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1.
Cancers (Basel) ; 13(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807786

RESUMO

Metabolic reprogramming promotes glioblastoma cell migration and invasion. Integrin αvß3 is one of the major integrin family members in glioblastoma multiforme cell surface mediating interactions with extracellular matrix proteins that are important for glioblastoma progression. The role of αvß3 integrin in regulating metabolic reprogramming and its mechanism of action have not been determined in glioblastoma cells. Integrin αvß3 engagement with osteopontin promotes glucose uptake and aerobic glycolysis, while inhibiting mitochondrial oxidative phosphorylation. Blocking or downregulation of integrin αvß3 inhibits glucose uptake and aerobic glycolysis and promotes mitochondrial oxidative phosphorylation, resulting in decreased migration and growth in glioblastoma cells. Pharmacological inhibition of focal adhesion kinase (FAK) or downregulation of protein arginine methyltransferase 5 (PRMT5) blocks metabolic shift toward glycolysis and inhibits glioblastoma cell migration and invasion. These results support that integrin αvß3 and osteopontin engagement plays an important role in promoting the metabolic shift toward glycolysis and inhibiting mitochondria oxidative phosphorylation in glioblastoma cells. The metabolic shift in cell energy metabolism is coupled to changes in migration, invasion, and growth, which are mediated by downstream FAK and PRMT5 in glioblastoma cells.

2.
Pharm Res ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33796952

RESUMO

PURPOSE: To address the issue of local drug delivery in tumor treatment, a novel nanoparticle-hydrogel superstructure, namely semi-interpenetrating polymer networks (semi-IPNs) hydrogel composed of poly (ethylene glycol) diacrylate (PEGDA) and hyaluronic acid (HA) and incorporated with paclitaxel (PTX) loaded PLGA nanoparticles (PEGDA-HA/PLGA-PTX), was prepared by in situ UV photopolymerization for the use of local drug delivery. METHODS: Using the gelation time, swelling rate and degradation rate as indicators, the optimal proportion of Irgacure 2959 initiator and the concentration of HA was screened and obtained for preparing hydrogels. Next, paclitaxel (PTX) loaded PLGA nanoparticles (PLGA-PTX NPs) were prepared by the emulsion solvent evaporation method. RESULTS: The mass ratio of the initiator was 1%, and the best concentration of HA was 5 mg/mL in PEGDA-HA hydrogel. In vitro experiments showed that PLGA-PTX NPs had similar cytotoxicity to free PTX, and the cell uptake ratio on NCI-H460 cells was up to 96% by laser confocal microscopy and flow cytometry. The drug release of the PEGDA-HA/PLGA-PTX hydrogel local drug delivery system could last for 13 days. In vivo experiments proved that PEGDAHA/PLGA-PTX hydrogel could effectively inhibit the tumor growth without causing toxic effects in mice. CONCLUSIONS: This study demonstrated that the PEGDA-HA/PLGA-PTX hydrogel is a promising local drug delivery system in future clinical applications for tumor therapy. A photopolymerized semi-interpenetrating polymer networks-based hydrogel incorporated with paclitaxel-loaded nanoparticles was fabricated by in situ UV photopolymerization, providing a promised nanoplatform for local chemotherapy of tumors.

3.
Water Res ; 197: 117094, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33836297

RESUMO

To reveal the role of ferrate self-decomposition and the fates of intermediate iron species [Fe(V)/Fe(IV) species] during ferrate oxidation, the reaction between ferrate and methyl phenyl sulfoxide (PMSO) at pH 7.0 was investigated as a model system in this study. Interestingly, the apparent second-order rate constants (kapp) between ferrate and PMSO was found to increase with ferrate dosage in the condition of excess ferrate in borate buffer. This ferrate dosage effect was diminished greatly in the condition of excess PMSO where ferrate self-decomposition was lessened largely, or counterbalanced by adding a strong complexing ligand (e.g. pyrophosphate) to sequester Fe(V) oxidation, demonstrating that the Fe(V) species derived from ferrate self-decomposition plays an important role in PMSO oxidation. A mechanistic kinetics model involving the ferrate self-decomposition and PMSO oxidation by Fe(VI), Fe(V) and Fe(IV) species was then developed and validated. The modeling results show that up to 99% of the PMSO oxidation was contributed by the ferrate self-decomposition resultant Fe(V) species in borate buffer, revealing that ferrate self-decomposition is also a self-activation process. The direct Fe(VI) oxidation of PMSO was impervious to presence of phosphate or Fe(III), while the Fe(V) oxidation pathway was strongly inhibited by phosphate complexation or enhanced with Fe(III). Similar ferrate dosage effect and its counterbalance by pyrophosphate as well as the Fe(III) enhancement were also observed in ferrate oxidation of micropollutants like carbamazepine, diclofenac and sulfamethoxazole, implying the general role of Fe(V) and promising Fe(III) enhancement during ferrate oxidation of micropollutants.

4.
Ultramicroscopy ; 225: 113284, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33872959

RESUMO

We present experimental observations of high order phase contrast in aberration corrected low energy electron microscopy (AC-LEEM). Phase contrast produced by atomic steps on a Ag (111) surface exhibits prominent high order interference fringes, which have not been reported before. These phase contrast features depend upon defocus and incident electron energy, similar to the prominent first order fringes observed previously and in agreement with Fourier optics (FO) model predictions. The comparison of experimental results and FO model simulations demonstrates that fringe amplitudes are strongly affected at large defocus by the source divergence. This effect is exploited to quantitatively determine the divergence, 0.055 ± 0.005 mrad, of the field emission source in AC-LEEM under the imaging conditions used. Although the divergence determines the spatial coherence of the illumination in microscopy, it has not been possible to characterize this key instrumental parameter in LEEM before.

5.
Am J Otolaryngol ; 42(5): 103040, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33873046

RESUMO

BACKGROUND: Tracheobronchial stent placement for malignant airway strictures has been proved to improve respiratory function, but experience for benign tracheobronchial stenoses is limited. The purpose of our study is to investigate the efficacy of covered expandable metallic stents, inserted through a suspension laryngoscope, treating tracheal stenosis following intubation or tracheostomy. METHODS: From 2010 to 2018, 67 adult patients with the benign tracheal stenosis, underwent stent placement, using a suspension laryngoscope. According to the date of stent placement and stent caliber, these patients have been subdivided into two groups: Group 1 (from 2010 to 2013, stent caliber ranging from 16 to 20 mm) and Group 2 (from 2014 to 2018, stent caliber ranging from 18 to 22 mm). Complications, related reinterventions, and long-term prognosis were retrospectively evaluated. RESULTS: Primary successful stent placement was achieved and symptoms were improved in all patients. Complications occurred in 27 (40.3%) cases. Among these, there were 14 (20.9%) cases with stent migration, 10 (14.93%) with granulation tissue formation and 3 (4.48%) with pneumonia. Stent migration in Group 1 was nearly 30% higher than that in Group 2 (P = 0.002). Five of the 8 patients who had placement of 16 mm stents had stent migration, more often than with 20 mm stents (P = 0.002). Ten patients' trachea had slight narrowing but without any symptoms. Six patients still had granulation tissue but without any growth at least two-year follow-up (2 patients whose stents were removed more than 1 year after placement). Even without tracheal narrowing and granulation tissue, 5 patients felt persistent shortness of breath. 92.5% of the patients reported to be satisfied with significant improvement in symptoms. CONCLUSIONS: Patients with tracheal obstruction secondary to intubation or tracheostomy can benefit from tracheal stents. Placing 16 mm stents might lead to stent migration more easily than 20 mm stents. Tracheal stents placed by a suspension laryngoscope provide a reasonable alternative to open surgery for patients with benign tracheal stenosis or obstruction.

6.
GM Crops Food ; : 1-13, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33877001

RESUMO

The cytochrome P450 (CYP) is a large and complex eukaryotic gene superfamily with enzymatic activities involved in several physiological and regulatory processes. As an objective, an in-silico genome-wide DNA methylation (5mC) analysis was performed in rice (Oryza sativa cv. Zhonghua11), and the epigenetic role of CYPs in two abiotic stresses was observed. Being a stable representative mark, DNA-methylation alters the gene expression under stressful environmental conditions. Rice plants under salinity and drought stresses were analyzed through MeDIP-chip hybridization, and 14 unique genes of the CYP family were identified in the rice genome with varying degrees of methylation. The gene structure, promoter sequences, and phylogenetic analysis were performed. Furthermore, the responses of CYPs to various abiotic stresses, including salinity, drought, and cold were revealed. Similarly, the expression profile of potential CYPs was also investigated under various phytohormone stresses, which revealed the potential involvement of CYPs to hormone regulations. Overall, the current study provides evidence for CYP's stress regulation and fundamental for further characterization and understanding their epigenetic roles in gene expression regulation and environmental stress regulation in higher plants.

