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1.
Mol Ther Nucleic Acids ; 17: 879-890, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31473584

RESUMO

Extracellular vesicles (EVs) mediate intercellular communications in the tumor microenvironment and contribute to the aggressive phenomenon of cancers. Although EVs in body fluids are supposed to be ideal biomarkers for cancer diagnosis and prognosis, it remains difficult to distinguish the tumor-derived EVs from those released by other tissues. We hypothesized that analyzing the EV-related molecules in tumor tissues would help to estimate the prognostic value of tumor-specific EVs. Here, we investigate the expression of coding genes of proteins carried by small EVs (sEVs) in primary lung adenocarcinoma. Based on the protein-protein interaction network, we identified three network modules (3-PPI-Mod) as a signature that could predict recurrence. This signature was validated in three independent datasets and demonstrated better prognostic value than signature generated from gene expression alone. Meanwhile, the high-risk subgroup assigned by the signature could benefit from adjuvant chemotherapy, although it was not beneficial in unselected patients. Two out of three modules were enriched by proteins identified in sEVs from non-small-cell lung cancer cells. Furthermore, the two modules were remarkably correlated with intratumoral hypoxia score. These results suggest that the 3-PPI-Mod signature was enriched in tumor-derived sEVs and could serve as a prognostic and predictive biomarker for lung adenocarcinoma.

2.
J Clin Neurosci ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31447358

RESUMO

BACKGROUND: Atherosclerosis in stroke-related vascular beds is the major cause of stroke. Studies demonstrated that multivascular atherosclerosis is prevalent in stroke patients and those with multivascular plaques had higher risk of recurrent stroke. OBJECTIVES: This study investigated the relationship between homocysteine and multivascular atherosclerosis in stroke-related vascular beds using magnetic resonance imaging. METHODS: Patients with recent ischemic cerebrovascular symptoms were enrolled and underwent three-dimensional magnetic resonance vessel wall imaging for intracranial arteries, extracranial carotid arteries and aortic arch. Traditional risk factors and homocysteine were measured. Presence of multivascular plaques defined as plaques in at least two stroke-related vascular beds on magnetic resonance imaging was determined. The relationship between homocysteine and characteristics of multivascular plaques was determined. RESULTS: Of 49 enrolled patients (mean age: 56.3 ±â€¯13.8 years; 35 males), 23 had multivascular plaques. Homocysteine (odds ratio, 1.17; 95% confidence interval, 1.02-1.34; p = 0.022) and age (odds ratio, 1.71; 95% confidence interval, 1.22-2.41; p = 0.002) were significantly associated with presence of multivascular plaques. The adjusted associations remained significant (both p < 0.05). In discriminating presence of multivascular plaques, the area-under-the-curve of age, homocysteine and combination of them was 0.79, 0.70 and 0.87 respectively. CONCLUSIONS: Homocysteine is independently associated with stroke-related multivascular plaques and combination of age and homocysteine has stronger predictive value.

3.
Br J Ophthalmol ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401553

RESUMO

BACKGROUND/AIMS: In order to address the eye care needs of the increasing numbers of elderly Chinese globally, there is a need for comprehensive understanding on the longitudinal trends of age-related eye diseases among Chinese. We herein report the key findings from the baseline Singapore Chinese Eye Study (SCES-1), and describe the rationale and methodology of the 6-year follow-up study (SCES-2). METHODS: 3353 Chinese adults who participated in the baseline SCES-1 (2009-2011) were invited for the 6-year follow-up SCES-2 (2015-2017). Examination procedures for SCES-2 included standardised ocular, systemic examinations and questionnaires identical to SCES-1. SCES-2 further included new examinations such as optical coherence tomography angiography, and questionnaires to evaluate health impact and economic burden of eye diseases. RESULTS: In SCES-1, the age-adjusted prevalence of best-corrected low vision (VA<6/12, better-seeing eye) and blindness (VA<6/60, better-seeing eye) were 3.4% and 0.2%, respectively. The prevalence rates for glaucoma, age related macular degeneration, and diabetic retinopathy (among diabetics) were 3.2%, 6.8%, 26.2%, respectively. Of the 3033 eligible individuals from SCES-1, 2661 participated in SCES-2 (response rate=87.7%). Comparing with those who did not attend SCES-2, those attended were younger, had higher SES (all p<0.001), but less likely to be a current smoker, to have diabetes, hypertension, hyperlipidaemia (all p≤0.025). CONCLUSIONS: Building on SCES-1, SCES-2 will be one of the few longitudinal population-based eye studies to report incidence, progression, and risk factors of major age-related eye diseases. Findings from this cohort may offer new insights, and provide useful reference information for other Chinese populations elsewhere.

