RESUMO
Mining stress induces deformation and fracture of the overlaying rock, which will result in water filling the separation layer if the aquifer finds access to abscission space along the fracture channels. Accurate detection is crucial to prevent water hazards induced by water-bearing fractures. The 3-D time-domain finite-difference method with Yee's grid was adopted to calculate full-space transient electromagnetic response; meanwhile, a typical geologic and geophysical model with a water-bearing block in an separation layer was built according to regional tectonics and stratigraphic developments. By using numerical simulation, the induced voltage and apparent resistivity for both vertical and horizontal components were acquired, and then an approximate inversion was carried out based on the "smoke ring" theory. The results indicate that the diffusion velocity of induced voltage is significantly affected by the water-bearing body in the fracture, and the horizontal velocity of induced voltage is lower than the vertical one. The induced voltage curves indicate that the horizontal response to an anomaly body is stronger than the vertical one, leading to a high apparent resistivity resolution of conductivity contrast and separation layer boundary in the horizontal direction. The results of 3-D simulation making use of a measured data model also demonstrate that the horizontal component of apparent resistivity can reflect the electrical structure in a better way; however, its ability to recognize the concealed and fine conductor is rather weak. Accordingly, the observation method or numerical interpolation method needs to be further improved for data processing and interpretation.
RESUMO
Background: The incidence rate of duodenal neuroendocrine tumors has been increasing in recent years. Endoscopic resection [ER; endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD)] is recommended for nonampullary duodenal neuroendocrine tumors (NAD-NETs) ≤10 mm in diameter that are confined to the submucosal layer and without lymph node or distant metastasis. However, the efficacy and safety of and indications for EMR/ESD remain unclear. Methods: Between November 2011 and April 2021, 12 NAD-NETs in 12 patients who underwent either EMR or ESD were analyzed retrospectively. The rates of en bloc resection, complete resection, pathologic complete resection, margin involvement, lymphovascular invasion, perineural invasion, complications and prognosis were determined during follow-up (median observation period 53.0 months). Results: EMR was performed for two tumors, and ESD was performed for ten tumors. En bloc resection was performed for both tumors (100%) in the EMR group, and complete resection was achieved in one case (50%). Pathological complete resection was achieved in one case (50%), while in the ESD group, these three rates were 90% (9/10), 80% (8/10), and 80% (8/10), respectively. Intraoperative perforation occurred in one patient (10%) during ESD treatment, with no intraoperative or delayed bleeding in either group. Recurrence and distant metastasis were not observed during the mean follow-up period of 53.0 months (range, 18-131 months). Conclusions: For NAD-NETs that measure ≤10 mm in size, are confined to the submucosal layer and have neither suspicious lymph nodes nor distant metastasis, ER (EMR and ESD) may be a safe, effective, and feasible endoscopic technique for removing them.
RESUMO
XPO1 is an attractive and promising therapeutic target frequently overexpressed in multiple hematological malignancies. The clinical use of XPO1 inhibitors in natural killer/T-cell lymphoma (NKTL) is not well documented. Here, we demonstrated that XPO1 overexpression is an indicator of poor prognosis in patients with NKTL. The compassionate use of the XPO1 inhibitor selinexor in combination with chemotherapy showed favorable clinical outcomes in three refractory/relapsed (R/R) NKTL patients. Selinexor induced complete tumor regression and prolonged survival in sensitive xenografts but not in resistant xenografts. Transcriptomic profiling analysis indicated that sensitivity to selinexor was correlated with deregulation of the cell cycle machinery, as selinexor significantly suppressed the expression of cell cycle-related genes. CDK4/6 inhibitors were identified as sensitizers that reversed selinexor resistance. Mechanistically, targeting CDK4/6 could enhance the anti-tumor efficacy of selinexor via the suppression of CDK4/6-pRb-E2F-c-Myc pathway in resistant cells, while selinexor alone could dramatically block this pathway in sensitive cells. Overall, our study provids a preclinical proof-of-concept for the use of selinexor alone or in combination with CDK4/6 inhibitors as a novel therapeutic strategy for patients with R/R NKTL.
