bluuebunny/crossref_metadata_2025 huggingface dataset:
Histone Acetyltransferase Activity of MOF Is Required for MLL-AF9 Leukemogenesis
Authors: Valerio Daria G. , Xu Haiming , Chen Chun-Wei , Hoshii Takayuki , Eisold Meghan E. , Delaney Christopher , Cusan Monica , Deshpande Aniruddha J. , Huang Chun-Hao , Lujambio Amaia , Zheng YuJun George , Zuber Johannes , Pandita Tej K. , Lowe Scott W. , Armstrong Scott A.
Published: February 2017

Chromatin-based mechanisms offer therapeutic targets in acute myeloid leukemia (AML) that are of great current interest. In this study, we conducted an RNAi-based screen to identify druggable chromatin regulator–based targets in leukemias marked by oncogenic rearrangements of the MLL gene. In this manner, we discovered the H4K16 histone acetyltransferase (HAT) MOF to be important for leukemia cell growth. Conditional deletion of Mof in a mouse model of MLL-AF9–driven leukemogenesis reduced tumor burden and prolonged host survival. RNA sequencing showed an expected downregulation of genes within DNA damage repair pathways that are controlled by MOF, as correlated with a significant increase in yH2AX nuclear foci in Mof-deficient MLL-AF9 tumor cells. In parallel, Mof loss also impaired global H4K16 acetylation in the tumor cell genome. Rescue experiments with catalytically inactive mutants of MOF showed that its enzymatic activity was required to maintain cancer pathogenicity. In support of the role of MOF in sustaining H4K16 acetylation, a small-molecule inhibitor of the HAT component MYST blocked the growth of both murine and human MLL-AF9 leukemia cell lines. Furthermore, Mof inactivation suppressed leukemia development in an NUP98-HOXA9–driven AML model. Taken together, our results establish that the HAT activity of MOF is required to sustain MLL-AF9 leukemia and may be important for multiple AML subtypes. Blocking this activity is sufficient to stimulate DNA damage, offering a rationale to pursue MOF inhibitors as a targeted approach to treat MLL-rearranged leukemias. Cancer Res; 77(7); 1753–62. ©2017 AACR.
Aberrant SYK Kinase Signaling Is Essential for Tumorigenesis Induced by TSC2 Inactivation
Authors: Cui Ye , Steagall Wendy K. , Lamattina Anthony M. , Pacheco-Rodriguez Gustavo , Stylianou Mario , Kidambi Pranav , Stump Benjamin , Golzarri Fernanda , Rosas Ivan O. , Priolo Carmen , Henske Elizabeth P. , Moss Joel , El-Chemaly Souheil
Published: February 2017

Somatic or germline mutations in the tuberous sclerosis complex (TSC) tumor suppressor genes are associated closely with the pathogenesis of lymphangioleiomyomatosis, a rare and progressive neoplastic disease that predominantly affects women in their childbearing years. Serum levels of the lymphangiogenic growth factor VEGF-D are elevated significantly in lymphangioleiomyomatosis. However, there are gaps in knowledge regarding VEGF-D dysregulation and its cellular origin in lymphangioleiomyomatosis. Here, we show that increased expression and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphangioleiomyomatosis patients contributes to tumor growth. Syk kinase inhibitors blocked Syk signaling and exhibited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenograft model of lymphangioleiomyomatosis. In TSC2-deficient cells, Syk signaling increased the expression of monocyte chemoattractant protein MCP-1, which in peripheral blood mononuclear cells (PBMC) stimulated the production of VEGF-D. In clinical isolates of PBMCs from lymphangioleiomyomatosis patients, VEGF-D expression was elevated. Furthermore, levels of VEGF-D and MCP-1 in patient sera correlated positively with each other. Our results illuminate the basis for lymphangioleiomyomatosis growth and demonstrate the therapeutic potential of targeting Syk in this and other settings driven by TSC genetic mutation. Cancer Res; 77(6); 1492–502. ©2017 AACR.
Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair
Authors: Lu Yanxin , Kwintkiewicz Jakub , Liu Yang , Tech Katherine , Frady Lauren N. , Su Yu-Ting , Bautista Wendy , Moon Seog In , MacDonald Jeffrey , Ewend Matthew G. , Gilbert Mark R. , Yang Chunzhang , Wu Jing
Published: February 2017

Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+ availability. Targeting the PARP DNA repair pathway extensively sensitized IDH1-mutated glioma cells to TMZ. Our findings demonstrate a novel molecular mechanism that defines chemosensitivity in IDH-mutated gliomas. Targeting PARP-associated DNA repair may represent a novel therapeutic strategy for gliomas. Cancer Res; 77(7); 1709–18. ©2017 AACR.
Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells
Authors: Tong Jingshan , Wang Peng , Tan Shuai , Chen Dongshi , Nikolovska-Coleska Zaneta , Zou Fangdong , Yu Jian , Zhang Lin
Published: February 2017

The Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells. In this setting, Mcl-1 degradation was induced by a variety of multikinase inhibitor drugs, where it relied upon GSK3β phosphorylation and FBW7-dependent ubiquitination. Specific blockade by genetic knock-in (KI) abolished apoptotic responses and conferred resistance to kinase inhibitors. Mcl-1-KI also suppressed the antiangiogenic and anti-hypoxic effects of kinase inhibitors in the tumor microenvironment. Interestingly, these same inhibitors also induced the BH3-only Bcl-2 family protein PUMA, which is required for apoptosis. Degradation-resistant Mcl-1 bound and sequestered PUMA from other prosurvival proteins to maintain cell survival, which was abolished by small-molecule Mcl-1 inhibitors. Our findings establish a pivotal role for Mcl-1 degradation in the response of colon cancer cells to targeted therapeutics, and they provide a useful rational platform to develop Mcl-1–targeting agents that can overcome drug resistance. Cancer Res; 77(9); 2512–21. ©2017 AACR.
Expression Profiling of Circulating Microvesicles Reveals Intercellular Transmission of Oncogenic Pathways
Authors: Milani Gloria , Lana Tobia , Bresolin Silvia , Aveic Sanja , Pastò Anna , Frasson Chiara , te Kronnie Geertruy
Published: February 2017

Circulating microvesicles have been described as important players in cell-to-cell communication carrying biological information under normal or pathologic condition. Microvesicles released by cancer cells may incorporate diverse biomolecules (e.g., active lipids, proteins, and RNA), which can be delivered and internalized by recipient cells, potentially altering the gene expression of recipient cells and eventually impacting disease progression. Leukemia in vitro model systems were used to investigate microvesicles as vehicles of protein-coding messages. Several leukemic cells (K562, LAMA-87, TOM-1, REH, and SHI-1), each carrying a specific chromosomal translocation, were analyzed. In the leukemic cells, these chromosomal translocations are transcribed into oncogenic fusion transcripts and the transfer of these transcripts was monitored from leukemic cells to microvesicles for each of the cell lines. Microarray gene expression profiling was performed to compare transcriptomes of K562-derived microvesicles and parental K562 cells. The data show that oncogenic BCR-ABL1 transcripts and mRNAs related to basic functions of leukemic cells were included in microvesicles. Further analysis of microvesicles cargo revealed a remarkable enrichment of transcripts related to cell membrane activity, cell surface receptors, and extracellular communication when compared with parental K562 cells. Finally, coculturing of healthy mesenchymal stem cells (MSC) with K562-derived microvesicles displayed the transfer of the oncogenic message, and confirmed the increase of target cell proliferation as a function of microvesicle dosage.

Implications: This study provides novel insight into tumor-derived microvesicles as carriers of oncogenic protein–coding messages that can potentially jeopardize cell-directed therapy, and spread to other compartments of the body. Mol Cancer Res; 15(6); 683–95. ©2017 AACR.
Evaluation of the CRUSADE Risk Score for Predicting Major Bleeding in Patients with Concomitant Kidney Dysfunction and Acute Coronary Syndromes
Authors: Sánchez-Martínez Marianela , Flores-Blanco Pedro J. , López-Cuenca Ángel A. , Sánchez-Galián María J. , Gómez-Molina Miriam , Cambronero-Sánchez Francisco , Guerrero-Pérez Esther , Valdés Mariano , Januzzi James L. , Manzano-Fernández Sergio
Published: February 2017

Background: Kidney dysfunction (KD) has been associated with increased risk for major bleeding (MB) in patients with acute coronary syndromes (ACS) and may be in part related to an underuse of evidence-based therapies. Our aim was to assess the predictive ability of the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) risk score in patients with concomitant ACS and chronic kidney disease. Methods: We conducted a retrospective analysis of a prospective registry including 1,587 ACS patients. In-hospital MB was prospectively recorded according to the CRUSADE and Bleeding Academic Research Consortium (BARC) criteria. KD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. Results: The predictive ability of the CRUSADE risk score was assessed by discrimination and calibration analyses. A total of 465 (29%) subjects had KD. In multivariate logistic regression analyses, we found high CRUSADE risk score values to be associated with a higher rate of in-hospital MB; however, among patients with KD, it was not associated with BARC MB. Regardless of the MB definition, the predictive ability of the CRUSADE score in patients with KD was lower: area under the curve (AUC) 0.71 versus 0.79, p = 0.03 for CRUSADE MB and AUC 0.65 versus 0.75, p = 0.02 for BARC MB. Hosmer-Lemeshow analyses showed a good calibration in all renal function subgroups for both MB definitions (all p values >0.3). Conclusions: The CRUSADE risk score shows a lower accuracy for predicting in-hospital MB in KD patients compared to those without KD.
Mean Platelet Volume in Heterozygous Beta Thalassaemia
Authors: Cikrikcioglu Mehmet Ali , Celik Kenan , Ekinci Iskender , Nasifov Muharrem , Toprak Aybala Erek , Cetin Guven , Genc Sema
Published: February 2017

