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1.
BMC Cancer ; 20(1): 255, 2020 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-32223744

RESUMO

BACKGROUND: The efficacy and safety of lapatinib plus capecitabine (LC or LX) versus trastuzumab plus chemotherapy in patients with HER-positive metastatic breast cancer who are resistant to trastuzumab is unknown. METHODS: We retrospectively analyzed data from breast cancer patients who began treatment with regimens of lapatinib plus capecitabine (LC or LX) or trastuzumab beyond progression (TBP) at eight hospitals between May 2010 and October 2017. RESULTS: Among 554 patients who had developed resistance to trastuzumab, the median PFS (progression free survival) was 6.77 months in the LX group compared with 5.6 months in the TBP group (hazard ratio 0.804; 95% CI, 0.67 to 0.96; P = 0.019). The central nervous system progression rate during treatment was 5.9% in the LX group and 12.5% in the TBP group (P = 0.018). CONCLUSION: The combination of lapatinib and capecitabine showed a prolonged PFS relative to TBP in patients who had progressed on trastuzumab.

2.
J Couns Psychol ; 67(2): 208-221, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32105127

RESUMO

Career adaptability is a critical psychological resource for adolescents during their transition from secondary to postsecondary education. Based on prospective data from 451 Chinese adolescents (M = 16.87, SD = 0.63; 46.3% female), this study examined the mediating role of adolescents' consideration of future consequences (CFCS) in the association between career-related parental behaviors and adolescents' career adaptability. Results demonstrated that career-related parental support at Wave 1 was associated positively with adolescents' career adaptability and its subdimensions (i.e., career concern, control, curiosity, and confidence) at Wave 3 (i.e., 10 months later). Adolescents' CFCS at Wave 2 (i.e., 5 months later after Wave 1) served as a mediator linking career-related parental support at Wave 1 and career concern, control, and curiosity, but not confidence at Wave 3. Neither parental lack of engagement nor interference at Wave 1 predicted adolescents' career adaptability at Wave 3. These results suggest that interventions assisting parents in performing supportive behaviors, such as engaging in adolescents' career exploration activities and offering information about various kinds of jobs, might be useful strategies to foster adolescents' curiosity and confidence in choosing future career paths. Additionally, counselors and parents may offer adolescents strategies to strengthen their abilities to consider the potential influences of their current behaviors on future career paths (e.g., prioritizing behaviors and activities related to their future career paths over activities that only provide immediate or short-term gratification) to promote their capabilities of coping with challenges during the career transition period. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

3.
Artigo em Inglês | MEDLINE | ID: mdl-31904892

RESUMO

Herein, we report a ruthenium-catalyzed redox-neutral α-alkylation of unsaturated alcohols based on a synergistic relay process involving olefin isomerization (chain walking) and umpolung hydrazone addition, which takes advantage of the interaction between the two rather inefficient individual reaction steps to enable an efficient overall process. This transformation shows the compatibility of hydrazone-type "carbanions" and active protons in a one-pot reaction, and at the same time achieves the first Grignard-type nucleophilic addition using olefinic alcohols as latent carbonyl groups, providing a higher yield of the corresponding secondary alcohol than the classical hydrazone addition to aldehydes does. A broad scope of unsaturated alcohols and hydrazones, including some complex structures, can be successfully employed in this reaction, which shows the versatility of this approach and its suitability as an alternative, efficient means for the generation of secondary and tertiary alcohols.

4.
Scand J Psychol ; 61(2): 237-242, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31943256

RESUMO

Emerging adulthood is characterized by pervasive changes in identity and relationships. These challenges can entail problems for subjective well-being, leading to depressive symptoms. The development of an autonomous-related self is considered crucial for emerging adults' personal growth and psychological well-being. Autonomous-related self is linked to self-esteem and secure attachment style, which are also protective factors for depression. The current research sought to investigate the relation between autonomous-related self and depressive symptoms, as well as the role of secure attachment style and self-esteem, in a sample of 356 Italian emerging adults. Gender differences were taken into account in preliminary analyses. Gender differences emerged for autonomous-related self and self-esteem, while secure attachment and depression levels were similar across gender. Our results suggest that autonomous-related self, mediated by self-esteem and secure attachment style, is a protective factor for emotional states of depression, controlling for social desirability. These findings emphasize the importance of taking autonomy and relatedness into account in emerging adulthood and represent a starting point for future studies.