4.
Proc Natl Acad Sci U S A ; 116(35): 17316-17322, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31409711

RESUMO

A descendant of the red algal lineage, diatoms are unicellular eukaryotic algae characterized by thylakoid membranes that lack the spatial differentiation of stroma and grana stacks found in green algae and higher plants. While the photophysiology of diatoms has been studied extensively, very little is known about the spatial organization of the multimeric photosynthetic protein complexes within their thylakoid membranes. Here, using cryo-electron tomography, proteomics, and biophysical analyses, we elucidate the macromolecular composition, architecture, and spatial distribution of photosystem II complexes in diatom thylakoid membranes. Structural analyses reveal 2 distinct photosystem II populations: loose clusters of complexes associated with antenna proteins and compact 2D crystalline arrays of dimeric cores. Biophysical measurements reveal only 1 photosystem II functional absorption cross section, suggesting that only the former population is photosynthetically active. The tomographic data indicate that the arrays of photosystem II cores are physically separated from those associated with antenna proteins. We hypothesize that the islands of photosystem cores are repair stations, where photodamaged proteins can be replaced. Our results strongly imply convergent evolution between the red and the green photosynthetic lineages toward spatial segregation of dynamic, functional microdomains of photosystem II supercomplexes.

5.
BMJ Open ; 9(8): e030041, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31455710

RESUMO

INTRODUCTION: Surgery is one of the primary treatments for lung cancer. The postoperative symptom burden experienced by patients with lung cancer is substantial, seriously delaying their recovery from surgery and impairing their quality of life. Patient-reported outcome (PRO)-based symptom management is increasingly regarded as an optimal model for patient-centred care. Currently, clinical trial-based evidence involving early-phase (immediately after surgery for up to 1 month) symptom management of lung cancer is lacking. We propose a randomised trial to evaluate the effect of a PRO-based symptom-monitoring programme with overthreshold alerts and responses for postoperative recovery in patients with lung cancer. METHODS AND ANALYSIS: The study will recruit 160 patients with lung cancer from six hospitals. The patients will be randomly allocated to the intervention group or control group in a ratio of 1:1. Patients in the intervention group will receive PRO-based symptom management from the specialists when their reported target symptom (pain, coughing, fatigue, disturbed sleep and shortness of breath) scores reach the preset threshold (score ≥4). Patients in the control group will not generate alerts and will follow the standard procedures for symptom management. All patients will receive symptom assessments via the MD Anderson Symptom Inventory-lung cancer module on the day before surgery, daily after surgery and twice a week after discharge until 4 weeks or the start of postoperative oncological treatment. The primary outcome-mean symptom threshold events-will be compared between the intervention and control group via independent sample Student's t-test. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of Sichuan Cancer Hospital on 22 November 2018 (No. SCCHEC-02-2018-045). This manuscript is based on V.2.0, 9 May 2019 of the protocol. The study results will be disseminated in publications in peer-reviewed journals and presentations at academic conferences. TRIALS REGISTRATION NUMBER: ChiCTR1900020846.

6.
BMJ Open ; 9(8): e028448, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31399453

RESUMO

INTRODUCTION: Lung cancer is the most common cancer and the leading cause of cancer death in China, as well as in the world. Late diagnosis is the main obstacle to improving survival. Currently, early detection methods for lung cancer have many limitations, for example, low specificity, risk of radiation exposure and overdiagnosis. Exhaled breath analysis is one of the most promising non-invasive techniques for early detection of lung cancer. The aim of this study is to identify volatile organic compound (VOC) biomarkers in lung cancer and to construct a predictive model for lung cancer based on exhaled breath analysis. METHODS AND ANALYSIS: The study will recruit 389 lung cancer patients in one cancer centre and 389 healthy subjects in two lung cancer screening centres. Bio-VOC breath sampler and Tedlar bag will be used to collect breath samples. Gas chromatography-mass spectrometry coupled with solid phase microextraction technique will be used to analyse VOCs in exhaled breath. VOC biomarkers with statistical significance and showing abilities to discriminate lung cancer patients from healthy subjects will be selected for the construction of predictive model for lung cancer. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of Sichuan Cancer Hospital on 6 April 2017 (No. SCCHEC-02-2017-011). The results of this study will be disseminated in presentations at academic conferences, publications in peer-reviewed journals and the news media. TRIAL REGISTRATION NUMBER: ChiCTR-DOD-17011134; Pre-results.

