Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice

Injury to the distal respiratory epithelium has been implicated as an underlying cause of idiopathic lung diseases. Mutations that result in SP-C deficiencies are linked to a small subset of spontaneous and familial cases of interstitial lung disease (ILD) and interstitial pulmonary fibrosis (IPF). Gene-targeted mice that lack SP-C (Sftpc−/−) develop an irregular ILD-like disease with age and are a model of the human SP-C related disease. In the current study, we investigated whether rapamycin could ameliorate bleomycin-induced fibrosis in the lungs of Sftpc−/− mice. Sftpc+/+ and −/− mice were exposed to bleomycin with either preventative administration of rapamycin or therapeutic administration beginning eight days after the bleomycin injury. Rapamycin-treatment increased weight loss and decreased survival of bleomycin-treated Sftpc+/+ and Sftpc−/− mice. Rapamycin did not reduce the fibrotic disease in the prophylactic or rescue experiments of either genotype of mice. Further, rapamycin treatment augmented airway resistance and reduced lung compliance of bleomycin-treated Sftpc−/− mice. Rapamycin treatment was associated with an increased expression of profibrotic Th2 cytokines and reduced expression of INF-γ. These findings indicate that novel therapeutics will be required to treat individuals with SP-C deficient ILD/IPF

A Feasibility Study on Indoor Localization and Multi-person Tracking Using Sparsely Distributed Camera Network with Edge Computing

Camera-based activity monitoring systems are becoming an attractive solution for smart building applications with the advances in computer vision and edge computing technologies. In this paper, we present a feasibility study and systematic analysis of a camera-based indoor localization and multi-person tracking system implemented on edge computing devices within a large indoor space. To this end, we deployed an end-to-end edge computing pipeline that utilizes multiple cameras to achieve localization, body orientation estimation and tracking of multiple individuals within a large therapeutic space spanning $1700m^2$, all while maintaining a strong focus on preserving privacy. Our pipeline consists of 39 edge computing camera systems equipped with Tensor Processing Units (TPUs) placed in the indoor space's ceiling. To ensure the privacy of individuals, a real-time multi-person pose estimation algorithm runs on the TPU of the computing camera system. This algorithm extracts poses and bounding boxes, which are utilized for indoor localization, body orientation estimation, and multi-person tracking. Our pipeline demonstrated an average localization error of 1.41 meters, a multiple-object tracking accuracy score of 88.6\%, and a mean absolute body orientation error of 29\degree. These results shows that localization and tracking of individuals in a large indoor space is feasible even with the privacy constrains

Mapping transmembrane residues of proteinase activated recpetor 2 (PAR2) that influence ligand-modulated calcium signaling

Proteinase-activated receptor 2 (PAR(2)) is a G protein -coupled receptor involved in metabolism, inflammation, and cancers. It is activated by proteolysis, which exposes a nascent N -terminal sequence that becomes a tethered agonist. Short synthetic peptides corresponding to this sequence also activate PAR(2), while small organic molecules show promising PAR(2) antagonism. Developing PAR(2) ligands into pharmaceuticals is hindered by a lack of knowledge of how synthetic ligands interact with and differentially modulate PAR(2). Guided by PAR(2) homology modeling and ligand docking based on bovine rhodopsin, followed by cross-checking with newer PAR(2) models based on ORL-1 and PART, site-directed mutagenesis of PAR(2) was used to investigate the pharmacology of three agonists (two synthetic agonists and trypsin-exposed tethered ligand) and one antagonist for modulation of PAR(2) signaling. Effects of 28 PAR2 mutations were examined for PAR(2)-mediated calcium mobilization and key mutants were selected for measuring ligand binding. Nineteen of twenty-eight PAR(2) mutations reduced the potency of at least one ligand by>10-fold. Key residues mapped predominantly to a cluster in the transmembrane (TM) domains of PAR(2), differentially influence intracellular Ca2+ induced by synthetic agonists versus a native agonist, and highlight subtly different TM residues involved in receptor activation. This is the first evidence highlighting the importance of the PAR(2) TM regions for receptor activation by synthetic PAR(2) agonists and antagonists. The trypsin-cleaved N-terminus that activates PAR(2) was unaffected by residues that affected synthetic peptides, challenging the widespread practice of substituting peptides for proteases to characterize PAR(2) physiology. (C) 2017 Elsevier Ltd. All rights reserved

Modeling anthropometric indices in relation to 10-year (2002-2012) incidence of cardiovascular disease, among apparently healthy individuals:the ATTICA study

