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Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.
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Predisposição Genética para Doença/genética , Herança Multifatorial/genética , Feminino , Redes Reguladoras de Genes/genética , Estudo de Associação Genômica Ampla/métodos , Hematopoese/genética , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Senescence and altered differentiation potential of bone marrow stromal cells (BMSCs) lead to age-related bone loss. As an important posttranscriptional regulatory pathway, alternative splicing (AS) regulates the diversity of gene expression and has been linked to induction of cellular senescence. However, the role of splicing factors in BMSCs during aging remains poorly defined. Herein, we found that the expression of the splicing factor Y-box binding protein 1 (YBX1) in BMSCs decreased with aging in mice and humans. YBX1 deficiency resulted in mis-splicing in genes linked to BMSC osteogenic differentiation and senescence, such as Fn1, Nrp2, Sirt2, Sp7, and Spp1, thus contributing to BMSC senescence and differentiation shift during aging. Deletion of Ybx1 in BMSCs accelerated bone loss in mice, while its overexpression stimulated bone formation. Finally, we identified a small compound, sciadopitysin, which attenuated the degradation of YBX1 and bone loss in old mice. Our study demonstrated that YBX1 governs cell fate of BMSCs via fine control of RNA splicing and provides a potential therapeutic target for age-related osteoporosis.
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Células-Tronco Mesenquimais , Osteoporose , Humanos , Camundongos , Animais , Osteogênese/genética , Envelhecimento/metabolismo , Senescência Celular , Diferenciação Celular/genética , Osteoporose/metabolismo , Células da Medula Óssea , Proteína 1 de Ligação a Y-Box/metabolismoRESUMO
Deciphering the intricate relationships between transcription factors (TFs), enhancers, and genes through the inference of enhancer-driven gene regulatory networks (eGRNs) is crucial in understanding gene regulatory programs in a complex biological system. This study introduces STREAM, a novel method that leverages a Steiner forest problem model, a hybrid biclustering pipeline, and submodular optimization to infer eGRNs from jointly profiled single-cell transcriptome and chromatin accessibility data. Compared to existing methods, STREAM demonstrates enhanced performance in terms of TF recovery, TF-enhancer linkage prediction, and enhancer-gene relation discovery. Application of STREAM to an Alzheimer's disease dataset and a diffuse small lymphocytic lymphoma dataset reveals its ability to identify TF-enhancer-gene relations associated with pseudotime, as well as key TF-enhancer-gene relations and TF cooperation underlying tumor cells.
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Elementos Facilitadores Genéticos , Redes Reguladoras de Genes , RNA-Seq , Análise de Célula Única , Análise de Célula Única/métodos , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Sequenciamento de Cromatina por Imunoprecipitação , Algoritmos , Biologia Computacional/métodos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Análise da Expressão Gênica de Célula ÚnicaRESUMO
Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts.
