bluuebunny/crossref_metadata_2025 huggingface dataset:
A Strategic Roadmap for Navigating Academic-Industry Collaborations in Information Systems Research
Authors: Marcolin Barbara L. , Saunders W. Chad
Published: July 2015

Research collaboration between industry and academia remains challenging despite progress being made on a number of fronts. We are not implying that all information systems researchers should be engaging in industry collaborations, nor should the value of critique and work exclusively addressing academic and other audiences be viewed as less valuable than those engaging industry. The intent is instead to encourage more industry collaboration, and for those considering such initiatives to roadmap the activities strategically giving consideration to the full range of activities required so reasonable tradeoffs can be made in the context of building longer-term sustainable relationships.

We develop a roadmap from literature that organizes the building blocks (component activities) needed to plan and implement strategic academic-industry collaborations over longer time horizons. Specifically, we identify the key themes or layers of (1) Strategic Business Problem(s), (2) Governance, (3) Funding Criteria, (4) Privacy, Security and Ethics, (5) Intellectual Property, (6) Research Design and (7) Recognized Outputs, which need to be in place if you are to succeed with academic-industry research.

The roadmap framework highlights the need to consider the implications of the components across each of the layers at a particular point in time (vertical slice), the relationship between layers (dependencies) and the need for aligning the various activities in a coordinated manner; otherwise success at one layer is often undermined by a lack of awareness or failure at another layer.

Our hope is that these themes (layers) facilitate organizing this collaboration in a systematic and coordinated manner to produce academic-industry collaborations that progressively improve over time.
Structure Determination of Natural Products by Mass Spectrometry
Authors: Biemann Klaus
Published: July 2015

I review laboratory research on the development of mass spectrometric methodology for the determination of the structure of natural products of biological and medical interest, which I conducted from 1958 to the end of the twentieth century. The methodology was developed by converting small peptides to their corresponding polyamino alcohols to make them amenable to mass spectrometry, thereby making it applicable to whole proteins. The structures of alkaloids were determined by analyzing the fragmentation of a known alkaloid and then using the results to deduce the structures of related compounds. Heparin-like structures were investigated by determining their molecular weights from the mass of protonated molecular ions of complexes with highly basic, synthetic peptides. Mass spectrometry was also employed in the analysis of lunar material returned by the Apollo missions. A miniaturized gas chromatograph mass spectrometer was sent to Mars on board of the two Viking 1976 spacecrafts.
Evolution of Orbitrap Mass Spectrometry Instrumentation
Authors: Eliuk Shannon , Makarov Alexander
Published: July 2015

We discuss the evolution of OrbitrapTMmass spectrometry (MS) from its birth in the late 1990s to its current role as one of the most prominent techniques for MS. The Orbitrap mass analyzer is the first high-performance mass analyzer that employs trapping of ions in electrostatic fields. Tight integration with the ion injection process enables the high-resolution, mass accuracy, and sensitivity that have become essential for addressing analytical needs in numerous areas of research, as well as in routine analysis. We examine three major families of instruments (related to the LTQ Orbitrap, Q Exactive, and Orbitrap Fusion mass spectrometers) in the context of their historical development over the past ten eventful years. We discuss as well future trends and perspectives of Orbitrap MS. We illustrate the compelling potential of Orbitrap-based mass spectrometers as (ultra) high-resolution platforms, not only for high-end proteomic applications, but also for routine targeted analysis.
Sodium butyrate stimulates NHE8 expression via its role on activating NHE8 basal promoter activity
Authors: Xu Hua , McCoy Anthony , Li Jing , Zhao Yang , Ghishan Fayez K.
Published: July 2015

Butyrate is a major metabolite in colonic lumen. It is produced from bacterial fermentation of dietary fiber. Butyrate has been shown to stimulate electroneutral sodium absorption through its regulation on sodium/hydrogen exchanger 3 (NHE3). Although NHE8, the newest addition of intestinal NHE family, is involved in sodium absorption in the intestinal tract, whether butyrate modulates NHE8 expression in the intestinal epithelial cells is not known. In the current study, we showed that butyrate treatment strongly induced NHE8 protein and NHE8 mRNA expression in human intestinal epithelial cells. Transfection with the human NHE8 promoter reporter constructs showed that butyrate treatment stimulated reporter gene expression at an amount comparable with its stimulation of NHE8 mRNA expression. Interestingly, a similar result was also observed in human NHE8 promoter transfected cells after trichostatin (TSA) treatment. Gel mobility shift assay identified an enhanced Sp3 protein binding on the human NHE8 basal promoter region upon butyrate stimulation. Furthermore, Sp3 acetylation modification is involved in butyrate-mediated NHE8 activation in Caco-2 cells. Our findings suggest that the mechanism of butyrate action on NHE8 expression involves enhanced Sp3 interaction at the basal promoter region of the human NHE8 gene promoter to activate NHE8 gene transcription. Thus butyrate is involved in intestinal regulation of NHE8 resulting enhanced sodium absorption.
Noninvasive calculation of the aortic blood pressure waveform from the flow velocity waveform: a proof of concept
Authors: Vennin Samuel , Mayer Alexia , Li Ye , Fok Henry , Clapp Brian , Alastruey Jordi , Chowienczyk Phil
Published: July 2015

