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1.
Zhongguo Yi Liao Qi Xie Za Zhi ; 43(5): 318-321, 2019 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-31625325

RESUMO

In order to diagnose and evaluate the human spinal lesions through the paravertebral muscles, a paravertebral muscle monitoring system based on surface EMG signals was designed. The system used surface mount electrodes to obtain the surface myoelectric signal (sEMG) of paravertebral muscle. The signal was filtered and amplified by the conditioning circuit. The signal was collected by the microcontroller NRF52832 and was sent to the mobile APP. After the signal was preprocessed by the wavelet threshold denoising algorithm in APP, the time and frequency characteristics of the sEMG signal reflecting the functional state of the muscle were extracted. The calculated characteristic parameters was displayed in real time in the application interface. The experimental results show that the system meets the design requirements in analog signal acquisition, digital processing of signals and calculation of characteristic parameters. The system has certain application value.

2.
Chaos ; 29(7): 073110, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31370423

RESUMO

Effects of a low-pass active filter (LPAF) on the transition processes from oscillation quenching to asymmetrical oscillation are explored for diffusively coupled oscillators. The low-pass filter part and the active part of LPAF exhibit different effects on the dynamics of these coupled oscillators. With the amplifying active part only, LPAF keeps the coupled oscillators staying in a nontrivial amplitude death (NTAD) and oscillation state. However, the additional filter is beneficial to induce a transition from a symmetrical oscillation death to an asymmetrical oscillation death and then to an asymmetrical oscillation state which is oscillating with different amplitudes for two oscillators. Asymmetrical oscillation state is coexisting with a synchronous oscillation state for properly presented parameters. With the attenuating active part only, LPAF keeps the coupled oscillators in rich oscillation quenching states such as amplitude death (AD), symmetrical oscillation death (OD), and NTAD. The additional filter tends to enlarge the AD domains but to shrink the symmetrical OD domains by increasing the areas of the coexistence of the oscillation state and the symmetrical OD state. The stronger filter effects enlarge the basin of the symmetrical OD state which is coexisting with the synchronous oscillation state. Moreover, the effects of the filter are general in globally coupled oscillators. Our results are important for understanding and controlling the multistability of coupled systems.

3.
Hum Immunol ; 80(10): 863-870, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31262519

RESUMO

Regulatory B (Breg) cells are a special subset of immunoregulatory cells with unique phenotypes and functions. In this study, human CD19+CD25high Breg cells were purified from human peripheral blood. Based on the coculture system of Breg cells and CD4+ T cells in vitro, Breg cells were found to promote the increase in regulatory T (Treg) cells while decreasing the number of Th17 cells. Breg cells regulate Treg cells through two processes: cell-cell contact and cytokines. TGF-ßsRII, a blocker of transforming growth factor-ß (TGF-ß), can attenuate the effects of Treg elevation, suggesting that TGF-ß is the main cytokine, while Breg cells rather than interleukin-10 (IL-10) regulate the differentiation of Treg cells. However, Th17 cells were mainly regulated by cytokines, without an obvious regulatory effect on cell-cell contacts. Breg cells may regulate Th17 cells by a pathway independent of TGF-ß and IL-6. The coculture of Breg cells and CD4+ T cells led to changes in the cytokine spectrum, which included significant increases in IL-4, IL-6 and IL-10 but not obvious changes in IL-2, IFN-γ and TNF. The inhibitory effect of Breg cells was weakened by blocking cell-cell contacts in cultures separated with the Transwell chamber because IL-10 decreased while IL-6 increased when compared with cocultured Breg and CD4+ T cells. When the IL-10 inhibitor IL-10sRα was added, IL-6 and TNF levels significantly increased, while treatment with the TGF-ß inhibitor TGF-ßsRII did not result in similar changes, suggesting that IL-10 is an important molecule to inhibit the proinflammatory factors IL-6 and TNF in this culture system.

