bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Zeamine Antibiotics Affect the Integrity of Bacterial Membranes
Authors: Masschelein Joleen , Clauwers Charlien , Stalmans Karen , Nuyts Koen , De Borggraeve Wim , Briers Yves , Aertsen Abram , Michiels Chris W. , Lavigne Rob 
Published: December 2014

ABSTRACT

The zeamines (zeamine, zeamine I, and zeamine II) constitute an unusual class of cationic polyamine-polyketide-nonribosomal peptide antibiotics produced by
Serratia plymuthica
RVH1. They exhibit potent bactericidal activity, killing a broad range of Gram-negative and Gram-positive bacteria, including multidrug-resistant pathogens. Examination of their specific mode of action and molecular target revealed that the zeamines affect the integrity of cell membranes. The zeamines provoke rapid release of carboxyfluorescein from unilamellar vesicles with different phospholipid compositions, demonstrating that they can interact directly with the lipid bilayer in the absence of a specific target. DNA, RNA, fatty acid, and protein biosynthetic processes ceased simultaneously at subinhibitory levels of the antibiotics, presumably as a direct consequence of membrane disruption. The zeamine antibiotics also facilitated the uptake of small molecules, such as 1-N-phenylnaphtylamine, indicating their ability to permeabilize the Gram-negative outer membrane (OM). The valine-linked polyketide moiety present in zeamine and zeamine I was found to increase the efficiency of this process. In contrast, translocation of the large hydrophilic fluorescent peptidoglycan binding protein PBD
KZ
-GFP was not facilitated, suggesting that the zeamines cause subtle perturbation of the OM rather than drastic alterations or defined pore formation. At zeamine concentrations above those required for growth inhibition, membrane lysis occurred as indicated by time-lapse microscopy. Together, these findings show that the bactericidal activity of the zeamines derives from generalized membrane permeabilization, which likely is initiated by electrostatic interactions with negatively charged membrane components.
Identification of a Wide Range of Motifs Inhibitory to Shiga Toxin by Affinity-Driven Screening of Customized Divalent Peptides Synthesized on a Membrane
Authors: Kato Mihoko , Watanabe-Takahashi Miho , Shimizu Eiko , Nishikawa Kiyotaka 
Published: December 2014

ABSTRACT

Shiga toxin (Stx), a major virulence factor of enterohemorrhagic
Escherichia coli
, binds to target cells through a multivalent interaction between its B-subunit pentamer and the cell surface receptor globotriaosylceramide, resulting in a remarkable increase in its binding affinity. This phenomenon is referred to as the “clustering effect.” Previously, we developed a multivalent peptide library that can exert the clustering effect and identified Stx neutralizers with tetravalent peptides by screening this library for high-affinity binding to the specific receptor-binding site of the B subunit. However, this technique yielded only a limited number of binding motifs, with some redundancy in amino acid selectivity. In this study, we established a novel technique to synthesize up to 384 divalent peptides whose structures were customized to exert the clustering effect on the B subunit on a single cellulose membrane. By targeting Stx1a, a major Stx subtype, the customized divalent peptides were screened to identify high-affinity binding motifs. The sequences of the peptides were designed based on information obtained from the multivalent peptide library technique. A total of 64 candidate motifs were successfully identified, and 11 of these were selected to synthesize tetravalent forms of the peptides. All of the synthesized tetravalent peptides bound to the B subunit with high affinities and effectively inhibited the cytotoxicity of Stx1a in Vero cells. Thus, the combination of the two techniques results in greatly improved efficiency in identifying biologically active neutralizers of Stx.
High-Resolution Taxonomic Profiling of the Subgingival Microbiome for Biomarker Discovery and Periodontitis Diagnosis
Authors: Szafranski Szymon P. , Wos-Oxley Melissa L. , Vilchez-Vargas Ramiro , Jáuregui Ruy , Plumeier Iris , Klawonn Frank , Tomasch Jürgen , Meisinger Christa , Kühnisch Jan , Sztajer Helena , Pieper Dietmar H. , Wagner-Döbler Irene 
Published: December 2014

