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1.
Immunity ; 50(1): 121-136.e5, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30594464

RESUMO

Dermal fibroblasts (dFBs) resist infection by locally differentiating into adipocytes and producing cathelicidin antimicrobial peptide in response to Staphylococcus aureus (S. aureus). Here, we show that neonatal skin was enriched with adipogenic dFBs and immature dermal fat that highly expressed cathelicidin. The pool of adipogenic and antimicrobial dFBs declined after birth, leading to an age-dependent loss of dermal fat and a decrease in adipogenesis and cathelidicin production in response to infection. Transforming growth factor beta (TGF-ß), which acted on uncommitted embryonic and adult dFBs and inhibited their adipogenic and antimicrobial function, was identified as a key upstream regulator of this process. Furthermore, inhibition of the TGF-ß receptor restored the adipogenic and antimicrobial function of dFBs in culture and increased resistance of adult mice to S. aureus infection. These results provide insight into changes that occur in the skin innate immune system between the perinatal and adult periods of life.


Assuntos
Envelhecimento/imunologia , Fibroblastos/fisiologia , Pele/metabolismo , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Gordura Subcutânea/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adipócitos/metabolismo , Adipogenia , Animais , Anti-Infecciosos/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Células Cultivadas , Embrião de Mamíferos , Humanos , Imunidade Inata , Camundongos , Catelicidinas
2.
Dermatol Surg ; 48(4): 441-448, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35165220

RESUMO

BACKGROUND: Lasers and energy-based devices (EBD) are popular treatments for skin rejuvenation and resurfacing. Achieving desired outcomes and avoiding complications require understanding the effects of these devices at a histologic level. Currently, no comprehensive review summarizing the histologic effects of laser and energy-based treatments exists. OBJECTIVE: To describe how lasers and EBD alter skin histology and improve the overall understanding of these devices. MATERIALS AND METHODS: A PubMed search was conducted for studies with histologic analysis of fractional picosecond laser, fractional radiofrequency microneedling, nonablative lasers, and ablative lasers. RESULTS: Fractional picosecond lasers induce intraepidermal and/or dermal vacuoles from laser-induced optical breakdown. Fractional radiofrequency microneedling delivers thermal energy to the dermis while sparing the epidermis, making it safer for patients with darker skin phototypes. Fractional nonablative lasers induce conical zones of coagulation of the epidermis and upper dermis. Ablative lasers vaporize the stratum corneum down to the dermis. Traditional ablative lasers cause diffuse vaporization while fractional ablative lasers generate columns of tissue ablation. CONCLUSION: Lasers and EBD are effective for skin resurfacing and rejuvenation and have different mechanisms with disparate targets in the skin. Safe and effective use of devices requires understanding the histologic laser-tissue interaction.


Assuntos
Terapia a Laser , Lasers de Gás , Lasers de Estado Sólido , Envelhecimento da Pele , Cicatriz/etiologia , Cicatriz/cirurgia , Humanos , Rejuvenescimento , Pele/patologia
3.
Am J Hum Genet ; 103(1): 154-162, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29961569

RESUMO

TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Adulto , Aminoácidos/genética , Criança , Pré-Escolar , Exoma/genética , Feminino , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Sistema de Sinalização das MAP Quinases/genética , Masculino , Anormalidades Musculoesqueléticas/genética , Fenótipo
4.
Proc Natl Acad Sci U S A ; 115(51): 13039-13044, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30478036

RESUMO

Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.


