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1.
Elife ; 92020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32876563

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) and transmissible gastroenteritis virus (TGEV) are two highly infectious and lethal viruses causing major economic losses to pig production. Here, we report generation of double-gene-knockout (DKO) pigs harboring edited knockout alleles for known receptor proteins CD163 and pAPN and show that DKO pigs are completely resistant to genotype 2 PRRSV and TGEV. We found no differences in meat-production or reproductive-performance traits between wild-type and DKO pigs, but detected increased iron in DKO muscle. Additional infection challenge experiments showed that DKO pigs exhibited decreased susceptibility to porcine deltacoronavirus (PDCoV), thus offering unprecedented in vivo evidence of pAPN as one of PDCoV receptors. Beyond showing that multiple gene edits can be combined in a livestock animal to achieve simultaneous resistance to two major viruses, our study introduces a valuable model for investigating infection mechanisms of porcine pathogenic viruses that exploit pAPN or CD163 for entry.


Assuntos
Antígenos CD13/deficiência , Infecções por Coronavirus/prevenção & controle , Coronavirus/patogenicidade , Gastroenterite Suína Transmissível/prevenção & controle , Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Receptores de Superfície Celular/deficiência , Vírus da Gastroenterite Transmissível/patogenicidade , Animais , Animais Geneticamente Modificados , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Composição Corporal , Antígenos CD13/genética , Antígenos CD13/imunologia , Coronavirus/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Suscetibilidade a Doenças , Gastroenterite Suína Transmissível/genética , Gastroenterite Suína Transmissível/imunologia , Gastroenterite Suína Transmissível/virologia , Técnicas de Silenciamento de Genes , Interações entre Hospedeiro e Microrganismos , Indústria de Embalagem de Carne , Fenótipo , Síndrome Respiratória e Reprodutiva Suína/genética , Síndrome Respiratória e Reprodutiva Suína/imunologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Sus scrofa/genética , Suínos , Vírus da Gastroenterite Transmissível/imunologia , Ganho de Peso
2.
Nat Commun ; 11(1): 4471, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901010

RESUMO

A human cell contains hundreds to thousands of mitochondrial DNA (mtDNA) packaged into nucleoids. Currently, the segregation and allocation of nucleoids are thought to be passively determined by mitochondrial fusion and division. Here we provide evidence, using live-cell super-resolution imaging, that nucleoids can be actively transported via KIF5B-driven mitochondrial dynamic tubulation (MDT) activities that predominantly occur at the ER-mitochondria contact sites (EMCS). We further demonstrate that a mitochondrial inner membrane protein complex MICOS links nucleoids to Miro1, a KIF5B receptor on mitochondria, at the EMCS. We show that such active transportation is a mechanism essential for the proper distribution of nucleoids in the peripheral zone of the cell. Together, our work identifies an active transportation mechanism of nucleoids, with EMCS serving as a key platform for the interplay of nucleoids, MICOS, Miro1, and KIF5B to coordinate nucleoids segregation and transportation.


Assuntos
DNA Mitocondrial/metabolismo , Retículo Endoplasmático/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/fisiologia , Animais , Transporte Biológico Ativo , Células COS , Células Cultivadas , Chlorocebus aethiops , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Humanos , Cinesina/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , Ratos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção , Proteínas rho de Ligação ao GTP/metabolismo
3.
Nat Commun ; 11(1): 4064, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792542

RESUMO

Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2LMW) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2LMW-/- mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS+/CD206+ TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment.


Assuntos
Fator 2 de Crescimento de Fibroblastos/metabolismo , Radioterapia/métodos , Animais , Linhagem Celular Tumoral , Fator 2 de Crescimento de Fibroblastos/genética , Células HT29 , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/efeitos da radiação , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nat Commun ; 11(1): 4343, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859940

RESUMO

Osteoarthritis (OA), primarily characterized by articular cartilage destruction, is the most common form of age-related degenerative whole-joint disease. No disease-modifying treatments for OA are currently available. Although OA is primarily characterized by cartilage destruction, our understanding of the processes controlling OA progression is poor. Here, we report the association of OA with increased levels of osteoclast-associated receptor (OSCAR), an immunoglobulin-like collagen-recognition receptor. In mice, OSCAR deletion abrogates OA manifestations, such as articular cartilage destruction, subchondral bone sclerosis, and hyaline cartilage loss. These effects are a result of decreased chondrocyte apoptosis, which is caused by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in induced OA. Treatments with human OSCAR-Fc fusion protein attenuates OA pathogenesis caused by experimental OA. Thus, this work highlights the function of OSCAR as a catabolic regulator of OA pathogenesis, indicating that OSCAR blockade is a potential therapy for OA.


