bluuebunny/crossref_metadata_2025 huggingface dataset:
Conclusion
Authors: Rett Jessica
Published: March 2015

This chapter contains a summary of the work and a discussion of its role in the larger frameworks of degree semantics and the semantics/pragmatics interface. It summarizes the main themes of the book with particular emphasis on the core proposal: that evaluativity arises in some adjectival constructions as the result of a conversational implicature.
Multiscale reaction-diffusion simulations with Smoldyn
Authors: Robinson Martin , Andrews Steven S. , Erban Radek
Published: March 2015

Summary: Smoldyn is a software package for stochastic modelling of spatial biochemical networks and intracellular systems. It was originally developed with an accurate off-lattice particle-based model at its core. This has recently been enhanced with the addition of a computationally efficient on-lattice model, which can be run stand-alone or coupled together for multiscale simulations using both models in regions where they are most required, increasing the applicability of Smoldyn to larger molecule numbers and spatial domains. Simulations can switch between models with only small additions to their configuration file, enabling users with existing Smoldyn configuration files to run the new on-lattice model with any reaction, species or surface descriptions they might already have.

Availability and Implementation: Source code and binaries freely available for download at www.smoldyn.org, implemented in C/C++ and supported on Linux, Mac OSX and MS Windows.

Contact:  martin.robinson@maths.ox.ac.uk

Supplementary Information: Supplementary data are available at Bioinformatics online and include additional details on model specification and modelling of surfaces, as well as the Smoldyn configuration file used to generate Figure 1.
Efficient visualization of high-throughput targeted proteomics experiments: TAPIR
Authors: Röst Hannes L. , Rosenberger George , Aebersold Ruedi , Malmström Lars
Published: March 2015

Motivation: Targeted mass spectrometry comprises a set of powerful methods to obtain accurate and consistent protein quantification in complex samples. To fully exploit these techniques, a cross-platform and open-source software stack based on standardized data exchange formats is required.

Results: We present TAPIR, a fast and efficient Python visualization software for chromatograms and peaks identified in targeted proteomics experiments. The input formats are open, community-driven standardized data formats (mzML for raw data storage and TraML encoding the hierarchical relationships between transitions, peptides and proteins). TAPIR is scalable to proteome-wide targeted proteomics studies (as enabled by SWATH-MS), allowing researchers to visualize high-throughput datasets. The framework integrates well with existing automated analysis pipelines and can be extended beyond targeted proteomics to other types of analyses.

Availability and implementation: TAPIR is available for all computing platforms under the 3-clause BSD license at https://github.com/msproteomicstools/msproteomicstools.

Contact:  lars@imsb.biol.ethz.ch

Supplementary information:  Supplementary data are available at Bioinformatics online.
4DGenome: a comprehensive database of chromatin interactions
Authors: Teng Li , He Bing , Wang Jiahui , Tan Kai
Published: March 2015

Motivation: The 3D structure of the genome plays a critical role in regulating gene expression. Recent progress in mapping technologies for chromatin interactions has led to a rapid increase in this kind of interaction data. This trend will continue as research in this burgeoning field intensifies.

Results: We describe the 4DGenome database that stores chromatin interaction data compiled through comprehensive literature curation. The database currently covers both low- and high-throughput assays, including 3C, 4C-Seq, 5C, Hi-C, ChIA-PET and Capture-C. To complement the set of interactions detected by experimental assays, we also include interactions predicted by a recently developed computational method with demonstrated high accuracy. The database currently contains ∼8 million records, covering 102 cell/tissue types in five organisms. Records in the database are described using a standardized file format, facilitating data exchange. The vast major of the interactions were assigned a confidence score. Using the web interface, users can query and download database records via a number of annotation dimensions. Query results can be visualized along with other genomics datasets via links to the UCSC genome browser. We anticipate that 4DGenome will be a valuable resource for investigating the spatial structure-and-function relationship of genomes.

Availability and Implementation:  4Dgenome is freely accessible at http://4dgenome.int-med.uiowa.edu. The database and web interface are implemented in MySQL, Apache and JavaScript with all major browsers supported.

Contact:  kai-tan@uiowa.edu

Supplementary Information:  Supplementary Materials are available at Bioinformatics online.
A novel motif-discovery algorithm to identify co-regulatory motifs in large transcription factor and microRNA co-regulatory networks in human
Authors: Liang Cheng , Li Yue , Luo Jiawei , Zhang Zhaolei
Published: March 2015

Motivation: Interplays between transcription factors (TFs) and microRNAs (miRNAs) in gene regulation are implicated in various physiological processes. It is thus important to identify biologically meaningful network motifs involving both types of regulators to understand the key co-regulatory mechanisms underlying the cellular identity and function. However, existing motif finders do not scale well for large networks and are not designed specifically for co-regulatory networks.

Results: In this study, we propose a novel algorithm CoMoFinder to accurately and efficiently identify composite network motifs in genome-scale co-regulatory networks. We define composite network motifs as network patterns involving at least one TF, one miRNA and one target gene that are statistically significant than expected. Using two published disease-related co-regulatory networks, we show that CoMoFinder outperforms existing methods in both accuracy and robustness. We then applied CoMoFinder to human TF-miRNA co-regulatory network derived from The Encyclopedia of DNA Elements project and identified 44 recurring composite network motifs of size 4. The functional analysis revealed that genes involved in the 44 motifs are enriched for significantly higher number of biological processes or pathways comparing with non-motifs. We further analyzed the identified composite bi-fan motif and showed that gene pairs involved in this motif structure tend to physically interact and are functionally more similar to each other than expected.

