bluuebunny/crossref_metadata_2025 huggingface dataset:
γ‐Tubulin complex in Trypanosoma brucei: molecular composition, subunit interdependence and requirement for axonemal central pair protein assembly
Authors: Zhou Qing , Li Ziyin
Published: July 2015

γ‐Tubulin complex constitutes a key component of the microtubule‐organizing center and nucleates microtubule assembly. This complex differs in complexity in different organisms: the budding yeast contains the γ‐tubulin small complex (γTuSC) composed of γ‐tubulin, gamma‐tubulin complex protein (GCP)2 and GCP3, whereas animals contain the γ‐tubulin ring complex (γTuRC) composed of γTuSC and three additional proteins, GCP4, GCP5 and GCP6. In Trypanosoma brucei, the composition of the γ‐tubulin complex remains elusive, and it is not known whether it also regulates assembly of the subpellicular microtubules and the spindle microtubules. Here we report that the γ‐tubulin complex in T. brucei is composed of γ‐tubulin and three GCP proteins, GCP2‐GCP4, and is primarily localized in the basal body throughout the cell cycle. Depletion of GCP2 and GCP3, but not GCP4, disrupted the axonemal central pair microtubules, but not the subpellicular microtubules and the spindle microtubules. Furthermore, we showed that the γTuSC is required for assembly of two central pair proteins and that γTuSC subunits are mutually required for stability. Together, these results identified an unusual γ‐tubulin complex in T. brucei, uncovered an essential role of γTuSC in central pair protein assembly, and demonstrated the interdependence of individual γTuSC components for maintaining a stable complex.
Clinical trial success rates of anti‐obesity agents: the importance of combination therapies
Authors: Hussain H. T. , Parker J. L. , Sharma A. M.
Published: July 2015

The objective of this study was to construct a clinical trial profile assessing the risk of drug failure among anti‐obesity agents. Research was conducted by looking at anti‐obesity therapies currently on the market or in clinical trials (phases I to III) conducted from 1998 to September 2014, with the exclusion of any drugs whose phase I trial was conducted prior to January 1998. This was completed primarily through a search on http://clinicaltrials.gov where a total of 51 drugs met the search criteria. The transition probabilities were then calculated based on various classifications and compared against industry standards. The transition probability of anti‐obesity agents was 8.50% whereas the transition probability of industry standards was 10.40%. Combination therapies had four times the transition probability than monotherapies, 40% and 4.75%, respectively. Therefore, it was determined that 92% of drugs fail during clinical trial testing for this indication and combination therapy appears to improve clinical trial success rates to 10‐fold.
Associations of cardiorespiratory fitness, physical activity, and adiposity with arterial stiffness in children
Authors: Veijalainen A. , Tompuri T. , Haapala E. A. , Viitasalo A. , Lintu N. , Väistö J. , Laitinen T. , Lindi V. , Lakka T. A.
Published: July 2015

Associations of cardiorespiratory fitness (CRF), physical activity (PA), sedentary behavior, and body fat percentage (BF%) with arterial stiffness and dilation capacity were investigated in 160 prepubertal children (83 girls) 6–8 years of age. We assessed CRF (watts/lean mass) by maximal cycle ergometer exercise test, total PA, structured exercise, unstructured PA, commuting to and from school, recess PA and total and screen‐based sedentary behavior by questionnaire, BF% using dual‐energy X‐ray absorptiometry, and arterial stiffness and dilation capacity using pulse contour analysis. Data were adjusted for sex and age. Poorer CRF (standardized regression coefficient β = −0.297, P < 0.001), lower unstructured PA (β = −0.162, P = 0.042), and higher BF% (β = 0.176, P = 0.044) were related to higher arterial stiffness. When CRF, unstructured PA, and BF% were in the same model, only CRF was associated with arterial stiffness (β = −0.246, P = 0.006). Poorer CRF was also related to lower arterial dilation capacity (β = 0.316, P < 0.001). Children with low CRF (< median) and high BF% (≥ median; P = 0.002), low CRF and low unstructured PA (< median; P = 0.006) or children with low unstructured PA and high BF% (P = 0.005) had higher arterial stiffness than children in the opposite halves of these variables. Poor CRF was independently associated with increased arterial stiffness and impaired arterial dilation capacity among children.
Changes from 1986 to 2006 in reasons for liking leisure‐time physical activity among adolescents
Authors: Wold B. , Littlecott H. , Tynjälä J. , Samdal O. , Moore L. , Roberts C. , Kannas L. , Villberg J. , Aarø L. E.
Published: July 2015

