ABSTRACT
Human pluripotent and trophoblast stem cells have been essential alternatives to blastocysts for understanding early human development1-4. However, these simple culture systems lack the complexity to adequately model the spatiotemporal cellular and molecular dynamics that occur during early embryonic development. Here we describe the reprogramming of fibroblasts into in vitro three-dimensional models of the human blastocyst, termed iBlastoids. Characterization of iBlastoids shows that they model the overall architecture of blastocysts, presenting an inner cell mass-like structure, with epiblast- and primitive endoderm-like cells, a blastocoel-like cavity and a trophectoderm-like outer layer of cells. Single-cell transcriptomics further confirmed the presence of epiblast-, primitive endoderm-, and trophectoderm-like cells. Moreover, iBlastoids can give rise to pluripotent and trophoblast stem cells and are capable of modelling, in vitro, several aspects of the early stage of implantation. In summary, we have developed a scalable and tractable system to model human blastocyst biology; we envision that this will facilitate the study of early human development and the effects of gene mutations and toxins during early embryogenesis, as well as aiding in the development of new therapies associated with in vitro fertilization.
Subject(s)
Blastocyst/cytology , Blastocyst/metabolism , Cell Culture Techniques , Cellular Reprogramming , Fibroblasts/cytology , Models, Biological , Transcriptome , Female , Fibroblasts/metabolism , Humans , In Vitro Techniques , Single-Cell Analysis , Stem Cells/cytology , Stem Cells/metabolism , Trophoblasts/cytologyABSTRACT
The reprogramming of human somatic cells to primed or naive induced pluripotent stem cells recapitulates the stages of early embryonic development1-6. The molecular mechanism that underpins these reprogramming processes remains largely unexplored, which impedes our understanding and limits rational improvements to reprogramming protocols. Here, to address these issues, we reconstruct molecular reprogramming trajectories of human dermal fibroblasts using single-cell transcriptomics. This revealed that reprogramming into primed and naive pluripotency follows diverging and distinct trajectories. Moreover, genome-wide analyses of accessible chromatin showed key changes in the regulatory elements of core pluripotency genes, and orchestrated global changes in chromatin accessibility over time. Integrated analysis of these datasets revealed a role for transcription factors associated with the trophectoderm lineage, and the existence of a subpopulation of cells that enter a trophectoderm-like state during reprogramming. Furthermore, this trophectoderm-like state could be captured, which enabled the derivation of induced trophoblast stem cells. Induced trophoblast stem cells are molecularly and functionally similar to trophoblast stem cells derived from human blastocysts or first-trimester placentas7. Our results provide a high-resolution roadmap for the transcription-factor-mediated reprogramming of human somatic cells, indicate a role for the trophectoderm-lineage-specific regulatory program during this process, and facilitate the direct reprogramming of somatic cells into induced trophoblast stem cells.
Subject(s)
Cellular Reprogramming/genetics , Gene Expression Regulation , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Trophoblasts/cytology , Trophoblasts/metabolism , Adult , Chromatin/genetics , Chromatin/metabolism , Ectoderm/cytology , Ectoderm/metabolism , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Humans , Transcription, GeneticABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder with poorly understood etiology. AD has several similarities with other "Western lifestyle" inflammatory diseases, where the gut microbiome and immune pathways have been associated. Previously, we and others have noted the involvement of metabolite-sensing GPCRs and their ligands, short-chain fatty acids (SCFAs), in protection of numerous Western diseases in mouse models, such as Type I diabetes and hypertension. Depletion of GPR43, GPR41, or GPR109A accelerates disease, whereas high SCFA yielding diets protect in mouse models. Here, we extended the concept that metabolite-sensing receptors and SCFAs may be a more common protective mechanism against Western diseases by studying their role in AD pathogenesis in the 5xFAD mouse model. Both male and female mice were included. Depletion of GPR41 and GPR43 accelerated cognitive decline and impaired adult hippocampal neurogenesis in 5xFAD and WT mice. Lack of fiber/SCFAs accelerated a memory deficit, whereas diets supplemented with high acetate and butyrate (HAMSAB) delayed cognitive decline in 5xFAD mice. Fiber intake impacted on microglial morphology in WT mice and microglial clustering phenotype in 5xFAD mice. Lack of fiber impaired adult hippocampal neurogenesis in both W and AD mice. Finally, maternal dietary fiber intake significantly affects offspring's cognitive functions in 5xFAD mice and microglial transcriptome in both WT and 5xFAD mice, suggesting that SCFAs may exert their effect during pregnancy and lactation. Together, metabolite-sensing GPCRs and SCFAs are essential for protection against AD, and reveal a new strategy for disease prevention.Significance Statement Alzheimer's disease (AD) is one of the most common neurodegenerative diseases; currently, there is no cure for AD. In our study, short-chain fatty acids and metabolite receptors play an important role in cognitive function and pathology in AD mouse model as well as in WT mice. SCFAs also impact on microglia transcriptome, and immune cell recruitment. Out study indicates the potential of specialized diets (supplemented with high acetate and butyrate) releasing high amounts of SCFAs to protect against disease.
