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Transcriptome-wide association study (TWAS) is a popular approach to dissect the functional consequence of disease associated non-coding variants. Most existing TWAS use bulk tissues and may not have the resolution to reveal cell-type specific target genes. Single-cell expression quantitative trait loci (sc-eQTL) datasets are emerging. The largest bulk- and sc-eQTL datasets are most conveniently available as summary statistics, but have not been broadly utilized in TWAS. Here, we present a new method EXPRESSO (EXpression PREdiction with Summary Statistics Only), to analyze sc-eQTL summary statistics, which also integrates 3D genomic data and epigenomic annotation to prioritize causal variants. EXPRESSO substantially improves existing methods. We apply EXPRESSO to analyze multi-ancestry GWAS datasets for 14 autoimmune diseases. EXPRESSO uniquely identifies 958 novel gene x trait associations, which is 26% more than the second-best method. Among them, 492 are unique to cell type level analysis and missed by TWAS using whole blood. We also develop a cell type aware drug repurposing pipeline, which leverages EXPRESSO results to identify drug compounds that can reverse disease gene expressions in relevant cell types. Our results point to multiple drugs with therapeutic potentials, including metformin for type 1 diabetes, and vitamin K for ulcerative colitis.
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Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo , Análisis de la Célula Individual , Humanos , Análisis de la Célula Individual/métodos , Estudio de Asociación del Genoma Completo/métodos , Predisposición Genética a la Enfermedad/genética , Transcriptoma/genética , Enfermedades Autoinmunes/genética , Polimorfismo de Nucleótido Simple , Herencia Multifactorial/genética , Perfilación de la Expresión Génica/métodosRESUMEN
The emergence of antibiotic resistance genes (ARGs) as contaminants in soil poses a significant threat to public health. Earthworms (Eisenia foetida), which are common inhabitants of soil, have been extensively studied for their influence on ARGs. However, the specific impact of earthworms on penicillin-related ARGs remains unclear. In this study, we investigate the role of earthworms in mitigating ARGs, specifically penicillin-related ARGs, in ampicillin-contaminated soil. Utilizing high-throughput quantitative PCR (HT-qPCR), we quantified a significant reduction in the relative abundance of penicillin-related ARGs in soil treated with earthworms, showing a decrease with a p-value of <0.01. Furthermore, high-throughput 16S rRNA gene sequencing revealed that earthworm intervention markedly alters the microbial community structure, notably enhancing the prevalence of specific bacterial phyla such as Proteobacteria, Firmicutes, Chloroflexi, and Tenericutes. Our findings not only demonstrate the effectiveness of earthworms in reducing the environmental load of penicillin-related ARGs but also provide insight into the alteration of microbial communities as a potential mechanism. This research contributes to our understanding of the role of earthworms in mitigating the spread of antibiotic resistance and provides valuable insights for the development of strategies to combat this global health issue.
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Ampicilina , Antibacterianos , Farmacorresistencia Microbiana , Oligoquetos , Microbiología del Suelo , Contaminantes del Suelo , Animales , Ampicilina/farmacología , Antibacterianos/farmacología , Farmacorresistencia Microbiana/genética , Bacterias/genética , Suelo/química , ARN Ribosómico 16S , Microbiota/efectos de los fármacos , Genes BacterianosRESUMEN
Photosynthetic diazotrophs expressing iron-only (Fe-only) nitrogenase can be developed into a promising biofertilizer, as it is independent on the molybdenum availability in the soil. However, the expression of Fe-only nitrogenase in diazotrophs is repressed by the fixed nitrogen of the soil, limiting the efficiency of nitrogen fixation in farmland with low ammonium concentrations that are inadequate for sustainable crop growth. Here, we succeeded in constitutively expressing the Fe-only nitrogenase even in the presence of ammonium by controlling the transcription of Fe-only nitrogenase gene cluster (anfHDGK) with the transcriptional activator of Mo nitrogenase (NifA*) in several different ways, indicating that the engineered NifA* strains can be used as promising chassis cells for efficient expression of different types of nitrogenases. When applied as a biofertilizer, the engineered Rhodopseudomonas palustris effectively stimulated rice growth, contributing to the reduced use of chemical fertilizer and the development of sustainable agriculture.