4.
J Psychiatr Res ; 115: 165-175, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31150948

RESUMO

Bipolar disorder (BPD) is a severe mental illness characterized by fluctuations in mood states, behaviors and energy levels. Growing evidence suggests that genes associated with specific illnesses tend to interact together and encode a tight protein-protein interaction (PPI) network, providing valuable information for understanding their pathogenesis. To gain insights into the genetic and physiological foundation of BPD, we conduct the physical PPI analysis of 184 BPD risk genes distilled from genome-wide association studies and exome sequencing studies. We have identified several hub genes (CAMK2A, HSP90AA1 and PLCG1) among those risk genes, and observed significant enrichment of the BPD risk genes in certain pathways such as calcium signaling, oxytocin signaling and circadian entrainment. Furthermore, while none of the 184 genetic risk genes are "well established" BPD drug targets, our PPI analysis showed that αCaMKII (encoded by CAMK2A) had direct physical PPIs with targets (HRH1, SCN5A and CACNA1E) of clinically used anti-manic BPD drugs, such as carbamazepine. We thus speculated that αCaMKII might be involved in the cellular pharmacological actions of those drugs. Using cultured rat primary cortical neurons, we found that carbamazepine treatment induced phosphorylation of αCaMKII in dose-dependent manners. Intriguingly, previous study showed that CAMK2A heterozygous knockout (CAMK2A+/-) mice exhibited infradian oscillation of locomotor activities that can be rescued by carbamazepine. Our data, in combination with previous studies, provide convergent evidence for the involvement of CAMK2A in the risk of BPD.

5.
Cell Prolif ; 52(4): e12631, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31038259

RESUMO

OBJECTIVES: Growth differentiation factor 11 (GDF11), an emerging secreted member of the TGF-beta superfamily, plays essential roles in development, physiology and multiple diseases; however, its role during adipogenic differentiation and the underlying mechanisms remains poorly understood. MATERIALS AND METHODS: Bone marrow-derived human mesenchymal stem cells (hMSCs) and 3T3-L1 pre-adipocytes were induced with adipogenic culture medium supplementing with different concentrations of recombinant GDF11 (rGDF11 0, 10, 50, 100 ng mL-1 ). Oil Red O staining, qRT-PCR analysis, Western blot analysis and immunofluorescence staining were performed to assay adipogenesis. RESULTS: For both hMSCs and 3T3-L1 pre-adipocytes, the presence of rGDF11 leads to a dose-dependent reduction of intracellular lipid droplet accumulation and suppressed adipogenic-related gene expression. Mechanically, GDF11 inhibits adipogenesis by activating Smad2/3-dependent TGF-beta signalling pathway, and these inhibitory effects could be restored by SB-431542, a pharmacological TGF-beta type I receptor inhibitor. CONCLUSIONS: Taken together, our data indicates that GDF11 inhibits adipogenic differentiation in both hMSCs and 3T3-L1 pre-adipocytes by activating Smad2/3-dependent TGF-beta signalling pathway.


Assuntos
Adipócitos/metabolismo , Adipogenia/fisiologia , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular/fisiologia , Fatores de Diferenciação de Crescimento/metabolismo , Transdução de Sinais/fisiologia , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células 3T3-L1 , Animais , Linhagem Celular , Expressão Gênica/fisiologia , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos
6.
Sensors (Basel) ; 19(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991644

RESUMO

A composite concrete column with encased fiber reinforced polymer (FRP) confined concrete cores (EFCCC) is proposed in this paper. The cross-sectional form of the EFCCC column is composed of several orderly arranged FRP confined concrete cores (FCCCs) surrounding a filled core concrete. This novel composite column has several advantages, such as higher compressive capacity, stronger FRP confinement, and ductile response. The compressive experiment is employed to investigate the compressive behavior of the EFCCC column with deferent parameters, such as outside concrete and stirrups. Test results show that the main failure mode of the EFCCC column with and without an outside concrete or stirrups is tensile fracture of the glass fiber reinforced polymer (GFRP) tubes. Compared to a reinforced concrete (RC) column, the strength and ductility of the EFCCC column was obviously improved by 20% and 500%, respectively. A finite element model (FEM) based on the Drucker-Prager (D-P) was developed that can accurately predict the axial compression behavior of the composite column with FRP confined concrete core. The predicted results obtained by using this FEM have excellent agreement with the experimental results.

