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1.
Radiother Oncol ; 145: 101-108, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31931288

RESUMO

BACKGROUND AND PURPOSE: To evaluate the prognostic value of MRI-detected residual retropharyngeal lymph node (RRLN) at three months after intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC) and second, to establish a nomogram for the pretherapy prediction of RRLN. MATERIALS AND METHODS: We included 1103 patients with NPC from two hospitals (Sun Yat-Sen University Cancer Center [SYSUCC, n = 901] and Dongguan People's Hospital [DGPH, n = 202]). We evaluated the prognostic value of RRLN using Cox regression model in SYSUCC cohort. We developed a nomogram for the pretherapy prediction of RRLN using logistic regression model in SYSUCC training cohort (n = 645). We assessed the performance of this nomogram in an internal validation cohort (SYSUCC validation cohort, n = 256) and an external independent cohort (DGPH validation cohort, n = 202). RESULTS: RRLN was an independent prognostic factor for OS (HR 2.08, 95% CI 1.32-3.29), DFS (HR 2.45, 95% CI 1.75-3.42), DMFS (HR 3.31, 95% CI 2.15-5.09), and LRRFS (HR 3.04, 95% CI 1.70-5.42). We developed a nomogram based on baseline Epstein-Barr virus DNA level and three RLN status-related features (including minimum axial diameter, extracapsular nodal spread, and laterality) that predicted an individual's risk of RRLN. Our nomogram showed good discrimination in the training cohort (C-index = 0.763). The favorable performance of this nomogram was confirmed in the internal and external validation cohorts. CONCLUSION: MRI-detected RRLN at three months after IMRT was an unfavorable prognostic factor for patients with NPC. We developed and validated an easy-to-use nomogram for the pretherapy prediction of RRLN.

2.
Stem Cell Res Ther ; 11(1): 19, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915074

RESUMO

Stem cell-derived sheet engineering has been developed as the next-generation treatment for myocardial infarction (MI) and offers attractive advantages in comparison with direct stem cell transplantation and scaffold tissue engineering. Furthermore, induced pluripotent stem cell-derived cell sheets have been indicated to possess higher potential for MI therapy than other stem cell-derived sheets because of their capacity to form vascularized networks for fabricating thickened human cardiac tissue and their long-term therapeutic effects after transplantation in MI. To date, stem cell sheet transplantation has exhibited a dramatic role in attenuating cardiac dysfunction and improving clinical manifestations of heart failure in MI. In this review, we retrospectively summarized the current applications and strategy of stem cell-derived cell sheet technology for heart tissue repair in MI.

3.
Gene ; 731: 144359, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31935509

RESUMO

FMRP is an RNA-binding protein, loss of which causes fragile X syndrome (FXS). FMRP has several isoforms resulted from alternative splicing (AS) of fragile X mental retardation 1 (FMR1) gene, but their biological functions are still poorly understood. In the analysis of alternatively spliced FMR1 transcripts in the blood cells from a patient with FXS-like phenotypes (normal CGG repeats and no mutation in coding sequence of FMR1), we identified three novel FMR1 transcripts that include a previously unidentified microexon (46 bp), terming the exon 9a. This microexon exists widely in unaffected individuals, inclusion of which introduces an in-frame termination codon. To address whether these exon 9a-containing transcripts could produce protein by evading nonsense-mediated decay (NMD), Western blot was used to analysis blood cell lysate from unaffected individuals and a 34 kDa protein that consistent in size with the molecular weight of the predicted truncated protein produced from mRNA with this microexon was found. Meanwhile, treatment of peripheral blood mononuclear cells with an inhibitor of NMD (Cycloheximide) did not result in significant increase in exon 9a-containing transcripts. Using confocal immunofluorescence, we found the truncated protein displayed both nuclear and cytoplasmic localization in HEK293T and HeLa cells due to lacking C-terminal domains including KH2, NES, and RGG, while the full-length FMRP protein mainly localized in the cytoplasm. Therefore, we hypothesize that the inclusion of this microexon to generate exon 9a-containing transcripts may regulate the normal functionality of FMRP, and the dysregulation of normal FMRP due to increased exon 9a-containing alternatively spliced transcripts in that patient may be associated with the manifestation of FXS phenotype.