Availability and implementation: CoMoFinder is implemented in Java and available for download at http://www.cs.utoronto.ca/∼yueli/como.html.

Contact:  luojiawei@hnu.edu.cn or zhaolei.zhang@utoronto.ca

Supplementary information:  supplementary data are available at Bioinformatics online.
Lopinavir/Ritonavir Monotherapy as Second-line Antiretroviral Treatment in Resource-Limited Settings: Week 104 Analysis of AIDS Clinical Trials Group (ACTG) A5230
Authors: Kumarasamy Nagalingeswaran , Aga Evgenia , Ribaudo Heather J. , Wallis Carole L. , Katzenstein David A. , Stevens Wendy S. , Norton Michael R. , Klingman Karin L. , Hosseinipour Mina C. , Crump John A. , Supparatpinyo Khuanchai , Badal-Faesen Sharlaa , Bartlett John A.
Published: March 2015

Background.  The AIDS Clinical Trials Group (ACTG) A5230 study evaluated lopinavir/ritonavir (LPV/r) monotherapy following virologic failure (VF) on first-line human immunodeficiency virus (HIV) regimens in Africa and Asia.

Methods.  Eligible subjects had received first-line regimens for at least 6 months and had plasma HIV-1 RNA levels 1000–200 000 copies/mL. All subjects received LPV/r 400/100 mg twice daily. VF was defined as failure to suppress to <400 copies/mL by week 24, or confirmed rebound to >400 copies/mL at or after week 16 following confirmed suppression. Subjects with VF added emtricitabine 200 mg/tenofovir 300 mg (FTC/TDF) once daily. The probability of continued HIV-1 RNA <400 copies/mL on LPV/r monotherapy through week 104 was estimated with a 95% confidence interval (CI); predictors of treatment success were evaluated with Cox proportional hazards models.

Results.  One hundred twenty-three subjects were enrolled. Four subjects died and 2 discontinued prematurely; 117 of 123 (95%) completed 104 weeks. Through week 104, 49 subjects met the primary endpoint; 47 had VF, and 2 intensified treatment without VF. Of the 47 subjects with VF, 41 (33%) intensified treatment, and 39 of 41 subsequently achieved levels <400 copies/mL. The probability of continued suppression <400 copies/mL over 104 weeks on LPV/r monotherapy was 60% (95% CI, 50%–68%); 80%–85% maintained levels <400 copies/mL with FTC/TDF intensification as needed. Ultrasensitive assays on specimens with HIV-1 RNA level <400 copies/mL at weeks 24, 48, and 104 revealed that 61%, 62%, and 65% were suppressed to <40 copies/mL, respectively.

Conclusions.  LPV/r monotherapy after first-line VF with FTC/TDF intensification when needed provides durable suppression of HIV-1 RNA over 104 weeks.

Clinical Trials Registration.  NCT00357552.
Lymph formation, composition and circulation: a proteomics perspective
Authors: Hansen Kirk C. , D’Alessandro Angelo , Clement Cristina C. , Santambrogio Laura
Published: March 2015

During the last 20 years a deeper understanding of the lymphatic circulatory system, lymph formation and composition has emerged. This review will examine the current knowledge on the organization of the lymphatic vascular tree, the formation of lymph from the extracellular fluid, lymph circulation and the lymph proteomic composition during physiological and pathological conditions. Formation of the lymph fluid is dependent on pressure gradients in the capillary beds and the composition of the endothelial cell glycocalyx, which acts as a molecular sieve. Fluid propulsion toward the draining node is dependent on the intrinsic pumping mechanism of the lymphangions and their unidirectional valves. The lymph ‘omics’ composition is dependent on the ultrafiltration of plasma proteins as well as proteins and molecules derived from the metabolic and catabolic activities of each parenchymal organ from which the lymph drains. Altogether, these new insights have brought about a new awareness of the importance of the lymphatic system in human physiology and pathology.
New RR Lyrae variables in binary systems
Authors: Hajdu G. , Catelan M. , Jurcsik J. , Dékány I. , Drake A. J. , Marquette J.-B.
Published: March 2015

Despite their importance, very few RR Lyrae (RRL) stars have been known to reside in binary systems. We report on a search for binary RRL in the OGLE-III Galactic bulge data. Our approach consists in the search for evidence of the light-travel time effect in so-called observed minus calculated (O−C) diagrams. Analysis of 1952 well-observed fundamental-mode RRL in the OGLE-III data revealed an initial sample of 29 candidates. We used the recently released OGLE-IV data to extend the baselines up to 17 yr, leading to a final sample of 12 firm binary candidates. We provide O−C diagrams and binary parameters for this final sample, and also discuss the properties of eight additional candidate binaries whose parameters cannot be firmly determined at present. We also estimate that ≳ 4 per cent of the RRL reside in binary systems.
Elastic properties of polycrystalline dense matter
Authors: Kobyakov D. , Pethick C. J.
Published: March 2015

Elastic properties of the solid regions of neutron star crusts and white dwarfs play an important role in theories of stellar oscillations. Matter in compact stars is presumably polycrystalline and, since the elastic properties of single crystals of such matter are very anisotropic, it is necessary to relate elastic properties of the polycrystal to those of a single crystal. We calculate the effective shear modulus of polycrystalline matter with randomly oriented crystallites using a self-consistent theory that has been very successful in applications to terrestrial materials and show that previous calculations overestimate the shear modulus by approximately 28 per cent.
The prevalence of weak magnetic fields in Herbig Ae stars: the case of PDS 2
Authors: Hubrig S. , Carroll T. A. , Schöller M. , Ilyin I.
Published: March 2015