7.
Sensors (Basel) ; 19(4)2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30781756

RESUMO

An innovative pultruded fiber reinforced polymer (FRP)⁻wood composite (PFWC) column with a lightweight southern pine wood core confined by outer FRP sheets was manufactured using an improved pultrusion process. Axial compression tests with both ends pinned as boundary conditions were employed to investigate the mechanical performance of such PFWC columns under concentric load. Through experimental investigations, the effects of the slenderness ratio on the failure modes and the axial load bearing capacities of the PFWC columns were evaluated. The failure modes showed that the specimens with a slenderness ratio less than 43.2 failed through compressive failure at junctions on FRP sheets, while those with slenderness ratios larger than 57.6 showed global buckling. Strain responses on specimens with different slenderness ratios are consistent with the observed failure modes. Finite element analysis was carried out to validate the experimental results, and satisfactory agreement was found between the failure modes and load⁻displacement curves. An empirical equation was developed with a new factor taking 0.65 into account to predict the load bearing capacities of the PFWC columns, and good agreement was found.

9.
Ann N Y Acad Sci ; 1440(1): 54-66, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30575056

RESUMO

Growth differentiation factor 11 (GDF11), a secreted member of the transforming growth factor-ß (TGF-ß) superfamily, has been reported to have the capacity to reverse age-related pathologic changes and regulate organ regeneration after injury; however, the role of GDF11 in fracture healing and bone repair is still unclear. Here, we established a fracture model in 12-week-old male mice to observe two healing states: the cartilaginous callus and bony callus formation phases. Our results showed that recombinant GDF11 (rGDF11) injection inhibits cartilaginous callus maturation and hard callus formation, thereby impairing fracture healing in vivo. In vitro, rGDF11 administration inhibited chondrocyte differentiation and maturation by phosphorylating SMAD2/3 protein and inhibiting RUNX2 expression. Notably, inhibition of TGF-ß activity by a SMAD-specific inhibitor attenuated GDF11 effects. Thus, our study demonstrates that, rather than acting as a rejuvenating agent, rGDF11 impairs fracture healing by inhibiting chondrocyte differentiation and maturation.

10.
Transl Psychiatry ; 8(1): 270, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30531795

RESUMO

Genetic analyses of psychiatric illnesses, such as bipolar disorder (BPD), have revealed essential information regarding the underlying pathological mechanisms. While such studies in populations of European ancestry have achieved prominent success, understanding the genetic risk factors of these illnesses (especially BPD) in Chinese population remains an urgent task. Given the lack of genome-wide association study (GWAS) of BPD in Chinese population from Mainland China, replicating the previously reported GWAS hits in distinct populations will provide valuable information for future GWAS analysis in Han Chinese. In the present study, we have recruited 1146 BPD cases and 1956 controls from Mainland China for genetic analyses, as well as 65 Han Chinese brain amygdala tissues for mRNA expression analyses. Using this clinical sample, one of the largest Han Chinese BPD samples till now, we have conducted replication analyses of 21 single nucleotide polymorphisms (SNPs) extracted from previous GWAS of distinct populations. Among the 21 tested SNPs, 16 showed the same direction of allelic effects in our samples compared with previous studies; 6 SNPs achieved nominal significance (p < 0.05) at one-tailed test, and 2 additional SNPs showed marginal significance (p < 0.10). Aside from replicating previously reported BPD risk SNPs, we herein also report several intriguing findings: (1) the SNP rs174576 was associated with BPD in our Chinese sample and in the overall global meta-analysis, and was significantly correlated with FADS1 mRNA in diverse public RNA-seq datasets as well as our in house collected Chinese amygdala samples; (2) two (partially) independent SNPs in MAD1L1 were both significantly associated with BPD in our Chinese sample, which was also supported by haplotype analysis; (3) a rare SNP rs78089757 in 10q26.13 region was a genome-wide significant variant for BPD in East Asians, and this SNP was near monomorphic in Europeans. In sum, these results confirmed several significant BPD risk genes. We hope this Chinese BPD case-control sample and the current brain amygdala tissues (with continuous increasing sample size in the near future) will provide helpful resources in elucidating the genetic and molecular basis of BPD in this major world population.


