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Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.
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Proteína Rica em Cisteína 61/metabolismo , Neurogênese/fisiologia , Transdução de Sinais , Células-Tronco Adultas/fisiologia , Animais , Encéfalo , Proteína Rica em Cisteína 61/genética , Epêndima/citologia , Epêndima/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismoRESUMO
This work explored neural network changes in early Parkinson's disease: Resting-state functional magnetic resonance imaging was used to investigate functional alterations in different stages of Parkinson's disease (PD). Ninety-five PD patients (50 early/mild and 45 early/moderate) and 37 healthy controls (HCs) were included. Independent component analysis revealed significant differences in intra-network connectivity, specifically in the default mode network (DMN) and right frontoparietal network (RFPN), in both PD groups compared to HCs. Inter-network connectivity analysis showed reduced connectivity between the executive control network (ECN) and DMN, as well as ECN-left frontoparietal network (LFPN), in early/mild PD. Early/moderate PD exhibited decreased connectivity in ECN-LFPN, ECN-RFPN, ECN-DMN, and DMN-auditory network, along with increased connectivity in LFPN-cerebellar network. Correlations were found between ECN-DMN and ECN-LFPN connections with UPDRS-III scores in early/mild PD. These findings suggest that PD progression involves dysfunction in multiple intra- and inter-networks, particularly implicating the ECN, and a wider range of abnormal functional networks may mark the progression of the disease.
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Encéfalo , Doença de Parkinson , Humanos , Mapeamento Encefálico/métodos , Doença de Parkinson/diagnóstico por imagem , Imageamento por Ressonância Magnética , Redes Neurais de ComputaçãoRESUMO
BACKGROUND: Older adults living in nursing home organizations are eager to get voluntary help, however, their past experiences with voluntary services are not satisfactory enough. To better carry out voluntary services and improve the effectiveness of services, it is necessary to have a deeper understanding of the experiences and needs of older adults for voluntary services. METHODS: The purposive sampling method was used to select 14 older adults from two nursing home organizations in Hangzhou and conduct semi-structured interviews, Collaizzi's seven-step method was used to analyze the data. RESULTS: Older adults in nursing home organizations have both beneficial experiences and unpleasant service experiences in the process of receiving voluntary services; Beneficial experiences include solving problems meeting needs and feeling warmth and care, while unpleasant service experiences include the formality that makes it difficult to benefit truly, lack of organization, regularity, sustainability, and the mismatch between service provision and actual demands. The needs for voluntary services mainly focuses on emotional comfort, Cultural and recreational, and knowledge acquisition. CONCLUSION: Older adults in nursing home organizations have varied voluntary experiences, and their voluntary service needs are diversified. Voluntary service needs of older adults should be accurately assessed, and voluntary service activities should be focused upon.
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Casas de Saúde , Pesquisa Qualitativa , Humanos , Casas de Saúde/organização & administração , Idoso , Feminino , Masculino , China , Idoso de 80 Anos ou mais , Entrevistas como Assunto , Voluntários/psicologia , Necessidades e Demandas de Serviços de Saúde , Avaliação das Necessidades , População do Leste AsiáticoRESUMO
Neurogenesis in the developing neocortex begins with the generation of the preplate, which consists of early-born neurons including Cajal-Retzius (CR) cells and subplate neurons. Here, utilizing the Ebf2-EGFP transgenic mouse in which EGFP initially labels the preplate neurons then persists in CR cells, we reveal the dynamic transcriptome profiles of early neurogenesis and CR cell differentiation. Genome-wide RNA-seq and ChIP-seq analyses at multiple early neurogenic stages have revealed the temporal gene expression dynamics of early neurogenesis and distinct histone modification patterns in early differentiating neurons. We have identified a new set of coding genes and lncRNAs involved in early neuronal differentiation and validated with functional assays in vitro and in vivo. In addition, at E15.5 when Ebf2-EGFP+ cells are mostly CR neurons, single-cell sequencing analysis of purified Ebf2-EGFP+ cells uncovers molecular heterogeneities in CR neurons, but without apparent clustering of cells with distinct regional origins. Along a pseudotemporal trajectory these cells are classified into three different developing states, revealing genetic cascades from early generic neuronal differentiation to late fate specification during the establishment of CR neuron identity and function. Our findings shed light on the molecular mechanisms governing the early differentiation steps during cortical development, especially CR neuron differentiation.
