bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay
Authors: Bozdagi Ozlem , Tavassoli Teresa , Buxbaum Joseph D 
Published: April 2013

Abstract

Background
Haploinsufficiency of SHANK3, due to either hemizygous gene deletion (termed 22q13 deletion syndrome or Phelan-McDermid syndrome) or to gene mutation, accounts for about 0.5% of the cases of autism spectrum disorder (ASD) and/or developmental delay, and there is evidence for a wider role for SHANK3 and glutamate signaling abnormalities in ASD and related conditions. Therapeutic approaches that reverse deficits in SHANK3-haploinsufficiency may therefore be broadly beneficial in ASD and in developmental delay.

Findings
We observed that daily intraperitoneal injections of human insulin-like growth factor 1 (IGF-1) over a 2-week period reversed deficits in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) signaling, long-term potentiation (LTP), and motor performance that we had previously reported in Shank3-deficient mice. Positive effects were observed with an IGF-1 peptide derivative as well.

Conclusions
We observed significant beneficial effects of IGF-1 in a mouse model of ASD and of developmental delay. Studies in mouse and human neuronal models of Rett syndrome also show benefits with IGF-1, raising the possibility that this compound may have benefits broadly in ASD and related conditions, even with differing molecular etiology. Given the extensive safety data for IGF-1 in children with short stature due to primary IGF-1 deficiency, IGF-1 is an attractive candidate for controlled clinical trials in SHANK3-deficiency and in ASD.
Inhaled aerosolized insulin ameliorates hyperglycemia-induced inflammatory responses in the lungs in an experimental model of acute lung injury
Authors: Fan Wei , Nakazawa Koichi , Abe Shinya , Inoue Miori , Kitagawa Masanobu , Nagahara Noriyuki , Makita Koshi 
Published: April 2013

Abstract
Introduction
Previous studies have shown that patients with diabetes mellitus appear to have a lower prevalence of acute lung injury. We assumed that insulin prescribed to patients with diabetes has an anti-inflammatory property and pulmonary administration of insulin might exert beneficial effects much more than intravenous administration.

Methods
Twenty-eight mechanically ventilated rabbits underwent lung injury by saline lavage, and then the animals were allocated into a normoglycemia group (NG), a hyperglycemia group (HG), an HG treated with intravenous insulin (HG-VI) group or an HG treated with aerosolized insulin (HG-AI) group with continuous infusion of different fluid solutions and treatments: normal saline, 50% glucose, 50% glucose with intravenous insulin, or 50% glucose with inhaled aerosolized insulin, respectively. After four hours of treatment, the lungs and heart were excised en bloc, and then high-mobility group B1 concentration in bronchoalveolar lavage fluid, interleukin-8 and toll-like receptor 4 mRNA expression in bronchoalveolar lavage fluid cells, and lung myeloperoxidase activity were measured.

Results
Treatment with both aerosolized insulin and intravenous insulin attenuated toll-like receptor 4 mRNA expressions in the bronchoalveolar lavage fluid cells. Interleukin-8 and toll-like receptor 4 mRNA expression was significantly lower in the HG-AI group than in the HG-IV group. The lung myeloperoxidase activity in the normal healthy group showed significantly lower levels compared to the NG group but not different compared to those of the HG, HG-VI and HG-AI groups.

Conclusions
The results suggest that insulin attenuates inflammatory responses in the lungs augmented by hyperglycemia in acute lung injury and the insulin's efficacy may be better when administered by aerosol.
Alcohol-induced IL-1β in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation
Authors: Lippai Dora , Bala Shashi , Petrasek Jan , Csak Timea , Levin Ivan , Kurt-Jones Evelyn A , Szabo Gyongyi 
Published: April 2013

