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OBJECTIVE: Self-rated health (SRH) has been documented as an important predictor of quality of life among the elderly and its risk factors are vision-specific among elderly males. The aim of this study was to clarify vision-specific risk factors to SRH among elderly females without dementia in Chinese urban areas. METHODS: From March to November 2012, 2147 elderly women in Liaoning Province of China were selected using a stratified sampling method. After cognitive screening, 1956 participants without dementia were finally enrolled. A questionnaire including SRH, visual ability and factors including demographic characteristics, physical conditions, lifestyle factors, social psychological status and social activities were analyzed. Multivariate logistic regression was used to clarify the association of SRH with risk factors, while stepwise multivariate logistic regression was used to examine the vision-specific associations with SRH. RESULTS: The mean age was 73.6 ± 5.82 (mean ± SD). The percentages of good SRH in good and impaired visual ability groups were 36.2% and 24.4%, respectively. Most characteristics between elderly females with different visual abilities were significantly different. Visual ability had interactions with physical conditions, lifestyle factors and social activities to affect SRH. Among elderly females with good visual ability, depressive symptoms, rather than chronic disease had the strongest association with good SRH followed by marital status, regular diet, going out alone to distant places, taking a walk, smoking and alcohol consumption. In the impaired visual ability group, going out alone to distant places had the strongest association with good SRH followed by chronic disease, filial piety, taking a walk, participating in entertainment, ethnicity, quality of sleep, worrying about falling and alcohol consumption. CONCLUSIONS: Good SRH status was at a low level especially among elderly females with impaired visual ability and the risk factors differed between elderly females with different visual abilities. Social psychological status was crucial for SRH among elderly females with good visual ability whereas physical conditions were prominent for impaired visual ability group.
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Estado de Salud , Población Urbana , Humanos , Femenino , Anciano , China/epidemiología , Factores de Riesgo , Población Urbana/estadística & datos numéricos , Trastornos de la Visión/epidemiología , Trastornos de la Visión/psicología , Anciano de 80 o más Años , Encuestas y Cuestionarios , Pueblos del Este de AsiaRESUMEN
SIGNIFICANCE STATEMENT: Polymorphisms of HLA genes may confer susceptibility to acute tubulointerstitial nephritis (ATIN), but small sample sizes and candidate gene design have hindered their investigation. The first genome-wide association study of ATIN identified two significant loci, risk haplotype DRB1*14-DQA1*0101-DQB1*0503 (DR14 serotype) and protective haplotype DRB1*1501-DQA1*0102-DQB1*0602 (DR15 serotype), with amino acid position 60 in the peptide-binding groove P10 of HLA-DR ß 1 key. Risk alleles were shared among different causes of ATIN and HLA genotypes associated with kidney injury and immune therapy response. HLA alleles showed the strongest association. The findings suggest that a genetically conferred risk of immune dysregulation is part of the pathogenesis of ATIN. BACKGROUND: Acute tubulointerstitial nephritis (ATIN) is a rare immune-related disease, accounting for approximately 10% of patients with unexplained AKI. Previous elucidation of the relationship between genetic factors that contribute to its pathogenesis was hampered because of small sample sizes and candidate gene design. METHODS: We undertook the first two-stage genome-wide association study and meta-analysis involving 544 kidney biopsy-defined patients with ATIN and 2346 controls of Chinese ancestry. We conducted statistical fine-mapping analysis, provided functional annotations of significant variants, estimated single nucleotide polymorphism (SNP)-based heritability, and checked genotype and subphenotype correlations. RESULTS: Two genome-wide significant loci, rs35087390 of HLA-DQA1 ( P =3.01×10 -39 ) on 6p21.32 and rs2417771 of PLEKHA5 on 12p12.3 ( P =2.14×10 -8 ), emerged from the analysis. HLA imputation using two reference panels suggested that HLA-DRB1*14 mainly drives the HLA risk association . HLA-DRB1 residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the HLA locus were 20.43% and 10.35%, respectively. Different clinical subphenotypes (drug-related or tubulointerstitial nephritis and uveitis syndrome) seemed to share the same risk alleles. However, the HLA risk genotype was associated with disease severity and response rate to immunosuppressive therapy. CONCLUSIONS: We identified two candidate genome regions associated with susceptibility to ATIN. The findings suggest that a genetically conferred risk of immune dysregulation is involved in the pathogenesis of ATIN.
