bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skeletal muscle mitochondrial protein synthesis and respiration in response to the energetic stress of an ultra-endurance race
Authors: Konopka Adam R. , Castor William M. , Wolff Christopher A. , Musci Robert V. , Reid Justin J. , Laurin Jaime L. , Valenti Zackary J. , Hamilton Karyn L. , Miller Benjamin F. 
Published: September 2017

The 2016 Colorado Trail Race (CTR) was an ultra-endurance mountain bike race in which competitors cycled for up to 24 h/day between altitudes of 1,675 and 4,025 m to complete 800 km and 21,000 m of elevation gain. In one athlete, we had the unique opportunity to characterize skeletal muscle protein synthesis and mitochondrial respiration in response to a normal activity control period (CON) and the CTR. We hypothesized that mitochondrial protein synthesis would be elevated and mitochondrial respiration would be maintained during the extreme stresses of the CTR. Titrated and bolus doses of ADP were provided to determine substrate-specific oxidative phosphorylation (OXPHOS) and electron transport system (ETS) capacities in permeabilized muscle fibers via high-resolution respirometry. Protein synthetic rates were determined by daily oral consumption of deuterium oxide (2H2O). The endurance athlete had OXPHOS (226 pmol·s−1·mg tissue−1) and ETS (231 pmol·s−1·mg tissue−1) capacities that rank among the highest published to date in humans. Mitochondrial (3.2-fold), cytoplasmic (2.3-fold), and myofibrillar (1.5-fold) protein synthesis rates were greater during CTR compared with CON. With titrated ADP doses, the apparent Km of ADP, OXPHOS, and ETS increased after the CTR. With provision of ADP boluses after the CTR, the addition of fatty acids (−12 and −14%) mitigated the decline in OXPHOS and ETS capacity during carbohydrate-supported respiration (−26 and −31%). In the face of extreme stresses during the CTR, elevated rates of mitochondrial protein synthesis may contribute to rapid adaptations in mitochondrial bioenergetics. NEW & NOTEWORTHY The mechanisms that maintain skeletal muscle function during extreme stresses remain incompletely understood. In the current study, greater rates of mitochondrial protein synthesis during the energetic demands of ultra-endurance exercise may contribute to rapid adaptations in mitochondrial bioenergetics. The endurance athlete herein achieved mitochondrial respiratory capacities among the highest published for humans. Greater mitochondrial protein synthesis during ultra-endurance exercise may contribute to improved mitochondrial respiration and serve as a mechanism to resist cellular energetic stresses.
Transplantation of iPS-Derived Tumor Cells with a Homozygous MHC Haplotype Induces GRP94 Antibody Production in MHC-Matched Macaques
Authors: Ishigaki Hirohito , Maeda Toshinaga , Inoue Hirokazu , Akagi Tsuyoshi , Sasamura Takako , Ishida Hideaki , Inubushi Toshiro , Okahara Junko , Shiina Takashi , Nakayama Misako , Itoh Yasushi , Ogasawara Kazumasa 
Published: September 2017

Abstract
Immune surveillance is a critical component of the antitumor response in vivo, yet the specific components of the immune system involved in this regulatory response remain unclear. In this study, we demonstrate that autoantibodies can mitigate tumor growth in vitro and in vivo. We generated two cancer cell lines, embryonal carcinoma and glioblastoma cell lines, from monkey-induced pluripotent stem cells (iPSC) carrying a homozygous haplotype of major histocompatibility complex (MHC, Mafa in Macaca fascicularis). To establish a monkey cancer model, we transplanted these cells into monkeys carrying the matched Mafa haplotype in one of the chromosomes. Neither Mafa-homozygous cancer cell line grew in monkeys carrying the matched Mafa haplotype heterozygously. We detected in the plasma of these monkeys an IgG autoantibody against GRP94, a heat shock protein. Injection of the plasma prevented growth of the tumor cells in immunodeficient mice, whereas plasma IgG depleted of GRP94 IgG exhibited reduced killing activity against cancer cells in vitro. These results indicate that humoral immunity, including autoantibodies against GRP94, plays a role in cancer immune surveillance. Cancer Res; 77(21); 6001–10. ©2017 AACR.
Class III PI3K Positively Regulates Platelet Activation and Thrombosis via PI(3)P-Directed Function of NADPH Oxidase
Authors: Liu Yangyang , Hu Mengjiao , Luo Dongjiao , Yue Ming , Wang Shuai , Chen Xiaoyan , Zhou Yangfan , Wang Yi , Cai Yanchun , Hu Xiaolan , Ke Yuehai , Yang Zhongzhou , Hu Hu 
Published: September 2017

