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1.
Blood ; 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39028876

RESUMO

Abatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first FDA-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URD-HCT). We investigated its impact in URD-HCT patients using Center for International Blood and Marrow Transplant Research data for 7/8-human leukocyte antigen (HLA)-mismatched (MMUD) or 8/8-HLA-matched (MUD) URD-HCT recipients between 2011-2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapse-free survival (RFS) for abatacept+CNI/MTX vs CNI/MTX, CNI/MTX+antithymocyte globulin (ATG), and post-transplant cyclophosphamide-based prophylaxis (PT-Cy); other outcomes included aGVHD, chronic GVHD, non-relapse mortality, and relapse. For 7/8-MMUDs, day-180 OS (primary endpoint supporting FDA approval) was significantly higher for abatacept+CNI/MTX vs CNI/MTX (98%vs75%; p=0.0028). Two-year OS was significantly higher for abatacept+CNI/MTX vs CNI/MTX (83%vs55%; p=0.0036), CNI/MTX+ATG (83%vs46%; p=0.0005) and similar to PT-Cy (80%vs68%; p=0.2325). Two-year RFS was significantly higher for abatacept+CNI/MTX vs CNI/MTX (74%vs49%; p=0.0098) and CNI/MTX+ATG (77%vs35%; p=0.0002), and similar vs PT-Cy (72%vs56%; p=0.1058). For 8/8-MUDs, 2-year OS was similar with abatacept+CNI/MTX vs CNI/MTX (70%vs62%; p=0.2569), CNI/MTX+ATG (75%vs64%; p=0.1048), and PT-Cy (74%vs69%; p=0.5543). Two-year RFS for abatacept+CNI/MTX was numerically higher vs CNI/MTX (63%vs52%; p=0.1497) with an improved hazard ratio (HR: 0.46 [0.25-0.86]), and vs CNI/MTX+ATG (66%vs55%; p=0.1193; HR: 0.39 [0.21-0.73]). Two-year RFS was similar vs PT-Cy (68%vs57%; p=0.2356; HR: 0.54 [0.26-1.11]). For both 7/8-MMUD and 8/8-MUD recipients, abatacept+CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX+ATG; outcomes were similar to PT-Cy-based regimens. Abatacept+CNI/MTX has potential to facilitate unrelated donor pool expansion for HCT.

2.
BMC Genomics ; 25(1): 346, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580907

RESUMO

BACKGROUND: The yak (Bos grunniens) is a large ruminant species that lives in high-altitude regions and exhibits excellent adaptation to the plateau environments. To further understand the genetic characteristics and adaptive mechanisms of yak, we have developed a multi-omics database of yak including genome, transcriptome, proteome, and DNA methylation data. DESCRIPTION: The Yak Genome Database ( http://yakgenomics.com/ ) integrates the research results of genome, transcriptome, proteome, and DNA methylation, and provides an integrated platform for researchers to share and exchange omics data. The database contains 26,518 genes, 62 transcriptomes, 144,309 proteome spectra, and 22,478 methylation sites of yak. The genome module provides access to yak genome sequences, gene annotations and variant information. The transcriptome module offers transcriptome data from various tissues of yak and cattle strains at different developmental stages. The proteome module presents protein profiles from diverse yak organs. Additionally, the DNA methylation module shows the DNA methylation information at each base of the whole genome. Functions of data downloading and browsing, functional gene exploration, and experimental practice were available for the database. CONCLUSION: This comprehensive database provides a valuable resource for further investigations on development, molecular mechanisms underlying high-altitude adaptation, and molecular breeding of yak.


Assuntos
Multiômica , Proteoma , Animais , Bovinos/genética , Proteoma/genética , Genoma , Transcriptoma , Anotação de Sequência Molecular
3.
BMC Genomics ; 25(1): 92, 2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38254015