Reasons for participating in physical activity (PA) may have changed in accordance with the general modernization of society. The aim is to examine changes in self‐reported reasons for liking leisure‐time physical activity (LTPA) and their association with self‐reported LTPA over a 20‐year period. Data were collected among nationally representative samples of 13‐year‐olds in Finland, Norway, and Wales in 1986 and 2006 (N = 9252) as part of the WHO cross‐national Health Behaviour in School‐aged Children (HBSC) study. Univariate ANOVAs to establish differences according to gender, year, and country were conducted. In all countries, 13‐year‐olds in 2006 tended to report higher importance in terms of achievement and social reasons than their counterparts in 1986, while changes in health reasons were minor. These reasons were associated with LTPA in a similar way at both time points. Health reasons for liking LTPA were considered most important, and were the strongest predictor of LTPA. The findings seem robust as they were consistent across countries and genders. Health education constitutes the most viable strategy for promoting adolescents' motivation for PA, and interventions and educational efforts could be improved by an increased focus on LTPA and sport as a social activity.
Popularity of Indonesian Adolescents: Do the Findings from the USA Generalize to a Muslim Majority Developing Country?
Authors: French Doran C. , Niu Li , Purwono Urip
Published: July 2015

This study investigated whether the pattern of behavior associated with popularity in the USA is also found in Indonesia. Participants were 452 7th (13 years) and 10th grade (16 years) Muslim students from West Java, Indonesia. Data were obtained from adolescents, peers, and teachers. Social preference and popularity were positively associated with prosocial behavior and number of mutual friends. Whereas social preference was positively associated with academic achievement and negatively associated with aggression, popularity was positively associated with aggression and tobacco use. These patterns of association are similar to those found in the United States. Indonesian society is highly hierarchical and popularity structures may build upon these stratifications.
Are Trade Preferences more Effective than Aid in Supporting Exports? Evidence from the ‘Everything But Arms’ Preference Scheme
Authors: Gradeva Katerina , Martínez‐Zarzoso Inmaculada
Published: July 2015

This study examines the effect of the ‘Everything But Arms’ (EBA) trade preferences regime on exports from the African, Caribbean and Pacific countries (ACP) to the European Union (EU). With this aim, an augmented gravity model is estimated for exports from the 79 ACP countries to the EU‐15 for the time period of 1995—2013 using panel data techniques. The results are used to quantify the effect of the eligibility for EBA preferences on the export performance of the ACP least developed countries (LDCs) and to relate it to the impact of official development assistance on exports. In addition to their separate effects, the combined impact of EBA and aid flows is examined. The main results do not provide evidence for an additional positive effect of the EBA agreement on the export performance of the ACP LDCs. However, receiving aid shows a significant and positive effect on exports from EBA‐eligible ACP countries to the EU‐15, supporting an EU development strategy that includes both sorts of assistance, aid and trade preferences.
Assessment quality of a nonuniform suspended sediment transport model under unsteady flow condition (case study: Aras River)
Authors: Merkhali Siavash P. , Ehteshami Majid , Sadrnejad Sayed‐Amir
Published: July 2015

This study presents a one‐dimensional, fully coupled numerical model for nonequilibrium suspended sediment transport that can be applied to channels and alluvial rivers. The accuracy of calculations was enhanced using a nonuniform size distribution, and evaluating probability of hiding and exposure effect of particles. This model is also capable of calculating the flocculation and temperature effect on sediment transport. In addition, the BOD and its influence on suspended sediment transport have been discussed. The study was conducted on the Aras River, Iran's third major river with a relatively high sediment concentration. To verify the model, water depth and sediment concentration of measured field data are compared with simulated data. Comparisons show a regression coefficient of more than 95% and mean computational error is less than 5%. The agreement of the data shows that the model is capable of predicting flow and suspended sediment transport with a correlation coefficient higher than 98%.
Kcnh2 and Kcnj8 interactively regulate skin wound healing and regeneration
Authors: Zhang Wengeng , Bei Marianna
Published: July 2015

Previous studies indicate that ion channels are mediators of bioelectricity promoting wound closure/regeneration in nonmammalian, lower vertebrate systems. The role of ion channels however in regeneration of wounds in mammalian systems that do not regenerate as adults is not yet defined. Using a mammalian model system that allows us to determine differentially expressed genes when skin regenerates and when skin does not regenerate after wound induction, we identified two potassium channels, kcnh2 and kcnj8, to be (1) differentially expressed between the two states and (2) highly expressed after wound induction at the nonregenerative state. We also found that kcnh2 small molecule inhibitor enhanced wound healing while kcnj8 small molecule inhibitor did not. In contrast, kcnj8 activator accelerated wound healing and even augmented the effect of kcnh2 inhibition. These results provide evidence for the first time that potassium channels may mediate skin wound healing and regeneration interactively.
Parallel Cell Mapping Method for Global Analysis of High-Dimensional Nonlinear Dynamical Systems1
Authors: Xiong Fu-Rui , Qin Zhi-Chang , Ding Qian , Hernández Carlos , Fernandez Jesús , Schütze Oliver , Sun Jian-Qiao
Published: July 2015

