Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 924
Filtrar
2.
Sensors (Basel) ; 20(5)2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32164283

RESUMO

A novel multi-classification method, which integrates the elastic net and probabilistic support vector machine, was proposed to solve this problem in cancer detection with gene expression profile data of platelets, whose problems mainly are a kind of multi-class classification problem with high dimension, small samples, and collinear data. The strategy of one-against-all (OVA) was employed to decompose the multi-classification problem into a series of binary classification problems. The elastic net was used to select class-specific features for the binary classification problems, and the probabilistic support vector machine was used to make the outputs of the binary classifiers with class-specific features comparable. Simulation data and gene expression profile data were intended to verify the effectiveness of the proposed method. Results indicate that the proposed method can automatically select class-specific features and obtain better performance of classification than that of the conventional multi-class classification methods, which are mainly based on global feature selection methods. This study indicates the proposed method is suitable for general multi-classification problems featured with high-dimension, small samples, and collinear data.

3.
Comput Methods Programs Biomed ; 191: 105349, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-32146210

RESUMO

OBJECTIVE: To observe the efficacy of distal tibial tuberosity high tibial osteotomy in treating medial compartment osteoarthritis of the knee. In the experiment, a medical image enhancement algorithm based on shear wave domain improved Gamma correction was implemented to process medical images in order to diagnose patients more effectively. METHODS: Sixty-five patients (13 males and 52 females) were included in the study who were treated with distal tibial tuberosity high tibial osteotomy, and the mean age of the patients was 63±6 years (range 49-73). All patients received X-Ray and MRI before surgery. We carefully studied and analyzed the findings, MRI findings and medical characteristics after using the shearlet domain to improve the Gamma correction method in order to enhance diagnostic accuracy. The improved image help us to judge the damage of the medial and lateral compartment more accurately. Weight bearing line (WBL) and femora-tibial Angle (FTA) were measured to evaluate the lower limb alignment before and 12 months after surgery. Visual analogue scale (VAS) scores, Hospital for Special Surgery (HSS) scores, the Westrn Ontario and Mcmaster Universities (WOMAC) scores were recorded to evaluate knee pain and function before surgery, 3 months and 6 months after surgery. RESULTS: The X-Ray and MRI scans of the patients were analyzed. After the shear wave shearlet domain is implemented, the image effect is significantly improved. 12 months after surgery, WBL was improved from 16.34±2.18% to 60.32±2.89% (p<0.05), FTA was improved from 171.17±1.87° to 179.83±2.14° (p<0.05). At 3 months and 12 months after surgery, VAS, HSS and WOMAC scores were significantly improved compared with baseline (p<0.05). CONCLUSION: Distal tibial tuberosity high tibial osteotomy is able to correct varus deformity, relieve knee pain and the functional dysfunction, indicating which had a significant short-term efficacy. The shear wave shearlet domain incorporates the Gamma correction method to effectively preserve the image details, which to achieve a more accurate diagnosis, and help us to judge the damage of the medial and lateral compartment more accurately.

4.
J Infect Dis ; 221(Supplement_2): S156-S163, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32176797

RESUMO

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) infections are associated with poor patient outcomes. Data on risk factors and molecular epidemiology of CRE in complicated intra-abdominal infections (cIAI) in China are limited. This study examined the risk factors of cIAI with CRE and the associated mortality based on carbapenem resistance mechanisms. METHODS: In this retrospective analysis, we identified 1024 cIAI patients hospitalized from January 1, 2013 to October 31, 2018 in 14 intensive care units in China. Thirty CRE isolates were genotyped to identify ß-lactamase-encoding genes. RESULTS: Escherichia coli (34.5%) and Klebsiella pneumoniae (21.2%) were the leading pathogens. Patients with hospital-acquired cIAI had a lower rate of E coli (26.0% vs 49.1%; P < .001) and higher rate of carbapenem-resistant Gram-negative bacteria (31.7% vs 18.8%; P = .002) than those with community-acquired cIAI. Of the isolates, 16.0% and 23.4% of Enterobacteriaceae and K pneumoniae, respectively, were resistant to carbapenem. Most carbapenemase-producing (CP)-CRE isolates carried blaKPC (80.9%), followed by blaNMD (19.1%). The 28-day mortality was 31.1% and 9.0% in patients with CRE vs non-CRE (P < .001). In-hospital mortality was 4.7-fold higher for CP-CRE vs non-CP-CRE infection (P = .049). Carbapenem-containing combinations did not significantly influence in-hospital mortality of CP and non-CP-CRE. The risk factors for 28-day mortality in CRE-cIAI included septic shock, antibiotic exposure during the preceding 30 days, and comorbidities. CONCLUSIONS: Klebsiella pneumoniae had the highest prevalence in CRE. Infection with CRE, especially CP-CRE, was associated with increased mortality in cIAI.