Objective—
Class III phosphoinositide 3-kinase, also known as VPS34 (vacuolar protein sorting 34), is a highly conserved enzyme regulating important cellular functions such as NADPH oxidase (NOX) assembly, membrane trafficking, and autophagy. Although VPS34 is expressed in platelets, its involvement in platelet activation remains unclear. Herein, we investigated the role of VPS34 in platelet activation and thrombus formation using VPS34 knockout mice.

Approach and Results—

Platelet-specific VPS34-deficient mice were generated and characterized. VPS34 deficiency in platelets did not influence tail bleeding time. In a ferric chloride–induced mesenteric arteriolar thrombosis model, VPS34
−/−
mice exhibited a prolonged vessel occlusion time compared with wild-type mice (42.05±4.09 versus 18.30±2.47 minutes). In an in vitro microfluidic whole-blood perfusion assay, thrombus formation on collagen under arterial shear was significantly reduced for VPS34
−/−
platelets. VPS34
−/−
platelets displayed an impaired aggregation and dense granule secretion in response to low doses of collagen or thrombin. VPS34 deficiency delayed clot retraction but did not influence platelet spreading on fibrinogen. We also demonstrated that VPS34 deficiency altered the basal level of autophagy in resting platelets and hampered NOX assembly and mTOR (mammalian target of rapamycin) signaling during platelet activation. Importantly, we identified the NOX-dependent reactive oxygen species generation as the major downstream effector of VPS34, which in turn can mediate platelet activation. In addition, by using a specific inhibitor 3-methyladenine, VPS34 was found to operate through a similar NOX-dependent mechanism to promote human platelet activation.

Conclusions—
Platelet VPS34 is critical for thrombosis but dispensable for hemostasis. VPS34 regulates platelet activation by influencing NOX assembly.
Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways
Authors: Nakao Tetsushi , Horie Takahiro , Baba Osamu , Nishiga Masataka , Nishino Tomohiro , Izuhara Masayasu , Kuwabara Yasuhide , Nishi Hitoo , Usami Shunsuke , Nakazeki Fumiko , Ide Yuya , Koyama Satoshi , Kimura Masahiro , Sowa Naoya , Ohno Satoko , Aoki Hiroki , Hasegawa Koji , Sakamoto Kazuhisa , Minatoya Kenji , Kimura Takeshi , Ono Koh 
Published: September 2017

Objective—
Abdominal aortic aneurysm (AAA) is an increasingly prevalent and ultimately fatal disease with no effective pharmacological treatment. Because matrix degradation induced by vascular inflammation is the major pathophysiology of AAA, attenuation of this inflammation may improve its outcome. Previous studies suggested that miR-33 (microRNA-33) inhibition and genetic ablation of miR-33 increased serum high-density lipoprotein cholesterol and attenuated atherosclerosis.

Approach and Results—

MiR-33a-5p expression in central zone of human AAA was higher than marginal zone. MiR-33 deletion attenuated AAA formation in both mouse models of angiotensin II– and calcium chloride–induced AAA. Reduced macrophage accumulation and monocyte chemotactic protein-1 expression were observed in calcium chloride–induced AAA walls in miR-33
−/−
mice. In vitro experiments revealed that peritoneal macrophages from miR-33
−/−
mice showed reduced matrix metalloproteinase 9 expression levels via c-Jun N-terminal kinase inactivation. Primary aortic vascular smooth muscle cells from miR-33
−/−
mice showed reduced monocyte chemotactic protein-1 expression by p38 mitogen-activated protein kinase attenuation. Both of the inactivation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were possibly because of the increase of ATP-binding cassette transporter A1 that is a well-known target of miR-33. Moreover, high-density lipoprotein cholesterol derived from miR-33
−/−
mice reduced expression of matrix metalloproteinase 9 in macrophages and monocyte chemotactic protein-1 in vascular smooth muscle cells. Bone marrow transplantation experiments indicated that miR-33–deficient bone marrow cells ameliorated AAA formation in wild-type recipients. MiR-33 deficiency in recipient mice was also shown to contribute the inhibition of AAA formation.

