bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluctuation in shear rate, with unaltered mean shear rate, improves brachial artery flow-mediated dilation in healthy, young men
Authors: Holder Sophie M. , Dawson Ellen A. , Brislane Áine , Hisdal Jonny , Green Daniel J. , Thijssen Dick H. J. 
Published: May 2019

Increase in mean shear stress represents an important and potent hemodynamic stimulus to improve conduit artery endothelial function in humans. No previous study has examined whether fluctuations in shear rate patterns, without altering mean shear stress, impacts conduit artery endothelial function. This study examined the hypothesis that 30-min exposure to fluctuations in shear rate patterns, in the presence of unaltered mean shear rate, improves brachial artery flow-mediated dilation. Fifteen healthy men (27.3 ± 5.0 yr) completed the study. Bilateral brachial artery flow-mediated dilation was assessed before and after unilateral exposure to 30 min of intermittent negative pressure (10 s, −40mmHg; 7 s, 0 mmHg) to induce fluctuation in shear rate, while the contralateral arm was exposed to a resting period. Negative pressure significantly increased shear rate, followed by a decrease in shear rate upon pressure release (both P < 0.001). Across the 30-min intervention, mean shear rate was not different compared with baseline ( P = 0.458). A linear mixed model revealed a significant effect of time observed for flow-mediated dilation ( P = 0.029), with exploratory post hoc analysis showing an increase in the intervention arm (∆FMD +2.0%, P = 0.008), but not in the contralateral control arm (∆FMD +0.5%, P = 0.664). However, there was no effect for arm ( P = 0.619) or interaction effect ( P = 0.096). In conclusion, we found that fluctuations in shear patterns, with unaltered mean shear, improves brachial artery flow-mediated dilation. These novel data suggest that fluctuations in shear pattern, even in the absence of altered mean shear, represent a stimulus to acute change in endothelial function in healthy individuals. NEW & NOTEWORTHY Intermittent negative pressure applied to the forearm induced significant fluctuations in antegrade and retrograde shear rate, while mean shear was preserved relative to baseline. Our exploratory study revealed that brachial artery flow-mediated dilation was significantly improved following 30-min exposure to intermittent negative pressure. Fluctuations in blood flow or shear rate, with unaltered mean shear, may have important implications for vascular health; however, further research is required to identify the underlying mechanisms and potential long-term health benefits.
Plantar mechanical stimulation prevents calcineurin-NFATc1 inactivation and slow-to-fast fiber type shift in rat soleus muscle under hindlimb unloading
Authors: Sharlo Kristina , Paramonova Inna , Turtikova Olga , Tyganov Sergey , Shenkman Boris 
Published: May 2019

The prevailing myosin isoform [myosin heavy chain (MyHC)] in a skeletal muscle determines contractile properties of the muscle. Under actual or simulated microgravity conditions such as human bed rest or rat hindlimb unloading, decrease in expression of MyHC of the slow type [MyHC I(β)] has been observed. It was demonstrated that increasing sensory input by performing plantar mechanical stimulation (PMS) on the soles of the feet results in an increase in neuromuscular activation of the lower limb muscles and may prevent slow-to-fast fiber type shift. The calcineurin-nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) signaling pathway is the main cascade regulating MyHC I(β) expression. The present study was aimed to analyze the states of the calcineurin-NFATc1 signaling cascade under conditions of PMS during rat hindlimb unloading. Male Wistar rats were randomly assigned to vivarium control groups and 1-day unloading (1HS), 3-day unloading (3HS), 1HS+PMS, and 3HS+PMS groups. We found that both 1 day and 3 days of unloading caused decrease in MyHC I(β) mRNA expression and decrease in glycogen synthase kinase-3β phosphorylation (Ser 9) that brought about the kinase activation, and these effects of unloading were prevented by PMS. Three days of unloading also caused increase in expression of calsarcin-2 (myozenin-I), which was found to be the endogenous calcineurin inhibitor. The level of calsarcin-2 expression in the 3HS+PMS group did not differ from the control group. Therefore, we conclude that PMS upregulates the calcineurin-NFATc1 signaling pathway and prevents unloading-induced MyHC I(β) decrease. NEW & NOTEWORTHY It is widely accepted that changes in the myosin phenotype during functional unloading (disuse) are determined by a decreased expression of the myosin heavy chain (MyHC) I(β) gene, and this decrease leads to changes of contractile and fatigue characteristics of soleus muscle. The calcineurin-nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) pathway is one of the most important signaling cascades regulating slow MyHC isoform expression. The present study is the first to show that plantar mechanical stimulation upregulates calcineurin-NFATc1 signaling in soleus muscles of hindlimb-unloaded rats.
Altered brain structure with preserved cortical motor activity after exertional hypohydration: a MRI study
Authors: Tan X. R. , Low I. C. C. , Stephenson M. C. , Kok T. , Nolte H. W. , Soong T. W. , Lee J. K. W. 
Published: May 2019