The cell mapping methods were originated by Hsu in 1980s for global analysis of nonlinear dynamical systems that can have multiple steady-state responses including equilibrium states, periodic motions, and chaotic attractors. The cell mapping methods have been applied to deterministic, stochastic, and fuzzy dynamical systems. Two important extensions of the cell mapping method have been developed to improve the accuracy of the solutions obtained in the cell state space: the interpolated cell mapping (ICM) and the set-oriented method with subdivision technique. For a long time, the cell mapping methods have been applied to dynamical systems with low dimension until now. With the advent of cheap dynamic memory and massively parallel computing technologies, such as the graphical processing units (GPUs), global analysis of moderate- to high-dimensional nonlinear dynamical systems becomes feasible. This paper presents a parallel cell mapping method for global analysis of nonlinear dynamical systems. The simple cell mapping (SCM) and generalized cell mapping (GCM) are implemented in a hybrid manner. The solution process starts with a coarse cell partition to obtain a covering set of the steady-state responses, followed by the subdivision technique to enhance the accuracy of the steady-state responses. When the cells are small enough, no further subdivision is necessary. We propose to treat the solutions obtained by the cell mapping method on a sufficiently fine grid as a database, which provides a basis for the ICM to generate the pointwise approximation of the solutions without additional numerical integrations of differential equations. A modified global analysis of nonlinear systems with transient states is developed by taking advantage of parallel computing without subdivision. To validate the parallelized cell mapping techniques and to demonstrate the effectiveness of the proposed method, a low-dimensional dynamical system governed by implicit mappings is first presented, followed by the global analysis of a three-dimensional plasma model and a six-dimensional Lorenz system. For the six-dimensional example, an error analysis of the ICM is conducted with the Hausdorff distance as a metric.
Effects of Surface Stress on the Phonon Properties in GaN Nanofilms
Authors: Luo Haonan , Zhu Linli
Published: July 2015

This work investigates the phonon properties such as phonon dispersion relation, average group velocity, and phonon density of state (DOS) theoretically in GaN nanofilm under various surface stress fields. By taking into account of the surface energy effects, the elasticity theory is presented to describe the confined phonons of nanofilms with different surface stresses. The calculation results show that the influence of surface stress on the phonon properties depends on the thickness of nanofilm. The negative surface stress leads to a higher average group velocity and corresponding lower phonon DOS. The positive surface stress has the opposite effect. The significant modification of thermal properties, e.g., phonon thermal conductivity, in GaN nanofilms is mostly stemmed from the change of phonon average group velocity and DOS by surface stress. These results suggest that the thermal or electrical properties in GaN nanofilms could be enhanced or reduced by tuning the surface stress acting on the films.
A Finite-Element Boundary Condition Setting Method for the Virtual Mounting of Compliant Components
Authors: Abenhaim Gad N. , Desrochers Alain , Tahan Antoine S. , Bigeon Jean
Published: July 2015

Using finite-element analysis (FEA) to numerically mount compliant components onto their inspection fixture is an approach proposed by researchers in the field of computational metrology. To address the shortcomings of the underlying principle of current methods, this paper presents a boundary displacement constrained (BDC) optimization using FEA. The optimization seeks to minimize the distance between corresponding points, in the scanned manufactured part and the nominal model, that are in unconstrained regions. This is done while maintaining that a distance between corresponding points in constrained regions (i.e., fixing points) remains within a specified contact distance. At the same time, the optimization limits the magnitude and direction of forces on boundary. In contrast to the current methods, postprocessing of the point cloud is not required since the method uses information retrieved from the FEA of the nominal model to estimate the manufactured part’s mechanical behavior. To investigate the performance of the proposed method, it is tested on ten (10) free-state simulated manufactured aerospace panels that differ in their level of induced deformation. Results are then compared to those obtained using the underlying principles of current methods.
Thermoforming and Structural Analysis of Combat Helmets
Authors: Cartwright Bruce K. , Lex Mulcahy N. , Chhor Allen O. , Thomas Stuart G. F. , Suryanarayana Madhusudan , Sandlin James D. , Crouch Ian G. , Naebe Minoo
Published: July 2015

To reduce combat casualties, military helmets are designed to provide protection against projectiles. Modern combat helmets are constructed of relatively lightweight composite materials that provide ballistic protection to the soldier. The manufacture of most composite helmets is labor intensive and involves the manual application and smoothing of individual layers of reinforcement to a concave mold surface. The recently developed double diaphragm deep drawing thermoforming process turns as-purchased, flat-form composite materials into structurally efficient three-dimensional shapes. Using this process, prototype shells have been produced and subsequently tested structurally. The success of the outcome has been greatly assisted through the use of specialized virtual prototyping techniques to provide insight into the thermoforming process of the shells and subsequently their structural performance by accounting for the actual fiber orientations of those finished shells.
Effect of Reeling on Sour Service Fatigue Crack Growth Behavior of Welded API5LX65 Line Pipe
Authors: Thodla Ramgopal , Gordon J. R. , Gui Feng
Published: July 2015

