bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Insights into the Adjacent Stem-Loop in Honey Bee Dicistroviruses That Promotes Internal Ribosome Entry Site-Mediated Translation and Viral Infection
Authors: Au Hilda H. T. , Elspass Valentina M. , Jan Eric 
Published: November 2017

ABSTRACT
All viruses must successfully harness the host translational apparatus and divert it toward viral protein synthesis. Dicistroviruses use an unusual internal ribosome entry site (IRES) mechanism whereby the IRES adopts a three-pseudoknot structure that accesses the ribosome tRNA binding sites to directly recruit the ribosome and initiate translation from a non-AUG start site. A subset of dicistroviruses, including the honey bee Israeli acute paralysis virus (IAPV), encode an extra stem-loop (stem-loop VI [SLVI]) 5′ adjacent to the intergenic region (IGR) IRES. Previously, the function of this additional stem-loop was unknown. Here, we provide mechanistic and functional insights into the role of SLVI in IGR IRES translation and in virus infection. Biochemical analyses of a series of mutant IRESs demonstrated that SLVI does not function in ribosome recruitment but is required for proper ribosome positioning on the IRES to direct translation. Using a chimeric infectious clone derived from the related cricket paralysis virus, we showed that the integrity of SLVI is important for optimal viral translation and viral yield. Based on structural models of ribosome-IGR IRES complexes, SLVI is predicted to be in the vicinity of the ribosome E site. We propose that SLVI of IAPV IGR IRES functionally mimics interactions of an E-site tRNA with the ribosome to direct positioning of the tRNA-like domain of the IRES in the A site.

IMPORTANCE
Viral internal ribosome entry sites are RNA elements and structures that allow some positive-sense monopartite RNA viruses to hijack the host ribosome to start viral protein synthesis. We demonstrate that a unique stem-loop structure is essential for optimal viral protein synthesis and for virus infection. Biochemical evidence shows that this viral stem-loop RNA structure impacts a fundamental property of the ribosome to start protein synthesis.
Klebsiella pneumoniae
Carbapenemase-2 (KPC-2), Substitutions at Ambler Position Asp179, and Resistance to Ceftazidime-Avibactam: Unique Antibiotic-Resistant Phenotypes Emerge from β-Lactamase Protein Engineering
Authors: Barnes Melissa D. , Winkler Marisa L. , Taracila Magdalena A. , Page Malcolm G. , Desarbre Eric , Kreiswirth Barry N. , Shields Ryan K. , Nguyen Minh-Hong , Clancy Cornelius , Spellberg Brad , Papp-Wallace Krisztina M. , Bonomo Robert A. 
Published: November 2017

ABSTRACT

The emergence of
Klebsiella pneumoniae
carbapenemases (KPCs), β-lactamases that inactivate “last-line” antibiotics such as imipenem, represents a major challenge to contemporary antibiotic therapies. The combination of ceftazidime (CAZ) and avibactam (AVI), a potent β-lactamase inhibitor, represents an attempt to overcome this formidable threat and to restore the efficacy of the antibiotic against Gram-negative bacteria bearing KPCs. CAZ-AVI-resistant clinical strains expressing KPC variants with substitutions in the Ω-loop are emerging. We engineered 19 KPC-2 variants bearing targeted mutations at amino acid residue Ambler position 179 in
Escherichia coli
and identified a unique antibiotic resistance phenotype. We focus particularly on the CAZ-AVI resistance of the clinically relevant Asp179Asn variant. Although this variant demonstrated less hydrolytic activity, we demonstrated that there was a prolonged period during which an acyl-enzyme intermediate was present. Using mass spectrometry and transient kinetic analysis, we demonstrated that Asp179Asn “traps” β-lactams, preferentially binding β-lactams longer than AVI owing to a decreased rate of deacylation. Molecular dynamics simulations predict that (i) the Asp179Asn variant confers more flexibility to the Ω-loop and expands the active site significantly; (ii) the catalytic nucleophile, S70, is shifted more than 1.5 Å and rotated more than 90°, altering the hydrogen bond networks; and (iii) E166 is displaced by 2 Å when complexed with ceftazidime. These analyses explain the increased hydrolytic profile of KPC-2 and suggest that the Asp179Asn substitution results in an alternative complex mechanism leading to CAZ-AVI resistance. The future design of novel β-lactams and β-lactamase inhibitors must consider the mechanistic basis of resistance of this and other threatening carbapenemases.

