bluuebunny/crossref_metadata_2025 huggingface dataset:
Low solubility in drug development: de-convoluting the relative importance of solvation and crystal packing
Authors: Docherty Robert , Pencheva Klimentina , Abramov Yuriy A
Published: April 2015

Objectives

An increasing trend towards low solubility is a major issue for drug development as formulation of low solubility compounds can be problematic. This paper presents a model which de-convolutes the solubility of pharmaceutical compounds into solvation and packing properties with the intention to understand the solubility limiting features.

Methods

The Cambridge Crystallographic Database was the source of structural information. Lattice energies were calculated via force-field based approaches using Materials Studio. The solvation energies were calculated applying quantum chemistry models using Cosmotherm software.

Key findings

The solubilities of 54 drug-like compounds were mapped onto a solvation energy/crystal packing grid. Four quadrants were identified were different balances of solvation and packing were defining the solubility. A version of the model was developed which allows for the calculation of the two features even in absence of crystal structure.

Conclusion

Although there are significant number of in-silico models, it has been proven very difficult to predict aqueous solubility accurately. Therefore, we have taken a different approach where the solubility is not predicted directly but is de-convoluted into two constituent features.
Preliminary study: fibre content in pet rabbit diets, crude fibre versus total dietary fibre
Authors: Molina J. , Martorell J. , Hervera M. , Pérez‐Accino J. , Fragua V. , Villaverde C.
Published: April 2015

Fibre is an important nutrient for rabbit health, and, on commercial pet rabbit packaging, it is labelled as crude fibre (CF). In several species, it is considered that CF is not an accurate representation of the fibre content in feedstuffs. The objective of this study was to compare the CF stated on the label (CFL) with laboratory analysis of CF (CFA) and the analysed content of total dietary fibre (TDF) in different commercial pet rabbit feeds. We selected 15 commercial diets and analysed CF and TDF. A mixed model was used to evaluate differences between CFL, CFA and TDF, and linear regression was performed to study the correlation between CFL and CFA with TDF. CFA and CFL were not significantly different (p = 0.836) in the feeds studied, and both were lower than TDF (p < 0.001). The correlations between TDF and both CFA and CFL were significant (p < 0.001 and p = 0.02, respectively), but the correlation was better with CFA (R = 0.86) than with CFL (R = 0.53). As expected, TDF content was higher than CF content, an average of two times. These results suggest that the CF content in rabbit diets reported on the label is not an appropriate indicator of their total fibre content, although further work with a larger sample size is required to confirm these results.
Evaluation of an extended‐release formulation of ceftiofur crystalline‐free acid in koi (Cyprinus carpio)
Authors: Grosset C. , Weber E. S. , Gehring R. , Sanchez‐Migallon Guzman D. , Campbell L. A. , Enz C. , Groff J. M. , Tell L. A.
Published: April 2015

The use of an extended release ceftiofur crystalline‐free acid formulation (CCFA, Excede For Swine®, Pfizer Animal Health) in koi was evaluated after administration of single intramuscular (i.m.) or intracoelomic (i.c.) doses. Twenty koi were divided randomly into a control group and four treatment groups (20 mg/kg i.m., 60 mg/kg i.m., 30 mg/kg i.c., and 60 mg/kg i.c.). Serum ceftiofur‐free acid equivalents (CFAE) concentrations were quantified. The pharmacokinetic data were analyzed using a nonlinear mixed‐effects approach. Following a CCFA injection of 60 mg/kg i.m., time durations that serum CFAE concentrations were above the target concentration of 4 μg/mL ranged from 0.4 to 2.5 weeks in 3 of 4 fish, while serum CFAE concentrations remained below 4 μg/mL for lower doses evaluated. Substantial inter‐individual variations and intra‐individual fluctuations of CFAE concentrations were observed for all treatment groups. Histological findings following euthanasia included aseptic granulomatous reactions, but no systemic adverse effects were detected. Given the unpredictable time vs. CFAE concentration profiles for treated koi, the authors would not recommend this product for therapeutic use in koi at this time. Further research would be necessary to correlate serum and tissue concentrations and to better establish MIC data for Aeromonas spp. isolated from naturally infected koi.
Mechanism of cell death in acute‐on‐chronic liver failure: a clinico‐pathologic‐biomarker study
Authors: Adebayo Danielle , Morabito Vincenzo , Andreola Fausto , Pieri Giulia , Luong Tu‐Vin , Dhillon Amar , Mookerjee Rajeshwar , Jalan Rajiv
Published: April 2015

Background & Aims

Mortality of patients who develop acute‐on‐chronic liver failure (ACLF) is unacceptably high but the predominant mode of cell death is unknown. The aim of this study was to evaluate whether plasma levels of caspase‐cleaved cytokeratin M30 (marker of apoptosis) and uncleaved cytokeratin M65 (marker of total cell death) are altered in ACLF patients and relate this to liver histology.

Methods

Twenty‐seven patients with acute decompensation of liver disease were divided into two groups: no‐ACLF (n = 11) or ACLF (n−16). Healthy controls (n = 8) and acute liver failure (ALF) patients (n = 10) were also enrolled. Cell death was assessed in plasma using an ELISA kit (M30 and M65). Simultaneous biopsy samples were analysed for M30 and caspase‐3 staining.

