Twist1 Controls Lung Vascular Permeability and Endotoxin-Induced Pulmonary Edema by Altering Tie2 Expression

Tight regulation of vascular permeability is necessary for normal development and deregulated vascular barrier function contributes to the pathogenesis of various diseases, including acute respiratory distress syndrome, cancer and inflammation. The angiopoietin (Ang)-Tie2 pathway is known to control vascular permeability. However, the mechanism by which the expression of Tie2 is regulated to control vascular permeability has not been fully elucidated. Here we show that transcription factor Twist1 modulates pulmonary vascular leakage by altering the expression of Tie2 in a context-dependent way. Twist1 knockdown in cultured human lung microvascular endothelial cells decreases Tie2 expression and phosphorylation and increases RhoA activity, which disrupts cell-cell junctional integrity and increases vascular permeability in vitro. In physiological conditions, where Ang1 is dominant, pulmonary vascular permeability is elevated in the Tie2-specific Twist1 knockout mice. However, depletion of Twist1 and resultant suppression of Tie2 expression prevent increase in vascular permeability in an endotoxin-induced lung injury model, where the balance of Angs shifts toward Ang2. These results suggest that Twist1-Tie2-Angs signaling is important for controlling vascular permeability and modulation of this mechanism may lead to the development of new therapeutic approaches for pulmonary edema and other diseases caused by abnormal vascular permeability

State-of-the-Art Review of Vortex-Induced Motions of Floating Offshore Wind Turbine Structures

The motivation for this study is the fast development of floating offshore wind energy and the immature methodology and engineering practice related to predictions of vortex-induced motions (VIM). Benefiting from the oil and gas industry, in the past several decades, extensive knowledge and experience on vortex-induced vibrations (VIV) on slender marine structures has been gained. As the learnings from these efforts should be transferred and adapted to the renewable energy industry, a state-of-the-art review on influential VIM research has been carried out in this paper, focusing on: (1) engineering practice, (2) model tests, (3) numerical calculation, and (4) field measurement. Engineering gaps and potential research topics are identified as future work.publishedVersio

ZBED6 Modulates the Transcription of Myogenic Genes in Mouse Myoblast Cells

ZBED6 is a recently discovered transcription factor, unique to placental mammals, that has evolved from a domesticated DNA transposon. It acts as a repressor at the IGF2 locus. Here we show that ZBED6 acts as a transcriptional modulator in mouse myoblast cells, where more than 700 genes were differentially expressed after Zbed6-silencing. The most significantly enriched GO term was muscle protein and contractile fiber, which was consistent with increased myotube formation. Twenty small nucleolar RNAs all showed increased expression after Zbed6-silencing. The co-localization of histone marks and ZBED6 binding sites and the effect of Zbed6-silencing on distribution of histone marks was evaluated by ChIP-seq analysis. There was a strong association between ZBED6 binding sites and the H3K4me3, H3K4me2 and H3K27ac modifications, which are usually found at active promoters, but no association with the repressive mark H3K27me3. Zbed6-silencing led to increased enrichment of active marks at myogenic genes, in agreement with the RNA-seq findings. We propose that ZBED6 preferentially binds to active promoters and modulates transcriptional activity without recruiting repressive histone modifications

Altered regulation and expression of genes by BET family of proteins in COPD patients

Correction: PLoS One 2018 12 (4): 0175997Background BET proteins (BRD2, BRD3, BRDT and BRD4) belong to the family of bromodomain containing proteins, which form a class of transcriptional co-regulators. BET proteins bind to acetylated lysine residues in the histones of nucleosomal chromatin and function either as co-activators or co-repressors of gene expression. An imbalance between HAT and HDAC activities resulting in hyperacetylation of histones has been identified in COPD. We hypothesized that pan-BET inhibitor (JQ1) treatment of BET protein interactions with hyperacety-lated sites in the chromatin will regulate excessive activation of pro-inflammatory genes in key inflammatory drivers of alveolar macrophages (AM) in COPD. Methods and findings Transcriptome analysis of AM from COPD patients indicated up-regulation of macrophage M1 type genes upon LPS stimulation. Pan-BET inhibitor JQ1 treatment attenuated expression of multiple genes, including pro-inflammatory cytokines and regulators of innate and adaptive immune cells. We demonstrated for the first time that JQ1 differentially modulated LPS-induced cytokine release from AM or peripheral blood mononuclear cells (PBMC) of COPD patients compared to PBMC of healthy controls. Using the BET regulated gene signature, we identified a subset of COPD patients, which we propose to benefit from BET inhibition. Conclusions This work demonstrates that the effects of pan-BET inhibition through JQ1 treatment of inflammatory cells differs between COPD patients and healthy controls, and the expression of BET protein regulated genes is altered in COPD. These findings provide evidence of histone hyperacetylation as a mechanism driving chronic inflammatory changes in COPD.Peer reviewe