Models of magnetically driven accretion and outflows reproduce many observational properties of T Tauri stars, but the picture is much less clear for the Herbig Ae/Be stars, due to the poor knowledge of their magnetic field strength and topology. The Herbig Ae star PDS 2 was previously included in two magnetic studies based on low-resolution spectropolarimetric observations. Only in one of these studies the presence of a weak mean longitudinal magnetic field was reported. In the present study, for the first time, high-resolution high accuracy radial velocity planet searcher (HARPS) spectropolarimetric observations of PDS 2 are used to investigate the presence of a magnetic field. A firm detection of a weak longitudinal magnetic field is achieved using the multiline singular value decomposition method for Stokes profile reconstruction (〈Bz〉 = 33 ± 5 G). To gain better knowledge of typical magnetic field strengths in late Herbig Be and Herbig Ae stars, we compiled previous magnetic field measurements, revealing that only very few stars have fields stronger than 200 G, and half of the sample possesses fields of about 100 G and less. These results challenge our current understanding of the magnetospheric accretion in intermediate-mass pre-main-sequence stars as they indicate that the magnetic fields in Herbig Ae/Be stars are by far weaker than those measured in T Tauri stars.
Near-infrared spectroscopy of M dwarfs. II. H2O molecule as an abundance indicator of oxygen
Authors: Tsuji Takashi , Nakajima Tadashi , Takeda Yoichi
Published: March 2015

Based on the near-infrared spectra (R ≈ 20000) of M dwarfs, oxygen abundances are determined from the rovibrational lines of H2O. Although H2O lines in M dwarfs are badly blended with each other and the continuum levels are depressed appreciably by the collective effect of the numerous H2O lines themselves, quantitative analysis of H2O lines has been carried out by referring to the pseudo-continua, consistently defined on the observed and theoretical spectra. For this purpose, the pseudo-continuum on the theoretical spectrum has been evaluated accurately by the use of the recent high-precision H2O line-list. Then, we propose a simple and flexible method of analyzing the equivalent widths (EWs) of blended features (i.e., not necessarily limited to single lines) by the use of a mini–curve-of-growth (CG), which is a small portion of the usual CG around the observed EW. The mini-CG is generated by using the theoretical EWs evaluated from the synthetic spectrum in exactly the same way as the EWs are measured from the observed spectrum. The observed EW is converted to the abundance by the use of the mini-CG, and the process is repeated for all the observed EWs line-by-line or blend-by-blend. In cool M dwarfs, almost all the oxygen atoms left after CO formation are in stable H2O molecules, which suffer little change for the uncertainties due to imperfect modelling of the photospheres. Thus the numerous H2O lines are excellent abundance indicators of oxygen. The oxygen abundances are determined to be log AO (AO = NO/NH) between −3.5 and −3.0 in 38 M dwarfs, but cannot be determined in four early M dwarfs in which H2O lines are detected only marginally. The resulting log AO/AC values plotted against log AC appear to be systematically smaller in the carbon-rich M dwarfs, showing the different formation histories of oxygen and carbon in the chemical evolution of the Galactic disk. Also, AO/AFe ratios in most M dwarfs are closer to the solar AO/AFe ratio, based on the classical high oxygen abundance rather than on the recently downward-revised low value.
International Liquidity and Exchange Rate Dynamics
*
Authors: Gabaix Xavier , Maggiori Matteo
Published: March 2015

We provide a theory of the determination of exchange rates based on capital flows in imperfect financial markets. Capital flows drive exchange rates by altering the balance sheets of financiers that bear the risks resulting from international imbalances in the demand for financial assets. Such alterations to their balance sheets cause financiers to change their required compensation for holding currency risk, thus affecting both the level and volatility of exchange rates. Our theory of exchange rate determination in imperfect financial markets not only helps rationalize the empirical disconnect between exchange rates and traditional macroeconomic fundamentals, it also has real consequences for output and risk sharing. Exchange rates are sensitive to imbalances in financial markets and seldom perform the shock absorption role that is central to traditional theoretical macroeconomic analysis. Our framework is flexible; it accommodates a number of important modeling features within an imperfect financial market model, such as nontradables, production, money, sticky prices or wages, various forms of international pricing-to-market, and unemployment.
White Blood Cell Count and C-Reactive Protein Variations After Posterior Surgery With Intraoperative Radiotherapy for Spinal Metastasis
Authors: Sugita Shurei , Hozumi Takahiro , Yamakawa Kiyofumi , Goto Takahiro , Kondo Taiji
Published: March 2015

Study Design:

Retrospective case series.

Objective:

To evaluate the feasibility of blood test parameters [white blood cell (WBC) count and C-reactive protein (CRP)] for predicting and diagnosing postoperative infection after posterior surgery with intraoperative radiotherapy (IORT) for spinal metastasis.

Summary of Background Data:

Posterior surgery with IORT is effective for treating spinal metastasis, as we previously reported. However, the procedure requires that the patient be transferred from the operating room to the irradiation room. In addition, the patient’s general status is often poor, and the risk of postoperative infection is high.

Materials and Methods:

A total of 279 patients who underwent IORT for the treatment of spinal metastasis between August 2004 and June 2013 were included in this study. The WBC count (/103 μL) and CRP level (mg/dL) were recorded in all patients preoperatively and on alternative days for up to 7 days after surgery. We assessed the development of surgical-site infection (SSI) for up to 1 month after surgery.

