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1.
Biomed Res Int ; 2020: 2641324, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32566675

RESUMO

During spaceflight, the homeostasis of the living body is threatened with cosmic environment including microgravity and irradiation. Traditional Chinese medicine could ameliorate the internal imbalance during spaceflight, but its mechanism is still unclear. In this article, we compared the difference of neuroendocrine-immune balance between simulated microgravity (S) and simulated microgravity and irradiation (SAI) environment. We also observed the antagonistic effect of SAI using a traditional Chinese medicine formula (TCMF). Wistar rats were, respectively, exposed under S using tail suspending and SAI using tail suspending and 60Co-gama irradiation exposure. The SAI rats were intervened with TCMF. The changes of hypothalamic-pituitary-adrenal (HPA) axis, splenic T-cell, celiac macrophages, and related cytokines were observed after 21 days. Compared with the normal group, the hyperfunction of HPA axis and celiac macrophages, as well as the hypofunction of splenic T-cells, was observed in both the S and SAI group. Compared with the S group, the levels of plasmatic corticotropin-releasing hormone (CRH), macrophage activity, and serous interleukin-6 (IL-6) in the SAI group were significantly reduced. The dysfunctional targets were mostly reversed in the TCMF group. Both S and SAI could lead to NEI imbalance. Irradiation could aggravate the negative feedback inhibition of HPA axis and macrophages caused by S. TCMF could ameliorate the NEI dysfunction caused by SAI.

2.
Clin Rheumatol ; 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32557257

RESUMO

OBJECTIVES: To explore the associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid (GC) efficacy, anxiety, depression, and health-related quality of life (HRQOL) in systemic lupus erythematosus (SLE) patients. METHODS: All subjects were collected from the First and the Second Affiliated Hospital of Anhui Medical University in Hefei, China, during 2011 to 2015. In the case-control study, 541 SLE patients and 543 controls were recruited. In the follow-up study, 466 patients completed the 12-week follow-up and then were divided into GC-sensitive and GC-insensitive groups. Genotyping was determined using Multiplex SNaPshot technique. Data were analyzed using chi-square test and univariate and multivariate logistic regression analyses. RESULTS: rs4713904, rs9368878, and rs7757037 of FKBP5 were associated with depression in SLE patients (rs4713904, PBH = 0.037; rs9368878, PBH = 0.001; rs7757037, PBH = 0.003). Moreover, rs4713904 was associated with GC efficacy in males with SLE (PBH = 0.011). The rs755658 of FKBP5 was associated with improvement in social function (PBH = 0.022) and mental component summary (PBH = 0.028). The rs4713907 of FKBP5 was related to improvement in total score of SF-36, bodily pain, and mental component summary score (all PBH = 0.018). Furthermore, the rs12582595 of FKBP4 was correlated with general health improvement (PBH = 0.033). No associations were seen between FKBP4/FKBP5 gene polymorphisms and SLE susceptibility and anxiety. CONCLUSIONS: FKBP5 gene polymorphisms may be associated with depression and GC efficacy of SLE patients. Meanwhile, the genetic polymorphisms of FKBP4 and FKBP5 genes may be associated with HRQOL improvement in SLE patients.Key Points• FKBP5 gene polymorphisms were associated with depression of SLE patients.• FKBP5 gene polymorphisms were associated with GC efficacy of SLE patients.• FKBP5 gene polymorphisms were associated with HRQOL improvement in SLE patients.• FKBP4 gene polymorphisms were associated with HRQOL improvement in SLE patients.

