bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression
Authors: Ohtsuka Yoshihisa , Kanagawa Motoi , Yu Chih-Chieh , Ito Chiyomi , Chiyo Tomoko , Kobayashi Kazuhiro , Okada Takashi , Takeda Shin'ichi , Toda Tatsushi 
Published: February 2015

Abstractα-Dystroglycanopathy (α-DGP) is a group of muscular dystrophy characterized by abnormal glycosylation of α-dystroglycan (α-DG), including Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease, Walker-Warburg syndrome and congenital muscular dystrophy type 1D (MDC1D), etc. LARGE, the causative gene for MDC1D, encodes a glycosyltransferase to form [-3Xyl-α1,3GlcAβ1-] polymer in the terminal end of the post-phosphoryl moiety, which is essential for α-DG function. It has been proposed that LARGE possesses the great potential to rescue glycosylation defects in α-DGPs regardless of causative genes. However, the in vivo therapeutic benefit of using LARGE activity is controversial. To explore the conditions needed for successful LARGE gene therapy, here we used Large-deficient and fukutin-deficient mouse models for MDC1D and FCMD, respectively. Myofibre-selective LARGE expression via systemic adeno-associated viral gene transfer ameliorated dystrophic pathology of Large-deficient mice even when intervention occurred after disease manifestation. However, the same strategy failed to ameliorate the dystrophic phenotype of fukutin-conditional knockout mice. Furthermore, forced expression of Large in fukutin-deficient embryonic stem cells also failed to recover α-DG glycosylation, however coexpression with fukutin strongly enhanced α-DG glycosylation. Together, our data demonstrated that fukutin is required for LARGE-dependent rescue of α-DG glycosylation and thus suggesting new directions for LARGE-utilizing therapy targeted to myofibres.
Optogenetic induction of contractile ability in immature C2C12 myotubes
Authors: Asano Toshifumi , Ishizuka Toru , Morishima Keisuke , Yawo Hiromu 
Published: February 2015

AbstractMyoblasts can be differentiated into multinucleated myotubes, which provide a well-established and reproducible muscle cell model for skeletal myogenesis in vitro. However, under conventional differentiation conditions, each myotube rarely exhibits robust contraction as well as sarcomere arrangement. Here, we applied trains of optical stimulation (OS) to C2C12 myotubes, which were genetically engineered to express a channelrhodopsin variant, channelrhodopsin-green receiver (ChRGR), to investigate whether membrane depolarization facilitates the maturation of myotubes. We found that light pulses induced membrane depolarization and evoked action potentials in ChRGR-expressing myotubes. Regular alignments of sarcomeric proteins were patterned periodically after OS training. In contrast, untrained control myotubes rarely exhibited the striated patterns. OS-trained and untrained myotubes also differed in terms of their resting potential. OS training significantly increased the number of contractile myotubes. Treatment with nifedipine during OS training significantly decreased the fraction of contractile myotubes, whereas tetrodotoxin was less effective. These results suggest that oscillations of membrane potential and intracellular Ca2+ accompanied by OS promoted sarcomere assembly and the development of contractility during the myogenic process. These results also suggest that optogenetic techniques could be used to manipulate the activity-dependent process during myogenic development.
Increased Efficiency in Small Molecule Organic Solar Cells Through the Use of a 56-π Electron Acceptor – Methano Indene Fullerene
Authors: Ryan James W. , Matsuo Yutaka 
Published: February 2015