Subject(s)
Alzheimer Disease , Microbiota , Female , Male , Pregnancy , Animals , Mice , Cognition , Dietary Fiber , Butyrates , Disease Models, AnimalABSTRACT
The canonical Wnt/ß-catenin pathway is crucial for early embryonic patterning, tissue homeostasis, and regeneration. While canonical Wnt/ß-catenin stimulation has been used extensively to modulate pluripotency and differentiation of pluripotent stem cells (PSCs), the mechanism of these two seemingly opposing roles has not been fully characterized and is currently largely attributed to activation of nuclear Wnt target genes. Here, we show that low levels of Wnt stimulation via ectopic expression of Wnt1 or administration of glycogen synthase kinase-3 inhibitor CHIR99021 significantly increases PSC differentiation into neurons, cardiomyocytes and early endodermal intermediates. Our data indicate that enhanced differentiation outcomes are not mediated through activation of traditional Wnt target genes but by ß-catenin's secondary role as a binding partner of membrane bound cadherins ultimately leading to the activation of developmental genes. In summary, fine-tuning of Wnt signaling to subthreshold levels for detectable nuclear ß-catenin function appears to act as a switch to enhance differentiation of PSCs into multiple lineages. Our observations highlight a mechanism by which Wnt/ß-catenin signaling can achieve dosage dependent dual roles in regulating self-renewal and differentiation. Stem Cells 2018;36:822-833.
Subject(s)
Pluripotent Stem Cells/metabolism , Wnt Signaling Pathway/genetics , beta Catenin/genetics , Animals , Cell Differentiation , Humans , Mice , Signal TransductionABSTRACT
OBJECTIVE: To investigate the expression and the effect of connective tissue growth factor (CTGF) on rheumatic myocardial fibrosis of rheumatic heart disease (RHD). METHODS: The papillary muscles samples were obtained from patients with RHD during mitral valve replacement.The expression of TGF-ß1, CTGF mRNA and CTGF protein were detected with semiquantitative RT-PCR technique and immunohistochemistry technologyin the papillary muscles cell from 41RHD patients and 20 normal papillary muscles samples.The area of myocardial fibrosis was measured by imaging analysis system. SPSS package was used to analyze the relationship between the expression of CTGF and the area of myocardial fibrosis. RESULTS: Compared with normal controls (PU 2.4±0.9), the mean level of CTGF protein expression in the papillary muscles samples of the RHD patients (PU 44.7±6.0) was significantly increased(P<0.01). The expression of CTGF protein in papillary muscles of RHD was positivelycorrelated with the expression of CTGFmRNA (r=0.862, P<0.01) and the area of myocardial fibrosis (r=0.856, P<0.01). CONCLUSIONS: Compared with normal controls, CTGF expression in the papillary muscles of the RHD patients is significantly increased, which suggests CTGF may play animportant role in myocardial fibrosis of RHD.
