Peroxisome Proliferator-Activated Receptors Protect against Apoptosis via 14-3-3

Peroxisome proliferator-activated receptors (PPARs) were reported to prevent cells from stress-induced apoptosis and protect tissues against ischemia-reperfusion injury. The underlying transcriptional mechanism is unclear. Recent reports indicate that the antiapoptotic actions of ligand-activated PPARδ and PPARγ are mediated through enhanced binding of PPAR to the promoter of 14-3-3ε and upregulation of 14-3-3ε expression. We propose that ligand-activated PPARα exerts its anti-apoptotic actions via the identical pathway. The PPAR to 14-3-3 transcriptional axis plays an important role in protection of cell and tissue integrity and is a target for drug discovery

Nestin Is Essential for Zebrafish Brain and Eye Development through Control of Progenitor Cell Apoptosis

BACKGROUND: Nestin is expressed in neural progenitor cells (NPC) of developing brain. Despite its wide use as an NPC marker, the function of nestin in embryo development is unclear. METHODOLOGY/PRINCIPAL FINDINGS: As nestin is conserved in zebrafish and its predicted sequence is clustered with the mammalian nestin orthologue, we used zebrafish as a model to investigate its role in embryogenesis. Injection of nestin morpholino (MO) into fertilized eggs induced time- and dose-dependent brain and eye developmental defects. Nestin morphants exhibited characteristic morphological changes including small head, small eyes and hydrocephalus. Histological examinations show reduced hind- and mid-brain size, dilated ventricle, poorly organized retina and underdeveloped lens. Injection of control nestin MO did not induce brain or eye changes. Nestin MO injection reduced expression of ascl1b (achaete-scute complex-like 1b), a marker of NPCs, without affecting its distribution. Nestin MO did not influence Elavl3/4 (Embryonic lethal, abnormal vision, Drosophila-like 3/4) (a neuronal marker), or otx2 (a midbrain neuronal marker), but severely perturbed cranial motor nerve development and axon distribution. To determine whether the developmental defects are due to excessive NPC apoptosis and/or reduced NPC proliferation, we analyzed apoptosis by TUNEL assay and acridine orange staining and proliferation by BrdU incorporation, pcna and mcm5 expressions. Excessive apoptosis was noted in hindbrain and midbrain cells. Apoptotic signals were colocalized with ascl1b. Proliferation markers were not significantly altered by nestin MO. CONCLUSION/SIGNIFICANCE: These results suggest that nestin is essential for zebrafish brain and eye development probably through control of progenitor cell apoptosis

Bovine Aorta Endothelial Cell Incubation with Interleukin 2: Morphological Changes Correlate with Enhanced Vascular Permeability

Interleukin 2 induced alterations in the morphology of bovine aortic endothelial cells in vitro. The changes observed in confluent cultures of bovine aortic endothelial cells included retraction and elongation of eel ls leading to enlarged gaps between cells quantified by image analysis. Purified IL-2 (1 U/ml medium) increased the gaps between endothelial cells 3-4-fold compared with control cultures. The effect was transient, since the cells reverted to their original morphology 6-12 hours after the removal of lL-2. Correlative scanning electron microscopy (SEM) studies using fresh bovine aorta showed a dose-dependent alteration of the endothelial surface by IL-2 characterized by rounding and elongation of endothelial cells and prominent perinuclear areas. Gaps between the endothelial cells were observed when aorta samples were incubated with 2 U of IL-2/ml of medium. This was confirmed by SEM, transmission electron microscopy and Evans blue dye staining. These results suggest that IL-2 caused morphological alterations in endothelial cells that enhanced the permeability of the vascular endothelium

THE UTILIZATION OF HIGH FREQUENCY PERCUSSIVE VENTILATION TO REDUCE EXTRACORPOREAL OXYGENATION MEMBRANE SUPPORT.

To minimize the chance of ventilator induced lung injury (VILI), in patients who develop adult respiratory distress syndrome ARDS), Extracorporeal Oxygenation Membrane (ECMO) is a common clinical intervention. The goal of venous-venous ECMO is to provide stable gas exchange, while the goal of the ventilator is to preserve the patient\u27s pulmonary mechanics and minimize VILI. When ECMO parameters are maximized and gas exchange is marginal, often then the ventilator is called upon to help improve or maintain gas exchange often requiring high pressures and oxygen delivery (FI02). An alternative strategy to meet this objective is to utilized high frequency percussive ventilation (HFPV) via the VDR-4 (Sandpoint, Idaho). HFPV provides both an endobronchial wedge via the percussive rate and an oscillatory plateau via the connective rate. With this strategy lower pressures and oxygen delivery can be employed and ECMO parameters can be often reduced. From Jan 2015 to Feb 2016 we utilized the VDR on fifteen V-V ECMO patients. Thirteen (86.7%) of fifteen patients both ECMO FIO2 and sweep were reduced with in twenty-four hours. (Table 1) HFPV pressures and FIO2 were maintain lower than 60% and airway pressure ≤ 40cmH20. (Table 1) Prior to placing on HFPV a pressure/tool measurement was performed to determine starting airway pressure and PEEP parameters to set on the VDR. Based on the above results, HFPV can help ECMO maintain gas exchange for patients at a lower FIO2 and sweep settings

YoloCurvSeg: You Only Label One Noisy Skeleton for Vessel-style Curvilinear Structure Segmentation

Weakly-supervised learning (WSL) has been proposed to alleviate the conflict between data annotation cost and model performance through employing sparsely-grained (i.e., point-, box-, scribble-wise) supervision and has shown promising performance, particularly in the image segmentation field. However, it is still a very challenging problem due to the limited supervision, especially when only a small number of labeled samples are available. Additionally, almost all existing WSL segmentation methods are designed for star-convex structures which are very different from curvilinear structures such as vessels and nerves. In this paper, we propose a novel sparsely annotated segmentation framework for curvilinear structures, named YoloCurvSeg, based on image synthesis. A background generator delivers image backgrounds that closely match real distributions through inpainting dilated skeletons. The extracted backgrounds are then combined with randomly emulated curves generated by a Space Colonization Algorithm-based foreground generator and through a multilayer patch-wise contrastive learning synthesizer. In this way, a synthetic dataset with both images and curve segmentation labels is obtained, at the cost of only one or a few noisy skeleton annotations. Finally, a segmenter is trained with the generated dataset and possibly an unlabeled dataset. The proposed YoloCurvSeg is evaluated on four publicly available datasets (OCTA500, CORN, DRIVE and CHASEDB1) and the results show that YoloCurvSeg outperforms state-of-the-art WSL segmentation methods by large margins. With only one noisy skeleton annotation (respectively 0.14%, 0.03%, 1.40%, and 0.65% of the full annotation), YoloCurvSeg achieves more than 97% of the fully-supervised performance on each dataset. Code and datasets will be released at https://github.com/llmir/YoloCurvSeg.Comment: 11 pages, 10 figures, submitted to IEEE Transactions on Medical Imaging (TMI

Modulation of Gene Expression in Key Survival Pathways During Daily Torpor in the Gray Mouse Lemur, Microcebus murinus

AbstractA variety of mammals employ torpor as an energy-saving strategy in environments of marginal or severe stress either on a daily basis during their inactive period or on a seasonal basis during prolonged multi-day hibernation. Recently, a few Madagascar lemur species have been identified as the only primates that exhibit torpor; one of these is the gray mouse lemur (Microcebus murinus). To explore the regulatory mechanisms that underlie daily torpor in a primate, we analyzed the expression of 28 selected genes that represent crucial survival pathways known to be involved in squirrel and bat hibernation. Array-based real-time PCR was used to compare gene expression in control (aroused) versus torpid lemurs in five tissues including the liver, kidney, skeletal muscle, heart, and brown adipose tissue. Significant differences in gene expression during torpor were revealed among genes involved in glycolysis, fatty acid metabolism, antioxidant defense, apoptosis, hypoxia signaling, and protein protection. The results showed upregulation of select genes primarily in liver and brown adipose tissue. For instance, both tissues showed elevated gene expression of peroxisome proliferator activated receptor gamma (ppargc), ferritin (fth1), and protein chaperones during torpor. Overall, the data show that the expression of only a few genes changed during lemur daily torpor, as compared with the broader expression changes reported for hibernation in ground squirrels. These results provide an indication that the alterations in gene expression required for torpor in lemurs are not as extensive as those needed for winter hibernation in squirrel models. However, identification of crucial genes with altered expression that support lemur torpor provides key targets to be explored and manipulated toward a goal of translational applications of inducible torpor as a treatment option in human biomedicine

Imiquimod 3.75% Cream Applied Daily to Treat Anogenital Warts: Combined Results from Women in Two Randomized, Placebo-Controlled Studies

Objective. To evaluate if new imiquimod formulations using a shorter treatment duration are safe and efficacious to treat anogenital warts. Methods. In two studies 534 women ≥12 years of age (mean 33.4) with 2–30 warts (mean 7.9) and total wart area ≥10 mm2 (mean 166.3) were randomized (1 : 2 : 2) to placebo (106), imiquimod 2.5% (212) or 3.75% (216) creams applied once daily until complete clearance or a maximum of 8 weeks. Results. For placebo, imiquimod 2.5% and 3.75%, respectively, complete clearance of all warts was achieved in 14.2%, 28.3%, and 36.6% of women (intent-to-treat, P = 0.008 imiquimod 2.5%, and P < 0.001 3.75% versus placebo). Mean changes in wart counts were −10.7%, −50.9%, and −63.5% (per-protocol, P < 0.001 each active versus placebo) and safety-related discontinuation rates 0.9%, 1.4%, and 2.3%. Conclusions. Imiquimod 3.75% applied daily for up to 8 weeks was well tolerated and superior to placebo in treating women with external anogenital warts