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1.
Soft Matter ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509149

RESUMO

Temperature-dependent X-ray scattering studies have been carried out on 4-undecyloxy-4'-cyanobiphenyl (11OCB) and 4-(12,12-dimethyltridecyloxy)-4'-cyanobiphenyl (t-Bu-11OCB) in the smectic A phase, from which their layer spacings and translational order parameters were obtained. Marked differences between the layer structures of the two compounds were demonstrated, showing that the addition of the t-Bu group results in a higher translational order parameter and wider layer spacing for t-Bu-11OCB than 11OCB. Fully atomistic MD simulations of both compounds run for >1000 ns demonstrated the spontaneous formation of smectic mesophases from isotropic starting geometries, and experimental trends in order parameters and absolute layer spacings were shown to be replicated well. Further analysis showed that both the aromatic head-groups and the alkyl tail-groups exhibit interdigitation in the simulated smectic phases of both compounds, and the difference in the layer structures between 11OCB and t-Bu-11OCB could be attributed mainly to a shape segregation effect arising from the addition of the bulky t-Bu end-group to the alkyl chain.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31419019

RESUMO

OBJECTIVES: To investigate whether age and valve size at implant contribute to outcomes after Melody transcatheter pulmonary valve replacement (TPVR). BACKGROUND: Patient age and valve size at implant contribute to longevity of surgical pulmonary valves. METHODS: All patients discharged with a Melody valve in the pulmonary position, as part of three prospective Melody valve multicenter studies, comprised the study cohort. Acute and time-related outcomes were analyzed according to age: children (≤12 years), adolescents (13-18 years), young adults (19-29 years), and older adults (≥30 years). RESULTS: Successful Melody valve implantation occurred in 49 children, 107 adolescents, 96 young adults, and 57 older adults. Pediatric patients (≤18 years) were more likely to have TPVR for conduit stenosis than adults (62% vs. 44%); children had the smallest conduits. After TPVR, pediatric and adult patients had similar decreases in right ventricular (RV) size by MRI, but adults had improved percentage predicted peak VO2 (58% preimplant to 64% postimplant, p = .02) and FEV1 (69% pre to 71% post, p = .005). Younger age was associated with shorter freedom from RVOT dysfunction, reintervention, and explant. Children had the shortest freedom from endocarditis (p = .041), but all other groups had 5-year freedom from endocarditis of ≥90%. CONCLUSIONS: Younger age was associated with shorter time to RVOT dysfunction, reintervention, and explant after Melody TPVR. Patients ≥13 years of age were at low risk for endocarditis and explant to 5 years. A better understanding of time-related outcomes by age will aid in the comparison of therapeutic options for TPVR candidates. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00740870 (NCT00740870), https://clinicaltrials.gov/ct2/show/NCT01186692 (NCT01186692), and https://clinicaltrials.gov/ct2/show/NCT00688571 (NCT00688571).

3.
Plant Cell Physiol ; 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31410481

RESUMO

The first genome sequenced resurrection plant Boea hygrometrica has been shown to be able to survive rapid air-drying after experiencing a slow soil-drying acclimation phase. Weighted gene co-expression analysis was used to study B. hygrometrica transcriptomic datasets. A network containing 22 modules was constructed and seven modules were found to be significantly related to desiccation response by enrichment analysis. Protein ubiquitination was observed to be a common process linked to hub genes in all seven modules. Ubiquitination modified proteins with diversified functions were identified using immunoprecipitation coupled to mass spectrometry. The lowest level of ubiquitination was noted at the full soil drying priming stage, which triggered the accumulation of protective protein BhLEA2. RY motif (CATGCA) was identified from the promoters of ubiquitination related genes that were down-regulated in the desiccated samples. In-silico analysis showed the negative regulation of ubiquitination related genes appeared to be mediated via a B3 domain-containing transcription repressor VAL1. This study suggests that priming may involve the transcriptional regulation of several major processes, and the transcriptional regulation of genes in protein ubiquitination may play a hub role to deliver acclimation signals to posttranslational level in the acquisition of desiccation tolerance in B. hygrometrica.