Assuntos
Apoptose/efeitos dos fármacos , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Osteoartrite/metabolismo , Osteoclastos/metabolismo , Receptores de Superfície Celular/metabolismo , Idoso , Animais , Cartilagem Articular/patologia , Condrócitos/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
5.
PLoS One ; 15(8): e0235575, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745084

RESUMO

The sugarcane borer (Diatraea saccharalis, Fabricius, 1794) is a devastating pest that causes millions of dollars of losses each year to sugarcane producers by reducing sugar and ethanol yields. The control of this pest is difficult due to its endophytic behavior and rapid development. Pest management through biotechnological approaches has emerged in recent years as an alternative to currently applied methods. Genetic information about the target pests is often required to perform biotechnology-based management. The genomic and transcriptomic data for D. saccharalis are very limited. Herein, we report a tissue-specific transcriptome of D. saccharalis larvae and a differential expression analysis highlighting the physiological characteristics of this pest in response to two different diets: sugarcane and an artificial diet. Sequencing was performed on the Illumina HiSeq 2000 platform, and a de novo assembly was generated. A total of 27,626 protein-coding unigenes were identified, among which 1,934 sequences were differentially expressed between treatments. Processes such as defence, digestion, detoxification, signaling, and transport were highly represented among the differentially expressed genes (DEGs). Furthermore, seven aminopeptidase genes were identified as candidates to encode receptors of Cry proteins, which are toxins of Bacillus thuringiensis used to control lepidopteran pests. Since plant-insect interactions have produced a considerable number of adaptive responses in hosts and herbivorous insects, the success of phytophagous insects relies on their ability to overcome challenges such as the response to plant defences and the intake of nutrients. In this study, we identified metabolic pathways and specific genes involved in these processes. Thus, our data strongly contribute to the knowledge advancement of insect transcripts, which can be a source of target genes for pest management.


Assuntos
Dieta , Mucosa Intestinal/metabolismo , Lepidópteros/genética , Transcriptoma , Aminopeptidases/genética , Aminopeptidases/metabolismo , Animais , Herbivoria/genética , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Lepidópteros/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo
6.
Nat Commun ; 11(1): 4285, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855390

RESUMO

Plant hormone cytokinins are perceived by a subfamily of sensor histidine kinases (HKs), which via a two-component phosphorelay cascade activate transcriptional responses in the nucleus. Subcellular localization of the receptors proposed the endoplasmic reticulum (ER) membrane as a principal cytokinin perception site, while study of cytokinin transport pointed to the plasma membrane (PM)-mediated cytokinin signalling. Here, by detailed monitoring of subcellular localizations of the fluorescently labelled natural cytokinin probe and the receptor ARABIDOPSIS HISTIDINE KINASE 4 (CRE1/AHK4) fused to GFP reporter, we show that pools of the ER-located cytokinin receptors can enter the secretory pathway and reach the PM in cells of the root apical meristem, and the cell plate of dividing meristematic cells. Brefeldin A (BFA) experiments revealed vesicular recycling of the receptor and its accumulation in BFA compartments. We provide a revised view on cytokinin signalling and the possibility of multiple sites of perception at PM and ER.


