bluuebunny/crossref_metadata_2025_split huggingface dataset:
The PDE Method for the Analysis of Randomized Load Balancing Networks
Authors: Aghajani Reza , Li Xingjie , Ramanan Kavita 
Published: January 2019

We introduce a new framework for the analysis of large-scale load balancing networks with general service time distributions, motivated by applications in server farms, distributed memory machines, cloud computing and communication systems. For a parallel server network using the so-called $SQ(d)$ load balancing routing policy, we use a novel representation for the state of the system and identify its fluid limit, when the number of servers goes to infinity and the arrival rate per server tends to a constant. The fluid limit is characterized as the unique solution to a countable system of coupled partial differential equations (PDE), which serve to approximate transient Quality of Service parameters such as the expected virtual waiting time and queue length distribution. In the special case when the service time distribution is exponential, our method recovers the well-known ordinary differential equation characterization of the fluid limit.
Furthermore, we develop a numerical scheme to solve the PDE, and demonstrate the efficacy of the PDE approximation by comparing it with Monte Carlo simulations. We also illustrate how the PDE can be used to gain insight into the performance of large networks in practical scenarios by analyzing relaxation times in a backlogged network. In particular, our numerical approximation of the PDE uncovers two interesting properties of relaxation times under the SQ(2) algorithm. Firstly, when the service time distribution is Pareto with unit mean, the relaxation time decreases as the tail becomes heavier. This is a priori counterintuitive given that for the Pareto distribution, heavier tails have been shown to lead to worse tail behavior in equilibrium. Secondly, for unit mean light-tailed service distributions such as the Weibull and lognormal, the relaxation time decreases as the variance increases. This is in contrast to the behavior observed under random routing, where the relaxation time increases with increase in variance.
Local arginase inhibition does not modulate cutaneous vasodilation or sweating in young and older men during exercise
Authors: Meade Robert D. , Fujii Naoto , McGarr Gregory W. , Alexander Lacy M. , Boulay Pierre , Sigal Ronald J. , Kenny Glen P. 
Published: January 2019

Age-related impairments in cutaneous vascular conductance (CVC) and sweat rate (SR) during exercise may result from increased arginase activity, which can attenuate endogenous nitric oxide (NO) production. We therefore evaluated whether arginase inhibition modulates these heat-loss responses in young ( n = 9, 23 ± 3 yr) and older ( n = 9, 66 ± 6 yr) men during two 30-min bouts of moderate-intensity cycling (Ex1 and Ex2) in the heat (35°C). CVC and SR were measured at forearm skin sites perfused with 1) lactated Ringer’s (control), 2) NG-nitro-L-arginine methyl ester (L-NAME; NO synthase-inhibited), or 3) Nω-hydroxy-nor-arginine and S-(2-boronoethyl)-l-cysteine (Nor-NOHA + BEC; arginase-inhibited). In both groups, CVC was reduced at L-NAME relative to control and Nor-NOHA + BEC (both P < 0.01). Likewise, SR was attenuated with L-NAME compared with control and Nor-NOHA + BEC during each exercise bout in the young men (all P ≤ 0.05); however, no influence of treatment on SR in the older men was observed ( P = 0.14). Based on these findings, we then evaluated responses in 7 older men (64 ± 7 yr) during passively induced elevations in esophageal temperature (∆Tes) equal to those in Ex1 (0.6°C) and Ex2 (0.8°C). L-NAME reduced CVC by 18 ± 20% CVCmaxat a ∆Tesof 0.8°C ( P = 0.03) compared with control, whereas Nor-NOHA + BEC augmented CVC by 20 ± 18% CVCmax, on average, throughout heating (both P ≤ 0.03). SR was not influenced by either treatment ( P = 0.80) Thus, arginase inhibition does not modulate CVC or SR during exercise in the heat but, consistent with previous findings, does augment CVC in older men during passive heating.NEW & NOTEWORTHY In the current study, we demonstrate that local arginase inhibition does not influence forearm cutaneous vasodilatory and sweating responses in young or older men during exercise-heat stress. Consistent with previous findings, however, we observed augmented cutaneous blood flow with arginase inhibition during whole-body passive heat stress. Thus, arginase differentially affects cutaneous vasodilation depending on the mode of heat stress but does not influence sweating during exercise or passive heating.
CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors
Authors: Majzner Robbie G. , Theruvath Johanna L. , Nellan Anandani , Heitzeneder Sabine , Cui Yongzhi , Mount Christopher W. , Rietberg Skyler P. , Linde Miles H. , Xu Peng , Rota Christopher , Sotillo Elena , Labanieh Louai , Lee Daniel W. , Orentas Rimas J. , Dimitrov Dimiter S. , Zhu Zhongyu , Croix Brad St , Delaidelli Alberto , Sekunova Alla , Bonvini Ezio , Mitra Siddhartha S. , Quezado Martha M. , Majeti Ravindra , Monje Michelle , Sorensen Poul H.B. , Maris John M. , Mackall Crystal L. 
Published: January 2019