Assuntos
Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Proteína Exportina 1 , Hidrazinas , Triazóis , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Exportina 1/antagonistas & inibidores , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Triazóis/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The prognosis of patients with peripheral T-cell lymphoma (PTCL) depends on bone marrow involvement (BMI). The bone marrow (BM) tumor microenvironment in PTCL remains unclear. We performed single-cell RNA sequencing (scRNA-seq) on 11 fresh BM samples from patients with BMI to reveal the associations of immune landscape and genetic variations with the prognosis of PTCL patients. Compared with PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL) had a higher number of T cells, lower number of lymphocytes, and greater inflammation. Immune heterogeneity in AITL is associated with prognosis. In particular, specific T-cell receptor (TCR) T cells are enriched in patients with good response to anti-CD30 therapy. We observed RhoA mutation-associated neoantigens. Chidamide-treated patients had a higher number of CD4+ regulatory cells and a better treatment response compared with other patients. In the nonresponder group, T-cell enrichment progressed to secondary B-cell enrichment and subsequently diffuse large B-cell lymphoma. Moreover, AITL patients with lymphoma-associated hemophagocytic syndrome had more T follicular helper (Tfh) cells with copy number variations in CHR5. To our knowledge, this study is the first to reveal the single-cell landscape of BM microenvironment heterogeneity in PTCL patients with BMI. scRNA-seq can be used to investigate the immune heterogeneity and genetic variations in AITL associated with prognosis.
Assuntos
Medula Óssea , Linfoma de Células T Periférico , Análise de Célula Única , Microambiente Tumoral , Humanos , Linfoma de Células T Periférico/imunologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Medula Óssea/patologia , Medula Óssea/imunologia , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Idoso , Mutação , Receptores de Antígenos de Linfócitos T/genética , Proteína rhoA de Ligação ao GTP/genética , Adulto , Heterogeneidade GenéticaRESUMO
BACKGROUND: The surge in critically ill COVID-19 patients caused a shortage of intensive care unit (ICU) beds. Some hospitals temporarily transformed general wards into ICUs to meet this pressing health care demand. AIM: This study aims to evaluate and analyse the risk factors in temporary ICU from the perspective of nurses. By identifying these factors, the goal is to provide actionable insights and recommendations for effectively establishing and managing temporary ICUs in similar crisis scenarios in the future. STUDY DESIGN: The study was conducted in China within a public hospital. Specifically, it focused on examining 62 nurses working in a temporary ICU that was converted from an infectious disease ward. The research utilized the Hazard Vulnerability Analysis (HVA) scoring method to identify potential threats, evaluate their probability, estimate their impact on specific organizations or regions and calculate the relative risk associated with such occurrences. RESULTS: Staff demonstrated the highest risk percentage (32.74%), with Stuff (16.11%), Space (15.19%) and System (11.30%) following suit. The most critical risk factors included insufficient knowledge and decision-making competence in critical care (56.14%), lacking decision-making abilities and skills in renal replacement therapy care (55.37%), inadequate decision-making capacity and relevant skills in respiratory support care (50.64%), limited decision-making capability in circulatory support care (45.73%) and unfamiliarity with work procedures or systems (42.09%). CONCLUSIONS: Urgent implementation of tailored training and support for temporary ICU nurses is paramount. Addressing capability and skill-related issues among these nurses supersedes resource availability, infrastructure, equipment and system considerations. Essential interventions must target challenges encompassing nurses' inability to perform critical treatment techniques autonomously and ensure standardized care. These measures are designed to heighten patient safety and elevate care quality during emergencies. These findings offer a viable avenue to mitigate potential moral distress, anxiety and depression among nurses, particularly those transitioning from non-critical care backgrounds. These nurses swiftly assimilate into temporary ICUs, and the study's insights offer practical guidance to alleviate their specific challenges. RELEVANCE TO CLINICAL PRACTICE: The study on risk factors for converting traditional wards into temporary ICU during the COVID-19 pandemic, especially from the perspective of nurses, provides crucial insights into the challenges and requirements for effectively establishing and managing these emergency settings. The findings highlight several key areas of concern and opportunities for improvement directly related to clinical practice, particularly in situations where there is a rapid need to adapt to increased demands for critical care. By addressing the identified risk factors through enhanced training, support systems, resource management, process improvements and cultivating a culture of adaptability, not only can the quality of care in temporary ICUs be improved, but also can the health care system be better prepared for future emergencies. These actions will help mitigate the risks associated with such conversions, ultimately benefiting patient safety, staff well-being and the overall effectiveness of health care services in crises.
