bluuebunny/crossref_metadata_2025 huggingface dataset:
Sparse Additive Regression on a Regular Lattice
Authors: Abramovich Felix , Lahav Tal
Published: July 2014

We consider estimation in a sparse additive regression model with the design points on a regular lattice. We establish the minimax convergence rates over Sobolev classes and propose a Fourier-based rate optimal estimator which is adaptive to the unknown sparsity and smoothness of the response function. The estimator is derived within a Bayesian formalism but can be naturally viewed as a penalized maximum likelihood estimator with the complexity penalties on the number of non-zero univariate additive components of the response and on the numbers of the non-zero coefficients of their Fourer expansions. We compare it with several existing counterparts and perform a short simulation study to demonstrate its performance.
Doubly Robust Estimation of the Local Average Treatment Effect Curve
Authors: Ogburn Elizabeth L. , Rotnitzky Andrea , Robins James M.
Published: July 2014

We consider estimation of the causal effect of a binary treatment on an outcome, conditionally on covariates, from observational studies or natural experiments in which there is a binary instrument for treatment. We describe a doubly robust, locally efficient estimator of the parameters indexing a model for the local average treatment effect conditionally on covariates V when randomization of the instrument is only true conditionally on a high dimensional vector of covariates X, possibly bigger than V. We discuss the surprising result that inference is identical to inference for the parameters of a model for an additive treatment effect on the treated conditionally on V that assumes no treatment–instrument interaction. We illustrate our methods with the estimation of the local average effect of participating in 401(k) retirement programmes on savings by using data from the US Census Bureau's 1991 Survey of Income and Program Participation.
Phenotypically matched vs. traditional screen method for preparing red blood cell units in patients with abnormal placentation: a decision analysis approach
Authors: Pham H. P. , Kim C. H. , Schwartz J.
Published: July 2014

Background

Patients with abnormal placentation are hospitalized approximately 21 days prior to scheduled delivery due to risk of peri‐partum bleeding. It is required to have at least one red blood cell (RBC) unit ready throughout hospitalization. This can be accomplished by performing a type and cross (T&C) every 72 h (traditional method) or providing phenotypically matched RBC units (alternative method).

Methods

A Markov‐based model was created to compare the cost‐benefits between these two methods. A patient either undergoes the traditional or alternative method. If the patient already made an antibody and/or has rare phenotypes requiring frozen RBC unit at admission, then she can only enter the traditional method. All patients receive a T&C at the end of the 21st day in order to prepare RBC units for scheduled delivery. Model parameters are derived from literature and institutional experiences.

Results

Simulation was run for modelling of the 21‐day hospitalization of each patient. The expected cost per RBC unit of the traditional method is significantly higher than the alternative method (876·59 vs. 608·32 USD, P‐value <0·01). For each RBC unit, 4·85 h of technician working time is saved by the alternative method. However, to be cost‐beneficial, the alternative method should be used only if the total cost of a RBC unit is <857·67 USD.

Conclusion

Our model demonstrated that preparing phenotypically matched RBC units at admission is more cost‐beneficial comparing to the traditional method of T&C every 72 h if the cost for the matched unit is <857·67 USD.
Topical 5‐azacytidine accelerates skin wound healing in rats
Authors: Gomes Fabiana S. , de‐Souza Gabriela F. , Nascimento Lucas F. , Arantes Eva L. , Pedro Rafael M. , Vitorino Daniele C. , Nunez Carla E. , Melo Lima Maria H. , Velloso Lício A. , Araújo Eliana P.
Published: July 2014

The development of new methods to improve skin wound healing may affect the outcomes of a number of medical conditions. Here, we evaluate the molecular and clinical effects of topical 5‐azacytidine on wound healing in rats. 5‐Azacytidine decreases the expression of follistatin‐1, which negatively regulates activins. Activins, in turn, promote cell growth in different tissues, including the skin. Eight‐week‐old male Wistar rats were submitted to 8.0‐mm punch‐wounding in the dorsal region. After 3 days, rats were randomly assigned to receive either a control treatment or the topical application of a solution containing 5‐azacytidine (10 mM) once per day. Photo documentation and sample collection were performed on days 5, 9, and 15. Overall, 5‐azacytidine promoted a significant acceleration of complete wound healing (99.7% ± 0.7.0 vs. 71.2% ± 2.8 on day 15; n = 10; p < 0.01), accompanied by up to threefold reduction in follistatin expression. Histological examination of the skin revealed efficient reepithelization and cell proliferation, as evaluated by the BrdU incorporation method. 5‐Azacytidine treatment also resulted in increased gene expression of transforming growth factor‐beta and the keratinocyte markers involucrin and cytokeratin, as well as decreased expression of cytokines such as tumor necrosis factor‐alpha and interleukin‐10. Lastly, when recombinant follistatin was applied to the skin in parallel with topical 5‐azacytidine, most of the beneficial effects of the drug were lost. Thus, 5‐azacytidine acts, at least in part through the follistatin/activin pathway, to improve skin wound healing in rodents.
Species delimitation in the Chinese bamboo partridge Bambusicola thoracica (Phasianidae; Aves)
Authors: Hung Chih‐Ming , Hung Hsin‐Yi , Yeh Chia‐Fen , Fu Yi‐Qiang , Chen De , Lei Fumin , Yao Cheng‐Te , Yao Chiou‐Ju , Yang Xiao‐Jun , Lai Yu‐Ting , Li Shou‐Hsien
Published: July 2014