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Compuestos de Amonio , Oryza , Fijación del Nitrógeno , Nitrogenasa/genética , Nitrogenasa/metabolismo , Nitrógeno/metabolismo , SueloRESUMEN
Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.
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Hipertensión , Proteoma , Humanos , Presión Sanguínea/genética , Proteoma/genética , Proteoma/metabolismo , Transcriptoma/genética , Multiómica , Hipertensión/metabolismo , Riñón/metabolismo , Proteínas de Transporte de Sodio-Glucosa/genética , Proteínas de Transporte de Sodio-Glucosa/metabolismoRESUMEN
With the continuous improvement of people 's living standards, people have put forward higher requirements for the safety and comfort of housing. Therefore, Inherent Defect Insurance, a financial method to guarantee the quality of construction projects, has also emerged. At present, China 's Inherent Defect Insurance has been gradually promoted, but its claim mechanism has not been analyzed and studied. From the perspective of construction engineering, this paper first makes a bibliometric analysis of the influencing factors of insurance claims that may be caused by construction engineering quality through VOSViewers, and the evaluation index system of inherent defects is constructed. Then, according to the influencing factors, the PSO-LSSVR model is adopted to fit the performance function of the inherent defects. Finally, based on the reliability design principle of engineering structure, the reliability index and failure probability of Inherent Defect Insurance are derived from the performance function of inherent defects. This paper also analyzes its application in insurance practice and determines the relationship between the number of insurance underwriting policies and the initial reserve of insurance at a certain risk level. This paper studies the probability of Inherent Defect Insurance by constructing the reliability model of inherent defect risks in construction quality, and analyzes the anti-risk ability of insurance companies from the perspective of claim, which provides scientific analysis methods and theoretical basis for the scientific decision-making of insurance companies.
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Because of lacking of head-to-head comparison between venetoclax and IDH1/IDH2 inhibitors (ivosidenib/enasidenib) for newly diagnosed unfit patients with acute myeloid leukemia (AML), the optimal option for these patients still remains undefined. We searched relevant published reports. Three RCTs with 180 IDH1 mutant and 165 IDH2 mutant patients were identified. Indirect comparison of OS using fixed effects network meta-analysis (NMA) models indicated venetoclax plus azacitidine (Ven-Aza) significantly improved survival than enasidenib plus azacitidine (Ena-Aza) (HR:0.30, p = 0.005) for those newly diagnosed patients with AML and IDH2 Mutation. And, for those IDH2 mutation patients, Ven-Aza also had the highest probability of 98.3% (OS analysis) and 84.0% (CR/CRi analysis) to be the best intervention among these first-line treatment regimens (Ven-Aza, Ena-Aza and Aza). And, there was a favorable trend towards Ven-Aza in survival analysis (HR:0.69, p = 0.42), when compared to ivosidenib plus azacitidine (Ivo-Aza) for those newly diagnosed patients with AML and IDH1 Mutation. For those IDH1 Mutation, venetoclax plus azacitidine (Ven-Aza) had the highest probability of 65.8% (OS analysis) and 73.0% (CR/CRi analysis) to be the best intervention among these first-line treatment regimens (Ven-Aza, ivosidenib plus azacitidine (Ivo-Aza) and azacitidine (Aza)). In conclusion, venetoclax plus azacitidine could be a good option for unfit newly diagnosed patients with acute myeloid leukemia and IDH1/2 mutation. Considering our limits (only trial data-based network meta-analysis et al.), future trials directly comparing these regimens are warranted.
