bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome Sequencing of the Plant Pathogen
Taphrina deformans
, the Causal Agent of Peach Leaf Curl
Authors: Cissé Ousmane H. , Almeida João M. G. C. F. , Fonseca Álvaro , Kumar Ajay Anand , Salojärvi Jarkko , Overmyer Kirk , Hauser Philippe M. , Pagni Marco 
Published: May 2013

ABSTRACT

Taphrina deformans
is a fungus responsible for peach leaf curl, an important plant disease. It is phylogenetically assigned to the Taphrinomycotina subphylum, which includes the fission yeast and the mammalian pathogens of the genus
Pneumocystis
. We describe here the genome of
T. deformans
in the light of its dual plant-saprophytic/plant-parasitic lifestyle. The 13.3-Mb genome contains few identifiable repeated elements (ca. 1.5%) and a relatively high GC content (49.5%). A total of 5,735 protein-coding genes were identified, among which 83% share similarities with other fungi. Adaptation to the plant host seems reflected in the genome, since the genome carries genes involved in plant cell wall degradation (e.g., cellulases and cutinases), secondary metabolism, the hallmark glyoxylate cycle, detoxification, and sterol biosynthesis, as well as genes involved in the biosynthesis of plant hormones. Genes involved in lipid metabolism may play a role in its virulence. Several locus candidates for putative
MAT
cassettes and sex-related genes akin to those of
Schizosaccharomyces pombe
were identified. A mating-type-switching mechanism similar to that found in ascomycetous yeasts could be in effect. Taken together, the findings are consistent with the alternate saprophytic and parasitic-pathogenic lifestyles of
T. deformans
.

IMPORTANCE
Peach leaf curl is an important plant disease which causes significant losses of fruit production. We report here the genome sequence of the causative agent of the disease, the fungus
Taphrina deformans
. The genome carries characteristic genes that are important for the plant infection process. These include (i) proteases that allow degradation of the plant tissues; (ii) secondary metabolites which are products favoring interaction of the fungus with the environment, including the host; (iii) hormones that are responsible for the symptom of severely distorted leaves on the host; and (iv) drug detoxification enzymes that confer resistance to fungicides. The availability of the genome allows the design of new drug targets as well as the elaboration of specific management strategies to fight the disease.
Light Sensing in Aspergillus fumigatus Highlights the Case for Establishing New Models for Fungal Photobiology
Authors: Idnurm Alexander 
Published: May 2013

ABSTRACT

Microbes inhabit diverse environmental locations, and many species need to shift their physiology between different niches. To do this effectively requires the accurate sensing of and response to the environment. For pathogens, exposure to light is one major change between a free-living saprophyte lifestyle and causation of disease within the host. However, how light may act as a signal to influence pathogenesis, on the side of either the host or the pathogen, is poorly understood. Research during the last 2 decades has uncovered aspects about the machinery for light sensing in a small number of fungi. Now, Fuller et al. have initiated studies into the role that light and two photosensor homologs play in the behavior of the ubiquitous fungal pathogen
Aspergillus fumigatus
[K. K. Fuller, C. S. Ringelberg, J. J. Loros, and J. C. Dunlap, mBio 4(2):e00142-13, 2013, doi:10.1128/mBio.00142-13]. Light represses the germination of
A. fumigatus
spores and enhances resistance to ultraviolet light, oxidative stresses, and cell wall perturbations. The phenotypes of the strains with mutations in the LreA and FphA homologs revealed that these sensors control some, but not all, responses to light. Furthermore, interactions occur between blue and red light signaling pathways, as has been described for a related saprophytic species,
Aspergillus nidulans
. Genome-wide transcript analyses found that about 2.6% of genes increase or decrease their transcript levels in response to light. This use of
A. fumigatus
establishes common elements between model filamentous species and pathogenic species, underscoring the benefits of extending photobiology to new species of fungi.
Mixin’ Up the ML Module System
Authors: Rossberg Andreas , Dreyer Derek 
Published: May 2013