Background/Aim: It is not known why cerebrovascular and cardiovascular ischaemic events are less frequently observed in heterozygous beta thalassaemia (HBT) patients than in the general population. However, we previously reported that serum levels of some platelet function markers, i.e. soluble CD40 ligand and soluble P-selectin, are lower in patients with HBT than in controls. A high mean platelet volume (MPV) is an indicator of in vivo platelet activation and may indicate a tendency to thrombosis. We investigated whether MPV is lower in HBT patients than in controls. Methods: Forty-eight patients with HBT were compared with 51 controls matched for gender, age, and BMI for MPV in a cross-sectional study. Results: The MPV was within the normal range and higher in the HBT group (9.64 ± 1.20 vs. 9.07 ± 082 fL, p = 0.006). The 2 groups were similar in terms of atherosclerosis risk factors and medications. After linear regression analysis, the MPV was correlated with HBT, sensitive CRP, and BMI. Conclusion: The higher MPV in patients with HBT could indicate platelet activation, and this may represent a dilemma. Higher MPV in the HBT group might have resulted from higher sympathetic nervous system activity, mild ineffective erythropoiesis, and haemolysis.
Prevalence of Occult Hepatitis C Virus Infection among Blood Donors in Jiangsu, China
Authors: Lin Hong , Chen Xian , Zhu Shaowen , Mao Ping , Zhu Shanshan , Liu Yanchun , Huang Chengyin , Sun Jun , Zhu Jin
Published: February 2017

Objective: In 2010, only 1 donor blood sample was found to be anti-hepatitis C virus (HCV) negative and HCV RNA positive, as detected by nucleic acid testing. In occult HCV infection (OCI), HCV RNA is found in peripheral blood mononuclear cells (PBMCs). We investigated the prevalence of OCI among blood donors. Methods: We collected 513 samples from 334 eligible and 179 deferred donors, including 55 anti-HCV-positive, 113 alanine aminotransferase (ALT)-elevated, and 11 hepatitis B virus surface antigen (HBsAg)-positive blood donors. PBMCs were isolated, the 5′-untranslated region of HCV RNA was amplified by reverse transcription nested PCR, and the genotype of the core region was determined. Results: No HCV RNA was detected among the eligible samples. Among the deferred donors, 15 (27.2%) had detectable HCV RNA in 55 anti-HCV PBMC specimens. HCV RNA was detected in 1 (9.1%) HBsAg-positive and 9 (8%) ALT-elevated samples. The prevalence of OCI in the blood donors was 2.2% (10/458). HCV genotypes were determined in 10 subjects, indicating that 2 (20.0%) were subtype 2a, 7 (70.0%) were 1b, and 1 (10%) was 6a. Conclusions: This study showed that OCI does exist among Chinese blood donors. However, to determine the epidemiology and outcome of this HCV infection, further follow-up with more participants and patients receiving blood components with OCI is needed.
Distal Middle Cerebral Artery Branch Recanalization Does Not Affect Final Lesion Volume in Ischemic Stroke
Authors: van Ginneken Verena , Gierhake Daniel , Audebert Heinrich J. , Fiebach Jochen B.
Published: February 2017

Background: Early recanalization in ischemic stroke is associated with favorable outcome. However, limited data are available on the effect of recanalization on infarct growth and functional outcome in stroke with distal middle cerebral artery (MCA) pathology. This study was aimed at determining the effect of recanalization in acute stroke patients with perfusion-diffusion mismatch and occlusion or high-grade stenosis of a distal MCA branch. Methods: We prospectively examined 34 consecutive stroke patients with perfusion-diffusion mismatch and M3 or M4 pathology within 24 h of symptom onset. The MRI protocol consisted of diffusion-weighted images (DWI), fluid-attenuated inversion recovery (FLAIR), T2*, perfusion-weighted imaging, time-of-flight magnetic resonance angiography at days 0, 1, and 4-6. Volume measurements were performed with MRIcron. Infarct growth was defined as the difference between lesion volumes on FLAIR at days 4-6 and DWI at day 0. Certified raters assessed modified Rankin Scale scores at discharge and day 90. Results: Twenty-four patients (71%) showed recanalization at day 1. Infarct growth was modest (median 2.4 mL, 95% CI 0.8-6.7) and not significantly different between patients with and without recanalization (p = 0.87). Functional outcome at discharge was good with 70% of patients suffering no significant disabilities. There was no association between functional outcome at discharge and recanalization (OR 2.1, 95% CI 0.4-13.0, p = 0.40) or infarct volume at days 4-6 (p = 0.40). Conclusions: The high rate of spontaneous recanalization and good functional outcome in patients with distal MCA pathology might obscure a potential benefit from recanalization in this population.
Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model
Authors: Zhang Yanqing , Liao Pingping , Zhu Meng’en , Li Wei , Hu Dan , Guan Siming , Chen Long
Published: February 2017