Although tropical and subtropical Asia harbour a high level of species diversity, their species richness can be underestimated because species which are in fact distinct have not been separately identified. In this study, we delimit Bambusicola thoracica into two full species, the Chinese bamboo partridge (B. thoracica) in continental Asia and the Taiwanese bamboo partridge (B. sonorivox) on the island of Taiwan, using coalescent‐based multilocus division and diagnosable vocalization patterns. Isolation‐with‐migration analysis indicated that the two bamboo partridges diverged approximately 1.8 million years ago, with gene flow present most probably during the early stages of their divergence. This conclusion supports the hypothesis that diverging lowland lineages spread across the Asian mainland, and continental islands have more opportunities for secondary contact than highland ones when the sea level was low. Our results imply that conservation of biodiversity in tropical and subtropical Asia could be hindered by overlooking numerous ‘hidden’ species and highlight the importance of re‐examining the taxonomic statuses of species in this region traditionally defined as polytypic.
Random walks on projective spaces
Authors: Benoist Yves , Quint Jean-François
Published: July 2014

Let $\def \xmlpi #1{}\def \mathsfbi #1{\boldsymbol {\mathsf {#1}}}\let \le =\leqslant \let \leq =\leqslant \let \ge =\geqslant \let \geq =\geqslant \def \Pr {\mathit {Pr}}\def \Fr {\mathit {Fr}}\def \Rey {\mathit {Re}}G$ be a connected real semisimple Lie group, $V$ be a finite-dimensional representation of $G$ and $\mu $ be a probability measure on $G$ whose support spans a Zariski-dense subgroup. We prove that the set of ergodic $\mu $-stationary probability measures on the projective space $\mathbb{P}(V)$ is in one-to-one correspondence with the set of compact $G$-orbits in $\mathbb{P}(V)$. When $V$ is strongly irreducible, we prove the existence of limits for the empirical measures. We prove related results over local fields as the finiteness of the set of ergodic $\mu $-stationary measures on the flag variety of $G$.
Matrix factorizations via Koszul duality
Authors: Tu Junwu
Published: July 2014

In this paper we prove a version of curved Koszul duality for $\def \xmlpi #1{}\def \mathsfbi #1{\boldsymbol {\mathsf {#1}}}\let \le =\leqslant \let \leq =\leqslant \let \ge =\geqslant \let \geq =\geqslant \def \Pr {\mathit {Pr}}\def \Fr {\mathit {Fr}}\def \Rey {\mathit {Re}}\mathbb{Z}/2\mathbb{Z}$-graded curved coalgebras and their cobar differential graded algebras. A curved version of the homological perturbation lemma is also obtained as a useful technical tool for studying curved (co)algebras and precomplexes. The results of Koszul duality can be applied to study the category of matrix factorizations $\mathsf{MF}(R,W)$. We show how Dyckerhoff’s generating results fit into the framework of curved Koszul duality theory. This enables us to clarify the relationship between the Borel–Moore Hochschild homology of curved (co)algebras and the ordinary Hochschild homology of the category $\mathsf{MF}(R,W)$. Similar results are also obtained in the orbifold case and in the graded case.
Vibration Damping of Thermal Barrier Coatings Containing Ductile Metallic Layers
Authors: Casadei Filippo , Bertoldi Katia , Clarke David R.
Published: July 2014

This paper explores the vibration damping properties of thermal barrier coatings (TBCs) containing thin plastically deformable metallic layers embedded in an elastic ceramic matrix. We develop an elastic–plastic dynamical model to study how work hardening, yield strain, and elastic modulus of the metal affect the macroscopic damping behavior of the coating. Finite element (FE) simulations validate the model and are used to estimate the damping capacity under axial and flexural vibration conditions. The model also provides an explanation for the widely observed nonlinear variation of the loss factor with strain in plasma-spayed TBCs. Furthermore, it facilitates the identification of multilayer configurations that maximize energy dissipation.
Trunk Angular Kinematics During Slip-Induced Backward Falls and Activities of Daily Living
Authors: Liu Jian , Lockhart Thurmon E.
Published: July 2014

Prior to developing any specific fall detection algorithm, it is critical to distinguish the unique motion features associated with fall accidents. The current study aimed to investigate the upper trunk angular kinematics during slip-induced backward falls and activities of daily living (ADLs). Ten healthy older adults (age = 75 ± 6 yr (mean ± SD)) were involved in a laboratory study. Sagittal trunk angular kinematics were measured using optical motion analysis system during normal walking, slip-induced backward falls, lying down, bending over, and various types of sitting down (SN). Trunk angular phase-plane plots were generated to reveal the motion features of falls. It was found that backward falls were characterized by a simultaneous occurrence of a slight trunk extension and an extremely high trunk extension velocity (peak average = 139.7 deg/s), as compared to ADLs (peak average = 84.1 deg/s). It was concluded that the trunk extension angular kinematics of falls were clearly distinguishable from those of ADLs from the perspective of angular phase-plane plot. Such motion features can be utilized in future studies to develop a new prior-to-impact fall detection algorithm.
Mechanical Characterization of Microcapsules With Membrane Permeability by Using Indentation Analysis
Authors: Bando Kiyoshi
Published: July 2014