5.
Nat Cell Biol ; 22(2): 167-174, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32029896

RESUMO

Branched-chain amino acid (BCAA) metabolism is potentially linked with development of pancreatic ductal adenocarcinoma (PDAC)1-4. BCAA transaminase 2 (BCAT2) was essential for the collateral lethality conferred by deletion of malic enzymes in PDAC and the BCAA-BCAT metabolic pathway contributed to non-small-cell lung carcinomas (NSCLCs) other than PDAC3,4. However, the underlying mechanism remains undefined. Here we reveal that BCAT2 is elevated in mouse models and in human PDAC. Furthermore, pancreatic tissue-specific knockout of Bcat2 impedes progression of pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1-Cre (KC) mice. Functionally, BCAT2 enhances BCAA uptake to sustain BCAA catabolism and mitochondrial respiration. Notably, BCAA enhances growth of pancreatic ductal organoids from KC mice in a dose-dependent manner, whereas addition of branched-chain α-keto acid (BCKA) and nucleobases rescues growth of KC organoids that is suppressed by BCAT2 inhibitor. Moreover, KRAS stabilizes BCAT2, which is mediated by spleen tyrosine kinase (SYK) and E3 ligase tripartite-motif-containing protein 21 (TRIM21). In addition, BCAT2 inhibitor ameliorates PanIN formation in KC mice. Of note, a lower-BCAA diet also impedes PDAC development in mouse models of PDAC. Thus, BCAT2-mediated BCAA catabolism is critical for development of PDAC harbouring KRAS mutations. Targeting BCAT2 or lowering dietary BCAA may have translational significance.

6.
Cell Death Dis ; 11(2): 140, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080168

RESUMO

Cardiac hypertrophy (CH) is an independent risk factor for many cardiovascular diseases, and is one of the primary causes of morbidity and mortality in elderly people. Pathological CH involves excessive protein synthesis, increased cardiomyocyte size, and ultimately the development of heart failure. Myotubularin-related protein 14 (MTMR14) is a member of the myotubularin (MTM)-related protein family, which is involved in apoptosis, aging, inflammation, and autophagy. However, its exact function in CH is still unclear. Herein, we investigated the roles of MTMR14 in CH. We show that MTMR14 expression was increased in hypertrophic mouse hearts. Mice deficient in heart MTMR14 exhibited an aggravated aortic-banding (AB)-induced CH phenotype. In contrast, MTMR14 overexpression prevented pressure overload-induced hypertrophy. At the molecular level, prevention of CH in the absence of MTMR14 involved elevations in Akt pathway components, which are key elements that regulate apoptosis and cell proliferation. These results demonstrate that MTMR14 is a new molecular target for the treatment of CH.

8.
Nature ; 579(7797): 152-157, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32076264

RESUMO

GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several psychiatric disorders1,2. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric Gs protein2, but it is unclear how GPR52 and Gs couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a Gs-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR523. A fully active state is achieved when Gs is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.


Assuntos
Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Regulação Alostérica , Sítio Alostérico , Motivos de Aminoácidos , Sequência de Aminoácidos , Apoproteínas/agonistas , Apoproteínas/química , Apoproteínas/metabolismo , Sítios de Ligação , Microscopia Crioeletrônica , Cristalografia por Raios X , Subunidades alfa Gs de Proteínas de Ligação ao GTP/química , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/ultraestrutura , Humanos , Ligantes , Modelos Moleculares , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/ultraestrutura
10.
J Pharm Biomed Anal ; 182: 113130, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32004773