Assuntos
DNA Mitocondrial/genética , Genes Mitocondriais , Herança Materna , Mitocôndrias/genética , Doenças Mitocondriais/genética , Herança Paterna , Adulto , Pré-Escolar , Bases de Dados Genéticas , Feminino , Genoma Mitocondrial , Humanos , Padrões de Herança , Masculino , Pessoa de Meia-Idade , Linhagem
5.
Mol Cell ; 48(2): 195-206, 2012 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-22959275

RESUMO

LIN28 is a conserved RNA-binding protein implicated in pluripotency, reprogramming, and oncogenesis. It was previously shown to act primarily by blocking let-7 microRNA (miRNA) biogenesis, but here we elucidate distinct roles of LIN28 regulation via its direct messenger RNA (mRNA) targets. Through crosslinking and immunoprecipitation coupled with high-throughput sequencing (CLIP-seq) in human embryonic stem cells and somatic cells expressing exogenous LIN28, we have defined discrete LIN28-binding sites in a quarter of human transcripts. These sites revealed that LIN28 binds to GGAGA sequences enriched within loop structures in mRNAs, reminiscent of its interaction with let-7 miRNA precursors. Among LIN28 mRNA targets, we found evidence for LIN28 autoregulation and also direct but differing effects on the protein abundance of splicing regulators in somatic and pluripotent stem cells. Splicing-sensitive microarrays demonstrated that exogenous LIN28 expression causes widespread downstream alternative splicing changes. These findings identify important regulatory functions of LIN28 via direct mRNA interactions.


Assuntos
Processamento Alternativo/genética , RNA Mensageiro , Proteínas de Ligação a RNA , Sítios de Ligação/genética , Células-Tronco Embrionárias , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Motivos de Nucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
6.
Dermatol Online J ; 25(11)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32045146

RESUMO

Atypical fibroxanthoma (AFX) is a rare cutaneous fibrohistiocytic tumor that typically arises on chronically sun-damaged skin, such as the head and neck, as a nondescript ulcerated papule, nodule, or tumor. The clinical prognosis is usually favorable and metastasis is rare. Pleomorphic dermal sarcoma (PDS), or undifferentiated pleomorphic sarcoma, is a recently introduced diagnostic moniker for AFX-like tumors with more aggressive clinical and histologic features such as necrosis and vascular invasion. The exact relationship between AFX and PDS has been debated. Diagnosis of these tumors is generally based on immunohistochemical staining to exclude other mimics. A wholly specific marker for this tumor does not exist, leading to diagnostic ambiguity in certain cases. Herein, we present a case of pleomorphic dermal sarcoma in a 53-year-old man with human immunodeficiency virus that displayed patchy S100 staining concerning for melanoma upon hospital pathology review. Next-generation sequencing analysis confirmed a mutation pattern consistent with published molecular signatures of AFX/PDS. In discussing this case, we review the current understanding of AFX/PDS and discuss diagnostic pitfalls, as well as emphasize on how next-generation sequencing techniques might improve accuracy in the diagnosis of tumors in the spectrum of AFX/PDS.


Assuntos
Infecções por HIV/complicações , Hospedeiro Imunocomprometido , Mutação , Sarcoma/patologia , Neoplasias Cutâneas/patologia , Diagnóstico Diferencial , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Melanoma/diagnóstico , Pessoa de Meia-Idade , Sarcoma/diagnóstico , Sarcoma/etiologia , Sarcoma/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética
7.
Am J Med Genet A ; 176(4): 973-979, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29423971

RESUMO

SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias. Both changes are within the CpG island in exon 21, separated by a 375 bp sequence. Next generation sequencing of PCR products revealed that the two variants are most frequently associated with each other. Sanger sequencing of the cloned PCR products further confirmed that both changes were on a single allele. The clinical presentation in this individual is consistent with other patients with a truncating mutation in exon 21, suggesting that the missense change contributes none or minimally to the phenotypes. This is the first report of two de novo mutations in one SHANK3 allele.


Assuntos
Alelos , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação , Proteínas do Tecido Nervoso/genética , Adolescente , Análise Mutacional de DNA , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Sequenciamento do Exoma
8.
Dermatol Online J ; 24(9)2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30677840

RESUMO

Ginseng is a popular herbal remedy derived from the plant roots of the Panax genus and has been used in traditional Asian medicine for thousands of years. In the United States, it has become increasingly popular and is taken for many conditions, including as an immune enhancer. Cutaneous adverse effects have been reported to occur following ginseng consumption, although detailed clinical descriptions are limited. A 60-year-old woman who repeatedly developed inflammatory papules following ginseng consumption is described and the characteristics of ginseng use in healthcare are reviewed.


Assuntos
Erupções Acneiformes/induzido quimicamente , Inflamação/induzido quimicamente , Panax/efeitos adversos , Erupções Acneiformes/etiologia , Feminino , Humanos , Inflamação/etiologia , Pessoa de Meia-Idade
11.
Mol Genet Metab ; 118(4): 264-71, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27233228

RESUMO

Mutations in the MUT gene, which encodes the mitochondrial enzyme methylmalonyl-CoA mutase, are responsible for the mut form of methylmalonic aciduria (MMA). In this study, a next generation sequencing (NGS) based gene panel was used to analyze 53 patients that had been diagnosed with mut MMA by somatic cell complementation analysis. A total of 54 different mutations in MUT were identified in 48 patients; 16 novel mutations were identified, including 1 initiation site mutation (c.2T>C [p.M1?]), 1 missense mutation (c.566A>T [p.N189I]), 2 nonsense mutations (c.129G>A [p.W43*] and c.1975C>T [p.Q659*]), 2 mutations affecting splice sites (c.753+3A>G and c.754-2A>G), 8 small insertions, deletions, and duplications (c.29dupT [p.L10Ffs*39], c.55dupG [p.V19Gfs*30], c.631_633delGAG [p.E211del], c.795_796insT [p.M266Yfs*7], c.1061delCinsGGA [p.S354Wfs*20], c.1065_1068dupATGG [p.S357Mfs*5], c.1181dupT [p.L394Ffs*30], c.1240delG [p.E414Kfs*17]), a large insertion (c.146_147ins279), and a large deletion involving exon 13. Phenotypic rescue and cDNA analysis were used to confirm that the c.146_147ins279 and c.631_633delGAG mutations were associated with the decreased methylmalonyl-CoA mutase function observed in the patient fibroblasts. In five patients, the NGS panel did not confirm the diagnosis made by complementation analysis. One of these patients was found to carry 2 novel mutations (c.433G > A [p.E145K] and c.511A>C [p.N171H]) in the SUCLG1 gene.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Metilmalonil-CoA Mutase/genética , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Células Cultivadas , Criança , Pré-Escolar , Códon sem Sentido/genética , Éxons/genética , Feminino , Fibroblastos/metabolismo , Humanos , Mutação INDEL/genética , Lactente , Masculino , Ácido Metilmalônico/metabolismo , Mitocôndrias/enzimologia , Mutação de Sentido Incorreto/genética , Fenótipo , Deleção de Sequência/genética , Succinato-CoA Ligases/genética , Adulto Jovem
12.
Mol Genet Metab ; 117(3): 363-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26827111

RESUMO

Next generation sequencing (NGS) based gene panel testing is increasingly available as a molecular diagnostic approach for inborn errors of metabolism. Over the past 40 years patients have been referred to the Vitamin B12 Clinical Research Laboratory at McGill University for diagnosis of inborn errors of cobalamin metabolism by functional studies in cultured fibroblasts. DNA samples from patients in which no diagnosis was made by these studies were tested by a NGS gene panel to determine whether any molecular diagnoses could be made. 131 DNA samples from patients with elevated methylmalonic acid and no diagnosis following functional studies of cobalamin metabolism were analyzed using the 24 gene extended cobalamin metabolism NGS based panel developed by Baylor Miraca Genetics Laboratories. Gene panel testing identified two or more variants in a single gene in 16/131 patients. Eight patients had pathogenic findings, one had a finding of uncertain significance, and seven had benign findings. Of the patients with pathogenic findings, five had mutations in ACSF3, two in SUCLG1 and one in TCN2. Thus, the NGS gene panel allowed for the presumptive diagnosis of 8 additional patients for which a diagnosis was not made by the functional assays.


Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Ácido Metilmalônico/metabolismo , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/genética , Vitamina B 12/metabolismo , Complexo Vitamínico B/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/genética , Pré-Escolar , Coenzima A Ligases/genética , Feminino , Testes Genéticos/métodos , Variação Genética , Genótipo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Técnicas de Diagnóstico Molecular , Mutação , Fenótipo , Succinato-CoA Ligases/genética
13.
J Biol Chem ; 289(14): 9741-53, 2014 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-24550391

RESUMO

This study was designed to examine the role of hydrogen sulfide (H2S) in the generation of oxidized low-density lipoprotein (ox-LDL)-stimulated monocyte chemoattractant protein 1 (MCP-1) from macrophages and possible mechanisms. THP-1 cells and RAW macrophages were pretreated with sodium hydrosulfide (NaHS) and hexyl acrylate and then treated with ox-LDL. The results showed that ox-LDL treatment down-regulated the H2S/cystathionine-ß-synthase pathway, with increased MCP-1 protein and mRNA expression in both THP-1 cells and RAW macrophages. Hexyl acrylate promoted ox-LDL-induced inflammation, whereas the H2S donor NaHS inhibited it. NaHS markedly suppressed NF-κB p65 phosphorylation, nuclear translocation, DNA binding activity, and recruitment to the MCP-1 promoter in ox-LDL-treated macrophages. Furthermore, NaHS decreased the ratio of free thiol groups in p65, whereas the thiol reductant DTT reversed the inhibiting effect of H2S on the p65 DNA binding activity. Most importantly, site-specific mutation of cysteine 38 to serine in p65 abolished the effect of H2S on the sulfhydration of NF-κB and ox-LDL-induced NF-κB activation. These results suggested that endogenous H2S inhibited ox-LDL-induced macrophage inflammation by suppressing NF-κB p65 phosphorylation, nuclear translocation, DNA binding activity, and recruitment to the MCP-1 promoter. The sulfhydration of free thiol group on cysteine 38 in p65 served as a molecular mechanism by which H2S inhibited NF-κB pathway activation in ox-LDL-induced macrophage inflammation.


Assuntos
Quimiocina CCL2/biossíntese , Gasotransmissores/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Lipoproteínas LDL/toxicidade , Macrófagos/metabolismo , Fator de Transcrição RelA/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Animais , Linhagem Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Quimiocina CCL2/genética , Regulação da Expressão Gênica/genética , Humanos , Inflamação/induzido quimicamente , Lipoproteínas LDL/farmacologia , Macrófagos/patologia , Camundongos , Fosforilação/efeitos dos fármacos , Fosforilação/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Fator de Transcrição RelA/genética
14.
Cardiol Young ; 25(6): 1182-90, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25597708

RESUMO

OBJECTIVE: To determine the optimal drug therapy for intravenous immunoglobulin-resistant Kawasaki disease. METHODS: Studies regarding drug therapy for intravenous immunoglobulin-resistant Kawasaki disease were selected from medical electronic databases including PubMed, Medline, Elsevier, and Springer Link. The effectiveness in terms of temperature recovery and coronary artery damage was compared between a second intravenous immunoglobulin treatment and glucocorticosteroid treatment for children with intravenous immunoglobulin-resistant Kawasaki disease using meta-analysis with Review Manager 5.3 software. Indices to evaluate the effects were body temperature, biomarker levels, and coronary artery lesions detected by echocardiography. Results are reported as relative risks or odds ratio with a 95% confidence interval and p<0.05. RESULTS: Meta-analysis included 52 patients in the second intravenous immunoglobulin treatment group and 75 patients in the glucocorticosteroid treatment control group from four studies that met our inclusion criteria. Temperatures of patients who received glucocorticosteroid treatment were effectively controlled compared with those who received a second intravenous immunoglobulin treatment (relative risk=0.73, 95% confidence interval: 0.58-0.92, p=0.007). There were no differences, however, in the incidence of coronary artery lesions between the two groups (odds ratio=1.55, 95% confidence interval: 0.57-4.20, p=0.39). CONCLUSIONS: Glucocorticosteroids are more effective in controlling body temperature compared with intravenous immunoglobulin re-treatment in intravenous immunoglobulin-resistant Kawasaki disease children; however, glucocorticosteroids and intravenous immunoglobulin re-treatment showed no difference in the prevention of coronary artery lesions.


Assuntos
Biomarcadores , Temperatura Corporal/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Glucocorticoides/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Vasos Coronários/diagnóstico por imagem , Ecocardiografia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Biochim Biophys Acta ; 1833(6): 1347-55, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23499876

RESUMO

Hydrogen sulfide (H2S) can modulate the proliferation of vascular smooth muscle cells. This study was designed to investigate the epigenetic control of vascular smooth muscle cell proliferation in response to H2S. Microarray analysis indicated that Brahma-related gene 1 (Brg1) and proliferation-related genes including proliferating cell nuclear antigen (Pcna), neurotrophin 3 (Ntf3) and platelet-derived growth factor subunit A (Pdgfα) were significantly downregulated by H2S in endothelin-1-stimulated proliferative vascular smooth muscle cells. Brg1 is the central catalytic subunit of the SWI/SNF apparatus (an ATP-dependent chromatin remodeling complex). Overexpression and knockdown of Brg1 confirmed that Brg1 was crucial for H2S-induced inhibition of vascular smooth muscle cell proliferation. A luciferase reporter assay, real-time PCR and Western blotting demonstrated that H2S inhibited Brg1 transcription and expression. A DNase I hypersensitivity assay revealed that H2S reversed endothelin-1-stimulated Pcna, Ntf3 and Pdgfα chromatin remodeling and vascular smooth muscle cell proliferation. A chromatin immunoprecipitation assay indicated that H2S inhibited the recruitment of Brg1 to the Pcna, Ntf3 and Pdgfα promoters. The results of this study indicate that H2S inhibits vascular smooth muscle cell proliferation via an epigenetic mechanism involving the inhibition of Brg1 transcription and expression, and by reducing the recruitment of Brg1 to the Pcna, Ntf3 and Pdgfα promoter regions.


Assuntos
Aorta/efeitos dos fármacos , Proliferação de Células , DNA Helicases/genética , Epigenômica , Regulação da Expressão Gênica , Sulfeto de Hidrogênio/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Aorta/citologia , Aorta/metabolismo , Apoptose , Biomarcadores/metabolismo , Western Blotting , Células Cultivadas , Imunoprecipitação da Cromatina , DNA Helicases/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Citometria de Fluxo , Perfilação da Expressão Gênica , Luciferases/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Neurotrofina 3/genética , Neurotrofina 3/metabolismo , Proteínas Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/metabolismo
16.
PLoS One ; 19(5): e0303686, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38781128

RESUMO

The intracellular protozoan parasite Leishmania causes leishmaniasis in humans, leading to serious illness and death in tropical and subtropical areas worldwide. Unfortunately, due to the unavailability of approved vaccines for humans and the limited efficacy of available drugs, leishmaniasis is on the rise. A comprehensive understanding of host-pathogen interactions at the molecular level could pave the way to counter leishmaniasis. There is growing evidence that several intracellular pathogens target RNA interference (RNAi) pathways in host cells to facilitate their persistence. The core elements of the RNAi system are complexes of Argonaute (Ago) proteins with small non-coding RNAs, also known as RNA-induced silencing complexes (RISCs). Recently, we have shown that Leishmania modulates Ago1 protein of host macrophages for its survival. In this study, we biochemically characterize the Ago proteins' interactome in Leishmania-infected macrophages compared to non-infected cells. For this, a quantitative proteomic approach using stable isotope labelling by amino acids in cell culture (SILAC) was employed, followed by purification of host Ago-complexes using a short TNRC6 protein-derived peptide fused to glutathione S-transferase beads as an affinity matrix. Proteomic-based detailed biochemical analysis revealed Leishmania modulated host macrophage RISC composition during infection. This analysis identified 51 Ago-interacting proteins with a broad range of biological activities. Strikingly, Leishmania proteins were detected as part of host Ago-containing complexes in infected cells. Our results present the first report of comprehensive quantitative proteomics of Ago-containing complexes isolated from Leishmania-infected macrophages and suggest targeting the effector complex of host RNAi machinery. Additionally, these results expand knowledge of RISC in the context of host-pathogen interactions in parasitology in general.


