical strength (9.2â MPa), together with high critical current density of 1.1â mA cm-2. Attributed to these merits of PL-ZCNF, the LiFePO4|PL-ZCNF|Li solid-state full-cell delivers exceptional rate capability and cycling performance (900â cycles at 5â C). Notably, the assembled pouch-cell can maintain steady operation over 1000â cycles with an impressive 93.7 % capacity retention at 0.5â C and 60 °C, highlighting the great potential of PL-ZCNF for practical applications.
RESUMO
T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a malignant neoplasm of immature lymphoblasts. Terminal deoxynucleotidyl transferase (TDT) is a template-independent DNA polymerase that plays an essential role in generating diversity for immunoglobulin genes. T-ALL/LBL patients with TDT- have a worse prognosis. However, how TDT- promotes the disease progression of T-ALL/LBL remains unknown. Here we analyzed the prognosis of T-ALL/LBL patients in Shanghai Children's Medical Center (SCMC) and confirmed that TDT- patients had a higher rate of recurrence and remission failure and worse outcomes. Cellular experiments demonstrated that TDT was involved in DNA damage repair. TDT knockout delayed DNA repair, arrested the cell cycle and decreased apoptosis to induce the accumulation of chromosomal abnormalities and tolerance to abnormal karyotypes. Our study demonstrated that the poor outcomes in TDT- T-ALL/LBL might be due to the drug resistance (VP16 and MTX) induced by chromosomal abnormalities. Our findings revealed novel functions and mechanisms of TDT in T-ALL/LBL and supported that hematopoietic stem cell transplantation (HSCT) might be a better choice for these patients.
Assuntos
Linfoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , DNA Nucleotidilexotransferase/genética , DNA Nucleotidilexotransferase/metabolismo , China , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , DNA Polimerase Dirigida por DNA/genética , Aberrações Cromossômicas , Resistência a MedicamentosRESUMO
BACKGROUND: UDP-glucuronate decarboxylase (also named UXS) converts UDP-glucuronic acid (UDP-GlcA) to UDP-xylose (UDP-Xyl) by decarboxylation of the C6-carboxylic acid of glucuronic acid. UDP-Xyl is an important sugar donor that is required for the synthesis of plant cell wall polysaccharides. RESULTS: In this study, we first carried out the genome-wide identification of NtUXS genes in tobacco. A total of 17 NtUXS genes were identified, which could be divided into two groups (Group I and II), and the Group II UXSs can be further divided into two subgroups (Group IIa and IIb). Furthermore, the protein structures, intrachromosomal distributions and gene structures were thoroughly analyzed. To experimentally verify the subcellular localization of NtUXS16 protein, we transformed tobacco BY-2 cells with NtUXS16 fused to the monomeric red fluorescence protein (mRFP) at the C terminus under the control of the cauliflower mosaic virus (CaMV) 35S promoter. The fluorescent signals of NtUXS16-mRFP were localized to the medial-Golgi apparatus. Contrary to previous predictions, protease digestion analysis revealed that NtUXS16 is not a type II membrane protein. Overexpression of NtUXS16 in Arabidopsis seedling in darkness led to a significant increase in hypocotyl length and a reduction in root length compared with the wild type. In summary, these results suggest Golgi apparatus localized-NtUXS16 plays an important role in hypocotyl and root growth in the dark. CONCLUSION: Our findings facilitate our understanding of the novel functions of NtUXS16 and provide insights for further exploration of the biological roles of NtUXS genes in tobacco.