Results:

SSI occurred in 41 patients (14.7%). The preoperative WBC count and CRP level did not differ between the infected and noninfected patients. The WBC counts on postoperative day (POD) 1 and POD 7 and the CRP levels on POD 7 were significantly higher in the infected patients (8.8 vs. 10.0, P=0.04; 6.1 vs. 8.8, P=0.002; 3.89 vs. 9.50, P<0.001). A receiver-operating characteristic curve analysis of the WBC count and CRP level for detecting SSI showed cutoff values of 9.6 (WBC count, POD 1), 6.5 (WBC count, POD 7), and 5.0 (CRP level, POD 7).

Conclusions:

A high WBC count and CRP level on POD 7 may be used to predict or detect SSI. In particular, a CRP level of 5.0 mg/dL on POD 7 strongly suggests the future development of SSI (sensitivity: 78%, specificity: 74%).
Well‐Defined and Reliable Clinical Outcome Assessments for Pediatric Crohn Disease
Authors: Sun Haihao , Papadopoulos Elektra J. , Hyams Jeffrey S. , Griebel Donna , Lee Jessica J. , Tomaino Juli , Mulberg Andrew E.
Published: March 2015

Objectives:

The aim of the present study was to identify areas for further development of clinical outcome assessment (COA) in pediatric Crohn disease (CD).

Methods:

The study analyzed the measurement properties of all existing COA tools for pediatric CD in literature and published registration trials of approved drugs for pediatric CD based on criteria described in Food and Drug Administration guidance for patient‐reported outcome (PRO) development.

Results:

The Pediatric Crohn's Disease Activity Index (PCDAI) and its derivatives (abbreviated, short, modified, and weighted PCDAIs) were reviewed. The Crohn's Disease Activity Index (CDAI) and Harvey‐Bradshaw index (HBI), designed for adult patients, have been adapted for use in a few pediatric CD studies. The use of PCDAI as an endpoint in Remicade and Humira trials led to the Food and Drug Administration–approved indication in pediatric CD. Common issues in measurement properties of COA tools included the absence of direct patient or caregivers' input to generate the items measuring signs and symptoms; absence of evidence demonstrating correlation with clinically relevant inflammation observed with endoscopic measures; lack of standardization in measurement, age‐appropriate interviewer script, and response rating criteria for the physician interviewer.

Conclusions:

Available evidence indicates that CDAI, HBI, and 5 versions of the PCDAI lack adequate measurement properties for use as a primary endpoint for phase 3 trials intended to support approval of products intended to treat pediatric CD. In order to facilitate pediatric drug development, a well‐defined, reliable, sensitive, and globally recognized PRO that measures signs and symptoms in children with CD and that can be used in conjunction with endoscopy‐based endpoints and/or biomarkers is sorely needed.
Fundamental formulae for wave-energy conversion
Authors: Falnes Johannes , Kurniawan Adi
Published: March 2015

The time-average wave power that is absorbed from an incident wave by means of a wave-energy conversion (WEC) unit, or by an array of WEC units—i.e. oscillating immersed bodies and/or oscillating water columns (OWCs)—may be mathematically expressed in terms of the WEC units' complex oscillation amplitudes, or in terms of the generated outgoing (diffracted plus radiated) waves, or alternatively, in terms of the radiated waves alone. Following recent controversy, the corresponding three optional expressions are derived, compared and discussed in this paper. They all provide the correct time-average absorbed power. However, only the first-mentioned expression is applicable to quantify the instantaneous absorbed wave power and the associated reactive power. In this connection, new formulae are derived that relate the ‘added-mass’ matrix, as well as a couple of additional reactive radiation-parameter matrices, to the difference between kinetic energy and potential energy in the water surrounding the immersed oscillating WEC array. Further, a complex collective oscillation amplitude is introduced, which makes it possible to derive, by a very simple algebraic method, various simple expressions for the maximum time-average wave power that may be absorbed by the WEC array. The real-valued time-average absorbed power is illustrated as an axisymmetric paraboloid defined on the complex collective-amplitude plane. This is a simple illustration of the so-called ‘fundamental theorem for wave power’. Finally, the paper also presents a new derivation that extends a recently published result on the direction-average maximum absorbed wave power to cases where the WEC array's radiation damping matrix may be singular and where the WEC array may contain OWCs in addition to oscillating bodies.
Eaten alive: cannibalism is enhanced by parasites
Authors: Bunke Mandy , Alexander Mhairi E. , Dick Jaimie T. A. , Hatcher Melanie J. , Paterson Rachel , Dunn Alison M.
Published: March 2015

Cannibalism is ubiquitous in nature and especially pervasive in consumers with stage-specific resource utilization in resource-limited environments. Cannibalism is thus influential in the structure and functioning of biological communities. Parasites are also pervasive in nature and, we hypothesize, might affect cannibalism since infection can alter host foraging behaviour. We investigated the effects of a common parasite, the microsporidianPleistophora mulleri, on the cannibalism rate of its host, the freshwater amphipodGammarus duebeni celticus. Parasitic infection increased the rate of cannibalism by adults towards uninfected juvenile conspecifics, as measured by adult functional responses, that is, the rate of resource uptake as a function of resource density. This may reflect the increased metabolic requirements of the host as driven by the parasite. Furthermore, when presented with a choice, uninfected adults preferred to cannibalize uninfected rather than infected juvenile conspecifics, probably reflecting selection pressure to avoid the risk of parasite acquisition. By contrast, infected adults were indiscriminate with respect to infection status of their victims, probably owing to metabolic costs of infection and the lack of risk as the cannibals were already infected. Thus parasitism, by enhancing cannibalism rates, may have previously unrecognized effects on stage structure and population dynamics for cannibalistic species and may also act as a selective pressure leading to changes in resource use.
Spermatozoa scattering by a microchannel feature: an elastohydrodynamic model
Authors: Montenegro-Johnson T. D. , Gadêlha H. , Smith D. J.
Published: March 2015

