bluuebunny/crossref_metadata_2025 huggingface dataset:
Redox potential as a master variable controlling pathways of metal reduction byGeobacter sulfurreducens
Authors: Levar Caleb E. , Hoffman Colleen L. , Dunshee Aubrey J. , Toner Brandy M. , Bond Daniel R.
Published: April 2016

Geobacter sulfurreducensuses at least two different pathways to transport electrons out of the inner membrane quinone pool before reducing acceptors beyond the outer membrane. When growing on electrodes poised at oxidizing potentials, the CbcL-dependent pathway operates at or below redox potentials of −0.10 V vs. the Standard Hydrogen Electrode (SHE), while the ImcH-dependent pathway operates only above this value. Here, we provide evidence thatG. sulfurreducensalso requires different electron transfer proteins for reduction of a wide range of Fe(III)- and Mn(IV)- (oxyhydr)oxides, and must transition from a high- to low-potential pathway during reduction of commonly studied soluble and insoluble metal electron acceptors. Freshly precipitated Fe(III)-(oxyhydr)oxides could not be reduced by mutants lacking the high potential pathway. Aging these minerals by autoclaving did not change their powder X-ray diffraction pattern, but restored reduction by mutants lacking the high-potential pathway. Mutants lacking the low-potential, CbcL-dependent pathway had higher growth yields with both soluble and insoluble Fe(III). Together, these data suggest that the ImcH-dependent pathway exists to harvest additional energy when conditions permit, and CbcL switches on to allow respiration closer to thermodynamic equilibrium conditions. With evidence of multiple pathways within a single organism, the study of extracellular respiration should consider not only the crystal structure or solubility of a mineral electron acceptor, but rather the redox potential, as this variable determines the energetic reward affecting reduction rates, extents, and final microbial growth yields in the environment.
Mixed Model Association with Family-Biased Case-Control Ascertainment
Authors: Hayeck Tristan , Zaitlen Noah A. , Loh Po-Ru , Pollack Samuela , Gusev Alexander , Patterson Nick , Price Alkes L.
Published: April 2016

Mixed models have become the tool of choice for genetic association studies; however, standard mixed model methods may be poorly calibrated or underpowered under family sampling bias and/or case-control ascertainment. Previously, we introduced a liability threshold based mixed model association statistic (LTMLM) to address case-control ascertainment in unrelated samples. Here, we consider family-biased case-control ascertainment, where cases and controls are ascertained non-randomly with respect to family relatedness. Previous work has shown that this type of ascertainment can severely bias heritability estimates; we show here that it also impacts mixed model association statistics. We introduce a family-based association statistic (LT-Fam) that is robust to this problem. Similar to LTMLM, LT-Fam is computed from posterior mean liabilities (PML) under a liability threshold model; however, LT-Fam uses published narrow-sense heritability estimates to avoid the problem of biased heritability estimation, enabling correct calibration. In simulations with family-biased case-control ascertainment, LT-Fam was correctly calibrated (averageχ2= 1.00), whereas Armitage Trend Test (ATT) and standard mixed model association (MLM) were mis-calibrated (e.g. averageχ2= 0.50-0.67 for MLM). LT-Fam also attained higher power in these simulations, with increases of up to 8% vs. ATT and 3% vs. MLM after correcting for mis-calibration. In 1,269 type 2 diabetes cases and 5,819 controls from the CARe cohort, downsampled to induce family-biased ascertainment, LT-Fam was correctly calibrated whereas ATT and MLM were again mis-calibrated (e.g. averageχ2= 0.60-0.82 for MLM). Our results highlight the importance of modeling family sampling bias in case-control data sets with related samples.
Functional metagenomics reveals novel β-galactosidases not predictable from gene sequences
Authors: Cheng Jiujun , Romantsov Tatyana , Engel Katja , Doxey Andrew C. , Rose David R. , Neufeld Josh D. , Charles Trevor
Published: April 2016

A soil metagenomic library carried in pJC8 (an IncP cosmid) was used for functional complementation for β-galactosidase activity in bothα-Proteobacteria (Sinorhizobium meliloti)andγ-Proteobacteria (Escherichia coli).Oneβ-galactosidase, encoded by overlapping clones selected in both hosts, was identified as a member of glycoside hydrolase family 2. ORFs obviously encoding possible β-galactosidases were not identified in 19 other clones that were only able to complementS. meliloti.Based on low sequence similarity to known glycoside hydrolases but not β-galactosidases, three ORFs were examined further. Biochemical analysis confirmed that all encodedβ-galactosidase activity. Bioinformatic and structural modeling implied that Lac161_ORF10 protein represented a novel enzyme family with a five-bladed propeller glycoside hydrolase domain.
Order under uncertainty: robust differential expression analysis using probabilistic models for pseudotime inference
Authors: Campbell Kieran , Yau Christopher
Published: April 2016

