bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between glucocerebrosidase mutations and Parkinson disease
Authors: Migdalska‐Richards Anna , Schapira Anthony H. V.
Published: February 2016

Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease, whereas Gaucher disease (GD) is the most frequent lysosomal storage disorder caused by homozygous mutations in the glucocerebrosidase (GBA1) gene. Increased risk of developing PD has been observed in both GD patients and carriers. It has been estimated that GBA1 mutations confer a 20‐ to 30‐fold increased risk for the development of PD, and that at least 7–10% of PD patients have a GBA1 mutation. To date, mutations in the GBA1 gene constitute numerically the most important risk factor for PD. The type of PD associated with GBA1 mutations (PD‐GBA1) is almost identical to idiopathic PD, except for a slightly younger age of onset and a tendency to more cognitive impairment. Importantly, the pathology of PD‐GBA1 is identical to idiopathic PD, with nigral dopamine cell loss, Lewy bodies, and neurites containing alpha‐synuclein. The mechanism by which GBA1 mutations increase the risk for PD is still unknown. However, given that clinical manifestation and pathological findings in PD‐GBA1 patients are almost identical to those in idiopathic PD individuals, it is likely that, as in idiopathic PD, alpha‐synuclein accumulation, mitochondrial dysfunction, autophagic impairment, oxidative and endoplasmic reticulum stress may contribute to the development and progression of PD‐GBA1. Here, we review the GBA1 gene, its role in GD, and its link with PD.

image

The impact of glucocerebrosidase 1 (GBA1) mutations on functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. GBA1 mutations resulting in production of misfolded glucocerebrosidase (GCase) significantly affect the ER functioning. Misfolded GCase trapped in the ER leads to both an increase in the ubiquitin–proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or endoplasmic reticulum‐associated degradation (ERAD). The prolonged activation of UPR and ERAD subsequently leads to increased apoptosis. The presence of misfolded GCase in the lysosomes together with a reduction in wild‐type GCase levels lead to a retardation of alpha‐synuclein degradation via chaperone‐mediated autophagy (CMA), which subsequently results in alpha‐synuclein accumulation and aggregation. Impaired lysosomal functioning also causes a decrease in the clearance of autophagosomes, and so their accumulation. GBA1 mutations perturb normal mitochondria functioning by increasing generation of free radical species (ROS) and decreasing adenosine triphosphate (ATP) production, oxygen consumption, and membrane potential. GBA1 mutations also lead to accumulation of dysfunctional and fragmented mitochondria.

This article is part of a special issue on Parkinson disease.
New method of neck surface electromyography for the evaluation of tongue‐lifting activity
Authors: Manda Y. , Maeda N. , Pan Q. , Sugimoto K. , Hashimoto Y. , Tanaka Y. , Kodama N. , Minagi S.
Published: February 2016

Elevation of the posterior part of the tongue is important for normal deglutition and speech. The purpose of this study was to develop a new surface electromyography (EMG) method to non‐invasively and objectively evaluate activity in the muscles that control lifting movement in the posterior tongue. Neck surface EMG (N‐EMG) was recorded using differential surface electrodes placed on the neck, 1 cm posterior to the posterior border of the mylohyoid muscle on a line orthogonal to the lower border of the mandible. Experiment 1: Three healthy volunteers (three men, mean age 37·7 years) participated in an evaluation of detection method of the posterior tongue lifting up movement. EMG recordings from the masseter, temporalis and submental muscles and N‐EMG revealed that i) N‐EMG was not affected by masseter muscle EMG and ii) N‐EMG activity was not observed during simple jaw opening and tongue protrusion, revealing the functional difference between submental surface EMG and N‐EMG. Experiment 2: Seven healthy volunteers (six men and one woman, mean age 27·9 years) participated in a quantitative evaluation of muscle activity. Tongue‐lifting tasks were perfor‐med, exerting a prescribed force of 20, 50, 100 and 150 gf with visual feedback. For all subjects, a significant linear relationship was observed bet‐ween the tongue‐lifting force and N‐EMG activity (P < 0·01). These findings indicate that N‐EMG can be used to quantify the force of posterior tongue lifting and could be useful to evaluate the effect of tongue rehabilitation in future studies.
The Effect of Different Water Temperatures on Retention Loss and Material Degradation of Locator Attachments
Authors: Chiu Lillian Pui Yuk , Vitale Nicola Di , Petridis Haralampos , McDonald Ailbhe
Published: February 2016

Purpose

To examine the changes in Locator attachments after exposure to different water temperatures and cyclic loading.

Materials and Methods

Four groups of pink Locator attachments (3.0 lb. light retention replacement patrix attachments; 10 per group) were soaked for the equivalent of 5 years of use in distilled water at the following temperatures: 20°C, 37°C, 60°C. One group was kept dry to test the effect of water. A universal testing machine was used to measure the retention force of each treated attachment during 5500 insertion and removal cycles, simulating approximately 5 years of use. The results were compared using Kruskal‐Wallis one‐way ANOVA by ranks. Surface changes of tested attachments were examined using scanning electron microscopy (SEM).

