bluuebunny/crossref_metadata_2025 huggingface dataset:
Digital Footprints: Opportunities and Challenges for Online Social Research
Authors: Golder Scott A. , Macy Michael W.
Published: June 2014

Online interaction is now a regular part of daily life for a demographically diverse population of hundreds of millions of people worldwide. These interactions generate fine-grained time-stamped records of human behavior and social interaction at the level of individual events, yet are global in scale, allowing researchers to address fundamental questions about social identity, status, conflict, cooperation, collective action, and diffusion, both by using observational data and by conducting in vivo field experiments. This unprecedented opportunity comes with a number of methodological challenges, including generalizing observations to the offline world, protecting individual privacy, and solving the logistical challenges posed by “big data” and web-based experiments. We review current advances in online social research and critically assess the theoretical and methodological opportunities and limitations.

[J]ust as the invention of the telescope revolutionized the study of the heavens, so too by rendering the unmeasurable measurable, the technological revolution in mobile, Web, and Internet communications has the potential to revolutionize our understanding of ourselves and how we interact…. [T]hree hundred years after Alexander Pope argued that the proper study of mankind should lie not in the heavens but in ourselves, we have finally found our telescope. Let the revolution begin. —Duncan Watts (2011 , p. 266)
60 Years AfterBrown: Trends and Consequences of School Segregation
Authors: Reardon Sean F. , Owens Ann
Published: June 2014

Since the Supreme Court's 1954 Brown v. Board of Education decision, researchers and policy makers have paid close attention to trends in school segregation. Here we review the evidence regarding trends and consequences of both racial and economic school segregation since Brown. The evidence suggests that the most significant declines in black-white school segregation occurred in the late 1960s and early 1970s. There is disagreement about the direction of more recent trends in racial segregation, largely driven by how one defines and measures segregation. Depending on the definition used, segregation has either increased substantially or changed little, although there are important differences in the trends across regions, racial groups, and institutional levels. Limited evidence on school economic segregation makes documenting trends difficult, but students appear to be more segregated by income across schools and districts today than in 1990. We also discuss the role of desegregation litigation, demographic changes, and residential segregation in shaping trends in both racial and economic segregation. We develop a general conceptual model of how and why school segregation might affect students and review the relatively thin body of empirical evidence that explicitly assesses the consequences of school segregation. We conclude with a discussion of aspects of school segregation on which further research is needed.
Panethnicity
Authors: Okamoto Dina , Mora G. Cristina
Published: June 2014

Panethnicity has become a significant form of identification across the globe. Categories, such as Latino and Asian American, but also identities, such as Yoruba and European, have been embraced by a growing number of individuals and institutions. In this article, we focus on three main issues: panethnic identification, the conditions under which panethnic categories are constructed, and recent directions in the field. We argue that panethnicity is characterized by a unique tension inherent in maintaining subgroup distinctions while generating a broader sense of solidarity. This tension distinguishes panethnicity as a form of ethnic expression because it places questions of subgroup diversity and cultural legitimacy at the forefront. As such, the study of panethnicity encourages researchers to take intragroup dynamics seriously and explore how conflicts between subgroups are often negotiated or muted in ethnic mobilization and categorization processes. We call for more research that moves beyond the US case study design and makes panethnic processes explicit in international research on race, ethnicity, and nationalism.
The Political Mobilization of Firms and Industries
Authors: Walker Edward T. , Rea Christopher M.
Published: June 2014

Corporate political activity is both a long-standing preoccupation and an area of innovation for sociologists. We examine the limitations of investigating business unity without focusing directly on processes and outcomes and then review studies of five types of business political action that offer lenses into corporate power in the United States: engagement in electoral politics, direct corporate lobbying, collective action through associations and coalitions, business campaigns in civil society, and political aspects of corporate responsibility. Through these avenues, we highlight four shifts since the 1970s: (a) increasing fragmentation of capitalist interests, (b) closer attention to links between business lobbying and firms' social embeddedness, (c) a turn away from the assumption that money buys political victories, and (d) new avenues of covert corporate influence. This body of research has reinvigorated the classic elitist/pluralist debate while also raising novel questions about how business actors are adapting to (and generating changes within) their sociopolitical environments.
Mechanisms of Virus Membrane Fusion Proteins
Authors: Kielian Margaret
Published: June 2014

Enveloped viruses infect host cells by a membrane fusion reaction that takes place at the cell surface or in intracellular compartments following virus uptake. Fusion is mediated by the membrane interactions and conformational changes of specialized virus envelope proteins termed membrane fusion proteins. This article discusses the structures and refolding reactions of specific fusion proteins and the methods for their study and highlights outstanding questions in the field.
Stress disrupts intestinal mucus barrier in rats via mucin O-glycosylation shift: prevention by a probiotic treatment
Authors: Silva Stéphanie Da , Robbe-Masselot Catherine , Ait-Belgnaoui Afifa , Mancuso Alessandro , Mercade-Loubière Myriam , Salvador-Cartier Christel , Gillet Marion , Ferrier Laurent , Loubière Pascal , Dague Etienne , Theodorou Vassilia , Mercier-Bonin Muriel
Published: June 2014