Assuntos
Transtorno Bipolar/genética , Proteínas de Ciclo Celular/genética , Ácidos Graxos Dessaturases/genética , Proteínas Nucleares/genética , Grupo com Ancestrais do Continente Asiático/genética , Transtorno Bipolar/epidemiologia , China/epidemiologia , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Fatores de Risco
11.
Anat Rec (Hoboken) ; 301(11): 1917-1927, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30288932

RESUMO

It is well known that nerves modulate the development and remodeling of blood vessels by releasing different neuropeptides and neurotransmitters. Secretoneurin (SN), a neuropeptide located in nerve fibers along blood vessels, acts as a pro-angiogenic agent and induces postnatal vasculogenesis. However, little is known about its involvement in arteriogenesis. In the present study, we tested the hypothesis that SN promotes arteriogenesis in a rat model of hind limb ischemia, as such, we evaluated the effect of this neuropeptide on proliferation and the production of adhesion and chemotaxis molecules in vascular smooth muscle cells (VSMCs), the main component that carries the burden of the transformation of a small arteriole into a large collateral vessel. In vivo, SN-immunoreactive nerve fibers were abundantly distributed in the adventitia of the collateral vessel. Moreover, administration of SN induced cell proliferation in the vascular wall and the infiltration of inflammatory cells/macrophages to promote collateral vessel growth. This was shown by an increased density of arterioles/arteries, together with a well-developed network of collateral vessels, and well-preserved skeletal muscles. In vitro, SN exerted proliferative effects on VSMCs and stimulated these cells to express adhesion molecules. In conclusion, our data demonstrate for the first time that SN acts as a mediator of inflammation, contributing to collateral vessel growth, in addition to directly stimulating cell proliferation in the vascular wall to promote collateral vessel growth in a rat model of hind limb ischemia. Anat Rec, 301:1917-1927, 2018. © 2018 Wiley Periodicals, Inc.

12.
EMBO J ; 37(20)2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30181118

RESUMO

The osteogenic differentiation of mesenchymal stem cells (MSCs) is governed by multiple mechanisms. Growing evidence indicates that ubiquitin-dependent protein degradation is critical for the differentiation of MSCs and bone formation; however, the function of ubiquitin-specific proteases, the largest subfamily of deubiquitylases, remains unclear. Here, we identify USP34 as a previously unknown regulator of osteogenesis. The expression of USP34 in human MSCs increases after osteogenic induction while depletion of USP34 inhibits osteogenic differentiation. Conditional knockout of Usp34 from MSCs or pre-osteoblasts leads to low bone mass in mice. Deletion of Usp34 also blunts BMP2-induced responses and impairs bone regeneration. Mechanically, we demonstrate that USP34 stabilizes both Smad1 and RUNX2 and that depletion of Smurf1 restores the osteogenic potential of Usp34-deficient MSCs in vitro Taken together, our data indicate that USP34 is required for osteogenic differentiation and bone formation.