4.
J Virol ; 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375582

RESUMO

Immune complex (IC) vaccines have been successfully used to increase immune responses against various pathogens, including HIV-1. Additionally, IC vaccines can induce qualitatively different antibody responses with distinct antigenic specificities compared to the same antigens used alone. Here we measured the HIV-1-specific antibody response in female New Zealand White rabbits after immunization with ICs made from BG505 SOSIP.664 trimers (BG505 trimers) and three different rabbit monoclonal antibodies (mAbs) with varying neutralization profiles. Two of the mAbs were specific for a hole in the glycan shield of the BG505 trimer while the third, which bound less avidly, was specific for determinants at the gp41/gp120 interface. We found that immunizing with one of the glycan hole-specific ICs resulted in lower levels of trimer-binding antibodies compared to vaccination with the uncomplexed trimer and that ICs made using either of the glycan hole-specific mAbs resulted in lower rates of anti-trimer antibody decay. We conclude that ICs based on mAbs that bound to the immunodominant glycan hole epitope likely diverted antibody responses, to some extent, away from this site and to other regions of the trimer. However, this outcome was not accompanied by a widening of the breadth or an increase in the potency of neutralizing antibody responses compared with uncomplexed trimers.IMPORTANCE Immunodominant epitopes may suppress immune responses to more desirable determinants, such as those that elicit potentially protective neutralizing antibody responses. To overcome this problem, we attempted to mask immunodominant glycan holes by immunizing rabbits with immune complexes (ICs) consisting of the BG505 SOSIP.664 gp140 trimer and monoclonal antibodies that target the glycan holes. We found that IC vaccination likely diverted antibody responses, to some extent, away from glycan holes and toward other regions of the trimer. IC vaccination resulted in a slower decay of HIV-1-specific antibodies than did immunization with uncomplexed trimer. We did not observe a widening of the breadth or an increase in the potency of neutralizing antibody responses compared to uncomplexed trimers. Our results suggest that selective epitope dampening of BG505 trimers by ICs is rather ineffective. However, IC vaccination may represent a novel means of increasing the duration of vaccine-induced antibody responses.

5.
Anal Chem ; 91(16): 10424-10431, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31333013

RESUMO

Diagnostics based on exosomes and other extracellular vesicles (EVs) are emerging as strategies for informing cancer progression and therapies, since the lipid content and macromolecular cargo of EVs can provide key phenotypic and genotypic information on the parent tumor cell and its microenvironment. We show that EVs derived from more invasive pancreatic tumor cells that express high levels of tumor-specific surface proteins and are composed of highly unsaturated lipids that increase membrane fluidity, exhibit significantly higher conductance versus those derived from less invasive tumor cells, based on dielectrophoresis measurements. Furthermore, through specific binding of the EVs to gold nanoparticle-conjugated antibodies, we show that these conductance differences can be modulated in proportion to the type as well as level of expressed tumor-specific antigens, thereby presenting methods for selective microfluidic enrichment and cytometry-based quantification of EVs based on invasiveness of their parent cell.

6.
Ultrasound Med Biol ; 45(10): 2736-2746, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31281009

RESUMO

Applications of ultrasound guidance for epidural injections are hindered by poor needle and epidural space visualization. This work presents an augmented reality (AR) ultrasound guidance system that addresses challenges in both needle visualization during navigation and epidural space identification for needle positioning. In this system, (i) B-mode ultrasound and the needle are visualized in a 3-D AR environment for improved navigation, and (ii) A-mode ultrasound, obtained from a custom-made single-element transducer housed at the needle tip, is used to identify the epidural space for improved needle positioning. Performance of the system was evaluated against ultrasound-only guidance in a phantom study with novice operators and an expert anesthesiologist. The procedure success rate was higher with the AR system (100%) than ultrasound-only guidance (57%). The AR system has the potential to improve procedure outcomes in terms of success rate, time, needle path-length and usability.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31301373