Background/Aims: Baicalin has been shown to be effective for various animal models of cardiovascular diseases, such as pulmonary hypertension, atherosclerosis and myocardial ischaemic injury. However, whether baicalin plays a role in cardiac hypertrophy remains unknown. Here we investigated the protective effects of baicalin on cardiac hypertrophy induced by pressure overload and explored the potential mechanisms involved. Methods: C57BL/6J-mice were treated with baicalin or vehicle following transverse aortic constriction or Sham surgery for up to 8 weeks, and at different time points, cardiac function and heart size measurement and histological and biochemical examination were performed. Results: Mice under pressure overload exhibited cardiac dysfunction, high mortality, myocardial hypertrophy, increased apoptosis and fibrosis markers, and suppressed cardiac expression of PPARα and PPARβ/δ. However, oral administration of baicalin improved cardiac dysfunction, decreased mortality, and attenuated histological and biochemical changes described above. These protective effects of baicalin were associated with reduced heart and cardiomyocyte size, lower fetal genes expression, attenuated cardiac fibrosis, lower expression of profibrotic markers, and decreased apoptosis signals in heart tissue. Moreover, we found that baicalin induced PPARα and PPARβ/δ expression in vivo and in vitro. Subsequent experiments demonstrated that long-term baicalin treatment presented no obvious cardiac lipotoxicity. Conclusions: The present results demonstrated that baicalin attenuates pressure overload induced cardiac dysfunction and ventricular remodeling, which would be due to suppressed cardiac hypertrophy, fibrosis, apoptosis and metabolic abnormality.
Mechanical Loading Improves Tendon-Bone Healing in a Rabbit Anterior Cruciate Ligament Reconstruction Model by Promoting Proliferation and Matrix Formation of Mesenchymal Stem Cells and Tendon Cells
Authors: Song Fanglong , Jiang Dawei , Wang Tianchen , Wang Yi , Chen Fengmei , Xu Guoxing , Kang Yifan , Zhang Yinquan
Published: February 2017

Background/Aims: This study investigated the effect of mechanical stress on tendon-bone healing in a rabbit anterior cruciate ligament (ACL) reconstruction model as well as cell proliferation and matrix formation in co-culture of bone-marrow mesenchymal stem cells (BMSCs) and tendon cells (TCs). Methods: The effect of continuous passive motion (CPM) therapy on tendon-bone healing in a rabbit ACL reconstruction model was evaluated by histological analysis, biomechanical testing and gene expressions at the tendon-bone interface. Furthermore, the effect of mechanical stretch on cell proliferation and matrix synthesis in BMSC/TC co-culture was also examined. Results: Postoperative CPM therapy significantly enhanced tendon-bone healing, as evidenced by increased amount of fibrocartilage, elevated ultimate load to failure levels, and up-regulated gene expressions of Collagen I, alkaline phosphatase, osteopontin, Tenascin C and tenomodulin at the tendon-bone junction. In addition, BMSC/TC co-culture treated with mechanical stretch showed a higher rate of cell proliferation and enhanced expressions of Collagen I, Collagen III, alkaline phosphatase, osteopontin, Tenascin C and tenomodulin than that of controls. Conclusion: These results demonstrated that proliferation and differentiation of local precursor cells could be enhanced by mechanical stimulation, which results in enhanced regenerative potential of BMSCs and TCs in tendon-bone healing.
Crushed sublingual versus oral ticagrelor administration strategies in patients with unstable angina
Authors: Barańska Malwina , Sikora Adam , Buszko Katarzyna , Siemińska Emilia , Marszałł Michał Piotr , Siller-Matula Jolanta , Jilma Bernd , Alexopoulos Dimitrios , Fabiszak Tomasz , Kubica Jacek , Niezgoda Piotr , Sikora Joanna
Published: February 2017

Oral administration of crushed ticagrelor tablets turned out to be an efficacious method that improves its pharmacokinetics and pharmacodynamics. This strategy, however, is unlikely to eliminate the drug-drug interaction in patients receiving intravenous morphine, as the impairment of the P2Y12 inhibitor absorption related to decreased propulsive motility of the gastro-intestinal tract is the most likely mechanism of interaction. Thus, we designed a pharmacokinetic and pharmacodynamic study setting the feasibility of platelet inhibition with a loading dose of ticagrelor given as crushed tablets sublingually compared with two other ticagrelor loading dose administration strategies: integral tablet given orally and crushed tablet given orally in patients with unstable angina. Ticagrelor and its metabolite AR-C124900XX plasma concentration was evaluated in nine time points (time frame of 6 hours) using liquid chromatography coupled with mass spectrometry; platelet reactivity was evaluated using multiple electrode aggregometry. The area under the plasma concentration-time curve for ticagrelor and AR-C124900XX was significantly higher in patients treated with crushed tablets given orally compared with crushed tablets given sublingually only within the first hour after loading dose (936.9 ± 898.0 vs 368.0 ± 422.4, p=0.042 and 103.4 ± 120.8 vs 31.3 ± 43.9, p=0.031, respectively). Moreover, we showed significantly stronger platelet inhibition in patients receiving crushed ticagrelor orally vs. sublingually at 30 and 45 min after the loading dose (p=0.024 and p=0.016, respectively). Therefore, the administration strategy of ticagrelor determines the pharmacokinetic and pharmacodynamic profile of both ticagrelor and its active metabolite AR-C124900XX.
Maria do Huambo: a life as a “native”. Colonization, legal status and racial discrimination in Angola (1926-1961)
Authors: Neto Maria da Conceição
Published: February 2017