Single cell gene expression profiling can be used to quantify transcriptional dynamics in temporal processes, such as cell differentiation, using computational methods to label each cell with a ‘pseudotime’ where true time series experimentation is too difficult to perform. However, owing to the high variability in gene expression between individual cells, there is an inherent uncertainty in the precise temporal ordering of the cells. Preexisting methods for pseudotime ordering have predominantly given point estimates precluding a rigorous analysis of the implications of uncertainty. We use probabilistic modelling techniques to quantify pseudotime uncertainty and propagate this into downstream differential expression analysis. We demonstrate that reliance on a point estimate of pseudotime can lead to inflated false discovery rates compared and that probabilistic approaches provide greater robustness and measures of the temporal resolution that can be obtained from pseudotime inference.
A new one-dimensional cadmium(II) coordination polymer incorporating 4-[4-(1H-imidazol-1-yl)phenyl]pyridine and 5-hydroxybenzene-1,3-dicarboxylate ligands
Authors: Zhang Zhi-Liang , Liu Jia-Cheng
Published: April 2016

The design and synthesis of new organic lgands is important to the rapid development of coordination polymers (CPs). However, CPs based on asymmetric ligands are still rare, mainly because such ligands are usually expensive and more difficult to synthesize. The new asymmetric ligand 4-[4-(1H-imidazol-1-yl)phenyl]pyridine (IPP) has been used to construct the title one-dimensional coordination polymer,catena-poly[[[aqua{4-[4-(1H-imidazol-1-yl-κN3)phenyl]pyridine}cadmium(II)]-μ-5-hydroxybenzene-1,3-dicarboxylato-κ3O1,O1′:O3] monohydrate], {[Cd(C8H4O5)(C14H11N3)2(H2O)]·H2O}n, under hydrothermal reaction of IPP with CdIIin the presence of 5-hydroxyisophthalic acid (5-OH-H2bdc). The CdIIcation is coordinated by two N atoms from two distinct IPP ligands, three carboxylate O atoms from two different 5-OH-bdc2−dianionic ligands and one water O atom in a distorted octahedral geometry. The cationic [Cd(IPP)2]2+nodes are linked by 5-OH-bdc2−ligands to generate a one-dimensional chain. These chains are extended into a two-dimensional layer structureviaO—H...O and O—H...N hydrogen bonds and π–π interactions.
Impact of electrical heating on effective thermal Insulation of a multi-layered winter clothing system for optimal heating efficiency
Authors: Park Huiju , Hwang Soo-kyung , Lee Joo-Young , Fan Jintu , Jeong Youngjin
Published: April 2016

Purpose

This paper investigated the impact of the distance of the heating unit from the body in a multi-layered winter clothing system on effective thermal insulation and heating efficiency.

Design/methodology/approach

To identify changes in the thermal insulation and heating efficiency of electrical heating in different layers inside a winter clothing ensemble, a series of thermal manikin tests was conducted. A multi-layered winter ensemble with and without activation of a heating unit was tested on the thermal manikin under two different ambient temperature conditions (10°C and -5°C).

Findings

Results show that the effective thermal insulation of test ensembles increased by 5-7% with the activation of the heating unit compared to that without the activation. The closer the heating unit to the body, the higher the effective thermal insulation was in both ambient temperature conditions. This trend was more significant at lower ambient temperature.

Research limitations/implications

The results of this study indicate that providing electric heating next to the skin is the most effective in increasing effective thermal insulation and decreasing body heat loss in both ambient temperature (-5°C and 10°C). This trend was more remarkable in colder environment at -5°C of ambient temperature as evidenced by sharp decrease in heating efficiency and effective thermal insulation with an increase in distance between the manikin skin and heating unit at -5°C of ambient temperature compared to at 10°C of ambient temperature.

Practical implications

Based on the results, it is expected that proximity heating next to the skin, in cold environment, may reduce the weight and size of the battery for the heating unit because of the higher efficiency of electric heating and the potentially immediate perception of warmth supported by the greatest increase in effective thermal insulation, as well as the lowest heat loss that comes with activation of heating on the first layer in cold environment.

Originality/value

The finding of this study provides guidelines to sportswear designers, textile scientists, sports enthusiasts, and civilians who consider electric heating benefits for improved thermal comfort and safety in cold environments, especially in the areas of outdoor and winter sports and in military service. The results of this study indicate that providing electric heating next to the skin is the most effective in increasing effective thermal insulation and decreasing body heat loss in both ambient temperature (-5°C and 10°C).
Constructing the female body: using female genital mutilation law to address genital-normalizing surgery on intersex children in the United States
Authors: Fraser Sylvan
Published: April 2016

Purpose

– The purpose of this paper is to explore the harms suffered by intersex children who are subjected to medically unnecessary genital-normalizing surgery (GNS) and the possible applicability of statutes prohibiting female genital mutilation (FGM) to certain cases of GNS to redress this harm in the USA.

Design/methodology/approach

– Consulting publications by medical researchers and intersex activists alike, this comment reviews the procedures undertaken as part of GNS (most commonly including clitoral reduction) and the reasons behind these procedures. It also parses the language of federal and state statutes prohibiting FGM in the USA.

Findings

– Surgical practices that include clitoral cutting when the procedure is not necessary to the health of the person on whom it is performed constitute FGM and are punishable under federal and certain state laws in the USA. GNS with clitoral reduction fits the definition of FGM because it is performed for cosmetic and social reasons, not medical necessity.

