bluuebunny/crossref_metadata_2025_split huggingface dataset:
A blindsnake that decapitates its termite prey
Authors: Mizuno T. , Kojima Y. 
Published: July 2015

AbstractAlmost all snakes swallow their prey whole. However, a few species are known as exceptions. Two species ofAsian crab‐eating snakes tear off crab legs and ingest them one at a time to eat prey that is otherwise too large. Two species of leptotyphlopid blindsnakes break off the head of termites or suck abdominal contents of termites, discarding remains of termites. Here, we show that a typhlopid blindsnakeIndotyphlops braminusdecapitates its termite prey and consumes only the thorax and abdomen. In our feeding trials,I. braminusdecapitated a median of 47% of termites they eat, while swallowing the remaining termites whole. Decapitation did not affect ingestion speed, and therefore, it is unlikely that decapitation assists for fast ingestion. Ingested termite heads often remain undigested in the feces, implying that the decapitation functions to remove an indigestible part of termites. Decapitation might also be related to circumvention of chemical defenses of termites because termite heads often contain toxic compounds. These observations showed unusual feeding behavior used by a basal snake, which could be associated with removal of indigestible and/or toxic parts of prey items.
Margaret Cavendish on Perception, Self‐Knowledge, and Probable Opinion
Authors: Boyle Deborah 
Published: July 2015

AbstractScholarly interest in Margaret Cavendish's philosophical views has steadily increased over the past decade, but her epistemology has received little attention, and no consensus has emerged; Cavendish has been characterized as a skeptic, as a rationalist, as presenting an alternative epistemology to both rationalism and empiricism, and even as presenting no clear theory of knowledge at all. This paper concludes that Cavendish was only a modest skeptic, for she believed that humans can achieve knowledge through sensitive and rational perception as well as through self‐knowledge and can form probable opinions through reasoning.
Philosophy and the Biology of Male Homosexuality
Authors: Lemeire Olivier , De Block Andreas 
Published: July 2015

AbstractThis paper is a review of how biological as well as other scientific theories, concepts and findings have been used to answer philosophical questions regarding the nature of male homosexuality. We argue that while these sciences are certainly relevant for present philosophical debates, few of the different philosophical issues surrounding male homosexuality can be settled by science alone. In the first section, we introduce a number of various essentialist and constructivist views on (male) homosexuality. The second section focuses on the innateness debate over homosexuality. In the last section, we assess the typically constructivist critiques of biological research into homosexuality.
Conscientious Objection by Health Care Professionals
Authors: Wester Gry 
Published: July 2015

AbstractCertain health care services and goods, although legal and often generally accepted in a society, are by some considered morally problematic. Debates on conscientious objection in health care try to resolve whether and when physicians, nurses and pharmacists should be allowed to refuse to provide medical services and goods because of their ethical or religious beliefs. These debates have most often focused on issues such as how to balance the interests of patients and health care professionals, and the compatibility of conscientious objection with professional obligations, but it is also possible to think about conscientious objection in terms of how to respond to moral disagreement and the requirements of liberal neutrality.
Non‐anaemic iron deficiency impairs response to pulmonary rehabilitation in COPD
Authors: Barberan‐Garcia Anael , Rodríguez Diego Agustín , Blanco Isabel , Gea Joaquim , Torralba Yolanda , Arbillaga‐Etxarri Ane , Barberà Joan Albert , Vilaró Jordi , Roca Josep , Orozco‐Levi Mauricio 
Published: July 2015