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Diferenciação Celular , Genômica , Neurogênese/genética , Neurônios/metabolismo , Lobo Temporal/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores , Diferenciação Celular/genética , Células Cultivadas , Córtex Cerebral/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Genes Reporter , Heterogeneidade Genética , Genômica/métodos , Histonas , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Neurônios/citologia , RNA Longo não Codificante/genética , Análise de Célula Única , Fatores de Transcrição , Sítio de Iniciação de TranscriçãoRESUMO
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a relatively uncommon autosomal-dominant genetic disorder, primarily attributed to mutations in the forkhead box L2 (FOXL2) gene. Albeit the involvement of protein-coding regions of FOXL2 has been observed in the majority of BPES cases, whether deficiencies in regulatory elements lead to the pathogenesis remains poorly understood. Herein, an autosomal-dominant BPES type II family was included. Peripheral venous blood has been collected, and genomic DNA has been extracted from leukocytes. A whole exome sequencing analysis has been performed and analyzed (Deposited in NODE database: OER422653). The promoter region of FOXL2 was amplified using polymerase chain reaction (PCR). The luciferase reporter assay was performed to identify the activity of this region. In this study, we present a Chinese family diagnosed with type II BPES, characterized by the presence of small palpebral fissures, ptosis, telecanthus, and epicanthus inversus. Notably, all male individuals within the family display polydactyly. A 225-bp deletion in the 556-bp 5'-upstream to transcription start site of FOXL2 , decorated by multiple histone modifications, was identified in affected members of the family. This deletion significantly decreased FOXL2 promoter activity, as measured by the luciferase assay. Conclusively, a novel 255-bp-deletion of the FOXL2 promoter was identified in Chinese families with BPES. Our results expand the spectrum of known FOXL2 mutations and provide additional insight into the genotype-phenotype relationships of the BPES pathogenesis. In addition, this study indicates the important role of genetic screening of cis-regulatory elements in testing heritable diseases.
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Blefarofimose , Blefaroptose , Anormalidades da Pele , Anormalidades Urogenitais , Humanos , Masculino , Proteína Forkhead Box L2/genética , Blefarofimose/genética , Blefarofimose/diagnóstico , Linhagem , Mutação , Regiões Promotoras Genéticas/genética , China , Luciferases/genéticaRESUMO
OBJECTIVES: This study aimed to investigate the integrative effects and mechanisms of transcutaneous electrical acustimulation (TEA) on postprocedural recovery from endoscopic retrograde cholangio-pancreatography (ERCP). MATERIALS AND METHODS: A total of 86 patients for elective ERCP were randomly ordered to receive TEA (n = 43) at acupoints PC6 and ST36 or Sham-TEA (n = 43) at sham points from 24 hours before ERCP (pre-ERCP) to 24 hours after ERCP (PE24). Scores of gastrointestinal (GI) motility-related symptoms and abdominal pain, gastric slow waves, and autonomic functions were recorded through the spectral analysis of heart rate variability; meanwhile, circulatory levels of inflammation cytokines of tumor necrosis factor-α (TNF-α) and interleukin (IL)-10 and GI hormones of motilin, ghrelin, cholecystokinin (CCK), and vasoactive intestinal peptide (VIP) were assessed by enzyme-linked immunosorbent assay. RESULTS: 1) TEA, but not Sham-TEA, decreased the post-ERCP GI motility-related symptom score (2.4 ± 2.6 vs 7.9 ± 4.6, p < 0.001) and abdominal pain score (0.5 ± 0.7 vs 4.1 ± 2.7, p < 0.001) at PE24, and decreased the post-ERCP hospital day by 20.0% (p ï¼0.05 