RESUMO

BACKGROUND: Gorals Naemorhedus resemble both goats and antelopes, which prompts much debate about the intragenus species delimitation and phylogenetic status of the genus Naemorhedus within the subfamily Caprinae. Their evolution is believed to be linked to the uplift of the Qinghai-Tibet Plateau (QTP). To better understand its phylogenetics, the genetic information is worth being resolved. RESULTS: Based on a sample from the eastern margin of QTP, we constructed the first reference genome for Himalayan goral Naemorhedus goral, using PacBio long-read sequencing and Hi-C technology. The 2.59 Gb assembled genome had a contig N50 of 3.70 Mb and scaffold N50 of 106.66 Mb, which anchored onto 28 pseudo chromosomes. A total of 20,145 protein-coding genes were predicted in the assembled genome, of which 99.93% were functionally annotated. Phylogenetically, the goral was closely related to muskox on the mitochondrial genome level and nested into the takin-muskox clade on the genome tree, rather than other so-called goat-antelopes. The cladogenetic event among muskox, takin and goral occurred sequentially during the late Miocene (~ 11 - 5 Mya), when the QTP experienced a third dramatic uplift with consequent profound changes in climate and environment. Several chromosome fusions and translocations were observed between goral and takin/muskox. The expanded gene families in the goral genome were mainly related to the metabolism of drugs and diseases, so as the positive selected genes. The Ne of goral continued to decrease since ~ 1 Mya during the Pleistocene with active glaciations. CONCLUSION: The high-quality goral genome provides insights into the evolution and valuable information for the conservation of this threatened group.


Assuntos
Antílopes , Animais , Antílopes/genética , Filogenia , Cabras/genética , Rearranjo Gênico , Cromossomos
4.
Cancer ; 130(11): 2031-2041, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38294959

RESUMO

INTRODUCTION: It was hypothesized that use of proton beam therapy (PBT) in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiation and consolidative immune checkpoint inhibition is associated with fewer unplanned hospitalizations compared with intensity-modulated radiotherapy (IMRT). METHODS: Patients with locally advanced non-small cell lung cancer treated between October 2017 and December 2021 with concurrent chemoradiation with either IMRT or PBT ± consolidative immune checkpoint inhibition were retrospectively identified. Logistic regression was used to assess the association of radiation therapy technique with 90-day hospitalization and grade 3 (G3+) lymphopenia. Competing risk regression was used to compare G3+ pneumonitis, G3+ esophagitis, and G3+ cardiac events. Kaplan-Meier method was used for progression-free survival and overall survival. Inverse probability treatment weighting was applied to adjust for differences in PBT and IMRT groups. RESULTS: Of 316 patients, 117 (37%) received PBT and 199 (63%) received IMRT. The PBT group was older (p < .001) and had higher Charlson Comorbidity Index scores (p = .02). The PBT group received a lower mean heart dose (p < .0001), left anterior descending artery V15 Gy (p = .001), mean lung dose (p = .008), and effective dose to immune circulating cells (p < .001). On inverse probability treatment weighting analysis, PBT was associated with fewer unplanned hospitalizations (adjusted odds ratio, 0.55; 95% CI, 0.38-0.81; p = .002) and less G3+ lymphopenia (adjusted odds ratio, 0.55; 95% CI, 0.37-0.81; p = .003). There was no difference in other G3+ toxicities, progression-free survival, or overall survival. CONCLUSIONS: PBT is associated with fewer unplanned hospitalizations, lower effective dose to immune circulating cells and less G3+ lymphopenia compared with IMRT. Minimizing dose to lymphocytes may be warranted, but prospective data are needed.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Quimiorradioterapia , Hospitalização , Neoplasias Pulmonares , Terapia com Prótons , Radioterapia de Intensidade Modulada , Humanos , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Radioterapia de Intensidade Modulada/métodos , Radioterapia de Intensidade Modulada/efeitos adversos , Feminino , Masculino , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Idoso , Pessoa de Meia-Idade , Hospitalização/estatística & dados numéricos , Terapia com Prótons/métodos , Terapia com Prótons/efeitos adversos , Quimiorradioterapia/métodos , Quimiorradioterapia/efeitos adversos , Estudos Retrospectivos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Linfopenia/etiologia , Anticorpos Monoclonais
5.
J Gene Med ; 26(2): e3673, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38404059