Sperm traverse their microenvironment through viscous fluid by propagating flagellar waves; the waveform emerges as a consequence of elastic structure, internal active moments and low Reynolds number fluid dynamics. Engineered microchannels have recently been proposed as a method of sorting and manipulating motile cells; the interaction of cells with these artificial environments therefore warrants investigation. A numerical method is presented for large-amplitude elastohydrodynamic interaction of active swimmers with domain features. This method is employed to examine hydrodynamic scattering by a model microchannel backstep feature. Scattering is shown to depend on backstep height and the relative strength of viscous and elastic forces in the flagellum. In a ‘high viscosity’ parameter regime corresponding to human sperm in cervical mucus analogue, this hydrodynamic contribution to scattering is comparable in magnitude to recent data on contact effects, being of the order of 5°–10°. Scattering can be positive or negative depending on the relative strength of viscous and elastic effects, emphasizing the importance of viscosity on the interaction of sperm with their microenvironment. The modulation of scattering angle by viscosity is associated with variations in flagellar asymmetry induced by the elastohydrodynamic interaction with the boundary feature.
Can differential nutrient extraction explain property variations in a predatory trap?
Authors: Blamires Sean J. , Piorkowski Dakota , Chuang Angela , Tseng Yi-Hsuan , Toft Søren , Tso I-Min
Published: March 2015

Predators exhibit flexible foraging to facilitate taking prey that offer important nutrients. Because trap-building predators have limited control over the prey they encounter, differential nutrient extraction and trap architectural flexibility may be used as a means of prey selection. Here, we tested whether differential nutrient extraction induces flexibility in architecture and stickiness of a spider's web by feeding
Nephila pilipes
live crickets (CC), live flies (FF), dead crickets with the web stimulated by flies (CD) or dead flies with the web stimulated by crickets (FD). Spiders in the CD group consumed less protein per mass of lipid or carbohydrate, and spiders in the FF group consumed less carbohydrates per mass of protein. Spiders from the CD group built stickier webs that used less silk, whereas spiders in the FF group built webs with more radii, greater catching areas and more silk, compared with other treatments. Our results suggest that differential nutrient extraction is a likely explanation for prey-induced spider web architecture and stickiness variations.
First report of neonatal sepsis due to Moesziomyces bullatus in a preterm low‐birth‐weight infant
Authors: Okolo Ojogba Mark , Van Diepeningen Anne D. , Toma Bose , Nnadi Nnaemeka Emmanuel , Ayanbimpe Mebi Grace , Onyedibe Ikenna Kenneth , Sabitu Mohammed Zaino , Banwat Benle Edmund , Groenewald Marizeth , Scordino Fabio , Egah Zanyul Daniel , Criseo Giuseppe , Romeo Orazio
Published: March 2015

Introduction:

Moesziomyces spp. are connected with poaceous plants (Grass family), and Moesziomyces bullatus is commonly associated with smut in pearl millet. Currently, the scientific knowledge of this pathogen is limited to only a few taxonomic studies and there are no clinical reports that describe the isolation of M. bullatus from humans.

Case presentation:

A female neonate born prematurely at 32 weeks of gestation was referred to the University Teaching Hospital in Jos, Nigeria, with a provisional diagnosis of preterm low birth weight at risk for sepsis. The birth weight of the newborn was 2000 g and her body temperature on admission was 34.3 °C. Blood cultures revealed the presence of a fungal isolate that was identified as M. bullatus by molecular methods. This fungus showed high MIC values for anidulafungin, caspofungin and micafungin, as well as fluconazole and 5‐flucytosine, and exhibited varying degrees of susceptibility to itraconazole, amphotericin B, posaconazole and voriconazole. To the best of our knowledge, this is the first case of a human M. bullatus bloodstream infection.

Conclusion:

Here, we report the first case of an unusual human infection caused by the fungal plant pathogen M. bullatus and highlight a high level of resistance to classical and modern antifungal drugs.
Fatal infections caused by methicillin‐resistant Staphylococcus aureus of clonal complex 398: case presentations and molecular epidemiology
Authors: Berning Christiane , Lanckohr Christian , Baumgartner Helmut , Drescher Mike , Becker Karsten , Peters Georg , Köck Robin , Kahl Barbara C.
Published: March 2015

Introduction:

Methicillin‐resistant Staphylococcus aureus (MRSA) of clonal complex (CC) 398 has emerged in livestock across Europe over the past 10 years.

Case presentation:

Case 1 was a patient with a history of destructive chronic polyarthritis and immunosuppressive therapy who presented with dyspnoea and pain in the shoulders, back and hips. Microbiological analysis of tissue samples, punctures and blood cultures revealed MRSA. Echocardiography showed mitral valve endocarditis. The patient was treated with daptomycin and fosfomycin. Case 2 was a patient presenting with pneumonia after lung transplantation. Respiratory specimens and perianal swabs revealed MRSA. The patient was treated with teicoplanin and linezolid. The patients did not recover from their infections and died. The isolates belonged to spa types t2576 (case 1) and t011 (case 2), to sequence type 398 within CC398 as determined by multilocus sequence typing and to staphylococcal cassette chromosome mec type 5. An IdentiBAC Microarray revealed the absence of a bacteriophage integrating into the hlb gene indicative of the livestock origin of the isolates. In 2013, 170 of 534 MRSA cases (31.8 %) among inpatients of the University Hospital Münster, Germany, were caused by closely related spa types clustering in one spa‐CC indicative of CC398. Two of 12 MRSA isolates from blood cultures (16.7 %) were caused by isolates associated with MRSA CC398.