Results

Plasma M30 value was significantly elevated in ACLF patients compared with healthy volunteers (P = 0.0001), it was also significantly higher in ACLF patients compared with no‐ACLF patients (P = 0.002). M65 levels were higher in ALF compared with ACLF patients (P = 0.002) but the apoptotic index defined by M30/M65 ratio was significantly higher in ACLF patients. Patients with extra‐hepatic failure had higher M30 levels compared with patients without organ failure (P = 0.03). M30 staining in liver was more marked in the patients with ACLF and was observed in all the patients that died.

Conclusions

The results of this study suggest that hepatocyte apoptosis is the predominant mode of cell death in ACLF, which can be identified in the peripheral blood. Further studies are required to validate our findings and to determine whether M30 can be used as a biomarker of apoptosis or as a target for therapy.
Application of Tissue Engineering to Pelvic Organ Prolapse and Stress Urinary Incontinence
Authors: CHAPPLE Christopher R. , OSMAN Nadir I. , MANGERA Altaf , HILLARY Christopher , ROMAN Sabiniano , BULLOCK Anthony , MACNEIL Sheila
Published: April 2015

Synthetic or biological materials can be used for the surgical repair of pelvic organ prolapse (POP) or stress urinary incontinence (SUI). While non‐degradable synthetic mesh has a low failure rate, it is prone to complications such as infection and erosion, particularly in the urological/gynecological setting when subject to chronic influences of gravity and intermittent, repetitive strain. Biological materials have lower complication rates, although allografts and xenografts have a high risk of failure and the theoretical risk of infection. Autografts are used successfully for the treatment of SUI and are not associated with erosion; however, can lead to morbidity at the donor site. Tissue engineering has thus become the focus of interest in recent years as researchers seek an ideal tissue remodeling material for urogynecological repair. Herein, we review the directions of current and future research in this exciting field. Electrospun poly‐L‐lactic acid (PLA) and porcine small intestine submucosa (SIS) are two promising scaffold material candidates. Adipose‐derived stem cells (ADSCs) appear to be a suitable cell type for scaffold seeding, and cells grown on scaffolds when subjected to repetitive biaxial strain show more appropriate biomechanical properties for clinical implantation. After implantation, an appropriate level of acute inflammation is important to precipitate moderate fibrosis and encourage tissue strength. New research directions include the use of bioactive materials containing compounds that may help facilitate integration of the new tissue. More research with longer follow‐up is needed to ascertain the most successful and safe methods and materials for pelvic organ repair and SUI treatment.
Integrating phylogeography and paleoecology to investigate the origin and dynamics of hybrid zones: insights from two widespreadNorthAmerican firs
Authors: Cinget Benjamin , de Lafontaine Guillaume , Gérardi Sébastien , Bousquet Jean
Published: April 2015

Secondary contact between closely related taxa routinely occurs during postglacial migrations. After initial contact, the location of hybrid zones may shift geographically or remain spatially stable over time in response to various selective pressures or neutral processes. Studying the extent and direction of introgression using markers having contrasted levels of gene flow can help unravel the historical dynamics of hybrid zones. Thanks to their contrasted maternal and paternal inheritance, resulting in different levels of gene flow for mitochondrial and chloroplastDNA(mtDNAand cpDNA), the Pinaceae stand out as a relevant biological model for this purpose. The objective of the study was to assess whether the hybrid zone betweenAbies balsameaandAbies lasiocarpa(two largely distributed Pinaceae) has moved or remained stable over time by analysing the distribution of cytoplasmicDNAvariation as well as published palaeobotanical data. Interspecific gene flow was higher for cpDNAthan mtDNAmarkers; hence, the geographic distribution of mitotypes was more congruent with species distributions than chlorotypes. This genetic signature was contrary to expectations under a moving hybrid zone scenario, as well as empirical observations in other conifers. Genetic evidence for this rare instance of stable hybrid zone was corroborated by the colonization chronology derived from published fossil data, indicating that the two fir species initially came into contact in the area corresponding to the current sympatric zone 11 kyr ago. While an explanatory analysis suggested the putative influence of various environmental factors on the relative abundance of cytoplasmic genome combinations, further research appears necessary to assess the role of both demographic history and selective factors in driving the dynamics of hybrid zones.
The evolution of novel host use is unlikely to be constrained by trade‐offs or a lack of genetic variation
Authors: Gompert Zachariah , Jahner Joshua P. , Scholl Cynthia F. , Wilson Joseph S. , Lucas Lauren K. , Soria‐Carrasco Victor , Fordyce James A. , Nice Chris C. , Buerkle C. Alex , Forister Matthew L.
Published: April 2015

The genetic and ecological factors that shape the evolution of animal diets remain poorly understood. For herbivorous insects, the expectation has been that trade‐offs exist, such that adaptation to one host plant reduces performance on other potential hosts. We investigated the genetic architecture of alternative host use by rearing individual Lycaeides melissa butterflies from two wild populations in a crossed design on two hosts (one native and one introduced) and analysing the genetic basis of differences in performance using genomic approaches. Survival during the experiment was highest when butterfly larvae were reared on their natal host plant, consistent with local adaptation. However, cross‐host correlations in performance among families (within populations) were not different from zero. We found that L. melissa populations possess genetic variation for larval performance and variation in performance had a polygenic basis. We documented very few genetic variants with trade‐offs that would inherently constrain diet breadth by preventing the optimization of performance across hosts. Instead, most genetic variants that affected performance on one host had little to no effect on the other host. In total, these results suggest that genetic trade‐offs are not the primary cause of dietary specialization in L. melissa butterflies.
Model Updating Technique Based on Modal Participation Factors for Beam Structures
Authors: Oh Byung Kwan , Kim Min Sun , Kim Yousok , Cho Tongjun , Park Hyo Seon
Published: April 2015

