bluuebunny/crossref_metadata_2025 huggingface dataset:
Prenatal Infection and Autism Spectrum Disorders in Childhood: A Population‐Based Case–Control Study in Taiwan
Authors: Fang Shao‐You , Wang Sabrina , Huang Nicole , Yeh Hsueh‐Han , Chen Chuan‐Yu
Published: May 2015

Background

Infection in pregnancy has long been linked with negative postnatal development and health. This study aims to assess the association between prenatal infections and autism spectrum disorders (ASDs) across three trimesters and to probe possible sex heterogeneity in such link.

Method

A total of 4184 children with incident ASDs and 16 734 matched children were identified from the 2000–2007 National Health Insurance Research Database. For each child, information pertaining to the mother's infection during pregnancy, sociodemographics, and medical history was retrieved from healthcare records. Conditional logistic analyses were carried out to estimate the strength of associations with adjustment for multiple comparisons.

Result

Pooled analyses demonstrated that having two or more outpatient visits for genital infection [adjusted odds ratio (aOR): 1.34; 95% confidence interval (95% CI) 1.12, 1.60; false discovery rate (FDR) < 0.01] and bacterial infection (aOR: 1.24; 95% CI 1.06, 1.43; FDR < 0.05) in the third trimester were slightly associated with increased risk of ASDs. No statistically significant sex differences were found.

Conclusion

The present study contributes updated population‐based evidence about the connection between prenatal infection and ASDs. Potential effect of bacterial and genital tract infections during the third trimester on risk of ASDs warrants further exploration.
Reduced forced vital capacity in Aboriginal Australians: Biology or missing evidence?
Authors: Hall Graham L. , Pearson Glenn
Published: May 2015

See article, page 766
Impact of HMG‐CoA reductase inhibitors on the incidence of polyomavirus‐associated nephropathy in renal transplant recipients with human BK polyomavirus viremia
Authors: Gabardi S. , Ramasamy S. , Kim M. , Klasek R. , Carter D. , Mackenzie M.R. , Chandraker A. , Tan C.S.
Published: May 2015

Background

Up to 20% of renal transplant recipients (RTR) will develop human BK polyomavirus (BKPyV) viremia. BKPyV viremia is a pre‐requisite of polyomavirus‐associated nephropathy (PyVAN). Risk of BKPyV infections increases with immunosuppression. Currently, the only effective therapy against PyVAN is reductions in immunosuppression, but this may increase the risk of rejection. In vitro data have shown that pravastatin dramatically decreased caveolin‐1 expression in human renal proximal tubular epithelial cells (HRPTEC) and suppressed BKPyV infection in these cells. Based on these data, we postulated that statin therapy may prevent the progression of BKPyV viremia to PyVAN.

Patients and methods

A multicenter, retrospective study was conducted in adult RTR transplanted between July 2005 and March 2012. All patients with documented BKPyV viremia (viral load >500 copies/mL on 2 consecutive tests) were included. Group I consisted of patients taking a statin before the BKPyV viremia diagnosis (n = 32), and Group II had no statin exposure before or after the BKPyV viremia diagnosis (n = 36). The primary endpoint was the incidence of PyVAN.

Results

Demographic data, transplant characteristics, and the degree of immunosuppression (i.e., induction/maintenance therapies, rejection treatment) were similar between the groups, with the exception of more diabetics in Group I. The incidence of PyVAN was comparable between the 2 groups (Group I = 28.1% vs. Group II = 41.7%; P = 0.312).

Conclusions

Despite the proven in vitro effectiveness of pravastatin preventing BKPyV infection in HRPTEC, statins at doses maximized for cholesterol lowering, in RTR with BKPyV viremia, did not prevent progression to PyVAN.
Information Foraging Across the Life Span: Search and Switch in Unknown Patches
Authors: Chin Jessie , Payne Brennan R. , Fu Wai‐Tat , Morrow Daniel G. , Stine‐Morrow Elizabeth A. L.
Published: May 2015

In this study, we used a word search puzzle paradigm to investigate age differences in the rate of information gain (RG; i.e., word gain as a function of time) and the cues used to make patch‐departure decisions in information foraging. The likelihood of patch departure increased as the profitability of the patch decreased generally. Both younger and older adults persisted past the point of optimality as defined by the marginal value theorem (Charnov, 1976), which assumes perfect knowledge of the foraging ecology. Nevertheless, there was evidence that adults were rational in terms of being sensitive to the change in RG for making the patch‐departure decisions. However, given the limitations in cognitive resources and knowledge about the ecology, the estimation of RG may not be accurate. Younger adults were more likely to leave the puzzle as the long‐term RG incrementally decreased, whereas older adults were more likely to leave the puzzle as the local RG decreased. However, older adults with better executive control were more likely to adjust their likelihood of patch‐departure decisions to the long‐term change in RG. Thus, age‐dependent reliance on the long‐term or local change in RG to make patch‐departure decisions might be due to individual differences in executive control.
Canine brain tumours: a model for the human disease?
Authors: Hicks J. , Platt S. , Kent M. , Haley A.
Published: May 2015

Canine brain tumours are becoming established as naturally occurring models of disease to advance diagnostic and therapeutic understanding successfully. The size and structure of the dog's brain, histopathology and molecular characteristics of canine brain tumours, as well as the presence of an intact immune system, all support the potential success of this model. The limited success of current therapeutic regimens such as surgery and radiation for dogs with intracranial tumours means that there can be tremendous mutual benefit from collaboration with our human counterparts resulting in the development of new treatments. The similarities and differences between the canine and human diseases are described in this article, emphasizing both the importance and limitations of canines in brain tumour research. Recent clinical veterinary therapeutic trials are also described to demonstrate the areas of research in which canines have already been utilized and to highlight the important potential benefits of translational research to companion dogs.
Attenuation of methylene blue dye during riverbank filtration through sandy aquifers
Authors: Mishra Shrinishtha , Kumar Pradeep
Published: May 2015

Although several studies have focused on the removal of organics and pathogens during riverbank filtration (RBF), no study has been carried out on the attenuation of dyes during RBF. In the present work, removal of methylene blue (MB) through aquifer materials collected from five RBF sites in India has been investigated. Brunauer Emmet Teller (BET) surface areas of the aquifer materials were 1.2–6.5 m2/g. Adsorption followed the pseudo‐second‐order kinetics and Langmuir isotherm, suggesting monolayer adsorption. Column results showed saturation capacity of 0.467–1.234 mg MB/g for different aquifer materials. Retardation factors for MB were found to be very high ranging from 430 to 987, due to its high hydrophobicity (octanol/water partition coefficient = 5.85). Results showed that BET surface area or the roughness played a very important role in the retardation of MB. Results suggest that the breakthrough of MB in a RBF well in sandy aquifers will take several years.
Critical Reflection: A Transformative Learning Process Integrating Theory and Evidence‐Based Practice
Authors: Kuennen Jacqueline K.
Published: May 2015

This column shares the best evidence‐based strategies and innovative ideas on how to facilitate the learning of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741‐6787
Molecular phylogeny and the underestimated species diversity of the endemic white‐bellied rat (Rodentia: Muridae:Niviventer) in Southeast Asia and China
Authors: Lu Liang , Ge Deyan , Chesters Douglas , Ho Simon Y. W. , Ma Ying , Li Guichang , Wen Zhixin , Wu Yongjie , Wang Jun , Xia Lin , Liu Jingli , Guo Tianyu , Zhang Xiaolong , Zhu Chaodong , Yang Qisen , Liu Qiyong
Published: May 2015

The white‐bellied rat,Niviventer, is a genus endemic to Southeast Asia and China. However, the interspecific phylogenetic relationships and species diversity of this genus remain poorly understood. In the present study, single and multi‐locus analyses were performed. Phylogenetic reconstruction on Cytochrome b (512 individuals, including data from Genbank) revealed five major clades with approximately 35 operational taxonomic units (OTUs), a number twice the existing taxonomy. The first clade (N. langbianisspecies group) was the earliest diverged. The second clade (N. fulvescensspecies group) diverged in Southeast Asia, the south and lower altitude regions of the Hengduan Mountains, and Southeast China. The third clade (theN. ehaspecies group) is endemic to high altitudes in Northwest Yunnan and the central region of Himalaya. The fourth clade (theN. andersonispecies group), is mainly confined to alpine regions of the Hengduan Mountains. The fifth clade (N. confucianusspecies group) is mainly distributed in the north and higher altitude regions of eastern Himalaya, the Hengduan Mountains and Taiwan, with the complex also invading central and northern China. Results from the combined dataset of four genes (Cytochrome b, Cytochrome oxidase subunit I, the D‐loop sequence of the mitochondrial genome and the first exon of the nuclear interphotoreceptor retinoid binding protein) for 82 representative individuals from China generally coincide with the result of the single gene, with 12OTUs identified. These results provide a preliminary framework for the existing classification of this highly diversified genus. The divergence time ofNiviventerbased on the four gene topology was dated to the late Miocene ~6.41 Ma. Significant differences were detected in the general body form changes among these units based on voucher specimens. Moreover, geometric morphometric analysis of the cranium shape of voucher specimens indicated significant differences among five major species groups. Shape divergence of the cranium among severalOTUs within theN. confucinauscomplex is also significant. Our results provide further evidence for rapid and highly underestimated diversification ofNiviventerboth in genetics and morphology.
Low haemoglobin concentration in Tibetan males is associated with greater high‐altitude exercise capacity
Authors: Simonson T. S. , Wei G. , Wagner H. E. , Wuren T. , Qin G. , Yan M. , Wagner P. D. , Ge R. L.
Published: May 2015

Key points

We hypothesized that sea‐level range haemoglobin concentration ([Hb]) at altitude, previously linked with adaptive genetic factors in Tibetans, would be associated with greater exercise capacity, explained by changes in steps of the oxygen transport system in this population.

In 21 Tibetan and 9 Han Chinese males resident at 4200–4300 m, we measured [Hb], ventilation, volumes of O2 and CO2 utilized at peak exercise ( and ), heart rate, cardiac output and arterial blood gas variables at peak exercise on a cycle ergometer and determined oxygen (O2) diffusion capacity in lung and muscle.

Tibetans with low [Hb] exhibit greater peak  kg–1, which was explained mostly by variation in cardiac output, ventilation and O2 diffusional conductances in muscle.

These results suggest that polycythaemia may be an excessive response to low at altitude.

Tibetans living at high altitude have adapted genetically such that many display a low erythropoietic response, resulting in near sea‐level haemoglobin (Hb) concentration. We hypothesized that absence of the erythropoietic response would be associated with greater exercise capacity compared to those with high [Hb] as a result of beneficial changes in oxygen transport. We measured, in 21 Tibetan males with [Hb] ranging from 15.2 g dl−1 to 22.9 g dl−1 (9.4 mmol l−1 to 14.2 mmol l−1), [Hb], ventilation, volumes of O2 and CO2 utilized at peak exercise ( and ), heart rate, cardiac output and arterial blood gas variables at peak exercise on a cycle ergometer at ∼4200 m. Lung and muscle O2 diffusional conductances were computed from these measurements. [Hb] was related (negatively) to  kg–1 (r = −0.45, P< 0.05), cardiac output kg–1 (QT kg–1, r = −0.54, P < 0.02), and O2 diffusion capacity in muscle (DM kg–1, r = −0.44, P<0.05), but was unrelated to ventilation, arterial partial pressure of O2 () or pulmonary diffusing capacity. Using multiple linear regression, variance in peak  kg–1 was primarily attributed to QT, DM, and (R2 = 0.88). However, variance in pulmonary gas exchange played essentially no role in determining peak . These results (1) show higher exercise capacity in Tibetans without the erythropoietic response, supported mostly by cardiac and muscle O2 transport capacity and ventilation rather than pulmonary adaptations, and (2) support the emerging hypothesis that the polycythaemia of altitude, normally a beneficial response to low cellular , may become maladaptive if excessively elevated under chronic hypoxia. The cause and effect relationships among [Hb], QT, DM, and remain to be elucidated.
Formation and Structure of Work Material in the Friction Stir Forming Process
Authors: Lazarevic Sladjan , Ogata Kenneth A. , Miller Scott F. , Kruger Grant H. , Carlson Blair E.
Published: May 2015

Friction stir forming (FSF) is a new environmentally friendly manufacturing process for lap joining of dissimilar materials. Fundamentally, this process is based on frictionally heating and mechanically stirring work material of the top piece in a plasticized state to form a mechanical interlocking joint within the bottom material. In this research, the significant process parameters were identified and optimized for Al 6014 alloy and mild steel using a design of experiments (DOE) methodology. The overall joint structure and grain microstructure were mapped as the FSF process progressed and the aluminum work material deformed through different stages. It was found that the work material within the joint exhibited two layers, thermomechanical affected zone, which formed due to the contact pressure and angular momentum of the tool, and heat affected formation zone, which was composed of work material formed through the hole in the steel sheet and into the anvil cavity. Two different geometries of anvil design were employed to investigate geometrical effects during FSF of the aluminum. It was found that the direction and amount of work material deformation under the tool varies from the center to the shoulder.
Thermal Modeling of Microfluidic Channels for Cooling High Power Resistors on Multilayer Organic Liquid Crystal Polymer Substrate
Authors: Lemtiri Chlieh Outmane , Khan Wasif T. , Papapolymerou John
Published: May 2015

Thermal management is an important aspect for any packaging technology incorporating high power devices. In this paper, we present an integrated microfluidic cooling solution for high power surface mount thin film resistors on liquid crystal polymer (LCP) substrate. High power resistors are mounted on top of a 50.8 μm (2 mil) LCP layer, a coolant can circulate, thanks to a micropump, inside a Duroid micromachined channel beneath the LCP layer in order to take away the generated heat. A thermal model is combined from existing thermal models in literature to predict the overall thermal resistance of the organic heat sink in the case of a moving coolant inside the microfluidic channel. Four sets of microfluidic channels with different thicknesses are fabricated and tested. Temperature measurements of resistors with different power ratings and sizes on top of these channels agree with the model predictions and the simulations in the case of static (nonmoving) and dynamic (moving) distilled (DI) water. With this integrated solution, the case temperature of the 40 W resistor, which is mounted on the 254 μm (10 mil) microchannel, can be cooled down to 121 °C at room temperature while the resistor is dissipating 23.2 W of power; this resistor fails to operate beyond 13.3 W in the absence of fluid circulation. This is, to the best of our knowledge, the best thermal cooling performance ever achieved on multilayer organic substrates.
Mass Loading Effects on Turbulence Modulation by Particle Clustering in Dilute and Moderately Dilute Channel Flows
Authors: Capecelatro Jesse , Desjardins Olivier
Published: May 2015

Wall-bounded particle-laden flows exhibit a variety of interesting phenomena that can greatly impact the underlying carrier-phase turbulence in practical systems. This work aims at investigating the effects of particle clustering on the carrier-phase turbulence in both dilute and moderately dilute channel flows via highly resolved Euler–Lagrange simulations. It is shown that the fluid turbulence departs significantly from the initially fully developed turbulent flow at moderate concentrations. In particular, the gas velocity retains a viscous sublayer at higher values of mass loading, but displays a strongly reduced boundary layer thickness and a flatter velocity profile compared to the dilute case. Furthermore, the flow orientation with respect to gravity is found to significantly impact the multiphase dynamics. Particles showed a preference to be in the near-wall region with significant volume fraction fluctuations when gravity opposed the mean flow direction, while particles accumulated at the channel center with less significant volume fraction fluctuations for flows with gravity aligned with the mean flow direction.
Collapse and Buckling Behaviors of Reinforced Thermoplastic Pipe Under External Pressure
Authors: Bai Yong , Wang Nuosi , Cheng Peng , Qiao Hongdong , Yu Binbin
Published: May 2015

The collapse and buckling behaviors of reinforced thermoplastic pipe (RTP) under external pressure are studied in this paper. A theoretical model which includes axial and shear deformation is applied based on the model initially proposed by Kyriakides and his coworkers. Simulation of the reinforced layers of RTP is simplified using equivalent stiffness method. The load–displacement relation of RTP under external pressure is obtained based on the theoretical model. A three-dimensional (3D) finite element model (FEM) is also built to simulate the response of RTP using the software abaqus. Numerical simulation results from abaqus are similar to those from theoretical model. Besides, external pressure tests for RTP are carried out and the test results are compared with the analyzed results. Finally, factors that influence the external pressure capacity are also studied.
Asymmetric Bifurcation of Initially Curved Nanobeam
Authors: Chen X. , Meguid S. A.
Published: May 2015

In this paper, we investigate the asymmetric bifurcation behavior of an initially curved nanobeam accounting for Lorentz and electrostatic forces. The beam model was developed in the framework of Euler–Bernoulli beam theory, and the surface effects at the nanoscale were taken into account in the model by including the surface elasticity and the residual surface tension. Based on the Galerkin decomposition method, the model was simplified as two degrees of freedom reduced order model, from which the symmetry breaking criterion was derived. The results of our work reveal the significant surface effects on the symmetry breaking criterion for the considered nanobeam.
Design Method for Screw Forming Cutter Based on Tooth Profile Composed of Discrete Points
Authors: Tang Qian , Zhang Yuanxun , Jiang Zhenwei , Yan Di
Published: May 2015

The forming method has been widely used for manufacturing screw rotors with helical profile. This paper takes the manufacturing of screws for screw pumps as an example and uses the cubic spline interpolation method to obtain the tooth profile of the screw forming cutter according to the tooth profile at any end section of screws composed of discrete points and based on the principle of gearing mesh. Furthermore, this paper studies the space enveloping and geometric characteristics between the screw and cutter during the manufacturing process, combines the shape of the contact line, which is generated due to the cooperative motion of the machine tool, screw, and cutter, with spatial location parameters, and thus innovatively proposes a design method for the screw forming cutter based on discrete points, namely, the form-position geometric method (FPGM). It can be seen after comparing the proposed method with the principle of gear meshing that the cutter-workpiece enveloping solution model, simplified by the FPGM, can overcome the key technical difficulty, i.e., it is difficult to accurately calculate the cusp of the tooth curve; meanwhile, the proposed method can improve the precision of the cutter tooth profile design. Finally, the feasibility and superiority of FPGM are verified by experiments.
A Comparison of the Effectiveness of Design Approaches for Human-Friendly Robots
Authors: Lauzier Nicolas , Gosselin Clément
Published: May 2015

In this paper, different measures for reducing the maximum contact force during blunt collisions between a robot and a human are evaluated using simulations. An existing collision model is adapted to include a nonlinear compliant covering, articular safety mechanisms (compliant joint and two types of torque limiters), and a collision detection system. Several scenarios are simulated in which the collision occurs at a low or high velocity, the head of the person (on which the collision occurs) is constrained by a wall or free to move and the reflected motor inertia is large or small compared to the link inertia. The results show that a torque limiter in series with each actuator has the potential to significantly improve safety without reducing the robot's performances.
Design and Modeling of a Large Amplitude Compliant Revolute Joint: The Helical Shape Compliant Joint
Authors: Bruyas Arnaud , Geiskopf Francois , Renaud Pierre
Published: May 2015

In this paper, the design and modeling of a large amplitude compliant revolute joint are introduced. Based on the implementation of multimaterial additive manufacturing (MM-AM), the joint is of interest for robotic contexts where the design of compact and accurate compliant mechanisms is required. The joint design is first experimentally proven to offer a large range of motion and satisfying kinetostatic properties. A parametric study is then conducted using numerical simulation to define the most interesting geometries. An experimental study is in a third step presented to estimate the rotational stiffness, including the manufacturing impact. A stiffness model is provided for relevant geometries, and their use is finally discussed in the context of compliant mechanism design.
Dimensional Synthesis of Open Path Generator of Four-Bar Mechanisms Using the Haar Wavelet
Authors: Sun Jianwei , Liu Wenrui , Chu Jinkui
Published: May 2015

This paper presents a synthesis method for the open path generation of a four-bar mechanism using the Haar wavelet. The synthesis method utilizes the wavelet transform and normalization to extract the wavelet output feature parameters (WOFP) of the open path. Analysis of the WOFP reveals a particular characteristic: for the same four-bar mechanism, not only do variations of the mechanism origin and angles and the proportional scaling of the linkage lengths have no influence on the details of the WOFP but the same holds true for the position of the point that generates the coupler curve. Based on this finding, a numerical atlas database comprises 192,596 groups of basic dimensional types was established and a method of matching recognition was proposed as well. According to the internal relationship of the wavelet characteristic dimension parameters (WCDP), the actual mechanism parameter values and position parameters of an objective four-bar mechanism can be calculated. Four examples are presented to verify the accuracy and practicality of the proposed theory.
Flexure-Based Active Needle for Enhanced Steering Within Soft Tissue
Authors: Datla Naresh V. , Hutapea Parsaoran
Published: May 2015

Flexible needles with enhanced steerability are desired in minimally invasive surgeries to reach target locations precisely and to bypass critical organs lying in the planned path. We have proposed a flexure-based active needle that enhances steerability by using a flexure element near the needle tip. Needle curvature is controlled by attached shape memory alloy (SMA) wires that apply actuator forces to bend the needle. Using actuator forces rather than axial rotation to control needle curvature minimizes placement errors due to torsional rigidity that is compromised by the flexure element. A prototype of the proposed needle was developed and was demonstrated in air, in tissue-mimicking gel, and in pig liver. Needle insertion studies with the prototype showed that increasing the wire diameter from 0.15 to 0.24 mm insignificantly affected the maximum needle tip deflection (19.4±0.3 mm for 150 mm insertion), but significantly increased the actuation current (from 0.60 to 1.04 A).
Evaluation of the Influence of Residual Stresses on Ductile Fracture
Authors: Bolinder Tobias , Faleskog Jonas
Published: May 2015

In this work, the significance of residual stresses on ductile fracture is investigated by a set of experiments that are analyzed by finite element simulations. The treatment of residual stresses as expressed in fracture assessment procedures such as R6 is believed to be very conservative for ductile materials, when fracture occurs at high primary loads. Earlier numerical studies have reinforced this belief. This is supported in the current study. Tests on notched 3PB specimens with and without residual stresses were conducted on two ferritic steels. The residual stresses were introduced by applying a compressive preload on notched specimens. The tests were designed to achieve crack initiation at load levels around the plastic limit load. The crack growth in the tests was measured by a compliance method and by color marking of the crack surface. The crack tip driving force J was evaluated numerically for specimens with and without residual stresses. The experimental results show that the residual stresses clearly contribute to J at low primary loads. However, this contribution diminishes as the primary loads increase. The experimental results were also compared with results evaluated using the R6 procedure. These comparisons revealed overly high conservatism in R6 for cases with residual stresses compared to the ones for cases without residual stresses where less conservatism was evident.
Elastic Leak for a Better Seal
Authors: Wang Zhengjin , Liu Qihan , Lou Yucun , Jin Henghua , Suo Zhigang
Published: May 2015

Elastomeric seals are widely used to block fluids of high pressure. When multiple seals are installed in series and the spaces between the seals contain compressible fluids (e.g., gas or gas–liquid mixture), the seals often damage sequentially, one after another. Here, we demonstrate that the serial seals achieve high sealing capacity if individual seals undergo elastic leak, without material damage. When individual seals leak elastically, fluid fills the spaces between the seals. Instead of damage one after another, all the seals share the load. The elastic leak of individual seals greatly amplifies collective sealing capacity of serial seals.
Tailoring the crystal structure of TiO2 thin films from the anatase to rutile phase
Authors: Kotake Haruka , Jia Junjun , Nakamura Shin-ichi , Okajima Toshihiro , Shigesato Yuzo
Published: May 2015

TiO2 films with various Sn concentrations were deposited on quartz substrates using rf reactive magnetron sputtering. The crystal structure was investigated by using x-ray diffraction, Raman spectroscopy, and transmission electron microscopy, and the chemical states of Ti and Sn were analyzed by x-ray absorption near edge structure (XANES) spectroscopy. Without Sn doping, TiO2 films change the crystal structure from rutile to anatase as the total gas pressure increases in the sputtering deposition. On the other hand, Sn doping induces the transformation of TiO2 crystalline structure from anatase to rutile phase, where the XANES spectra implied that Sn substitutes into Ti site of rutile TiO2. Atomic force microscope analyses revealed that the Sn-doped TiO2 films exhibited a flat surface with the roughness of approximately 2 nm.
The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway
Authors: Sjölin-Goodfellow Hanna , Frushicheva Maria P. , Ji Qinqin , Cheng Debra A. , Kadlecek Theresa A. , Cantor Aaron J. , Kuriyan John , Chakraborty Arup K. , Salomon Arthur R. , Weiss Arthur
Published: May 2015

The kinase ZAP-70 has both positive and negative functions in T cell signaling.
A molecular switch in the scaffold NHERF1 enables misfolded CFTR to evade the peripheral quality control checkpoint
Authors: Loureiro Cláudia A. , Matos Ana Margarida , Dias-Alves Ângela , Pereira Joana F. , Uliyakina Inna , Barros Patrícia , Amaral Margarida D. , Matos Paulo
Published: May 2015

A molecular switch in a scaffolding protein enables a misfolded, but partially functional, cystic fibrosis protein to evade a quality control checkpoint.
ERK reinforces actin polymerization to power persistent edge protrusion during motility
Authors: Mendoza Michelle C. , Vilela Marco , Juarez Jesus E. , Blenis John , Danuser Gaudenz
Published: May 2015

ERK signaling enables the leading edge of moving cells to generate enough force to sustain forward movement.
Impact of Ciprofloxacin and Clindamycin Administration on Gram-Negative Bacteria Isolated from Healthy Volunteers and Characterization of the Resistance Genes They Harbor
Authors: Card Roderick M. , Mafura Muriel , Hunt Theresa , Kirchner Miranda , Weile Jan , Rashid Mamun-Ur , Weintraub Andrej , Nord Carl Erik , Anjum Muna F.
Published: May 2015

The aim of this study was to assess the impact of ciprofloxacin, clindamycin, and placebo administration on culturable Gram-negative isolates and the antibiotic resistance genes they harbor. Saliva and fecal samples were collected from healthy human volunteers before and at intervals, up to 1 year after antibiotic administration. Samples were plated on selective and nonselective media to monitor changes in different colony types or bacterial species. Following ciprofloxacin administration, there was a decrease of
Escherichia coli
in feces and after clindamycin administration a decrease of
Bacteroides
in feces and
Leptotrichia
in saliva, which all returned to pretreatment levels within 1 to 4 months. Ciprofloxacin administration also resulted in an increase in ciprofloxacin-resistant
Veillonella
in saliva, which persisted for 12 months. Additionally, 949 aerobic and anaerobic isolates purified from ciprofloxacin- and clindamycin-containing plates were screened for the presence of resistance genes. Resistance gene carriage was widespread in isolates from all three treatment groups, and no association was observed between genes and antibiotic administration. Although the anaerobic component of the microbiota was not a major reservoir of aerobe-associated antimicrobial resistance (AMR) genes, we detected the sulfonamide resistance gene
sul2
in anaerobic isolates. The longitudinal nature of the study allowed identification of distinct
Escherichia coli
clones harboring multiple resistance genes, including one carrying an extended-spectrum β-lactamase
bla
CTX-M
group 9 gene, which persisted in the gut for up to 4 months. This study provided insight into the effects of antibiotic administration on healthy microbiota and the diversity of resistance genes harbored therein.
Gametocyte Clearance Kinetics Determined by Quantitative Magnetic Fractionation in Melanesian Children with Uncomplicated Malaria Treated with Artemisinin Combination Therapy
Authors: Karl Stephan , Laman Moses , Moore Brioni R. , Benjamin John , Koleala Tamarah , Ibam Clemencia , Kasian Bernadine , Siba Peter M. , Waltmann Andreea , Mueller Ivo , Woodward Robert C. , St. Pierre Timothy G. , Davis Timothy M. E.
Published: May 2015

Quantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 Papua New Guinean children with uncomplicated
Plasmodium falciparum
and/or
Plasmodium vivax
malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. There was an initial rise in peripheral
P. falciparum
gametocyte density with both treatments, but it was more pronounced in the artemisinin-naphthoquine group. Model-derived estimates of the median pretreatment sequestered gametocyte population were 21/μl for artemether-lumefantrine and 61/μl for artemisinin-naphthoquine (
P
< 0.001). The median time for
P. falciparum
gametocyte density to fall to <2.5/μl (below which transmission becomes unlikely) was 16 days in the artemether-lumefantrine group and 20 days in artemisinin-naphthoquine group (
P
< 0.001). Gametocyte prevalence modeling suggested that artemisinin-naphthoquine-treated children became gametocytemic faster (median, 2.2 days) than artemether-lumefantrine-treated children (median, 5.3 days;
P
< 0.001) and had a longer median
P. falciparum
gametocyte carriage time per individual (20 versus 13 days;
P
< 0.001). Clearance of
P. vivax
gametocytes was rapid (within 3 days) in both groups; however, consistent with the reappearance of asexual forms in the main trial, nearly 40% of children in the artemether-lumefantrine group developed
P. vivax
gametocytemia between days 28 and 42 compared with 3% of children in the artemisinin-naphthoquine group. These data suggest that artemisinin is less active than artemether against sequestered gametocytes. Greater initial gametocyte release after artemisinin-naphthoquine increases the period of potential
P. falciparum
transmission by 4 days relative to artemether-lumefantrine, but the longer elimination half-life of naphthoquine than of lumefantrine suppresses
P. vivax
recurrence and consequent gametocytemia.
Retrograde Trafficking Inhibitor of Shiga Toxins Reduces Morbidity and Mortality of Mice Infected with Enterohemorrhagic Escherichia coli
Authors: Secher T. , Shima A. , Hinsinger K. , Cintrat J. C. , Johannes L. , Barbier J. , Gillet D. , Oswald E.
Published: May 2015

The most deadly outbreak of
Escherichia coli
O104:H4 occurred in Europe in 2011. Here, we evaluated the effects of the retrograde trafficking inhibitor Retro-2
cycl
in a murine model of
E. coli
O104:H4 infection. Systemic treatment with Retro-2
cycl
significantly reduced body weight loss and improved clinical scores and survival rates for O104:H4-infected mice. The present data established that Retro-2
cycl
contributes to the protection of mice against O104:H4 infection and may represent a novel approach to limit Shiga toxin-producing
Escherichia coli
(STEC)-induced toxicity.
bla
CTX-M-1/9/1
Hybrid Genes May Have Been Generated from
bla
CTX-M-15
on an IncI2 Plasmid
Authors: Liu Lanping , He Dandan , Lv Luchao , Liu Wuling , Chen Xiaojie , Zeng Zhenling , Partridge Sally R. , Liu Jian-Hua
Published: May 2015