RESUMO
Graft-versus-host disease (GVHD) is a major life-threatening complication that occurs after allogeneic hematopoietic cell transplantation (HCT). While adult tissue stem cells have been identified as targets of GVHD in the skin and gut, their role in hepatic GVHD is yet to be clarified. In the current study, we explored the fate of bile duct stem cells (BDSCs), capable of generating liver organoids in vitro, during hepatic GVHD after allogeneic HCT. We observed a significant expansion of biliary epithelial cells (BECs) upon injury early after allogeneic HCT. Organoid-forming efficiency from the bile duct was also significantly increased early after allogeneic HCT. Subsequently, the organoid-forming efficiency from bile ducts was markedly decreased in association with the reduction of BECs and the elevation of plasma concentrations of bilirubin, suggesting that GVHD targets BDSCs and impairs the resilience of BECs. The growth of liver organoids in the presence of liver-infiltrating mononuclear cells from allogeneic recipients, but not from syngeneic recipients, significantly reduced in a TGF-ï¢-dependent manner. Administration of SB-431542, an inhibitor of TGF-ß signaling, from day 14 to day 28 protected organoid-forming BDSCs against GVHD and mitigated biliary dysfunction after allogeneic HCT, suggesting that BDSCs are a promising therapeutic target for hepatic GVHD.
RESUMO
BACKGROUND: Monosaccharide transporter (MST) family, as a carrier for monosaccharide transport, plays an important role in carbon partitioning and widely involves in plant growth and development, stress response, and signaling transduction. However, little information on the MST family genes is reported in maize (Zea mays), especially in response to abiotic stresses. In this study, the genome-wide identification of MST family genes was performed in maize. RESULT: A total of sixty-six putative members of MST gene family were identified and divided into seven subfamilies (including SPT, PMT, VGT, INT, pGlcT, TMT, and ERD) using bioinformatics approaches, and gene information, phylogenetic tree, chromosomal location, gene structure, motif composition, and cis-acting elements were investigated. Eight tandem and twelve segmental duplication events were identified, which played an important role in the expansion of the ZmMST family. Synteny analysis revealed the evolutionary features of MST genes in three gramineous crop species. The expression analysis indicated that most of the PMT, VGT, and ERD subfamilies members responded to osmotic and cadmium stresses, and some of them were regulated by ABA signaling, while only a few members of other subfamilies responded to stresses. In addition, only five genes were induced by NaCl stress in MST family. CONCLUSION: These results serve to understand the evolutionary relationships of the ZmMST family genes and supply some insight into the processes of monosaccharide transport and carbon partitioning on the balance between plant growth and development and stress response in maize.