AbstractOrganic solar cells (OSCs) offer the possibility of harnessing the sun's ubiquitous energy in a low-cost, environmentally friendly and renewable manner. OSCs based on small molecule semiconductors (SMOSCs) – have made a substantial improvement in recent years and are now achieving power conversion efficiencies (PCEs) that match those achieved for polymer:fullerene OSCs. To date, all efficient SMOSCs have relied on the same fullerene acceptor, PCBM, in order to achieve high performance. The use of PCBM however, is unfavourable due to its low lying LUMO level, which limits the open-circuit voltage (VOC). Alternative fullerene derivatives with higher lying LUMOs are thus required to improve the VOC. The challenge, however, is to prevent the typical concomitant decrease in the short circuit current density (JSC) when using a higher LUMO fullerene. In this communication, we address the issue by applying methano indene fullerene, MIF, a bis-functionalised C60 fullerene that has a LUMO level 140 mV higher than PCBM, in solution processed SMOSCs with a well known small molecule donor, DPP(TBFu)2. MIF-based devices show an improved VOC of 140 mV over PC61BM and only a small decrease in the JSC, with the PCE increasing to 5.1% (vs. 4.5% for PC61BM).
Live cell immunogold labelling of RNA polymerase II
Authors: Orlov Igor , Schertel Andreas , Zuber Guy , Klaholz Bruno , Drillien Robert , Weiss Etienne , Schultz Patrick , Spehner Danièle 
Published: February 2015

AbstractLabeling nuclear proteins with electron dense probes in living cells has been a major challenge due to their inability to penetrate into nuclei. We developed a lipid-based approach for delivering antibodies coupled to 0.8 nm ultrasmall gold particles into the nucleus to label RNA polymerase II. Focussed Ion Beam slicing coupled to Scanning Electron Microscopy (FIB/SEM) enabled visualization of entire cells with probe localization accuracy in the 10 nm range.
Handedness and the X chromosome: The role of androgen receptor CAG-repeat length
Authors: Arning Larissa , Ocklenburg Sebastian , Schulz Stefanie , Ness Vanessa , Gerding Wanda M. , Hengstler Jan G. , Falkenstein Michael , Epplen Jörg T. , Güntürkün Onur , Beste Christian 
Published: February 2015

AbstractPrenatal androgen exposure has been suggested to be one of the factors influencing handedness, making the androgen receptor gene (AR) a likely candidate gene for individual differences in handedness. Here, we examined the relationship between the length of the CAG-repeat in AR and different handedness phenotypes in a sample of healthy adults of both sexes (n = 1057). Since AR is located on the X chromosome, statistical analyses in women heterozygous for CAG-repeat lengths are complicated by X chromosome inactivation. We thus analyzed a sample of women that were homozygous for the CAG-repeat length (n = 77). Mixed-handedness in men was significantly associated with longer CAG-repeat blocks and women homozygous for longer CAG-repeats showed a tendency for stronger left-handedness. These results suggest that handedness in both sexes is associated with the AR CAG-repeat length, with longer repeats being related to a higher incidence of non-right-handedness. Since longer CAG-repeat blocks have been linked to less efficient AR function, these results implicate that differences in AR signaling in the developing brain might be one of the factors that determine individual differences in brain lateralization.
GADD34 inhibits activation-induced apoptosis of macrophages through enhancement of autophagy
Authors: Ito Sachiko , Tanaka Yuriko , Oshino Reina , Aiba Keiko , Thanasegaran Suganya , Nishio Naomi , Isobe Ken-ichi 
Published: February 2015

AbstractAutophagy is a common physiological function in all eukaryotes. The process is induced by depletion of nutrients including amino acids. GADD34 is expressed following DNA damage, ER stresses and amino acid deprivation. Here, we investigated the effects of GADD34 on autophagy and cell activation in macrophages. The deprivation of tyrosine and cysteine markedly induced the expression of GADD34 in macrophages. LPS stimulation combined with tyrosine/cysteine-deprivation initially activated macrophages, but then shifted to cell death in late phase of stimulation. When LPS stimulation was combined with tyrosine/cysteine-deprivation, a deficiency of GADD34 enhanced cell activation signaling such as Src-family, Erk1/2, p38 MAPK and Akt. In the late phase of stimulation, a deficiency of GADD34 increased apoptosis more than that in wild-type macrophages. Further we found that mTOR-S6K signaling was highly enhanced in GADD34-deficient macrophages compared with wild-type cells when cells were treated by LPS combined with tyrosine/cysteine-deprivation. LC3-II was increased by LPS stimulation combined with tyrosine/cysteine-deprivation. Defective GADD34 reduced LC3-II and autophagosome formation induced by LPS-stimulation and tyrosine/cysteine-deprivation compared with that seen in wild-type macrophages. These results indicates that GADD34 enhances autophagy and suppresses apoptosis stimulated by LPS combined with amino acid deprivation through regulation of mTOR signaling pathway in macrophages.
Sulphur geodynamic cycle
Authors: Kagoshima Takanori , Sano Yuji , Takahata Naoto , Maruoka Teruyuki , Fischer Tobias P. , Hattori Keiko 
Published: February 2015