ML modules provide hierarchical namespace management, as well as fine-grained control over the propagation of type information, but they do not allow modules to be broken up into mutually recursive, separately compilable components. Mixin modules facilitate recursive linking of separately compiled components, but they are not hierarchically composable and typically do not support type abstraction. We synthesize the complementary advantages of these two mechanisms in a novel module system design we call MixML.A MixML module is like an ML structure in which some of the components are specified but not defined. In other words, it unifies the ML structure and signature languages into one. MixML seamlessly integrates hierarchical composition, translucent ML-style data abstraction, and mixin-style recursive linking. Moreover, the design of MixML is clean and minimalist; it emphasizes how all the salient, semantically interesting features of the ML module system (and several proposed extensions to it) can be understood simply as stylized uses of a small set of orthogonal underlying constructs, with mixin composition playing a central role.We provide a declarative type system for MixML, including two important extensions: higher-order modules, and modules as first-class values. We also present a sound and complete, three-pass type-checking algorithm for this system. The operational semantics of MixML is defined by an elaboration translation into an internal core language called LTG---namely, a polymorphic lambda calculus with single-assignment references and recursive type generativity---which employs a linear type and kind system to track definedness of term and type imports.
Two new economic models for privacy
Authors: Mahmood Shah , Desmedt Yvo 
Published: May 2013

Private data is leaked more and more in our society. Wikileaks, Facebook, and identity theft are just three examples. So, modeling privacy is important. Cryptographers do not provide methods to address whether data should remain private or not. The use of entropy does not reflect the cost associated with the loss of private data.
In this paper we provide two economic models for privacy. Our first model is a lattice structured extension of attack graphs. Our second model is a stochastic almost combinatorial game, where two or more players can make stochastic moves in an almost combinatorial setup. In both models, a user can decide attempting transitions between states, representing a user's private information, based on multiple criterion including the cost of an attempt, the probability of success, the number of earlier attempts to obtain this private information and (possibly) the available budget.
In a variant of our models we use multigraphs. We use this when a transition between two states could be performed in different ways. To reduce the increase in complexity, we introduce a technique converting the multigraph to a simple directed graph. We discuss the advantages and disadvantages of this conversion. We also briefly discuss potential uses of our privacy models.
Mining large streams of user data for personalized recommendations
Authors: Amatriain Xavier 
Published: May 2013

The Netflix Prize put the spotlight on the use of data mining and machine learning methods for predicting user preferences. Many lessons came out of the competition. But since then, Recommender Systems have evolved. This evolution has been driven by the greater availability of different kinds of user data in industry and the interest that the area has drawn among the research community. The goal of this paper is to give an up-to-date overview of the use of data mining approaches for personalization and recommendation. Using Netflix personalization as a motivating use case, I will describe the use of different kinds of data and machine learning techniques.
After introducing the traditional approaches to recommendation, I highlight some of the main lessons learned from the Netflix Prize. I then describe the use of recommendation and personalization techniques at Netflix. Finally, I pinpoint the most promising current research avenues and unsolved problems that deserve attention in this domain.
MEK1/2 Inhibition Decreases Lactate in BRAF-Driven Human Cancer Cells
Authors: Falck Miniotis Maria , Arunan Vaitha , Eykyn Thomas R. , Marais Richard , Workman Paul , Leach Martin O. , Beloueche-Babari Mounia 
Published: May 2013

Abstract
The RAS/BRAF/MEK/ERK signaling pathway is a central driver in cancer with many BRAF and MEK inhibitors being evaluated in clinical trials. Identifying noninvasive biomarkers of early pharmacodynamic responses is important for development of these targeted drugs. As increased aerobic glycolysis is often observed in cancer, we hypothesized that MEK1/2 (MAP2K1/MAP2K2) inhibitors may reduce lactate levels as detected by magnetic resonance spectroscopy (MRS), as a metabolic biomarker for the pharmacodynamic response. MRS was used to monitor intracellular and extracellular levels of lactate in human cancer cells in vitro and in melanoma tumors ex vivo. In addition, we used 1H MRS and a fluorescent glucose analog to evaluate the effect of MEK inhibition on glucose uptake. MEK1/2 signaling inhibition reduced extracellular lactate levels in BRAF-dependent cells but not BRAF-independent cells. The reduction in extracellular lactate in BRAF-driven melanoma cells was time-dependent and associated with reduced expression of hexokinase-II driven by c-Myc depletion. Taken together, these results reveal how MEK1/2 inhibition affects cancer cell metabolism in the context of BRAF oncogene addiction. Furthermore, they offer a preclinical proof-of-concept for the use of MRS to measure lactate as a noninvasive metabolic biomarker for pharmacodynamic response to MEK1/2 inhibition in BRAF-driven cancers. Cancer Res; 73(13); 4039–49. ©2013 AACR.
Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors
Authors: Chettouh Hamza , Fartoux Laetitia , Aoudjehane Lynda , Wendum Dominique , Clapéron Audrey , Chrétien Yves , Rey Colette , Scatton Olivier , Soubrane Olivier , Conti Filomena , Praz Françoise , Housset Chantal , Rosmorduc Olivier , Desbois-Mouthon Christèle 
Published: May 2013

