bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter Evaluation of a Modified Cefoxitin Disk Diffusion Method and PBP2a Testing To Predict
mecA
-Mediated Oxacillin Resistance in Atypical Staphylococcus aureus
Authors: Miller Shelley A. , Karichu James , Kohner Peggy , Cole Nicolynn , Hindler Janet A. , Patel Robin , Richter Sandra , Humphries Romney M.
Published: December 2016

Phenotypic variants of
Staphylococcus aureus
that display small colonies, reduced pigmentation, and decreased hemolysis and/or coagulase activity are periodically isolated by the clinical laboratory. Antimicrobial susceptibility testing (AST) of these isolates is complicated, because many do not grow on routine AST media, including Mueller-Hinton agar (MHA) and cation-adjusted Mueller-Hinton broth. This multicenter study evaluated cefoxitin disk diffusion for 37 atypical
S. aureus
isolates (156 readings) with MHA supplemented with 5% sheep's blood (BMHA), using
mecA
PCR as the reference standard. The correlation of two commercial PBP2a assays with
mecA
PCR was also assessed. Ten isolates were negative and 27 positive for
mecA
. No major errors for cefoxitin were observed, but 19.5% very major errors (VMEs) were observed at 24 h of incubation, and 17.2% VMEs were observed at 48 h. The proportions of VMEs ranged from 14.7 to 23.0% at 24 h, and from 13.3 to 17.6% at 48 h, across three testing laboratories. PBP2a tests were performed from growth on BMHA and blood agar plates (BAP), with and without cefoxitin disk induction. The Alere PBP2a SA culture colony test sensitivities for
mecA
were 90.0% with uninduced growth and 97.4% with induced growth from BMHA. On BAP, sensitivity was 96.0% with induced growth. The sensitivities of the Oxoid PBP2′ latex agglutination test were 85.7% with uninduced growth and 93.9% with induced growth from BMHA and 95.9% with induced growth on BAP. On the basis of these data, we recommend that laboratories perform only
mecA
PCR and/or PBP2a tests when requested to perform AST on atypical isolates of
S. aureus
.
The Human Cytomegalovirus IE1 Protein Antagonizes PML Nuclear Body-Mediated Intrinsic Immunity via the Inhibition of PML
De Novo
SUMOylation
Authors: Schilling Eva-Maria , Scherer Myriam , Reuter Nina , Schweininger Johannes , Muller Yves A. , Stamminger Thomas
Published: December 2016

PML nuclear bodies (NBs) are accumulations of cellular proteins embedded in a scaffold-like structure built by SUMO-modified PML/TRIM19. PML and other NB proteins act as cellular restriction factors against human cytomegalovirus (HCMV); however, this intrinsic defense is counteracted by the immediate early protein 1 (IE1) of HCMV. IE1 directly interacts with the PML coiled-coil domain via its globular core region and disrupts NB foci by inducing a loss of PML SUMOylation. Here, we demonstrate that IE1 acts via abrogating the
de novo
SUMOylation of PML. In order to overcome reversible SUMOylation dynamics, we made use of a cell-based assay that combines inducible IE1 expression with a SUMO mutant resistant to SUMO proteases. Interestingly, we observed that IE1 expression did not affect preSUMOylated PML; however, it clearly prevented
de novo
SUMO conjugation. Consistent results were obtained by
in vitro
SUMOylation assays, demonstrating that IE1 alone is sufficient for this effect. Furthermore, IE1 acts in a selective manner, since K160 was identified as the main target lysine. This is strengthened by the fact that IE1 also prevents As
2
O
3
-mediated hyperSUMOylation of K160, thereby blocking PML degradation. Since IE1 did not interfere with coiled-coil-mediated PML dimerization, we propose that IE1 affects PML autoSUMOylation either by directly abrogating PML E3 ligase function or by preventing access to SUMO sites. Thus, our data suggest a novel mechanism for how a viral protein counteracts a cellular restriction factor by selectively preventing the
de novo
SUMOylation at specific lysine residues without affecting global protein SUMOylation.

IMPORTANCE
The human cytomegalovirus IE1 protein acts as an important antagonist of a cellular restriction mechanism that is mediated by subnuclear structures termed PML nuclear bodies. This function of IE1 is required for efficient viral replication and thus constitutes a potential target for antiviral strategies. In this paper, we further elucidate the molecular mechanism for how IE1 antagonizes PML NBs. We show that tight binding of IE1 to PML interferes with the
de novo
SUMOylation of a distinct lysine residue that is also the target of stress-mediated hyperSUMOylation of PML. This is of importance since it represents a novel mechanism used by a viral antagonist of intrinsic immunity. Furthermore, it highlights the possibility of developing small molecules that specifically abrogate this PML-antagonistic activity of IE1 and thus inhibit viral replication.
Inhibition of an Aquatic Rhabdovirus Demonstrates Promise of a Broad-Spectrum Antiviral for Use in Aquaculture
Authors: Balmer Bethany F. , Powers Rachel L. , Zhang Ting-Hu , Lee Jihye , Vigant Frederic , Lee Benhur , Jung Michael E. , Purcell Maureen K. , Snekvik Kevin , Aguilar Hector C.
Published: December 2016