13.
Phys Chem Chem Phys ; 20(32): 20856-20862, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30066712

RESUMO

The reverse process of dye molecule adsorption on the surface of nanoparticles, that is, the desorption process, has long been neglected in the field of dye-sensitized solar cells (DSCs). It is crucial to develop an in situ technology that controls the rate of dye desorption. Meanwhile, controlling the coverage of dye-sensitized films is still a major challenge. The work presented in this paper applies a simple and effective method to study the in situ mass change responses on dye-sensitized TiO2 films over different potential ranges. The result shows that dye molecule desorption is accompanied by the adsorption of ions in solution. Due to this parasitic adsorption process, the frequency responses in the electrochemical quartz crystal microbalance (EQCM) test cannot be completely attributable to dye molecule desorption. We established a new model to eliminate the impact of this parasitic adsorption process. The kinetics of in situ desorption of dye molecules on sensitized TiO2 nanoparticles in a high-concentration solution was studied. We found that the in situ desorption of dye could be described by pseudo-first-order kinetics. The results suggest that the dye in situ desorption rate is dependent on the bias voltage, and the coverage of dye on the surface of TiO2 films can be further controlled. In-depth research of the dye desorption process is theoretically significant to study DSC stability, new dye synthesis and complex interface structures.

14.
Mol Neuropsychiatry ; 4(1): 30-34, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29998116

RESUMO

Genome-wide association studies suggest that rs1064395 in the neurocan gene (NCAN) is a potential risk factor for bipolar disorder (BPD), and further replication analyses in larger independent samples are needed. We herein analyzed rs1064395 in a Han Chinese sample of 1,146 BPD cases and 2,031 controls, followed by a meta-analysis of BPD samples from worldwide populations including a total of 15,318 cases and 91,990 controls. The meta-analysis found that rs1064395 showed a genome-wide significant association with BPD (p = 4.92 × 10-9, OR = 1.126 for the A allele), although it did not reach the significance level in the Han Chinese sample (p = 0.415, OR = 1.070 for the A allele). We also examined the association between the single nucleotide polymorphisms and major depressive disorder (MDD) given the presumed genetic overlap between BPD and MDD, and rs1064395 was also associated with MDD (p = 0.0068, OR = 1.067 for the A allele) in a meta-analysis of 14,543 cases and 14,856 controls. Our data provide further evidence for the involvement of NCAN in the genetic susceptibility to BPD and also implicate its broader role in major mood disorders.

15.
BMC Psychiatry ; 18(1): 149, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29801445

RESUMO

BACKGROUND: Accumulating evidences indicated that mitochondrial abnormalities were associated with bipolar disorder. As a sensitive index of mitochondrial function and biogenesis, Mitochondrial DNA copy number (mtDNAcn) may be involved in the pathophysiology of bipolar disorder. METHODS: Leukocyte relative mtDNAcn was measured by quantitative polymerase chain reaction in subjects with BD (n = 131) in manic, depressive, and euthymic symptoms. Thirty-four healthy individuals were used as comparison control. BD clinical symptomatology was evaluated by Young Mania Rating Scale (YMRS), Hamilton Depression Scale (HAM-D), Clinical Global Impression-Bipolar Disorder-Severity of Illness Scale (CGI-BD-S), and the Positive and Negative Syndrome Scale (PANSS). RESULTS: Compared to healthy controls, BD patients with manic and depressive symptoms presented significantly decreased mtDNAcn levels (p-value = 0.009 and 0.041, respectively). No significant differences were detected in mtDNAcn between euthymic patients and healthy controls. The mtDNAcn was negatively correlated with the number of relapses in manic patients (ß = - 0.341, p = 0.044). CONCLUSIONS: Our study described the first evidence of (1) a significant decline of mtDNAcn in manic BD patients, (2) a similar decreased level of mtDNAcn between manic and depressed BD patients, (3) a negative correlation of mtDNAcn with number of relapses in patients suffering from manic states. Alterations of mtDNAcn in manic and depressed patients, which may reflect disturbances of energy metabolism, supported the role of mitochondrial abnormalities in the pathophysiology of BD.