Originality/value

– Acknowledging GNS with clitoral reduction as FGM is a crucial strategy to ensure that female-assigned intersex children’s rights to bodily autonomy are protected to the same extent as non-intersex children’s rights. Intersex legal activists in the USA should press for enforcement of FGM statutes as to female-assigned intersex children until the medical practitioners who continue to defend and perform GNS see the procedures as illegal genital mutilation.
Snap Transitions of Pressurized Graphene Blisters
Authors: Wang Peng , Liechti Kenneth M. , Huang Rui
Published: April 2016

Blister tests are commonly used to determine the mechanical and interfacial properties of thin film materials with recent applications for graphene. This paper presents a numerical study on snap transitions of pressurized graphene blisters. A continuum model is adopted combining a nonlinear plate theory for monolayer graphene with a nonlinear traction–separation relation for van der Waals interactions. Three types of blister configurations are considered. For graphene bubble blisters, snap-through and snap-back transitions between pancake-like and dome-like shapes are predicted under pressure-controlled conditions. For center-island graphene blisters, snap transitions between donut-like and dome-like shapes are predicted under both pressure and volume control. Finally, for the center-hole graphene blisters, growth is stable under volume or N-control but unstable under pressure control. With a finite hole depth, the growth may start with a snap transition under N-control if the hole is relatively deep. The numerical results provide a systematic understanding on the mechanics of graphene blisters, consistent with previously reported experiments. Of particular interest is the relationship between the van der Waals interactions and measurable quantities in corresponding blister tests, with which both the adhesion energy of graphene and the equilibrium separation for the van der Waals interactions may be determined. In comparison with approximate solutions based on membrane analyses, the numerical method offers more accurate solutions that may be used in conjunction with experiments for quantitative characterization of the interfacial properties of graphene and other two-dimensional (2D) membrane materials.
Lattice Approach in Continuum and Fracture Mechanics
Authors: Mohammadipour Amir , Willam Kaspar
Published: April 2016

This study reveals some aspects of lattice formulations to analyze the strain concentration of a famous classic problem in solid mechanics at two different mechanics perspectives: continuum and fracture. A 2D plane stress square panel with a single circular hole is discretized based on Voronoi tessellation. A superelliptic formulation is used to distribute lattice computational points over the panel. From the perspective of linear elasticity under uniaxial and biaxial loading, translational and rotational degrees-of-freedom are considered at each computational node of the lattice to obtain strain concentration factors (SCFs) around the circular perforation. It is observed that the lattice approach is able to approximate the elastic SCFs of three, four, and two in uniaxial, biaxial shear, and equibiaxial tension loadings, respectively. To study the linear elasticity and fracture mechanic (LEFM) and Griffith energy balance in uniaxial loading, a brittle lattice erosion technique is used to compute the energy release rate determined by change in the global stiffness matrix of the mesh with respect to crack extension. This fracture energy is then used to determine the mode I stress intensity factor of the crack emanating from the hole which is validated by the analytical formulation for the same problem. The comparison shows that both methods give very close results for the mode I stress intensity factor. Being simple in terms of constitutive formulation and failure criterion for erosion of brittle material, and also using a propagating crack extension approach, the lattice formulation is used to determine the fracture properties of cohesive/frictional material.
Modeling the Abrupt Buckling Transition in dsDNA During Supercoiling
Authors: Ivenso Ikenna D.
Published: April 2016

When deoxyribonucleic (DNA), held at a fixed tension, is subjected to torsional deformations, it responds by forming plectonemic supercoils accompanied by a reduction in its end-to-end extension. This transition from the extended state to the supercoiled state is marked by an abrupt buckling of the DNA accompanied by a rapid “hopping” of the DNA between the extended and supercoiled states. This transition is studied by means of Brownian dynamics simulations using a discrete wormlike-chain (dWLC) model of DNA. The simulations reveal, among other things, the distinct regimes that occur during DNA supercoiling and the probabilities of states within the buckling transition regime.
Positively charged supported lipid bilayer formation on gold surfaces for neuronal cell culture
Authors: Choi Sung-Eun , Greben Kyrylo , Wördenweber Roger , Offenhäusser Andreas
Published: April 2016

Supported lipid bilayers are widely used as cell membrane models and sensor platforms, but the usage on gold surface needs additional surface modification or optimized experimental conditions. In this work, the authors show lipid bilayer formation on plasma activated gold surfaces in physiological conditions without any other modification if at least 30% positively charged lipids are present. Details of bilayer formation from small unilamellar vesicles were monitored using quartz crystal microbalance with dissipation in both basic and acidic environment. The authors also confirmed that this positively charged bilayer system can sustain primary cortical neuron growth and lipid transfer. This method will provide simple means to construct biomimetic interface on gold electrodes.
Control of broadband optically generated ultrasound pulses using binary amplitude holograms
Authors: Brown Michael D. , Jaros Jiri , Cox Ben T. , Treeby Bradley E.
Published: April 2016

In this work, the use of binary amplitude holography is investigated as a mechanism to focus broadband acoustic pulses generated by high peak-power pulsed lasers. Two algorithms are described for the calculation of the binary holograms; one using ray-tracing, and one using an optimization based on direct binary search. It is shown using numerical simulations that when a binary amplitude hologram is excited by a train of laser pulses at its design frequency, the acoustic field can be focused at a pre-determined distribution of points, including single and multiple focal points, and line and square foci. The numerical results are validated by acoustic field measurements from binary amplitude holograms, excited by a high peak-power laser.
Effects of age on speech and voice quality ratings
Authors: Goy Huiwen , Kathleen Pichora-Fuller M. , van Lieshout Pascal
Published: April 2016

