Plasminogen Activator Inhibitor-1 Suppresses Profibrotic Responses in Fibroblasts from Fibrotic Lungs

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive interstitial scarification. A hallmark morphological lesion is the accumulation of myofibroblasts or fibrotic lung fibroblasts (FL-fibroblasts) in areas called fibroblastic foci. We previously demonstrated that the expression of both urokinase-type plasminogen activator (uPA) and the uPA receptor are elevated in FL-fibroblasts from the lungs of patients with IPF. FL-fibroblasts isolated from human IPF lungs and from mice with bleomycin-induced pulmonary fibrosis showed an increased rate of proliferation compared with normal lung fibroblasts (NL-fibroblasts) derived from histologically “normal” lung. Basal expression of plasminogen activator inhibitor-1 (PAI-1) in human and murine FL-fibroblasts was reduced, whereas collagen-I and α-smooth muscle actin were markedly elevated. Conversely, alveolar type II epithelial cells surrounding the fibrotic foci in situ, as well as those isolated from IPF lungs, showed increased activation of caspase-3 and PAI-1 with a parallel reduction in uPA expression. Transduction of an adenovirus PAI-1 cDNA construct (Ad-PAI-1) suppressed expression of uPA and collagen-I and attenuated proliferation in FL-fibroblasts. On the contrary, inhibition of basal PAI-1 in NL-fibroblasts increased collagen-I and α-smooth muscle actin. Fibroblasts isolated from PAI-1-deficient mice without lung injury also showed increased collagen-I and uPA. These changes were associated with increased Akt/phosphatase and tensin homolog proliferation/survival signals in FL-fibroblasts, which were reversed by transduction with Ad-PAI-1. This study defines a new role of PAI-1 in the control of fibroblast activation and expansion and its role in the pathogenesis of fibrosing lung disease and, in particular, IPF.     

Up-regulation of Thrombospondin-2 in Akt1-null Mice Contributes to Compromised Tissue Repair Due to Abnormalities in Fibroblast Function

Vascular remodeling is essential for tissue repair and is regulated by multiple factors, including thrombospondin-2 (TSP2) and hypoxia/VEGF-induced activation of Akt. In contrast to TSP2 knock-out (KO) mice, Akt1 KO mice have elevated TSP2 expression and delayed tissue repair. To investigate the contribution of increased TSP2 to Akt1 KO mice phenotypes, we generated Akt1/TSP2 double KO (DKO) mice. Full-thickness excisional wounds in DKO mice healed at an accelerated rate when compared with Akt1 KO mice. Isolated dermal Akt1 KO fibroblasts expressed increased TSP2 and displayed altered morphology and defects in migration and adhesion. These defects were rescued in DKO fibroblasts or after TSP2 knockdown. Conversely, the addition of exogenous TSP2 to WT cells induced cell morphology and migration rates that were similar to those of Akt1 KO cells. Akt1 KO fibroblasts displayed reduced adhesion to fibronectin with manganese stimulation when compared with WT and DKO cells, revealing an Akt1-dependent role for TSP2 in regulating integrin-mediated adhesions; however, this effect was not due to changes in β1 integrin surface expression or activation. Consistent with these results, Akt1 KO fibroblasts displayed reduced Rac1 activation that was dependent upon expression of TSP2 and could be rescued by a constitutively active Rac mutant. Our observations show that repression of TSP2 expression is a critical aspect of Akt1 function in tissue repair.     

Morphine and cocaine increase serum‐ and glucocorticoid‐inducible kinase 1 activity in the ventral tegmental area

Drugs of abuse modulate the function and activity of the mesolimbic dopamine circuit. To identify novel mediators of drug‐induced neuroadaptations in the ventral tegmental area (VTA), we performed RNA sequencing analysis on VTA samples from mice administered repeated saline, morphine, or cocaine injections. One gene that was similarly up‐regulated by both drugs was serum‐ and glucocorticoid‐inducible kinase 1 (SGK1). SGK1 activity, as measured by phosphorylation of its substrate N‐myc downstream regulated gene (NDRG), was also increased robustly by chronic drug treatment. Increased NDRG phosphorylation was evident 1 but not 24 h after the last drug injection. SGK1 phosphorylation itself was similarly modulated. To determine the role of increased SGK1 activity on drug‐related behaviors, we over‐expressed constitutively active (CA) SGK1 in the VTA. SGK1‐CA expression reduced locomotor sensitization elicited by repeated cocaine, but surprisingly had the opposite effect and promoted locomotor sensitization to morphine, without affecting the initial locomotor responses to either drug. SGK1‐CA expression did not significantly affect morphine or cocaine conditioned place preference, although there was a trend toward increased conditioned place preference with both drugs. Further characterizing the role of this kinase in drug‐induced changes in VTA may lead to improved understanding of neuroadaptations critical to drug dependence and addiction.