RESUMO

BACKGROUND: 15-Lipoxygenase 1 (15LO1) is expressed in airway epithelial cells in patients with type 2-high asthma in association with eosinophilia. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also associated with type 2 inflammation and eosinophilia. CCL26/eotaxin 3 has been reported to be regulated by 15LO1 in lower airway epithelial cells. However, its relation to 15LO1 in patients with CRSwNP or mechanisms for its activation are unclear. OBJECTIVE: We sought to evaluate 15LO1 and CCL26 expression in nasal epithelial cells (NECs) from patients with CRSwNP and healthy control subjects (HCs) and determine whether 15LO1 regulates CCL26 in NECs through extracellular signal-regulated kinase (ERK) activation. METHODS: 15LO1, CCL26, and phosphorylated ERK were evaluated in NECs from patients with CRSwNP and HCs. 15LO1/CCL26 and CCL26/cytokeratin 5 were colocalized by means of immunofluorescence. IL-13-stimulated NECs were cultured at an air-liquid interface with or without 15-lipoxygenase 1 gene (ALOX15) Dicer-substrate short interfering RNAs (DsiRNA) transfection, a specific 15LO1 enzymatic inhibitor, and 2 ERK inhibitors. Expression of 15LO1 and CCL26 mRNA and protein was analyzed by using quantitative RT-PCR, Western blotting, and ELISA. RESULTS: 15LO1 expression was increased in nasal polyp (NP) epithelial cells compared with middle turbinate epithelial cells from patients with CRSwNP and HCs. 15LO1 expression correlated with CCL26 expression and colocalized with CCL26 expression in basal cells of the middle turbinate and NPs from patients with CRSwNP. In primary NECs in vitro, IL-13 induced 15LO1 and CCL26 expression. 15LO1 knockdown and inhibition decreased IL-13-induced ERK phosphorylation and CCL26 expression. ERK inhibition (alone) similarly decreased IL-13-induced CCL26. Phosphorylated ERK expression was increased in NECs from CRSwNP subjects and positively correlated with both 15LO1 and CCL26 expression. CONCLUSIONS: 15LO1 expression is increased in NP epithelial cells and contributes to CCL26 expression through ERK activation. 15LO1 could be considered a novel therapeutic target for CRSwNP.

8.
Ann Surg ; 270(4): 675-680, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31348044

RESUMO

OBJECTIVE: To determine the impact of radiofrequency (RF) and microwave (MW) energy compared to direct cautery on metatstatic colon cancer growth. BACKGROUND: Hepatic ablation with MW and RF energy creates a temperature gradient around a target site with temperatures known to create tissue injury and cell death. In contrast, direct heat application (cautery) vaporizes tissue with a higher site temperature but reduced heat gradient on surrounding tissue. We hypothesize that different energy devices create variable zones of sublethal injury that may promote tumor recurrence. To test this hypothesis we applied MW, RF, and cautery to normal murine liver with a concomitant metastatic colon cancer challenge. METHODS: C57/Bl6 mice received hepatic thermal injury with MW, RF, or cautery to create a superficial 3-mm lesion immediately after intrasplenic injection of 50K MC38 colon cancer cells. Thermal imaging recorded tissue temperature during ablation and for 10 seconds after energy cessation. Hepatic tumor location and volume was determined at day 7. RESULTS: Cautery demonstrated the highest maximum tissue temperatures (129°C) with more rapid return to baseline compared to MW or RF energy. All mice had metastasis at the ablation site. Mean tumor volume was significantly greater in the MW (95.3 mm; P = 0.007) and RF (55.7 mm; P = 0.015) than cautery (7.13 mm). There was no difference in volume between MW and RF energy (P = 0.2). CONCLUSIONS: Hepatic thermal ablation promotes colon cancer metastasis at the injury site. MV and RF energy result in greater metastatic volume than cautery. These data suggest that the method of energy delivery promotes local metastasis.