16.
Proc Natl Acad Sci U S A ; 115(16): E3749-E3758, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29618612

RESUMO

The pathogenesis of parathyroid gland hyperplasia is poorly understood, and a better understanding is essential if there is to be improvement over the current strategies for prevention and treatment of secondary hyperparathyroidism. Here we investigate the specific role of Klotho expressed in the parathyroid glands (PTGs) in mediating parathyroid hormone (PTH) and serum calcium homeostasis, as well as the potential interaction between calcium-sensing receptor (CaSR) and Klotho. We generated mouse strains with PTG-specific deletion of Klotho and CaSR and dual deletion of both genes. We show that ablating CaSR in the PTGs increases PTH synthesis, that Klotho has a pivotal role in suppressing PTH in the absence of CaSR, and that CaSR together with Klotho regulates PTH biosynthesis and PTG growth. We utilized the tdTomato gene in our mice to visualize and collect PTGs to reveal an inhibitory function of Klotho on PTG cell proliferation. Chronic hypocalcemia and ex vivo PTG culture demonstrated an independent role for Klotho in mediating PTH secretion. Moreover, we identify an interaction between PTG-expressed CaSR and Klotho. These findings reveal essential and interrelated functions for CaSR and Klotho during parathyroid hyperplasia.


Assuntos
Glucuronidase/fisiologia , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/biossíntese , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Osso e Ossos/patologia , Cálcio/metabolismo , Cálcio na Dieta/administração & dosagem , Feminino , Glucuronidase/deficiência , Glucuronidase/genética , Homeostase , Hipercalcemia/genética , Hipercalcemia/patologia , Hiperparatireoidismo/genética , Hiperparatireoidismo/patologia , Hiperplasia , Hipocalcemia/metabolismo , Hipofosfatemia/genética , Hipofosfatemia/patologia , Imunoprecipitação , Rim/patologia , Masculino , Camundongos , Glândulas Paratireoides/patologia , Hormônio Paratireóideo/genética , Mapeamento de Interação de Proteínas , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores Acoplados a Proteínas-G/deficiência , Receptores Acoplados a Proteínas-G/genética
17.
Oncol Rep ; 39(4): 1853-1859, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29393475

RESUMO

The primary reasons for the treatment failure of patients with oral tongue squamous cell carcinoma (OTSCC) are metastasis and tumor recurrence. Identifying the exact mechanisms underlying metastasis is a key point in improving patient prognosis. It has been reported that a hypoxic microenvironment plays an important role during the metastasis of malignancies. We found that the expression of fibronectin type III domain containing 3B (FNDC3B) is positively correlated with lymph node metastasis and advanced cTNM stage of OTSCC by IHC assay and correlation analysis. Furthermore, we found that knockdown of FNDC3B could suppress the migratory and invasive abilities of OTSCC cells. In addition, treating OTSCC cells with CoCl2 (a hypoxia mimetic agent) upregulated the mRNA and protein expression of FNDC3B via HIF-1α. Moreover, the resultant increase in FNDC3B expression significantly induced epithelial-mesenchymal transition (EMT) in OTSCC cells. The present study elucidated the important role played by FNDC3B in OTSCC metastasis and indicates FNDC3B as a potential target for the treatment of OTSCC metastasis. However, many questions remain to be explored.


Assuntos
Carcinoma de Células Escamosas/genética , Fibronectinas/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias da Língua/genética , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Hipóxia Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Cobalto/farmacologia , Transição Epitelial-Mesenquimal/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Língua/patologia , Microambiente Tumoral/genética
18.
J Physiol ; 596(8): 1341-1355, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29377142

