bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sympathetic nervous system activation reduces contraction-induced rapid vasodilation in the leg of humans independent of age
Authors: Hughes William E. , Kruse Nicholas T. , Casey Darren P. 
Published: April 2017

Contraction-induced rapid vasodilation is attenuated similarly in the upper and lower limbs of older adults. In the forearm, this attenuation is in part due to a greater sympathetic vasoconstriction. We examined whether the age-related reduction in contraction-induced vasodilation in the leg is also due to a sympathetic vasoconstrictive mechanism. Thirteen young (24 ± 1 yr) and twelve older adults (67 ± 1 yr) performed single-leg knee extension at 20 and 40% of work-rate maximum (WRmax) during control and cold-pressor test (CPT) conditions. Femoral artery diameter and blood velocity were measured using Doppler ultrasound. Vascular conductance (VC; ml·min−1·mmHg−1) was calculated using blood flow (ml/min) and mean arterial pressure (mmHg). Peak (ΔVC from baseline) and total VC were blunted in older adults during control conditions across exercise intensities ( P < 0.05). Peak and total VC were reduced during CPT in both age groups across exercise intensities ( P < 0.05). The relative change (i.e., %reduction; CPT vs. control) in peak (−25 ± 5 vs. −22 ± 4% at 20% WRmax; and −21 ± 6 vs. −27 ± 5% at 40% WRmax; P = 0.42–0.55) and total VC (−28 ± 5 vs. −36 ± 6% at 20% WRmax; and −22 ± 8 vs. −33 ± 5% at 40% WRmax; P = 0.23–0.34) were similar between young and older adults. When matched for absolute workload (~10 W), age differences persisted in peak VC ( P < 0.05) under both conditions, with similar relative changes in peak and total VC during CPT. Our data suggest that 1) sympathetic stimulation reduces contraction-induced rapid vasodilation in the leg of young and older adults similarly; and 2) enhanced sympathetic vasoconstriction does not fully explain age-related differences in contraction-induced vasodilation within the leg. NEW & NOTEWORTHY Aging is associated with attenuated contraction-induced rapid onset vasodilation (ROV). Within the forearm, this attenuation is partially due to enhanced sympathetic vasoconstriction. In the current study, we found that sympathetic vasoconstriction reduces contraction-induced ROV within the leg of both young and older adults, with the magnitude of change being similar between age groups. Our current results suggest that age-related attenuations in contraction-induced ROV within the leg are not fully explained by a sympathetic vasoconstrictor mechanism.
Eight weeks of local vibration training increases dorsiflexor muscle cortical voluntary activation
Authors: Souron Robin , Farabet Adrien , Féasson Léonard , Belli Alain , Millet Guillaume Y. , Lapole Thomas 
Published: April 2017