The effect of reeling on the fatigue crack growth rate (FCGR) behavior of welded pipe was investigated both in-air as well as in sour environment. The FCGR behavior of the reeled pipe in various notch locations, such as parent pipe (PP), weld center line (WCL), and heat affected zone (HAZ), did not exhibit any effect of reeling (i.e., the properties in the strained and aged conditions were similar to the as-fabricated welds). Frequency scan FCGR tests in sour environment (pH = 5/0.0031 MPa H2S) exhibited maximum FCGR in the range of 10× to 35× higher than the in-air values at frequencies in the range of 3–1 mHz and 3× to 5× at frequencies in the range of 0.3 Hz (risers). In sour service, WCL exhibited better fatigue performance than the PP and HAZ in all conditions. Fatigue performance of PP and WCL was independent of reeling. The poorest fatigue performance was observed in unstrained HAZ. Fatigue performance of HAZ extrados (side last strained in compression) and intrados (side last strained in tension) was similar and better than unstrained HAZ. It was also found that the FCGR in sour environments was controlled by the internal hydrogen due to bulk charging from the sour environment. The overall conclusion is that reeling has no detrimental effect on sour service fatigue crack growth behavior, i.e., sour service fatigue performance of reeled pipe is the same as unreeled pipe.
Design, Control, and Experimental Validation of a Handshaking Reactive Robotic Interface
Authors: Pedemonte Nicolò , Laliberté Thierry , Gosselin Clément
Published: July 2015

The objective of this work is to develop a communication system that allows two people to shake hands while being in different locations. To this end, a novel haptic interface that is capable of performing a robotic handshake is designed and built. At the final stage of the project, the system will be composed of two such interfaces. In this paper, the attention is focused on the development of the haptic interface itself. The design process and the control strategy are first discussed. Then, an experimental session is proposed in order to analyze the robotic handshake performed by the interface. The collected data will be used to tune the interface’s behavior in the context of the communication system.
Selective robust optimization: A new intensity‐modulated proton therapy optimization strategy
Authors: Li Yupeng , Niemela Perttu , Liao Li , Jiang Shengpeng , Li Heng , Poenisch Falk , Zhu X. Ronald , Siljamaki Sami , Vanderstraeten Reynald , Sahoo Narayan , Gillin Michael , Zhang Xiaodong
Published: July 2015

Purpose:

To develop a new robust optimization strategy for intensity‐modulated proton therapy as an important step in translating robust proton treatment planning from research to clinical applications.

Methods:

In selective robust optimization, a worst‐case‐based robust optimization algorithm is extended, and terms of the objective function are selectively computed from either the worst‐case dose or the nominal dose. Two lung cancer cases and one head and neck cancer case were used to demonstrate the practical significance of the proposed robust planning strategy. The lung cancer cases had minimal tumor motion less than 5 mm, and, for the demonstration of the methodology, are assumed to be static.

Results:

Selective robust optimization achieved robust clinical target volume (CTV) coverage and at the same time increased nominal planning target volume coverage to 95.8%, compared to the 84.6% coverage achieved with CTV‐based robust optimization in one of the lung cases. In the other lung case, the maximum dose in selective robust optimization was lowered from a dose of 131.3% in the CTV‐based robust optimization to 113.6%. Selective robust optimization provided robust CTV coverage in the head and neck case, and at the same time improved controls over isodose distribution so that clinical requirements may be readily met.

Conclusions:

Selective robust optimization may provide the flexibility and capability necessary for meeting various clinical requirements in addition to achieving the required plan robustness in practical proton treatment planning settings.
Characteristic image quality of a third generation dual‐source MDCT scanner: Noise, resolution, and detectability
Authors: Solomon Justin , Wilson Joshua , Samei Ehsan
Published: July 2015

Purpose:

The purpose of this work was to assess the inherent image quality characteristics of a new multidetector computed tomography system in terms of noise, resolution, and detectability index as a function of image acquisition and reconstruction for a range of clinically relevant settings.

Methods:

A multisized image quality phantom (37, 30, 23, 18.5, and 12 cm physical diameter) was imaged on a SOMATOM Force scanner (Siemens Medical Solutions) under variable dose, kVp, and tube current modulation settings. Images were reconstructed with filtered back projection (FBP) and with advanced modeled iterative reconstruction (ADMIRE) with iterative strengths of 3, 4, and 5. Image quality was assessed in terms of the noise power spectrum (NPS), task transfer function (TTF), and detectability index for a range of detection tasks (contrasts of approximately 45, 90, 300, −900, and 1000 HU, and 2–20 mm diameter) based on a non‐prewhitening matched filter model observer with eye filter.

Results:

Image noise magnitude decreased with decreasing phantom size, increasing dose, and increasing ADMIRE strength, offering up to 64% noise reduction relative to FBP. Noise texture in terms of the NPS was similar between FBP and ADMIRE (<5% shift in peak frequency). The resolution, based on the TTF, improved with increased ADMIRE strength by an average of 15% in the TTF 50% frequency for ADMIRE‐5. The detectability index increased with increasing dose and ADMIRE strength by an average of 55%, 90%, and 163% for ADMIRE 3, 4, and 5, respectively. Assessing the impact of mA modulation for a fixed average dose over the length of the phantom, detectability was up to 49% lower in smaller phantom sections and up to 26% higher in larger phantom sections for the modulated scan compared to a fixed tube current scan. Overall, the detectability exhibited less variability with phantom size for modulated scans compared to fixed tube current scans.

