julilili42/papers huggingface dataset:
Scalable kernels for graphs with continuous attributes
2013-12-05

While graphs with continuous node attributes arise in many applications, state-of-the-art graph kernels for comparing continuous-attributed graphs suffer from a high runtime complexity. For instance, the popular shortest path kernel scales as O(n4), where n is the number of nodes. In this paper, we present a class of graph kernels with computational complexity O(n 2(m+log n+δ2 +d)), where is the graph diameter, m is the number of edges, and d is the dimension of the node attributes. Due to the sparsity and small diameter of real-world graphs, these kernels typically scale comfortably to large graphs. In our experiments, the presented kernels outperform state-of-the-art kernels in terms of speed and accuracy on classification benchmark datasets.
Rapid Distance-Based Outlier Detection via Sampling
2013-12-05

Distance-based approaches to outlier detection are popular in data mining, as they do not require to model the underlying probability distribution, which is particu-larly challenging for high-dimensional data. We present an empirical comparison of various approaches to distance-based outlier detection across a large number of datasets. We report the surprising observation that a simple, sampling-based scheme outperforms state-of-the-art techniques in terms of both efficiency and ef-fectiveness. To better understand this phenomenon, we provide a theoretical anal-ysis why the sampling-based approach outperforms alternative methods based on k-nearest neighbor search. 1
Active Transport and Diffusion Barriers Restrict Joubert Syndrome-Associated ARL13B/ARL-13 to an Inv-like Ciliary Membrane Subdomain
2013-12-05

Cilia are microtubule-based cell appendages, serving motility, chemo-/mechano-/photo- sensation, and developmental signaling functions. Cilia are comprised of distinct structural and functional subregions including the basal body, transition zone (TZ) and inversin (Inv) compartments, and defects in this organelle are associated with an expanding spectrum of inherited disorders including Bardet-Biedl syndrome (BBS), Meckel-Gruber Syndrome (MKS), Joubert Syndrome (JS) and Nephronophthisis (NPHP). Despite major advances in understanding ciliary trafficking pathways such as intraflagellar transport (IFT), how proteins are transported to subciliary membranes remains poorly understood. Using Caenorhabditis elegans and mammalian cells, we investigated the transport mechanisms underlying compartmentalization of JS-associated ARL13B/ARL-13, which we previously found is restricted at proximal ciliary membranes. We now show evolutionary conservation of ARL13B/ARL-13 localisation to an Inv-like subciliary membrane compartment, excluding the TZ, in many C. elegans ciliated neurons and in a subset of mammalian ciliary subtypes. Compartmentalisation of C. elegans ARL-13 requires a C-terminal RVVP motif and membrane anchoring to prevent distal cilium and nuclear targeting, respectively. Quantitative imaging in more than 20 mutants revealed differential contributions for IFT and ciliopathy modules in defining the ARL-13 compartment; IFT-A/B, IFT-dynein and BBS genes prevent ARL-13 accumulation at periciliary membranes, whereas MKS/NPHP modules additionally inhibit ARL-13 association with TZ membranes. Furthermore, in vivo FRAP analyses revealed distinct roles for IFT and MKS/NPHP genes in regulating a TZ barrier to ARL-13 diffusion, and intraciliary ARL-13 diffusion. Finally, C. elegans ARL-13 undergoes IFT-like motility and quantitative protein complex analysis of human ARL13B identified functional associations with IFT-B complexes, mapped to IFT46 and IFT74 interactions. Together, these findings reveal distinct requirements for sequence motifs, IFT and ciliopathy modules in defining an ARL-13 subciliary membrane compartment. We conclude that MKS/NPHP modules comprise a TZ barrier to ARL-13 diffusion, whereas IFT genes predominantly facilitate ARL-13 ciliary entry and/or retention via active transport mechanisms.
Targeted Ablation of Crb1 and Crb2 in Retinal Progenitor Cells Mimics Leber Congenital Amaurosis
2013-12-05