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Estudio de Asociación del Genoma Completo , Nefritis Intersticial , Humanos , Cadenas HLA-DRB1/genética , Nefritis Intersticial/genética , Genotipo , Cadenas alfa de HLA-DQ/genética , Haplotipos , Alelos , Predisposición Genética a la EnfermedadRESUMEN
This study conducted statistics on the special review applications for Class â ¡ innovative medical devices in Shanghai from April 2020 to April 2023. It summarized and analyzed common problems in the innovation review application stage, and gave suggestions for applicants and reviewers in order to further improve the quality of innovation application and improve the pass rate of innovation applications.
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Equipos y Suministros , China , InvencionesRESUMEN
The inability to synthesize hierarchical structures with independently tailored nanoscale and mesoscale features limits the discovery of next-generation multifunctional materials. Here we present a predictable molecular self-assembly strategy to craft nanostructured materials with a variety of phase-in-phase hierarchical morphologies. The compositionally anisotropic building blocks employed in the assembly process are formed by multicomponent graft block copolymers containing sequence-defined side chains. The judicious design of various structural parameters in the graft block copolymers enables broadly tunable compositions, morphologies and lattice parameters across the nanoscale and mesoscale in the assembled structures. Our strategy introduces advanced design principles for the efficient creation of complex hierarchical structures and provides a facile synthetic platform to access nanomaterials with multiple precisely integrated functionalities.
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Nanoestructuras , Nanoestructuras/química , Polímeros/químicaRESUMEN
Self-assembled nanogratings, inscribed by femtosecond laser writing in volume, are demonstrated in multicomponent alkali and alkaline earth containing alumino-borosilicate glasses. The laser beam pulse duration, pulse energy, and polarization, were varied to probe the nanogratings existence as a function of laser parameters. Moreover, laser-polarization dependent form birefringence, characteristic of nanogratings, was monitored through retardance measurements using polarized light microscopy. Glass composition was found to drastically impact the formation of nanogratings. For a sodium alumino-borosilicate glass, a maximum retardance of 168â nm (at 800 fs and 1000 nJ) could be measured. The effect of composition is discussed based on SiO2 content, B2O3/Al2O3 ratio, and the Type II processing window is found to decrease as both (Na2O + CaO)/Al2O3 and B2O3/Al2O3 ratios increase. Finally, an interpretation in the ability to form nanogratings from a glass viscosity viewpoint, and its dependency with respect to the temperature, is demonstrated. This work is brought into comparison with previously published data on commercial glasses, which further indicates the strong link between nanogratings formation, glass chemistry, and viscosity.
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The thermal stability of self-assembled porous nanogratings inscribed by an infrared femtosecond (fs) laser in five commercial glasses (BK7, soda lime, 7059, AF32, and Eagle XG) is monitored using step isochronal annealing experiments. Their erasure, ascertained by retardance measurements and attributed to the collapse of nanopores, is well predicted from the Rayleigh-Plesset (R-P) equation. This finding is thus employed to theoretically predict the erasure of nanogratings in the context of any time-temperature process (e.g., thermal annealing, laser irradiation process). For example, in silica glass (Suprasil CG) and using a simplified form of the R-P equation, nanogratings composed of 50 nm will erase within â¼30m i n, â¼1µs, and â¼30n s at temperatures of â¼1250∘ C, 2675°C, and 3100°C, respectively. Such conclusions are expected to provide guidelines to imprint nanogratings in oxide glasses (for instance, in the choice of laser parameters) or to design appropriate thermal annealing protocols for temperature sensing.
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This publisher's note contains corrections to Appl. Opt.62, 6794 (2023)APOPAI0003-693510.1364/AO.496351.
