Uncoupling Protein 2 Increases Susceptibility to Lipopolysaccharide-Induced Acute Lung Injury in Mice

Uncoupling protein 2 (UCP2) is upregulated in patients with systemic inflammation and infection, but its functional role is unclear. We up- or downregulated UCP2 expression using UCP2 recombinant adenovirus or the UCP2 inhibitor, genipin, in lungs of mice, and investigated the mechanisms of UCP2 in ALI. UCP2 overexpression in mouse lungs increased LPS-induced pathological changes, lung permeability, lung inflammation, and lowered survival rates. Furthermore, ATP levels and mitochondrial membrane potential were decreased, while reactive oxygen species production was increased. Additionally, mitogen-activated protein kinases (MAPKs) activity was elevated, which increased the sensitivity to LPS-induced apoptosis and inflammation. LPS-induced apoptosis and release of inflammatory factors were alleviated by pretreatment of the Jun N-terminal kinase (JNK) inhibitor SP600125 or the p38 MAPK inhibitor SB203580, but not by the extracellular signal-regulated kinase (ERK) inhibitor PD98059 in UCP2-overexpressing mice. On the other hand, LPS-induced alveolar epithelial cell death and inflammation were attenuated by genipin. In conclusion, UCP2 increased susceptibility to LPS-induced cell death and pulmonary inflammation, most likely via ATP depletion and activation of MAPK signaling following ALI in mice

Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia

Autophagy is a genetically regulated process of adaptation to metabolic stress and was recently shown to be involved in the treatment response of chronic myeloid leukemia (CML). However, in vivo data are limited and the molecular mechanism of autophagy regulators in the process of leukemogenesis is not completely understood. Here we show that Beclin-1 knockdown, but not Atg5 deletion in a murine CML model leads to a reduced leukemic burden and results in a significantly prolonged median survival of targeted mice. Further analyses of murine cell lines and primary patient material indicate that active BCR-ABL directly interacts with BECLIN-1 and phosphorylates its tyrosine residues 233 and 352, resulting in autophagy suppression. By using phosphorylation-deficient and phosphorylation-mimic mutants, we identify BCR-ABL induced BECLIN-1 phosphorylation as a crucial mechanism for BECLIN-1 complex formation: interaction analyses exhibit diminished binding of the positive autophagy regulators UVRAG, VPS15, ATG14 and VPS34 and enhanced binding of the negative regulator Rubicon to BCR-ABL-phosphorylated BECLIN-1. Taken together, our findings show interaction of BCR-ABL and BECLIN-1 thereby highlighting the importance of BECLIN-1-mediated autophagy in BCR-ABL+ cells

Is left-behind a real reason for children\u27s social cognition deficit? An fNIRS study on the effect of social interaction on left-behind preschooler\u27s prefrontal activation

The left-behind phenomenon, caused by parent out-migration, has become a common social issue and might lead to long-term and potential risks for children in rural areas of China. It is important to investigate the effect of social interaction on prefrontal activation of left-behind children in China because of possible effects of parent out-migration on children\u27s social cognition. We recruited 81 rural Chinese preschoolers aged 52-76 months (mean = 64.98 ± 6.321 months) preschoolers with three different statuses of parental out-migration (including non-, partially, and completely left-behind children). Using functional Near-Infrared Spectroscopy (fNIRS), we compared behavior and brain activation and in three groups (non-, partially-, completely-left-behind children) under two different social interaction conditions (child-teacher and child-stranger situation). Results revealed that initiating joint attention (IJA) may evoke higher brain activation than responding to joint attention (RJA) in the prefrontal cortex (PFC), especially in the case of initiating joint attention with the stranger. In addition, the activation of joint attention was positively correlated with children\u27s language score, cognitive flexibility, and facial expression recognition. More importantly, partially-left-behind children evoked higher brain activation in the IJA condition and presented a higher language level than completely/non-left-behind children. The current study provides insight into the neural basis of left-behind children\u27s development and revealed for the first time that family economic level and left-behind status may contribute to the lower social cognition

Targeting Oncoprotein Stability Overcomes Drug Resistance Caused by FLT3 Kinase Domain Mutations

<div><p>FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.</p></div

Underwater Optical Imaging: Key Technologies and Applications Review

The challenges associated with acquiring the clear images of objects in underwater environment are difficult to overcome due to the absorptive and scattering nature of seawater. Recently, the research community has focused on mitigating these effects. The recent developments in image enhancement algorithms and strategies of signal light enhancement have brought improvement in some application areas. In this work, we review the six most common methods based on signal light enhancement. We present the individual working mechanisms, latest representative advances, and suitable application conditions. Moreover, we also present a detailed comparison of these techniques. In each technique, we present their applicable environments and conditions according to the following indicators: operating distance (from 2 attenuation lengths (AL) to 13.5 AL), resolution (from centimeter to millimeter), and field of view (FOV). By summarizing and analyzing the existing problems that restrict the underwater optical imaging techniques, the future development trends are prospected

HSP90 inhibitors induce selective toxicity in cells expressing FLT3 mutants.

<p>32D cells stably expressing FLT3 mutants were treated with HSP90 inhibitors Geldanamycin (A), 17-AAG (B) or 17-DMAG (C) for 48 hours and analyzed by FACS following propidium iodide staining. (D) Schematic representation of the efficacy of HSP90 inhibitors against both the kinase inhibitor sensitive as well as inhibitor resistant FLT3 mutants: (a) FLT3-ITD is stabilized by HSP90 resulting in cellular transformation, (b) FLT3-ITD is sensitive to kinase inhibitors that lead to death of cells expressing them, (c) Secondary mutations in FLT3-ITD kinase domain abrogate inhibitor binding leading to resistance towards kinase inhibitors and (d) Treatment with HSP90 inhibitors leads to degradation of both FLT3-ITD as well as drug-resistant mutants resulting in selective cytotoxicity towards FLT3-expressing cells.</p