bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia
Authors: Lee Reggie H. , Couto e Silva Alexandre , Lerner Francesca M. , Wilkins Carl S. , Valido Stephen E. , Klein Daniel D. , Wu Celeste Y. , Neumann Jake T. , Della-Morte David , Koslow Stephen H. , Minagar Alireza , Lin Hung Wen 
Published: November 2016

Sympathetic nervous system activity is increased after cardiopulmonary arrest, resulting in vasoconstrictor release from the perivascular sympathetic nerves of cerebral arteries. However, the pathophysiological function of the perivascular sympathetic nerves in the ischemic brain remains unclear. A rat model of global cerebral ischemia (asphyxial cardiac arrest, ACA) was used to investigate perivascular sympathetic nerves of cerebral arteries via bilateral decentralization (preganglionic lesion) of the superior cervical ganglion (SCG). Decentralization of the SCG 5 days before ACA alleviated hypoperfusion and afforded hippocampal neuroprotection and improved functional outcomes. These studies can provide further insights into the functional mechanism(s) of the sympathetic nervous system during ischemia. NEW & NOTEWORTHY Interruption of the perivascular sympathetic nerves can alleviate CA-induced hypoperfusion and neuronal cell death in the CA1 region of the hippocampus to enhance functional learning and memory.
Pulmonary vascular collagen content, not cross-linking, contributes to right ventricular pulsatile afterload and overload in early pulmonary hypertension
Authors: Wang Zhijie , Schreier David A. , Abid Hinnah , Hacker Timothy A. , Chesler Naomi C. 
Published: November 2016

Hypoxic pulmonary hypertension (HPH) is associated with pulmonary artery (PA) remodeling and right ventricular (RV) overload. We have previously uncovered collagen-mediated mechanisms of proximal PA stiffening in early HPH by manipulating collagen degradation and cross-linking using a transgenic mouse strain and a potent collagen cross-link inhibitor, β-aminopropionitrile (BAPN). However, the roles of collagen in distal PA remodeling, overall RV afterload, and RV hypertrophy in HPH remain unknown. Here, we used the same experimental strategy to investigate the effect of pulmonary vascular collagen content and cross-linking on steady and pulsatile RV afterload and on RV hypertrophy in early HPH. Collagenase-resistant mice (Col1a1R/R) and their littermate controls (Col1a1+/+) were exposed to normobaric hypoxia for 10 days with or without BAPN treatment. In vivo pulmonary vascular impedance, a comprehensive measure of RV afterload, was measured via simultaneous RV catheterization and echocardiography. Morphology and collagen accumulation were examined using histological techniques and ELISA in lungs and RVs. In both mouse strains, BAPN did not limit increases in pulmonary arterial pressure or pulmonary vascular resistance, indicating a negligible effect of either collagen content or cross-linking on steady RV afterload. However, BAPN prevented the increase in pulse pressure and RV hypertrophy in Col1a1+/+ mice and these effects were absent in Col1a1R/R mice, suggesting a role for PA collagen content, not cross-linking, in the pulsatile RV afterload. Moreover, we found a significant correlation between pulse pressure and RV hypertrophy, indicating an important role for pulsatile RV afterload in RV overload in early HPH. NEW & NOTEWORTHY The present study found an important role for collagen content, but not collagen cross-linking, in the pulsatile right ventricular (RV) afterload, which is correlated with RV hypertrophy. These results uncover a new collagen-mediated mechanical mechanism of RV dysfunction in early pulmonary hypertension progression. Furthermore, our results suggest that measures and metrics of pulsatile hemodynamics such as pulse pressure and pulse wave velocity are potentially important to cardiovascular mortality in patients with pulmonary hypertension.
Rates of performance loss and neuromuscular activity in men and women during cycling: evidence for a common metabolic basis of muscle fatigue
Authors: Sundberg Christopher W. , Hunter Sandra K. , Bundle Matthew W. 
Published: November 2016