Development in the central nervous system is highly dependent on the regulation of the switch from progenitor cell proliferation to differentiation, but the molecular and cellular events controlling this process remain poorly understood. Here, we report that ablation of Crb1 and Crb2 genes results in severe impairment of retinal function, abnormal lamination and thickening of the retina mimicking human Leber congenital amaurosis due to loss of CRB1 function. We show that the levels of CRB1 and CRB2 proteins are crucial for mouse retinal development, as they restrain the proliferation of retinal progenitor cells. The lack of these apical proteins results in altered cell cycle progression and increased number of mitotic cells leading to an increased number of late-born cell types such as rod photoreceptors, bipolar and Müller glia cells in postmitotic retinas. Loss of CRB1 and CRB2 in the retina results in dysregulation of target genes for the Notch1 and YAP/Hippo signaling pathways and increased levels of P120-catenin. Loss of CRB1 and CRB2 result in altered progenitor cell cycle distribution with a decrease in number of late progenitors in G1 and an increase in S and G2/M phase. These findings suggest that CRB1 and CRB2 suppress late progenitor pool expansion by regulating multiple proliferative signaling pathways.
It is all in the noise: Efficient multi-task Gaussian process inference with structured residuals
2013-12-05

Multi-task prediction methods are widely used to couple regressors or classification models by sharing information across related tasks. We propose a multi-task Gaussian process approach for modeling both the relatedness between regressors and the task correlations in the residuals, in order to more accurately identify true sharing between regressors. The resulting Gaussian model has a covariance term in form of a sum of Kronecker products, for which efficient parameter inference and out of sample prediction are feasible. On both synthetic examples and applications to phenotype prediction in genetics, we find substantial benefits of modeling structured noise compared to established alternatives.
B Cells Contribute to Heterogeneity of IL-17 Producing Cells in Rheumatoid Arthritis and Healthy Controls
2013-12-05

Secretion of the proinflammatory cytokine Interleukin-17A (IL-17A) is the hallmark of a unique lineage of CD4 T cells designated Th17 cells, which may play a crucial role in the pathogenesis of rheumatoid arthritis (RA) and many autoimmune diseases. Recently, IL-17-producing cells other than T cells have been described, including diverse innate immune cells. Here, we show that the cellular sources of IL-17A in RA include a significant number of non-T cells. Multicolour fluorescence analysis of IL-17-expressing peripheral blood mononuclear cells (PBMC) revealed larger proportions of IL-17+CD3- non-T cells in RA patients than in healthy controls (constitutive, 13.6% vs. 8.4%, and after stimulation with PMA/ionomycin 17.4% vs. 7.9% p &lt; 0.001 in both cases). The source of IL-17 included CD3-CD56+ NK cells, CD3-CD14+ myeloid cells as well as the expected CD3+CD4+ Th17 cells and surprisingly a substantial number of CD3-CD19+ B cells. The presence of IL-17A-expressing B cells was confirmed by specific PCR of peripheral MACS-sorted CD19+ B cells, as well as by the analysis of different EBV-transformed B cell lines. Here we report for the first time that in addition to Th17 cells and different innate immune cells B cells also contribute to the IL-17A found in RA patients and healthy controls.
Plant polyphenols in the treatment of age‐associated diseases: Revealing the pleiotropic effects of icariin by network analysis
2013-12-05

Polyphenols are a broad class of compounds. Some are ingested in substantial quantities from nutritional sources, more are produced by medicinal plants, and some of them are taken as drugs. It is becoming clear, that a single polyphenol is impacting several cellular pathways. Thus, a network approach is becoming feasible, describing the interaction of a single polyphenol with cellular networks. Here we have selected icariin to draw a prototypic network of icariin activities. Icariin appears to be a promising drug to treat major age‐related diseases, like neurodegeneration, memory and depressive disorders, chronic inflammation, diabetes, and osteoporosis. It interacts with several relevant pathways, like PDE , TGF‐ß , MAPK , PPAR , NOS , IGF , Sirtuin , and others. Such networks will be useful to future comparative studies of complex effects of polyphenols.
TALE-PvuII Fusion Proteins – Novel Tools for Gene Targeting
2013-12-05

Zinc finger nucleases (ZFNs) consist of zinc fingers as DNA-binding module and the non-specific DNA-cleavage domain of the restriction endonuclease FokI as DNA-cleavage module. This architecture is also used by TALE nucleases (TALENs), in which the DNA-binding modules of the ZFNs have been replaced by DNA-binding domains based on transcription activator like effector (TALE) proteins. Both TALENs and ZFNs are programmable nucleases which rely on the dimerization of FokI to induce double-strand DNA cleavage at the target site after recognition of the target DNA by the respective DNA-binding module. TALENs seem to have an advantage over ZFNs, as the assembly of TALE proteins is easier than that of ZFNs. Here, we present evidence that variant TALENs can be produced by replacing the catalytic domain of FokI with the restriction endonuclease PvuII. These fusion proteins recognize only the composite recognition site consisting of the target site of the TALE protein and the PvuII recognition sequence (addressed site), but not isolated TALE or PvuII recognition sites (unaddressed sites), even at high excess of protein over DNA and long incubation times. In vitro, their preference for an addressed over an unaddressed site is > 34,000-fold. Moreover, TALE-PvuII fusion proteins are active in cellula with minimal cytotoxicity.
Associations of Forest Type, Parasitism and Body Condition of Two European Passerines, Fringilla coelebs and Sylvia atricapilla
2013-12-05