5.
Angew Chem Int Ed Engl ; 59(5): 1786-1796, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31432596

RESUMO

Transition-metal-catalyzed cross-couplings between aromatic electrophiles and nucleophiles have revolutionized modern chemical syntheses. Nevertheless, transition-metal-free approaches are preferable, considering the various issues caused by metal catalysts. This Minireview summarizes the recent progress in the light-enabled transition-metal-free formation of carbon-carbon and carbon-heteroatom bonds in aromatics, which opens a new avenue in aromatic reactions. From the mechanistic perspective, it classifies different reaction types of aryl electrophiles in an excited state with various nucleophiles. We believe this will provide more rationales for metal-free aromatic substitutions and cross-couplings with light, and guide the development of novel transformations of aromatic compounds facilitated by light.

6.
Gene Ther ; 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31819202

RESUMO

Recombinant adeno-associated viral (AAV) vectors are frequently used to deliver DNA into cells and are currently the leading platform for therapeutic gene delivery in humans. Presently, there is a need for optimized AAV vectors with improved transduction efficiencies in target tissues. In these studies, an engineered albumin-binding consensus domain (ABDCon) peptide was incorporated into the AAV9 capsid via fusion to the N-terminus of the AAV9 VP2 capsid protein to generate a variant AAV9 capsid with albumin-binding properties. The variant capsid, called AAV9-ABDCon, formed viable genome-containing vector particles and exhibited binding to human serum albumin. The AAV9 capsid, on the other hand, was not found to bind to human serum albumin by the methods used in this study. In C57BL/6J mice, AAV9-ABDCon achieved significantly higher levels of liver transduction compared with AAV9 following intravenous administration. These findings show that incorporation of the ABDCon peptide into the capsid VP2 N-terminus may be a potential method to augment AAV-mediated liver-directed gene delivery.

7.
Int J Biol Macromol ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31756473

RESUMO

A novel sustained-release matrix tablet was developed through wet granulation by using oxidized konjac glucomannan-cassava starch (OKGM-CS) and sucrose esters (SE) as excipients. OKGM-CS treated by dry heat exhibited low solubility and swelling power, indicating that it might be a potential adjuvant for sustained-release drug formulations. SE incorporation significantly decreased the porosity and swelling rates of tablets and retarded drug release. Tablets containing SE with an HLB value of 5 displayed better sustained-release performance, the cumulative release decreased from 94.36% to 83.29% and MDT increased from 4.50 h to 5.79 h. All these findings suggest the potential of OKGM-CS and SE as novel sustained-release agents for matrix tablets.

8.
Genes (Basel) ; 10(11)2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31739562

RESUMO

Leaves are one of the most important organs of plants, and yet, the association between leaf color and consumable traits remains largely unclear. Tea leaves are an ideal study system with which to investigate the mechanism of how leaf coloration affects palatability, since tea is made from the leaves of the crop Camellia sinensis. Our genomic resequencing analysis of a tea cultivar ZiJuan (ZJ) with purple leaves and altered flavor revealed genetic variants when compared with the green-leaf, wild type cultivar YunKang(YK). RNA-Seq based transcriptomic comparisons of the bud and two youngest leaves in ZJ and YK identified 93%, 9% and 5% expressed genes that were shared in YK- and ZJ-specific cultivars, respectively. A comparison of both transcript abundance and particular metabolites revealed that the high expression of gene UFGT for anthocyanin biosynthesis is responsible for purple coloration, which competes with the intermediates for catechin-like flavanol biosynthesis. Genes with differential expression are enriched in response to stress, heat and defense, and are casually correlated with the environmental stress of ZJ plant origin in the Himalayas. In addition, the highly expressed C4H and LDOX genes for synthesizing flavanol precursors, ZJ-specific CLH1 for degrading chlorophyll, alternatively spliced C4H and FDR and low photosynthesis also contributed to the altered color and flavor of ZJ. Thus, our study provides a better molecular understanding of the effect of purple coloration on leaf flavor, and helps to guide future engineering improvement of palatability.