RESUMO

The development of biotherapeutic proteins requires the use of efficient analytical methods to support their manufacturing process and quality control (QC). Analytical approaches at intact and middle-up levels emerged as promising alternatives to bottom-up strategies for protein characterization as they require less sample amount and simplified sample handling, thus reducing the overall turn-around time. This study describes, for the first time, the development of an automated liquid chromatography-mass spectrometry (LC-MS) workflow comprised of an immobilized IdeS-HPLC column for on-line sample digestion, followed by a reversed-phase liquid chromatography (RPLC) for protein subunit separation, and a high-resolution MS for molecular weight analysis. A proof of concept study was described here for the characterization of a therapeutic mAb and a bsAb. For the mAb, this automated workflow enabled rapid characterization of post-translational modifications (PTMs) such as N-glycosylation, glycation and N-terminal lysine. For the bsAb, the same workflow was successfully employed to identify product impurities due to chain pairing. The sample analysis using this workflow can be accomplished within less than one day. This workflow demonstrated its potential as a multi-attribute method for characterization of therapeutic proteins.

11.
Nat Commun ; 11(1): 888, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060291

RESUMO

NDH-1 is a key component of the cyclic-electron-transfer around photosystem I (PSI CET) pathway, an important antioxidant mechanism for efficient photosynthesis. Here, we report a 3.2-Å-resolution cryo-EM structure of the ferredoxin (Fd)-NDH-1L complex from the cyanobacterium Thermosynechococcus elongatus. The structure reveals three ß-carotene and fifteen lipid molecules in the membrane arm of NDH-1L. Regulatory oxygenic photosynthesis-specific (OPS) subunits NdhV, NdhS and NdhO are close to the Fd-binding site whilst NdhL is adjacent to the plastoquinone (PQ) cavity, and they play different roles in PSI CET under high-light stress. NdhV assists in the binding of Fd to NDH-1L and accelerates PSI CET in response to short-term high-light exposure. In contrast, prolonged high-light irradiation switches on the expression and assembly of the NDH-1MS complex, which likely contains no NdhO to further accelerate PSI CET and reduce ROS production. We propose that this hierarchical mechanism is necessary for the survival of cyanobacteria in an aerobic environment.

12.
Mol Cancer ; 19(1): 30, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32059672

RESUMO

Circular RNAs (circRNAs) are a new class of non-coding RNAs formed by covalently closed loops through backsplicing. Recent methodologies have enabled in-depth characterization of circRNAs for identification and potential functions. CircRNAs play important roles in various biological functions as microRNA sponges, transcriptional regulators and combining with RNA binding proteins. Recent studies indicated that some cytoplasmic circRNAs can be effectively translated into detectable peptides, which enlightened us on the importance of circRNAs in cellular physiology function. Internal Ribosome Entry site (IRES)- and N6-methyladenosines (m6A)-mediated cap-independent translation initiation have been suggested to be potential mechanism for circRNA translation. To date, several translated circRNAs have been uncovered to play pivotal roles in human cancers. In this review, we introduced the properties and functions of circRNAs, and characterized the possible mechanism of translation initiation and complexity of the translation ability of circRNAs. We summarized the emerging functions of circRNA-encoded proteins in human cancer. The works on circRNA translation will open a hidden human proteome, and enhance us to understand the importance of circRNAs in human cancer, which has been poorly explored so far.

13.
J Cardiovasc Electrophysiol ; 31(2): 579-592, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31930579

RESUMO

Cardiac arrhythmias constitute a major public health problem. Pharmacological intervention remains mainstay to their clinical management. This, in turn, depends upon systematic drug classification schemes relating their molecular, cellular, and systems effects to clinical indications and therapeutic actions. This approach was first pioneered in the 1960s Vaughan-Williams classification. Subsequent progress in cardiac electrophysiological understanding led to a lag between the fundamental science and its clinical translation, partly addressed by The working group of the European Society of Cardiology (1991), which, however, did not emerge with formal classifications. We here utilize the recent Revised Oxford Classification Scheme to review antiarrhythmic drug pharmacology. We survey drugs and therapeutic targets offered by the more recently characterized ion channels, transporters, receptors, intracellular Ca2+ handling, and cell signaling molecules. These are organized into their strategic roles in cardiac electrophysiological function. Following analysis of the arrhythmic process itself, we consider (a) pharmacological agents directly targeting membrane function, particularly the Na+ and K+ ion channels underlying depolarizing and repolarizing events in the cardiac action potential. (b) We also consider agents that modify autonomic activity that, in turn, affects both the membrane and (c) the Ca2+ homeostatic and excitation-contraction coupling processes linking membrane excitation to contractile activation. Finally, we consider (d) drugs acting on more upstream energetic and structural remodeling processes currently the subject of clinical trials. Such systematic correlations of drug actions and arrhythmic mechanisms at different molecular to systems levels of cardiac function will facilitate current and future antiarrhythmic therapy.