7.
J Autism Dev Disord ; 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31267289

RESUMO

Little is known about the relationship between sensory processing problems and sleep disturbances, emotional and behavioral problems and mealtime behavioral problems in Chinese children with autism spectrum disorders (ASDs). This study examined those relationships in Chinese preschool children with ASD using a case-control design. Atypical sensory processing was associated with increased risks of sleep disturbances, emotional and behavioral problems, and abnormal mealtime behaviors in the children with ASD, whereas sensory processing problems were significantly correlated with abnormal mealtime behaviors only in the typically developing children. Based on our findings, clinicians must collect information about sensory problems when a child with ASD experiences sleep disturbances and emotional and behavioral problems or presents abnormal mealtime behaviors.

8.
Br J Ophthalmol ; 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272959

RESUMO

BACKGROUND/AIMS: To evaluate the association between systemic medications and cortical cataract prevalence in an Asian population. METHODS: The Singapore Epidemiology of Eye Diseases Study recruited 10 033 Chinese, Malay and Indian residents aged 40+ years living in Singapore. Information on medication use was collected at interview using questionnaires. The presence and severity of cortical cataract were assessed from lens photographs using the modified Wisconsin Cataract Grading System. Associations between medications and the presence of cortical cataract were assessed using logistic regression. Associations between medications and greater severity of cortical cataract (none, minimal, early and late) were assessed using ordinal logistic regression. RESULTS: A total of 8965 participants were included, the mean age was 57.6 (SD=9.8) years, and 4555 (50.8%) were women. After adjusting for age, gender, ethnicity, body mass index, smoking status, socioeconomic status, hypertension, hyperlipidaemia, diabetes, duration of diabetes and cardiovascular disease, ACE inhibitors (OR=1.27; 95% CI 1.05 to 1.55), fibrates (OR=1.57; 95% CI 1.05 to 2.35), alpha-glucosidase inhibitors (AGIs) (OR=1.85; 95% CI 1.13 to 3.02) and insulin (OR=1.80; 95% CI 1.11 to 2.93) were significantly associated with the presence of cortical cataract. Further adjusting for concurrent medication use did not alter these associations. Consistently, the four medications were also associated with a greater severity level of cortical cataract. CONCLUSION: ACE inhibitors, fibrates and AGIs were associated with increased prevalence of cortical cataract in this Asian population, independent of the presence of hypertension, hyperlipidaemia and diabetes, respectively. Whether they contribute to the risk of cortical cataract needs confirmation in longitudinal studies.

9.
Cancer Lett ; 461: 56-64, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31319137

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with dismal 5-year survival. Extracellular matrix protein 1 (ECM1) was identified as one of the most downregulated genes by transcriptomic analysis of normal esophageal/ESCC paired tissue samples. ECM1 plays oncogenic roles in cancer development in various cancer types. However, little is known about its role in ESCC. In vivo and in vitro functional assays coupled with analyses on public datasets and detailed molecular and mechanistic analyses were used to study the gene. We demonstrate that as opposed to the previously identified oncogenic role of ECM1a, ECM1b is a novel tumor suppressor in ESCC. ECM1 is significantly downregulated in ESCC and several other squamous cell carcinomas. ECM1b encodes a cellular protein that suppresses MYC protein expression and MTORC1 signaling activity. MTORC2 inactivation leads to suppressed MYC expression and MTORC1 signaling. ECM1b localizes to the endoplasmic reticulum and suppresses MTORC2 activation by inhibiting MTORC2/ribosome association. By regulating MTORC2/MYC/MTORC1 signaling, ECM1b suppresses general protein translation and enhances chemosensitivity. We provide evidence establishing a novel role of ECM1 in cancer that suggests ECM1b as a biomarker for ESCC disease management.