9.
Genes (Basel) ; 10(11)2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717469

RESUMO

Basic helix-loop-helix (bHLH) transcription factor (TF) family is commonly found in eukaryotes, which is one of the largest families of regulator proteins. It plays an important role in plant growth and development, as well as various biotic and abiotic stresses. However, a comprehensive analysis of the bHLH family has not been reported in Brassica oleracea. In this study, we systematically describe the BobHLHs in the phylogenetic relationships, expression patterns in different organs/tissues, and in response to chilling stress, and gene and protein characteristics. A total of 234 BobHLH genes were identified in the B. oleracea genome and were further clustered into twenty-three subfamilies based on the phylogenetic analyses. A large number of BobHLH genes were unevenly located on nine chromosomes of B. oleracea. Analysis of RNA-Seq expression profiles revealed that 21 BobHLH genes exhibited organ/tissue-specific expression. Additionally, the expression of six BobHLHs (BobHLH003, -048, -059, -093, -109, and -148) were significantly down-regulated in chilling-sensitive cabbage (CS-D9) and chilling-tolerant cabbage (CT-923). At 24h chilling stress, BobHLH054 was significantly down-regulated and up-regulated in chilling-treated CS-D9 and CT-923. Conserved motif characterization and exon/intron structural patterns showed that BobHLH genes had similar structures in the same subfamily. This study provides a comprehensive analysis of BobHLH genes and reveals several candidate genes involved in chilling tolerance of B. oleracea, which may be helpful to clarify the roles of bHLH family members and understand the regulatory mechanisms of BobHLH genes in response to the chilling stress of cabbage.

10.
PLoS One ; 14(10): e0223169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31609968

RESUMO

High levels of self-control are found to be associated with greater life satisfaction. To further understand this relationship, the current study examined two questions: (1) whether too much self-control reduces, rather than increases, life satisfaction, as argued by some scholars; and (2) whether engaging in prosocial behavior explains the "self-control-life satisfaction" link. To this end, we conducted survey research among adolescents (N = 1,009), university students (N = 2,620), and adult workers (N = 500). All participants answered the same self-control and life satisfaction measures, whereas prosocial behavior was assessed using different scales across samples. Results of two-line regressions failed to reveal significant inverted-U shaped association between self-control and life satisfaction across samples. Moreover, results of mediation analyses showed that across samples, high levels of self-control were related to greater life satisfaction and this association was partly mediated by prosocial behavior. In conclusion, there is no evidence showing that too much self-control impairs life satisfaction. Engaging in prosocial behavior partly explains how high self-control relates to greater well-being.

11.
Medicine (Baltimore) ; 98(41): e17549, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593136

RESUMO

BACKGROUND: The study aimed to evaluate and compare the dosimetric parameters of incidental irradiation to internal mammary node (IMN) from inverse intensity-modulated radiotherapy (I-IMRT) and field-in-field IMRT (F-IMRT), and 3-dimensional conformal radiotherapy (3D-CRT) in patients after breast-conservation surgery (BCS). METHODS: Eighty-four patients with BCS were selected. The breast, tumor bed, and IMN, including intercostal spaces (ICS) 1 to 3, were contoured. Three plans were generated. The prescription doses for the breast and tumor bed were 50.4 Gy/28 F and 60.2 Gy/28 F, respectively. If there was no tumor bed boost, patient was treated with 50 Gy/25 F for the whole breast only. The IMN was not included in planning target volume. RESULTS: The median mean dose (Dmean) of the IMNtotal (ICS 1-3) was 2740.2 cGy, 2973.9 cGy, and 2951.4 cGy for I-IMRT, F-IMRT, and 3D-CRT, respectively. Differences were not detected between any of the plans. After separating ICS 1 to 3 for further analysis, neither of the Dmean of ICS 1 to 2 was significantly different between the plans. However, for ICS 3, the median Dmean was highest for I-IMRT, and those for 3D-CRT and F-IMRT were not significantly different. After separating the 3 techniques for further analysis, the median Dmean was highest in ICS 3 and lowest in ICS 1 for all the 3 techniques. CONCLUSION: All 3 techniques failed to attain an adequate dose to cure subclinical disease, and there were no significant differences among the 3 techniques. It is risky to avoid IMN irradiation (IMNI) using any of the 3 techniques during whole-breast radiotherapy in women with indications for elective IMNI. However, in era of systematic therapy, whether the incidental dose could meet clinical acquirements needs further follow-up.