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Virtually all of the dietary potassium intake is absorbed in the intestine, over 90% of which is excreted by the kidneys regarded as the most important organ of potassium excretion in the body. The renal excretion of potassium results primarily from the secretion of potassium by the principal cells in the aldosterone-sensitive distal nephron (ASDN), which is coupled to the reabsorption of Na+ by the epithelial Na+ channel (ENaC) located at the apical membrane of principal cells. When Na+ is transferred from the lumen into the cell by ENaC, the negativity in the lumen is relatively increased. K+ efflux, H+ efflux, and Cl- influx are the 3 pathways that respond to Na+ influx, that is, all these 3 pathways are coupled to Na+ influx. In general, Na+ influx is equal to the sum of K+ efflux, H+ efflux, and Cl- influx. Therefore, any alteration in Na+ influx, H+ efflux, or Cl- influx can affect K+ efflux, thereby affecting the renal K+ excretion. Firstly, Na+ influx is affected by the expression level of ENaC, which is mainly regulated by the aldosterone-mineralocorticoid receptor (MR) pathway. ENaC gain-of-function mutations (Liddle syndrome, also known as pseudohyperaldosteronism), MR gain-of-function mutations (Geller syndrome), increased aldosterone levels (primary/secondary hyperaldosteronism), and increased cortisol (Cushing syndrome) or deoxycorticosterone (hypercortisolism) which also activate MR, can lead to up-regulation of ENaC expression, and increased Na+ reabsorption, K+ excretion, as well as H+ excretion, clinically manifested as hypertension, hypokalemia and alkalosis. Conversely, ENaC inactivating mutations (pseudohypoaldosteronism type 1b), MR inactivating mutations (pseudohypoaldosteronism type 1a), or decreased aldosterone levels (hypoaldosteronism) can cause decreased reabsorption of Na+ and decreased excretion of both K+ and H+, clinically manifested as hypotension, hyperkalemia, and acidosis. The ENaC inhibitors amiloride and Triamterene can cause manifestations resembling pseudohypoaldosteronism type 1b; MR antagonist spironolactone causes manifestations similar to pseudohypoaldosteronism type 1a. Secondly, Na+ influx is regulated by the distal delivery of water and sodium. Therefore, when loss-of-function mutations in Na+-K+-2Cl- cotransporter (NKCC) expressed in the thick ascending limb of the loop and in Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule (Bartter syndrome and Gitelman syndrome, respectively) occur, the distal delivery of water and sodium increases, followed by an increase in the reabsorption of Na+ by ENaC at the collecting duct, as well as increased excretion of K+ and H+, clinically manifested as hypokalemia and alkalosis. Loop diuretics acting as NKCC inhibitors and thiazide diuretics acting as NCC inhibitors can cause manifestations resembling Bartter syndrome and Gitelman syndrome, respectively. Conversely, when the distal delivery of water and sodium is reduced (e.g., Gordon syndrome, also known as pseudohypoaldosteronism type 2), it is manifested as hypertension, hyperkalemia, and acidosis. Finally, when the distal delivery of non-chloride anions increases (e.g., proximal renal tubular acidosis and congenital chloride-losing diarrhea), the influx of Cl- in the collecting duct decreases; or when the excretion of hydrogen ions by collecting duct intercalated cells is impaired (e.g., distal renal tubular acidosis), the efflux of H+ decreases. Both above conditions can lead to increased K+ secretion and hypokalemia. In this review, we focus on the regulatory mechanisms of renal potassium excretion and the corresponding diseases arising from dysregulation.