3.
J Affect Disord ; 272: 58-65, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32379621

RESUMO

The right inferior frontal gyrus (rIFG) is a key cortical node in the circuits of emotion and cognitive control, and it has been frequently associated with bipolar disorder (BP); however, a reliable pattern of aberrant rIFG activation and connectivity in bipolar disorder has yet to be established. To further elucidate rIFG abnormalities in different states of bipolar disorder, we examined activation and functional connectivity (FC) in five subregions of rIFG in bipolar disorder. A total of 83 participants, including those with bipolar depression (BPD; n = 25) and bipolar mania (BPM; n = 37) along with healthy control (HC) subjects (n = 26), were examined by resting state functional magnetic resonance imaging (rs-fMRI). Both BPD and BPM groups showed higher values of amplitude of low-frequency fluctuations (ALFF) than healthy control in four of the five rIFG subregions except cluster 2(posterior-ventral rIFG). Using five subregions of rIFG as seeds, the decreased FC in bipolar disorder was mainly between posterior-ventral rIFG(cluster 2) and multiple brain regions including the postcentral gyrus, the precentral gyrus, paracentral lobule, lingual Gyrus, fusiform and cerebellum posterior lobe. These results indicated that local activity and FC were altered within specific subregions of the rIFG in BP. These findings may provide the distinct functional connectivity of rIFG subregions in BP and suggest that the cluster2 (posterior-ventral rIFG) circuitry plays a crucial role in BP. Also, such abnormalities might help define a more precise intervention targets.

4.
Oral Oncol ; 105: 104686, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32283514

RESUMO

OBJECTIVES: To explore the role of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) and CCRT plus adjuvant chemotherapy (AC) in locoregionally advanced nasopharyngeal carcinoma (LANPC). MATERIALS AND METHODS: The propensity score-matched (PSM) method was adopted to balance variables. We identified independent prognostic factors using Cox regression analysis and compared outcomes between two chemotherapy treatment combinations for patients in different subgroups. RESULTS: A total of 550 patients were selected by one-to-two PSM. Survival outcomes for the matched data set indicated that the IC + CCRT group achieved higher 5-year overall survival (OS; 89.3% vs 85.3%, P = 0.119), failure-free survival (FFS; 80.2% vs 79.0%, P = 0.722) and distant metastasis-free survival (DMFS; 87.4% vs 84.4%, P = 0.322) compared with CCRT + AC, although this was statistically non-significant. Subgroup analysis revealed that IC + CCRT was associated with significantly improved OS (Hazard ratio [HR] = 2.68, 95% Confidence interval [CI] = 1.16-6.22, P = 0.017), FFS (HR = 1.94, 95% CI = 1.06-3.57, P = 0.029) and locoregional relapse-free survival (LRRFS; HR = 2.63, 95% CI = 1.04-6.68, P = 0.034) in T3 disease. Moreover, this combination of treatment could significantly prolong OS (HR = 3.72, 95% CI = 1.41-9.80, P = 0.004) in N2 disease. However, the superiority of CCRT + AC was only observed in LRRFS (HR = 0.18, 95% CI 0.04-0.79, P = 0.010) for the T4 subgroup. CONCLUSION: IC + CCRT should be strongly considered by patients with LANPC, especially those with T3 or N2 disease.

5.
J Hematol Oncol ; 13(1): 22, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188475

RESUMO

Methylation of RNA and DNA, notably in the forms of N6-methyladenosine (m6A) and 5-methylcytosine (5mC) respectively, plays crucial roles in diverse biological processes. Currently, there is a lack of knowledge regarding the cross-talk between m6A and 5mC regulators. Thus, we systematically performed a pan-cancer genomic analysis by depicting the molecular correlations between m6A and 5mC regulators across ~ 11,000 subjects representing 33 cancer types. For the first time, we identified cross-talk between m6A and 5mC methylation at the multiomic level. Then, we further established m6A/5mC epigenetic module eigengenes by combining hub m6A/5mC regulators and informed a comprehensive epigenetic state. The model reflected status of the tumor-immune-stromal microenvironment and was able to predict patient survival in the majority of cancer types. Our results lay a solid foundation for epigenetic regulation in human cancer and pave a new road for related therapeutic targets.

6.
J Org Chem ; 85(4): 2597-2606, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-31917921

RESUMO

Selectivities in (4 + 2) and (2 + 2) cycloadditions of keteniminium cations with 1,3-dienes studied experimentally by Ghosez et al. were explored with ωB97X-D density functional theory. Reactions of keteniminium cations with 1,3-dienes are influenced by the s-cis or s-trans nature of the diene. s-Trans dienes react to give an intermediate enamine that leads to favored formation of (2 + 2) cycloadducts across the keteniminium C-C bond. The first step of the cycloaddition is rate-determining, and reaction occurs by attack on the central carbon of the keteniminium cation and subsequent C-C bond formation. In contrast, s-cis constrained dienes lead to preferential formation of (4 + 2) products by both stepwise and concerted mechanisms involving regioselective addition to the keteniminium C-N bond. Diels-Alder reaction occurs via a concerted mechanism if the diene termini are held in close proximity, as in cyclopentadiene.