RESUMO

BACKGROUND: Breast cancer (BC), a malignant tumor, is a significant cause of death and disability among women globally. Recent research indicates that copy number variation plays a crucial role in tumor development. In this study, we employed the Single-Cell Variational Aneuploidy Analysis (SCEVAN) algorithm to differentiate between malignant and non-malignant cells, aiming to identify genetic signatures with prognostic relevance for predicting patient survival. METHODS: We analyzed gene expression profiles and associated clinical data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Using the SCEVAN algorithm, we distinguished malignant from non-malignant cells and investigated cellular interactions within the tumor microenvironment (TME). We categorized TCGA samples based on differentially expressed genes (DEGs) between these cell types. Subsequent Kyoto Encyclopedia of Genes and Genomes pathway analysis was conducted. Additionally, we developed polygenic models for the DEGs using least absolute shrinkage and selection operator-penalized Cox regression analysis. To assess the prognostic accuracy of these characteristics, we generated Kaplan-Meier and receiver operating characteristic curves from training and validation datasets. We also monitored the expression variations of prognostic genes across the pseudotime of malignant cells. Patients were divided into high-risk and low-risk groups based on median risk scores to compare their TME and identify potential therapeutic agents. Lastly, polymerase chain reaction was used to validate seven pivotal genes. RESULTS: The SCEVAN algorithm identified distinct malignant and non-malignant cells in GSE180286. Cellchat analysis revealed significantly increased cellular communication, particularly between fibroblasts, endothelial cells and malignant cells. The DEGs were predominantly involved in immune-related pathways. TCGA samples were classified into clusters A and B based on these genes. Cluster A, enriched in immune pathways, was associated with poorer prognosis, whereas cluster B, predominantly involved in circadian rhythm pathways, showed better outcomes. We constructed a 14-gene prognostic signature, validated in a 1:1 internal TCGA cohort and external GEO datasets (GSE42568 and GSE146558). Kaplan-Meier analysis confirmed the prognostic signature's accuracy (p < 0.001). Receiver operating characteristic curve analysis demonstrated the predictive reliability of these prognostic features. Single-cell pseudotime analysis with monocle2 highlighted the distinct expression trends of these genes in malignant cells, underscoring the intratumoral heterogeneity. Furthermore, we explored the differences in TME between high- and low-risk groups and identified 16 significantly correlated drugs. CONCLUSION: Our findings suggest that the 14-gene prognostic signature could serve as a novel biomarker for forecasting the prognosis of BC patients. Additionally, the immune cells and pathways in different risk groups indicate that immunotherapy may be a crucial component of treatment strategies for BC patients.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Prognóstico , Variações do Número de Cópias de DNA , Células Endoteliais , Reprodutibilidade dos Testes , RNA , Microambiente Tumoral/genética
6.
BMC Med ; 22(1): 282, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38972973

RESUMO

BACKGROUND: The advances in deep learning-based pathological image analysis have invoked tremendous insights into cancer prognostication. Still, lack of interpretability remains a significant barrier to clinical application. METHODS: We established an integrative prognostic neural network for intrahepatic cholangiocarcinoma (iCCA), towards a comprehensive evaluation of both architectural and fine-grained information from whole-slide images. Then, leveraging on multi-modal data, we conducted extensive interrogative approaches to the models, to extract and visualize the morphological features that most correlated with clinical outcome and underlying molecular alterations. RESULTS: The models were developed and optimized on 373 iCCA patients from our center and demonstrated consistent accuracy and robustness on both internal (n = 213) and external (n = 168) cohorts. The occlusion sensitivity map revealed that the distribution of tertiary lymphoid structures, the geometric traits of the invasive margin, the relative composition of tumor parenchyma and stroma, the extent of necrosis, the presence of the disseminated foci, and the tumor-adjacent micro-vessels were the determining architectural features that impacted on prognosis. Quantifiable morphological vector extracted by CellProfiler demonstrated that tumor nuclei from high-risk patients exhibited significant larger size, more distorted shape, with less prominent nuclear envelope and textural contrast. The multi-omics data (n = 187) further revealed key molecular alterations left morphological imprints that could be attended by the network, including glycolysis, hypoxia, apical junction, mTORC1 signaling, and immune infiltration. CONCLUSIONS: We proposed an interpretable deep-learning framework to gain insights into the biological behavior of iCCA. Most of the significant morphological prognosticators perceived by the network are comprehensible to human minds.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Aprendizado Profundo , Humanos , Colangiocarcinoma/patologia , Prognóstico , Neoplasias dos Ductos Biliares/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Processamento de Imagem Assistida por Computador/métodos , Idoso
7.
Expert Rev Mol Med ; 26: e15, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38621674

RESUMO

In mammals, the skin acts as a barrier to prevent harmful environmental stimuli from entering the circulation. CYP450s are involved in drug biotransformation, exogenous and endogenous substrate metabolism, and maintaining the normal physiological function of the skin, as well as facilitating homeostasis of the internal environment. The expression pattern of CYP450s in the skin is tissue-specific and thus differs from the liver and other organs. The development of skin topical medications, and knowledge of the toxicity and side effects of these medications require a detailed understanding of the expression and function of skin-specific CYP450s. Thus, we summarized the expression of CYP450s in the skin, their function in endogenous metabolic physiology, aberrant CYP450 expression in skin diseases and the influence of environmental variables and medications. This information will serve as a crucial foundation for future studies on the skin, as well as for the design and development of new drugs for skin diseases including topical medications.