Legal dualism characterized colonial rule in all European empires in Africa in the twentieth century, despite some conceptual and practical differences among them. In the case of Angola, Mozambique and Guinea (the Portuguese colonies where a legal “Native Statute” was imposed from 1926 to 1961) that was an essential part of the colonial doctrine, with deep economic, political, and social implications. Using the example of Maria, a fictional character based on research exploring a wide range of sources, this text highlights what living under such a “Statute” meant for people’s everyday lives. It also reveals how much it was, in fact, a legal barrier to the social mobility of the majority of the colonized population, even when economic and cultural changes opened the way for such advances
Effects of Upgrade Versus De Novo Cardiac Resynchronization Therapy on Clinical Response and Long-Term Survival
Authors: Vamos Mate , Erath Julia W. , Bari Zsolt , Vagany Denes , Linzbach Sven P. , Burmistrava Tatsiana , Israel Carsten W. , Duray Gabor Z. , Hohnloser Stefan H.
Published: February 2017

Background—

Benefits of cardiac resynchronization therapy (CRT) on morbidity and mortality in selected patients are well known. Although the number of upgrade procedures from single- or dual-chamber devices to CRT is increasing, there are only sparse data on the outcomes of upgrade procedures compared with de novo CRT. This study aimed to evaluate clinical response and survival in patients receiving de novo versus upgrade CRT defibrillator therapy.

Methods and Results—

Prospectively collected outcome data were compared in patients undergoing de novo or upgrade CRT defibrillator implantation at 3 implant centers in Germany and Hungary. Clinical response was defined as an improvement by at least one New York Heart Association (NYHA) functional class. CRT implantation was performed in 552 consecutive patients of whom 375 underwent a de novo and 177 an upgrade procedure. Upgrade patients were more often implanted for secondary prevention, suffered more often from atrial fibrillation, chronic kidney disease, diabetes mellitus, and dyslipidemia, and had more often a non-LBBB (left bundle branch block) wide QRS complex, and lower left ventricular ejection fraction. Upgrade procedures were associated with a lower response rate compared to the de novo group (57% versus 69%,
P
univariate=0.008,
P
multivariate=0.021). During the follow-up of 37±28 months, survival was worse after upgrade compared with de novo CRT defibrillator implantations (hazard ratio, 1.65; 95% confidence interval, 1.22–2.24;
P
=0.001) even after careful adjustment for important baseline variables (adjusted hazard ratio, 1.68; 95% confidence interval, 1.20–2.34;
P
=0.002) and after propensity-score matching (propensity-adjusted hazard ratio, 1.79; 95% confidence interval, 1.08–2.95;
P
=0.023).

Conclusions—

Both clinical response and long-term survival were less favorable in patients undergoing CRT upgrade compared to de novo implantations.
Targets and End Points in Cardiac Autonomic Denervation Procedures
Authors: Rivarola Esteban W. , Hachul Denise , Wu Tan , Pisani Cristiano , Hardy Carina , Raimundi Fabrizio , Melo Sissy , Darrieux Francisco , Scanavacca Mauricio
Published: February 2017

Background—

Autonomic denervation is an alternative approach for patients with symptomatic bradycardia. No consensus exists on the critical targets and end points of the procedure. The aim of this study was to identify immediate end points and critical atrial regions responsible for vagal denervation.

Methods and Results—

We enrolled 14 patients (50% men; age: 34.0±13.8 years) with cardioinhibitory syncope, advanced atrioventricular block or sinus arrest, and no structural heart disease. Anatomic mapping of ganglionated plexuses was performed, followed by radiofrequency ablation. Heart rate, sinus node recovery time, Wenckebach cycle length, and atrial-His (AH) interval were measured before and after every radiofrequency pulse. Wilcoxon signed-rank test was used for comparison. Significant shortening of the R-R interval (
P
=0.0009), Wenckebach cycle length (
P
=0.0009), and AH intervals (
P
=0.0014) was observed after ablation. The heart rate elevation was 23.8±12.5%, and the Wenckebach cycle length and AH interval shortening was 18.1±11% and 24.6±19%, respectively. Atropine bolus injection (0.04 mg/kg) did not increase heart rate further. Targeting a single spot of the left side (64% of the patients) or right side (36%) of the interatrial septum was observed to be responsible for ≥80% of the final R-R and AH interval shortening during ablation.

Conclusions—

Targeting specific sites of the interatrial septum is followed by an increase in heart rate and atrioventricular nodal conduction properties and might be critical for vagal attenuation. The R-R interval, Wenckebach cycle length, and AH interval shortening, associated with a negative response to atropine, could be considered immediate end points of the procedure.
Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis
Authors: Förstermann Ulrich , Xia Ning , Li Huige
Published: February 2017