Abstract
Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal–regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC. Cancer Res; 73(13); 3974–86. ©2013 AACR.
IGF-1R Targeting Increases the Antitumor Effects of DNA-Damaging Agents in SCLC Model: An Opportunity to Increase the Efficacy of Standard Therapy
Authors: Ferté Charles , Loriot Yohann , Clémenson Céline , Commo Frederic , Gombos Andrea , Bibault Jean-Emmanuel , Fumagalli Ingrid , Hamama Saad , Auger Nathalie , Lahon Benoit , Chargari Cyrus , Calderaro Julien , Soria Jean-Charles , Deutsch Eric 
Published: May 2013

Abstract
Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146, and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 showed single-agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both cisplatin and IR in vitro. The triple combination R1507-cisplatin-IR led to a dramatic delay in tumor growth compared with cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis, and survival. Finally, we identified that the nucleotide excision repair pathway was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting. Mol Cancer Ther; 12(7); 1213–22. ©2013 AACR.
Prospective Multicenter Randomized Intermediate Biomarker Study of Oral Contraceptive versus Depo-Provera for Prevention of Endometrial Cancer in Women with Lynch Syndrome
Authors: Lu Karen H. , Loose David S. , Yates Melinda S. , Nogueras-Gonzalez Graciela M. , Munsell Mark F. , Chen Lee-may , Lynch Henry , Cornelison Terri , Boyd-Rogers Stephanie , Rubin Mary , Daniels Molly S. , Conrad Peggy , Milbourne Andrea , Gershenson David M. , Broaddus Russell R. 
Published: May 2013

Abstract
Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population. Cancer Prev Res; 6(8); 774–81. ©2013 AACR.
Bone Marrow–Derived Gr1+ Cells Can Generate a Metastasis-Resistant Microenvironment Via Induced Secretion of Thrombospondin-1
Authors: Catena Raúl , Bhattacharya Nandita , El Rayes Tina , Wang Suming , Choi Hyejin , Gao Dingcheng , Ryu Seongho , Joshi Natasha , Bielenberg Diane , Lee Sharrell B. , Haukaas Svein A. , Gravdal Karsten , Halvorsen Ole J. , Akslen Lars A. , Watnick Randolph S. , Mittal Vivek 
Published: May 2013

Abstract
Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow–derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow–specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1+ donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1+ bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1+ myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1+ cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer.
Significance: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow–derived Gr1+ myeloid cells. A 5-amino acid peptide with Tsp-1–inducing activity was identified as a therapeutic agent against metastatic cancer. Cancer Discov; 3(5); 578–89. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 471
Sphingomyelin Synthase 2 Activity and Liver Steatosis
Authors: Li Yue , Dong Jibin , Ding Tingbo , Kuo Ming-Shang , Cao Guoqing , Jiang Xian-Cheng , Li Zhiqiang 
Published: May 2013

Objective—
Sphingolipid de novo biosynthesis is related to nonalcoholic fatty liver disease or hepatic steatosis. However, the mechanism is still unclear. Sphingomyelin synthase (SMS), using ceramide as one of the substrates to produce sphingomyelin, sits at the crossroads of sphingolipid biosynthesis. SMS has 2 isoforms: SMS1 and SMS2. SMS2 is the major isoform in liver.