8.
Phys Rev E ; 100(5-1): 052409, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31869999

RESUMO

Natural enzymes often have enormous catalytic power developed by evolution. Revealing the underlying physical strategy used by enzymes to achieve high catalysis efficiency is one of the central focuses in the field of biological physics. Our recent work demonstrated that multisubstrate enzymes can utilize steric frustration encountered in the substrate-product cobound complex to overcome the bottleneck of the enzymatic cycle [W. Li et al., Phys. Rev. Lett. 122, 238102 (2019)10.1103/PhysRevLett.122.238102]. However, the key atomic-level interactions by which the steric frustration contributes to the enzymatic cycle remain elusive. In this work we study the microscopic mechanism for the role of the substrate-product frustration on the key physical steps in the enzymatic cycle of adenylate kinase (AdK), a multisubstrate enzyme catalyzing the reversible phosphoryl transfer reaction ATP+AMP⇋ADP+ADP. By using atomistic molecular dynamics simulations with enhanced sampling, we showed that the competitive interactions from the phosphate groups of the substrate ATP and product ADP in the ATP-ADP cobound complex of the AdK lead to local frustration in the binding pockets. Such local frustration disrupts the hydrogen bond network around the binding pockets, which causes lowered barrier height for the opening of the enzyme conformations and expedited release of the bottleneck product ADP. Our results directly demonstrated from the atomistic level that the local frustration in the active sites of the enzyme can be utilized to facilitate the key physical steps of the enzymatic cycle, providing numerical evidence to the predictions of the previous theoretical work.


Assuntos
Adenilato Quinase/metabolismo , Simulação de Dinâmica Molecular , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Adenilato Quinase/química , Sítios de Ligação , Cinética , Ligação Proteica , Conformação Proteica , Termodinâmica
9.
J Chem Phys ; 151(17): 174115, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703523

RESUMO

Over this past decade, we combined the idea of stochastic resolution of identity with a variety of electronic structure methods. In our stochastic Kohn-Sham density functional theory (DFT) method, the density is an average over multiple stochastic samples, with stochastic errors that decrease as the inverse square root of the number of sampling orbitals. Here, we develop a stochastic embedding density functional theory method (se-DFT) that selectively reduces the stochastic error (specifically on the forces) for a selected subsystem(s). The motivation, similar to that of other quantum embedding methods, is that for many systems of practical interest, the properties are often determined by only a small subsystem. In stochastic embedding DFT, two sets of orbitals are used: a deterministic one associated with the embedded subspace and the rest, which is described by a stochastic set. The method agrees exactly with deterministic calculations in the limit of a large number of stochastic samples. We apply se-DFT to study a p-nitroaniline molecule in water, where the statistical errors in the forces on the system (the p-nitroaniline molecule) are reduced by an order of magnitude compared with nonembedding stochastic DFT.

10.
ACS Omega ; 4(6): 10494-10501, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31460146

RESUMO

The wide applications of nanomaterials in industry and our daily life have raised growing concerns on their toxicity to human body. Increasing evidence links the cytotoxicity of nanoparticles to the disruption of cellular signaling pathways. Here, we report a computational study on the mechanisms of the cytotoxicity of carbon nanotubes (CNTs) by investigating the direct impacts of CNTs on the functional motions of calmodulin (CaM), which is one of the most important signaling proteins in a cell, and its signaling function relies on the Ca2+ binding-coupled conformational switching. Computational simulations with a coarse-grained model showed that binding of CNTs modifies the conformational equilibrium of CaM and induces the closed-to-open conformational transition, leading to the loss of its Ca2+-sensing ability. In addition, the binding of CNTs drastically increases the calcium affinity of CaM, which may disrupt the Ca2+ homeostasis in a cell. These results suggest that the binding of hydrophobic nanotubes not only inhibits the signaling function of CaM as a calcium sensor but also renders CaM to toxic species through sequestering Ca2+ from other competing calcium-binding proteins, suggesting a new physical mechanism of the cytotoxicity of nanoparticles.