Conclusions:

Image quality increased with increasing dose and decreasing phantom size. The CT system exhibited nonlinear noise and resolution properties, especially at very low‐doses, large phantom sizes, and for low‐contrast objects. Objective image quality metrics generally increased with increasing dose and ADMIRE strength, and with decreasing phantom size. The ADMIRE algorithm could offer comparable image quality at reduced doses or improved image quality at the same dose. The use of tube current modulation resulted in more consistent image quality with changing phantom size.
Robust PET‐guided intensity‐modulated radiation therapy
Authors: Li H. , Bissonnette J. P. , Purdie T. , Chan T. C. Y.
Published: July 2015

Purpose:

Functional image guided intensity‐modulated radiation therapy has the potential to improve cancer treatment quality by basing treatment parameters such as heterogeneous dose distributions information derived from imaging. However, such heterogeneous dose distributions are subject to imaging uncertainty. In this paper, the authors develop a robust optimization model to design plans that are desensitized to imaging uncertainty.

Methods:

Starting from the pretreatment fluorodeoxyglucose‐positron emission tomography scans, the authors use the raw voxel standard uptake values (SUVs) as input into a series of intermediate functions to transform the SUV into a desired dose. The calculated desired doses were used as an input into a robust optimization model to generate beamlet intensities. For each voxel, the authors assume that the true SUV cannot be observed but instead resides in an interval centered on the nominal (i.e., observed) SUV. Then the authors evaluated the nominal and robust solutions through a simulation study. The simulation considered the effect of the true SUV being different from the nominal SUV on the quality of the treatment plan. Treatment plans were compared on the metrics of objective function value and tumor control probability (TCP).

Results:

Computational results demonstrate the potential for improvements in tumor control probability and deviation from the desired dose distribution compared to a nonrobust model while maintaining acceptable tissue dose.

Conclusions:

Robust optimization can help design treatment plans that are more stable in the presence of image value uncertainties.
A contactless approach for respiratory gating in PET using continuous‐wave radar
Authors: Ersepke Thomas , Büther Florian , Heß Mirco , Schäfers Klaus P.
Published: July 2015

Purpose:

Respiratory gating is commonly used to reduce motion artifacts in positron emission tomography (PET). Clinically established methods for respiratory gating in PET require contact to the patient or a direct optical line between the sensor and the patient's torso and time consuming preparation. In this work, a contactless method for capturing a respiratory signal during PET is presented based on continuous‐wave radar.

Methods:

The proposed method relies on the principle of emitting an electromagnetic wave and detecting the phase shift of the reflected wave, modulated due to the respiratory movement of the patient's torso. A 24 GHz carrier frequency was chosen allowing wave propagation through plastic and clothing with high reflections at the skin surface. A detector module and signal processing algorithms were developed to extract a quantitative respiratory signal. The sensor was validated using a high precision linear table. During volunteer measurements and [18F] FDG PET scans, the radar sensor was positioned inside the scanner bore of a PET/computed tomography scanner. As reference, pressure belt (one volunteer), depth camera‐based (two volunteers, two patients), and PET data‐driven (six patients) signals were acquired simultaneously and the signal correlation was quantified.

Results:

The developed system demonstrated a high measurement accuracy for movement detection within the submillimeter range. With the proposed method, small displacements of 25 μm could be detected, not considerably influenced by clothing or blankets. From the patient studies, the extracted respiratory radar signals revealed high correlation (Pearson correlation coefficient) to those derived from the external pressure belt and depth camera signals (r = 0.69–0.99) and moderate correlation to those of the internal data‐driven signals (r = 0.53–0.70). In some cases, a cardiac signal could be visualized, due to the representation of the mechanical heart motion on the skin.

Conclusions:

Accurate respiratory signals were obtained successfully by the proposed method with high spatial and temporal resolution. By working without contact and passing through clothing and blankets, this approach minimizes preparation time and increases the convenience of the patient during the scan.
Clinical research: Should patients pay to play?
Authors: Emanuel Ezekiel J. , Joffe Steven , Grady Christine , Wendler David , Persad Govind
Published: July 2015

Permitting patients to pay for participation in clinical research threatens the principles of social value and fair subject-selection as well as robust clinical trial design.
Why location is (still) everything
Authors: Dronca Roxana
Published: July 2015

The frequency and prognostic association of molecular markers in colorectal carcinoma differ with anatomic tumor site.
The persistent life of IgA
Authors: Faith Jeremiah
Published: July 2015

The IgA repertoire persists in mice and humans despite perturbations to the intestinal microbiota.
Science Translational Medicine
Podcast: 29 July 2015
Authors: Emanuel Ezekiel J. , VanHook Annalisa M.
Published: July 2015

Ezekiel Emanuel discusses the ethical issues around having patients pay for participation in clinical trials.
Bacterial Cell Enlargement Requires Control of Cell Wall Stiffness Mediated by Peptidoglycan Hydrolases
Authors: Wheeler Richard , Turner Robert D. , Bailey Richard G. , Salamaga Bartłomiej , Mesnage Stéphane , Mohamad Sharifah A. S. , Hayhurst Emma J. , Horsburgh Malcolm , Hobbs Jamie K. , Foster Simon J.
Published: July 2015

