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1.
Anal Chim Acta ; 1183: 338966, 2021 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-34627513

RESUMO

CircRNA is a type of covalently closed circular RNA molecule that serves as a potential biomarker for the disease early diagnosis and clinical researches. To achieve living cell imaging of specific circRNA, we developed a novel graphene oxide (GO)-based catalytic hairpin assembly (CHA) and hybridization chain reaction (HCR) signal dual amplification system (GO-CHA-HCR, abbreviated GO-AR) for circ-Foxo3 imaging in living cells. The developed system consists of four types of designed hairpin DNA HP1, HP2, H1, and fluorophore-labeled H2, which are absorbed on the GO nanosheets surface leading to fluorescence quenching. In the presence of circ-Foxo3, the CHA cycle was initiated to form a hybrid chain with split fragments, which triggered the HCR cycle to generate dsDNA nanowires that were then released from GO. This process recovered the quenched fluorescence, realizing two-stage signal amplification. The GO-AR system effectively improved the signal-to-noise ratio compared to the traditional GO-CHA and GO-HCR detection system. The detection limit of circ-Foxo3 was as low as 15 pM with excellent sensitivity and selectivity. In addition, the enzyme-free sensing system was successfully applied in living cell circRNA imaging and serum circRNA detection, indicating its high potential in clinical diagnostics.


Assuntos
Grafite , RNA Circular , DNA/genética , Hibridização de Ácido Nucleico
2.
Natl Sci Rev ; 8(8): nwaa191, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34691703

RESUMO

Marine diatoms construct their hierarchically ordered, three-dimensional (3D) external structures called frustules through precise biomineralization processes. Recapitulating the remarkable architectures and functions of diatom frustules in artificial materials is a major challenge that has important technological implications for hierarchically ordered composites. Here, we report the construction of highly ordered, mineralized composites based on fabrication of complex self-supporting porous structures-made of genetically engineered amyloid fusion proteins and the natural polysaccharide chitin-and performing in situ multiscale protein-mediated mineralization with diverse inorganic materials, including SiO2, TiO2 and Ga2O3. Subsequently, using sugar cubes as templates, we demonstrate that 3D fabricated porous structures can become colonized by engineered bacteria and can be functionalized with highly photoreactive minerals, thereby enabling co-localization of the photocatalytic units with a bacteria-based hydrogenase reaction for a successful semi-solid artificial photosynthesis system for hydrogen evolution. Our study thus highlights the power of coupling genetically engineered proteins and polysaccharides with biofabrication techniques to generate hierarchically organized mineralized porous structures inspired by nature.

4.
Toxicology ; 461: 152926, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34481902

RESUMO

Ochratoxin A (OTA) is one of the mycotoxins, which widely pollutes food systems and seriously threatens human health. OTA's target organ is the kidney. Exosome, as one of the extracellular vesicles, could be secreted by all kinds of cells. It contains different proteins, nucleic acid, and lipid, which are decided by their donor cells and could be uptake by the recipient cells, release their contents, and affect the recipient cell's life activity. In this study, a 24 h-treatment with 5 µM OTA was found to significantly reduce the cell viability of HEK293 cells and meanwhile to provide a sufficient quantity of exosomes, thus this concentration and time were selected for subsequent experiments. In addition, exosomes extracted by ultracentrifugation had higher purity, fewer impurities, and uniform morphology than that by the ExoQuick-TC kit. Furthermore, these exosomes increased ROS levels and decreased mitochondrial membrane potential in HEK293 cells. By RNA-seq, the cytotoxicity mechanisms induced by OTA-treated HEK293 cell-derived exosomes (EXO-OTA) and OTA were mainly the metabolism of proteins and the cell cycle respectively. Also, it proved that exosomes deliver partial OTA-induced cytotoxicity.

5.
Cells ; 10(6)2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207111

RESUMO

Decellularization efforts must balance the preservation of the extracellular matrix (ECM) components while eliminating the nucleic acid and cellular components. Following effective removal of nucleic acid and cell components, decellularized ECM (dECM) can be solubilized in an acidic environment with the assistance of various enzymes to develop biological scaffolds in different forms, such as sheets, tubular constructs, or three-dimensional (3D) hydrogels. Each organ or tissue that undergoes decellularization requires a distinct and optimized protocol to ensure that nucleic acids are removed, and the ECM components are preserved. The objective of this study was to optimize the decellularization process for dECM isolation from human lung tissues for downstream 2D and 3D cell culture systems. Following protocol optimization and dECM isolation, we performed experiments with a wide range of dECM concentrations to form human lung dECM hydrogels that were physically stable and biologically responsive. The dECM based-hydrogels supported the growth and proliferation of primary human lung fibroblast cells in 3D cultures. The dECM is also amenable to the coating of polyester membranes in Transwell™ Inserts to improve the cell adhesion, proliferation, and barrier function of primary human bronchial epithelial cells in 2D. In conclusion, we present a robust protocol for human lung decellularization, generation of dECM substrate material, and creation of hydrogels that support primary lung cell viability in 2D and 3D culture systems.


Assuntos
Técnicas de Cultura de Células/métodos , Pulmão/citologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/fisiologia , Humanos , Hidrogéis/administração & dosagem , Pulmão/efeitos dos fármacos , Engenharia Tecidual/métodos , Tecidos Suporte/química
6.
J Immunother Cancer ; 9(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34230111

RESUMO

T-cell receptor sequencing (TCRseq) enables tracking of T-cell clonotypes recognizing the same antigen over time and across biological compartments. TCRseq has been used to test if cross-reactive antitumor T cells are responsible for development of immune-related adverse events (irAEs) following immune checkpoint blockade. Prior studies have interpreted T-cell clones shared among the tumor and irAE as evidence supporting this, but interpretations of these findings are challenging, given the constraints of TCRseq. Here we capitalize on a rare opportunity to understand the impact of potential confounders, such as sample size, tissue compartment, and collection batch/timepoint, on the relative proportion of shared T-cell clones between an irAE and tumor specimens. TCRseq was performed on tumor-involved and -uninvolved tissues, including an irAE, that were obtained throughout disease progression and at the time of rapid autopsy from a patient with renal cell carcinoma treated with programmed death-1 (PD-1) blockade. Our analyses show significant effects of these confounders on our ability to understand T-cell receptor overlap, and we present mitigation strategies and study design recommendations to reduce these errors. Implementation of these strategies will enable more rigorous TCRseq-based studies of immune responses in human tissues, particularly as they relate to antitumor T-cell cross-reactivity in irAEs following checkpoint blockade.

7.
Nature ; 596(7870): 126-132, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34290408

RESUMO

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.


Assuntos
Antígenos de Neoplasias/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação da Expressão Gênica , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Células Cultivadas , Humanos , Memória Imunológica , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA-Seq , Receptores de Interleucina-7/imunologia , Análise de Célula Única , Transcriptoma/genética , Microambiente Tumoral
8.
Nat Protoc ; 16(8): 3954-3980, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34215863

RESUMO

Naive human pluripotent stem cells (hPSCs) can be used to generate mature human cells of all three germ layers in mouse-human chimeric embryos. Here, we describe a protocol for generating mouse-human chimeric embryos by injecting naive hPSCs converted from the primed state. Primed hPSCs are treated with a mammalian target of rapamycin inhibitor (Torin1) for 3 h and dissociated to single cells, which are plated on mouse embryonic fibroblasts in 2iLI medium, a condition essentially the same for culturing mouse embryonic stem cells. After 3-4 d, bright, dome-shaped colonies with mouse embryonic stem cell morphology are passaged in 2iLI medium. Established naive hPSCs are injected into mouse blastocysts, which produce E17.5 mouse embryos containing 0.1-4.0% human cells as quantified by next-generation sequencing of 18S ribosomal DNA amplicons. The protocol is suitable for studying the development of hPSCs in mouse embryos and may facilitate the generation of human cells, tissues and organs in animals.


Assuntos
Quimera/embriologia , Embrião de Mamíferos/fisiologia , Células-Tronco Embrionárias/fisiologia , Fibroblastos/fisiologia , Células-Tronco Pluripotentes/fisiologia , Amidas/farmacologia , Animais , Embrião de Mamíferos/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Feminino , Humanos , Camundongos , Naftiridinas/farmacologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Piridinas/farmacologia
9.
ACS Biomater Sci Eng ; 7(7): 2900-2925, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34275294

RESUMO

Tissue building does not occur exclusively during development. Even after a whole body is built from a single cell, tissue building can occur to repair and regenerate tissues of the adult body. This confers resilience and enhanced survival to multicellular organisms. However, this resiliency comes at a cost, as the potential for misdirected tissue building creates vulnerability to organ deformation and dysfunction-the hallmarks of disease. Pathological tissue morphogenesis is associated with fibrosis and cancer, which are the leading causes of morbidity and mortality worldwide. Despite being the priority of research for decades, scientific understanding of these diseases is limited and existing therapies underdeliver the desired benefits to patient outcomes. This can largely be attributed to the use of two-dimensional cell culture and animal models that insufficiently recapitulate human disease. Through the synergistic union of biological principles and engineering technology, organ-on-a-chip systems represent a powerful new approach to modeling pathological tissue morphogenesis, one with the potential to yield better insights into disease mechanisms and improved therapies that offer better patient outcomes. This Review will discuss organ-on-a-chip systems that model pathological tissue morphogenesis associated with (1) fibrosis in the context of injury-induced tissue repair and aging and (2) cancer.


Assuntos
Dispositivos Lab-On-A-Chip , Neoplasias , Animais , Fibrose , Humanos , Morfogênese , Engenharia Tecidual
10.
ACS Biomater Sci Eng ; 7(7): 2964-2972, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34275295

RESUMO

Vasculature is a key component of many biological tissues and helps to regulate a wide range of biological processes. Modeling vascular networks or the vascular interface in organ-on-a-chip systems is an essential aspect of this technology. In many organ-on-a-chip devices, however, the engineered vasculatures are usually designed to be encapsulated inside closed microfluidic channels, making it difficult to physically access or extract the tissues for downstream applications and analysis. One unexploited benefit of tissue extraction is the potential of vascularizing, perfusing, and maturing the tissue in well-controlled, organ-on-a-chip microenvironments and then subsequently extracting that product for in vivo therapeutic implantation. Moreover, for both modeling and therapeutic applications, the scalability of the tissue production process is important. Here we demonstrate the scalable production of perfusable and extractable vascularized tissues in an "open-top" 384-well plate (referred to as IFlowPlate), showing that this system could be used to examine nanoparticle delivery to targeted tissues through the microvascular network and to model vascular angiogenesis. Furthermore, tissue spheroids, such as hepatic spheroids, can be vascularized in a scalable manner and then subsequently extracted for in vivo implantation. This simple multiple-well plate platform could not only improve the experimental throughputs of organ-on-a-chip systems but could potentially help expand the application of model systems to regenerative therapy.


Assuntos
Microvasos , Neovascularização Patológica , Humanos , Fígado , Microfluídica , Modelos Biológicos
11.
Trends Biotechnol ; 39(8): 753-754, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103169

RESUMO

Bioprinting offers unprecedented control in the 3D deposition of cells and biomaterials, but reproducing tissue microarchitecture and cell diversity remains challenging. Brassard et al. now overcome these limitations by bioprinting organoid-forming stem cells at high densities. This study opens new possibilities for controlling tissue structural complexities across multiple length scales.


Assuntos
Bioimpressão , Células-Tronco , Materiais Biocompatíveis , Impressão Tridimensional , Células-Tronco/citologia , Engenharia Tecidual
12.
Cryobiology ; 101: 105-114, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33989617

RESUMO

Germplasm preservation of livestock or endangered animals and expansion of germline stem cells are important. The purpose of this study is to investigate whether supplementation of trehalose to the freezing medium (FM) reduces tissular damage and improves the quality of testicular cells in the cryopreserved bovine testicular tissues. We herein established an optimized protocol for the cryopreservation of bovine testicular tissues, and the isolation as well as culture of bovine germ cells containing spermatogonial stem cells (SSCs) from these tissues. The results showed that FM containing 10% dimethyl sulfoxide (Me2SO/DMSO), 10% knockout serum replacement (KSR) and 20% trehalose (FM5) combined with the uncontrolled slow freezing (USF) procedures has the optimized cryoprotective effect on bovine testicular tissues. The FM5 + USF protocol reduced the cell apoptosis, maintained high cell viability, supported the structural integrity and seminiferous epithelial cohesion similar to that in the fresh tissues. Viable germ cells containing SSCs were effectively isolated from these tissues and they maintained germline marker expressions in the co-testicular cells and co-mouse embryonic fibroblasts (MEF) feeder culture systems respectively, during the short-term culture. Additionally, upregulated transcriptions of spermatogenic differentiation marker C-KIT and meiotic marker SYCP3 were detected in these cells after retinoic acid-induced differentiation. Together, FM5 + USF is suitable for the cryopreservation of bovine testicular tissues, with benefits of reducing the apoptosis, maintaining the cell viability, supporting the testicular structure integrity, and sustaining the survival and differentiation potential of bovine germ cells containing SSCs.


Assuntos
Criopreservação , Trealose , Animais , Bovinos , Sobrevivência Celular , Criopreservação/métodos , Crioprotetores/farmacologia , Dimetil Sulfóxido , Fibroblastos , Masculino , Camundongos , Espermatogônias , Testículo , Trealose/farmacologia
13.
J Clin Invest ; 131(10)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33830946

RESUMO

BACKGROUNDRecent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODSWe used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTSMemory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients.FUNDINGNIH funding (U54CA260492, P30CA006973, P41EB028239, R01AI153349, R01AI145435-A1, R21AI149760, and U19A1088791) was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institute of Biomedical Imaging and Bioengineering. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University Provost, and The Bill and Melinda Gates Foundation provided funding for this study.


Assuntos
Linfócitos T CD4-Positivos/imunologia , COVID-19/imunologia , Epitopos de Linfócito T/imunologia , Memória Imunológica , Receptores de Antígenos de Linfócitos T/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Reações Cruzadas , Feminino , Humanos , Células Jurkat , Masculino , Pessoa de Meia-Idade
14.
Nat Protoc ; 16(4): 2158-2189, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33790475

RESUMO

Owing to their high spatiotemporal precision and adaptability to different host cells, organ-on-a-chip systems are showing great promise in drug discovery, developmental biology studies and disease modeling. However, many current micro-engineered biomimetic systems are limited in technological application because of culture media mixing that does not allow direct incorporation of techniques from stem cell biology, such as organoids. Here, we describe a detailed alternative method to cultivate millimeter-scale functional vascularized tissues on a biofabricated platform, termed 'integrated vasculature for assessing dynamic events', that enables facile incorporation of organoid technology. Utilizing the 3D stamping technique with a synthetic polymeric elastomer, a scaffold termed 'AngioTube' is generated with a central microchannel that has the mechanical stability to support a perfusable vascular system and the self-assembly of various parenchymal tissues. We demonstrate an increase in user familiarity and content analysis by situating the scaffold on a footprint of a 96-well plate. Uniquely, the platform can be used for facile connection of two or more tissue compartments in series through a common vasculature. Built-in micropores enable the studies of cell invasion involved in both angiogenesis and metastasis. We describe how this protocol can be applied to create both vascularized cardiac and hepatic tissues, metastatic breast cancer tissue and personalized pancreatic cancer tissue through incorporation of patient-derived organoids. Platform assembly to populating the scaffold with cells of interest into perfusable functional vascularized tissue will require 12-14 d and an additional 4 d if pre-polymer and master molds are needed.


Assuntos
Vasos Sanguíneos/fisiologia , Dispositivos Lab-On-A-Chip , Organoides/fisiologia , Perfusão , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Tecidos Suporte/química
15.
Genome Biol ; 22(1): 119, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33892774

RESUMO

BACKGROUND: Millennia of directional human selection has reshaped the genomic architecture of cultivated cotton relative to wild counterparts, but we have limited understanding of the selective retention and fractionation of genomic components. RESULTS: We construct a comprehensive genomic variome based on 1961 cottons and identify 456 Mb and 357 Mb of sequence with domestication and improvement selection signals and 162 loci, 84 of which are novel, including 47 loci associated with 16 agronomic traits. Using pan-genome analyses, we identify 32,569 and 8851 non-reference genes lost from Gossypium hirsutum and Gossypium barbadense reference genomes respectively, of which 38.2% (39,278) and 14.2% (11,359) of genes exhibit presence/absence variation (PAV). We document the landscape of PAV selection accompanied by asymmetric gene gain and loss and identify 124 PAVs linked to favorable fiber quality and yield loci. CONCLUSIONS: This variation repertoire points to genomic divergence during cotton domestication and improvement, which informs the characterization of favorable gene alleles for improved breeding practice using a pan-genome-based approach.

16.
Plant Physiol Biochem ; 162: 468-475, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33752135

RESUMO

Expansins are nonenzymatic cell wall proteins that play significant role in plant development as well as stress responses. Hereby, an expansin-like gene, GhEXLB2 was isolated from a cotton (Gossypium hirsutum L.) protoplast with suppression subtractive hybridization to characterize and study its responses against abiotic stresses. GhEXLB2 is the cell-wall localized protein. The expression of GhEXLB2 level was significantly high under polyethylene glycol and salt treatments. GhEXLB2 was further characterized in vitro by cloning and transformation into cotton. Cotton plants overexpressing GhEXLB2 showed enhanced drought tolerance at germination, seedling and flowering stages. After polyethylene glycol (PEG) treatment at germination stage, the length of main root and hypocotyl of overexpressing lines was significantly longer than YZ1 (wild type) and RNAi lines. In addition, H2O2 and malondialdehyde (MDA) contents were lower, while superoxide dismutase (SOD) and peroxidase (POD) activity was detected higher in overexpressing seedlings. On the other hand, higher SOD and POD activity was detected in overexpressing lines than WT plants in soil. In addition, water use efficiency (WUE), soluble sugar, and chlorophyll contents were also significantly greater in overexpressing plants. The present study revealed that GhEXLB2 play crucial role in enhancing drought resistivity in cotton.


Assuntos
Secas , Gossypium , Regulação da Expressão Gênica de Plantas , Gossypium/genética , Gossypium/metabolismo , Peróxido de Hidrogênio , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Tolerância ao Sal , Estresse Fisiológico/genética
17.
Clin Epigenetics ; 13(1): 47, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663600

RESUMO

BACKGROUND: Maternal smoking affects more than half a million pregnancies each year in the US and is known to result in fetal growth restriction as measured by lower birthweight and its associated long-term consequences. Maternal smoking also has been linked to altered fetal DNA methylation (DNAm). However, what remains largely unexplored is whether these DNAm alterations are merely markers of smoking exposure or if they also have implications for health outcomes. This study tested the hypothesis that fetal DNAm mediates the effect of maternal smoking on newborn birthweight. METHODS: This study included mother-newborn pairs from a US predominantly urban, low-income multi-ethnic birth cohort. DNAm in cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip. After standard quality control and normalization procedures, an epigenome-wide association study (EWAS) of maternal smoking was performed using linear regression models, controlling for maternal age, education, race, parity, pre-pregnancy body mass index, alcohol consumption, gestational age, maternal pregestational/gestational diabetes, child sex, cord blood cell compositions and batch effects. To quantify the degree to which cord DNAm mediates the smoking-birthweight association, the VanderWeele-Vansteelandt approach for single mediator and structural equational model for multiple mediators were used, adjusting for pertinent covariates. RESULTS: The study included 954 mother-newborn pairs. Among mothers, 165 (17.3%) ever smoked before or during pregnancy. Newborns with smoking exposure had on average 258 g lower birthweight than newborns without exposure (P < 0.001). Using a false discovery rate (FDR) < 0.05 as the significance cutoff, the EWAS identified 38 differentially methylated CpG sites associated with maternal smoking. Of those, 17 CpG sites were mapped to previously reported genes: GFI1, AHRR, CYP1A1, and CNTNAP2; 8 of those, located in the first three genes, were Bonferroni significantly associated with newborn birthweight and mediated the smoking-birthweight association. The combined mediation effect of the three genes explained 67.8% of the smoking-birthweight association. CONCLUSIONS: Our study not only lends further support that maternal smoking alters fetal DNAm in a multiethnic population, but also suggests that fetal DNAm substantially mediates the maternal smoking-birthweight association. Our findings, if further validated, indicate that DNAm modification is likely an important pathway by which maternal smoking impairs fetal growth and, perhaps, even long-term health outcomes.

18.
Allergy Asthma Clin Immunol ; 17(1): 18, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33588931

RESUMO

INTRODUCTION: Angiotensin Converting Enzyme Inhibitors (ACEI) are a common cause of Emergency Room presentation for angioedema. Although no treatment guidelines exist, C1 esterase inhibitor concentrate (C1-INH) is used on an off label basis for management of ACEI acquired angioedema (ACEI AAE). OBJECTIVE: To evaluate the efficacy of C1-INH in management of ACEI AAE at our local centers. RESULTS: Nine patients, from 3 academic sites, were identified through Allergy Service consultation data and records from Diagnostic Services Manitoba, Canada from 2010-2020. The majority of the patients (n = 8/9) required endotracheal intubation prior to the initiation of C1-INH. Overall, approximately 56% of patients (n = 5/9) had resolution of angioedema ranging between 12 and 17 h, with a median time of 13.5 h, and no recurrence after the administration of C1-INH concentrate. One patient had transient symptom resolution in 14 h, however, recurrence of angioedema required re-intubation. The remainder of patients (n = 4/9), had resolution of angioedema between 22 and 72 h, with a median time of 33.75 h. CONCLUSION: Our findings demonstrate continued ambivalence of the efficacy and role of C1-INH concentrate in the treatment of ACEI AAE, secondary to multiple uncontrolled confounding factors. Further research into characterizing a subgroup of intubated patients in our study that responded to C1-INH concentrate needs to be completed.

19.
ACS Biomater Sci Eng ; 7(3): 1000-1021, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33591735

RESUMO

Cardiovascular diseases (CVD) are the leading cause of death around the world, being responsible for 31.8% of all deaths in 2017 (Roth, G. A. et al. The Lancet 2018, 392, 1736-1788). The leading cause of CVD is ischemic heart disease (IHD), which caused 8.1 million deaths in 2013 (Benjamin, E. J. et al. Circulation 2017, 135, e146-e603). IHD occurs when coronary arteries in the heart are narrowed or blocked, preventing the flow of oxygen and blood into the cardiac muscle, which could provoke acute myocardial infarction (AMI) and ultimately lead to heart failure and death. Cardiac regenerative therapy aims to repair and refunctionalize damaged heart tissue through the application of (1) intramyocardial cell delivery, (2) epicardial cardiac patch, and (3) acellular biomaterials. In this review, we aim to examine these current approaches and challenges in the cardiac regenerative therapy field.


Assuntos
Materiais Biocompatíveis , Engenharia Tecidual , Coração , Miocárdio , Tecidos Suporte
20.
Mol Immunol ; 132: 30-40, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33540227

RESUMO

Psoriasis is a refractory inflammatory skin disease affecting 2 %-3 % of the world population, characterized by the infiltration and hyper-proliferation of inflammatory cells and aberrant differentiation of keratinocytes. Targeting the IL-23/ Th17 axis has been well recognized as a promising therapeutic strategy, as the IL-23/ Th17 signal plays a vital role in the pathology of psoriasis. Three pentacyclic triterpene compounds isolated from loquat leaves have been reported with significant inhibitory effects on RORγt transcription activity and Th17 cell differentiation, and excellent performance in preventing lupus nephritis pathogenesis. However, the potential effects of these pentacyclic triterpene compounds on psoriasis remain unknown. In this study, we demonstrated the potent therapeutic effects of these pentacyclic triterpene compounds on psoriasis. These three pentacyclic triterpene compounds significantly alleviated skin inflammation as well as aberrant keratinocyte proliferation in an imiquimod-induced mouse psoriasis model. These compounds also inhibited the infiltration of immune cells and the level of pro-inflammatory cytokine in the dermis, as well as the cells number and changed the cytokine profiling expression of Th17 cells. These compounds could reduce the amount of CD4+ and CD8+ T cells in local lymph node, but not in spleen, which is different from hydrocortisone, the positive control treatment. These results suggest better performance of these compounds than steroids on treating psoriasis with less side effects on the integrated immune system. In summary, our findings uncover the potent therapeutic effects of pentacyclic triterpene compounds on psoriasis, providing potential candidate compounds for drug development.


Assuntos
Eriobotrya/química , Hiperplasia/tratamento farmacológico , Inflamação/tratamento farmacológico , Triterpenos Pentacíclicos/uso terapêutico , Folhas de Planta/química , Psoríase/tratamento farmacológico , Células Th17/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Epiderme/patologia , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Imiquimode/toxicidade , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/metabolismo , Triterpenos Pentacíclicos/farmacologia , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Células Th17/imunologia , Células Th17/metabolismo
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