11.
Medicine (Baltimore) ; 98(32): e16592, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393358

RESUMO

RATIONALE: Refractory nasopharyngeal carcinoma is challenging to treat and at present there is no standard treatment or any good choice. PATIENT CONCERNS: Although the three patients in our case reports had already underwent multiple treatments before, they still suffered from disease recurrence of nasopharyngeal carcinoma. DIAGNOSIS: They were diagnosed as refractory nasopharyngeal carcinoma. INTERVENTIONS: A continuous infusion of Endostar, an antiangiogenic agent, combined with chemotherapy and radiation therapy was given to treat the patients. OUTCOMES: Patients showed complete or partial response to the combined therapy as evidenced by regression of tumors and decrease in plasma Epstein-Barr virus (EBV) DNA load. LESSONS: Continuous infusions of Endostar in combination with chemotherapy and/or radiation therapy showed promising efficacy and safety. The combination therapy indicates a new approach to treat refractory nasopharyngeal carcinoma.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Endostatinas/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Adulto , Quimiorradioterapia/métodos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia
12.
Phys Rev Lett ; 122(23): 238102, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31298900

RESUMO

The enormous catalytic power of natural enzymes relies on the ability to overcome the bottleneck event in the enzymatic cycle, yet the underlying physical mechanisms are not fully understood. Here, by performing molecular simulations of the whole enzymatic cycle for a model multisubstrate enzyme with a dynamic energy landscape model, we show that multisubstrate enzymes can utilize steric frustration to facilitate the rate-limiting product-release step. During the enzymatic cycles, the bottleneck product is actively squeezed out by the binding of a new substrate at the neighboring site through the population of a substrate-product cobound complex, in which the binding pockets are frustrated due to steric incompatibility. Such steric frustration thereby enables an active mechanism of product release driven by substrate-binding energy, facilitating the enzymatic cycle.


Assuntos
Enzimas/química , Enzimas/metabolismo , Modelos Químicos , Adenilato Quinase/química , Adenilato Quinase/metabolismo , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade , Termodinâmica
13.
Oral Oncol ; 95: 150-156, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31345383

RESUMO

OBJECTIVE: In nasopharyngeal carcinoma (NPC), the staging category of parotid lymph node (PLN) metastasis is not explicitly defined, resulting in varied classifications and treatment strategies in clinical practice. This study aimed to determine the prognostic value and optimal staging category of PLN metastasis in NPC. MATERIALS AND METHODS: With the NPC database from a big-data platform, 10,126 patients with primarily diagnosed, non-metastatic NPC and treated with intensity modulated radiotherapy at our center from 2009 to 2015 were analyzed in this study. RESULTS: In total, 43/10126 patients (0.4%) were diagnosed with histologically verified PLN metastasis at initial diagnosis. Of these, 88.4% (38/43) had enlarged lymph nodes in level II and 34.9% (15/43) in level Ib. Compared with patients without PLN metastasis, those with PLN metastasis had higher risk of disease failure (adjusted hazard ratio [HR], 1.770), distant metastasis (HR, 1.907), and regional recurrence (HR, 3.649), with similar 3-year disease-free survival (70.0% vs. 71.1%) and distant metastasis-free survival (74.8% vs. 77.4%) with patients with N3 disease. Of note, 10/43 patients had regional recurrence: six had recurrent lymph nodes in level Ib; and four of these six patients had no identifiable level Ib lymph nodes on pretreatment imaging. CONCLUSION: PLN metastasis was associated with high risk of distant metastasis and regional recurrence, and patients with PLN metastasis had similar outcome compared with patients with N3 disease. Regional recurrences in rare levels, such as level Ib, were common in patients with PLN metastasis at initial diagnosis.

14.
N Engl J Med ; 381(12): 1124-1135, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31150573

RESUMO

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Quimioterapia de Indução , Carcinoma Nasofaríngeo/tratamento farmacológico , Adolescente , Adulto , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução/efeitos adversos , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/terapia , Análise de Sobrevida , Adulto Jovem
15.
Nat Struct Mol Biol ; 26(6): 501-509, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160784

RESUMO

The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyl-transfer RNA 3'-CCA end is improperly docked in the peptidyl transferase center. Selections of messenger RNAs from mRNA libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination or even enhance translation, depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins of therapeutic interest.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Ribossomos/efeitos dos fármacos , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Modelos Moleculares , RNA Mensageiro/metabolismo , RNA de Transferência/metabolismo , Ribossomos/metabolismo
16.
J Phys Chem B ; 123(25): 5216-5228, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31242743