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Alcalosis , Síndrome de Bartter , Síndrome de Gitelman , Hiperpotasemia , Hipertensión , Hipopotasemia , Seudohipoaldosteronismo , Humanos , Síndrome de Bartter/genética , Síndrome de Bartter/metabolismo , Seudohipoaldosteronismo/genética , Seudohipoaldosteronismo/metabolismo , Potasio/metabolismo , Aldosterona/metabolismo , Hipopotasemia/metabolismo , Síndrome de Gitelman/metabolismo , Hiperpotasemia/metabolismo , Relevancia Clínica , Canales Epiteliales de Sodio/genética , Canales Epiteliales de Sodio/metabolismo , Túbulos Renales Distales/metabolismo , Sodio/metabolismo , Alcalosis/metabolismo , Agua/metabolismo , Riñón/metabolismoRESUMEN
BACKGROUND: Deinococcus radiodurans (D. radiodurans) is best known for its extreme resistance to diverse environmental stress factors, including ionizing radiation (IR), ultraviolet (UV) irradiation, oxidative stress, and high temperatures. Robust DNA repair system and antioxidant system have been demonstrated to contribute to extreme resistance in D. radiodurans. However, practically all studies on the mechanism underlying D. radiodurans's extraordinary resistance relied on the treated strain during the post-treatment recovery lag phase to identify the key elements involved. The direct gene or protein changes of D. radiodurans after stress have not yet been characterized. RESULTS: In this study, we performed a proteomics profiling on D. radiodurans right after the heavy ion irradiation treatment, to discover the altered proteins that were quickly responsive to IR in D. radiodurans. Our study found that D. radiodurans shown exceptional resistance to 12C6+ heavy ion irradiation, in contrast to Escherichia coli (E.coli) strains. By using iTRAQ (Isobaric Tags for Relative and Absolute Quantitation)-based quantitative mass spectrometry analysis, the kinetics of proteome changes induced by various dosages of 12C6+ heavy ion irradiation were mapped. The results revealed that 452 proteins were differentially expressed under heavy ion irradiation, with the majority of proteins being upregulated, indicating the upregulation of functional categories of translation, TCA cycle (Tricarboxylic Acid cycle), and antioxidation regulation under heavy ion irradiation. CONCLUSIONS: This study shows how D. radiodurans reacts to exposure to 12C6+ heavy ion irradiation in terms of its overall protein expression profile. Most importantly, comparing the proteome profiling of D. radiodurans directly after heavy ion irradiation with research on the post-irradiation recovery phase would potentially provide a better understanding of mechanisms underlying the extreme radioresistance in D. radiodurans.
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Deinococcus , Iones Pesados , Deinococcus/genética , Deinococcus/metabolismo , Deinococcus/efectos de la radiación , Proteoma/metabolismo , Proteómica , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Escherichia coli/genética , Antioxidantes/metabolismoRESUMEN
Although exhaustion and cynicism are two dimensions of burnout, due to professionalism, they have different influence on the turnover intentions of medical social workers. Using a sample of 405 medical social workers in China, this study found that the influence mechanisms of exhaustion and cynicism on turnover intention are different. Social work educational background has a significant moderation effect on the relationships between exhaustion, cynicism, and turnover intention. A moderation effect of organizational type was also observed, although it was not significant.
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Agotamiento Profesional , Intención , Humanos , Trabajadores Sociales , Reorganización del Personal , Servicio Social , Satisfacción en el Trabajo , Encuestas y CuestionariosRESUMEN
The development of novel metal organic framework (MOF) friction power generation materials with high stability is important. This paper reports the first example of a double-helix metal chain organic framework with a network structure (ZUT-8). ZUT-8 shows high chemical stability, functional adjustability, and excellent output performance of friction power generation, which is superior to traditional coordination polymer materials. The cathodic protection system with ZUT-8 can prevent metal corrosion significantly. The output performance can be improved effectively by enhancing the conjugate effect of the linker. The theoretical calculation results showed that an increase in the degree of conjugation could significantly reduce the band gap, thereby affecting the friction power output signal. This study opens the door to constructing MOF materials with a double-helix metal chain and will promote their potential applications in self-powered electrochemical cathodic protection.