Abstract

Purpose:
Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system.

Experimental Design:
We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models.

Results:
B7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3.

Conclusions:
B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.
The RUNX Transcriptional Coregulator, CBFβ, Suppresses Migration of ER+ Breast Cancer Cells by Repressing ERα-Mediated Expression of the Migratory Factor TFF1
Authors: Pegg Henry J. , Harrison Hannah , Rogerson Connor , Shore Paul 
Published: January 2019

Abstract

Core binding factor β (CBFβ), the essential coregulator of RUNX transcription factors, is one of the most frequently mutated genes in estrogen receptor–positive (ER+) breast cancer. Many of these mutations are nonsense mutations and are predicted to result in loss of function, suggesting a tumor suppressor role for CBFβ. However, the impact of missense mutations and the loss of CBFβ in ER+ breast cancer cells have not been determined. Here we demonstrate that missense mutations in CBFβ accumulate near the Runt domain–binding region. These mutations inhibit the ability of CBFβ to form CBFβ–Runx–DNA complexes. We further show that deletion of CBFβ, using CRISPR-Cas9, in ER+ MCF7 cells results in an increase in cell migration. This increase in migration is dependent on the presence of ERα. Analysis of the potential mechanism revealed that the increase in migration is driven by the coregulation of Trefoil factor 1 (TFF1) by CBFβ and ERα. RUNX1–CBFβ acts to repress ERα-activated expression of TFF1. TFF1 is a motogen that stimulates migration and we show that knockdown of TFF1 in CBFβ−/− cells inhibits the migratory phenotype. Our findings reveal a new mechanism by which RUNX1–CBFβ and ERα combine to regulate gene expression and a new role for RUNX1–CBFβ in the prevention of cell migration by suppressing the expression of the motogen TFF1.

Implications:
Mutations in CBFβ contribute to the development of breast cancer by inducing a metastatic phenotype that is dependent on ER.
Admission Levels of DKK1 (Dickkopf-1) Are Associated With Future Cardiovascular Death in Patients With Acute Coronary Syndromes
Authors: Ueland Thor , Åkerblom Axel , Ghukasyan Tatevik , Michelsen Annika E. , Becker Richard C. , Bertilsson Maria , Himmelmann Anders , James Stefan K. , Siegbahn Agneta , Storey Robert F. , Kontny Frederic , Aukrust Pål , Wallentin Lars ,   for the PLATO Investigators
Published: January 2019

Objective—
The Wnt/wingless signaling antagonist DKK1 (dickkopf-1) regulates platelet-mediated inflammation and may contribute to plaque destabilization. We hypothesized that DKK1 would be associated with cardiovascular outcomes.