Assuntos
Sistema Enzimático do Citocromo P-450 , Pele , Humanos , Pele/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Animais , Dermatopatias/metabolismo
8.
Small ; 20(31): e2311703, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38459649

RESUMO

High tap density electrodes play a vital role in developing rechargeable batteries with high volumetric capacities, however, developing advanced electrodes with satisfied capacity, excellent structural stability, and achieving the resulted batteries with a high initial Coulombic efficiency (ICE) and good rate capability with long lifespan simultaneously, are still an intractable challenge. Herein, an ultrahigh ICE of 94.1% and stable cycling of carbon-free iron selenides anode is enabled with a high tap density of 2.57 g cm-3 up to 4000 cycles at 5 A g-1 through strain-modulating by constructing a homologous heterostructure. Systematical characterization and theoretical calculation show that the self-adaptive homologous heterointerface alleviates the stress of the iron selenide anodes during cycling processes and subsequently improves the stability of the assembled batteries. Additionally, the well-formed homologous heterostructure also contributes to the rapid Na+ diffusion kinetic, increased charge transfer, and good reversibility of the transformation reactions, endowing the appealing rate capability of carbon-free iron selenides. The proposed design strategy provides new insight and inspiration to aid in the ongoing quest for advanced electrode materials with high tap densities and excellent stability.

9.
Plant Biotechnol J ; 22(6): 1536-1548, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38226779

RESUMO

Salvianolic acids (SA), such as rosmarinic acid (RA), danshensu (DSS), and their derivative salvianolic acid B (SAB), etc. widely existed in Lamiaceae and Boraginaceae families, are of interest due to medicinal properties in the pharmaceutical industries. Hundreds of studies in past decades described that 4-coumaroyl-CoA and 4-hydroxyphenyllactic acid (4-HPL) are common substrates to biosynthesize SA with participation of rosmarinic acid synthase (RAS) and cytochrome P450 98A (CYP98A) subfamily enzymes in different plants. However, in our recent study, several acyl donors and acceptors included DSS as well as their ester-forming products all were determined in SA-rich plants, which indicated that previous recognition to SA biosynthesis is insufficient. Here, we used Salvia miltiorrhiza, a representative important medicinal plant rich in SA, to elucidate the diversity of SA biosynthesis. Various acyl donors as well as acceptors are catalysed by SmRAS to form precursors of RA and two SmCYP98A family members, SmCYP98A14 and SmCYP98A75, are responsible for different positions' meta-hydroxylation of these precursors. SmCYP98A75 preferentially catalyses C-3' hydroxylation, and SmCYP98A14 preferentially catalyses C-3 hydroxylation in RA generation. In addition, relative to C-3' hydroxylation of the acyl acceptor moiety in RA biosynthesis, SmCYP98A75 has been verified as the first enzyme that participates in DSS formation. Furthermore, SmCYP98A enzymes knockout resulted in the decrease and overexpression leaded to dramatic increase of SA accumlation. Our study provides new insights into SA biosynthesis diversity in SA-abundant species and versatility of CYP98A enzymes catalytic preference in meta-hydroxylation reactions. Moreover, CYP98A enzymes are ideal metabolic engineering targets to elevate SA content.


Assuntos
Sistema Enzimático do Citocromo P-450 , Salvia miltiorrhiza , Hidroxilação , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Salvia miltiorrhiza/metabolismo , Salvia miltiorrhiza/genética , Salvia miltiorrhiza/enzimologia , Polifenóis/metabolismo , Polifenóis/biossíntese , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Alcenos
10.
Plant Biotechnol J ; 22(8): 2173-2185, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38497586

RESUMO

Adzuki bean (Vigna angularis) is an important legume crop cultivated in over 30 countries worldwide. We developed a high-quality chromosome-level reference genome of adzuki bean cultivar Jingnong6 by combining PacBio Sequel long-read sequencing with short-read and Hi-C technologies. The assembled genome covers 97.8% of the adzuki bean genome with a contig N50 of approximately 16 Mb and a total of 32 738 protein-coding genes. We also generated a comprehensive genome variation map of adzuki bean by whole-genome resequencing (WGRS) of 322 diverse adzuki beans accessions including both wild and cultivated. Furthermore, we have conducted comparative genomics and a genome-wide association study (GWAS) on key agricultural traits to investigate the evolution and domestication. GWAS identified several candidate genes, including VaCycA3;1, VaHB15, VaANR1 and VaBm, that exhibited significant associations with domestication traits. Furthermore, we conducted functional analyses on the roles of VaANR1 and VaBm in regulating seed coat colour. We provided evidence for the highest genetic diversity of wild adzuki (Vigna angularis var. nipponensis) in China with the presence of the most original wild adzuki bean, and the occurrence of domestication process facilitating transition from wild to cultigen. The present study elucidates the genetic basis of adzuki bean domestication traits and provides crucial genomic resources to support future breeding efforts in adzuki bean.