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Sepsis is a life-threatening inflammatory syndrome secondary to infection. Thanks to the advances of antibiotics and life-supporting techniques, the mortality of sepsis has been decreasing in recent decades. Nevertheless, sepsis-associated encephalopathy (SAE) is still common in septic patients, which promotes the mortality of septic patients and results in cognitive dysfunction in survivors. Full understanding and effective medicine in the treatment of SAE is currently scant. Here, we revealed a novel role of cGAS signaling in the pathogenesis of SAE. Deficiency of cGas significantly restored cognitive impairment in sepsis mice model. The restoration may attribute to the recovery of neo-neuron decline that associated with the decrease of activated microglia and astrocytes in the hippocampus of cGas-deficient mice. In addition, type I interferon (IFN) signaling, a downstream of cGAS pathway, was boosted in the hippocampus of septic mice, which was dramatically attenuated by deleting cGas. Moreover, administration of recombinant IFNß markedly reversed the protection of ablation of cGas in the cognitive impairment in sepsis. Collectively, cGAS promotes the pathogenesis of SAE by up-regulating type I IFN signaling. Blocking cGAS may be a promising strategy for preventing encephalopathy in sepsis.
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Modelos Animales de Enfermedad , Nucleotidiltransferasas/genética , Encefalopatía Asociada a la Sepsis/genética , Transducción de Señal/genética , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Interferón Tipo I/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , Neuronas/metabolismo , Nucleotidiltransferasas/deficiencia , Sustancias Protectoras/metabolismo , Sepsis/genética , Sepsis/metabolismo , Sepsis/fisiopatología , Encefalopatía Asociada a la Sepsis/metabolismoRESUMEN
Phase 2 and phase 3 clinical studies showed that hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) efficiently increased hemoglobin levels in both dialysis-dependent and non-dialysis-dependent chronic kidney disease (CKD) patients. However, the effects of HIF-PHIs on iron regulation have not been consistent among clinical trials. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate the effects of six HIF-PHIs on iron regulation in non-dialysis CKD patients. Electronic databases were searched from inception to April 20, 2020, for eligible studies. Changes from baseline in transferrin saturation (TSAT), total iron-binding capacity (TIBC), iron, ferritin, and hepcidin levels were pooled using the inverse-variance method and presented as the mean difference (MD) or standardized MD (SMD) with 95 % confidence intervals (CIs). Meta-analysis of the included studies showed that, in non-dialysis-dependent CKD patients, HIF-PHIs decreased TSAT (MD, -4.51; 95 % CI, -5.81 to -3.21), ferritin (MD, -47.29; 95 % CI, -54.59 to -40.00) and hepcidin (SMD, -0.94; 95 % CI, -1.25 to -0.62), increased TIBC (MD, 9.15; 95 % CI, 7.08-11.22), and did not affect serum iron (MD, -0.31; 95 % CI, -2.05 to 1.42) despite enhanced erythropoiesis. This systematic review suggests that HIF-PHIs promote iron utilization in non-dialysis-dependent CKD patients. Importantly, HIF-PHIs are associated with increased transferrin levels (and TIBC), leading to reduced TSAT. Therefore, the reduction of TSAT after HIF-PHIs should not be interpreted as iron deficiency.
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Anemia/tratamiento farmacológico , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Hierro/metabolismo , Inhibidores de Prolil-Hidroxilasa/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Anemia/metabolismo , Humanos , Inhibidores de Prolil-Hidroxilasa/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Renal Crónica/metabolismoRESUMEN
To date, the overall response rate to checkpoint blockade remains unsatisfactory, partially due to the limited understanding of the tumor immune microenvironment. The retinoic acid-related orphan receptor γt (RORγt) is the key transcription factor of T helper cell 17 (Th17) cells and plays an essential role in tumor immunity. In this study, we used JG-1, a potent and selective small-molecule RORγt agonist to evaluate the therapeutic potential and mechanism of action of targeting RORγt in tumor immunity. JG-1 promotes Th17 cells differentiation and inhibition of regulatory T (Treg) cells differentiation. JG-1 demonstrates robust tumor growth inhibition in multiple syngeneic models and shows a synergic effect with the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibody. In tumors, JG-1 not only promotes Th17 cells differentiation and increases C-C Motif Chemokine Receptor 6 (CCR6)- Chemokine (C-C motif) ligand 20 (CCL20) expression, but also inhibits both the expression of transforming growth factor-ß1 (TGF-ß1) and the differentiation and infiltration of Treg cells. In summary, JG-1 is a lead compound showing a potent activity in vitro and robust tumor growth inhibition in vivo with synergetic effects with anti-CTLA-4.