Major reactive oxygen species (ROS)–producing systems in vascular wall include NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase, xanthine oxidase, the mitochondrial electron transport chain, and uncoupled endothelial nitric oxide (NO) synthase. ROS at moderate concentrations have important signaling roles under physiological conditions. Excessive or sustained ROS production, however, when exceeding the available antioxidant defense systems, leads to oxidative stress. Animal studies have provided compelling evidence demonstrating the roles of vascular oxidative stress and NO in atherosclerosis. All established cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, and smoking enhance ROS generation and decrease endothelial NO production. Key molecular events in atherogenesis such as oxidative modification of lipoproteins and phospholipids, endothelial cell activation, and macrophage infiltration/activation are facilitated by vascular oxidative stress and inhibited by endothelial NO. Atherosclerosis develops preferentially in vascular regions with disturbed blood flow (arches, branches, and bifurcations). The fact that these sites are associated with enhanced oxidative stress and reduced endothelial NO production is a further indication for the roles of ROS and NO in atherosclerosis. Therefore, prevention of vascular oxidative stress and improvement of endothelial NO production represent reasonable therapeutic strategies in addition to the treatment of established risk factors (hypercholesterolemia, hypertension, and diabetes mellitus).
Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension
Authors: Chen Jiwang , Sysol Justin R. , Singla Sunit , Zhao Shuangping , Yamamura Aya , Valdez-Jasso Daniela , Abbasi Taimur , Shioura Krystyna M. , Sahni Sakshi , Reddy Vamsi , Sridhar Arvind , Gao Hui , Torres Jaime , Camp Sara M. , Tang Haiyang , Ye Shui Qing , Comhair Suzy , Dweik Raed , Hassoun Paul , Yuan Jason X.-J. , Garcia Joe G.N. , Machado Roberto F.
Published: February 2017

Background:

Pulmonary arterial hypertension is a severe and progressive disease, a hallmark of which is pulmonary vascular remodeling. Nicotinamide phosphoribosyltransferase (NAMPT) is a cytozyme that regulates intracellular nicotinamide adenine dinucleotide levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation, and inhibits apoptosis. We hypothesized that NAMPT promotes pulmonary vascular remodeling and that inhibition of NAMPT could attenuate pulmonary hypertension.

Methods:

Plasma, mRNA, and protein levels of NAMPT were measured in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension and in the lungs of rodent models of pulmonary hypertension.
Nampt
+/−
mice were exposed to 10% hypoxia and room air for 4 weeks, and the preventive and therapeutic effects of NAMPT inhibition were tested in the monocrotaline and Sugen hypoxia models of pulmonary hypertension. The effects of NAMPT activity on proliferation, migration, apoptosis, and calcium signaling were tested in human pulmonary artery smooth muscle cells.

Results:

Plasma and mRNA and protein levels of NAMPT were increased in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension, as well as in lungs of rodent models of pulmonary hypertension.
Nampt
+/−
mice were protected from hypoxia-mediated pulmonary hypertension. NAMPT activity promoted human pulmonary artery smooth muscle cell proliferation via a paracrine effect. In addition, recombinant NAMPT stimulated human pulmonary artery smooth muscle cell proliferation via enhancement of store-operated calcium entry by enhancing expression of Orai2 and STIM2. Last, inhibition of NAMPT activity attenuated monocrotaline and Sugen hypoxia–induced pulmonary hypertension in rats.

Conclusions:

Our data provide evidence that NAMPT plays a role in pulmonary vascular remodeling and that its inhibition could be a potential therapeutic target for pulmonary arterial hypertension.
Competent Geometric Semantic Genetic Programming for Symbolic Regression and Boolean Function Synthesis
Authors: Pawlak Tomasz P. , Krawiec Krzysztof
Published: February 2017

Program semantics is a promising recent research thread in Genetic Programming (GP). Over a dozen semantic-aware search, selection, and initialization operators for GP have been proposed to date. Some of these operators are designed to exploit the geometric properties of semantic space, while others focus on making offspring effective, that is, semantically different from their parents. Only a small fraction of previous works aimed at addressing both of these features simultaneously. In this article, we propose a suite of competent operators that combine effectiveness with geometry for population initialization, mate selection, mutation, and crossover. We present a theoretical rationale behind these operators and compare them experimentally to operators known from literature on symbolic regression and Boolean function synthesis benchmarks. We analyze each operator in isolation as well as verify how they fare together in an evolutionary run, concluding that the competent operators are superior on a wide range of performance indicators, including best-of-run fitness, test-set fitness, and program size.
Evaluation and Analysis of White Space in Wu Guanzhong’s Chinese Paintings
Authors: Fan ZhenBao , Zhang Kang , Zheng XianJun Sam
Published: February 2017

This article reports on a recent study that examines the effect of white space on perception of Chinese paintings. The authors investigate whether white space in Chinese paintings is not simply a blank background space but rather meaningful for aesthetic perception. Applying a computational saliency model to analyze the influence of white space on viewers’ visual information processing, the authors conducted an eye-tracking experiment. As a case study, they analyzed paintings by a well-known artist, Wu Guanzhong, and collected users’ subjective aesthetic ratings. Their results show that white space is not just a silent background: It is intentionally designed to convey certain information and has a significant effect on viewers’ aesthetic experience.
Review of Marmasoma White with lectotype designation of M. sumptuosum White and an identification key to the Australasian/Oceanian genera of
Ecliminae (Diptera, Bombyliidae)
Authors: RODRIGUES PAULA FERNANDA MOTTA , MCALISTER ERICA , LAMAS CARLOS JOSÉ EINICKER
Published: February 2017

The bombyliid genus Marmasoma White is restricted to Australia. Marmasoma sumptuosum White, the only known species of the genus, is studied and a lectotype and paralectotypes are designated. Based on the type series and on additional material, a redescription of the species is presented and the main characters of the external morphology of adults are illustrated and photographed, including male and female genitalia. In addition, the remarkable aedeagus of M. sumptuosum, unique among all Ecliminae species by the presence of serrated projections on its apical portion, is described and photographed in detail for the first time. An identification key to the Australasian/Oceanian genera of Ecliminae and a distribution map with the known geographic records of Marmasoma are also included.
Discovery of Neopanorpa chillcotti Byers (Mecoptera: Panorpidae) from Tibet, China, with discussion of its generic status
Authors: WANG MENG , HUA BAO-ZHEN
Published: February 2017