This article proposes a model updating technique based on modal participation factors for a beam structure. In this model updating technique, the error functions of the dynamic characteristic differences between measurement and model are generated as the number of modes under consideration and minimized using the multiobjective optimization techniques. A modal influence factor defined by modal participation factors for each mode is presented for the selection of the best solution from among Pareto solutions. The selection rule represented in this article makes it possible to reflect the contributions of each mode on the behavior of a structure. The model is updated using natural frequencies measured in an impact hammer test of a beam structure and the validity of the updated model is confirmed by the strain responses measured from the test. It is found that the bending stiffness of the beam structure as the parameter for model updating can be identified by the proposed techniques. Furthermore, through comparing the models updated by the simple sum model updating and the technique in this research, it is verified that the proposed technique is more appropriate for the model updating.
Sensory cues of a top‐predator indirectly control a reef fish mesopredator
Authors: del Mar Palacios Maria , Warren Donald T. , McCormick Mark I.
Published: April 2015

Behavioural trophic cascades highlight the importance of indirect/risk effects in the maintenance of healthy trophic‐level links in complex ecosystems. However, there is limited understanding on how the loss of indirect top–down control can cascade through the food‐web to modify lower level predator–prey interactions. Using a reef fish food‐web, our study examines behavioural interactions among predators to assess how fear elicited by top‐predator cues (visual and chemical stimuli) can alter mesopredator behaviour and modify their interaction with resource prey. Under experimental conditions, the presence of any cue (visual, chemical, or both) from the top‐predator (coral troutPlectropomus leopardus) strongly restricted the distance swum, area explored and foraging activity of the mesopredator (dottybackPseudochromis fuscus), while indirectly triggering a behavioural release of the resource prey (recruits of the damselfishPomacentruschrysurus). Interestingly, the presence of a large non‐predator species (thicklip wrasseHemigymnus melapterus) also mediated the impact of the mesopredator on prey, as it provoked mesopredators to engage in an ‘inspection’ behaviour, while significantly reducing their feeding activity. Our study describes for the first time a three‐level behavioural cascade of coral reef fish and stresses the importance of indirect interactions in marine food‐webs.
Mineral status of premature infants in early life and linear growth at age 3
Authors: Isojima Tsuyoshi , Kushima Reiko , Goishi Keiji , Tsuchida Shinya , Watanabe Toyoko , Takahashi Naoto , Kitanaka Sachiko
Published: April 2015

Background

Preterm infants are at significant risk of reduced bone mineral content and subsequent bone disease (metabolic bone disease of prematurity, MBDP). MBDP is frequently found in very low‐birthweight (VLBW) infants, but long‐term height prognosis is not well known.

Methods

VLBW infants from two major neonatal intensive care units were studied. Medical records were reviewed. A total of 143 subjects were analyzed after excluding subjects who died, or who had severe complications that could affect linear growth, Silver–Russell syndrome, severe cholestasis, and/or chromosomal abnormality. The relationship between MBDP and height at age 3 was investigated.

Results

Height standard deviation score (SDS) at age 3 negatively correlated with peak serum alkaline phosphatase (ALP) activity in early life (r = −0.30, P = 0.0003) and positively correlated with serum phosphorus (P) at peak ALP (r = 0.33, P = 0.0002). In addition, serum P independently affected height SDS at 3 years of age (β = 0.19, P = 0.018), and was significantly different between infants with and without catch‐up growth in height (difference: 0.23 mmol/L, 95%CI: 0.09–0.36, P = 0.0010).

Conclusions

MBDP, particularly hypophosphatemia in the early period of life, is associated with linear growth until 3 years of age in VLBW infants.
Does Anti‐Hispanic Bias Motivate Opposition to Non‐English Languages?*
Authors: Shin Heeju , Leal David L. , Ellison Christopher G.
Published: April 2015

Contemporary political debates about language policy in the United States focus on three primary policy issues: bilingual education in public schools, English‐only legislation, and the access of non‐English speaking citizens to political rights. Using the “Multi‐Ethnic United States” module from the 2000 General Social Survey (GSS), this article tests multiple attitudinal, behavioral, demographic, and contextual hypotheses for how Anglos and African Americans view bilingual policy issues. We examine the role of linguistic contact, self‐interest, group threat, and discriminatory views of Latinos, finding that the latter—as measured by the “Three Ds” (Derogation, Disrespect, and Distance)—are the strongest predictors of attitudes toward bilingualism. Distance (social distance from Latinos) is consistently significant, disrespect (doubts about Latino contributions to the United States.) is mostly significant, and derogation (Latino stereotypes) is occasionally significant. Also, political ideology and knowledge of a non‐English language play important roles in the formation of favorable bilingualism opinions. However, the self‐interest and group threat variables were largely insignificant. Taken together, these findings indicate the importance of understanding how policy views may be structured by opinions about out‐group individuals and cultures. Language can serve as a proxy for immigrants themselves, as negative attitudes toward Latinos are associated with negative attitudes toward bilingualism.
A comprehensive analysis of peptides presented by HLA‐A1
Authors: Giam K. , Ayala‐Perez R. , Illing P. T. , Schittenhelm R. B. , Croft N. P. , Purcell A. W. , Dudek N. L.
Published: April 2015

