bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated expression of the V-ATPase C subunit triggers JNK-dependent cell invasion and overgrowth in a Drosophila epithelium
Authors: Petzoldt Astrid G. , Gleixner Eva Maria , Fumagalli Arianna , Vaccari Thomas , Simons Matias 
Published: January 2013

Summary
The C subunit of the vacuolar H+-ATPase or V-ATPase regulates the activity and assembly of the proton pump at cellular membranes. It has been shown to be strongly upregulated in oral squamous cell carcinoma, a highly metastatic epithelial cancer. In addition, increased V-ATPase activity appears to correlate with invasiveness of cancer cells, but the underlying mechanism is largely unknown. Using the Drosophila wing imaginal epithelium as an in vivo model system, we demonstrate that overexpression of Vha44, the Drosophila orthologue of the C subunit, causes a tumor-like tissue transformation in cells of the wing epithelium. Overexpressing cells are excluded from the epithelium and acquire invasive properties while displaying high apoptotic rates. Blocking apoptosis in these cells unmasks a strong proliferation stimulus, leading to overgrowth. Furthermore, we show that excess Vha44 greatly increases acidification of endocytic compartments and interferes with endosomal trafficking. As a result, cargoes such as GFP-Lamp1 and Notch accumulate in highly acidified enlarged endolysosomal compartments. Consistent with previous reports on the endocytic activation of Eiger/JNK signaling, we find that V-ATPase stimulation by Vha44 causes JNK signaling activation whereas downmodulation of JNK signaling rescues the invasive phenotypes. In summary, our in vivo-findings demonstrate that increased levels of V-ATPase C subunit induce a Eiger/JNK-dependent cell transformation within an epithelial organ that recapitulates early carcinoma stages.
The fraction of strongly bound cross-bridges is increased in mice that carry the myopathy-linked myosin heavy chain mutation MYH4L342Q
Authors: Lindqvist Johan , Iwamoto Hiroyuki , Blanco Gonzalo , Ochala Julien 
Published: January 2013

Summary
Myosinopathies have emerged as a new group of diseases and are caused by mutations in genes encoding myosin heavy chain (MyHC) isoforms. One major hallmark of these diseases is skeletal muscle weakness or paralysis, but the underlying molecular mechanisms remain unclear. Here, we have undertaken a detailed functional study of muscle fibers from Myh4arl mice, which carry a mutation that provokes an L342Q change within the catalytic domain of the type IIb skeletal muscle myosin protein MYH4. Because homozygous animals develop rapid muscle-structure disruption and lower-limb paralysis, they must be killed by postnatal day 13, so all experiments were performed using skeletal muscles from adult heterozygous animals (Myh4arl/+). Myh4arl/+ mice contain MYH4L342Q expressed at 7% of the levels of the wild-type (WT) protein and are overtly and histologically normal. However, mechanical and X-ray diffraction pattern analyses of single membrane-permeabilized fibers revealed, upon maximal Ca2+ activation, higher stiffness as well as altered meridional and equatorial reflections in Myh4arl/+ mice when compared with age-matched WT animals. Under rigor conditions, by contrast, no difference was observed between Myh4arl/+ and WT mice. Altogether, these findings prove that, in adult MYH4L342Q heterozygous mice, the transition from weak to strong myosin cross-bridge binding is facilitated, increasing the number of strongly attached myosin heads, thus enhancing force production. These changes are predictably exacerbated in the type IIb fibers of homozygous mice, in which the embryonic myosin isoform is fully replaced by MYH4L342Q, leading to a hypercontraction, muscle-structure disruption and lower-limb paralysis. Overall, these findings provide important insights into the molecular pathogenesis of skeletal myosinopathies.
Light-driven hydrogen evolution system with glutamic-acid-modified
zinc porphyrin as photosensitizer and [FeFe]-hydrogenase model as
catalyst
Authors: Yu Shan , Wang Feng , Wang Jing-Jing , Wang Hong-Yan , Chen Bin , Feng Ke , Tung Chen-Ho , Wu Li-Zhu 
Published: January 2013