15.
Chin Med J (Engl) ; 133(2): 183-189, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31929368

RESUMO

BACKGROUND: Obstetric hemorrhage is a major cause of maternal death during cesarean delivery. The objective of this retrospective observational study was to evaluate the efficacy and safety of intra-operative cell salvage (IOCS) in cesarean section. METHODS: We included a total of 361 patients diagnosed with central placenta previa who underwent cesarean section from May 2016 to December 2018. In this study, 196 patients received autologous transfusion using IOCS (IOCS group) and 165 patients accepted allogeneic blood transfusion (ABT group). Propensity score matched analysis was performed to balance differences in the baseline variables between the IOCS group and ABT group. Patients in the IOCS group were matched 1:1 to patients in the ABT group. RESULTS: After propensity score matching, 137 pairs of cases between the two groups were successfully matched and no significant differences in baseline characteristics were found between the IOCS group and ABT group. Patients in the IOCS group were associated with significantly shorter length of hospital stay, compared with ABT group (8.9 ±â€Š4.1 days vs. 10.3 ±â€Š5.2 days, t = -2.506, P = 0.013). The postoperative length of hospital stay was 5.3 ±â€Š1.4 days for patients in the IOCS group and 6.6 ±â€Š3.6 days for those in the ABT group (t = -4.056, P < 0.001). The post-operative hemoglobin level in the IOCS group and ABT group was 101.3 ±â€Š15.4 and 96.3 ±â€Š16.6 g/L, respectively, which were significantly different (t = 2.615, P = 0.009). Allogeneic red blood cell transfusion was significantly lower at 0 unit (range: 0-11.5 units) in the IOCS group when compared with 2 units (range: 1-20 units) in the ABT group (P < 0.001). CONCLUSIONS: This retrospective observational study using propensity score matched analysis suggested that IOCS was associated with shorter length of postoperative hospital stay and higher post-operative hemoglobin levels during cesarean delivery.

16.
Soft Matter ; 16(6): 1636-1641, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31960008

RESUMO

In this paper, we developed a novel morphing surface technique consisting of a 3D printed miniature groove structure and injected stimuli-responsive hydrogel pattern, which is capable of switching between lipophilicity and oleophobicity under certain stimuli. Under swelling, the geometrical change of the hydrogel will buckle the surface due to the structural confinement and create a continuous transition of surface topology. Thus, it will yield a change in the surface wetting property from oleophilic to super-oleophobic with a contact angle of oil of 85° to 165°. We quantitatively investigate this structure-property relationship using finite element analysis and analytical modeling, and the simulation results and the modeling are in good agreement with the experimental ones. This morphing surface also holds potential to be developed into an autonomous system for future sub-sea/off-shore engineering applications to separate oil and water.

17.
Cancer Imaging ; 20(1): 7, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937372

RESUMO

BACKGROUND: The difficulty of assessment of neoadjuvant chemotherapeutic response preoperatively may hinder personalized-medicine strategies that depend on the results from pathological examination. METHODS: A total of 191 patients with high-grade osteosarcoma (HOS) were enrolled retrospectively from November 2013 to November 2017 and received neoadjuvant chemotherapy (NCT). A cutoff time of November 2016 was used to divide the training set and validation set. All patients underwent diagnostic CTs before and after chemotherapy. By quantifying the tumor regions on the CT images before and after NCT, 540 delta-radiomic features were calculated. The interclass correlation coefficients for segmentations of inter/intra-observers and feature pair-wise correlation coefficients (Pearson) were used for robust feature selection. A delta-radiomics signature was constructed using the lasso algorithm based on the training set. Radiomics signatures built from single-phase CT were constructed for comparison purpose. A radiomics nomogram was then developed from the multivariate logistic regression model by combining independent clinical factors and the delta-radiomics signature. The prediction performance was assessed using area under the ROC curve (AUC), calibration curves and decision curve analysis (DCA). RESULTS: The delta-radiomics signature showed higher AUC than single-CT based radiomics signatures in both training and validation cohorts. The delta-radiomics signature, consisting of 8 selected features, showed significant differences between the pathologic good response (pGR) (necrosis fraction ≥90%) group and the non-pGR (necrosis fraction < 90%) group (P < 0.0001, in both training and validation sets). The delta-radiomics nomogram, which consisted of the delta-radiomics signature and new pulmonary metastasis during chemotherapy showed good calibration and great discrimination capacity with AUC 0.871 (95% CI, 0.804 to 0.923) in the training cohort, and 0.843 (95% CI, 0.718 to 0.927) in the validation cohort. The DCA confirmed the clinical utility of the radiomics model. CONCLUSION: The delta-radiomics nomogram incorporating the radiomics signature and clinical factors in this study could be used for individualized pathologic response evaluation after chemotherapy preoperatively and help tailor appropriate chemotherapy and further treatment plans.

