Integrin-mediated regulation of TGFβ in fibrosis

AbstractFibrosis is a major cause of morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only effective treatment for end-stage fibrotic disease. However, demand for donor organs greatly outstrips supply, and so effective anti-fibrotic treatments are urgently required. In recent years, the integrin family of cell adhesion receptors has gained prominence as key regulators of chronic inflammation and fibrosis. Fibrosis models in multiple organs have demonstrated that integrins have profound effects on the fibrotic process. There is now abundant in vivo data demonstrating critical regulatory roles for integrins expressed on different cell types during tissue fibrogenesis. In this review, we will examine the ways in which integrins regulate these processes and discuss how the manipulation of integrins using function blocking antibodies and small molecule inhibitors may have clinical utility in the treatment of patients with a broad range of fibrotic diseases. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease

Integrin-mediated regulation of TGFβ in fibrosis

AbstractFibrosis is a major cause of morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only effective treatment for end-stage fibrotic disease. However, demand for donor organs greatly outstrips supply, and so effective anti-fibrotic treatments are urgently required. In recent years, the integrin family of cell adhesion receptors has gained prominence as key regulators of chronic inflammation and fibrosis. Fibrosis models in multiple organs have demonstrated that integrins have profound effects on the fibrotic process. There is now abundant in vivo data demonstrating critical regulatory roles for integrins expressed on different cell types during tissue fibrogenesis. In this review, we will examine the ways in which integrins regulate these processes and discuss how the manipulation of integrins using function blocking antibodies and small molecule inhibitors may have clinical utility in the treatment of patients with a broad range of fibrotic diseases. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease

Liver zonation, revisited

The concept of hepatocyte functional zonation is well established, with differences in metabolism and xenobiotic processing determined by multiple factors including oxygen and nutrient levels across the hepatic lobule. However, recent advances in single‐cell genomics technologies, including single‐cell and nuclei RNA sequencing, and the rapidly evolving fields of spatial transcriptomic and proteomic profiling have greatly increased our understanding of liver zonation. Here we discuss how these transformative experimental strategies are being leveraged to dissect liver zonation at unprecedented resolution and how this new information should facilitate the emergence of novel precision medicine‐based therapies for patients with liver disease

Web Honeypots for Spies

This paper appeared in the Intl. Conf. on Computational Science and Computational Intelligence, December 2018, Las Vegas, NV, USAWe are building honeypots for document-collecting spies who are searching the Web for intelligence information. The goal is to develop tools for assessing the relative degree of interest elicited by users in representative documents. One experiment set up a site with bait documents and used two site-monitoring tools, Google Analytics and AWStats, to analyze the traffic. Much of this traffic was automated (“bots”), and showed some interesting differences in the retrieval frequency of documents. We also analyzed bot traffic on a similar real site, the library site at our school. In nearly one million requests, we concluded 64% were bots. 46 did identify themselves as bots, 40 came from blacklisted sites, and 12 gave demonstrably false user identifications.Naval Postgraduate School Foundatio

Selective Myeloid Depletion of Galectin-3 Offers Protection Against Acute and Chronic Lung Injury

Rationale: Galectin-3 (Gal-3) is an immune regulator and an important driver of fibrosis in chronic lung injury, however, its role in acute lung injury (ALI) remains unknown. Previous work has shown that global deletion of galectin-3 reduces collagen deposition in a bleomycin-induced pulmonary fibrosis model (MacKinnon et al., Am. J. Respir. Crit. Care Med., 2012, 185, 537–46). An inhaled Gal-3 inhibitor, GB0139, is undergoing Phase II clinical development for idiopathic pulmonary fibrosis (IPF). This work aims to elucidate the role of Gal-3 in the myeloid and mesenchymal compartment on the development of acute and chronic lung injury. Methods:LgalS3(fl/fl) mice were generated and crossed with mice expressing the myeloid (LysM) and mesenchymal (Pdgfrb) cre drivers to yield LysM-cre (+/-) /LgalS3 (fl/fl) and Pdgfrb-cre (+/-) /LgalS3 (fl/fl) mice. The response to acute (bleomycin or LPS) or chronic (bleomycin) lung injury was compared to globally deficient Gal-3 (−/−) mice. Results: Myeloid depletion of Gal-3 led to a significant reduction in Gal-3 expression in alveolar macrophages and neutrophils and a reduction in neutrophil recruitment into the interstitium but not into the alveolar space. The reduction in interstitial neutrophils corelated with decreased levels of pulmonary inflammation following acute bleomycin and LPS administration. In addition, myeloid deletion decreased Gal-3 levels in bronchoalveolar lavage (BAL) and reduced lung fibrosis induced by chronic bleomycin. In contrast, no differences in BAL Gal-3 levels or fibrosis were observed in Pdgfrb-cre (+/-) /LgalS3 (fl/fl) mice. Conclusions: Myeloid cell derived Galectin-3 drives acute and chronic lung inflammation and supports direct targeting of galectin-3 as an attractive new therapy for lung inflammation