10.
Eur J Med Chem ; 179: 100-108, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247372

RESUMO

Synthetic peptide vaccines based on epitopes derived from the conserved region of M-protein are proving to be a realistic option for protection against group A streptococcus (GAS). However, peptide epitopes alone are poorly immunogenic due to lack of pathogen-associated structural patterns. Therefore, we developed a GAS peptide vaccine based on combined lipidic TLR 2 agonist and self-adjuvanting polymers. We synthesized three α-poly-l-glutamic acid (PGA) conjugated lipopeptides composed of 2-amino-d,l-hexadecanoic acid, GAS B-cell peptide epitope J8 (QAEDKVKQSREAKKQVEKALKQLEDKVQ) and universal T-helper epitope PADRE (AKFVAAWTLKAAA) in different spatial arrangements. The anionic lipopeptide conjugates formed nanoparticles via ionic-complexation with a cationic polymer, trimethyl chitosan (TMC). We demonstrated that the spatial arrangement of vaccine components has a significant influence on peptide conformation and particle formation and, as such, contributes to the differential efficacy and opsonin-mediated killing potential of nanovaccines. Nanoparticles carrying branched helical lipopeptide with T-helper epitope on free N-termini (NP3) stimulated the most potent humoral immune responses. Lipopeptides without TMC (LP1-LP3) and TMC nanoparticles of peptide alone (without lipid) NP (P1) were poor inducers of antibody production, indicating that both TMC and lipid are required to induce a strong opsonic immune response.

11.
Sci Total Environ ; 686: 555-567, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185403

RESUMO

Nitrogen (N) leakage in paddy fields can cause groundwater pollution. In this study, we conducted a split-plot field experiment over 2 years to compare N leakage in a rice-duck co-culture system and a rice monoculture system with different fertilizer treatments. Four treatments were applied to each field, with consistent N inputs in each fertilizer treatment: no fertilizer (RD and RM, respectively), chemical fertilizer (RDF and RMF, respectively), organic fertilizer (RDO and RMO, respectively), and a mixture of 70% chemical and 30% organic fertilizers (RDFO and RMFO, respectively). In both years, rice-duck co-culture system had lower N leakage than the rice monoculture for the same fertilizer treatment, with average reductions of 14.3 ±â€¯0.1%, 13.5 ±â€¯4.5% and 10.5 ±â€¯3.3% for RDFO, RDF and RDO, respectively. Within the rice-duck co-culture system, the average N leakage across both years was 36.3 ±â€¯6.3% lower in RDO and 16.9 ±â€¯11.5% lower in RDFO than in RMF. RDFO gave the highest grain yield compared with RDF and RDO, average reached 10.35 t ha-1 across both years. In conclusion, our results suggested that rice-duck co-culture reduces environmental risks by controlling N leakage and increasing agricultural productivity. Compared with other treatments in this research, RDFO was the most recommended agricultural production mode in this region because it can reduce the inputs of chemical fertilizer, control nitrogen leakage and increase rice yield.


Assuntos
Agricultura/métodos , Fertilizantes , Nitrogênio/análise , Poluentes Químicos da Água/análise , China
12.
Mol Med Rep ; 20(2): 995-1006, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173223

RESUMO

Berberine, a natural isoquinoline alkaloid derived from Berberis species, has been reported to have anticancer effects. However, the mechanisms of action in human colorectal cancer (CRC) are not well established to date. In the present study, the cell cytotoxicity effect of berberine on human CRC cells, as well as the possible mechanisms involved, was investigated. The results of the cell viability and apoptosis assay revealed that treatment of CRC cells with berberine resulted in inhibition of cell viability and activation of cell apoptosis in a concentration­dependent manner. To reveal the underlying mechanism of berberine­induced anti­tumor activity and cell apoptosis, RNA­sequencing followed by reverse­transcription quantitative PCR were performed. In addition, RNA immunoprecipitation, chromatin immunoprecipitation and western blot analysis were used to identify the functional regulation of CASC2/EZH2/BCL2 axis in berberine­induced CRC cell apoptosis. The data revealed that lncRNA CASC2 was upregulated by berberine treatment. Gain­ or loss­of­function assays suggested that lncRNA CASC2 was required for the berberine­induced inhibition of cell viability and activation of cell apoptosis. Subsequently, the downstream antiapoptotic gene BCL2 was identified as a functional target of the berberine/CASC2 mechanism, as BCL2 reversed the berberine/CASC2­induced cell cytotoxicity. lncRNA CASC2 silenced BCL2 expression by binding to the promoter region of BCL2 in an EZH2­dependent manner. In summary, berberine may be a novel therapeutic agent for CRC and lncRNA CASC2 may serve as an important therapeutic target to improve the anticancer effect of berberine.