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Anticuerpos/uso terapéutico , Antineoplásicos/uso terapéutico , Antígeno CTLA-4/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Animales , Antineoplásicos/farmacología , Linfocitos B/efectos de los fármacos , Antígeno CTLA-4/inmunología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Ganglios Linfáticos/citología , Ratones Endogámicos C57BL , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Transducción de Señal/efectos de los fármacos , Bazo/citología , Linfocitos T/efectos de los fármacos , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
BACKGROUND: A high level of total cholesterol is associated with several lipid metabolism disorders, including atherosclerosis and cardiovascular diseases. ATP-binding cassette (ABC) transporter A1 (ABCA1) and miR-33-5p play crucial roles in atherosclerosis by controlling cholesterol efflux. While citrate is a precursor metabolite for lipid and cholesterol synthesis, little is known about the association between citrate synthase (CS) and cholesterol efflux. This study investigated the role of the miR-33-5p/ABCA1/CS axis in regulating cholesterol efflux in vascular endothelial cells (VECs). MATERIALS AND METHODS: VECs were treated with oxidized low-density lipoprotein cholesterol (ox-LDL), or pretreated with plasmids overexpressing CS, ABCA1, siRNAs against CS and ABCA1, and an miR-33-5p inhibitor. Cell apoptosis, cellular senescence-associated ß-galactosidase activity, inflammation, and cholesterol efflux were detected. RESULTS: Treatment with ox-LDL decreased ABCA1 and CS levels and increased miR-33-5p expression and apoptosis in dose-dependent manners. In contrast, treatment with the miR-33-5p inhibitor and ABCA1 and CS overexpression plasmids inhibited the above-mentioned ox-LDL-induced changes. In addition, treatment with ox-LDL decreased cholesterol efflux, induced aging, and promoted the production of inflammatory cytokines (i.e., IL-6 and tumor necrosis factor TNF-α), as well as the expression of Bax and Caspase 3 proteins in VECs. All these changes were rescued by miR-33-5p inhibition and ABCA1 and CS overexpression. The inhibition of ABCA1 and CS by siRNAs eliminated the effects mediated by the miR-33-5p inhibitor, and knockdown of CS eliminated the effects of ABCA1 on VECs. CONCLUSIONS: This study demonstrated the crucial roles played by the miR-33-5p/ABCA1/CS axis in regulating cholesterol efflux, inflammation, apoptosis, and aging in VECs, and also suggested the axis as a target for managing lipid metabolism disorders.
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Transportador 1 de Casete de Unión a ATP/metabolismo , Colesterol/metabolismo , Citrato (si)-Sintasa/metabolismo , Células Endoteliales/metabolismo , MicroARNs/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Apoptosis , Células Cultivadas , Senescencia Celular , Citrato (si)-Sintasa/genética , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Regulación de la Expresión Génica , Humanos , Lipoproteínas LDL/farmacología , MicroARNs/genéticaRESUMEN
A series of 6-substituted carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators were discovered through 6-position modification guided by insights from the crystallographic profiles of the "short" inverse agonist 6. With the increase in the size of the 6-position substituents, the "short" inverse agonist 6 first reversed its function to agonists and then to "long" inverse agonists. The cocrystal structures of RORγt complexed with the representative "short" inverse agonist 6 (PDB: 6LOB), the agonist 7d (PDB: 6LOA) and the "long" inverse agonist 7h (PDB: 6LO9) were revealed by X-ray analysis. However, minor differences were found in the binding modes of "short" inverse agonist 6 and "long" inverse agonist 7h. To further reveal the molecular mechanisms of different RORγt inverse agonists, we performed molecular dynamics simulations and found that "short" or "long" inverse agonists led to different behaviors of helixes H11, H11', and H12 of RORγt. The "short" inverse agonist 6 destabilizes H11' and dislocates H12, while the "long" inverse agonist 7h separates H11 and unwinds H12. The results indicate that the two types of inverse agonists may behave differently in downstream signaling, which may help identify novel inverse agonists with different regulatory mechanisms.