18.
J Pharmacol Sci ; 142(4): 131-139, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31992491

RESUMO

N-methyl berbamine (N-MB) is a berberine derivative. Its analogue berbamine has been reported to have remarkable antiarrhythmic and ischemic protective effects. However, the pharmacological effects of N-MB are ill-defined. In this study, molecular docking was used to evaluate the binding of N-MB to CaV1.2 Ca2+ and KV11.1 K+ channels, and the effects of N-MB on action potential and ionic currents were observed in the ventricular myocytes of rabbits, HEK293 cells stably transfected with the hCaV1.2 gene and CHO cells stably transfected with hERG (human ether-a-go-go related gene). The results showed that N-MB was able to bind to both CaV1.2 and KV11.1 channels. Following a perfusion with N-MB, the durations of action potentials (APD20, APD50 and APD90) were extended, and the outward tail current, Itail, as well as the hERG current, IhERG, were inhibited, while the amplitude of action potential (APA) was only slightly reduced. N-MB also decreased the peak amplitude of the L-type Ca2+ channel current, ICaL, as well as the CaV1.2 current, ICaV1.2; this may limit the prolongation of APD. In conclusion, N-MB is a potent and natural antiarrhythmic multitarget drug that may elicit its antiarrhythmic effect through blocking both Ca2+ and K+ channel currents.

19.
J Hazard Mater ; 389: 122091, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-31972529

RESUMO

Roxarsone is a phenyl-substituted arsonic acid comprising both arsenate and benzene rings. Few adsorbents are designed for the effective capture of both the organic and inorganic moieties of ROX molecules. Herein, nano zerovalent iron (nZVI) particles were incorporated on the surface of sludge-based biochar (SBC) to fabricate a dual-affinity sorbent that attracts both the arsenate and benzene rings of ROX. The incorporation of nZVI particles significantly increased the binding affinity and sorption capacity for ROX molecules compared to pristine SBC and pure nZVI. The enhanced elimination of ROX molecules was ascribed to synergetic adsorption and degradation reactions, through π-π* electron donor/acceptor interactions, H-bonding, and As-O-Fe coordination. Among these, the predominate adsorption force was As-O-Fe coordination. During the sorption process, some ROX molecules were decomposed into inorganic arsenic and organic metabolites by the reactive oxygen species (ROS) generated during the early stages of the reaction. The degradation pathways of ROX were proposed according to the oxidation intermediates. This work provides a theoretical and experimental basis for the design of adsorbents according to the structure of the target pollutant.

20.
Chemosphere ; 247: 125850, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31931314

RESUMO

Bioremediation of heavy metal-contaminated soil using metal-resistant microbes is a promising remediation technology. However, as exogenous bacteria sometimes struggle to survive and grow when introduced to new soils, it is important to develop appropriate carriers for microbial populations. In this study, we report a novel approach to remediating Cd-contaminated rice paddy soil using biochar-supported microbial cell composites (BMCs) produced from agricultural waste (cornstalks). Pot experiments showed that amendment with BMC was more efficient at reducing root and grain Cd content than pure bacteria, while improving soil Cd fractionation toward more stabilized and less labile forms. Bacteria in the BMC medium grew more readily with more abundant metabolites than those raised in free cells, probably because biochar provides shelter via porous structures (as confirmed by scanning electron microscopy) as well as additional nutrients. Overall, the improved long-term production of microbial biomass caused by BMC inoculation results in a higher remediation efficiency. Our results demonstrate the feasibility of using biochar as an appropriate carrier for metal-tolerant bacteria to remediate Cd-contaminated paddy fields.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA