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1.
Macromol Rapid Commun ; : e2100116, 2021 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-33938056

RESUMEN

Polymer-based film capacitors with high breakdown strength and excellent flexibility are crucial in the field of advanced electronic devices and electric power systems. Although massive works are carried to enhance the energy storage performances, it is still a great challenge to improve the energy density of polymer composites under the premise of large-scale industrial production. Herein, a general strategy is proposed to improve the intrinsic breakdown strength and energy storage performances by blending core-shell structured methyl methacrylate-butadiene-styrene (MBS) rubber particles into a polymer matrix. Good compatibility and uniform dispersion state of MBS particles are observed in the matrix. Polarizing microscopy images show that blended films exhibit clear reduction of crystalline grains with the addition of MBS particles. Accordingly, an increased breakdown strength of 515 MV m-1 and discharged energy density of 12.33 J cm-3 are observed in poly(vinylidene fluoride-co-hexafluoropropylene)-based composite films. Through comprehensive characterizations, it is believed that the superior energy storage performance of composite films is attributed to decreased crystalline grains, improved mechanical properties, and restriction on carrier motion. These results provide a novel design of dielectric polymers for high breakdown strength and discharged energy density applications.

2.
J Appl Clin Med Phys ; 2021 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-33934511

RESUMEN

PURPOSE: Our study aimed to improve the dosimetry of post modified radical mastectomy intensity-modulated radiotherapy (PMRM-IMRT) for left-sided breast cancer patients by tailoring and minimizing PTV expansion three-dimensionally utilizing 4D CT combined with on-board cone beam CT (CBCT). METHODS: We enrolled a total of 10 consecutive left-sided breast cancer patients to undergo PMRM-IMRT. We measured the intra-fractional CTV displacement attributed to respiratory movement by defining 9 points on the left chest wall and quantifying their displacement by using the 4D CT, and measured the inter-fractional CTV displacement resulting from the integrated effect of respiratory movement, thoracic deformation and set up errors by using CBCT. We created 3 different PMRM-IMRT plans for each of the patients using PTVt (tailored PTV expansion three-dimensionally), PTV0.5 and PTV0.7 (isotropic 0.5- cm and isotropic 0.7- cm expanding margin of CTV), respectively. We performed paired samples t test to establish a hierarchy in terms of plan quality and dosimetric benefits. P < 0.05 was considered statistically significant. RESULTS: The inter-fractional CTV displacement (2.6 ± 2.2 mm vertically, 2.8 ± 2.3 mm longitudinally, and 1.7 ± 1.2 mm laterally) measured by CBCT was much larger than the intra-fractional one (0.5 ± 0.5 mm vertically, 0.5 ± 1.0 mm longitudinally, and 0.3 ± 0.3 mm laterally, respectively) measured by 4D CT. Intensity-modulated radiotherapy with tailored PTV expansion based on inter-fractional CTV displacement had dosimetrical advantages over those with PTV0.5 or those with PTV0.7 owing to its perfect PTV dose coverage and better OARs sparing(especially of heart and left lung). CONCLUSION: The CTV displacement in PMRM-IMRT predominantly arises from inter-fraction rather than from intra-fraction during natural respiration and differs in 3 coordinate axes either inter-fractionally or intra-fractionally. Tailoring and minimizing PTV expansion three-dimensionally significantly improves the dosimetry of PMRM-IMRT for left-sided breast cancer patients.