Results

The exposure to 60°C water significantly increased the percentage of retention loss in Locator attachments (p < 0.05) compared to the 20°C water group and significantly reduced the final retention force compared to the other groups (p < 0.05). SEM examinations revealed severe cracking and material degradation in Locator attachments after exposure to 60°C water and cyclic loading, which were not evident in other groups. Cracking was observed after exposure to 60˚C water before cyclic loading.

Conclusions

Exposure to 60°C water, potentially similar to denture cleansing procedures, could cause cracking in Locator attachments. Cracking is associated with hydrolytic degradation of nylon at 60°C. The change in structure could result in a significant loss of retention.
A Late Mesoproterozoic 40Ar/39Ar age for a melt breccia from the Keurusselkä impact structure, Finland
Authors: Schmieder Martin , Jourdan Fred , Moilanen Jarmo , Buchner Elmar , Öhman Teemu
Published: February 2016

Field investigations in the eroded central uplift of the ≤30 km Keurusselkä impact structure, Finland, revealed a thin, dark melt vein that intersects the autochthonous shatter cone‐bearing target rocks near the homestead of Kirkkoranta, close to the center of the impact structure. The petrographic analysis of quartz in this melt breccia and the wall rock granite indicate weak shock metamorphic overprint not exceeding ~8–10 GPa. The mode of occurrence and composition of the melt breccia suggest its formation as some kind of pseudotachylitic breccia. 40Ar/39Ar dating of dark and clast‐poor whole‐rock chips yielded five concordant Late Mesoproterozoic miniplateau ages and one plateau age of 1151 ± 10 Ma [± 11 Ma] (2σ; MSWD = 0.11; P = 0.98), considered here as the statistically most robust age for the rock. The new 40Ar/39Ar age is incompatible with ~1.88 Ga Svecofennian tectonism and magmatism in south‐central Finland and probably reflects the Keurusselkä impact, followed by impact‐induced hydrothermal chloritization of the crater basement. In keeping with the crosscutting relationships in the outcrop and the possible influence of postimpact alteration, the Late Mesoproterozoic 40Ar/39Ar age of ~1150 Ma should be treated as a minimum age for the impact. The new 40Ar/39Ar results are consistent with paleomagnetic results that suggested a similar age for Keurusselkä, which is shown to be one of the oldest impact structures currently known in Europe and worldwide.
Development and validation of a large, modular test meal with liquid and solid components for assessment of gastric motor and sensory function by non‐invasive imaging
Authors: Parker H. L. , Tucker E. , Hoad C. L. , Pal A. , Costigan C. , Hudders N. , Perkins A. , Blackshaw E. , Gowland P. , Marciani L. , Fox M. R.
Published: February 2016

Background

Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study introduces the large ‘Nottingham Test Meal’ (NTM) for assessment of gastric motor and sensory function by non‐invasive imaging.

Methods

NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and 12 solid agar‐beads (0 kcal) with known breaking strength. Gastric fullness and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gastric emptying (GE) were measured in 24 healthy volunteers (HVs) by gastric scintigraphy (GS) and magnetic resonance imaging (MRI). The contribution of secretion to gastric volume was assessed. Parameters that describe GE were calculated from validated models. Inter‐observer agreement and reproducibility were assessed.

Key Results

NTM produced moderate fullness (VAS ≥30) but no more than mild dyspeptic symptoms (VAS <30) in 24 HVs. Stable binding of meal components to labels in gastric conditions was confirmed. Distinct early and late‐phase GE were detected by both modalities. Liquid GE half‐time was median 49 (95% CI: 36–62) min and 68 (57–71) min for GS and MRI, respectively. Differences between GS and MRI measurements were explained by the contribution of gastric secretion. Breaking strength for agar‐beads was 0.8 N/m2 such that median 25 (8–50) % intact agar‐beads and 65 (47–74) % solid material remained at 120 min on MRI and GS, respectively. Good reproducibility for liquid GE parameters was present and GE was not altered by agar‐beads.

Conclusions & Inferences

The NTM provided an objective assessment of gastric motor and sensory function. The results were reproducible and liquid emptying was not affected by non‐nutrient agar‐beads. The method is potentially suitable for clinical practice.
Serum Vitamin D Levels Not Associated with Atopic Dermatitis Severity
Authors: Robl Renata , Uber Marjorie , Abagge Kerstin Taniguchi , Lima Monica Nunes , Carvalho Vânia Oliveira
Published: February 2016

Backgound/objectives

The objective of the current study was to determine the relationship between serum vitamin D levels and the severity of atopic dermatitis (AD) in a Brazilian population.

Methods

This was a cross‐sectional study of patients younger than 14 years of age seen from April to November 2013. All patients fulfilled the Hanifin and Rajka Diagnostic Criteria for AD diagnosis. Disease severity was determined using the SCORing Atopic Dermatitis index and classified as mild (<25), moderate (25–50), or severe (>50). Serum vitamin D levels were classified as sufficient (≥30 ng/mL), insufficient (29–21 ng/mL), or deficient (≤20 ng/mL).