ABSTRACT

The oral microbiome plays a key role for caries, periodontitis, and systemic diseases. A method for rapid, high-resolution, robust taxonomic profiling of subgingival bacterial communities for early detection of periodontitis biomarkers would therefore be a useful tool for individualized medicine. Here, we used Illumina sequencing of the V1-V2 and V5-V6 hypervariable regions of the 16S rRNA gene. A sample stratification pipeline was developed in a pilot study of 19 individuals, 9 of whom had been diagnosed with chronic periodontitis. Five hundred twenty-three operational taxonomic units (OTUs) were obtained from the V1-V2 region and 432 from the V5-V6 region. Key periodontal pathogens like
Porphyromonas gingivalis
,
Treponema denticola
, and
Tannerella forsythia
could be identified at the species level with both primer sets. Principal coordinate analysis identified two outliers that were consistently independent of the hypervariable region and method of DNA extraction used. The linear discriminant analysis (LDA) effect size algorithm (LEfSe) identified 80 OTU-level biomarkers of periodontitis and 17 of health. Health- and periodontitis-related clusters of OTUs were identified using a connectivity analysis, and the results confirmed previous studies with several thousands of samples. A machine learning algorithm was developed which was trained on all but one sample and then predicted the diagnosis of the left-out sample (jackknife method). Using a combination of the 10 best biomarkers, 15 of 17 samples were correctly diagnosed. Training the algorithm on time-resolved community profiles might provide a highly sensitive tool to detect the onset of periodontitis.
Immunization with the Entamoeba histolytica Surface Metalloprotease EhMSP-1 Protects Hamsters from Amebic Liver Abscess
Authors: Roncolato Eduardo C. , Teixeira José E. , Barbosa José E. , Zambelli Ramalho Leandra N. , Huston Christopher D. 
Published: December 2014

ABSTRACTDiarrhea and amebic liver abscesses due to invasiveEntamoeba histolyticainfections are an important cause of morbidity and mortality in the developing world.Entamoeba histolyticaadherence and cell migration, two phenotypes linked to virulence, are both aberrant in trophozoites deficient in the metallosurface protease EhMSP-1, which is a homologue of theLeishmaniavaccine candidate leishmanolysin (GP63). We examined the potential of EhMSP-1 for use as a vaccine antigen to protect against amebic liver abscesses. First, existing serum samples from South Africans naturally infected withE. histolyticawere examined by enzyme-linked immunosorbent assay (ELISA) for the presence of EhMSP-1-specific IgG. Nine of 12 (75%) people with anti-E. histolyticaIgG also had EhMSP-1-specific IgG antibodies. We next used a hamster model of amebic liver abscess to determine the effect of immunization with a mixture of four recombinant EhMSP-1 protein fragments. EhMSP-1 immunization stimulated a robust IgG antibody response. Furthermore, EhMSP-1 immunization of hamsters reduced development of severe amebic liver abscesses following intrahepatic injection ofE. histolyticaby a combined rate of 68% in two independent animal experiments. Purified IgG from immunized compared to control animals bound to the surface ofE. histolyticatrophozoites and accelerated amebic lysis via activation of the classical complement cascade. We concluded that EhMSP-1 is a promising antigen that warrants further study to determine its full potential as a target for therapy and/or prevention of invasive amebiasis.
THEMIS Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis
Authors: Torre Sabrina , Faucher Sebastien P. , Fodil Nassima , Bongfen Silayuv E. , Berghout Joanne , Schwartzentruber Jeremy A. , Majewski Jacek , Lathrop Mark , Cooper Andrea M. , Vidal Silvia M. , Gros Philippe 
Published: December 2014