IMPORTANCE
Antibiotic resistance is emerging at unprecedented rates and threatens to reach crisis levels. One key mechanism of resistance is the breakdown of β-lactam antibiotics by β-lactamase enzymes. KPC-2 is a β-lactamase that inactivates carbapenems and β-lactamase inhibitors (e.g., clavulanate) and is prevalent around the world, including in the United States. Resistance to the new antibiotic ceftazidime-avibactam, which was designed to overcome KPC resistance, had already emerged within a year. Using protein engineering, we uncovered a mechanism by which resistance to this new drug emerges, which could arm scientists with the ability to forestall such resistance to future drugs.
Autophagy-Related Protein ATG18 Regulates Apicoplast Biogenesis in Apicomplexan Parasites
Authors: Bansal Priyanka , Tripathi Anuj , Thakur Vandana , Mohmmed Asif , Sharma Pushkar 
Published: November 2017

ABSTRACT

Mechanisms by which 3′-phosphorylated phosphoinositides (3′-PIPs) regulate the development of apicomplexan parasites
Plasmodium falciparum
and
Toxoplasma gondii
are poorly understood. The catabolic process of autophagy, which is dependent on autophagy-related proteins (ATGs), is one of the major targets of 3′-PIPs in yeast and mammals. In the present study, we identified autophagy-related protein ATG18 as an effector of 3′-PIPs in these parasites.
P
.
falciparum
ATG18 (PfATG18) and
T
.
gondii
ATG18 (TgATG18) interact with 3′-PIPs but exhibited differences in their specificity of interaction with the ligand PIP. The conditional knockdown of
T
.
gondii
or
P
.
falciparum
ATG18 (Tg/PfATG18) impaired replication of parasites and resulted in their delayed death. Intriguingly, ATG18 depletion resulted in the loss of the apicomplexan parasite-specific nonphotosynthetic plastid-like organelle apicoplast, which harbors the machinery for biosynthesis of key metabolites, and the interaction of ATG18 to phosphatidylinositol 3-phosphate (PI3P) was critical for apicoplast inheritance. Furthermore, ATG18 regulates membrane association and apicoplast localization of ATG8. These findings provide insights into a novel noncanonical role of ATG18 in apicoplast inheritance. This function of ATG18 in organelle biogenesis is unprecedented in any organism and may be conserved across most apicomplexan parasites.

IMPORTANCE
Typically, autophagy is a catabolic process utilized by cells for their survival upon encountering nutrient-limiting conditions. The autophagy machinery is very tightly regulated, and autophagy-related genes (ATGs) play a pivotal role in this process. In the present study, we report a novel noncanonical function of autophagy-related protein ATG18 in inheritance of the nonphotosynthetic plastid-like organelle apicoplast in apicomplexan parasites
Plasmodium
and
Toxoplasma
. ATG18 depletion in these parasites resulted in “delayed death,” which was the result of loss of apicoplast and impaired parasite division. Pf/TgATG18 interact with 3′-phosphorylated PIPs, which guide their cellular localization in the parasite, which is essential for their function.
In Vivo
Behavior of the Tandem Glycine Riboswitch in
Bacillus subtilis
Authors: Babina Arianne M. , Lea Nicholas E. , Meyer Michelle M. 
Published: November 2017

ABSTRACT

In many bacterial species, the glycine riboswitch is composed of two homologous ligand-binding domains (aptamers) that each bind glycine and act together to regulate the expression of glycine metabolic and transport genes. While the structure and molecular dynamics of the tandem glycine riboswitch have been the subject of numerous
in vitro
studies, the
in vivo
behavior of the riboswitch remains largely uncharacterized. To examine the proposed models of tandem glycine riboswitch function in a biologically relevant context, we characterized the regulatory activity of mutations to the riboswitch structure in
Bacillus subtilis
using β-galactosidase assays. To assess the impact disruptions to riboswitch function have on cell fitness, we introduced these mutations into the native locus of the tandem glycine riboswitch within the
B. subtilis
genome. Our results indicate that glycine does not need to bind both aptamers for regulation
in vivo
and mutations perturbing riboswitch tertiary structure have the most severe effect on riboswitch function and gene expression. We also find that in
B. subtilis
, the glycine riboswitch-regulated
gcvT
operon is important for glycine detoxification.