Approach and Results—

To investigate the relationship between liver SMS2 activity–mediated sphingolipid changes and hepatic steatosis, we used 2 mouse models:
Sms2
liver-specific transgenic and
Sms2
knockout mice. We found that
Sms2
liver-specific transgenic livers have lower ceramide and higher sphingomyelin, whereas
Sms2
knockout livers have higher ceramide and lower sphingomyelin. We also found that liver
Sms2
overexpression promoted fatty acid uptake and liver steatosis, whereas
Sms2
deficiency had an opposite effect in comparison with their respective controls. Importantly, the exogenous ceramide supplementation to Huh7 cells, a human hepatoma cell line, reduced the expression of peroxisome proliferator-activated receptor γ2 and its target genes,
Cd36
and
Fsp27
. Peroxisome proliferator-activated receptor γ reporter analysis confirmed this phenomenon. Furthermore, peroxisome proliferator-activated receptor γ antagonist treatment significantly decreased triglyceride accumulation in
Sms2
liver-specific transgenic liver.

Conclusions—

We attributed these effects to ceramide that can suppress peroxisome proliferator-activated receptor γ2, thus reducing the expression of
Cd36
and
Fsp27
and reducing liver steatosis. After all, SMS2 inhibition in the liver could diminish liver steatosis.
Foot Drop Stimulation Versus Ankle Foot Orthosis After Stroke
Authors: Kluding Patricia M. , Dunning Kari , O’Dell Michael W. , Wu Samuel S. , Ginosian Jivan , Feld Jody , McBride Keith 
Published: May 2013

Background and Purpose—
Drop foot after stroke may be addressed using an ankle foot orthosis (AFO) or a foot drop stimulator (FDS). The Functional Ambulation: Standard Treatment versus Electric Stimulation Therapy (FASTEST) trial was a multicenter, randomized, single-blinded trial comparing FDS and AFO for drop foot among people ≥3 months after stroke with gait speed ≤0.8 m/s.

Methods—
Participants (n=197; 79 females and 118 males; 61.14±11.61 years of age; time after stroke 4.55±4.72 years) were randomized to 30 weeks of either FDS or a standard AFO. Eight dose-matched physical therapy sessions were provided to both groups during the first 6 weeks of the trial.

Results—
There was significant improvement within both groups from baseline to 30 weeks in comfortable gait speed (95% confidence interval for mean change, 0.11–0.17 m/s for FDS and 0.12–0.18 m/s for AFO) and fast gait speed. However, no significant differences in gait speed were found in the between-group comparisons. Secondary outcomes (standard measures of body structure and function, activity, and participation) improved significantly in both groups, whereas user satisfaction was significantly higher in the FDS group than in the control group.

Conclusions—
Using either an FDS or an AFO for 30 weeks yielded clinically and statistically significant improvements in gait speed and other functional outcomes. User satisfaction was higher in the FDS group. Although both groups did receive intervention, this large clinical trial provides evidence that FDS or AFO with initial physical therapy sessions can provide a significant and clinically meaningful benefit even years after stroke.

Clinical Trial Registration Information—

URL:
http://www.clinicaltrials.gov
. Unique Identifier: NCT01138995.
The FireFader: Simple, Open-Source, and Reconfigurable Haptic Force Feedback for Musicians
Authors: Berdahl Edgar , Kontogeorgakopoulos Alexandros 
Published: May 2013

The FireFader is a simple haptic force-feedback device that is optimized for introducing musicians to haptics. It is based upon a single-degree-of-freedom potentiometer fader coupled to a DC motor, also known as a “motorized fader.” A light is connected in parallel with the motor to help communicate the force's strength visually. The FireFader consists of only open-source hardware and open-source software elements. Consequently, it is relatively easy for users to repurpose it into new projects involving varying kinds and numbers of motors and sensors. An open-source device driver for the FireFader allows it to be linked to a computer via USB so that the computer can perform the feedback control calculations. For example, the computer can simulate the acoustics of a virtual musical instrument to concurrently synthesize sound and calculate the motor force as a function of the fader position. The serial connection over USB increases the latency of the control signal compared to embedded implementations, but the serial connection facilitates easier programming via the computer, and the force feedback can be automatically disabled when the user is not touching the fader. Some new devices derived from the FireFader design are presented.