vs Sham-TEA); 2) TEA improved the average gastric percentage of normal slow waves and dominant frequency by 34.6% and 33.3% at PE24, respectively (both p < 0.001 vs Sham-TEA); 3) TEA, but not Sham-TEA, reversed the ERCP-induced increase of TNF-α but not IL-10 at PE24, reflected as a significantly lower level of TNF-α in the TEA group than in the Sham-TEA group (1.6 ± 0.5 pg/mL vs 2.1 ± 0.9 pg/mL, p ï¼ 0.01); 4) compared with Sham-TEA, TEA increased vagal activity by 37.5% (p ï¼ 0.001); and 5) TEA caused a significantly higher plasma level of ghrelin (1.5 ± 0.8 ng/ml vs 1.1 ± 0.7 ng/ml, p ï¼ 0.05) but not motilin, VIP, or CCK than did Sham-TEA at PE24. CONCLUSION: TEA at PC6 and ST36 accelerates the post-ERCP recovery, reflected as the improvement in GI motility and amelioration of abdominal pain, and suppression of the inflammatory cytokine TNF-α may mediate through both autonomic and ghrelin-related mechanisms.
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Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling is a significant component of the innate immune system and functions as a vital sentinel mechanism to monitor cellular and tissue aberrations in microbial invasion and organ injury. cGAS, a cytosolic DNA sensor, is specialized in recognizing abnormally localized cytoplasmic double-stranded DNA (dsDNA) and catalyzes the formation of a second messenger cyclic-GMP-AMP (cGAMP), which initiates a cascade of type â interferon and inflammatory responses mediated by STING. Micronucleus, a byproduct of chromosomal missegregation during anaphase, is also a significant contributor to cytoplasmic dsDNA. These unstable subcellular structures are susceptible to irreversible nuclear envelope rupture, exposing genomic dsDNA to the cytoplasm, which potently recruits cGAS and activates STING-mediated innate immune signaling and its downstream activities, including type â interferon and classical nuclear factor-κB (NF-κB) signaling pathways lead to senescence, apoptosis, autophagy activating anti-cancer immunity or directly killing tumor cells. However, sustained STING activation-induced endoplasmic reticulum stress, activated chronic type â interferon and nonclassical NF-κB signaling pathways remodel immunosuppressive tumor microenvironment, leading to immune evasion and facilitating tumor metastasis. Therefore, activated cGAS-STING signaling plays a dual role of suppressing or facilitating tumor growth in tumorigenesis and therapy. This review elaborates on research advances in mechanisms of micronucleus inducing activation of cGAS-STING signaling and its implications in tumorigenesis and therapeutic strategies of malignant tumors.
Assuntos
Interferon Tipo I , NF-kappa B , Humanos , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , DNA , Carcinogênese , Microambiente TumoralRESUMO
The genus Culicoides includes biting midges, some of which are vectors for viruses that cause diseases in humans and animals. Knowledge of the roles of Culicoides in viral ecology is inadequate. We collected ~300 000 samples of Culicoides and mosquitoes in 15 representative regions within Yunnan, China. Using mosquitoes as reference vectors, we designed a comparative virome strategy to study the viral composition, diversity, hosts and spatiotemporal distribution of Culicoides. A map of viromes in Culicoides and mosquitoes in Yunan province, China, was constructed. At the same locations, Culicoides and mosquitoes usually share a similar viral diversity. At least 10 important pathogenic viruses were detected from Culicoides. Many novel viruses were discovered, including 21 segmented viruses of Flaviviridae, 180 viruses of Monjiviricetes and 130 viruses of Bunyavirales. The findings demonstrate that Culicoides is an important part of viral ecology and should be studied and monitored for potentially emerging viruses.