The aim of this study was to evaluate the effects of an 8-wk local vibration training (LVT) program on functional and corticospinal properties of dorsiflexor muscles. Forty-four young subjects were allocated to a training (VIB, n = 22) or control (CON, n = 22) group. The VIB group performed twenty-four 1-h sessions (3 sessions/wk) of 100-Hz vibration applied to the right tibialis anterior. Both legs were tested in each group before training (PRE), after 4 (MID) and 8 (POST) wk of training, and 2 wk after training (POST2W). Maximal voluntary contraction (MVC) torque was assessed, and transcranial magnetic stimulation (TMS) was used to evaluate cortical voluntary activation (VATMS), motor evoked potential (MEP), cortical silent period (CSP), and input-output curve parameters. MVC was significantly increased for VIB at MID for right and left legs [+7.4% ( P = 0.001) and +6.2% ( P < 0.01), respectively] and remained significantly greater than PRE at POST [+12.0% ( P < 0.001) and +10.1% ( P < 0.001), respectively]. VATMS was significantly increased for right and left legs at MID [+4.4% ( P < 0.01) and +4.7% ( P < 0.01), respectively] and at POST [+4.9% ( P = 0.001) and +6.2% ( P = 0.001), respectively]. These parameters remained enhanced in both legs at POST2W. MEP and CSP recorded during MVC and input-output curve parameters did not change at any time point for either leg. Despite no changes in excitability or inhibition being observed, LVT seems to be a promising method to improve strength through an increase of maximal voluntary activation, i.e., neural adaptations. Local vibration may thus be further considered for clinical or aging populations. NEW & NOTEWORTHY The effects of a local vibration training program on cortical voluntary activation measured with transcranial magnetic stimulation were assessed for the first time in dorsiflexors, a functionally important muscle group. We observed that training increased maximal voluntary strength likely because of the strong and repeated activation of Ia spindle afferents during vibration training that led to changes in the cortico-motoneuronal pathway, as demonstrated by the increase in cortical voluntary activation.
The effects of physical exercise on nonmotor symptoms and on neuroimmune RAGE network in experimental parkinsonism
Authors: Viana Sofia D. , Pita Inês R. , Lemos Cristina , Rial Daniel , Couceiro Patrícia , Rodrigues-Santos Paulo , Caramelo Francisco , Carvalho Félix , Ali Syed F. , Prediger Rui D. , Fontes Ribeiro Carlos A. , Pereira Frederico C. 
Published: April 2017

Parkinson's disease (PD) prodromal stages comprise neuropsychiatric perturbations that critically compromise a patient’s quality of life. These nonmotor symptoms (NMS) are associated with exacerbated innate immunity, a hallmark of overt PD. Physical exercise (PE) has the potential to improve neuropsychiatric deficits and to modulate immune network including receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in distinct pathological settings. Accordingly, the present study aimed to test the hypothesis that PE 1) alleviates PD NMS and 2) modulates neuroimmune RAGE network in experimental PD. Adult Wistar rats subjected to long-term mild treadmill were administered intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probed for PD NMS before the onset of motor abnormalities. Twelve days after MPTP, neuroimmune RAGE network transcriptomics (real-time quantitative PCR) was analyzed in frontal cortex, hippocampus, and striatum. Untrained MPTP animals displayed habit-learning and motivational deficits without gross motor impairments (cued version of water-maze, splash, and open-field tests, respectively). A suppression of RAGE and neuroimmune-related genes was observed in frontal cortex on chemical and physical stressors (untrained MPTP: RAGE, TLR5 and -7, and p22 NADPH oxidase; saline-trained animals: RAGE, TLR1 and -5 to -11, TNF-α, IL-1β, and p22 NADPH oxidase), suggesting the recruitment of compensatory mechanisms to restrain innate inflammation. Notably, trained MPTP animals displayed normal cognitive/motivational performances. Additionally, these animals showed normal RAGE expression and neuroprotective PD-related DJ-1 gene upregulation in frontal cortex when compared with untrained MPTP animals. These findings corroborate PE efficacy in improving PD NMS and newly identify RAGE network as a neural substrate for exercise intervention. Additional research is warranted to unveil functional consequences of PE-induced modulation of RAGE/DJ-1 transcriptomics in PD premotor stages. NEW & NOTEWORTHY This study newly shows that physical exercise (PE) corrects nonmotor symptoms of the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of experimental parkinsonism. Additionally, we show that suppression of neuroimmune receptor for advanced glycation end products (RAGE) network occurs in frontal cortex on chemical (MPTP) and physical (PE) interventions. Finally, PE normalizes frontal cortical RAGE transcriptomics and upregulates the neuroprotective DJ-1 gene in the intranasal MPTP model of experimental parkinsonism.
Frequency tagging to track the neural processing of contrast in fast, continuous sound sequences
Authors: Nozaradan Sylvie , Mouraux André , Cousineau Marion 
Published: April 2017

