Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulating YAP and Phospho-YAP in Keratinocyte Responses to Mechanical Forces

Desmoglein 3 (Dsg3) plays a crucial role in cell-cell adhesion and tissue integrity. Increasing evidence suggests that Dsg3 acts as a regulator of cellular mechanotransduction, but little is known about its direct role in mechanical force transmission. The present study investigated the impact of cyclic strain and substrate stiffness on Dsg3 expression and its role in mechanotransduction in keratinocytes. A direct comparison was made with E-cadherin, a well-characterized mechanosensor. Exposure of oral and skin keratinocytes to equiaxial cyclic strain promoted changes in the expression and localization of junction assembly proteins. The knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. Importantly, the study demonstrated that Dsg3 regulates the expression and localization of yes-associated protein (YAP), a mechanosensory, and an effector of the Hippo pathway. Furthermore, we showed that Dsg3 formed a complex with phospho-YAP and sequestered it to the plasma membrane, while Dsg3 depletion had an impact on both YAP and phospho-YAP in their response to mechanical forces, increasing the sensitivity of keratinocytes to the strain or substrate rigidity-induced nuclear relocation of YAP and phospho-YAP. Plakophilin 1 (PKP1) seemed to be crucial in recruiting the complex containing Dsg3/phospho-YAP to the cell surface since its silencing affected Dsg3 junctional assembly with concomitant loss of phospho-YAP at the cell periphery. Finally, we demonstrated that this Dsg3/YAP pathway has an influence on the expression of YAP1 target genes and cell proliferation. Together, these findings provide evidence of a novel role for Dsg3 in keratinocyte mechanotransduction

Zebrafish: A See-Through Host and a Fluorescent Toolbox to Probe Host–Pathogen Interaction

In many ways, the zebrafish represents a hybrid between mouse and invertebrate infection models. Powerful forwardgenetic tools that have made invertebrates justifiably famous are not only relatively accessible in the zebrafish, but have been exploited to yield new insights into human infectious diseases, including leprosy and tuberculosis [1]. Transgenic technologies have enabled detailed, non-invasive in vivo visualization of macrophages and neutrophils in pitched battle with bacteria and fungi [2,3]. Reverse genetics with morpholinos, vivo-morpholinos, and zinc-finger nucleases (but unfortunately not homologous recombination, which for the moment remains out of reach in this organism) enable examination of the roles of specific genes during infection. Flexible genetic systems such as Gal4-UAS and Cre-Lox permit tissue-specific transformation and ablation ([3]; Figure 1)

Comparison of Artificial Neural Network and Logistic Regression Models for Predicting In-Hospital Mortality after Primary Liver Cancer Surgery

BACKGROUND: Since most published articles comparing the performance of artificial neural network (ANN) models and logistic regression (LR) models for predicting hepatocellular carcinoma (HCC) outcomes used only a single dataset, the essential issue of internal validity (reproducibility) of the models has not been addressed. The study purposes to validate the use of ANN model for predicting in-hospital mortality in HCC surgery patients in Taiwan and to compare the predictive accuracy of ANN with that of LR model. METHODOLOGY/PRINCIPAL FINDINGS: Patients who underwent a HCC surgery during the period from 1998 to 2009 were included in the study. This study retrospectively compared 1,000 pairs of LR and ANN models based on initial clinical data for 22,926 HCC surgery patients. For each pair of ANN and LR models, the area under the receiver operating characteristic (AUROC) curves, Hosmer-Lemeshow (H-L) statistics and accuracy rate were calculated and compared using paired T-tests. A global sensitivity analysis was also performed to assess the relative significance of input parameters in the system model and the relative importance of variables. Compared to the LR models, the ANN models had a better accuracy rate in 97.28% of cases, a better H-L statistic in 41.18% of cases, and a better AUROC curve in 84.67% of cases. Surgeon volume was the most influential (sensitive) parameter affecting in-hospital mortality followed by age and lengths of stay. CONCLUSIONS/SIGNIFICANCE: In comparison with the conventional LR model, the ANN model in the study was more accurate in predicting in-hospital mortality and had higher overall performance indices. Further studies of this model may consider the effect of a more detailed database that includes complications and clinical examination findings as well as more detailed outcome data

Disease-Free Survival after Hepatic Resection in Hepatocellular Carcinoma Patients: A Prediction Approach Using Artificial Neural Network

Background: A database for hepatocellular carcinoma (HCC) patients who had received hepatic resection was used to develop prediction models for 1-, 3- and 5-year disease-free survival based on a set of clinical parameters for this patient group. Methods: The three prediction models included an artificial neural network (ANN) model, a logistic regression (LR) model, and a decision tree (DT) model. Data for 427, 354 and 297 HCC patients with histories of 1-, 3- and 5-year disease-free survival after hepatic resection, respectively, were extracted from the HCC patient database. From each of the three groups, 80 % of the cases (342, 283 and 238 cases of 1-, 3- and 5-year disease-free survival, respectively) were selected to provide training data for the prediction models. The remaining 20 % of cases in each group (85, 71 and 59 cases in the three respective groups) were assigned to validation groups for performance comparisons of the three models. Area under receiver operating characteristics curve (AUROC) was used as the performance index for evaluating the three models. Conclusions: The ANN model outperformed the LR and DT models in terms of prediction accuracy. This study demonstrated the feasibility of using ANNs in medical decision support systems for predicting disease-free survival based on clinical databases in HCC patients who have received hepatic resection