Neopanorpa chillcotti Byers, 1971 was originally described from Kathmandu in Nepal and is now found to be distributed in Gyirong, Tibet in China. The species is redescribed and illustrated based on new material from China and Nepal. The generic status of this species is briefly discussed.
New species of Parotocinclus (Siluriformes: Loricariidae) from coastal drainages of Rio de Janeiro, southeastern Brazil
Authors: ROXO FÁBIO F. , MELO BRUNO F. , SILVA GABRIEL S. C. , OLIVEIRA CLAUDIO
Published: February 2017

A new species of Parotocinclus is described from tributaries of rio São João, an Atlantic coastal river of Rio de Janeiro, southeastern Brazil. The new species is distinguished from its congeners by the possession of a triangular patch of dark pigmentation on the anterior portion of the dorsal-fin base, a fully developed adipose fin, complete exposure of the ventral surface of the pectoral girdle, and a distinctive pigmentation pattern of the caudal fin. The caudal fin has a hyaline background with a large black blotch covering its anterior portion, tapering irregularly through distal portions of the ventral lobe with a hyaline rounded area, and a small patch of dark pigmentation on distal portions of the dorsal lobe.
Codex Sinaiticus and the use of manuscripts in the Early Church
Authors: Böttrich Christfried
Published: February 2017

Codex Sinaiticus, the world’s oldest and most complete manuscript of a Greek Bible (4th century) has a complicated and exciting history. Re-discovered by the German Theologian Constantin von Tischendorf (1844/1859), the already split codex was transferred to Europe (Leipzig, St. Petersburg, London). The donation of its major part to Tsar Alexander II in 1869 caused controversies about ownership during the 20th century. Some years ago, the four different parts were, virtually, united again. This was the starting point for a new and intensive examination of this precious manuscript. The present article discusses some old issues in the light of new insights.
Raccontare la giustizia
Authors: Jansen Monica , Urban Maria Bonaria
Published: February 2017

Dalle varie riflessioni critiche sul rapporto tra letteratura e giustizia e tra narrazione e legge si può dedurre che alla letteratura venga attribuita la facoltà di “fare giustizia” e alla legge il potenziale di produrre delle storie. Anche se le opinioni divergono sull’effettivo valore trasformativo della letteratura di fronte alla legge, nel panorama italiano sembra prevalere l’idea che la letteratura possa offrire uno strumento conoscitivo per raggiungere una giustizia poetica e fare esperienza della verità. Tale compito etico, che viene attribuito a una narrativa che svolge la funzione di “estetica documentale”, si collega al complicato passaggio dalla Prima alla Seconda Repubblica, riassunto comunemente con la formula di “memoria divisa”. Gli esempi letterari presi in esame dagli anni Sessanta ad oggi, si caratterizzano attraverso le loro ibridizzazioni di genere, le dimensioni transmediali, performative e metanarrative. Da Giuseppe Fava a Gianrico Carofiglio, da Franco Fortini a Giampaolo Pansa, si trasmette il bisogno di una giustizia sociale che si concretizza attraverso un’indagine critica dell’apparato giuridico e attraverso la formulazione di una giustizia metaforica. Anche la raccolta di racconti Giudici e il fumetto Carlo Giuliani. Il ribelle di Genova dimostrano come la letteratura usi la transmedialità e la performatività per coinvolgere il lettore e arrivare a una giustizia che sia anche un “atto culturale”.
Religiousness, Spirituality, and Substance Use: A Genetically Sensitive Examination and Critique
Authors: Nedelec Joseph L. , Richardson George , Silver Ian A.
Published: February 2017

A growing literature has linked religiousness and spirituality (R/S) to substance use and abuse. However, it is not clear that R/S has causal effects on substance use. Currently, there is a relative lack of genetically sensitive examinations in the literature attendant to R/S effects. Given that behavioral genetic analyses have illustrated the influence of genetic factors on substance use and adherence to R/S worldviews, genetic confounding is a concern. The current study employed a sample of monozygotic twins discordant on religiousness, spirituality, and spiritual transformation to assess effects on substance use and abuse. Bivariate and multivariate models indicated a general lack of effect of R/S on substance use and abuse but did illustrate a dampening influence of religiousness on general (but not problematic) alcohol use. The findings highlight the importance of controlling for genetic and shared familial factors in examinations of the religiousness–spirituality–substance use nexus.
An Observational Study of Score Study Practices Among Undergraduate Instrumental Music Education Majors
Authors: Silvey Brian A. , Montemayor Mark , Baumgartner Christopher M.
Published: February 2017