13.
Ann Nucl Med ; 33(9): 657-670, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31218571

RESUMO

OBJECTIVES: To investigate the role of the traditional and radiomic parameters of 18F-FDG PET for predicting the outcomes of patients with esophageal squamous cell carcinoma (SqCC). METHODS: Forty-four patients with primary esophageal SqCC who underwent neoadjuvant chemoradiotherapy (CCRT) followed by esophagectomy (tri-modality treatment) were retrospectively analyzed. All patients underwent 18F-FDG PET/CT before and after neoadjuvant CCRT. The radiomic features were calculated using the pre-treatment PET scan. Pre-treatment radiomic features and changes in the PET-derived traditional parameters after neoadjuvant CCRT were analyzed according to the pathological response to esophagectomy, disease-free survival (DFS), and overall survival (OS). We further developed a scoring system based on the independent survival prognosticators and compared our model to the traditional TNM staging system and surgical pathology. RESULTS: A pre-treatment primary tumor histogram entropy ≥ 3.69 predicts an unfavorable response to neoadjuvant CCRT (OR = 19.25, p = 0.009). An SUVmax reduction ratio ≤ 0.76, a pre-treatment primary tumor code similarity ≤ 0.0235, and incomplete pathological remission were independently associated with poor OS (p = 0.019, 0.033, and 0.038, respectively) and DFS (p = 0.049, 0.021, and 0.009, respectively). The three survival prognosticators were used to construct a scoring system (score 0-1, 2, and 3). Patients with a score of 2 or 3 had a significantly worse survival outcome than those with a score of 0-1 (HRs for OS: 3.58 for score 2, and 15.19 for score 3, p < 0.001; HRs for DFS: 1.39 for score 2 and 6.04 for score 3, p = 0.001).This survival prediction model was superior to the traditional TNM staging system (p < 0.001 versus p = 0.061 for OS, and p = 0.001 versus p = 0.027 for DFS) and the model based on surgical pathology (p < 0.001 versus p = 0.049 for OS, and p = 0.001 versus p = 0.022 for DFS). CONCLUSIONS: The 18F-FDG PET-derived radiomic parameter is useful for predicting the surgical pathological response in patients with esophageal SqCC treated with the tri-modality method. Using a combination of traditional and radiomic PET parameters with clinical profiles enables better stratification of patients into subgroups with various survival rates.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31159212

RESUMO

Integrated rice-frog farming (IRFF), as a mode of ecological farming, is fundamental in realizing sustainable development in agriculture. Yet its production of greenhouse gas (GHG) emissions remains unclear. Here, a randomized plot field experiment was performed to study the GHG emissions for various farming systems during the rice growing season. The farming systems included: conventional farming (CF), green integrated rice-frog farming (GIRF), and organic integrated rice-frog farming (OIRF). Results indicate that the cumulative methane (CH4) emissions from the whole growth period were divergent for the three farming systems, with OIRF having the highest value and CF having the lowest. For nitrous oxide (N2O) emissions, the order is reversed. IRFF significantly increased the dissolved oxygen (DO), soil redox potential (Eh), total organic carbon (TOC) content, and soil C:N ratio, which is closely related to GHG emissions in rice fields. Additionally, the average emissions of carbon dioxide (CO2) from soils during rice growing seasons ranged from 2312.27 to 2589.62 kg ha-1 and showed no significant difference in the three treatments. Rice yield in the GIRF and OIRF were lower (2.0% and 16.7%) than the control. The CH4 emissions contributed to 83.0-96.8% of global warming potential (GWP). Compared to CF, the treatment of GIRF and OIRF increased the GWP by 41.3% and 98.2% during the whole growing period of rice, respectively. IRFF significantly increased greenhouse gas intensity (GHGI, 0.79 kg CO2-eq ha-1 grain yield), by 91.1% over the control. Compared to the OIRF, GIRF decreased the GHGI by approximately 39.4% (0.59 kg CO2-eq ha-1 grain yield), which was 44.2% higher than that of the control. The results of structural equation model showed that the contribution of fertilization to CH4 emissions in paddy fields was much greater than that of frog activity. Moreover, frog activity could decrease GWP by reducing CH4 emissions from rice fields. And while GIRF showed a slight increase in GHG emissions, it could still be considered as a good strategy for providing an environmentally-friendly option in maintaining crop yield in paddy fields.