Mechanical modeling of the deformation of a liquid-filled spherical microcapsule indented by a sharp truncated-cone indenter was proposed, in which membrane permeability was taken into account. The change in the internal volume of the microcapsule due to fluid permeation was calculated on the basis of Kedem and Katchalsky equations (1958, “Thermodynamic Analysis of the Permeability of Biological Membranes to Non-electrolytes,” Biochim. Biophys. Acta, 27, pp. 229–246). The membrane hydraulic permeability, membrane initial stretch, and effective osmotic pressure difference across the membrane of an alginate–poly(l)lysine–alginate (APA) microcapsule were identified by fitting calculated and measured force–displacement curves. The difference between deformed shapes with and without membrane permeability was shown, suggesting the spatial resolution of image analysis performed to measure the membrane permeability from the volume loss. The influences of changes in permeability, initial stretch, and a parameter β, used for determining the effective osmotic pressure difference, on the force–displacement relationship were examined, and mechanisms causing changes in the force–displacement relationship were discussed.
Surface-enhanced Raman scattering and gap-mode tip-enhanced Raman scattering investigations of phthalocyanine molecules on gold nanostructured substrates
Authors: Sheremet Evgeniya , Rodriguez Raul D. , Zahn Dietrich R. T. , Milekhin Alexander G. , Rodyakina Ekaterina E. , Latyshev Alexander V.
Published: July 2014

This study reports the use of surface-enhanced Raman scattering (SERS) and tip-enhanced Raman scattering (TERS), both independent and in combination, to investigate Raman enhancement of films under different confinement geometries. The experiments are performed on ultrathin cobalt phthalocyanine (CoPc) films deposited on specially designed SERS structures. The SERS structures are fabricated by electron-beam lithography and contain nanostructured gold films and gold dimer arrays with controlled size and internanocluster distance. Such structures allow investigation of the effects of nanocluster size and internanocluster distance, excitation wavelength, and polarization of light upon the electromagnetic SERS enhancement. Significant enhancement of the Raman scattering by CoPc is observed under 632.8 nm excitation because of the double resonance originating from the energy match between the laser excitation and the localized surface plasmon and electronic transitions in CoPc. The SERS signal of CoPc is further enhanced by decreasing the internanocluster distance. Maximum SERS enhancement occurs when the polarization of the incident light is perpendicular to the dimer axis. Under 514.5 nm excitation, nanostructured gold films give greater enhancement than any of the nanocluster arrays, with the highest enhancement realized using the so-called “gap-mode TERS” wherein the SERS structures are probed in the TERS condition. The TERS experiment is performed using a customized TERS setup and all-metal atomic force microscopy tips custom fabricated. In terms of obtaining the ultimate sensitivity in Raman spectroscopy, further enhancement is achieved by confining the electromagnetic field in a gap between two metallic nanostructures either by using SERS or by combining SERS and TERS.
Human tRNA synthetase catalytic nulls with diverse functions
Authors: Lo Wing-Sze , Gardiner Elisabeth , Xu Zhiwen , Lau Ching-Fun , Wang Feng , Zhou Jie J. , Mendlein John D. , Nangle Leslie A. , Chiang Kyle P. , Yang Xiang-Lei , Au Kin-Fai , Wong Wing Hung , Guo Min , Zhang Mingjie , Schimmel Paul
Published: July 2014

Evolving from an enzyme and into a regulator

Proteins, the work-horses of the cell, are made on a messenger RNA (mRNA) template. An enzyme called aminoacyl tRNA synthetases (AARSs) attaches the correct amino acid to a transfer RNA so that mRNA is accurately translated. Over evolution, additional sequences have been added to AARSs. Lo
et al.
found a large number of AARS variants in which the domain responsible for enzyme function was deleted. Ninety-four such variants had diverse signaling activities. Thus, AARSs are used both as enzymes and alternately as regulators of signaling pathways.

Science
, this issue p.
328
Imaging charge transfer in iodomethane upon x-ray photoabsorption
Authors: Erk Benjamin , Boll Rebecca , Trippel Sebastian , Anielski Denis , Foucar Lutz , Rudek Benedikt , Epp Sascha W. , Coffee Ryan , Carron Sebastian , Schorb Sebastian , Ferguson Ken R. , Swiggers Michele , Bozek John D. , Simon Marc , Marchenko Tatiana , Küpper Jochen , Schlichting Ilme , Ullrich Joachim , Bostedt Christoph , Rolles Daniel , Rudenko Artem
Published: July 2014

Tightly tracking charge migration

Electron transfer dynamics underlie many chemical and biochemical reactions. Erk
et al.
examined the charge migration between individual carbon and iodine atoms during dissociation of iodomethane (ICH
3
) molecules (see the Perspective by Pratt). After initiating scission of the C-I bond with a relatively low-energy laser pulse, they introduced a higher-energy x-ray pulse to instigate ionization and charge migration. Delaying the arrival time of the x-ray pulse effectively varied the separation distance being probed as the fragments steadily drifted apart. The experimental approach should also prove useful for future studies of charge transfer dynamics in different molecular or solid-state systems.

Science
, this issue p.
288
; see also p.
267
Alarm over biosafety blunders
Authors: Cohen Jon
Published: July 2014

Lapses stoke debate about flu virus research.
A radical change in peer review
Authors: Mervis Jeffrey
Published: July 2014

A pilot project to ease pressure on NSF's vaunted peer-review system required grant applicants to review seven competing proposals.
Proteins and a pregnancy woe
Authors: Whitehead Nadia
Published: July 2014

Surprising insight into preeclampsia may offer early warning for at-risk women.
Draft Genome Sequencing of Vibrio cholerae O1 El Tor Isolates Collected in the Russian Federation from Imported Cholera Cases
Authors: Kuleshov Konstantin V. , Vodop'ianov Sergey O. , Dedkov Vladimir G. , Markelov Mikhail L. , Kermanov Anton V. , Kruglikov Vladimir D. , Vodop'ianov Alexey S. , Pisanov Ruslan V. , Chemisova Olga S. , Mazrukho Alexey B. , Titova Svetlana V. , Shipulin German A.
Published: July 2014

We report the draft genome sequencing of five
Vibrio cholerae
O1 El Tor clinical isolates collected in the Russian Federation from imported cholera cases in 2006, 2010, and 2012. In the initial phylogenetic analysis, one isolate clustered with the Haiti/Nepal-4 group.
Draft Genome Sequence of
Deinococcus
sp. Strain RL Isolated from Sediments of a Hot Water Spring
Authors: Mahato Nitish Kumar , Tripathi Charu , Verma Helianthous , Singh Neha , Lal Rup
Published: July 2014

Deinococcus
sp. strain RL, a moderately thermophilic bacterium, was isolated from sediments of a hot water spring in Manikaran, India. Here, we report the draft genome (2.79 Mbp) of this strain, which contains 62 contigs and 2,614 coding DNA sequences, with an average G+C content of 69.4%.
Evaluation of FilmArray and Verigene Systems for Rapid Identification of Positive Blood Cultures
Authors: Bhatti M. M. , Boonlayangoor S. , Beavis K. G. , Tesic V.
Published: July 2014

The Verigene tests for Gram-positive and Gram-negative organisms in blood culture and the FilmArray blood culture identification panel were assessed for their ability to identify pathogens from positive blood cultures. Both platforms correctly identified bacteria in 92% of monomicrobial cultures analyzed, with times to identification that were significantly shorter than those for identification from subcultures.
Prolidase Is Required for Early Trafficking Events during Influenza A Virus Entry
Authors: Pohl Marie O. , Edinger Thomas O. , Stertz Silke
Published: July 2014

Influenza A virus (IAV) entry is a multistep process that requires the interaction of the virus with numerous host factors. In this study, we demonstrate that prolidase (PEPD) is a cellular factor required by IAV for successful entry into target cells. PEPD was selected as a candidate during an entry screen performed on nonvalidated primary hits from previously published genome-wide small interfering RNA (siRNA) screens. siRNA-mediated depletion of PEPD resulted in the decreased growth of IAV during mono- and multicycle growth. This growth defect was independent of cell type or virus strain. Furthermore, IAV restriction was apparent as early as 3 h postinfection, and experiments in the absence of protein biosynthesis revealed that the nuclear import of viral ribonucleoprotein complexes (vRNPs) was already blocked in the absence of PEPD. These results led us to investigate which step during entry was affected. Receptor expression, IAV attachment, or IAV internalization was not dependent on the presence of PEPD. However, when looking at the distribution of incoming IAV particles in PEPD-knockdown cells, we found a localization pattern that differed from that in control cells: IAV mostly localized to the cell periphery, and consequently, viral particles displayed reduced colocalization with early and late endosome markers and fusion between viral and endosomal membranes was strongly reduced. Finally, experiments using a competitive inhibitor of PEPD catalytic activity suggested that the enzymatic function of the dipeptidase is required for its proviral effect on IAV entry. In sum, this study establishes PEPD as a novel entry factor required for early endosomal trafficking of IAV.

IMPORTANCE
Influenza A virus (IAV) continues to be a constant threat to public health. As IAV relies on its host cell for replication, the identification of host factors required by the virus is of importance. First, such studies often reveal novel functions of cellular factors and can extend our knowledge of cellular processes. Second, we can further our understanding of processes that are required for the entry of IAV into target cells. Third, the identification of host factors that contribute to IAV entry will increase the number of potential targets for the development of novel antiviral drugs that are of urgent need. Our study identifies prolidase (PEPD) to be a novel entry factor required by IAV for correct routing within the endosomal compartment following virus internalization. Thereby, we link PEPD, which has been shown to play a role during collagen recycling and growth factor signaling, to early events of viral infection.
Annexin V Incorporated into Influenza Virus Particles Inhibits Gamma Interferon Signaling and Promotes Viral Replication
Authors: Berri Fatma , Haffar Ghina , Lê Vuong Ba , Sadewasser Anne , Paki Katharina , Lina Bruno , Wolff Thorsten , Riteau Béatrice
Published: July 2014

During the budding process, influenza A viruses (IAVs) incorporate multiple host cell membrane proteins. However, for most of them, their significance in viral morphogenesis and infectivity remains unknown. We demonstrate here that the expression of annexin V (A5) is upregulated at the cell surface upon IAV infection and that a substantial proportion of the protein is present in lipid rafts, the site of virus budding. Western blotting and immunogold analysis of highly purified IAV particles showed the presence of A5 in the virion. Significantly, gamma interferon (IFN-γ)-induced Stat phosphorylation and IFN-γ-induced 10-kDa protein (IP-10) production in macrophage-derived THP-1 cells was inhibited by purified IAV particles. Disruption of the IFN-γ signaling pathway was A5 dependent since downregulation of its expression or its blockage reversed the inhibition and resulted in decreased viral replication
in vitro
. The functional significance of these results was also observed
in vivo
. Thus, IAVs can subvert the IFN-γ antiviral immune response by incorporating A5 into their envelope during the budding process.