Hypohydration exceeding 2% body mass can impair endurance capacity. It is postulated that the brain could be perturbed by hypohydration, leading to impaired motor performance. We investigated the neural effects of hypohydration with magnetic resonance imaging (MRI). Ten men were dehydrated to approximately −3% body mass by running on a treadmill at 65% maximal oxygen consumption (V̇o2max) before drinking to replace either 100% [euhydration (EU)] or 0% [hypohydration (HH)] of fluid losses. MRI was performed before start of trial (baseline) and after rehydration phase (post) to evaluate brain structure, cerebral perfusion, and functional activity. Endurance capacity assessed with a time-to-exhaustion run at 75% V̇o2maxwas reduced with hypohydration (EU: 45.2 ± 9.3 min, HH: 38.4 ± 10.7 min; P = 0.033). Mean heart rates were comparable between trials (EU: 162 ± 5 beats/min, HH: 162 ± 4 beats/min; P = 0.605), but the rate of rise in rectal temperature was higher in HH trials (EU: 0.06 ± 0.01°C/min, HH: 0.07 ± 0.02°C/min; P < 0.01). In HH trials, a reduction in total brain volume (EU: +0.7 ± 0.6%, HH: −0.7 ± 0.9%) with expansion of ventricles (EU: −2.7 ± 1.6%, HH: +3.7 ± 3.3%) was observed, and vice versa in EU trials. Global and regional cerebral perfusion remained unchanged between conditions. Functional activation in the primary motor cortex in left hemisphere during a plantar-flexion task was similar between conditions (EU: +0.10 ± 1.30%, HH: −0.11 ± 0.31%; P = 0.637). Our findings demonstrate that with exertional hypohydration, brain volumes were altered but the motor-related functional activity was unperturbed.NEW & NOTEWORTHY Dehydration occurs rapidly during prolonged or intensive physical activity, leading to hypohydration if fluid replenishment is insufficient to replace sweat losses. Altered hydration status poses an osmotic challenge for the brain, leading to transient fluctuations in brain tissue and ventricle volumes. Therefore, the amount of fluid ingestion during exercise plays a critical role in preserving the integrity of brain architecture. These structural changes, however, did not translate directly to motor functional deficits in a simple motor task.
Using injury cost functions from a predictive single-compartment model to assess the severity of mechanical ventilator-induced lung injuries
Authors: Mellenthin Michelle M. , Seong Siyeon A. , Roy Gregory S. , Bartolák-Suki Elizabeth , Hamlington Katharine L. , Bates Jason H. T. , Smith Bradford J. 
Published: May 2019

Identifying safe ventilation patterns for patients with acute respiratory distress syndrome remains challenging because of the delicate balance between gas exchange and selection of ventilator settings to prevent further ventilator-induced lung injury (VILI). Accordingly, this work seeks to link ventilator settings to graded levels of VILI to identify injury cost functions that predict injury by using a computational model to process pressures and flows measured at the airway opening. Pressure-volume loops were acquired over the course of ~2 h of mechanical ventilation in four different groups of BALB/c mice. A cohort of these animals were subjected to an injurious bronchoalveolar lavage before ventilation. The data were analyzed with a single-compartment model that predicts recruitment/derecruitment and tissue distension at each time step in measured pressure-volume loops. We compared several injury cost functions to markers of VILI-induced blood-gas barrier disruption. Of the cost functions considered, we conclude that mechanical power dissipation and strain heterogeneity are the best at distinguishing between graded levels of injury and are good candidates for forecasting the development of VILI. NEW & NOTEWORTHY This work uses a predictive single-compartment model and injury cost functions to assess graded levels of mechanical ventilator-induced lung injury. The most promising measures include strain heterogeneity and mechanical power dissipation.
Graded reductions in preexercise muscle glycogen impair exercise capacity but do not augment skeletal muscle cell signaling: implications for CHO periodization
Authors: Hearris Mark A. , Hammond Kelly M. , Seaborne Robert A. , Stocks Ben , Shepherd Sam O. , Philp Andrew , Sharples Adam P. , Morton James P. , Louis Julien B. 
Published: May 2019

