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Cigarette smoking (CS) is the leading cause of COPD, and identifying the pathways that are driving pathogenesis in the airway due to CS exposure can aid in the discovery of novel therapies for COPD. An additional barrier to the identification of key pathways that are involved in the CS-induced pathogenesis is the difficulty in building relevant and high throughput models that can recapitulate the phenotypic and transcriptomic changes associated with CS exposure. To identify these drivers, we have developed a cigarette smoke extract (CSE)-treated bronchosphere assay in 384-well plate format that exhibits CSE-induced decreases in size and increase in luminal secretion of MUC5AC. Transcriptomic changes in CSE-treated bronchospheres resemble changes that occur in human smokers both with and without COPD compared to healthy groups, indicating that this model can capture human smoking signature. To identify new targets, we ran a small molecule compound deck screening with diversity in target mechanisms of action and identified hit compounds that attenuated CSE induced changes, either decreasing spheroid size or increasing secreted mucus. This work provides insight into the utility of this bronchopshere model to examine human respiratory disease impacted by CSE exposure and the ability to screen for therapeutics to reverse the pathogenic changes caused by CSE.

Context Rhizoma drynariae total flavonoids (RDTF) are used to treat fractures. CD31hiEmcnhi vessels induced by PDGF-BB secreted by osteoclast precursors, together with osteoblasts and osteoclasts, constitute the ternary regulatory mechanism of bone tissue reconstruction. Objective This study aimed to determine whether RDTF can promote bone tissue remodeling and induce membrane growth in the rat Masquelet model and to explore its molecular mechanism based on the ternary regulation theory. Methods Thirty-six SD rats were randomized to three groups: blank, induced membrane, and RDTF treatment (n = 12/group). The gross morphological characteristics of the new bone tissue were observed after 6 weeks. Sixty SD rats were also randomized to five groups: blank, induction membrane, low-dose RDTF, medium-dose RDTF, and high-dose RDTF (n = 12/group). After 4 weeks, immunohistochemistry and western blot were used to detect the expression of membrane tissue-related proteins. The mRNA expression of key factors of ternary regulation was analyzed by qRT-PCR. Results RDTF positively affected angiogenesis and bone tissue reconstruction in the bone defect area. RDTF could upregulate the expression of key factors (PDGF-BB, CD31, and endomucin), VEGF, and HMGB1 mRNA and proteins in the ternary regulation pathway. Discussion and conclusion Although the expected CD31hiEmcnhi vessels in the induction membrane were not observed, this study confirmed that RDTF could promote the secretion of angiogenic factors in the induced membrane. The specific mechanisms still need to be further studied.

Terrestrial ecosystems greatly contribute to carbon (C) emission reduction targets through photosynthetic C uptake.Net primary production (NPP) represents the amount of atmospheric C fixed by plants and accumulated as biomass. The Three-North Shelterbelt Program (TNSP) zone accounts for more than 40% of China's landmass. This zone has been the scene of several large-scale ecological restoration efforts since the late 1990s, and has witnessed significant changes in climate and human activities.Assessing the relative roles of different causal factors on NPP variability in TNSP zone is very important for establishing reasonable local policies to realize the emission reduction targets for central government. In this study, we examined the relative roles of drought and land cover conversion(LCC) on inter-annual changes of TNSP zone for 2001-2010. We applied integrated correlation and decomposition analyses to a Standardized Evapotranspiration Index (SPEI) and MODIS land cover dataset. Our results show that the 10-year average NPP within this region was about 420 Tg C. We found that about 60% of total annual NPP over the study area was significantly correlated with SPEI (p

We performed a pilot proteogenomic study to compare lung adenocarcinoma to lung squamous cell carcinoma using quantitative proteomics (6-plex TMT) combined with a customized Affymetrix GeneChip. Using MaxQuant software, we identified 51,001 unique peptides that mapped to 7,241 unique proteins and from these identified 6,373 genes with matching protein expression for further analysis. We found a minor correlation between gene expression and protein expression; both datasets were able to independently recapitulate known differences between the adenocarcinoma and squamous cell carcinoma subtypes. We found 565 proteins and 629 genes to be differentially expressed between adenocarcinoma and squamous cell carcinoma, with 113 of these consistently differentially expressed at both the gene and protein levels. We then compared our results to published adenocarcinoma versus squamous cell carcinoma proteomic data that we also processed with MaxQuant. We selected two proteins consistently overexpressed in squamous cell carcinoma in all studies, MCT1 (SLC16A1) and GLUT1 (SLC2A1), for further investigation. We found differential expression of these same proteins at the gene level in our study as well as in other public gene expression datasets. These findings combined with survival analysis of public datasets suggest that MCT1 and GLUT1 may be potential prognostic markers in adenocarcinoma and druggable targets in squamous cell carcinoma. Data are available via ProteomeXchange with identifier PXD002622.

Calcineurin B-like protein-interacting protein kinases (CIPKs) have been found to be responsive to abiotic stress. However, their precise functions and the related molecular mechanisms in abiotic stress tolerance are not completely understood, especially in wheat. In the present study, TaCIPK29 was identified as a new member of CIPK gene family in wheat. TaCIPK29 transcript increased after NaCl, cold, methyl viologen (MV), abscisic acid (ABA) and ethylene treatments. Over-expression of TaCIPK29 in tobacco resulted in increased salt tolerance, which was demonstrated by higher germination rates, longer root lengths and better growth status of transgenic tobacco plants compared to controls when both were treated with salt stress. Physiological measurements indicated that transgenic tobacco seedlings retained high K(+)/Na(+) ratios and Ca(2+) content by up-regulating some transporter genes expression and also possessed lower H2O2 levels and reduced membrane injury by increasing the expression and activities of catalase (CAT) and peroxidase (POD) under salt stress. Moreover, transgenic lines conferred tolerance to oxidative stress by increasing the activity and expression of CAT. Finally, TaCIPK29 was located throughout cells and it preferentially interacted with TaCBL2, TaCBL3, NtCBL2, NtCBL3 and NtCAT1. Taken together, our results showed that TaCIPK29 functions as a positive factor under salt stress and is involved in regulating cations and reactive oxygen species (ROS) homeostasis.

The AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). We have uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. Mice expressing activated Ack1 specifically in the prostate exhibit AKT Tyr176-phosphorylation and develop murine prostatic intraepithelial neoplasia (mPINs). Further, expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast cancer patients. Thus, RTK/Ack1/AKT pathway provides a novel target for drug discovery.

The AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). We have uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. Mice expressing activated Ack1 specifically in the prostate exhibit AKT Tyr176-phosphorylation and develop murine prostatic intraepithelial neoplasia (mPINs). Further, expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast cancer patients. Thus, RTK/Ack1/AKT pathway provides a novel target for drug discovery. [ABSTRACT FROM AUTHOR]

The Low-profile Visualized Intraluminal Support (LVIS) device is a new generation of self-expanding braided stent recently introduced in China for stent assisted coiling of intracranial aneurysms. The aim of our study is to evaluate the feasibility, safety, and efficacy of the LVIS device in reconstructive treatment of vertebral artery dissecting aneurysms (VADAs).We retrospectively reviewed the neurointerventional database of our institution from June 2014 to May 2016. Patients who underwent endovascular treatment of VADAs with LVIS stents were included in this study. Clinical presentation, aneurysmal characteristics, technical feasibility, procedural complications, and angiographic and clinical follow-up results were evaluated.38 patients with VADAs who underwent treatment with LVIS stent were identified, including 3 ruptured VADAs. All VADAs were successfully treated with reconstructive techniques including the stent-assisted coiling (n = 34) and stenting only (n = 4). Post-procedural complications developed in 3 patients (7.9%) including two small brainstem infarctions and one delayed thromboembolic event. Complications resulted in one case of minor permanent morbidity (2.6%). There was no procedure-related mortality. The follow-up angiogram was available in 30 patients at an average of 8.3 months (range, 2 to 30 months), which revealed complete occlusion in 23 patients (76.7%), residual neck in five patients (16.7%), and residual sac in two patients (6.7%). The follow-up of 25 aneurysms with incomplete immediate occlusion revealed 22 aneurysms (88%) with improvement in the Raymond class. One aneurysm (3.3%) showed recanalization and required retreatment. Clinical followed-up at 5-28 months (mean 14.1 months) was achieved in 36 patients because two patients died of pancreatic cancer and basal ganglia hemorrhage, respectively. No new neurologic deterioration or aneurysm (re)bleeding was observed.Our preliminary experience with reconstruction of VADAs with the LVIS device demonstrates that this treatment approach is feasible with good short-term angiographic and clinical outcomes. Long-term and larger cohort studies are necessary to determine long-term outcomes of this therapy.

INTRODUCTIONFew studies focused on predictors of unfavorable outcomes (modified Rankin Scale, 2-6) after reconstructive treatment of the ruptured intracranial spontaneous vertebral artery dissection aneurysms (ris-VADAs), which was evaluated based on 57 reconstructed lesions in this study.METHODSResults of 57 consecutive patients (M:F = 29∶28; median age, 48 years; range, 27 to 69 years) harboring 57 ris-VADAs, which were treated with coils combined with single stent(n = 32), double overlapping stents (n = 16), and triple overlapping stents (n = 9) between October 2000 to March 2011, were retrospectively reviewed and analyzed.RESULTSThe available (n = 54) mean durations of angiographic and clinical follow-ups were 27 months (range, 12 to 78) and 62 months (range, 12 to 132), respectively. The involvement of PICA (p = 0.004), size of lesions (p = 0.000), quantity of stent (p = 0.001), and coil type (p = 0.002) affected the immediate obliteration grade, which was only risk factor for angiographic recurrences (p = 0.031). Although the post-treatment outcomes did not differ between single stent and multiple stents (p = 0.434), 5 angiographic recurrences, 1 rebleeding and 1 suspected rebleeding, all occurred in partial obliteration after single-stent-assisted coiling. Progressive thrombosis and in-stent obliteration were not detected on follow-up angiograms. Older age (odds ratio [OR] = 1.090; 95% confidence interval [CI], 1.004-1.184; p = 0.040) and unfavorable Hunt-Hess scale (OR = 4.289; 95%CI, 1.232-14.933; p = 0.022) were independent predictors of unfavorable outcomes in the reconstructed ris-VADAs.CONCLUSIONSImmediate obliteration grade was only risk factor for angiographic recurrence after reconstructive treatment. Unfavorable Hunt-Hess grade and older age were independent predictors of unfavorable outcomes in ris-VADAs.