bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shedding light on developmental ERK signaling with genetically encoded biosensors
Authors: Nakamura Akinobu , Goto Yuhei , Kondo Yohei , Aoki Kazuhiro 
Published: August 2021

ABSTRACT
The extracellular signal-regulated kinase (ERK) pathway governs cell proliferation, differentiation and migration, and therefore plays key roles in various developmental and regenerative processes. Recent advances in genetically encoded fluorescent biosensors have unveiled hitherto unrecognized ERK activation dynamics in space and time and their functional importance mainly in cultured cells. However, ERK dynamics during embryonic development have still only been visualized in limited numbers of model organisms, and we are far from a sufficient understanding of the roles played by developmental ERK dynamics. In this Review, we first provide an overview of the biosensors used for visualization of ERK activity in live cells. Second, we highlight the applications of the biosensors to developmental studies of model organisms and discuss the current understanding of how ERK dynamics are encoded and decoded for cell fate decision-making.
ELAC2/RNaseZ-linked cardiac hypertrophy in Drosophila melanogaster
Authors: Migunova Ekaterina , Theophilopoulos Joanna , Mercadante Marisa , Men Jing , Zhou Chao , Dubrovsky Edward B. 
Published: August 2021

ABSTRACT
A severe form of infantile cardiomyopathy (CM) has been linked to mutations in ELAC2, a highly conserved human gene. It encodes Zinc phosphodiesterase ELAC protein 2 (ELAC2), which plays an essential role in the production of mature tRNAs. To establish a causal connection between ELAC2 variants and CM, here we used the Drosophila melanogaster model organism, which carries the ELAC2 homolog RNaseZ. Even though RNaseZ and ELAC2 have diverged in some of their biological functions, our study demonstrates the use of the fly model to study the mechanism of ELAC2-related pathology. We established transgenic lines harboring RNaseZ with CM-linked mutations in the background of endogenous RNaseZ knockout. Importantly, we found that the phenotype of these flies is consistent with the pathological features in human patients. Specifically, expression of CM-linked variants in flies caused heart hypertrophy and led to reduction in cardiac contractility associated with a rare form of CM. This study provides first experimental evidence for the pathogenicity of CM-causing mutations in the ELAC2 protein, and the foundation to improve our understanding and diagnosis of this rare infantile disease.
This article has an associated First Person interview with the first author of the paper.
Identification of candidate miRNA biomarkers for facioscapulohumeral muscular dystrophy using DUX4-based mouse models
Authors: Nunes Andreia M. , Ramirez Monique , Jones Takako I. , Jones Peter L. 
Published: August 2021

ABSTRACT
Facioscapulohumeral muscular dystrophy (FSHD) is caused by misexpression of DUX4 in skeletal myocytes. As DUX4 is the key therapeutic target in FSHD, surrogate biomarkers of DUX4 expression in skeletal muscle are critically needed for clinical trials. Although no natural animal models of FSHD exist, transgenic mice with inducible DUX4 expression in skeletal muscles rapidly develop myopathic phenotypes consistent with FSHD. Here, we established a new, more-accurate FSHD-like mouse model based on chronic DUX4 expression in a small fraction of skeletal myonuclei that develops pathology mimicking key aspects of FSHD across its lifespan. Utilizing this new aged mouse model and DUX4-inducible mouse models, we characterized the DUX4-related microRNA signatures in skeletal muscles, which represent potential biomarkers for FSHD. We found increased expression of miR-31-5p and miR-206 in muscles expressing different levels of DUX4 and displaying varying degrees of pathology. Importantly, miR-206 expression is significantly increased in serum samples from FSHD patients compared with healthy controls. Our data support miR-31-5p and miR-206 as new potential regulators of muscle pathology and miR-206 as a potential circulating biomarker for FSHD.
This article has an associated First Person interview with the first author of the paper.
A three-dimensional spheroid-specific role for Wnt–β-catenin and Eph–ephrin signaling in nasopharyngeal carcinoma cells
Authors: Yi Canhui , Lai Sook Ling , Tsang Chi Man , Artemenko Margarita , Shuen Tang Maggie Kei , Pang Stella W. , Lo Kwok Wai , Tsao Sai Wah , Wong Alice Sze Tsai 
Published: August 2021