3.
Environ Technol ; : 1-14, 2021 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-33945450

RESUMEN

In this paper, the effect of different crystal forms of Al2O3 on fluoride removal was studied. All crystal forms of Al2O3 were based on the same boehmite precursor and were obtained using a hydrothermal and calcination method. γ-Al2O3 had higher fluoride removal performance (52.15 mg/g) compared with θ-Al2O3 and α-Al2O3. Density functional theory (DFT) calculations confirmed that fluoride removal was greatest for γ-Al2O3, followed by θ-Al2O3 and α-Al2O3, and γ-Al2O3 possessed the strongest fluoride binding energy (-3.93 eV). The typical adsorption behaviour was consistent with the Langmuir model and pseudo-second-order model, indicating chemical and monolayer adsorption. Different metal ions were used to modify γ-Al2O3, and lanthanum had the best effect. Lanthanum oxide was shown to play an important role in fluoride removal. The best La/Al doping ratio was 20 At%. The adsorption process of the composite was also consistent with chemical and monolayer adsorption. When the La/Al doping rate was 20%, the adsorption capacity reached 94.64 mg/g. Compared with γ-Al2O3 (1.39 × 10-7 m/s), the adsorption rate of 20La-Al2O3 was 3.93 × 10-7 m/s according to the mass transfer model. Furthermore, DFT was used to provide insight into the adsorption mechanism, which was mainly driven by electrostatic attraction and ion exchange.

4.
Plant Cell ; 2021 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-33871640

RESUMEN

Myosin motors are essential players in secretory vesicle trafficking and exocytosis in yeast and mammalian cells; however, similar roles in plants remain a matter for debate, at least for diffusely-growing cells. Here, we demonstrate that Arabidopsis (Arabidopsis thaliana) myosin XIK, via its globular tail domain (GTD), participates in the vesicle tethering step of exocytosis through direct interactions with the exocyst complex. Specifically, myosin XIK GTD bound directly to several exocyst subunits in vitro and functional fluorescently-tagged XIK colocalized with multiple exocyst subunits at plasma membrane (PM)-associated stationary foci. Moreover, genetic and pharmacological inhibition of myosin XI activity reduced the rate of appearance and lifetime of stationary exocyst complexes at the PM. By tracking single exocytosis events of cellulose synthase (CESA) complexes (CSCs) with high spatiotemporal resolution imaging and pair-wise colocalization of myosin XIK, exocyst subunits and CESA6, we demonstrated that XIK associates with secretory vesicles earlier than exocyst and is required for the efficient localization and normal dynamic behavior of exocyst complex at the PM tethering site. This study reveals an important functional role for myosin XI in secretion and provides insights about the dynamic regulation of exocytosis in plants.

5.
Plant J ; 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33793980

RESUMEN

Endosidin20 (ES20) is a recently identified cellulose biosynthesis inhibitor (CBI) that targets the catalytic site of plant cellulose synthase (CESA). Here, we screened over 600 ES20 analogs and identified nine active analogs named ES20-1 to ES20-9. Among these, endosidin20-1 (ES20-1) had stronger inhibitory effects on plant growth and cellulose biosynthesis than ES20. At the biochemical level, we demonstrated that ES20-1, like ES20, directly interacts with CESA6. At the cellular level, this molecule, like ES20, induced the accumulation of cellulose synthase complexes at the Golgi apparatus and inhibited their secretion to the plasma membrane. Like ES20, ES20-1 likely targets the catalytic site of CESA. However, through molecular docking analysis using a modeled structure of full-length CESA6, we found that both ES20 and ES20-1 might have another target site at the transmembrane regions of CESA6. Besides ES20, other CBIs such as isoxaben, C17, and flupoxam are widely used tools to dissect the mechanism of cellulose biosynthesis and are also valuable resources for the development of herbicides. Here, based on mutant genetic analysis and molecular docking analysis, we have identified the potential target sites of these CBIs on a modeled CESA structure. Some bacteria also produce cellulose, and both ES20 and ES20-1 inhibited bacterial cellulose biosynthesis. Therefore, we conclude that ES20-1 is a more potent analog of ES20 that inhibits intrinsic cellulose biosynthesis in plants, and both ES20 and ES20-1 show an inhibitory effect on bacterial growth and cellulose synthesis, making them excellent tools for exploring the mechanisms of cellulose biosynthesis across kingdoms.