Assuntos
Mama/cirurgia , Radiometria/métodos , Radioterapia Conformacional/efeitos adversos , Radioterapia de Intensidade Modulada/efeitos adversos , Adulto , Idoso , Mama/patologia , Mama/efeitos da radiação , Feminino , Humanos , Linfonodos/patologia , Linfonodos/efeitos da radiação , Mastectomia Segmentar/métodos , Mediastino/patologia , Mediastino/efeitos da radiação , Pessoa de Meia-Idade , Radioterapia Conformacional/métodos , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos , Parede Torácica/efeitos da radiação
12.
Perspect Psychol Sci ; 14(6): 967-1005, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31491364

RESUMO

Self-control plays a significant role in positive youth development. Although numerous self-control challenges occur during adolescence, some adolescents control themselves better than others. Parenting is considered a critical factor that distinguishes adolescents with good self-control from those with poor self-control, but existing findings are inconsistent. This meta-analysis summarizes the overall relationship between parenting and self-control among adolescents aged 10 to 22 years. The analysis includes 191 articles reporting 1,540 effect sizes (N = 164,459). The results show that parenting is associated with adolescents' self-control both concurrently (r = .204, p < .001) and longitudinally (r = .157, p < .001). Longitudinal studies also reveal that adolescents' self-control influences subsequent parenting (r = .155, p < .001). Moderator analyses show that the effect sizes are largely invariant across cultures, ethnicities, age of adolescents, and parent and youth gender. Our results point to the importance of parenting in individual differences in adolescent self-control and vice versa.

13.
JCO Clin Cancer Inform ; 3: 1-15, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31419181

RESUMO

PURPOSE: The aim of the current study was to assess treatment concordance and adherence to National Comprehensive Cancer Network breast cancer treatment guidelines between oncologists and an artificial intelligence advisory tool. PATIENTS AND METHODS: Study cases of patients (N = 1,977) who were at high risk for recurrence or who had metastatic disease and cell types for which the advisory tool was trained were obtained from the Chinese Society for Clinical Oncology cancer database (2012 to 2017). A cross-sectional observational study was performed to examine treatment concordance and guideline adherence among an artificial intelligence advisory tool and 10 oncologists with varying expertise-three fellows, four attending physicians, and three chief physicians. In a blinded fashion, each oncologist provided treatment advice on an average of 198 cases and the advisory tool on all cases (N = 1,977). Results are reported as rates and logistic regression odds ratios. RESULTS: Concordance for the recommended treatment was 0.56 for all physicians and higher for fellows compared with chief and attending physicians (0.68 v 0.54; 0.49; P = .001). Concordance differed by hormone receptor subtype-TNM stage, with the lowest for hormone receptor-positive human epidermal growth factor receptor 2/neu-positive cancers (0.48) and highest for triple-negative breast cancers (0.71) across most TNM stages. Adherence to National Comprehensive Cancer Network guidelines was higher for oncologists compared with the advisory tool (0.96 v 0.82; P < .003) and lower for fellows compared with attending physicians (0.93 v 0.98; 0.96; P = .04). CONCLUSION: Study findings reflect a complex breast cancer case mix, the limits of medical knowledge regarding optimum treatment, clinician practice patterns, and use of a tool that reflects expertise from one cancer center. Additional research in different practice settings is needed to understand the tool's scalability and its impact on treatment decisions and clinical and health services outcomes.

14.
J Org Chem ; 84(20): 12705-12721, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31441304

RESUMO

Cross-coupling reaction between two C-H bonds has become a fundamental strategy in synthetic organic chemistry. With its increasing importance in green chemistry, atom economy, and step economy, its development has sky-rocketed within the last 20 years, with the term "cross-dehydrogenative coupling (CDC)" popularized and progressed by the group of Li and others to describe direct Y-Z bond formations from Y-H and Z-H bonds under oxidative conditions. Among all types of CDC reactions, the C-C bond formations are of prime importance in building up the molecular complexity but their categorization currently remains disarray due to a wide diversity, resulting in frequent display in separate topics. In this Perspective, a contemporary categorization via C-H activation strategies is presented herein, which could be vital for future CDC designs. With this mechanism-based categorization and discussion, we wish that this minireview will help more synthetic chemists gain insight into the design of CDC reactions and inspires more ideas on this topic.

15.
Chem Sci ; 10(19): 5018-5024, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31183051

RESUMO

Minisci alkylation is of prime importance for its applicability in functionalizing diverse heteroarenes, which are core structures in many bioactive compounds. In alkyl radical generation processes, precious metal catalysts, high temperatures and excessive oxidants are generally involved, which lead to sustainability and safety concerns. Herein we report a new strategy using diacetyl (2,3-butanedione) as an abundant, visible light-sensitive and "traceless" hydrogen atom abstractor to achieve metal-free cross-dehydrogenative Minisci alkylation under mild conditions. Mechanistic studies supported hydrogen atom transfer (HAT) between an activated C(sp3)-H substrate and diacetyl. Moreover, with the assistance of di-tert-butyl peroxide (DTBP), the scope of the reaction could be extended to strong aliphatic C-H bonds via diacetyl-mediated energy transfer. The robustness of this strategy was demonstrated by functionalizing complex molecules such as quinine, fasudil, nicotine, menthol and alanine derivatives.

16.
Technol Cancer Res Treat ; 18: 1533033819853847, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31159668

RESUMO

OBJECTIVE: To compare differences in setup error assessment and correction between planar kilovolt images and cone beam computed tomography images for external beam partial breast irradiation during free breathing. METHODS: Nineteen patients who received external beam partial breast irradiation after breast-conserving surgery were recruited. Interfraction setup error was acquired using planar kilovolt images and cone beam computed tomography. After online setup correction, the residual error was calculated, and the setup error was compared. The residual error and setup margin were quantified for planar kilovolt and cone beam computed tomography images. RESULTS: The largest setup error was observed in the anteroposterior direction for both cone beam computed tomography and planar kilovolt imaging (-1.45 mm, 1.74 mm). The cone beam computed tomography-based setup error (systematic error [Σ]) was less than the planar kilovolt images based on Σ in the anteroposterior direction (-1.2 mm vs 2.00 mm; P = .005), and no significant differences were observed for random error (σ) in 3 dimensions ( P = .948, .376, .314). After online setup correction, cone beam computed tomography significantly reduced the residual setup error compared with planar kilovolt images in the anteroposterior direction (Σ: -0.20 mm vs 0.50 mm, P = .008; σ: 0.45 mm vs 1.34 mm, P = .002). The cone beam computed tomography-based setup margin was smaller than the planar kilovolt image-based setup margin in the anteroposterior direction (-1.39 mm vs 5.57 mm, P = .003; 0.00 mm vs 3.20 mm, P = .003). CONCLUSIONS: Discrepancy between the setup errors observed with planar kilovolt and cone beam computed tomography was obvious in the anteroposterior direction. Compared to cone beam computed tomography, the elapsed treatment time was smaller when the initial alignment used kilovolt planar imaging. Whether using planar kilovolt or cone beam computed tomography, residual errors can be reduced to 1.5 mm for external beam partial breast irradiation procedures.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/radioterapia , Tomografia Computadorizada de Feixe Cônico , Planejamento da Radioterapia Assistida por Computador , Radioterapia Guiada por Imagem , Tomografia Computadorizada de Feixe Cônico/métodos , Feminino , Humanos , Metástase Neoplásica , Estadiamento de Neoplasias , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Guiada por Imagem/métodos , Radioterapia Guiada por Imagem/normas
17.
Chem Sci ; 10(18): 4775-4781, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31160954

RESUMO

Primary anilines are essential building blocks to synthesize various pharmaceuticals, agrochemicals, pigments, electronic materials, and others. To date, the syntheses of primary anilines mostly rely on the reduction of nitroarenes or the transition-metal-catalyzed Ullmann, Buchwald-Hartwig and Chan-Lam cross-coupling reactions with ammonia, in which non-renewable petroleum-based chemicals are typically used as feedstocks via multiple step syntheses. A long-standing scientific challenge is to synthesize various primary anilines directly from renewable sources. Herein, we report a general method to directly convert a broad range of phenols into the corresponding primary anilines with the cheap and widely available hydrazine as both amine and hydride sources with simple Pd/C as the catalyst.

18.
Colloids Surf B Biointerfaces ; 180: 429-440, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31085461

RESUMO

A novel glutathione-responsive (GSH-responsive) star-like amphiphilic polymer (C12H25)14-ß-CD-(S-S-mPEG)7 (denoted as CCSP) was designed for efficient antitumor drug delivery. The amphiphilic ß-cyclodextrin (ß-CD) self-polymerize in water to form a sphere with a diameter of 40-50 nm. The secondary hydroxyl groups of ß-CD were modified by dodecyl to form a hydrophobic core and the primary hydroxyl groups of ß-CD were decorated with PEG through disulfide bond to form a hydrophilic shell. Since the hydrophobic cavity of ß-CD was maintained, the hydrophobic core formed by dodecyl as well as cavity of ß-CD provided CCSP with a loading content as high as 39.6 wt%. Importantly, DOX@CCSP exhibited low drug leakage and negligible cytotoxicity in non-reductive physiological environment, while it showed rapid release and high cytotoxicity in reductive tumorous environment via the breakage of disulfide bond. In view of the above-mentioned advantages of DOX@CCSP nanocarriers such as high loading content, proper size, favorable stimulus-response release performance and low leakage, it is believed that CCSP may offer great potential to be used as an intelligent nanocarrier for anticancer drug delivery.


Assuntos
Antineoplásicos/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , beta-Ciclodextrinas/química , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Cabras , Células HEK293 , Hemólise/efeitos dos fármacos , Humanos , Camundongos Nus , Nanopartículas/ultraestrutura , Polietilenoglicóis/química , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição Tecidual/efeitos dos fármacos
19.
Curr Genet ; 65(6): 1355-1365, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31087129

RESUMO

The E3 ubiquitin ligases are key regulators of protein ubiquitination, which have been shown to be involved in a variety of cellular responses to both biotic and abiotic stresses in eukaryotes. However, the E3 ubiquitin ligase homologues in the soil-borne plant pathogen Plasmodiophora brassicae, the causal agent of clubroot disease of crucifer crops worldwide, remain largely unknown. In this study, we characterized secreted E3 ubiquitin ligases, a group of proteins known to be involved in virulence in many pathogens, in a plasmodiophorid P. brassicae. Genome-wide search in the P. brassicae genome retrieved 139 putative E3 ubiquitin ligases, comprising of 115 RING, 15 HECT, 1 HECT-like, and 8 U-box E3 ubiquitin ligases. Among these E3 ubiquitin ligases, 11 RING, 1 U-box, and 3 HECT were found to harbor signal peptide. Based on published RNA-seq data (Schwelm et al. in Sci Rep 5:11153, 2015), we found that these genes were differentially expressed in distinct life stages including germinating spores, maturing spores, and plasmodia. We characterized one potential secreted E3 ubiquitin ligase, PbRING1 (PBRA_000499). Yeast invertase assay showed that PbRING1 harbors a functional N-terminal signal peptide. PbRING1 also harbors a really interested new gene (RING) domain at its C terminus, which was found to display the E3 ligase activity in vitro. Collectively, this study provides a comprehensive insight into the reservoir of putative secreted E3 ligases in P. brassicae.

20.
Skelet Muscle ; 9(1): 16, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133057

RESUMO

BACKGROUND: Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily. The GDF11 propeptide, which is derived from the GDF11 precursor protein, blocks the activity of GDF11 and its homolog, myostatin, which are both potent inhibitors of muscle growth. Thus, treatment with GDF11 propeptide may be a potential therapeutic strategy for diseases associated with muscle atrophy like sarcopenia and the muscular dystrophies. Here, we evaluate the impact of GDF11 propeptide-Fc (GDF11PRO-Fc) gene delivery on skeletal muscle in normal and dystrophic adult mice. METHODS: A pull-down assay was used to obtain physical confirmation of a protein-protein interaction between GDF11PRO-Fc and GDF11 or myostatin. Next, differentiated C2C12 myotubes were treated with AAV6-GDF11PRO-Fc and challenged with GDF11 or myostatin to determine if GDF11PRO-Fc could block GDF11/myostatin-induced myotube atrophy. Localized expression of GDF11PRO-Fc was evaluated via a unilateral intramuscular injection of AAV9-GDF11PRO-Fc into the hindlimb of C57BL/6J mice. In mdx mice, intravenous injection of AAV9-GDF11PRO-Fc was used to achieve systemic expression. The impact of GDF11PRO-Fc on muscle mass, function, and pathological features were assessed. RESULTS: GDF11PRO-Fc was observed to bind both GDF11 and myostatin. In C2C12 myotubes, expression of GDF11PRO-Fc was able to mitigate GDF11/myostatin-induced atrophy. Following intramuscular injection in C57BL/6J mice, increased grip strength and localized muscle hypertrophy were observed in the injected hindlimb after 10 weeks. In mdx mice, systemic expression of GDF11PRO-Fc resulted in skeletal muscle hypertrophy without a significant change in cardiac mass after 12 weeks. In addition, grip strength and rotarod latency time were improved. Intramuscular fibrosis was also reduced in treated mdx mice; however, there was no change seen in central nucleation, membrane permeability to serum IgG or serum creatine kinase levels. CONCLUSIONS: GDF11PRO-Fc induces skeletal muscle hypertrophy and improvements in muscle strength via inhibition of GDF11/myostatin signaling. However, GDF11PRO-Fc does not significantly improve the dystrophic pathology in mdx mice.

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