4.
Mol Genet Genomic Med ; 8(1): e1041, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31830381

RESUMO

BACKGROUND: Marfan syndrome (MFS) is an inherited connective tissue disease that mainly involves Fibrillin-1 (FBN1) mutations and aortic manifestations. In this study, we investigated the correlations between the FBN1 genotype-phenotype and aortic events (aortic dissection and aortic aneurysm) in patients with Marfan syndrome. METHODS: Genotype and phenotype information was evaluated in 180 patients with MFS. DNA sequencing was performed on each patient. According to the clinical manifestation, these patients were split into two groups: the aortic dissection group and the aortic aneurysm group. Aortic wall tissue was obtained from Marfan patients who underwent surgery and was used for staining. RESULTS: A total of 180 patients with FBN1 mutations were grouped into four categories: 90 with missense mutations, 32 with splicing mutations, 29 with frameshift mutations, and 29 with nonsense mutations. There was a significantly higher frequency of frameshift and nonsense mutations observed in aortic dissection than in aortic aneurysm (25.58% vs. 4.35%, p = .005; 25.58% vs. 8.70%, p = .033, respectively;), while missense mutations showed a higher frequency in aortic aneurysm than in aortic dissection (69.57% vs. 32.56%, respectively; p < .001) and a higher rate of lens dislocation (34.78% vs. 13.95%, respectively; p = .008). Pathological staining showed that elastic fibers were sparser in patients with a frameshift and nonsense mutations, and the smooth muscle cells were sparser and more disorganized than those observed in patients with missense mutations. CONCLUSION: This study showed that FBN1 gene frameshift and nonsense mutations are more common in patients with aortic dissection and may have meaningful guidance for the treatment of Marfan syndrome patients.

5.
Nat Commun ; 10(1): 4284, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537810

RESUMO

Highly specific Cas9 nucleases derived from SpCas9 are valuable tools for genome editing, but their wide applications are hampered by a lack of knowledge governing guide RNA (gRNA) activity. Here, we perform a genome-scale screen to measure gRNA activity for two highly specific SpCas9 variants (eSpCas9(1.1) and SpCas9-HF1) and wild-type SpCas9 (WT-SpCas9) in human cells, and obtain indel rates of over 50,000 gRNAs for each nuclease, covering ~20,000 genes. We evaluate the contribution of 1,031 features to gRNA activity and develope models for activity prediction. Our data reveals that a combination of RNN with important biological features outperforms other models for activity prediction. We further demonstrate that our model outperforms other popular gRNA design tools. Finally, we develop an online design tool DeepHF for the three Cas9 nucleases. The database, as well as the designer tool, is freely accessible via a web server, http://www.DeepHF.com/ .


Assuntos
Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Aprendizado Profundo , Edição de Genes/métodos , RNA Guia/genética , Animais , Sequência de Bases/genética , Linhagem Celular Tumoral , Endonucleases/metabolismo , Células HEK293 , Células HeLa , Humanos , Mutação INDEL/genética , Internet , Camundongos , Regiões Promotoras Genéticas/genética
6.
Nat Cell Biol ; 21(9): 1152-1163, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31481791

RESUMO

Ca2+/calmodulin-dependent kinase II (CaMKII) is a multifunctional serine/threonine kinase family, and its δ isoform is predominant in the heart. Excessive CaMKII activation plays a pivotal role in the pathogenesis of severe heart conditions, including myocardial infarction, cardiomyopathy and heart failure. However, the identity of CaMKII splice variants and the mechanism(s) underlying CaMKII-mediated cardiac pathology remain elusive. Here, we show that CaMKII-δ9, the most abundant CaMKII-δ splice variant in human heart, potently promotes cardiomyocyte death, cardiomyopathy and heart failure by disrupting cardiomyocyte genome stability. Mechanistically, CaMKII-δ9, but not the previously well-studied CaMKII-δ2 and CaMKII-δ3, targets the ubiquitin-conjugating enzyme E2T (UBE2T) for phosphorylation and degradation, disrupting UBE2T-dependent DNA repair and leading to the accumulation of DNA damage and genome instability. These findings not only reveal a crucial role of CaMKII in the regulation of DNA repair, but also mark the CaMKII-δ9-UBE2T-DNA damage pathway as an important therapeutic target for cardiomyopathy and heart failure.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Reparo do DNA/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Cálcio/metabolismo , Cardiomiopatias/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Camundongos , Miócitos Cardíacos/metabolismo , Fosforilação , Isoformas de Proteínas/metabolismo , Enzimas de Conjugação de Ubiquitina/genética
7.
Nano Lett ; 19(11): 7588-7597, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31398289