15.
Sci Total Environ ; 688: 380-388, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31233918

RESUMO

In freshwater aquaculture ponds, cyanobacterial blooms and microcystins (MCs) pollution have attracted considerable attention due to their toxic effects. To provide an insight into cyanobacterial problems in aquaculture ponds, MCs distribution, bioaccumulation, and Microcystis genotype succession in a fishpond were investigated from May 2017 to November 2017. The distribution of MCs in filtered water, seston, and sediment varied considerably among months. MCs concentrations in filtered water, seston, and sediment ranged from 1.16 to 3.66 µg/L, 0.64 to 13.98 µg/g DW, and 1.34 to 5.90 µg/g DW, respectively. In addition, chemical oxygen demand was positively correlated with sestonic MCs concentrations. MCs concentrations accumulated in different tissues of market-size fish were in the order of liver > kidney > intestine > muscle. MCs content in muscle was 4.3 times higher than the WHO recommended tolerable daily intake level. Twenty-four ITS genotypes of Microcystis were identified from a total of 653 sequences. During the survey period, considerable genotype variation and rapid genotype succession were observed and dominant genotype was absent. A redundancy analysis revealed that Microcystis genotypes could significantly influence the variations in the proportions of the potentially toxic Microcystis, which could in turn influence the MCs concentrations in seston.

16.
Nat Chem ; 11(7): 605-614, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209296

RESUMO

Fractal topologies, which are statistically self-similar over multiple length scales, are pervasive in nature. The recurrence of patterns in fractal-shaped branched objects, such as trees, lungs and sponges, results in a high surface area to volume ratio, which provides key functional advantages including molecular trapping and exchange. Mimicking these topologies in designed protein-based assemblies could provide access to functional biomaterials. Here we describe a computational design approach for the reversible self-assembly of proteins into tunable supramolecular fractal-like topologies in response to phosphorylation. Guided by atomic-resolution models, we develop fusions of Src homology 2 (SH2) domain or a phosphorylatable SH2-binding peptide, respectively, to two symmetric, homo-oligomeric proteins. Mixing the two designed components resulted in a variety of dendritic, hyperbranched and sponge-like topologies that are phosphorylation-dependent and self-similar over three decades (~10 nm-10 µm) of length scale, in agreement with models from multiscale computational simulations. Designed assemblies perform efficient phosphorylation-dependent capture and release of cargo proteins.


Assuntos
Proteínas de Bactérias/metabolismo , Fractais , Agregados Proteicos , Proteínas Recombinantes de Fusão/metabolismo , Algoritmos , Proteínas de Bactérias/genética , Escherichia coli/química , Humanos , Modelos Químicos , Modelos Moleculares , Fosforilação , Engenharia de Proteínas/métodos , Multimerização Proteica , Proteínas Recombinantes de Fusão/genética , Domínios de Homologia de src/genética , Quinases da Família src/metabolismo
17.
Bioorg Med Chem ; 27(14): 3082-3088, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176567

RESUMO

Short peptides derived from virulent pathogen proteins are promising antigens for the development of vaccines against infectious diseases. However, in order to mimic the danger signals associated with natural infection and stimulate an adaptive immune response, peptide antigens must be co-delivered with immune adjuvants. In this study, a group A streptococcus (GAS) M-protein derived B-cell epitope: J8, and universal T-helper epitope P25 containing peptides, were chemically coupled with different anionic amino acid-based polymers. The poly(anionic amino acid)-peptide antigen conjugates were mixed with trimethyl chitosan (TMC) to produce self-adjuvanting nanoparticulate vaccine candidates. TMC from two different sources were used to analyse their effect on immunogenicity. The nanoparticles produced from a peptide modified with 10 residues of polyglutamic acid and fungal TMC (NP5) stimulated production of the highest levels of serum antibodies in outbred mice. These antibodies were opsonic against all clinical GAS isolates tested.