Subject(s)
Connective Tissue Growth Factor/metabolism , Papillary Muscles/metabolism , Rheumatic Heart Disease/metabolism , Connective Tissue Growth Factor/genetics , Fibrosis , Humans , Immunohistochemistry , Myocardium/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolismABSTRACT
Signaling by TGF-ß/Smad3 plays a key role in renal fibrosis. As obesity is one of the major risk factors of chronic and end-stage renal disease, we studied the role of Smad3 signaling in the pathogenesis of obesity-related renal disease. After switching to a high fat diet, the onset of Smad3 C-terminal phosphorylation, increase in albuminuria, and the early stages of peripheral and renal insulin resistance occurred at 1 day, and 4 and 8 weeks, respectively, in C57BL/6 mice. The loss of synaptopodin, a functional marker of podocytes, and phosphorylation of the Smad3 linker region (T179 and S213) appeared after 4 weeks of the high fat diet. This suggests a temporal pattern of Smad3 signaling activation leading to kidney injury and subsequent insulin resistance in the development of obesity-related renal disease. In vivo, Smad3 knockout attenuated the high fat diet-induced proteinuria, renal fibrosis, overall podocyte injury, and mitochondrial dysfunction in podocytes. In vitro palmitate caused a rapid activation of Smad3 in 30 min, loss of synaptopodin in 2 days, and impaired insulin signaling in 3 days in isolated mouse podocytes. Blockade of either Smad3 phosphorylation by SIS3 (a Smad3 inhibitor) or T179 phosphorylation by flavopiridol (a CDK9 inhibitor) prevented the palmitate-induced loss of synaptopodin and mitochondrial function in podocytes. Thus, Smad3 signaling plays essential roles in obesity-related renal disease and may be a novel therapeutic target.
Subject(s)
Obesity/complications , Obesity/metabolism , Podocytes/metabolism , Signal Transduction , Smad3 Protein/deficiency , Animals , Cells, Cultured , Dietary Fats/administration & dosage , Enzyme Inhibitors/pharmacology , Fibrosis , Flavonoids/pharmacology , Gene Knockdown Techniques , Insulin/metabolism , Insulin Resistance , Isoquinolines/pharmacology , Male , Mice , Mice, Inbred C57BL , Microfilament Proteins/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Palmitic Acid/pharmacology , Phosphorylation/drug effects , Piperidines/pharmacology , Podocytes/drug effects , Protective Factors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Pyrroles/pharmacology , Signal Transduction/drug effects , Smad3 Protein/geneticsABSTRACT
OBJECTIVES: The association between blood pressure and frailty outcome in the middle-aged and older population remains controversial. This study aimed to examine the relationship between trajectories of systolic blood pressure (SBP) and new-onset frailty. DESIGN: Cohort study with a 7-year follow-up. SETTING AND PARTICIPANTS: Data were derived from 4 waves (2011, 2013, 2015 and 2018) of the China Health and Retirement Longitudinal Study and 6168 participants aged ≥45 years were included in the study. METHODS: The frailty index (FI) was constructed based on 40 scored items, with FI ≥ 0.25 defined as frailty. We identified the 5-year trajectory of SBP by latent class trajectory modeling. The association between SBP trajectories and frailty was explored based on hazard ratios (HR) by four Cox proportional hazards models. Furthermore, we also investigated the relationship between mean SBP and systolic blood pressure variability (SBPV) and frailty. RESULTS: 6168 participants were included in this study with a mean age of 59 years. We identified five trajectories based on SBP, which are maintained low-stable SBP (T0), moderate-stable SBP (T1), remitting then increasing SBP (T2), increasing then remitting SBP (T3), and remaining stable at high SBP levels (T4). During the 7-year follow-up period, frailty outcome occurred in 1415 participants. After adjusting for other confounders, the two trajectories labeled "T2" and "T4" were associated with a higher risk of frailty compared with T0. In addition, elevated SBP and increased SBPV were associated with risk of frailty. CONCLUSIONS: Higher risk of frailty occurred in two trajectories, remitting then increasing and remaining stable at high SBP levels, were associated with a relatively higher risk of frailty.