Approach and Results—

We determined DKK1 levels in serum samples obtained before randomization, at discharge, and 1 and 6 months in a subset of 5165 patients with acute coronary syndromes in the PLATO trial (Platelet Inhibition and Patient Outcomes; NCT00391872). The median (interquartile range) DKK1 concentrations were 0.61 (0.20–1.27) ng/mL at baseline and increased during follow-up. The hazard ratio (95% CIs) for the composite end point (cardiovascular death, nonprocedural spontaneous myocardial infarction, or stroke) during 1 year of follow-up, per 50% increase in baseline DKK1 concentration, was 1.06 (1.02–1.10),
P
=0.0011, and remained significant in fully adjusted analysis with 14 conventional clinical and demographic and 6 biochemical variables, including NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-TnT (high-sensitivity troponin T), and GDF-15 (growth differentiation factor 15; 1.05 [1.00–1.09];
P
=0.028). This association was mainly driven by the association with cardiovascular death, where a gradual increase in event rates was observed with increasing quartiles of DKK1 (2.7%, 3.0%, 4.3%, and 5.0%) and remained significant and unmodified in fully adjusted analysis (hazard ratio, 1.10 [1.04–1.17];
P
=0.002). Change in DKK1 and levels at 1 month were unrelated to outcomes. A modifying effect of ticagrelor on DKK1 discharge levels was observed but not associated with prognosis.

Conclusions—
In patients with acute coronary syndromes treated with dual antiplatelet treatment, admission DKK1 levels were independently associated with a composite of cardiovascular death, myocardial infarction, or stroke and with cardiovascular death alone.
Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery
Authors: Aragam Krishna G. , Chaffin Mark , Levinson Rebecca T. , McDermott Gregory , Choi Seung Hoan , Shoemaker M. Benjamin , Haas Mary E. , Weng Lu-Chen , Lindsay Mark E. , Smith J. Gustav , Newton-Cheh Christopher , Roden Dan M. , London Barry ,   For the GRADE Investigators, Wells Quinn S. , Ellinor Patrick T. , Kathiresan Sekar , Lubitz Steven A. , Bloom Heather L. , Dudley Samuel C. , Shalaby Alaa A. , Weiss Raul , Gutmann Rebecca , Saba Samir 
Published: January 2019

Background:
Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery.

Methods:
We defined all-cause HF among 488 010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4158) and echocardiographic data (n=30 201).

Results:

We identified 7382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (
P
<1×10
–6
), the majority linked to upstream HF risk factors, ie, coronary artery disease (
CDKN2B-AS1
and
MAP3K7CL
) and atrial fibrillation (
PITX2
). Refining the HF phenotype yielded a subset of 2038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in dilated cardiomyopathy (
BAG3
,
CLCNKA-ZBTB17
). Dilated cardiomyopathy signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. In addition, analyses of loss-of-function variants implicated
BAG3
as a disease susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%; odds ratio,12.03;
P
=3.62×10
–5
).

Conclusions:
We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independently of clinical HF risk factors and that are associated with subclinical left ventricular dysfunction.
The N
6
-Methyladenosine mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy
Authors: Dorn Lisa E. , Lasman Lior , Chen Jing , Xu Xianyao , Hund Thomas J. , Medvedovic Mario , Hanna Jacob H. , van Berlo Jop H. , Accornero Federica 
Published: January 2019

Background:

N
6
-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. The role of m6A mRNA methylation in the heart is not known.

Methods:
To determine the role of m6A methylation in the heart, we isolated primary cardiomyocytes and performed m6A immunoprecipitation followed by RNA sequencing. We then generated genetic tools to modulate m6A levels in cardiomyocytes by manipulating the levels of the m6A RNA methylase methyltransferase-like 3 (METTL3) both in culture and in vivo. We generated cardiac-restricted gain- and loss-of-function mouse models to allow assessment of the METTL3-m6A pathway in cardiac homeostasis and function.

Results:
We measured the level of m6A methylation on cardiomyocyte mRNA, and found a significant increase in response to hypertrophic stimulation, suggesting a potential role for m6A methylation in the development of cardiomyocyte hypertrophy. Analysis of m6A methylation showed significant enrichment in genes that regulate kinases and intracellular signaling pathways. Inhibition of METTL3 completely abrogated the ability of cardiomyocytes to undergo hypertrophy when stimulated to grow, whereas increased expression of the m6A RNA methylase METTL3 was sufficient to promote cardiomyocyte hypertrophy both in vitro and in vivo. Finally, cardiac-specific METTL3 knockout mice exhibit morphological and functional signs of heart failure with aging and stress, showing the necessity of RNA methylation for the maintenance of cardiac homeostasis.