Estimation of aortic and left ventricular (LV) pressure usually requires measurements that are difficult to acquire during the imaging required to obtain concurrent LV dimensions essential for determination of LV mechanical properties. We describe a novel method for deriving aortic pressure from the aortic flow velocity. The target pressure waveform is divided into an early systolic upstroke, determined by the water hammer equation, and a diastolic decay equal to that in the peripheral arterial tree, interposed by a late systolic portion described by a second-order polynomial constrained by conditions of continuity and conservation of mean arterial pressure. Pulse wave velocity (PWV, which can be obtained through imaging), mean arterial pressure, diastolic pressure, and diastolic decay are required inputs for the algorithm. The algorithm was tested using 1) pressure data derived theoretically from prespecified flow waveforms and properties of the arterial tree using a single-tube 1-D model of the arterial tree, and 2) experimental data acquired from a pressure/Doppler flow velocity transducer placed in the ascending aorta in 18 patients (mean ± SD: age 63 ± 11 yr, aortic BP 136 ± 23/73 ± 13 mmHg) at the time of cardiac catheterization. For experimental data, PWV was calculated from measured pressures/flows, and mean and diastolic pressures and diastolic decay were taken from measured pressure (i.e., were assumed to be known). Pressure reconstructed from measured flow agreed well with theoretical pressure: mean ± SD root mean square (RMS) error 0.7 ± 0.1 mmHg. Similarly, for experimental data, pressure reconstructed from measured flow agreed well with measured pressure (mean RMS error 2.4 ± 1.0 mmHg). First systolic shoulder and systolic peak pressures were also accurately rendered (mean ± SD difference 1.4 ± 2.0 mmHg for peak systolic pressure). This is the first noninvasive derivation of aortic pressure based on fluid dynamics (flow and wave speed) in the aorta itself.
Dynamic exercise training prevents exercise pressor reflex overactivity in spontaneously hypertensive rats
Authors: Mizuno Masaki , Iwamoto Gary A. , Vongpatanasin Wanpen , Mitchell Jere H. , Smith Scott A.
Published: July 2015

Cardiovascular responses to exercise are exaggerated in hypertension. We previously demonstrated that this heightened cardiovascular response to exercise is mediated by an abnormal skeletal muscle exercise pressor reflex (EPR) with important contributions from its mechanically and chemically sensitive components. Exercise training attenuates exercise pressor reflex function in healthy subjects as well as in heart failure rats. However, whether exercise training has similar physiological benefits in hypertension remains to be elucidated. Thus we tested the hypothesis that the EPR overactivity manifest in hypertension is mitigated by exercise training. Changes in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in response to muscle contraction, passive muscle stretch, and hindlimb intra-arterial capsaicin administration were examined in untrained normotensive Wistar-Kyoto rats (WKYUT; n = 6), exercise-trained WKY (WKYET; n = 7), untrained spontaneously hypertensive rats (SHRUT; n = 8), and exercise-trained SHR (SHRET; n = 7). Baseline MAP after decerebration was significantly decreased by 3 mo of wheel running in SHRET (104 ± 9 mmHg) compared with SHRUT (125 ± 10 mmHg). As previously reported, the pressor and renal sympathetic responses to muscle contraction, stretch, and capsaicin administration were significantly higher in SHRUT than WKYUT. Exercise training significantly attenuated the enhanced contraction-induced elevations in MAP (SHRUT: 53 ± 11 mmHg; SHRET: 19 ± 3 mmHg) and RSNA (SHRUT: 145 ± 32%; SHRET: 57 ± 11%). Training produced similar attenuating effects in SHR during passive stretch and capsaicin administration. These data demonstrate that the abnormally exaggerated EPR function that develops in hypertensive rats is significantly diminished by exercise training.
ADAM12: a genetic modifier of preclinical peripheral arterial disease
Authors: Dokun Ayotunde O. , Chen Lingdan , Okutsu Mitsuharu , Farber Charles R. , Hazarika Surovi , Jones W. Schuyler , Craig Damian , Marchuk Douglas A. , Lye R. John , Shah Svati H. , Annex Brian H.
Published: July 2015

In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD. We compared expression of genes within LSq-1 in Balb/c mice, which normally show poor outcomes following experimental PAD, with that in C57Bl/6 mice, which normally show favorable outcomes, and found that a disintegrin and metalloproteinase gene 12 ( ADAM12) had the most differential expression. Augmentation of ADAM12 expression in vivo improved outcomes following experimental PAD in Balb/c mice, whereas knockdown of ADAM12 made outcomes worse in C57Bl/6 mice. In vitro, ADAM12 expression modulates endothelial cell proliferation, survival, and angiogenesis in ischemia, and this appeared to be dependent on tyrosine kinase with Ig-like and EGF-like domain 2 (Tie2) activation. ADAM12 is sufficient to modify PAD severity in mice, and this likely occurs through regulation of Tie2.
Inhibition of Uncoupling Protein 2 Attenuates Cardiac Hypertrophy Induced by Transverse Aortic Constriction in Mice
Authors: Ji Xiao-Bing , Li Xiu-Rong , Hao-Ding  , Sun Qi , Zhou Yang , Wen Ping , Dai Chun-Sun , Yang Jun-Wei
Published: July 2015