Three hybrid CTX-M β-lactamases, CTX-M-64, CTX-M-123, and CTX-M-132, with N and C termini matching CTX-M-1 group enzymes and centers matching CTX-M-9 group enzymes, have been identified. The hybrid gene sequences suggested recombination between
bla
CTX-M-15
and
bla
CTX-M-14
, the two most common
bla
CTX-M
variants worldwide. However,
bla
CTX-M-64
and
bla
CTX-M-123
are found in an IS
Ecp1-bla
CTX-M
transposition unit with a 45-bp “spacer,” rather than the 48 bp usually associated with
bla
CTX-M-15
, and 112 bp of IncA/C plasmid backbone. This is closer to the context of
bla
CTX-M-55
, which has one nucleotide difference from
bla
CTX-M-15
, on IncI2 plasmid pHN1122-1. Here, we characterized an IncI2 plasmid carrying
bla
CTX-M-15
with a 45-bp spacer (pHNY2-1) by complete sequencing and also sequenced IncI2 plasmids carrying
bla
CTX-M-64
(pHNAH46-1) or
bla
CTX-M-132
(pHNLDH19) and an IncI1 plasmid carrying
bla
CTX-M-123
(pHNAH4-1). pHNY2-1 has the same IS
Ecp1-bla
CTX-M
-IncA/C insertion as pHN1122-1, pHNAH46-1, and pHNLDH19, and all four plasmid backbones are almost identical. pHNAH4-1 (IncI1 sequence type 108 [ST108]) carries a transposition unit that includes a 2,720-bp fragment of the IncI2 backbone, suggesting IS
Ecp1
-mediated transfer of
bla
CTX-M
-IncA/C-IncI2 to an IncI1 plasmid. All three hybrid
bla
CTX-M
genes may have resulted from recombination between
bla
CTX-M-14
and
bla
CTX-M-15
with a 45-bp spacer on an IncI2 plasmid. Five additional
Escherichia coli
isolates of different sequence types from different provinces, farms, and/or animals had
bla
CTX-M-64
on a pHNAH46-1-like IncI2 plasmid and 9 had
bla
CTX-M-123
on a pHNAH4-1-like IncI1 ST108 plasmid. Thus, epidemic IncI plasmids may be responsible for the spread of
bla
CTX-M-64
and
bla
CTX-M-123
between different animals and different locations in China.
MEDI4893* Promotes Survival and Extends the Antibiotic Treatment Window in a Staphylococcus aureus Immunocompromised Pneumonia Model
Authors: Hua L. , Cohen T. S. , Shi Y. , Datta V. , Hilliard J. J. , Tkaczyk C. , Suzich J. , Stover C. K. , Sellman B. R.
Published: May 2015

Immunocompromised individuals are at increased risk of
Staphylococcus aureus
pneumonia. Neutralization of alpha-toxin (AT) with the monoclonal antibody (MAb) MEDI4893* protects normal mice from
S. aureus
pneumonia; however, the effects of the MAb in immunocompromised mice have not been reported. In this study, passive immunization with MEDI4893* increased survival rates and reduced bacterial numbers in the lungs in an immunocompromised murine
S. aureus
pneumonia model. Lungs from infected mice exhibited alveolar epithelial damage, protein leakage, and bacterial overgrowth, whereas lungs from mice passively immunized with MEDI4893* retained a healthy architecture, with an intact epithelial barrier. Adjunctive therapy or prophylaxis with a subtherapeutic MEDI4893* dose combined with subtherapeutic doses of vancomycin or linezolid improved survival rates, compared with the monotherapies. Furthermore, coadministration of MEDI4893* with vancomycin or linezolid extended the antibiotic treatment window. These data suggest that MAb-mediated neutralization of AT holds promise in strategies for prevention and adjunctive therapy among immunocompromised patients.
Ecological Effect of Ceftaroline-Avibactam on the Normal Human Intestinal Microbiota
Authors: Rashid Mamun-Ur , Rosenborg Staffan , Panagiotidis Georgios , Söderberg-Löfdal Karin , Weintraub Andrej , Nord Carl Erik
Published: May 2015

Ceftaroline-avibactam is a new combination of the antibiotic ceftaroline with a novel non-β-lactam β-lactamase inhibitor, avibactam. The purpose of the present study was to investigate the effect of ceftaroline-avibactam on the human intestinal microbiota. Fourteen healthy volunteers received ceftaroline-avibactam (600 mg ceftaroline fosamil and 600 mg avibactam) intravenously over 2 h every 8 h on days 1 to 6 and as a single dose on day 7. Fecal samples were collected on day −1 (within 24 h of the first infusion on day 1) and on days 2, 5, 7, 9, 14, and 21.Escherichia colinumbers decreased during the study and normalized on day 21. An increased number ofKlebsiellabacteria appeared on day 14 and normalized on day 21. The number of other enterobacteria decreased during the study, and the number of enterococci decreased from days 2 to 7 and normalized on day 9.Candidanumbers increased from days 5 to 9 and normalized after day 14. The number of lactobacilli decreased during the study and recovered on day 14. The number of bifidobacteria decreased on day 2 and normalized on day 21. The number ofBacteroidesbacteria was unchanged.Clostridium difficilenumbers decreased on days 7 and 9 and increased on days 14 and 21. A toxigenicC. difficilestrain was detected in one volunteer on day 21 with no reported adverse events. Plasma samples were collected on days −1, 2, 5, and 7. Ceftaroline and avibactam concentrations were 0 to 34.5 mg/liter and 0 to 61.6 mg/liter, respectively, in plasma and 0 to 35.4 mg/kg and 0 to 98.5 mg/kg, respectively, in feces. (This study is registered in the European Clinical Trials Database [https://eudract.ema.europa.eu/] under number EudraCT 2012 004921-25.)
Identification of New Natural CphA Metallo-β-Lactamases CphA4 and CphA5 in Aeromonas veronii and Aeromonas hydrophila Isolates from Municipal Sewage in Central Italy
Authors: Bottoni Carlo , Marcoccia Francesca , Compagnoni Chiara , Colapietro Martina , Sabatini Alessia , Celenza Giuseppe , Segatore Bernardetta , Maturo Maria Giovanna , Amicosante Gianfranco , Perilli Mariagrazia
Published: May 2015