9.
EMBO Mol Med ; 11(7): e9982, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31273933

RESUMO

Due to compromised homologous recombination (HR) repair, BRCA1- and BRCA2-mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2-deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2-deficient cells, including olaparib-resistant and cisplatin-resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2-deficient xenografts and inhibits growth of olaparib-resistant patient-derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication-associated DNA double-strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2-compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA-deficient tumours.

10.
Food Res Int ; 123: 662-673, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31285016

RESUMO

Winemaking results in a significant amount of sediments that are formed in the tanks, the vats and in the bottles before and after fermentation. Little is known about the biochemical composition of these sediments apart from the fact that they are assumed to be derived in large part from the grape matrix. Glycan microarray technology offers a relatively rapid means to track the polysaccharides from their origin in the grape material and throughout the various steps in the winemaking process. In this study Comprehensive Microarray Polymer Profiling (CoMPP) was used to investigate the glycan-rich composition of particularly white grapes during winemaking and then investigate the effects of recombinant and commercial enzyme formulations on wine sediment compositions. The gross lees or sediments produced in the absence of enzymes were found to be composed of an abundance of homogalacturonans, rhamnogalacturonans, arabinans and galactans in addition to an abundance of extensins and arabinogalactan proteins. The addition of enzymes was shown to strip off the homogalacturonan and much of the rhamnogalacturonan with its side chains revealing a sediment layer composed almost exclusively of extensins and arabinogalactan proteins. The effect of winemaking techniques was shown to have an effect on the glycan-rich wine sediment compositions and holds implications for the management of gross lees in a winery environment.

11.
Cell Host Microbe ; 25(6): 873-883.e5, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31194940

RESUMO

The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as a site of vulnerability. We delineate X-ray and cryo-electron microscopy (cryo-EM) structures of bnAb ACS202, from an HIV-infected elite neutralizer, with an FP and with a soluble Env trimer (AMC011 SOSIP.v4.2) derived from the same patient. We show that ACS202 CDRH3 forms a "ß strand" interaction with the exposed hydrophobic FP and recognizes a continuous region of gp120, including a conserved N-linked glycan at N88. A cryo-EM structure of another previously identified bnAb VRC34.01 with AMC011 SOSIP.v4.2 shows that it also penetrates through glycans to target the FP. We further demonstrate that the FP can twist and present different conformations for recognition by bnAbs, which enables approach to Env from diverse angles. The variable recognition of FP by bnAbs thus provides insights for vaccine design.

12.
Int Forum Allergy Rhinol ; 9(7): 759-765, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31162888

RESUMO

BACKGROUND: Chronic rhinosinusitis (CRS) is a significant manifestation of cystic fibrosis (CF) with wide-ranging symptom and disease severity. The goal of the study was to determine clinical variables that correlate with outcome measures of disease severity. METHODS: A prospective, longitudinal, observational study of 33 adults with symptomatic CRS treated in a CF-focused otolaryngology clinic was performed. Symptom severity, the presence of rhinosinusitis exacerbations, and endoscopic appearance were assessed, and regression analysis was used to determine clinical predictors of disease outcome. RESULTS: Thirty-three adults with CF-CRS were included in the study and followed for a mean of 15 months. Rhinosinusitis exacerbations occurred in 61% of participants during the study, and female sex increased the odds of presenting with an exacerbation visit. Sinus disease exacerbations were associated with an odds ratio of 2.07 for presenting with a pulmonary exacerbation at the next visit. CF-related diabetes was found to be associated with worse symptoms and endoscopic appearance. Infection with Staphylococcus aureus predicted worsening of symptoms, whereas infections with Pseudomonas aeruginosa improved over time. Allergic rhinitis was associated with worse endoscopic appearance, and nasal steroid use was associated with improved endoscopic appearance. CONCLUSION: Sex, CF-related diabetes, sinonasal infection status, allergic rhinitis, and nasal steroid use may all modulate severity of CF-CRS in adults. Sinusitis exacerbation may be a precursor to pulmonary exacerbation.