Results

A total of 105 patients met the inclusion criteria. Mild AD was diagnosed in 58 (55.2%) children, moderate in 24 (22.8%), and severe in 23 (21.9%). Vitamin D deficiency was observed in 45 individuals (42.9%). Of these, 24 (53.3%) had mild AD, 13 (28.9%) moderate, and 8 (17.7%) severe. Insufficient vitamin D levels were found in 45 (42.9%) individuals; 24 (53.3%) had mild AD, 9 (20.0%) moderate, and 12 (26.7%) severe. Of the 15 individuals (14.2%) with sufficient vitamin D levels, 10 (60.7%) had mild AD, 2 (13.3%) moderate, and 3 (20.0%) severe. The mean vitamin D level was 22.1 ± 7.3 ng/mL in individuals with mild AD, 20.8 ± 6.5 ng/mL in those with moderate AD, and 21.9 ± 9.3 ng/mL in those with severe AD. Variables such as sex, age, skin phototype, season of the year, and bacterial infection were not significantly associated with vitamin D levels.

Conclusion

Levels of 25‐hydroxyvitamin D were deficient or insufficient in 85% of the children, but serum vitamin D concentrations were not significantly related to AD severity.
Water‐Holding and Transport Properties of Skin Stratum Corneum of Infants and Toddlers Are Different from Those of Adults: Studies in Three Geographical Regions and Four Ethnic Groups
Authors: Mack Mary Catherine , Chu Melissa R. , Tierney Neena K. , Ruvolo Eduardo , Stamatas Georgios N. , Kollias Nikiforos , Bhagat Kamlesh , Ma Lin , Martin Katharine M.
Published: February 2016

Background/Objective

Epidermal structure, function, and composition are different in white infants and adults. We investigated whether ethnicity and location contribute to differences in functional and clinical measurements of skin barrier function during the first years of life and in adults.

Methods

Children (n= 397, ages 3–49 mos) and women (n= 117, mean age 31 yrs) were enrolled at independent centers in Beijing, China (ethnic Chinese), Skillman, New Jersey (white, African American), and Mumbai, India (ethnic South Asian). Water barrier properties of the stratum corneum were assessed using high‐frequency conductance and transepidermal water loss (TEWL) on the dorsal forearm and upper inner arm. Digital imaging was used to evaluate facial erythema and scaling.

Results

Despite differences in local climate, TEWL was similar in adults. In children, conductance and TEWL decreased monotonically from age 3 months to 4 years. In children from Beijing, TEWL values were higher in both arm locations than in children in Mumbai and Skillman. No significant differences were observed in TEWL or conductance between the white and African American groups.

Conclusion

In general, TEWL and conductance were greater on the upper inner arm than the dorsal forearm. Erythema and scaling were observed most often in subjects from Beijing and most infrequently in subjects from Mumbai. Stratum corneum water barrier properties were different in children and adults. Although there may be differences in these properties between ethnic groups in childhood, TEWL values were similar in adults across the three geographic locations and four ethnicities.
Relativity and Three Four‐dimensionalisms
Authors: Gilmore Cody , Costa Damiano , Calosi Claudio
Published: February 2016

Relativity theory is often said to support something called ‘the four‐dimensional view of reality’. But there are at least three different views that sometimes go by this name. One is ‘spacetime unitism’ (as we call it), according to which there is a spacetime manifold, and if there are such things as points of space or instants of time, these are just spacetime regions of different sorts: thus space and time are not separate manifolds. A second is the B‐theory of time, according to which the past, present, and future are all equally real and there is nothing metaphysically special about the present. A third is perdurantism, according to which persisting material objects (rocks, trees, and human beings) are made up of different temporal parts located at different times. We sketch routes from relativity to unitism and to the B‐theory. We then discuss some routes to perdurantism, via the B‐theory and via unitism.
Novel Human Three‐Domain Antibody Fragments Against sTNFα as Well as tmTNFα with High Affinity Generated by the Combination of Ribosome Display and E. coli Expression System
Authors: Zhao X.‐L. , Tian L.‐F. , Zhang S.‐J. , Li J.‐M. , Feng H. , Wang L.‐M. , Wang S. , Wang J. , Wang T. , Chen W.‐Q.
Published: February 2016

Human tumour necrosis factor α (hTNFα) has been proved to be a validated therapeutic target in a number of immune‐mediated inflammatory diseases (IMIDs). Fully human monoclonal antibodies (mAbs) that can neutralize soluble hTNFα (sTNFα) as well as transmembrane hTNFα (tmTNFα) are more desirable hTNFα antagonists. Here, we report that novel anti‐hTNFα human low‐molecular‐weight MAbs have been selected and identified using both sTNFα and tmTNFα as target antigens by the combination of ribosome display and E. coli expression system for the first time. As a newly born engineering small molecular antibody, three‐domain antibody fragment (VH/κ) provides an alternative promising molecular principle to generate biological agents for TNFα‐dependent IMIDs. In this study, a panel of novel human VH/κs (F09, F21, F49 and F409) with high affinity (10−10–10−9 mol/l) to neutralize sTNFα as well as tmTNFα was generated by the combination of ribosome display and E. coli expression system. Among the four clones, F21 and F409 could reduce cytotoxicity on L929 cells induced by sTNFα as well as tmTNFα effectively, and both of them had great potential to inhibit hTNFα‐mediated NF‐κB activation. Soluble F21 and F409 were also able to inhibit the binding of hTNFα to TNFR1 and TNFR2. The new human antibodies described here have desirable capability to neutralize sTNFα as well as tmTNFα effectively with high affinity and reasonable stability; this may provide an alternative approach for patients who are not responding adequately to currently available anti‐TNFα agents.
Identification and Modelling of Translational and Axial Symmetries and their Hierarchical Structures in Building Footprints by Formal Grammars
Authors: Dehbi Youness , Gröger Gerhard , Plümer Lutz
Published: February 2016

Buildings and other man‐made objects, for many reasons such as economical or aesthetic, are often characterized by their symmetry. The latter predominates in the design of building footprints and building parts such as façades. Thus the identification and modeling of this valuable information facilitates the reconstruction of these buildings and their parts. This article presents a novel approach for the automatic identification and modelling of symmetries and their hierarchical structures in building footprints, providing an important prior for façade and roof reconstruction. The uncertainty of symmetries is explicitly addressed using supervised machine learning methods, in particular Support Vector Machines (SVMs). Unlike classical statistical methods, for SVMs assumptions on the a priori distribution of the data are not required. Both axial and translational symmetries are detected. The quality of the identified major and minor symmetry axes is assessed by a least squares based adjustment. Context‐free formal grammar rules are used to model the hierarchical and repetitive structure of the underlying footprints. We present an algorithm which derives grammar rules based on the previously acquired symmetry information and using lexical analysis describing regular patterns and palindrome‐like structures. This offers insights into the latent structures of building footprints and therefore describes the associated façade in a relational and compact way.
Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation
Authors: Kapustin A. N. , Shanahan C. M.
Published: February 2016

Vascular smooth muscle cell (VSMC) phenotypic conversion from a contractile to ‘synthetic’ state contributes to vascular pathologies including restenosis, atherosclerosis and vascular calcification. We have recently found that the secretion of exosomes is a feature of ‘synthetic’ VSMCs and that exosomes are novel players in vascular repair processes as well as pathological vascular thrombosis and calcification. Pro‐inflammatory cytokines and growth factors as well as mineral imbalance stimulate exosome secretion by VSMCs, most likely by the activation of sphingomyelin phosphodiesterase 3 (SMPD3) and cytoskeletal remodelling. Calcium stress induces dramatic changes in VSMC exosome composition and accumulation of phosphatidylserine (PS), annexin A6 and matrix metalloproteinase‐2, which converts exosomes into a nidus for calcification. In addition, by presenting PS, VSMC exosomes can also provide the catalytic surface for the activation of coagulation factors. Recent data showing that VSMC exosomes are loaded with proteins and miRNA regulating cell adhesion and migration highlight VSMC exosomes as potentially important communication messengers in vascular repair. Thus, the identification of signalling pathways regulating VSMC exosome secretion, including activation of SMPD3 and cytoskeletal rearrangements, opens up novel avenues for a deeper understanding of vascular remodelling processes.

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Continuous Solar Carbothermal Reduction of Aerosolized ZnO Particles Under Vacuum in a Directly Irradiated Vertical-Tube Reactor
Authors: Brkic Majk , Koepf Erik , Meier Anton
Published: February 2016

A solar-driven aerosolized particle reactor under vacuum was tested for carbothermal reduction of zinc oxide using concentrated solar power. The reactor concept is based on the downward flow of zinc oxide and carbon particles, which are indirectly heated by an opaque intermediate solar absorption tube. The particles are rapidly heated to reaction temperature and reduced within residence times of less than 1 s. In the continuous feeding experiments, maximum sustained temperatures close to 2000 K and heating rates as fast as 1400 K min−1 could be achieved for pressures between 1 and 1000 mbar. Reactant conversions of up to 44% were obtained at 1000 mbar. It was found that a reduction in system pressure leads to a decreased particle residence time (as low as 0.09 s), and therefore low conversion (as low as 1%), thus partially diminishing the positive thermodynamic effects of vacuum operation. Experimental results validate the robust and versatile reactor concept, and simultaneously highlight the necessity of balancing the system design in order to optimize the conflicting influence of vacuum operation and reacting particle residence time.
Novel Manufacturing Route for Scale Up Production of Terahertz Technology Devices
Authors: Penchev P. , Shang X. , Dimov S. , Lancaster M.
Published: February 2016