We examined the effects of graded muscle glycogen on exercise capacity and modulation of skeletal muscle signaling pathways associated with the regulation of mitochondrial biogenesis. In a repeated-measures design, eight men completed a sleep-low, train-low model comprising an evening glycogen-depleting cycling protocol followed by an exhaustive exercise capacity test [8 × 3 min at 80% peak power output (PPO), followed by 1-min efforts at 80% PPO until exhaustion] the subsequent morning. After glycogen-depleting exercise, subjects ingested a total of 0 g/kg (L-CHO), 3.6 g/kg (M-CHO), or 7.6 g/kg (H-CHO) of carbohydrate (CHO) during a 6-h period before sleeping, such that exercise was commenced the next morning with graded ( P < 0.05) muscle glycogen concentrations (means ± SD: L-CHO: 88 ± 43, M-CHO: 185 ± 62, H-CHO: 278 ± 47 mmol/kg dry wt). Despite differences ( P < 0.05) in exercise capacity at 80% PPO between trials (L-CHO: 18 ± 7, M-CHO: 36 ± 3, H-CHO: 44 ± 9 min), exercise induced comparable AMPKThr172 phosphorylation (~4-fold) and PGC-1α mRNA expression (~5-fold) after exercise and 3 h after exercise, respectively. In contrast, neither exercise nor CHO availability affected the phosphorylation of p38MAPKThr180/Tyr182 or CaMKIIThr268 or mRNA expression of p53, Tfam, CPT-1, CD36, or PDK4. Data demonstrate that when exercise is commenced with muscle glycogen < 300 mmol/kg dry wt, further graded reductions of 100 mmol/kg dry weight impair exercise capacity but do not augment skeletal muscle cell signaling. NEW & NOTEWORTHY We provide novel data demonstrating that when exercise is commenced with muscle glycogen below 300 mmol/kg dry wt (as achieved with the sleep-low, train-low model) further graded reductions in preexercise muscle glycogen of 100 mmol/kg dry wt reduce exercise capacity at 80% peak power output by 20–50% but do not augment skeletal muscle cell signaling.
Sildenafil enhances central hemodynamic responses to exercise, but not V̇o2peak, in people with diabetes mellitus
Authors: Roberts Timothy J. , Burns Andrew T. , MacIsaac Richard J. , MacIsaac Andrew I. , Prior David L. , La Gerche André 
Published: May 2019

Exercise capacity is frequently reduced in people with diabetes mellitus (DM), and the contribution of pulmonary microvascular dysfunction remains undefined. We hypothesized that pulmonary microvascular disease, measured by a novel exercise echocardiography technique termed pulmonary transit of agitated contrast (PTAC), would be greater in subjects with DM and that the use of pulmonary vasodilator agent sildenafil would improve exercise performance by reducing right ventricular afterload. Forty subjects with DM and 20 matched controls performed cardiopulmonary exercise testing and semisupine exercise echocardiography 1 h after placebo or sildenafil ingestion in a double-blind randomized crossover design. The primary efficacy end point was exercise capacity (V̇o2peak) while secondary measures included pulmonary vascular resistance, cardiac output, and change in PTAC. DM subjects were aged 44 ± 13 yr, 73% male, with 16 ± 10 yr DM history. Sildenafil caused marginal improvements in echocardiographic measures of biventricular systolic function in DM subjects. Exercise-induced increases in pulmonary artery systolic pressure and pulmonary vascular resistance were attenuated with sildenafil, while heart rate (+2.4 ±1.2 beats/min, P = 0.04) and cardiac output (+322 ± 21 ml, P = 0.03) improved. However, the degree of PTAC did not change ( P = 0.93) and V̇o2peak did not increase following sildenafil as compared with placebo (V̇o2peak: 31.8 ± 9.7 vs. 32.1 ± 9.5 ml·min−1·kg−1, P = 0.42). We conclude that sildenafil administration causes modest acute improvements in central hemodynamics but does not improve exercise capacity. This may be due to the mismatch in action of sildenafil on the pulmonary arteries rather than the distal pulmonary microvasculature and potential adverse effects on peripheral oxygen extraction. NEW & NOTEWORTHY This is one of the largest and most comprehensive studies of cardiopulmonary exercise performance in people with diabetes mellitus and to our knowledge the first to assess the effect of sildenafil using detailed echocardiographic measures during incremental exercise. Sildenafil attenuated the rise in pulmonary vascular resistance while augmenting cardiac output and intriguingly heart rate, without conferring any improvement in exercise capacity. The enhanced central hemodynamic indexes may have been offset by reduced peripheral O2 extraction.
Daily heat treatment maintains mitochondrial function and attenuates atrophy in human skeletal muscle subjected to immobilization
Authors: Hafen Paul S. , Abbott Kaitlin , Bowden Jennifer , Lopiano Ryan , Hancock Chad R. , Hyldahl Robert D. 
Published: May 2019

Skeletal muscle immobilization leads to atrophy, decreased metabolic health, and substantial losses in function. Animal models suggest that heat stress can provide protection against atrophy in skeletal muscle. This study investigated the effects of daily heat therapy on human skeletal muscle subjected to 10 days of immobilization. Muscle biopsies were collected, and MRIs were analyzed from the vastus lateralis of 23 healthy volunteers (11 women, 12 men) before and after either 10 days of immobilization with a daily sham treatment (Imm) or with a targeted, daily 2-h heat treatment using pulsed shortwave diathermy (Imm + H). Diathermy increased intramuscular temperature 4.2 ± 0.29°C ( P < 0.0001), with no change during sham treatment. As a result, heat shock protein (HSP)70 and HSP90 increased ( P < 0.05) following Imm + H (25 ± 6.6 and 20 ± 7.4%, respectively) but were unaltered with Imm only. Heat treatment prevented the immobilization-induced loss of coupled (−27 ± 5.2% vs. −8 ± 6.0%, P = 0.0041) and uncoupled (−25 ± 7.0% vs. −10 ± 3.9%, P = 0.0302) myofiber respiratory capacity. Likewise, heat treatment prevented the immobilization-induced loss of proteins associated with all five mitochondrial respiratory complexes ( P < 0.05). Furthermore, decreases in muscle cross-sectional area following Imm were greater than Imm + H at both the level of the whole muscle (−7.6 ± 0.96% vs. −4.5 ± 1.09%, P = 0.0374) and myofiber (−10.8 ± 1.52% vs. −5.8 ± 1.49%, P = 0.0322). Our findings demonstrate that daily heat treatments, applied during 10 days of immobilization, prevent the loss of mitochondrial function and attenuate atrophy in human skeletal muscle. NEW & NOTEWORTHY Limb immobilization results in substantial decreases in skeletal muscle size, function, and metabolic capacity. To date, there are few, if any, interventions to prevent the deleterious effects of limb immobilization on skeletal muscle health. Heat stress has been shown to elicit a stress response, resulting in increased heat shock protein expression and improved mitochondrial function. We show that during 10 days of lower-limb immobilization in humans, daily exposure to heat stress maintains mitochondrial respiratory capacity and attenuates atrophy in skeletal muscle. Our findings suggest that heat stress may serve as an effective therapeutic strategy to attenuate the decreases of muscle mass and metabolic function that accompany periods of disuse.
The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells
Authors: Nechiporuk Tamilla , Kurtz Stephen E. , Nikolova Olga , Liu Tingting , Jones Courtney L. , D'Alessandro Angelo , Culp-Hill Rachel , d'Almeida Amanda , Joshi Sunil K. , Rosenberg Mara , Tognon Cristina E. , Danilov Alexey V. , Druker Brian J. , Chang Bill H. , McWeeney Shannon K , Tyner Jeffrey W. 
Published: May 2019

AbstractTo study mechanisms underlying resistance to the BCL2 inhibitor venetoclax in acute myeloid leukemia (AML), we used a genome-wide CRISPR/Cas9 screen to identify gene knockouts resulting in drug resistance. We validated TP53, BAX, and PMAIP1 as genes whose inactivation results in venetoclax resistance in AML cell lines. Resistance to venetoclax resulted from an inability to execute apoptosis driven by BAX loss, decreased expression of BCL2, and/or reliance on alternative BCL2 family members such as BCL2L1. The resistance was accompanied by changes in mitochondrial homeostasis and cellular metabolism. Evaluation of TP53 knockout cells for sensitivities to a panel of small-molecule inhibitors revealed a gain of sensitivity to TRK inhibitors. We relate these observations to patient drug responses and gene expression in the Beat AML dataset. Our results implicate TP53, the apoptotic network, and mitochondrial functionality as drivers of venetoclax response in AML and suggest strategies to overcome resistance.Significance:AML is challenging to treat due to its heterogeneity, and single-agent therapies have universally failed, prompting a need for innovative drug combinations. We used a genetic approach to identify genes whose inactivation contributes to drug resistance as a means of forming preferred drug combinations to improve AML treatment.See related commentary by Savona and Rathmell, p. 831.This article is highlighted in the In This Issue feature, p. 813
Weak Lips? A Possible Merger of /i:/ and /y:/ in Gothenburg
Authors: Gross Johan , Forsberg Julia 
Published: May 2019