Despite well-known intestinal epithelial barrier impairment and visceral hypersensitivity in irritable bowel syndrome (IBS) patients and IBS-like models, structural and physical changes in the mucus layer remain poorly understood. Using a water avoidance stress (WAS) model, we aimed at evaluating whether 1) WAS modified gut permeability, visceral sensitivity, mucin expression, biochemical structure of O-glycans, and related mucus physical properties, and 2) whether Lactobacillus farciminis treatment prevented these alterations. Wistar rats received orally L. farciminis or vehicle for 14 days; at day 10, they were submitted to either sham or 4-day WAS. Intestinal paracellular permeability and visceral sensitivity were measured in vivo. The number of goblet cells and Muc2 expression were evaluated by histology and immunohistochemistry, respectively. Mucosal adhesion of L. farciminis was determined ex situ. The mucin O-glycosylation profile was obtained by mass spectrometry. Surface imaging of intestinal mucus was performed at nanoscale by atomic force microscopy. WAS induced gut hyperpermeability and visceral hypersensitivity but did not modify either the number of intestinal goblet cells or Muc2 expression. In contrast, O-glycosylation of mucins was strongly affected, with the appearance of elongated polylactosaminic chain containing O-glycan structures, associated with flattening and loss of the mucus layer cohesive properties. L. farciminis bound to intestinal Muc2 and prevented WAS-induced functional alterations and changes in mucin O-glycosylation and mucus physical properties. WAS-induced functional changes were associated with mucus alterations resulting from a shift in O-glycosylation rather than from changes in mucin expression. L. farciminis treatment prevented these alterations, conferring epithelial and mucus barrier strengthening.
Roles for Nkx2–5 and Gata3 in the ontogeny of the murine smooth muscle gastric ligaments
Authors: Prakash Ajay , Udager Aaron M. , Saenz David A. , Gumucio Deborah L.
Published: June 2014

The gastric ligaments are superficial cord-like structures, located on the lesser curvature of the stomach, that extend from the pylorus to the esophagus. These ligaments have been documented in a wide variety of mammalian species, including humans, but their composition and ontogeny is unexplored. Here, we demonstrate that, during ontogeny, the gastric ligaments are first visible as extensions from a C-shaped domain of Gata3-expressing cells that surround the future pylorus; this domain will later give rise to the pyloric outer longitudinal muscle (OLM). The open ends of the C are located ventrally, and, beginning at embryonic day (E) 13.5, the ligaments grow anteriorly from these points. Whereas most other ligaments of the stomach are neurovascular in nature, the gastric ligaments are composed of smooth muscle cells that mature between E14.5 and E16.5. The gastric ligaments coexpress the transcription factors Gata3, Nkx2–5, and Sox9, and germline loss of Gata3 or conditional deletion of Nkx2–5 abrogates Sox9 expression and impairs gastric ligament smooth muscle development; similar phenotypes were previously seen in the OLM. In accord with this molecular contiguity between the OLM and gastric ligaments, three-dimensional image reconstruction highlights physical contiguity between these smooth muscle structures, suggesting that they may work together as a unit to control flexure of the pyloric region, a function similar to the ligament of Treitz at the duodenojejunal junction. These findings may have implications for our understanding of normal pyloric sphincter function, as well as the common human congenital pathology idiopathic hypertrophic pyloric stenosis.
Long-term obesity promotes alterations in diastolic function induced by reduction of phospholamban phosphorylation at serine-16 without affecting calcium handling
Authors: Lima-Leopoldo Ana Paula , Leopoldo André S. , da Silva Danielle C. T. , do Nascimento André F. , de Campos Dijon H. S. , Luvizotto Renata A. M. , de Deus Adriana F. , Freire Paula P. , Medeiros Alessandra , Okoshi Katashi , Cicogna Antonio C.
Published: June 2014

Few studies have evaluated the relationship between the duration of obesity, cardiac function, and the proteins involved in myocardial calcium (Ca2+) handling. We hypothesized that long-term obesity promotes cardiac dysfunction due to a reduction of expression and/or phosphorylation of myocardial Ca2+-handling proteins. Thirty-day-old male Wistar rats were distributed into two groups ( n = 10 each): control (C; standard diet) and obese (Ob; high-fat diet) for 30 wk. Morphological and histological analyses were assessed. Left ventricular cardiac function was assessed in vivo by echocardiographic evaluation and in vitro by papillary muscle. Cardiac protein expression of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a), calsequestrin, L-type Ca2+channel, and phospholamban (PLB), as well as PLB serine-16 phosphorylation (pPLB Ser16) and PLB threonine-17 phosphorylation (pPLB Thr17) were determined by Western blot. The adiposity index was higher (82%) in Ob rats than in C rats. Obesity promoted cardiac hypertrophy without alterations in interstitial collagen levels. Ob rats had increased endocardial and midwall fractional shortening, posterior wall shortening velocity, and A-wave compared with C rats. Cardiac index, early-to-late diastolic mitral inflow ratio, and isovolumetric relaxation time were lower in Ob than in C. The Ob muscles developed similar baseline data and myocardial responsiveness to increased extracellular Ca2+. Obesity caused a reduction in cardiac pPLB Ser16and the pPLB Ser16/PLB ratio in Ob rats. Long-term obesity promotes alterations in diastolic function, most likely due to the reduction of pPLB Ser16, but does not impair the myocardial Ca2+entry and recapture to SR.
A novel ultrasound technique to measure genioglossus movement in vivo
Authors: Kwan Benjamin C. H. , Butler Jane E. , Hudson Anna L. , McKenzie David K. , Bilston Lynne E. , Gandevia Simon C.
Published: June 2014