Subject(s)
Blood Pressure , Frailty , Humans , Male , Female , Blood Pressure/physiology , Middle Aged , Frailty/epidemiology , Aged , Longitudinal Studies , China/epidemiology , Frail Elderly/statistics & numerical data , Proportional Hazards Models , Risk Factors , Cohort Studies , Geriatric Assessment/methods , Geriatric Assessment/statistics & numerical data , Hypertension/epidemiology , Follow-Up StudiesABSTRACT
Single-cell RNA sequencing (scRNA-seq) has enabled the identification of novel gene signatures and cell heterogeneity in numerous tissues and diseases. Here we review the use of this technology for Fuchs' Endothelial Corneal Dystrophy (FECD). FECD is the most common indication for corneal endothelial transplantation worldwide. FECD is challenging to manage because it is genetically heterogenous, can be autosomal dominant or sporadic, and progress at different rates. Single-cell RNA sequencing has enabled the discovery of several FECD subtypes, each with associated gene signatures, and cell heterogeneity. Current FECD treatments are mainly surgical, with various Rho kinase (ROCK) inhibitors used to promote endothelial cell metabolism and proliferation following surgery. A range of emerging therapies for FECD including cell therapies, gene therapies, tissue engineered scaffolds, and pharmaceuticals are in preclinical and clinical trials. Unlike conventional disease management methods based on clinical presentations and family history, targeting FECD using scRNA-seq based precision-medicine has the potential to pinpoint the disease subtypes, mechanisms, stages, severities, and help clinicians in making the best decision for surgeries and the applications of therapeutics. In this review, we first discuss the feasibility and potential of using scRNA-seq in clinical diagnostics for FECD, highlight advances from the latest clinical treatments and emerging therapies for FECD, integrate scRNA-seq results and clinical notes from our FECD patients and discuss the potential of applying alternative therapies to manage these cases clinically.
ABSTRACT
Spermatogenesis is a complex biological process that requires precise regulation of gene expression in the germ cells and their surrounding somatic cells. Some testis-specific genes are involved in different stages of spermatogenesis; however, the precise mechanisms of stage-specific spermatogenesis are still not elucidated. In this study, we first examined the expression patterns of SYCP3, Tnp2, CDH1, glial cell-line-derived neurotropic factor (GDNF) and GFRA1 mRNAs on post-natal days (PNDs) 2, 4, 6, 8, 10, 12, 15, 20, 25 and 30 in rat testis. SYCP3 mRNA was firstly detected from PND 15, while Tnp2 transcript was only found on PND 30. CDH1 mRNA was highly expressed before PND 6, but decreased dramatically on PND 8, then gradually increased until it started to decrease after 12 dpp. Low GDNF and GFRA1 mRNAs were found before PND 6, but gradually increased to the peak on PND 12, then gradually decreased to low level. According to the expression patterns of CDH1, GDNF and GFRA1, we hypothesized that PNDs 6-10 are critical period in the early spermatogenesis. We, therefore, explored gene expression pattern on PNDs 6, 8 and 10 using cDNA microarray. 700 (PND 8 vs PND 6), 4519 (PND 10 vs PND 8), and 4298 (PND 10 vs PND 6) differentially expressed genes (≥ 2-fold) were identified from the comparisons, which cover thousands of gene ontology categories (GO terms) and hundreds of signalling pathways. High consistency between microarray data and quantative real-time PCR (qRT-PCR) was verified from five genes (LOC686076, Trib3, Cxcl6, LOC682508 and C2cd4d). These data provide more information to understand the precisely regulatory mechanism at the early stage of spermatogenesis.
Subject(s)
Gene Expression Profiling/veterinary , Testis/growth & development , Testis/metabolism , Aging , Animals , Cell Cycle Proteins/genetics , Female , Glial Cell Line-Derived Neurotrophic Factor/genetics , Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics , Male , Microarray Analysis/veterinary , RNA, Messenger/analysis , Rats , Rats, Wistar , Real-Time Polymerase Chain Reaction/veterinary , Spermatogenesis/physiology , Testis/chemistryABSTRACT
The impact of aging on intestinal stem cells (ISCs) has not been fully elucidated. In this study, we identified widespread epigenetic and transcriptional alterations in old ISCs. Using a reprogramming algorithm, we identified a set of key transcription factors (Egr1, Irf1, FosB) that drives molecular and functional differences between old and young states. Overall, by dissecting the molecular signature of aged ISCs, our study identified transcription factors that enhance the regenerative capacity of ISCs.
ABSTRACT
Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood samples collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3+CD4+ T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1ß and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.
Subject(s)
Bronchopulmonary Dysplasia , Interleukin-13 , Animals , Bronchopulmonary Dysplasia/etiology , Bronchopulmonary Dysplasia/pathology , Bronchopulmonary Dysplasia/prevention & control , Female , Humans , Infant, Newborn , Infant, Premature , Inflammation/complications , Lung/pathology , Mice , PregnancyABSTRACT
The partial oxidation of dimethyl ether (DME) was investigated using the structured catalyst Rh/Al2O3/Al. The porous Al2O3 layer was synthesized on the aluminum plate through anodic oxidation in an oxalic-acid solution. It was observed that about 20 nm nanopores were well developed in the Al2O3 layer. The thickness of Al2O3 layer can be adjusted by controlling the anodizing time and current density. After pore-widening and hot-water treatment, the Al2O3/Al plate was calcined at 500 degrees C for 3 h. The obtained delta-Al2O3 had a specific surface area of 160 m2/g, making it fit to be used as a catalyst support. A microchannel reactor was designed and fabricated to evaluate the catalytic activity of Rh/Al2O3/Al in the partial oxidation of DME. The structured catalyst showed an 86% maximum hydrogen yield at 450 degrees C. On the other hand, the maximum syngas yield by a pack-bed-type catalyst could be attained by using a more than fivefold Rh amount compared to that used in the structured Rh/Al2O3/Al catalyst.
ABSTRACT
Objective: To explore the role and mechanism of long non-coding RNA RP11-159K7.2 in the progression of sinonasal squamous cell carcinoma (SNSCC). Methods: Sixty-five cases of SNSCC tissues and adjacent tissues were selected from the Department of Otorhinolaryngology Head and Neck Surgery, the Second Affiliated Hospital of Harbin Medical University from 2009 to 2014. The expression of RP11-159K7.2 in SNSCC and adjacent tissues was detected by RNAscope in situ hybridization to observe its association with prognosis. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated proteins 9 (CRISPR/Cas9) was used to knockout the expression of RP11-159K7.2 in RPMI-2650 cells (SNSCC cell line). Cell counting kit-8 (CCK-8), wound healing and Transwell were performed to observe the changes of proliferation, migration and invasion of SNSCC cells in vitro after down-regulation of RP11-159K7.2. Moreover, the growth of xenograft in nude mice after down-regulation of RP11-159K7.2 was examined in vivo. Mechanically, the protein chip, Western blot and RNA immunoprecipitation were performed to identify the proteins bound by RP11-159K7.2. SPSS 17.0 was used for statistical analysis. Results: The expression of RP11-159K7.2 in SNSCC tissue was significantly higher than that in adjacent tissues. RP11-159K7.2 expression was closely related with T grade, nodal metastasis and differentiation of SNSCC (χ2 value was 4.697, 4.235 and 10.753, respectively, all P<0.05). The five-year survival rate of RP11-159K7.2 high expression patients was significantly lower than that of RP11-159K7.2 low expression ones (P=0.013 7). After the down-regulation of RP11-159K7.2, the proliferation, migration and invasion ability of SNSCC cells decreased significantly, and the growth of SNSCC xenograft was significantly inhibited. There were 31 candidate proteins that may bind to RP11-159K7.2. RP11-159K7.2 directly bound to nuclear factor-κB (NF-κB) in SNSCC cells, and the regulation of RP11-159K7.2 on the proliferation and invasion of SNSCC cells depended on NF-κB. Conclusion: The increased expression of RP11-159K7.2 in SNSCC may serve as a potential molecular marker for SNSCC prognosis assessment. It is currently considered that the carcinogenic mechanism of RP11-159K7.2 in SNSCC is related to the regulation of NF-κB protein.