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Carbazoles/farmacología , Cristalografía , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Receptores de Ácido Retinoico/agonistas , Carbazoles/síntesis química , Simulación de Dinámica Molecular , Estructura Molecular , Relación Estructura-Actividad , Receptor de Ácido Retinoico gammaRESUMEN
BACKGROUND: Diabetes mellitus has become an increasing global health burden with rapid growing prevalence. Patients with diabetes have higher susceptibility to acute kidney injury (AKI). Liver transplantation (LT) predisposes the kidney to injury. However, the association between diabetes and AKI in LT patients remains unclear. METHODS: We conducted a retrospective cohort study examining risk factors for AKI in patients undergone orthotopic LT. Potential risk factors including baseline estimated glomerular filtration rate (eGFR), the model for end-stage liver disease (MELD) score, diabetes, hypertension and intraoperative blood loss were screened. The primary endpoint was AKI occurrence. Multivariate logistic regression was used to analyze the association between potential risk factors and AKI. RESULTS: A total of 291 patients undergone orthotopic LT were included in the present study. Among them, 102 patients (35.05%) developed AKI within 5 days after LT. Diabetes was identified as an independent risk factor for AKI. Patients who developed AKI had worse graft function recovery and higher mortality within 14 days after LT compared to those who did not develop AKI. AKI patients with diabetes had a significant decline of eGFR within the first postoperative year, compared with patients who did not develop AKI and who developed AKI but without diabetes. CONCLUSIONS: Diabetes is an independent risk factor for AKI after orthotopic LT. AKI is associated with delayed graft function recovery and higher mortality in short-term postoperative period. Diabetic patients who developed AKI after LT experience a faster decline of eGFR within the first year after surgery.
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Lesión Renal Aguda , Diabetes Mellitus , Enfermedad Hepática en Estado Terminal , Trasplante de Hígado , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Enfermedad Hepática en Estado Terminal/diagnóstico , Enfermedad Hepática en Estado Terminal/epidemiología , Enfermedad Hepática en Estado Terminal/cirugía , Receptores ErbB , Tasa de Filtración Glomerular , Humanos , Trasplante de Hígado/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Aromaticity, one of the most fundamental concepts in chemistry, has attracted considerable attention from both theoreticians and experimentalists. Much effort on aromaticity in organometallics has been devoted to metallabenzene and derivatives. In comparison, aromaticity in other organometallics is less developed. This Account describes how our group has performed quantum chemical calculations to examine aromaticity in recently synthesized novel organometallic complexes. By collaborations with experimentalists, we have extended several aromaticity concepts into organometallics to highlight the power of transition metals. In general, the transition metal could participate in delocalization either out of rings or in the rings. We examined the former by probing the possibility of transition metal substituents in hyperconjugative aromaticity, where the metal is out of the rings. Calculations on tetraaurated heteroaryl complexes reveal that incorporation of the aurated substituents at the nitrogen atom can convert nonaromaticity in the parent indolium into aromaticity in the aurated one due to hyperconjugation, thus extending the concept of hyperconjugative aromaticity to heterocycles with transition metal substituents. More importantly, further analysis indicates that the aurated substituents can perform better than traditional main-group substituents. Recently, we also probed the strongest aromatic cyclopentadiene and pyrrolium rings by hyperconjugation of transition metal substituents. Moreover, theoretical calculations suggest that one electropositive substituent is able to induce aromaticity; whereas one electronegative substituent prompts nonaromaticity rather than antiaromaticity. We also probed the possibility of Craig-type Möbius aromaticity in organometallic chemistry, where the position of the transition metals is in the rings. According to the electron count and topology, aromaticity can be classified as Hückel-type and Möbius-type. In comparison with numerous Hückel aromatics containing 4 n+2 π-electrons, Möbius aromatics with 4 n π-electrons, especially the Craig-type species, are particularly limited. We first examined aromaticity in osmapentalynes. Theoretical calculations reveal that incorporation of the osmium center not only reduces the ring strain of the parent pentalyne, but also converts Hückel antiaromaticity in the parent pentalyne into Craig-type Möbius aromaticity in metallapentalynes. Further studies show that the transition metal fragments can also make both 16e and 18e osmapentalenes aromatic, indicating that the Craig-type Möbius aromaticity in osmapentalyne is rooted in osmapentalenes. In addition, Möbius aromaticity is also possible in dimetalla[10]annulenes, where the lithium atoms are not spectator cations but play an important role due to their bonding interaction with the diene moieties. We then examined the possibility of σ-aromaticity in an unsaturated ring. Traditional π-aromaticity is used to describe the π-conjugation in fully unsaturated rings; whereas σ-aromaticity may stabilize fully saturated rings with delocalization caused by σ-electron conjugation. We found that the unsaturated three-membered ring in cyclopropaosmapentalene is σ-aromatic. Very recently, we extended σ-aromaticity into in a fully unsaturated ring. The concepts and examples presented here show the importance of interplay and union between experiment and theory in developing novel aromatic systems and, especially, the indispensable role of computational study in rationalization of unconventional aromaticity. All these findings highlight the strong power of transition metals originating from participation of d orbitals in aromaticity, opening an avenue to the design of unique metalla-aromatics.