Human leukocyte antigen (HLA)‐A1 is one of the most common Caucasian HLA‐A alleles. Here, we describe the comprehensive analysis of the HLA‐A*01:01 ligand repertoire with the identification of 4735 naturally processed and presented peptides derived from 2477 source proteins. We found HLA‐A*01:01 bound an equivalent number of ligands of 9 or 10 amino acids in length as well as being remarkably tolerant of even longer peptides. Indeed close to half of the HLA‐A1 bound peptides identified ranged between 11 and 13 amino acids in length. These longer peptides contained the strong canonical motif of and acidic E/D residue at position 3 (P3) and Y at the C‐terminus (CΩ), a motif that was still apparent in peptides of up to 18 amino acids in length. The identification of this large database of natural ligands will facilitate the refinement of predictive algorithms particularly with respect to longer peptide ligands.
Chronic bilateral renal denervation reduces cardiac hypertrophic remodelling but not β‐adrenergic responsiveness in hypertensive type 1 diabetic rats
Authors: Thaung H. P. Aye , Yao Yimin , Bussey Carol T. , Hughes Gillian , Jones Peter P. , Bahn Andrew , Sammut Ivan A. , Lamberts Regis R.
Published: April 2015

New Findings

What is the central question of this study?

Can bilateral renal denervation, an effective antihypertensive treatment in clinical and experimental studies, improve cardiac β‐adrenoceptor responsiveness in a diabetic model with underlying hypertension?

What is the main finding and its importance?

Bilateral renal denervation did not affect β‐adrenergic responsiveness in the diabetic hypertensive rat heart, but denervation reduced the hypertension‐induced concentric hypertrophic remodelling. This suggests that the positive haemodynamic changes induced by renal denervation are most likely to reflect an attenuation of sympathetic effects on the systemic vasculature and/or the renal function rather than direct sympathetic modulation of the heart.

Bilateral renal denervation (BRD) has been shown to normalise blood pressure in clinical and experimental studies of hypertension by reducing systemic sympathetic output. This study determined the effect of BRD on cardiac β‐adrenoceptor (AR) responsiveness in a diabetic model with underlying hypertension using the transgenic (mRen‐2)27 rats. Bilateral renal denervation or sham surgeries were conducted repeatedly at 3, 6 and 9 weeks in Ren‐2 rats with or without streptozotocin (STZ)‐induced diabetes (4 × n = 7); Sprague–Dawley rats (n = 6) served as control animals. Cardiac function was determined in isolated hearts at 18 weeks of age. Normalised left ventricular developed pressure and relaxation was recorded in response to incremental concentrations of the β‐AR agonist isoprenaline (from 10−10 to 10−7 m) or the β3‐AR agonist BRL37344 (from 10−13 to 10−6 m). Expression levels of β1‐AR were determined by Western blot. Both inotropic and lusitropic β‐AR responsiveness was reduced in the hypertensive diabetic hearts, but these responses were unaltered after BRD. Expression levels of β1‐AR were increased after BRD (Sham, 0.85 ± 0.11 versus 1.01 ± 0.05 a.u.; BRD, 1.45 ± 0.11 versus 1.46 ± 0.07 a.u.; Ren‐2 versus Ren‐2 STZ, P < 0.05 versus Sham). No effect of β3‐AR agonist stimulation with BRL37344 was observed. Interestingly, BRD increased left ventricular diastolic volume in both the Ren‐2 and the Ren‐2 STZ groups. Bilateral renal denervation did not restore the attenuated cardiac β‐AR responsiveness in the diabetic hypertensive rats, but it reduced the extent of hypertension‐induced concentric hypertrophic remodelling. Thus, the haemodynamic protection offered by renal denervation appears to reflect an attenuated sympathetic innervation of the systemic vasculature and/or kidney rather than a direct cardiac effect.
Temperature Ratio Effects on Bluff-Body Wake Dynamics Using Large Eddy Simulation and Proper Orthogonal Decomposition
Authors: Blanchard Ryan , Ng Wing , Vandsburger Uri
Published: April 2015

In this article, we describe the use of proper orthogonal decomposition (POD) to investigate how the dominant wake structures of a bluff-body-stabilized turbulent premixed flame are affected by the heat released by the flame itself. The investigation uses a validated large eddy simulation (LES) to simulate the dynamics of the bluff-body's wake (Blanchard et al., 2014, “Simulating Bluff-Body Flameholders: On the Use of Proper Orthogonal Decomposition for Wake Dynamics Validation,” ASME J. Eng. Gas Turbines Power, 136(12), p. 122603; Blanchard et al., 2014, “Simulating Bluff-Body Flameholders: On the Use of Proper Orthogonal Decomposition for Combustion Dynamics Validation,” ASME J. Eng. Gas Turbines Power, 136(12), p. 121504). The numerical simulations allow the effect of heat release, shown as the ratio of the burned to unburned temperatures, to be varied independently from the Damköhler number. Five simulations are reported with varying fractions of the heat release ranging from 0% to 100% of the value of the baseline experiment. The results indicate similar trends reported qualitatively by others, but by using POD to isolate the dominant heat release modes of each simulation, the decomposed data can clearly show how the previously reported flow structures transition from asymmetric shedding in the case of zero heat-release to a much weaker, but fully symmetric shedding mode in the case of full heat release with a much more elongated and stable wake.
Optimization of leaf margins for lung stereotactic body radiotherapy using a flattening filter‐free beam
Authors: Wakai Nobuhide , Sumida Iori , Otani Yuki , Suzuki Osamu , Seo Yuji , Isohashi Fumiaki , Yoshioka Yasuo , Hasegawa Masatoshi , Ogawa Kazuhiko
Published: April 2015

Purpose:

The authors sought to determine the optimal collimator leaf margins which minimize normal tissue dose while achieving high conformity and to evaluate differences between the use of a flattening filter‐free (FFF) beam and a flattening‐filtered (FF) beam.