Most bacterial cells are enclosed in a single macromolecule of the cell wall polymer, peptidoglycan, which is required for shape determination and maintenance of viability, while peptidoglycan biosynthesis is an important antibiotic target. It is hypothesized that cellular enlargement requires regional expansion of the cell wall through coordinated insertion and hydrolysis of peptidoglycan. Here, a group of (apparent glucosaminidase) peptidoglycan hydrolases are identified that are together required for cell enlargement and correct cellular morphology of
Staphylococcus aureus
, demonstrating the overall importance of this enzyme activity. These are Atl, SagA, ScaH, and SagB. The major advance here is the explanation of the observed morphological defects in terms of the mechanical and biochemical properties of peptidoglycan. It was shown that cells lacking groups of these hydrolases have increased surface stiffness and, in the absence of SagB, substantially increased glycan chain length. This indicates that, beyond their established roles (for example in cell separation), some hydrolases enable cellular enlargement by making peptidoglycan easier to stretch, providing the first direct evidence demonstrating that cellular enlargement occurs via modulation of the mechanical properties of peptidoglycan.

IMPORTANCE
Understanding bacterial growth and division is a fundamental problem, and knowledge in this area underlies the treatment of many infectious diseases. Almost all bacteria are surrounded by a macromolecule of peptidoglycan that encloses the cell and maintains shape, and bacterial cells must increase the size of this molecule in order to enlarge themselves. This requires not only the insertion of new peptidoglycan monomers, a process targeted by antibiotics, including penicillin, but also breakage of existing bonds, a potentially hazardous activity for the cell. Using
Staphylococcus aureus
, we have identified a set of enzymes that are critical for cellular enlargement. We show that these enzymes are required for normal growth and define the mechanism through which cellular enlargement is accomplished, i.e., by breaking bonds in the peptidoglycan, which reduces the stiffness of the cell wall, enabling it to stretch and expand, a process that is likely to be fundamental to many bacteria.
Pediatric Cystic Fibrosis Sputum Can Be Chemically Dynamic, Anoxic, and Extremely Reduced Due to Hydrogen Sulfide Formation
Authors: Cowley Elise S. , Kopf Sebastian H. , LaRiviere Alejandro , Ziebis Wiebke , Newman Dianne K.
Published: July 2015

Severe and persistent bacterial lung infections characterize cystic fibrosis (CF). While several studies have documented the microbial diversity within CF lung mucus, we know much less about the inorganic chemistry that constrains microbial metabolic processes and their distribution. We hypothesized that sputum is chemically heterogeneous both within and between patients. To test this, we measured microprofiles of oxygen and sulfide concentrations as well as pH and oxidation-reduction potentials in 48 sputum samples from 22 pediatric patients with CF. Inorganic ions were measured in 20 samples from 12 patients. In all cases, oxygen was depleted within the first few millimeters below the sputum-air interface. Apart from this steep oxycline, anoxia dominated the sputum environment. Different sputum samples exhibited a broad range of redox conditions, with either oxidizing (16 mV to 355 mV) or reducing (−300 to −107 mV) potentials. The majority of reduced samples contained hydrogen sulfide and had a low pH (2.9 to 6.5). Sulfide concentrations increased at a rate of 0.30 µM H
2
S/min. Nitrous oxide was detected in only one sample that also contained sulfide. Microenvironmental variability was observed both within a single patient over time and between patients. Modeling oxygen dynamics within CF mucus plugs indicates that anoxic zones vary as a function of bacterial load and mucus thickness and can occupy a significant portion of the mucus volume. Thus, aerobic respiration accounts only partially for pathogen survival in CF sputum, motivating research to identify mechanisms of survival under conditions that span fluctuating redox states, including sulfidic environments.

IMPORTANCE
Microbial infections are the major cause of morbidity and mortality in people living with CF, and yet microbial growth and survival in CF airways are not well understood. Insufficient information about the chemistry of the
in vivo
environment contributes to this knowledge gap. Our documentation of variable redox states corresponding to the presence or absence of sulfide begins to fill this void and motivates understanding of how different opportunistic pathogens adapt in these dynamic environments. Given the changing chemical state of CF sputum over time, it is important to consider a spectrum of aerobic and anaerobic lifestyles when studying CF pathogens in the laboratory. This work not only provides relevant constraints that can shape the design of laboratory experiments, it also suggests that sulfide might be a useful proxy for assessing the redox state of sputum in the clinic.
Genomic Adaptations to the Loss of a Conserved Bacterial DNA Methyltransferase
Authors: Gonzalez Diego , Collier Justine
Published: July 2015

CcrM is an orphan DNA methyltransferase nearly universally conserved in a vast group of
Alphaproteobacteria.
In
Caulobacter crescentus
, it controls the expression of key genes involved in the regulation of the cell cycle and cell division. Here, we demonstrate, using an experimental evolution approach, that
C. crescentus
can significantly compensate, through easily accessible genetic changes like point mutations, the severe loss in fitness due to the absence of CcrM, quickly improving its growth rate and cell morphology in rich medium. By analyzing the compensatory mutations genome-wide in 12 clones sampled from independent Δ
ccrM
populations evolved for ~300 generations, we demonstrated that each of the twelve clones carried at least one mutation that potentially stimulated
ftsZ
expression, suggesting that the low intracellular levels of FtsZ are the major burden of Δ
ccrM
mutants. In addition, we demonstrate that the phosphoenolpyruvate-carbohydrate phosphotransfer system (PTS) actually modulates
ftsZ
and
mipZ
transcription, uncovering a previously unsuspected link between metabolic regulation and cell division in
Alphaproteobacteria
. We present evidence that point mutations found in genes encoding proteins of the PTS provide the strongest fitness advantage to Δ
ccrM
cells cultivated in rich medium despite being disadvantageous in minimal medium. This environmental sign epistasis might prevent such mutations from getting fixed under changing natural conditions, adding a plausible explanation for the broad conservation of CcrM.