IMPORTANCE
The glycine riboswitch is a unique
cis
-acting mRNA element that contains two tandem homologous glycine-binding domains that act on a single expression platform to regulate gene expression in response to glycine. While many
in vitro
experiments have characterized the tandem architecture of the glycine riboswitch, little work has investigated the behavior of this riboswitch
in vivo
. In this study, we analyzed the proposed models of tandem glycine riboswitch regulation in the context of its native locus within the
Bacillus subtilis
genome and examined how disruptions to glycine riboswitch function impact organismal fitness. Our work offers new insights into riboswitch function
in vivo
and reinforces the potential of riboswitches as novel antimicrobial targets.
Ode on a random urn (functional pearl)
Authors: Lampropoulos Leonidas , Spector-Zabusky Antal , Foner Kenneth 
Published: November 2017

We present the urn, a simple tree-based data structure that supports sampling from and updating discrete probability distributions in logarithmic time. We avoid the usual complexity of traditional self-balancing binary search trees by not keeping values in a specific order. Instead, we keep the tree maximally balanced at all times using a single machine word of overhead: its size.
Urns provide an alternative interface for the frequency combinator from the QuickCheck library that allows for asymptotically more efficient sampling from dynamically-updated distributions. They also facilitate backtracking in property-based random testing, and can be applied to such complex examples from the literature as generating well-typed lambda terms or information flow machine states, demonstrating significant speedups.
Well-typed music does not sound wrong (experience report)
Authors: Szamozvancev Dmitrij , Gale Michael B. 
Published: November 2017

Music description and generation are popular use cases for Haskell, ranging from live coding libraries to automatic harmonisation systems. Some approaches use probabilistic methods, others build on the theory of Western music composition, but there has been little work done on checking the correctness of musical pieces in terms of voice leading, harmony, and structure. Haskell's recent additions to the type-system now enable us to perform such analysis statically.
We present our experience of implementing a type-level model of classical music and an accompanying EDSL which enforce the rules of classical music at compile-time, turning composition mistakes into compiler errors. Along the way, we discuss the strengths and limitations of doing this in Haskell and demonstrate that the type system of the language is fully capable of expressing non-trivial and practical logic specific to a particular domain.
A meta-EDSL for distributed web applications
Authors: Ekblad Anton 
Published: November 2017

We present a domain-specific language for constructing and configuring web applications distributed across any number of networked, heterogeneous systems. Our language is embedded in Haskell, provides a common framework for integrating components written in third-party EDSLs, and enables type-safe, access-controlled communication between nodes, as well as effortless sharing and movement of functionality between application components. We give an implementation of our language and demonstrate its applicability by using it to implement several important components of distributed web applications, including RDBMS integration, load balancing, and fine-grained sandboxing of untrusted third party code.
The rising popularity of cloud computing and heterogeneous computer architectures is putting a strain on conventional programming models, which commonly assume that one application executes on one machine, or at best on one out of several identical machines. With our language, we take the first step towards a programming model better suited for a computationally multicultural future.
Streaming irregular arrays
Authors: Clifton-Everest Robert , McDonell Trevor L. , Chakravarty Manuel M. T. , Keller Gabriele 
Published: November 2017

Previous work has demonstrated that it is possible to generate efficient and highly parallel code for multicore CPUs and GPUs from combinator-based array languages for a range of applications. That work, however, has been limited to operating on flat, rectangular structures without any facilities for irregularity or nesting.
In this paper, we show that even a limited form of nesting provides substantial benefits both in terms of the expressiveness of the language (increasing modularity and providing support for simple irregular structures) and the portability of the code (increasing portability across resource-constrained devices, such as GPUs). Specifically, we generalise Blelloch's flattening transformation along two lines: (1) we explicitly distinguish between definitely regular and potentially irregular computations; and (2) we handle multidimensional arrays. We demonstrate the utility of this generalisation by an extension of the embedded array language Accelerate to include irregular streams of multidimensional arrays. We discuss code generation, optimisation, and irregular stream scheduling as well as a range of benchmarks on both multicore CPUs and GPUs.
P-MartCancer–Interactive Online Software to Enable Analysis of Shotgun Cancer Proteomic Datasets
Authors: Webb-Robertson Bobbie-Jo M. , Bramer Lisa M. , Jensen Jeffrey L. , Kobold Markus A. , Stratton Kelly G. , White Amanda M. , Rodland Karin D. 
Published: November 2017

Abstract
P-MartCancer is an interactive web-based software environment that enables statistical analyses of peptide or protein data, quantitated from mass spectrometry–based global proteomics experiments, without requiring in-depth knowledge of statistical programming. P-MartCancer offers a series of statistical modules associated with quality assessment, peptide and protein statistics, protein quantification, and exploratory data analyses driven by the user via customized workflows and interactive visualization. Currently, P-MartCancer offers access and the capability to analyze multiple cancer proteomic datasets generated through the Clinical Proteomics Tumor Analysis Consortium at the peptide, gene, and protein levels. P-MartCancer is deployed as a web service (https://pmart.labworks.org/cptac.html), alternatively available via Docker Hub (https://hub.docker.com/r/pnnl/pmart-web/). Cancer Res; 77(21); e47–50. ©2017 AACR.
Computational Radiomics System to Decode the Radiographic Phenotype
Authors: van Griethuysen Joost J.M. , Fedorov Andriy , Parmar Chintan , Hosny Ahmed , Aucoin Nicole , Narayan Vivek , Beets-Tan Regina G.H. , Fillion-Robin Jean-Christophe , Pieper Steve , Aerts Hugo J.W.L. 
Published: November 2017

Abstract
Radiomics aims to quantify phenotypic characteristics on medical imaging through the use of automated algorithms. Radiomic artificial intelligence (AI) technology, either based on engineered hard-coded algorithms or deep learning methods, can be used to develop noninvasive imaging-based biomarkers. However, lack of standardized algorithm definitions and image processing severely hampers reproducibility and comparability of results. To address this issue, we developed PyRadiomics, a flexible open-source platform capable of extracting a large panel of engineered features from medical images. PyRadiomics is implemented in Python and can be used standalone or using 3D Slicer. Here, we discuss the workflow and architecture of PyRadiomics and demonstrate its application in characterizing lung lesions. Source code, documentation, and examples are publicly available at www.radiomics.io. With this platform, we aim to establish a reference standard for radiomic analyses, provide a tested and maintained resource, and to grow the community of radiomic developers addressing critical needs in cancer research. Cancer Res; 77(21); e104–7. ©2017 AACR.
Explore, Visualize, and Analyze Functional Cancer Proteomic Data Using the Cancer Proteome Atlas
Authors: Li Jun , Akbani Rehan , Zhao Wei , Lu Yiling , Weinstein John N. , Mills Gordon B. , Liang Han 
Published: November 2017

Abstract
Reverse-phase protein arrays (RPPA) represent a powerful functional proteomic approach to elucidate cancer-related molecular mechanisms and to develop novel cancer therapies. To facilitate community-based investigation of the large-scale protein expression data generated by this platform, we have developed a user-friendly, open-access bioinformatic resource, The Cancer Proteome Atlas (TCPA, http://tcpaportal.org), which contains two separate web applications. The first one focuses on RPPA data of patient tumors, which contains &gt;8,000 samples of 32 cancer types from The Cancer Genome Atlas and other independent patient cohorts. The second application focuses on the RPPA data of cancer cell lines and contains &gt;650 independent cell lines across 19 lineages. Many of these cell lines have publicly available, high-quality DNA, RNA, and drug screening data. TCPA provides various analytic and visualization modules to help cancer researchers explore these datasets and generate testable hypotheses in an effective and intuitive manner. Cancer Res; 77(21); e51–54. ©2017 AACR.
Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma
Authors: Reap Elizabeth A. , Suryadevara Carter M. , Batich Kristen A. , Sanchez-Perez Luis , Archer Gary E. , Schmittling Robert J. , Norberg Pamela K. , Herndon James E. , Healy Patrick , Congdon Kendra L. , Gedeon Patrick C. , Campbell Olivia C. , Swartz Adam M. , Riccione Katherine A. , Yi John S. , Hossain-Ibrahim Mohammed K. , Saraswathula Anirudh , Nair Smita K. , Dunn-Pirio Anastasie M. , Broome Taylor M. , Weinhold Kent J. , Desjardins Annick , Vlahovic Gordana , McLendon Roger E. , Friedman Allan H. , Friedman Henry S. , Bigner Darell D. , Fecci Peter E. , Mitchell Duane A. , Sampson John H. 
Published: November 2017

Abstract
Median survival for glioblastoma (GBM) remains &lt;15 months. Human cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T-cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)–specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated (R = 0.7371, P = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.
Significance: A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. Cancer Res; 78(1); 256–64. ©2017 AACR.
PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models
Authors: Meehan Terrence F. , Conte Nathalie , Goldstein Theodore , Inghirami Giorgio , Murakami Mark A. , Brabetz Sebastian , Gu Zhiping , Wiser Jeffrey A. , Dunn Patrick , Begley Dale A. , Krupke Debra M. , Bertotti Andrea , Bruna Alejandra , Brush Matthew H. , Byrne Annette T. , Caldas Carlos , Christie Amanda L. , Clark Dominic A. , Dowst Heidi , Dry Jonathan R. , Doroshow James H. , Duchamp Olivier , Evrard Yvonne A. , Ferretti Stephane , Frese Kristopher K. , Goodwin Neal C. , Greenawalt Danielle , Haendel Melissa A. , Hermans Els , Houghton Peter J. , Jonkers Jos , Kemper Kristel , Khor Tin O. , Lewis Michael T. , Lloyd K.C. Kent , Mason Jeremy , Medico Enzo , Neuhauser Steven B. , Olson James M. , Peeper Daniel S. , Rueda Oscar M. , Seong Je Kyung , Trusolino Livio , Vinolo Emilie , Wechsler-Reya Robert J. , Weinstock David M. , Welm Alana , Weroha S. John , Amant Frédéric , Pfister Stefan M. , Kool Marcel , Parkinson Helen , Butte Atul J. , Bult Carol J. 
Published: November 2017

Abstract
Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models has hampered the ability of researchers to find relevant PDX models and associated data. Here we present the PDX models minimal information standard (PDX-MI) for reporting on the generation, quality assurance, and use of PDX models. PDX-MI defines the minimal information for describing the clinical attributes of a patient's tumor, the processes of implantation and passaging of tumors in a host mouse strain, quality assurance methods, and the use of PDX models in cancer research. Adherence to PDX-MI standards will facilitate accurate search results for oncology models and their associated data across distributed repository databases and promote reproducibility in research studies using these models. Cancer Res; 77(21); e62–66. ©2017 AACR.
NDEx 2.0: A Clearinghouse for Research on Cancer Pathways
Authors: Pratt Dexter , Chen Jing , Pillich Rudolf , Rynkov Vladimir , Gary Aaron , Demchak Barry , Ideker Trey 
Published: November 2017

Abstract
We present NDEx 2.0, the latest release of the Network Data Exchange (NDEx) online data commons (www.ndexbio.org) and the ways in which it can be used to (i) improve the quality and abundance of biological networks relevant to the cancer research community; (ii) provide a medium for collaboration involving networks; and (iii) facilitate the review and dissemination of networks. We describe innovations addressing the challenges of an online data commons: scalability, data integration, data standardization, control of content and format by authors, and decentralized mechanisms for review. The practical use of NDEx is presented in the context of a novel strategy to foster network-oriented communities of interest in cancer research by adapting methods from academic publishing and social media. Cancer Res; 77(21); e58–61. ©2017 AACR.