Conclusions:

Our study identified METTL3-mediated methylation of mRNA on
N
6
-adenosines as a dynamic modification that is enhanced in response to hypertrophic stimuli and is necessary for a normal hypertrophic response in cardiomyocytes. Enhanced m6A RNA methylation results in compensated cardiac hypertrophy, whereas diminished m6A drives eccentric cardiomyocyte remodeling and dysfunction, highlighting the critical importance of this novel stress-response mechanism in the heart for maintaining normal cardiac function.
Endothelial Hypoxia-Inducible Factor-2α Is Required for the Maintenance of Airway Microvasculature
Authors: Jiang Xinguo , Tian Wen , Tu Allen B. , Pasupneti Shravani , Shuffle Eric , Dahms Petra , Zhang Patrick , Cai Haoliang , Dinh Thanh T. , Liu Bo , Cain Corey , Giaccia Amato J. , Butcher Eugene C. , Simon M. Celeste , Semenza Gregg L. , Nicolls Mark R. 
Published: January 2019

Background:
Hypoxia-inducible factors (HIFs), especially HIF-1α and HIF-2α, are key mediators of the adaptive response to hypoxic stress and play essential roles in maintaining lung homeostasis. Human and animal genetics studies confirm that abnormal HIF correlates with pulmonary vascular pathology and chronic lung diseases, but it remains unclear whether endothelial cell HIF production is essential for microvascular health. The large airway has an ideal circulatory bed for evaluating histological changes and physiology in genetically modified rodents.

Methods:
The tracheal microvasculature of mice, with conditionally deleted or overexpressed HIF-1α or HIF-2α, was evaluated for anatomy, perfusion, and permeability. Angiogenic signaling studies assessed vascular changes attributable to dysregulated HIF expression. An orthotopic tracheal transplantation model further evaluated the contribution of individual HIF isoforms in airway endothelial cells.

Results:

The genetic deletion of
Hif-2α
but not
Hif-1α
caused tracheal endothelial cell apoptosis, diminished pericyte coverage, reduced vascular perfusion, defective barrier function, overlying epithelial abnormalities, and subepithelial fibrotic remodeling. HIF-2α promoted microvascular integrity in airways through endothelial angiopoietin-1/TIE2 signaling and Notch activity. In functional tracheal transplants, HIF-2α deficiency in airway donors accelerated graft microvascular loss, whereas HIF-2α or angiopoietin-1 overexpression prolonged transplant microvascular perfusion. Augmented endothelial HIF-2α in transplant donors promoted airway microvascular integrity and diminished alloimmune inflammation.

Conclusions:
Our findings reveal that the constitutive expression of endothelial HIF-2α is required for airway microvascular health.
Association Between Sleep Apnea and Blood Pressure Control Among Blacks
Authors: Johnson Dayna A. , Thomas S. Justin , Abdalla Marwah , Guo Na , Yano Yuichiro , Rueschman Michael , Tanner Rikki M. , Mittleman Murray A. , Calhoun David A. , Wilson James G. , Muntner Paul , Redline Susan 
Published: January 2019

Background:
Blacks have a high prevalence of hypertension and uncontrolled blood pressure (BP), each of which may be partially explained by untreated sleep apnea. We investigated the association of sleep apnea with uncontrolled BP and resistant hypertension in blacks.

Methods:

Between 2012 and 2016, Jackson Heart Sleep Study participants (N=913) underwent an in-home Type 3 sleep apnea study, clinic BP measurements, and anthropometry. Moderate or severe obstructive sleep apnea (OSA) was defined as a respiratory event index ≥15, and nocturnal hypoxemia was quantified as percent sleep time with <90% oxyhemoglobin saturation. Prevalent hypertension was defined as either a systolic BP ≥130 mm Hg or diastolic BP
>
80mm Hg, use of antihypertensive medication, or self-report of a diagnosis of hypertension. Controlled BP was defined as systolic BP <130 mm Hg and diastolic BP <80 mm Hg; uncontrolled BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with use of 1 to 2 classes of antihypertensive medication; and resistant BP as systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg with the use of ≥3 classes of antihypertensive medication (including a diuretic) or use of ≥4 classes of antihypertensive medication regardless of BP level. Multinomial logistic regression models were fit to determine the association between OSA severity and uncontrolled BP or resistant hypertension (versus controlled BP) after multivariable adjustment.

Results:
The analytic sample with hypertension (N=664) had a mean age of 64.0 (SD,10.6) years, and were predominately female (69.1%), obese (58.6%), and college educated (51.3%). Among the sample, 25.7% had OSA, which was untreated in 94% of participants. Overall, 48% of participants had uncontrolled hypertension and 14% had resistant hypertension. After adjustment for confounders, participants with moderate or severe OSA had a 2.0 times higher odds of resistant hypertension (95% confidence interval [CI], 1.14–3.67). Each standard deviation higher than <90% oxyhemoglobin saturation was associated with an adjusted odds ratio for resistant hypertension of 1.25 (95% CI 1.01–1.55). OSA and <90% oxyhemoglobin saturation were not associated with uncontrolled BP.

Conclusion:
Untreated moderate or severe OSA is associated with increased odds of resistant hypertension. These results suggest that untreated OSA may contribute to inadequate BP control in blacks.
Left Atrial Electromechanical Remodeling Following 2 Years of High-Intensity Exercise Training in Sedentary Middle-Aged Adults
Authors: McNamara David A. , Aiad Norman , Howden Erin , Hieda Michinari , Link Mark S. , Palmer Dean , Samels Mitchel , Everding Braden , Ng Jason , Adams-Huet Beverley , Opondo Mildred , Sarma Satyam , Levine Benjamin D. 
Published: January 2019

Background:
Moderate intensity exercise is associated with a decreased incidence of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk. We evaluated the effects of 24 months of high intensity exercise training on left atrial (LA) mechanical and electric remodeling in sedentary, healthy middle-aged adults.

Methods:
Sixty-one participants (53±5 years) were randomized to 10 months of exercise training followed by 14 months of maintenance exercise or stretching/balance control. Fourteen Masters athletes were added for comparison. Left ventricular (LV) and LA volumes underwent 3D echocardiographic assessment, and signal-averaged electrocardiographs for filtered P-wave duration and atrial late potentials were completed at 0, 10, and 24 months. Extended ambulatory monitoring was performed at 0 and 24 months. Within and between group differences from baseline were compared using mixed-effects model repeated-measures analysis.

Results:

Fifty-three participants completed the study (25 control, 28 exercise) with 88±11% adherence to assigned exercise sessions. In the exercise group, both LA and LV end diastolic volumes increased proportionately (19% and 17%, respectively) after 10 months of training (peak training load). However, only LA volumes continued to increase with an additional 14 months of exercise training (LA volumes 55%; LV end diastolic volumes 15% at 24 months versus baseline;
P
<0.0001 for all). The LA:LV end diastolic volumes ratio did not change from baseline to 10 months, but increased 31% from baseline in the Ex group (
P
<0.0001) at 24 months, without a change in controls. There were no between group differences in the LA ejection fraction, filtered P-wave duration, atrial late potentials, and premature atrial contraction burden at 24 months and no atrial fibrillation was detected. Compared with Masters athletes, the exercise group demonstrated lower absolute LA and LV volumes, but had a similar LA:LV ratio after 24 months of training.

Conclusions:
Twenty-four months of high intensity exercise training resulted in LA greater than LV mechanical remodeling with no observed electric remodeling. Together, these data suggest different thresholds for electrophysiological and mechanical changes may exist in response to exercise training, and provide evidence supporting a potential mechanism by which high intensity exercise training leads to atrial fibrillation.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02039154.