AbstractEvaluation of volcanic and hydrothermal fluxes to the surface environments is important to elucidate the geochemical cycle of sulphur and the evolution of ocean chemistry. This paper presents S/3He ratios of vesicles in mid-ocean ridge (MOR) basalt glass together with the ratios of high-temperature hydrothermal fluids to calculate the sulphur flux of 100 Gmol/y at MOR. The S/3He ratios of high-temperature volcanic gases show sulphur flux of 720 Gmol/y at arc volcanoes (ARC) with a contribution from the mantle of 2.9%, which is calculated as 21 Gmol/y. The C/S flux ratio of 12 from the mantle at MOR and ARC is comparable to the C/S ratio in the surface inventory, which suggests that these elements in the surface environments originated from the upper mantle.
Bioluminescence based biosensors for quantitative detection of enterococcal peptide–pheromone activity reveal inter-strain telesensing in vivo during polymicrobial systemic infection
Authors: La Rosa Sabina Leanti , Solheim Margrete , Diep Dzung B. , Nes Ingolf F. , Brede Dag Anders 
Published: February 2015

AbstractEnterococcus faecalis is a significant threat in the nosocomial setting due to the emergence of isolates that are multi-antibiotic resistant, refractory to the available therapies and equipped with a variety of pathogenicity determinants. This bacterium uses quorum-sensing systems to regulate its physiological processes, including the expression of virulence traits, to adapt and proliferate within a host. Here, we describe the construction and application of two bioluminescence-based reporter systems for the direct detection of the quorum-sensing regulated expression of (i) the gelatinase biosynthesis-activating pheromone (GBAP) and (ii) the cytolysin small subunit (CylLS) in natural samples. The two E. faecalis reporters conditionally expressed bioluminescence in the presence of GBAP and CylLS both in the supernatants of liquid cultures and in an agar-overlay assay in as little as three hours, with a high level of sensitivity. Biosensors employed to investigate the interaction between the fsr and cyl systems revealed that fsr impeded CylLS activity by 75%. Furthermore, we identified a clinical E. faecalis isolate that acted as a biological cheater, producing cytolysin only upon sensing CylLS-producers in its environment. This isolate enhanced its virulence during polymicrobial systemic infection of Galleria mellonella.
Long non-coding RNA-DANCR in human circulating monocytes: a potential biomarker associated with postmenopausal osteoporosis
Authors: Tong Xiang , Gu Peng-cheng , Xu San-zhong , Lin Xiang-jin 
Published: February 2015

Abstract
Osteoporosis is a common disease characterized by low bone mineral density (BMD) and low trauma fractures, mainly resulting from exceeding bone resorption by osteoclasts over bone formation by osteoblasts. Circulating monocytes are directly involved in osteoclastogenesis, and lncRNAs are believed to be involved in the osteoblast differentiation. However, no study has been conducted to identify the roles of lncRNA in circulating monocytes associated with human osteoporosis. In this study, we found significant upregulation of DANCR in the blood mononuclear cells (MNCs) from low-BMD patients with the qRT-PCR analyses. We further found that DANCR promoted the expression of IL6 and TNF-α at both mRNA level and protein level in MNCs. After deletion of DANCR with siRNAs, the levels of IL6 and TNF-α are decreased in the MNCs from low-BMD postmenopausal women. Moreover, DANCR level was correlated with IL6 and TNF-α in postmenopausal women with low BMD. Furthermore, we found that DANCR-induced IL6 and TNF-α in MNCs had bone-resorbing activity. These results indicate that DANCR is involved in the pathology of osteoporosis and may be as a biomarker for postmenopausal osteoporosis.
Umbilical cord occlusions in near-term ovine fetus induce increased beat-to-beat heart rate variability correlating to decreases in neuroinflammation: a case for the afferent cholinergic anti-inflammatory pathway?
Authors: Frasch M. G. , Szynkaruk M. , Prout A.P. , Nygard K. , Veldhuizen R. , Hammond R. , Richardson B.S 
Published: February 2015

AbstractSupported by grants from the Canadian Institute of Health Research (CIHR) and Lawson Health Research Institute (LHRI) Internal Research Fund (MGF and BSR); CIHR, Fonds de la recherche en santé du Québec (FRSQ) (MGF). BSR is the recipient of the Canada Research Chair in Fetal and Neonatal Health and Development.Neuroinflammationin uteromay contribute to brain injury resulting in life long neurological disabilities. The pivotal role of the efferent cholinergic anti-inflammatory pathway (CAP) in controlling inflammation has been described in adults, but its importance in the fetus is unknown. Moreover, it is unknown whether CAP may also exert anti-inflammatory effects on the brain via CAP’s afferent component of the vagus nerve. Based on multiple clinical studies in adults and our own work in fetal autonomic nervous system, we gauged the degree of CAP activityin vivousing heart rate variability measures reflecting fluctuations in vagus nerve activity. Measuring microglial activation in the ovine fetal brain near-term, we showin vivothat afferent fetal CAP may translate increased vagal cholinergic signaling into suppression of cerebral inflammation in response to near-term hypoxic acidemia as might occur during labour. Our findings suggest a new control mechanism of fetal neuroinflammation via the vagus nerve, providing novel possibilities for its non-invasive monitoringin uteroand for targeted treatment.
The positive inside rule is stronger when followed by a transmembrane helix
Authors: Virkki Minttu T. , Peters Christoph , Nilsson Daniel , Sörensen Therese , Cristobal Susana , Wallner Björn , Elofsson Arne 
Published: February 2015

AbstractThe translocon recognizes transmembrane helices with sufficient level of hydrophobicity and inserts them into the membrane. However, sometimes less hydrophobic helices are also recognized. Positive inside rule, orientational preferences of and specific interactions with neighboring helices have been shown to aid in the recognition of these helices, at least in artificial systems. To better understand how the translocon inserts marginally hydrophobic helices, we studied three naturally occurring marginally hydrophobic helices, which were previously shown to require the subsequent helix for efficient translocon recognition. We find no evidence for specific interactions when we scan all residues in the subsequent helices. Instead, we identify arginines located at the N-terminal part of the subsequent helices that are crucial for the recognition of the marginally hydrophobic transmembrane helices, indicating that the positive inside rule is important. However, in two of the constructs these arginines do not aid in the recognition without the rest of the subsequent helix, i.e. the positive inside rule alone is not sufficient. Instead, the improved recognition of marginally hydrophobic helices can here be explained as follows; the positive inside rule provides an orientational preference of the subsequent helix, which in turn allows the marginally hydrophobic helix to be inserted, i.e. the effect of the positive inside rule is stronger if positively charged residues are followed by a transmembrane helix. Such a mechanism can obviously not aid C-terminal helices and consequently we find that the terminal helices in multi-spanning membrane proteins are more hydrophobic than internal helices.
Cryptic and not-so-cryptic species in the complex “Holothuria (Thymiosycia) imaptiens” (Forsskål, 1775) (Echinodermata: Holothuroidea: Holothuriidae)
Authors: Michonneau François 
Published: February 2015

AbstractIdentifying accurately species is critical for our understanding of patterns of diversity and speciation. However, for many organisms with simple and variable morphological traits, the characters traditionally used by taxonomists to identify species might lead to a considerable under appreciation of their diversity. Recent advances in molecular-data based computational methods have considerably improved our ability to identify and test species limits. Here, we use an integrative approach to delineate species in a complex of sea cucumbers. We used a three-step approach to show that “Holothuria impatiens”, a common, shallow-water species, occurring across the Indo-Pacific, the Western Atlantic and the Mediterranean Sea, targeted locally by fisheries, is a complex of at least 13 species. (1) We used the Generalized Mixed Yule Coalescent (GMYC) model to identify putative species withouta priorihypotheses. In the process, we also show that the number of putative species estimated with GMYC can be affected considerably by the priors used to build the input tree. (2) We assessed based on coloration patterns and distributional information, the most relevant hypothesis. This approach allowed us to identify unambiguously 9 species. However, some of the lineages consistently assigned to belong to different species using GMYC, are occurring in sympatry and are not differentiated morphologically. (3) We used Bayes factors to compare competing models of species assignment using the multispecies coalescent as implemented in *BEAST. This approach allowed us to validate that the species identified using GMYC were likely reproductively isolated. Estimates of the timing of diversification also showed that these species diverged less than 2 Ma, which is the fastest case of closely related species occurring in sympatry for a marine metazoan. Our study demonstrates how clarifying species limits contribute to refining our understanding of speciation.
Partitioning heritability by functional category using GWAS summary statistics
Authors: Finucane Hilary K. , Bulik-Sullivan Brendan , Gusev Alexander , Trynka Gosia , Reshef Yakir , Loh Po-Ru , Anttilla Verneri , Xu Han , Zang Chongzhi , Farh Kyle , Ripke Stephan , Day Felix , Consortium ReproGen ,   Schizophrenia Working Group of the Psychiatric Genetics Consortium,   The RACI Consortium, Purcell Shaun , Stahl Eli , Lindstrom Sara , Perry John R.B. , Okada Yukinori , Raychaudhuri Soumya , Daly Mark , Patterson Nick , Neale Benjamin M. , Price Alkes L. 
Published: February 2015

AbstractRecent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here, we analyze a broad set of functional elements, including cell-type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits spanning a total of 1.3 million phenotype measurements. To enable this analysis, we introduce a new method for partitioning heritability from GWAS summary statistics while controlling for linked markers. This new method is computationally tractable at very large sample sizes, and leverages genome-wide information. Our results include a large enrichment of heritability in conserved regions across many traits; a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers; and many cell-type-specific enrichments including significant enrichment of central nervous system cell types in body mass index, age at menarche, educational attainment, and smoking behavior. These results demonstrate that GWAS can aid in understanding the biological basis of disease and provide direction for functional follow-up.
Segmentation of Noisy Signals Generated By a Nanopore
Authors: Schreiber Jacob , Karplus Kevin 
Published: February 2015

ABSTRACTNanopore-based single-molecule sequencing techniques exploit ionic current steps produced as biomolecules pass through a pore to reconstruct properties of the sequence. A key task in analyzing complex nanopore data is discovering the boundaries between these steps, which has traditionally been done in research labs by hand. We present an automated method of analyzing nanopore data, by detecting regions of ionic current corresponding to the translocation of a biomolecule, and then segmenting the region. The segmenter uses a divide-and-conquer method to recursively discover boundary points, with an implementation that works several times faster than real time and that can handle low-pass filtered signals.
Bayesian priors for tree calibration: Evaluating two new approaches based on fossil intervals
Authors: Norris Ryan W. , Strope Cory L. , McCandlish David M. , Stoltzfus Arlin 
Published: February 2015

AbstractBackground:Studies of diversification and trait evolution increasingly rely on combining molecular sequences and fossil dates to infer time-calibrated phylogenetic trees. Available calibration software provides many options for the shape of the prior probability distribution of ages at a node to be calibrated, but the question of how to assign a Bayesian prior from limited fossil data remains open.Results:We introduce two new methods for generating priors based upon (1) the interval between the two oldest fossils in a clade, i.e., the penultimate gap (PenG), and (2) the ghost lineage length (GLin), defined as the difference between the oldest fossils for each of two sister lineages. We show that PenG and GLin/2 are point estimates of the interval between the oldest fossil and the true age for the node. Furthermore, given either of these quantities, we derive a principled prior distribution for the true age. This prior is log-logistic, and can be implemented approximately in existing software. Using simulated data, we test these new methods against some other approaches.Conclusions:When implemented as approaches for assigning Bayesian priors, the PenG and GLin methods increase the accuracy of inferred divergence times, showing considerably more precision than the other methods tested, without significantly greater bias. When implemented as approaches to post-hoc scaling of a tree by linear regression, the PenG and GLin methods exhibit less bias than other methods tested. The new methods are simple to use and can be applied to a variety of studies that call for calibrated trees.