IMPORTANCE
In bacteria, DNA methylation has a variety of functions, including the control of DNA replication and/or gene expression. The cell cycle-regulated DNA methyltransferase CcrM modulates the transcription of many genes and is critical for fitness in
Caulobacter crescentus
. Here, we used an original experimental evolution approach to determine which of its many targets make CcrM so important physiologically. We show that populations lacking CcrM evolve quickly, accumulating an excess of mutations affecting, directly or indirectly, the expression of the
ftsZ
cell division gene. This finding suggests that the most critical function of CcrM in
C. crescentus
is to promote cell division by enhancing FtsZ intracellular levels. During this work, we also discovered an unexpected link between metabolic regulation and cell division that might extend to other
Alphaproteobacteria
.
Diagnostic outcomes following childhood non-specific abdominal pain: a record-linkage study
Authors: Thornton G C D , Goldacre M J , Goldacre R , Howarth L J
Published: July 2015

Aims

Non-specific abdominal pain (NSAP) is the most common diagnosis on discharge following admission for abdominal pain in childhood. Our aim was to determine the risk of subsequent hospital diagnosis of organic and functional gastroenterological conditions following a diagnosis of NSAP, and to assess the persistence of this risk.

Methods

An NSAP cohort of 268 623 children aged 0–16 years was constructed from linked English Hospital Episode Statistics from 1999 to 2011. The control cohort (1 684 923 children, 0–16 years old) comprised children hospitalised with unrelated conditions. Clinically relevant outcomes were selected and standardised rate ratios were calculated.

Results

From the NSAP cohort, 15 515 (5.8%) were later hospitalised with bowel pathology and 13 301 (5%) with a specific functional disorder. Notably, there was a 4.84 (95% CI 4.45 to 5.27) times greater risk of Crohn's disease following NSAP and a 4.23 (4.13 to 4.33) greater risk of acute appendicitis than in the control cohort. The risk of irritable bowel syndrome (IBS) was 7.22 (6.65 to 7.85) times greater following NSAP. The risks of inflammatory bowel disease (IBD), IBS and functional disorder (unspecified) were significantly increased in all age groups except <2-year-olds. The risk of underlying bowel pathology remained raised up to 10 years after first diagnosis with NSAP.

Conclusions

Only a small proportion of those with NSAP go on to be hospitalised with underlying bowel pathology. However, their risk is increased even at 10 years after the first hospital admission with NSAP. Diagnostic strategies need to be assessed and refined and active surveillance employed for children with NSAP.
How well do health professionals interpret diagnostic information? A systematic review
Authors: Whiting Penny F , Davenport Clare , Jameson Catherine , Burke Margaret , Sterne Jonathan A C , Hyde Chris , Ben-Shlomo Yoav
Published: July 2015

Objective

To evaluate whether clinicians differ in how they evaluate and interpret diagnostic test information.

Design

Systematic review.

Data sources

MEDLINE, EMBASE and PsycINFO from inception to September 2013; bibliographies of retrieved studies, experts and citation search of key included studies.

Eligibility criteria for selecting studies

Primary studies that provided information on the accuracy of any diagnostic test (eg, sensitivity, specificity, likelihood ratios) to health professionals and that reported outcomes relating to their understanding of information on or implications of test accuracy.

Results

We included 24 studies. 6 assessed ability to define accuracy metrics: health professionals were less likely to identify the correct definition of likelihood ratios than of sensitivity and specificity. –25 studies assessed Bayesian reasoning. Most assessed the influence of a positive test result on the probability of disease: they generally found health professionals’ estimation of post-test probability to be poor, with a tendency to overestimation. 3 studies found that approaches based on likelihood ratios resulted in more accurate estimates of post-test probability than approaches based on estimates of sensitivity and specificity alone, while 3 found less accurate estimates. 5 studies found that presenting natural frequencies rather than probabilities improved post-test probability estimation and speed of calculations.

Conclusions

Commonly used measures of test accuracy are poorly understood by health professionals. Reporting test accuracy using natural frequencies and visual aids may facilitate improved understanding and better estimation of the post-test probability of disease.
Effectiveness and cost-effectiveness of telephone-based support versus usual care for treatment of pressure ulcers in people with spinal cord injury in low-income and middle-income countries: study protocol for a 12-week randomised controlled trial
Authors: Arora Mohit , Harvey Lisa Anne , Hayes Alison Joy , Chhabra Harvinder Singh , Glinsky Joanne Valentina , Cameron Ian Douglas , Lavrencic Lucija , Arumugam Narkeesh , Hossain Sohrab , Bedi Parneet Kaur
Published: July 2015

Introduction

Pressure ulcers are a common and severe complication of spinal cord injury, particularly in low-income and middle-income countries where people often need to manage pressure ulcers alone and at home. Telephone-based support may help people in these situations to manage their pressure ulcers. The aim of this study is to determine the effectiveness and cost-effectiveness of telephone-based support to help people with spinal cord injury manage pressure ulcers at home in India and Bangladesh.