The quality of communication may be affected by listeners' perception of talkers' characteristics. This study examined if there were effects of talker and listener age on the perception of speech and voice qualities. Younger and older listeners judged younger and older talkers' gender and age, then rated speech samples on pleasantness, naturalness, clarity, ease of understanding, loudness, and the talker's suitability to be an audiobook reader. For the same talkers, listeners also rated voice samples on pleasantness, roughness, and power. Younger and older talkers were perceived to be similar on most qualities except age. Younger and older listeners rated talkers similarly, except that younger listeners perceived younger voices to be more pleasant and less rough than older voices. For vowel samples, younger listeners were more accurate than older listeners at age estimation, while older listeners were more accurate than younger listeners at gender identification, suggesting that younger and older listeners differ in their evaluation of specific talker characteristics. Thus, the perception of quality was generally more affected by the age of the listener than the age of the talker, and age-related differences between listeners depended on whether voice or speech samples were used and the rating being made.
A “datathon” model to support cross-disciplinary collaboration
Authors: Aboab Jerôme , Celi Leo Anthony , Charlton Peter , Feng Mengling , Ghassemi Mohammad , Marshall Dominic C. , Mayaud Louis , Naumann Tristan , McCague Ned , Paik Kenneth E. , Pollard Tom J. , Resche-Rigon Matthieu , Salciccioli Justin D. , Stone David J.
Published: April 2016

A “datathon” model combines complementary knowledge and skills to formulate inquiries and drive research that addresses information gaps faced by clinicians.
Singly Flagellated Pseudomonas aeruginosa Chemotaxes Efficiently by Unbiased Motor Regulation
Authors: Cai Qiuxian , Li Zhaojun , Ouyang Qi , Luo Chunxiong , Gordon Vernita D.
Published: April 2016

Pseudomonas aeruginosa
is an opportunistic human pathogen that has long been known to chemotax. More recently, it has been established that chemotaxis is an important factor in the ability of
P. aeruginosa
to make biofilms. Genes that allow
P. aeruginosa
to chemotax are homologous with genes in the paradigmatic model organism for chemotaxis,
Escherichia coli
. However,
P. aeruginosa
is singly flagellated and
E. coli
has multiple flagella. Therefore, the regulation of counterclockwise/clockwise flagellar motor bias that allows
E. coli
to efficiently chemotax by runs and tumbles would lead to inefficient chemotaxis by
P. aeruginosa
, as half of a randomly oriented population would respond to a chemoattractant gradient in the wrong sense. How
P. aeruginosa
regulates flagellar rotation to achieve chemotaxis is not known. Here, we analyze the swimming trajectories of single cells in microfluidic channels and the rotations of cells tethered by their flagella to the surface of a variable-environment flow cell. We show that
P. aeruginosa
chemotaxes by symmetrically increasing the durations of both counterclockwise and clockwise flagellar rotations when swimming up the chemoattractant gradient and symmetrically decreasing rotation durations when swimming down the chemoattractant gradient. Unlike the case for
E. coli
, the counterclockwise/clockwise bias stays constant for
P. aeruginosa
. We describe
P. aeruginosa
’s chemotaxis using an analytical model for symmetric motor regulation. We use this model to do simulations that show that, given
P. aeruginosa
’s physiological constraints on motility, its distinct, symmetric regulation of motor switching optimizes chemotaxis.

IMPORTANCE
Chemotaxis has long been known to strongly affect biofilm formation by the opportunistic human pathogen
P. aeruginosa
, whose essential chemotaxis genes have homologues in
E. coli
, which achieves chemotaxis by biasing the relative probability of counterclockwise and clockwise flagellar rotation. However, the physiological difference between multiflagellated
E. coli
and singly flagellated
P. aeruginosa
implies that biased motor regulation should prevent
P. aeruginosa
populations from chemotaxing efficiently. Here, we used experiments, analytical modeling, and simulations to demonstrate that
P. aeruginosa
uses unbiased, symmetric regulation of the flagellar motor to maximize its chemotaxis efficiency. This mode of chemotaxis was not previously known and demonstrates a new variant of a paradigmatic signaling system in an important human pathogen.
SpoVG Is a Conserved RNA-Binding Protein That Regulates Listeria monocytogenes Lysozyme Resistance, Virulence, and Swarming Motility
Authors: Burke Thomas P. , Portnoy Daniel A.
Published: April 2016

In this study, we sought to characterize the targets of the abundant
Listeria monocytogenes
noncoding RNA Rli31, which is required for
L. monocytogenes
lysozyme resistance and pathogenesis. Whole-genome sequencing of lysozyme-resistant suppressor strains identified loss-of-expression mutations in the promoter of
spoVG
, and deletion of
spoVG
rescued lysozyme sensitivity and attenuation
in vivo
of the
rli31
mutant. SpoVG was demonstrated to be an RNA-binding protein that interacted with Rli31
in vitro.
The relationship between Rli31 and SpoVG is multifaceted, as both the
spoVG
-encoded protein and the
spoVG
5′-untranslated region interacted with Rli31. In addition, we observed that
spoVG
-deficient bacteria were nonmotile in soft agar and suppressor mutations that restored swarming motility were identified in the gene encoding a major RNase in Gram-positive bacteria, RNase J1. Collectively, these findings suggest that SpoVG is similar to global posttranscriptional regulators, a class of RNA-binding proteins that interact with noncoding RNA, regulate genes in concert with RNases, and control pleiotropic aspects of bacterial physiology.