AbstractBackground and objectiveNon‐anaemic iron deficiency (NAID) might alter the oxygen pathway in health and disease. The current study aims at assessing the impact of NAID on aerobic capacity in patients with chronic obstructive pulmonary disease (COPD).MethodsA prospective sample of 70 non‐anaemic COPD patients candidate to participate in an 8‐week pulmonary rehabilitation (PR) programme was studied. Incremental cycling exercise to peak oxygen uptake (V'O2peak) and constant work‐rate exercise at 80% V'O2peak to exhaustion were assessed pre‐ and post‐PR. Training‐induced increase of endurance time (ET) ≥33%, which represented the minimal clinically important difference, classified patients as responders to exercise training.ResultsThe prevalence of NAID was 48% (n = 34) showing no relationship with the Global Initiative for Chronic Obstructive Lung Disease stages (P = 0.209). Patients with NAID showed lower pre‐training ET (P = 0.033) and V'O2peak (P = 0.007) than normal iron status (NIS) patients after adjustment for potential covariates. Significant training‐induced physiological changes were seen in the NIS group (ΔV'O2peak 68(132) mL/min; P = 0.009), but not in the NAID group (ΔV'O2peak 26 (126) mL/min; P = 0.269). The NAID group showed lower percentage of responders to training (56%) than the NIS group (78%) (P = 0.041).ConclusionsCOPD patients with NAID showed lower pre‐training aerobic capacity and reduced training‐induced response than NIS patients after adjusting for potential confounding variables.
Outsourcing, Importing and Innovation: Evidence from Firm‐level Data for Emerging Economies
Authors: Fritsch Ursula , Görg Holger 
Published: July 2015

AbstractThis paper investigates two sourcing strategies of firms, outsourcing and importing, and links these to innovation activities. The authors examine this empirically using firm‐level data for 28 emerging market economies and find robust evidence that outsourcing increases the likelihood to spend on R&D and via this channel raises innovation output, whereas importing increases innovation output, but not R&D. The results hold when implementing an instrumental variables approach. It is found that results crucially depend on the institutional environment in the economy, e.g. property rights and intellectual property rights protection. The results suggest that better institutions magnify the gains from importing, but not from outsourcing. EU countries also reap additional positive innovation effects from importing compared with non‐EU countries.
Development and Psychometric Properties of the Classroom Peer Context Questionnaire
Authors: Boor‐Klip Henrike J. , Segers Eliane , Hendrickx Marloes M. H. G. , Cillessen Antonius H. N. 
Published: July 2015

AbstractChildren's view on the peer context in their classroom may differ from that of other informants, but no measure systematically examines children's own view. Therefore, we developed the Classroom Peer Context Questionnaire (CPCQ) and evaluated its reliability, validity, and stability in two studies. In Study 1, 464 children (Mage = 10.8 years, 53.2% girls) from 18 Grade 5 classrooms participated in 2 waves of data collection. In Study 2, 1538 children (Mage = 10.6 years, 47.2% girls) from 59 Grade 5 classrooms participated in 3 waves of data collection. Exploratory factor analyses in Study 1 revealed 5 dimensions labeled comfort, cooperation, conflict, cohesion, and isolation. Confirmatory factor analyses in Study 2 supported these 5 dimensions. Study 2 also demonstrated good reliability, validity, and stability for each dimension. Researchers and professionals in schools may use the CPCQ to obtain reliable and quick information on how children perceive the peer context in their classroom.
A hybrid approach for fusing 4D‐MRI temporal information with 3D‐CT for the study of lung and lung tumor motion
Authors: Yang Y. X. , Teo S.‐K. , Van Reeth E. , Tan C. H. , Tham I. W. K. , Poh C. L. 
Published: July 2015

Purpose:Accurate visualization of lung motion is important in many clinical applications, such as radiotherapy of lung cancer. Advancement in imaging modalities [e.g., computed tomography (CT) and MRI] has allowed dynamic imaging of lung and lung tumor motion. However, each imaging modality has its advantages and disadvantages. The study presented in this paper aims at generating synthetic 4D‐CT dataset for lung cancer patients by combining both continuous three‐dimensional (3D) motion captured by 4D‐MRI and the high spatial resolution captured by CT using the authors’ proposed approach.Methods:A novel hybrid approach based on deformable image registration (DIR) and finite element method simulation was developed to fuse a static 3D‐CT volume (acquired under breath‐hold) and the 3D motion information extracted from 4D‐MRI dataset, creating a synthetic 4D‐CT dataset.Results:The study focuses on imaging of lung and lung tumor. Comparing the synthetic 4D‐CT dataset with the acquired 4D‐CT dataset of six lung cancer patients based on 420 landmarks, accurate results (average error <2 mm) were achieved using the authors’ proposed approach. Their hybrid approach achieved a 40% error reduction (based on landmarks assessment) over using only DIR techniques.Conclusions:The synthetic 4D‐CT dataset generated has high spatial resolution, has excellent lung details, and is able to show movement of lung and lung tumor over multiple breathing cycles.
Hydrolysis of Clavulanate by Mycobacterium tuberculosis β-Lactamase BlaC Harboring a Canonical SDN Motif
Authors: Soroka Daria , Li de la Sierra-Gallay Inès , Dubée Vincent , Triboulet Sébastien , van Tilbeurgh Herman , Compain Fabrice , Ballell Lluis , Barros David , Mainardi Jean-Luc , Hugonnet Jean-Emmanuel , Arthur Michel 
Published: July 2015

ABSTRACT

Combinations of β-lactams with clavulanate are currently being investigated for tuberculosis treatment. Since
Mycobacterium tuberculosis
produces a broad spectrum β-lactamase, BlaC, the success of this approach could be compromised by the emergence of clavulanate-resistant variants, as observed for inhibitor-resistant TEM variants in enterobacteria. Previous analyses based on site-directed mutagenesis of BlaC have led to the conclusion that this risk was limited. Here, we used a different approach based on determination of the crystal structure of β-lactamase Bla
MAb
of
Mycobacterium abscessus
, which efficiently hydrolyzes clavulanate. Comparison of Bla
MAb
and BlaC allowed for structure-assisted site-directed mutagenesis of BlaC and identification of the G
132
N substitution that was sufficient to switch the interaction of BlaC with clavulanate from irreversible inactivation to efficient hydrolysis. The substitution, which restored the canonical SDN motif (SDG→SDN), allowed for efficient hydrolysis of clavulanate, with a more than 10
4
-fold increase in
k
cat
(0.41 s
−1
), without affecting the hydrolysis of other β-lactams. Mass spectrometry revealed that acylation of BlaC and of its G
132
N variant by clavulanate follows similar paths, involving sequential formation of two acylenzymes. Decarboxylation of the first acylenzyme results in a stable secondary acylenzyme in BlaC, whereas hydrolysis occurs in the G
132
N variant. The SDN/SDG polymorphism defines two mycobacterial lineages comprising rapidly and slowly growing species, respectively. Together, these results suggest that the efficacy of β-lactam–clavulanate combinations may be limited by the emergence of resistance. β-Lactams active without clavulanate, such as faropenem, should be prioritized for the development of new therapies.
In
Vitro
Efficacy of Antiviral Compounds against Enterovirus D68
Authors: Rhoden Eric , Zhang Mingyu , Nix W. Allan , Oberste M. Steven 
Published: July 2015

ABSTRACT

In 2014, the United States experienced a large outbreak of severe respiratory illness associated with enterovirus D68 (EV-D68). We used a homogeneous, cell-based assay to assess the antiviral activity of compounds developed for EV/rhinovirus infection or other indications. Three of 15 compounds were highly active against all four strains tested (the prototype and three 2014 strains), with 50% effective concentrations of 0.0012 to 0.027 μM. Additional studies are needed to assess their
in vivo
efficacy against EV-D68.
Identification and Characterization of a Novel Family of Selective Antifungal Compounds (CANBEFs) That Interfere with Fungal Protein Synthesis
Authors: Mircus Gabriel , Albert Nathaniel , Ben-Yaakov Dafna , Chikvashvili Dodo , Shadkchan Yona , Kontoyiannis Dimitrios P. , Osherov Nir 
Published: July 2015