An intermolecular light-driven hydrogen evolution system with free
glutamic-acid-modified zinc tetra(p-phenyl) porphyrin
(Glu-ZnP) as a photosensitizer and
[Fe2(CO)6(μ-adt)C6H5] [μ-adt =
N(CH2S)2] (Badt) as a catalyst has
been constructed. Using phenylmercaptan (BSH) as electron donor
and acetic acid (HOAc) as proton source, hydrogen was obtained after irradiation
with visible light for 2 h; the efficiency is comparable to that of the similar
intramolecular dyad. Steady-state and time-resolved spectroscopy and cyclic
voltammetry show that both the first and the second electron transfer from
singlet
1*

Glu-ZnP to
Badt and reduced Badt are
thermodynamically feasible. However, the competition of electron transfer from
singlet
1*

Glu-ZnP to Badt
with intersystem crossing from singlet

1*

Glu-ZnP to triplet

3*

Glu-ZnP, inefficient
electron transfer from triplet

3*

Glu-ZnP to
Badt, and the lower energy of triplet

3*

Glu-ZnP and possible

3*

Badt to that of yielded
charge-separated state of
Glu-ZnP

+·
-Badt
−· were
believed to be the obstacles for efficient hydrogen evolution.
Dimerization and Viscosity of Acetic Acid Vapor
Authors: Vogel Eckhard , Bich Eckard 
Published: January 2013

Abstract
Results of new relative measurements on the vapor of acetic acid are reported. The measurements were based on a single calibration at room temperature with a theoretically calculated viscosity value of argon. Nineteen isochoric series, differing in density, were performed in an all-quartz oscillating-disk viscometer from 298 to 598 K and for densities between 0.5 and 61 mol m-3. The uncertainty of the experimental data is ±0.5% at low densities and ±(0.3−0.4)% at high densities increasing with temperature. This is inferior compared with measurements on simple gases due to adsorption effects on quartz at low temperatures and to thermal decomposition at high temperatures. Isotherms recalculated from the original isochoric data show with decreasing density a strong curvature with negative slope, particularly at low temperatures. The further evaluation accounts for the fact that a strong dimerization depending on temperature occurs in acetic acid vapor. The isotherms, resulting from an association model which considers additional interactions between monomers and dimers, show a smaller curvature in terms of the mole fraction of monomers. Viscosity values for monomers and dimers were deduced using a simplified equation for the viscosity of a gas mixture. These values are restricted to 570 K due to thermal decomposition and low mole fractions of the dimers at high temperature. Furthermore, viscosity values for the saturated vapor could be determined at low temperatures.
Atorvastatin administration is associated with dose-related changes in IGF bioavailability
Authors: Narayanan Ram P , Gittins Matthew , Siddals Kirk W , Oliver Robert L , Hudson Julie E , White Anne , Durrington Paul , Davies Robert R , Rutter Martin K , Gibson J Martin 
Published: January 2013

ObjectiveIGF levels, their binding proteins (IGFBPs) and high-dose statin therapy have been linked to the development of diabetes. We aimed to identify whether atorvastatin caused dose-related changes in IGF proteins.Design and methodsWe measured IGF1, IGF2, IGFBP1 and IGFBP3 concentrations at baseline, 6 and 12 months in Protection Against Nephropathy in Diabetes with Atorvastatin trial participants with type 2 diabetes randomised to 10 mg (n=59) vs 80 mg (n=60) of atorvastatin (n=119; mean (s.d.): age 64 (10) years; 83% male; HbA1c 61 (10) mmol/mol; blood pressure 131/73 mmHg).ResultsAtorvastatin was associated with overall reductions in circulating IGF1, IGF2 and IGFBP3 concentrations (P<0.05 for all changes). The adjusted mean (95% CI) between-group differences that indicate dose-related changes in IGF proteins were not significant for IGF1: −3 (−21 to 14) ng/ml; IGF2: −23 (−65 to 18) ng/ml and IGFBP3: −0.34 (−0.71 to 0.03) μg/ml, negative values indicating numerically greater lowering with high dose. The IGFBP1 concentration did not change with atorvastatin therapy overall but the adjusted mean (95% CI) between-group difference indicating a dose-related change in log IGFBP1 was highly significant −0.41 (−0.69 to 0.13, P=0.004).ConclusionIGF1, IGF2 and IGFBP3 concentrations decreased following atorvastatin therapy. A differential effect of low- vs high-dose atorvastatin on IGFBP1 concentrations was observed with likely implications for IGF bioavailability. The dose-related differential impact of atorvastatin treatment on concentration of IGF proteins merits investigation as a mechanism to explain the worsening of glucose tolerance with statin therapy.
A Computational Approach to Developing Mathematical Models of Polyploid Meiosis
Authors: Rehmsmeier Marc 
Published: January 2013