ABSTRACT
One of the greatest unmet needs hindering the successful treatment of nasopharyngeal carcinomas (NPCs) is for representative physiological and cost-effective models. Although Epstein–Barr virus (EBV) infection is consistently present in NPCs, most studies have focused on EBV-negative NPCs. For the first time, we established and analyzed three-dimensional (3D) spheroid models of EBV-positive and EBV-negative NPC cells and compared these to classical two-dimensional (2D) cultures in various aspects of tumor phenotype and drug responses. Compared to 2D monolayers, the 3D spheroids showed significant increases in migration capacity, stemness characteristics, hypoxia and drug resistance. Co-culture with endothelial cells, which mimics essential interactions in the tumor microenvironment, effectively enhanced spheroid dissemination. Furthermore, RNA sequencing revealed significant changes at the transcriptional level in 3D spheroids compared to expression in 2D monolayers. In particular, we identified known (VEGF, AKT and mTOR) and novel (Wnt–β-catenin and Eph–ephrin) cell signaling pathways that are activated in NPC spheroids. Targeting these pathways in 3D spheroids using FDA-approved drugs was effective in monoculture and co-culture. These findings provide the first demonstration of the establishment of EBV-positive and EBV-negative NPC 3D spheroids with features that resemble advanced and metastatic NPCs. Furthermore, we show that NPC spheroids have potential use in identifying new drug targets.
Cardiorespiratory Fitness, Fat Mass, and Cardiometabolic Health with Endothelial Function, Arterial Elasticity, and Stiffness
Authors: AGBAJE ANDREW O. , BARKER ALAN R. , TUOMAINEN TOMI-PEKKA 
Published: August 2021

ABSTRACT

Purpose
This study aimed to determine whether estimated cardiorespiratory fitness (CRF), fat mass (FM), lean mass (LM), and adiponectin bidirectionally associate with arterial function and structure and if CRF mediates the relationship between cardiometabolic health and arterial outcomes in 9- to 11-yr-old children drawn from the Avon Longitudinal Study of Parents and Children birth cohort, United Kingdom.

Methods
Brachial artery flow-mediated dilation (FMD), distensibility coefficient (DC), and carotid–radial pulse wave velocity (PWV) were measured by ultrasonography; CRF was measured during the submaximal ergometer test; total FM, trunk FM, and LM were measured by dual-energy x-ray absorptiometry; plasma adiponectin was measured by enzyme assay; and cardiometabolic health was computed based on the International Diabetes Federation criteria for diagnosing metabolic syndrome. We tested bidirectionality by including CRF, FM, LM, and adiponectin as exposures and FMD, DC, and PWV as outcomes, alternatively.

Results
Among 5566 participants (2816 (51%) girls; median age, 9.75 yr), CRF per body mass0.21 was directly related to DC (β (95% confidence interval) = 0.004 (<0.0001 to 0.008); P = 0.046), whereas CRF per LM0.54 was inversely associated with PWV (−0.034 (−0.063 to −0.003); 0.032) after adjusting for covariates. These associations remained in bidirectional analyses. Total FM, trunk FM, and LM were bidirectionally and positively associated with FMD and DC. Total FM and trunk FM but not LM had bidirectional and inverse associations with PWV. Adiponectin was not related to FMD, DC, or PWV. CRF partially mediated the associations of cardiometabolic health with FMD (1.5% mediation), DC (12.1% mediation), and PWV (3.5% mediation).