RESUMO

KEY POINTS: T-wave alternans (TWA) and T-wave lability (TWL) are precursors of ventricular arrhythmias in long QT syndrome; however, the mechanistic link remains to be clarified. Computer simulations show that action potential duration (APD) prolongation and slowed heart rates promote APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos can exacerbate pre-existing or induce de novo APD dispersion, which combines with enhanced ICa,L to result in premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs can directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or further exacerbate the APD dispersion to cause spontaneous initiation of ventricular arrhythmias. Experiments conducted in transgenic long QT rabbits show that PVC alternans occurs at slow heart rates, preceding spontaneous intuition of ventricular arrhythmias. ABSTRACT: T-wave alternans (TWA) and irregular beat-to-beat T-wave variability or T-wave lability (TWL), the ECG manifestations of action potential duration (APD) alternans and variability, are precursors of ventricular arrhythmias in long QT syndromes. TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In the present study, we used computer simulations and experiments of a transgenic rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarization-mediated APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos exacerbated pre-existing APD dispersion and, in addition, APD chaos could also induce APD dispersion de novo via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced ICa,L , resulted in a tissue-scale dynamical instability that gave rise to the spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval, which further exacerbated the APD dispersion giving rise to the spontaneous occurrence of ventricular arrhythmias. Slow heart rate-induced PVC alternans was observed in experiments of transgenic LQT2 rabbits under isoproterenol, which was associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, in agreement with the theoretical predictions.

19.
J Hematol Oncol ; 10(1): 168, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29065888

RESUMO

BACKGROUND: Nuclear receptors (NRs) can regulate gene expression; therefore, they are classified as transcription factors. Despite the extensive research carried out on NRs, still several issues including (1) the expression profile of NRs in human tissues, (2) how the NR expression is modulated during atherosclerosis and metabolic diseases, and (3) the overview of the role of NRs in inflammatory conditions are not fully understood. METHODS: To determine whether and how the expression of NRs are regulated in physiological/pathological conditions, we took an experimental database analysis to determine expression of all 48 known NRs in 21 human and 17 murine tissues as well as in pathological conditions. RESULTS: We made the following significant findings: (1) NRs are differentially expressed in tissues, which may be under regulation by oxygen sensors, angiogenesis pathway, stem cell master regulators, inflammasomes, and tissue hypo-/hypermethylation indexes; (2) NR sequence mutations are associated with increased risks for development of cancers and metabolic, cardiovascular, and autoimmune diseases; (3) NRs have less tendency to be upregulated than downregulated in cancers, and autoimmune and metabolic diseases, which may be regulated by inflammation pathways and mitochondrial energy enzymes; and (4) the innate immune sensor inflammasome/caspase-1 pathway regulates the expression of most NRs. CONCLUSIONS: Based on our findings, we propose a new paradigm that most nuclear receptors are anti-inflammatory homeostasis-associated molecular pattern receptors (HAMPRs). Our results have provided a novel insight on NRs as therapeutic targets in metabolic diseases, inflammations, and malignancies.


Assuntos
Mineração de Dados/métodos , Receptores Citoplasmáticos e Nucleares/metabolismo , Homeostase , Humanos , Receptores Citoplasmáticos e Nucleares/análise
20.
Gigascience ; 6(8): 1-12, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28873964

RESUMO

Nacre, the iridescent material found in pearls and shells of molluscs, is formed through an extraordinary process of matrix-assisted biomineralization. Despite recent advances, many aspects of the biomineralization process and its evolutionary origin remain unknown. The pearl oyster Pinctada fucata martensii is a well-known master of biomineralization, but the molecular mechanisms that underlie its production of shells and pearls are not fully understood. We sequenced the highly polymorphic genome of the pearl oyster and conducted multi-omic and biochemical studies to probe nacre formation. We identified a large set of novel proteins participating in matrix-framework formation, many in expanded families, including components similar to that found in vertebrate bones such as collagen-related VWA-containing proteins, chondroitin sulfotransferases, and regulatory elements. Considering that there are only collagen-based matrices in vertebrate bones and chitin-based matrices in most invertebrate skeletons, the presence of both chitin and elements of collagen-based matrices in nacre suggests that elements of chitin- and collagen-based matrices have deep roots and might be part of an ancient biomineralizing matrix. Our results expand the current shell matrix-framework model and provide new insights into the evolution of diverse biomineralization systems.


Assuntos
Calcificação Fisiológica/genética , Genoma , Genômica , Pinctada/fisiologia , Animais , Redes Reguladoras de Genes , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Nácar/genética , Nácar/metabolismo , Proteômica
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