The human auditory system presents a remarkable ability to detect rapid changes in fast, continuous acoustic sequences, as best illustrated in speech and music. However, the neural processing of rapid auditory contrast remains largely unclear, probably due to the lack of methods to objectively dissociate the response components specifically related to the contrast from the other components in response to the sequence of fast continuous sounds. To overcome this issue, we tested a novel use of the frequency-tagging approach allowing contrast-specific neural responses to be tracked based on their expected frequencies. The EEG was recorded while participants listened to 40-s sequences of sounds presented at 8Hz. A tone or interaural time contrast was embedded every fifth sound (AAAAB), such that a response observed in the EEG at exactly 8 Hz/5 (1.6 Hz) or harmonics should be the signature of contrast processing by neural populations. Contrast-related responses were successfully identified, even in the case of very fine contrasts. Moreover, analysis of the time course of the responses revealed a stable amplitude over repetitions of the AAAAB patterns in the sequence, except for the response to perceptually salient contrasts that showed a buildup and decay across repetitions of the sounds. Overall, this new combination of frequency-tagging with an oddball design provides a valuable complement to the classic, transient, evoked potentials approach, especially in the context of rapid auditory information. Specifically, we provide objective evidence on the neural processing of contrast embedded in fast, continuous sound sequences.NEW & NOTEWORTHY Recent theories suggest that the basis of neurodevelopmental auditory disorders such as dyslexia might be an impaired processing of fast auditory changes, highlighting how the encoding of rapid acoustic information is critical for auditory communication. Here, we present a novel electrophysiological approach to capture in humans neural markers of contrasts in fast continuous tone sequences. Contrast-specific responses were successfully identified, even for very fine contrasts, providing direct insight on the encoding of rapid auditory information.
SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells
Authors: Redd Priscilla S. , Ibrahim Mohammed L. , Klement John D. , Sharman Sarah K. , Paschall Amy V. , Yang Dafeng , Nayak-Kapoor Asha , Liu Kebin 
Published: April 2017

Abstract
Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T-cell receptor and STAT1, thus inhibiting T-cell activation and the antitumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1− and immature CD11b+Gr1+ myeloid cells in vivo. Strikingly, although IRF8 was silenced in tumor-induced MDSCs, iNOS expression was significantly elevated in tumor-induced MDSCs, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathologic conditions. Furthermore, tumor-induced MDSCs exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B–H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions. Cancer Res; 77(11); 2834–43. ©2017 AACR.
eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth
Authors: Strnadel Jan , Choi Sunkyu , Fujimura Ken , Wang Huawei , Zhang Wei , Wyse Meghan , Wright Tracy , Gross Emilie , Peinado Carlos , Park Hyun Woo , Bui Jack , Kelber Jonathan , Bouvet Michael , Guan Kun-Liang , Klemke Richard L. 
Published: April 2017

Abstract
In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment. Although eIF5A-PEAK1 signaling contributes to multiple aggressive cancer cell phenotypes, the downstream signaling processes that mediate these responses are uncharacterized. Through proteomics and informatic analyses of PEAK1-depleted PDAC cells, we defined protein translation, cytoskeleton organization, and cell-cycle regulatory pathways as major pathways controlled by PEAK1. Biochemical and functional studies revealed that the transcription factors YAP1 and TAZ are key targets of eIF5A-PEAK1 signaling. YAP1/TAZ coimmunoprecipitated with PEAK1. Interfering with eIF5A-PEAK1 signaling in PDAC cells inhibited YAP/TAZ protein expression, decreasing expression of stem cell–associated transcription factors (STF) including Oct4, Nanog, c-Myc, and TEAD, thereby decreasing three-dimensional (3D) tumor sphere growth. Conversely, amplified eIF5A-PEAK1 signaling increased YAP1/TAZ expression, increasing expression of STF and enhancing 3D tumor sphere growth. Informatic interrogation of mRNA sequence databases revealed upregulation of the eIF5A-PEAK1-YAP1-TEAD signaling module in PDAC patients. Taken together, our findings indicate that eIF5A-PEAK1-YAP signaling contributes to PDAC development by regulating an STF program associated with increased tumorigenicity. Cancer Res; 77(8); 1997–2007. ©2017 AACR.
Drug Resistance Mechanisms in Colorectal Cancer Dissected with Cell Type–Specific Dynamic Logic Models
Authors: Eduati Federica , Doldàn-Martelli Victoria , Klinger Bertram , Cokelaer Thomas , Sieber Anja , Kogera Fiona , Dorel Mathurin , Garnett Mathew J. , Blüthgen Nils , Saez-Rodriguez Julio 
Published: April 2017