Cellular heterogeneity of the developing worker honey bee (Apis mellifera) pupa: a single cell transcriptomics analysis

It is estimated that animals pollinate 87.5% of flowering plants worldwide and that managed honey bees (Apis mellifera) account for 30-50% of this ecosystem service to agriculture. In addition to their important role as pollinators, honey bees are well-established insect models for studying learning and memory, behaviour, caste differentiation, epigenetic mechanisms, olfactory biology, sex determination and eusociality. Despite their importance to agriculture, knowledge of honey bee biology lags behind many other livestock species. In this study we have used scRNA-Seq to map cell types to different developmental stages of the worker honey bee (prepupa at day 11 and pupa at day 15), and sought to determine their gene signatures and thereby provide potential functional annotations for as yet poorly characterized genes. To identify cell type populations we examined the cell-to-cell network based on the similarity of the single-cells’ transcriptomic profiles. Grouping similar cells together we identified 63 different cell clusters of which 15 clusters were identifiable at both stages. To determine genes associated with specific cell populations or with a particular biological process involved in honey bee development, we used gene co-expression analysis. We combined this analysis with literature mining, the honey bee protein atlas and Gene Ontology analysis to determine cell cluster identity. Of the cell clusters identified, 9 were related to the nervous system, 7 to the fat body, 14 to the cuticle, 5 to muscle, 4 to compound eye, 2 to midgut, 2 to hemocytes and 1 to malpighian tubule/pericardial nephrocyte. To our knowledge, this is the first whole single cell atlas of honey bees at any stage of development and demonstrates the potential for further work to investigate their biology of at the cellular level

Does Graded Prognostic Assessment outperform Recursive Partitioning Analysis in patients with moderate prognosis brain metastases?

AIM: To compare the clinical utility of the Recursive Partitioning Analysis (RPA) and Graded Prognostic Assessment (GPA) in predicting outcomes for moderate prognosis patients with brain metastases. METHODS & MATERIALS: We reviewed 101 whole brain radiotherapy cases. RPA and GPA were calculated. Overall survival was compared. RESULTS: Sixty-eight patients had moderate prognosis. RPA patient characteristics for increased death hazard were ≤10 WBRT fractions or no surgery/radiosurgery. GPA patients had increased death risk with no surgery/radiosurgery or lower Karnofsky Performance Status. CONCLUSION: The indices have similar predicted survival. Patients scored by RPA with longer radiation schedules had longer survival; patients scored by GPA did not. This indicates GPA is more clinically useful, leaving less room for subjective treatment choices

Green chemiluminescence from a bis-cyclometalated iridium(III) complex with an ancillary bathophenanthroline disulfonate ligand

The reaction of a fluorinated iridium complex with cerium(IV) and organic reducing agents generates an intense emission with a significant hypsochromic shift compared to contemporary chemically-initiated luminescence from metal complexes

Origins of fibrosis:pericytes take centre stage

Pericytes are ubiquitous perivascular cells that have recently attracted interest as potential myofibroblast precursors. In turn, myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis. Given the worldwide burden of fibrotic disease and paucity of therapeutic options available to halt its progression, elucidating the origins of myofibroblasts is of prime importance. The advent of genetic strategies that permit fate-mapping of specific cell populations through permanent and heritable expression of reporter proteins has begun to shed light on the source of the fibrogenic myofibroblast. Here we discuss recent studies in multiple organs that highlight the central role of pericytes in the origins of fibrosis