Conclusions—
These data strongly suggest that inhibition of miR-33 will be effective as a novel strategy for treating AAA.
Potential Cardiovascular and Total Mortality Benefits of Air Pollution Control in Urban China
Authors: Huang Chen , Moran Andrew E. , Coxson Pamela G. , Yang Xueli , Liu Fangchao , Cao Jie , Chen Kai , Wang Miao , He Jiang , Goldman Lee , Zhao Dong , Kinney Patrick L. , Gu Dongfeng 
Published: September 2017

Background:
Outdoor air pollution ranks fourth among preventable causes of China’s burden of disease. We hypothesized that the magnitude of health gains from air quality improvement in urban China could compare with achieving recommended blood pressure or smoking control goals.

Methods:

The Cardiovascular Disease Policy Model–China projected coronary heart disease, stroke, and all-cause deaths in urban Chinese adults 35 to 84 years of age from 2017 to 2030 if recent air quality (particulate matter with aerodynamic diameter ≤2.5 µm, PM
2.5
) and traditional cardiovascular risk factor trends continue. We projected life-years gained if urban China were to reach 1 of 3 air quality goals: Beijing Olympic Games level (mean PM
2.5
, 55 μg/m
3
), China Class II standard (35 μg/m
3
), or World Health Organization standard (10 μg/m
3
). We compared projected air pollution reduction control benefits with potential benefits of reaching World Health Organization hypertension and tobacco control goals.

Results:

Mean PM
2.5
reduction to Beijing Olympic levels by 2030 would gain ≈241,000 (95% uncertainty interval, 189 000–293 000) life-years annually. Achieving either the China Class II or World Health Organization PM
2.5
standard would yield greater health benefits (992 000 [95% uncertainty interval, 790 000–1 180 000] or 1 827 000 [95% uncertainty interval, 1 481 00–2 129 000] annual life-years gained, respectively) than World Health Organization–recommended goals of 25% improvement in systolic hypertension control and 30% reduction in smoking combined (928 000 [95% uncertainty interval, 830 000–1 033 000] life-years).

Conclusions:
Air quality improvement in different scenarios could lead to graded health benefits ranging from 241 000 life-years gained to much greater benefits equal to or greater than the combined benefits of 25% improvement in systolic hypertension control and 30% smoking reduction.
Prospective Association of Physical Activity and Heart Failure Hospitalizations Among Black Adults With Normal Ejection Fraction: The Jackson Heart Study
Authors: Koo Patrick , Gjelsvik Annie , Choudhary Gaurav , Wu Wen‐Chih , Wang Wei , McCool F. Dennis , Eaton Charles B. 
Published: September 2017

Background

Given high rates of obesity, hypertension, and diabetes mellitus, black persons are at risk to develop heart failure. The association of moderate to vigorous physical activity (
MVPA
) and heart failure in black adults is underresearched. The purpose of this study was to explore whether greater
MVPA
was associated with lower risk of heart failure hospitalizations (HFHs) among black adults with normal ejection fractions.

Methods and Results

We performed a prospective analysis of 4066 black adults who participated in the Jackson Heart Study and who had physical activity measured, had normal ejection fraction on 2‐dimensional echocardiograms, and were followed for 7 years for incident HFH. We used Cox proportional regression analyses adjusted for age, sex, body mass index, smoking status, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, coronary heart disease, atrial fibrillation, and chronic kidney disease and examined effect modification by sex and body mass index. Of the eligible population, 1925 participants, according to the duration of
MVPA
, had poor health (0 minutes/week), 1332 had intermediate health (1–149 minutes/week), and 809 had ideal health (≥150 minutes/week). There were 168 incident
HFHs
. MVPA for intermediate and ideal health was associated with decreasing risk of incident
HFH
(hazard ratio: 0.70 [95% confidence interval, 49–1.00] and 0.35 [95% confidence interval, 0.19–0.64], respectively;
P
trend
=0.003). The full model revealed hazard ratios of 0.74 [95% confidence interval, 0.52–1.07] and 0.41 [95% confidence interval, 0.22–0.74], respectively. There was no effect modification between
MVPA
and body mass index or sex on incident
HFH
.

Conclusions

A dose‐response relationship between increasing levels of
MVPA
and protection from incident
HFH
was found in black men and women with normal ejection fractions.
Frequency of Adverse Event Monitoring in Ambulatory Patients on Amiodarone or Dofetilide
Authors: Rickard Joshua P. , Negrelli Jenna , Olson Jeffery L. , Dick Travis 
Published: September 2017

Background: Published studies state that adherence to regular laboratory assessments for anti-arrhythmic drugs is as low as 20%. Monitoring adherence is important as other studies have shown that up to 93% of patients on amiodarone experience an adverse drug event leading to a potentially lethal event. Objective: To determine whether patients prescribed amiodarone or dofetilide are being monitored according to package labeling and guideline recommendations for adverse events. Methods: Patients prescribed amiodarone or dofetilide from a 2-year period were eligible for inclusion. Patients with ventricular arrhythmias, prescribed more than 1 anti-arrhythmic agent, or received anti-arrhythmic monitoring outside the health-care system were excluded. Adherence to monitoring parameters was assessed according to labeled recommendations and published guidelines. The primary objective was to determine the frequency of baseline and follow-up monitoring recommendations for patients receiving amiodarone or dofetilide. The secondary objective was to determine rates of adverse drug events. Results: One hundred patients were evaluated (amiodarone n = 50, dofetilide n = 50). Average rates of baseline and follow-up amiodarone monitoring parameters were 55% and 57%, respectively. Average rates of baseline and follow-up dofetilide monitoring were 99.6% and 85%, respectively. There was a statistically significant difference in abnormally elevated thyroid-stimulating hormone levels (8%-30%, P ≤ .005) after patients were prescribed amiodarone. Twelve percent of patients taking dofetilide had an increase in QTc interval by >15%. Conclusions: Amiodarone adverse event monitoring was lower than dofetilide in this cohort. Improving the monitoring of these agents may decrease morbidity risk in this population.
Who is Overdosing? An Updated Picture of Overdose Deaths From 2008 to 2015
Authors: Eigner Gregory , Henriksen Brian , Huynh Philip , Murphy David , Brubaker Christopher , Sanders Jana , McMahan Deborah 
Published: September 2017

Purpose: To determine the role of opioids in drug overdose deaths in Allen County, Indiana between January 1, 2008, and December 31, 2015. Methods: File review of 418 overdose deaths was performed using Indiana State Department of Health death certificates available through the Allen County Coroner’s Office. Data from autopsy and toxicology reports and coroner-requested prescribing data from Indiana’s Prescription Monitoring Program were reviewed. Cause of death and available data were analyzed to identify patterns and trends related to overdose deaths. Results: Four hundred eighteen drug overdose deaths were identified (336 accidental, 66 intentional, and 16 undetermined). Mean age was 42.5 years, 88.5% were Caucasian, and 68.7% were employed. The majority of deaths occurred at a place of residence (71.4%) and with other people present (57.5% of the time). Depression was the most common comorbidity identified. The most common drug classes identified by toxicology were opioids, followed by benzodiazepines. Significant increases in both heroin (35% of deaths in 2015 versus 8.2% in 2013) and fentanyl (30% of deaths in 2015 versus 2.2% in 2011) were observed. Conclusions: Drug overdose continues to be a significant cause of death in Allen County. The majority of deaths were accidental and in relatively young, employed individuals. Prevention and awareness strategies should be encouraged, given that the majority of overdose deaths occurred at a place of residence with other people frequently present. Additional concerns about patterns of drug use were confirmed with marked increases in both heroin and fentanyl contributing to overdose deaths in the latter part of the study.
Frontline Science: Proliferation of Ly6C+ monocytes during urinary tract infections is regulated by IL-6 trans-signaling
Authors: Dixit Akanksha , Bottek Jenny , Beerlage Anna-Lena , Schuettpelz Jana , Thiebes Stephanie , Brenzel Alexandra , Garbers Christoph , Rose-John Stefan , Mittrücker Hans-Willi , Squire Anthony , Engel Daniel R 
Published: September 2017

Abstract
Ly6C+ monocytes are important components of the innate immune defense against infections. These cells have been shown to proliferate in the bone marrow of mice with systemic infections. However, the proliferative capacity of Ly6C+ monocytes in infected peripheral tissues as well as the associated regulatory mechanisms remain unclear. In this study, we analyzed the proliferative capacity of Ly6C+ monocytes in the urinary bladder after infection with uropathogenic E. coli, one of the most prevalent pathogen worldwide, and in LPS-induced peritonitis. We show that Ly6C+ monocytes proliferated in the bladder after infection with uropathogenic E. coli and in the peritoneum after intraperitoneal injection of LPS. We identified IL-6, a molecule that is highly expressed in infections, as a crucial regulator of Ly6C+ monocyte proliferation. Inhibition of IL-6 via administration of antibodies against IL-6 or gp130 impeded Ly6C+ monocyte proliferation. Furthermore, repression of IL-6 trans-signaling via administration of soluble gp130 markedly reduced the proliferation of Ly6C+ monocytes. Overall, this study describes the proliferation of Ly6C+ monocytes using models of urinary tract infection and LPS-induced peritonitis. IL-6 trans-signaling was identified as the regulator of Ly6C+ monocyte proliferation.
Improving life expectancy in people with serious mental illness: Should we place more emphasis on primary prevention?
Authors: Ilyas Athif , Chesney Edward , Patel Rashmi 
Published: September 2017

SummaryPeople with serious mental illness have a reduced life expectancy that is partly attributable to increased cardiovascular disease. One approach to address this is regular physical health monitoring. However, physical health monitoring is poorly implemented in everyday clinical practice and there is little evidence to suggest that it improves physical health. We argue that greater emphasis should be placed on primary prevention strategies such as assertive smoking cessation, dietary and exercise interventions and more judicious psychotropic prescribing.
Role of the ECM in notochord formation, function and disease
Authors: Trapani Valeria , Bonaldo Paolo , Corallo Diana 
Published: September 2017

ABSTRACT
The notochord is a midline structure common to all chordate animals; it provides mechanical and signaling cues for the developing embryo. In vertebrates, the notochord plays key functions during embryogenesis, being a source of developmental signals that pattern the surrounding tissues. It is composed of a core of vacuolated cells surrounded by an epithelial-like sheath of cells that secrete a thick peri-notochordal basement membrane made of different extracellular matrix (ECM) proteins. The correct deposition and organization of the ECM is essential for proper notochord morphogenesis and function. Work carried out in the past two decades has allowed researchers to dissect the contribution of different ECM components to this embryonic tissue. Here, we will provide an overview of these genetic and mechanistic studies. In particular, we highlight the specific functions of distinct matrix molecules in regulating notochord development and notochord-derived signals. Moreover, we also discuss the involvement of ECM synthesis and its remodeling in the pathogenesis of chordoma, a malignant bone cancer that originates from remnants of notochord remaining after embryogenesis.
Human microcephaly ASPM protein is a spindle pole-focusing factor that functions redundantly with CDK5RAP2
Authors: Tungadi Elsa A. , Ito Ami , Kiyomitsu Tomomi , Goshima Gohta 
Published: September 2017

ABSTRACT
Nonsense mutations in the ASPM gene have been most frequently identified among familial microcephaly patients. Depletion of the Drosophila orthologue (asp) causes spindle pole unfocusing during mitosis in multiple cell types. However, it remains unknown whether human ASPM has a similar function. Here, by performing CRISPR-based gene knockout (KO) and RNA interference combined with auxin-inducible degron, we show that ASPM functions in spindle pole organisation during mitotic metaphase redundantly with another microcephaly protein, CDK5RAP2 (also called CEP215), in human tissue culture cells. Deletion of the ASPM gene alone did not affect spindle morphology or mitotic progression. However, when the pericentriolar material protein CDK5RAP2 was depleted in ASPM KO cells, spindle poles were unfocused during prometaphase, and anaphase onset was significantly delayed. The phenotypic analysis of CDK5RAP2-depleted cells suggested that the pole-focusing function of CDK5RAP2 is independent of its known function to localise the kinesin-14 motor HSET (also known as KIFC1) or activate the γ-tubulin complex. Finally, a hypomorphic mutation identified in ASPM microcephaly patients similarly caused spindle pole unfocusing in the absence of CDK5RAP2, suggesting a possible link between spindle pole disorganisation and microcephaly.