RESUMO

Copper ions are important cofactors of many metalloproteins. The binding dynamics of proteins to the copper ion is important for biological functions but is less understood at the microscopic level. What are the key factors determining the recognition and the stabilization of the copper ion during the binding? Our work investigates the binding dynamics of the copper ion with a simple system (the N-terminus of PrP) using simulation methods. To precisely characterize the protein?ion interaction, we build up an effective copper?peptide force field based on quantum chemistry calculations. In our model, the effects of charge transfer, protonation/deprotonation, and induced polarization are considered. With this force field, we successfully characterize the local structures and the complex interactions of the octapeptide around the copper ion. Furthermore, using an enhanced sampling method, the binding/unbinding processes of the copper ion with the octapeptide are simulated. Free-energy landscapes are generated in consequence, and multiple binding pathways are characterized. It is observed that various native ligands contribute differently to the binding processes. Some residues are related to the capture of the ion (behaving like ?arm?s), and some others contribute to the stabilization of the coordination structure (acting like ?core?s). These different interactions induce various pathways. Besides, a nonnative binding ligand is determined, and it has essential contributions and modulations to the binding pathways. With all these results, the picture of copper?octapeptide binding is outlined. These features are believed to happen in many ion?peptide interactions, such as the cooperative stabilization between the coordinations with neighboring backbone nitrogens and an auxiliary intermediate coordination with the neighboring oxygen from the N-terminal direction. We believe that our studies are valuable to understand the complicated ion?peptide binding processes.

17.
Proc Natl Acad Sci U S A ; 116(28): 13958-13963, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31243148

RESUMO

In the disease familial amyloidosis, Finnish type (FAF), also known as AGel amyloidosis (AGel), the mechanism by which point mutations in the calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood in the intact protein. Here, we provide a structural and biochemical characterization of the FAF variants. X-ray crystallography structures of the FAF mutant gelsolins demonstrate that the mutations do not significantly disrupt the calcium-free conformations of gelsolin. Small-angle X-ray-scattering (SAXS) studies indicate that the FAF calcium-binding site mutants are slower to activate, whereas G167R is as efficient as the wild type. Actin-regulating studies of the gelsolins at the furin cleavage pH (6.5) show that the mutant gelsolins are functional, suggesting that they also adopt relatively normal active conformations. Deletion of gelsolin domains leads to sensitization to furin cleavage, and nanobody-binding protects against furin cleavage. These data indicate instability in the second domain of gelsolin (G2), since loss or gain of G2-stabilizing interactions impacts the efficiency of cleavage by furin. To demonstrate this principle, we engineered non-FAF mutations in G3 that disrupt the G2-G3 interface in the calcium-activated structure. These mutants led to increased furin cleavage. We carried out molecular dynamics (MD) simulations on the FAF and non-FAF mutant G2-G3 fragments of gelsolin. All mutants showed an increase in the distance between the center of masses of the 2 domains (G2 and G3). Since G3 covers the furin cleavage site on G2 in calcium-activated gelsolin, this suggests that destabilization of this interface is a critical step in cleavage.


Assuntos
Amiloidose/genética , Distrofias Hereditárias da Córnea/genética , Furina/química , Gelsolina/química , Conformação Proteica , Actinas/química , Actinas/genética , Amiloidose/patologia , Sítios de Ligação/genética , Cálcio/química , Distrofias Hereditárias da Córnea/patologia , Cristalografia por Raios X , Furina/genética , Gelsolina/genética , Gelsolina/ultraestrutura , Predisposição Genética para Doença , Humanos , Simulação de Dinâmica Molecular , Mutação/genética , Ligação Proteica/genética , Domínios Proteicos/genética
18.
ACS Appl Mater Interfaces ; 11(22): 20535-20544, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31081609