6.
J Investig Med ; 2021 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-33875612

RESUMEN

Immune activation complicates HIV despite antiretroviral therapy (ART). Indoleamine 2,3 dioxygenase (IDO) catabolizes tryptophan (T) to kynurenine (K), regulating immune activity, and IDO activity increases with age. This study examines the relationship of IDO activity, bacterial translocation, and aging in people living with HIV (PLWH) on ART. Samples and data from PLWH on ART from the Centers for AIDS Research Network of Integrated Clinical Systems and from matched HIV-uninfected patients (controls) from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study were analyzed. The ratio of K to T (K:T) and neopterin were indicators of inflammation; 16S ribosomal DNA (16S rDNA) and lipopolysaccharide (LPS) were markers of bacterial translocation. Samples and data from 205 PLWH and 99 controls were analyzed. PLWH had higher K:T values across all ages, with a significant relationship between age and K:T for both groups. CD4 count or CD4 nadir had no association with K:T. There was no positive association between level of 16S rDNA or LPS detection and K:T. K:T and neopterin were associated. PLWH had elevated IDO activity, at younger ages, despite ART. This study suggests K:T ratio increases with age in both groups and is elevated in PLWH at all ages compared with age-matched controls.

7.
Environ Health Perspect ; 129(4): 47007, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33826413

RESUMEN

BACKGROUND: Common genetic variation in the arsenic methyltransferase (AS3MT) gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in AS3MT could have even larger effects on AME, but their contribution to AME has not been investigated. OBJECTIVES: We estimated the impact of rare, protein-coding variation in AS3MT on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants. METHODS: We generated targeted DNA sequencing data for the coding regions of AS3MT for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, n=2,434), Strong Heart Study (SHS, n=868), and New Hampshire Skin Cancer Study (NHSCS, n=666). We assessed the collective effects of rare (allele frequency <1%), protein-altering AS3MT variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure). RESULTS: We identified 23 carriers of rare-protein-altering AS3MT variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6-10% lower in carriers compared with noncarriers in HEALS [ß=-9.4 (95% CI: -13.9, -4.8)], SHS [ß=-6.9 (95% CI: -13.6, -0.2)], and NHSCS [ß=-8.7 (95% CI: -15.6, -2.2)]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ß=-8.7 (95% CI: -11.9, -5.4)]. DISCUSSION: Rare, protein-altering variants in AS3MT were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5-0.7%) carry these variants, they are associated with a 6-10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152.

8.
Cancer Res ; 2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33863778

RESUMEN

Extracellular adenosine in tumors can suppress immune responses and promote tumor growth. Adenosine deaminase 2 (ADA2) converts adenosine into inosine. The role of ADA2 in cancer and whether it can target adenosine for cancer therapy has not been investigated. Here we show that increased ADA2 expression is associated with increased patient survival and enrichment of adaptive immune response pathways in several solid tumor types. Several ADA2 variants were created to improve catalytic efficiency, and PEGylation was used to prolong systemic exposure. In mice, PEGylated ADA2 (PEGADA2) inhibited tumor growth by targeting adenosine in an enzyme activity-dependent manner and thereby modulating immune responses. These findings introduce endogenous ADA2 expression as a prognostic factor and PEGADA2 as a novel immunotherapy for cancer.

9.
Mol Neurobiol ; 2021 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-33914267

RESUMEN

Alzheimer's disease is a progressive neurodegenerative disorder characterized by extracellular amyloid beta peptides and neurofibrillary tangles consisted of intracellular hyperphosphorylated Tau in the hippocampus and cerebral cortex. Most of the mutations in key genes that code for amyloid precursor protein can lead to significant accumulation of these peptides in the brain and cause Alzheimer's disease. Moreover, some point mutations in amyloid precursor protein can cause familial Alzheimer's disease, such as Swedish mutation (KM670/671NL) and A673V mutation. However, recent studies have found that the A673T mutation in amyloid precursor protein gene can protect against Alzheimer's disease, even if it is located next to the Swedish mutation (KM670/671NL) and at the same site as A673V mutation, which are pathogenic. It makes us curious about the protective A673T mutation. Here, we summarize the most recent insights of A673T mutation, focus on their roles in protective mechanisms against Alzheimer's disease, and discuss their involvement in future treatment.