Upper airway muscles are important in maintaining airway patency. Visualization of their dynamic motion should allow measurement, comparison, and further understanding of their roles in healthy subjects and those with upper airway disorders. Currently, there are few clinically feasible real-time imaging methods. Methods such as tagged magnetic resonance imaging have documented movement of genioglossus (GG), the largest upper airway dilator. Inspiratory movement was largest in the posterior region of GG. This study aimed to develop a novel ultrasound (US) method to measure GG movement in real time. We tested 20 healthy, awake subjects (21–38 yr) breathing quietly in the supine posture with the head in a neutral position. US images were collected using a transducer positioned submentally. Image correlation analysis measured regional displacement of GG within a grid of points in the midsagittal plane throughout the respiratory cycle. Typically, motion began before inspiratory flow in an anteroinferior direction and peaked in midinspiration. Average peak displacements of the anterior, posterior, superior, and inferior grid points were 0.44 ± 0.23 (mean ± SD), 0.57 ± 0.35, 0.38 ± 0.20, and 0.62 ± 0.41 mm, respectively. Largest displacements occurred in the most inferoposterior part (0.70 ± 0.48 mm). This method had good intrarater repeatability within the same testing session, as well as across sessions. We have devised a simple noninvasive US method, which should be a useful tool to assess GG movement in normal subjects and those with sleep-disordered breathing.
A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets
Authors: Taguchi Ayumu , Taylor Allen D. , Rodriguez Jaime , Çeliktaş Müge , Liu Hui , Ma Xiaotu , Zhang Qing , Wong Chee-Hong , Chin Alice , Girard Luc , Behrens Carmen , Lam Wan L. , Lam Stephen , Minna John D. , Wistuba Ignacio I. , Gazdar Adi F. , Hanash Samir M.
Published: June 2014

Cancer/testis (CT) antigens are potential immunotherapeutic targets in cancer. However, the expression of particular antigens is limited to a subset of tumors of a given type. Thus, there is a need to identify antigens with complementary expression patterns for effective therapeutic intervention. In this study, we searched for genes that were distinctly expressed at a higher level in lung tumor tissue and the testes compared with other nontumor tissues and identified members of the VCX/Y gene family as novel CT antigens. VCX3A, a member of the VCX/Y gene family, was expressed at the protein level in approximately 20% of lung adenocarcinomas and 35% of squamous cell carcinomas, but not expressed in normal lung tissues. Among CT antigens with concordant mRNA and protein expression levels, four CT antigens, XAGE1, VCX, IL13RA2, and SYCE1, were expressed, alone or in combination, in about 80% of lung adenocarcinoma tumors. The CT antigen VCX/Y gene family broadens the spectrum of CT antigens expressed in lung adenocarcinomas for clinical applications. Cancer Res; 74(17); 4694–705. ©2014 AACR.
Definition of PKC-α, CDK6, and MET as Therapeutic Targets in Triple-Negative Breast Cancer
Authors: Hsu Yi-Hsin , Yao Jun , Chan Li-Chuan , Wu Ting-Jung , Hsu Jennifer L. , Fang Yueh-Fu , Wei Yongkun , Wu Yun , Huang Wen-Chien , Liu Chien-Liang , Chang Yuan-Ching , Wang Ming-Yang , Li Chia-Wei , Shen Jia , Chen Mei-Kuang , Sahin Aysegul A. , Sood Anil , Mills Gordon B. , Yu Dihua , Hortobagyi Gabriel N. , Hung Mien-Chie
Published: June 2014

Triple-negative breast cancer (TNBC) is a highly heterogeneous and recurrent subtype of breast cancer that lacks an effective targeted therapy. To identify candidate therapeutic targets, we profiled global gene expression in TNBC and breast tumor-initiating cells with a patient survival dataset. Eight TNBC-related kinases were found to be overexpressed in TNBC cells with stem-like properties. Among them, expression of PKC-α, MET, and CDK6 correlated with poorer survival outcomes. In cases coexpressing two of these three kinases, survival rates were lower than in cases where only one of these kinases was expressed. In functional tests, two-drug combinations targeting these three kinases inhibited TNBC cell proliferation and tumorigenic potential in a cooperative manner. A combination of PKC-α-MET inhibitors also attenuated tumor growth in a cooperative manner in vivo. Our findings define three kinases critical for TNBC growth and offer a preclinical rationale for their candidacy as effective therapeutic targets in treating TNBC. Cancer Res; 74(17); 4822–35. ©2014 AACR.
Live-Cell Imaging of Invasion and Intravasation in an Artificial Microvessel Platform
Authors: Wong Andrew D. , Searson Peter C.
Published: June 2014

Methods to visualize metastasis exist, but additional tools to better define the biologic and physical processes underlying invasion and intravasation are still needed. One difficulty in studying metastasis stems from the complexity of the interface between the tumor microenvironment and the vascular system. Here, we report the development of an investigational platform that positions tumor cells next to an artificial vessel embedded in an extracellular matrix. On this platform, we used live-cell fluorescence microscopy to analyze the complex interplay between metastatic cancer cells and a functional artificial microvessel that was lined with endothelial cells. The platform recapitulated known interactions, and its use demonstrated the capabilities for a systematic study of novel physical and biologic parameters involved in invasion and intravasation. In summary, our work offers an important new tool to advance knowledge about metastasis and candidate antimetastatic therapies. Cancer Res; 74(17); 4937–45. ©2014 AACR.
The Future of Cancer Therapy: Selecting Patients Likely to Respond to PD1/L1 Blockade
Authors: Ribas Antoni , Tumeh Paul C.
Published: June 2014