IMPORTANCE
spoVG
is widely conserved among bacteria; however, the function of this gene has remained unclear since its initial characterization in 1977. Mutation of
spoVG
impacts various phenotypes in Gram-positive bacteria, including methicillin resistance, capsule formation, and enzyme secretion in
Staphylococcus aureus
and also asymmetric cell division, hemolysin production, and sporulation in
Bacillus subtilis
. Here, we demonstrate that
spoVG
mutant strains of
Listeria monocytogenes
are hyper-lysozyme resistant, hypervirulent, nonmotile, and misregulate genes controlling carbon metabolism. Furthermore, we demonstrate that SpoVG is an RNA-binding protein. These findings suggest that SpoVG has a role in
L. monocytogenes
, and perhaps in other bacteria, as a global gene regulator. Posttranscriptional gene regulators help bacteria adapt to various environments and coordinate differing aspects of bacterial physiology. SpoVG may help the organism coordinate environmental growth and virulence to survive as a facultative pathogen.
The CpxQ sRNA Negatively Regulates Skp To Prevent Mistargeting of β-Barrel Outer Membrane Proteins into the Cytoplasmic Membrane
Authors: Grabowicz Marcin , Koren Daria , Silhavy Thomas J.
Published: April 2016

The promoter most strongly induced upon activation of the Cpx two-component envelope stress response is the
cpxP
promoter. The 3′ untranscribed region (UTR) of the
cpxP
transcript is shown to produce a small RNA (sRNA), CpxQ. We investigated the role of CpxQ in combating envelope stress. Remarkably, the two effectors specified by the transcript are deployed to combat distinct stresses in different cellular compartments. CpxP acts in both a regulatory negative-feedback loop and as an effector that combats periplasmic protein misfolding. We find that CpxQ combats toxicity at the inner membrane (IM) by downregulating the synthesis of the periplasmic chaperone Skp. Our data indicate that this regulation prevents Skp from inserting β-barrel outer membrane proteins (OMPs) into the IM, a lethal event that likely collapses the proton motive force. Our findings suggest that Skp can fold and directly insert OMPs into a lipid bilayer
in vivo
without the aid of the Bam complex.

IMPORTANCE
Skp is a well-characterized periplasmic chaperone that binds unfolded OMPs. Surprisingly, we find that Skp can catalyze the folding and mistargeting of OMPs into the inner membrane without the aid of the other cellular proteins that normally assemble OMPs. Several OMPs function as diffusion pores. Accordingly, their mistargeting is lethal because it depolarizes the inner membrane. We show that the most highly expressed transcript of the Cpx stress response produces an sRNA from the 3′ UTR, CpxQ, which combats this potential toxicity by downregulating Skp production. Defects in OMP assembly trigger the σ
E
response to upregulate factors, including Skp, that promote OMP folding. The Cpx response downregulates σ
E
. Our findings reveal that this heretofore puzzling hierarchy exists to protect the inner membrane.
Characterization of a Novel Orthomyxo-like Virus Causing Mass Die-Offs of Tilapia
Authors: Bacharach Eran , Mishra Nischay , Briese Thomas , Zody Michael C. , Kembou Tsofack Japhette Esther , Zamostiano Rachel , Berkowitz Asaf , Ng James , Nitido Adam , Corvelo André , Toussaint Nora C. , Abel Nielsen Sandra Cathrine , Hornig Mady , Del Pozo Jorge , Bloom Toby , Ferguson Hugh , Eldar Avi , Lipkin W. Ian
Published: April 2016

Tilapia are an important global food source due to their omnivorous diet, tolerance for high-density aquaculture, and relative disease resistance. Since 2009, tilapia aquaculture has been threatened by mass die-offs in farmed fish in Israel and Ecuador. Here we report evidence implicating a novel orthomyxo-like virus in these outbreaks. The tilapia lake virus (TiLV) has a 10-segment, negative-sense RNA genome. The largest segment, segment 1, contains an open reading frame with weak sequence homology to the influenza C virus PB1 subunit. The other nine segments showed no homology to other viruses but have conserved, complementary sequences at their 5′ and 3′ termini, consistent with the genome organization found in other orthomyxoviruses.
In situ
hybridization indicates TiLV replication and transcription at sites of pathology in the liver and central nervous system of tilapia with disease.

IMPORTANCE
The economic impact of worldwide trade in tilapia is estimated at $7.5 billion U.S. dollars (USD) annually. The infectious agent implicated in mass tilapia die-offs in two continents poses a threat to the global tilapia industry, which not only provides inexpensive dietary protein but also is a major employer in the developing world. Here we report characterization of the causative agent as a novel orthomyxo-like virus, tilapia lake virus (TiLV). We also describe complete genomic and protein sequences that will facilitate TiLV detection and containment and enable vaccine development.
Resveratrol Attenuates Trimethylamine-
N
-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota
Authors: Chen Ming-liang , Yi Long , Zhang Yong , Zhou Xi , Ran Li , Yang Jining , Zhu Jun-dong , Zhang Qian-yong , Mi Man-tian
Published: April 2016

The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-
N
-oxide (TMAO)-induced AS in ApoE
−/−
mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera
Lactobacillus
and
Bifidobacterium
, which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA) deconjugation and fecal excretion in C57BL/6J and ApoE
−/−
mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis, and increased cholesterol 7a-hydroxylase (CYP7A1) expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression. In mice treated with antibiotics, RSV neither decreased TMAO levels nor increased hepatic BA synthesis. Additionally, RSV-induced inhibition of TMAO-caused AS was also markedly abolished by antibiotics. In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis.

