bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mcl-1 Phosphorylation without Degradation Mediates Sensitivity to HDAC Inhibitors by Liberating BH3-Only Proteins
Authors: Tong Jingshan , Zheng Xingnan , Tan Xiao , Fletcher Rochelle , Nikolovska-Coleska Zaneta , Yu Jian , Zhang Lin 
Published: June 2018

AbstractMcl-1, a prosurvival Bcl-2 family protein, is frequently overexpressed in cancer cells and plays a critical role in therapeutic resistance. It is well known that anticancer agents induce phosphorylation of Mcl-1, which promotes its binding to E3 ubiquitin ligases and subsequent proteasomal degradation and apoptosis. However, other functions of Mcl-1 phosphorylation in cancer cell death have not been well characterized. In this study, we show in colon cancer cells that histone deacetylase inhibitors (HDACi) induce GSK3β-dependent Mcl-1 phosphorylation, but not degradation or downregulation. The in vitro and in vivo anticancer effects of HDACi were dependent on Mcl-1 phosphorylation and were blocked by genetic knock-in of a Mcl-1 phosphorylation site mutant. Phosphorylation-dead Mcl-1 maintained cell survival by binding and sequestering BH3-only Bcl-2 family proteins PUMA, Bim, and Noxa, which were upregulated and necessary for apoptosis induction by HDACi. Resistance to HDACi mediated by phosphorylation-dead Mcl-1 was reversed by small-molecule Mcl-1 inhibitors that liberated BH3-only proteins. These results demonstrate a critical role of Mcl-1 phosphorylation in mediating HDACi sensitivity through a novel and degradation-independent mechanism. These results provide new mechanistic insights on how Mcl-1 maintains cancer cell survival and suggest that Mcl-1–targeting agents are broadly useful for overcoming therapeutic resistance in cancer cells.Significance: These findings present a novel degradation–independent function of Mcl-1 phosphorylation in anticancer therapy that could be useful for developing new Mcl-1–targeting agents to overcome therapeutic resistance. Cancer Res; 78(16); 4704–15. ©2018 AACR.
Comprehensive Safety Analysis of Venetoclax Monotherapy for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia
Authors: Davids Matthew S. , Hallek Michael , Wierda William , Roberts Andrew W. , Stilgenbauer Stephan , Jones Jeffrey A. , Gerecitano John F. , Kim Su Young , Potluri Jalaja , Busman Todd , Best Andrea , Verdugo Maria E. , Cerri Elisa , Desai Monali , Hillmen Peter , Seymour John F. 
Published: June 2018

Abstract
Purpose: The oral BCL-2 inhibitor venetoclax is an effective therapy for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including disease with high-risk genomic features such as chromosome 17p deletion [del(17p)] or progressive disease following B-cell receptor pathway inhibitors.
Patients and Methods: We conducted a comprehensive analysis of the safety of 400 mg daily venetoclax monotherapy in 350 patients with CLL using an integrated dataset from three phase I/II studies.
Results: Median age was 66 years and 60% had del(17p). Patients had received a median of three prior therapies (range: 0–15); 42% previously received ibrutinib or idelalisib. Median duration of exposure to venetoclax was 16 months (0–56). In the pooled analysis, the most common adverse events (AE) of any grade were diarrhea (41%), neutropenia (40%), nausea (39%), anemia (31%), fatigue (28%), and upper respiratory tract infection (25%). The most common grade 3/4 AEs were neutropenia (37%), anemia (17%), and thrombocytopenia (14%). With the current 5-week ramp-up dosing, the incidence of laboratory TLS was 1.4% (2/166), none had clinical sequelae, and all of these patients were able to ramp-up to a daily dose of 400 mg. Grade 3/4 neutropenia was manageable with growth factor support and dose adjustments; the incidence of serious infections in these patients was 15%. Ten percent of patients discontinued venetoclax due to AEs and 8% died while on study, with the majority of deaths in the setting of disease progression.
Conclusions: Venetoclax as a long-term continuous therapy is generally well tolerated in patients with R/R CLL when initiated with the current treatment algorithm. Clin Cancer Res; 24(18); 4371–9. ©2018 AACR.
СУЧАСНІ АСПЕКТИ ВИКЛАДАННЯ КУРСУ НЕВРОЛОГІЇ ЛІКАРЯМ-ІНТЕРНАМ НА КАФЕДРІ МЕДИЦИНИ НЕВІДКЛАДНИХ СТАНІВ
Authors: Zozulya I. S. , Volosovets A. O. , Zozulya A. I. , Bobrova V. I. 
Published: June 2018

Мета роботи – розробка і впровадження нових методів навчання в клініко-педагогічну практику викладання дисципліни невідкладної неврології лікарям-інтернам на кафедрі медицини невідкладних станів.Основна частина. Впроваджено в процес викладання матеріалу нові способи передачі навчальної інформації від викладача до інтернів. Текстова структура лекційних презентацій з неврології була значно модифікована за допомогою наочних схем та навчальних відеофільмів. Крім того, змінився формат проведення самих лекцій з безперервної подачі інформації в напрямку “викладач – студент” на динамічний діалог із постановкою проблемних питань та залучення інтернів до наукової дискусії й активного обговорення практичного матеріалу. Важливим елементом було також доповнення теоретичного лекційного матеріалу ілюстраціями у вигляді клінічних випадків з власної неврологічної практики викладачів.Висновок. Запровадження у педагогічну практику нових методів навчання та передачі інформації з урахуванням фізіологічних та психологічних особливостей сучасних інтернів дозволяє покращити рівень підготовки з дисципліни невідкладної неврології серед лікарів-інтернів на кафедрі медицини невідкладних станів.
Stroke and Cardiovascular Outcomes in Patients With Carotid Disease Undergoing Transcatheter Aortic Valve Replacement
Authors: Kochar Ajar , Li Zhuokai , Harrison J. Kevin , Hughes G. Chad , Thourani Vinod H. , Mack Michael J. , Matsouaka Roland A. , Cohen David J. , Peterson Eric D. , Jones W. Schuyler , Vemulapalli Sreekanth 
Published: June 2018

Background—
Stroke is a serious complication of both transcatheter aortic valve replacement (TAVR) and carotid artery disease (CD). The implications of CD in patients undergoing TAVR are unclear.

Methods and Results—
The Society of Thoracic Surgeons and American College of Cardiology Transcatheter Valve Therapies Registry, consisting of data from consecutive US TAVR cases during the years 2013 to 2015, was linked to Medicare claims data to ascertain 30-day and 1-year cumulative incidence rates of stroke and all-cause mortality. We compared 30-day and 1-year stroke and mortality outcomes between patients with no-CD and patients with moderate, severe, and occlusive CD and adjusted for baseline covariates using proportional hazards models. Among 29 143 patients undergoing TAVR across 390 US sites, 22% had CD. Patients with CD had higher rates of prior hypertension, diabetes mellitus, stroke, and myocardial infarction. Observed in-hospital stroke rates were 2.0% among no-CD, 2.5% among moderate CD, 3.0% among severe CD, and 2.6% among occlusive CD. There was no association between the presence of CD and 30-day stroke (adjusted hazard ratio, 1.16; 95% confidence interval, 0.94–1.43) or mortality (adjusted hazard ratio, 1.10; 95% confidence interval, 0.95–1.28). There was no association between CD and 1-year stroke (adjusted hazard ratio, 1.03; 95% confidence interval, 0.86–1.24) or mortality (adjusted hazard ratio, 1.02; 95% confidence interval, 0.93–1.12). Furthermore, there was no significant risk-adjusted association between severity of CD and 30-day or 1-year stroke or mortality.

Conclusions—
CD is common among TAVR patients, present in 1 of 5. CD was not associated with an increased risk of stroke or mortality at 30 day or 1 year. Post-TAVR stroke seems to be because of mechanisms other than CD.
Physical Activity and Incident Cardiovascular Disease in Women: Is the Relation Modified by Level of Global Cardiovascular Risk?
Authors: Chomistek Andrea K. , Cook Nancy R. , Rimm Eric B. , Ridker Paul M. , Buring Julie E. , Lee I.‐Min 
Published: June 2018

Background

The inverse association between physical activity and cardiovascular disease (
CVD
) is well‐ established and has previously been shown in people with and without single
CVD
risk factors. We examined whether level of global cardiovascular risk, on the basis of the pooled cohort equation or Reynolds risk score, which include multiple risk factors, modified the physical activity–
CVD
association.

Methods and Results

Participants in the prospective WHS (Women's Health Study; n=27 536) reported their leisure‐time physical activity at study entry (1992–1995) and during follow‐up through 2013. Participants were divided into 10‐year cardiovascular risk groups on the basis of the pooled cohort equation and Reynolds risk score. The primary outcome was incident total
CVD
. The
CVD
hazard ratio for active (≥500 kcal/wk of physical activity) compared with inactive (<500 kcal/wk) individuals was 0.73 (95% confidence interval, 0.66–0.80) in multivariable models. This association was not modified by level of cardiovascular risk; physical activity was inversely associated with
CVD
within all pooled cohort equation and Reynolds risk score groups (
P
=0.17 and
P
=0.66 for interaction, respectively). When the joint association of physical activity and level of cardiovascular risk was examined, women with higher risk on the basis of either the pooled cohort equation or Reynolds risk score had higher
CVD
rates compared with those at low risk, regardless of physical activity. However, among women at both high and low risk, being physically active was associated with lower risk of
CVD
events.

Conclusions

In this large prospective cohort of women, level of global cardiovascular risk did not modify the inverse association between leisure‐time physical activity and incident
CVD
. Thus, promoting physical activity is important in women at both low and high cardiovascular risk.
Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation
Authors: Zhu Juan , Liu Kewei , Huang Kaibin , Gu Yong , Hu Yafang , Pan Suyue , Ji Zhong 
Published: June 2018

Background
Sudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation.

Methods and Results
Rats were subjected to 9‐minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP‐activated protein kinase (AMPK), and autophagy activation were assessed at indicated time points within the first 7 days after return of spontaneous circulation. Our results showed that metformin pretreatment elevated the 7‐day survival rate from 55% to 85% and significantly reduced neurologic deficit scores. Moreover, metformin ameliorated CA‐induced neuronal degeneration and glial activation in the hippocampal CA1 region, which was accompanied by augmented AMPK phosphorylation and autophagy activation in affected neuronal tissue. Inhibition of AMPK or autophagy with pharmacological inhibitors abolished metformin‐afforded neuroprotection, and augmented autophagy induction by metformin treatment appeared downstream of AMPK activation.

Conclusions
Taken together, our data demonstrate, for the first time, that metformin confers neuroprotection against ischemic brain injury after CA/cardiopulmonary resuscitation by augmenting AMPK‐dependent autophagy activation.
Machine Learning: Deepest Learning as Statistical Data Assimilation Problems
Authors: Abarbanel Henry D. I. , Rozdeba Paul J. , Shirman Sasha 
Published: June 2018

We formulate an equivalence between machine learning and the formulation of statistical data assimilation as used widely in physical and biological sciences. The correspondence is that layer number in a feedforward artificial network setting is the analog of time in the data assimilation setting. This connection has been noted in the machine learning literature. We add a perspective that expands on how methods from statistical physics and aspects of Lagrangian and Hamiltonian dynamics play a role in how networks can be trained and designed. Within the discussion of this equivalence, we show that adding more layers (making the network deeper) is analogous to adding temporal resolution in a data assimilation framework. Extending this equivalence to recurrent networks is also discussed. We explore how one can find a candidate for the global minimum of the cost functions in the machine learning context using a method from data assimilation. Calculations on simple models from both sides of the equivalence are reported. Also discussed is a framework in which the time or layer label is taken to be continuous, providing a differential equation, the Euler-Lagrange equation and its boundary conditions, as a necessary condition for a minimum of the cost function. This shows that the problem being solved is a two-point boundary value problem familiar in the discussion of variational methods. The use of continuous layers is denoted “deepest learning.” These problems respect a symplectic symmetry in continuous layer phase space. Both Lagrangian versions and Hamiltonian versions of these problems are presented. Their well-studied implementation in a discrete time/layer, while respecting the symplectic structure, is addressed. The Hamiltonian version provides a direct rationale for backpropagation as a solution method for a certain two-point boundary value problem.
Introduction
Authors: Tseronis Assimakis , Pollaroli Chiara 
Published: June 2018

Abstract
In this introductory paper to the special issue, we briefly discuss literature from argumentation studies, pragmatics, and multimodal analysis in order to show how pragmatics has benefited argumentation studies until now, and how it can also benefit multimodal analysis. In the last section we introduce the papers of this issue that focus on the question how pragmatics can benefit multimodal argumentation in particular.
The affordances and constraints of situation and genre
Authors: Forceville Charles , Kjeldsen Jens E. 
Published: June 2018

Abstract
Visuals are generally considered to be rich in information, but also to be open to many different interpretations. As a consequence, many argumentation scholars doubt that visuals can constitute argumentation (e.g. Fleming, 1996; Johnson, 2003, 2010; Patterson, 2010). In this paper, we argue that the rhetorical and argumentative potential of visuals and multimodal texts is strengthened if they belong to recognizable genres, genres being governed by discourse-internal factors as well as situational/pragmatic understanding. The genre of traffic signs can draw on specific genre conventions thanks to these signs’ highly coded nature. As a consequence, traffic signs constitute an exemplary category to make the point that visuals and multimodal texts can function rhetorically or even argumentatively. We support our claim by first analysing a number of unusual instances of the genre and then discussing a few visual and multimodal signs whose argumentative potential no longer depends on specific traffic-related circumstances but crucially depends on the pretence that they are traffic signs.
Integrating Data Rescue into the Classroom
Authors: Ryan Ciara , Duffy Catriona , Broderick Ciaran , Thorne Peter W. , Curley Mary , Walsh Séamus , Daly Conor , Treanor Mairéad , Murphy Conor 
Published: June 2018

AbstractOver much of the globe, the temporal extent of meteorological records is limited, yet a wealth of data remains in paper or image form in numerous archives. To date, little attention has been given to the role that students might play in efforts to rescue these data. Here we summarize an ambitious research-led, accredited teaching experiment in which undergraduate students successfully transcribed more than 1,300 station years of daily precipitation data and associated metadata across Ireland over the period 1860–1939. We explore i) the potential for integrating data rescue activities into the classroom, ii) the ability of students to produce reliable transcriptions and, iii) the learning outcomes for students. Data previously transcribed by Met Éireann (Ireland’s National Meteorological Service) were used as a benchmark against which it was ascertained that students were as accurate as the professionals. Details on the assignment, its planning and execution, and student-aids used are provided. The experience highlights the benefits that can accrue for data rescue through innovative collaboration between national meteorological services and academic institutions. At the same time, students have gained valuable learning outcomes and firsthand understanding of the processes that underpin data rescue and analysis. The success of the project demonstrates the potential to extend data rescue in the classroom to other universities, thus providing both an enriched learning experience for the students and a lasting legacy to the scientific community.
Comments on “The Gulf Stream Convergence Zone in the Time-Mean Winds”
Authors: Plougonven Riwal , Foussard Alexis , Lapeyre Guillaume 
Published: June 2018

Abstract
In a recent study, O’Neill et al. analyzed the divergence of surface winds above the northwest Atlantic. In the time mean, a band of convergence is found, overlying the southern flank of the Gulf Stream. To quantify the impact of synoptic storms, the authors proposed to compare the time-mean divergence with the divergence averaged in the absence of rain. In the resulting conditional-average field, divergence was found to be positive nearly everywhere. O'Neill et al. concluded that this absence of convergence precludes the Ekman-balanced mass adjustment to be responsible for the atmospheric response above the Gulf Stream. Using a simplistic toy model as well as a numerical simulation representative of a storm track, we show that the absence of negative divergence values purely results from the correlation between rain and convergence: the conditional average based on the absence of rain necessarily implies a shift toward positive divergence values. In consequence, we argue that conditional statistics (based on the absence of rain or removing extreme values in the divergence field), as produced by O’Neill et al., do not allow conclusions on the mechanisms underlying the atmospheric response to the Gulf Stream. They nevertheless highlight the essential role of synoptic storms in shaping the divergence field in instantaneous fields.
Note on the Rate of Restratification in the Baroclinic Spindown of Fronts
Authors: Callies Jörn , Ferrari Raffaele 
Published: June 2018

AbstractThis paper revisits how the restratifying buoyancy flux generated by baroclinic mixed layer instabilities depends on environmental conditions. The frontal spindown is shown to produce buoyancy fluxes that increase significantly beyond the previously proposed and widely used scaling (f is the Coriolis parameter, Λ is the geostrophic shear, and H is the mixed layer depth), irrespective of whether the initial front is broad or narrow. This increase occurs after the initial phase of the nonlinear evolution, when the baroclinic eddies grow in size and develop velocities significantly in excess of the scaling assumption V ~ ΛH. Implications for parameterizing the restratification caused by baroclinic mixed layer instabilities in coarse-resolution models are discussed.
Tornado Warnings at Night: Who Gets the Message?
Authors: Mason Lisa Reyes , Ellis Kelsey N. , Winchester Betsy , Schexnayder Susan 
Published: June 2018

Abstract
Nocturnal tornadoes are a public health threat, over twice as likely to have fatalities as tornadoes during the day. While tornado warning receipt is an important factor in models of individual behavioral response, receipt of warnings at night has not been studied in the literature to date. This study uses survey data from a random sample of Tennessee residents (N = 1804) who were randomly assigned to day or night versions of a near-identical survey instrument. Bivariate and logistic regression analyses compare chance of warning receipt, warning sources, and predictors of warning receipt for day versus night scenarios of a tornadic event. Over 80% of participants asked about a daytime tornado said there was a high/very high chance of receiving the warning, compared to fewer than 50% of participants asked about a nighttime event. Whereas demographic and cognitive factors helped predict tornado warning receipt during the day, cognitive and geographic factors were salient for the night. Perceived county risk and prior experience with a tornado were positively associated with chance of nighttime receipt, while belief that luck is an important factor in surviving a tornado and living in east (compared to west) Tennessee were negatively associated. Future research should consider partnering with the National Weather Service, emergency managers, and local media to increase the likelihood that people will receive tornado warnings at night and to better understand the role that cognitive factors and particular beliefs play in individual efforts to ensure that warnings are received.
Templates of flat pericardial patterns for precise aortic cusp extension
Authors: Izzat Mohammad Bashar , Alkhayat Mohammad Mouath 
Published: June 2018

Background Aortic cusp extension is a subjective and operator-dependent technique. In order to facilitate surgical correction of aortic cusp retraction and reestablishment of adequate cusp coaptation, we sought to develop new templates that can be used to cut flat pericardial sheets into precise cusp extension patches. Methods Each template was designed as a two-dimensional unwrap of the natural geometry of a complete aortic cusp, and a series of templates were made available to correspond with all potential aortic cusp sizes. Based on these templates, aortic cusp extension was performed in 2 patients (aged 54 and 43 years) with significant retraction of the noncoronary aortic cusps and severe aortic valve insufficiency. In each patient, extension of the retracted native noncoronary cusp was undertaken using a bovine pericardial patch that matched the size of adjacent nondiseased native aortic cusps. Results Achieving geometrically perfect aortic cusp extensions was uncomplicated, and intraoperative transesophageal echocardiography confirmed satisfactory aortic valve repairs (aortic insufficiency < 1+ and low transvalvular gradients). Early follow-up transthoracic echocardiography confirmed that all valve cusps met at similar heights in the aortic root, and that their excursions were virtually identical. Conclusions The newly designed templates can be used to cut flat pericardial sheets into exact cusp extension patches, and initial clinical experience indicates that they are useful in performing precise aortic cusp extension procedures and restoring adequate aortic valve competence.