Conclusions
Associations of poor cardiometabolic health with adverse arterial structure and function in childhood may be mitigated by increasing CRF. Higher CRF was associated with better arterial structure whereas higher total FM and trunk FM were associated with better arterial function and structure. In the reverse analysis, healthy arterial structure and function were independently associated with increased total FM and trunk FM, suggesting an “arterial paradox.”
Physical Activity and Total Daily Energy Expenditure in Older US Adults: Constrained versus Additive Models
Authors: WILLIS ERIK A. , CREASY SETH A. , SAINT-MAURICE PEDRO F. , KEADLE SARAH KOZEY , PONTZER HERMANN , SCHOELLER DALE , TROIANO RICHARD P. , MATTHEWS CHARLES E. 
Published: August 2021

ABSTRACT

Purpose
This study aimed to examine the shape of the relationship between physical activity (PA) and total energy expenditure (TEE) and to explore the role of energy balance status (negative, stable, positive) in influencing this association.

Methods
Cross-sectional. Participants were 584 older adults (50–74 yr) participating in the Interactive Diet and Activity Tracking in AARP study. TEE was assessed by doubly labeled water and PA by accelerometer. The relationship between PA and TEE was assessed visually and using nonlinear methods (restricted cubic splines). Percent weight change (>3%) over a 6-month period was used as a proxy measurement of energy balance status.

Results
TEE generally increased with increasing deciles of PA averaging 2354 (SD, 351) kcal·d−1 in the bottom decile to 2693 (SD, 480) kcal·d−1 in the top decile. Cubic spline models showed an approximate linear association between PA and TEE (linear relation, P < 0.0001; curvature, P = 0.920). Results were similar in subgroup analyses for individuals classified as stable or positive energy balance. For those in negative energy balance, TEE was generally flat with increasing deciles of PA averaging 2428 (SD, 285) kcal·d−1 in the bottom decile to 2372 (SD, 560) kcal·d−1 in the top decile.

Conclusions
Energy balance status seems to play an important role in the relationship between PA and TEE. When in a positive energy balance, the relationship between TEE and PA was consistent with an additive model; however, when energy balance was negative, TEE seems to be consistent with a constrained model. These findings support PA for weight gain prevention by increasing TEE; however, the effect of PA on TEE during periods of weight loss may be limited. An adequately powered, prospective study is warranted to confirm these exploratory findings.
Acute Cardiopulmonary and Muscle Oxygenation Responses to Normocapnic Hyperpnea Exercise in COPD
Authors: OUESLATI FERID , SAEY DIDIER , VÉZINA FÉLIX-ANTOINE , NADREAU ÉRIC , MARTIN MICKAËL , MALTAIS FRANÇOIS 
Published: August 2021

ABSTRACT

Purpose
This study aimed to investigate cardiorespiratory responses and intercostal muscle oxygenation during normocapnic hyperpnea exercise in chronic obstructive pulmonary disease (COPD).

Methods
Twenty-two patients with COPD performed a cardiopulmonary cycling exercise test to assess peak oxygen consumption (V˙O2peak) and minute ventilation (V˙
Epeak). They also performed a normocapnic hyperpnea exercise alone, at 50%–60% of V˙
Epeak to exhaustion, using a respiratory device (Spirotiger) connected to a gas analyzer to monitor V˙O2, V˙
E, and end-tidal CO2 partial pressure. Cardiac output, and intercostal and vastus lateralis muscle oxygenation were continuously measured during exercise using finger photoplethysmography and near-infrared spectroscopy, respectively. Arterial blood gases (arterial PCO2) and inspiratory capacity were obtained at rest and at the end of hyperpnea exercise.

