bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of performance fatigability during a self-paced exercise
Authors: Azevedo Rafael de Almeida , Cruz Ramon , Couto Patrícia , Silva-Cavalcante Marcos David , Boari Daniel , Lima-Silva Adriano E. , Millet Guillaume Y. , Bertuzzi Romulo 
Published: July 2019

Pacing during a high-intensity cycling time trial (TT) appears to prevent premature task failure, but the performance fatigability during a self-paced exercise is currently unknown. Therefore, the current study characterized the time course of performance fatigability during a 4-km TT. Eleven male cyclists performed three separated TTs in a crossover, counterbalanced design. The TTs lasted until the end of the fast-start (FS; 600 ± 205 m), even-pace (EP; 3,600 ± 190 m), and end-spurt (ES; 4,000 m) phases. Performance fatigability was characterized by using isometric maximal voluntary contractions (IMVCs), whereas the muscle activation [i.e., voluntary activation (VA)] and contractile function of knee extensors [e.g., peak torque of potentiated twitches (TwPt)] were evaluated using electrically evoked contractions performed before and 1 min after each specific part of the trial. Gas exchange, power output (PO), and electromyographic activity (EMG) were also recorded. EMG/PO showed an abrupt increase followed by a continuous decrease toward the end of FS, resulting in a drop in IMVC (−12%), VA (−8%), and TwPt (−23%). EMG/PO was stable during EP, with no additional drop on IMVC, VA, or TwPt (−12%, −6%, and −22%, respectively). EMG/PO increased abruptly during the ES, but there was no change in IMVCs, VA, or TwPt (−13%, −8%, and −26%, respectively). These findings demonstrate that the performance fatigability during a self-paced exercise is characterized by a large drop in contractile function and muscle activation at the beginning of the trial (i.e., FS), without additional change during the middle and end phases (i.e., EP and ES). NEW & NOTEWORTHY The time course of performance fatigability throughout a self-paced exercise is currently unknown. The results showed that a large amount of muscle activation and contractile function impairments are attained early on a self-paced exercise (first ∼15% of the total time trial distance) and maintained throughout the test. This novel finding characterizes the performance fatigability from a contractile function and muscle activation perspective, which brings new insights for future studies focused on real-world exercise training and competition.
Vascular-ventricular coupling during exercise is not affected by exaggerated blood pressures in endurance-trained athletes
Authors: Currie Katharine D. , Sasson Zion , Goodman Jack M. 
Published: July 2019

This study sought to examine whether cardiovascular performance during exercise, assessed using the vascular-ventricular coupling index (VVC), was affected by exaggerated blood pressure (EBP) responses in endurance-trained athletes. Subjects were middle-aged endurance-trained men and women. Blood pressure measurements and left ventricular echocardiography were performed in a semiupright position at rest and during steady-state cycling at workloads that elicited 100–110 beats/min ( stage 1) and 130–140 beats/min ( stage 2). These data were used to calculate effective arterial elastance index ( EaI), left ventricular end-systolic elastance index ( ELVI), and their ratio (VVC). Additional measurements of left ventricular volumes and function (i.e., stroke volume, cardiac output, and longitudinal strain) and indirect assessments of peripheral vascular function (i.e., total arterial compliance and peripheral vascular resistance) were examined. Fourteen subjects with EBP (EBP+, 50% men) and 14 sex-matched subjects without EBP (EBP−) participated, with results presented as EBP+ versus EBP−. EaI and ELVI increased from rest to exercise while VVC decreased, but only ELVI was different between groups at stage 1 [7.6 (1.8) vs. 6.4 (1.0) mmHg·ml−1·m−2, P = 0.045] and stage 2 [10.3 (1.6) vs. 8.0 (1.7) mmHg·ml−1·m−2, P < 0.001]. Additional comparisons revealed no group difference in the contribution of the Frank-Starling mechanism or left ventricular and peripheral vascular function during exercise. The cardiovascular adjustment to exercise in athletes with EBP is achieved through a matched increase in both EaI and ELVI, and the absence of between-group differences in left ventricular or peripheral vascular function suggests that other factors may contribute to the EBP response. NEW & NOTEWORTHY Cardiovascular performance during submaximal exercise, assessed using vascular-ventricular coupling, is unaffected by exaggerated blood pressure (EBP) responses in endurance-trained athletes. The underlying mechanisms of EBP in athletes remain unknown as changes in left ventricular and peripheral vascular function during exercise were similar in athletes with and without EBP.
Exogenous neuromodulation of spinal neurons induces beta-band coherence during self-sustained discharge of hind limb motor unit populations
Authors: Thompson Christopher K. , Johnson Michael D. , Negro Francesco , Mcpherson Laura Miller , Farina Dario , Heckman Charles J. 
Published: July 2019

The spontaneous or self-sustained discharge of spinal motoneurons can be observed in both animals and humans. Although the origins of this self-sustained discharge are not fully known, it can be generated by activation of persistent inward currents intrinsic to the motoneuron. If self-sustained discharge is generated exclusively through this intrinsic mechanism, the discharge of individual motor units will be relatively independent of one another. Alternatively, if increased activation of premotor circuits underlies this prolonged discharge of spinal motoneurons, we would expect correlated activity among motoneurons. Our aim is to assess potential synaptic drive by quantifying coherence during self-sustained discharge of spinal motoneurons. Electromyographic activity was collected from 20 decerebrate animals using a 64-channel electrode grid placed on the isolated soleus muscle before and following intrathecal administration of methoxamine, a selective α1-noradrenergic agonist. Sustained muscle activity was recorded and decomposed into the discharge times of ~10–30 concurrently active individual motor units. Consistent with previous reports, the self-sustained discharge of motor units occurred at low mean discharge rates with low-interspike variability. Before methoxamine administration, significant low-frequency coherence (<2 Hz) was observed, while minimal coherence was observed within higher frequency bands. Following intrathecal administration of methoxamine, increases in motor unit discharge rates and strong coherence in both the low-frequency and 15- to 30-Hz beta bands were observed. These data demonstrate beta-band coherence among motor units can be observed through noncortical mechanisms and that neuromodulation of spinal/brainstem neurons greatly influences coherent discharge within spinal motor pools.NEW & NOTEWORTHY The correlated discharge of spinal motoneurons is often used to describe the input to the motor pool. We demonstrate spinal/brainstem neurons devoid of cortical input can generate correlated motor unit discharge in the 15- to 30-Hz beta band, which is amplified through neuromodulation. Activity in the beta band is often ascribed to cortical drive in humans; however, these data demonstrate the capability of the mammalian segmental motor system to generate and modulate this coherent state of motor unit discharge.
Dietary nitrate supplementation enhances cerebrovascular CO2 reactivity in a sex-specific manner
Authors: Fan Jui-Lin , O’Donnell Terrence , Gray Clint Lee , Croft Kevin , Noakes Annabel Kate , Koch Henrietta , Tzeng Yu-Chieh 
Published: July 2019

Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction, and increased NO has the potential to enhance cerebral blood flow (CBF). Dietary supplementation with sodium nitrate, a precursor of NO, could improve cerebrovascular function, but this has not been investigated. In 17 individuals, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg−1·day −1) on cerebrovascular function using a randomized, single-blinded placebo-controlled crossover design. We hypothesized that 7-day dietary nitrate supplementation increases CBF response to CO2 (cerebrovascular CO2 reactivity) and cerebral autoregulation (CA). We assessed middle cerebral artery blood velocity (MCAv) and blood pressure (BP) at rest and during CO2 breathing. Transfer function analysis was performed on resting beat-to-beat MCAv and BP to determine CA, from which phase, gain, and coherence of the BP-MCAv data were derived. Dietary nitrate elevated plasma nitrate concentration by ~420% ( P < 0.001) and lowered gain ( d = 1.2, P = 0.025) and phase of the BP-MCAv signal compared with placebo treatment ( d = 0.7, P = 0.043), while coherence was unaffected ( P = 0.122). Dietary nitrate increased the MCAv-CO2 slope in a sex-specific manner (interaction: P = 0.016). Dietary nitrate increased the MCAv-CO2 slope in men ( d = 1.0, P = 0.014 vs. placebo), but had no effect in women ( P = 0.919). Our data demonstrate that dietary nitrate greatly increased cerebrovascular CO2 reactivity in healthy individuals, while its effect on CA remains unclear. The selective increase in the MCAv-CO2 slope observed in men indicates a clear sexual dimorphic role of NO in cerebrovascular function. NEW & NOTEWORTHY We found dietary nitrate supplementation improved the brain blood vessels’ response to CO2, cerebrovascular CO2 reactivity, without affecting blood pressure in a group of healthy individuals. Meanwhile, the effect of dietary nitrate on the relationship between blood pressure and brain blood flow, cerebral autoregulation, was inconclusive. The improvement in cerebrovascular CO2 reactivity was only observed in the male participants, alluding to a sex difference in the effect of dietary nitrate on brain blood flow control. Our findings indicate that dietary nitrate could be an effective strategy to enhance cerebrovascular CO2 reactivity.
Receptor Tyrosine Kinase Signaling Networks Define Sensitivity to ERBB Inhibition and Stratify Kras-Mutant Lung Cancers
Authors: Talwelkar Sarang S. , Nagaraj Ashwini S. , Devlin Jennifer R. , Hemmes Annabrita , Potdar Swapnil , Kiss Elina A. , Saharinen Pipsa , Salmenkivi Kaisa , Mäyränpää Mikko I. , Wennerberg Krister , Verschuren Emmy W. 
Published: July 2019

Abstract
Most non–small cell lung cancers (NSCLC) contain nontargetable mutations, including KRAS, TP53, or STK11/LKB1 alterations. By coupling ex vivo drug sensitivity profiling with in vivo drug response studies, we aimed to identify drug vulnerabilities for these NSCLC subtypes. Primary adenosquamous carcinoma (ASC) or adenocarcinoma (AC) cultures were established from KrasG12D/+;Lkb1fl/fl (KL) tumors or AC cultures from KrasG12D/+;p53fl/fl (KP) tumors. Although p53-null cells readily propagated as conventional cultures, Lkb1-null cells required conditional reprograming for establishment. Drug response profiling revealed short-term response to MEK inhibition, yet long-term clonogenic assays demonstrated resistance, associated with sustained or adaptive activation of receptor tyrosine kinases (RTK): activation of ERBBs in KL cultures, or FGFR in AC cultures. Furthermore, pan-ERBB inhibition reduced the clonogenicity of KL cultures, which was exacerbated by combinatorial MEK inhibition, whereas combinatorial MEK and FGFR inhibition suppressed clonogenicity of AC cultures. Importantly, in vivo studies confirmed KL-selective sensitivity to pan-ERBB inhibition, which correlated with high ERBB ligand expression and activation of ERBB receptors, implying that ERBB network activity may serve as a predictive biomarker of drug response. Interestingly, in human NSCLCs, phosphorylation of EGFR or ERBB3 was frequently detected in ASCs and squamous cell carcinomas. We conclude that analysis of in situ ERBB signaling networks in conjunction with ex vivo drug response profiling and biochemical dissection of adaptive RTK activities may serve as a valid diagnostic approach to identify tumors sensitive to ERBB network inhibition.
The Altered Transcriptome and DNA Methylation Profiles of Docetaxel Resistance in Breast Cancer PDX Models
Authors: Gómez-Miragaya Jorge , Morán Sebastián , Calleja-Cervantes Maria Eréndira , Collado-Sole Alejandro , Paré Laia , Gómez Antonio , Serra Violeta , Dobrolecki Lacey E. , Lewis Michael T. , Diaz-Lagares Angel , Eroles Pilar , Prat Aleix , Esteller Manel , González-Suárez Eva 
Published: July 2019

Abstract

Taxanes are standard therapy in clinical practice for metastatic breast cancer; however, primary or acquired chemoresistance are a common cause of mortality. Breast cancer patient-derived xenografts (PDX) are powerful tools for the study of cancer biology and drug treatment response. Specific DNA methylation patterns have been associated to different breast cancer subtypes but its association with chemoresistance remains unstudied. Aiming to elucidate docetaxel resistance mechanisms, we performed genome-wide DNA methylation in breast cancer PDX models, including luminal and triple-negative breast cancer (TNBC) models sensitive to docetaxel, their matched models after emergence of chemoresistance and residual disease after short-term docetaxel treatment. We found that DNA methylation profiles from breast cancer PDX models maintain the subtype-specific methylation patterns of clinical samples. Two main DNA methylation clusters were found in TNBC PDX and remain stable during the emergence of docetaxel resistance; however, some genes/pathways were differentially methylated according to docetaxel response. A DNA methylation signature of resistance able to segregate TNBC based on chemotherapy response was identified. Transcriptomic profiling of selected sensitive/resistant pairs and integrative analysis with methylation data demonstrated correlation between some differentially methylated and expressed genes in docetaxel-resistant TNBC PDX models. Multiple gene expression changes were found after the emergence of docetaxel resistance in TNBC. DNA methylation and transcriptional changes identified between docetaxel-sensitive and -resistant TNBC PDX models or residual disease may have predictive value for chemotherapy response in TNBC.

Implications:
Subtype-specific DNA methylation patterns are maintained in breast cancer PDX models. While no global methylation changes were found, we uncovered differentially DNA methylated and expressed genes/pathways associated with the emergence of docetaxel resistance in TNBC.
Glycoproteomic Analysis of the Aortic Extracellular Matrix in Marfan Patients
Authors: Yin (殷晓科) Xiaoke , Wanga Shaynah , Fellows Adam L. , Barallobre-Barreiro Javier , Lu Ruifang , Davaapil Hongorzul , Franken Romy , Fava Marika , Baig Ferheen , Skroblin Philipp , Xing Qiuru , Koolbergen David R. , Groenink Maarten , Zwinderman Aeilko H. , Balm Ron , de Vries Carlie J.M. , Mulder Barbara J.M. , Viner Rosa , Jahangiri Marjan , Reinhardt Dieter P. , Sinha Sanjay , de Waard Vivian , Mayr Manuel 
Published: July 2019

Objective:
Marfan syndrome (MFS) is caused by mutations in FBN1 (fibrillin-1), an extracellular matrix (ECM) component, which is modified post-translationally by glycosylation. This study aimed to characterize the glycoproteome of the aortic ECM from patients with MFS and relate it to aortopathy.

Approach and Results:
ECM extracts of aneurysmal ascending aortic tissue from patients with and without MFS were enriched for glycopeptides. Direct N-glycopeptide analysis by mass spectrometry identified 141 glycoforms from 47 glycosites within 35 glycoproteins in the human aortic ECM. Notably, MFAP4 (microfibril-associated glycoprotein 4) showed increased and more diverse N-glycosylation in patients with MFS compared with control patients. MFAP4 mRNA levels were markedly higher in MFS aortic tissue. MFAP4 protein levels were also increased at the predilection (convexity) site for ascending aorta aneurysm in bicuspid aortic valve patients, preceding aortic dilatation. In human aortic smooth muscle cells, MFAP4 mRNA expression was induced by TGF (transforming growth factor)-β1 whereas siRNA knockdown of MFAP4 decreased FBN1 but increased elastin expression. These ECM changes were accompanied by differential gene expression and protein abundance of proteases from ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family and their proteoglycan substrates, respectively. Finally, high plasma MFAP4 concentrations in patients with MFS were associated with a lower thoracic descending aorta distensibility and greater incidence of type B aortic dissection during 68 months follow-up.

Conclusions:
Our glycoproteomics analysis revealed that MFAP4 glycosylation is enhanced, as well as its expression during the advanced, aneurysmal stages of MFS compared with control aneurysms from patients without MFS.
Apolipoprotein E4 Expression Causes Gain of Toxic Function in Isogenic Human Induced Pluripotent Stem Cell-Derived Endothelial Cells
Authors: Rieker Claus , Migliavacca Eugenia , Vaucher Angélique , Mayer Fiona C. , Baud Gilles , Marquis Julien , Charpagne Aline , Hegde Nagabhooshan , Guignard Laurence , McLachlan Michael , Pooler Amy M. 
Published: July 2019

Objective:

The ApoE (apolipoprotein) allele epsilon 4 is a major genetic risk factor for Alzheimer disease, cardiovascular disorders, and stroke, indicating that it significantly impacts cerebral and vascular systems. However, very little is known about how
APOE
genotype affects brain endothelial cells, which form a network of tight junctions to regulate communication between the brain and circulating blood factors.

Approach and Results:

Here, we present a novel model of endothelial dysfunction using isogenic human induced pluripotent stem cell-derived cells harboring different alleles of the
APOE
gene, specifically ApoE 3/3, 3/4, and 4/4. We show for the first time that ApoE4 expression by endothelial cells is sufficient to cause a toxic gain of cellular dysfunction. Using RNAseq, we found significant effects of ApoE4 on signaling pathways involved in blood coagulation and barrier function. These changes were associated with altered cell function, including increased binding of platelets to ECs with the 3/4 or 4/4 genotype. ApoE4-positive cells exhibited a proinflammatory state and prothrombotic state, evidenced by higher secretion of Aβ (amyloid-β) 40 and 42, increased release of cytokines, and overexpression of the platelet-binding protein VWF (vonWillebrand factor). Immunohistochemistry of human brain Alzheimer disease brains also showed increased VWF expression with the ApoE4/4 genotype. Finally, pharmacological inhibition of inflammation in ECs by celastrol rescued overexpression of VWF in cells expressing ApoE4.

Conclusions:
These cells provide novel insight into ApoE4-mediated endothelial dysfunction and provide a new platform to test potential therapies for vascular disorders.
Short-Acting Anti-VWF (von Willebrand Factor) Aptamer Improves the Recovery, Survival, and Hemostatic Functions of Refrigerated Platelets
Authors: Chen Wenchun , Voos Kayleigh M. , Josephson Cassandra D. , Li Renhao 
Published: July 2019

Objective:
Refrigeration-induced binding of VWF (von Willebrand factor) to platelets contributes to the rapid clearance of refrigerated platelets. In this study, we investigate whether inhibiting VWF binding by a DNA-based aptamer ameliorates the clearance of refrigerated platelets without significantly impeding hemostatic functions.

Approach and Results:

Platelets were refrigerated with or without aptamer ARC1779 for 48 hours. VWF binding, the effective lifetime of ARC1779, platelet post-transfusion recovery and survival, and the hemostatic function were measured. ARC1779 treatment during refrigeration inhibited the platelet-VWF interaction. ARC1779-treated refrigerated murine platelets exhibited increased post-transfusion recovery and survival than untreated ones (recovery of ARC1779-treated platelets: 76.7±5.5%; untreated: 63.7±0.8%;
P
<0.01. Half-life: 31.4±2.36 hours versus 28.1±0.86 hours;
P
<0.05). A similar increase was observed for refrigerated human platelets (recovery: 49.4±4.4% versus 36.8±2.1%,
P
<0.01; half-life: 9.2±1.5 hours versus 8.7±0.9 hours, ns). The effective lifetime of ARC1779 in mice was 2 hours. Additionally, ARC1779 improved the long-term (2 hours after transfusion) hemostatic function of refrigerated platelets (tail bleeding time of mice transfused with ARC1779-treated refrigerated platelets: 160±65 seconds; untreated: 373±96 seconds;
P
<0.01). The addition of an ARC1779 antidote before transfusion improved the immediate (15 minutes after transfusion) hemostatic function (bleeding time of treated platelets: 149±21 seconds; untreated: 320±36 seconds;
P
<0.01).

Conclusions:
ARC1779 improves the post-transfusion recovery of refrigerated platelets and preserves the long-term hemostatic function of refrigerated platelets. These results suggest that a short-acting inhibitor of the platelet-VWF interaction may be a potential therapeutic option to improve refrigeration of platelets for transfusion treatment.
Association Between ApoA-I (Apolipoprotein A-I) Immune Complexes and Adverse Cardiovascular Events—Brief Report
Authors: Henson David , Tahhan Ayman Samman , Nardo David , Quyyumi Arshed Ali , Venditto Vincent J. 
Published: July 2019

Objective:
The immune response is linked to the progression of atherosclerotic cardiovascular disease (CVD). Free autoantibodies targeting ApoA-I (apolipoprotein A-I) have been identified as a component of the inflammatory milieu in patients and have a moderate association with CVD progression. Based on the presence of these antibodies and the high concentration of circulating ApoA-I, we hypothesized that antibodies bound to ApoA-I as an immune complex would be predictive of incident adverse CVD outcomes.

Approach and Results:

The presence of ApoA-I/IgG immune complexes (ICs) in plasma was confirmed by ELISA in 3 subject cohorts. Characterization of the protein components of ApoAI/IgG ICs indicate that ICs are not correlated with total ApoA-I concentration and are enriched in the anti-inflammatory subclass, IgG4, relative to total plasma IgG (>30% versus 6%). In 359 patients with coronary artery disease (CAD), there were 71 incident adverse CVD events (death, myocardial infarction, and stroke) during a median 4.1-year follow-up. In Cox proportional hazard regression analysis, low levels of ApoA-I/IgG ICs were independent predictors of adverse cardiovascular outcomes after adjustment for age, sex, diabetes mellitus, estimated glomerular filtration rate, presence of obstructive CAD, heart failure, total cholesterol, and HDL (high-density lipoprotein) cholesterol (adjusted hazard ratio of 1.90 [95% CI, 1.03–3.49;
P
=0.038] between the lowest and the highest tertiles).

Conclusions:
Low levels of ApoA-I/IgG ICs are associated with an increased risk of adverse events in patients with CAD, raising their potential to be used as a biomarker to predict CVD progression.