The durations that muscular force and power outputs can be sustained until failure fall predictably on an exponential decline between an individual’s 3-s burst maximum to the maximum performance they can sustain aerobically. The exponential time constants describing these rates of performance loss are similar across individuals, suggesting that a common metabolically based mechanism governs muscle fatigue; however, these conclusions come from studies mainly on men. To test whether the same physiological understanding can be applied to women, we compared the performance-duration relationships and neuromuscular activity between seven men [23.3 ± 1.9 (SD) yr] and seven women (21.7 ± 1.8 yr) from multiple exhaustive bouts of cycle ergometry. Each subject performed trials to obtain the peak 3-s power output (Pmax), the mechanical power at the aerobic maximum (Paer), and 11–14 constant-load bouts eliciting failure between 3 and 300 s. Collectively, men and women performed 180 exhaustive bouts spanning an ~6-fold range of power outputs (118–1116 W) and an ~35-fold range of trial durations (8–283 s). Men generated 66% greater Pmax(956 ± 109 W vs. 632 ± 74 W) and 68% greater Paer(310 ± 47 W vs. 212 ± 15 W) than women. However, the metabolically based time constants describing the time course of performance loss were similar between men (0.020 ± 0.003/s) and women (0.021 ± 0.003/s). Additionally, the fatigue-induced increases in neuromuscular activity did not differ between the sexes when compared relative to the pedal forces at Paer. These data suggest that muscle fatigue during short-duration dynamic exercise has a common metabolically based mechanism determined by the extent that ATP is resynthesized by anaerobic metabolism.NEW & NOTEWORTHY Although men and women differed considerably in their absolute cycling performances, there was no sex difference in the metabolically based exponential time constant that described the performance-duration relationship. Similarly, the fatigue-induced increases in neuromuscular activity were not different between the sexes when compared from a metabolic perspective. These data suggest that men and women have similar rate-limiting mechanisms for short-duration dynamic exercise that are determined by the extent the exercise is supported by anaerobic metabolism.
TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding
Authors: Petrova Penka S. , Viller Natasja Nielsen , Wong Mark , Pang Xinli , Lin Gloria H.Y. , Dodge Karen , Chai Vien , Chen Hui , Lee Vivian , House Violetta , Vigo Noel T. , Jin Debbie , Mutukura Tapfuma , Charbonneau Marilyse , Truong Tran , Viau Stephane , Johnson Lisa D. , Linderoth Emma , Sievers Eric L. , Maleki Vareki Saman , Figueredo Rene , Pampillo Macarena , Koropatnick James , Trudel Suzanne , Mbong Nathan , Jin Liqing , Wang Jean C.Y. , Uger Robert A. 
Published: November 2016

Abstract
Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47–SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication.
Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails.
Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo, TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies.
Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4); 1068–79. ©2016 AACR.
The Efflux Transporter ABCG2 Maintains Prostate Stem Cells
Authors: Sabnis Neha G. , Miller Austin , Titus Mark A. , Huss Wendy J. 
Published: November 2016