IMPORTANCE
Many enveloped viruses, including influenza A viruses, bud from the plasma membrane of their host cells and incorporate cellular surface proteins into viral particles. However, for the vast majority of these proteins, only the observation of their incorporation has been reported. We demonstrate here that the host protein annexin V is specifically incorporated into influenza virus particles during the budding process. Importantly, we showed that packaged annexin V counteracted the antiviral activity of gamma interferon
in vitro
and
in vivo
. Thus, these results showed that annexin V incorporated in the viral envelope of influenza viruses allow viral escape from immune surveillance. Understanding the role of host incorporated protein into virions may reveal how enveloped RNA viruses hijack the host cell machinery for their own purposes.
Rooting the Phylogenetic Tree of Middle East Respiratory Syndrome Coronavirus by Characterization of a Conspecific Virus from an African Bat
Authors: Corman Victor Max , Ithete Ndapewa Laudika , Richards Leigh Rosanne , Schoeman M. Corrie , Preiser Wolfgang , Drosten Christian , Drexler Jan Felix
Published: July 2014

The emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes lethal respiratory infections mainly on the Arabian Peninsula. The evolutionary origins of MERS-CoV are unknown. We determined the full genome sequence of a CoV directly from fecal material obtained from a South African
Neoromicia capensis
bat (NeoCoV). NeoCoV shared essential details of genome architecture with MERS-CoV. Eighty-five percent of the NeoCoV genome was identical to MERS-CoV at the nucleotide level. Based on taxonomic criteria, NeoCoV and MERS-CoV belonged to one viral species. The presence of a genetically divergent S1 subunit within the NeoCoV
spike
gene indicated that intraspike recombination events may have been involved in the emergence of MERS-CoV. NeoCoV constitutes a sister taxon of MERS-CoV, placing the MERS-CoV root between a recently described virus from African camels and all other viruses. This suggests a higher level of viral diversity in camels than in humans. Together with serologic evidence for widespread MERS-CoV infection in camelids sampled up to 20 years ago in Africa and the Arabian Peninsula, the genetic data indicate that camels act as sources of virus for humans rather than vice versa. The majority of camels on the Arabian Peninsula is imported from the Greater Horn of Africa, where several
Neoromicia
species occur. The acquisition of MERS-CoV by camels from bats might have taken place in sub-Saharan Africa. Camelids may represent mixing vessels for MERS-CoV and other mammalian CoVs.

IMPORTANCE
It is unclear how, when, and where the highly pathogenic MERS-CoV emerged. We characterized the full genome of an African bat virus closely related to MERS-CoV and show that human, camel, and bat viruses belong to the same viral species. The bat virus roots the phylogenetic tree of MERS-CoV, providing evidence for an evolution of MERS-CoV in camels that preceded that in humans. The revised tree suggests that humans are infected by camels rather than vice versa. Although MERS-CoV cases occur mainly on the Arabian Peninsula, the data from this study together with serologic and molecular investigations of African camels indicate that the initial host switch from bats may have taken place in Africa. The emergence of MERS-CoV likely involved exchanges of genetic elements between different viral ancestors. These exchanges may have taken place either in bat ancestors or in camels acting as mixing vessels for viruses from different hosts.
Seed Sequence-Matched Controls Reveal Limitations of Small Interfering RNA Knockdown in Functional and Structural Studies of Hepatitis C Virus NS5A-MOBKL1B Interaction
Authors: Chung Hyo-Young , Gu Meigang , Buehler Eugen , MacDonald Margaret R. , Rice Charles M.
Published: July 2014

Hepatitis C virus (HCV) is a widespread human pathogen causing liver cirrhosis and cancer. Similar to the case for other viruses, HCV depends on host and viral factors to complete its life cycle. We used proteomic and yeast two-hybrid approaches to elucidate host factors involved in HCV nonstructural protein NS5A function and found that MOBKL1B interacts with NS5A. Initial experiments with small interfering RNA (siRNA) knockdown suggesting a role in HCV replication led us to examine the interaction using biochemical and structural approaches. As revealed by a cocrystal structure of a core MOBKL1B-NS5A peptide complex at 1.95 Å, NS5A binds to a hydrophobic patch on the MOBKL1B surface. Biosensor binding assays identified a highly conserved, 18-amino-acid binding site in domain II of NS5A, which encompasses residues implicated in cyclophilin A (CypA)-dependent HCV RNA replication. However, a CypA-independent HCV variant had reduced replication in MOBKL1B knockdown cells, even though its NS5A does not interact with MOBKL1B. These discordant results prompted more extensive studies of MOBKL1B gene knockdowns, which included additional siRNAs and specifically matched seed sequence siRNA controls. We found that reduced virus replication after treating cells with MOBKL1B siRNA was actually due to off-target inhibition, which indicated that the initial finding of virus replication dependence on the MOBKL1B-NS5A interaction was incorrect. Ultimately, using several approaches, we found no relationship of the MOBKL1B-NS5A interaction to virus replication. These findings collectively serve as a reminder to investigators and scientific reviewers of the pervasive impact of siRNA off-target effects on interpretation of biological data.

IMPORTANCE
Our study illustrates an underappreciated shortcoming of siRNA gene knockdown technology. We initially identified a cellular protein, MOBKL1B, as a binding partner with the NS5A protein of hepatitis C virus (HCV). MOBKL1B siRNA, but not irrelevant RNA, treatment was associated with both reduced virus replication and the absence of MOBKL1B. Believing that HCV replication depended on the MOBKL1B-NS5A interaction, we carried out structural and biochemical analyses. Unexpectedly, an HCV variant lacking the MOBKL1B-NS5A interaction could not replicate after cells were treated with MOBKL1B siRNA. By repeating the MOBKL1B siRNA knockdowns and including seed sequence-matched siRNA instead of irrelevant siRNA as a control, we found that the MOBKL1B siRNAs utilized had off-target inhibitory effects on virus replication. Collectively, our results suggest that stricter controls must be utilized in all RNA interference (RNAi)-mediated gene knockdown experiments to ensure sound conclusions and a reliable scientific knowledge database.
Dynamic Regulation of Host Restriction Factor Expression over the Course of HIV-1 Infection
In Vivo
Authors: Raposo Rui André Saraiva , Abdel-Mohsen Mohamed , Deng Xutao , Hecht Frederick M. , Pilcher Christopher D. , Pillai Satish K. , Nixon Douglas F.
Published: July 2014

In this study, we investigated the expression levels of host restriction factors in six untreated HIV-1-positive patients over the course of infection. We found that the host restriction factor gene expression profile consistently increased over time and was significantly associated with CD4
+
T cell activation and viral load. Our data are among the first to demonstrate the dynamic nature of host restriction factors
in vivo
over time.
The safety of intravitreal bevacizumab monotherapy in adult ophthalmic conditions: systematic review
Authors: Poku Edith , Rathbone John , Wong Ruth , Everson-Hock Emma , Essat Munira , Pandor Abdullah , Wailoo Allan
Published: July 2014

Objectives

To assess the safety of intravitreal bevacizumab (IVB) as a monotherapy and to evaluate the relationship between quality of treatment and adverse events.

Data sources

Cochrane Library, Ovid MEDLINE, MEDLINE in-process, Ovid EMBASE and Toxicology Literature Online (TOXLINE) from January 2009 to May 2012. Studies included in an earlier systematic review were also assessed for inclusion.

Study eligibility criteria, participants and interventions

Randomised controlled trials (RCTs), controlled trials or observational studies including ≥10 participants reporting adverse events data following IVB monotherapy as a primary treatment in patients (aged 18 years or more) with any eye condition were included.

Study appraisal and synthesis methods

Study selection was undertaken independently by a minimum of two reviewers using pre-defined criteria. Data abstraction and quality assessment were performed by one reviewer, and then checked by a second reviewer. Study quality was assessed for only RCTs in accordance to the Cochrane Risk of Bias Tool. Additional items relating to safety data were also assessed. Results were tabulated or meta-analysed as appropriate.

Results

22 RCTs and 67 observational studies were included. Only two RCTs reported valid safety data. Rates of serious adverse events following treatment were low. There was insufficient data to explore the relationship between the incidence of adverse events and quality of IVB injection.

Limitations

A majority of relevant existing studies were characterised by small sample sizes, unclear diagnostic criteria and reporting of safety outcomes.

Conclusions and implications of key findings

Available evidence demonstrates low rates of serious local and systemic adverse events following treatment. However, the role of IVB quality in the incidence of adverse events remains unclear. Robust evidence is needed to examine the relationship between the incidence of adverse events and variables such as injection techniques, pre-existing risk factors (eg, immunosuppression, cross-contamination) and quality of IVB treatment.
Veterinary care of sick and injured mallards
Authors: Bexton Steve , Couper David
Published: July 2014

Mallards (Anas platyrynchus) are found throughout the Northern hemisphere. Their adaptability to different habitats means they often live in proximity to humans, putting them at increased risk from man‐made hazards. Sick and injured mallards are regularly rescued and taken to veterinary practices; they are tolerant of captivity and relatively easy to care for, making them ideal candidates for rehabilitation. The minimum required of a veterinary surgeon is to provide first aid care and alleviate suffering before transferring them to a local wildlife rehabilitator. This article describes some of the common conditions seen in mallards and how veterinary surgeons can best care for and treat them.
Comments on the dilemma in the June issue: ‘A stitch in time. . . ’
Authors: Magalhães‐Sant'Ana Manuel
Published: July 2014

The dilemma in the June issue of In Practice concerned a number of ewes with inexpertly stitched vulvas. The client at a large sheep farm had called about difficult lambings, but while there you noticed that in some cases the ewes' sutures had ripped through the tissue (In Practice, June 2014, volume 36, pages 310‐311). Paul Roger suggested that the best way forward might be to first consider how avoidable the situation was and whether the corrective action taken by the farmer was at all in the best interest of the ewes. He proposed that if the Bühner method hadn't been used, along with anaesthetic, analgesia, anti‐inflammatories and antibiotics, then the client would need to be educated. It should be stressed that such action could be interpreted as inflicting unnecessary suffering and an offence under the Animal Welfare Act 2006; the farmer should also be encouraged to use veterinary services more often to help plan strategies to prevent similar incidents in the future.
Extending postoperative opioid analgesia in dogs 2. Transdermal drug administration
Authors: Murrell Jo , Flaherty Derek
Published: July 2014