Abstract

Background/Aims:
This study investigates a possible merger in the early stages between /i:/ and /y:/ among young speakers in Gothenburg, Sweden.
Methods:
(1) A large-scale online perception experiment testing listeners’ abilities to identify the two vowels and (2) acoustic analysis of 705 vowels from 19 speakers.
Results:
The perception study shows that listeners classify the horizontally centralized /y:/ as /i:/, both in isolated vowel items and in items containing the full word. This indicates that /y:/ is moving into the perceptual space of /i:/. Listeners also classify the unmerged /y:/ as /i:/ when listening to [y:] in isolation, indicating that lip rounding is a perceptually weak feature, for this centralized vowel, in this variety. The acoustic analysis shows that /i:/ tends to be produced as [ɨ:], and that there is no acoustic difference between /i:/ and /y:/ in measurements correlated with the first two formants, i.e. lip rounding is the most important distinctive feature.
Conclusion:
Results point in the direction of an incipient vowel merger, following a merger-by-approximation model. These results indicate a lack of perceptual strength of an articulatory feature in the disappearing phoneme, namely lip rounding, and the consequent perceptual similarities between the horizontally centralized [ɨ:] and /y:/.
Development and Internal Validation of a Prediction Model to Estimate the Probability of Left-Ventricular Diastolic Dysfunction in Stable Maintenance Hemodialysis Patients without Clinical Heart Failure
Authors: Sun Linlin , Ji Yongqiang , Wang Yanzhe , Zhu Dingyu , Chen Fuhua , Zhang Nan , Shen E , Wang Xiaoxia 
Published: May 2019

<b><i>Objective:</i></b> To develop and internally validate a multivariable prediction model based on simple clinical record data and laboratory tests and to estimate the probability of left-ventricular diastolic dysfunction (LVDD) in stable maintenance hemodialysis (MHD) patients without clinical heart failure. <b><i>Design:</i></b> Cross-sectional study. <b><i>Setting and Participants:</i></b> In all, 181 patients on MHD without clinical heart failure were eligible from the dialysis center of Tongren Hospital, Shanghai Jiao Tong University School of Medicine between October 2017 and September 2018. <b><i>Outcomes:</i></b> LVDD detected by echocardiography. <b><i>Measurements:</i></b> We performed multivariable logistic regression using demographic, clinical, and laboratory data to identify predictors of LVDD with internal validation by using 200 bootstrap replications. <b><i>Results:</i></b> Overall, 78 out of 181 (43.1%) patients were affected by LVDD. Predictors included in the LVDD Model were high-sensitive cardiac troponin T (OR 5.91 per 1-ln unit; 95% CI 2.17–16.13), B-type natriuretic peptide (OR 2.35 per 1-ln unit; 95% CI 1.14–4.86), and dialysis vintage (OR 1.04 per 1-month; 95% CI 1.01–1.07). The area (AUC) under the receiver operating characteristic curve of the Model was 0.871 (95% CI 0.811–0.932, <i>p</i> &#x3c; 0.001). The calibration plot showed good agreement between predicted and observed probabilities with a calibration slope of 1.023 and intercept of –0.010. After internal validation, the Model maintained excellent discrimination (AUC 0.858, 95% CI 0.798–0.919) and good calibration (slope of 1.079, 95% CI 1.058–1.097 and intercept of –0.120, 95% CI –0.142 to –0.093). LVDD Model &#x3c;0.23 can be used to rule out (sensitivity = 87.3%, negative likelihood ratio = 12.7%) and ≥0.44 can be used to rule in (specificity = 87.6%, positive likelihood ratio = 12.4%) echocardiography diagnosed LVDD. <b><i>Limitation:</i></b> External validation of the Model will be required. <b><i>Conclusions:</i></b> A model using routinely available simple clinical record data and laboratory tests can accurately predict the risk of LVDD in stable MHD patients. The Model and its cutoff values may be useful for early diagnosis and intervention of LVDD.