Conclusion:

Livestock‐associated MRSA CC398 is emerging as a cause of human infections. This observation is alarming and should inspire future efforts to control MRSA in livestock, forestall community spread and monitor changes of the occurrence of MRSA CC398 among cases of human infections.
Retrocalcaneal septic bursitis as a complication of a delayed‐healing heel wound
Authors: Gomez Eric , Stuart David , Chernev Ivan
Published: March 2015

Introduction:

Bursitis may arise from non‐infectious and infectious aetiologies. Clinically, distinguishing one from the other can be challenging. Aseptic retrocalcaneal bursitis is a common disorder among athletes and physically active people. In contrast, infectious (septic) bursitis, although a common diagnosis in the olecranon and prepatellar bursa, has rarely been reported in the retrocalcaneal bursa.

Case presentation:

Here, we present an unusual case of retrocalcaneal septic bursitis as a complication of a delayed‐healing heel wound in a patient with underlying calcific insertional Achilles tendinopathy and aseptic retrocalcaneal bursitis.

Conclusion:

Physicians should be aware of this clinical entity as a possible complication of a heel wound and initiate appropriate management if an infectious process is suspected.
Two distinct modes for propagation of histone PTMs across the cell cycle
Authors: Alabert Constance , Barth Teresa K. , Reverón-Gómez Nazaret , Sidoli Simone , Schmidt Andreas , Jensen Ole N. , Imhof Axel , Groth Anja
Published: March 2015

Epigenetic states defined by chromatin can be maintained through mitotic cell division. However, it remains unknown how histone-based information is transmitted. Here we combine nascent chromatin capture (NCC) and triple-SILAC (stable isotope labeling with amino acids in cell culture) labeling to track histone modifications and histone variants during DNA replication and across the cell cycle. We show that post-translational modifications (PTMs) are transmitted with parental histones to newly replicated DNA. Di- and trimethylation marks are diluted twofold upon DNA replication, as a consequence of new histone deposition. Importantly, within one cell cycle, all PTMs are restored. In general, new histones are modified to mirror the parental histones. However, H3K9 trimethylation (H3K9me3) and H3K27me3 are propagated by continuous modification of parental and new histones because the establishment of these marks extends over several cell generations. Together, our results reveal how histone marks propagate and demonstrate that chromatin states oscillate within the cell cycle.
Principles of designing interpretable optogenetic behavior experiments
Authors: Allen Brian D. , Singer Annabelle C. , Boyden Edward S.
Published: March 2015

Over the last decade, there has been much excitement about the use of optogenetic tools to test whether specific cells, regions, and projection pathways are necessary or sufficient for initiating, sustaining, or altering behavior. However, the use of such tools can result in side effects that can complicate experimental design or interpretation. The presence of optogenetic proteins in cells, the effects of heat and light, and the activity of specific ions conducted by optogenetic proteins can result in cellular side effects. At the network level, activation or silencing of defined neural populations can alter the physiology of local or distant circuits, sometimes in undesired ways. We discuss how, in order to design interpretable behavioral experiments using optogenetics, one can understand, and control for, these potential confounds.
One- and two-dimensional polymers from proline and calcium bromide
Authors: Lamberts Kevin , Şerb Mihaela-Diana , Englert Ulli
Published: March 2015

Reactions of calcium bromide with enantiopure and racemic proline in aqueous solution lead to two solids in which the zwitterionic amino acid acts as a bridging ligand between neighbouring cations. Depending on the chirality of the amino acid, topologically very different products are obtained. With racemic proline, bromide acts as a simple uncoordinated counter-anion for the cationic heterochiral chains incatena-poly[[aquacalcium(II)]-μ-aqua-μ3-DL-proline-μ2-DL-proline], {[Ca(C5H9NO2)2(H2O)2]Br2}n. In agreement with chemical intuition, only carboxylate and aqua O atoms coordinate the alkaline earth cation in a low-symmetry arrangement. In contrast, L-proline affords the two-dimensional network poly[dibromidobis(μ2-L-proline)calcium(II)], [CaBr2(C5H9NO2)2]n, with an unexpected CaBr2unit in a more regular coordination sphere.
A new two-dimensional anionic cadmium(II) polymer constructed through thiocyanate coordination bridges
Authors: Wang Hui-Ting , Wang Xiao-Li
Published: March 2015

A new cadmium–thiocyanate complex, poly[4-(dimethylamino)pyridin-1-ium [di-μ-thiocyanato-κ2N:S;κ2S:N-thiocyanato-κN-cadmium(II)]], {(C7H11N2)[Cd(NCS)3]}n, was synthesized by the reaction of cadmium thiocyanate and 4-(dimethylamino)pyridine hydrochloride in aqueous solution. In the crystal structure, each CdIIion is square-pyramidally coordinated by three N and two S atoms from five different thiocyanate ligands, four of which are bridging. The thiocyanate ligands play different roles in the build up of the structure; one role results in the formation of [Cd2(NCS)2] building blocks, while the other links the building blocks and cationsviaN—H...S hydrogen bonds. The N—H...S hydrogen bonds and weak π–π stacking interactions are involved in the formation of both a two-dimensional network structure and the supramolecular network.
Crystallization and preliminary X-ray crystallographic analysis of the sclerostin-neutralizing Fab AbD09097
Authors: Boschert Verena , Muth Eva-Maria , Knappik Achim , Frisch Christian , Mueller Thomas D.
Published: March 2015

The secreted cystine-knot protein sclerostin was first identified from genetic screening of patients suffering from the rare bone-overgrowth diseases sclerosteosis and van Buchem disease. Sclerostin acts a negative regulator of bone growth through inhibiting the canonical Wnt signalling cascade by binding to and blocking the Wnt co-receptor LRP5/6. Its function in blocking osteoblastogenesis makes it an important target for osteoanabolic therapy approaches to treat osteoporosis, which is characterized by a progressive decrease in bone mass and density. In this work, the production, crystallization and preliminary X-ray diffraction data analysis of a sclerostin-neutralizing human Fab antibody fragment, AbD09097, obtained from a naive antibody library are reported. Crystals of the Fab AbD09097 belonged to space groupP21, with unit-cell parametersa= 45.19,b= 78.49,c= 59.20 Å, β = 95.71° and diffracted X-rays to a resolution of 1.8 Å.
The X-ray structure of human P-cadherin EC1-EC2 in a closed conformation provides insight into the type I cadherin dimerization pathway
Authors: Dalle Vedove Andrea , Lucarelli Anna Paola , Nardone Valentina , Matino Angelica , Parisini Emilio
Published: March 2015

Cadherins are a large family of calcium-dependent proteins that mediate cellular adherens junction formation and tissue morphogenesis. To date, the most studied cadherins are those classified as classical, which are further divided into type I or type II depending on selected sequence features. Unlike other members of the classical cadherin family, a detailed structural characterization of P-cadherin has not yet been fully obtained. Here, the high-resolution crystal structure determination of the closed form of human P-cadherin EC1-EC2 is reported. The structure shows a novel, monomeric packing arrangement that provides a further snapshot in the yet-to-be-achieved complete description of the highly dynamic cadherin dimerization pathway. Moreover, this is the first multidomain cadherin fragment to be crystallized and structurally characterized in its closed conformation that does not carry any extra N-terminal residues before the naturally occurring aspartic acid at position 1. Finally, two clear alternate conformations are observed for the critical Trp2 residue, suggestive of a transient, metastable state. The P-cadherin structure and packing arrangement shown here provide new and valuable information towards the complete structural characterization of the still largely elusive cadherin dimerization pathway.
Structural basis of the substrate specificity of the FPOD/FAOD family revealed by fructosyl peptide oxidase fromEupenicillium terrenum
Authors: Gan Weiqiong , Gao Feng , Xing Keke , Jia Minze , Liu Haiping , Gong Weimin
Published: March 2015

The FAOD/FPOD family of proteins has the potential to be useful for the longterm detection of blood glucose levels in diabetes patients. A bottleneck for this application is to find or engineer a FAOD/FPOD family enzyme that is specifically active towards α-fructosyl peptides but is inactive towards other types of glycated peptides. Here, the crystal structure of fructosyl peptide oxidase fromEupenicillium terrenum(EtFPOX) is reported at 1.9 Å resolution. In contrast to the previously reported structure of amadoriase II, EtFPOX has an open substrate entrance to accommodate the large peptide substrate. The functions of residues critical for substrate selection are discussed based on structure comparison and sequence alignment. This study reveals the first structural details of group I FPODs that prefer α-fructosyl substrates and could provide significant useful information for uncovering the mechanism of substrate specificity of FAOD/FPODs and guidance towards future enzyme engineering for diagnostic purposes.
Structure of the omalizumab Fab
Authors: Jensen Rasmus K. , Plum Melanie , Tjerrild Luna , Jakob Thilo , Spillner Edzard , Andersen Gregers Rom
Published: March 2015

Omalizumab is a humanized anti-IgE antibody that inhibits the binding of IgE to its receptors on mast cells and basophils, thus blocking the IgE-mediated release of inflammatory mediators from these cells. Omalizumab binds to the Fc domains of IgE in proximity to the binding site of the high-affinity IgE receptor Fc∊RI, but the epitope and the mechanisms and conformations governing the recognition remain unknown. In order to elucidate the molecular mechanism of its anti-IgE activity, the aim was to analyse the interaction of omalizumab with human IgE. Therefore, IgE Fc C∊2–4 was recombinantly produced in mammalian HEK-293 cells. Functionality of the IgE Fc was proven by ELISA and mediator-release assays. Omalizumab IgG was cleaved with papain and the resulting Fab was purified by ion-exchange chromatography. The complex of IgE Fc with omalizumab was prepared by size-exclusion chromatography. However, crystals containing the complex were not obtained, suggesting that the process of crystallization favoured the dissociation of the two proteins. Instead, two structures of the omalizumab Fab with maximum resolutions of 1.9 and 3.0 Å were obtained. The structures reveal the arrangement of the CDRs and the position of omalizumab residues known from prior functional studies to be involved in IgE binding. Thus, the structure of omalizumab provides the structural basis for understanding the function of omalizumab, allows optimization of the procedure for complex crystallization and poses questions about the conformational requirements for anti-IgE activity.
Expression, purification, crystallization and preliminary crystallographic analysis of a GH20 β-N-acetylglucosaminidase from the marine bacteriumVibrio harveyi
Authors: Meekrathok Piyanat , Bürger Marco , Porfetye Arthur T. , Vetter Ingrid R. , Suginta Wipa
Published: March 2015