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Aminopiridinas , Compuestos Bicíclicos Heterocíclicos con Puentes , Glicina/análogos & derivados , Leucemia Mieloide Aguda , Piridinas , Sulfonamidas , Triazinas , Humanos , Metaanálisis en Red , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Azacitidina/uso terapéutico , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Isocitrato Deshidrogenasa/genéticaRESUMEN
Metals usually served as the active sites of the heterogeneous bifunctional electro-Fenton reaction, which faced the challenge of poor stability under acidic or even neutral conditions. Exploring a metal-free heterogeneous bifunctional electro-Fenton catalyst can effectively solve the above problems. In this work, a stable metal-free heterogeneous bifunctional boron-modified porous carbon catalyst (BTA-1000) was synthesized. For the BTA-1000 catalyst, the yield of H2O2 (294 mg/L) significantly increased. The degradation rate of phenol by BTA-1000 (0.242 min-1) increased by an order of magnitude, compared with the porous carbon catalyst (0.0105 min-1). The BTA catalyst could rapidly degrade industrial dye wastewater, and its specific energy consumption was 5.52 kW h kg-1 COD-1, lower than that in previous reports (6.38-7.4 kW h kg-1 COD-1). DFT and XPS revealed that CâO and -BC2O groups jointly promoted the generation of H2O2, and the -BCO2 group played dominant roles in the generation of â¢OH because the oxygen atom near the electron-giving groups (-BCO2 group) facilitated the formation of hydrogen bond and H2O2 adsorption. This work gained deep insights into the reaction mechanism of the boron-modified porous carbon catalyst, which helped to guide the development of metal-free heterogeneous bifunctional electro-Fenton catalysts.
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Peróxido de Hidrógeno , Contaminantes Químicos del Agua , Peróxido de Hidrógeno/química , Contaminantes Orgánicos Persistentes , Boro , Oxidación-Reducción , Contaminantes Químicos del Agua/análisis , Electrodos , Carbono , Metales , CatálisisRESUMEN
The treatment of breast cancer can potentially impose a burden on the heart, leading to an increased risk of heart failure. Studies have shown that more than half of breast cancer patients die from non-tumor-related causes, with cardiovascular disease (CVD) being the leading cause of death. However, the underlying mechanism linking breast cancer prognosis and heart failure remains unclear. To investigate this, we conducted an analysis where we compared the differentially expressed genes (DEGs) in early and advanced breast cancer with genes associated with heart failure. This analysis revealed 18 genes that overlapped between the two conditions, with 15 of them being related to immune function. This suggests that immune pathways may play a role in the prognosis of breast cancer patients with heart failure. Using gene expression data from 1260 breast cancer patients, we further examined the impact of these 15 genes on survival time. Additionally, through enrichment analysis, we explored the functions and pathways associated with these genes in relation to breast cancer and heart failure. By constructing a transformer model, we discovered that the expression patterns of these 15 genes can accurately predict the occurrence of heart failure. The model achieved an AUC of 0.86 and an AUPR of 0.91. Moreover, through analysis of single-cell sequencing data from breast cancer patients undergoing PD-1 treatment and experiencing heart failure, we identified a significant number of cell-type-specific genes that were shared between both diseases. This suggests that changes in gene expression in immune cells following breast cancer treatment may be associated with the development of heart failure.
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Neoplasias de la Mama , Enfermedades Cardiovasculares , Insuficiencia Cardíaca , Humanos , Femenino , Neoplasias de la Mama/genética , Mama , Insuficiencia Cardíaca/genética , Corazón , Microambiente Tumoral/genéticaRESUMEN
Because of lacking of head-to-head comparison among recently effective novel agents' combination regimens for newly diagnosed patients with mantle-cell lymphoma (MCL) who are ineligible for intensive therapy like autologous stem-cell transplantation, the optimal option for these patients still remains undefined. We searched relevant published reports. Three randomized controlled trials with 1459 subjects were identified. In the network meta-analysis, ibrutinib plus bendamustine and rituximab (Ibru + BR) significantly improved progression-free survival (PFS) when compared to bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP; hazard ratio [HR]: 0.55, p = .03) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; HR: 0.35, p < .001) for newly diagnosed patients with MCL ineligible for intensive therapy. Among these first-line treatment regimens (Ibru + BR, VR-CAP, R-CHOP, and BR), Ibru + BR had the highest probability of 94.9% to be the best intervention in PFS analysis. No significant difference was found in adverse events analysis. Our data indicated that Ibru + BR seemed to prolong the PFS when compared to VR-CAP and R-CHOP for newly diagnosed patients with MCL ineligible for intensive therapy. Considering our limits, prospective clinical trials directly comparing these regimens are warranted.