13.
Biol Rev Camb Philos Soc ; 94(5): 1685-1700, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31134732

RESUMO

The root cap releases cells that produce massive amounts of mucilage containing polysaccharides, proteoglycans, extracellular DNA (exDNA) and a variety of antimicrobial compounds. The released cells - known as border cells or border-like cells - and mucilage secretions form networks that are defined as root extracellular traps (RETs). RETs are important players in root immunity. In animals, phagocytes are some of the most abundant white blood cells in circulation and are very important for immunity. These cells combat pathogens through multiple defence mechanisms, including the release of exDNA-containing extracellular traps (ETs). Traps of neutrophil origin are abbreviated herein as NETs. Similar to phagocytes, plant root cap-originating cells actively contribute to frontline defence against pathogens. RETs and NETs are thus components of the plant and animal immune systems, respectively, that exhibit similar compositional and functional properties. Herein, we describe and discuss the formation, molecular composition and functional similarities of these similar but different extracellular traps.

14.
Congenit Heart Dis ; 14(4): 600-608, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31038848

RESUMO

INTRODUCTION: Liver fibrosis and cirrhosis are late complications in Fontan palliation. Liver biopsy is the gold standard. The goal of this study is to correlate transjugular liver biopsy (TJLB) in the setting of Fontan palliation with noninvasive testing and hemodynamics. METHODS: Between August 2014 and July 2017, 49 Fontan patients underwent TJLB. All the patients had hemodynamic evaluation, 28 patients had MRE (magnetic resonance elastography) and 40 patients had cardiopulmonary exercise test. Histologic liver fibrosis was quantitated using traditional histologic scoring systems and a modified Ishak congestive hepatic fibrosis score. RESULTS: Median age 17.8 years, median time since Fontan 15.2 years. Primary diagnosis and Fontan type were variables, but predominantly LV morphology (30/49), lateral tunnel Fontan (29/49), originally fenestrated (37/49), and 11/49 had a pacemaker. Histologic fibrosis correlated with MRE (R = 0.62, P ≤ .001). Histologic fibrosis and MRE correlated with Fontan pressure (R = 0.38, P = .008 & R = 0.59, P ≤ .001). Morphology of the single ventricle did not correlate with liver fibrosis. The presence of a fenestration resulted in a higher cardiac index (P = .026) but did not resulted in lower liver fibrosis (P = .64). CONCLUSION: Noninvasive tests, such as MRE, may be suitable for longitudinal follow-up in patients with single ventricle physiology. Our data suggest that there is reasonable correlation of MRE liver stiffness with biopsy scoring systems and Fontan pressures. We demonstrated the feasibility of TJLB in the setting of Fontan palliation and demonstrated its correlation with noninvasive measures particularly MRE. We recommend selective use of TJLB when MRE score is >5 KPa or when there are other clinical signs of cirrhosis.

15.
EMBO Mol Med ; 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127019

RESUMO

Due to compromised homologous recombination (HR) repair, BRCA1- and BRCA2-mutated tumours accumulate DNA damage and genomic rearrangements conducive of tumour progression. To identify drugs that target specifically BRCA2-deficient cells, we screened a chemical library containing compounds in clinical use. The top hit was chlorambucil, a bifunctional alkylating agent used for the treatment of chronic lymphocytic leukaemia (CLL). We establish that chlorambucil is specifically toxic to BRCA1/2-deficient cells, including olaparib-resistant and cisplatin-resistant ones, suggesting the potential clinical use of chlorambucil against disease which has become resistant to these drugs. Additionally, chlorambucil eradicates BRCA2-deficient xenografts and inhibits growth of olaparib-resistant patient-derived tumour xenografts (PDTXs). We demonstrate that chlorambucil inflicts replication-associated DNA double-strand breaks (DSBs), similarly to cisplatin, and we identify ATR, FANCD2 and the SNM1A nuclease as determinants of sensitivity to both drugs. Importantly, chlorambucil is substantially less toxic to normal cells and tissues in vitro and in vivo relative to cisplatin. Because chlorambucil and cisplatin are equally effective inhibitors of BRCA2-compromised tumours, our results indicate that chlorambucil has a higher therapeutic index than cisplatin in targeting BRCA-deficient tumours.

16.
Congenit Heart Dis ; 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31083775

RESUMO

BACKGROUND/OBJECTIVE: Stenting the ductus arteriosus (DAS) has become an alternative to surgical systemic to pulmonary artery shunts in neonates with ductal-dependent pulmonary blood flow (PBF). Femoral approach for a vertical ductus can be difficult secondary to the acute angle and tortuous course, thus alternative access sites have been explored. Carotid access complications have been reported in 5%-10%. The extensive use of an axillary arterial approach in the United States has not been reported. The aim of this study is to describe our experience with DAS using the axillary approach. METHODS: We reviewed all patients with DAS with an axillary approach in neonates with ductal-dependent PBF (May 2017-May 2018) in our institution. Procedural reports, angiograms, and clinical records of all consecutive patients were reviewed. Procedural technique, procedural outcomes, adverse events, and post-hospital courses are reported. RESULTS: Seven consecutive patients who received DAS utilizing axillary approach. All patients had ductal-dependent PBF through a vertical, tortuous ductus. Five had pulmonary atresia or near atresia, one had compromised PBF due to dynamic subvalvar obstruction, and one had Tetralogy of Fallot with isolated left pulmonary artery. Axillary access with 3.3 or 4 French sheath was obtained using ultrasound guidance. Bare metal coronary stents were deployed successfully in all. Intra-procedure, one developed in stent thrombus requiring re-stenting. There were no procedural mortalities or major adverse events from axillary access. There is a steep learning curve. Hemostasis was achieved with manual compression. Two patients had reintervention at 6-8 weeks. All patients underwent successful planned surgeries. CONCLUSIONS: This series suggests DAS in neonates utilizing an axillary approach is a feasible and effective alternative for establishing PBF. Axillary arterial approach may be preferred as there is no risk to neurological sequelae and very low risk of limb complications. Larger series are needed to validate this approach.

17.
Int J Comput Assist Radiol Surg ; 14(7): 1227-1235, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115756

RESUMO

PURPOSE: Transcatheter, beating heart repair techniques for mitral valve regurgitation is a very active area of development. However, it is difficult to both simulate and predict the clinical outcomes of mitral repairs, owing to the complexity of mitral valve geometry and the influence of hemodynamics. We aim to produce a workflow for manufacturing dynamic patient-specific models to simulate the mitral valve for transcatheter repair applications. METHODS: In this paper, we present technology and associated workflow, for using transesophageal echocardiography to generate dynamic physical replicas of patient valves. We validate our workflow using six patient datasets representing patients with unique or particularly challenging pathologies as selected by a cardiologist. The dynamic component of the models and their resultant potential as procedure planning tools is due to a dynamic pulse duplicator that permits the evaluation of the valve models experiencing realistic hemodynamics. RESULTS: Early results indicate the workflow has excellent anatomical accuracy and the ability to replicate regurgitation pathologies, as shown by colour Doppler ultrasound and anatomical measurements comparing patients and models. Analysis of all measurements successfully resulted in t critical two-tail > t stat and p values > 0.05, thus demonstrating no statistical difference between the patients and models, owing to high fidelity morphological replication. CONCLUSIONS: Due to the combination of a dynamic environment and patient-specific modelling, this workflow demonstrates a promising technology for simulating the complete morphology of mitral valves undergoing transcatheter repairs.