Opioid drugs are pivotal to the effective management of acute pain in dogs, and, for this reason, they are the ‘gold standard’ agents for the treatment of postsurgical pain. While most veterinary surgeons will administer these drugs for the immediate post‐operative period, it is less common to maintain opioid analgesia in animals that have been returned home to the owner. The first article in this two‐part series on extending postoperative opioid analgesia in dogs focused on administration of these drugs by the oral route, and emphasised some of the inherent limitations (Murrell and Flaherty 2014). This article examines how opioid analgesia can be maintained postoperatively using the transdermal route.
Clinical examination and diseases of the fundus in dogs
Authors: Smith Kerry
Published: July 2014

The fundus, which can be examined through the pupil by ophthalmoscopy, is the posterior part of the interior of the eye and comprises the tapetal and nontapetal fundus, retinal vasculature and optic nerve head. As well as providing significant information about a dog's visual status and ocular health, it is the only area of the body where the vascular and nervous systems can be examined directly and thus alert us to signs of systemic disease that may not yet have manifested elsewhere. This article guides the practitioner through the clinical examination of the fundus in dogs, and highlights some common conditions.
Managing mare dystocia in the field
Authors: Pynn Ollie
Published: July 2014

Dystocia or difficult parturition is one of the real emergencies faced by the equine veterinary surgeon, and effective management is essential for the survival of both the foal and mare, and for the mare's subsequent fertility. Dystocia is most commonly caused by abnormalities of fetal presentation, position or posture, but can also result from fetal oversize, congenital defects of the fetus, or maternal factors such as pelvic abnormalities or uterine inertia. The incidence of dystocia has been reported to be between 4 and 10 per cent of all births. Dystocia may be daunting to the inexperienced practitioner, but needn't be if approached in a methodical way. The aim is always to deliver a live foal as quickly as possible and with minimal interference and trauma to the mare. This article discusses how to identify dystocia and ways to aid successful delivery of the foal.
The recent economic recession and self-rated health in Estonia, Lithuania and Finland: a comparative cross-sectional study in 2004–2010
Authors: Reile Rainer , Helakorpi Satu , Klumbiene Jurate , Tekkel Mare , Leinsalu Mall
Published: July 2014

Background

The late-2000s financial crisis had a severe impact on the national economies on a global scale. In Europe, the Baltic countries were among those most affected with more than a 20% decrease in per capita gross domestic product in 2008–2009. In this study, we explored the effects of economic recession on self-rated health in Estonia and Lithuania using Finland, a neighbouring Nordic welfare state, as a point of reference.

Methods

Nationally representative cross-sectional data for Estonia (n=10 966), Lithuania (n=7249) and Finland (n=11 602) for 2004–2010 were analysed for changes in age-standardised prevalence rates of less-than-good self-rated health and changes in health inequalities using logistic regression analysis.

Results

The prevalence of less-than-good self-rated health increased slightly (albeit not statistically significantly) in all countries during 2008–2010. This was in sharp contrast to the statistically significant decline in the prevalence of less-than-good health in 2004–2008 in Estonia and Lithuania. Health disparities were larger in Estonia and Lithuania when compared to Finland, but decreased in 2008–2010 (in men only). In Finland, both the prevalence of less-than-good health and health disparities remained fairly stable throughout the period.

Conclusions

Despite the rapid economic downturn, the short-term health effects in Estonia and Lithuania did not differ from those in Finland, although the recession years marked the end of the previous positive trend in self-rated health. The reduction in health disparities during the recession indicates that different socioeconomic groups were affected disproportionately; however, the reasons for this require further research.
Increased usage of special educational services by children born to mothers with systemic lupus erythematosus and antiphospholipid antibodies
Authors: Marder Wendy , Romero Vivian C , Ganser Martha A , Hyzy Margaret A , Gordon Caroline , McCune W J , Somers Emily C
Published: July 2014

Introduction

Surveys of long-term health and developmental outcomes of children born to mothers with systemic lupus erythematosus (SLE) have suggested an increase in learning disabilities among these children. We performed this observational study to investigate the relationship between maternal autoantibodies and antiphospholipid antibody syndrome (APS) in maternal lupus patients and neurocognitive development among their offspring.

Methods

SLE mothers with at least one live birth postlupus diagnosis were enrolled. Data on maternal medical/obstetric history and children's perinatal/medical history were collected by structured interview and medical record reviews. The primary outcome was requirement for special educational (SE) services, a proxy for developmental delays. Multiple logistic regression modelling was used to examine associations between APS and autoantibodies with SE usage, accounting for SLE disease severity and potential confounders.

Results

Data on 38 mothers and 60 offspring were analysed: SE service usage was reported for 15 of 60 (25%) offspring. Maternal APS history was significantly associated with increased use of SE services among offspring, including after adjustment for lupus anticoagulant (LA) positivity and potential confounders (OR 5.5–9.4 for delays age ≥2; p<0.05). The presence of LA, but not other antiphospholipid antibodies, was also associated with increased SE services usage.