Background: Uncoupling protein 2 (UCP2) is critical in regulating energy metabolism. Due to the significant change in energy metabolism of myocardium upon pressure overload, we hypothesize that UCP2 could contribute to the etiology of cardiac hypertrophy. Methods: Adult male C57BL/6J mice were subjected to pressure overload by using transverse aortic constriction (TAC), and then received genipin (a UCP2 selective inhibitor; 25 mg/kg/d, ip) or vehicle for three weeks prior to histologic assessment of myocardial hypertrophy. ATP concentration, ROS level, and myocardial apoptosis were also examined. A parallel set of experiments was also conducted in UCP2-/- mice. Results: TAC induced left ventricular hypertrophy, as reflected by increased ventricular weight/thickness and increased size of myocardial cell (vs. sham controls). ATP concentration was decreased; ROS level was increased. Apoptosis and fibrosis markers were increased. TAC increased mitochondrial UCP2 expression in the myocardium at both mRNA and protein levels. Genipin treatment attenuated cardiac hypertrophy and the histologic/biochemical changes described above. Hypertrophy and associated changes induced by TAC in UCP2-/- mice were much less pronounced than in WT mice. Conclusions: Blocking UCP2 expression attenuates cardiac hypertrophy induced by pressure overload.
PGE2 Modulates GABAA Receptors via an EP1 Receptor-Mediated Signaling Pathway
Authors: Yang Guang , Dong Wen-Hao , Hu Chang-Long , Mei Yan-Ai
Published: July 2015

Aims: PGE2 is one of the most abundant prostanoids in mammalian tissues, but its effect on neuronal receptors has not been well investigated. This study examines the effect of PGE2 on GABAA receptor currents in rat cerebellar granule neurons. Methods: GABAA currents were recorded using a patch-clamp technique. Cell surface and total protein of GABAA β1/2/3 subunits was carried out by Western blot analysis. Results: Upon incubation of neurons with PGE2 (1 µM) for 60 minutes, GABAA currents were significantly potentiated. This PGE2-driven effect could be blocked by PKC or CaMKII inhibitors as well as EP1 receptor antagonist, and mimicked by PMA or EP1 receptor agonist. Furthermore, Western blot data showed that PGE2 did not increase the total expression level of GABAA receptors, but significantly increased surface levels of GABAA β1/2/3 subunits after 1 h of treatment. Consistently, both PKC and CaMKII inhibitors were able to reduce PGE2-induced increases in cell surface expression of GABAA receptors. Conclusion: Activation of either the PKC or CaMKII pathways by EP1 receptors mediates the PGE2-induced increase in GABAA currents. This suggests that upregulation of postsynaptic GABAA receptors by PGE2 may have profound effects on cerebellar functioning under physiological and pathological conditions.
Pax4 Expression does not Transduce Pancreatic Alpha Cells to Beta Cells
Authors: Chen Ling , Zhang Jing , Zhang Zhuo , Chu Yaping , Song Bing , Cai Wang
Published: July 2015

Background/Aims: The lack of available beta cells greatly limits the use of beta cell transplantation as a therapy for diabetes. Thus, generation of beta cells from other sources is substantially required. Pax4 has been shown to induce reprograming of alpha cells into beta cells during embryogenesis. Nevertheless, whether expression of Pax4 in adult alpha cells could trigger this alpha-to-beta cell reprogramming is unknown. Methods: Here we generated an adeno-associated virus carrying Pax4 and GFP under a CMV promoter (AAV-Pax4). We used AAV-Pax4 to transduce a mouse alpha cell line in vitro, and to transduce primary alpha cells in diabetic mice. Reprogramming was examined by double immunostaining and by changes in beta cell number. The effects on blood glucose were evaluated by fasting blood glucose and glucose response. Results: In vitro, Pax4 overexpression neither induced insulin expression, nor suppressed glucagon expression in alpha cells. In vivo, Pax4 overexpression failed to increase beta cell number, and did not alter hyperglycemia and glucose response in diabetic mice. Conclusion: Pax4 expression is not sufficient to transduce pancreatic alpha cells into beta cells. Overexpression of Pax4 in alpha cells may not increase functional beta cell number in diabetic patients.
Up-Regulation Mttp and Apob Gene Expression in Rat Liver is Related to Post-Lipectomy Hypertriglyceridemia
Authors: Dettlaff-Pokora Agnieszka , Sledzinski Tomasz , Swierczynski Julian
Published: July 2015

Background/Aims: The aim of this study was to explain the molecular basis for elevated concentrations of circulating triglycerides (TAGs) after partial surgical removal of adipose tissue (lipectomy) in rats. Methods: The levels of mRNA and protein: a) involved in synthesis of fatty acids and TAGs; b) participating in TAG-rich lipoproteins assembly and secretion; and c) transcription factors essential for maintaining TAG homeostasis were determined by RT-PCR and Western Blot in the livers of control and lipectomized rats. Results: Partial lipectomy was associated with increase: a) in serum and liver concentration of TAGs, and b) in the liver levels of mRNA of microsomal TAG transfer protein (MTP) and apolipoprotein B-100 (ApoB-100). These changes were tightly associated with up-regulation of Hnf1a and Hnf4a gene expression in the liver. Lipectomy was also reflected by a significant increase in the expression of genes encoding: a) fatty acid synthase (FASN), b) glycerol 3-phosphate acyltransferase 1 (GPAT1), diacylglycerol acyltransferases 1 and 2 (DGAT1 and DGAT2), c) spot 14 protein (S14) and SREBP-1 in the liver. Conclusion: Coordinated up-regulation of Mttp, Apob, Hnf1a, Hnf4a, Fasn, Gpam and Dgat (1 and 2) gene expressions may contribute to the increase in circulating and liver concentrations of TAGs after lipectomy in an experimental rat model.
Proliferation and Cytokine Production of Human Mesangial Cells Stimulated by Secretory IgA Isolated from Patients with IgA Nephropathy
Authors: Liang Yan , Zhang Junjun , Zhou Yali , Xing Guolan , Zhao Guoqiang , Liu Zhangsuo
Published: July 2015