RESUMO

Terahertz (THz) modulators are always realized by dynamically manipulating the conversion between different resonant modes within a single unit cell of an active metasurface. In this Letter, to achieve real high-speed THz modulation, we present a staggered netlike two-dimensional electron gas (2DEG) nanostructure composite metasurface that has two states: a collective state with massive surface resonant characteristics and an individual state with meta-atom resonant characteristics. By controlling the electron transport of the nanoscale 2DEG with an electrical grid, collective-individual state conversion can be realized in this composite metasurface. Unlike traditional resonant mode conversion confined in meta-units, this state conversion enables the resonant modes to be flexibly distributed throughout the metasurface, leading to a frequency shift of nearly 99% in both the simulated and experimental transmission spectra. Moreover, such a mechanism can effectively suppress parasitic modes and significantly reduce the capacitance of the metasurface. Thereby, this composite metasurface can efficiently control the transmission characteristics of THz waves with high-speed modulations. As a result, 93% modulation depth is observed in the static experiment and modulated sinusoidal signals up to 3 GHz are achieved in the dynamic experiment, while the -3 dB bandwidth can reach up to 1 GHz. This tunable collective-individual state conversion may have great application potential in wireless communication and coded imaging.

8.
Cell Death Dis ; 10(8): 610, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31406109

RESUMO

Muscle LIM protein (MLP, CSRP3) is a key regulator of striated muscle function, and its mutations can lead to both hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in patients. However, due to lack of human models, mechanisms underlining the pathogenesis of MLP defects remain unclear. In this study, we generated a knockout MLP/CSRP3 human embryonic stem cell (hESC) H9 cell line using CRISPR/Cas9 mediated gene disruption. CSRP3 disruption had no impact on the cardiac differentiation of H9 cells and led to confirmed MLP deficiency in hESC-derived cardiomyocytes (ESC-CMs). MLP-deficient hESC-CMs were found to develop phenotypic features of HCM early after differentiation, such as enlarged cell size, multinucleation, and disorganized sarcomeric ultrastructure. Cellular phenotypes of MLP-deficient hESC-CMs subsequently progressed to mimic heart failure (HF) by 30 days post differentiation, including exhibiting mitochondrial damage, increased ROS generation, and impaired Ca2+ handling. Pharmaceutical treatment with beta agonist, such as isoproterenol, was found to accelerate the manifestation of HCM and HF, consistent with transgenic animal models of MLP deficiency. Furthermore, restoration of Ca2+ homeostasis by verapamil prevented the development of HCM and HF phenotypes, suggesting that elevated intracellular Ca2+ concentration is a central mechanism for pathogenesis of MLP deficiency. In summary, MLP-deficient hESC-CMs recapitulate the pathogenesis of HCM and its progression toward HF, providing an important human model for investigation of CSRP3/MLP-associated disease pathogenesis. More importantly, correction of the autonomous dysfunction of Ca2+ handling was found to be an effective method for treating the in vitro development of cardiomyopathy disease phenotype.