ABSTRACTWe identify anN-ethyl-N-nitrosourea (ENU)-induced I23N mutation in the THEMIS protein that causes protection against experimental cerebral malaria (ECM) caused by infection withPlasmodium bergheiANKA.ThemisI23Nhomozygous mice show reduced CD4+and CD8+T lymphocyte numbers. ECM resistance inP. bergheiANKA-infectedThemisI23Nmice is associated with decreased cerebral cellular infiltration, retention of blood-brain barrier integrity, and reduced proinflammatory cytokine production. THEMISI23Nprotein expression is absent from mutant mice, concurrent with the decreased THEMISI23Nstability observedin vitro. Biochemical studiesin vitroand functional complementationin vivoinThemisI23N/+:Lck−/+doubly heterozygous mice demonstrate that functional coupling of THEMIS to LCK tyrosine kinase is required for ECM pathogenesis. Damping of proinflammatory responses inThemisI23Nmice causes susceptibility to pulmonary tuberculosis. Thus, THEMIS is required for the development and ultimately the function of proinflammatory T cells.ThemisI23Nmice can be used to study the newly discovered association ofTHEMIS(6p22.33) with inflammatory bowel disease and multiple sclerosis.
Ethylmalonyl Coenzyme A Mutase Operates as a Metabolic Control Point in Methylobacterium extorquens AM1
Authors: Good Nathan M. , Martinez-Gomez N. Cecilia , Beck David A. C. , Lidstrom Mary E. 
Published: December 2014

ABSTRACT

The metabolism of one- and two-carbon compounds by the methylotrophic bacterium
Methylobacterium extorquens
AM1 involves high carbon flux through the ethylmalonyl coenzyme A (ethylmalonyl-CoA) pathway (EMC pathway). During growth on ethylamine, the EMC pathway operates as a linear pathway carrying the full assimilatory flux to produce glyoxylate, malate, and succinate. Assimilatory carbon enters the ethylmalonyl-CoA pathway directly as acetyl-CoA, bypassing pathways for formaldehyde oxidation/assimilation and the regulatory mechanisms controlling them, making ethylamine growth a useful condition to study the regulation of the EMC pathway. Wild-type
M. extorquens
cells were grown at steady state on a limiting concentration of succinate, and the growth substrate was then switched to ethylamine, a condition where the cell must make a sudden switch from utilizing the tricarboxylic acid (TCA) cycle to using the ethylmalonyl-CoA pathway for assimilation, which has been an effective strategy for identifying metabolic control points. A 9-h lag in growth was observed, during which butyryl-CoA, a degradation product of ethylmalonyl-CoA, accumulated, suggesting a metabolic imbalance. Ethylmalonyl-CoA mutase activity increased to a level sufficient for the observed growth rate at 9 h, which correlated with an upregulation of RNA transcripts for
ecm
and a decrease in the levels of ethylmalonyl-CoA. When the wild-type strain overexpressing
ecm
was tested with the same substrate switchover experiment, ethylmalonyl-CoA did not accumulate, growth resumed earlier, and, after a transient period of slow growth, the culture grew at a higher rate than that of the control. These findings demonstrate that ethylmalonyl-CoA mutase is a metabolic control point in the EMC pathway, expanding our understanding of its regulation.
New Tools for Comparing Microscopy Images: Quantitative Analysis of Cell Types in Bacillus subtilis
Authors: van Gestel Jordi , Vlamakis Hera , Kolter Roberto 
Published: December 2014

ABSTRACT

Fluorescence microscopy is a method commonly used to examine individual differences between bacterial cells, yet many studies still lack a quantitative analysis of fluorescence microscopy data. Here we introduce some simple tools that microbiologists can use to analyze and compare their microscopy images. We show how image data can be converted to distribution data. These data can be subjected to a cluster analysis that makes it possible to objectively compare microscopy images. The distribution data can further be analyzed using distribution fitting. We illustrate our methods by scrutinizing two independently acquired data sets, each containing microscopy images of a doubly labeled
Bacillus subtilis
strain. For the first data set, we examined the expression of
srfA
and
tapA
, two genes which are expressed in surfactin-producing and matrix-producing cells, respectively. For the second data set, we examined the expression of
eps
and
tapA
; these genes are expressed in matrix-producing cells. We show that
srfA
is expressed by all cells in the population, a finding which contrasts with a previously reported bimodal distribution of
srfA
expression. In addition, we show that
eps
and
tapA
do not always have the same expression profiles, despite being expressed in the same cell type: both operons are expressed in cell chains, while single cells mainly express
eps
. These findings exemplify that the quantification and comparison of microscopy data can yield insights that otherwise would go unnoticed.
Successful management of cutaneous pythiosis in a dog with subsequent cutaneous vasculitis
Authors: Mercer Jacqueline , White Amelia , Kennis Bob 
Published: December 2014