18.
Nat Commun ; 10(1): 2355, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142746

RESUMO

Stabilized HIV-1 envelope glycoproteins (Env) that resemble the native Env are utilized in vaccination strategies aimed at inducing broadly neutralizing antibodies (bNAbs). To limit the exposure of rare isolate-specific antigenic residues/determinants we generated a SOSIP trimer based on a consensus sequence of all HIV-1 group M isolates (ConM). The ConM trimer displays the epitopes of most known bNAbs and several germline bNAb precursors. The crystal structure of the ConM trimer at 3.9 Å resolution resembles that of the native Env trimer and its antigenic surface displays few rare residues. The ConM trimer elicits strong NAb responses against the autologous virus in rabbits and macaques that are significantly enhanced when it is presented on ferritin nanoparticles. The dominant NAb specificity is directed against an epitope at or close to the trimer apex. Immunogens based on consensus sequences might have utility in engineering vaccines against HIV-1 and other viruses.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/imunologia , Epitopos/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Animais , Sequência Consenso , Macaca , Multimerização Proteica , Coelhos
19.
Molecules ; 24(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934961

RESUMO

The leaves and twigs of the desiccation-tolerant medicinal shrub Myrothamnus flabellifolia are harvested for use in traditional and commercial teas and cosmetics due to their phenolic properties. The antioxidant and pharmacological value of this plant has been widely confirmed; however, previous studies typically based their findings on material collected from a single region. The existence of phenolic variability between plants from different geographical regions experiencing different rainfall regimes has thus not been sufficiently evaluated. Furthermore, the anthocyanins present in this plant have not been assessed. The present study thus used an untargeted liquid chromatography-tandem-mass spectrometry approach to profile phenolics in M. flabellifolia material collected from three climatically distinct (high, moderate, and low rainfall) regions representing the western, southern, and eastern extent of the species range in southern Africa. Forty-one putative phenolic compounds, primarily flavonoids, were detected, nine of which are anthocyanins. Several of these compounds are previously unknown from M. flabellifolia. Using multivariate statistics, samples from different regions could be distinguished by their phenolic profiles, supporting the existence of regional phenolic variability. This study indicates that significant phenolic variability exists across the range of M. flabellifolia, which should inform both commercial and traditional cultivation and harvesting strategies.


Assuntos
Magnoliopsida/química , Metaboloma , Metabolômica , Fenóis/análise , Cosméticos/análise , Ecossistema , Geografia , Magnoliopsida/metabolismo , Metabolômica/métodos , Extratos Vegetais/análise , Extratos Vegetais/química , Chá/química
20.
Cell ; 177(7): 1903-1914.e14, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31031007

RESUMO

Xenograft cell transplantation into immunodeficient mice has become the gold standard for assessing pre-clinical efficacy of cancer drugs, yet direct visualization of single-cell phenotypes is difficult. Here, we report an optically-clear prkdc-/-, il2rga-/- zebrafish that lacks adaptive and natural killer immune cells, can engraft a wide array of human cancers at 37°C, and permits the dynamic visualization of single engrafted cells. For example, photoconversion cell-lineage tracing identified migratory and proliferative cell states in human rhabdomyosarcoma, a pediatric cancer of muscle. Additional experiments identified the preclinical efficacy of combination olaparib PARP inhibitor and temozolomide DNA-damaging agent as an effective therapy for rhabdomyosarcoma and visualized therapeutic responses using a four-color FUCCI cell-cycle fluorescent reporter. These experiments identified that combination treatment arrested rhabdomyosarcoma cells in the G2 cell cycle prior to induction of apoptosis. Finally, patient-derived xenografts could be engrafted into our model, opening new avenues for developing personalized therapeutic approaches in the future.

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