IMPORTANCE
Recently, trimethylamine-
N
-oxide (TMAO) has been identified as a novel and independent risk factor for promoting atherosclerosis (AS) partially through inhibiting hepatic bile acid (BA) synthesis. The gut microbiota plays a key role in the pathophysiology of TMAO-induced AS. Resveratrol (RSV) is a natural phytoalexin with prebiotic benefits. A growing body of evidence supports the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling of the gut microbiota. The current study showed that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling. And RSV-induced hepatic BA neosynthesis was partially mediated through downregulating the enterohepatic farnesoid X receptor-fibroblast growth factor 15 axis. These results offer new insights into the mechanisms responsible for RSV’s anti-AS effects and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases.
Gliotoxin Suppresses Macrophage Immune Function by Subverting Phosphatidylinositol 3,4,5-Trisphosphate Homeostasis
Authors: Schlam Daniel , Canton Johnathan , Carreño Marvin , Kopinski Hannah , Freeman Spencer A. , Grinstein Sergio , Fairn Gregory D.
Published: April 2016

Aspergillus fumigatus, an opportunistic fungal pathogen, spreads in the environment by releasing numerous conidia that are capable of reaching the small alveolar airways of mammalian hosts. In otherwise healthy individuals, macrophages are responsible for rapidly phagocytosing and eliminating these conidia, effectively curbing their germination and consequent invasion of pulmonary tissue. However, under some circumstances, the fungus evades phagocyte-mediated immunity and persists in the respiratory tree. Here, we report thatA. fumigatusescapes macrophage recognition by strategically targeting phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] metabolism through gliotoxin, a potent immunosuppressive mycotoxin. Time-lapse microscopy revealed that, in response to the toxin, macrophages cease to ruffle, undergo abrupt membrane retraction, and fail to phagocytose large targets effectively. Gliotoxin was found to prevent integrin activation and interfere with actin dynamics, both of which are instrumental for phagocytosis; similar effects were noted in immortalized and primary phagocytes. Detailed studies of the underlying molecular mechanisms of toxicity revealed that inhibition of phagocytosis is attributable to impaired accumulation of PtdIns(3,4,5)P3and the associated dysregulation of downstream effectors, including Rac and/or Cdc42. Strikingly, in response to the diacylglycerol mimetic phorbol 12-myristate 13-acetate, gliotoxin-treated macrophages reactivate beta integrins, reestablish actin dynamics, and regain phagocytic capacity, despite the overt absence of plasmalemmal PtdIns(3,4,5)P3. Together, our findings identify phosphoinositide metabolism as a critical upstream target of gliotoxin and also indicate that increased diacylglycerol levels can bypass the requirement for PtdIns(3,4,5)P3signaling during membrane ruffling and phagocytosis.

IMPORTANCEAspergillus fumigatusis the most frequent cause of human infections in theAspergillusgenus. In immunocompromised populations, invasive aspergillosis (IA) is associated with a mortality rate of up to 90%, and current antifungal therapies have failed to prevent or reverse the infection. Therefore, a deeper understanding of the interactions betweenA. fumigatusand its host is required. In healthy humans, alveolar macrophages can ingest and eliminate fungal spores, thus limiting their germination into mycotoxin-producing hyphae. Our studies reveal that gliotoxin—the most abundantAspergillusmycotoxin—undermines the ability of phagocytes to carry out their protective functions. By targeting PtdIns(3,4,5)P3signaling and downregulating phagocytic immune defenses, the toxin could also exacerbate polymicrobial infections. Notably, we were able to reverse gliotoxin toxicity by addition of diacylglycerol analogues, which may provide the basis for therapeutic interventions.
Choleduodenal fistula with gastric outlet obstruction
Authors: Dong Matthew , Guerron Alfredo Daniel , Morris-Stiff Gareth , Chalikonda Sricharan
Published: April 2016

Bouveret's syndrome, cholecystoduodenal fistula with gastric outlet obstruction secondary to an impacted gallstone, is a rare but serious complication of cholelithiasis. We report the case of a 69-year-old woman who presented with epigastric pain and vomiting in whom cross-sectional imaging revealed a duodenal mass with cholecystoduodenal fistula and pneumobilia. Endoscopic evaluation identified a large gallstone obstructing the pyloric channel. She underwent laparotomy and stone extraction with pyloroplasty, had an unremarkable recovery. She was asymptomatic at 15 months follow-up.
Unicystic plexiform ameloblastoma with mural proliferation: a full-blown lesion
Authors: Anchlia Sonal , Bahl Sumit , Vyas Siddharth , Raju Godishala Swamy Sugunakar
Published: April 2016