10.
Cardiovasc Diabetol ; 20(1): 58, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33648518

RESUMEN

BACKGROUND: Adults who have experienced multiple cardiovascular disease (CVD) events have a very high risk for additional events. Diabetes and chronic kidney disease (CKD) are each associated with an increased risk for recurrent CVD events following a myocardial infarction (MI). METHODS: We compared the risk for recurrent CVD events among US adults with health insurance who were hospitalized for an MI between 2014 and 2017 and had (1) CVD prior to their MI but were free from diabetes or CKD (prior CVD), and those without CVD prior to their MI who had (2) diabetes only, (3) CKD only and (4) both diabetes and CKD. We followed patients from hospital discharge through December 31, 2018 for recurrent CVD events including coronary, stroke, and peripheral artery events. RESULTS: Among 162,730 patients, 55.2% had prior CVD, and 28.3%, 8.3%, and 8.2% had diabetes only, CKD only, and both diabetes and CKD, respectively. The rate for recurrent CVD events per 1000 person-years was 135 among patients with prior CVD and 110, 124 and 171 among those with diabetes only, CKD only and both diabetes and CKD, respectively. Compared to patients with prior CVD, the multivariable-adjusted hazard ratio for recurrent CVD events was 0.92 (95%CI 0.90-0.95), 0.89 (95%CI: 0.85-0.93), and 1.18 (95%CI: 1.14-1.22) among those with diabetes only, CKD only, and both diabetes and CKD, respectively. CONCLUSION: Following MI, adults with both diabetes and CKD had a higher risk for recurrent CVD events compared to those with prior CVD without diabetes or CKD.

11.
Med Sci Monit ; 27: e932375, 2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33762569

RESUMEN

An editorial decision has been made to retract this manuscript due to breach of publishing guidelines, following the identification of non-original and manipulated figures. Reference: Jun Liu, Yan Liu, Yan Liu, Lei Huang, Guoliang Wang, Jun Wang, Xiangang Xu, Chengxian Shi, Jianzhao Huang: Anticancer Action of Psilostachyin-A in 5-Fluorouracil-Resistant Human Liver Carcinoma are Mediated Through Autophagy Induction, G2/M Phase Cell Cycle Arrest and Inhibiting Extracellular-Signal-Regulated Kinase/Mitogen Activated Protein Kinase (ERK/MAPK) Signaling Pathway. Med Sci Monit 2019; 25:6711-6718. 10.12659/MSM.916635.

12.
Med Sci Monit ; 27: e929774, 2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33724979

RESUMEN

BACKGROUND MicroRNAs (miRNAs) are novel biomarkers that are important in tumorigenesis and cancer treatment resistance. miR-451 is expressed in human papillary thyroid carcinoma (PTC) tissues and is associated with tumor progression. This study investigated the molecular mechanism associated with the effects of miR-451 on B-CPAP human PTC cells in vitro. MATERIAL AND METHODS Binding of miRNAs to the 3' untranslated region (3'UTR) of messenger RNA (mRNA) was determined with a luciferase reporter assay. miRNAs and plasmids were transfected into human PTC B-CPAP cells with Lipofectamine 2000 Transfection Reagent. Cell viability was tested with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. The levels of miRNAs and mRNA were determined with quantitative polymerase chain reaction and protein levels were analyzed with immunoblotting. RESULTS miR-451 bound to wild-type but not mutant 3'-UTR of activating transcription factor 2 (ATF2). MiR-451 mimics inhibited the growth of B-CPAP cells and reduced mRNA and protein levels in ATF2, whereas miR-451 inhibitors promoted the growth of B-CPAP cells and increased mRNA and protein levels in ATF2. CONCLUSIONS miR-451 directly bound to the 3'UTR of ATF2, decreased mRNA and protein levels in ATF2, and inhibited growth of B-CPAP cells. Our findings suggest that miR-451 may be a potential therapeutic target for PTC.

13.
Aging (Albany NY) ; 13(4): 4962-4975, 2021 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-33668040

RESUMEN

Long noncoding RNAs (lncRNAs) have been identified to be dysregulated in multiple cancer types, which are speculated to be of vital significance in regulating several hallmarks of cancer biology. Triple-negative breast cancer (TNBC) is acknowledged as an aggressive subtype of breast cancer. In this study, we found the lncRNA LINC00472 was poorly expressed in TNBC tissues and cells. Overexpression of LINC00472 could inhibit the proliferation, invasion and migration of MDA-MB-231 cells. On the contrary, minichromosome maintenance complex component 6 (MCM6) was highly expressed in TNBC tissues and MDA-MB-231 cells due to suppressed methylation. LINC00472 induced site-specific DNA methylation and reduced the MCM6 expression by recruiting DNA methyltransferases into the MCM6 promoter. Since the restoration of MCM6 weakened the tumor-suppressive effect of LINC00472 on MDA-MB-231 cells, LINC00472 potentially acted as a tumor suppressor by inhibiting MCM6. In addition, in vivo experiments further substantiated that overexpression of LINC00472 inhibited tumor growth and metastasis to lungs by decreasing the expression of MCM6. Overall, the present study demonstrated that LINC00472-mediated epigenetic silencing of MCM6 contributes to the prevention of tumorigenesis and metastasis in TNBC, providing an exquisite therapeutic target for TNBC.

14.
Talanta ; 227: 122207, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33714475

RESUMEN

Since December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused millions of deaths and seriously threatened the safety of human life; indeed, this situation is worsening and many people are infected with the new coronavirus every day. Therefore, it is very important to understand patients' degree of infection and infection history through antibody testing. Such information is useful also for the government and hospitals to formulate reasonable prevention policies and treatment plans. In this paper, we develop a lateral flow immunoassay (LFIA) method based on superparamagnetic nanoparticles (SMNPs) and a giant magnetoresistance (GMR) sensing system for the simultaneously quantitative detection of anti-SARS-CoV-2 immunoglobulin M (IgM) and G (IgG). A simple and time-effective co-precipitation method was utilized to prepare the SMNPs, which have good dispersibility and magnetic property, with an average diameter of 68 nm. The Internet of Medical Things-supported GMR could transmit medical data to a smartphone through the Bluetooth protocol, making patient information available for medical staff. The proposed GMR system, based on SMNP-supported LFIA, has an outstanding advantage in cost-effectiveness and time-efficiency, and is easy to operate. We believe that the suggested GMR based LFIA system will be very useful for medical staff to analyze and to preserve as a record of infection in COVID-19 patients.


Asunto(s)
Anticuerpos Antivirales/sangre , Inmunoensayo/métodos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , /inmunología , Animales , Anticuerpos Inmovilizados/química , Anticuerpos Inmovilizados/inmunología , Anticuerpos Antivirales/inmunología , Bovinos , Teléfono Celular , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Internet de las Cosas , Límite de Detección , Fenómenos Magnéticos
15.
J Clin Invest ; 131(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33720048

RESUMEN

Chronic HIV-1 infection is generally characterized by progressive CD4+ T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of CD4+ T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4+ T cells, which revealed that pyroptotic and apoptotic CD4+ T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in CD4+ T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1-infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in CD4+ T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in CD4+ T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment.

16.
Front Cell Infect Microbiol ; 11: 608352, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33680989

RESUMEN

Listeriosis, caused by Listeria monocytogenes, is a severe food-borne infection. The nationwide surveillance in China concerning listeriosis is urgently needed. In the present study, 144 L. monocytogenes isolates were collected from the samples of blood, cerebrospinal fluid (CSF), and fetal membrane/placenta in China for 12 years from 2008 to 2019. We summarized these listeriosis patients' demographical and clinical features and outcomes. The susceptibility profile for 12 antibiotics was also determined by the broth microdilution method. Multilocus sequence typing (MLST) and serogroups of these listeria isolates were analyzed to designate epidemiological types. We enrolled 144 cases from 29 healthcare centers, including 96 maternal-neonatal infections, 33 cases of bacteremia, 13 cases of neurolisteriosis, and two cutaneous listeriosis. There were 31 (59.6%) fetal loss in 52 pregnant women and four (9.8%) neonatal death in 41 newborns. Among the 48 nonmaternal-neonatal cases, 12.5% (6/48) died, 41.7% (20/48) were female, and 64.6% (31/48) occurred in those with significant comorbidities. By MLST, the strains were distinguished into 23 individual sequence types (STs). The most prevalent ST was ST87 (49 isolates, 34.0%), followed by ST1 (18, 12.5%), ST8 (10, 6.9%), ST619 (9, 6.3%), ST7 (7, 4.9%) and ST3 (7, 4.9%). Furthermore, all L. monocytogenes isolates were uniformly susceptible to penicillin, ampicillin, and meropenem. In summary, our study highlights a high genotypic diversity of L. monocytogenes strains causing clinical listeriosis in China. Furthermore, a high prevalence of ST87 and ST1 in the listeriosis should be noted.

17.
J Neuroinflammation ; 18(1): 62, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33648537

RESUMEN

BACKGROUND: Intracerebral hemorrhage (ICH), a devastating subtype of stroke, is associated with high mortality and morbidity. Neuroinflammation is an important factor leading to ICH-induced neurological injuries. C-C Chemokine Receptor 4 (CCR4) plays an important role in enhancing hematoma clearance after ICH. However, it is unclear whether CCR4 activation can ameliorate neuroinflammation and apoptosis of neurons following ICH. The aim of the present study was to examine the effects of recombinant CCL17 (rCCL17)-dependent CCR4 activation on neuroinflammation and neuronal apoptosis in an intrastriatal autologous blood injection ICH model, and to determine whether the PI3K/AKT/Foxo1 signaling pathway was involved. METHODS: Two hundred twenty-six adult (8-week-old) male CD1 mice were randomly assigned to sham and ICH surgery groups. An intrastriatal autologous blood injection ICH model was used. rCCL17, a CCR4 ligand, was delivered by intranasal administration at 1 h, 3 h, and 6 h post-ICH. CCL17 antibody was administrated by intraventricular injection at 1 h post-ICH. C021, a specific inhibitor of CCR4 and GDC0068, an AKT inhibitor were delivered intraperitoneally 1 h prior to ICH induction. Brain edema, neurobehavioral assessments, western blotting, Fluoro-Jade C staining, terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunofluorescence staining were conducted. RESULTS: Endogenous expression of CCL17 and CCR4 were increased following ICH, peaking at 5 days post-induction. CCR4 was found to co-localize with microglia, neurons, and astrocytes. rCCL17 treatment decreased brain water content, attenuated short- and long-term neurological deficits, deceased activation of microglia/macrophages and infiltration of neutrophils, and inhibited neuronal apoptosis in the perihematomal region post-ICH. Moreover, rCCL17 treatment post-ICH significantly increased the expression of CCR4, PI3K, phosphorylated AKT, and Bcl-2, while Foxo1, IL-1ß, TNF-α, and Bax expression were decreased. The neuroprotective effects of rCCL17 were reversed with the administration of C021 or GDC0068. CONCLUSIONS: rCCL17-dependent CCR4 activation ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the PI3K/AKT/Foxo1 signaling pathway after ICH. Thus, activation of CCR4 may provide a promising therapeutic approach for the early management of ICH.

18.
PLoS One ; 16(3): e0247752, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33661942

RESUMEN

BACKGROUND/AIMS: Isoalantolactone (IATL) is one of multiple isomeric sesquiterpene lactones and is isolated from inula helenium. IATL has multiple functions such as antibacterial, antihelminthic and antiproliferative activities. IATL also inhibits pancreatic cancer proliferation and induces apoptosis by increasing ROS production. However, the detailed mechanism of IATL-mediated pancreatic cancer apoptosis remains largely unknown. METHODS: In current study, pancreatic carcinoma cell lines (PANC-1, AsPC-1, BxPC-3) and a mouse xenograft model were used to determine the mechanism of IATL-mediated toxic effects. RESULTS: IATL (20µM) inhibited pancreatic adenocarcinoma cell lines proliferation in a time-dependent way; while scratch assay showed that IATL significantly inhibited PANC-1 scratch closure (P<0.05); Invasion assays indicated that IATL significantly attenuated pancreatic adenocarcinoma cell lines invasion on matrigel. Signal analysis showed that IATL inhibited pancreatic adenocarcinoma cell proliferation by blocking EGF-PI3K-Skp2-Akt signal axis. Moreover, IATL induced pancreatic adenocarcinoma cell apoptosis by increasing cytosolic Caspase3 and Box expression. This apoptosis was mediated by inhibition of canonical wnt signal pathway. Finally, xenograft studies showed that IATL also significantly inhibited pancreatic adenocarcinoma cell proliferation and induced pancreatic adenocarcinoma cell apoptosis in vivo. CONCLUSIONS: IATL inhibits pancreatic cancer proliferation and induces apoptosis on cellular and in vivo models. Signal pathway studies reveal that EGF-PI3K-Skp2-Akt signal axis and canonical wnt pathway are involved in IATL-mediated cellular proliferation inhibition and apoptosis. These studies indicate that IATL may provide a future potential therapy for pancreatic cancer.

19.
Metab Eng ; 2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33713797

RESUMEN

S-Adenosyl-L-methionine (SAM) is an important intracellular metabolite and widely used for treatment of various diseases. Although high level production of SAM had been achieved in yeast, novel metabolic engineering strategies are needed to further enhance SAM production for industrial applications. Here genome-scale engineering (GSE) was performed to identify new targets for SAM overproduction using the multi-functional genome-wide CRISPR (MAGIC) system, and the effects of these newly identified targets were further validated in industrial yeast strains. After 3 rounds of FACS screening and characterization, numerous novel targets for enhancing SAM production were identified. In addition, transcriptomic and metabolomic analyses were performed to investigate the molecular mechanisms for enhanced SAM accumulation. The best combination (upregulation of SNZ3, RFC4, and RPS18B) improved SAM productivity by 2.2-fold and 1.6-fold in laboratory and industrial yeast strains, respectively. Using GSE of laboratory yeast strains to guide industrial yeast strain engineering presents an effective approach to design microbial cell factories for industrial applications.

20.
Brain Inj ; 35(5): 547-553, 2021 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-33645359

RESUMEN

BACKGROUND: External validation is necessary before  its clinical recommendation in new setting. The aim is to externally validate Glasgow Coma Scale-pupils score (GCS-P) in neurocritical patients and to compare its performances with Glasgow Coma Scale (GCS) and its derivatives. METHODS: GCS-P at admission was calculated for individual based on the model developed by Brennan et al. Area under the receiver operating characteristic curves (AUCs), Nagelkerke's R2 and Brier scores were used to assess external validity of GCS-P to predict mortality in neurocritical patients and to compare predictive performance with GCS and its derivatives. SUBJECTS: 4372 neurocritical patients from intensive care units of Beth Israel Deaconess Medical Center, United States between 2001 and 2012. RESULTS: GCS-P showed good discrimination (AUC 0.847 for in-hospital mortality and 0.774 for ninety-day mortality), modest calibration (Nagelkerke's R2 33.1% for in-hospital mortality and 23.3% for ninety-day mortality). Predictive performances of GCS and its derivatives was inferior to GCS-P. CONCLUSIONS: GCP-P discriminated well in between death in neurocritical patients. GCP-P improved predictive performance for short-term mortality over GCS and its derivatives in neurocritical patients. It would be a simple, early and reasonable daily routine option for prognosis assessment in neurocritical setting.

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