Methods:

Sixteen lung cancer patients scheduled for stereotactic body radiotherapy underwent treatment planning for a 7 MV FFF and a 6 MV FF beams to the planning target volume (PTV) with a range of leaf margins (−3 to 3 mm). Forty grays per four fractions were prescribed as a PTV D95. For PTV, the heterogeneity index (HI), conformity index, modified gradient index (GI), defined as the 50% isodose volume divided by target volume, maximum dose (Dmax), and mean dose (Dmean) were calculated. Mean lung dose (MLD), V20 Gy, and V5 Gy for the lung (defined as the volumes of lung receiving at least 20 and 5 Gy), mean heart dose, and Dmax to the spinal cord were measured as doses to organs at risk (OARs). Paired t‐tests were used for statistical analysis.

Results:

HI was inversely related to changes in leaf margin. Conformity index and modified GI initially decreased as leaf margin width increased. After reaching a minimum, the two values then increased as leaf margin increased (“V” shape). The optimal leaf margins for conformity index and modified GI were −1.1 ± 0.3 mm (mean ± 1 SD) and −0.2 ± 0.9 mm, respectively, for 7 MV FFF compared to −1.0 ± 0.4 and −0.3 ± 0.9 mm, respectively, for 6 MV FF. Dmax and Dmean for 7 MV FFF were higher than those for 6 MV FF by 3.6% and 1.7%, respectively. There was a positive correlation between the ratios of HI, Dmax, and Dmean for 7 MV FFF to those for 6 MV FF and PTV size (R = 0.767, 0.809, and 0.643, respectively). The differences in MLD, V20 Gy, and V5 Gy for lung between FFF and FF beams were negligible. The optimal leaf margins for MLD, V20 Gy, and V5 Gy for lung were −0.9 ± 0.6, −1.1 ± 0.8, and −2.1 ± 1.2 mm, respectively, for 7 MV FFF compared to −0.9 ± 0.6, −1.1 ± 0.8, and −2.2 ± 1.3 mm, respectively, for 6 MV FF. With the heart inside the radiation field, the mean heart dose showed a V‐shaped relationship with leaf margins. The optimal leaf margins were −1.0 ± 0.6 mm for both beams. Dmax to the spinal cord showed no clear trend for changes in leaf margin.

Conclusions:

The differences in doses to OARs between FFF and FF beams were negligible. Conformity index, modified GI, MLD, lung V20 Gy, lung V5 Gy, and mean heart dose showed a V‐shaped relationship with leaf margins. There were no significant differences in optimal leaf margins to minimize these parameters between both FFF and FF beams. The authors’ results suggest that a leaf margin of −1 mm achieves high conformity and minimizes doses to OARs for both FFF and FF beams.
Direct observation of structure-function relationship in a nucleic acid–processing enzyme
Authors: Comstock Matthew J. , Whitley Kevin D. , Jia Haifeng , Sokoloski Joshua , Lohman Timothy M. , Ha Taekjip , Chemla Yann R.
Published: April 2015

Engineering superenzyme function

Understanding how protein domains and subunits operate is critical for engineering novel functions into proteins. Arslan
et al.
introduced intramolecular crosslinks between two domains of the
Escherichia coli
helicase Rep, which unwinds DNA. By inserting linkers of different lengths, the domains can be held either “open” or “closed.” The closed conformation activates the helicase, but it can also generate super-helicases capable of unzipping long stretches of DNA at high speed and with considerable force. Comstock
et al.
used optical tweezers and fluorescence microscopy to simultaneously measure the structure and function of the bacterial helicase UvrD. They monitored its DNA winding and unwinding activity and its shape during these activities. The motor domain also has a “closed” conformation during DNA unwinding and switches to a reversed “open” conformation during the zipping-up interaction.

Science
, this issue p.
344
and p.
352
Engineering of a superhelicase through conformational control
Authors: Arslan Sinan , Khafizov Rustem , Thomas Christopher D. , Chemla Yann R. , Ha Taekjip
Published: April 2015

Engineering superenzyme function

Understanding how protein domains and subunits operate is critical for engineering novel functions into proteins. Arslan
et al.
introduced intramolecular crosslinks between two domains of the
Escherichia coli
helicase Rep, which unwinds DNA. By inserting linkers of different lengths, the domains can be held either “open” or “closed.” The closed conformation activates the helicase, but it can also generate super-helicases capable of unzipping long stretches of DNA at high speed and with considerable force. Comstock
et al.
used optical tweezers and fluorescence microscopy to simultaneously measure the structure and function of the bacterial helicase UvrD. They monitored its DNA winding and unwinding activity and its shape during these activities. The motor domain also has a “closed” conformation during DNA unwinding and switches to a reversed “open” conformation during the zipping-up interaction.