Abstract
Genomic features are used as biomarkers of sensitivity to kinase inhibitors used widely to treat human cancer, but effective patient stratification based on these principles remains limited in impact. Insofar as kinase inhibitors interfere with signaling dynamics, and, in turn, signaling dynamics affects inhibitor responses, we investigated associations in this study between cell-specific dynamic signaling pathways and drug sensitivity. Specifically, we measured 14 phosphoproteins under 43 different perturbed conditions (combinations of 5 stimuli and 7 inhibitors) in 14 colorectal cancer cell lines, building cell line–specific dynamic logic models of underlying signaling networks. Model parameters representing pathway dynamics were used as features to predict sensitivity to a panel of 27 drugs. Specific parameters of signaling dynamics correlated strongly with drug sensitivity for 14 of the drugs, 9 of which had no genomic biomarker. Following one of these associations, we validated a drug combination predicted to overcome resistance to MEK inhibitors by coblockade of GSK3, which was not found based on associations with genomic data. These results suggest that to better understand the cancer resistance and move toward personalized medicine, it is essential to consider signaling network dynamics that cannot be inferred from static genotypes. Cancer Res; 77(12); 3364–75. ©2017 AACR.
HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2
Authors: Hanker Ariella B. , Garrett Joan T. , Estrada Mónica Valeria , Moore Preston D. , Ericsson Paula González , Koch James P. , Langley Emma , Singh Sharat , Kim Phillip S. , Frampton Garrett M. , Sanford Eric , Owens Philip , Becker Jennifer , Groseclose M. Reid , Castellino Stephen , Joensuu Heikki , Huober Jens , Brase Jan C. , Majjaj Samira , Brohée Sylvain , Venet David , Brown David , Baselga José , Piccart Martine , Sotiriou Christos , Arteaga Carlos L. 
Published: April 2017

AbstractPurpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2+) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.Experimental Design: HER2+ BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples.Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro. Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2+ early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathologic complete response in patients with HER2+ early breast cancer treated with neoadjuvant anti-HER2 therapy.Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. Clin Cancer Res; 23(15); 4323–34. ©2017 AACR.
Hepatic Ketogenesis Induced by Middle Cerebral Artery Occlusion in Mice
Authors: Koch Konrad , Berressem Dirk , Konietzka Jan , Thinnes Anna , Eckert Gunter P. , Klein Jochen 
Published: April 2017

Background
Ketone bodies are known to substitute for glucose as brain fuel when glucose availability is low. Ketogenic diets have been described as neuroprotective. Similar data have been reported for triheptanoin, a fatty oil and anaplerotic compound. In this study, we monitored the changes of energy metabolites in liver, blood, and brain after transient brain ischemia to test for ketone body formation induced by experimental stroke.

Methods and Results
Mice were fed a standard carbohydrate‐rich diet or 2 fat‐rich diets, 1 enriched in triheptanoin and 1 in soybean oil. Stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by reperfusion. Mice were sacrificed, and blood plasma and liver and brain homogenates were obtained. In 1 experiment, microdialysis was performed. Metabolites (eg glucose, β‐hydroxybutyrate, citrate, succinate) were determined by gas chromatography–mass spectrometry. After 90 minutes of brain ischemia, β‐hydroxybutyrate levels were dramatically increased in liver, blood, and brain microdialysate and brain homogenate, but only in mice fed fat‐rich diets. Glucose levels were changed in the opposite manner in blood and brain. Reperfusion decreased β‐hydroxybutyrate and increased glucose within 60 minutes. Stroke‐induced ketogenesis was blocked by propranolol, a β‐receptor antagonist. Citrate and succinate were moderately increased by fat‐rich diets and unchanged after stroke.