Many enveloped viruses cause devastating disease in aquaculture, resulting in significant economic impact. LJ001 is a broad-spectrum antiviral compound that inhibits enveloped virus infections by specifically targeting phospholipids in the lipid bilayer via the production of singlet oxygen (
1
O
2
). This stabilizes positive curvature and decreases membrane fluidity, which inhibits virus-cell membrane fusion during viral entry. Based on data from previous mammalian studies and the requirement of light for the activation of LJ001, we hypothesized that LJ001 may be useful as a preventative and/or therapeutic agent for infections by enveloped viruses in aquaculture. Here, we report that LJ001 was more stable with a prolonged inhibitory half-life at relevant aquaculture temperatures (15°C), than in mammalian studies at 37°C. When LJ001 was preincubated with our model virus, infectious hematopoietic necrosis virus (IHNV), infectivity was significantly inhibited
in vitro
(using the epithelioma papulosum cyprini [EPC] fish cell line) and
in vivo
(using rainbow trout fry) in a dose-dependent and time-dependent manner. While horizontal transmission of IHNV in a static cohabitation challenge model was reduced by LJ001, transmission was not completely blocked at established antiviral doses. Therefore, LJ001 may be best suited as a therapeutic for aquaculture settings that include viral infections with lower virus-shedding rates than IHNV or where higher viral titers are required to initiate infection of naive fish. Importantly, our data also suggest that LJ001-inactivated IHNV elicited an innate immune response in the rainbow trout host, making LJ001 potentially useful for future vaccination approaches.

IMPORTANCE
Viral diseases in aquaculture are challenging because there are few preventative measures and/or treatments. Broad-spectrum antivirals are highly sought after and studied because they target common components of viruses. In our studies, we used LJ001, a broad-spectrum antiviral compound that specifically inhibits enveloped viruses. We used the fish rhabdovirus infectious hematopoietic necrosis virus (IHNV) as a model to study aquatic enveloped virus diseases and their inhibition. We demonstrated inhibition of IHNV by LJ001 both in cell culture as well as in live fish. Additionally, we showed that LJ001 inhibited the transmission of IHNV from infected fish to healthy fish, which lays the groundwork for using LJ001 as a possible therapeutic for aquatic viruses. Our results also suggest that virus inactivated by LJ001 induces an immune response, showing potential for future preventative (e.g., vaccine) applications.
Random versus Cell Cycle-Regulated Replication Initiation in Bacteria: Insights from Studying Vibrio cholerae Chromosome 2
Authors: Ramachandran Revathy , Jha Jyoti , Paulsson Johan , Chattoraj Dhruba
Published: December 2016

Bacterial chromosomes initiate replication at a fixed time in the cell cycle, whereas there is generally no particular time for plasmid replication initiation or chromosomal replication initiation from integrated plasmids. In bacteria with divided genomes, the replication system of one of the chromosomes typically resembles that of bacteria with undivided genomes, whereas the remaining chromosomes have plasmid-like replication systems. For example, in
Vibrio cholerae
, a bacterium with two chromosomes (chromosome 1 [Chr1] and Chr2), the Chr1 system resembles that of the
Escherichia coli
chromosome, and the Chr2 system resembles that of iteron-based plasmids. However, Chr2 still initiates replication at a fixed time in the cell cycle and thus offers an opportunity to understand the molecular basis for the difference between random and cell cycle-regulated modes of replication. Here we review studies of replication control in Chr2 and compare it to those of plasmids and chromosomes. We argue that although the Chr2 control mechanisms in many ways are reminiscent of those of plasmids, they also appear to combine more regulatory features than are found on a typical plasmid, including some that are more typical of chromosomes. One of the regulatory mechanisms is especially novel, the coordinated timing of replication initiation of Chr1 and Chr2, providing the first example of communication between chromosomes for replication initiation.
Improving care for heart failure patients in primary care, GPs' perceptions: a qualitative evidence synthesis
Authors: Smeets Miek , Van Roy Sara , Aertgeerts Bert , Vermandere Mieke , Vaes Bert
Published: December 2016

Objectives

General practitioners (GPs) play a key role in heart failure (HF) management. Despite multiple guidelines, the management of patients with HF in primary care is suboptimal. Therefore, all the qualitative evidence concerning GPs’ perceptions of managing HF in primary care was synthesised to identify barriers and facilitators for optimal care, and ideas for improvement.

Design

Qualitative evidence synthesis.

Methods

Searches of MEDLINE, EMBASE, Web of Science and CINAHL databases up to 20/12/2015 were conducted. The Critical Appraisal Skills Programme's checklist for qualitative research was used for quality assessment. Thematic analysis was used as method of analysis.

Results

Of 5427 articles, 18 qualitative articles were included. Findings were organised in HF-specific factors, patient factors, physician factors and contextual factors. GPs’ uncertainty in all areas of HF management was highlighted. HF management started with an uncertain diagnosis, leading to difficulties with communication, treatment and advance care planning. Lack of access to specialised care and lack of knowledge were identified as important contributors to this uncertainty. In an effort to overcome this, strategies bringing evidence into practice should be promoted. GPs expressed the need for a multidisciplinary chronic care approach for HF. However, mixed experiences were noted with regard to interprofessional collaboration.