Assuntos
Proteínas de Arabidopsis/metabolismo , Membrana Celular/metabolismo , Citocininas/metabolismo , Retículo Endoplasmático/metabolismo , Corantes Fluorescentes/química , Proteínas Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Arabidopsis/citologia , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Brefeldina A/farmacologia , Citocininas/química , Corantes Fluorescentes/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Meristema/citologia , Meristema/metabolismo , Plantas Geneticamente Modificadas , Proteínas Quinases/genética , Receptores de Superfície Celular/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Medicine (Baltimore) ; 99(22): e20413, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32481435

RESUMO

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is an autosomal recessive hepatorenal fibrocystic syndrome. The majority of ARPKD patients progress to end-stage renal disease. Precise molecular diagnosis of ARPKD has proven valuable for understanding its mechanism and selecting optimal therapy. METHODS: A Chinese family with ARPKD was recruited in current study. The clinical characteristics of ARPKD patient were collected from medical records and the potential responsible genes were studied by the whole exome sequencing (WES). Candidate pathogenic variants were validated by Sanger sequencing. RESULTS: Both renal manifestation and hepatobiliary phenotype were observed. WES revealed compound heterozygous mutations of polycystic kidney and hepatic disease 1 genes, NM_138694: c.751G>T, (p.Asp251Tyr) and c.3998_4004delACCTGAA (p.Asn1333Thr fs × 13), which were confirmed by Sanger sequencing. Moreover, the mutations in the proband and its affected sib were co-segregated with the phenotype. CONCLUSIONS: The novel mutation in polycystic kidney and hepatic disease 1 gene identified by WES might be molecular pathogenic basis of this disorder.


Assuntos
Rim Policístico Autossômico Recessivo/genética , Sequenciamento Completo do Exoma , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Criança , China , Feminino , Predisposição Genética para Doença/genética , Humanos , Mutação de Sentido Incorreto/genética , Receptores de Superfície Celular/genética , Deleção de Sequência/genética , Sequenciamento Completo do Exoma/métodos
8.
PLoS One ; 15(6): e0235071, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574212

RESUMO

Cystic kidney diseases are a very heterogeneous group of chronic kidney diseases. The diagnosis is usually based on clinical and ultrasound characteristics and the final diagnosis is often difficult to be made. Next-generation sequencing (NGS) may help the clinicians to find the correct final diagnosis. The aim of our study was to test the diagnostic yield of NGS and its ability to improve the diagnosis precision in a heterogeneous group of children with cystic kidney diseases. Next-generation sequencing of genes responsible for the formation of cystic kidneys was performed in 31 unrelated patients with various clinically diagnosed cystic kidney diseases gathered at the Department of Pediatrics of Motol University Hospital in Prague between 2013 and 2018. The underlying pathogenic variants were detected in 71% of patients (n = 22), no or only one (in case of autosomal recessive inheritance) pathogenic variant was found in 29% of patients (n = 9). The result of NGS correlated with the clinical diagnosis made before the NGS in 55% of patients (n = 17), in the remaining 14 children (45%) the result of NGS revealed another type of cystic kidney disease that was suspected clinically before or did not find causal mutation in suspected genes. The most common unexpected findings were variants in nephronophthisis (NPHP) genes in children with clinically suspected autosomal recessive polycystic kidney disease (ARPKD, n = 4). Overall, 24 pathogenic or probably pathogenic variants were detected in the PKHD1 gene, 8 variants in the TMEM67 gene, 4 variants in the PKD1 gene, 2 variants in the HNF1B gene and 2 variants in BBS1 and NPHP1 genes, respectively. NGS is a valuable tool in the diagnostics of various forms of cystic kidney diseases. Its results changed the clinically based diagnoses in 16% (n = 5) of the children.


Assuntos
Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Renais Císticas/genética , Mutação , Rim Policístico Autossômico Recessivo/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Criança , Pré-Escolar , Proteínas do Citoesqueleto/genética , República Tcheca , Feminino , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Lactente , Recém-Nascido , Doenças Renais Císticas/diagnóstico , Masculino , Proteínas Associadas aos Microtúbulos/genética , Rim Policístico Autossômico Recessivo/diagnóstico , Receptores de Superfície Celular/genética , Canais de Cátion TRPP/genética
9.
Artigo em Inglês | MEDLINE | ID: mdl-32580277

RESUMO

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, inherited disorder characterized by a congenital absence of conjugate horizontal eye movements with progressive scoliosis developing in childhood and adolescence. Mutations in the Roundabout (ROBO3) gene located on chromosome 11q23-25 are responsible for the development of horizontal gaze palsy and progressive scoliosis. However, some studies redefined the locus responsible for this pathology to a 9-cM region. This study carried out a systematic review in which 25 documents were analyzed, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. The search was made in the following electronic databases from January 1995 to October 2019: PubMed, Scopus, Web of Science, PEDRO, SPORT Discus, and CINAHL. HGPPS requires a multidisciplinary diagnostic approach, in which magnetic resonance imaging might be the first technique to suggest the diagnosis, which should be verified by an analysis of the ROBO3 gene. This is important to allow for adequate ocular follow up, apply supportive therapies to prevent the rapid progression of scoliosis, and lead to appropriate genetic counseling.


Assuntos
Transtornos da Motilidade Ocular , Oftalmoplegia Externa Progressiva Crônica , Receptores de Superfície Celular , Escoliose , Adolescente , Criança , Feminino , Humanos , Masculino , Mutação , Oftalmoplegia Externa Progressiva Crônica/genética , Receptores de Superfície Celular/genética , Receptores Imunológicos , Escoliose/genética
10.
Nature ; 583(7814): 127-132, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32555459

RESUMO

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment1,2. Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells3,4 and has a beneficial role in wound-healing responses5,6. Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis1,7. Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity1,2,8-10. Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR)11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.


Assuntos
Envelhecimento/patologia , Senescência Celular/imunologia , Cirrose Hepática/terapia , Longevidade/imunologia , Neoplasias Pulmonares/terapia , Receptores de Antígenos Quiméricos/imunologia , Rejuvenescimento , Linfócitos T/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Animais , Tetracloreto de Carbono , Feminino , Xenoenxertos , Humanos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Linfócitos T/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo
11.
Proc Natl Acad Sci U S A ; 117(26): 14978-14986, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32554490

RESUMO

AB5 bacterial toxins and polyomaviruses induce membrane curvature as a mechanism to facilitate their entry into host cells. How membrane bending is accomplished is not yet fully understood but has been linked to the simultaneous binding of the pentameric B subunit to multiple copies of glycosphingolipid receptors. Here, we probe the toxin membrane binding and internalization mechanisms by using a combination of superresolution and polarized localization microscopy. We show that cholera toxin subunit B (CTxB) can induce membrane curvature only when bound to multiple copies of its glycosphingolipid receptor, GM1, and the ceramide structure of GM1 is likely not a determinant of this activity as assessed in model membranes. A mutant CTxB capable of binding only a single GM1 fails to generate curvature either in model membranes or in cells, and clustering the mutant CTxB-single-GM1 complexes by antibody cross-linking does not rescue the membrane curvature phenotype. We conclude that both the multiplicity and specific geometry of GM1 binding sites are necessary for the induction of membrane curvature. We expect this to be a general rule of membrane behavior for all AB5 toxins and polyomaviruses that bind glycosphingolipids to invade host cells.


Assuntos
Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Toxina da Cólera/farmacologia , Receptores de Superfície Celular/metabolismo , Animais , Células COS , Membrana Celular/metabolismo , Chlorocebus aethiops , Receptores de Superfície Celular/genética
12.
PLoS One ; 15(5): e0233383, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428035

RESUMO

ERECTA gene family encodes leucine-rich repeat receptor-like kinases that control major aspects of plant development such as elongation of aboveground organs, leaf initiation, development of flowers, and epidermis differentiation. To clarify the importance of ERECTA signaling for the development of soybean (Glycine max), we expressed the dominant-negative ERECTA gene from Arabidopsis thaliana that is truncated in the kinase domain (AtΔKinase). Expression of AtΔKinase in soybean resulted in the short stature, reduced number of leaves, reduced leaf surface area and enhanced branching in the transgenic plants. The transgenic AtΔKinase soybean plants exhibited increased tolerance to water deficit stress due to the reduction of total leaf area and reduced transpiration compared to the wild-type plants. Production of seeds in AtΔKinase lines was higher compared to wild type at regular conditions of cultivation and after exposure to drought stress. Transgenic seedlings expressing AtΔKinase were also able to withstand salt stress better than the wild-type. Established results demonstrated the significance of native soybean genes (GmER and GmERL) in development and stress response of soybean, and suggested that the truncated ERECTA gene of Arabidopsis thaliana can be used to manipulate the growth and stress response of different crop species.


Assuntos
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/farmacologia , Receptores de Superfície Celular/genética , Soja/crescimento & desenvolvimento , Estresse Fisiológico/efeitos dos fármacos , Arabidopsis , Proteínas de Arabidopsis/metabolismo , Folhas de Planta/metabolismo , Plantas Geneticamente Modificadas , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Soja/anatomia & histologia
13.
Radiology ; 295(3): 736-740, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32421468

RESUMO

HistoryA 13-year-old girl was born to consanguineous parents. She presented with mild intellectual impairment, convergent strabismus, horizontal gaze palsy, and bilateral abducens palsy. Vertical gaze was preserved, and no abnormalities suggesting facial paralysis were noted. In addition, she reported progressive back pain since she was 5 years old. Other symptoms were denied. No medications or related drugs had been administered thus far. The patient underwent brain MRI for further evaluation. Current and previous spine radiographs were also reviewed.


Assuntos
Análise Mutacional de DNA , Oftalmoplegia Externa Progressiva Crônica/genética , Receptores de Superfície Celular/genética , Escoliose/genética , Adolescente , Consanguinidade , Feminino , Humanos , Imagem por Ressonância Magnética , Oftalmoplegia Externa Progressiva Crônica/diagnóstico por imagem , Doenças Raras , Escoliose/diagnóstico por imagem
14.
Medicine (Baltimore) ; 99(19): e20113, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384486

RESUMO

Autosomal recessive polycystic kidney disease (ARPKD) is the most common inherited childhood-onset renal disease, with underlying ciliopathy, and varies widely in clinical severity. The aim of this study was to describe the most severe form of ARPKD, with a fatal clinical course, and its association with mutations in polycystic kidney and hepatic disease 1 (fibrocystin) (PKHD1). Clinical, imaging, pathological, and molecular genetic findings were reviewed in patients prenatally affected with ARPKD and their families.Five unrelated Korean families, including 9 patients, were analyzed. Among the 9 patients, 2 fetuses died in utero, 6 patients did not survive longer than a few days, and 1 patient survived for 5 months with ventilator support and renal replacement therapy. A total of 6 truncating mutations (all nonsense) and 4 missense mutations were detected in a compound heterozygous state, including 4 novel mutations. The most severe phenotypes were shared among all affected patients in each family, irrespective of mutation types.Our data suggest a strong genotype-phenotype relationship in ARPKD, with minimal intra-familial heterogeneity. These findings are important for informing future reproductive planning in affected families.


Assuntos
Rim Policístico Autossômico Recessivo/genética , Rim Policístico Autossômico Recessivo/mortalidade , Receptores de Superfície Celular/genética , Feto Abortado , Feminino , Genótipo , Humanos , Recém-Nascido , Masculino , Mutação , Fenótipo , Rim Policístico Autossômico Recessivo/patologia , República da Coreia , Índice de Gravidade de Doença
15.
Proc Natl Acad Sci U S A ; 117(22): 12295-12305, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424104

RESUMO

The mechanisms that regulate germinal center (GC) B cell responses in the spleen are not fully understood. Here we use a combination of pharmacologic and genetic approaches to delete SIGN-R1+ marginal zone (MZ) macrophages and reveal their specific contribution to the regulation of humoral immunity in the spleen. We find that while SIGN-R1+ macrophages were not essential for initial activation of B cells, they were required for maturation of the response and development of GC B cells. These defects could be corrected when follicular helper T (Tfh) cells were induced before macrophage ablation or when Tfh responses were enhanced. Moreover, we show that in the absence of SIGN-R1+ macrophages, DCIR2+ dendritic cells (DCs), which play a key role in priming Tfh responses, were unable to cluster to the interfollicular regions of the spleen and were instead displaced to the MZ. Restoring SIGN-R1+ macrophages to the spleen corrected positioning of DCIR2+ DCs and rescued the GC B cell response. Our study reveals a previously unappreciated role for SIGN-R1+ macrophages in regulation of the GC reaction and highlights the functional specification of macrophage subsets in the MZ compartment.


Assuntos
Linfócitos B/imunologia , Moléculas de Adesão Celular/imunologia , Centro Germinativo/imunologia , Lectinas Tipo C/imunologia , Macrófagos/imunologia , Receptores de Superfície Celular/imunologia , Baço/imunologia , Animais , Moléculas de Adesão Celular/genética , Lectinas Tipo C/genética , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Superfície Celular/genética , Linfócitos T Auxiliares-Indutores
16.
PLoS One ; 15(5): e0231813, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442167

RESUMO

The interactions between membrane receptors and their endogenous ligands are key interactions in organisms. Recently, we have shown that a high number of genes encoding human receptors appeared at the same moment as their ligand in the animal tree of life. However, a set of receptors appeared before their present ligand. Different scenarios have been proposed to explain how a receptor can be conserved if its ligand is not yet appeared. However, these scenarios have been proposed individually and have never been studied in a global way. In this study, we investigated 30 mammalian pairs of ligand/receptor for which the first ligand appeared after its receptor in the tree of life, by using common indexes of selection, and proposed different scenarios explaining the earlier appearance of a receptor relative to its ligand. Based on 3D structural studies, our indexes allowed us to classify the evolution of these partners into different scenarios: 1) a scenario where the binding interface of the receptor is already present and under purifying selection before the appearance of the ligand; 2) a scenario where the binding interface seems to have appeared progressively, and 3) a scenario where the binding site seems to have been reshuffled since its appearance. As some scenarios were confirmed by the literature, we concluded that simple indexes can give a good highlight of the evolutive history of two partners that did not appear at the same time. Based on these scenarios, we also hypothesize that the replacement of a ligand by another is a frequent phenomenon during evolution.


Assuntos
Sítios de Ligação/genética , Evolução Molecular , Ligantes , Ligação Proteica/genética , Receptores de Superfície Celular , Sequência de Aminoácidos/genética , Animais , Simulação por Computador , Humanos , Modelos Moleculares , Conformação Molecular , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo
17.
PLoS Pathog ; 16(5): e1008501, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32369532

RESUMO

Plant-parasitic nematodes cause huge agricultural economic losses. Two major families of Bacillus thuringiensis crystal proteins, Cry5 and Cry6, show nematicidal activity. Previous work showed that binding to midgut receptors is a limiting step in Cry toxin mode of action. In the case of Cry5Ba, certain Caenorhabditis elegans glycolipids were identified as receptors of this toxin. However, the receptors for Cry6 toxin remain unknown. In this study, the C. elegans CUB-like-domain containing protein RBT-1, released by phosphatidylinositol-specific phospholipase C (PI-PLC), was identified as a Cry6Aa binding protein by affinity chromatography. RBT-1 contained a predicted glycosylphosphatidylinositol (GPI) anchor site and was shown to locate in lipid rafts in the surface of the midgut cells. Western ligand blot assays and ELISA binding analysis confirmed the binding interaction between Cry6Aa and RBT-1 showing high affinity and specificity. In addition, the mutation of rbt-1 gene decreased the susceptibility of C. elegans to Cry6Aa but not that of Cry5Ba. Furthermore, RBT-1 mediated the uptake of Cry6Aa into C. elegans gut cells, and was shown to be involved in triggering pore-formation activity, indicating that RBT-1 is required for the interaction of Cry6Aa with the nematode midgut cells. These results support that RBT-1 is a functional receptor for Cry6Aa.


Assuntos
Bacillus thuringiensis/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Endotoxinas/metabolismo , Proteínas Hemolisinas/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/microbiologia , Proteínas de Caenorhabditis elegans/genética , Microdomínios da Membrana/genética , Microdomínios da Membrana/metabolismo , Mutação , Oligossacarídeos/genética , Oligossacarídeos/metabolismo , Receptores de Superfície Celular/genética
18.
FASEB J ; 34(5): 6008-6016, 2020 05.
Artigo em Inglês | MEDLINE | ID: covidwho-46910

RESUMO

The sudden outbreak of COVID-19 has led to more than seven thousand deaths. Unfortunately, there are no specific drugs available to cure this disease. Type 2 taste receptors (TAS2Rs) may play an important role in host defense mechanisms. Based on the idea of host-directed therapy (HDT), we performed a negative co-expression analysis using big data of 60 000 Affymetrix expression arrays and 5000 TCGA data sets to determine the functions of TAS2R10, which can be activated by numerous bitter substances. Excitingly, we found that the main functions of TAS2R10 involved controlling infectious diseases caused by bacteria, viruses, and parasites, suggesting that TAS2R10 is a key trigger of host defense pathways. To quickly guide the clinical treatment of 2019-nCoV, we searched currently available drugs that are agonists of TAS2Rs. We identified many cheap, available, and safe medicines, such as diphenidol, quinine, chloroquine, artemisinin, chlorpheniramine, yohimbine, and dextromethorphan, which may target the most common symptoms caused by 2019-nCoV. We suggest that a cocktail-like recipe of existing bitter drugs may help doctors to fight this catastrophic disease and that the general public may drink or eat bitter substances, such as coffee, tea, or bitter vegetables, to reduce the risk of infection.


Assuntos
Antivirais/uso terapêutico , Biologia Computacional , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Receptores Acoplados a Proteínas-G/agonistas , Antivirais/farmacologia , Betacoronavirus , Bases de Dados Genéticas , Bases de Dados de Produtos Farmacêuticos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pandemias , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas-G/genética
19.
Nat Cell Biol ; 22(4): 389-400, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231305

RESUMO

In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3α/ß and Mek1/2 (2i) instructs a self-renewing ground state whose endogenous inducers are unknown. Here we show that the axon guidance cue Netrin-1 promotes naive pluripotency by triggering profound signalling, transcriptomic and epigenetic changes in mESCs. Furthermore, we demonstrate that Netrin-1 can substitute for blockade of Gsk3α/ß and Mek1/2 to sustain self-renewal of mESCs in combination with leukaemia inhibitory factor and regulates the formation of the mouse pluripotent blastocyst. Mechanistically, we reveal how Netrin-1 and the balance of its receptors Neo1 and Unc5B co-regulate Wnt and MAPK pathways in both mouse and human ESCs. Netrin-1 induces Fak kinase to inactivate Gsk3α/ß and stabilize ß-catenin while increasing the phosphatase activity of a Ppp2r2c-containing Pp2a complex to reduce Erk1/2 activity. Collectively, this work identifies Netrin-1 as a regulator of pluripotency and reveals that it mediates different effects in mESCs depending on its receptor dosage, opening perspectives for balancing self-renewal and lineage commitment.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas do Tecido Nervoso/genética , Receptores de Netrina/genética , Netrina-1/genética , Receptores de Superfície Celular/genética , Via de Sinalização Wnt/genética , Animais , Linhagem Celular , Embrião de Mamíferos , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , MAP Quinase Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos SCID , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Netrina/metabolismo , Netrina-1/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Receptores de Superfície Celular/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
20.
FASEB J ; 34(5): 6008-6016, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32281695

RESUMO

The sudden outbreak of COVID-19 has led to more than seven thousand deaths. Unfortunately, there are no specific drugs available to cure this disease. Type 2 taste receptors (TAS2Rs) may play an important role in host defense mechanisms. Based on the idea of host-directed therapy (HDT), we performed a negative co-expression analysis using big data of 60 000 Affymetrix expression arrays and 5000 TCGA data sets to determine the functions of TAS2R10, which can be activated by numerous bitter substances. Excitingly, we found that the main functions of TAS2R10 involved controlling infectious diseases caused by bacteria, viruses, and parasites, suggesting that TAS2R10 is a key trigger of host defense pathways. To quickly guide the clinical treatment of 2019-nCoV, we searched currently available drugs that are agonists of TAS2Rs. We identified many cheap, available, and safe medicines, such as diphenidol, quinine, chloroquine, artemisinin, chlorpheniramine, yohimbine, and dextromethorphan, which may target the most common symptoms caused by 2019-nCoV. We suggest that a cocktail-like recipe of existing bitter drugs may help doctors to fight this catastrophic disease and that the general public may drink or eat bitter substances, such as coffee, tea, or bitter vegetables, to reduce the risk of infection.


Assuntos
Antivirais/uso terapêutico , Biologia Computacional , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Receptores Acoplados a Proteínas-G/agonistas , Antivirais/farmacologia , Betacoronavirus , Bases de Dados Genéticas , Bases de Dados de Produtos Farmacêuticos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pandemias , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas-G/genética
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