Abstract
Prostate stem cells (PSC) are characterized by their intrinsic resistance to androgen deprivation therapy (ADT), possibly due to the lack of androgen receptor (AR) expression. PSCs resistance to ADT and PSC expansion in castration resistant prostate cancer (CRPC) has sparked great interest in using differentiation therapy as an adjuvant to ADT. Understanding the mechanisms, by which PSCs maintain their undifferentiated phenotype, thus has important implications in differentiation therapy. In the prostate, the ATP binding cassette sub-family G member 2 (ABCG2) transporters, which enrich for AR-positive, ADT-resistant PSCs, play an important role in regulating the intracellular androgen levels by effluxing androgens. We hypothesized that the ABCG2-mediated androgen efflux is responsible for maintaining PSCs in an undifferentiated state. Using the HPr-1-AR (nontumorigenic) and CWR-R1 (tumorigenic) prostate cell lines, it was demonstrated that inhibiting the ABCG2-mediated androgen efflux, with Ko143 (ABCG2 inhibitor), increased the nuclear AR expression due to elevated intracellular androgen levels. Increased nuclear translocation of AR is followed by increased expression of AR regulated genes, a delayed cell growth response, and increased luminal differentiation. Furthermore, Ko143 reduced tumor growth rates in mice implanted with ABCG2-expressing CWR-R1 cells. In addition, Ko143-treated mice had more differentiated tumors as evidenced by an increased percentage of CK8+/AR+ luminal cells and decreased percentage of ABCG2-expressing cells. Thus, inhibiting ABCG2-mediated androgen efflux forces the PSCs to undergo an AR-modulated differentiation to an ADT-sensitive luminal phenotype.
Implications: This study identifies the mechanism by which the prostate stem cell marker, ABCG2, plays a role in prostate stem cell maintenance and provides a rationale for targeting ABCG2 for differentiation therapy in prostate cancer. Mol Cancer Res; 15(2); 128–40. ©2016 AACR.
Inflammatory Obesity Phenotypes, Gender Effects, and Subclinical Atherosclerosis in African Americans
Authors: Lin Albert , Lacy Mary E. , Eaton Charles , Correa Adolfo , Wu Wen-Chih 
Published: November 2016

Objective—
Reasons for variations in atherosclerotic burden among individuals with similar levels of obesity are poorly understood, especially in African Americans. This study examines whether high-sensitivity C-reactive protein (hsCRP) is useful for discriminating between benign and high-risk obesity phenotypes for subclinical atherosclerosis in African Americans.

Approach and Results—

Participants from the Jackson Heart Study (n=4682) were stratified into 4 phenotypes based on the presence of National Heart and Lung and Blood Institute definition of obesity or obesity-equivalent (body mass index ≥30 or body mass index 25–30 with waist circumference >102 cm in men and >88 cm in women) and inflammation by hsCRP ≥2 mg/L. Using multivariate regression models, we conducted cross-sectional analyses of the association between inflammatory obesity phenotypes and subclinical atherosclerosis determined by carotid intima–media thickness or coronary artery calcium scores. Sex-specific analyses were conducted given significant interaction for gender (
P
=0.03). The prevalence of obesity or equivalent was 65%, of which 30% did not have inflammation. Conversely, 37% of nonobese individuals had inflammation. Among nonobese men, hsCRP ≥2 mg/L identified a subset of individuals with higher carotid intima–media thickness (adjusted mean difference =0.05, 95% confidence interval 0.02, 0.08 mm) compared with their noninflammatory counterparts. Among obese men, hsCRP <2 mg/L identified a subset of individuals with lower coronary artery calcium compared with their inflammatory counterparts. Among women, associations between hsCRP and carotid intima–media thickness or coronary artery calcium were not found.

Conclusions—
In the largest African American population-based cohort to date, hsCRP was useful in identifying a subset of nonobese men with higher carotid intima–media thickness, but not in women. hsCRP did not identify a subset of obese individuals with less subclinical atherosclerosis.
Map3k8 Modulates Monocyte State and Atherogenesis in ApoE
−/−
Mice
Authors: Sanz-Garcia Carlos , Sánchez Ángela , Contreras-Jurado Constanza , Cales Carmela , Barranquero Cristina , Muñoz Marta , Merino Ramón , Escudero Paula , Sanz Maria-Jesús , Osada Jesús , Aranda Ana , Alemany Susana 
Published: November 2016

Objective—
Map3k8 (Cot/Tpl2) activates the MKK1/2-ERK1/2, MAPK pathway downstream from interleukin-1R, tumor necrosis factor-αR, NOD-2R (nucleotide-binding oligomerization domain-like 2R), adiponectinR, and Toll-like receptors. Map3k8 plays a key role in innate and adaptive immunity and influences inflammatory processes by modulating the functions of different cell types. However, its role in atherogenesis remains unknown. In this study, we analyzed the role of this kinase in this pathology.

Approach and Results—

We show here that Map3k8 deficiency results in smaller numbers of Ly6C
high
CD11c
low
and Ly6C
low
CD11c
high
monocytes in ApoE
−
/−
mice fed a high-fat diet (HFD). Map3k8
−/−
ApoE
−/−
monocytes displayed high rates of apoptosis and reduced amounts of Nr4a1, a transcription factor known to modulate apoptosis in Ly6C
low
CD11c
high
monocytes. Map3k8
−/−
ApoE
−/−
splenocytes and macrophages showed irregular patterns of cytokine and chemokine expression. Map3k8 deficiency altered cell adhesion and migration in vivo and decreased CCR2 expression, a determinant chemokine receptor for monocyte mobilization, on circulating Ly6C
high
CD11c
low
monocytes. Map3k8
−/−
ApoE
−/−
mice fed an HFD showed decreased cellular infiltration in the atherosclerotic plaque, with low lipid content. Lesions had similar size after Map3k8
+/+
ApoE
−/−
bone marrow transplant into Map3k8
−/−
ApoE
−/−
and Map3k8
+/+
ApoE
−/−
mice fed an HFD, whereas smaller plaques were observed after the transplantation of bone marrow lacking both ApoE and Map3k8.

Conclusions—

Map3k8 decreases apoptosis of monocytes and enhances CCR2 expression on Ly6C
high
CD11c
low
monocytes of ApoE
−/−
mice fed an HFD. These findings explain the smaller aortic lesions in ApoE
−/−
mice with Map3k8
−/−
ApoE
−/−
bone marrow cells fed an HFD, supporting further studies of Map3k8 as an antiatherosclerotic target.
Lipoprotein(a) Levels and Recurrent Vascular Events After First Ischemic Stroke
Authors: Lange Kristin S. , Nave Alexander H. , Liman Thomas G. , Grittner Ulrike , Endres Matthias , Ebinger Martin 
Published: November 2016

Background and Purpose—
The association of elevated lipoprotein(a) (Lp(a)) levels and the incidence of cardiovascular disease, especially coronary heart disease and ischemic stroke, is well established. However, evidence on the association between Lp(a) levels and residual vascular risk in stroke survivors is lacking. We aimed to elucidate the risk for recurrent cardiovascular and cerebrovascular events in the patients with first-ever ischemic stroke with elevated Lp(a).

Methods—
All patients with acute ischemic stroke who participated in the prospective Berlin C&S study (Cream & Sugar) between January 2009 and August 2014 with available 12-month follow-up data and stored blood samples were eligible for inclusion. Lp(a) levels were determined in serum samples using an isoform-insensitive nephelometry assay. We assessed the risk for the composite vascular end point of ischemic stroke, transient ischemic attack, myocardial infarction, nonelective coronary revascularization, and cardiovascular death with elevated Lp(a) defined as >30 mg/dL using Cox regression analyses.

Results—

Of 465 C&S study participants, 250 patients were included into this substudy with a median National Institutes of Health Stroke Scale score of 2 (1–4). Twenty-six patients (10%) experienced a recurrent vascular event during follow-up. Among patients with normal Lp(a) levels, 11 of 157 subjects (7%) experienced an event at a median time of 161 days (interquartile range, 19–196 days), whereas in patients with elevated Lp(a) levels, 15 of 93 subjects (16%) experienced an event at a median time of 48 days (interquartile range, 9–194 days;
P
=0.026). The risk for a recurrent event was significantly higher in patients with elevated Lp(a) levels after adjustment for potential confounders (hazard ratio, 2.60; 95% confidence interval, 1.19–5.67;
P
=0.016).

Conclusions—
Elevated Lp(a) levels are associated with a higher risk for combined vascular event recurrence in patients with acute, first-ever ischemic stroke. This finding should be validated in larger, multicenter trials.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01378468.
Microsurgery for ARUBA Trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation)–Eligible Unruptured Brain Arteriovenous Malformations
Authors: Wong Johnny , Slomovic Alana , Ibrahim George , Radovanovic Ivan , Tymianski Michael 
Published: November 2016

Background and Purpose—
The management of unruptured brain arteriovenous malformations (ubAVMs) remains controversial despite ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation), a controlled trial that suggested superiority of conservative management over intervention. However, microsurgery occurred in only 14.9% of ARUBA intervention cases, raising concerns about the study’s generalizability. Our purpose was to evaluate whether, in a larger ARUBA-eligible ubAVM population, microsurgery produces acceptable outcomes.

Methods—
Demographic data, AVM characteristics, and treatment outcomes were evaluated in 155 ARUBA-eligible bAVMs treated with microsurgery between 1994 and 2014. Outcomes were rates of early disabling deficits and permanent disabling deficits with modified Rankin Scale score ≥3 or any permanent neurological deficits with modified Rankin Scale score ≥1. Covariates associated with outcomes were determined by regression analysis.

Results—

Of 977 AVM patients, 155 ARUBA-eligible patients had microsurgical resection (71.6% surgery only and 25.2% with preoperative embolization). Mean follow-up was 36.1 months. Complete obliteration was achieved in 94.2% after initial surgery and 98.1% on final angiography. Early disabling deficits and permanent disabling deficits occurred in 12.3% and 4.5%, respectively, whereas any permanent neurological deficit (modified Rankin Scale score ≥1) occurred in 16.1%. Among ubAVM of Spetzler–Martin grades 1 and 2, complete obliteration occurred in 99.2%, with early disabling deficits and permanent disabling deficits occurring in 9.3% and 3.4%, respectively. Major bleeding was the only significant predictor of early disabling deficits on multivariate analysis (
P
<0.001).

Conclusions—
Microsurgery in this cohort produced less disabling deficits than ARUBA with similar morbidity and AVM obliteration as other cohort series. This disparity between our results and ARUBA suggests that future controlled trials should focus on the safety and efficacy of microsurgery with or without adjunctive embolization in carefully selected ubAVM patients.
Between Tritheism and Sabellianism
Authors: Krausmüller Dirk 
Published: November 2016

This article focuses on two confessions of faith, which were composed in the late eleventh century by the philosopher John Italos and by the monk Nicetas Stethatos. In-depth analysis of selected passages shows that the two men subscribed to a Trinitarian theology that could be considered heretical. They denied the existence of a common divine substance that could safeguard the oneness of God and instead emphasised the closeness of the hypostases to each other, which made it impossible for them to accord to the hypostases the distinguishing function that the Cappadocians had given them. Thus it can be argued that it was their Tritheism that pushed them towards a ‘Sabellian’ solution.
Eddy Influences on the Strength of the Hadley Circulation: Dynamic and Thermodynamic Perspectives
Authors: Singh Martin S. , Kuang Zhiming , Tian Yang 
Published: November 2016

Abstract
The strength of the equinoctial Hadley circulation (HC) is investigated in idealized simulations conducted on an equatorial beta plane in which the zonal width of the domain is varied to either permit or suppress large-scale eddies. The presence of such eddies is found to amplify the HC by a factor of 2–3 in simulations with slab-ocean boundary conditions or with a simple representation of ocean heat transport. Additional simulations in which the eddy forcing is prescribed externally indicate that this amplification is primarily associated with large-scale eddy momentum fluxes rather than large-scale eddy heat fluxes. These results contrast with results from simulations with fixed distributions of sea surface temperature (SST), in which the HC strength has been found to be relatively insensitive to large-scale eddy momentum fluxes.
In both the interactive- and fixed-SST cases, the influence of nonlinear momentum advection by the mean flow complicates efforts to use the angular-momentum budget to constrain the HC strength. However, a strong relationship is found between the HC strength and a measure of the meridional gradient of boundary layer entropy, indicating a possible thermodynamic control on the HC strength. In simulations with interactive SSTs, meridional eddy momentum fluxes affect the boundary layer entropy by inducing a low-level frictional flow that reduces the ability of the HC to transport heat poleward. This allows for the maintenance of a large meridional entropy gradient in the presence of a strong HC. The results highlight the potential utility of a thermodynamic perspective for understanding the HC in flow regimes for which dynamical constraints may be difficult to apply.