Science
, this issue p.
344
and p.
352
A strong magnetic field in the jet base of a supermassive black hole
Authors: Martí-Vidal Ivan , Muller Sébastien , Vlemmings Wouter , Horellou Cathy , Aalto Susanne
Published: April 2015

The polarized mark of magnetic fields

Powerful twin jets of plasma often reach more than tens of thousands of light-years from their base in an active galactic nucleus (AGN). Astronomers are still at work investigating what can corral the jets so tightly and propel them so far. Martí-Vidal
et al.
may have found the answer hiding in polarized light signals that show evidence of a phenomenon called Faraday rotation. This measure can indicate the strength of the magnetic field present, which for the AGN PKS 1830-211 is as strong as a few Gauss. The knowledge that magnetic fields have a driving role brings us closer to understanding this phenomenon.

Science
, this issue p.
311
Improve customs systems to monitor global wildlife trade
Authors: Chan Hon-Ki , Zhang Huarong , Yang Feng , Fischer Gunter
Published: April 2015

Widely used trade codes lack taxonomic granularity
Whole-Genome Sequencing in Outbreak Analysis
Authors: Gilchrist Carol A. , Turner Stephen D. , Riley Margaret F. , Petri William A. , Hewlett Erik L.
Published: April 2015

In addition to the ever-present concern of medical professionals about epidemics of infectious diseases, the relative ease of access and low cost of obtaining, producing, and disseminating pathogenic organisms or biological toxins mean that bioterrorism activity should also be considered when facing a disease outbreak. Utilization of whole-genome sequencing (WGS) in outbreak analysis facilitates the rapid and accurate identification of virulence factors of the pathogen and can be used to identify the path of disease transmission within a population and provide information on the probable source. Molecular tools such as WGS are being refined and advanced at a rapid pace to provide robust and higher-resolution methods for identifying, comparing, and classifying pathogenic organisms. If these methods of pathogen characterization are properly applied, they will enable an improved public health response whether a disease outbreak was initiated by natural events or by accidental or deliberate human activity. The current application of next-generation sequencing (NGS) technology to microbial WGS and microbial forensics is reviewed.
Implementation of Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry in Routine Clinical Laboratories Improves Identification of Coagulase-Negative Staphylococci and Reveals the Pathogenic Role of Staphylococcus lugdunensis
Authors: Argemi Xavier , Riegel Philippe , Lavigne Thierry , Lefebvre Nicolas , Grandpré Nicolas , Hansmann Yves , Jaulhac Benoit , Prévost Gilles , Schramm Frédéric
Published: April 2015

The use of matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) for staphylococcal identification is now considered routine in laboratories compared with the conventional phenotypical methods previously used. We verified its microbiological relevance for identifying the main species of coagulase-negative staphylococci (CoNS) by randomly selecting 50 isolates. From 1 January 2007 to 31 August 2008, 12,479 staphylococci were isolated with phenotypic methods, of which 4,594 were identified as
Staphylococcus aureus
and 7,885 were coagulase negative staphylococci. Using MALDI-TOF MS from 1 January 2011 to 31 August 2012, 14,913 staphylococci were identified, with 5,066 as
S. aureus
and 9,847 as CoNS. MALDI-TOF MS allowed the identification of approximately 85% of the CoNS strains, whereas only 14% of the CoNS strains were identified to the species level with phenotypic methods because they were often considered contaminants. Furthermore, the use of MALDI-TOF MS revealed the occurrence of recently characterized
Staphylococcus
species, such as
S. pettenkoferi
,
S. condimenti
, and
S. piscifermentans
. Microbiological relevance analysis further revealed that some species displayed a high rate of microbiological significance, i.e., 40% of the
S. lugdunensis
strains included in the analysis were associated with infection risk. This retrospective microbiological study confirms the role of MALDI-TOF MS in clinical settings for the identification of staphylococci with clinical consequences. The species distribution reveals the occurrence of the recently identified species
S. pettenkoferi
and putative virulent species, including
S. lugdunensis
.
Development and Validation of a Laboratory-Developed Multiplex Real-Time PCR Assay on the BD Max System for Detection of Herpes Simplex Virus and Varicella-Zoster Virus DNA in Various Clinical Specimens
Authors: Pillet Sylvie , Verhoeven Paul O. , Epercieux Amélie , Bourlet Thomas , Pozzetto Bruno
Published: April 2015

A multiplex real-time PCR (quantitative PCR [qPCR]) assay detecting herpes simplex virus (HSV) and varicella-zoster virus (VZV) DNA together with an internal control was developed on the BD Max platform combining automated DNA extraction and an open amplification procedure. Its performance was compared to those of PCR assays routinely used in the laboratory, namely, a laboratory-developed test for HSV DNA on the LightCycler instrument and a test using a commercial master mix for VZV DNA on the ABI7500fast system. Using a pool of negative cerebrospinal fluid (CSF) samples spiked with either calibrated controls for HSV-1 and VZV or dilutions of a clinical strain that was previously quantified for HSV-2, the empirical limit of detection of the BD Max assay was 195.65, 91.80, and 414.07 copies/ml for HSV-1, HSV-2, and VZV, respectively. All the samples from HSV and VZV DNA quality control panels (Quality Control for Molecular Diagnostics [QCMD], 2013, Glasgow, United Kingdom) were correctly identified by the BD Max assay. From 180 clinical specimens of various origins, 2 CSF samples were found invalid by the BD Max assay due to the absence of detection of the internal control; a concordance of 100% was observed between the BD Max assay and the corresponding routine tests. The BD Max assay detected the PCR signal 3 to 4 cycles earlier than did the routine methods. With results available within 2 h on a wide range of specimens, this sensitive and fully automated PCR assay exhibited the qualities required for detecting simultaneously HSV and VZV DNA on a routine basis.
Electronic-cigarette use among young people in Wales: evidence from two cross-sectional surveys
Authors: Moore Graham , Hewitt Gillian , Evans John , Littlecott Hannah J , Holliday Jo , Ahmed Nilufar , Moore Laurence , Murphy Simon , Fletcher Adam
Published: April 2015

Objectives

To examine the prevalence of electronic(e)-cigarette use, prevalence of e-cigarette and tobacco use by age, and associations of e-cigarette use with sociodemographic characteristics, tobacco and cannabis use among young people in Wales.

Design

Data from two nationally-representative cross-sectional surveys undertaken in 2013–2014. Logistic regression analyses, adjusting for school-level clustering, examined sociodemographic characteristics of e-cigarette use, and associations between e-cigarette use and smoking.

Setting

Primary and secondary schools in Wales.

Participants

Primary-school children aged 10–11 (n=1601) and secondary-school students aged 11–16 (n=9055).

Results

Primary-school children were more likely to have used e-cigarettes (5.8%) than tobacco (1.6%). Ever use of e-cigarettes remained more prevalent than ever use of tobacco until age 14–15. Overall, 12.3% of secondary-school students (aged 11–16) reported ever using e-cigarettes, with no differences according to gender, ethnicity or family affluence. The percentage of ‘never smokers’ reporting having used e-cigarettes was 5.3% at age 10–11 to 8.0% at age 15–16. The proportion of children who had ever used an e-cigarette and reported currently smoking increased from 6.9% among 10–11 year olds to 39.2% in 15–16 year olds. Only 1.5% (n=125) of 11–16 year-olds, including 0.3% of never smokers, reported regular e-cigarette use (use at least once a month). Current weekly smokers were 100 times more likely than non-smokers to report regular e-cigarette use (relative risk ratio (RRR=121.15; 95% CI 57.56 to 254.97). Regular e-cigarette use was also more likely among those who had smoked cannabis (RRR 53.03; 95% CI 38.87 to 80.65).

Conclusions

Many young people (including never-smokers) have tried e-cigarettes. However, regular use is less common, and is associated with tobacco cigarette use. Longitudinal research is needed to understand age-related trajectories of e-cigarette use and to understand the temporal nature of relationships between e-cigarette and tobacco use.
Introducing consultant outpatient clinics to community settings to improve access to paediatrics: an observational impact study
Authors: McLeod Hugh , Heath Gemma , Cameron Elaine , Debelle Geoff , Cummins Carole
Published: April 2015

Objectives

In line with a national policy to move care ‘closer to home’, a specialist children's hospital in the National Health Service in England introduced consultant-led ‘satellite’ clinics to two community settings for general paediatric outpatient services. Objectives were to reduce non-attendance at appointments by providing care in more accessible locations and to create new physical clinic capacity. This study evaluated these satellite clinics to inform further development and identify lessons for stakeholders.

Methods

Impact of the satellite clinics was assessed by comparing community versus hospital-based clinics across the following measures: (1) non-attendance rates and associated factors (including patient characteristics and travel distance) using a logistic regression model; (2) percentage of appointments booked within local catchment area; (3) contribution to total clinic capacity; (4) time allocated to clinics and appointments; and (5) clinic efficiency, defined as the ratio of income to staff-related costs.

Results

Satellite clinics did not increase attendance beyond their contribution to shorter travel distance, which was associated with higher attendance. Children living in the most-deprived areas were 1.8 times more likely to miss appointments compared with those from least-deprived areas. The satellite clinics’ contribution to activity in catchment areas and to total capacity was small. However, one of the two satellite clinics was efficient compared with most hospital-based clinics.

Conclusions

Outpatient clinics were relocated in pragmatically chosen community settings using a ‘drag and drop’ service model. Such clinics have potential to improve access to specialist paediatric healthcare, but do not provide a panacea. Work is required to improve attendance as part of wider efforts to support vulnerable families. Satellite clinics highlight how improved management could contribute to better use of existing capacity.
Flow diversion treatment of complex bifurcation aneurysms beyond the circle of Willis: a single-center series with special emphasis on covered cortical branches and perforating arteries
Authors: Gawlitza Matthias , Januel Anne-Christine , Tall Philippe , Bonneville Fabrice , Cognard Christophe
Published: April 2015

Background

Data regarding anatomic and clinical results of flow diversion treatment in complex bifurcation aneurysms of the anterior circulation are scarce.

Objective

To present our results of treatment of these lesions with special emphasis on the fate of ‘jailed’ cortical branches and perforating arteries.

Methods

Seventeen patients were treated with flow diverters (FDs) for 18 aneurysms of the middle cerebral artery bifurcation (n=13) and the anterior communicating artery complex (n=5). Nineteen cortical branches were covered. A single FD was used in all patients.

Results

At latest follow-up (mean 7.9 months; range 3–36; median 4.0) 2/19 (10.5%) of the covered branches were occluded, 9/19 (47.4%) showed a decreased caliber and the remaining branches were unchanged. All branch modifications were clinically asymptomatic. Mortality and permanent morbidity were 0%. Symptomatic ischemic events in perforator territories occurred in three patients (17.6%), which were reversible in all of them within 24 h. Follow-up MRI disclosed asymptomatic lacunar defects corresponding to covered perforating artery territories in five patients (29.4%). Altogether, perforator lesions—symptomatic and asymptomatic—occurred in 7/17 patients (41.2%). 33.3% of the aneurysms were occluded at latest follow-up; decreased diameters were seen in the other 66.7%.

Conclusions

Flow diversion of bifurcation aneurysms is feasible with low rates of permanent morbidity and mortality. Caliber reduction and asymptomatic occlusion of covered cortical branches seems to be common, yet ischemic complications are rather linked to perforator occlusions. Our results on aneurysm occlusion rates are preliminary and longer follow-up periods are warranted.
The influence of system delay on 30-day and on long-term mortality in patients with anterior versus non-anterior ST-segment elevation myocardial infarction: a cohort study
Authors: Postma Sonja , Dambrink Jan-Henk E , Gosselink A T Marcel , Ottervanger Jan Paul , Kolkman Evelien , ten Berg Jurrien M , Suryapranata Harry , van ‘t Hof Arnoud W J
Published: April 2015

Aim

To evaluate the relationship between system delay and 30-day and long-term mortality in patients with anterior versus non-anterior ST-elevation myocardial infarction (STEMI).

Methods

We conducted a prospective observational cohort study. Patients with STEMI who were transported to the Isala Hospital, Zwolle, and underwent primary percutaneous coronary intervention (pPCI) from 2005 until 2010 were included. These patients were divided into quartiles of system delay (time from first medical contact until reperfusion therapy): Q1–Q4.

Results

In total, 3041 patients were included in our study. 41% (n=1253) of the patients had an anterior myocardial infarction (MI) and 59% of the patients (n=1788) had a non-anterior MI. Only in patients with an anterior MI, prolonged system delay was associated with a higher mortality (30-day Q1: 2.6%, Q2: 3.1%, Q3: 6.8%, Q4: 7.4%, p=0.001; long-term Q1: 12.8%, Q2: 13.7%, Q3: 24.1%, Q4: 22.6%, p<0.001). After multivariable adjustment, prolonged system delay was associated with a higher 30-day and long-term mortality in patients with an anterior MI (30 day Q2: HR 1.18, 95% CI (0.46 to 3.00), Q3: HR 2.45, 95% CI (1.07 to 5.63), Q4: HR 2.25, 95% CI (0.97 to 5.25)); long-term Q2: HR 1.09, 95% CI (0.71 to 1.68), Q3: HR 1.68, 95% CI (1.13 to 2.49), Q4: HR 1.55, 95% CI (1.03 to 2.33)), but not in patients with a non-anterior MI.

Conclusions

Prolonged system delay significantly increased short-term as well as long-term mortality in patients with an anterior MI. This effect was not demonstrated in patients with a non-anterior MI. Therefore, it is of the greatest importance to minimise system delay in patients who present with an anterior MI.
Spherical-shell accretion onto the black hole–torus system
Authors: Donmez Orhan
Published: April 2015

The general relativistic hydrodynamical simulation of the spherical-shell accretion onto the stable torus around non-rotating and rotating black holes isotropically falling from a finite distance are constructed for the first time. This type of accretion might be used to explain the dynamics of the torus. The accreted matter sonically, supersonically or highly supersonically interacts with a torus and forms a newly developed dynamical structure. This spherical-shell changes the angular momentum of the torus and mediates torus instabilities which cause the termination of the torus. The impact of the rest-mass density of the perturbation is also studied which found that the high density perturbation destroys the torus in a few dynamical times. It is also found that the dumping time of the matter is much larger for the torus around a rotating black hole. On the other hand, the Papaloizou–Pringle instability from the spherical-shell accretion appears to be much more softer than the former perturbations which are called the Bondi–Hoyle accretion and accretion of the bulk of gas. The Papaloizou–Pringle instability is damped in a short time scale immediately after their formation.
Early T Cell Activation: Integrating Biochemical, Structural, and Biophysical Cues
Authors: Malissen Bernard , Bongrand Pierre
Published: April 2015

T cells carry out the formidable task of identifying small numbers of foreign antigenic peptides rapidly and specifically against a very noisy environmental background of endogenous self-peptides. Early steps in T cell activation have thus fascinated biologists and are among the best-studied models of cell stimulation. This remarkable process, critical in adaptive immune responses, approaches and even seems to exceed the limitations set by the physical laws ruling molecular behavior. Despite the enormous amount of information concerning the nature of molecules involved in the T cell antigen receptor (TCR) signal transduction network, and the description of the nanoscale organization and real-time analysis of T cell responses, the general principles of information gathering and processing remain incompletely understood. Here we review currently accepted key data on TCR function, discuss the limitations of current research strategies, and suggest a novel model of TCR triggering and a few promising ways of going further into the integration of available data.
Ion Channels in Innate and Adaptive Immunity
Authors: Feske Stefan , Wulff Heike , Skolnik Edward Y.
Published: April 2015

Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy.