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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic polyarticular pain, and its main pathological features include inflammatory cell infiltration, synovial fibroblast proliferation, and cartilage erosion. Immune cells, synovial cells and neuroendocrine factors play pivotal roles in the pathophysiological mechanism underlying rheumatoid arthritis. Biological clock genes regulate immune cell functions, which is linked to rhythmic changes in arthritis pathology. Additionally, the interaction between biological clock genes and neuroendocrine factors is also involved in rhythmic changes in rheumatoid arthritis. This review provides an overview of the contributions of circadian rhythm genes to RA pathology, including their interaction with the immune system and their involvement in regulating the secretion and function of neuroendocrine factors. A molecular understanding of the role of the circadian rhythm in RA may offer insights for effective disease management.
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Cathodic CO2 adsorption and activation is essential for high-temperature CO2 electrolysis in solid oxide electrolysis cells (SOECs). However, the component of oxygen ionic conductor in the cathode displays limited electrocatalytic activity. Herein, stable single Ruthenium (Ru) atoms are anchored on the surface of oxygen ionic conductor (Ce0.8 Sm0.2 O2-δ , SDC) via the strong covalent metal-support interaction, which evidently modifies the electronic structure of SDC surface for favorable oxygen vacancy formation and enhanced CO2 adsorption and activation, finally evoking the electrocatalytic activity of SDC for high-temperature CO2 electrolysis. Experimentally, SOEC with the Ru1 /SDC-La0.6 Sr0.4 Co0.2 Fe0.8 O3-δ cathode exhibits a current density as high as 2.39â A cm-2 at 1.6â V and 800 °C. This work expands the application of single atom catalyst to the high-temperature electrocatalytic reaction in SOEC and provides an efficient strategy to tailor the electronic structure and electrocatalytic activity of SOEC cathode at the atomic scale.
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African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.
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Glomerulosclerose Segmentar e Focal , Humanos , Glomerulosclerose Segmentar e Focal/genética , Apolipoproteína L1/genética , Predisposição Genética para Doença , Fatores de Risco , Genótipo , Apolipoproteínas/genéticaRESUMO
PURPOSE: Previous work identified rare variants in DSTYK associated with human congenital anomalies of the kidney and urinary tract (CAKUT). Here, we present a series of mouse and human studies to clarify the association, penetrance, and expressivity of DSTYK variants. METHODS: We phenotypically characterized Dstyk knockout mice of 3 separate inbred backgrounds and re-analyzed the original family segregating the DSTYK c.654+1G>A splice-site variant (referred to as "SSV" below). DSTYK loss of function (LOF) and SSVs were annotated in individuals with CAKUT, epilepsy, or amyotrophic lateral sclerosis vs controls. A phenome-wide association study analysis was also performed using United Kingdom Biobank (UKBB) data. RESULTS: Results demonstrate â¼20% to 25% penetrance of obstructive uropathy, at least, in C57BL/6J and FVB/NJ Dstyk-/- mice. Phenotypic penetrance increased to â¼40% in C3H/HeJ mutants, with mild-to-moderate severity. Re-analysis of the original family segregating the rare SSV showed low penetrance (43.8%) and no alternative genetic causes for CAKUT. LOF DSTYK variants burden showed significant excess for CAKUT and epilepsy vs controls and an exploratory phenome-wide association study supported association with neurological disorders. CONCLUSION: These data support causality for DSTYK LOF variants and highlights the need for large-scale sequencing studies (here >200,000 cases) to accurately assess causality for genes and variants to lowly penetrant traits with common population prevalence.
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Epilepsia , Sistema Urinário , Anormalidades Urogenitais , Animais , Camundongos , Humanos , Penetrância , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Anormalidades Urogenitais/genética , Rim/anormalidades , Fatores de Risco , Epilepsia/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genéticaRESUMO
Black Americans have a significantly higher risk of developing chronic kidney disease (CKD), especially focal segmental glomerulosclerosis (FSGS), than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of Black Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1 -associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.
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Solid oxide electrolysis cells provide a practical solution for the direct conversion of CO2 to other chemicals (i.e. CO), however, an in-depth mechanistic understanding of the dynamic reconstruction of active sites for perovskite cathodes during CO2 electrolysis remains a great challenge. Herein, we identify that iridium-doped Sr2Fe1.45Ir0.05Mo0.5O6-δ (SFIrM) perovskite displays a dynamic electrochemical reconstruction feature during CO2 electrolysis with abundant exsolution of highly dispersed IrFe alloy nanoparticles on the SFIrM surface. The in situ reconstructed IrFe@SFIrM interfaces deliver a current density of 1.46 A cm-2 while maintaining over 99% CO Faradaic efficiency, representing a 25.8% improvement compared with the Sr2Fe1.5Mo0.5O6-δ counterpart. In situ electrochemical spectroscopy measurements and density functional theory calculations suggest that the improved CO2 electrolysis activity originates from the facilitated formation of carbonate intermediates at the IrFe@SFIrM interfaces. Our work may open the possibility of using an in situ electrochemical poling method for CO2 electrolysis in practice.
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Perovskites exhibit excellent high-temperature oxygen evolution reaction (OER) activities as the anodes of solid oxide electrolysis cells (SOECs). However, the relationship between ion ordering and OER performances is rarely investigated. Herein, a series of PrBaCo2-x Fex O5+δ perovskites with tailored ion orderings are constructed. Physicochemical characterizations and density functional theory calculations confirm that the oxygen bulk migration and surface transport capacities as well as the OER activities are promoted by the A-site cation ordering, but weakened by the oxygen vacancy ordering. Hence, SOEC with the A-site-ordered and oxygen-vacancy-disordered PrBaCo2 O5+δ anode exhibits the highest performance of 3.40â A cm-2 at 800 °C and 2.0â V. This work sheds light on the critical role of ion orderings in the high-temperature OER performance and paves a new way for screening novel anode materials of SOECs.
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A novel facultatively aerobic bacterium designated SY8 was isolated from a peanut rhizosphere soil sample collected in Jiangsu Province, China. Cells are Gram-stain-positive, rod-shaped, and agar colonies are creamy, opaque, and usually rhizoidal. Strain growth occurs at 30 - 45 °C (optimum 30 °C), pH 4.0 - 10.0 (optimum pH 6.0) and 0 - 4% (w/v) NaCl (optimum 2%) in Luria-Bertani medium. Phylogenetic analysis of the 16S rRNA gene sequences indicated that strain SY8 forms a distinct lineage in the clade of genus Bacillus and is related to Bacillus pseudomycoides DSM 12442 T (99.9%). Phylogenetic analysis of the concatenated gene sequences of 16S rRNA, gryB and rpoD also indicated that strain SY8 forms a distinct lineage in Bacillus. Calculation of the average nucleotide identities and the digital DNA-DNA hybridization values between strain SY8 and the related type Bacillus strains further revealed that strain SY8 represents a distinct species. The predominant cellular fatty acids are iso C15:0 (28.7%) and summed feature 3 (C16:1ω7c and/or C16:1ω6c) (10.3%). The major polar lipids consisted of diphosphatidyl glycerol, phosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidylinositol, and three unidentified phospholipids. The major menaquinone of SY8 was MK-7. Based on phenotypic, phylogenetic, chemotaxonomic, and genomic features, strain SY8 represents a novel species of the genus Bacillus. The name Bacillus arachidis sp. nov. is proposed with strain SY8T (= CCTCC AB 2021100 T=LMG 32409 T) designated as the type strain.
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Bacillus , Fabaceae , Arachis , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , Fabaceae/genética , Ácidos Graxos , Fosfatidilgliceróis , Filogenia , RNA Ribossômico 16S/genética , Rizosfera , Análise de Sequência de DNA , Solo , Microbiologia do SoloRESUMO
Hepatic stellate cells (HSCs) play an important role in the initiation and development of liver fibrogenesis, and abnormal glucose metabolism is increasingly being considered a crucial factor controlling phenotypic transformation in HSCs. However, the role of the factors affecting glycolysis in HSCs in the experimental models of liver fibrosis has not been completely elucidated. In this study, we showed that glycolysis was significantly enhanced, while the expression of brain and muscle arnt-like protein-1 (Bmal1) was downregulated in fibrotic liver tissues of mice, primary HSCs, and transforming growth factor-ß1 (TGF-ß1)-induced LX2 cells. Overexpression of Bmal1 in TGF-ß1-induced LX2 cells blocked glycolysis and inhibited the proliferation and phenotypic transformation of activated HSCs. We further confirmed the protective effect of Bmal1 in liver fibrosis by overexpressing Bmal1 from hepatic adeno-associated virus 8 in mice. In addition, we also showed that the regulation of glycolysis by Bmal1 is mediated by the isocitrate dehydrogenase 1/α-ketoglutarate (IDH1/α-KG) pathway. Collectively, our results indicated that a novel Bmal1-IDH1/α-KG axis may be involved in regulating glycolysis of activated HSCs and might hence be used as a therapeutic target for alleviating liver fibrosis.
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Fatores de Transcrição ARNTL/metabolismo , Glicólise , Células Estreladas do Fígado/metabolismo , Isocitrato Desidrogenase/metabolismo , Cirrose Hepática/metabolismo , Fatores de Transcrição ARNTL/fisiologia , Animais , Western Blotting , Cromatografia Líquida de Alta Pressão , Citometria de Fluxo , Células Estreladas do Fígado/patologia , Cirrose Hepática/fisiopatologia , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND AND AIMS: Alcoholic fatty liver (AFL) is a liver disease caused by long-term excessive drinking and is characterized by hepatic steatosis. Understanding the regulatory mechanism of steatosis is essential for the treatment of AFL. Rev-erbα is a member of the Rev-erbs family of nuclear receptors, playing an important role in regulating lipid metabolism. However, its functional role in AFL and its underlying mechanism remains unclear. RESULTS: Rev-erbα was upregulated in the liver of EtOH-fed mice and EtOH-treated L-02 cells. Further, Rev-erbα activation exacerbates steatosis in L-02 cells. Inhibition/downexpression of Rev-erbα improved steatosis. Mechanistically, autophagy activity was inhibited in vivo and vitro. Interestingly, inhibition/downexpression of Rev-erbα enhanced autophagy. Furthermore, silencing of Rev-erbα up-regulated the nuclear expression of Bmal1. Autophagy activity was inhibited and steatosis was deteriorated after EtOH-treated L-02 cells were cotransfected with Rev-erbα shRNA and Bmal1 siRNA. CONCLUSIONS: Rev-erbα induces liver steatosis, which promotes the progression of AFL. Our study reveals a novel steatosis regulatory mechanism in AFL and suggest that Rev-erbα might be a potential therapeutic target for AFL.
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CO2 electroreduction by solid oxide electrolysis cells (SOECs) can not only attenuate the greenhouse effect, but also convert surplus electrical energy into chemical energy. The adsorption and activation of CO2 on the cathode play an important role in the SOEC performance. La0.6 Sr0.4 Co0.2 Fe0.8 O3-δ -Ce0.8 Sm0.2 O2-δ (LSCF-SDC; SDC=samarium-doped ceria) is a promising SOEC cathode. However, its electrocatalytic activity still needs to be improved. In this study, Pt/SDC interfaces are constructed by decorating Pt nanoparticles onto the SDC surface. Electrochemical measurements indicate that the polarization resistance of the SOEC is decreased from 0.308 to 0.120â Ω cm2 , and the current density is improved from 0.913 to 1.420â A cm-2 at 1.6â V and 800 °C. Physicochemical characterizations suggest that construction of the Pt/SDC interfaces increases the oxygen vacancy concentration on the cathode and boosts CO2 adsorption and dissociation, which leads to enhanced CO2 electroreduction performance in SOECs.
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Oxidative dehydrogenation of ethane (ODE) is limited by the facile deep oxidation and potential safety hazards. Now, electrochemical ODE reaction is incorporated into the anode of a solid oxide electrolysis cell, utilizing the oxygen species generated at anode to catalytically convert ethane. By infiltrating γ-Al2 O3 onto the surface of La0.6 Sr0.4 Co0.2 Fe0.8 O3-δ -Sm0.2 Ce0.8 O2-δ (LSCF-SDC) anode, the ethylene selectivity reaches as high as 92.5 %, while the highest ethane conversion is up to 29.1 % at 600 °C with optimized current and ethane flow rate. Density functional theory calculations and inâ situ X-ray photoelectron spectroscopy characterizations reveal that the Al2 O3 /LSCF interfaces effectively reduce the amount of adsorbed oxygen species, leading to improved ethylene selectivity and stability, and that the formation of Al-O-Fe alters the electronic structure of interfacial Fe center with increased density of state around Fermi level and downshift of the empty band, which enhances ethane adsorption and conversion.
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In the version of this article initially published, affiliation 38 incorrectly read "ICNU-Nephrology and Urology Department, Barcelona, Spain"; "Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain" is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article.