ABSTRACTAlcohol-induced neuroinflammation is mediated by proinflammatory cytokines, including IL-1β. IL-1β production requires caspase-1 activation by inflammasomes—multiprotein complexes that are assembled in response to danger signals. We hypothesized that alcohol-induced inflammasome activation contributes to increased IL-1β in the brain. WT and TLR4-, NLRP3-, and ASC-deficient (KO) mice received an ethanol-containing or isocaloric control diet for 5 weeks, and some received the rIL-1ra, anakinra, or saline treatment. Inflammasome activation, proinflammatory cytokines, endotoxin, and HMGB1 were measured in the cerebellum. Expression of inflammasome components (NLRP1, NLRP3, ASC) and proinflammatory cytokines (TNF-α, MCP-1) was increased in brains of alcohol-fed compared with control mice. Increased caspase-1 activity and IL-1β protein in ethanol-fed mice indicated inflammasome activation. TLR4 deficiency protected from TNF-α, MCP-1, and attenuated alcohol-induced IL-1β increases. The TLR4 ligand, LPS, was not increased in the cerebellum. However, we found up-regulation of acetylated and phosphorylated HMGB1 and increased expression of the HMGB1 receptors (TLR2, TLR4, TLR9, RAGE) in alcohol-fed mice. NLRP3- or ASC-deficient mice were protected from caspase-1 activation and alcohol-induced IL-1β increase in the brain. Furthermore, in vivo treatment with rIL-1ra prevented alcohol-induced inflammasome activation and IL-1β, TNF-α, and acetylated HMGB1 increases in the cerebellum. Conversely, intracranial IL-1β administration induced TNF-α and MCP-1 in the cerebellum. In conclusion, alcohol up-regulates and activates the NLRP3/ASC inflammasome, leading to caspase-1 activation and IL-1β increase in the cerebellum. IL-1β amplifies neuroinflammation, and disruption of IL-1/IL-1R signaling prevents alcohol-induced inflammasome activation and neuroinflammation. Increased levels of acetylated and phosphorylated HMGB1 may contribute to alcoholic neuroinflammation.
Midterm Results of 58 Fractures of the Coronoid Process of the Ulna and their Concomitant Injuries
Authors: Kiene J , Wäldchen J , Paech A , Jürgens Ch , Schulz A.P 
Published: April 2013

Background:In general, fractures of the coronoid process are rare and usually occur in combination with additional elbow joint injuries. The treatment of these injuries aims to regain a stable as well as a flexible and loadable joint. Although there is currently little evidence, therapy recommendations remain controversial. Therefore, the aim of this study was to prognostically determine relevant factors for therapy recommendation by analysing a representative patient population of two trans-regional trauma centres.Material and Methods:Seventy-seven patients with a fracture of the coronoid process were treated within an 8-year period (2001 to 2009). After an average of 48 months (SD 31), treatment outcome of 58 patients (75%) was acquired. The results were statistically analysed.Results:The average age of the patient was 51.8 years (SD 13.6); 36 were male and 34 had a fracture on the right arm. Applying the fracture types of the coronoid process in accordance with Regan/Morrey, the result was: Type I (19), II (17) and III (22). Further injuries were also detected: 40 radial head fractures, 17 proximal ulnar fractures and 2 fractures of the olecranon. A luxation was detected in 44 of the 58 patients (76%). The patients’ average MEPS (Mayo Elbow Performance Score) was 80.6 points (SD 18), with significant differences between the various therapy strategies. Fifteen% of the coronoid process fractures were reconstructable to a limited extent only by means of osteosynthesis. In 33% of the patients, instabilities remained. The average extension/flexion came to 107° (SD 28), and pronation and supination 153° (SD 38).Conclusion:At present, a surgical therapy of ligamentary injuries cannot be statistically justified. A stable osseous reconstruction appears to make more sense. The strongest negative prognostic parameters in our patient population were: therapy with an external fixator, immobilisation for more than 21 days, the occurrence of complications and unstable osteosyntheses on the coronoid process.
Developmental plasticity, genetic assimilation, and the evolutionary diversification of sexual expression in Solanum
Authors: Diggle Pamela K. , Miller Jill S. 
Published: April 2013