Assuntos
Genoma de Planta , Estudo de Associação Genômica Ampla , Vigna , Genoma de Planta/genética , Vigna/genética , Cromossomos de Plantas/genética , Domesticação , Variação Genética , Genômica , Produtos Agrícolas/genética , Fenótipo
11.
Basic Res Cardiol ; 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39158697

RESUMO

Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) and the underlying mechanisms remain unclear. This study investigated the role of STAT3-microRNA(miRNA)-targeted protein axis in VE against breast cancer-induced cardiac injury.VE for 4 weeks not only improved cardiac function of transgenic breast cancer female mice [mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT +)] compared with littermate mice with no cancer (MMTV-PyMT -), but also increased myocardial STAT3 tyrosine 705 phosphorylation. Significantly more obvious cardiac fibrosis, smaller cardiomyocyte size, lower cell viability, and higher serum tumor necrosis factor (TNF)-α were shown in MMTV-PyMT + mice compared with MMTV-PyMT - mice, which were ameliorated by VE. However, VE did not influence the tumor growth. MiRNA sequencing identified that miR-181a-5p was upregulated and miR-130b-3p was downregulated in VE induced-cardioprotection. Myocardial injection of Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutations abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a (the precursor of miR-181a-5p) and HOX transcript antisense RNA (HOTAIR, sponged miR-130b-3p) in isolated cardiomyocytes. Furthermore, miR-181a-5p targeting PTEN and miR-130b-3p targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved in AC-16 cells. These findings indicated that VE protects against breast cancer-induced cardiac injury via activating STAT3 to promote miR-181a-5p targeting PTEN and to promote HOTAIR to sponge miR-130b-3p targeting Zbtb20, helping to develop new targets in exercise therapy for breast cancer-induced cardiac injury.

12.
J Transl Med ; 22(1): 307, 2024 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528561

RESUMO

OBJECTIVE: Long QT syndrome type 7 (Andersen-Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism. METHODS AND RESULTS: We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs. The spontaneous pulsation rate of myocardial cells in the mutation group was significantly lower than that in the repair CRISPR group, the action potential duration was prolonged, and the Kir2.1 current of the inward rectifier potassium ion channel was decreased, which is consistent with the clinical symptoms of ATS patients. Only ZNF528, a chromatin-accessible TF related to pathogenicity, was continuously regulated beginning from the cardiac mesodermal precursor cell stage (day 4), and continued to be expressed at low levels, which was identified by WGCNA method and verified with ATAC-seq data in the mutation group. Subsequently, it indicated that seven pathways were downregulated (all p < 0.05) by used single sample Gene Set Enrichment Analysis to evaluate the overall regulation of potassium-related pathways enriched in the transcriptome and proteome of late mature CMs. Among them, the three pathways (GO: 0008076, GO: 1990573 and GO: 0030007) containing the mutated gene KCNJ2 is involved that are related to the whole process by which a potassium ion enters the cell via the inward rectifier potassium channel to exert its effect were inhibited. The other four pathways are related to regulation of the potassium transmembrane pathway and sodium:potassium exchange ATPase (p < 0.05). ZNF528 small interfering (si)-RNA was applied to hiPSC-derived cardiomyocytes for CRISPR group to explore changes in potassium ion currents and growth and development related target protein levels that affect disease phenotype. Three consistently downregulated proteins (KCNJ2, CTTN and ATP1B1) associated with pathogenicity were verificated through correlation and intersection analysis. CONCLUSION: This study uncovers TFs and target proteins related to electrophysiology and developmental pathogenicity in ATS myocardial cells, obtaining novel targets for potential therapeutic candidate development that does not rely on gene editing.