Ameloblastoma is the most common aggressive benign odontogenic tumour of the jaws and has received considerable attention due to its frequency, clinical subtypes and high tendency to infiltrate and recur. There are various types of this tumour and confusion still exists among clinicians as to its correct classification. Multicystic ameloblastoma is the most frequent subtype while unicystic ameloblastoma can be considered a variant of the solid or multicystic subtype. Unicystic ameloblastoma is considered a less aggressive tumour with a variable recurrence rate. However, its frequency is often underestimated. Ameloblastoma is often asymptomatic, presenting as a slowly enlarging facial swelling or an incidental finding on radiograph. It is seen in all age groups but is most commonly diagnosed in the third and fourth decades. We report a case of unusual unicystic ameloblastoma and present its clinical, radiological and full-blown histological changes and treatment modalities, providing new insights into ameloblastomas.
Hypothyroid cardiomyopathy in a patient post-doxorubicin chemotherapy
Authors: Silver Adam Jeffrey , Patel Hena N , Okwuosa Tochi
Published: April 2016

Hypothyroidism may cause decreased cardiac output and heart failure—and when severe, bradycardia and pericardial effusions may develop. Chemotherapies, particularly doxorubicin, are known and often irreversible causes of cardiomyopathy. As such, when cardiomyopathy develops in patients who have been exposed to anthracycline chemotherapy, the importance of ruling out other reversible causes such as hypothyroidism cannot be overstated. We present a case of acute systolic heart failure in a patient post-doxorubicin chemotherapy and radiation therapy for alveolar rhabdomyosarcoma, found to have severe hypothyroidism as a reversible cause of cardiomyopathy.
Biologic Treatment Registry Across Canada (BioTRAC): a multicentre, prospective, observational study of patients treated with infliximab for ankylosing spondylitis
Authors: Rahman Proton , Choquette Denis , Bensen William G , Khraishi Majed , Chow Andrew , Zummer Michel , Shaikh Saeed , Sheriff Maqbool , Dixit Sanjay , Sholter Dalton , Psaradellis Eliofotisti , Sampalis John S , Letourneau Vincent , Lehman Allen J , Nantel François , Rampakakis Emmanouil , Otawa Susan , Shawi May
Published: April 2016

Objectives

To describe the profile of patients with ankylosing spondylitis (AS) treated with infliximab in Canadian routine care and to assess the effectiveness and safety of infliximab in real world.

Setting

46 primary care rheumatology practices across Canada.

Participants

303 biological-naïve patients with AS or patients previously treated with a biological for <6 months and who were eligible for infliximab treatment as per routine care within the Biologic Treatment Registry Across Canada (BioTRAC).

Intervention

Not applicable (non-interventional study).

Primary and secondary outcomes

Effectiveness was assessed with changes in disease parameters (AS Disease Activity Score (ASDAS), Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), Health Assessment Questionnaire Disease Index (HAQ-DI), physician global assessment of disease activity (MDGA), patient global disease activity (PtGA), back pain, C-reactive protein, erythrocyte sedimentation rate (ESR), morning stiffness). Safety was assessed with the incidence of adverse events (AEs).

Results

Of the 303 patients included, 44.6% were enrolled in 2005–2007 and 55.4% in 2008–2013. Patients enrolled in 2005–2007 had significantly higher MDGA and ESR at baseline while all other disease parameters examined were numerically higher with the exception of PtGA. Treatment with infliximab significantly (p<0.001) improved all disease parameters over time in both groups. At 6 months, 56% and 31% of patients achieved clinically important (change≥1.1) and major (change≥2.0) improvement in ASDAS, respectively; at 48 months, these proportions increased to 75% and 50%, respectively. Among patients unemployed due to disability at baseline, 12.1% returned to work (mean Kaplan-Meier (KM)-based time=38.8 months). The estimated retention rate at 12 and 24 months was 78.3% and 60.1%, respectively. The profile and incidence of AEs were comparable to data previously reported for tumour necrosis factor-α inhibitors.

Conclusions

Characteristics of patients with AS at infliximab initiation changed over time towards lower disease activity and shorter disease duration. Infliximab treatment significantly reduced disease activity independent of treatment initiation year, although patients enrolled in recent years achieved lower disease activity over 48 months.

Trial registration number

NCT00741793.
Cancer and non-cancer mortality among French uranium cycle workers: the TRACY cohort
Authors: Samson Eric , Piot Irwin , Zhivin Sergey , Richardson David B , Laroche Pierre , Serond Ana-Paula , Laurier Dominique , Laurent Olivier
Published: April 2016

Objectives

The health effects of internal contamination by radionuclides, and notably by uranium, are poorly characterised. New cohorts of uranium workers are needed to better examine these effects. This paper analyses for the first time the mortality profile of the French cohort of uranium cycle workers. It considers mortality from cancer and non-cancer causes.

Methods

The cohort includes workers employed at least 6 months between 1958 and 2006 in French companies involved in the production of nuclear fuel. Vital status and causes of death were collected from French national registries. Workers were followed-up from 1 January 1968 to 31 December 2008. Standardised mortality ratios (SMRs) were computed based on mortality rates for the French general population.

Results

The cohort includes 12 649 workers (88% men). The average length of follow-up is 27 years and the mean age at the end of the study is 60 years. Large mortality deficits are observed for non-cancer causes of death such as non-cancer respiratory diseases (SMR=0.51 (0.41 to 0.63)) and circulatory diseases (SMR=0.68 (0.62 to 0.74)). A mortality deficit of lower magnitude is also observed for all cancers combined (SMR (95% CI): 0.76 (0.71 to 0.81)). Pleural mesothelioma is elevated (SMR=2.04 (1.19 to 3.27)).