Conclusions

The main challenges identified in this synthesis were how to deal with GPs’ uncertainty about clinical practice, how to bring evidence into practice and how to work together as a multiprofessional team. These barriers were situated predominantly on the physician and contextual level. Targets to improve GPs’ HF care were identified.
Possible radii of compact stars: A relativistic approach
Authors: Kalam Mehedi , Hossein Sk Monowar , Molla Sajahan
Published: December 2016

The inner structure of compact stars is checked from theoretical as well as observational points of view. In this paper, we determine the possible radii of six compact stars: two binary millisecond pulsars, namely PSR J1614-2230 and PSR J1903+327, studied by [P. B. Demorest, T. Pennucci, S. M. Ransom, M. S. E. Roberts and W. T. Hessels, Nature 467, 1081 (2010)] and four X-ray binaries, namely Cen X-3, SMC X-1, Vela X-1 and Her X-1 studied by [M. L. Rawls et al., Astrophys. J. 730, 25 (2011)]. Interestingly, we see that density of the star does not vanishes at the boundary though it is maximum at the center which implies that these compact stars may be treated as strange stars rather than neutron stars. We propose a stiff equation of state (EoS) relating to pressure with matter density. We also obtain compactness (u) and surface redshift (Z[Formula: see text]) for the above-mentioned stars and compare it with the recent observational data.
Comparison of O- and C-models on pseudosphere
Authors: Grigoryan G. V. , Grigoryan R. P. , Tyutin I. V.
Published: December 2016

We present a mathematically rigorous quantum-mechanical treatment of a two-dimensional nonrelativistic quantum dual theories (with oscillator- and Coulomb-like potentials) on pseudosphere. We construct all self-adjoint Schrödinger operators for these theories and present solutions of the corresponding spectral problems. We show, that there is one-to-one correspondence between spectral points of the energy-coupling constant planes not only for discrete, but also for continuous spectra and corresponding eigenfunctions forming the complete orthonormalized systems.
Effect of aluminum trace dimension on electro-migration failure in flip-chip package
Authors: Liu Peisheng , Fan Guangming , Liu Yahong , Yang Longlong , Miao Xiaoyong
Published: December 2016

A 3D model of flip-chip package is established and thermal–electrical coupling is analyzed. The effect of the width of Aluminum (Al) trace on electro-migration mechanism is also studied. Reducing rates of the hot-spot temperature, the max Joule heating, the max temperature gradient and the max current density are defined to research the effects of the Al trace thickness and the UBM thickness on electro-migration.
New nonbinary quantum codes with larger distance constructed from BCH codes over 𝔽q2
Authors: Xu Gen , Li Ruihu , Fu Qiang , Ma Yuena , Guo Luobin
Published: December 2016

This paper concentrates on construction of new nonbinary quantum error-correcting codes (QECCs) from three classes of narrow-sense imprimitive BCH codes over finite field [Formula: see text] ([Formula: see text] is an odd prime power). By a careful analysis on properties of cyclotomic cosets in defining set [Formula: see text] of these BCH codes, the improved maximal designed distance of these narrow-sense imprimitive Hermitian dual-containing BCH codes is determined to be much larger than the result given according to Aly et al. [S. A. Aly, A. Klappenecker and P. K. Sarvepalli, IEEE Trans. Inf. Theory 53, 1183 (2007)] for each different code length. Thus families of new nonbinary QECCs are constructed, and the newly obtained QECCs have larger distance than those in previous literature.
First-principles study on codoping effect to enhance photocatalytic activity of anatase TiO2
Authors: Bai Yujie , Zhang Qinfang , Zheng Fubao , Yang Yun , Meng Qiangqiang , Zhu Lei , Wang Baolin
Published: December 2016

Codopant is an effective approach to modify the bandgap and band edge positions of transition metal oxide. Here, the electronic structures as well as the optical properties of pristine, mono-doped (N/P/Sb) and codoped (Sb, N/P) anatase TiO2 have been systematically investigated based on density functional theory calculations. It is found that mono-doped TiO2 exhibits either unoccupied or partially occupied intermediate state within the energy gap, which promotes the recombination of electron-hole pairs. However, the presence of (Sb, N/P) codopant not only effectively reduces the width of bandgap by introducing delocalized occupied intermediate states, but also adjusts the band edge alignment to enhance the hydrogen evolution activity of TiO2. Moreover, the optical absorption spectrum for (Sb, N/P) codoped TiO2, which is favored under oxygen-rich condition, demonstrates the improvement of its visible light absorption. These findings will promote the potential application of (Sb, N/P) codoped TiO2 photocatalysis for water splitting under visible light irradiation.
Uncovering the effective interval of resolution parameter across multiple community optimization measures
Authors: Li Hui-Jia , Cheng Qing , Mao He-Jin , Wang Huanian , Chen Junhua
Published: December 2016

The study of community structure is a primary focus of network analysis, which has attracted a large amount of attention. In this paper, we focus on two famous functions, i.e., the Hamiltonian function [Formula: see text] and the modularity density measure [Formula: see text], and intend to uncover the effective thresholds of their corresponding resolution parameter [Formula: see text] without resolution limit problem. Two widely used example networks are employed, including the ring network of lumps as well as the ad hoc network. In these two networks, we use discrete convex analysis to study the interval of resolution parameter of [Formula: see text] and [Formula: see text] that will not cause the misidentification. By comparison, we find that in both examples, for Hamiltonian function [Formula: see text], the larger the value of resolution parameter [Formula: see text], the less resolution limit the network suffers; while for modularity density [Formula: see text], the less resolution limit the network suffers when we decrease the value of [Formula: see text]. Our framework is mathematically strict and efficient and can be applied in a lot of scientific fields.
Scheelite (CaWO4)-type microphosphors: Facile synthesis, structural characterization and photoluminescence properties
Authors: Han Yuanyuan , Wang Dan , Liang Danyang , Wang Shiqi , Lu Guoxin , Wang Xiaoyu , Pei Nana
Published: December 2016