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Linfoma de Células del Manto , Adulto , Humanos , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/tratamiento farmacológico , Rituximab , Clorhidrato de Bendamustina/uso terapéutico , Prednisona/uso terapéutico , Metaanálisis en Red , Estudios Prospectivos , Vincristina/efectos adversos , Doxorrubicina/uso terapéutico , Ciclofosfamida/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Because of lacking of head-to-head comparison among polatuzumab (Pola) vedotin and other novel agents for untreated diffuse large B-cell lymphoma (DLBCL), the optimal option remains undefined. We searched twelve relevant published reports, covering 8376 subjects. Interestingly, the PFS benefit with Pola-R-CHP over other regimens was found prominently in those B-cell-like type (ABC-type) patients. For those ABC-type patients, the PFS advantage with Pola-R-CHP was statistically significant, when compared to R-CHOP+Bort (HR: 0.52, P=0.02), R-CHOP+Ibru (HR: 0.43, P=0.001), R-CHOP+Lena (HR: 0.51, P=0.009), G-CHOP (HR: 0.46, P=0.008), and R-CHOP (HR: 0.40, P<0.001). Meanwhile, for those germinal center B-cell-like (GCB) type patients, no PFS advantage with Pola-R-CHP was found when compared to R-CHOP+Bort (HR: 1.18, P=0.46), R-CHOP+Lena (HR: 1.21, P=0.45), G-CHOP (HR: 1.39, P=0.14), R-CHOP-14 (HR: 0.94, P=0.82), and R-CHOP (HR: 1.00, P=1). The PFS advantage with Pola-R-CHP over other regimens might be confined to those patients of ABC-type DLBCL.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B Grandes Difuso , Humanos , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/efectos adversos , Doxorrubicina/efectos adversos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Metaanálisis en Red , Prednisona/efectos adversos , Rituximab/uso terapéutico , Vincristina/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Systemic lupus erythematosus is a heritable autoimmune disease that predominantly affects young women. To improve our understanding of genetic etiology, we conduct multi-ancestry and multi-trait meta-analysis of genome-wide association studies, encompassing 12 systemic lupus erythematosus cohorts from 3 different ancestries and 10 genetically correlated autoimmune diseases, and identify 16 novel loci. We also perform transcriptome-wide association studies, computational drug repurposing analysis, and cell type enrichment analysis. We discover putative drug classes, including a histone deacetylase inhibitor that could be repurposed to treat lupus. We also identify multiple cell types enriched with putative target genes, such as non-classical monocytes and B cells, which may be targeted for future therapeutics. Using this newly assembled result, we further construct polygenic risk score models and demonstrate that integrating polygenic risk score with clinical lab biomarkers improves the diagnostic accuracy of systemic lupus erythematosus using the Vanderbilt BioVU and Michigan Genomics Initiative biobanks.
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Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Humanos , Femenino , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Antimony (Sb) has been pursued as a promising anode material for sodium-ion batteries (SIBs). However, it suffers from severe volume expansion during the sodiation-desodiation process. Encapsulating Sb into a carbon matrix can effectively buffer the volume change of Sb. However, the sluggish Na+ diffusion kinetics in traditional carbon shells is still a bottleneck for achieving high-rate performance in Sb/C composite materials. Here we design and synthesize a yolk-shell Sb@Void@graphdiyne (GDY) nanobox (Sb@Void@GDY NB) anode for high-rate and long cycle life SIBs. The intrinsic in-plane cavities in GDY shells offer three-dimensional Na+ transporting channels, enabling fast Na+ diffusion through the GDY shells. Electrochemical kinetics analyses show that the Sb@Void@GDY NBs exhibit faster Na+ transport kinetics than traditional Sb@C NBs. In situ transmission electron microscopy analysis reveals that the hollow structure and the void space between Sb and GDY successfully accommodate the volume change of Sb during cycling, and the plastic GDY shell maintains the structural integrity of NBs. Benefiting from the above structural merits, the Sb@Void@GDY NBs exhibit excellent rate capability and extraordinary cycling stability.
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The World Health Organization predicts that over the next several years, depression will become the most important mental health issue globally. Growing evidence shows that the flower buds of Hemerocallis citrina Baroni (H. citrina) possess antidepressant properties. In the search for new anti-depression drugs, a total of 15 phenylpropanoids and 22 flavonoids were isolated and identified based on spectral data (1D and 2D NMR, HR-ESI-MS, UV) from H. citrina. Among them, compound 8 was a novel compound, while compounds 1-4, 6, 9, 10, 15, 17, 24-26, 28, and 37 were isolated for the first time from Hemerocallis genus. To study the antidepressant activity of phenylpropanoids and flavonoids fractions from H. citrina, macroporous resin was used to enrich them under the guidance of UV characteristics. UHPLC-MS/MS was applied to identify the constituents of the enriched fractions. According to behavioral tests and biochemical analyses, it showed that phenylpropanoid and flavonoid fractions from H. citrina can improve the depressive-like mental state of chronic unpredictable mild stress (CUMS) rats. This might be accomplished by controlling the amounts of the inflammatory proteins IL-6, IL-1ß, and TNF-α in the hippocampus as well as corticosterone in the serum. Thus, the monomer compounds were tested for their anti-neuroinflammatory activity and their structure-activity relationship was discussed in further detail.
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Hemerocallis , Animales , Antidepresivos/farmacología , Corticosterona , Flavonoides/farmacología , Hemerocallis/química , Interleucina-6 , Ratas , Estrés Psicológico/metabolismo , Espectrometría de Masas en Tándem , Factor de Necrosis Tumoral alfaRESUMEN
Maize (Zea mays L.) is one of the most widely distributed and important crops in China. Maize ear differentiation plays an important role grain yield formation. However, it is unclear if ear and root morphophysiology status affects yield formation by altering ear differentiation and development under different nitrogen (N) conditions. The aim of this study is to understand how the ear differentiation and development are affected by ear and root morphophysiology traits, as affected by the N rate. The experiment consisted of two N rates: high nitrogen (180 kg ha-1), and low nitrogen (60 kg ha-1). Two N-efficient varieties (NEVs) and two N-inefficient varieties (NIVs) were grown in the field. The results showed higher nitrogen accumulation and grain yield in NEVs than in NIVs, which was mainly attributed to the increased N uptake by the larger root system under both N conditions. Under high N conditions, among ear differentiation-related traits, only FR was significantly positively correlated with grain yield, and NEVs ensure FR through higher N concentration and ZR content in ear at the fertilization stage. Under low N conditions, NEVs obtained higher FP, SR and FR through higher N concentration and IAA in ear at the early stage of ear differentiation, maintained lower AR and BTL by higher RA, R-ZR and E-ZR at the late stage of ear growth. These results suggest that NEVs have a more complex mechanism for obtaining higher grain yield under low N conditions than N sufficiency, and that phytohormones play an important role in this process.
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Nitrógeno , Zea mays , Grano Comestible , Reguladores del Crecimiento de las Plantas , Estructuras de las PlantasRESUMEN
By dissolving copper chloride in [Bmim]Cl (1-butyl-3-methylimidazolium chloride), chloride ions can coordinate with copper ions and form [CuCl4]2-, thereby inducing the solution being hydrophobic. In the present work, hydrogen bonds between [Bmim]+ and anions are analyzed and discussed by two-dimensional correlation spectroscopy. Time-dependent attenuated total reflection spectroscopy (ATR-FTIR) is introduced to monitor the hygroscopic process of [Bmim]2[CuCl4] and [Bmim]Cl in situ. Hygroscopic capacity and rate of [Bmim]2[CuCl4] shrink compared with [Bmim]Cl. The change of water molecular clusters has been studied by second-derivative spectra in the hygroscopic process. The behaviors of water molecular in the two ionic liquids are also distinctive.
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Cloruros , Líquidos Iónicos , Cobre , Interacciones Hidrofóbicas e Hidrofílicas , Líquidos Iónicos/química , Análisis Espectral , AguaRESUMEN
Transcriptome-wide association studies (TWAS) are popular approaches to test for association between imputed gene expression levels and traits of interest. Here, we propose an integrative method PUMICE (Prediction Using Models Informed by Chromatin conformations and Epigenomics) to integrate 3D genomic and epigenomic data with expression quantitative trait loci (eQTL) to more accurately predict gene expressions. PUMICE helps define and prioritize regions that harbor cis-regulatory variants, which outperforms competing methods. We further describe an extension to our method PUMICE +, which jointly combines TWAS results from single- and multi-tissue models. Across 79 traits, PUMICE + identifies 22% more independent novel genes and increases median chi-square statistics values at known loci by 35% compared to the second-best method, as well as achieves the narrowest credible interval size. Lastly, we perform computational drug repurposing and confirm that PUMICE + outperforms other TWAS methods.
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Estudio de Asociación del Genoma Completo , Transcriptoma , Reposicionamiento de Medicamentos , Epigenómica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Genómica , Humanos , Polimorfismo de Nucleótido Simple , Transcriptoma/genéticaRESUMEN
Regression is a commonly used statistical model. It is the conditional mean of the response given covariates µ(x)=E(Y|X=x) . However, in some practical problems, the interest is the conditional mean of the response given the covariates belonging to some set A. Notably, in precision medicine and subgroup analysis in clinical trials, the aim is to identify subjects who benefit the most from the treatment, or identify an optimal set in the covariate space which manifests treatment favoritism if a subject's covariates fall in this set and the subject is classified to the favorable treatment subgroup. Existing methods for subgroup analysis achieve this indirectly by using classical regression. This motivates us to develop a new type of regression: set-regression, defined as µ(A)=E(Y|X∈A) which directly addresses the subgroup analysis problem. This extends not only the classical regression model but also improves recursive partitioning and support vector machine approaches, and is particularly suitable for objectives involving optimization of the regression over sets, such as subgroup analysis. We show that the new versatile set-regression identifies the subgroup with increased accuracy. It is easy to use. Simulation studies also show superior performance of the proposed method in finite samples.