Vibrio harveyiβ-N-acetylglucosaminidase (VhGlcNAcase) is a new member of the GH20 glycoside hydrolase family responsible for the complete degradation of chitin fragments, withN-acetylglucosamine (GlcNAc) monomers as the final products. In this study, the crystallization and preliminary crystallographic data of wild-typeVhGlcNAcase and its catalytically inactive mutant D437A in the absence and the presence of substrate are reported. Crystals of wild-typeVhGlcNAcase were grown in 0.1 Msodium acetate pH 4.6, 1.4 Msodium malonate, while crystals of the D437A mutant were obtained in 0.1 Mbis-tris pH 7.5, 0.1 Msodium acetate, 20% PEG 3350. X-ray data from the wild-type and the mutant crystals were collected at a synchrotron-radiation light source and were complete to a resolution of 2.5 Å. All crystals were composed of the same type of dimer, with the substrateN,N′-diacetylglucosamine (GlcNAc2or diNAG) used for soaking was cleaved by the active enzyme, leaving only a single GlcNAc molecule bound to the protein.
Complex assembly, crystallization and preliminary X-ray crystallographic analysis of the human Rod–Zwilch–ZW10 (RZZ) complex
Authors: Altenfeld Anika , Wohlgemuth Sabine , Wehenkel Annemarie , Vetter Ingrid R. , Musacchio Andrea
Published: March 2015

The spindle-assembly checkpoint (SAC) monitors kinetochore–microtubule attachment during mitosis. In metazoans, the three-subunit Rod–Zwilch–ZW10 (RZZ) complex is a crucial SAC component that interacts with additional SAC-activating and SAC-silencing components, including the Mad1–Mad2 complex and cytoplasmic dynein. The RZZ complex contains two copies of each subunit and has a predicted molecular mass of ∼800 kDa. Given the low abundance of the RZZ complex in natural sources, its recombinant reconstitution was attempted by co-expression of its subunits in insect cells. The RZZ complex was purified to homogeneity and subjected to systematic crystallization attempts. Initial crystals containing the entire RZZ complex were obtained using the sitting-drop method and were subjected to optimization to improve the diffraction resolution limit. The crystals belonged to space groupP31(No. 144) orP32(No. 145), with unit-cell parametersa=b= 215.45,c= 458.7 Å, α = β = 90.0, γ = 120.0°.
Structure of dihydrodipicolinate synthase from the commensal bacteriumBacteroides thetaiotaomicronat 2.1 Å resolution
Authors: Mank Nicholas , Arnette Amy , Klapper Vince , Offermann Lesa , Chruszcz Maksymilian
Published: March 2015

Dihydrodipicolinate synthase (DapA) catalyzes the first committed step of the diaminopimelate biosynthetic pathway of lysine. It has been shown to be an essential enzyme in many bacteria and has been the subject of research to generate novel antibiotics. However, this pathway is present in both pathogenic and commensal bacteria, and antibiotics targeting DapA may interfere with normal gut colonization.Bacteroides thetaiotaomicronis a Gram-negative commensal bacterium that makes up a large proportion of the normal microbiota of the human gut. The structure of DapA fromB. thetaiotaomicron(BtDapA) has been determined. This structure will help to guide the generation of selectively active antibiotic compounds targeting DapA.
Structure of the ABL2/ARG kinase in complex with dasatinib
Authors: Ha Byung Hak , Simpson Mark Adam , Koleske Anthony J. , Boggon Titus J.
Published: March 2015

ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases. ARG plays important roles in cell morphogenesis, motility, growth and survival, and many of these biological roles overlap with the cellular functions of the ABL kinase. Chronic myeloid leukemia (CML) is associated with constitutive ABL kinase activation resulting from fusion between parts of the breakpoint cluster region (BCR) andABL1genes. Similarly, fusion of theETV6(Tel) andARGgenes drives some forms of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Dasatinib is a tyrosine kinase inhibitor used for the treatment of CML by inhibiting ABL, and while it also inhibits ARG, there is currently no structure of ARG in complex with dasatinib. Here, the co-crystal structure of the mouse ARG catalytic domain with dasatinib at 2.5 Å resolution is reported. Dasatinib-bound ARG is found in the DFG-in conformation although it is nonphosphorylated on the activation-loop tyrosine. In this structure the glycine-rich P-loop is found in a relatively open conformation compared with other known ABL family–inhibitor complex structures.
Analytical ultracentrifugation and preliminary X-ray studies of the chloroplast envelope quinone oxidoreductase homologue fromArabidopsis thaliana
Authors: Mas y mas Sarah , Giustini Cécile , Ferrer Jean-Luc , Rolland Norbert , Curien Gilles , Cobessi David
Published: March 2015

Quinone oxidoreductases reduce a broad range of quinones and are widely distributed among living organisms. The chloroplast envelope quinone oxidoreductase homologue (ceQORH) fromArabidopsis thalianabinds NADPH, lacks a classical N-terminal and cleavable chloroplast transit peptide, and is transported through the chloroplast envelope membrane by an unknown alternative pathway without cleavage of its internal chloroplast targeting sequence. To unravel the fold of this targeting sequence and its substrate specificity, ceQORH fromA. thalianawas overexpressed inEscherichia coli, purified and crystallized. Crystals of apo ceQORH were obtained and a complete data set was collected at 2.34 Å resolution. The crystals belonged to space groupC2221, with two molecules in the asymmetric unit.