Conclusions

Maternal APS and LA were independently associated with increased usage of special educational services among offspring of women with SLE.
Enhancement of renal oxidative stress by injection of angiotensin II into the paraventricular nucleus in renal ischemia–reperfusion injury
Authors: Seifi Behjat , Kadkhodaee Mehri , Bakhshi Enayatollah , Ranjbaran Mina , Ahghari Parisa , Rastegar Tayebeh
Published: July 2014

This study was designed to investigate whether microinjection of angiotensin II (Ang II) into the hypothalamic paraventricular nucleus (PVN) in renal ischemia–reperfusion (IR) injury has any effect on renal oxidative stress and damage through renal sympathetic nerve activity (RSNA). One week before the induction of left renal IR injury, right nephrectomy was performed and a cannula was placed into the right PVN. Rats were then distributed among 4 groups (n = 6); Sham, IR, IR + Ang II, and IR + Ang II + losartan. Renal IR injury was induced by clamping the left renal artery for 45 min followed by 24 h reperfusion. Losartan (0.3 μg) and Ang II (3 ng) were microinjected into the PVN at 20 min and 10 min, respectively, before the induction of IR injury. Ang II increased plasma creatinine, urinary NAG activity, and histological changes, and enhanced RSNA compared with the IR group (p < 0.05). Ang II increased malondialdehyde (MDA) levels and reduced superoxide dismutase (SOD) activity in the kidney compared with IR injury. Losartan caused a reduction in plasma creatinine, urinary NAG activity, histological changes, renal sympathetic nerve activity (RSNA), and renal MDA levels, and increased renal SOD activity compared with the IR group (p < 0.05). These data demonstrated that increased RSNA activity, via microinjection of Ang II into the PVN, exaggerated renal IR injury by inducing oxidative stress in the kidney.
An approach to decrease dimensions of field-effect transistors without p–n-junctions
Authors: Pankratov E. L. , Bulaeva E. A.
Published: July 2014

It has been recently shown, that manufacturing p–n-junctions, field-effect and bipolar transistors, thyristors in a multilayer structure by diffusion or ion implantation under condition of optimization of dopant and/or radiation defects leads to increasing sharpness of p–n-junctions (both single p–n-junctions and p–n-junctions, which include into their system). In this situation, one can also obtain increase of homogeneity of dopant in doped area. In this paper, we consider manufacturing a field-effect heterotransistor without p–n-junction. Optimization of technological process with using inhomogeneity of heterostructure gives us possibility to manufacture transistors to be more compact.
Customer Churn Prediction Based on Feature Clustering and Nonparallel Support Vector Machine
Authors: Zhao Xi , Shi Yong , Lee Jongwon , Kim Heung Kee , Lee Heeseok
Published: July 2014

Bank customer churn prediction is one of the key businesses for modern commercial banks. Recently, various methods have been investigated to identify the customers who would leave away. This paper proposed a new framework based on feature clustering and classification technique to help commercial banks make an effective decision on customer churn problem. The proposed method benefits from the result of data explorations, clusters the customer features, and makes a decision with a state-of-the-art classifier. When facing the data with large amount of missing items, it does not directly remove the features by some subjective threshold, but clusters the features through the consideration of the relationship and the missing ratio. Real-world data from a major commercial bank of China verifies the feasibility of our framework in industrial applications.
The Emerging Role of microRNAs and Nutrition in Modulating Health and Disease
Authors: Ross Sharon A. , Davis Cindy D.
Published: July 2014

Understanding the molecular mechanisms that inform how diet and dietary supplements influence health and disease is an active research area. One such mechanism concerns the role of diet in modulating the activity and function of microRNAs (miRNAs). miRNAs are small noncoding RNA molecules that are involved in posttranscriptional gene silencing and have been shown to control gene expression in diverse biological processes including development, differentiation, cell proliferation, metabolism, and inflammation as well as in human diseases. Recent evidence described in this review highlights how dietary factors may influence cancer, cardiovascular disease, type 2 diabetes mellitus, obesity, and nonalcoholic fatty liver disease through modulation of miRNA expression. Additionally, circulating miRNAs are emerging as putative biomarkers of disease, susceptibility, and perhaps dietary exposure. Research needs to move beyond associations in cells and animals to understanding the direct effects of diet and dietary supplements on miRNA expression and function in human health and disease.
Parvoviruses: Small Does Not Mean Simple
Authors: Cotmore Susan F. , Tattersall Peter
Published: July 2014

Parvoviruses are small, rugged, nonenveloped protein particles containing a linear, nonpermuted, single-stranded DNA genome of ∼5 kb. Their limited coding potential requires optimal adaptation to the environment of particular host cells, where entry is mediated by a variable program of capsid dynamics, ultimately leading to genome ejection from intact particles within the host nucleus. Genomes are amplified by a continuous unidirectional strand-displacement mechanism, a linear adaptation of rolling circle replication that relies on the repeated folding and unfolding of small hairpin telomeres to reorient the advancing fork. Progeny genomes are propelled by the viral helicase into the preformed capsid via a pore at one of its icosahedral fivefold axes. Here we explore how the fine-tuning of this unique replication system and the mechanics that regulate opening and closing of the capsid fivefold portals have evolved in different viral lineages to create a remarkably complex spectrum of phenotypes.