The purpose of this study was to investigate undergraduate instrumental music education majors’ score study practices as they related to the effectiveness of their simulated conducting. Participants ( N = 30) were video recorded in two sessions in which they completed a 20-min score study session and a simulated conducting performance. In the first score study session, all 30 conductors studied Mini-Suite for Band, Movement 1. In Session 2, participants studied Portrait of a Clown but this time either with a model recording ( n = 15) or without one ( n = 15). We computed the overall duration of participants’ score study behaviors for both pieces. Additional data included graduate students’ evaluations of participants’ post–score study conducting performances and an inventory of participants’ score study markings. We found a significant difference in the proportion of time spent in score studying activities between the model and no-model condition conductors, with more time spent in gesturing when studying along with a model. Evaluations of participants’ conducting revealed no differences between those conductors who used a model and those who did not while studying Portrait of a Clown. Our analysis of conductors’ score markings revealed a small number of notable differences between stronger/weaker conductors and between model/no-model conditions. Implications for undergraduate conductor preparation programs are discussed.
The Moderating Effects of Antisocial Personality Disorder on the Relationship Between Serious Mental Illness and Types of Prison Infractions
Authors: Matejkowski Jason
Published: February 2017

Inmates with serious mental illness (SMI) or antisocial personality disorder (APD) average higher rates of disciplinary infractions than inmates without these conditions. This study builds upon these lines of research by examining the relationships among SMI and various types of prison misconduct, and whether these relationships are moderated by the presence of APD. SMI was observed significantly related to annual rates of both violent and serious nonviolent misconduct. APD moderated the relationship between SMI and serious nonviolent charges but not the relationship between SMI and violent charges. Implications for inmate management and classification practices aimed at ameliorating misconduct are discussed.
Assessing Workplace Accommodation Requests Among Older Workers
Authors: Dong Shengli
Published: February 2017

As one ages, the chance of acquiring functional limitations increases dramatically. Thus, a remarkably high proportion of older workers will likely qualify for workplace accommodations. The current study aimed to gain an understanding of subgroups of older workers who were less likely to request and receive accommodations, associations of psychosocial factors (i.e., workplace supports, employees’ knowledge of the Americans With Disabilities Act [ADA] and accommodations, and whether an individual has a work goal) with requesting and receiving accommodations, and differences on these psychosocial factors within various demographic subgroups of older workers. Two hundred thirty-one individuals 50 years and older recruited from multiple national organizations and rehabilitation agencies participated in this study through an online survey. The study found that the psychosocial factors were positively associated with requesting and receiving accommodations. In addition, participants who were less likely to request and receive accommodations reported lower scores in the psychosocial factors. Practical implications for rehabilitation counselors and further research are discussed.
Body armor for stab and spike protection, Part 1: Scientific literature review
Authors: Nayak Rajkishore , Crouch Ian , Kanesalingam Sinnappoo , Ding Jie , Tan Ping , Lee Bin , Miao Menghe , Ganga Deepak , Wang Lijing
Published: February 2017

Since the invention of small arms ammunition, the human torso has required protection from hand-gun bullets, and today’s civil and military personnel are regularly clad in soft body armor systems to cope with these threats. However, increasingly, the threat spectrum has widened to include a plethora of both edged and pointed weapons. Over the past two decades in particular, this has required development of either specific soft armors to defeat that particular threat, or the development of multi-threat vests that can resist both hand-gun bullets and knife and spike attacks. In this review, we provide more details about the various material combinations that are used to defeat a knife or spike, since these armor materials are a lot different from the conventional aramid fabrics, and numerous, widely-different solutions are being pursued. The penetration mechanisms associated with the various forms of attack—stabbing and slashing—are discussed, as well as the use of new fibers, shear thickening fluids, and nano-materials in developing these body armor systems.
The Effects of Zero Tolerance Policies on Black Girls: Using Critical Race Feminism and Figured Worlds to Examine School Discipline
Authors: Hines-Datiri Dorothy , Carter Andrews Dorinda J.
Published: February 2017

Black girls are more likely to be suspended or expelled through exclusionary discipline than their female counterparts, but continue to be overlooked and understudied. This article presents a case for using critical race feminism and figured worlds as theoretical frameworks for examining the effects of zero tolerance policies on Black girls. We use these frameworks to explore how adults’ implementation of disciplinary policies not only affects the racial and gender identity development of Black girls, but perpetuates anti-Black discipline and represents behavioral responses to White femininity that may not align with Black girls’ femininity and identification with school.
The boomerang effect: innovation in the blogs of mainstream news sites, 2008–2012
Authors: Mitchelstein Maria Eugenia , Boczkowski Pablo J , Wagner Maria Celeste
Published: February 2017

This article examines the tension between the possibilities afforded by innovations in news production and the normalizing force of established routines through a quantitative and qualitative study of blogging in five leading news sites in the United States over a 5-year period (2008–2012). The quantitative examination shows that the prevalence of the native storytelling features of blogs in the online editions of these sites was higher in 2008 than in 2012, with this decrease being relatively gradual during this period. The qualitative analysis suggests that during 2008, a significant minority of blogs in established news organizations operated as spaces that presented news in a personal and opinionated tone. This novelty wore down gradually, and by 2012, the vast majority of blogs exhibited a preponderance of the straight-news storytelling format, and blogs were used mostly as a vehicle for disseminating breaking news. The discussion draws on these findings to reflect on the theoretical and methodological implications of the study for accounts of innovation in journalism and the news.