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The tumor suppressor protein p53 is a central governor of various cellular signals. It is well accepted that ubiquitination as well as ubiquitin-like (UBL) modifications of p53 protein is critical in the control of its activity. Interferon-stimulated gene 15 (ISG15) is a well-known UBL protein with pleiotropic functions, serving both as a free intracellular molecule and as a modifier by conjugating to target proteins. Initially, attentions have historically focused on the antiviral effects of ISG15 pathway. Remarkably, a significant role in the processes of autophagy, DNA repair, and protein translation provided considerable insight into the new functions of ISG15 pathway. Despite the deterministic revelation of the relation between ISG15 and p53, the functional consequence of p53 ISGylation appears somewhat confused. More important, more recent studies have hinted p53 ubiquitination or other UBL modifications that might interconnect with its ISGylation. Here, we aim to summarize the current knowledge of p53 ISGylation and the differences in other significant modifications, which would be beneficial for the development of p53-based cancer therapy.
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Citocinas/metabolismo , Neoplasias/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitinação , Ubiquitinas/metabolismo , Animais , Antineoplásicos/uso terapêutico , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Estabilidade Proteica , Proteólise , Sumoilação , Proteína Supressora de Tumor p53/genética , Ubiquitinação/efeitos dos fármacosRESUMO
Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.
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Variações do Número de Cópias de DNA/genética , Rim/anormalidades , Sistema Urinário/anormalidades , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Deleção Cromossômica , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , MasculinoRESUMO
Hematopoietic stem cell (HSC) maintenance depends on extrinsic cues. Currently, only local signals arising from the bone marrow niche have been shown to maintain HSCs. However, it is not known whether systemic factors also sustain HSCs. We assessed the physiological source of thrombopoietin (TPO), a key cytokine required for maintaining HSCs. Using TpoDsRed-CreER knock-in mice, we showed that TPO is expressed by hepatocytes but not by bone marrow cells. Deletion of Tpo from hematopoietic cells, osteoblasts, or bone marrow mesenchymal stromal cells does not affect HSC number or function. However, when Tpo is deleted from hepatocytes, bone marrow HSCs are depleted. Thus, a cross-organ factor, circulating TPO made in the liver by hepatocytes, is required for bone marrow HSC maintenance. Our results demonstrate that systemic factors, in addition to the local niche, are a critical extrinsic component for HSC maintenance.
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Células-Tronco Hematopoéticas/fisiologia , Hepatócitos/metabolismo , Fígado/metabolismo , Trombopoetina/fisiologia , Animais , Deleção de Genes , Técnicas de Introdução de Genes , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Camundongos Mutantes , Trombopoetina/genéticaRESUMO
BACKGROUND: To explore the effects of Shenmai (SM) injection on the values of cardiac output (CO), stroke volume (SV), and the ejection fraction (EF) in patients treated with off-pump coronary artery bypass graft (OPCABG). METHODS: Forty patients undergoing OPCABG were randomly divided into SM group (nâ=â20) and the 5% glucose (G) group (nâ=â20). The control liquids were injected from the beginning of the operation to the start of coronary artery bypass graft (CABG). The values of CO, SV, and EF before induction (t1), at the beginning of operation (t2), 30 minutes after the start of operation (t3), at the beginning of coronary artery bypass graft (t4), at the end of coronary artery bypass graft (CABG) (t5), and at the end of operation (t6) were recorded. RESULTS: The values of CO, SV, and EF in the patients of SM group at t3 to t6 were found to be significantly higher than those at t1 (Pâ<â.05). The values of CO, SV, and EF in the patients of G group were found to be increased at t5 and t6 (Pâ<â.05). At t3 and t4, the values of CO, SV, and EF in SM group were significantly higher than those in the G group (Pâ<â.05). CONCLUSION: In patients with OPCABG, the infusion of SM injection can effectively increase the values of CO, SV, and EF and increase the safety of anesthesia management.
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Débito Cardíaco/efeitos dos fármacos , Ponte de Artéria Coronária sem Circulação Extracorpórea/efeitos adversos , Medicamentos de Ervas Chinesas/uso terapêutico , Volume Sistólico/efeitos dos fármacos , Idoso , Ponte de Artéria Coronária sem Circulação Extracorpórea/métodos , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0 × 10-5 for novel LOF, increased to p = 4.1 × 10-6 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3 × 10-7). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.