Subject(s)
Carcinoma, Squamous Cell , RNA, Long Noncoding , Animals , Carcinoma, Squamous Cell/genetics , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Nude , Neoplasm Transplantation , Prognosis , RNA, Long Noncoding/geneticsABSTRACT
Cellular identity is ultimately dictated by the interaction of transcription factors with regulatory elements (REs) to control gene expression. Advances in epigenome profiling techniques have significantly increased our understanding of cell-specific utilization of REs. However, it remains difficult to dissect the majority of factors that interact with these REs due to the lack of appropriate techniques. Therefore, we developed TINC: TALE-mediated isolation of nuclear chromatin. Using this new method, we interrogated the protein complex formed at the Nanog promoter in embryonic stem cells (ESCs) and identified many known and previously unknown interactors, including RCOR2. Further interrogation of the role of RCOR2 in ESCs revealed its involvement in the repression of lineage genes and the fine-tuning of pluripotency genes. Consequently, using the Nanog promoter as a paradigm, we demonstrated the power of TINC to provide insight into the molecular makeup of specific transcriptional complexes at individual REs as well as into cellular identity control in general.
Subject(s)
Genetic Loci , Human Embryonic Stem Cells/metabolism , Multiprotein Complexes/metabolism , Nanog Homeobox Protein/metabolism , Co-Repressor Proteins/metabolism , Human Embryonic Stem Cells/cytology , HumansABSTRACT
OBJECTIVE: To investigate the prevalence of low back pain (LBP) and axial spondyloarthritis (SpA) in a Chinese Han population. METHODS: A face-to-face investigation was performed in the Han population of Dalang Town, Yangshan County, Guangdong Province, China, using a questionnaire established in France in 1999. First the clinical features associated with SpA were investigated, then the human leucocyte antigen (HLA)-B27 and sacroiliac joint radiographic examinations were carried out. Finally, the diagnosis of SpA was determined by rheumatologists. RESULTS: A total of 13 315 subjects participated in the study and 10 921 were aged >16 years; of these, 787 (7.21%) had LBP. There were 92 axial SpA patients (0.782% in subjects >16 years old and 11.96% in subjects with LBP). There were 29 (0.253%) cases of ankylosing spondylitis (AS), 60 (0.507%) undifferentiated axial SpA (USpA), and three (0.022%) psoriatic arthritis (PsA). Patients in the SpA groups had higher percentages in onset <40 years, insidious onset, morning stiffness, and affected for >3 months compared with those in other LBP groups. Simultaneous symptoms associated with spondylitis, such as buttock pain, heel pain, psoriasis, and SpA family history, were more commonly present. Of the axial SpA patients, 82.67% were HLA-B27 positive, clearly a greater percentage than those (11.65%) in other LBP groups. CONCLUSIONS: The survey questionnaire for SpA in this study is useful for axial SpA screening in China. In southern China, the prevalence of LBP is 7.21%. The prevalence of axial SpA is 0.782%. USpA is the most common subtype of SpA, followed by AS.
Subject(s)
Asian People , Axis, Cervical Vertebra , Low Back Pain/ethnology , Population Surveillance , Spondylarthritis/ethnology , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , China/epidemiology , Female , HLA-B27 Antigen/analysis , Humans , Male , Middle Aged , Prevalence , Retrospective Studies , Sex Distribution , Spondylarthritis/immunology , Young AdultABSTRACT
The feasibility of inducing rheumatic myocarditis lesions in Lewis rats by immunization with formalin-killed group A Streptococcus was evaluated. The rats were divided into three groups. Group A was immunized by injecting formalin-killed group A Streptococcus suspended in complete Freund's adjuvant (CFA) into the hind-foot pads and repeat immunization was given 1 week later by subcutaneous injection into the belly. The rats were then sacrificed 3 weeks after the initial immunization. In group B, the rats received the same initial immunization as group A, but the repeat immunization was carried out at 1, 2 and 3 weeks after the initial immunization and the rats were sacrificed 6 weeks after the initial immunization. Group C was a control group with the rats injected with saline/CFA and sacrificed on the same schedule as group A. Heart pathology sections showed that myocarditis lesions, focal inflammatory cell infiltration in interstitial near small vessels and valvulitis were induced in Lewis rats following immunization with formalin-killed group A Streptococcus.