Background/Aims: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis, and often aggravates by mucosal infection. Secretory IgA (SIgA) is the dominant immunoglobulin in mucosal immunity, and is deposited in the mesangium in IgAN. The biological effects of SIgA on mesangial cells are poorly understood. Methods: Deposition of SIgA in frozen renal sections from IgAN patients was detected and the association between deposition of SIgA and patients characteristics was analyzed. The biological effects of SIgA and polymeric IgA (pIgA) on human renal mesangial cells were compared. We also studied the molecular mechanism of microRNA regulating the inflammatory effects of SIgA on mesangial cells. Results: Fifty-five of 176 patients had SIgA deposition with higher incidence of infection history and hematuria, lower serum cystatin C, β2 microglobulin, blood urea nitrogen and T-grade in the Oxford classification, compared with patients without SIgA deposition. SIgA stimulated mesangial cells at a higher ratio of proliferation and higher production of interleukin (IL)-6, IL-8, monocyte chemotactic protein 1, transforming growth factor-β1 and fibronectin, compared with SIgA from healthy volunteers. The proliferation and cytokines production in mesangial cells stimulated by SIgA were significantly lower than that stimulated by pIgA. miR-16 targeted the 3′-untranslated region of IL-6 and suppressed its translation in mesangial cells induced by SIgA. Conclusions: The biological effects of SIgA on mesangial cells differ from those of pIgA. SIgA stimulates mesangial cell proliferation and production of proinflammatory cytokines. IL-6 production is regulated by miR-16 in mesangial cells.
The Effects of Dasatinib in Experimental Acute Respiratory Distress Syndrome Depend on Dose and Etiology
Authors: Oliveira Gisele P. , Silva Johnatas D. , Marques Patricia S. , Gonçalves-de-Albuquerque Cassiano F. , Santos Heloísa L. , Vascocellos Ana Paula , Takiya Christina M. , Morales Marcelo M. , Pelosi Paolo , Mócsai Attila , de Castro-Faria-Neto Hugo C. , Rocco Patricia R.M.
Published: July 2015

Background/Aims: Evidence suggests that tyrosine-kinase inhibitors may attenuate lung inflammation and fibrosis in experimental acute respiratory distress syndrome (ARDS). We hypothesized that dasatinib, a tyrosine-kinase inhibitor, might act differently depending on the ARDS etiology and the dose. Methods: C57/BL6 mice were divided to be pre-treated with dasatinib (1mg/kg or 10mg/kg) or vehicle (1% dimethyl-sulfoxide) by oral gavage. Thirty-minutes after pre-treatment, mice were subdivided into control (C) or ARDS groups. ARDS animals received Escherichia coli lipopolysaccharide intratracheally (ARDSp) or intraperitoneally (ARDSexp). A new dose of dasatinib or vehicle was administered at 6 and 24h. Results: Forty-eight hours after ARDS induction, dasatinib 1mg/kg yielded: improved lung morphofunction and reduced cells expressing toll-like receptor (TLR)-4 in lung, independent of ARDS etiology; reduced neutrophil and levels of interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-β in ARDSp. The higher dose of dasatinib caused no changes in lung mechanics, diffuse alveolar damage, neutrophil, or cells expressing TLR4, but increased IL-6, vascular endothelial growth factor (VEGF), and cells expressing Fas receptor in lung in ARDSp. In ARDSexp, it improved lung morphofunction, increased VEGF, and reduced cells expressing TLR4. Conclusion: Dasatinib may have therapeutic potential in ARDS independent of etiology, but careful dose monitoring is required.
Cerebral Artery Remodeling in Rodent Models of Subarachnoid Hemorrhage
Authors: Guvenc Tuna Bilge , Lachkar Nadia , de Vos Judith , Bakker Erik N.T.P. , VanBavel Ed
Published: July 2015

Vasospasm is known to contribute to delayed cerebral ischemia following subarachnoid hemorrhage (SAH). We hypothesized that vasospasm initiates structural changes within the vessel wall, possibly aggravating ischemia and leading to resistance to vasodilator treatment. We therefore investigated the effect of blood on cerebral arteries with respect to contractile activation and vascular remodeling. In vitro experiments on rodent basilar and middle cerebral arteries showed a gradual contraction in response to overnight exposure to blood. After incubation with blood, a clear inward remodeling was found, reducing the caliber of the passive vessel. The transglutaminase inhibitor L682.777 fully prevented this remodeling. Translation of the in vitro findings to an in vivo SAH model was attempted in rats, using both a single prechiasmatic blood injection model and a double cisterna magna injection model, and in mice, using a single prechiasmatic blood injection. However, we found no substantial changes in active or passive biomechanical properties in vivo. We conclude that extravascular blood can induce matrix remodeling in cerebral arteries, which reduces vascular caliber. This remodeling depends on transglutaminase activity. However, the current rodent SAH models do not permit in vivo confirmation of this mechanism.
Population Pharmacokinetics and Therapeutic Efficacy of Febuxostat in Patients with Severe Renal Impairment
Authors: Hira Daiki , Chisaki Yugo , Noda Satoshi , Araki Hisazumi , Uzu Takashi , Maegawa Hiroshi , Yano Yoshitaka , Morita Shin-ya , Terada Tomohiro
Published: July 2015