Results
The hyperpnea exercise lasted 576 ± 277 s at a V˙
E of 34.5 ± 12.1 L·min−1 (58% ± 6% of V˙
Epeak), a respiratory rate of 22 ± 4 breaths per minute, and a tidal volume of 1.43 ± 0.43 L. From rest to the end of hyperpnea exercise, V˙O2 increased by 0.35 ± 0.16 L·min−1 (P < 0.001), whereas end-tidal CO2 partial pressure and arterial PCO2 decreased by ~2 mm Hg (P = 0.031) and ~5 mm Hg (P = 0.002, n = 13), respectively. Moreover, inspiratory capacity fell from 2.44 ± 0.84 L at rest to 1.96 ± 0.59 L (P = 0.002). During the same period, heart rate and cardiac output increased from 69 ± 12 bpm and 4.94 ± 1.15 L·min−1 at rest to 87 ± 17 bpm (P = 0.002) and 5.92 ± 1.58 L·min−1 (P = 0.007), respectively. During hyperpnea exercise, intercostal deoxyhemoglobin and total hemoglobin increased by 14.26% ± 13.72% (P = 0.001) and 8.69% ± 12.49% (P = 0.003) compared with their resting value. However, during the same period, vastus lateralis oxygenation remained stable (P > 0.05).

Conclusions
In patients with COPD, normocapnic hyperpnea exercise provided a potent cardiorespiratory physiological stimulus, including dynamic hyperinflation, and increased intercostal deoxyhemoglobin consistent with enhanced requirement for muscle O2 extraction.
Membrane Proteins Increase with the Repeated Bout Effect
Authors: SIDKY SYLVIA R. , INGALLS CHRISTOPHER P. , LOWE DAWN A. , BAUMANN CORY W. 
Published: August 2021

ABSTRACT

Purpose
The ability of skeletal muscle to adapt to eccentric (ECC) contraction-induced injury is known as the repeated bout effect (RBE). Despite the RBE being a well-established phenomenon observed in skeletal muscle, cellular and molecular events particularly those at the membranes that contribute to the adaptive potential of muscle have yet to be established. Therefore, the purpose of this study was to examine how membrane-associated proteins respond to the RBE.

Methods
Anterior crural muscles of C57BL/6 female mice (3–5 months) were subjected to repeated bouts of in vivo ECCs, with isometric torque being measured immediately before and after injury. A total of six bouts were completed with 7 d between each bout. Protein content of dystrophin, β-sarcoglycan, and junctophilin were then assessed via immunoblotting in injured and uninjured muscles.

Results
When expressed relative to preinjury isometric torque of bout 1, deficits in postinjury isometric torque during bout 2 (38%) did not differ from bout 1 (36%; P = 0.646) and were attenuated during bouts 3 through 6 (range, 24%–15%; P ≤ 0.014). Contents of dystrophin, β-sarcoglycan, and junctophilin did not change immediately after a single bout of 50 maximal ECCs (P ≥ 0.155); however, as a result of repeated bouts, contents of dystrophin, β-sarcoglycan, and junctophilin all increased compared with muscles that completed one or no bouts of ECC contractions (P ≤ 0.003).

Conclusions
The RBE represents a physiological measure of skeletal muscle plasticity. Here, we demonstrate that repeated bouts of ECC contractions increase contents of dystrophin, β-sarcoglycan, and junctophilin and attenuate postinjury torque deficits. Given our results, accumulation of membrane-associated proteins likely contributes to strength adaptations observed after repeated bouts of ECC contractions.
Weekly Frequency of Meeting the Physical Activity Guidelines and Cardiometabolic Health in Children and Adolescents
Authors: WHITE DAVID A. , WILLIS ERIK A. , PTOMEY LAUREN T. , GORCZYCA ANNA M. , DONNELLY JOSEPH E. 
Published: August 2021

ABSTRACT
The current physical activity (PA) guidelines for children and adolescents in the United States recommend ≥60 min of moderate- to vigorous-intensity PA (MVPA), 7 d·wk−1 for cardiometabolic health (CmH) benefits. Although the duration and intensity components of the PA guidelines have been rigorously studied, the frequency (7 d·wk−1) component has not been thoroughly researched.

Purpose
This study aimed to examine the association of the frequency component of the weekly PA guidelines on CmH in youth.

Methods
Cross-sectional accelerometer data from the 2003–2006 National Health and Nutrition Examination Survey included youth age 6–18 yr with ≥4 d, ≥10 h of wear time, and averaging ≥60 min·d−1 of MVPA (n = 656). Participants were categorized into quartiles based on the proportion of days where they met the guidelines (≥60 min of MVPA). CmH variables were categorized as weight status/body anthropometrics, blood pressure, cholesterol, and fasting serum laboratory results. Propensity score weighting was applied to quartiles, and general linear modeling was used to compare associations of quartiles with CmH variables.

Results
Results are displayed as percent of days meeting guidelines (DMG; 95% confidence interval): MVPA in minutes per week: Q1 (n = 156; DMG = 45.8% (43.4%–48.1%); MVPA 467.5, min·wk−1), Q2 (n = 165; DMG = 62.6% (61.6%–63.7%); MVPA, 474.4 min·wk−1), Q3 (n = 148; DMG = 75% (74.1%–75.8%); MVPA, 446.5 min·wk−1), Q4 (n = 187; DMG = 92.2% (87.7%–96.6%); MVPA, 453.2 min·wk−1). After adjusting for confounders and multiple comparisons, there were no clinically significant differences in weight status/body anthropometrics, blood pressure, cholesterol, or fasting serum laboratory results between DMG quartiles.

Conclusions
We found no association between the proportion of DMG and CmH in children and adolescents. Our study suggests that achieving an overall weekly average of 60 min·d−1 of MVPA seems to be sufficient for CmH regardless of the 7 d·wk−1 frequency requirement of the PA guideline.
Sea grapes extract improves blood glucose, total cholesterol, and PGC-1α in rats fed on cholesterol- and fat-enriched diet
Authors: Kuswari Mury , Nurkolis Fahrul , Mayulu Nelly , Ibrahim Faisal Maulana , Taslim Nurpudji Astuti , Wewengkang Defny Silvia , Sabrina Nindy , Arifin Ghafur Rasyid , Mantik Keren Esther Kristina , Bahar Muhammad Rahimi , Rifqiyati Najda , Rompies Ronald , Augusta Piko Satria , Permatasari Happy Kurnia 
Published: August 2021

Background: Sea grapes or Caulerpa racemosa have a lot of phytochemical content, especially unsaturated fatty acids that are beneficial for health. This study aims to evaluate the effects of sea grapes extract on blood glucose levels, total cholesterol-, and Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α in male Wistar rats, which were given per-oral (p.o.) cholesterol- and carbohydrates fat-enriched diets (CFED). Methods: Forty male Wistar albino rats weighing between 200 – 250 g were used for this study. Animals were randomly distributed into four groups of ten animals each. Group A served as control (received standard dry pellet diet). Rats in group B were fed on CFED for 4 weeks. Groups C and D were fed on CFED and were administered 150 and 450 mg/kg of sea grapes extract (p.o.), respectively. Results: Group C rats indicated a blood glucose reduction and an increase in PGC-1α serum, in comparison to group D (p<0.05). There were no significant differences between group C and D in blood cholesterol reduction (high dose of the extract did not have significant effects) (p=0.222), and both groups had the same effect in lowering total cholesterol in rats. Conclusion: Sea grapes extract is proven to improve blood glucose, total cholesterol, and PGC-1α levels in rats fed with CFED.
Dynamic SOFA score assessments to predict outcomes after acute admission of octogenarians to the intensive care unit
Authors: Loyrion Emmanuelle , Agier Lydiane , Trouve-Buisson Thibaut , Gavazzi Gaetan , Schwebel Carole , Bosson Jean-Luc , Payen Jean-François 
Published: August 2021

Background
Identifying which octogenarians could benefit most from continuing critical care is challenging. We aimed to see if responses to therapies using the sequential organ failure assessment (SOFA) score on day 4 after unplanned admission to the intensive care unit (ICU) could be associated with short-term mortality.