It is conceivable that, in the near future, an assay that defines the likelihood of a patient with advanced cancer to respond to immunotherapy based on PD1/L1 blockade will be the initial decision point to select the treatment of patients with any cancer type. Clin Cancer Res; 20(19); 4982–4. ©2014 AACR.
Antiphospholipid Antibodies and Cerebellar Ataxia: A Clinical Analysis and Literature Review
Authors: Chen Wei-Hsi , Chen Chang-Hung , Chui Chi , Lui Chun-Chung , Chen Chung-Jen , Yin Hsin-Ling
Published: June 2014

Background: Although it has been established that antiphospholipid antibodies (APAbs) bind to and modulate the signaling of cerebellar neurons in vitro, the clinical correlation between increased APAbs and cerebellar ataxia has rarely been investigated. Methods: We reviewed 10 patients presenting with cerebellar ataxia with increased blood APAbs from our database along with 3 APAb-associated cerebellar ataxia patients in the literature. Results: Of these 10 patients, 4 exhibited a subacute onset of progressive ataxia, and there were no significant structural changes in their brains that appeared to be responsible for the symptoms. Another 6 showed a chronic course of ataxia, and shared similar morphological changes that included symmetrical lesions in bilateral hemispheres, periventricular lucency and central and temporal atrophy of varying severity; the cerebellum was spared. The predominant APAbs for subacute and chronic ataxia were the anti-beta2-glycoprotein I antibody and anticardiolipin antibody, respectively. Cancer was found in 1 patient with subacute ataxia and in 4 with chronic ataxia. The removal of the cancer, the plasmapheresis and immunosuppressive therapy successfully abolished the ataxia and increased APAb levels in all 5 patients. Conclusions: The relation between APAbs and nonvascular neurological disorders, such as cerebellar ataxia, should be further studied. APAbs may mediate neurological deficits via different mechanisms such as structural damage or functional neurotoxicity. Clinically, the examination of blood APAb levels is recommended for patients with cerebellar ataxia without a determined cause, and the further survey of systemic cancers in the case of APAb positivity is also recommended. Finally, plasmapheresis is a reasonable and effective treatment for APAb-associated cerebellar ataxia.
Effects of Naproxen on Immune Responses in a Colchicine-Induced Rat Model of Alzheimer's Disease
Authors: Sil Susmita , Goswami Ananda Raj , Dutta Goutam , Ghosh Tusharkanti
Published: June 2014

Background: The components of the immune system have been indicated to be linked with the neurotoxicity in Alzheimer's disease (AD). The participation of the immune system in the neurodegeneration in a rat model of colchicine-induced AD has not been explored. Methods: In the present study, hippocampal neurodegeneration along with reactive oxygen species (ROS), nitrite and TNF-α in the hippocampus and some systemic immune responses were measured after 15 and 21 days of intracerebroventricular colchicine injection in rats and again after oral administration of different doses of the anti-inflammatory drug naproxen in AD rats. Results: Chromatolysis and amyloid plaques were found along with higher ROS, nitrite and TNF-α levels in the hippocampus of colchicine-induced AD rats, and these changes were prevented by naproxen in a dose-dependent manner. Alterations in immunological parameters [increased phagocytic activity of white blood cells and splenic polymorphonuclear cells (PMN), increased cytotoxicity and decreased leucocyte adhesive inhibition index (LAI) of splenic mononuclear cells (MNC)] were also observed in colchicine-injected rats, which showed a dose-dependent recovery after oral administration of naproxen in AD rats. The number of plaques, chromatolysis of Nissl granules, TNF-α, nitrite and ROS levels in the hippocampus, phagocytic activity of splenic PMN and LAI of splenic MNC in AD rats showed greater changes in the 21- than in the 15-day study, and the recovery of these parameters after administration of naproxen differed between the two study durations. Conclusion: The present study shows that colchicine-induced neurodegeneration is time dependent and mediated by cyclooxygenase-induced neuroinflammation, which is reflected in the systemic immunological responses.
Exploring Alzheimer Molecular Pathology in Down's Syndrome Cerebrospinal Fluid
Authors: Portelius Erik , Soininen Hilkka , Andreasson Ulf , Zetterberg Henrik , Persson Rita , Karlsson Gösta , Blennow Kaj , Herukka Sanna-Kaisa , Mattsson Niklas
Published: June 2014

Background: Individuals with Down's syndrome (DS) develop early Alzheimer's disease (AD) with β-amyloid (Aβ) plaque pathology. The extra amyloid precursor protein (APP) gene copy in DS is believed to result in a 50% increase in Aβ production, but it is unclear how this relates to the development of other AD hallmarks, including axonal degeneration and microglia cell activation, and to other neurological problems in DS, including disturbed sleep regulation. Objective: To evaluate if cerebrospinal fluid (CSF) biomarkers for cerebral amyloidosis, axonal degeneration, microglial activation and sleep regulation were altered in young and old patients with DS, and if these biomarkers were related to altered Aβ and APP metabolism, reflected by CSF levels of different Aβ and APP peptides. Methods: CSF from DS patients (n = 12) and healthy controls (n = 20) were analyzed for Aβ peptides (Aβ1-42, AβX-38/40/42), secreted APP species (sAPPα/β), biomarkers for AD-like axonal degeneration [total tau (T-tau), phosphorylated tau], microglial activation (YKL-40, CC chemokine ligand 2) and orexin-A, which is a peptide involved in sleep regulation. We compared biomarker levels between groups and tested for relations between biomarkers, disease stage and age. Results: Several of the markers were specifically increased in DS, including AβX-40, sAPPα and sAPPβ. Οrexin-A was significantly decreased in DS and correlated with Aβ and sAPP. Orexin-A decreased with age in DS, while T-tau and YKL-40 increased with age. Conclusion: Down's patients have increased APP and Aβ production and increased microglial activation with age. The orexin-A metabolism is disturbed in DS and may be linked to APP and Aβ production. Biomarker studies of DS may contribute to our understanding of the amyloidogenic and neurodegenerative process in AD.
MRI Predicts Remission at 1 Year in First-Episode Schizophrenia in Females with Larger Striato-Thalamic Volumes
Authors: Fung Germaine , Cheung Charlton , Chen Eric , Lam Carmen , Chiu Cindy , Law Chi-wing , Leung Mei-Kei , Deng Michelle , Cheung Vinci , Qi Li , Nailin Yao , Tai Kin-shing , Yip Lawrance , Suckling John , Sham Pak , McAlonan Gráinne , Chua Siew-eng
Published: June 2014

Background/Aims: The Remission in Schizophrenia Working Group has defined remission as ‘a low-mild symptom intensity level, maintained for a minimum of 6 months, where such symptoms do not affect an individual's behaviour' [Andreasen et al.: Am J Psychiatry 2005;162:441-449]. Since brain morphology relates to symptomatology, treatment and illness progression, MRI may assist in predicting remission. Methods: Thirty-nine patients newly diagnosed with DSM-IV schizophrenia underwent MRI brain scan prior to antipsychotic exposure. The Global Assessment of Functioning (GAF) score was entered into a voxel-based analysis to evaluate its relationship with cerebral grey matter volume from the baseline MRI. We entered age, total intracranial volume and intake GAF score as co-variates. Males and females were analysed separately because gender is a potent determinant of outcome. Results: Males had lower GAF scores than females, both at intake and at 1 year. Males comprised only 40% (12 out of 39) of the early remission group. For females only, early remission was strongly and positively correlated with bilateral lentiform and striatal volumes. For males, there was no such relationship. Conclusion: Larger striato-thalamic volume correlated with early remission in females only. These baseline MRI findings were unlikely to be confounded by antipsychotic treatment and chronicity. These brain morphological markers show gender dimorphism and may assist in the prediction of early remission in newly diagnosed schizophrenia.
Niacinamide - Mechanisms of Action and Its Topical Use in Dermatology
Authors: Wohlrab Johannes , Kreft Daniela
Published: June 2014

Niacinamide, an amide of vitamin B3 (niacin), is a hydrophilic endogenous substance. Its effects after epicutaneous application have long been described in the literature. Given a sufficient bioavailability, niacinamide has antipruritic, antimicrobial, vasoactive, photo-protective, sebostatic and lightening effects depending on its concentration. Within a complex metabolic system niacinamide controls the NFκB-mediated transcription of signalling molecules by inhibiting the nuclear poly (ADP-ribose) polymerase-1 (PARP-1). Niacinamide is a well-tolerated and safe substance often used in cosmetics. Clinical data for its therapeutic use in various dermatoses can increasingly be found in the literature. Although the existing data are not sufficient for a scientifically founded evaluation, it can be stated that the use of niacinamide in galenic preparations for epicutaneous application offers most interesting prospects.
Playing a Part in Research? University Students' Attitudes to Direct-To-Consumer Genomics
Authors: Vayena Effy , Ineichen Christian , Stoupka Elia , Hafen Ernst
Published: June 2014

Aims: This study examined the attitudes of 1,146 Swiss University students to direct-to-consumer (DTC) genomic testing and to genomic research participation. Methods: Data were collected through a self-completion online questionnaire by students from 2 higher education institutions in Zurich, Switzerland. The survey aimed to capture motivation for undergoing or refraining from genomic testing, reactions to mock genetic risk results, and views about contributing data to scientific research. Descriptive and inferential statistics were used for the analysis. Results: A total of 1.5% of the students had undergone testing. Most respondents were studying natural sciences and were interested in undergoing DTC genomic testing. The main motive was to contribute their data to scientific research, followed closely by their interest to find out disease risks and personal traits. Overall, 41% of the respondents were not interested in DTC tests. The primary reasons were concerns about receiving potentially worrying results. There was a significant correlation between studying natural sciences, as opposed to the humanities, and interest in undergoing testing. Male respondents were more interested in testing compared to females. There was a strong interest in genetic research participation and notably limited privacy concerns. Conclusion: Although 59% of the respondents were interested in DTC genomic testing, they were not likely to be affected by them or act upon them. This raises questions about concerns relating to potential risks of DTC genomics users and users' understanding of genetic information including their awareness of privacy risks. Furthermore, the strong interest in genetic research participation signals an underexplored personal utility of genomic testing which needs to be both better understood and better harnessed.
Discordance between Self-Report and Genetic Confirmation of Sickle Cell Disease Status in African-American Adults
Authors: Bean Christopher J. , Hooper W. Craig , Ellingsen Dorothy , DeBaun Michael R. , Sonderman Jennifer , Blot William J.
Published: June 2014

Background: Sickle cell disease (SCD) is an autosomal recessive genetic disorder, with persons heterozygous for the mutation said to have the sickle cell trait (SCT). Serious adverse effects are mainly limited to those with SCD, but the distinction between disease and trait is not always clear to the general population. We sought to determine the accuracy of self-reported SCD when compared to genetic confirmation. Methods: From stratified random samples of Southern Community Cohort Study participants, we sequenced the β- globin gene in 51 individuals reporting SCD and 75 individuals reporting no SCD. Results: The median age of the group selected was 53 years (range 40-69) with 29% male. Only 5.9% of the 51 individuals reporting SCD were confirmed by sequencing, with the remaining 62.7% having SCT, 5.9% having hemoglobin C trait, and 25.5% having neither SCD nor trait. Sequencing results of the 75 individuals reporting no SCD by contrast were 100% concordant with self-report. Conclusions: Misreporting of SCD is common in an older adult population, with most persons reporting SCD in this study being carriers of the trait and a sizeable minority completely unaffected. The results from this pilot survey support the need for increased efforts to raise community awareness and knowledge of SCD.
Choroidal Thickness of the Papillomacular Region in Young Healthy Individuals
Authors: Rossou Ellen , Abegão Pinto Luis , Vandewalle Evelien , Cassiman Catherine , Willekens Koen , Stalmans Ingeborg
Published: June 2014

Purpose: To characterize the choroidal thickness of the papillomacular region in young healthy individuals using spectral-domain optical coherence tomography (SD-OCT). Methods: Papillary and macular SD-OCT scans were obtained using an enhanced depth imaging mode. Digital retinography was used to assess any overlapping areas and to determine the papillomacular region. Spearman's correlations were used to explore the relationship between the different regional choroidal thicknesses. Results: Sixty-three volunteers aged 21.6 ± 1.1 years were included. There was a significant asymmetry in choroidal thickness throughout the 10-mm length model (p < 0.001). While the choroid was shown to thicken as the distance from the optic disc increased (p < 0.001), each of the 500-µm blocks of the papillomacular region were significantly thinner than their nasal counterparts (p < 0.02 in all pairwise comparisons). Conclusion: In young healthy individuals, the choroid under the papillomacular region appears to be thinner than in other areas. These differences could relate to specificities of the retina overlying this region.
Comparing the Effect of Prazosin and Hydroxyzine on Sleep Quality in Patients Suffering from Posttraumatic Stress Disorder
Authors: Ahmadpanah Mohammad , Sabzeiee Parasto , Hosseini Seyed Mohammad , Torabian Saadat , Haghighi Mohammad , Jahangard Leila , Bajoghli Hafez , Holsboer-Trachsler Edith , Brand Serge
Published: June 2014

Objectives: In light of the high prevalence of sleep disorders in patients suffering from posttraumatic stress disorder (PTSD), this study sought to compare the effect of prazosin and hydroxyzine on sleep quality in this patient group. Methods: A total of 100 patients suffering from PTSD were assessed (mean age = 35.51 years, SD = 6.41; 28% females). Next, they were randomly assigned to one of three treatment groups: prazosin (33 patients), hydroxyzine (34 patients) or placebo (33 patients). The trial lasted for 8 weeks. The patients' sleep quality was assessed using the Pittsburgh Sleep Quality Index. Items taken from the Mini International Neuropsychiatric Interview were used to operationalize PTSD. Results: Compared to controls, patients treated with prazosin and hydroxyzine reported improved sleep and less nightmares. Improvement was greatest in patients treated with prazosin compared to hydroxyzine and placebo. Improvement in sleep was associated with an amelioration of their PTSD symptoms. Conclusion: Both prazosin and hydroxyzine can be used to treat psychopharmacological sleep disorders and nightmares in patients suffering from PTSD, also leading to reductions in PTSD symptoms.
Cerebrospinal Venous Outflow in Multiple Sclerosis Patients versus Fatigue and/or Depression
Authors: Hagens Marloes H.J. , Hoogervorst Erwin L.J. , Frequin Stephan T.F.M. , Tromp Selma C.
Published: June 2014

Background: Endovascular treatment of impaired cerebrospinal venous outflow has been suggested to improve the overall quality of life in multiple sclerosis (MS) patients. Fatigue and depression are key factors in measuring the quality of life in MS patients. Objective: In the present study, we investigated the correlation between anomalous venous outflow and the seriousness of fatigue and depression in MS patients and healthy controls. Methods: Five cerebrospinal venous outflow parameters were measured in 20 MS patients and age- and sex-matched controls using extra- and transcranial Colour Doppler sonography. All patients and volunteers filled out the Fatigue Severity Scale (FSS) and Hospital Anxiety Depression Subscale (HADS). Results: Nine abnormal parameters were found in 8 MS patients, whereas five abnormal parameters were found in 3 healthy controls (no significant difference). Only 1 MS patient met the criteria for chronic cerebrospinal venous insufficiency compared to 2 healthy controls. No significant differences were found in the FSS and HADS scores between patients with and without abnormal cerebrospinal venous outflow parameters. Conclusions: We found no significantly impaired cerebrospinal venous outflow in patients with MS versus sex- and age-matched controls. Furthermore, we did not find any correlation between anxiety or depression and impaired venous outflow in MS patients.
The X Chromosome Is Necessary for Somatic Development in the Dioecious Silene latifolia: Cytogenetic and Molecular Evidence and Sequencing of a Haploid Genome
Authors: Soukupova Magda , Nevrtalova Eva , Čížková Jana , Vogel Ivan , Cegan Radim , Hobza Roman , Vyskot Boris
Published: June 2014