The aim of the present study was to determine the influence of severe renal dysfunction (estimated glomerular filtration rate <30 ml/min/1.73 m2, including hemodialysis) on the pharmacokinetics and therapeutic effects of febuxostat using a population pharmacokinetic analysis. This study recruited patients with hyperuricemia who were initially treated with allopurinol, but were switched to febuxostat, and it consists of 2 sub-studies: a pharmacokinetic study (26 patients) and retrospective efficacy evaluation study (51 patients). The demographic and clinical data of patients were collected from electronic medical records. Plasma febuxostat concentrations were obtained at each hospital visit. Population pharmacokinetic modeling was performed with NONMEM version 7.2. A total of 128 plasma febuxostat concentrations from 26 patients were used in the population pharmacokinetic analysis. The data were best described by a 1-compartment model with first order absorption. Covariate analysis revealed that renal function did not influence the pharmacokinetics of febuxostat, whereas actual body weight significantly influenced apparent clearance and apparent volume of distribution. The retrospective efficacy analysis showed the favorable therapeutic response of febuxostat switched from allopurinol in patients with moderate to severe renal impairment. No serious adverse event associated with febuxostat was observed irrespective of renal function. The population pharmacokinetic analysis and therapeutic analysis of febuxostat revealed that severe renal dysfunction had no influence on the pharmacokinetic parameters of febuxostat. These results suggest that febuxostat is tolerated well by patients with severe renal impairment.
MicroRNA-200a Targets EGFR and c-Met to Inhibit Migration, Invasion, and Gefitinib Resistance in Non-Small Cell Lung Cancer
Authors: Zhen Qiang , Liu Junfeng , Gao Lina , Liu Jiabao , Wang Renfeng , Chu Weiwei , Zhang Yaxiao , Tan Guoliang , Zhao Xiaojian , Lv Baolei
Published: July 2015

Lung cancer, especially non-small cell lung cancer (NSCLC), is the major cause of cancer death worldwide. Mutations in epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met), both of which are receptor tyrosine kinases, have been identified in a considerable percentage of NSCLC patients. EGFR and c-Met share the same downstream pathways and cooperate not only in promoting metastasis but also in conferring resistance to tyrosine kinase inhibitor (TKI) therapies in NSCLC. MicroRNAs (miRNAs) are a family of small non-coding RNAs, usually 21-25 nucleotides long, and are critical in regulating gene expression. Abnormal miRNA expression has been implicated in the initiation and progression in many forms of cancers, including lung cancer. In this study, we found that miR-200a is downregulated in NSCLC cells, where it directly targets the 3′-UTR of both EGFR and c-Met mRNA. Overexpression of miR-200a in NSCLC cells significantly downregulates both EGFR and c-Met levels and severely inhibits cell migration and invasion. Moreover, in NSCLC cell lines that are resistant to gefitinib, a drug often used in TKI therapies to treat NSCLC, miR-200a expression is able to render the cells much more sensitive to the drug treatment.
Early Antidepressant Treatment and All-Cause 30-Day Mortality in Patients with Ischemic Stroke
Authors: Mortensen Janne Kaergaard , Johnsen Søren Paaske , Larsson Heidi , Andersen Grethe
Published: July 2015

Background: Antidepressants, in particular selective serotonin reuptake inhibitors, have been associated with antithrombotic and neuroprotective properties and their more widespread use has been suggested in stroke recovery. However, data are sparse on their effects on the clinical outcome, including mortality, associated with early antidepressant treatment after stroke. We aimed to study all-cause 30-day mortality related to early antidepressant treatment in patients with ischemic stroke. Methods: We did a population-based follow-up study identifying patients from the Danish Stroke Registry admitted in the former Aarhus County from 2003 to 2010. During this time, initiation of antidepressant treatment during admission was registered in the Danish Stoke Registry. The registry also holds clinical information including stroke type, stroke severity and quality of in-hospital stroke care. Information on vital status and covariates including comorbidities and co-medication was obtained from the following population-based medical registries: the Danish Civil Registration System, Danish Medicines Agency's Medical Register and The Danish National Patients Registry. Information was linked using the unique civil registration number assigned to all Danish residents. Multivariable logistic regression was used to compute the adjusted odds ratio (OR) of 30-day mortality in patients treated with antidepressants during admission as compared to patients not treated. In addition, we did stratified analyses on sex, age, stroke severity and propensity score-matched analyses as well as multiple imputation. Results: Among 5,070 consecutive first-ever stroke patients without prior antidepressant treatment, 955 (18.8%) started antidepressant treatment during admission with a median time from admission until treatment of 5 days (interquartile range 2-11). The proportion of patients with severe stroke was higher among treated patients as compared to that among non-treated patients. The adjusted OR of 30-day mortality was 0.28 (95% confidence interval (CI) 0.18-0.43) for patients treated during admission as compared to patients not treated during admission. Stratification by stroke severity showed signs of effect modification, stratification by sex and age did not. Included in the propensity score-matched analyses were 1,908 patients matched 1:1. The propensity score-matched adjusted OR of death within 30 days was 0.31 (95% CI 0.19-0.49). Conclusion: Although early antidepressant treatment was more often started in patients with severe stroke, treatment was associated with significantly lower mortality. This result requires replication in randomized trials; however, it indicates that early start of antidepressant treatment after stroke may be safe and a more routine use may be feasible.
Effects of Extended-Release Nicotinic Acid on Apolipoprotein (a) Kinetics in Hypertriglyceridemic Patients
Authors: Croyal Mikaël , Ouguerram Khadija , Passard Maxime , Ferchaud-Roucher Véronique , Chétiveaux Maud , Billon-Crossouard Stéphanie , de Gouville Anne-Charlotte , Lambert Gilles , Krempf Michel , Nobécourt Estelle
Published: July 2015

Objective—

To determine the mechanisms by which extended-release nicotinic acid reduces circulating lipoprotein (a) concentrations in hypertriglyceridemic patients.