Abstract
Mathematical models of meiosis that relate offspring to parental genotypes through parameters such as meiotic recombination frequency have been difficult to develop for polyploids. Existing models have limitations with respect to their analytic potential, their compatibility with insights into mechanistic aspects of meiosis, and their treatment of model parameters in terms of parameter dependencies. In this article I put forward a computational approach to the probabilistic modeling of meiosis. A computer program enumerates all possible paths through the phases of replication, pairing, recombination, and segregation, while keeping track of the probabilities of the paths according to the various parameters involved. Probabilities for classes of genotypes or phenotypes are added, and the resulting formulas are simplified by the symbolic-computation system Mathematica. An example application to autotetraploids results in a model that remedies the limitations of previous models mentioned above. In addition to the immediate implications, the computational approach presented here can be expected to be useful through opening avenues for modeling a host of processes, including meiosis in higher-order ploidies.
Vps Factors Are Required for Efficient Transcription Elongation in Budding Yeast
Authors: Gaur Naseem A , Hasek Jiri , Brickner Donna Garvey , Qiu Hongfang , Zhang Fan , Wong Chi-Ming , Malcova Ivana , Vasicova Pavla , Brickner Jason H , Hinnebusch Alan G 
Published: January 2013

Abstract
There is increasing evidence that certain Vacuolar protein sorting (Vps) proteins, factors that mediate vesicular protein trafficking, have additional roles in regulating transcription factors at the endosome. We found that yeast mutants lacking the phosphatidylinositol 3-phosphate [PI(3)P] kinase Vps34 or its associated protein kinase Vps15 display multiple phenotypes indicating impaired transcription elongation. These phenotypes include reduced mRNA production from long or G+C-rich coding sequences (CDS) without affecting the associated GAL1 promoter activity, and a reduced rate of RNA polymerase II (Pol II) progression through lacZ CDS in vivo. Consistent with reported genetic interactions with mutations affecting the histone acetyltransferase complex NuA4, vps15Δ and vps34Δ mutations reduce NuA4 occupancy in certain transcribed CDS. vps15Δ and vps34Δ mutants also exhibit impaired localization of the induced GAL1 gene to the nuclear periphery. We found unexpectedly that, similar to known transcription elongation factors, these and several other Vps factors can be cross-linked to the CDS of genes induced by Gcn4 or Gal4 in a manner dependent on transcriptional induction and stimulated by Cdk7/Kin28-dependent phosphorylation of the Pol II C-terminal domain (CTD). We also observed colocalization of a fraction of Vps15-GFP and Vps34-GFP with nuclear pores at nucleus–vacuole (NV) junctions in live cells. These findings suggest that Vps factors enhance the efficiency of transcription elongation in a manner involving their physical proximity to nuclear pores and transcribed chromatin.
A Novel Generalized Ridge Regression Method for Quantitative Genetics
Authors: Shen Xia , Alam Moudud , Fikse Freddy , Rönnegård Lars 
Published: January 2013

AbstractAs the molecular marker density grows, there is a strong need in both genome-wide association studies and genomic selection to fit models with a large number of parameters. Here we present a computationally efficient generalized ridge regression (RR) algorithm for situations in which the number of parameters largely exceeds the number of observations. The computationally demanding parts of the method depend mainly on the number of observations and not the number of parameters. The algorithm was implemented in the R package bigRR based on the previously developed package hglm. Using such an approach, a heteroscedastic effects model (HEM) was also developed, implemented, and tested. The efficiency for different data sizes were evaluated via simulation. The method was tested for a bacteria-hypersensitive trait in a publicly available Arabidopsis data set including 84 inbred lines and 216,130 SNPs. The computation of all the SNP effects required &lt;10 sec using a single 2.7-GHz core. The advantage in run time makes permutation test feasible for such a whole-genome model, so that a genome-wide significance threshold can be obtained. HEM was found to be more robust than ordinary RR (a.k.a. SNP-best linear unbiased prediction) in terms of QTL mapping, because SNP-specific shrinkage was applied instead of a common shrinkage. The proposed algorithm was also assessed for genomic evaluation and was shown to give better predictions than ordinary RR.
Correcting Coalescent Analyses for Panel-Based SNP Ascertainment
Authors: McGill James R , Walkup Elizabeth A , Kuhner Mary K 
Published: January 2013