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Exoma , Exoma/genética , Frequência do Gene/genética , Humanos , Estudos Prospectivos , Sequenciamento do Exoma/métodos , Sequenciamento Completo do GenomaRESUMO
ConspectusThe development of catalytic activation modes provides a reliable and effective platform for designing new enantioselective reactions and preparing chiral molecules with diverse structures. Chiral aldehyde catalysis is an attractive concept in asymmetric catalysis, which utilizes a chiral aldehyde catalyst to promote the asymmetric hydroamination of allylic amines, the asymmetric α-functionalization of primary amines, or the asymmetric transamination of α-keto esters. Typically, the chiral aldehyde-catalyzed asymmetric α-functionalization of primary amines provides an efficient and straightforward method for the synthesis of α-functionalized chiral amines, which does not require any additional protection or deprotection manipulations of the amine group. However, achieving catalytic stereoselective transformations with high efficiency and enantioselectivity by this strategy has remained an intractable challenge.This Account summarizes our endeavors in the development and application of chiral aldehyde catalysis. Using a chiral aldehyde as a catalyst, we reported the catalytic asymmetric α-C alkylation of 2-aminomalonate with 3-indolylmethanol in 2014, which represents the first chiral aldehyde-catalyzed asymmetric α-functionalization of an activated primary amine. Subsequently, several axially chiral aldehyde catalysts were continuously prepared by using chiral BINOL as the starting material, and their applications in asymmetric synthesis were explored. On the one hand, they were used as organocatalysts to realize the various transformations of α-amino acid esters, such as asymmetric 1,4-addition toward conjugated enones/α,ß-unsaturated diesters and cyclic 1-azadienes as well as asymmetric α-arylation/allylation and benzylation with corresponding halohydrocarbons. Notably, taking advantage of the difference in the distribution of catalytic sites between two chiral aldehyde catalysts, we disclosed chiral aldehyde-catalyzed diastereodivergent 1,6-conjugated addition and Mannich reactions. On the other hand, the potential for the cooperative catalysis of a chiral aldehyde with a transition metal has also been demonstrated. Enabled by the combination of a chiral aldehyde, a palladium complex, and a Lewis acid, the enantioselective α-allylation of amino acid esters with allyl alcohol esters was established. Moreover, the ternary catalytic system has been successfully used for the α-functionalization of amino acid esters with 1,3-dienes, allenes, allenylic alcohol esters, 1,3-disubstituted allyl alcohol esters, and arylmethanol esters as well as the asymmetric cascade Heck-alkylation reaction. The combination of a chiral aldehyde and nickel complex allows for the asymmetric α-propargylation of amino acid esters with propargylic alcohol esters and provides excellent enantioselectivities. These transformations provide a large library of optically active amines and amino acids. With those chiral amino acid esters as key building blocks, the synthesis or formal synthesis of multiple natural products and biologically significant unnatural molecules was accomplished. This includes the stereodivergent synthesis of natural pyrrolizidine alkaloid NP25302 and the formal synthesis of natural product (S)-hypoestestatin 1 and manzacidin C, clinical candidate compound (+)-AG-041R, and somatostatin mimetics. It is fully anticipated that chiral aldehyde catalysis will soon witness rapid expansion both in the development of novel asymmetric transformations and in innovative applications for constructing optically active nitrogen-containing molecules with significant values.
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Hematopoietic stem/progenitor cell (HSPC)-based anti-HIV-1 gene therapy holds great promise to eradicate HIV-1 or to provide long-term remission through a continuous supply of anti-HIV-1 gene-modified cells without ongoing antiretroviral therapy. However, achieving sufficient engraftment levels of anti-HIV gene-modified HSPC to provide therapeutic efficacy has been a major limitation. Here, we report an in vivo selection strategy for anti-HIV-1 gene-modified HSPC by introducing 6-thioguanine (6TG) chemoresistance through knocking down hypoxanthine-guanine phosphoribosyl transferase (HPRT) expression using RNA interference (RNAi). We developed a lentiviral vector capable of co-expressing short hairpin RNA (shRNA) against HPRT alongside two anti-HIV-1 genes: shRNA targeting HIV-1 co-receptor CCR5 and a membrane-anchored HIV-1 fusion inhibitor, C46, for efficient in vivo selection of anti-HIV-1 gene-modified human HSPC. 6TG-mediated preconditioning and in vivo selection significantly enhanced engraftment of HPRT-knockdown anti-HIV-1 gene-modified cells (>2-fold, p < 0.0001) in humanized bone marrow/liver/thymus (huBLT) mice. Viral load was significantly reduced (>1 log fold, p < 0.001) in 6TG-treated HIV-1-infected huBLT mice compared to 6TG-untreated mice. We demonstrated that 6TG-mediated preconditioning and in vivo selection considerably improved engraftment of HPRT-knockdown anti-HIV-1 gene-modified HSPC and repopulation of anti-HIV-1 gene-modified hematopoietic cells in huBLT mice, allowing for efficient HIV-1 inhibition.