Pirfenidone in idiopathic pulmonary fibrosis:expert panel discussion on the management of drug-related adverse events

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.Correction in: Advances in Therapy, Volume 31, Issue 5, pp 575-576 , doi: 10.1007/s12325-014-0118-8</p

The addition of rituximab to chemotherapy improves overall survival in mantle cell lymphoma—a pooled trials analysis

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting. We report long-term outcomes of a pooled trials analysis comparing Cyclophosphamide, Doxorubicine, Vincristine, Prednisone (CHOP) to R-CHOP in MCL to confirm efficacy on failure free survival (FFS) and OS in relevant subgroups. Untreated, adult MCL patients of two prospective trials assigned to CHOP or R-CHOP were included. Primary endpoints were FFS and OS, secondary endpoints included duration of response (DOR), secondary malignancies and OS after relapse. Between 1996 and 2003, 385 MCL patients were assigned to CHOP (201) or R-CHOP (184). After a median follow-up of 13.4 years, the addition of Rituximab significantly improved FFS (1.36 vs. 2.07 years, HR 0.62 (0.50–0.77)), OS (4.84 vs. 5.81 years, HR 0.78 (0.61–0.99)) and DOR (1.48 vs. 2.08 years, HR 0.67 (0.53–0.86)). Furthermore, Rituximab improved survival across different MCL risk groups. In a post-hoc analysis of OS after relapse comparing patients receiving chemotherapy with / without rituximab, rituximab maintained efficacy with a median OS of 3.10 vs. 2.11 years (HR 0.70, 0.54–0.91). The rate of secondary malignancies was 0.5 and 3.9% for hematological and 7 and 8% for non-hematological malignancies for CHOP and R-CHOP patients, respectively. We present mature results of a pooled MCL cohort, demonstrating prolonged FFS, OS and DOR for the combined immuno-chemotherapy, confirming the standard of care in first line treatment

Toxic/Bioactive Peptide Synthesis Genes Rearranged by Insertion Sequence Elements Among the Bloom-Forming Cyanobacteria Planktothrix

It has been generally hypothesized that mobile elements can induce genomic rearrangements and influence the distribution and functionality of toxic/bioactive peptide synthesis pathways in microbes. In this study, we performed in depth genomic analysis by completing the genomes of 13 phylogenetically diverse strains of the bloom-forming freshwater cyanobacteria Planktothrix spp. to investigate the role of insertion sequence (IS) elements in seven pathways. Chromosome size varied from 4.7–4.8 Mbp (phylogenetic Lineage 1 of P. agardhii/P. rubescens thriving in shallow waterbodies) to 5.4–5.6 Mbp (Lineage 2 of P. agardhii/P. rubescens thriving in deeper physically stratified lakes and reservoirs) and 6.3–6.6 Mbp (Lineage 3, P. pseudagardhii/P. tepida including planktic and benthic ecotypes). Although the variation in chromosome size was positively related to the proportion of IS elements (1.1–3.7% on chromosome), quantitatively, IS elements and other paralogs only had a minor share in chromosome size variation. Thus, the major part of genomic variation must have resulted from gene loss processes (ancestor of Lineages 1 and 2) and horizontal gene transfer (HGT). Six of seven peptide synthesis gene clusters were found located on the chromosome and occurred already in the ancestor of P. agardhii/P. rubescens, and became partly lost during evolution of Lineage 1. In general, no increased IS element frequency in the vicinity of peptide synthesis gene clusters was observed. We found a higher proportion of IS elements in ten breaking regions related to chromosomal rearrangements and a tendency for colocalization of toxic/bioactive peptide synthesis gene clusters on the chromosome

Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2

Pathogenic variants in ACTN2, coding for alpha-actinin 2, are known to be rare causes of Hyper-trophic Cardiomyopathy. However, little is known about the underlying disease mechanisms. Adult heterozygous mice carrying the Actn2 p.Met228Thr variant were phenotyped by echocar-diography. For homozygous mice, viable E15.5 embryonic hearts were analysed by High Reso-lution Episcopic Microscopy and wholemount staining, complemented by unbiased proteomics, qPCR and Western blotting. Heterozygous Actn2 p.Met228Thr mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy. By contrast, the variant is embryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological abnormalities. Molecular analyses, including unbiased proteomics, identified quantitative abnormalities in sarcomeric parameters, cell cycle defects and mitochondrial dys-function. The mutant alpha-actinin protein is found to be destabilised, associated with increased activity of the ubiquitin-proteosomal system. This missense variant in alpha-actinin renders the protein less stable. In response, the ubiquitin-proteosomal system is activated; a mechanism which has been implicated in cardiomyopathies previously. In parallel, lack of functional al-pha-actinin is thought to cause energetic defects through mitochondrial dysfunction. This seems, together with cell cycle defects, the likely cause of death of the embryos. The defects also have wide-ranging morphological consequences

Prediction of Adipose Browning Capacity by Systematic Integration of Transcriptional Profiles

Activation and recruitment of thermogenic cells in human white adipose tissues ("browning'') can counteract obesity and associated metabolic disorders. However, quantifying the effects of therapeutic interventions on browning remains enigmatic. Here, we devise a computational tool, named ProFAT (profiling of fat tissue types), for quantifying the thermogenic potential of heterogeneous fat biopsies based on prediction of white and brown adipocyte content from raw gene expression datasets. ProFAT systematically integrates 103 mouse-fat-derived transcriptomes to identify unbiased and robust gene signatures of brown and white adipocytes. We validate ProFAT on 80 mouse and 97 human transcriptional profiles from 14 independent studies and correctly predict browning capacity upon various physiological and pharmacological stimuli. Our study represents the most exhaustive comparative analysis of public data on adipose biology toward quantification of browning after personalized medical intervention. ProFAT is freely available and should become increasingly powerful with the growing wealth of transcriptomics data

Amide Proton Transfer Contrast Distribution in Different Brain Regions in Young Healthy Subjects

ObjectivesTo define normal signal intensity values of amide proton transfer-weighted (APTw) magnetic resonance (MR) imaging in different brain regions.Materials and MethodsTwenty healthy subjects (9 females, mean age 29 years, range 19 – 37 years) underwent MR imaging at 3 Tesla. 3D APTw (RF saturation B1,rms = 2 μT, duration 2 s, 100% duty cycle) and 2D T2-weighted turbo spin echo (TSE) images were acquired. Postprocessing (image fusion, ROI measurements of APTw intensity values in 22 different brain regions) was performed and controlled by two independent neuroradiologists. Values were measured separately for each brain hemisphere. A subject was scanned both in prone and supine position to investigate differences between hemispheres. A mixed model on a 5% significance level was used to assess the effect of gender, brain region and side on APTw intensity values.ResultsMean APTw intensity values in the hippocampus and amygdala varied between 1.13 and 1.57%, in the deep subcortical nuclei (putamen, globus pallidus, head of caudate nucleus, thalamus, red nucleus, substantia nigra) between 0.73 and 1.84%, in the frontal, occipital and parietal cortex between 0.56 and 1.03%; in the insular cortex between 1.11 and 1.15%, in the temporal cortex between 1.22 and 1.37%, in the frontal, occipital and parietal white matter between 0.32 and 0.54% and in the temporal white matter between 0.83 and 0.89%. APTw intensity values were significantly impacted both by brain region (p &lt; 0.001) and by side (p &lt; 0.001), whereby overall values on the left side were higher than on the right side (1.13 vs. 0.9%). Gender did not significantly impact APTw intensity values (p = 0.24). APTw intensity values between the left and the right side were partially reversed after changing the position of one subject from supine to prone.ConclusionWe determined normal baseline APTw intensity values in different anatomical localizations in healthy subjects. APTw intensity values differed both between anatomical regions and between left and right brain hemisphere