Subject(s)
Formaldehyde/pharmacology , Myocarditis/microbiology , Streptococcus pyogenes/drug effects , Streptococcus pyogenes/pathogenicity , Animals , Arthritis/chemically induced , Arthritis/metabolism , Arthritis/pathology , Body Weight/drug effects , Disease Models, Animal , Myocarditis/pathology , RatsABSTRACT
Double neutron star (DNS) merger events are promising candidates of short gamma-ray burst (sGRB) progenitors as well as high-frequency gravitational wave (GW) emitters. On August 17, 2017, such a coinciding event was detected by both the LIGO-Virgo gravitational wave detector network as GW170817 and Gamma-Ray Monitor on board NASA's Fermi Space Telescope as GRB 170817A. Here, we show that the fluence and spectral peak energy of this sGRB fall into the lower portion of the distributions of known sGRBs. Its peak isotropic luminosity is abnormally low. The estimated event rate density above this luminosity is at least [Formula: see text] Gpc-3 yr-1, which is close to but still below the DNS merger event rate density. This event likely originates from a structured jet viewed from a large viewing angle. There are similar faint soft GRBs in the Fermi archival data, a small fraction of which might belong to this new population of nearby, low-luminosity sGRBs.
ABSTRACT
14 C-labeled YH4808, a novel potassium-competitive acid blocker, was intravenously administered as a microtracer at 80 µg (11.8 kBq or 320 nCi) concomitantly with the nonradiolabeled oral drug at 200 mg to determine the absolute bioavailability and to assess the effect of pharmacogenomics on the oral absorption of YH4808. The absolute bioavailability was low and highly variable (mean, 10.1%; range, 2.3-19.3%), and M3 and M8, active metabolites of YH4808, were formed 22.6- and 38.5-fold higher after oral administration than intravenous administration, respectively. The product of the fraction of an oral YH4808 dose entering the gut wall and the fraction of YH4808 passing on to the portal circulation was larger in subjects carrying the variants of the CHST3, SLC15A1, and SULT1B1 genes. A combined LC+AMS is a useful tool to construct a rich and highly informative pharmacokinetic knowledge core in early clinical drug development at a reasonable cost.
Subject(s)
Anti-Ulcer Agents/administration & dosage , Drug Design , Mass Spectrometry/methods , Pharmacogenetics , Potassium Channel Blockers/administration & dosage , Administration, Intravenous , Administration, Oral , Adult , Anti-Ulcer Agents/pharmacokinetics , Biological Availability , Carbon Radioisotopes , Humans , Male , Potassium Channel Blockers/pharmacokineticsABSTRACT
A major concern in natural drug research is that many substances with potent biological activity in vitro are unable to generate good activity in vivo owing to their poor water-solubility, poor permeability and/or poor stability. The permeability of drug candidates across the intestinal mucosa is one of the most important factors in defining drug bioavailability and biological activity. In order to screen promising compounds for further investigation, a non-everted rat intestinal sac model has been developed successfully to assay the permeability of natural compounds and to predict their human absorption. In this system, the drug solution was placed in non-everted intestinal sacs (NEIS), which were placed in an acceptor solution and the permeability of drug across intestine walls was determined. The feasibility of this method has been validated and demonstrated for 11 model compounds chosen from currently marketed drugs whose human fraction absorbed (Fa) data have been reported. The results of the studies indicate that a good relationship exists between the permeability of the model drugs and their corresponding Fa data. The permeability of 13 natural compounds was evaluated using this system. Only fraxinellone and vitexin-7-glucoside exhibited high intestinal permeability, and predictive of excellent human absorption, which awaits confirmation from further investigation in vivo. This model provides an alternative method to everted intestinal sacs for the evaluation of in vitro permeability in rats, and for estimating human absorption of drugs. It may therefore hold great promise for oral absorption screening of new drug candidates.