Approach and Results—

Eight nondiabetic, obese male subjects (aged 48±12 years; body mass index, 31.2±1.8 kg/m
2
) with hypertriglyceridemia (triglycerides, 226±78 mg/dL) were enrolled in an 8 week, double blind, placebo-controlled cross-over study. At the end of each treatment phase, fasted subjects received a 10 µmol/L per kg bolus injection of [5,5,5-
2
H
3
]-
l
-Leucine immediately followed by constant infusion of [5,5,5-
2
H
3
]-
l
-Leucine (10 µmol L
−1
kg
−1
h
−1
) for 14 hours, and blood samples were collected. A liquid chromatography–tandem mass spectrometry method was used to study apolipoprotein (a) (Apo(a)) kinetics. The fractional catabolic rate of Apo(a) was calculated with a single compartmental model using the apolipoprotein B100 (ApoB100) containing very low density lipoprotein tracer enrichment as a precursor pool. Extended-release nicotinic acid decreased plasma triglycerides (−46%;
P
=0.023), raised high-density lipoprotein cholesterol (+20%;
P
=0.008), and decreased Apo(a) plasma concentrations (−20%;
P
=0.008). Extended-release nicotinic acid also decreased ApoB100 (22%;
P
=0.008) and proprotein convertase subtilisin/kexin type 9 (PCSK9, −29%;
P
=0.008) plasma concentrations. Apo(a) fractional catabolic rate and production rates were decreased by 37% (0.58±0.28 versus 0.36±0.19 pool/d;
P
=0.008) and 50% (1.4±0.8 versus 0.7±0.4 nmol/kg per day;
P
=0.008), respectively.

Conclusions—

Extended-release nicotinic acid treatment decreased Apo(a) plasma concentrations by 20%, production rates by 50%, and catabolism by 37%. ApoB100 and PCSK9 concentrations were also decreased by treatment, but no correlation was found with Apo(a) kinetic parameters.
Orai3 Surface Accumulation and Calcium Entry Evoked by Vascular Endothelial Growth Factor
Authors: Li Jing , Bruns Alexander-Francisco , Hou Bing , Rode Baptiste , Webster Peter J. , Bailey Marc A. , Appleby Hollie L. , Moss Nicholas K. , Ritchie Judith E. , Yuldasheva Nadira Y. , Tumova Sarka , Quinney Matthew , McKeown Lynn , Taylor Hilary , Prasad K. Raj , Burke Dermot , O’Regan David , Porter Karen E. , Foster Richard , Kearney Mark T. , Beech David J.
Published: July 2015

Objective—

Vascular endothelial growth factor (VEGF) acts, in part, by triggering calcium ion (Ca
2+
) entry. Here, we sought understanding of a Synta66-resistant Ca
2+
entry pathway activated by VEGF.

Approach and Results—

Measurement of intracellular Ca
2+
in human umbilical vein endothelial cells detected a Synta66-resistant component of VEGF-activated Ca
2+
entry that occurred within 2 minutes after VEGF exposure. Knockdown of the channel-forming protein Orai3 suppressed this Ca
2+
entry. Similar effects occurred in 3 further types of human endothelial cell. Orai3 knockdown was inhibitory for VEGF-dependent endothelial tube formation in Matrigel in vitro and in vivo in the mouse. Unexpectedly, immunofluorescence and biotinylation experiments showed that Orai3 was not at the surface membrane unless VEGF was applied, after which it accumulated in the membrane within 2 minutes. The signaling pathway coupling VEGF to the effect on Orai3 involved activation of phospholipase Cγ1, Ca
2+
release, cytosolic group IV phospholipase A2α, arachidonic acid production, and, in part, microsomal glutathione S-transferase 2, an enzyme which catalyses the formation of leukotriene C
4
from arachidonic acid. Shear stress reduced microsomal glutathione S-transferase 2 expression while inducing expression of leukotriene C
4
synthase, suggesting reciprocal regulation of leukotriene C
4
–synthesizing enzymes and greater role of microsomal glutathione S-transferase 2 in low shear stress.

Conclusions—

VEGF signaling via arachidonic acid and arachidonic acid metabolism causes Orai3 to accumulate at the cell surface to mediate Ca
2+
entry and downstream endothelial cell remodeling.
Contribution of Rare and Common Genetic Variants to Plasma Lipid Levels and Carotid Stiffness and Geometry
Authors: Proust Carole , Empana Jean-Philippe , Boutouyrie Pierre , Alivon Maureen , Challande Pascal , Danchin Nicolas , Escriou Guillaume , Esslinger Ulrike , Laurent Stéphane , Li Zhenlin , Pannier Bruno , Regnault Veronique , Thomas Frederique , Jouven Xavier , Cambien François , Lacolley Patrick
Published: July 2015

Background—

We assess the contribution of common and rare putatively functional genetic variants (most of them coding) present on the Illumina exome Beadchip to the variability of plasma lipids and stiffness of the common carotid artery.

Methods and Results—

Measurements were obtained from 2283 men and 1398 women, and after filtering and exclusion of monomorphic variants, 32 827 common (minor allele frequency >0.01) and 68 770 rare variants were analyzed. A large fraction of the heritability of plasma lipids is attributable to variants present on the array, especially for triglycerides (fraction of variance attributable to measured genotypes:
V
(G)/
V
p
=31.4%,
P
<3.1×10
–11
) and high-density lipoprotein cholesterol (
V
(G)/
V
p
=26.4%,
P
<4.2×10
–12
). Plasma lipids were associated with common variants located in known candidate genes, but no implication of rare variants could be established. Gene sets for plasma lipids, blood pressure, and coronary artery disease were defined on the basis of recent meta-analyses of genome-wide association studies. We observed a strong association between the plasma lipids gene set and plasma lipid variables, but none of the 3 genome-wide association studies gene sets was associated with the carotid parameters. Significant
V
(G)/
V
p
ratios were observed for external (14.5%,
P
<2.7×10
–5
) and internal diameter (13.4%,
P
<4.3×10
–4
), stiffness (12.5%,
P
<8.0×10
–4
), intima-media thickness (10.6%,
P
<7.9×10
–4
), and wall cross-sectional area (13.2%,
P
<2.4×10
–5
). A significant association was observed between the common rs2903692 polymorphism of the
CLEC16A
gene and the internal diameter (
P
<4.3×10
–7
).

Conclusions—

These results suggest an involvement of
CLEC16A
, a gene that has been reported to be associated with immune disorders, in the modulation of carotid vasodilatation.
Embolic Strokes of Undetermined Source in the Athens Stroke Registry
Authors: Ntaios George , Papavasileiou Vasileios , Milionis Haralampos , Makaritsis Konstantinos , Vemmou Anastasia , Koroboki Eleni , Manios Efstathios , Spengos Konstantinos , Michel Patrik , Vemmos Konstantinos
Published: July 2015

Background and Purpose—

Information about outcomes in Embolic Stroke of Undetermined Source (ESUS) patients is unavailable. This study provides a detailed analysis of outcomes of a large ESUS population.

Methods—

Data set was derived from the Athens Stroke Registry. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group criteria. End points were mortality, stroke recurrence, functional outcome, and a composite cardiovascular end point comprising recurrent stroke, myocardial infarction, aortic aneurysm rupture, systemic embolism, or sudden cardiac death. We performed Kaplan–Meier analyses to estimate cumulative probabilities of outcomes by stroke type and Cox-regression to investigate whether stroke type was outcome predictor.

Results—

2731 patients were followed-up for a mean of 30.5±24.1months. There were 73 (26.5%) deaths, 60 (21.8%) recurrences, and 78 (28.4%) composite cardiovascular end points in the 275 ESUS patients. The cumulative probability of survival in ESUS was 65.6% (95% confidence intervals [CI], 58.9%–72.2%), significantly higher compared with cardioembolic stroke (38.8%, 95% CI, 34.9%–42.7%). The cumulative probability of stroke recurrence in ESUS was 29.0% (95% CI, 22.3%–35.7%), similar to cardioembolic strokes (26.8%, 95% CI, 22.1%–31.5%), but significantly higher compared with all types of noncardioembolic stroke. One hundred seventy-two (62.5%) ESUS patients had favorable functional outcome compared with 280 (32.2%) in cardioembolic and 303 (60.9%) in large-artery atherosclerotic. ESUS patients had similar risk of composite cardiovascular end point as all other stroke types, with the exception of lacunar strokes, which had significantly lower risk (adjusted hazard ratio, 0.70 [95% CI, 0.52–0.94]).

Conclusions—

Long-term mortality risk in ESUS is lower compared with cardioembolic strokes, despite similar rates of recurrence and composite cardiovascular end point. Recurrent stroke risk is higher in ESUS than in noncardioembolic strokes.
Genetic Factors Influencing Coagulation Factor XIII B-Subunit Contribute to Risk of Ischemic Stroke
Authors: Hanscombe Ken B. , Traylor Matthew , Hysi Pirro G. , Bevan Stephen , Dichgans Martin , Rothwell Peter M. , Worrall Bradford B. , Seshadri Sudha , Sudlow Cathie ,   the METASTROKE Consortium,   the Wellcome Trust Case Control Consortium 2, Williams Frances M.K. , Markus Hugh S. , Lewis Cathryn M.
Published: July 2015

Background and Purpose—

Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes.

Methods—

Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls—the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke.

Results—

One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest
P
=5.7×10
−04
); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest
P
=1.8×10
−04
) and the cardioembolic subtype (smallest
P
=1.7×10
−04
). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=−0.71,
P
=0.01) and the cardioembolic subtype (rG=−0.80,
P
=0.03).