RESUMO

For the stretchable electrode, strong interface adhesion is the primary guarantee for long service life, and the maximization of the tensile limit with remarkable electrical stability can expand the scope of its use. Here, a cost-effective strategy is proposed to fabricate a high-adhesion stretchable electrode. By modifying dopamine and functionalized silane on a polydimethylsiloxane (PDMS) substrate in sequence before the electroless deposition process, super-high adhesion up to 3.1 MPa is achieved between the PDMS substrate and silver layer, and the electrode exhibits extraordinary conductivity of 4.0 × 107 S/m. This process is also suitable for other common flexible substrates and metals. Moreover, inspired by the micro-/nanostructure on the surface of lotus leaf, a biomimetic elastomeric micropore film with a uniformly distributed micropore is fabricated by the one-step soft lithography replication process. The electrode exhibits a large tensile limit exceeding 70% uniaxial tensile and superior electrical stability from 6.3 to 11.5 Ω under 20% uniaxial tensile for more than 10 000 cycles. This study seeks a promising method to manufacture stretchable electrodes with high adhesion, large tensile limit, and excellent electrical stability, showing great potential to detect various biological signals including joint movement, surface electromyography, and so forth.

19.
Clin Cancer Res ; 25(14): 4271-4279, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30975664

RESUMO

PURPOSE: We aimed to evaluate the value of deep learning on positron emission tomography with computed tomography (PET/CT)-based radiomics for individual induction chemotherapy (IC) in advanced nasopharyngeal carcinoma (NPC). EXPERIMENTAL DESIGN: We constructed radiomics signatures and nomogram for predicting disease-free survival (DFS) based on the extracted features from PET and CT images in a training set (n = 470), and then validated it on a test set (n = 237). Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were applied to evaluate the discriminatory ability of radiomics nomogram, and compare radiomics signatures with plasma Epstein-Barr virus (EBV) DNA. RESULTS: A total of 18 features were selected to construct CT-based and PET-based signatures, which were significantly associated with DFS (P < 0.001). Using these signatures, we proposed a radiomics nomogram with a C-index of 0.754 [95% confidence interval (95% CI), 0.709-0.800] in the training set and 0.722 (95% CI, 0.652-0.792) in the test set. Consequently, 206 (29.1%) patients were stratified as high-risk group and the other 501 (70.9%) as low-risk group by the radiomics nomogram, and the corresponding 5-year DFS rates were 50.1% and 87.6%, respectively (P < 0.0001). High-risk patients could benefit from IC while the low-risk could not. Moreover, radiomics nomogram performed significantly better than the EBV DNA-based model (C-index: 0.754 vs. 0.675 in the training set and 0.722 vs. 0.671 in the test set) in risk stratification and guiding IC. CONCLUSIONS: Deep learning PET/CT-based radiomics could serve as a reliable and powerful tool for prognosis prediction and may act as a potential indicator for individual IC in advanced NPC.

20.
BMC Complement Altern Med ; 19(1): 84, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975110

RESUMO

BACKGROUND: Fructus Psoraleae is the seed of Psoralea corylifolia Linn. Fructus Psoraleae has been shown to be effective in treating some skin diseases, such as vitiligo. As a main ingredient in five types of herbs in the Qubaibabuqi tablet formula, Fructus Psoraleae plays an important role in the treatment of vitiligo. Fructus Psoraleae has potential hepatotoxicity, thus Qubaibabuqi tablets also have potential liver toxicity. CASE PRESENTATION: A 53-year-old woman who was diagnosed with vitiligo in September 2017 was treated with Qubaibabuqi tablets. After approximately 7 months of treatment, the patient developed a severe, diffuse yellow staining of the skin and sclera in March 2018. On admission, she was diagnosed with acute cholestatic hepatitis associated with Fructus Psoraleae. Despite receiving active treatment, her condition rapidly deteriorated and she died 5 days later due to acute liver failure and multiple organ dysfunction. To the best of our knowledge, there are only six reported cases of liver injury associated with Fructus Psoraleae described in the English language literature; however, cases of acute liver failure associated with the use of Fructus Psoraleae have not been described. CONCLUSION: As a main ingredient in the Qubaibabuqi tablet formula, Fructus Psoraleae has potential hepatotoxicity. This potentially fatal adverse effect should be considered when physicians prescribe Qubaibabuqi tablets.


Assuntos
Medicamentos de Ervas Chinesas/efeitos adversos , Falência Hepática Aguda/induzido quimicamente , Psoralea , Adulto , Colecistite Aguda/induzido quimicamente , Medicamentos de Ervas Chinesas/uso terapêutico , Evolução Fatal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vitiligo/tratamento farmacológico , Adulto Jovem
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