The advances in the Terahertz (THz) technology drive the needs for the design and manufacture of waveguide devices that integrate complex three-dimensional (3D) miniaturized components with meso- and micro-scale functional features and structures. Typical dimensions of the waveguide functional structures are in the range from 200 μm to 50 μm and dimensions decrease with the increase in the operating frequency of the waveguide devices. Technological requirements that are critical for achieving the desired microwave filtering performance of the waveguides include geometrical accuracy, alignment between functional features and surface integrity. In this context, this paper presents a novel manufacturing route for the scaled-up production of THz components that integrate computer numerical control (CNC) milling and laser micromachining. A solution to overcome the resulting tapering of the laser-machined structures while achieving a high accuracy and surface integrity of the machined features is applied in this research. In addition, an approach for two-side processing of waveguide structures within one laser machining setup is described. The capabilities of the proposed manufacturing process chain are demonstrated on two THz waveguide components that are functionally tested to assess the effects of the achieved machining results on devices' performance. Experimental results show that the proposed process chain can address the manufacturing requirements of THz waveguide filters, in particular the process chain is capable of producing filters with geometrical accuracy better than 10 μm, side wall taper angle deviation of less than 1 deg from vertical (90 deg), waveguide cavities corner radius better than 15 μm, and surface roughness (Sa) better than 1.5 μm. The manufacturing efficiency demonstrated in this feasibility study also provides sufficient evidences to argue that the proposed multistage manufacturing technique is a very promising solution for the serial production of small to medium batches of THz waveguide components. Finally, analyses of the manufacturing capabilities of the proposed process chain and the photoresist-based technologies were performed to clearly demonstrate the advantages of the proposed process chain over current waveguide fabrication solutions.
Micromechanical Analyses of Debonding and Matrix Cracking in Dual-Phase Materials
Authors: Legarth Brian Nyvang , Yang Qingda
Published: February 2016

Failure in elastic dual-phase materials under transverse tension is studied numerically. Cohesive zones represent failure along the interface and the augmented finite element method (A-FEM) is used for matrix cracking. Matrix cracks are formed at an angle of 55 deg−60 deg relative to the loading direction, which is in good agreement with experiments. Matrix cracks initiate at the tip of the debond, and for equi-biaxial loading cracks are formed at both tips. For elliptical reinforcement the matrix cracks initiate at the narrow end of the ellipse. The load carrying capacity is highest for ligaments in the loading direction greater than that of the transverse direction.
Two-Dimensional Elastodynamic Scattering by a Finite Flat Crack
Authors: Emets V. F. , Rogowski J.
Published: February 2016

The diffraction of elastic harmonic waves by a finite plane tunnel crack is studied. A solution is derived from an analysis of the integral equations describing the problem, using the Wiener–Hopf technique and the method of compound asymptotic expansions. Taking into account the successive reflections of Rayleigh waves from crack tips, an approximate analytical solution is expressed in a closed-form that is computationally effective and yields accurate results in the resonance region of dimensionless wave numbers. Both direct and inverse scattering problems are considered.
Right–Left Differences in Knee Extension Stiffness for the Normal Rat Knee: In Vitro Measurements Using a New Testing Apparatus
Authors: Markolf Keith L. , Evseenko Denis , Petrigliano Frank
Published: February 2016

Knee stiffness following joint injury or immobilization is a common clinical problem, and the rat has been used as a model for studies related to joint stiffness and limitation of motion. Knee stiffness measurements have been reported for the anesthetized rat, but it is difficult to separate the contributions of muscular and ligamentous restraints to the recorded values. in vitro testing of isolated rat knees devoid of musculature allows measurement of joint structural properties alone. In order to measure the effects of therapeutic or surgical interventions designed to alter joint stiffness, the opposite extremity is often used as a control. However, right–left stiffness differences for the normal rat knee have not been reported in the literature. If stiffness changes observed for a treatment group are within the normal right–left variation, validity of the results could be questioned. The objectives of this study were to utilize a new testing apparatus to measure right–left stiffness differences during knee extension in a population of normal rat knees and to document repeatability of the stiffness measurements on successive testing days. Moment versus rotation curves were recorded for 15 right–left pairs of normal rat knees on three consecutive days, with overnight specimen storage in a refrigerator. Each knee was subjected to ten loading–unloading cycles, with the last loading curve used for analysis. Angular rotation (AR), defined here as the change in flexion–extension angle from a specified applied joint moment, is commonly used as a measure of overall joint stiffness. For these tests, ARs were measured from the recorded test curves with a maximum applied extension moment of 100 g cm. Mean rotations for testing days 2 and 3 were 0.81–1.25 deg lower (p < 0.001) than for day 1, but were not significantly different from each other. For each testing day, mean rotations for right knees were 1.12–1.30 deg greater (p < 0.001) than left knees. These right–left stiffness differences should be considered when interpreting the results of knee treatment studies designed to alter knee stiffness when using the opposite extremity as a control.
Unveiling Protein Kinase A Targets in Cryptococcus neoformans Capsule Formation
Authors: Alspaugh J. Andrew
Published: February 2016