Methods
In this prospective observational cohort study, data from 4 ICUs in a University Hospital included SOFA scores on admission and day 4, along with preadmission measurements of frailty, comorbidities, nutritional status and number of medications. Outcome measures included mortality and loss of autonomy on day 90 after admission.

Results
Eighty-seven critically ill patients aged 80 years or older with preadmission functional independence and no missing SOFA score data on day 4 were studied (primary analyses). The mortality rate on day 90 was 30%. In a univariate Cox model, the SOFA score on day 4 was significantly associated with mortality rate: hazard ratio = 1.18 per one-point increase, 95% confidence interval (CI), 1.08 to 1.28 (p<0.001). A SOFA score of 6 or more on day 4 could correctly classify 75% of patients who died on day 90, with a sensitivity of 54% and a specificity of 84%. After adjustment, the SOFA score on day 4, neurological failure on admission and the number of preadmission medications were significantly associated with mortality on day 90, with an area under the receiver operating characteristic curve of 0.81 (95% CI, 0.71 to 0.91). These findings were confirmed in a sensitivity analysis with 109 patients. Preadmission frailty was the only variable independently associated with loss of autonomy in the 49 surviving patients.

Conclusion
Measuring SOFA score on day 4 and preadmission frailty could help predict mortality and loss of autonomy on day 90 in octogenarians after their acute admission to the ICU.
Diarrhea treatment center (DTC) based diarrheal disease surveillance in settlements in the wake of the mass influx of forcibly displaced Myanmar national (FDMN) in Cox’s Bazar, Bangladesh, 2018
Authors: Faruque Abu S. G. , Khan Azharul Islam , Islam S. M. Rafiqul , Nahar Baitun , Hossain M. Nasif , Widiati Yulia , Hasan A. S. M. Mainul , Prajapati Mukeshkumar , Kim Minjoon , Vandenent Maya , Ahmed Tahmeed 
Published: August 2021

Background
In August 2017, after a large influx of forcibly displaced Myanmar nationals (FDMN) in Cox’s Bazar, Bangladesh diarrhea treatment centers (DTCs) were deployed. This study aims to report the clinical, epidemiological, and laboratory characteristics of the hospitalized patients.

Methods
The study followed cross-sectional design. In total 1792 individuals were studied. Other than data, a single, stool specimen was subjected to one step rapid visual diagnostic test for Vibrio cholerae. The provisionally diagnosed specimens of cholera cases were inoculated into Cary-Blair Transport Medium; then sent to the laboratory of icddr,b in Dhaka to isolate the colony as well as perform antibiotic susceptibility tests. Data were analyzed by STATA and analyses included descriptive as well as analytic methods.

Results
Of the total 1792 admissions in 5 DTCs, 729 (41%) were from FDMN settlements; children <5 years contributed the most (n = 981; 55%). Forty percent (n = 716) were aged 15 years and above, and females were predominant (n = 453; 63%). Twenty-eight percent (n = 502) sought treatment within 24h of the onset of diarrhea. FDMN admissions within 24h were low compared to host hospitalization (n = 172, 24% vs. n = 330, 31%; p<0.001). Seventy-two percent (n = 1295) had watery diarrhea; more common among host population than FDMN (n = 802; 75% vs. n = 493; 68%; p<0.001). Forty-four percent admissions (n = 796) had some or severe dehydration, the later was common in FDMN (n = 46; 6% vs. n = 36; 3%, p = 0.005). FDMN often used public taps (n = 263; 36%), deep tube-well (n = 243; 33%), and shallow tube well (n = 188; 26%) as the source of drinking water. Nearly 96% (n = 698) of the admitted FDMN used pit latrines as opposed to 79% (n = 842) from the host community (p<0.001). FDMN children were often malnourished. None of the FDMN reported cholera.

Conclusion
No diarrhea outbreak was detected, but preparedness for surges and response readiness are warranted in this emergency and crisis setting.