Assuntos
Síndrome de Andersen , Células-Tronco Pluripotentes Induzidas , Humanos , Síndrome de Andersen/diagnóstico , Síndrome de Andersen/genética , Cromatina/metabolismo , Transcriptoma , Mutação/genética , Miócitos Cardíacos/metabolismo , Potássio/metabolismo
13.
Plant Cell Environ ; 47(6): 2274-2287, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38488789

RESUMO

The 18O enrichment (Δ18O) of cellulose (Δ18OCel) is recognized as a unique archive of past climate and plant function. However, there is still uncertainty regarding the proportion of oxygen in cellulose (pex) that exchanges post-photosynthetically with medium water of cellulose synthesis. Particularly, recent research with C3 grasses demonstrated that the Δ18O of leaf sucrose (Δ18OSuc, the parent substrate for cellulose synthesis) can be much higher than predicted from daytime Δ18O of leaf water (Δ18OLW), which could alter conclusions on photosynthetic versus post-photosynthetic effects on Δ18OCel via pex. Here, we assessed pex in leaves of perennial ryegrass (Lolium perenne) grown at different atmospheric relative humidity (RH) and CO2 levels, by determinations of Δ18OCel in leaves, Δ18OLGDZW (the Δ18O of water in the leaf growth-and-differentiation zone) and both Δ18OSuc and Δ18OLW (adjusted for εbio, the biosynthetic fractionation between water and carbohydrates) as alternative proxies for the substrate for cellulose synthesis. Δ18OLGDZW was always close to irrigation water, and pex was similar (0.53 ± 0.02 SE) across environments when determinations were based on Δ18OSuc. Conversely, pex was erroneously and variably underestimated (range 0.02-0.44) when based on Δ18OLW. The photosynthetic signal fraction in Δ18OCel is much more constant than hitherto assumed, encouraging leaf physiological reconstructions.


Assuntos
Dióxido de Carbono , Celulose , Umidade , Isótopos de Oxigênio , Folhas de Planta , Sacarose , Folhas de Planta/metabolismo , Celulose/metabolismo , Dióxido de Carbono/metabolismo , Sacarose/metabolismo , Isótopos de Oxigênio/metabolismo , Lolium/metabolismo , Lolium/crescimento & desenvolvimento , Lolium/fisiologia , Atmosfera , Fotossíntese , Água/metabolismo
14.
Plant Cell Environ ; 47(9): 3590-3604, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39031544

RESUMO

The response of mesophyll conductance (gm) to CO2 plays a key role in photosynthesis and ecosystem carbon cycles under climate change. Despite numerous studies, there is still debate about how gm responds to short-term CO2 variations. Here we used multiple methods and looked at the relationship between stomatal conductance to CO2 (gsc) and gm to address this aspect. We measured chlorophyll fluorescence parameters and online carbon isotope discrimination (Δ) at different CO2 mole fractions in sunflower (Helianthus annuus L.), cowpea (Vigna unguiculata L.), and wheat (Triticum aestivum L.) leaves. The variable J and Δ based methods showed that gm decreased with an increase in CO2 mole fraction, and so did stomatal conductance. There were linear relationships between gm and gsc across CO2 mole fractions. gm obtained from A-Ci curve fitting method was higher than that from the variable J method and was not representative of gm under the growth CO2 concentration. gm could be estimated by empirical models analogous to the Ball-Berry model and the USO model for stomatal conductance. Our results suggest that gm and gsc respond in a coordinated manner to short-term variations in CO2, providing new insight into the role of gm in photosynthesis modelling.


Assuntos
Dióxido de Carbono , Helianthus , Células do Mesofilo , Estômatos de Plantas , Triticum , Dióxido de Carbono/metabolismo , Estômatos de Plantas/fisiologia , Células do Mesofilo/fisiologia , Células do Mesofilo/metabolismo , Triticum/fisiologia , Triticum/metabolismo , Helianthus/fisiologia , Helianthus/metabolismo , Isótopos de Carbono , Fotossíntese/fisiologia , Fabaceae/fisiologia , Clorofila/metabolismo , Folhas de Planta/fisiologia , Folhas de Planta/metabolismo
15.
Opt Express ; 32(9): 16052-16064, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38859242

RESUMO

Lidar is an effective remote sensing method to obtain the vertical distribution of aerosols, and how to select the aerosol extinction-backscattering ratio (AE-BR) during the inversion process is a key step to guarantee the accuracy of the lidar inversion of aerosol optical thickness (AOD) and aerosol extinction coefficient profile (AECP). In this paper, an inversion algorithm for AOD and AECP based on a genetic BP (GA-BP) neural network is proposed. Simultaneous measurements are carried out using CE318 sun photometer and lidar, and the mapping relationship between the lidar echo signal and AOD is established based on the genetic BP (GA-BP) neural network method, which achieves the accurate inversion of AOD with an absolute error mean value of 0.0156. Based on the AOD output from the GA-BP neural network, the real-time best AE- BR to improve the inversion accuracy of AECP. Finally, practical tests show that the method achieves accurate inversion of AOD, determines the range of AE-BR from 20-50sr, realizes real-time dynamic correction of AECP, and has strong generalization ability and applicability in practical situations.