Assuntos
Proteínas Argonautas , Macrófagos , Proteínas Argonautas/metabolismo , Proteínas Argonautas/genética , Humanos , Macrófagos/parasitologia , Macrófagos/metabolismo , Proteômica/métodos , Leishmania/metabolismo , Interferência de RNA , Leishmaniose/parasitologia , Leishmaniose/metabolismo
17.
Int J Womens Dermatol ; 10(2): e152, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38854891

RESUMO

Background: In some hidradenitis suppurativa (HS) clinical trial study arms, there is an unexpected decline in efficacy between the penultimate visit and the prespecified primary endpoint week, which we have termed a "wobble." Objective: We aimed to establish how often study arms in HS programs wobble. Methods: In a retrospective review, we identified HS clinical trials listed on ClinicalTrials.gov testing systemic, nonantibiotic medications that utilized Hidradenitis Suppurativa Clinical Response (HiSCR) as an outcome measure. We identified study arms demonstrating greater improvement in a visit prior to the primary endpoint week. Baseline subject characteristics were compared between studies with HiSCR wobble and no HiSCR wobble. Results: A total of 21 studies (randomized control trial [RCT], n = 14; open-label, n = 7) with 35 study drug arms (RCT, n = 27; open-label, n = 8) and 14 placebo arms were identified. HiSCR wobble occurred significantly more often in RCT compared to open-label study drug arms (11/27 [40.7%] vs 0/8 [0%]). In RCT study arms with HiSCR wobble, baseline draining fistula counts were significantly lower (2.3 vs 3.2), and numerically fewer Hurley stage 3 patients (33.2% vs 42.5%), lower weighted total abscess and nodule counts (12.1 vs 12.6), lower weighted dermatology life quality index scores (12.5 vs 14.5), and a higher proportion of female patients (63.9% vs 58.3%) were observed. Limitations: Include low number of HS clinical trials and insufficient data reported in many studies to assess for wobble, degree of wobble, and to compare all baseline characteristics. Conclusion: Nonlinear improvement in study arm response occurs in some HS RCTs. Potential contributing factors include a higher proportion of less severe patients at baseline and more female patients.

18.
Blood Adv ; 8(4): 1002-1017, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38127268

RESUMO

ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) can be complicated by life-threatening organ toxicity and infection necessitating intensive care. Epidemiologic data have been limited by single-center studies, poor database granularity, and a lack of long-term survivors. To identify contemporary trends in intensive care unit (ICU) use and long-term outcomes, we merged data from the Center for International Blood and Marrow Transplant Research and the Virtual Pediatric Systems databases. We identified 6995 pediatric patients with HCT aged ≤21 years who underwent first allogeneic HCT between 2008 and 2014 across 69 centers in the United States or Canada and followed patients until the year 2020. ICU admission was required for 1067 patients (8.3% by day +100, 12.8% by 1 year, and 15.3% by 5 years after HCT), and was linked to demographic background, pretransplant organ toxicity, allograft type and HLA-match, and the development of graft-versus-host disease or malignancy relapse. Survival to ICU discharge was 85.7%, but more than half of ICU survivors required ICU readmission, leading to 52.5% and 42.6% survival at 1- and 5-years post-ICU transfer, respectively. ICU survival was worse among patients with malignant disease, poor pretransplant organ function, and alloreactivity risk factors. Among 1-year HCT survivors, those who required ICU in the first year had 10% lower survival at 5 years and developed new dialysis-dependent renal failure at a greater rate (P<.001). Thus, although ICU management is common and survival to ICU discharge is high, ongoing complications necessitate recurrent ICU admission and lead to a poor 1-year outcome in select patients who are at high risk.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Estados Unidos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplantados , Transplante Homólogo/efeitos adversos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Cuidados Críticos
19.
J Pediatr ; 163(4): 1169-73.e2, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23726544

RESUMO

OBJECTIVES: To evaluate the use of erythrocytic hydrogen sulfide (H2S) in predicting the therapeutic efficacy of midodrine hydrochloride for children with postural orthostatic tachycardia syndrome (POTS). STUDY DESIGN: Fifty-five children were included in this study, involving 28 children with POTS (POTS group) and 27 healthy children (control group). Children in the POTS group received midodrine hydrochloride treatment. Erythrocytic H2S production was measured; a receiver operating characteristic curve was used to assess if erythrocytic H2S could predict the therapeutic response to midodrine hydrochloride treatment. RESULTS: H2S production from erythrocytes was significantly higher in the POTS group than in the control group (P < .01). H2S production was also significantly higher in responders to midodrine hydrochloride than in non-responders (P < .05). The change in symptom score and baseline erythrocytic H2S production had a positive linear relationship (P < .01). There was also a positive correlation with the change in heart rate (P < .05). The receiver operating characteristic curve showed an area under curve value of 0.813. Erythrocytic H2S production yielded a sensitivity of 78.9% and a specificity of 77.8% in predicting the efficacy of midodrine hydrochloride therapy for children with POTS. CONCLUSION: Erythrocytic H2S could serve as a useful predictor of therapeutic response to midodrine hydrochloride in children with POTS.


Assuntos
Eritrócitos/metabolismo , Sulfeto de Hidrogênio/sangue , Midodrina/uso terapêutico , Síndrome da Taquicardia Postural Ortostática/sangue , Síndrome da Taquicardia Postural Ortostática/diagnóstico , Área Sob a Curva , Estudos de Casos e Controles , Criança , Pré-Escolar , Eletrocardiografia , Eritrócitos/citologia , Feminino , Frequência Cardíaca , Humanos , Masculino , Curva ROC , Sensibilidade e Especificidade , Simpatomiméticos/uso terapêutico
20.
Plant Physiol ; 160(1): 165-77, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22829318

RESUMO

To study the regulatory and functional differentiation between the mesophyll (M) and bundle sheath (BS) cells of maize (Zea mays), we isolated large quantities of highly homogeneous M and BS cells from newly matured second leaves for transcriptome profiling by RNA sequencing. A total of 52,421 annotated genes with at least one read were found in the two transcriptomes. Defining a gene with more than one read per kilobase per million mapped reads as expressed, we identified 18,482 expressed genes; 14,972 were expressed in M cells, including 53 M-enriched transcription factor (TF) genes, whereas 17,269 were expressed in BS cells, including 214 BS-enriched TF genes. Interestingly, many TF gene families show a conspicuous BS preference in expression. Pathway analyses reveal differentiation between the two cell types in various functional categories, with the M cells playing more important roles in light reaction, protein synthesis and folding, tetrapyrrole synthesis, and RNA binding, while the BS cells specialize in transport, signaling, protein degradation and posttranslational modification, major carbon, hydrogen, and oxygen metabolism, cell division and organization, and development. Genes coding for several transporters involved in the shuttle of C(4) metabolites and BS cell wall development have been identified, to our knowledge, for the first time. This comprehensive data set will be useful for studying M/BS differentiation in regulation and function.


Assuntos
Diferenciação Celular , Células do Mesofilo/citologia , Feixe Vascular de Plantas/citologia , Transcriptoma , Zea mays/citologia , Parede Celular/genética , Parede Celular/metabolismo , Mapeamento Cromossômico , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Células do Mesofilo/metabolismo , Fotossíntese , Células Vegetais/metabolismo , Epiderme Vegetal/genética , Epiderme Vegetal/metabolismo , Folhas de Planta/citologia , Folhas de Planta/genética , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Feixe Vascular de Plantas/genética , Feixe Vascular de Plantas/metabolismo , Plasmodesmos/genética , Plasmodesmos/metabolismo , Biossíntese de Proteínas , Transporte Proteico , Protoplastos/citologia , Protoplastos/metabolismo , RNA de Plantas/análise , RNA de Plantas/genética , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Zea mays/genética , Zea mays/metabolismo
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