ABSTRACT

Invasive mycotic infections have become more common during recent decades, posing an increasing threat to public health. However, despite the growing needs, treatments for invasive fungal infections remain unsatisfactory and are limited to a small number of antifungals. The aim of this study was to identify novel fungal cell wall inhibitors from a library of small chemical compounds using a conditional protein kinase C (PKC)-expressing strain of
Aspergillus nidulans
sensitive to cell wall-active agents. Eight “hit” compounds affecting cell wall integrity were identified from a screen of 35,000 small chemical compounds. Five shared a common basic molecular structure of 4-
c
hloro-6-
a
rylamino-7-
n
itro-
be
nzo
f
urazane (CANBEF). The most potent compound, CANBEF-24, was characterized further and was shown to inhibit the growth of pathogenic
Aspergillus
,
Candida
,
Fusarium
, and
Rhizopus
isolates at micromolar concentrations but not to affect the growth of mammalian cell lines. CANBEF-24 demonstrated strong synergy in combination with caspofungin, an antifungal that inhibits cell wall biosynthesis. Genetic and biochemical analyses with
Aspergillus nidulans
and
Saccharomyces cerevisiae
indicated that CANBEFs selectively inhibit fungal rRNA maturation and protein synthesis, suggesting that their effect on the cell wall is indirect. CANBEFs were nontoxic in insect (
Galleria mellonella
,
Drosophila melanogaster
) and mouse models of fungal infection. Preliminary evidence showing no therapeutic benefit in these models suggests that further cycles of optimization are needed for the development of this novel class of compounds for systemic use.
Population Pharmacokinetic Modeling of Itraconazole and Hydroxyitraconazole for Oral SUBA-Itraconazole and Sporanox Capsule Formulations in Healthy Subjects in Fed and Fasted States
Authors: Abuhelwa Ahmad Y. , Foster David J. R. , Mudge Stuart , Hayes David , Upton Richard N. 
Published: July 2015

ABSTRACT
Itraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies.
Contrasting
Ex Vivo
Efficacies of “Reversed Chloroquine” Compounds in Chloroquine-Resistant Plasmodium falciparum and P. vivax Isolates
Authors: Wirjanata Grennady , Sebayang Boni F. , Chalfein Ferryanto , Prayoga  , Handayuni Irene , Noviyanti Rintis , Kenangalem Enny , Poespoprodjo Jeanne Rini , Burgess Steven J. , Peyton David H. , Price Ric N. , Marfurt Jutta 
Published: July 2015

ABSTRACT

Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance
ex vivo
. Between March to October 2011 and January to September 2013, two “reversed chloroquine” (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of
Plasmodium falciparum
(
n
= 41) and
Plasmodium vivax
(
n
= 45) in Papua, Indonesia, using a modified
ex vivo
schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant
P. falciparum
and
P. vivax
field isolates. For
P. falciparum
, the median 50% inhibitory concentrations (IC
50
s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (
P
< 0.001 and
P
= 0.036, respectively). The corresponding values for
P. vivax
were 19.0, 60.0, and 60.9 nM (
P
< 0.001 and
P
= 0.018, respectively). There was a significant correlation between IC
50
s of CQ and PL69 (Spearman's rank correlation coefficient [
r
s
] = 0.727,
P
< 0.001) and PL106 (

r
s

= 0.830,
P
< 0.001) in
P. vivax
but not in
P. falciparum
. Both RCQs were equally active against the ring and trophozoite stages of
P. falciparum
, but in
P. vivax
, PL69 and PL106 showed less potent activity against trophozoite stages (median IC
50
s, 130.2 and 172.5 nM) compared to ring stages (median IC
50
s, 17.6 and 91.3 nM). RCQ compounds have enhanced
ex vivo
activity against CQ-resistant clinical isolates of
P. falciparum
and
P. vivax
, suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two
Plasmodium
species.
In Vitro
Virology Profile of Tenofovir Alafenamide, a Novel Oral Prodrug of Tenofovir with Improved Antiviral Activity Compared to That of Tenofovir Disoproxil Fumarate
Authors: Callebaut Christian , Stepan George , Tian Yang , Miller Michael D. 
Published: July 2015

ABSTRACT

Tenofovir alafenamide (TAF) is an investigational oral prodrug of the HIV-1 nucleotide reverse transcriptase inhibitor tenofovir (TFV). Tenofovir disoproxil fumarate (TDF) is another TFV prodrug, widely used for the treatment of HIV-1 infection. TAF is converted mostly intracellularly to TFV and, in comparison to TDF, achieves higher tenofovir diphosphate (TFV-DP) levels in peripheral blood mononuclear cells. As a result, TAF has demonstrated potent anti-HIV-1 activity at lower doses than TDF in monotherapy studies. Here, the
in vitro
virology profile of TAF was evaluated and compared to that of TDF. TAF displayed potent antiviral activity against all HIV-1 groups/subtypes, as well as HIV-2. TAF exhibited minimal changes in the drug concentration needed to inhibit 50% of viral spread (EC
50
) upon removal of the prodrug, similar to TDF, demonstrating intracellular antiviral persistence. While TAF and TDF exhibited comparable potencies in the absence of serum pretreatment, TAF maintained activity in the presence of human serum, whereas TDF activity was significantly reduced. This result demonstrates TAF's improved plasma stability over TDF, which is driven by the different metabolic pathways of the two prodrugs and is key to TAF's improved
in vivo
antiviral activity. The activity of TAF is specific for HIV, as TAF lacked activity against a large panel of human viruses, with the exception of herpes simplex virus 2, where weak TAF antiviral activity was observed, as previously observed with TFV. Finally,
in vitro
combination studies with antiretroviral drugs from different classes showed additive to synergistic interactions with TAF, consistent with ongoing clinical studies with TAF in fixed-dose combinations with multiple other antiretroviral drugs for the treatment of HIV.
AAC(3)-XI, a New Aminoglycoside 3-
N
-Acetyltransferase from Corynebacterium striatum
Authors: Galimand Marc , Fishovitz Jennifer , Lambert Thierry , Barbe Valérie , Zajicek Jaroslav , Mobashery Shahriar , Courvalin Patrice 
Published: July 2015

ABSTRACT

Corynebacterium striatum
BM4687 was resistant to gentamicin and tobramycin but susceptible to kanamycin A and amikacin, a phenotype distinct among Gram-positive bacteria. Analysis of the entire genome of this strain did not detect any genes for known aminoglycoside resistance enzymes. Yet, annotation of the coding sequences identified 12 putative acetyltransferases or GCN5-related
N
-acetyltransferases. A total of 11 of these coding sequences were also present in the genomes of other
Corynebacterium
spp. The 12th coding sequence had 55 to 60% amino acid identity with acetyltransferases in
Actinomycetales
. The gene was cloned in
Escherichia coli
, where it conferred resistance to aminoglycosides by acetylation. The protein was purified to homogeneity, and its steady-state kinetic parameters were determined for dibekacin and kanamycin B. The product of the turnover of dibekacin was purified, and its structure was elucidated by high-field nuclear magnetic resonance (NMR), indicating transfer of the acetyl group to the amine at the C-3 position. Due to the unique profile of the reaction, it was designated aminoglycoside 3-
N
-acetyltransferase type XI.
Breeding Strategy To Generate Robust Yeast Starter Cultures for Cocoa Pulp Fermentations
Authors: Meersman Esther , Steensels Jan , Paulus Tinneke , Struyf Nore , Saels Veerle , Mathawan Melissa , Koffi Jean , Vrancken Gino , Verstrepen Kevin J. 
Published: July 2015

ABSTRACT

Cocoa pulp fermentation is a spontaneous process during which the natural microbiota present at cocoa farms is allowed to ferment the pulp surrounding cocoa beans. Because such spontaneous fermentations are inconsistent and contribute to product variability, there is growing interest in a microbial starter culture that could be used to inoculate cocoa pulp fermentations. Previous studies have revealed that many different fungi are recovered from different batches of spontaneous cocoa pulp fermentations, whereas the variation in the prokaryotic microbiome is much more limited. In this study, therefore, we aimed to develop a suitable yeast starter culture that is able to outcompete wild contaminants and consistently produce high-quality chocolate. Starting from specifically selected
Saccharomyces cerevisiae
strains, we developed robust hybrids with characteristics that allow them to efficiently ferment cocoa pulp, including improved temperature tolerance and fermentation capacity. We conducted several laboratory and field trials to show that these new hybrids often outperform their parental strains and are able to dominate spontaneous pilot scale fermentations, which results in much more consistent microbial profiles. Moreover, analysis of the resulting chocolate showed that some of the cocoa batches that were fermented with specific starter cultures yielded superior chocolate. Taken together, these results describe the development of robust yeast starter cultures for cocoa pulp fermentations that can contribute to improving the consistency and quality of commercial chocolate production.