16.
Insect Mol Biol ; 33(3): 246-258, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38323672

RESUMO

Molybdenum cofactor sulfurase (MoCoS) is a key gene involved in the uric acid metabolic pathway that activates xanthine dehydrogenase to synthesise uric acid. Uric acid is harmful to mammals but plays crucial roles in insects, one of which is the immune responses. However, the function of Bombyx mori MoCoS in response to BmNPV remains unclear. In this study, BmMoCoS was found to be relatively highly expressed in embryonic development, gonads and the Malpighian tubules. In addition, the expression levels of BmMoCoS were significantly upregulated in three silkworm strains with different levels of resistance after virus infection, suggesting a close link between them. Furthermore, RNAi and overexpression studies showed that BmMoCoS was involved in resistance to BmNPV infection, and its antivirus effects were found to be related to the regulation of uric acid metabolism, which was uncovered by inosine- and febuxostat-coupled RNAi and overexpression. Finally, the BmMoCoS-mediated uric acid pathway was preliminarily confirmed to be a potential target to protect silkworms from BmNPV infection. Overall, this study provides new evidence for elucidating the molecular mechanism of silkworms in response to BmNPV infection and new strategies for the prevention of viral infections in sericulture.


Assuntos
Bombyx , Proteínas de Insetos , Nucleopoliedrovírus , Animais , Bombyx/enzimologia , Bombyx/genética , Bombyx/virologia , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Larva/metabolismo , Larva/crescimento & desenvolvimento , Larva/virologia , Metaloproteínas/metabolismo , Metaloproteínas/genética , Cofatores de Molibdênio , Nucleopoliedrovírus/fisiologia , Interferência de RNA , Ácido Úrico/metabolismo
17.
Insect Mol Biol ; 2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38613398

RESUMO

The silkworm (Bombyx mori) is an important model lepidopteran insect and can be used to identify pesticide resistance-related genes of great significance for biological control of pests. Uridine diphosphate glucosyltransferases (UGTs), found in all organisms, are the main secondary enzymes involved in the metabolism of heterologous substances. However, it remains uncertain if silkworm resistance to fenpropathrin involves UGT. This study observes significant variations in BmUGT expression among B. mori strains with variable fenpropathrin resistance post-feeding, indicating BmUGT's role in fenpropathrin detoxification. Knockdown of BmUGT with RNA interference and overexpression of BmUGT significantly decreased and increased BmN cell activity, respectively, indicating that BmUGT plays an important role in the resistance of silkworms to fenpropathrin. In addition, fenpropathrin residues were significantly reduced after incubation for 12 h with different concentrations of a recombinant BmUGT fusion protein. Finally, we verified the conservation of UGT to detoxify fenpropathrin in Spodoptera exigua: Its resistance to fenpropathrin decreased significantly after knocking down SeUGT. In a word, UGT plays an important role in silkworm resistance to fenpropathrin by directly degrading the compound, a function seen across other insects. The results of this study are of great significance for breeding silkworm varieties with high resistance and for biological control of pests.

18.
J Nutr ; 154(3): 940-948, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38215939

RESUMO

BACKGROUND: Gangliosides are crucial for early-life cognition and immunity development. However, limited data exist on gangliosides within the Chinese population, and maternal-to-fetal/infant ganglioside transport remains unclear. OBJECTIVES: This study aimed to investigate gangliosides concentrations and trajectories in Chinese human milk during the first 400 d of lactation, and seek to understand gangliosides transmission between mother and offspring. METHODS: This study involved 921 cross-sectional participants providing human milk samples across 0-400 d of lactation and 136 longitudinal participants offering maternal plasma, cord plasma, and human milk samples within the first 45 d postpartum. Ultrahigh-performance liquid chromatography-tandem mass spectrometry was used for the quantification of gangliosides. RESULTS: Human milk GM3 (Neu5Acα2-3Galß1-4GlcßCer) concentration increased from 2.29 ± 1.87 to 13.93 ± 4.82 µg/mL, whereas GD3 (Neu5Acα2-8Neu5Acα2-3Galß1-4GlcßCer) decreased from 17.94 ± 6.41 to 0.30 ± 0.50 µg/mL during the first 400 d postpartum (all P < 0.05). Consistent results were observed in cross-sectional and longitudinal participants. GD3 concentration gradually increased from maternal plasma (1.58 µg/mL) through cord plasma (2.05 µg/mL) to colostrum (21.35 µg/mL). Significant positive correlations were observed between maternal and cord plasma for both GM3 (r = 0.30, P < 0.001) and GD3 (r = 0.35, P < 0.001), and maternal plasma GD3 also correlated positively with colostrum concentrations (r = 0.21, P = 0.015). Additionally, in maternal and cord plasma, gangliosides were mainly linked with 16- and 18-carbon fatty acids. However, human milk GM3 showed a broad spectrum of fatty acid chain lengths, whereas GD3 was primarily tied to very long-chain fatty acids (≥20 carbon). CONCLUSIONS: We identified an increase in GM3 and a decrease in GD3 concentration in human milk, with GD3 notably more concentrated in cord plasma and colostrum. Importantly, ganglioside concentrations in maternal plasma positively correlated with those in cord plasma and colostrum. Our findings contribute to the existing Chinese data on gangliosides and enhance understanding of their transmission patterns from mother to offspring. This trial was registered at chictr.org.cn as ChiCTR1800015387.