18.
Proc Natl Acad Sci U S A ; 116(28): 14144-14153, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31235597

RESUMO

Epstein-Barr virus (EBV) induces histone modifications to regulate signaling pathways involved in EBV-driven tumorigenesis. To date, the regulatory mechanisms involved are poorly understood. In this study, we show that EBV infection of epithelial cells is associated with aberrant histone modification; specifically, aberrant histone bivalent switches by reducing the transcriptional activation histone mark (H3K4me3) and enhancing the suppressive mark (H3K27me3) at the promoter regions of a panel of DNA damage repair members in immortalized nasopharyngeal epithelial (NPE) cells. Sixteen DNA damage repair family members in base excision repair (BER), homologous recombination, nonhomologous end-joining, and mismatch repair (MMR) pathways showed aberrant histone bivalent switches. Among this panel of DNA repair members, MLH1, involved in MMR, was significantly down-regulated in EBV-infected NPE cells through aberrant histone bivalent switches in a promoter hypermethylation-independent manner. Functionally, expression of MLH1 correlated closely with cisplatin sensitivity both in vitro and in vivo. Moreover, seven BER members with aberrant histone bivalent switches in the EBV-positive NPE cell lines were significantly enriched in pathway analysis in a promoter hypermethylation-independent manner. This observation is further validated by their down-regulation in EBV-infected NPE cells. The in vitro comet and apurinic/apyrimidinic site assays further confirmed that EBV-infected NPE cells showed reduced DNA damage repair responsiveness. These findings suggest the importance of EBV-associated aberrant histone bivalent switch in host cells in subsequent suppression of DNA damage repair genes in a methylation-independent manner.

19.
ACS Appl Mater Interfaces ; 11(25): 22457-22463, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31194506

RESUMO

Copper sulfide has been regarded as a promising thermoelectric material with relatively high thermoelectric performance and abundant resource. Large-scale synthesis and low-cost production of high-performance thermoelectric materials are keys to widespread application of thermoelectric technology. Here, Cu2- xS particles encapsulated in a thin carbon shell are fabricated by a scalable wet chemical method (19.7 g/batch). The synthesized particles go through the crystal-phase transition from orthorhombic to tetragonal during high-temperature annealing and sintering. After the phase transition, electrical conductivity of this composite (Cu2- xS@C) increases by approximately 50% compared to that of the pure Cu2- xS sample, and can be attibuted to an increase in carrier concentration. Phonon scattering interface formation and superionic phase of Cu2- xS@C results in very low lattice thermal conductivity of 0.22 W m-1 K-1, and maximum thermoelectric figure of merit ( ZT) of 1.04 at 773 K, which is excellent for thermoelectric performance in pure-phase copper sulfide produced via chemical synthesis. This discovery sets the stage for the use of facile wet chemical synthesis methods for large-scale transition-metal chalcogenide thermoelectric material production.

20.
Stem Cell Res Ther ; 10(1): 173, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196160

RESUMO

BACKGROUND: Hematopoietic stem cell (HSC) transplantation has been widely applied to the treatment of malignant blood diseases. However, limited number of functional HSCs hinders successful transplantation. The purpose of our current study is to develop a new and cost-efficient medium formulation that could greatly enhance the expansion of HSCs while retaining their long-term repopulation and hematopoietic properties for effective clinical transplantation. METHODS: Enriched human CD34+ cells and mobilized nonhuman primate peripheral blood CD34+ cells were expanded with a new, cost-efficient expansion medium formulation, named hematopoietic expansion medium (HEM), consisting of various cytokines and nutritional supplements. The long-term repopulation potential and hematologic-lineage differentiation ability of expanded human cells were studied in the non-obese diabetic/severe combined immunodeficiency mouse model. Furthermore, the efficacy and safety studies were performed by autologous transplantation of expanded primate cells in the nonhuman primate model. RESULTS: HEM could effectively expand human CD34+ cells by up to 129 fold within 9 days. Expanded HSCs retained long-term repopulation potential and hematologic-lineage differentiation ability, as indicated by (1) maintenance (over unexpanded HSCs) of immunophenotypes of CD38-CD90+CD45RA-CD49f+ in CD34+ cells after expansion; (2) significant presence of multiple human hematopoietic lineages in mouse peripheral blood and bone marrow following primary transplantation; (3) enrichment (over unexpanded HSCs) in SCID-repopulating cell frequency measured by limiting dilution analysis; and (4) preservation of both myeloid and lymphoid potential among human leukocytes from mouse bone marrow in week 24 after primary transplantation or secondary transplantation. Moreover, the results of autologous transplantation in nonhuman primates demonstrated that HEM-expanded CD34+ cells could enhance hematological recovery after myelo-suppression. All primates transplanted with the expanded autologous CD34+ cells survived for over 18 months without any noticeable abnormalities. CONCLUSIONS: Together, these findings demonstrate promising potential for the utility of HEM to improve expansion of HSCs for clinical application.

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