9.
Biomed Opt Express ; 10(8): 3789-3799, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31452975

RESUMO

We theoretically and experimentally demonstrate a label-free terahertz biosensor with ultrahigh sensitivity and distinctive discretion. By constructing a metal-air-metal (MAM) metamaterial perfect absorber (MPA) with a metallic paired-ring resonator array, a hollow microfluidic channel, and a backed reflector, a novel dual-band absorptive sensing platform is proposed in the THz range. The near field coupling by dipole-induced trapped modes and the magnetic momentum caused a vertical to transverse power flux that dramatically enhanced the electromagnetic field on top of the metasurface and in the microfluidic channel, respectively. Both the resonant modes exhibit perfect absorption and produce ultrahigh normalized sensitivities of 0.47/RIU (refractive index unit, RIU) and 0.51/RIU at 0.76 THz and 1.28 THz, respectively. Compared with conventional microfluidic sensors, the salient advantages of our design are the perfect spatial overlap for light-matter interaction and polarization insensitivity. Characterized by THz time domain spectroscopic absorption quantification measurements with different concentrations of bovine serum albumin (BSA), the proposed sensor exhibits promising applications in microfluidic biosensing.

10.
Org Lett ; 21(16): 6499-6503, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31343888

RESUMO

Here we provide an unprecedented biofactory where fluorescent dye-like complex xanthenes could be produced in an engineered Escherichia coli. Feeding the strain with toluquinol or hydroquinones resulted in production of novel "unnatural" natural products including four arthrocolins embedded with indolyltriphenyl quaternary carbons. Arthrocolins A-C potently inhibited various human cancer cell lines including paclitaxel-resistant cell line A549/Taxol and methicillin-resistant Staphylococcus aureus and immensely restored the sensitivity of intractable fluconazole-resistant human pathogen Candida albicans to fluconazole.

11.
Biochem Biophys Res Commun ; 515(4): 586-592, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31178132

RESUMO

The differentiation of human induced pluripotent stem cells (hiPSCs) into osteoblasts provides a new paradigm in the field of bone tissue regeneration. The embryoid body (EB) differentiation method is commonly used for the osteogenic differentiation of hiPSCs. However, the spontaneous differentiation process of EBs is poorly understood, as evidenced by the inconsistency of the suspension time among previously reported studies as well as the low osteoblastic differentiation efficiency of hiPSCs. In the present study, we investigated the effects of the suspension culture time of EBs on the osteogenic differentiation of hiPSCs. Under chemically defined conditions, the expression of key genes related to presomitic mesoderm, neural crest, mesenchymal and pre-osteoblast cells in EBs derived from hiPSCs was examined daily by quantitative RT-PCR. Then, EBs with varying times in suspension (3, 5, 7 or 10 days) were attached onto gelatine surfaces, and their osteoblastic differentiation efficiencies after 14 days of culture in osteogenic induction medium were determined. Our results showed that EBs derived from hiPSCs subjected to 4 days of suspension culture produced the most mesenchymal stem cells, and exhibited the best osteogenic differentiation efficiency. Our research is valuable to standardizing, the time in suspension for the osteogenic differentiation of hiPSCs through the EB method, and facilitated the development of a high-efficiency in vitro osteogenic differentiation system for hiPSCs.

12.
Clin Sci (Lond) ; 133(13): 1387-1399, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31239293

RESUMO

Recent evidence has shown that cardiomyocytes (CMs) can proliferate at a low level after myocardial infarction (MI), but it is insufficient to reestablish heart function. Several microRNAs (miRNAs) have been proven to sufficiently induce rodent CM proliferation. However, whether miRNAs identified in rodents can promote human CM proliferation is unknown due to the poorly conserved functions of miRNAs among species. In the present study, we demonstrate that i) expression of microRNA-302d (miR-302d) decreased significantly during CM differentiation from human pluripotent stem cells (hPSCs) from day 4 to day 18; ii) miR-302d efficiently promoted proliferation of hPSC-derived CMs; iii) miR-302d promoted CM proliferation by targeting LATS2 in the Hippo pathway; and iv) RNA-sequencing analysis revealed that overexpression of miR-302d induced changes in gene expression, which mainly converged on the cell cycle. Our study provides further evidence for the therapeutic potential of miR-302d.