Two new natural CphA metallo-β-lactamases, the CphA4 and CphA5 enzymes, were identified in water samples from municipal sewage in central Italy. Compared to CphA, the CphA4 and CphA5 enzymes showed numerous point mutations. These enzymes have a narrow spectrum of substrates focused on carbapenems only. CphA5 showed
k
cat
values about 40-, 12-, and 97-fold higher than those observed for CphA4 versus imipenem, ertapenem, and biapenem, respectively.
The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis
Authors: Makarov Vadim , Neres João , Hartkoorn Ruben C. , Ryabova Olga B. , Kazakova Elena , Šarkan Michal , Huszár Stanislav , Piton Jérémie , Kolly Gaëlle S. , Vocat Anthony , Conroy Trent M. , Mikušová Katarína , Cole Stewart T.
Published: May 2015

8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-
d
-ribose 2′-oxidase (DprE1) and display nanomolar bactericidal activity against
Mycobacterium tuberculosis
in vitro
. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity. Here, we report the synthesis and characterization of the pyrrole-benzothiazinones PyrBTZ01 and PyrBTZ02, non-nitro-benzothiazinones that retain significant antimycobacterial activity, with MICs of 0.16 μg/ml against
M. tuberculosis
. These compounds inhibit DprE1 with 50% inhibitory concentration (IC
50
) values of <8 μM and present favorable
in vitro
absorption-distribution-metabolism-excretion/toxicity (ADME/T) and
in vivo
pharmacokinetic profiles. The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency.
Clonal Dissemination of OXA-370-Producing Klebsiella pneumoniae in Rio de Janeiro, Brazil
Authors: Pereira Polyana Silva , Borghi Mirla , de Araújo Carlos Felipe Machado , Aires Caio Augusto Martins , Oliveira Jane Cleide Ribeiro , Asensi Marise Dutra , Carvalho-Assef Ana Paula D'Alincourt
Published: May 2015

Enzymes of the OXA-48 family have become some of the most important beta-lactamases in the world. A new OXA-48 variant (OXA-370) was first described for anEnterobacter hormaecheistrain isolated in Rio Grande do Sul (southern region of Brazil) in 2013. Here we report detection of theblaOXA-370gene in 24 isolates belonging to threeEnterobacteriaceaespecies (22Klebsiella pneumoniaeisolates, 1Enterobacter cloacaeisolate, and 1Enterobacter aerogenesisolate) collected from five hospitals in Rio de Janeiro, Brazil, in 2013 and 2014. The isolates showed a multidrug resistance profile, and 12.5% were resistant to polymyxin B. BesidesblaOXA-370, no other carbapenemase genes were observed by PCR, whereasblaOXA-1was found in all isolates and 22 isolates (91.6%) possessedblaCTX-M-15. Molecular typing of theK. pneumoniaeisolates by pulsed-field gel electrophoresis (PFGE) showed the presence of two clonal groups, i.e., KpA (21 isolates) and KpB (1 isolate). KpA was characterized as sequence type 16 (ST16) and KpB as ST1041 by multilocus sequence typing (MLST). ST16 has been observed for KPC-producingK. pneumoniaein Rio de Janeiro. Plasmid analysis performed with six representative OXA-370-producing isolates showed plasmids harboring theblaOXA-370gene in all strains, ranging from 25 kb to 150 kb. This study suggests that there is an urgent need to investigate the presence of OXA-370 and dissemination of theK. pneumoniaeST16 clone carrying this gene in Brazil.
Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission
Authors: Caimano Melissa J. , Dunham-Ems Star , Allard Anna M. , Cassera Maria B. , Kenedy Melisha , Radolf Justin D.
Published: May 2015

Borrelia burgdorferi
, the Lyme disease spirochete, couples environmental sensing and gene regulation primarily via the Hk1/Rrp1 two-component system (TCS) and Rrp2/RpoN/RpoS pathways. Beginning with acquisition, we reevaluated the contribution of these pathways to spirochete survival and gene regulation throughout the enzootic cycle. Live imaging of
B. burgdorferi
caught in the act of being acquired revealed that the absence of RpoS and the consequent derepression of tick-phase genes impart a Stay signal required for midgut colonization. In addition to the behavioral changes brought on by the RpoS-off state, acquisition requires activation of cyclic di-GMP (c-di-GMP) synthesis by the Hk1/Rrp1 TCS;
B. burgdorferi
lacking either component is destroyed during the blood meal. Prior studies attributed this dramatic phenotype to a metabolic lesion stemming from reduced glycerol uptake and utilization. In a head-to-head comparison, however, the
B. burgdorferi
Δ
glp
mutant had a markedly greater capacity to survive tick feeding than
B. burgdorferi
Δ
hk1
or Δ
rrp1
mutants, establishing unequivocally that glycerol metabolism is only one component of the protection afforded by c-di-GMP. Data presented herein suggest that the protective response mediated by c-di-GMP is multifactorial, involving chemotactic responses, utilization of alternate substrates for energy generation and intermediary metabolism, and remodeling of the cell envelope as a means of defending spirochetes against threats engendered during the blood meal. Expression profiling of c-di-GMP-regulated genes through the enzootic cycle supports our contention that the Hk1/Rrp1 TCS functions primarily, if not exclusively, in ticks. These data also raise the possibility that c-di-GMP enhances the expression of a subset of RpoS-dependent genes during nymphal transmission.