bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of thiostrepton as a pharmacological approach to rescue misfolded alpha-sarcoglycan mutant proteins from degradation
Authors: Hoch Lucile , Henriques Sara F. , Bruge Celine , Marsolier Justine , Benabides Manon , Bourg Nathalie , Tournois Johana , Mahé Gurvan , Morizur Lise , Jarrige Margot , Bigot Anne , Richard Isabelle , Nissan Xavier 
Published: May 2019

AbstractLimb-girdle muscular dystrophy type 2D (LGMD2D) is characterized by a progressive proximal muscle weakness. LGMD2D is caused by mutations in the gene encoding α-sarcoglycan (α-SG), a dystrophin-associated glycoprotein that plays a key role in the maintenance of sarcolemma integrity in striated muscles. We report here on the development of a new in vitro high-throughput screening assay that allows the monitoring of the proper localization of the most prevalent mutant form of α-SG (R77C substitution). Using this assay, we screened a library of 2560 FDA-approved drugs and bioactive compounds and identified thiostrepton, a cyclic antibiotic, as a potential drug to repurpose for LGMD2D treatment. Characterization of the thiostrepton effect revealed a positive impact on R77C-α-SG and other missense mutant protein localization (R34H, I124T, V247M) in fibroblasts overexpressing these proteins. Finally, further investigations of the molecular mechanisms of action of the compound revealed an inhibition of the chymotrypsin-like activity of the proteasome 24 h after thiostrepton treatment and a synergistic effect with bortezomib, an FDA-approved proteasome inhibitor. This study reports on the first in vitro model for LGMD2D that is compatible with high-throughput screening and proposes a new therapeutic option for LGMD2D caused by missense mutations of α-SG.
Comprehensive Analysis of Animal Models of Cardiovascular Disease using Multiscale X-Ray Phase Contrast Tomography
Authors: Dejea Hector , Garcia-Canadilla Patricia , Cook Andrew C. , Guasch Eduard , Zamora Monica , Crispi Fatima , Stampanoni Marco , Bijnens Bart , Bonnin Anne 
Published: May 2019

AbstractCardiovascular diseases (CVDs) affect the myocardium and vasculature, inducing remodelling of the heart from cellular to whole organ level. To assess their impact at micro and macroscopic level, multi-resolution imaging techniques that provide high quality images without sample alteration and in 3D are necessary: requirements not fulfilled by most of current methods. In this paper, we take advantage of the non-destructive time-efficient 3D multiscale capabilities of synchrotron Propagation-based X-Ray Phase Contrast Imaging (PB-X-PCI) to study a wide range of cardiac tissue characteristics in one healthy and three different diseased rat models. With a dedicated image processing pipeline, PB-X-PCI images are analysed in order to show its capability to assess different cardiac tissue components at both macroscopic and microscopic levels. The presented technique evaluates in detail the overall cardiac morphology, myocyte aggregate orientation, vasculature changes, fibrosis formation and nearly single cell arrangement. Our results agree with conventional histology and literature. This study demonstrates that synchrotron PB-X-PCI, combined with image processing tools, is a powerful technique for multi-resolution structural investigation of the heart ex-vivo. Therefore, the proposed approach can improve the understanding of the multiscale remodelling processes occurring in CVDs, and the comprehensive and fast assessment of future interventional approaches.
Continuous Objective Assessment of Near Work
Authors: Williams Rachel , Bakshi Suyash , Ostrin Edwin J. , Ostrin Lisa A. 
Published: May 2019

AbstractEvidence regarding the role of near work in myopia is conflicting. We developed the RangeLife, a device for continuous, objective measurement of working distance. Four devices were built, calibrated, and validated. Then, adult subjects wore the device on weekdays and weekend days, while simultaneously wearing an actigraph device for objective measurements of light exposure and activity. Subjects maintained an activity log and answered a visual activity questionnaire. RangeLife data were downloaded and binned into 0.10 m intervals. Objective diopter hours (dh), a weighted measure of near work, were calculated. Diopter hours for all subjects were significantly higher on weekdays (14.73 ± 4.67 dh) compared to weekends (11.90 ± 4.84 dh, p = 0.05). 94 ± 1.85% of near and intermediate viewing distances were recorded when the subjects were exposed to mesopic and indoor photopic light levels (<1000 lux), and 80.03 ± 2.11% during periods of sedentary physical activity (<320 counts per minute). Subjective reports of time viewing near and intermediate distances significantly overestimated objective measures (p = 0.002). The RangeLife was shown to provide reliable measures of viewing distance, and can be further utilized to understand potential influences of viewing behaviors on refractive error.
Thallium(I) treatment induces nucleolar stress to stop protein synthesis and cell growth
Authors: Chou Yi-Ting , Lo Kai-Yin 
Published: May 2019