The protein kinase A (PKA) signal transduction pathway has been associated with pathogenesis in many fungal species. Geddes and colleagues [mBio 7(1):e01862-15, 2016, doi:10.1128/mBio.01862-15] used quantitative proteomics approaches to define proteins with altered abundance during protein kinase A (PKA) activation and repression in the opportunistic human fungal pathogen
Cryptococcus neoformans
. They observed an association between microbial PKA signaling and ubiquitin-proteasome regulation of protein homeostasis. Additionally, they correlated these processes with expression of polysaccharide capsule on the fungal cell surface, the main virulence-associated phenotype in this organism. Not only are their findings important for microbial pathogenesis, but they also support similar associations between human PKA signaling and ubiquitinated protein accumulation in neurodegenerative diseases.
The Membrane Protein of Severe Acute Respiratory Syndrome Coronavirus Functions as a Novel Cytosolic Pathogen-Associated Molecular Pattern To Promote Beta Interferon Induction via a Toll-Like-Receptor-Related TRAF3-Independent Mechanism
Authors: Wang Yi , Liu Li
Published: February 2016

Most of the intracellular pattern recognition receptors (PRRs) reside in either the endolysosome or the cytoplasm to sense pathogen-derived RNAs, DNAs, or synthetic analogs of double-stranded RNA (dsRNA), such as poly(I:C). However, it remains elusive whether or not a pathogen-derived protein can function as a cytosolic pathogen-associated molecular pattern (PAMP). In this study, we demonstrate that delivering the membrane gene of severe acute respiratory syndrome coronavirus (SARS-CoV) into HEK293T, HEK293ET, and immobilized murine bone marrow-derived macrophage (J2-Mφ) cells significantly upregulates beta interferon (IFN-β) production. Both NF-κB and TBK1-IRF3 signaling cascades are activated by M gene products. M protein rather than M mRNA is responsible for M-mediated IFN-β induction that is preferentially associated with the activation of the Toll-like receptor (TLR) adaptor proteins MyD88, TIRAP, and TICAM2 but not the RIG-I signaling cascade. Blocking the secretion of M protein by brefeldin A (BFA) failed to reverse the M-mediated IFN-β induction. The antagonist of both TLR2 and TLR4 did not impede M-mediated IFN-β induction, indicating that the driving force for the activation of IFN-β production was generated from inside the cells. Inhibition of TRAF3 expression by specific small interfering RNA (siRNA) did not prevent M-mediated IFN-β induction. SARS-CoV pseudovirus could induce IFN-β production in an M rather than M(V68A) dependent manner, since the valine-to-alanine alteration at residue 68 in M protein markedly inhibited IFN-β production. Overall, our study indicates for the first time that a pathogen-derived protein is able to function as a cytosolic PAMP to stimulate type I interferon production by activating a noncanonical TLR signaling cascade in a TRAF3-independent manner.

IMPORTANCE
Viral protein can serve as a pathogen-associated molecular pattern (PAMP) that is usually recognized by certain pathogen recognition receptors (PRRs) on the cell surface, such as Toll-like receptor 2 (TLR2) and TLR4. In this study, we demonstrate that the membrane (M) protein of SARS-CoV can directly promote the activation of both beta interferon (IFN-β) and NF-κB through a TLR-related signaling pathway independent of TRAF3. The driving force for M-mediated IFN-β production is most likely generated from inside the cells. M-mediated IFN-β induction was confirmed at the viral infection level since a point mutation at the V68 residue of M markedly inhibited SARS-CoV pseudovirally induced IFN-β production. Thus, the results indicate for the first time that SARS-CoV M protein may function as a cytosolic PAMP to stimulate IFN-β production by activating a TLR-related TRAF3-independent signaling cascade.
Lambda Interferon Restructures the Nasal Microbiome and Increases Susceptibility to Staphylococcus aureus Superinfection
Authors: Planet Paul J. , Parker Dane , Cohen Taylor S. , Smith Hannah , Leon Justinne D. , Ryan Chanelle , Hammer Tobin J. , Fierer Noah , Chen Emily I. , Prince Alice S.
Published: February 2016

Much of the morbidity and mortality associated with influenza virus respiratory infection is due to bacterial coinfection with pathogens that colonize the upper respiratory tract such as methicillin-resistant
Staphylococcus aureus
(MRSA) and
Streptococcus pneumoniae
. A major component of the immune response to influenza virus is the production of type I and III interferons. Here we show that the immune response to infection with influenza virus causes an increase and restructuring of the upper respiratory microbiota in wild-type (WT) mice but not in

Il28r
−/−

mutant mice lacking the receptor for type III interferon. Mice lacking the IL-28 receptor fail to induce STAT1 phosphorylation and expression of its regulator, SOCS1.

Il28r
−/−

mutant mice have increased expression of interleukin-22 (IL-22), as well as Ngal and RegIIIγ, in the nasal cavity, the source of organisms that would be aspirated to cause pneumonia. Proteomic analysis reveals changes in several cytoskeletal proteins that contribute to barrier function in the nasal epithelium that may contribute to the effects of IL-28 signaling on the microbiota. The importance of the effects of IL-28 signaling in the pathogenesis of MRSA pneumonia after influenza virus infection was confirmed by showing that WT mice nasally colonized before or after influenza virus infection had significantly higher levels of infection in the upper airways, as well as significantly greater susceptibility to MRSA pneumonia than
Il28r
−/−
mutant mice did. Our results suggest that activation of the type III interferon in response to influenza virus infection has a major effect in expanding the upper airway microbiome and increasing susceptibility to lower respiratory tract infection.

IMPORTANCE
S. aureus
and influenza virus are important respiratory pathogens, and coinfection with these organisms is associated with significant morbidity and mortality. The ability of influenza virus to increase susceptibility to
S. aureus
infection is less well understood. We show here that influenza virus leads to a change in the upper airway microbiome in a type III interferon-dependent manner. Mice lacking the type III interferon receptor have altered STAT1 and IL-22 signaling. In coinfection studies, mice without the type III interferon receptor had significantly less nasal
S. aureus
colonization and subsequent pneumonia than infected WT mice did. This work demonstrates that type III interferons induced by influenza virus contribute to nasal colonization and pneumonia due to
S. aureus
superinfection.
Immigrant mothers and access to prenatal care: evidence from a regional population study in Italy
Authors: Chiavarini Manuela , Lanari Donatella , Minelli Liliana , Pieroni Luca , Salmasi Luca
Published: February 2016

Objectives

We addressed the question of whether use of adequate prenatal care differs between foreign-born and Italian mothers and estimated the extent to which unobservable characteristics bias results.

Setting

This study is on primary care and especially on adequate access to prenatal healthcare services by immigrant mothers.

Participants

Approximately 37 000 mothers of both Italian and foreign nationality were studied. Data were obtained from the Standard Certificate of Live Birth between 2005 and 2010 in Umbria.

Results

Estimates from the bivariate probit model indicate that immigrant mothers are three times more likely to make fewer than four prenatal visits (OR=3.35) and 1.66 times more likely to make a late first visit (OR=1.66). The effect is found to be strongest for Asian women.

Conclusions

Standard probit models lead to underestimation of the probability of inadequate use of prenatal care services by immigrant women, whereas bivariate probit models, which allow us to consider immigrant status as an endogenous variable, estimated ORs to be three times larger than those obtained with univariate models.
Exploring provision of Innovative Community Education Placements (ICEPs) for junior doctors in training: a qualitative study
Authors: Griffin Ann , Jones Melvyn M , Khan Nada , Park Sophie , Rosenthal Joe , Chrysikou Vasiliki
Published: February 2016

Objective

Medical education in community settings is an essential ingredient of doctors’ training and a key factor in recruiting general practitioners (GP). Health Education England's report ‘Broadening the Foundation’ recommends foundation doctors complete 4-month community placements. While Foundation GP schemes exist; other community settings, are not yet used for postgraduate training. The objective of this study was to explore how community-based training of junior doctors might be expanded into possible ‘innovative community education placements’ (ICEPs), examining opportunities and barriers to these developments.

Design

A qualitative study where semistructured interviews were undertaken and themes were generated deductively from the research questions, and iteratively from transcripts.

Setting

UK community healthcare.

Participants

Stakeholders from UK Community healthcare providers and undergraduate GP and community educators.

Results

Nine participants were interviewed; those experienced in delivering community-based undergraduate education, and others working in community settings that had not previously trained doctors. Themes identified were practicalities such as ‘finance and governance’, ‘communication and interaction’, ‘delivery of training’ and ‘perceptions of community’. ICEPs were willing to train Foundation doctors. However, concerns were raised that large numbers and inadequate resources could undermine the quality of educational opportunities, and even cause reputational damage. Organisation was seen as a challenge, which might be best met by placing some responsibility with trainees to manage their placements. ICEP providers agreed that defined service contribution by trainees was required to make placements sustainable, and enhance learning. ICEPs stated the need for positive articulation of the learning value of placements to learners and stakeholders.

Conclusions

This study highlighted the opportunities for foundation doctors to gain specialist and generalist knowledge in ICEPs from diverse clinical teams and patients. We recommend in conclusion ways of dealing with some of the perceived barriers to training.
CD10-positive myoepithelial cells are usually prominent around in situ lobular neoplasia of the breast and much less prominent or absent in DCIS
Authors: Shousha Sami , Forbes Georgina , Hopkins Ilona , Wright Josephine Anne
Published: February 2016

Aims

To study the relationship between the neoplastic cells of in situ lobular neoplasia (ILN) and ductal carcinoma in situ (DCIS) and the surrounding CD10-positive myoepithelial cells.

Materials and methods

Twenty consecutive cases of ILN and 51 of DCIS were stained for CD10 using the immunoperoxidase technique. The presence of CD10-positive cells was assessed semiquantitatively on a scale of 0–3 where 0 indicates their absence and 3 indicates the presence of multiple layers, which can be focal.