Pseudotumoural soft tissue lesions of the hand and wrist: a pictorial review

Mimickers of soft tissue tumours in the hand and wrist are more frequent than true neoplastic lesions. Pseudotumours belong to a large and heterogeneous group of disorders, varying from normal anatomical variants, cystic lesions, post-traumatic lesions, skin lesions, inflammatory and infectious lesions, non-neoplastic vascular lesions, metabolic disorders (crystal deposition disease and amyloidosis) and miscellaneous disorders. Although the imaging approach to pseudotumoural lesions is often very similar to the approach to “true” soft tissue tumoral counterparts, further management of these lesions is different. Biopsy should be performed only in doubtful cases, when the diagnosis is unclear. Therefore, the radiologist plays a pivotal role in the diagnosis of these lesions. Awareness of the normal anatomy and existence and common imaging presentation of these diseases, in combination with relevant clinical findings (clinical history, age, location and skin changes), enables the radiologist to make the correct diagnosis in most cases, thereby limiting the need for invasive procedures

T Cell-Intrinsic and -Extrinsic Contributions of the IFNAR/STAT1-Axis to Thymocyte Survival

STAT1 is an essential part of interferon signaling, and STAT1-deficiency results in heightened susceptibility to infections or autoimmunity in both mice and humans. Here we report that mice lacking the IFNα/β-receptor (IFNAR1) or STAT1 display impaired deletion of autoreactive CD4+CD8+-T-cells. Strikingly, co-existence of WT T cells restored thymic elimination of self-reactive STAT1-deficient CD4+CD8+-T cells. Analysis of STAT1-deficient thymocytes further revealed reduced Bim expression, which was restored in the presence of WT T cells. These results indicate that type I interferons and STAT1 play an important role in the survival of MHC class I-restricted T cells in a T cell intrinsic and non-cell intrinsic manner that involves regulation of Bim expression through feedback provided by mature STAT1-competent T cells

Biomechanical analysis of the lumbar spine on facet joint force and intradiscal pressure - a finite element study

<p>Abstract</p> <p>Background</p> <p>Finite element analysis results will show significant differences if the model used is performed under various material properties, geometries, loading modes or other conditions. This study adopted an FE model, taking into account the possible asymmetry inherently existing in the spine with respect to the sagittal plane, with a more geometrically realistic outline to analyze and compare the biomechanical behaviour of the lumbar spine with regard to the facet force and intradiscal pressure, which are associated with low back pain symptoms and other spinal disorders. Dealing carefully with the contact surfaces of the facet joints at various levels of the lumbar spine can potentially help us further ascertain physiological behaviour concerning the frictional effects of facet joints under separate loadings or the responses to the compressive loads in the discs.</p> <p>Methods</p> <p>A lumbar spine model was constructed from processes including smoothing the bony outline of each scan image, stacking the boundary lines into a smooth surface model, and subsequent further processing in order to conform with the purpose of effective finite element analysis performance. For simplicity, most spinal components were modelled as isotropic and linear materials with the exception of spinal ligaments (bilinear). The contact behaviour of the facet joints and changes of the intradiscal pressure with different postures were analyzed.</p> <p>Results</p> <p>The results revealed that asymmetric responses of the facet joint forces exist in various postures and that such effect is amplified with larger loadings. In axial rotation, the facet joint forces were relatively larger in the contralateral facet joints than in the ipsilateral ones at the same level. Although the effect of the preloads on facet joint forces was not apparent, intradiscal pressure did increase with preload, and its magnitude increased more markedly in flexion than in extension and axial rotation.</p> <p>Conclusions</p> <p>Disc pressures showed a significant increase with preload and changed more noticeably in flexion than in extension or in axial rotation. Compared with the applied preloads, the postures played a more important role, especially in axial rotation; the facet joint forces were increased in the contralateral facet joints as compared to the ipsilateral ones at the same level of the lumbar spine.</p

Carotid Artery Intima-Media Thickness, Carotid Plaque and Coronary Heart Disease and Stroke in Chinese

Background: Our aim was to prospectively investigate the association between carotid artery intima-media thickness (IMT) as well as carotid plaque and incidence of coronary heart disease (CHD) and stroke in Chinese, among whom data are limited. Methods and Findings: We conducted a community-based cohort study composed of 2190 participants free of cardiovascular disease at baseline in one community. During a median 10.5-year follow up, we documented 68 new cases of coronary heart disease and 94 cases of stroke. The multivariate relative risks (RRs) associated with a change of 1 standard deviation of maximal common carotid IMT were 1.38 (95% confidence interval [CI], 1.12–1.70) for CHD and 1.47 (95% CI, 1.28–1.69) for stroke. The corresponding RRs with internal carotid IMT were 1.47 (95% CI, 1.21–1.79) for CHD and 1.52 (95% CI, 1.31–1.76) for stroke. Carotid plaque measured by the degree of diameter stenosis was also significantly associated with increased risk of CHD (p for trend<0.0001) and stroke (p for trend<0.0001). However, these associations were largely attenuated when adjusting for IMT measurements. Conclusions: This prospective study indicates a significant association between carotid IMT and incidence of CHD and stroke in Chinese adults. These measurements may be useful for cardiovascular risk assessment and stratification in Chinese