Assuntos
Proteínas de Transporte de Monossacarídeos , Família Multigênica , Filogenia , Proteínas de Plantas , Estresse Fisiológico , Zea mays , Zea mays/genética , Zea mays/fisiologia , Estresse Fisiológico/genética , Proteínas de Transporte de Monossacarídeos/genética , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Evolução Molecular , Reguladores de Crescimento de Plantas/farmacologia , Reguladores de Crescimento de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Genes de PlantasRESUMO
Immunotherapy has transformed the treatment of advanced melanoma. However, up to two-thirds of patients experience disease progression after initially achieving a response to immunotherapy. Furthermore, most research has focused on cutaneous melanoma rather than acral or mucosal melanoma, although the latter predominates in Asian populations. In this review, we examine and summarize current definitions of resistance to immunotherapy and the epidemiology of resistance to PD-1 inhibition. We also review the available literature on molecular mechanisms of resistance, including how the tumor mutational landscape and tumor microenvironments of immunotherapy-resistant acral and mucosal melanomas may influence resistance. Finally, we review strategies for overcoming resistance to PD-1 inhibition and summarize completed studies and ongoing clinical trials. Our review highlights that improving the understanding of resistance mechanisms, optimizing existing therapies and further studying high-risk populations would maximize the potential of immunotherapy and result in optimized treatment outcomes for patients with melanoma.
RESUMO
Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.
Assuntos
Aurora Quinase A , Proteína de Ligação a CREB , Proteínas Proto-Oncogênicas c-myc , Mutações Sintéticas Letais , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Aurora Quinase A/antagonistas & inibidores , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Apoptose/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ABSTRACT: Because multiple myeloma (MM) poses a formidable therapeutic challenge despite recent progress, exploring novel targets is crucial. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) emerges as a promising paracaspase with druggable potential, especially unexplored in MM. Our study provided compelling evidence demonstrating a statistically significant elevation of MALT1 expression in human primary MM cells. Moreover, elevated MALT1 expression was associated with a poorer prognosis in MM. Genetic deletion of MALT1 reduced cell growth, colony formation, and tumor growth in vivo. Pharmacological inhibition with 1 µM of a small-molecular MALT1 inhibitor, Mi-2, effectively inhibited cell growth, inducing mitochondria-dependent apoptotic cell death. Mechanistically, MALT1 inhibition disrupted diverse signal transduction pathways, notably impeding nuclear factor κB (NF-κB). Significantly, the inhibition of MALT1 demonstrated a substantial suppression of NF-κB activation by elevating inhibitor of NF-κB, disrupting the nuclear localization of p65 and c-REL. This effect was observed in both the basal state and when stimulated by B-cell maturation antigen, highlighting the pivotal role of MALT1 inhibition in influencing MM cell survival. It was noteworthy that Mi-2 induces properties associated with immunogenic cell death (ICD), as evidenced by increased calreticulin, adenosine triphosphate release, and high-mobility group protein B1 upregulation, consequently triggering ICD-associated immune activation and enhancing CD8+ T-cell cytotoxicity in vitro. In conclusion, our research highlights MALT1 as a promising druggable target for therapeutic interventions in MM, providing insights into its molecular mechanisms in MM progression.
Assuntos
Antígeno de Maturação de Linfócitos B , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Mieloma Múltiplo , NF-kappa B , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , NF-kappa B/metabolismo , Animais , Camundongos , Antígeno de Maturação de Linfócitos B/metabolismo , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Tobacco-specific nitrosamines (TSNAs) are a group of toxic substances specific to tobacco. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a tobacco-specific nitrosamine measurable in urine with a much longer half-life than cotinine. We aimed to examine the association between urinary tobacco-specific NNAL and HPV infection among American women. We used cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2014 to collect details on their urinary NNAL, HPV infection status, and other essential variables. The association between dietary urinary NNAL and HPV infection status was analyzed by using a weighted multivariate logistic regression model, and stratified subgroup analysis. In total, 5197 participants aged 18-59 years were identified, with overall prevalence of high-risk and low-risk HPV infection of 22.0% and 19.1%, respectively. The highest quartile of NNAL(Q4) was more positively associated with low-risk HPV infection than the lowest quartile of NNAL(Q1) (OR = 1.83 (1.35,2.50), p<0.001). the highest quartile of NNAL(Q4) was more positively associated with high-risk HPV infection than the lowest quartile of NNAL(Q1) (OR = 2.20 (1.57,3.08), p < 0.001). In subgroup analyses, the positive correlation between urinary NNAL levels and low-risk HPV infection status was inconsistent in marital status and BMI (interaction p < 0.05). The positive association of urinary NNAL levels with high-risk HPV infection status was inconsistent in smoking and BMI. (interaction p < 0.05). Tobacco-specific NNAL levels positively correlate with high- and low-risk HPV. Future well-designed longitudinal studies are still needed to validate the effect of tobacco exposure on HPV infection by NNAL.
Assuntos
Nitrosaminas , Inquéritos Nutricionais , Infecções por Papillomavirus , Piridinas , Humanos , Feminino , Nitrosaminas/urina , Adulto , Infecções por Papillomavirus/urina , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Estudos Transversais , Estados Unidos/epidemiologia , Piridinas/urina , Nicotiana , PrevalênciaRESUMO
Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.
Assuntos
Aminopiridinas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Inibidores de Histona Desacetilases , Linfoma Extranodal de Células T-NK , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Benzamidas/administração & dosagem , Benzamidas/uso terapêutico , Benzamidas/efeitos adversos , Idoso , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/patologia , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Adulto , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaAssuntos
Imunoconjugados , Doença de Paget Extramamária , Receptor ErbB-2 , Humanos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/metabolismo , Imunoconjugados/uso terapêutico , Feminino , Masculino , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Pessoa de Meia-Idade , Antineoplásicos Imunológicos/uso terapêutico , Idoso de 80 Anos ou maisRESUMO
Multiple sclerosis (MS) was defined as a rare disease in China due to its low prevalence. For a long time, interferon ß was the only approved disease-modifying therapy (DMT). Since the first oral DMT was approved in 2018, DMT approval accelerated, and seven DMTs were approved within 5 years. With an increasing number of DMTs being prescribed in clinical practice, it is necessary to discuss the standardized MS treatment algorithms depending on the disease activity and DMT availability. In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country.
Treatment algorithms of relapsing multiple sclerosis in China In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country: 1) CIS and RRMS account for more than 90% of the MS patients and most of them are mild to moderate; 2) MS patients should initiate DMT treatments as soon as the disease has been diagnosed in order to reduce the risk of disease progression; 3) Patients who have been diagnosed with MS should start treatment with fundamental DMTs unless the disease course has been highly active; 4) MAGNIMS score may be a suitable and simplified assessment tool for measuring treatment response to DMTs; 5) Patients treated with corticosteroids and NSIS should be switched to the standardized DMT treatment during remission in accordance with disease activity.
RESUMO
BACKGROUND: Culex pipiens pallens and Culex pipiens quinquefasciatus are the dominant species of Culex mosquitoes in China and important disease vectors. Long-term use of insecticides can cause mutations in the voltage-gated sodium channel (vgsc) gene of mosquitoes, but little is known about the current status and evolutionary origins of vgsc gene in different geographic populations. Therefore, this study aimed to determine the current status of vgsc genes in Cx. p. pallens and Cx. p. quinquefasciatus in China and to investigate the evolutionary inheritance of neighboring downstream introns of the vgsc gene to determine the impact of insecticides on long-term evolution. METHODS: Sampling was conducted from July to September 2021 in representative habitats of 22 provincial-level administrative divisions in China. Genomic DNA was extracted from 1308 mosquitoes, the IIS6 fragment of the vgsc gene on the nerve cell membrane was amplified using polymerase chain reaction, and the sequence was used to evaluate allele frequency and knockdown resistance (kdr) frequency. MEGA 11 was used to construct neighbor-joining (NJ) tree. PopART was used to build a TCS network. RESULTS: There were 6 alleles and 6 genotypes at the L1014 locus, which included the wild-type alleles TTA/L and CTA/L and the mutant alleles TTT/F, TTC/F, TCT/S and TCA/S. The geographic populations with a kdr frequency less than 20.00% were mainly concentrated in the regions north of 38° N, and the geographic populations with a kdr frequency greater than 80.00% were concentrated in the regions south of 30° N. kdr frequency increased with decreasing latitude. And within the same latitude, the frequency of kdr in large cities is relatively high. Mutations were correlated with the number of introns. The mutant allele TCA/S has only one intron, the mutant allele TTT/F has three introns, and the wild-type allele TTA/L has 17 introns. CONCLUSIONS: Cx. p. pallens and Cx. p. quinquefasciatus have developed resistance to insecticides in most regions of China. The neighboring downstream introns of the vgsc gene gradually decreased to one intron with the mutation of the vgsc gene. Mutations may originate from multiple mutation events rather than from a single origin, and populations lacking mutations may be genetically isolated.
Assuntos
Culex , Culicidae , Inseticidas , Piretrinas , Canais de Sódio Disparados por Voltagem , Animais , Inseticidas/farmacologia , Íntrons/genética , Mosquitos Vetores/genética , Culex/genética , Mutação , Canais de Sódio Disparados por Voltagem/genética , Resistência a Inseticidas/genéticaRESUMO
Importance: Myasthenia gravis (MG) is caused by autoantibodies that disrupt the neuromuscular junction. The neonatal fragment crystallizable receptor (FcRn) antagonists, efgartigimod and rozanolixizumab, reduce immunoglobulin G (IgG) level in the circulation and alleviate symptoms in patients with generalized MG. Objective: To examine the efficacy and safety profile of batoclimab, a monoclonal IgG1 antibody, in patients with generalized MG. Design, Setting, and Participants: This was a multicenter randomized clinical trial conducted from September 15, 2021, to June 29, 2022, at 27 centers in China. Adult patients 18 years or older with generalized MG were screened, and those who were antibody positive were enrolled. Intervention: Eligible patients received batoclimab or matching placebo in addition to standard of care. Each treatment cycle consisted of 6 weekly subcutaneous injections of batoclimab, 680 mg, or matching placebo followed by 4 weeks of observation. A second treatment cycle was conducted in patients who required continuing treatment. Main Outcome and Measure: The primary outcome was sustained improvement, as defined by a 3-point or greater reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score from baseline for 4 or more consecutive weeks in the first cycle in individuals who were positive for acetylcholine receptor or muscle-specific kinase antibodies. Results: A total of 178 adult patients with generalized MG were screened, 132 were randomly assigned, 131 tested positive for antibodies, and 1 tested negative for antibodies. A total of 132 patients (mean [SE] age, 43.8 [13.6] years; 88 women [67.2%]) were enrolled. The rate of sustained MG-ADL improvement in the first cycle in antibody-positive patients was 31.3% (20 of 64) in the placebo group vs 58.2% (39 of 67) in the batoclimab group (odds ratio, 3.45; 95% CI, 1.62-7.35; P = .001). The MG-ADL score diverged between the 2 groups as early as week 2. The mean (SE) maximum difference in MG-ADL score reduction occurred 1 week after the last dose (day 43, 1.7 [0.3] in the placebo group vs 3.6 [0.3] in the batoclimab group; group difference, -1.9; 95% CI, -2.8 to -1.0; nominal P < .001). The rates of treatment-related and severe treatment-emergent adverse events in patients were 36.9% (24 of 65) and 7.7% (5 of 65) in the placebo group vs 70.1% (47 of 67) and 3.0% (2 of 67) in the batoclimab group, respectively. Conclusions and Relevance: Batoclimab increased the rate of sustained MG-ADL improvement and was well tolerated in adult patients with generalized MG. Clinical effects and the extent of IgG reduction were similar to those previously reported for efgartigimod and rozanolixizumab. Future studies of large sample size are needed to further understand the safety profile of batoclimab. Trial Registration: ClinicalTrials.gov Identifier: NCT05039190.