A three‐year‐old, spayed female, Belgian Malinois from southwestern Alabama was presented to our referral hospital for a 75‐day history of progressively lichenified, mildly ulcerated lesions on the left front limb. Histopathology and fungal culture revealed Pythium insidiosum. The limb was amputated and the patient was treated with itraconazole 8.8 mg/kg oral once daily and terbinafine 33 mg/kg oral once daily. Cutaneous vasculitis occurred on day 28 of treatment, which may have constituted either a fixed drug eruption or an immune complex reaction to infection or immunotherapy. The skin lesions were mild and completely excised, so drugs were continued for three‐and‐a‐half months total with no other adverse reactions. At 12 months after presentation, the patient is currently disease‐free with no signs of pythiosis recurrence.
On teaching *how to design programs*
Authors: Ramsey Norman 
Published: December 2014

This paper presents a personal, qualitative case study of a first course using
How to Design Programs
and its functional teaching languages. The paper reconceptualizes the book's six-step design process as an eight-step design process ending in a new "review and refactor" step. It recommends specific approaches to students' difficulties with function descriptions, function templates, data examples, and other parts of the design process. It connects the process to interactive "world programs." It recounts significant, informative missteps in course design and delivery. Finally, it identifies some unsolved teaching problems and some potential solutions.
Pattern matching without K
Authors: Cockx Jesper , Devriese Dominique , Piessens Frank 
Published: December 2014

Dependent pattern matching is an intuitive way to write programs and proofs in dependently typed languages. It is reminiscent of both pattern matching in functional languages and case analysis in on-paper mathematics. However, in general it is incompatible with new type theories such as homotopy type theory (HoTT). As a consequence, proofs in such theories are typically harder to write and to understand. The source of this incompatibility is the reliance of dependent pattern matching on the so-called K axiom - also known as the uniqueness of identity proofs - which is inadmissible in HoTT. The Agda language supports an experimental criterion to detect definitions by pattern matching that make use of the K axiom, but so far it lacked a formal correctness proof.In this paper, we propose a new criterion for dependent pattern matching without K, and prove it correct by a translation to eliminators in the style of Goguen et al. (2006). Our criterion both allows more good definitions than existing proposals, and solves a previously undetected problem in the criterion offered by Agda. It has been implemented in Agda and is the first to be supported by a formal proof. Thus it brings the benefits of dependent pattern matching to contexts where we cannot assume K, such as HoTT. It also points the way to new forms of dependent pattern matching, for example on higher inductive types.
Depending on types
Authors: Weirich Stephanie 
Published: December 2014

Is Haskell a dependently typed programming language? Should it be? GHC's many type-system features, such as Generalized Algebraic Datatypes (GADTs), datatype promotion, multiparameter type classes, and type families, give programmers the ability to encode domain-specific invariants in their types. Clever Haskell programmers have used these features to enhance the reasoning capabilities of static type checking. But really, how far have we come? Could we do more?
In this talk, I will discuss dependently typed programming in Haskell, through examples, analysis and comparisons with modern full-spectrum dependently typed languages, such as Coq, Agda and Idris. What sorts of dependently typed programming can be done in Haskell now? What could GHC learn from these languages? Conversely, what lessons can GHC offer in return?
PREDATOR
Authors: Liu Tongping , Tian Chen , Hu Ziang , Berger Emery D. 
Published: December 2014

False sharing is a notorious problem for multithreaded applications that can drastically degrade both performance and scalability. Existing approaches can precisely identify the sources of false sharing, but only report false sharing actually observed during execution; they do not generalize across executions. Because false sharing is extremely sensitive to object layout, these detectors can easily miss false sharing problems that can arise due to slight differences in memory allocation order or object placement decisions by the compiler. In addition, they cannot predict the impact of false sharing on hardware with different cache line sizes.
This paper presents PREDATOR, a predictive software-based false sharing detector. PREDATOR generalizes from a single execution to precisely predict false sharing that is latent in the current execution. PREDATOR tracks accesses within a range that could lead to false sharing given different object placement. It also tracks accesses within virtual cache lines, contiguous memory ranges that span actual hardware cache lines, to predict sharing on hardware platforms with larger cache line sizes. For each, it reports the exact program location of predicted false sharing problems, ranked by their projected impact on performance. We evaluate PREDATOR across a range of benchmarks and actual applications. PREDATOR identifies problems undetectable with previous tools, including two previously-unknown false sharing problems, with no false positives. PREDATOR is able to immediately locate false sharing problems in MySQL and the Boost library that had eluded detection for years.
Trace driven dynamic deadlock detection and reproduction
Authors: Samak Malavika , Ramanathan Murali Krishna 
Published: December 2014

Dynamic analysis techniques have been proposed to detect potential deadlocks. Analyzing and comprehending each potential deadlock to determine whether the deadlock is feasible in a real execution requires significant programmer effort. Moreover, empirical evidence shows that existing analyses are quite imprecise. This imprecision of the analyses further void the manual effort invested in reasoning about non-existent defects.
In this paper, we address the problems of imprecision of existing analyses and the subsequent manual effort necessary to reason about deadlocks. We propose a novel approach for deadlock detection by designing a dynamic analysis that intelligently leverages execution traces. To reduce the manual effort, we replay the program by making the execution follow a schedule derived based on the observed trace. For a real deadlock, its feasibility is automatically verified if the replay causes the execution to deadlock.
We have implemented our approach as part of WOLF and have analyzed many large (upto 160KLoC) Java programs. Our experimental results show that we are able to identify 74% of the reported defects as true (or false) positives automatically leaving very few defects for manual analysis. The overhead of our approach is negligible making it a compelling tool for practical adoption.
Triolet
Authors: Rodrigues Christopher , Jablin Thomas , Dakkak Abdul , Hwu Wen-Mei 
Published: December 2014

Functional algorithmic skeletons promise a high-level programming interface for distributed-memory clusters that free developers from concerns of task decomposition, scheduling, and communication. Unfortunately, prior distributed functional skeleton frameworks do not deliver performance comparable to that achievable in a low-level distributed programming model such as C with MPI and OpenMP, even when used in concert with high-performance array libraries. There are several causes: they do not take advantage of shared memory on each cluster node; they impose a fixed partitioning strategy on input data; and they have limited ability to fuse loops involving skeletons that produce a variable number of outputs per input.
We address these shortcomings in the Triolet programming language through a modular library design that separates concerns of parallelism, loop nesting, and data partitioning. We show how Triolet substantially improves the parallel performance of algorithms involving array traversals and nested, variable-size loops over what is achievable in Eden, a distributed variant of Haskell. We further demonstrate how Triolet can substantially simplify parallel programming relative to C with MPI and OpenMP while achieving 23--100% of its performance on a 128-core cluster.
Portable, MPI-interoperable coarray fortran
Authors: Yang Chaoran , Bland Wesley , Mellor-Crummey John , Balaji Pavan 
Published: December 2014

The past decade has seen the advent of a number of parallel programming models such as Coarray Fortran (CAF), Unified Parallel C, X10, and Chapel. Despite the productivity gains promised by these models, most parallel scientific applications still rely on MPI as their data movement model. One reason for this trend is that it is hard for users to incrementally adopt these new programming models in existing MPI applications. Because each model use its own runtime system, they duplicate resources and are potentially error-prone. Such independent runtime systems were deemed necessary because MPI was considered insufficient in the past to play this role for these languages.
The recently released MPI-3, however, adds several new capabilities that now provide all of the functionality needed to act as a runtime, including a much more comprehensive one-sided communication framework. In this paper, we investigate how MPI-3 can form a runtime system for one example programming model, CAF, with a broader goal of enabling a single application to use both MPI and CAF with the highest level of interoperability.