13.
J Cell Mol Med ; 23(7): 4627-4639, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31106979

RESUMO

Doxorubicin (DOX) is widely used to treat various cancers affecting adults and children; however, its clinical application is limited by its cardiotoxicity. Previous studies have shown that children are more susceptible to the cardiotoxic effects of DOX than adults, which may be related to different maturity levels of cardiomyocyte, but the underlying mechanisms are not fully understood. Moreover, researchers investigating DOX-induced cardiotoxicity caused by human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have shown that dexrazoxane, the recognized cardioprotective drug for treating DOX-induced cardiotoxicity, does not alleviate the toxicity of DOX on hiPSC-CMs cultured for 30 days. We have suggested that this may be ascribed to the immaturity of the 30 days hiPSC-CMs. In this study, we investigated the mechanisms of DOX induced cardiotoxicity in cardiomyocytes of different maturity. We selected 30-day-old and 60-day-old hiPSC-CMs (day 30 and day 60 groups), which we term 'immature' and 'relatively mature' hiPSC-CMs, respectively. The day 30 CMs were found to be more susceptible to DOX than the day 60 CMs. DOX leads to more ROS (reactive oxygen species) production in the day 60 CMs than in the relatively immature group due to increased mitochondria number. Moreover, the day 60 CMs mainly expressed topoisomerase IIß presented less severe DNA damage, whereas the day 30 CMs dominantly expressed topoisomerase IIα exhibited much more severe DNA damage. These results suggest that immature cardiomyocytes are more sensitive to DOX as a result of a higher concentration of topoisomerase IIα, which leads to more DNA damage.

14.
Biomed Res Int ; 2019: 1420216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119151

RESUMO

Background: Continued debates exist regarding the optimal temperature during hypothermic circulatory arrest in aortic arch repair for patients with type A aortic dissection. This study seeks to examine whether the use of moderate hypothermic circulatory arrest in a pig model provides comparable vital organ protection outcomes to the use of deep hypothermic circulatory arrest. Methods: Thirteen pigs were randomly assigned to 30 minutes of hypothermic circulatory arrest without cerebral perfusion at 15°C (n = 5), 25°C (n = 5), and a control group (n = 3). The changes in standard laboratory tests and capacity for protection against apoptosis in different vital organs were monitored with different temperatures of hypothermic circulatory arrest management in pig model to determine which temperature was optimal for hypothermic circulatory arrest. Results: There were no significant differences in the capacity for protection against apoptosis in vital organs between 2 groups (p > 0.05, respectively). Compared with the moderate hypothermic circulatory arrest group, the deep hypothermic circulatory arrest group had no significant advantages in terms of the biologic parameters of any other organs (p > 0.05). Conclusions: Compared with deep hypothermic circulatory arrest, moderate hypothermic circulatory arrest is a moderate technique that has similar advantages with regard to the levels of biomarkers of injury and capacity for protection against apoptosis in vital organs.


Assuntos
Apoptose/genética , Parada Circulatória Induzida por Hipotermia Profunda , Hipotermia Induzida , Miocárdio/metabolismo , Aneurisma Dissecante/genética , Aneurisma Dissecante/patologia , Aneurisma Dissecante/terapia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Caspase 3/genética , Circulação Cerebrovascular/genética , Parada Cardíaca Induzida/métodos , Humanos , Rim/irrigação sanguínea , Rim/metabolismo , Fígado/irrigação sanguínea , Fígado/metabolismo , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Suínos , Proteína X Associada a bcl-2/genética
15.
J Cell Mol Med ; 23(7): 4666-4678, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31033175

RESUMO

The traditional Chinese herb Lonicerae Japonicae Flos has shown significant clinical benefits in the treatment of heart failure, but the mechanism remains unclear. As the main active ingredient found in the plasma after oral administration of Lonicerae Japonicae Flos, chlorogenic acid (CGA) has been reported to possess anti-inflammatory, anti-oxidant and anti-apoptosis function. We firstly confirmed the cardioprotective effects of CGA in transverse aortic constriction (TAC)-induced heart failure mouse model, through mitigating the TNF-α-induced toxicity. We further used TNF-α-induced cardiac injury in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to elucidate the underlying mechanisms. CGA pre-treatment could reverse TNF-α-induced cellular injuries, including improved cell viability, increased mitochondrial membrane potential and inhibited cardiomyocytes apoptosis. We then examined the NF-κB/p65 and major mitogen-activated protein kinases (MAPKs) signalling pathways involved in TNF-α-induced apoptosis of hiPSC-CMs. Importantly, CGA can directly inhibit NF-κB signal by suppressing the phosphorylation of NF-κB/p65. As for the MAPKs, CGA suppressed the activity of only c-Jun N-terminal kinase (JNK), but enhanced extracellular signal-regulated kinase1/2 (ERK1/2) and had no effect on p38. In summary, our study revealed that CGA has profound cardioprotective effects through inhibiting the activation of NF-κB and JNK pathway, providing a novel therapeutic alternative for prevention and treatment of heart failure.