Silene latifolia (or white campion) possesses a well-established sex determination system with a dominant Y chromosome in males (the mammalian type). The heteromorphic sex chromosomes X and Y in S. latifolia largely stopped recombination; thus, we can expect a gradual genetic degeneration of the Y chromosome. It is well proven that neither diploid nor polyploid S. latifolia sporophytes can survive without at least one X, so the only life stage possessing the Y as the sole sex chromosome is the male gametophyte (pollen tube), while the female gametophyte seems to be X-dependent. Previous studies on anther-derived plants of this species showed that the obtained plants (largely haploid or dihaploid) were phenotypically and cytologically female. In this paper, we provide molecular evidence for the inviability of plants lacking the X chromosome. Using sex-specific PCR primers, we show that all plantlets and plants derived from anther cultures are female. In studying anther-derived diploid females by sequencing of X-linked markers, we demonstrate that these plants are really homozygous dihaploids. A haploid regenerant plant was sequenced (8× genome coverage) using Illumina technology. Genome data are disposable in the EMBL database as a standard for full genome and X chromosome assembly in this model species. Homozygous dihaploids were back-crossed with males to yield a progeny useful for the study of the evolution of the Y chromosome.
Reliability of Nine Programs of Topological Predictions and Their Application to Integral Membrane Channel and Carrier Proteins
Authors: Reddy Abhinay , Cho Jaehoon , Ling Sam , Reddy Vamsee , Shlykov Maksim , Saier Milton H.
Published: June 2014

We evaluated topological predictions for nine different programs, HMMTOP, TMHMM, SVMTOP, DAS, SOSUI, TOPCONS, PHOBIUS, MEMSAT-SVM (hereinafter referred to as MEMSAT), and SPOCTOPUS. These programs were first evaluated using four large topologically well-defined families of secondary transporters, and the three best programs were further evaluated using topologically more diverse families of channels and carriers. In the initial studies, the order of accuracy was: SPOCTOPUS > MEMSAT > HMMTOP > TOPCONS > PHOBIUS > TMHMM > SVMTOP > DAS > SOSUI. Some families, such as the Sugar Porter Family (2.A.1.1) of the Major Facilitator Superfamily (MFS; TC #2.A.1) and the Amino Acid/Polyamine/Organocation (APC) Family (TC #2.A.3), were correctly predicted with high accuracy while others, such as the Mitochondrial Carrier (MC) (TC #2.A.29) and the K+ transporter (Trk) families (TC #2.A.38), were predicted with much lower accuracy. For small, topologically homogeneous families, SPOCTOPUS and MEMSAT were generally most reliable, while with large, more diverse superfamilies, HMMTOP often proved to have the greatest prediction accuracy. We next developed a novel program, TM-STATS, that tabulates HMMTOP, SPOCTOPUS or MEMSAT-based topological predictions for any subdivision (class, subclass, superfamily, family, subfamily, or any combination of these) of the Transporter Classification Database (TCDB; www.tcdb.org) and examined the following subclasses: α-type channel proteins (TC subclasses 1.A and 1.E), secreted pore-forming toxins (TC subclass 1.C) and secondary carriers (subclass 2.A). Histograms were generated for each of these subclasses, and the results were analyzed according to subclass, family and protein. The results provide an update of topological predictions for integral membrane transport proteins as well as guides for the development of more reliable topological prediction programs, taking family-specific characteristics into account.
CSL112 Enhances Biomarkers of Reverse Cholesterol Transport After Single and Multiple Infusions in Healthy Subjects
Authors: Gille Andreas , Easton Rachael , D’Andrea Denise , Wright Samuel D. , Shear Charles L.
Published: June 2014

Objective—

The ability of apolipoprotein A-I (apoA-I) to transport cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. To gauge the potential of infused apoA-I to transport cholesterol, we quantified cholesterol transport markers in human subjects infused with a novel formulation of apoA-I (CSL112).

Approach and Results—

CSL112 was infused into human subjects in single (57 subjects) and multiple (36 subjects) ascending dose trials. Pharmacokinetic and biomarker assessments were conducted before and after infusions. CSL112 caused an immediate, up to 3-fold elevation of apoA-I and subsequent movement of tissue cholesterol into plasma. Cholesterol appeared first as unesterified cholesterol in the high-density lipoprotein (HDL) fraction and was promptly esterified by lecithin cholesterol acyltransferase. HDL cholesterol increased up to 81±16.5%. Underlying this movement of cholesterol was an immediate and strong rise in the ability of plasma to promote cholesterol efflux from cells ex vivo. CSL112 had its greatest impact on the fraction of efflux mediated by ATP-binding cassette transporter A1 (ABCA1), a cholesterol transporter induced in cholesterol-loaded tissues such as plaque. ABCA1-dependent efflux capacity increased ≤630±421% and total efflux capacity by ≤192±40%. In keeping with this finding, we observed a profound rise in very small HDL, also known as preβ1-HDL, the preferred substrate for ABCA1. Very small HDL increased ≤3596±941%. Elevations in apoA-I, cholesterol efflux, and very small HDL were dose-proportional over a wide range. No significant changes in atherogenic lipids were observed at any dose.

Conclusions—

Infusion of CSL112 elevates the ability of plasma to withdraw cholesterol from cells. Preferential elevation of ABCA1-dependent efflux may target atherosclerotic plaque for cholesterol removal, making CSL112 a promising candidate therapy for acute coronary syndrome.
Regulation of High-Density Lipoprotein on Hematopoietic Stem/Progenitor Cells in Atherosclerosis Requires Scavenger Receptor Type BI Expression
Authors: Gao Mingming , Zhao Dong , Schouteden Sarah , Sorci-Thomas Mary G. , Van Veldhoven Paul P. , Eggermont Kristel , Liu George , Verfaillie Catherine M. , Feng Yingmei
Published: June 2014

Objective—

Recently, we demonstrated that scavenger receptor type BI (SR-BI), a high-density lipoprotein (HDL) receptor, was expressed on murine hematopoietic stem/progenitor cells (HSPC) and infusion of reconstituted HDL and purified human apolipoprotein A-I (apoA-I) suppressed HSPC proliferation. We hypothesized that SR-B1 expression is required for the observed antiproliferative effects of HDL on HSPC.

