bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 482: Modeling PKP2 Mutation Associated Arrhythmogenic Cardiomyopathy With CRISPR-edited iPSC-derived Cardiomyocytes in Engineered Cardiac Tissues
Authors: Zhang Kehan , Tomp Samuel , Ewoldt Jourdan K , Toepfer Christopher N , Chopra Anant , Seidman Christine E , Seidman Jonathan G , Chen Christopher S 
Published: October 2019

Arrhythmogenic cardiomyopathy (ACM), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a leading cause of sudden death among young adults. Over half of ACM cases are associated with inherited desmosome gene mutations, most commonly in the gene PKP2 which encodes plakophilin-2. One of the obstacles to better understanding ACM pathogenesis is the lack of appropriate models which encompass the early stages of disease development; this imposes significant constraints on the advancement of clinical therapies. The recent advent of human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) has enabled the development of models for studying human cardiac cell biology and pathology. In this work, we combine hiPSC-CMs, CRISPR/Cas9 genome editing, and engineered cardiac tissue platforms to develop human in vitro systems for investigating the molecular mechanisms of ACM pathogenesis.
Isogenic control and mutant cell lines of hiPSC-CMs harboring ACM-associated PKP2 mutations were generated using CRISPR/Cas9 technology. Specifically, the PKP2tv cell line has an early truncation in plakophilin-2 that mimics PKP2 c.235C>T found in multiple family lineages. The effects of the PKP2tv mutation on cardiac tissue contractility were characterized using a 3D cardiac micro-tissue (CMT) platform. CMTs composed of PKP2tv cardiomyocytes were shown to have significantly decreased contractile forces compared to the control, which recapitulates the reduced ventricular systolic function seen in ACM patients. This result demonstrated the feasibility of using the hiPSC-derived tissue-engineering model to recapitulate ACM disease phenotype and allow for future investigation into the disease mechanisms.
Abstract 546: Exploring MCUb Function in the Heart and Its Role in Ischemia Reperfusion Injury
Authors: Huo Jiuzhou , Grimes Kelly , Sargent Michelle , York Allen , Kwong Jennifer , Molkentin Jeff 
Published: October 2019

Mitochondrial calcium alterations can promote oxidative metabolism to match increasing functional demands during stress stimulation. However, mitochondrial calcium overload-induced cell death contributes to the pathogenesis of several cardiac disorders including ischemia reperfusion injury. The mitochondrial calcium uniporter (MCU) complex is the only identified transporter that permits rapid calcium uptake into mitochondria. While the biological function of the MCU pore-forming subunit has been annotated, much less is known about the MCUb protein, a high similarity paralog that is part of the greater MCU complex. The goal of our study was to investigate the biological function of MCUb, its role in mitochondrial calcium uptake, and its contribution to the pathogenesis of ischemia reperfusion injury in the heart. To address these questions, we generated both MCUb overexpressing mice as well as MCUb null mice.
We observed that the cardiac-specific overexpression of MCUb inhibited mitochondrial calcium uptake, although basal mitochondrial calcium levels remained unchanged. Genetic ablation of MCUb, conversely, did not influence mitochondrial calcium uptake in the heart. MCUb null mice did not have differences in cardiac function by echocardiography, nor were tissue histological changes observed. This lack of an overt phenotype in MCUb null mice may be attributable to very low or even absent expression in the heart at baseline.
However, induction of MCUb protein was observed in the hearts of mice subjected to ischemia reperfusion injury. Thus, mice were challenged with one-hour ischemia followed by 24-hour reperfusion and the ischemic area/area at risk was analyzed. Deletion of MCUb did not change the initial infarct size of the heart. However, MCUb null mice showed decreased fractional shortening 4-weeks after the ischemic injury. Gravimetric analysis as well as histological examination further supported the conclusion that MCUb deletion exacerbated damage in the heart after ischemia reperfusion injury. We are currently investigating the underlying mechanisms of this greater functional deficit.
Abstract 827: Single-cell Transcriptomic Profiling Provides Insights Into Disease-related Processes During Hypertrophic Cardiomyopathy
Authors: Eding Joep , Wright Clark Maya , de Leeuw Anne , Molenaar Bas , Vink Aryan , Michels Michelle , van der Velden Jolanda , van Rooij Eva 
Published: October 2019

Hypertrophic cardiomyopathy (HCM) is a genetic disease usually caused by a heterozygous mutation in a sarcomeric gene. Histologically, HCM is characterized by a heterogeneous population of hypertrophic, disorganized cardiomyocytes and fibrosis of heart tissue. This hypertrophic growth can lead to outflow tract obstruction which can ultimately lead to progressive heart failure due to cardiac overload.
Here we use single-cell RNA sequencing (scRNA-Seq) on septal myectomy samples from patients suffering from HCM to interrogate cellular heterogeneity in disease context. Using our previously optimized digestion and sorting protocol we were able to obtain good quality RNA for single cell analysis. Bioinformatic clustering analysis of single cell transcriptomes revealed 8 transcriptomically distinct subpopulations of cardiomyocytes. Our data indicate an NPPA/NPPB enriched cluster of cells and show TTN to function as an important determinant of the cellular heterogeneity. Correlation analysis links TTN expression to the expression of, among others, cardiomyopathy-associated protein (CMYA) 5 and 3, while there appears to be a negative correlation with, among others, TMEM212. We were able to confirm these correlations by RT-PCR on bulk RNA in an additional cohort of 97 HCM myectomy samples. Additionally, immuno-histochemical staining on myectomy samples and explanted HCM hearts confirmed the transcriptional heterogeneity among cardiomyocytes. A unique advantage of FACS-based single cell sorting cardiomyocytes is the availability of index data for the sorted cells. Correlation analysis of forward scatter, as a proxy for cell size, confirmed both well-known stress markers MYL2 and MYL7 and additional genes to be upregulated in the larger cells. In summary, we show that FACS-based sorting of HCM cardiomyocytes allows for scRNA-Seq of intact cardiomyocytes. Initial analyses of the data could be validated in a wider cohort of comparable samples, showing reliability of the data. Finally, incorporation of index data reveals genes correlated with cell size. Further interrogation of this data has the potential to reveal novel insights into the pathogenesis of HCM.
Abstract 852: The Pathological Role of Coagulation Factors in Promoting Brown Adipose Tissue Dysfunction and Systemic Metabolic Disorder in Obesity
Authors: Hayashi Yuka , Shimizu Ippei , Yoshida Yohko , Ikegami Ryutaro , Katsuumi Goro , Suda Masayoshi , Fujiki Shinya , Minamino Tohru 
Published: October 2019

Obese individuals are predisposed to cardio-metabolic disorders. Brown adipose tissue (BAT) is an active metabolic organ abundant with mitochondria, and studies suggest a potential role of BAT in the maintenance of metabolic health in rodents and humans. Metabolic stress causes BAT dysfunction, but the underlying mechanisms are largely unknown. Coagulation factor Xa (FXa) is critically involved in a coagulation cascade, and it is also known to mediate biological effects by the activation of protease-activated receptor (PAR)-signaling. Accumulating evidence shows that PAR1 contributes to tissue remodeling in cardiovascular system. Here we show a previously unknown role of FXa-PAR signaling in promoting BAT dysfunction and systemic metabolic disorder in a murine dietary obese model.
Imposing a high fat diet (HFD) on C57BL/6NCr mice led to a marked increase in tissue factor (TF), coagulation factor VII and FXa in BAT. TF-FVIIa (activated form of FVII)-FXa complex is known to activate PAR1, and we found a significant increase in PAR1 expression in BAT upon metabolic stress. Administration of a FXa inhibitor ameliorated BAT whitening, improved thermogenic response and systemic glucose intolerance upon dietary obesity. In contrast, administration of warfarin did not show any phenotype in BAT. BAT specific TF and PAR1 over-expression model showed significant whitening of this tissue, which was associated with systemic glucose intolerance. BAT specific PAR1 KO mice improved glucose intolerance and thermogenic response under a metabolically stressed condition. In differentiated brown adipocytes, FXa markedly increased mitochondrial reactive oxygen species (ROS) and reduced mitochondrial membrane potential. Inhibition of PAR1 ameliorated FXa-induced mitochondrial ROS production and reduction in membrane potential. We also found that plasma FXa level did not increase in obese mice as well as in obese individuals. These results suggest the previously unknown role of coagulation systems in promoting BAT dysfunction, leading to systemic metabolic disorders. Maintenance of BAT homeostasis through the suppression of FXa-PAR1 signaling would become a new therapeutic target for obesity and diabetes
Saving Some Inequality for Young Adulthood? Social Origin Differences in ‘Re’-enrollment in Postsecondary Education in the United States, Sweden, and Germany
Authors: Weiss Felix 
Published: October 2019

Abstract
In this article, three country contexts are compared with regard to inequality by social origin in late enrollment in post-secondary education. Countries differ in the frequency at which young adults leave the labor market and (re)-enroll. This article discusses how inequality in late entry into education by social origin can be linked to characteristics of the education system and the labor market. Two cases with education systems that welcome adult learners and offer many second chances – Sweden and the US – are contrasted with the German system before its recent reforms. Systems with a welcoming environment for adult learners in higher education are shown to have higher educational inequalities in later transitions, while inequality in earlier transitions is lower.
Alcibiades’ Akrasia: Reason for Wrongdoing?
Authors: Shanahan Colm 
Published: October 2019

Abstract
I will argue that, due to the level of attention given to comparing and contrasting Socratic Intellectualism with the Republic, the question of the possibility of akrasia in Plato’s thought has not yet been adequately formulated. I will instead be focusing on Plato’s Symposium, situating Alcibiades at its epicentre and suggesting that his case should be read as highlighting some of Plato’s concerns with Socratic Intellectualism. These concerns arise from the following position of Socratic Intellectualism: knowing the greater good will necessarily entail doing good, and will thereby remove the motivational content of prior knowledge of what is good. Through Alcibiades, Plato explores the possibility of a negative reaction to knowledge of the greater good. Importantly, rather than simply arising as a result of being overcome by the passions, Alcibiades’ negative reaction assumes that rational freedom is required to reject the greater good (virtue) in favour of the lesser.
The Rise and Demise of the Boys’ Company
Authors: Agyekum Humphrey Asamoah 
Published: October 2019

Abstract
Graduates of Ghana's defunct Army Boys’ Company, a specialized military training institution for boys, participated to varying degrees in all five successful coups in the West African country. Most significantly, their prominent role in the coups of 1979 and 1981 catapulted them into the heart of the Ghanaian political arena. They thus became political actors; a position with far reaching consequences for the Boys’ Company. Coups in Ghana have received considerable academic attention. However, the focus of this body of literature tended to be on the coup leaders with rarely any attention for the soldiers who facilitate the power seizures by conducting the fighting. This article addresses this lacunae by assessing how the so-called “ex-Boys” radicalized politically, while bringing to the fore their experience at the Army Boys’ Company and in the military. Additionally, the article scrutinizes the conditions that led to demise of the Boys’ Company.
Megaflashes: Just How Long Can a Lightning Discharge Get?
Authors: Lyons Walter A. , Bruning Eric C. , Warner Tom A. , MacGorman Donald R. , Edgington Samantha , Tillier Clemens , Mlynarczyk Janusz 
Published: October 2019

AbstractThe existence of mesoscale lightning discharges on the order of 100 km in length has been known since the radar-based findings of Ligda in the mid-1950s. However, it took the discovery of sprites in 1989 to direct significant attention to horizontally extensive “megaflashes” within mesoscale convective systems (MCSs). More recently, 3D Lightning Mapping Arrays (LMAs) have documented sprite-initiating lightning discharges traversing several hundred kilometers. One such event in a 2007 Oklahoma MCS having an LMA-derived length of 321 km, has been certified by the WMO as the longest officially documented lightning flash. The new Geostationary Lightning Mapper (GLM) sensor on GOES-16/17 now provides an additional tool suited to investigating mesoscale lightning. On 22 October 2017, a quasi-linear convective system moved through the central United States. At 0513 UTC, the GLM indicated a lightning discharge originated in northern Texas, propagated north-northeast across Oklahoma, fortuitously traversed the Oklahoma LMA (OKLMA), and finally terminated in southeastern Kansas. This event is explored using the OKLMA, the National Lightning Detection Network (NLDN), and the GLM. The NLDN reported 17 positive cloud-to-ground flashes (+CGs), 23 negative CGs (−CGs), and 37 intracloud flashes (ICs) associated with this massive discharge, including two +CGs capable of inducing sprites, with others triggering upward lightning from tall towers. Combining all available data confirms the megaflash, which illuminated 67,845 km2, was at least 500 km long, greatly exceeding the current official record flash length. Yet even these values are being superseded as GLM data are further explored, revealing that such vast discharges may not be all that uncommon.
Emergency nurse practitioners’ use of a modified Edinburgh red eye diagnostic algorithm: Prospective observational study
Authors: Chuk Lee‐Kwan , Chung Josephine Yuen‐Man , Lau Henry Hing‐Wai , Leung Ling Yan , Hung Kevin KC , Graham Colin A 
Published: October 2019

Background:Emergency nurse practitioners have traditionally been reluctant to treat acute red eyes in Hong Kong emergency departments. The Edinburgh Red Eye Diagnostic Algorithm is the only validated tool to assist non‐ophthalmologists to make diagnoses.Objectives:This study investigates the utility of a modified version used by emergency nurse practitioners.Methods:This is a prospective single‐centre cohort study in a university hospital emergency department in Hong Kong, comparing red eye patients seen by emergency nurse practitioners with the aid of the algorithm to patients seen by emergency doctors. Data on patient‐reported symptom severity were obtained on the day of consultation and information on resolution of symptoms at 1 week following emergency department attendance via telephone interviews.Results:A convenience sample of 50 patients was recruited to the emergency nurse practitioner group and 130 patients were recruited to the doctors’ group over 9 weeks. Reductions in symptom severity were seen in both groups (>70% in both groups reported moderate to very severe discomfort on day 0; ~90% in both groups reported none or mild discomfort on day 7). There was no difference between the two groups (p = 0.55, analysis of covariance). Symptom resolution was reported in 96% in the emergency nurse practitioner group and 98.5% in the doctor's group, which was not statistically significant (p = 0.31, χ2 test).Conclusion:Emergency nurse practitioners using the Edinburgh Red Eye Algorithm to manage red eye patients in a Hong Kong emergency department achieve similar patient‐reported outcomes compared to emergency department doctor consultations.
One firm, two countries, one workplace model? The case of Foxconn’s internationalisation
Authors: Andrijasevic Rutvica , Sacchetto Devi , Pun Ngai 
Published: October 2019

AbstractThis article aims to provide insight into the employment relations in China-based multinational companies internationalising to Europe, a still relatively unexplored topic. We investigate the transfer of work and employment practices from Foxconn’s manufacturing headquarters in mainland China to its subsidiaries in Czechia and the factors that influence the firm’s internationalisation of production. By drawing upon original ethnographic fieldwork, the study makes a two-fold contribution. First, it shows the analytical inadequacy of the ‘latecomer’ model which assumes that the Chinese firm is an asset seeker. Second, it illustrates the relevance of diversity of labour and non-institutionalised forms of workers’ agency for theorisation of internationalisation. These topics are still insufficiently addressed by the literature that favours managerial agency and the model of distinctive and stable national labour forces. The study contributes to the theoretical debates on internationalisation by illustrating the limits of the national institutionalist perspective, the importance of considering a multi-scalar analytical framework and the relevance of labour composition in shaping multinational employment relations.
How long should we continue crizotinib in ALK translocation-positive inflammatory myofibroblastic tumors? Long-term complete response with crizotinib and review of the literature
Authors: Alan Ozkan , Kuzhan Okan , Koca Sinan , Telli Tugba Akin , Basoglu Tugba , Ercelep Ozlem , Filinte Deniz , Sengul Yildiz , Arikan Huseyin , Kaya Serap , Babacan Nalan Akgul , Dane Faysal , Yumuk Perran Fulden 
Published: October 2019

Introduction Inflammatory myofibroblastic tumor is a rare disease which is typically seen in children and young adults. Approximately half of the inflammatory myofibroblastic tumors contain translocations that result in over-expression of anaplastic lymphoma kinase gene. Herein, we present two anaplastic lymphoma kinase-positive cases with long-term remission with crizotinib. We do not know how long these therapies need to be continued. Case reports We present two cases of inflammatory myofibroblastic tumor treated with anaplastic lymphoma kinase inhibitor therapies: an 8-year-old Turkish boy and a 21-year-old Caucasian man. Management and outcome Two cases, both with good tumor control under crizotinib, but one who progressed on drug holiday, responded again to the same drug, and had a very short period of response after restarting crizotinib. Conclusion A molecular-targeted drug (anaplastic lymphoma kinase inhibitor) was found to be extremely effective as selective therapy for inflammatory myofibroblastic tumor with anaplastic lymphoma kinase translocation. Here, we want to emphasize the continuation of this treatment after achieving a good response until progression or a major side effect.
Risk factors and clinical outcomes in chronic coronary and peripheral artery disease: An analysis of the randomized, double-blind COMPASS trial
Authors: Vanassche Thomas , Verhamme Peter , Anand Sonia S , Shestakovska Olga , Fox Keith AA , Bhatt Deepak L , Avezum Alvaro , Alings Marco , Aboyans Victor , Maggioni Aldo P , Widimsky Petr , Berkowitz Scott D , Yusuf Salim , Connolly Stuart J , Eikelboom John W , Bosch Jackie 
Published: October 2019

Aims Secondary prevention in patients with coronary artery disease and peripheral artery disease involves antithrombotic therapy and optimal control of cardiovascular risk factors. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) study, adding low-dose rivaroxaban on top of aspirin lowered cardiovascular events, but there is limited data about risk factor control in secondary prevention. We studied the association between risk factor status and outcomes, and the impact of risk factor status on the treatment effect of rivaroxaban, in a large contemporary population of patients with coronary artery disease or peripheral artery disease. Methods and results We reported ischemic events (cardiovascular death, stroke, or myocardial infarction) in participants from the randomized, double-blind COMPASS study by individual risk factor (blood pressure, smoking status, cholesterol level, presence of diabetes, body mass index, and level of physical activity), and by number of risk factors. We compared rates and hazard ratios of patients treated with rivaroxaban plus aspirin vs aspirin alone within each risk factor category and tested for interaction between risk factor status and antithrombotic regimen. Complete baseline risk factor status was available in 27,117 (99%) patients. Status and number of risk factors were both associated with increased risk of ischemic events. Rates of ischemic events (hazard ratio 2.2; 95% confidence interval 1.8–2.6) and cardiovascular death (hazard ratio 2.0; 1.5–2.7) were more than twofold higher in patients with 4–6 compared with 0–1 risk factors ( p < 0.0001 for both). Rivaroxaban reduced event rates independently of the number of risk factors ( p interaction 0.93), with the largest absolute benefit in patients with the highest number of risk factors. Conclusion More favorable risk factor status and low-dose rivaroxaban were independently associated with lower risk of cardiovascular events.
Aging in the Context of HIV/AIDS: Spaces for Renegotiation and Recomposition of Mutual Solidarity in Burkina Faso
Authors: Ouedraogo Ramatou , Attané Anne , Gyasi Razak M 
Published: October 2019

Purpose: The HIV-infected older people in sub-Saharan Africa are inevitably vulnerable to chronic health-related conditions, yet the needed social support for these people is mostly inadequate. Drawing on the anthropology of disease and health paradigms, this study explores the recomposition of multidimensional and multidirectional nature of mutual familial support for older people living with or affected by HIV/AIDS in Burkina Faso. Methods: We conducted multiple in-depth interviews among 147 individuals recruited from nonprofit organizations in Ouagadougou, Bobo-Dioulasso, Ouahigouya, and Yako through 2 projects funded by the National Agency for AIDS Research. Thematic and narrative analytical frameworks were used to analyze the data. Results: We found that older people suffered serious socioeconomic and psychological challenges associated with HIV/AIDS. Older people were particularly vulnerable to the double burden of HIV/AIDS and caregiving responsibility for family members infected with the disease. However, the infected older people who received adequate treatment and familial support regained sociocultural positions as agents for cultural transition and material/emotional resources. Conclusions: Although HIV/AIDS potentially renegotiated the nature, intensity, and direction of familial support for vulnerable older people, the extrafamily solidarity seems an integral part of the great cycle of reciprocity and intrafamily mutual support. Health and policy interventions targeted at strengthening the interpersonal relationships and support for HIV/AIDS-infected and HIV/AIDS-affected older people are needed to improve their independence and well-being.
The transcriptome of CMML monocytes is highly inflammatory and reflects leukemia-specific and age-related alterations
Authors: Franzini Anca , Pomicter Anthony D. , Yan Dongqing , Khorashad Jamshid S. , Tantravahi Srinivas K. , Than Hein , Ahmann Jonathan M. , O’Hare Thomas , Deininger Michael W. 
Published: October 2019

Key Points
CMML monocytes exhibit a proinflammatory transcriptional signature, contributing to malignant expansion and increased cardiovascular risk.