16.
J Pineal Res ; 67(2): e12579, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30958896

RESUMO

Exercise-induced physiological hypertrophy provides protection against cardiovascular disease, whereas disease-induced pathological hypertrophy leads to heart failure. Emerging evidence suggests pleiotropic roles of melatonin in cardiac disease; however, the effects of melatonin on physiological vs pathological cardiac hypertrophy remain unknown. Using swimming-induced physiological hypertrophy and pressure overload-induced pathological hypertrophy models, we found that melatonin treatment significantly improved pathological hypertrophic responses accompanied by alleviated oxidative stress in myocardium but did not affect physiological cardiac hypertrophy and oxidative stress levels. As an important mediator of melatonin, the retinoid-related orphan nuclear receptor-α (RORα) was significantly decreased in human and murine pathological hypertrophic cardiomyocytes, but not in swimming-induced physiological hypertrophic murine hearts. In vivo and in vitro loss-of-function experiments indicated that RORα deficiency significantly aggravated pathological cardiac hypertrophy, and notably weakened the anti-hypertrophic effects of melatonin. Mechanistically, RORα mediated the cardioprotection of melatonin in pathological hypertrophy mainly by transactivation of manganese-dependent superoxide dismutase (MnSOD) via binding to the RORα response element located in the promoter region of the MnSOD gene. Furthermore, MnSOD overexpression reversed the pro-hypertrophic effects of RORα deficiency, while MnSOD silencing abolished the anti-hypertrophic effects of RORα overexpression in pathological cardiac hypertrophy. Collectively, our findings provide the first evidence that melatonin exerts an anti-hypertrophic effect on pathological but not physiological cardiac hypertrophy via alleviating oxidative stress through transactivation of the antioxidant enzyme MnSOD in a RORα-dependent manner.


Assuntos
Cardiomegalia/metabolismo , Melatonina/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Mutantes , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Superóxido Dismutase/genética
17.
Nat Commun ; 10(1): 1925, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028288

RESUMO

Water can freeze into diverse ice polymorphs depending on the external conditions such as temperature (T) and pressure (P). Herein, molecular dynamics simulations show evidence of a high-density orthorhombic phase, termed ice χ, forming spontaneously from liquid water at room temperature under high-pressure and high external electric field. Using free-energy computations based on the Einstein molecule approach, we show that ice χ is an additional phase introduced to the state-of-the-art T-P phase diagram. The χ phase is the most stable structure in the high-pressure/low-temperature region, located between ice II and ice VI, and next to ice V exhibiting two triple points at 6.06 kbar/131.23 K and 9.45 kbar/144.24 K, respectively. A possible explanation for the missing ice phase in the T-P phase diagram is that ice χ is a rare polarized ferroelectric phase, whose nucleation/growth occurs only under very high electric fields.

18.
Stem Cell Res ; 36: 101414, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30870686

RESUMO

Marfan syndrome (MFS) is a heritable connective tissue disease caused by mutations in FBN1, encoding the extracellular matrix protein fibrillin-1. In this study, we generated human induced pluripotent stem cells (iPSCs) from dermal fibroblasts of an MFS patient with the p. E2130K (c. 6388G > A) mutation. The generated hiPSC line had a normal karyotype, showed robust expression of pluripotency markers and was able to differentiate into all three germ layers in vivo. This cell line can provide a platform for understanding the pathogenic mechanisms of MFS related to FBN1 mutations. Resource table.