RESUMO
Artificial photosynthesis provides a sustainable strategy for producing usable fuels and fine chemicals and attracts broad research interest. However, conventional approaches suffer from low reactivity or low selectivity. Herein, we demonstrate that photocatalytic reduction of CO2 coupled with selective oxidation of aromatic alcohol into corresponding syngas and aromatic aldehydes can be processed efficiently and fantastically over the designed S-scheme ZnIn2S4@CdS core-shell hollow nanocage under visible light. In the ZnIn2S4@CdS heterostructure, the photoexcited electrons and holes with weak redox capacities are eliminated, while the photoexcited electrons and holes with powder redox capacities are separated spatially and preserved on the desired active sites. Therefore, even if there are no cocatalysts and no vacancies, ZnIn2S4@CdS exhibits high reactivity. For instance, the CO production of ZnIn2S4@CdS is about 3.2 and 3.4 times higher than that of pure CdS and ZnIn2S4, respectively. More importantly, ZnIn2S4@CdS exhibits general applicability and high photocatalytic stability. Trapping agent experiments, 13CO2 isotopic tracing, in situ characterizations, and theoretical calculations reveal the photocatalytic mechanism. This study provides a new strategy to design efficient and selective photocatalysts for dual-function redox reactions by tailoring the active sites and regulating vector separation of photoexcited charge carriers.
RESUMO
Kernel weight is a critical agronomic trait in maize production. Many genes are related to kernel weight but only a few of them have been applied to maize breeding and cultivation. Here, we identify a novel function of maize mitogen-activated protein kinase 6 (ZmMPK6) in the regulation of maize kernel weight. Kernel weight was reduced in zmmpk6 mutants and increased in ZmMPK6-overexpressing lines. In addition, starch granules, starch content, protein content, and grain-filling characteristics were also affected by the ZmMPK6 expression level. ZmMPK6 is mainly localized in the nucleus and cytoplasm, widely distributed across various tissues, and is expressed during kernel development, which is consistent with its role in kernel weight. Thus, these results provide new insights into the role of ZmMPK6, a mitogen-activated protein kinase, in maize kernel weight, and could be applied to further molecular breeding for kernel quality and yield in maize.
Assuntos
Proteínas de Plantas , Sementes , Zea mays , Zea mays/genética , Zea mays/crescimento & desenvolvimento , Zea mays/metabolismo , Zea mays/enzimologia , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Sementes/crescimento & desenvolvimento , Sementes/genética , Sementes/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genéticaRESUMO
Hybrid rice (Oryza sativa) generally outperforms its inbred parents in yield and stress tolerance, a phenomenon termed heterosis, but the underlying mechanism is not completely understood. Here, we combined transcriptome, proteome, physiological, and heterosis analyses to examine the salt response of super hybrid rice Chaoyou1000 (CY1000). In addition to surpassing the mean values for its two parents (mid-parent heterosis), CY1000 exhibited a higher reactive oxygen species scavenging ability than both its parents (over-parent heterosis or heterobeltiosis). Nonadditive expression and allele-specific gene expression assays showed that the glutathione S-transferase gene OsGSTU26 and the amino acid transporter gene OsAAT30 may have major roles in heterosis for salt tolerance, acting in an overdominant fashion in CY1000. Furthermore, we identified OsWRKY72 as a common transcription factor that binds and regulates OsGSTU26 and OsAAT30. The salt-sensitive phenotypes were associated with the OsWRKY72paternal genotype or the OsAAT30maternal genotype in core rice germplasm varieties. OsWRKY72paternal specifically repressed the expression of OsGSTU26 under salt stress, leading to salinity sensitivity, while OsWRKY72maternal specifically repressed OsAAT30, resulting in salinity tolerance. These results suggest that the OsWRKY72-OsAAT30/OsGSTU26 module may play an important role in heterosis for salt tolerance in an overdominant fashion in CY1000 hybrid rice, providing valuable clues to elucidate the mechanism of heterosis for salinity tolerance in hybrid rice.