Methods and analysis

A multicentre (3 sites), prospective, assessor-blinded, parallel, randomised controlled trial will be undertaken. 120 participants with pressure ulcers on the sacrum, ischial tuberosity or greater trochanter of the femur secondary to spinal cord injury will be randomly assigned to a Control or Intervention group. Participants in the Control group will receive usual community care. That is, they will manage their pressure ulcers on their own at home but will be free to access whatever healthcare support they can. Participants in the Intervention group will also manage their pressure ulcers at home and will also be free to access whatever healthcare support they can, but in addition they will receive weekly telephone-based support and advice for 12 weeks (15–25 min/week). The primary outcome is the size of the pressure ulcer at 12 weeks. 13 secondary outcomes will be measured reflecting other aspects of pressure ulcer resolution, depression, quality of life, participation and satisfaction with healthcare provision. An economic evaluation will be run in parallel and will include a cost-effectiveness and a cost-utility analysis.

Ethics and dissemination

Ethical approval was obtained from the Institutional Ethics Committee at each site. The results of this study will be disseminated through publications and presented at national and international conferences.

Trial registration number

ACTRN12613001225707.
Prediction and prognostication of neurological deterioration in patients with acute ICH: a hospital-based cohort study
Authors: Ovesen Christian , Christensen Anders Fogh , Havsteen Inger , Krarup Hansen Christine , Rosenbaum Sverre , Kurt Engin , Christensen Hanne
Published: July 2015

Objective

Patients with intracerebral haemorrhage (ICH) are at high risk of neurological deterioration (ND). We aimed at establishing predictors of early ND (END) as well as late ND (LND) and at exploring the impact of neurological stability during the first week on long-term prognosis.

Design

We conducted this study as a retrospective cohort study. ND was evaluated based on the consciousness and severity of neurological symptoms. ND during the first 24 h after admission was defined as early ND and from 24 h to 7 days as LND. Patients were followed up until February 2015.

Participants

We included 300 patients with acute ICH (≤4.5 h from symptom onset) who were admitted to our institution from March 2009 to January 2015.

Setting

Section of Acute Neurology, Department of Neurology, Bispebjerg Hospital is a specialised referral centre receiving patients with acute stroke from the entire capital region of Denmark.

Results

We found that a spot sign on CT angiography (OR 10.7 CI 4.79 to 24.3) and extensive degree of interventricular haemorrhage (IVH) (OR 8.73 CI 2.87 to 26.5) were independent predictors of END, whereas a degree of comorbidity (Charlton Index), admission stroke severity and degree of IVH predicted LND. On follow-up imaging, haematoma expansion was independently associated with END (OR 6.1 CI 2.2 to 17.3), and expansion of IVH was independently associated with both END (OR 1.7 CI 1.2 to 2.3 per point increase) and LND (OR 2.3 CI 1.3 to 4.2 per point increase). ND during the first week was associated with a 1-year mortality of 60.5%, compared with 9.2% among the patients who remained stable.

Conclusions

These results suggest that stability during the first week entails an optimistic prognosis. A relatively easy and effective risk stratification of END and LND is possible on admission based on the spot sign, IVH and clinical parameters.
Social inequality in pre-pregnancy BMI and gestational weight gain in the first and second pregnancy among women in Sweden
Authors: Holowko Natalie , Chaparro M Pia , Nilsson Karina , Ivarsson Anneli , Mishra Gita , Koupil Ilona , Goodman Anna
Published: July 2015

Background

High pre-pregnancy body mass index (BMI) and inappropriate gestational weight gain (GWG) are associated with adverse short and long-term maternal and neonatal outcomes and may act as modifiable risk factors on the path to overweight/obesity, but their social patterning is not well established. This study investigates the association of education with BMI and GWG across two consecutive pregnancies.

Methods

The study includes 163 352 Swedish women, having their first and second singleton birth in 1982–2010. In both pregnancies, we investigated the association of women's education with (1) pre-pregnancy weight status and (2) adequacy of GWG. We used multinomial logistic regression, adjusting for child's birth year, mother's age and smoking status.

Results

Overall, the odds of starting either pregnancy at an unhealthy BMI were higher among women with a low education compared to more highly-educated women. Lower education also predicted a greater increase in BMI between pregnancies, with this effect greatest among women with excessive GWG in the first pregnancy (p<0.0001 for interaction). Education was also inversely associated with odds of excessive GWG in both pregnancies among healthy weight status women, but this association was absent or even weakly reversed among overweight and obese women.

Conclusions

Lower educated women had the largest BMI increase between pregnancies, and these inequalities were greatest among women with excessive GWG in the first pregnancy. The importance of a healthy pre-pregnancy BMI, appropriate GWG and a healthy postpartum weight should be communicated to all women, which may assist in reducing existing social inequalities in body weight.