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Ceratopogonidae/virologia , Culicidae/virologia , Vírus de RNA de Cadeia Positiva/classificação , Viroma , AnimaisRESUMO
Cantharidin (CTD), extracted from the traditional Chinese medicine mylabris, has shown significant curative effects against a variety of tumors, but its clinical application is limited by its high toxicity. Studies have revealed that CTD can cause toxicity in the kidneys; however, the underlying molecular mechanisms remain unclear. In this study, we investigated the toxic effects in mouse kidneys following CTD treatment by pathological and ultrastructure observations, biochemical index detection, and transcriptomics, and explored the underlying molecular mechanisms by RNA sequencing (RNA-seq). The results showed that after CTD exposure, the kidneys had different degrees of pathological damage, altered uric acid and creatinine levels in serum, and the antioxidant indexes in tissues were significantly increased. These changes were more pronounced at medium and high doses of CTD. RNA-seq analysis revealed 674 differentially expressed genes compared with the control group, of which 131 were upregulated and 543 were downregulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that many differentially expressed genes were closely related to the stress response, the CIDE protein family, and the transporter superfamily, as well as the MAPK, AMPK, and HIF-1 pathways. The reliability of the RNA-seq results was verified by qRT-PCR of the six target genes. These findings offer insight into the molecular mechanisms of renal toxicity caused by CTD and provide an important theoretical basis for the clinical treatment of CTD-induced nephrotoxicity.
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Cantaridina , Transcriptoma , Camundongos , Animais , Cantaridina/toxicidade , Reprodutibilidade dos Testes , Perfilação da Expressão Gênica , Análise de Sequência de RNARESUMO
Neuromuscular electrical stimulation (NMES) is a novel treatment method that stimulates patients' swallowing functions. This systemic review was designed to evaluate the impact of NMES on dysphagia in stroke patients. Databases including PubMed, Embase, Web of Science, and Cochrane Library were searched from the date of establishment to January 28th, 2022. Two investigators identified all included studies and compared the swallowing function after NMES treatment with traditional therapy (TT). The Cochrane risk bias assessment tool was utilized to analyze the quality of included studies. Research outcomes included Swallowing Quality of Life (SWAL-QoL), Penetration-Aspiration Scale (PAS), Functional Oral Intake Scale (FOIS), Dysphagia Outcomes and Severity Scale (DOSS), the Repeat Salivary Swallowing Test (RSST), and Water Swallowing Test (WST). We extracted the mean and standard deviation of specific outcomes at the baseline level and after the treatment in both NMES and TT groups for subsequent meta-analysis. 9 randomized controlled trials (RCTs) and quasi-RCTs were included, and remarkable differences were found between patients treated with or without NMES in respect of FOIS scores (SMD = 0.48; 95% CI 0.26-0.70, P < 0.0001), PAS scores (SMD = - 0.56; 95% CI 1.01-0.10, P = 0.02), and SWAL-QoL scores (SMD = 0.57; 95% CI 0.00-1.14, P = 0.05). No significant difference was manifested in WST, RSST, and DOSS (SMD: - 0.02; 95% CI 0.38-0.35, P = 0.93). Evidence suggests that NMES is more effective for post-stroke dysphagia patients than treatment without NMES.
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ABSTRACT: Bone morphogenetic protein 4 (BMP4) is a proinflammatory factor. The expression of BMP4 is reduced in the adipose and enhanced in the myocardium and vascular during obesity. It is possibly involved in the process of inflammatory response of the myocardium and vascular. Obesity, often regarded as a risk factor for cardiovascular diseases, is a kind of inflammatory response. This study aimed to investigate the relationship of BMP4 with obesity and cardiovascular disease. Ob/ob mice were used as the experimental group, and C57BL/6 mice were used as the control group. The two groups were further divided into 2 subgroups based on the mice carrying adenovirus-encoding shRNA for BMP4 or Lac Z genes. The messenger RNA and protein levels of BMP4, interleukin-1ß, and interleukin-9 were significantly higher in the myocardial tissue and aorta of ob/ob+ Lac Z shRNA than those in the other 3 groups, whereas the levels in the ob/ob+ BMP4 shRNA group were significantly decreased and comparable with those in the control groups. BMP4 is significantly upregulated in the myocardial tissue and aorta of obese mice, and this suggests that BMP4 is an risk factor involved in the local inflammatory response.
Assuntos
Inflamação , Obesidade , Animais , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Inflamação/genética , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Miocárdio/metabolismo , Obesidade/genética , Obesidade/metabolismo , RNA Interferente PequenoRESUMO
A highly permselective nanofiltration membrane was engineered via zwitterionic copolymer assembly regulated interfacial polymerization (IP). The copolymer was molecularly synthesized using single-step free-radical polymerization between 2-methacryloyloxyethyl phosphorylcholine (MPC) and 2-aminoethyl methacrylate hydrochloride (AEMA) (P[MPC-co-AEMA]). The dynamic network of P[MPC-co-AEMA] served as a regulator to precisely control the kinetics of the reaction by decelerating the transport of piperazine toward the water/hexane interface, forming a polyamide (PA) membrane with ultralow thickness of 70 nm, compared to that of the pristine PA (230 nm). Concomitantly, manipulating the phosphate moieties of P[MPC-co-AEMA] integrated into the PA matrix enabled the formation of ridge-shaped nanofilms with loose internal architecture exhibiting enhanced inner-pore interconnectivity. The resultant P[MPC-co-AEMA]-incorporated PA membrane exhibited a high water permeance of 15.7 L·m-2·h-1·bar-1 (more than 3-fold higher than that of the pristine PA [4.4 L·m-2·h-1·bar-1]), high divalent salt rejection of 98.3%, and competitive mono-/divalent ion selectivity of 52.9 among the state-of-the-art desalination membranes.
Assuntos
Membranas Artificiais , Polímeros , Nylons , Polimerização , ÁguaRESUMO
The surface area of the human cerebral cortex undergoes dramatic expansion during late fetal development, leading to cortical folding, an evolutionary feature not present in rodents. Microcephaly is a neurodevelopmental disorder defined by an abnormally small brain, and many gene mutations have been found to be associated with primary microcephaly. However, mouse models generated by ablating primary microcephaly-associated genes often fail to recapitulate the severe loss of cortical surface area observed in individuals with this pathology. Here, we show that a mouse model with deficient expression of high-mobility group nucleosomal binding domain 2 (HMGN2) manifests microcephaly with reduced cortical surface area and almost normal radial corticogenesis, with a pattern of incomplete penetrance. We revealed that altered cleavage plane and mitotic delay of ventricular radial glia may explain the rising ratio of intermediate progenitor cells to radial glia and the displacement of neural progenitor cells in microcephalic mutant mice. These led to decreased self-renewal of the radial glia and reduction in lateral expansion. Furthermore, we found that HMGN2 protected corticogenesis by maintaining global chromatin accessibility mainly at promoter regions, thereby ensuring the correct regulation of the transcriptome. Our findings underscore the importance of the regulation of chromatin structure in cortical development and highlight a mouse model with critical insights into the etiology of microcephaly.
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Córtex Cerebral/embriologia , Montagem e Desmontagem da Cromatina , Proteína HMGN2/metabolismo , Microcefalia/metabolismo , Animais , Córtex Cerebral/metabolismo , Feminino , Deleção de Genes , Regulação da Expressão Gênica no Desenvolvimento , Proteína HMGN2/análise , Proteína HMGN2/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcefalia/genéticaRESUMO
MOTIVATION: Many methods have been developed to estimate immune cell composition from tissue transcriptomes. One common characteristic of these methods is that they are trained using a set of general immune cell transcriptomes that ignores tissue specificities. However, as immune cells are localized in different tissues, they may have distinct expression profiles. Hence, calculations that use general signature matrices may hinder the deconvolution accuracy. RESULTS: This study used single cell RNA-sequencing (scRNA-Seq) data from different mouse tissues instead of general signature expression values to generate tissue-specific signature gene matrices that are used as the input of the deconvolution model. First, the transcriptome of immune cells in each tissue was extracted from scRNA-Seq data and used to construct the entire expression matrix of tissue immune cells. Then, after comparing different gene selection strategies, the expressions of 162 seq-ImmuCC derived signature genes in tissue immune cell scRNA-Seq data were regarded as the tissue specific signature matrices. Finally, a modest improvement in performance was observed in multiple tissues that refer to a traditional general signature matrix in the deconvolution model. With the fast accumulation of scRNA-Seq data, the introduction of these data into an estimation of immune cell compositions for different tissues will open a new window for avoiding tissue bias for immune cell expression. AVAILABILITY AND IMPLEMENTATION: The signature matrices were available at https://github.com/wuaipinglab/ImmuCC/tree/master/tissue_immucc/SignatureMatrix). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Perfilação da Expressão Gênica , Transcriptoma , Animais , Sequência de Bases , Camundongos , Análise de Sequência de RNA , Análise de Célula ÚnicaRESUMO
Angiogenesis in the developing cerebral cortex accompanies cortical neurogenesis. However, the precise mechanisms underlying cortical angiogenesis at the embryonic stage remain largely unknown. Here, we show that radial glia-derived vascular cell adhesion molecule 1 (VCAM1) coordinates cortical vascularization through different enrichments in the proximal and distal radial glial processes. We found that VCAM1 was highly enriched around the blood vessels in the inner ventricular zone (VZ), preventing the ingrowth of blood vessels into the mitotic cell layer along the ventricular surface. Disrupting the enrichment of VCAM1 surrounding the blood vessels by a tetraspanin-blocking peptide or conditional deletion of Vcam1 gene in neural progenitor cells increased angiogenesis in the inner VZ. Conversely, VCAM1 expressed in the basal endfeet of radial glial processes promoted angiogenic sprouting from the perineural vascular plexus (PNVP). In utero, overexpression of VCAM1 increased the vessel density in the cortical plate, while knockdown of Vcam1 accomplished the opposite. In vitro, we observed that VCAM1 bidirectionally affected endothelial cell proliferation in a concentration-dependent manner. Taken together, our findings identify that distinct concentrations of VCAM1 around VZ blood vessels and the PNVP differently organize cortical angiogenesis during late embryogenesis.
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Proliferação de Células/genética , Córtex Cerebral/embriologia , Células Endoteliais/metabolismo , Células Ependimogliais/metabolismo , Neovascularização Fisiológica/genética , Molécula 1 de Adesão de Célula Vascular/genética , Animais , Proliferação de Células/efeitos dos fármacos , Córtex Cerebral/irrigação sanguínea , Ventrículos Cerebrais/irrigação sanguínea , Ventrículos Cerebrais/embriologia , Células Endoteliais/citologia , Células Ependimogliais/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Técnicas In Vitro , Camundongos , Camundongos Knockout , Neovascularização Fisiológica/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
BACKGROUND: Adherence to chronic obstructive pulmonary disease (COPD) maintenance medication is important for managing symptoms and exacerbation risk, and is associated with reduced mortality, hospitalizations, and costs. This study compared on-treatment exacerbations, medical costs, and medication adherence in patients with COPD initiating treatment with umeclidinium/vilanterol (UMEC/VI) or tiotropium (TIO). METHODS: This retrospective matched cohort study selected patients from Optum's de-identified Clinformatics Data Mart database who initiated maintenance treatment with UMEC/VI or TIO between 01/01/2014 and 12/31/2017 (index date defined as the first dispensing). Eligible patients were ≥ 40 years of age and had ≥ 12 months continuous health plan coverage pre- and post-index; ≥ 1 medical claim for COPD pre-index or on the index date; no moderate/severe COPD-related exacerbations on the index date; no asthma diagnosis pre- or post-index; no maintenance medication fills containing inhaled corticosteroids, long-acting ß2-agonists, or long-acting muscarinic antagonists pre-index or on the index date; and no fills for both UMEC/VI and TIO on the index date. Outcomes included time-to-first (Kaplan-Meier analysis) and rates of on-treatment COPD-related moderate/severe exacerbations, medication adherence (proportion of days covered [PDC] and proportion of adherent patients [PDC ≥ 0.8]), and COPD-related medical costs per patient per month (PPPM). Propensity score matching was used to adjust for potential confounders. RESULTS: Each cohort included 3929 matched patients. Kaplan-Meier rates of on-treatment COPD-related exacerbations were similar between cohorts (hazard ratio at 12 months; overall: 0.93, moderate: 0.92, severe: 1.07; all p > 0.05). UMEC/VI versus TIO initiators had significantly higher adherence (mean PDC: 0.44 vs 0.37; p < 0.001; proportion with PDC ≥ 0.8: 22.0% vs 16.4%; p< 0.001) and significantly lower mean on-treatment COPD-related total medical costs ($867 vs $1095 PPPM; p = 0.028), driven by lower outpatient visit costs. CONCLUSIONS: These findings provide valuable information for physicians considering UMEC/VI or TIO as initial maintenance therapy options for patients with COPD.
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Adesão à Medicação , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/economia , Administração por Inalação , Corticosteroides/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Bases de Dados Factuais , Combinação de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Pontuação de Propensão , Quinuclidinas/efeitos adversos , Estudos Retrospectivos , Tempo para o Tratamento , Brometo de Tiotrópio/efeitos adversos , Estados UnidosRESUMO
Oligomerization of stromal interacting molecule 1 (STIM1) promotes store-operated calcium entry (SOCE); however, the mechanism of STIM1 aggregation is unclear. Here, using the lepidopteran insect and agricultural pest cotton bollworm (Helicoverpa armigera) as a model and immunoblotting, RT-qPCR, RNA interference (RNAi), and ChIP assays, we found that the steroid hormone 20-hydroxyecdysone (20E) up-regulates STIM1 expression via G protein-coupled receptors (GPCRs) and the 20E nuclear receptor (EcRB1). We also identified an ecdysone-response element (EcRE) in the 5'-upstream region of the STIM1 gene and also noted that STIM1 is located in the larval midgut during metamorphosis. STIM1 knockdown in larvae delayed pupation time, prevented midgut remodeling, and decreased 20E-induced gene transcription. STIM1 knockdown in a H. armigera epidermal cell line, HaEpi, repressed 20E-induced calcium ion influx and apoptosis. Moreover, 20E-induced STIM1 clustering to puncta and translocation toward the cell membrane. Inhibitors of GPCRs, phospholipase C (PLC), and inositol trisphosphate receptor (IP3R) repressed 20E-induced STIM1 phosphorylation, and we found that two GPCRs are involved in 20E-induced STIM1 phosphorylation. 20E-induced STIM1 phosphorylation on Ser-485 through protein kinase C (PKC), and we observed that Ser-485 phosphorylation is critical for STIM1 clustering, interaction with calcium release-activated calcium channel modulator 1 (Orai1), calcium ion influx, and 20E-induced apoptosis. These results suggest that 20E up-regulates STIM1 phosphorylation for aggregation via GPCRs, followed by interaction with Orai1 to induce SOCE, thereby promoting apoptosis in the midgut during insect metamorphosis.
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Cálcio/metabolismo , Ecdisterona/farmacologia , Agregados Proteicos/efeitos dos fármacos , Molécula 1 de Interação Estromal/metabolismo , Animais , Apoptose/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Larva/metabolismo , Lepidópteros/efeitos dos fármacos , Lepidópteros/crescimento & desenvolvimento , Lepidópteros/metabolismo , Metamorfose Biológica/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Interação Estromal/deficiência , Molécula 1 de Interação Estromal/genética , Regulação para Cima/efeitos dos fármacosRESUMO
Cajal-Retzius (CR) cells are one of the earliest populations of neurons in the cerebral cortex of rodents and primates, and they play a critical role in corticogenesis and cortical lamination during neocortical development. However, a comprehensive morphological and physiological profile of CR cells in the mouse neocortex has not yet been established. Here, we systematically investigated the dynamic development of CR cells in Tg(Ebf2-EGFP)58Gsat/Mmcd mice. The morphological complexity, membrane activities and presynaptic inputs of CR cells coordinately increase and reach a plateau at P5-P9 before regressing. Using 3D reconstruction, we delineated a parallel-stratification pattern of the axonal extension of CR cells. Furthermore, we found that the morphological structure and presynaptic inputs of CR cells were disturbed in Reelin-deficient mice. These findings confirm that CR cells undergo a transient maturation process in layer 1 before disappearing. Importantly, Reelin deficiency impairs the formation of synaptic connections onto CR cells. In conclusion, our results provide insights into the rapid maturation and axonal stratification of CR cells in layer 1. These findings suggest that both the electrophysiological activities and the morphology of CR cells provide vital guidance for the modulation of early circuits, in a Reelin-dependent manner.
Assuntos
Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Neurônios/citologia , Neurônios/fisiologia , Animais , Axônios/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/análise , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/fisiologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/fisiologia , Proteínas de Fluorescência Verde/análise , Potenciais da Membrana , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Neurônios/metabolismo , Proteína Reelina , Serina Endopeptidases/genética , Serina Endopeptidases/fisiologiaRESUMO
During early development, signaling centers, such as the cortical hem and the preoptic area (POA), are critical for telencephalic patterning. However, the mechanisms underlying the maintenance of signal centers are poorly understood. Here, we report that the transcription factor Foxg1 is required to confine the POA, a resource of Sonic Hedgehog (Shh) that is pivotal for ventral telencephalic development. Cell-specific deletion of Foxg1 achieved by crossing Foxg1fl/fl with Dbx1-cre or Nestin-CreER combined with tamoxifen induction results in a dramatic expansion of the POA accompanied by the significantly increased activity of the Shh signaling pathway. Ventral pattern formation was severely impaired. Moreover, we demonstrated that Foxg1 directly represses Dbx1 to restrict the POA. Furthermore, we found that the ventral pallium was expanded, which might also contribute to the observed patterning defects. These findings will improve our understanding of the maintenance of signal centers and help to elucidate the mechanisms underlying ventral telencephalic patterning.
Assuntos
Padronização Corporal/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Homeodomínio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/fisiologia , Telencéfalo/embriologia , Animais , Camundongos , Camundongos TransgênicosRESUMO
The juxtaglomerular cell tumor (JCT) is a rare renal tumor. We re-evaluated the clinicopathologic features of 21 JCTs to summarize their variable morphologies. Immunohistochemical, fluorescent in situ hybridization and periodic acid-Schiff stains were routinely performed, and four JCT cases were detected via transmission electron microscopy. The 21 JCTs involved five males and 16 females, ranging in age from 19 years to 69 years (mean, 36.9 years; median, 34 years). The tumors were composed of large, small, or spindle cells with a round, oval or polygonal shape, arranged in various growth patterns. Both necrosis (1/21) and mitosis (2/21, with 1/50HFP, 8/50HFP) was rarely appreciated. All cases were immunoreactive for renin and CD34 (21/21), and few were positive for α-SMA (13/21;11/21, focally; 2/21, diffusely,), CD117 (9/21, focally) and synaptophysin (3/21, focally). Ultrastructurally, all four cases exhibited secretory granules in varying sizes in the cytoplasm, two of which exhibited cellular junctions. Almost all cases (20/21) had a favorable prognosis, but one succumbed due to bone and hepatic metastases, which corresponds to malignant JCT. Our study demonstrates that JCTs may have atypical clinical presentations and variable histologic appearances. A familiarity with these features may contribute to a correct diagnosis.