Abstract
Single-nucleotide polymorphism (SNP) data are routinely obtained by sequencing a region of interest in a small panel, constructing a chip with probes specific to sites found to vary in the panel, and using the chip to assay subsequent samples. The size of the chip is often reduced by removing low-frequency alleles from the set of SNPs. Using coalescent estimation of the scaled population size parameter, Θ, as a test case, we demonstrate the loss of information inherent in this procedure and develop corrections for coalescent analysis of SNPs obtained via a panel. We show that more accurate Θ-estimates can be recovered if the panel size is known, but at considerable computational cost as the panel individuals must be explicitly modeled in the analysis. We extend this technique to apply to the case where rare alleles have been omitted from the SNP panel. We find that when appropriate corrections for panel ascertainment and rare-allele omission are used, the biases introduced by ascertainment are largely correctable, but recovered estimates are less accurate than would be obtained with fully sequenced data. This method is then applied to recombinant multiple population data to investigate the effects of recombination and migration on the estimate of Θ.
Genetic Dissection of a Major Anthocyanin QTL Contributing to Pollinator-Mediated Reproductive Isolation Between Sister Species ofMimulus
Authors: Yuan Yao-Wu , Sagawa Janelle M , Young Riane C , Christensen Brian J , Bradshaw Harvey D 
Published: January 2013

AbstractPrezygotic barriers play a major role in the evolution of reproductive isolation, which is a prerequisite for speciation. However, despite considerable progress in identifying genes and mutations responsible for postzygotic isolation, little is known about the genetic and molecular basis underlying prezygotic barriers. The bumblebee-pollinated Mimulus lewisii and the hummingbird-pollinated M. cardinalis represent a classic example of pollinator-mediated prezygotic isolation between two sister species in sympatry. Flower color differences resulting from both carotenoid and anthocyanin pigments contribute to pollinator discrimination between the two species in nature. Through fine-scale genetic mapping, site-directed mutagenesis, and transgenic experiments, we demonstrate that a single-repeat R3 MYB repressor, ROSE INTENSITY1 (ROI1), is the causal gene underlying a major quantitative trait locus (QTL) with the largest effect on anthocyanin concentration and that cis-regulatory change rather than coding DNA mutations cause the allelic difference between M. lewisii and M. cardinalis. Together with the genomic resources and stable transgenic tools developed here, these results suggest that Mimulus is an excellent platform for studying the genetics of pollinator-mediated reproductive isolation and the molecular basis of morphological evolution at the most fundamental level—gene by gene, mutation by mutation.
Nonself Recognition Through Intermolecular Disulfide Bond Formation of Ribonucleotide Reductase in Neurospora
Authors: Smith Robert P , Wellman Kenji , Haidari Leila , Masuda Hirohisa , Smith Myron L 
Published: January 2013

Abstract
Type I ribonucleotide reductases (RNRs) are conserved across diverse taxa and are essential for the conversion of RNA into DNA precursors. In Neurospora crassa, the large subunit of RNR (UN-24) is unusual in that it also has a nonself recognition function, whereby coexpression of Oak Ridge (OR) and Panama (PA) alleles of un-24 in the same cell leads to growth inhibition and cell death. We show that coexpressing these incompatible alleles of un-24 in N. crassa results in a high molecular weight UN-24 protein complex. A 63-amino-acid portion of the C terminus was sufficient for un-24PA incompatibility activity. Redox active cysteines that are conserved in type I RNRs and essential for their catalytic function were found to be required for incompatibility activity of both UN-24OR and UN-24PA. Our results suggest a plausible model of un-24 incompatibility activity in which the formation of a complex between the incompatible RNR proteins is potentiated by intermolecular disulfide bond formation.
Compensatory Evolution and the Origins of Innovations
Authors: Rajon Etienne , Masel Joanna 
Published: January 2013