Conclusions—

Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype.
Resveratrol Preconditioning Induces a Novel Extended Window of Ischemic Tolerance in the Mouse Brain
Authors: Koronowski Kevin B. , Dave Kunjan R. , Saul Isabel , Camarena Vladimir , Thompson John W. , Neumann Jake T. , Young Juan I. , Perez-Pinzon Miguel A.
Published: July 2015

Background and Purpose—

Prophylactic treatments that afford neuroprotection against stroke may emerge from the field of preconditioning. Resveratrol mimics ischemic preconditioning, reducing ischemic brain injury when administered 2 days before global ischemia in rats. This protection is linked to silent information regulator 2 homologue 1 (Sirt1) and enhanced mitochondrial function possibly through its repression of uncoupling protein 2. Brain-derived neurotrophic factor (BDNF) is another neuroprotective protein associated with Sirt1. In this study, we sought to identify the conditions of resveratrol preconditioning (RPC) that most robustly induce neuroprotection against focal ischemia in mice.

Methods—

We tested 4 different RPC paradigms against a middle cerebral artery occlusion model of stroke. Infarct volume and neurological score were calculated 24 hours after middle cerebral artery occlusion. Sirt1-chromatin binding was evaluated by ChIP-qPCR. Percoll gradients were used to isolate synaptic fractions, and changes in protein expression were determined via Western blot analysis. BDNF concentration was measured using a BDNF-specific ELISA assay.

Results—

Although repetitive RPC induced neuroprotection from middle cerebral artery occlusion, strikingly one application of RPC 14 days before middle cerebral artery occlusion showed the most robust protection, reducing infarct volume by 33% and improving neurological score by 28%. Fourteen days after RPC, Sirt1 protein was increased 1.5-fold and differentially bound to the uncoupling protein 2 and BDNF promoter regions. Accordingly, synaptic uncoupling protein 2 level decreased by 23% and cortical BDNF concentration increased 26%.

Conclusions—

RPC induces a novel extended window of ischemic tolerance in the brain that lasts for at least 14 days. Our data suggest that this tolerance may be mediated by Sirt1 through upregulation of BDNF and downregulation of uncoupling protein 2.
Urban Water-Supply Reinvention
Authors: Luthy Richard G. , Sedlak David L.
Published: July 2015

Cities in drought-prone regions of the American West and Australia provide examples of innovative approaches to utilizing local water resources to achieve more resilient water supplies. Geographical realities, population growth, and favorable economic conditions can create the impetus for investments in new technologies, while support by activist groups and NGOs can encourage more sustainable approaches using locally sourced water. New approaches–whether desalination, stormwater use, water recycling, or potable reuse–share a common path to mass adoption. After a period of piloting and demonstration-scale projects, water providers with few options become early adopters of new technologies. And after the early adopters have gained experience and have used it to support the new approaches, the costs and risks of failure decrease for other providers. Thus, a wider cross section can adopt the new approach. The pioneering projects described herein are the first stage of the reinvention of our urban water systems.
A Fast Algorithm for Learning Overcomplete Dictionary for Sparse Representation Based on Proximal Operators
Authors: Li Zhenni , Ding Shuxue , Li Yujie
Published: July 2015

We present a fast, efficient algorithm for learning an overcomplete dictionary for sparse representation of signals. The whole problem is considered as a minimization of the approximation error function with a coherence penalty for the dictionary atoms and with the sparsity regularization of the coefficient matrix. Because the problem is nonconvex and nonsmooth, this minimization problem cannot be solved efficiently by an ordinary optimization method. We propose a decomposition scheme and an alternating optimization that can turn the problem into a set of minimizations of piecewise quadratic and univariate subproblems, each of which is a single variable vector problem, of either one dictionary atom or one coefficient vector. Although the subproblems are still nonsmooth, remarkably they become much simpler so that we can find a closed-form solution by introducing a proximal operator. This leads to an efficient algorithm for sparse representation. To our knowledge, applying the proximal operator to the problem with an incoherence term and obtaining the optimal dictionary atoms in closed form with a proximal operator technique have not previously been studied. The main advantages of the proposed algorithm are that, as suggested by our analysis and simulation study, it has lower computational complexity and a higher convergence rate than state-of-the-art algorithms. In addition, for real applications, it shows good performance and significant reductions in computational time.
Land Privatization in Nineteenth-century Ottoman Palestine
Authors: Solomonovich Nadav , Kark Ruth
Published: July 2015

This article examines land privatization in late nineteenth-century Ottoman Palestine through the extension of possession in miri lands, on the one hand, and its transformation into fee-simple property through change in land category classification (i.e., miri to mülk), on the other. Using primary sources, particularly Ottoman documents and correspondence of the German Consulate in Jerusalem, we analyze this process, as reflected in several cases involving foreign subjects and Ottoman authorities. We argue that privatization began as informal violations of the law, proceeded with the struggle of landholders against authorities who tried to reverse the process, and ended in victory for the landholders after the state ceded to their demands, inter alia, as a result of pressure from foreign nations and their consuls. Thus did de facto land privatization become de jure privatization.
Ukraine’s Fault Lines: The Quest for Regional Hegemony in the Post-Soviet Space
Authors: Alenga David
Published: July 2015

This paper presents a critique of the European Union’s flagship Eastern Partnership Initiative (EaP) within the context of its geopolitical ramifications on the political crisis in Ukraine. It particularly highlights the role of the Russian Federation as the principal protagonists and its quest to counter the EU’s normative power within their shared neighborhood. The EaP has among its goals promoting a broad range of political and economic reforms with the partner states with the view to help them deepen liberal democratic values and enhanced security and stability within the framework of an enhanced Association Agreement. The Kremlin believes the EaP undermines Russian interest in the region. This paper therefore presents a critical analysis of the contending dynamics of the competing efforts to use Ukraine as the launching pad to reshape the post-Cold War regional order.