19.
World J Gastroenterol ; 25(3): 378-387, 2019 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-30686905

RESUMO

BACKGROUND: Cirrhosis is a chronic late stage liver disease associated with hepatitis viruses, alcoholism, and metabolic disorders, such as Wilson disease (WD). There are no clear markers or clinical features that define cirrhosis originating from these disparate origins. We hypothesized that cirrhosis is not one disease and cirrhosis of different etiology may have differential clinical hepatic features. AIM: To delineate the liver features between WD-associated cirrhosis and hepatitis B-associated cirrhosis in the Chinese population. METHODS: In this observational study, we reviewed the medical data of consecutive inpatients who had WD-associated cirrhosis or hepatitis B-associated cirrhosis from January 2010 to August 2018, and excluded patients who had carcinoma, severe heart or pulmonary diseases, or other liver diseases. According to the etiology of cirrhosis, patients were divided into two groups: WD-associated cirrhosis group (60 patients) and hepatitis B-associated cirrhosis group (56 patients). The liver fibrosis degree, liver function indices, and portal hypertension features of these patients were compared between the two groups. RESULTS: No inter-group differences were observed in the diagnostic liver fibrosis markers, however, clinical features clearly defined the origin of cirrhosis. WD-associated cirrhosis patients (16-29 years) had lower levels of alanine transaminase, aspartate transaminase, and bilirubin, lower prothrombin time, lower incidence of hepatic encephalopathy, and lower portal vein diameter (P < 0.05), compared to cirrhosis resulting from hepatitis B in older patients (45-62 years). Importantly, they had decreased risks of progression from Child-Pugh grade A to B (odds ratio = 0.046, 95% confidence interval: 0.006-0.387, P = 0.005) and of ascites (odds ratio = 0.08, 95% confidence interval: 0.01-0.48, P = 0.005). Conversely, WD-associated cirrhosis patients had a higher risk of splenomegaly (odds ratio = 4.15, 95% confidence interval: 1.38-12.45, P = 0.011). CONCLUSION: WD-associated cirrhosis presents a higher risk of splenomegaly associated with leukopenia and thrombocytopenia, although revealing milder liver dysfunction and portal hypertension symptoms, which recommends WD patients to be monitored for associated complications.


Assuntos
Hepatite B Crônica/complicações , Degeneração Hepatolenticular/complicações , Hipertensão Portal/etiologia , Cirrose Hepática/etiologia , Fígado/patologia , Adolescente , Adulto , Biomarcadores/análise , China/epidemiologia , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Degeneração Hepatolenticular/sangue , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/diagnóstico por imagem , Leucopenia/epidemiologia , Leucopenia/etiologia , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/virologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/virologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Veia Porta/diagnóstico por imagem , Veia Porta/patologia , Estudos Retrospectivos , Esplenomegalia/diagnóstico por imagem , Esplenomegalia/epidemiologia , Esplenomegalia/etiologia , Trombocitopenia/epidemiologia , Trombocitopenia/etiologia , Adulto Jovem
20.
J Cell Mol Med ; 23(3): 1687-1697, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30636376

RESUMO

Tissue damage and its associated-inflammation act as tumour initiators or propagators. AMP-activated protein kinase (AMPK) is activated by environmental or nutritional stress factors, such as hypoxia, glucose deprivation, and other cell injury factors, to regulate cell energy balance and differentiation. We previously have reported that AMPKα2 deficiency resulted in the energy deprivation in tumour-bearing liver and the enhanced-hepatocyte death. In this study, AMPKα2 knockout mice and the liver metastasis model of colon cancer cells were used to address the role of AMPKα isoforms in tumour inflammation. First, we found that the AMPKα2 deficiency exacerbated the liver injury and recruitment of macrophages. Meanwhile, although compensatory expression of AMPKα1 was not significant after AMPKα2 knockout, AMPKα1 phosphorylation was elevated in remnant liver in AMPKα2 knockout mice, which was positively associated with the enhanced energy deprivation in the AMPKα2 deficient mice. Furthermore, the activated AMPKα1 in macrophage contributed to its polarizing to tumour-associated phenotype. Thus, the enhanced tumour-associated inflammation and activation of AMPKα1 in the AMPKα2 deficient mice may exacerbate the tumour development by affecting the tumour inflammatory microenvironment. Our study suggests that the two isoforms of AMPKα, AMPKα1 and AMPKα2 play different roles in controlling tumour development.

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