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Modelos Estadísticos , Proyectos de Investigación , Ensayos Clínicos como Asunto , Simulación por Computador , Humanos , Análisis de Regresión , Máquina de Vectores de SoporteRESUMEN
Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced non-small-cell lung cancer (NSCLC), the optimal option for these patients still remains undefined. We searched published reports that described the activity and safety of those novel ALK inhibitors (lorlatinib, alectinib and brigatinib) for ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. Five randomized controlled trials were identified, covering 1111 subjects. In the network meta-analysis, lorlatinib seemed to prolong progression free survival than brigatinib (Hazard Ratio: 0.57, P = 0.03) and alectinib (Hazard ratio: 0.65, P = 0.05) for previously untreated patients with ALK-positive advanced NSCLC as assessed by the independent review committee. Meanwhile, lorlatinib significantly improved significant progression free survival than brigatinib (Hazard ratio: 0.57, P = 0.03) and alectinib (Hazard ratio: 0.59, P = 0.03) for ALK inhibitor-naive patients. Among lorlatinib, alectinib, brigatinib, and crizotinib, lorlatinib had the highest probability to reach the best overall confirmed response rates (probability of 48%) and intracranial confirmed response rates (probability of 44%). No significant difference was found among them in overall survival and adverse events analysis. In terms of progression free survival, our results indicated that lorlatinib was the best treatment choice for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. The future head-to-head trials assessing the relative efficacy of lorlatinib, alectinib and brigatinib were warranted.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Aminopiridinas , Quinasa de Linfoma Anaplásico , Carbazoles , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Lactamas , Neoplasias Pulmonares/tratamiento farmacológico , Metaanálisis en Red , Compuestos Organofosforados , Piperidinas , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles , PirimidinasRESUMEN
Flowering and fruit set are important traits affecting fruit quality and yield in rabbiteye blueberry (Vaccinium ashei). Intense efforts have been made to elucidate the influence of vernalization and phytohormones on flowering, but the molecular mechanisms of flowering and fruit set remain unclear. To unravel these mechanisms, we performed transcriptome analysis to explore blueberry transcripts from flowering to early fruit stage. We divided flowering and fruit set into flower bud (S2), initial flower (S3), bloom flower (S4), pad fruit (S5), and cup fruit (S6) based on phenotype and identified 1,344, 69, 658, and 189 unique differentially expressed genes (DEGs) in comparisons of S3/S2, S4/S3, S5/S4, and S6/S5, respectively. There were obviously more DEGs in S3/S2 and S5/S4 than in S4/S3, and S6/S5, suggesting that S3/S2 and S5/S4 represent major transitions from buds to fruit in blueberry. GO and KEGG enrichment analysis indicated these DEGs were mostly enriched in phytohormone biosynthesis and signaling, transporter proteins, photosynthesis, anthocyanins biosynthesis, disease resistance protein and transcription factor categories, in addition, transcript levels of phytohormones and transporters changed greatly throughout the flowering and fruit set process. Gibberellic acid and jasmonic acid mainly acted on the early stage of flowering development like expression of the florigen gene FT, while the expression of auxin response factor genes increased almost throughout the process from bud to fruit development. Transporter proteins were mainly associated with minerals during the early flowering development stage and sugars during the early fruit stage. At the early fruit stage, anthocyanins started to accumulate, and the fruit was susceptible to diseases such as fungal infection. Expression of the transcription factor MYB86 was up-regulated during initial fruit development, which may promote anthocyanin accumulation. These results will aid future studies exploring the molecular mechanism underlying flowering and fruit set of rabbiteye blueberry.
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Arándanos Azules (Planta)/genética , Flores/genética , Frutas/genética , Regulación de la Expresión Génica de las Plantas , Transcriptoma , Antocianinas , Arándanos Azules (Planta)/crecimiento & desarrollo , Perfilación de la Expresión Génica , Transducción de Señal/genéticaRESUMEN
Electrodeionization (EDI) technology is limited by low regeneration efficiency of ion exchange resins, requirements of high-quality influent water, fouling of the ion exchange membrane and electrode, etc. In this work, a novel bed type called a compound bed in which cation and anion exchange resins were near the cation and anion exchange membrane and placed in layers, was proposed to implement high-efficiency regeneration of ion exchange resins. The influence of different operating conditions on the regeneration efficiency of ion exchange resins was elucidated as well. The regeneration efficiency of ion exchange resins could reach 73.1%, when the device was operated for 5 h under current density of 9 mA/cm2, with a cation and anion exchange resins ratio of 2: 3, influent water conductivity of 1,360 µS/cm and hardness of 400 mg/L. Therefore, the proposed compound bed structure not only widened the inlet water conditions, but also achieved the high-efficiency regeneration of ion exchange resins and anti-fouling of membranes and electrodes.