Human-induced forest modification can alter parasite-host interactions and might change the persistence of host populations. We captured individuals of two widespread European passerines (Fringilla coelebs and Sylvia atricapilla) in southwestern Germany to disentangle the associations of forest types and parasitism by haemosporidian parasites on the body condition of birds. We compared parasite prevalence and parasite intensity, fluctuating asymmetries, leukocyte numbers, and the heterophil to lymphocyte ratio (H/L-ratio) among individuals from beech, mixed-deciduous and spruce forest stands. Based on the biology of bird species, we expected to find fewer infected individuals in beech or mixed-deciduous than in spruce forest stands. We found the highest parasite prevalence and intensity in beech forests for F. coelebs. Although, we found the highest prevalence in spruce forests for S. atricapilla, the highest intensity was detected in beech forests, partially supporting our hypothesis. Other body condition or health status metrics, such as the heterophil to lymphocyte ratio (H/L-ratio), revealed only slight differences between bird populations inhabiting the three different forest types, with the highest values in spruce for F. coelebs and in mixed-deciduous forests for S. atricapilla. A comparison of parasitized versus non-parasitized individuals suggests that parasite infection increased the immune response of a bird, which was detectable as high H/L-ratio. Higher infections with blood parasites for S. atricapilla in spruce forest indicate that this forest type might be a less suitable habitat than beech and mixed-deciduous forests, whereas beech forests seem to be a suboptimal habitat regarding parasitism for F. coelebs.
Energy-sensitive regulation of Na+/K+-ATPase by Janus kinase 2
2013-12-05

Janus kinase 2 (JAK2) contributes to intracellular signaling of leptin and erythropoietin, hormones protecting cells during energy depletion. The present study explores whether JAK2 is activated by energy depletion and regulates Na + /K + -ATPase, the major energy-consuming pump. In Jurkat cells, JAK2 activity was determined by radioactive kinase assay, phosphorylated JAK2 detected by Western blotting, ATP levels measured by luciferase assay, as well as Na + /K + -ATPase α1-subunit transcript and protein abundance determined by real-time PCR and Western blotting, respectively. Ouabain-sensitive K + -induced currents ( I pump ) were measured by whole cell patch clamp. I pump was further determined by dual-electrode voltage clamp in Xenopus oocytes injected with cRNA-encoding JAK2, active V617F JAK2, or inactive K882E JAK2. As a result, in Jurkat T cells, JAK2 activity significantly increased following energy depletion by sodium azide (NaN 3 ) or 2,4- dinitro phenol (DNP). DNP- and NaN 3 -induced decrease of cellular ATP was significantly augmented by JAK2 inhibitor AG490 and blunted by Na + /K + -ATPase inhibitor ouabain. DNP decreased and AG490 enhanced I pump as well as Na + /K + -ATPase α1-subunit transcript and protein abundance. The α1-subunit transcript levels were also enhanced by signal transducer and activator of transcription-5 inhibitor CAS 285986-31-4. In Xenopus oocytes, I pump was significantly decreased by expression of JAK2 and V617F JAK2 but not of K882E JAK2, effects again reversed by AG490. In V617F JAK2-expressing Xenopus oocytes, neither DNP nor NaN 3 resulted in further decline of I pump . In Xenopus oocytes, the effect of V617F JAK2 on I pump was not prevented by inhibition of transcription with actinomycin. In conclusion, JAK2 is a novel energy-sensing kinase that curtails energy consumption by downregulating Na + /K + -ATPase expression and activity.
Determining the Higgs spin and parity in the di-photon decay channel using gluon polarization
2013-12-05