7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 322-327, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812394

RESUMO

OBJECTIVE: To construct an acute myeloid leukemia cell line stably expressing CD123-CLL1 so as to provide an "in vitro" model for studying the role of CD123 and CLL-1 in leukemia and the treatment targeting CD123 and CLL-1. METHODS: The recombinant plasmid of lentivirus was constructed by synthesizing CD123 and CLL-1 sequences and PCR homologous recombination. The lentivirus vector was packaged by three-plasmid packaging system. After collecting the supernatant of lentivirus, the virus titer was determined by quantitative PCR. K562 leukemia cells were collected and transtected with virus supernatant. Leukemia cell line stably expressing the target gene were screened by purinomycin. The expression levels of CD123 and CLL-1 were detected by RT-PCR and flow cytometry. RESULTS: The lentiviral vector was successfully constructed, and identified by agarose gel electrophoresis and gene sequencing, then the virus titer of the supernatant was up to 5.81×108 after quantitative PCR assay. The K562 leukemia cell line obtained positive expression cells after being infected by puromycin. The high expression of CD123 and CLL-1 was confirmed by RT-PCR, while the significantly high expression of CD123 and CLL-1 was confirmed by flow cytometry. CONCLUSION: Lentiviral vector expressing CD123-CLL1 has been successfully constructed, and K562 leukemia cell line stably expressing CD123 and CLL-1 has been successfully obtained.


Assuntos
Subunidade alfa de Receptor de Interleucina-3 , Leucemia Linfocítica Crônica de Células B , Linhagem Celular Tumoral , Vetores Genéticos , Humanos , Células K562 , Lentivirus/genética , Leucemia Linfocítica Crônica de Células B/genética , Plasmídeos , Transfecção
8.
Stroke ; : STROKEAHA120030226, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33840227

RESUMO

BACKGROUND AND PURPOSE: The general cardiovascular Framingham risk score (FRS) identifies adults at increased risk for stroke. We tested the hypothesis that baseline FRS is associated with the presence of postmortem cerebrovascular disease (CVD) pathologies. METHODS: We studied the brains of 1672 older decedents with baseline FRS and measured CVD pathologies including macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. We employed a series of logistic regressions to examine the association of baseline FRS with each of the 5 CVD pathologies. RESULTS: Average age at baseline was 80.5±7.0 years and average age at death was 89.2±6.7 years. A higher baseline FRS was associated with higher odds of macroinfarcts (odds ratio, 1.10 [95% CI, 1.07-1.13], P<0.001), microinfarcts (odds ratio, 1.04 [95% CI, 1.01-1.07], P=0.009), atherosclerosis (odds ratio, 1.07 [95% CI, 1.04-1.11], P<0.001), and arteriolosclerosis (odds ratio, 1.04 [95% CI, 1.01-1.07], P=0.005). C statistics for these models ranged from 0.537 to 0.595 indicating low accuracy for predicting CVD pathologies. FRS was not associated with the presence of cerebral amyloid angiopathy. CONCLUSIONS: A higher FRS score in older adults is associated with higher odds of some, but not all, CVD pathologies, with low discrimination at the individual level. Further work is needed to develop a more robust risk score to identify adults at risk for accumulating CVD pathologies.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33852283

RESUMO

Selective hydrogenation of CO2 to methanol is a "two birds, one stone" technology to mitigate the greenhouse effect and solve the energy demand-supply deficit. Cu-based catalysts can effectively catalyze this reaction but suffer from low catalytic stability caused by the sintering of Cu species. Here, we report a series of zeolite-fixed catalysts Cu/ZnOx(Y)@Na-ZSM-5 (Y is the mass ratios of Cu/Zn in the catalysts) with core-shell structures to overcome this issue and strengthen the transformation. Fascinatingly, in this work, we first employed bimetallic metal-organic framework, CuZn-HKUST-1, nanoparticles (NPs) as a sacrificial agent to introduce ultrasmall Cu/ZnOx NPs (∼2 nm) into the crystalline particles of the Na-ZSM-5 zeolite via a hydrothermal synthesis method. The catalytic results showed that the optimized zeolite-encapsulated Cu/ZnOx(1.38)@Na-ZSM-5 catalyst exhibited the space time yield of methanol (STYMeOH) of 44.88 gMeOH·gCu-1·h-1, much more efficient than the supported Cu/ZnOx/Na-ZSM-5 catalyst (13.32 gMeOH·gCu-1·h-1) and industrial Cu/ZnO/Al2O3 catalyst (8.46 gMeOH·gCu-1·h-1) under identical conditions. Multiple studies demonstrated that the confinement in the zeolite formwork affords an intimate surrounding for the active phase to create synergies and avoid the separation of Cu-ZnOx interfaces, which results in an improved performance. More importantly, in the long-term test, the Cu/ZnOx(1.38)@Na-ZSM-5 catalyst exhibited constant STYMeOH with superior durability benefitted from its fixed structure. The current findings demonstrate the importance of confinement effects in designing highly efficient and stable methanol synthesis catalysts.

10.
Cell Death Dis ; 12(4): 405, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33854041

RESUMO

p62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.

11.
J Environ Manage ; 288: 112446, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33823435

RESUMO

Biosorption of dye by microbes and the extracellular polymeric substances (EPS) were of great environmental significance, especially for the dye-degrading and EPS-producing strain. Previous studies were mainly focused on the adsorption capacities and regeneration properties of pure culture, few were on the biosorption of dyes by the dye-degraders and the contributions of EPS on adsorption. In this study, a dye-degrading and EPS-producing strain i.e., Klebsiella oxytoca was used to evaluate its removal capacity to methylene blue. The maximum adsorption capacity (qe) by the strain was calculated as 145 mg g-1, which is superior to many reported bio-adsorbents and some synthetic materials. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy results suggested that CO, -NH2 and P-OH groups were involved in the adsorption. High pressure steam sterilization (HPSS) increased the hydrophilicity of cell wall but did not significantly change the cell structure. Compared with the dead resting cell (DRC), the relative higher qe obtained by live resting cell (LRC) possibly due to the loss of some cell structure during the HPSS process. Adsorption experiments by EPS-free LRC, confocal laser microscope and three-dimensional excitation-emission matrix fluorescence spectroscopy results confirmed that the EPS played a role in the adsorption of MB dye. The adsorption characteristics of the dye-degrader and the contributions of EPS on adsorption were investigated in detail in this study. The results were benefit for better understanding of the interaction mechanisms between the dye molecules and cells that before the biodegradation process, which were of great significance for the practical usage of residual sludge on removal of dyes.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33676832

RESUMO

OBJECTIVES: Inadequate financial and health literacy presents a formidable public health and economic challenge in old age. This study investigated declining financial and health literacy in relation to decision making performance, scam susceptibility and psychological wellbeing. DESIGN: Longitudinal study. SETTING: A community-based cohort in Northeastern Illinois, USA. PARTICIPANTS: One thousand fourty-six older adults who were free of dementia at baseline and underwent annual clinical and literacy assessments. MEASUREMENTS: Financial and health literacy, decision making, scam susceptibility, and psychological wellbeing were assessed using validated instruments. Linear mixed effects models estimated person-specific rates of change in financial and health literacy, and multivariable regression analyses examined the associations of declining literacy with subsequent levels of decision making, scam susceptibility, and psychological wellbeing. RESULTS: The mean age was 81 years and 76% were female. Over up to 10 years of annual follow-ups, the average financial and health literacy score dropped 1 percentage point a year. Substantial variability in decline was observed between participants. Faster decline in financial and health literacy was associated with poorer decision making, higher scam susceptibility, and lower psychological wellbeing. Notably, these associations were above and beyond the baseline literacy level and persisted even after controlling for cognition. CONCLUSIONS: Most community-dwelling older adults experience decline in financial and health literacy over time, but decline is not inevitable. Declining literacy is related to poorer decision making, greater scam susceptibility and lower wellbeing. These findings suggest that efforts to mitigate declining financial and health literacy may promote independence and wellbeing in old age.

13.
GM Crops Food ; : 1-16, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33678114

RESUMO

The prohibitins (PHB) are SPFH domain-containing proteins found in the prokaryotes to eukaryotes. The plant PHBs are associated with a wide range of biological processes, including senescence, development, and responses to biotic and abiotic stresses. The PHB proteins are identified and characterized in the number of plant species, such as Arabidopsis, rice, maize, and soybean. However, no systematic identification of PHB proteins was performed in Solanum lycopersicum. In this study, we identified 16 PHB proteins in the tomato genome. The analysis of conserved motifs and gene structure validated the phylogenetic classification of tomato PHB proteins. It was observed that various members of tomato PHB proteins undergo purifying selection based on the Ka/Ks ratio and are targeted by four families of miRNAs. Moreover, SlPHB proteins displayed a very unique expression pattern in different plant parts including fruits at various development stages. It was found that SlPHBs processed various development-related and phytohormone responsive cis-regulatory elements in their promoter regions. Furthermore, the exogenous phytohormones treatments (Abscisic acid, indole-3-acetic acid, gibberellic acid, methyl jasmonate) salt and drought stresses induce the expression of SlPHB. Moreover, the subcellular localization assay revealed that SlPHB5 and SlPHB10 were located in the mitochondria. This study systematically summarized the general characterization of SlPHBs in the tomato genome and provides a foundation for the functional characterization of PHB genes in tomato and other plant species.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33682700

RESUMO

BACKGROUND: Ischemia reperfusion usually results in certain degree of damage to the myocardium, which is called myocardial ischemia/reperfusion (I/R) injury. OBJECTIVE: Previous studies have found that Sirt1 plays a critical role in I/R injury by protecting cardiac function. SRT1460 is the activator for Sirt1 that participates in the regulation of various diseases. However, whether SRT1460 has any effects on myocardial I/R injury needs further study. METHODS: The I/R rat model and H/R H9C2 model were established to simulate myocardial I/R injury. The infarct area of the rat heart was examined through TTC staining. The EF and FS of rats were detected through echocardiography. The levels of CK-MB, LDH, MDA, SOD and CK in cardiac tissues, serum or H9C2 cells were measured using commercial kits. Cell viability was assessed through MTT assay. Apoptosis was determined through flow cytometry analysis. Sirt1 expression was measured through western blot. RESULTS: Our work found that SRT1460 reduced the infarct area of the heart induced by myocardial I/R injury. In addition, SRT1460 was confirmed to ameliorate cardiac dysfunction induced by myocardial I/R injury. Further exploration discovered that SRT1460 weakened oxidative stress induced by myocardial I/R injury. Findings from in vitro assays demonstrated that SRT1460 relieved injury of H/R-treated H9C2 cells. Finally, rescue assays proved that Sirt1 knockdown reversed the protective effects of SRT1460 on the injury of H/R-treated H9C2 cells. CONCLUSION: Sirt1 activated by SRT1460 protected against myocardial I/R injury. This discovery may offer new sights on the treatment of myocardial I/R injury.

15.
Water Res ; 195: 116973, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33677242

RESUMO

Though hydroxylamine (NH2OH) is effective for accelerating pollutants degradation in Fenton and Fenton-like systems, the effect of anions simultaneously introduced by the hydroxylamine salts have always been ignored. Herein, effect of two commonly used hydroxylamine salts, hydroxylamine hydrochloride (NH2OH·HCl) and hydroxylamine sulfate [(NH2OH)2·H2SO4], for the degradation of dimethyl phthalate (DMP) in peroxymonosulfate (PMS)/Fe(II) system was comparatively investigated. Degradation efficiency of DMP with NH2OH·HCl was 1.6 times of that with same dosages of (NH2OH)2·H2SO4. SO4·-, Fe(IV) and ·OH formed in the PMS/Fe(II)/NH2OH system, but ·OH was the major species for DMP degradation. Addition of Cl- significantly improved the production of ·OH and Cl·, and the exposure dose of ·OH (CT·OH) was more than 10 times that of CTCl· as the concentration of Cl- increased to 1 mM. Calculations based on branching ratios of Cl· and ·OH indicated that the reactions of Cl- with SO4·- and Cl· with H2O were not the only production sources of ·OH in the system. Further experiments with methyl phenyl sulfoxide (PMSO) as the probe indicated that Cl- would facilitate the shift of reactive species from Fe(IV) to radicals (SO4·- or ·OH) in the system. Both hydroxylation and nitration intermediate products were detected in the oxidation of DMP. Cl- promoted the formation of hydroxylation intermediates and reduced the formation of nitration intermediates. This study revealed for the first time that Cl- could shift reactive species from Fe(IV) to radicals in PMS/Fe(II) system, raising attention to the influence of the coexisting anions (especially Cl-) for pollutants oxidation in iron-related oxidation processes.


Assuntos
Cloretos , Peróxidos , Compostos Ferrosos , Ferro , Oxirredução
16.
Brain ; 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33742668

RESUMO

The aging brain is vulnerable to a wide array of neuropathologies. Prior work estimated that the three most studied of these, Alzheimer's disease (AD), infarcts, and Lewy bodies, account for about 40% of the variation in late life cognitive decline. However, that estimate did not incorporate many other diseases that are now recognized as potent drivers of cognitive decline (e.g. limbic predominant age-related TDP-43 encephalopathy [LATE-NC], hippocampal sclerosis, other cerebrovascular conditions). We examined the degree to which person-specific cognitive decline in old age is driven by a wide array of neuropathologies. 1,164 deceased participants from two longitudinal clinical-pathologic studies, the Rush Memory and Aging Project and Religious Orders Study, completed up to 24 annual evaluations including 17 cognitive performance tests and underwent brain autopsy. Neuropathologic examinations provided 11 pathologic indices, including markers of AD, non-AD neurodegenerative diseases (i.e. LATE-NC, hippocampal sclerosis, Lewy bodies), and cerebrovascular conditions (i.e. macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis). Mixed effects models examined the linear relation of pathologic indices with global cognitive decline, and random change point models examined the relation of the pathologic indices with the onset of terminal decline and rates of preterminal and terminal decline. Cognition declined an average of about 0.10 unit per year (estimate = -0.101, SE = 0.003, p < 0.001) with considerable heterogeneity in rates of decline (variance estimate for the person-specific slope of decline was 0.0094, p < 0.001). When considered separately, 10 of the 11 pathologic indices were associated with faster decline and accounted for between 2 and 34% of the variation in decline, respectively. When considered simultaneously, the 11 pathologic indices together accounted for a total of 43% of the variation in decline; AD-related indices accounted for 30-36% of the variation, non-AD neurodegenerative indices 4-10%, and cerebrovascular indices 3-8%. Finally, the 11 pathologic indices combined accounted for less than a third of the variation in the onset of terminal decline (28%) and rates of preterminal (32%) and terminal decline (19%). Although age-related neuropathologies account for a large proportion of the variation in late life cognitive decline, considerable variation remains unexplained even after considering a wide array of neuropathologies. These findings highlight the complexity of cognitive aging and have important implications for the ongoing effort to develop effective therapeutics and identify novel treatment targets.

17.
Front Immunol ; 12: 552429, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717057

RESUMO

Isolated central nervous system involvement in multiple myeloma (CNS-MM) is rare and carries extremely poor prognosis. Chimeric antigen receptor T cell therapy (CART) targeting B-cell maturation antigen (BCMA) is demonstrated as a promising strategy in MM treatment, but the clinical safety and efficacy of BCMA-CART against isolated CNS-MM remain elusive. Here we report on a 56-year-old male with refractory isolated CNS-MM who received autologous BCMA-CART therapy and developed grade 4 neurological complications. Cerebrospinal fluid (CSF) analyses showed significant expansion of CART cells and a substantially elevated interleukin-6 (IL-6) level. Intravenous methylprednisolone was administered and the symptoms resolved gradually. Unexpectedly, the level of IL-6 in the CSF was maintained for another 3 days even after the relief of the neurological symptoms. A partial response was achieved and sustained for 5.5 months. This is the first report describing a patient with isolated CNS-MM treated using BCMA-CART therapy. The results demonstrated that BCMA-CART cells administered intravenously trafficked into the CSF, eradicated tumor cells, and induced severe but reversible neurological adverse events. This single-patient report suggests that BCMA-CART therapy can be considered as an alternative option for isolated CNS-MM. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03196414.

18.
Plant Sci ; 306: 110848, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33775373

RESUMO

Red-fleshed apple fruits are popular because of their high flavonoid content. Although MdMYB10 and its homologs have been identified as crucial regulators of the fruit coloring process, other transcription factors (TFs) contributing to the differences in flesh coloration have not been fully characterized. In this study, we investigated the regulatory effects of MdWRKY41 on anthocyanin and proanthocyanidin (PA) synthesis in red-fleshed apples. The overexpression of MdWRKY41 in red-fleshed apple calli inhibited anthocyanin and PA accumulation by downregulating the expression of a MYB TF gene (MdMYB12) and specific structural genes (MdLAR, MdUFGT, and MdANR). Furthermore, MdWRKY41 was shown to interact with MdMYB16 to form a complex that can further suppress MdANR and MdUFGT expression. Interestingly, MdWRKY41 was targeted by the photoresponse factor MdHY5 and inhibited its transcription. Overall, our findings provide insights into a novel MdHY5-MdWRKY41-MdMYB regulatory module influencing anthocyanin and PA synthesis in red-fleshed apple fruits.


Assuntos
Antocianinas/biossíntese , Antocianinas/genética , Malus/genética , Malus/metabolismo , Proantocianidinas/biossíntese , Proantocianidinas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Quimera , Produtos Agrícolas/genética , Produtos Agrícolas/metabolismo , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Pigmentação/genética
19.
J Mater Chem B ; 9(11): 2623-2630, 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33666613

RESUMO

Dietary restriction (DR), as a natural intervention, not only benefits the neuroendocrine system, but also has an antiaging action. Acetylcholinesterase (AChE) is one of the most important bioactive substances and plays a major part in choline changes in the aging process. Thus, we aim to evaluate the effect of DR on AChE in the brains of aging animals. In this study, we synthesize a NIR fluorescent probe BD-AChE for the real-time and in situ monitoring of AChE level changes in living cells and living mice, notably in brains. In situ visualization with BD-AChE verified a decrease in the AchE level in the brains of mice aging models. Evidently, the prepared probe has the excellent capability of measuring AChE variation in the brains of aging mice with DR via NIR fluorescence bioimaging, indicating that long-term DR can effectively affect AChE levels in the brain. The attenuation of AChE level in the brain of aging mice after DR could be helpful in infering the advantageous impact of DR on age-related neurodegenerative disease, as a better treatment alternative in the future.

20.
J Chromatogr A ; 1643: 462043, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33780879

RESUMO

An imaged capillary isoelectric focusing (icIEF) - UV fluorescence imaging detection method is described for the direct charge heterogeneity characterization of recombinant human erythropoietin (rhEPO) drug products (DPs). rhEPO is one of the most important protein therapeutics for biopharmaceutical industry worldwide. As a heavily glycosylated protein therapeutic, its charge heterogeneity must be carefully monitored in each step of manufacturing and storage. Current charge characterization methods suffer from challenges to characterize rhEPO DPs, due to low sensitivity of the method and potential for interference from the DP's formulation. The method described herein leverages the separation power of imaged cIEF separation combined with the increased sensitivity afforded by UV fluorescence imaging detection and requires no pre-treatment of the DP sample prior to analysis. The method was evaluated initially using a simulated DP, and subsequently a mini method validation was performed using a commercial rhEPO DP sample according to the guideline set by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The limit of quantitation (LOQ) of the method is validated to be 20.3 IU/mL (or 0.10 µg/mL), which is approximately 100 times more sensitive than CZE - UV absorption detection method. To demonstrate the applicability of the method for use, 8 different commercial rhEPO DPs with concentrations ranging from 2000 IU/mL - 10,000 IU/mL were successfully evaluated. This method allows for sensitive, rapid analysis of low concentration rhEPO drug products without sample pre-treatment to provide critical charge heterogeneity information.

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