• Premise of the study: For over a century, it has been hypothesized that selection can convert an environmentally induced phenotype (i.e., plasticity) into a fixed (constitutively produced) phenotype, a process known as genetic assimilation. While evidence of assimilation is accumulating, the role of plasticity generally and assimilation specifically in evolutionary diversification has rarely been examined from a comparative phylogenetic perspective.• Methods: We combined experimental analyses of plasticity with ancestral state reconstructions to examine the evolutionary dynamics of sexual expression in two well‐characterized sections (Acanthophora and Lasiocarpa) in Solanum subgenus Leptostemonum. We examined sexual expression phenotypes and the proportion of staminate flowers produced under contrasting resource conditions in 10 species and combined these data with previous studies.• Key results: Staminate flower production was phenotypically plastic for nine of 14 species and unaffected by treatment in five species. Two of the nonplastic species bore few staminate flowers, and three constitutively produced large numbers of staminate flowers. For individuals and species producing staminate flowers, these flowers occurred in a distinctive architectural pattern that was qualitatively the same in both plastic and nonplastic species. Parsimony and Bayesian reconstructions demonstrate that plasticity is ancestral among the species studied.• Conclusions: Plasticity has been lost independently in sections Acanthophora and Lasiocarpa, and the consequence of its loss results in evolutionary diversification of sexual expression. In section Acanthophora, loss of plasticity represents a reversion to production of predominantly hermaphroditic flowers. In contrast, the fixed production of staminate flowers in Lasiocarpa has the hallmarks of evolution via genetic assimilation.
Imprinting of Lymphocytes with Melanoma Antigens Acquired by Trogocytosis Facilitates Identification of Tumor-Reactive T Cells
Authors: Eisenberg Galit , Uzana Ronny , Pato Aviad , Frankenburg Shoshana , Merims Sharon , Yefenof Eitan , Ferrone Soldano , Peretz Tamar , Machlenkin Arthur , Lotem Michal 
Published: April 2013

Abstract
Trogocytosis is a contact-dependent intercellular transfer of membrane fragments and associated molecules from APCs to effector lymphocytes. We previously demonstrated that trogocytosis also occurs between tumor target and cognate melanoma Ag-specific cytotoxic T cells (CTL). In this study, we show that, following trogocytosis, immune effector cells acquire molecular components of the tumor, including surface Ags, which are detectable by specific mAbs. We demonstrate that CD8+ and CD4+ T cells from melanoma patients’ PBMC and tumor-infiltrating lymphocytes (TIL) capture melanoma Ags, enabling identification of trogocytosing lymphocytes by staining with Ag-specific Abs. This finding circumvents the necessity of tumor prelabeling, which in the past was mandatory to detect membrane-capturing T cells. Through the detection of melanoma Ags on TIL, we sorted trogocytosing T cells and verified their preferential reactivity and cytotoxicity. Furthermore, tumor Ag–imprinted T cells were detected at low frequency in fresh TIL cultures shortly after extraction from the tumor. Thus, T cell imprinting by tumor Ags may allow the enrichment of melanoma Ag-specific T cells for research and potentially even for the adoptive immunotherapy of patients with cancer.
Mammalian Target of Rapamycin Regulates IL-10 and Resistance to Pseudomonas aeruginosa Corneal Infection
Authors: Foldenauer Megan E. B. , McClellan Sharon A. , Berger Elizabeth A. , Hazlett Linda D. 
Published: April 2013

Abstract
IL-10 is important in the resistance response of BALB/c mice to experimental Pseudomonas aeruginosa corneal infection. However, the cellular mechanisms by which this anti-inflammatory cytokine is regulated remain unknown. Because the mammalian target of rapamycin (mTOR) regulates IL-10 in other disease models, the present study tested its role in bacterial keratitis. After infection, corneas of rapamycin versus control-treated BALB/c mice showed worsened disease, and real-time RT-PCR confirmed that mTOR mRNA levels were significantly decreased. Rapamycin treatment also increased clinical score, polymorphonuclear neutrophil (PMN) infiltration (determined by myeloperoxidase assay), and bacterial load, but it diminished PMN bactericidal activity. Inhibition of mTOR also led to elevated mRNA and protein levels of IL-12p40, matrix metalloproteinase 9, and inducible NO synthase, whereas mRNA and protein levels of IL-10, its regulator/effector STAT-3, and suppressor of cytokine signaling 3 (a proinflammatory cytokine regulator) were decreased. Furthermore, mTOR inhibition reduced levels of proapoptotic caspase-3 and increased levels of B cell lymphoma-2 (antiapoptotic), indicative of delayed apoptosis. mTOR inhibition also altered genes related to TLR signaling, including elevation of TLR4, TLR5, and IL-1R1, with decreases in IL-1R-associated kinase 1 and an inhibitor of NF-κB, NF-κB inhibitor–like 1. Rapamycin treatment also increased levels of IFN-γ and CCAAT/enhancer binding protein, β, a gene that regulates expression of preprotachykinin-A (the precursor of substance P). Collectively, these data, as well as a rescue experiment using rIL-10 together with rapamycin, which decreased PMN in cornea, provide concrete evidence that mTOR regulates IL-10 in P. aeruginosa–induced bacterial keratitis and is critical to balancing pro- and anti-inflammatory events, resulting in better disease outcome.
Proposed NASA Budget Includes Asteroid Capture but Cuts Planetary Science and Education
Authors: Balcerak Ernie 
Published: April 2013

The Obama administration's proposed $17.7 billion budget for NASA for fiscal year (FY) 2014 provides $105 million for several asteroid‐related initiatives, including preliminary studies for a potential mission that would capture an asteroid and drag it into orbit around the Moon. The agency's total proposed budget is down slightly compared to FY 2012 (see Table ; comparisons are to FY 2012 because government agencies had been operating on a continuing resolution for 2013 and final spending levels for 2013 were not available at the time the president released his proposed 2014 budget).
Pharmacokinetics of nebivolol in the rat: low oral absorption, loss in the gut and systemic stereoselectivity
Authors: Sanaee Forugh , Valente Neves Daniel , Lanchote Vera Lucia , Jamali Fakhreddin 
Published: April 2013

ABSTRACTNebivolol is a third‐generation β1‐adrenoceptor blocker with β3 agonistic properties (AR). It has a low oral bioavailability that is speculated to be due to its hepatic first‐pass metabolism. Inflammation is known to suppress the clearance of drugs with efficient hepatic metabolism. However, inflammation does not influence nebivolol clearance. Therefore, we looked into the mechanism involved in the drug's low bioavailability and stereoselectivity. Single 1 mg/kg i.v. or intraperitoneal (i.p.) or 2 mg/kg oral doses were administered to male Sprague‐Dawley rats and the plasma nebivolol concentration was measured using chiral and achiral assays. The passage of nebivolol enantiomers through the gut was also measured using everted rat sacs. The serum protein binding of the enantiomers was studied in vitro using the ultrafiltration method. Plasma nebivolol concentrations were significantly lower after p.o., but not after i.p., compared with i.v. doses suggesting the gut as the site of pre‐systemic loss. Approximately 50% of the enantiomers were lost during 90 min incubation in the presence of gut. Only 0.1% of the added drug crossed the gut wall with no evidence of stereoselectivity. Thus stereoselectivity in the pharmacokinetics of nebivolol (+ > ‐) is likely at the level of plasma protein binding. The low nebivolol bioavailability is due to its loss in the gut as well as its limited permeability through the intestinal wall. Copyright © 2013 John Wiley & Sons, Ltd.
Enhanced FK506 production in Streptomyces tsukubaensis by rational feeding strategies based on comparative metabolic profiling analysis
Authors: Xia Menglei , Huang Di , Li Shanshan , Wen Jianping , Jia Xiaoqiang , Chen Yunlin 
Published: April 2013

ABSTRACTFK506, a widely used immunosuppressant, is produced by industrial fermentation processes using various Streptomyces species. However, the low titer becomes a bottleneck for its application and industrialization. It urgently required a full understanding of the biological mechanisms for FK506 overproduction. Towards this end, comparative metabolomics approach was employed to analyze metabolite concentrations difference of Streptomyces tsukubaensis cultivated in two media with low and high productivities. Initially, 98 intracellular metabolites were identified and 13 metabolites involved in five pathways were determined to be directly correlated with FK506 biosynthesis. Then in‐depth analysis elucidated how those key factors exerted influence on FK506 biosynthesis. Many previously unreported metabolites were shown to play an important role in FK506 biosynthesis and provided potential regulation points for external manipulation. Based on such key information, rationally designed feeding strategy was carried out. Results showed that the FK506 yield increased from 251 to 405 mg/L, whereas, by‐products FK520 and 37,38‐dihydro‐FK506 decreased by 31% and 39%, respectively, compared with the values of control. To our knowledge, it is the first study to apply the comparative metabolomics method to identify key metabolites to promote the FK506 production. The strategies developed here can easily be extended to titer improvement of other important microbial natural products and process optimization. Biotechnol. Bioeng. 2013;110: 2717–2730. © 2013 Wiley Periodicals, Inc.
Not worth the extra cost? Diluting the differentiation ability of highly rated products by altering the meaning of rating scale levels
Authors: Meißner Martin , Heinzle Stefanie Lena , Decker Reinhold 
Published: April 2013

ABSTRACTOver the last decade, the use of rating scales has grown in popularity in various fields, including customer online reviews and energy labels. Rating scales convey important information on attributes of products or services that consumers evaluate in their purchase decisions. By applying multidimensional scaling, this paper reveals that the meaning of the levels of a rating scale can be altered by manipulating the labeling of the rating scale levels. The study reveals that consumers perceive product attributes as being more similar if the labels share similar or identical linguistic or visual characteristics. In addition, two choice‐based conjoint studies examine whether the way consumers make their choices among products can be influenced by changing the labeling of rating scale levels. The results show that a manipulation of the meaning of rating scale levels diminishes both the importance of the rating scale information and consumers' willingness to pay a premium for a rating upgrade. Copyright © 2013 John Wiley & Sons, Ltd.
Length of left anterior descending coronary artery determines prognosis in acute anterior wall myocardial infarction
Authors: Ilia Reuben , Weinstein Jean Marc , Wolak Arik , Gilutz Harel , Cafri Carlos 
Published: April 2013

BackgroundThe left anterior descending artery (LAD) supplies blood to a large part of the myocardium. However, the amount of myocardium supplied varies depending on the length of the LAD and as a result, occlusion of its proximal portion may influence outcome. We investigated the prognosis of patients with anterior wall myocardial infarction as the initial presentation of coronary disease who underwent primary percutaneous coronary intervention (PPCI) in our institution due to isolated proximal LAD occlusion.MethodsWe retrospectively analyzed all patients that underwent PPCI in our institution from 2002 to June 2012. The individuals who fulfilled the above criteria constituted the study group. We recorded demographic, clinical, and angiographic data as well as mortality during the study period.ResultsOf 2,532 patients undergoing PPCI, 196 had isolated proximal LAD occlusion. In 112 of them (57%), the LAD wrapped around the apex (group A) and in the remaining 84 (43%), the LAD terminated at or before the apex (group B). At univariate analysis, patients in group A were found to be older (P = 0.04). Over the study period, 28% of patients in group A died in comparison to 2.4% in group B (P < 0.01). When differentiating between cardiac and non‐cardiac death, both were also significantly higher in group A (P < 0.01). At multivariate analysis, the strongest predictor of death was long LAD versus shorter LAD (HR 9.1, 95% CI 1.1–76, P = 0.04).ConclusionWrap‐around LAD is a strong predictor of prognosis in patients with anterior wall MI undergoing PPCI to isolated proximal LAD occlusion. In addition, those with a shorter LAD have an excellent prognosis. © 2013 Wiley Periodicals, Inc.
One‐Pot Synthesis of Tetrafluoro‐ and Tetrachlorofluorescein Derivatives and Their Stabilization by β‐Cyclodextrin
Authors: Tan Li‐Li , Yang Ying‐Wei , Liu Yi‐Pu , Zhang Sean Xiao‐An 
Published: April 2013

AbstractA highly efficient one‐pot procedure for the preparation of fluorescein‐based dyes with relatively high yield was investigated. Significantly, introduction of these fluoro and chloro functional groups and forming host‐guest complexes with cyclodextrins partially enhanced the photostability of these dyes.