Scheelite (CaWO4)-type microphosphors were synthesized by the precipitation method assisted with cetyltrimethyl ammonium bromide (CTAB). All compounds crystallized in the tetragonal structure with space group [Formula: see text] (No. 88). FE-SEM micrographs illustrate the spherical-like morphologies and rough surface. PL spectra indicate the broad emission peak maximum at 613 nm under UV excitation. Luminescence decay curves monitored by [Formula: see text] transition ([Formula: see text] nm) of Eu[Formula: see text] in doped CaWO4 are presented, the curves exhibit a single-exponential feature and the lifetime for doped CaWO4 is 0.61 ms.
The energy band structure of Si and Ge nanolayers
Authors: Wu Xueke , Huang Weiqi , Huang Zhongmei , Qin Chaojie , Tang Yanlin
Published: December 2016

First-principles calculation based on density functional theory (DFT) with the generalized gradient approximation (GGA) were carried out to investigate the energy band gap structure of Si and Ge nanofilms. Calculation results show that the band gaps of Si(111) and Ge(110) nanofilms are indirect structures and independent of film thickness, the band gaps of Si(110) and Ge(100) nanofilms could be transfered into the direct structure for nanofilm thickness of less than a certain value, and the band gaps of Si(100) and Ge(111) nanofilms are the direct structures in the present model thickness range (about 7 nm). Moreover, the changes of the band gaps on the Si and Ge nanofilms follow the quantum confinement effects. It will be a good way to obtain direct band gap emission in Si and Ge materials, and to develop Si and Ge laser on Si chip.
Random Fuzzy Repairable Coherent Systems with Independent Components
Authors: Liu Ying , Li Xiaozhong , Zhang Yiying
Published: December 2016

Nondeterministic variables of certain distributions are employed to represent uncertain lifetimes and repair times in repairable systems, which are usually treated as stochastic variables and the probability distributions of the stochastic variables have crisp parameters. However, in practice, the parameters may not be precisely represented due to a lack of sufficient data. The main purpose of this paper is to apply the random fuzzy theory to the establishment of repairable coherent system models. Then the expressions of limiting availability and steady state failure frequency of the random fuzzy coherent systems are proposed, respectively. Finally, some numerical examples are given for illustration.
Similarity-Based Approach for Group Decision Making with Multi-Granularity Linguistic Information
Authors: Lin Jian , Chen Riqing , Zhang Qiang
Published: December 2016

The aim of this article is to investigate the approach for multi-attribute group decision-making, in which the attribute values take the form of multi-granularity multiplicative linguistic information. Firstly, to process multiple sources of decision information assessed in different multiplicative linguistic label sets, a method for transforming multi-granularity multiplicative linguistic information into multiplicative trapezoidal fuzzy numbers is proposed. Then, a formula for ranking multiplicative trapezoidal fuzzy numbers is given based on geometric mean. Furthermore, the concept of similarity degree between two multiplicative trapezoidal fuzzy numbers is defined. The attribute weights are obtained by solving some optimization models. An effective approach for group decision making with multi-granularity multiplicative linguistic information is developed based on the ordered weighted geometric mean operator and proposed formulae. Finally, a practical example is provided to illustrate the practicality and validity of the proposed method.
Fubini Theorems for Capacities
Authors: Wang Hongxia
Published: December 2016

Capacity plays an important role in many areas. A capacity is usually studied under the assumption that it is concave (or convex). In this paper, we perform a further investigation on the Fubini Theorems for concave (or convex) capacities given by Ghirardato (1997) and Chateauneuf and Lefort (2008). We extend Fubini Theorems for capacities to a larger class of functions, which are both μ1-Choquet integrable and μ2-Choquet integrable, not to restrict only on slice-comonotonic functions.
Frontside Versus Backside Laser Injection
Authors: Castro Stephan De , Dutertre Jean-Max , Rouzeyre Bruno , Natale Giorgio Di , Flottes Marie-Lise
Published: December 2016

The development of cryptographic devices was followed by the development of so-called implementation attacks, which are intended to retrieve secret information exploiting the hardware itself. Among these attacks, fault attacks can be used to disturb the circuit while performing a computation to retrieve the secret. Among possible means of injecting a fault, laser beams have proven to be accurate and powerful. The laser can be used to illuminate the circuit either from its frontside (i.e., where metal interconnections are first encountered) or from the backside (i.e., through the substrate). Historically, frontside injection was preferred because it does not require the die to be thinned. Nevertheless, due to the increasing integration of metal layers in modern technologies, frontside injections do not allow targeting of any desired location. Indeed, metal lines act as mirrors, and they reflect and refract most of the energy provided by the laser beam. Conversely, backside injections, although more difficult to set up, allow an increase of the resolution of the target location and remove the drawbacks of the frontside technique. This article compares experimental results from frontside and backside fault injections. The effectiveness of the two techniques is measured in terms of exploitable errors on an AES circuit (i.e., errors that can be used to extract the value of the secret key used during the encryption process). We will show, conversely to what is generally assumed, that frontside injection can provide even better results compared to backside injection, especially for low-cost beams with a large laser spot.
Mathematical foundations for social computing
Authors: Chen Yiling , Ghosh Arpita , Kearns Michael , Roughgarden Tim , Vaughan Jennifer Wortman
Published: December 2016

Social computing benefits from mathematical foundations, but research has barely scratched the surface.
A Simplified Phase Model for Simulation of Oscillator-Based Computing Systems
Authors: Fang Yan , Yashin Victor V. , Jennings Brandon B. , Chiarulli Donald M. , Levitan Steven P.
Published: December 2016

Building oscillator-based computing systems with emerging nano-device technologies has become a promising solution for unconventional computing tasks like computer vision and pattern recognition. However, simulation and analysis of these computing systems is both time and compute intensive due to the nonlinearity of new devices and the complex behavior of coupled oscillators. In order to speed up the simulation of coupled oscillator systems, we propose a simplified phase model to perform phase and frequency synchronization prediction based on a synthesis of earlier models. Our model can predict the frequency-locking behavior with several orders of magnitude speedup compared to direct evaluation, enabling the effective and efficient simulation of the large numbers of oscillators required for practical computing systems. We demonstrate the oscillator-based computing paradigm with three applications, pattern matching, convolution, and image segmentation. The simulation with these models are respectively sped up by factors of 780, 300, and 1120 in our tests.
Extracting 3D objects from photographs using 3-sweep
Authors: Chen Tao , Zhu Zhe , Hu Shi-Min , Cohen-Or Daniel , Shamir Ariel
Published: December 2016

We introduce an interactive technique to extract and manipulate simple 3D shapes in a single photograph. Such extraction requires an understanding of the shape's components, their projections, and their relationships. These cognitive tasks are simple for humans, but particularly difficult for automatic algorithms. Thus, our approach combines the cognitive abilities of humans with the computational accuracy of the machine to create a simple modeling tool. In our interface, the human draws three strokes over the photograph to generate a 3D component that snaps to the outline of the shape. Each stroke defines one dimension of the component. Such human assistance implicitly segments a complex object into its components, and positions them in space. The computer reshapes the component to fit the image of the object in the photograph as well as to satisfy various inferred geometric constraints between components imposed by a global 3D structure. We show that this intelligent interactive modeling tool provides the means to create editable 3D parts quickly. Once the 3D object has been extracted, it can be quickly edited and placed back into photos or 3D scenes, permitting object-driven photo editing tasks which are impossible to perform in image-space.
Learning to learn
Authors: Denning Peter J. , Flores Gloria
Published: December 2016

Do you get stuck when it is time to learn something new? Read this.
The plasma membrane metal-ion transporter ZIP14 contributes to nontransferrin-bound iron uptake by human β-cells
Authors: Coffey Richard , Knutson Mitchell D.
Published: December 2016

The relationship between iron and β-cell dysfunction has long been recognized as individuals with iron overload display an increased incidence of diabetes. This link is usually attributed to the accumulation of excess iron in β-cells leading to cellular damage and impaired function. Yet, the molecular mechanism(s) by which human β-cells take up iron has not been determined. In the present study, we assessed the contribution of the metal-ion transporters ZRT/IRT-like protein 14 and 8 (ZIP14 and ZIP8) and divalent metal-ion transporter-1 (DMT1) to iron uptake by human β-cells. Iron was provided to the cells as nontransferrin-bound iron (NTBI), which appears in the plasma during iron overload and is a major contributor to tissue iron loading. We found that overexpression of ZIP14 and ZIP8, but not DMT1, resulted in increased NTBI uptake by βlox5 cells, a human β-cell line. Conversely, siRNA-mediated knockdown of ZIP14, but not ZIP8, resulted in 50% lower NTBI uptake in βlox5 cells. In primary human islets, knockdown of ZIP14 also reduced NTBI uptake by 50%. Immunofluorescence analysis of islets from human pancreatic sections localized ZIP14 and DMT1 nearly exclusively to β-cells. Studies in primary human islets suggest that ZIP14 protein levels do not vary with iron status or treatment with IL-1β. Collectively, these observations identify ZIP14 as a major contributor to NTBI uptake by β-cells and suggest differential regulation of ZIP14 in primary human islets compared with other cell types such as hepatocytes.
Aspirin therapy reduces the ability of platelets to promote colon and pancreatic cancer cell proliferation: Implications for the oncoprotein c-MYC
Authors: Mitrugno Annachiara , Sylman Joanna L. , Ngo Anh T. P. , Pang Jiaqing , Sears Rosalie C. , Williams Craig D. , McCarty Owen J. T.
Published: December 2016

Aspirin, an anti-inflammatory and antithrombotic drug, has become the focus of intense research as a potential anticancer agent owing to its ability to reduce tumor proliferation in vitro and to prevent tumorigenesis in patients. Studies have found an anticancer effect of aspirin when used in low, antiplatelet doses. However, the mechanisms through which low-dose aspirin works are poorly understood. In this study, we aimed to determine the effect of aspirin on the cross talk between platelets and cancer cells. For our study, we used two colon cancer cell lines isolated from the same donor but characterized by different metastatic potential, SW480 (nonmetastatic) and SW620 (metastatic) cancer cells, and a pancreatic cancer cell line, PANC-1 (nonmetastatic). We found that SW480 and PANC-1 cancer cell proliferation was potentiated by human platelets in a manner dependent on the upregulation and activation of the oncoprotein c-MYC. The ability of platelets to upregulate c-MYC and cancer cell proliferation was reversed by an antiplatelet concentration of aspirin. In conclusion, we show for the first time that inhibition of platelets by aspirin can affect their ability to induce cancer cell proliferation through the modulation of the c-MYC oncoprotein.
Cardiac remodeling and increased central venous pressure underlie elevated stroke volume and cardiac output of seawater-acclimated rainbow trout
Authors: Brijs Jeroen , Sandblom Erik , Dekens Esmée , Näslund Joacim , Ekström Andreas , Axelsson Michael
Published: December 2016