Abstract
Cryptic genetic sequences have attenuated effects on phenotypes. In the classic view, relaxed selection allows cryptic genetic diversity to build up across individuals in a population, providing alleles that may later contribute to adaptation when co-opted—e.g., following a mutation increasing expression from a low, attenuated baseline. This view is described, for example, by the metaphor of the spread of a population across a neutral network in genotype space. As an alternative view, consider the fact that most phenotypic traits are affected by multiple sequences, including cryptic ones. Even in a strictly clonal population, the co-option of cryptic sequences at different loci may have different phenotypic effects and offer the population multiple adaptive possibilities. Here, we model the evolution of quantitative phenotypic characters encoded by cryptic sequences and compare the relative contributions of genetic diversity and of variation across sites to the phenotypic potential of a population. We show that most of the phenotypic variation accessible through co-option would exist even in populations with no polymorphism. This is made possible by a history of compensatory evolution, whereby the phenotypic effect of a cryptic mutation at one site was balanced by mutations elsewhere in the genome, leading to a diversity of cryptic effect sizes across sites rather than across individuals. Cryptic sequences might accelerate adaptation and facilitate large phenotypic changes even in the absence of genetic diversity, as traditionally defined in terms of alternative alleles.
Breakdown in the Process of Incipient Speciation inAnopheles gambiae
Authors: Nwakanma Davis C , Neafsey Daniel E , Jawara Musa , Adiamoh Majidah , Lund Emily , Rodrigues Amabelia , Loua Kovana M , Konate Lassana , Sy Ngayo , Dia Ibrahima , Awolola T Samson , Muskavitch Marc A T , Conway David J 
Published: January 2013

AbstractUnderstanding genetic causes and effects of speciation in sympatric populations of sexually reproducing eukaryotes is challenging, controversial, and of practical importance for controlling rapidly evolving pests and pathogens. The major African malaria vector mosquito Anopheles gambiae sensu stricto (s.s.) is considered to contain two incipient species with strong reproductive isolation, hybrids between the M and S molecular forms being very rare. Following recent observations of higher proportions of hybrid forms at a few sites in West Africa, we conducted new surveys of 12 sites in four contiguous countries (The Gambia, Senegal, Guinea-Bissau, and Republic of Guinea). Identification and genotyping of 3499 A. gambiae s.s. revealed high frequencies of M/S hybrid forms at each site, ranging from 5 to 42%, and a large spectrum of inbreeding coefficient values from 0.11 to 0.76, spanning most of the range expected between the alternative extremes of panmixia and assortative mating. Year-round sampling over 2 years at one of the sites in The Gambia showed that M/S hybrid forms had similar relative frequencies throughout periods of marked seasonal variation in mosquito breeding and abundance. Genome-wide scans with an Affymetrix high-density single-nucleotide polymorphism (SNP) microarray enabled replicate comparisons of pools of different molecular forms, in three separate populations. These showed strong differentiation between M and S forms only in the pericentromeric region of the X chromosome that contains the molecular form-specific marker locus, with only a few other loci showing minor differences. In the X chromosome, the M/S hybrid forms were more differentiated from M than from S forms, supporting a hypothesis of asymmetric introgression and backcrossing.
A Novel Interaction Between Aging and ER Overload in a Protein Conformational Dementia
Authors: Schipanski Angela , Lange Sascha , Segref Alexandra , Gutschmidt Aljona , Lomas David A , Miranda Elena , Schweizer Michaela , Hoppe Thorsten , Glatzel Markus 
Published: January 2013

AbstractIntraneuronal deposition of aggregated proteins in tauopathies, Parkinson disease, or familial encephalopathy with neuroserpin inclusion bodies (FENIB) leads to impaired protein homeostasis (proteostasis). FENIB represents a conformational dementia, caused by intraneuronal polymerization of mutant variants of the serine protease inhibitor neuroserpin. In contrast to the aggregation process, the kinetic relationship between neuronal proteostasis and aggregation are poorly understood. To address aggregate formation dynamics, we studied FENIB in Caenorhabditis elegans and mice. Point mutations causing FENIB also result in aggregation of the neuroserpin homolog SRP-2 most likely within the ER lumen in worms, recapitulating morphological and biochemical features of the human disease. Intriguingly, we identified conserved protein quality control pathways to modulate protein aggregation both in worms and mice. Specifically, downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation, while mice overexpressing a polymerizing mutant of neuroserpin undergo transient induction of the UPR in young but not in aged mice. Thus, we find that perturbations of proteostasis through impairment of the heat shock response or altered UPR signaling enhance neuroserpin accumulation in vivo. Moreover, accumulation of neuroserpin polymers in mice is associated with an age-related induction of the UPR suggesting a novel interaction between aging and ER overload. These data suggest that targets aimed at increasing UPR capacity in neurons are valuable tools for therapeutic intervention.