Aims: Body fat accumulation is implicated in the development of cardiovascular disease (CVD). Our objective was to explore potential associations between anthropometric indices and the 10-year CVD incidence in Greek adults without previous CVD. Methods: During 2001–2, we enrolled 3042 adults without CVD from the general population of Attica, Greece. In 2011–2, the 10-year study follow-up was performed, recording the CVD incidence in 1958 participants with baseline body mass index (BMI) ≥18.5 kg/m2. Results: The study 10-year CVD incidence was 15.8%, exhibiting a gradual increase according to the baseline body mass index (BMI) category. Baseline BMI ≥30 kg/m2 was related with significantly higher 10-year CVD risk compared to BMI <25 kg/m2, even after adjustment for age and other known CVD risk factors. Baseline BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio and waist-to-hip-to-height ratio were independently associated with the 10-year CVD risk in multi-adjusted models. Gender-specific analyses showed that these associations were more evident in men compared to women, with baseline BMI exhibiting an independent association with the 10-year CVD incidence in men. Conclusions: Our results indicate that even simple anthropometric indices exhibit independent associations with CVD risk in a representative sample of the Greek general population without previous CVD

Differential Expression of Chemokine and Matrix Re-Modelling Genes Is Associated with Contrasting Schistosome-Induced Hepatopathology in Murine Models

The pathological outcomes of schistosomiasis are largely dependent on the molecular and cellular mechanisms of the host immune response. In this study, we investigated the contribution of variations in host gene expression to the contrasting hepatic pathology observed between two inbred mouse strains following Schistosoma japonicum infection. Whole genome microarray analysis was employed in conjunction with histological and immunohistochemical analysis to define and compare the hepatic gene expression profiles and cellular composition associated with the hepatopathology observed in S. japonicum-infected BALB/c and CBA mice. We show that the transcriptional profiles differ significantly between the two mouse strains with high statistical confidence. We identified specific genes correlating with the more severe pathology associated with CBA mice, as well as genes which may confer the milder degree of pathology associated with BALB/c mice. In BALB/c mice, neutrophil genes exhibited striking increases in expression, which coincided with the significantly greater accumulation of neutrophils at granulomatous regions seen in histological sections of hepatic tissue. In contrast, up-regulated expression of the eosinophil chemokine CCL24 in CBA mice paralleled the cellular influx of eosinophils to the hepatic granulomas. Additionally, there was greater down-regulation of genes involved in metabolic processes in CBA mice, reflecting the more pronounced hepatic damage in these mice. Profibrotic genes showed similar levels of expression in both mouse strains, as did genes associated with Th1 and Th2 responses. However, imbalances in expression of matrix metalloproteinases (e.g. MMP12, MMP13) and tissue inhibitors of metalloproteinases (TIMP1) may contribute to the contrasting pathology observed in the two strains. Overall, these results provide a more complete picture of the molecular and cellular mechanisms which govern the pathological outcome of hepatic schistosomiasis. This improved understanding of the immunopathogenesis in the murine model schistosomiasis provides the basis for a better appreciation of the complexities associated with chronic human schistosomiasis

αv integrins: key regulators of tissue fibrosis

Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction and eventual organ failure. Therefore, the development of effective anti-fibrotic therapies is urgently required. During fibrogenesis, complex interplay occurs between cellular and extracellular matrix components of the wound healing response. Integrins, a family of transmembrane cell adhesion molecules, play a key role in mediating intercellular and cell-matrix interactions. Thus, integrins provide a major node of communication between the extracellular matrix, inflammatory cells, fibroblasts and parenchymal cells and, as such, are intimately involved in the initiation, maintenance and resolution of tissue fibrosis. Modulation of members of the αv integrin family has exhibited profound effects on fibrosis in multiple organs and disease states. In this review, we discuss the current knowledge of the mechanisms of αv-integrin-mediated regulation of fibrogenesis and show that the therapeutic targeting of specific αv integrins represents a promising avenue to treat patients with a broad range of fibrotic diseases

Oncogenic Properties of Apoptotic Tumor Cells in Aggressive B Cell Lymphoma

BACKGROUND: Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. RESULTS: Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased "in situ transcriptomics" analysis-gene expression profiling of laser-captured TAMs to establish their activation signature in situ-we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. CONCLUSIONS: In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The life-course impact of smoking on hypertension, myocardial infarction and respiratory diseases

The Author(s) 2017. The objective of this study was to examine the impact of smoking on respiratory diseases, hypertension and myocardial infarction, with a particular focus from a life-course perspective. In this study, 28,577 males from a Chinese longitudinal survey were analysed. The effects of smoking on the risk of respiratory diseases, hypertension and myocardial infarction were assessed from a life-course perspective and a current view separately. No significant associations were found between smoking and the risk of incident respiratory diseases, hypertension and myocardial infarction in the group younger than 35. Among study participants aged between 36-55 and 56-80, smoking was positively associated with the risk of incident respiratory diseases, hypertension and myocardial infarction from the life-course perspective, and the risk increased with age. In contrast, the results from a current view showed inverse associations between smoking and the risk of the diseases mentioned above. Our findings highlight that it is essential to quantify the effects of smoking from a life-course perspective in future research and to suggest that smokers quit smoking as soon as possible, regardless of the temporary side effects of quitting