Summary Gluons inside an unpolarized proton are in general linearly polarized with a direction andmagnitude depending on their transverse momentum. This polarization can, in principle, be usedto determine the spin and parity of the newly found Higgs-like boson at the LHC as proposed in[10]. We have here elaborated on the perturbative calculation of the degree of polarization, whichwas used in [10]. Numerical results have been given for the degree of polarization as a functionof the longitudinal momentum fraction x and the transverse momentum jk T j, for various choices ofthe gauge link direction (or hadron energy) z 2 (2nP) 2 =n 2 . At the values of x and z relevant forHiggs production at the LHC the degree of polarization is substantial, reaching up to values largerthan 70%. Acknowledgments This work was supported in part by the German Bundesministerium fur Bildung und For-schung (BMBF), grant no. 05P12VTCTG. References [1]G. Aad et al. [ATLAS Collaboration], Phys. Lett. B 716, 1 (2012)[2]S. Chatrchyan et al. [CMS Collaboration], Phys. Lett. B 716, 30 (2012)[3]S. Y. Choi, D. J. Miller, M. M. Muhlleitner and P. M. Zerwas, Phys. Lett. B 553, 61 (2003)[4]Y. Gao, A. V. Gritsan, Z. Guo, K. Melnikov, M. Schulze and N. V. Tran, Phys. Rev. D 81, 075022(2010)[5]S. Bolognesi, Y. Gao, A. V. Gritsan, K. Melnikov, M. Schulze, N. V. Tran and A. Whitbeck, Phys.Rev. D 86, 095031 (2012)[6]S. Y. Choi, M. M. Muhlleitner and P. M. Zerwas, Phys. Lett. B 718, 1031 (2013)[7]J. Ellis, R. Fok, D. S. Hwang, V. Sanz and T. You, Eur. Phys. J. C 73, 2488 (2013)[8]D. Boer, W. J. den Dunnen, C. Pisano, M. Schlegel and W. Vogelsang, Phys. Rev. Lett. 108, 032002(2012)[9]W. J. den Dunnen, D. Boer, C. Pisano, M. Schlegel and W. Vogelsang, arXiv:1205.6931 [hep-ph].[10]D. Boer, W. J. den Dunnen, C. Pisano and M. Schlegel, Phys. Rev. Lett. 111, 032002 (2013)[11]X. -d. Ji, J. -P. Ma and F. Yuan, JHEP 0507, 020 (2005)[12]P. Sun, B. -W. Xiao and F. Yuan, Phys. Rev. D 84, 094005 (2011)[13]J. P. Ma, J. X. Wang and S. Zhao, Phys. Rev. D 88, 014027 (2013)[14]P. J. Mulders and J. Rodrigues, Phys. Rev. D 63, 094021 (2001)[15]A. D. Martin, W. J. Stirling, R. S. Thorne and G. Watt, Eur. Phys. J. C 63, 189 (2009)
Tools for calculations in color space
2013-12-05

Both the higher energy and the initial state colored partons contribute to making exact calculations in QCD color space more important at the LHC than at its predecessors. This is applicable whether the method of assessing QCD is fixed order calculation, resummation, or parton showers. In this talk we discuss tools for tackling the problem of performing exact color summed calculations. We start with theoretical tools in the form of the (standard) trace bases and the orthogonal multiplet bases (for which a general method of construction was recently presented). Following this, we focus on two new packages for performing color structure calculations: one easy to use Mathematica package, ColorMath, and one C++ package, ColorFull, which is suitable for more demanding calculations, and for interfacing with event generators.
Dominant‐negative effects of KCNQ2 mutations are associated with epileptic encephalopathy
2013-12-07

Objective Mutations in KCNQ2 and KCNQ3 , encoding the voltage‐gated potassium channels K V 7.2 and K V 7.3, are known to cause benign familial neonatal seizures mainly by haploinsufficiency. Here, we set out to determine the disease mechanism of 7 de novo missense KCNQ2 mutations that were recently described in patients with a severe epileptic encephalopathy including pharmacoresistant seizures and pronounced intellectual disability. Methods Mutations were inserted into the KCNQ2 cDNA. Potassium currents were recorded using 2‐microelectrode voltage clamping, and surface expression was analyzed by a biotinylation assay in cRNA‐injected Xenopus laevis oocytes. Results We observed a clear loss of function for all mutations. Strikingly, 5 of 7 mutations exhibited a drastic dominant‐negative effect on wild‐type K V 7.2 or K V 7.3 subunits, either by globally reducing current amplitudes (3 pore mutations) or by a depolarizing shift of the activation curve (2 voltage sensor mutations) decreasing potassium currents at the subthreshold level at which these channels are known to critically influence neuronal firing. One mutation significantly reduced surface expression. Application of retigabine, a recently marketed K V 7 channel opener, partially reversed these effects for the majority of analyzed mutations. Interpretation The development of severe epilepsy and cognitive decline in children carrying 5 of the 7 studied KCNQ2 mutations can be related to a dominant‐negative reduction of the resulting potassium current at subthreshold membrane potentials. Other factors such as genetic modifiers have to be postulated for the remaining 2 mutations. Retigabine or similar drugs may be used as a personalized therapy for this severe disease. Ann Neurol 2014;75:382–394
The Transition From Sublexical to Lexical Processing in a Consistent Orthography: An Eye-Tracking Study
2013-12-07