Substantial increases in cardiac output (CO), stroke volume (SV), and gastrointestinal blood flow are essential for euryhaline rainbow trout ( Oncorhyncus mykiss) osmoregulation in seawater. However, the underlying hemodynamic mechanisms responsible for these changes are unknown. By examining a range of circulatory and cardiac morphological variables of seawater- and freshwater-acclimated rainbow trout, the present study revealed a significantly higher central venous pressure (CVP) in seawater-acclimated trout (~0.09 vs. −0.02 kPa). This serves to increase cardiac end-diastolic volume in seawater and explains the elevations in SV (~0.41 vs. 0.27 ml/kg) and CO (~21.5 vs. 14.2 ml·min−1·kg−1) when compared with trout in freshwater. Furthermore, these hemodynamic modifications coincided with a significant increase in the proportion of compact myocardium, which may be necessary to compensate for the increased wall tension associated with a larger stroke volume. Following a temperature increase from 10 to 16.5°C, both acclimation groups exhibited similar increases in heart rate (Q10of ~2), but SV tended to decrease in seawater-acclimated trout despite the fact that CVP was maintained in both groups. This resulted in CO of seawater- and freshwater-acclimated trout stabilizing at a similar level after warming (~26 ml·min−1·kg−1). The consistently higher CVP of seawater-acclimated trout suggests that factors other than compromised cardiac filling constrained the SV and CO of these individuals at high temperatures. The present study highlights, for the first time, the complex interacting effects of temperature and water salinity on cardiovascular responses in a euryhaline fish species.
Angiotensinogen import in isolated proximal tubules: evidence for mitochondrial trafficking and uptake
Authors: Wilson Bryan A. , Cruz-Diaz Nildris , Su Yixin , Rose James C. , Gwathmey TanYa M. , Chappell Mark C.
Published: December 2016

The renal proximal tubules are a key functional component of the kidney and express the angiotensin precursor angiotensinogen; however, it is unclear the extent that tubular angiotensinogen reflects local synthesis or internalization. Therefore, the current study established the extent to which angiotensinogen is internalized by proximal tubules and the intracellular distribution. Proximal tubules were isolated from the kidney cortex of male sheep by enzymatic digestion and a discontinuous Percoll gradient. Tubules were incubated with radiolabeled125I-angiotensinogen for 2 h at 37°C in serum/phenol-free DMEM/F12 media. Approximately 10% of exogenous125I-angiotensinogen was internalized by sheep tubules. Subcellular fractionation revealed that 21 ± 4% of the internalized125I-angiotensinogen associated with the mitochondrial fraction with additional labeling evident in the nucleus (60 ± 7%), endoplasmic reticulum (4 ± 0.5%), and cytosol (15 ± 4%; n = 4). Subsequent studies determined whether mitochondria directly internalized125I-angiotensinogen using isolated mitochondria from renal cortex and human HK-2 proximal tubule cells. Sheep cortical and HK-2 mitochondria internalized125I-angiotensinogen at a comparable rate of (33 ± 9 vs. 21 ± 10 pmol·min−1·mg protein−1; n = 3). Lastly, unlabeled angiotensinogen (100 nM) competed for125I-angiotensinogen uptake to a greater extent than human albumin in HK-2 mitochondria (60 ± 2 vs. 16 ± 13%; P < 0.05, n = 3). Collectively, our data demonstrate angiotensinogen import and subsequent trafficking to the mitochondria in proximal tubules. We conclude that this pathway may constitute a source of the angiotensinogen precursor for the mitochondrial expression of angiotensin peptides.
Castration alters protein balance after high-frequency muscle contraction
Authors: Steiner Jennifer L. , Fukuda David H. , Rossetti Michael L. , Hoffman Jay R. , Gordon Bradley S.
Published: December 2016

Resistance exercise increases muscle mass by shifting protein balance in favor of protein accretion. Androgens independently alter protein balance, but it is unknown whether androgens alter this measure after resistance exercise. To answer this, male mice were subjected to sham or castration surgery 7–8 wk before undergoing a bout of unilateral, high-frequency, electrically induced muscle contractions in the fasted or refed state. Puromycin was injected 30 min before euthanasia to measure protein synthesis. The tibialis anterior was analyzed 4 h postcontraction. In fasted mice, neither basal nor stimulated rates of protein synthesis were affected by castration despite lower phosphorylation of mechanistic target of rapamycin in complex 1 (mTORC1) substrates [p70S6K1 (Thr389) and 4E-BP1 (Ser65)]. Markers of autophagy (LC3 II/I ratio and p62 protein content) were elevated by castration, and these measures remained elevated above sham values after contractions. Furthermore, in fasted mice, the protein content of Regulated in Development and DNA Damage 1 (REDD1) was correlated with LC3 II/I in noncontracted muscle, whereas phosphorylation of uncoordinated like kinase 1 (ULK1) (Ser757) was correlated with LC3 II/I in the contracted muscle. When mice were refed before contractions, protein synthesis and mTORC1 signaling were not affected by castration in either the noncontracted or contracted muscle. Conversely, markers of autophagy remained elevated in the muscles of refed, castrated mice even after contractions. These data suggest the castration-mediated elevation in baseline autophagy reduces the absolute positive shift in protein balance after muscle contractions in the refed or fasted states.