Assuntos
Gangliosídeos , Leite Humano , Gravidez , Feminino , Humanos , Leite Humano/química , Gangliosídeos/análise , Estudos de Coortes , Estudos Transversais , Ácidos Graxos , Carbono , China
19.
Pharmacol Res ; 199: 107042, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38142878

RESUMO

Drugs acting on dopamine D2 receptors are widely used for the treatment of several neuropsychiatric disorders, including schizophrenia and depression. Social deficits are a core symptom of these disorders. Pharmacological manipulation of dopamine D2 receptors (Drd2), a Gi-coupled subtype of dopamine receptors, in the medial prefrontal cortex (mPFC) has shown that Drd2 is implicated in social behaviors. However, the type of neurons expressing Drd2 in the mPFC and the underlying circuit mechanism regulating social behaviors remain largely unknown. Here, we show that Drd2 were mainly expressed in pyramidal neurons in the mPFC and that the activation of the Gi-pathway in Drd2+ pyramidal neurons impaired social behavior in male mice. In contrast, the knockdown of D2R in pyramidal neurons in the mPFC enhanced social approach behaviors in male mice and selectively facilitated the activation of mPFC neurons projecting to the nucleus accumbens (NAc) during social interaction. Remarkably, optogenetic activation of mPFC-to-NAc-projecting neurons mimicked the effects of conditional D2R knockdown on social behaviors. Altogether, these results demonstrate a cell type-specific role for Drd2 in the mPFC in regulating social behavior, which may be mediated by the mPFC-to-NAc pathway.


Assuntos
Células Piramidais , Receptores de Dopamina D2 , Camundongos , Masculino , Animais , Receptores de Dopamina D2/metabolismo , Células Piramidais/fisiologia , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Núcleo Accumbens/fisiologia , Comportamento Social
20.
World J Urol ; 42(1): 23, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38197979

RESUMO

PURPOSE: To retrospectively investigate the safety and efficacy of radiotherapy combined with chemotherapy for recurrent metastatic renal pelvic and ureteral carcinoma. METHODS: 109 patients were enrolled in this study, including 44 patients in the radiochemotherapy group and 65 patients in the chemotherapy group. Propensity score matching (PSM) was used to balance the baseline characteristics of the two groups by 1:1 matching. Kaplan-Meier method was used to calculate PFS and OS. Cox regression model was used for multivariate analysis. The side effects were evaluated by CTCAE v5.0 RESULTS: The median follow-up time was 14.5 months. Multivariate analysis showed that radiotherapy was a good independent prognostic factor for OS (HR: 0.327, 95% CI 0.157-0.680, P = 0.003). After matching, there were 40 patients in both groups, and the median PFS and OS in the radiochemotherapy group were longer than those in the chemotherapy group (PFS: 10.4 vs. 6.7 months, P = 0.035; OS: 43.5 vs. 18.8 months, P < 0.001). In addition, in the radiochemotherapy group, patients treated with radiotherapy before first-line chemotherapy failure had a longer PFS than those treated with radiotherapy after chemotherapy failure (median PFS: 15.7 vs. 6 months, P = 0.003). There was no significant difference in the incidence of grade 3-4 toxicities between the two groups (52.3% vs. 50.8%, P = 0.878). CONCLUSION: For patients with recurrent metastatic renal pelvic and ureteral carcinoma, radiotherapy combined with chemotherapy is well tolerable and expected to bring long-term survival benefits, and the benefits of early interventional radiotherapy may be more obvious.


Assuntos
Carcinoma , Neoplasias Ureterais , Humanos , Estudos Retrospectivos , Neoplasias Ureterais/tratamento farmacológico , Pelve Renal
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