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Existing research has elucidated the critical role of long noncoding RNAs (lncRNAs) in the progression of multiple human cardiovascular diseases, including atherosclerosis (AS). Nonetheless, whether long noncoding RNA LOXL1 antisense RNA 1 (LOXL1-AS1) regulates the biological functions in AS is exceedingly limited. In this research, we detected through reverse transcription-quantitative polymerase chain reaction that LOXL1-AS1 expression was markedly upregulated in patients with AS. The role of LOXL1-AS1 in vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) was unmasked by functional assays. Moreover, knockdown of LOXL1-AS1 exerted suppressive effect on proliferation and migration whereas accelerated apoptosis in VSMCs and HUVECs. Molecular mechanism assays revealed that signal transducer and activator of transcription 3 (STAT3) functioned as a transcription activator of LOXL1-AS1 in VSMCs and HUVECs. In addition, miR-515-5p was manifested to bind with LOXL1-AS1 (or STAT3) in VSMCs and HUVECs. Furthermore, LOXL1-AS1 could elevate STAT3 expression by sponging miR-515-5p in VSMCs and HUVECs. More importantly, rescue assays delineated that inhibited expression of miR-515-5p or elevated expression of STAT3 could reverse the restraining effect of LOXL1-AS1 depletion on the progression of AS in HUVECs. All these findings revealed the role of a LOXL1-AS1/miR-515-5p/STAT3 positive feedback loop in AS.
Asunto(s)
Aterosclerosis/metabolismo , Movimiento Celular , Proliferación Celular , Células Endoteliales de la Vena Umbilical Humana/metabolismo , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , ARN Largo no Codificante/metabolismo , Factor de Transcripción STAT3/metabolismo , Aterosclerosis/genética , Aterosclerosis/patología , Estudios de Casos y Controles , Células Cultivadas , Retroalimentación Fisiológica , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , MicroARNs/genética , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/patología , Placa Aterosclerótica , ARN Largo no Codificante/genética , Factor de Transcripción STAT3/genética , Transducción de SeñalRESUMEN
Coordination polymer {[Co3L2(H2O)6]·2H2O}n goes through aqueous-phase single-crystal-to-single-crystal (SC-SC) central metal exchange to produce {[Cu3L2(H2O)6]·2H2O}n. The daughter product presents a higher proton conductivity of 0.004 S cm-1 at 95 °C and 100% RH, increasing by 50-fold relative to the parent product. The water vapor adsorption reveals that the uptake capacity of 2 reaches 145.08 mg/g, which is 7.5 times that of 1 (19.36 mg/g). High water affinity is confirmed by the smaller water contact angle of 2. Replacing water vapor with vapors of dilute hydrochloric acid and ammonia, the improvement of proton conductivity is also realized. Exchanged products all give enhanced conductivities in different vapor atmospheres, which shows that the aqueous-phase central metal exchange is a judicious choice for the preparation of excellent proton conducting coordination polymers.