NEW & NOTEWORTHY In the absence of androgens, markers of autophagy were elevated, and these could not be normalized by muscle contractions. In the fasted state, REDD1 was identified as a potential contributor to autophagy in noncontracted muscle, whereas phosphorylation of ULK1 may contribute to this process in the contracted muscle. In the refed state, markers of autophagy remain elevated in both noncontracted and contracted muscles, but the relationship with REDD1 and ULK1 (Ser757) no longer existed.
A 33-Year-Old Man with Gynaecomastia and Galactorrhea as the First Symptoms of Graves Hyperthyroidism
Authors: Khoohaphatthanakul Somdul , Sriwijitkamol Apiradee
Published: December 2016

Graves’ hyperthyroidism has a various number of well-recognized manifestations. Galactorrhea is a rare manifestation in this disease. We describe a 33-year-old man who presented with the symptoms of hyperthyroidism, gynaecomastia, and galactorrhea for 2 months. Physical examination revealed goitre, gynaecomastia, and galactorrhea, bilaterally. Laboratory investigations demonstrated high free thyroxine with suppressed thyroid-stimulating hormone level together with elevated anti-TSH receptor; therefore, the diagnosis of Graves’ disease was confirmed. Other investigations to elucidate the etiology of galactorrhea were normal, so the galactorrhea was hypothesized to be caused by Graves’ disease. The gynaecomastia and galactorrhea resolved with the successful treatment of hyperthyroidism. Although the galactorrhea is extremely rare in thyrotoxicosis male patients, to the best of our knowledge, this is the third case which reported gynaecomastia and galactorrhea in male patient who presented with thyrotoxicosis.
The Roles of Exercise and Yoga in Ameliorating Depression as a Risk Factor for Cognitive Decline
Authors: Mathersul Danielle C. , Rosenbaum Simon
Published: December 2016

Currently, there are no effective pharmaceutical treatments to reduce cognitive decline or prevent dementia. At the same time, the global population is aging, and rates of dementia and mild cognitive impairment (MCI) are on the rise. As such, there is an increasing interest in complementary and alternative interventions to treat or reduce the risk of cognitive decline. Depression is one potentially modifiable risk factor for cognitive decline and dementia. Notably, exercise and yoga are two interventions known to both reduce symptoms of depression and improve cognitive function. The current review discusses the efficacy of exercise and yoga to ameliorate depression and thereby reduce the risk of cognitive decline and potentially prevent dementia. Potential mechanisms of change, treatment implications, and future directions are discussed.
Cdk5 Directly Targets Nuclear p21CIP1 and Promotes Cancer Cell Growth
Authors: Huang Pao-Hsuan , Chen Mei-Chih , Peng Yu-Ting , Kao Wei-Hsiang , Chang Chih-Hsiang , Wang Yun-Chi , Lai Chih-Ho , Hsieh Jer-Tsong , Wang Jo-Hsin , Lee Yueh-Tsung , Lin Eugene , Yue Chia-Herng , Wang Hsin-Yi , You Shuen-Chi , Lin Ho
Published: December 2016

The significance of Cdk5 in cell-cycle control and cancer biology has gained increased attention. Here we report the inverse correlation between the protein levels of Cdk5 and p21CIP1 from cell-based and clinical analysis. Mechanistically, we identify that Cdk5 overexpression triggers the proteasome-dependent degradation of p21CIP1 through a S130 phosphorylation in a Cdk2-independent manner. Besides, the evidence from cell-based and clinical analysis shows that Cdk5 primarily regulates nuclear p21CIP1 protein degradation. S130A-p21CIP1 mutant enables to block either its protein degradation or the increase of cancer cell growth caused by Cdk5. Notably, Cdk5-triggered p21CIP1 targeting primarily appears in S-phase, while Cdk5 overexpression increases the activation of Cdk2 and its interaction with DNA polymerase δ. The in vivo results show that Cdk2 might play an important role in the downstream signaling to Cdk5. In summary, these findings suggest that Cdk5 in a high expression status promotes cancer growth by directly and rapidly releasing p21CIP1-dependent cell-cycle inhibition and subsequent Cdk2 activation, which illustrates an oncogenic role of Cdk5 potentially applied for future diagnosis and therapy. Cancer Res; 76(23); 6888–900. ©2016 AACR.
The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia
Authors: Herman Sarah E.M. , Montraveta Arnau , Niemann Carsten U. , Mora-Jensen Helena , Gulrajani Michael , Krantz Fanny , Mantel Rose , Smith Lisa L. , McClanahan Fabienne , Harrington Bonnie K. , Colomer Dolors , Covey Todd , Byrd John C. , Izumi Raquel , Kaptein Allard , Ulrich Roger , Johnson Amy J. , Lannutti Brian J. , Wiestner Adrian , Woyach Jennifer A.
Published: December 2016

Purpose: Acalabrutinib (ACP-196) is a novel, potent, and highly selective Bruton tyrosine kinase (BTK) inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the antitumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL).

Experimental Design: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model. Mice received either vehicle or acalabrutinib formulated into the drinking water.

Results: Utilizing biochemical assays, we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared with ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects, including decreased phosphorylation of PLCγ2, ERK, and significant inhibition of CLL cell proliferation. Furthermore, tumor burden in the spleen of the mice treated with acalabrutinib was significantly decreased compared with vehicle-treated mice. Similarly, in the TCL1 adoptive transfer model, decreased phosphorylation of BTK, PLCγ2, and S6 was observed. Most notably, treatment with acalabrutinib resulted in a significant increase in survival compared with mice receiving vehicle.

Conclusions: Treatment with acalabrutinib potently inhibits BTK in vivo, leading to on-target decreases in the activation of key signaling molecules (including BTK, PLCγ2, S6, and ERK). In two complementary mouse models of CLL, acalabrutinib significantly reduced tumor burden and increased survival compared with vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared with ibrutinib while demonstrating significant antitumor efficacy in vivo on par with ibrutinib. Clin Cancer Res; 23(11); 2831–41. ©2016 AACR.
The Impact of Health Care Appointment Non-Adherence on Graft Outcomes in Kidney Transplantation
Authors: Taber David J. , Fleming James N. , Fominaya Cory E. , Gebregziabher Mulugeta , Hunt Kelly J. , Srinivas Titte R. , Baliga Prabhakar K. , McGillicuddy John W. , Egede Leonard E.
Published: December 2016

Background: Non-adherence to medication is a well-studied and known cause of late allograft loss, but it is difficult to measure and prospectively monitor. The aim of this study was to assess if appointment non-adherence was correlated with medication non-adherence and a predictor of graft outcomes. Methods: This was a longitudinal cohort study that used the National United States Renal Data System and veterans affairs health records data with time-to-event analyses conducted to assess the impact on graft and patient survival. Results: The number of transplants that were included in the analysis was 4,646 (3,656 with complete records); 14.6% of patients had an appointment no show rate of ≥12% (non-adherence). Appointment and medication non-adherence were highly correlated and both were significant independent predictors of outcomes. Those with appointment non-adherence had 1.5 times the risk of acute rejection (22.0 vs. 14.7%, p < 0.0001) and a 65% higher risk of graft loss (adjusted hazards ratio (aHR) 1.65, 95% CI 1.38-1.97, p < 0.0001). There was a significant interaction between appointment and medication non-adherence; those with appointment and medication non-adherence were at very high risk of graft loss (aHR 4.18, 95% CI 3.39-5.15, p < 0.0001), compared to those with only appointment non-adherence (aHR 1.39, 95% CI 0.97-2.01, p = 0.0766) or only medication non-adherence (aHR 2.44, 95% CI 2.11-2.81, p < 0.0001). Conclusion: These results demonstrate that non-adherence to health care appointments is a significant and independent risk factor for graft loss.
Increased Plasma IgE Accelerate Atherosclerosis in Secreted IgM Deficiency
Authors: Tsiantoulas Dimitrios , Bot Ilze , Ozsvar-Kozma Maria , Göderle Laura , Perkmann Thomas , Hartvigsen Karsten , Conrad Daniel H. , Kuiper Johan , Mallat Ziad , Binder Christoph J.
Published: December 2016

Rationale:

Deficiency of secreted IgM (
sIgM
−/−
) accelerates atherosclerosis in
Ldlr
−/−
mice. Several atheroprotective effects of increased levels of IgM antibodies have been suggested, including preventing inflammation induced by oxidized low-density lipoprotein and promoting apoptotic cell clearance. However, the mechanisms by which the lack of sIgM promotes lesion formation remain unknown.

Objective:

To identify the mechanisms by which sIgM deficiency accelerates atherosclerosis in mice.

Methods and Results:

We here show that both
sIgM
−/−
and
Ldlr
−/−
sIgM
−/−
mice develop increased plasma IgE titers because of impaired generation of B cells expressing the low-affinity IgE receptor CD23, which mediates the clearance of IgE antibodies. We further report that
Ldlr
−/−
sIgM
−/−
mice exhibit increased numbers of activated mast cells and neutrophils in the perivascular area of atherosclerotic plaques. Treatment with an anti-IgE–neutralizing antibody fully reversed vascular inflammation and accelerated atherosclerotic lesion formation in cholesterol-fed
Ldlr
−/−
sIgM
−/−
mice.

Conclusions:

Thus, our data identify a previously unsuspected mechanism by which sIgM deficiency aggravates atherosclerosis.
A Sociological Approach to the Russian Constitution
Authors: Smirnova Maria , Thornhill Chris
Published: December 2016

This article promotes a distinctive sociological interpretation of the Russian Constitution. Much literature on Russian constitutional law is defined by the claim that the Constitution has little factual reality and limited foundation in society. This article challenges this view on two grounds. It argues that there are two deep-lying social processes that underlie the Constitution, and condition its evolution: the Constitution is shaped (a) by the importance of constitutional law for the stabilization of governance structures; (b) by the resultant relative autonomy of judicial practices, which means that legal exchanges (especially litigation) have formative impact on the constitutional order. On both grounds, the Russian Constitution is locked into cycles of societal norm construction. To understand the sociological linkages in which the constitution is located, we require a complex construction of society, and we need to observe how different practices within the legal system affect and even produce constitutional laws.
The Geographies and Methodologies of Religion in the Journal of Early Modern History
Authors: Clossey Luke
Published: December 2016

Looking at historiography and methodology for the risks of Eurocentrism and presentism, this essay reflects on the study of the history of religion in the two decades of the Journal of Early Modern History’s life to date. It first counts the locations of the subjects of the Journal’s articles, both generally and specifically on religion, to measure patterns in geographical focus. Considering the language these articles use to describe religion, the essay then draws a contrast between treating religion on its own terms and adapting a more analytical, though invasive, approach. Andrew Gow’s emphasis on continuity between the medieval and the early-modern inspires a late-traditional perspective that avoids both eurocentrism and presentism.