Approach and Results—

SR-BI–deficient (SR-BI
−/−
) mice and wild-type controls were fed on chow or high-fat diet (HFD) for 8 to 10 weeks. Under chow diet, a significant increase in Lin
−
Sca1
+
cKit
+
cells (LSK cells, so-called HSPC) was found in the bone marrow of SR-BI
−/−
mice when compared with wild-type mice. HFD induced a further expansion of CD150
+
CD48
-
LSK cells (HSC), HSPC, and granulocyte monocyte progenitors in SR-BI
−/−
mice. Injection of reactive oxygen species inhibitor N-acetylcysteine attenuated HFD-induced HSPC expansion, leukocytosis, and atherosclerosis in SR-BI
−/−
mice. ApoA-I infusion inhibited HSPC cell proliferation, Akt phosphorylation and reactive oxygen species production in HSPC and plaque progression in low-density lipoprotein receptor knockout (LDLr
−/−
) apoA-I
−/−
mice on HFD but had no effect on SR-BI
−/−
mice on HFD. Transplantation of SR-BI
−/−
bone marrow cells into irradiated LDLr
−/−
recipients resulted in enhanced white blood cells reconstitution, inflammatory cell production, and plaque development. In patients with coronary heart disease, HDL levels were negatively correlated with white blood cells count and HSPC frequency in the peripheral blood. By flow cytometry, SR-BI expression was detected on human HSPC.

Conclusions—

SR-BI plays a critical role in the HDL-mediated regulation HSPC proliferation and differentiation, which is associated with atherosclerosis progression.
Interleukin-13 Deficiency Aggravates Healing and Remodeling in Male Mice After Experimental Myocardial Infarction
Authors: Hofmann Ulrich , Knorr Susanne , Vogel Benjamin , Weirather Johannes , Frey Anna , Ertl Georg , Frantz Stefan
Published: June 2014

Background—

Activation of innate immunity, especially infiltration of monocytes, is critical for proper wound healing and scar formation after myocardial infarction (MI). Therefore, we tested the hypothesis that interleukin-13 (IL-13), which influences the differentiation of monocytes/macrophages and has profibrotic properties, modulates wound healing and remodeling after MI.

Methods and Results—

MI was induced by permanent ligation of the left coronary artery in both male and female wild-type (WT)/IL-13
−/−
mice. Real-time polymerase chain reaction demonstrated that expression of IL-13 was induced in left and right ventricular myocardium of WT mice within days in response to MI. Fifty-six–day survival was significantly impaired (65% in WT versus 34% in IL-13
−/−
) in male but not female IL-13
−/−
(55% in WT versus 54% in IL-13
−/−
) mice. Serial echocardiography showed significantly increased left ventricular dilation in male IL-13
−/−
compared with WT mice starting from day 1 after MI, despite comparable infarct size. Fluorescence-activated cell sorter analysis revealed less leukocyte infiltration in male IL-13
−/−
mice on day 3. Real-time polymerase chain reaction analysis demonstrated reduced expression of marker genes of alternative activation in monocytes sorted from the infarct zone of male IL-13
−/−
in comparison with WT mice on day 3 after MI.

Conclusions—

Genetic deficiency of IL-13 worsens outcome after MI in male mice. Our data indicate that IL-13 regulates leukocyte recruitment and induces M2-like monocyte/macrophage differentiation, which modifies wound healing within the infarct zone.
30-Year Mortality After Venous Thromboembolism
Authors: Søgaard Kirstine Kobberøe , Schmidt Morten , Pedersen Lars , Horváth–Puhó Erzsébet , Sørensen Henrik Toft
Published: June 2014

Background—

Studies on long-term mortality after venous thromboembolism (VTE) are sparse.

Methods and Results—

Using Danish medical databases, we conducted a 30-year nationwide population-based cohort study of 128 223 patients with first-time VTE (1980–2011) and a comparison cohort of 640 760 people from the general population (without VTE) randomly matched by sex, year of birth, and calendar period. The mortality risks for patients with deep venous thrombosis (DVT) and pulmonary embolism (PE) were markedly higher than for the comparison cohort during the first year, especially within the first 30 days (3.0% and 31% versus 0.4%). Using Cox regression, we assessed mortality rate ratios (MRRs) with 95% confidence intervals (CIs). The overall 30-year MRR was 1.55 (95% CI, 1.53–1.57) for DVT and 2.77 (95% CI, 2.74–2.81) for PE. The 30-day MRR was 5.38 (95% CI, 5.00–5.80) for DVT and 80.87 (95% CI, 76.02–86.02) for PE. Over time, the 30-day MRR was consistently 5- to 6-fold increased for DVT, whereas it improved for PE from 138 (95% CI, 125–153) in 1980 to 1989 to 36.08 (95% CI, 32.65–39.87) in 2000 to 2011. The 1- to 10-year and 11- to 30-year MRRs remained 25% to 40% increased after both DVT and PE but were 3- to 5-fold increased after DVT and 6- to 11-fold increased after PE when VTE was considered the immediate cause of death.

Conclusions—

Patients with VTE are at increased risk of dying, especially within the first year after diagnosis, but also during the entire 30 years of follow-up, with VTE as an important cause of death. Although 30-day mortality after DVT remained fairly constant over the last 3 decades, it improved markedly for PE.