We studied the transition in predominant reading strategy from serial sublexical processing to more parallel lexical processing as a function of word familiarity in German children of Grades 2, 3, 4, and adults. High-frequency words, low-frequency words, and nonwords of differing length were embedded in sentences and presented in an eye-tracking paradigm. The size of the word length effect was used as an indicator of serial sublexical decoding. When controlling for the generally higher processing times in younger readers, the effect of length over reading development was not direct but modulated by familiarity: Length effects were comparable between items of differing familiarity for Grade 2, whereas from Grade 3, length effects increased with decreasing familiarity. These findings suggest that Grade 2 children apply serial sublexical decoding as a default reading strategy to most items, whereas reading by direct lexical access is increasingly dominant in more experienced readers.
Genetic assessment of familial and early‐onset Parkinson's disease in a Greek population
2013-12-07

Background and purpose Although the first mutation associated with Parkinson's disease ( PD ) was identified several years ago in the alpha‐synuclein ( SNCA ) gene in families of Greek and Italian ancestry, a more systematic study of this and other known PD mutations has not been performed in the Greek population. Methods A genetic analysis in 111 familial or sporadic with early‐onset (≤50 years, EO ) PD patients was performed for the presence of the A53T SNCA mutation. In separate subgroups of these patients, further mutations in the SNCA , LRRK 2, Parkin, PINK 1 and DJ ‐1 genes were searched for. Additionally, a subgroup of familial cases was analysed for mutations in the glucocerebrosidase ( GBA ) gene. Results In total, five patients (4.5% of our whole population) were identified with the A53T SNCA mutation, two with a heterozygote dosage mutation and one with a heterozygote point mutation in the Parkin gene, and seven patients (10.3% of our familial cohort) with GBA gene mutations. Conclusions The A53T mutation in the SNCA gene, although uncommon, does represent a cause of PD in the Greek population, especially of familial EOPD with autosomal dominant inheritance. GBA mutations in the familial cohort tested here were as common as in a cohort of sporadic cases previously examined from the same centres. For the remainder of the genes, genetic defects that could definitively account for the disease were not identified. These results suggest that further Mendelian traits that lead to PD in the Greek population remain to be identified.
ERK2-dependent reactivation of Akt mediates the limited response of tumor cells with constitutive K-RAS activity to PI3K inhibition
2013-12-09

K-RAS mutated (K-RASmut) non-small cell lung cancer (NSCLC) cells are resistant to EGFR targeting strategies. We investigated the impact of K-RAS activity irrespective of mutational status in the EGFR-independent increase in clonogenic cell survival. An analysis of the K-RAS activity status revealed a constitutively high K-RAS activity in K-RASmut NSCLC cells and also in head and neck squamous cell carcinoma (HNSCC) cells overexpressing wild-type K-RAS (K-RASwt). Similar to K-RAS-mutated cells, increased K-RAS activity in HNSCC cells overexpressing K-RASwt was associated with the stimulated production of the EGFR ligand amphiregulin and resistance to EGFR tyrosine kinase (EGFR-TK) inhibitors such as erlotinib. Expression of mutated K-RAS stimulated Akt phosphorylation and increased plating efficiency. Conversely, knockdown of K-RAS in K-RASmut NSCLC cells and in HNSCC cells presenting overexpression of K-RASwt resulted in sensitization to the anti-clonogenic activity of erlotinib. K-RAS activity results in EGFR-dependent and EGFR-independent Akt activity. The short-term treatment (2 h) of cells with EGFR-TK or PI3K inhibitors (erlotinib and PI-103) resulted in the repression of Akt activation, whereas long-term treatment (24 h) with inhibitors led to the reactivation of Akt and improved clonogenicity. The Akt re-activation was MAPK-ERK2-dependent and associated with a lack of complete response to anti-clonogenic activity of PI-103. A complete response was observed when PI-103 was combined with MEK inhibitor PD98059. Together, clonogenicity inhibition in tumor cells presenting constitutive K-RAS activity independent of K-RAS mutational status can be achieved by targeting of EGFR downstream pathways, i.e., PI3K alone or the combination of PI3K and MAPK inhibitors.