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HIV-1 , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Animais , HIV-1/fisiologia , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Medula Óssea/metabolismo , Tioguanina/metabolismo , Tioguanina/farmacologia , RNA Interferente Pequeno/genéticaRESUMO
Different brain cell types play distinct roles in brain development and disease. Molecular characterization of cell-specific mechanisms using cell type-specific approaches at the protein (proteomic) level can provide biological and therapeutic insights. To overcome the barriers of conventional isolation-based methods for cell type-specific proteomics, in vivo proteomic labeling with proximity-dependent biotinylation of cytosolic proteins using biotin ligase TurboID, coupled with mass spectrometry (MS) of labeled proteins, emerged as a powerful strategy for cell type-specific proteomics in the native state of cells without the need for cellular isolation. To complement in vivo proximity labeling approaches, in vitro studies are needed to ensure that cellular proteomes using the TurboID approach are representative of the whole-cell proteome and capture cellular responses to stimuli without disruption of cellular processes. To address this, we generated murine neuroblastoma (N2A) and microglial (BV2) lines stably expressing cytosolic TurboID to biotinylate the cellular proteome for downstream purification and analysis using MS. TurboID-mediated biotinylation captured 59% of BV2 and 65% of N2A proteomes under homeostatic conditions. TurboID labeled endolysosome, translation, vesicle, and signaling proteins in BV2 microglia and synaptic, neuron projection, and microtubule proteins in N2A neurons. TurboID expression and biotinylation minimally impacted homeostatic cellular proteomes of BV2 and N2A cells and did not affect lipopolysaccharide-mediated cytokine production or resting cellular respiration in BV2 cells. MS analysis of the microglial biotin-labeled proteins captured the impact of lipopolysaccharide treatment (>500 differentially abundant proteins) including increased canonical proinflammatory proteins (Il1a, Irg1, and Oasl1) and decreased anti-inflammatory proteins (Arg1 and Mgl2).
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Microglia , Proteoma , Animais , Camundongos , Microglia/metabolismo , Proteoma/metabolismo , Biotina/metabolismo , Proteômica/métodos , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Linhagem Celular , Neurônios/metabolismo , BiotinilaçãoRESUMO
BACKGROUND: In 2016, China has implemented the World Health Organization's "treat all" policy. We aimed to assess the impact of significant improvements in the 95-95-95 targets on population-level human immunodeficiency virus (HIV) transmission dynamics and incidence. METHODS: We focused on 3 steps of the HIV care continuum: diagnosed, on antiretroviral therapy, and achieving viral suppression. The molecular transmission clusters were inferred using HIV-TRACE. New HIV infections were estimated using the incidence method in the European Centre for Disease Prevention and Control HIV Modelling Tool. RESULTS: Between 2004 and 2023, the national HIV epidemiology database recorded 2.99 billion person-times of HIV tests and identified 1 976 878 new diagnoses. We noted a roughly "inverted-V" curve in the clustering frequency, with the peak recorded in 2014 (67.1% [95% confidence interval, 63.7%-70.5%]), concurrent with a significant improvement in the 95-95-95 targets from 10-13-<71 in 2005 to 84-93-97 in 2022. Furthermore, we observed a parabolic curve for a new infection with the vertex occurring in 2010. CONCLUSIONS: In general, it was suggested that the improvements in the 95-95-95 targets were accompanied by a reduction in both the population-level HIV transmission rate and incidence. Thus, China should allocate more effort to the first "95" target to achieve a balanced 95-95-95 target.
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BACKGROUND: National treatment guidelines of China evolving necessitates population-level surveillance of transmitted drug resistance (TDR) to inform or update HIV treatment strategies. METHODS: We analyzed the demographic, clinical, and virologic data obtained from people with HIV (PWH) residing in 31 provinces of China who were newly diagnosed between 2018 and 2023. Evidence of TDR was defined by the World Health Organization list for surveillance of drug resistance mutations. RESULTS: Among the 22 124 PWH with protease and reverse transcriptase sequences, 965 (4.36%; 95% CI, 4.1-4.63) had at least 1 TDR mutation. The most frequent TDR mutations were nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.39%; 95% CI, 2.19%-2.59%), followed by nucleoside reverse transcriptase inhibitor mutations(1.35%; 95% CI, 1.2%-1.5%) and protease inhibitor mutations (1.12%; 95% CI, .98%-1.26%). The overall protease and reverse transcriptase TDR increased significantly from 4.05% (95% CI, 3.61%-4.52%) in 2018 to 5.39% (95% CI, 4.33%-6.57%) in 2023. A low level of integrase strand transfer inhibitor TDR was detected in 9 (0.21%; 95% CI, .1%-.38%) of 4205 PWH. CONCLUSIONS: Presently, the continued use of NNRTI-based first-line antiretroviral therapy regimen for HIV treatment has been justified.
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Alzheimer's disease (AD) is a neurodegenerative disease, and mild cognitive impairment (MCI) is considered a transitional stage between healthy aging and dementia. Early detection of MCI can help slow down the progression of AD. At present, there are few studies exploring the characteristics of abnormal dynamic brain activity in AD. This article uses a method called leading eigenvector dynamics analysis (LEiDA) to study resting-state functional magnetic resonance imaging (rs-fMRI) data of AD, MCI, and cognitively normal (CN) participants. By identifying repetitive states of phase coherence, intergroup differences in brain dynamic activity indicators are examined, and the neurobehavioral scales were used to assess the relationship between abnormal dynamic activities and cognitive function. The results showed that in the indicators of occurrence probability and lifetime, the globally synchronized state of the patient group decreased. The activity state of the limbic regions significantly detected the difference between AD and the other two groups. Compared to CN, AD and MCI have varying degrees of increase in default and visual region activity states. In addition, in the analysis related to the cognitive scales, it was found that individuals with poorer cognitive abilities were less active in the globally synchronized state and more active in limbic region activity state and visual region activity state. Taken together, these findings reveal abnormal dynamic activity of resting-state networks in patients with AD and MCI, provide new insights into the dynamic analysis of brain networks, and contribute to a deeper understanding of abnormal spatial dynamic patterns in AD patients.NEW & NOTEWORTHY Alzheimer's disease (AD) is a neurodegenerative disease, but few studies have explored the characteristics of abnormal dynamic brain activity in AD patients. Here, our report reveals the abnormal dynamic activity of the patients' resting-state network, providing new insights into the dynamic analysis of brain networks and helping to gain a deeper understanding of the abnormal spatial dynamic patterns in AD patients.
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Doença de Alzheimer , Disfunção Cognitiva , Imageamento por Ressonância Magnética , Rede Nervosa , Humanos , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/diagnóstico por imagem , Feminino , Idoso , Masculino , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Rede Nervosa/diagnóstico por imagem , Pessoa de Meia-Idade , Encéfalo/fisiopatologia , Encéfalo/diagnóstico por imagem , Descanso , Idoso de 80 Anos ou maisRESUMO
The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.
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Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteína Beclina-1/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , AVC Isquêmico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Autofagia , Linhagem Celular , Modelos Animais de Doenças , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Camundongos , Estresse Oxidativo , FosforilaçãoRESUMO
In this comprehensive genome-wide study, we identified and classified 83 Xylanase Inhibitor Protein (XIP) genes in wheat, grouped into five distinct categories, to enhance understanding of wheat's resistance to Fusarium head blight (FHB), a significant fungal threat to global wheat production. Our analysis reveals the unique distribution of XIP genes across wheat chromosomes, particularly at terminal regions, suggesting their role in the evolutionary expansion of the gene family. Several XIP genes lack signal peptides, indicating potential alternative secretion pathways that could be pivotal in plant defense against FHB. The study also uncovers the sequence homology between XIPs and chitinases, hinting at a functional diversification within the XIP gene family. Additionally, the research explores the association of XIP genes with plant immune mechanisms, particularly their linkage with plant hormone signaling pathways like abscisic acid and jasmonic acid. XIP-7A3, in particular, demonstrates a significant increase in expression upon FHB infection, highlighting its potential as a key candidate gene for enhancing wheat's resistance to this disease. This research not only enriches our understanding of the XIP gene family in wheat but also provides a foundation for future investigations into their role in developing FHB-resistant wheat cultivars. The findings offer significant implications for wheat genomics and breeding, contributing to the development of more resilient crops against fungal diseases.
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Resistência à Doença , Fusarium , Doenças das Plantas , Proteínas de Plantas , Triticum , Triticum/genética , Triticum/microbiologia , Triticum/imunologia , Fusarium/fisiologia , Doenças das Plantas/microbiologia , Doenças das Plantas/genética , Doenças das Plantas/imunologia , Resistência à Doença/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Imunidade Vegetal/genética , Estudo de Associação Genômica Ampla , Genes de Plantas , Genoma de Planta , FilogeniaRESUMO
PURPOSE: Although changes in circulating tumour DNA (ctDNA) in breast cancer are well described, the kinetics of their fluctuations has not been described over short timescales. We investigated ctDNA dynamics during alternating cycles of chemotherapy and hormonal treatment in pre-treated patients with oestrogen receptor-positive metastatic breast cancer. METHODS: Patients received alternating, 9-week cycles of eribulin and aromatase inhibitors (AIs). The clinical primary endpoint, progression-free survival (PFS), was monitored at 3, 6 and 9 months; secondary endpoints, clinical benefit rate (CBR), safety and tolerability profiles, were also assessed. Importantly, ctDNA fluctuations were monitored using the Oncomine™ Breast cfDNA assay to test whether biomarkers may change rapidly between chemotherapy and aromatase inhibitor (AI) treatment in the setting of advanced breast cancer, potentially reflecting disease dynamics. RESULTS: The median PFS was 202 days (95% CI: 135-undefined) and 235 days (95% CI: 235-undefined) at 6 and 9 months, respectively, with a 50% CBR at both 6 and 9 months. Dynamic changes in ctDNA were observed in short timescales between chemotherapy and AI treatment and support the clinical benefit (CB) seen in individual patients and, critically, appear informative of acquired resistance in real time. CONCLUSION: Changes in ctDNA can occur rapidly and reflect changes in patients' clinical tumour responses (NCT02681523).
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Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores da Aromatase , Neoplasias da Mama , DNA Tumoral Circulante , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Biomarcadores Tumorais/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Neoplasias da Mama/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Furanos/uso terapêutico , Furanos/administração & dosagem , Cetonas , Metástase Neoplásica , Policetídeos de Poliéter , Resultado do TratamentoRESUMO
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, progressive in nature, and known to have a negative impact on mortality, morbidity, and quality of life. Patients requiring acute termination of AF to restore sinus rhythm are subjected to electrical cardioversion, which requires sedation and therefore hospitalization due to pain resulting from the electrical shocks. However, considering the progressive nature of AF and its detrimental effects, there is a clear need for acute out-of-hospital (i.e., ambulatory) cardioversion of AF. In the search for shock-free cardioversion methods to realize such ambulatory therapy, a method referred to as optogenetics has been put forward. Optogenetics enables optical control over the electrical activity of cardiomyocytes by targeted expression of light-activated ion channels or pumps and may therefore serve as a means for cardioversion. First proof-of-principle for such light-induced cardioversion came from in vitro studies, proving optogenetic AF termination to be very effective. Later, these results were confirmed in various rodent models of AF using different transgenes, illumination methods, and protocols, whereas computational studies in the human heart provided additional translational insight. Based on these results and fueled by recent advances in molecular biology, gene therapy, and optoelectronic engineering, a basis is now being formed to explore clinical translations of optoelectronic control of cardiac rhythm. In this review, we discuss the current literature regarding optogenetic cardioversion of AF to restore normal rhythm in a shock-free manner. Moreover, key translational steps will be discussed, both from a biological and technological point of view, to outline a path toward realizing acute shock-free ambulatory termination of AF.
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Fibrilação Atrial , Humanos , Fibrilação Atrial/tratamento farmacológico , Cardioversão Elétrica , Qualidade de Vida , CoraçãoRESUMO
A new form of pancake bouncing is discovered in this work when a droplet impacts onto micro-structured superhydrophobic surfaces in an environment pressure less than 2 kPa, and an unprecedented reduction of contact time by ≈85% is obtained. The mechanisms of forming this unique phenomenon are examined by combining experimental observation, numeical modelling and an improved theoretical model for the overpressure effect arising from the vaporisation inside micro-scaled structures. The competition among the vapor overpressure effect, the droplet impact force, and the surface adhesion determines if the pancake bouncing behavior could occur. After the lift-off the lamella, the pancake bouncing is initiated and its subsequent dynamics is controlled by the internal momentum transfer. Complementary to the prior studies, this work enriches the knowledge of droplet dynamics in low pressure, which allows new strategies of surface morphology engineering for droplet control, an area of high importance for many engineering applications.
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IMPORTANCE: Many plant viruses are transmitted by insect vectors in a circulative manner. For efficient transmission, the entry of the virus from vector hemolymph into the primary salivary gland (PSG) is a step of paramount importance. Yet, vector components mediating virus entry into PSG remain barely characterized. Here, we demonstrate the role of clathrin-mediated endocytosis and early endosomes in begomovirus entry into whitefly PSG. Our findings unravel the key components involved in begomovirus transport within the whitefly body and transmission by their whitefly vectors and provide novel clues for blocking begomovirus transmission.
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Begomovirus , Endocitose , Hemípteros , Animais , Begomovirus/fisiologia , Clatrina/metabolismo , Endossomos , Hemípteros/metabolismo , Hemípteros/virologia , Doenças das Plantas , Glândulas Salivares/metabolismo , Glândulas Salivares/virologiaRESUMO
BACKGROUND: Atopic dermatitis (AD) is a common chronic skin disorder in children. We aimed to investigate trends and regional disparities of burden in paediatric AD at global, regional and national levels, and to explore potential associated factors. METHODS: Based on data from Global Burden of Disease study 2019, we assessed trends in burden of AD aged <19 years from 1990 to 2019, including prevalent and incident cases, age-standardised prevalence and age-standardised incidence. For potential associated factors, correlations of above trends and indexes of socio-economic status (sociodemographic index, SDI) and health service coverage (universal health coverage index, UHCI) were evaluated. We conducted decomposition analysis to understand the net contribution of population-level factors and their contribution proportions on changes of prevalent and incident cases, including age structure, population change and epidemiological change. RESULTS: Global prevalent and incident cases of paediatric AD increased by about 5.7 and 0.7 million between 1990 and 2019, respectively. Global age-standardised prevalence and incidence decreased by -0.17% (-0.19% to -0.16%) and -0.12% (-0.13% to -0.11%) per year from 1990 to 2019, respectively. Regionally, the highest increase of prevalent and incident cases was in low SDI region (by 96.77% and 84.85%); the highest decrease of age-standardised prevalence and incidence was in high SDI regions (by -0.20% and -0.27% per year). The correlation analyses identified significant negative correlations between trends and SDI and UHCI. Population change was a major driver of case rise; epidemiological change and age structure showed negative impact of case rise. Regional disparities in contribution of three population-level factors were seen, including net contribution direction (positive or negative) and contribution proportion levels. CONCLUSION: Global paediatric AD case numbers increased, primarily due to population growth. Prevalence and incidence decreased slightly. Geographic inequalities were seen. Developing region-specific strategies targeting potential factors is essential to reduce paediatric AD burden.
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Phosphorus (P) is an essential nutrient, but easily fixed in soils. Therefore, most of soil P exists in the form of inaccessible organic phosphorus (Po), particularly phytate-P. Root-associated purple acid phosphatases (PAPs) are considered to play a crucial role in phosphate (Pi) scavenging in soils. However, evidence for regulating root-associated PAPs in utilization of extracellular phytate-P remain largely unknown in plants at both transcriptional and posttranslational levels. In this study, a Pi-starvation responsive GmPAP15a was identified in soybean (Glycine max). Overexpressing GmPAP15a led to significant increases in root-associated phytase activities, as well as total P content when phytate-P was supplied as the sole P resource in soybean hairy roots. Meanwhile, mass spectrometry (MS) analysis showed GmPAP15a was glycosylated at Asn144 and Asn502 , and its glycan structures of N-linked oligosaccharide chains exhibited microheterogeneity. Moreover, two homologues of AtPHR1, GmPHR9 and GmPHR32 were found to activate GmPAP15a transcription through luciferase activity analysis. Taken together, it is strongly suggested that GmPAP15a plays a vital role in phytate-P utilization in soybean, which might be regulated at both transcriptional and glycosylation modification levels. Our results highlight the GmPHR9/GmPHR32-GmPAP15a signalling pathway might present, and control phytate-P utilization in soybean.
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Glycine max , Ácido Fítico , Glycine max/metabolismo , Glicosilação , Ácido Fítico/metabolismo , Proteínas de Plantas/metabolismo , Raízes de Plantas/metabolismo , Fósforo/metabolismo , SoloRESUMO
Multiple Arabidopsis H+ /Cation exchangers (CAXs) participate in high-capacity transport into the vacuole. Previous studies have analysed single and double mutants that marginally reduced transport; however, assessing phenotypes caused by transport loss has proven enigmatic. Here, we generated quadruple mutants (cax1-4: qKO) that exhibited growth inhibition, an 85% reduction in tonoplast-localised H+ /Ca transport, and enhanced tolerance to anoxic conditions compared to CAX1 mutants. Leveraging inductively coupled plasma mass spectrometry (ICP-MS) and synchrotron X-ray fluorescence (SXRF), we demonstrate CAX transporters work together to regulate leaf elemental content: ICP-MS analysis showed that the elemental concentrations in leaves strongly correlated with the number of CAX mutations; SXRF imaging showed changes in element partitioning not present in single CAX mutants and qKO had a 40% reduction in calcium (Ca) abundance. Reduced endogenous Ca may promote anoxia tolerance; wild-type plants grown in Ca-limited conditions were anoxia tolerant. Sequential reduction of CAXs increased mRNA expression and protein abundance changes associated with reactive oxygen species and stress signalling pathways. Multiple CAXs participate in postanoxia recovery as their concerted removal heightened changes in postanoxia Ca signalling. This work showcases the integrated and diverse function of H+ /Cation transporters and demonstrates the ability to improve anoxia tolerance through diminishing endogenous Ca levels.
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Proteínas de Arabidopsis , Arabidopsis , Cálcio/metabolismo , Antiporters/genética , Antiporters/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cátions/metabolismo , Plantas/metabolismoRESUMO
Hyperspectral cameras face challenging spatial-spectral resolution trade-offs and are more affected by shot noise than RGB photos taken over the same total exposure time. Here, we present a colorization algorithm to reconstruct hyperspectral images from a grayscale guide image and spatially sparse spectral clues. We demonstrate that our algorithm generalizes to varying spectral dimensions for hyperspectral images, and show that colorizing in a low-rank space reduces compute time and the impact of shot noise. To enhance robustness, we incorporate guided sampling, edge-aware filtering, and dimensionality estimation techniques. Our method surpasses previous algorithms in various performance metrics, including SSIM, PSNR, GFC, and EMD, which we analyze as metrics for characterizing hyperspectral image quality. Collectively, these findings provide a promising avenue for overcoming the time-space-wavelength resolution trade-off by reconstructing a dense hyperspectral image from samples obtained by whisk or push broom scanners, as well as hybrid spatial-spectral computational imaging systems.