     

A Cross-Lingual Similarity Measure for Detecting Biomedical Term Translations

Bilingual dictionaries for technical terms such as biomedical terms are an important resource for machine translation systems as well as for humans who would like to understand a concept described in a foreign language. Often a biomedical term is first proposed in English and later it is manually translated to other languages. Despite the fact that there are large monolingual lexicons of biomedical terms, only a fraction of those term lexicons are translated to other languages. Manually compiling large-scale bilingual dictionaries for technical domains is a challenging task because it is difficult to find a sufficiently large number of bilingual experts. We propose a cross-lingual similarity measure for detecting most similar translation candidates for a biomedical term specified in one language (source) from another language (target). Specifically, a biomedical term in a language is represented using two types of features: (a) intrinsic features that consist of character n-grams extracted from the term under consideration, and (b) extrinsic features that consist of unigrams and bigrams extracted from the contextual windows surrounding the term under consideration. We propose a cross-lingual similarity measure using each of those feature types. First, to reduce the dimensionality of the feature space in each language, we propose prototype vector projection (PVP)—a non-negative lower-dimensional vector projection method. Second, we propose a method to learn a mapping between the feature spaces in the source and target language using partial least squares regression (PLSR). The proposed method requires only a small number of training instances to learn a cross-lingual similarity measure. The proposed PVP method outperforms popular dimensionality reduction methods such as the singular value decomposition (SVD) and non-negative matrix factorization (NMF) in a nearest neighbor prediction task. Moreover, our experimental results covering several language pairs such as English–French, English–Spanish, English–Greek, and English–Japanese show that the proposed method outperforms several other feature projection methods in biomedical term translation prediction tasks.     

Value of DSA in the Diagnostic Workup of Pulsatile Tinnitus

ObjectivesPulsatile tinnitus (PT) is a rare complaint, but can be a symptom of life-threatening disease. It is often caused by vascular pathologies, e.g. dural arteriovenous fistula (dAVF), arteriovenous malformation (AVM) or vascularized tumors. The current diagnostic pathway includes clinical examination, cranial MRI and additional DSA. The aim of this study was to evaluate the diagnostic impact of DSA in the diagnostic workup of patients with PT in comparison to MRI alone.MethodsRetrospectively, 54 consecutive patients with pulsatile tinnitus were evaluated. All patients had a diagnostic workup including cranial MRI and DSA. MRI examinations were blinded to the results of DSA and retrospectively analyzed in consensus by two experienced neuroradiologists. The MR-examinations were evaluated for each performed sequence separately: time-of-flight-angiography, ce-MRA, T2, ce-T1-sequence and ce-T1-sequence with fat saturation.Results37 of the 54 patients revealed a pathology explaining PT on MRI, which was detected by the readers in 100% and proofed by means of DSA. 24 dAVF, four paraganglioma, two AVM and seven more pathologies were described. All patients without pathology on MRI did also not show any pathology in DSA.ConclusionsMR imaging is sufficient to exclude pathology in patients with pulsatile tinnitus.     

Environmental pressure rather than ongoing hybridization is responsible for an altitudinal cline in the morphologies of two oaks

在相关类群之间的接触区,表型变异可能源于遗传和/或环境梯度。本研究旨在阐明两种栎属植物[Quercus crispula (QCC)和 Q. mongolicoides (QCM)],在其接触区沿海拔梯度形成叶片形态表型变异的原因。对于源自接触区48个个体和QCC和QCM的每个参照 种群24个个体样本,我们测定其6种叶片形态特征,同时记录13个核微卫星位点的基因型。我们通过构建模型解释表型变异(叶片形态)与环境(海拔)和遗传(参照种群世系)梯度的关系。研究结果表明,形态和遗传标记均能较好地区分参照种群中的两个品种。我们能够确认形态和遗传标记的作用。接触区种群内的个体具有略偏向QCM分支的中间世系,其形态分布与参照种群中两个变种的形态分布重叠。海拔会显著影响叶片形态性状,而遗传对叶片形态性状无显著影响。接触区种群的世系和种间杂合性分布与F₂或后代杂交种中的分布相似。这些结果表明,在两种栎属植物QCC和QCM之间的接触区,并没有发生杂交,但环境压力通过表型可塑性和/或功能基因的变异,导致了其在形态性状上的海拔梯度效应。