Conclusions
We conclude that brain ischemia induces the formation of β‐hydroxybutyrate (ketogenesis) in the liver and the consumption of β‐hydroxybutyrate in the brain. This effect seems to be mediated by β‐adrenergic receptors.
Blood Pressure and Arterial Stiffness in Kenyan Adolescents With α
+
Thalassemia
Authors: Etyang Anthony O. , Khayeka‐Wandabwa Christopher , Kapesa Sailoki , Muthumbi Esther , Odipo Emily , Wamukoya Marylene , Ngomi Nicholas , Haregu Tilahun , Kyobutungi Catherine , Tendwa Metrine , Makale Johnstone , Macharia Alex , Cruickshank J. Kennedy , Smeeth Liam , Scott J. Anthony G. , Williams Thomas N. 
Published: April 2017

Background

Recent studies have discovered that α‐globin is expressed in blood vessel walls where it plays a role in regulating vascular tone. We tested the hypothesis that blood pressure (BP) might differ between normal individuals and those with α
+
thalassemia, in whom the production of α‐globin is reduced.

Methods and Results

The study was conducted in Nairobi, Kenya, among 938 adolescents aged 11 to 17 years. Twenty‐four‐hour ambulatory BP monitoring and arterial stiffness measurements were performed using an arteriograph device. We genotyped for α
+
thalassemia by polymerase chain reaction. Complete data for analysis were available for 623 subjects; 223 (36%) were heterozygous (−α/αα) and 47 (8%) were homozygous (−α/−α) for α
+
thalassemia whereas the remaining 353 (55%) were normal (αα/αα). Mean 24‐hour systolic
BP
±
SD
was 118±12 mm Hg in αα/αα, 117±11 mm Hg in −α/αα, and 118±11 mm Hg in −α/−α subjects, respectively. Mean 24‐hour diastolic
BP
±
SD
in these groups was 64±8, 63±7, and 65±8 mm Hg, respectively. Mean pulse wave velocity (
PWV
)±
SD
was 7±0.8, 7±0.8, and 7±0.7 ms
−1
, respectively. No differences were observed in
PWV
and any of the 24‐hour
ambulatory BP monitoring‐
derived measures between those with and without α
+
thalassemia.

Conclusions

These data suggest that the presence of α
+
thalassemia does not affect BP and/or arterial stiffness in Kenyan adolescents.
Estimation of Depolarization Ratio Using Weather Radars with Simultaneous Transmission/Reception
Authors: Ryzhkov Alexander , Matrosov Sergey Y. , Melnikov Valery , Zrnic Dusan , Zhang Pengfei , Cao Qing , Knight Michael , Simmer Clemens , Troemel Silke 
Published: April 2017

AbstractA new methodology for estimating the depolarization ratio (DR) by dual-polarization radars with simultaneous transmission/reception of orthogonally polarized waves together with traditionally measured differential reflectivity ZDR, correlation coefficient ρhυ, and differential phase ΦDP in a single mode of operation is suggested. This depolarization ratio can serve as a proxy for circular depolarization ratio measured by radars with circular polarization. The suggested methodology implies the use of a high-power phase shifter to control the system differential phase on transmission and a special signal processing to eliminate the detrimental impact of differential phase on the estimate of DR. The feasibility of the suggested approach has been demonstrated by retrieving DR from the standard polarimetric variables and the raw in-phase I and quadrature Q components of radar signals and by implementing the scheme on a C-band radar with simultaneous transmission/reception of horizontally and vertically polarized waves. Possible practical implications of using DR include the detection of hail and the determination of its size above the melting layer, the discrimination between various habits of ice aloft, and the possible identification and quantification of riming, which is associated with the presence of supercooled cloud water. Some examples of these applications are presented.