Conclusions

A healthy worker effect is observed in this new cohort of workers involved in the uranium cycle. Collection of individual information on internal uranium exposure as well as other risk factors is underway, to allow for the investigation of uranium-related risks.
Community social capital and tooth loss in Japanese older people: a longitudinal cohort study
Authors: Koyama Shihoko , Aida Jun , Saito Masashige , Kondo Naoki , Sato Yukihiro , Matsuyama Yusuke , Tani Yukako , Sasaki Yuri , Kondo Katsunori , Ojima Toshiyuki , Yamamoto Tatsuo , Tsuboya Toru , Osaka Ken
Published: April 2016

Objective

To date, no study has prospectively examined the association between social capital (SC) in the community and oral health. The aim of this longitudinal cohort study was to examine the association between both community-level and individual-level SC and tooth loss in older Japanese people.

Design

Prospective cohort study

Setting

We utilised data from the Japan Gerontological Evaluation Study (JAGES) performed in 2010 and 2013 and conducted in 525 districts.

Participants

The target population was restricted to non-institutionalised people aged 65 years or older. Participants included 51 280 people who responded to two surveys and who had teeth at baseline.

Primary outcome measure

The primary outcome measure was loss of remaining teeth, measured by the downward change of any category of remaining teeth, between baseline and follow-up.

Results

The mean age of the participants was 72.5 years (SD=5.4). During the study period, 8.2% (n=4180) lost one or more of their remaining teeth. Among three community-level SC variables obtained from factor analysis, an indicator of civic participation significantly reduced the risk of tooth loss (OR 0.93; 95% CI 0.88 to 0.99). The individual-level SC variables ‘hobby activity participation’ and ‘sports group participation’ were also associated with a reduced risk of tooth loss (OR 0.88; 95% CI 0.81 to 0.95 and OR 0.90; 95% CI 0.82 to 0.99, respectively).

Conclusions

Living in a community with rich SC and individuals with good SC is associated with lower incidence of tooth loss among older Japanese people.
Cardiovascular mortality sex differentials in selected East Asian and Western populations
Authors: Zhao Jiaying , Booth Heather , Dear Keith , Tu Edward Jow-Ching
Published: April 2016

Background

Explaining patterns in the sex ratio (male/female) of cardiovascular disease (CVD) mortality would improve understanding of mortality transitions under modernisation. Little research has examined secular trends in this ratio across populations, taking age and cohort into account. We examine cohort effects in the ratios of CVD mortality (including ischaemic heart disease and cerebrovascular disease) among 4 East Asian populations that vary in the timing of their modernisation, and assess the effect of smoking on these patterns in comparison with Western populations.

Methods

The sequential method for log-linear models is applied to analyse age, period and cohort effects for sex ratios. Age and cohort effects are fitted first, with population as offset; period effects are fitted in a second model using the fitted values from the first model as the offset. Lung cancer mortality serves as a proxy for smoking.

Results

Increases in sex ratios of CVD mortality began in earlier cohorts in Western than in East Asian populations. Once begun, increases were more rapid in East Asia. The cohort effect for the sex ratio of CVD mortality differs from that for lung cancer mortality. Trends in sex ratios of CVD mortality by cohort are similar before and after adjustment for lung cancer mortality in East Asia; the increasing trend across 1900–1945 cohorts is maintained in Western populations after adjustment.

Conclusions

The sex ratio of CVD mortality has increased across successive cohorts living in increasingly modernised environments. There is scant evidence that this increase is attributable to changing sex-specific rates of smoking.
Hemodynamic differences between unstable and stable unruptured aneurysms independent of size and location: a pilot study
Authors: Brinjikji Waleed , Chung Bong Jae , Jimenez Carlos , Putman Christopher , Kallmes David F , Cebral Juan R
Published: April 2016

Background

While clinical and angiographic risk factors for intracranial aneurysm instability are well established, it is reasonable to postulate that intra-aneurysmal hemodynamics also have a role in aneurysm instability.

Objective

To identify hemodynamic characteristics that differ between radiologically unstable and stable unruptured intracranial aneurysms.

Materials and methods

12 pairs of unruptured intracranial aneurysms with a 3D rotational angiographic set of images and followed up longitudinally without treatment were studied. Each pair consisted of one stable aneurysm (no change on serial imaging) and one unstable aneurysm (demonstrated growth of at least 1 mm diameter or ruptured during follow-up) of matching size (within 10%) and locations. Patient-specific computational fluid dynamics models were created and run under pulsatile flow conditions. Relevant hemodynamic and geometric variables were calculated and compared between groups using the paired Wilcoxon test.

Results

The area of the aneurysm under low wall shear stress (low shear stress area (LSA)) was 2.26 times larger in unstable aneurysms than in stable aneurysms (p=0.0499). The mean aneurysm vorticity was smaller by a factor of 0.57 in unstable aneurysms compared with stable aneurysms (p=0.0499). No statistically significant differences in geometric variables or shape indices were found.

Conclusions

This pilot study suggests there may be hemodynamic differences between unstable and stable unruptured cerebral aneurysms. In particular, the area under low wall shear stress was larger in unstable aneurysms. These findings should be considered tentative until confirmed by future larger studies.