AbstractThallium is considered as an emergent contaminant owing to its potential use in the superconductor alloys. The monovalent thallium, Tl(I), is highly toxic to the animals as it can affect numerous metabolic processes. Here we observed that Tl(I) decreased protein synthesis and phosphorylated eukaryotic initiation factor 2α. Although Tl(I) has been shown to interact with the sulfhydryl groups of proteins and cause the accumulation of reactive oxygen species, it did not activate endoplasmic reticulum stress. Notably, the level of 60S ribosomal subunit showed significant under-accumulation after the Tl(I) treatment. Given that Tl(I) shares similarities with potassium in terms of the ionic charge and atomic radius, we proposed that Tl(I) occupies certain K+-binding sites and inactivates the ribosomal function. However, we observed neither activation of ribophagy nor acceleration of the proteasomal degradation of 60S subunits. On the contrary, the ribosome synthesis pathway was severely blocked, i.e., the impairment of rRNA processing, deformed nucleoli, and accumulation of 60S subunits in the nucleus were observed. Although p53 remained inactivated, the decreased c-Myc and increased p21 levels indicated the activation of nucleolar stress. Therefore, we proposed that Tl(I) interfered the ribosome synthesis, thus resulting in cell growth inhibition and lethality.
Long DCL4-substrate dsRNAs efficiently induce RNA interference in plant cells
Authors: Kakiyama Sayaka , Tabara Midori , Nishibori Yuki , Moriyama Hiromitsu , Fukuhara Toshiyuki 
Published: May 2019

AbstractRNA interference (RNAi) is induced by the direct transfer of double-stranded RNAs (dsRNAs) into protoplasts prepared from Arabidopsis thaliana seedlings. In this protoplast RNAi system, we compared the efficacies of various-sized dsRNAs (between 21 and 139 nucleotides [nt]) for inducing RNAi and assessed the dsRNA-cleaving activities of Dicer-like 3 (DCL3) and 4 (DCL4). After the direct transfer of dsRNAs into protoplasts, cleaved RNA products of 21 nt were detected from long 130- or 500-nt dsRNAs by DCL4 but not from 37-nt dsRNAs. These results indicate that DCL4 preferentially cleaves long dsRNAs in protoplasts, consistent with our previous biochemical data regarding the substrate specificity of DCL4. Direct transfer of long dsRNAs of approximately 130 nt into protoplasts induces RNAi much more effectively (by approximately 60- to 400-fold) than direct transfer of short 37-nt dsRNAs. Although transfer of 21-nt dsRNAs into protoplasts induced RNAi without DCL4 activity, the induction of RNAi was less effective (by approximately 0.01-fold) compared with long dsRNAs. These results indicate that cleavage of long dsRNAs exceeding 100 nt by DCL4 into 21-nt dsRNAs is essential for efficient induction of RNAi in plant cells.
Bile-duct proliferation as an unexpected side-effect after AAV2-LDLR gene transfer to rabbit liver
Authors: Hytönen Elisa , Laurema Anniina , Kankkonen Hanna , Miyanohara Atsushi , Kärjä Vesa , Hujo Mika , Laham-Karam Nihay , Ylä-Herttuala Seppo 
Published: May 2019

AbstractFamilial hypercholesterolemia (FH) is an inherited disease of lipoprotein metabolism caused by a defect in the LDL receptor (LDLR) leading to severe hypercholesterolemia, and associated with an increased risk of coronary heart disease and myocardial infarction. We have developed a gene therapy protocol for FH using AAV2, AAV9 and lentiviral vectors and tested safety and efficacy in LDL receptor deficient Watanabe Heritable Hyperlipidemic rabbits. We show that LV-LDLR produced a significant long-lasting decrease in total serum cholesterol whereas AAV9-LDLR resulted only in a transient decrease and AAV2-LDLR failed to reduce serum cholesterol levels. A significant pathological side effect, bile-duct proliferation, was seen in the liver of AAV2-LDLR rabbits associated with an increased expression of Cyr61 matricellular protein. Special attention should be given to liver changes in gene therapy applications when genes affecting cholesterol and lipoprotein metabolism are used for therapy.
The dynamic relationships between the active and catabolic vitamin D metabolites, their ratios, and associations with PTH
Authors: Tang Jonathan C. Y. , Jackson Sarah , Walsh Neil P. , Greeves Julie , Fraser William D. ,   Bioanalytical Facility team, Ball Nicole , Dutton John , Nicholls Holly , Piec Isabelle , Washbourne Christopher J. 
Published: May 2019

AbstractVitamin D status, assessed by serum concentration of 25(OH)D, is the prime candidate marker for many disease-association studies, but the interplay between the subsequent 1,25-dihydroxyvitamin D (1,25(OH)2D) and 24,25-dihydroxyvitamin D (24,25(OH)2D) metabolites is unclear. In this study, we conducted an analysis from a large cohort of healthy, physically fit, young army recruits (n = 940). We found a significant, inverse relationship between serum 25(OH)D and 1,25(OH)2D:24,25(OH)2D vitamin D metabolite ratio (VMR) (r2Exp = 0.582, p < 0.0001), and demonstrated a significant association with increasing PTH concentration (p < 0.001). Circannual rhythms were evident for all vitamin D metabolites and VMRs except for 1,25(OH)2D when fitted to Cosinor curves. We estimated 1,25(OH)2D:24,25(OH)2D VMR of ≥35 to be the threshold value for vitamin D insufficiency, and ≥51 to be predictive of vitamin D deficiency. Our three-dimensional model provides mechanistic insight into the vitamin D-PTH endocrine system, and further substantiates the role of 24,25(OH)2D in human physiology. The model sets a new paradigm for vitamin D treatment strategy, and may help the establishment of vitamin D-adjusted PTH reference intervals. The study was approved by the UK Ministry of Defence research ethics committee (MODREC 165/Gen/10 and 692/MoDREC/15). ClinicalTrials.gov Identifier NCT02416895.
Open-ocean polynyas and deep convection in the Southern Ocean
Authors: Cheon Woo Geun , Gordon Arnold L. 
Published: May 2019

AbstractAn open-ocean polynya is a large ice-free area surrounded by sea ice. The Maud Rise Polynya in the Southern Ocean occasionally occurs during the austral winter and spring seasons in the vicinity of Maud Rise near the Greenwich Meridian. In the mid-1970s the Maud Rise Polynya served as a precursor to the more persistent, larger Weddell Polynya associated with intensive open-ocean deep convection. However, the Maud Rise Polynya generally does not lead to a Weddell Polynya, as was the situation in the September to November of 2017 occurrence of a strong Maud Rise Polynya. Using diverse, long-term observation and reanalysis data, we found that a combination of weakly stratified ocean near Maud Rise and a wind induced spin-up of the cyclonic Weddell Gyre played a crucial role in generating the 2017 Maud Rise Polynya. More specifically, the enhanced flow over the southwestern flank of Maud Rise intensified eddy activity, weakening and raising the pycnocline. However, in 2018 the formation of a Weddell Polynya was hindered by relatively low surface salinity associated with the positive Southern Annular Mode, in contrast to the 1970s’ condition of a prolonged, negative Southern Annular Mode that induced a saltier surface layer and weaker pycnocline.
Handgrip strength attenuates the adverse effects of overweight on cardiometabolic risk factors among collegiate students but not in individuals with higher fat levels
Authors: Garcia-Hermoso Antonio , Tordecilla-Sanders Alejandra , Correa-Bautista Jorge Enrique , Peterson Mark D. , Izquierdo Mikel , Prieto-Benavides Daniel , Sandoval-Cuellar Carolina , González-Ruíz Katherine , Ramírez-Vélez Robinson 
Published: May 2019

AbstractThe aims of this study are to (i) examine a clustered metabolic syndrome composite score (MetScore) and fatness among college students across body mass index (BMI) categories, and (ii) determine whether fit individuals have lower MetScores, fewer individual metabolic syndrome components, and lower fatness than unfit individuals across BMI categories. A total of 1,795 participants aged >18 years who participated in The FUPRECOL Study were selected for the present analyses. Handgrip strength was tested by a grip dynamometer and used to classify adults as fit or unfit. Among all participants, MetScore, percentage of body fat, and visceral adiposity increased linearly across the BMI categories among college students (all P < 0.001). Individuals who were overweight and fit had a lower MetScore (−0.6 SD; P = 0.02), body fat percentage (−2.6%; P < 0.001) and visceral adiposity (−0.2; P = 0.01) than unfit peers. Moderately fit obese individuals had significantly lower visceral fat levels than unfit obese peers (−3.0; P = 0.03). These results suggest that having adequate handgrip strength-a proxy of overall strength capacity-may attenuate obesity-related cardiometabolic risk. Moreover, weight loss should be recommended to all individuals with obesity, even among those who are currently considered fit.
Functional diversity drives ecosystem multifunctionality in a Pinus yunnanensis natural secondary forest
Authors: Huang Xiaobo , Su Jianrong , Li Shuaifeng , Liu Wande , Lang Xuedong 
Published: May 2019

AbstractIt is essential to understand how the loss of biodiversity impacts both ecosystem function (EF) and multifunctionality (EMF). Previous studies have mostly focused on predicting how species richness (SR) impacts EMF, while the effect of functional diversity (FD) on EMF remains unclear. Specifically, we know little about the primary functional drivers impacting EMF compared with SR. Therefore, we analysed 8 ecosystem functions within 58 natural secondary forest plots to investigate the effect of FD on both individual EF and EMF. Our results suggest that SR and FD had very significant positive effects on plant phosphorus, soil available phosphorus, and soil total nitrogen. FD explained significantly more variations in these functional responses than SR for individual ecosystem functioning. We also used a multiple threshold approach to test the effect of SR and FD on EMF. We found that FD and SR were positively related to EMF regardless of whether low-level function or high-level function was desired, but FD had a larger effect than SR. Based on the averaging approach, OLS regression, multivariate linear regression model and random forest analysis, we found that SR and FD were both drivers of EMF but that FD had a stronger effect and could explain more variation. As such, we conclude that FD drives ecosystem multifunctionality more than SR.
Ligustilide, a major bioactive component of Angelica sinensis, promotes bone formation via the GPR30/EGFR pathway
Authors: Yang F. , Lin Z. W. , Huang T. Y. , Chen T. T. , Cui J. , Li M. Y. , Hua Y. Q. 
Published: May 2019

AbstractAngelica sinensis (Oliv.) Diels is a widely-used traditional Chinese herbal medicine in treating osteoporosis. Ligustilide (LIG) is the main component of A. sinensis and is considered to be the most effective biologically active ingredient in this plant. LIG has been found to have multiple pharmacological activities, such as anti-atherosclerosis, neuroprotection, anticancer, anti-inflammatory and analgesic. However, little is known regarding its anti-osteoporotic effects. The aims of this study were to investigate any protective effect of LIG on bone formation. The results showed that LIG significantly ameliorated inhibition of bone formation in zebrafish caused by prednisolone. LIG promoted osteoblast differentiation, including that of the pre-osteoblastic cell line MC3T3-E1 and bone marrow mesenchymal stem cells. LIG greatly improved the viability of MC3T3-E1 cells exposed to H2O2, attenuated H2O2-induced apoptosis and increased the expression of Bcl-2. Furthermore, LIG treatment lead to marked activation of phosphorylated EGFR and ERK1/2. These effects could be obviously inhibited by blocking GPR30 signaling with the specific inhibitor G15. Collectively, the results reveal that GPR30 is a positive switch for LIG to increase bone formation via regulation of EGFR, and these results provide evidence for the potential of LIG to treat osteoporosis.
Artificial reefs facilitate tropical fish at their range edge
Authors: Paxton Avery B. , Peterson Charles H. , Taylor J. Christopher , Adler Alyssa M. , Pickering Emily A. , Silliman Brian R. 
Published: May 2019

AbstractSpatial planning increasingly incorporates theoretical predictions that artificial habitats assist species movement at or beyond range edges, yet evidence for this is uncommon. We conducted surveys of highly mobile fauna (fishes) on artificial habitats (reefs) on the southeastern USA continental shelf to test whether, in comparison to natural reefs, artificial reefs enhance local abundance and biomass of fishes at their poleward range margins. Here, we show that while temperate fishes were more abundant on natural reefs, tropical, and subtropical fishes exhibited higher abundances and biomasses on deep (25–35 m) artificial reefs. Further analyses reveal that this effect depended on feeding guilds because planktivorous and piscivorous but not herbivorous fishes were more abundant on artificial reefs. This is potentially due to heightened prey availability on and structural complexity of artificial reefs. Our findings demonstrate that artificial habitats can facilitate highly mobile species at range edges and suggest these habitats assist poleward species movement.
Hierarchical self-assembly and emergent function of densely glycosylated peptide nanofibers
Authors: Restuccia Antonietta , Seroski Dillon T. , Kelley Karen L. , O’Bryan Christopher S. , Kurian Justin J. , Knox Kevin R. , Farhadi Shaheen A. , Angelini Thomas E. , Hudalla Gregory A. 
Published: May 2019

AbstractGlycosylation alters protein form and function by establishing intermolecular forces that mediate specific interactions while preventing non-specific aggregation. Self-assembled peptide nanofibers modified with carbohydrates are increasingly used as biomaterials to mimic glycosylated protein function, yet the influence of carbohydrate conjugates on nanofiber structure remains poorly defined. Here we show that a dense carbohydrate surface layer can facilitate hierarchical organization of peptide nanofibers into anisotropic networks. Glycosylated peptide nanofibers remain dispersed in dilute conditions, whereas non-glycosylated nanofibers tend to aggregate. In crowded conditions, some glycosylated nanofibers laterally associate and align. This behavior depends on carbohydrate chemistry, particularly hydroxyls, suggesting involvement of short-range attractive forces. Macroscopic gels fabricated from densely glycosylated peptide nanofibers are resistant to non-specific interactions with proteins, mammalian cells, and bacteria, yet selectively bind lectins, analogous to natural low-fouling mucosal barriers. Collectively, these observations demonstrate that glycosylation can inform structure in addition to endowing function to peptide-based supramolecular biomaterials.
Effect of Auditory Task Type on Physiological and Subjective Measures of Listening Effort in Individuals With Normal Hearing
Authors: Lau Marcy K. , Hicks Candace , Kroll Tobias , Zupancic Steven 
Published: May 2019

PurposeListening effort has traditionally been measured using subjective rating scales and behavioral measures. Recent physiological measures of listening effort have utilized pupil dilation. Using a combination of physiological and subjective measures of listening effort, this study aimed to identify differences in listening effort during 2 auditory tasks: sentence recognition and word recognition.MethodPupil dilation and subjective ratings of listening effort were obtained for auditory tasks utilizing AzBio sentences recognition and Northwestern University Auditory Test No. 6 words recognition, across 3 listening situations: in quiet, at +6 dB signal-to-noise ratio, and at 0 dB signal-to-noise ratio. Task accuracy was recorded for each of the 6 conditions, as well as peak pupil dilation and a subjective rating of listening effort.ResultsA significant impact of listening situation (quiet vs. noise) and task type (sentence recognition vs. word recognition) on both physiological and subjective measures was found. There was a significant interaction between listening situation and task type, suggesting that contextual cues may only be beneficial when audibility is uncompromised. The current study found no correlation between the physiological and subjective measures, possibly suggesting that these measures analyze different aspects of cognitive effort in a listening task.
Resolving the extended stellar atmospheres of asymptotic giant branch stars at (sub)millimetre wavelengths
Authors: Vlemmings W. H. T. , Khouri T. , Olofsson H. 
Published: May 2019

Context. The initial conditions for mass loss during the asymptotic giant branch (AGB) phase are set in their extended atmospheres, where, among others, convection and pulsation driven shocks determine the physical conditions.
Aims. High resolution observations of AGB stars at (sub)millimetre wavelengths can now directly determine the morphology, activity, density, and temperature close to the stellar photosphere.
Methods. We used Atacama Large Millimeter/submillimeter Array (ALMA) high angular resolution observations to resolve the extended atmospheres of four of the nearest AGB stars: W Hya, Mira A, R Dor, and R Leo. We interpreted the observations using a parameterised atmosphere model.
Results. We resolve all four AGB stars and determine the brightness temperature structure between 1 and 2 stellar radii. For W Hya and R Dor we confirm the existence of hotspots with brightness temperatures > 3000 to 10 000 K. All four stars show deviations from spherical symmetry. We find variations on a timescale of days to weeks, and for R Leo we directly measure an outward motion of the millimetre wavelength surface with a velocity of at least 10.6 ± 1.4 km s−1. For all objects but W Hya we find that the temperature-radius and size-frequency relations require the existence of a (likely inhomogeneous) layer of enhanced opacity.
Conclusions. The ALMA observations provide a unique probe of the structure of the extended AGB atmosphere. We find highly variable structures of hotspots and likely convective cells. In the future, these observations can be directly compared to multi-dimensional chromosphere and atmosphere models that determine the temperature, density, velocity, and ionisation structure between the stellar photosphere and the dust formation region. However, our results show that for the best interpretation, both very accurate flux calibration and near-simultaneous observations are essential.
Langzeitfolgen des Intensivaufenthalts
Authors: Jeitziner Marie-Madlen , Jenni-Moser Béatrice , Pooe Eliane 
Published: May 2019

ZusammenfassungDer Aufenthalt auf einer Intensivstation ist für viele Betroffene ein
traumatisches Ereignis. Noch lange nach der Entlassung können sich diverse
Einschränkungen zeigen, auch über einen langen Zeitraum hinweg. Der folgende
Beitrag zeigt Ursachen, Risikofaktoren und klinische Darstellung dieses
sogenannten Post-Intensive Care Syndromes.