Results

Ninety per cent of ILN cases scored 3, compared with none of DCIS (p=0.0001). There was a significant relationship between DCIS grade and CD10 score, with the mean scores being 1.43, 0.82 and 0.5 for low, intermediate and high grade, respectively. CD10-positive cells were always present around low-grade DCIS, but absent in 27% of high-grade cases. CD10-positive cells were more frequent in ER-positive than in ER-negative DCIS, and in HER2-negative than in HER2-positive cases, but the difference was not statistically significant.

Conclusions

There is a distinct relationship between the type and grade of in situ neoplasia of the breast and the surrounding CD10-positive myoepithelial cells, suggesting the presence of a ‘cross talk’ between the two elements.
The role of distributed education in recruitment and retention of family physicians
Authors: Lee Joseph , Walus Andrzej , Billing Rajeev , Hillier Loretta M
Published: February 2016

Background

Distributed medical education (DME) programmes, in which training occurs in underserviced areas, have been established as a strategy to increase recruitment and retention of new physicians following graduation to these areas. Little is known about what makes physicians remain in the area in which they train.

Objectives

To explore the factors that contributed to family physician's decisions to practice in an underserviced area following graduation from a DME programme.

Methods

Semistructured inperson interviews were conducted with 19 family physicians who graduated from a DME residency training programme. Programme records were reviewed to identify practice location of DME programme graduates.

Results

Of the 32 graduates to date from this DME programme, 66% (N=21) and all of the interview participants established their practices in this region after completing their residency training. Five key themes were identified from the interview analysis as impacting physicians' decisions to establish their practice in an underserviced area following graduation: familial ties to the region, practice opportunities, positive clerkship and residency experiences, established relationships with specialists and services in the area and lifestyle opportunities afforded by the location.

Conclusions

This study suggests that DME programmes can be an effective strategy for equalising the distribution of family physicians and highlights the ways in which these programmes can facilitate recruitment and retention in underserviced areas, including being responsive to residents' personal preferences and objectives for learning and shaping their residency experiences to meet to these objectives.
A state-space approach to incorporating environmental effects on recruitment in an age-structured assessment model with an application to southern New England yellowtail flounder
Authors: Miller Timothy J. , Hare Jonathan A. , Alade Larry A.
Published: February 2016

The state-space model framework provides a natural, probabilistic approach to stock assessment by modeling the stochastic nature of population survival and recruitment separately from sampling uncertainty inherent in observations on the population. We propose a state-space assessment model that is expanded to simultaneously treat environmental covariates as stochastic processes and estimate their effects on recruitment. We apply the model to southern New England yellowtail flounder (Limanda ferruginea) using data from the most recent benchmark assessment to evaluate evidence for effects of the mid-Atlantic cold pool and spawning stock biomass on recruitment. Based on Akaike’s information criterion, both the cold pool and spawning stock biomass were important predictors of recruitment and led to annual variation in estimated biomass reference points and associated yield. We also demonstrate the effect of the stochasticity of the mid-Atlantic cold pool on short-term forecasts of the stock size, biomass reference point, and stock status.
The effects of motor rehabilitation training on clinical symptoms and serum BDNF levels in Parkinson’s disease subjects
Authors: Angelucci Francesco , Piermaria Jacopo , Gelfo Francesca , Shofany Jacob , Tramontano Marco , Fiore Marco , Caltagirone Carlo , Peppe Antonella
Published: February 2016

Increasing evidence suggests that motor rehabilitation may delay Parkinson’s disease (PD) progression. Moreover, parallel treatments in animals up-regulate brain-derived neurotrophic factor (BDNF). Thus, we investigated the effect of a motor rehabilitation protocol on PD symptoms and BDNF serum levels. Motor rehabilitation training consisted of a cycle of 20 days/month of physiotherapy divided in 3 daily sessions. Clinical data were collected at the beginning, at the end, and at 90 days follow-up. BDNF serum levels were detected by ELISA at 0, 7, 14, 21, 30, and 90 days. The follow-up period had a duration of 60 days (T30–T90). The results showed that at the end of the treatment (day 30), an improvement in extrapyramidal signs (UPDRS III; UPDRS III – Gait and Balance items), motor (6 Minute Walking Test), and daily living activities (UPDRS II; PDQ-39) was observed. BDNF levels were increased at day 7 as compared with baseline. After that, no changes in BDNF were observed during the treatment and in the successive follow-up. This study demonstrates that motor rehabilitation training is able to ameliorate PD symptoms and to increase temporarily BDNF serum levels. The latter effect may potentially contribute to the therapeutic action.
Development of new PCR-based markers specific for chromosome arms of rye (Secale cereale L.)
Authors: Qiu Ling , Tang Zong-xiang , Li Meng , Fu Shu-lan
Published: February 2016

PCR-based rye (Secale cereale L.) chromosome-specific markers can contribute to the effective utilization of elite genes of rye in wheat (Triticum aestivum L.) breeding programs. In the present study, 578 new PCR-based rye-specific markers have been developed by using specific length amplified fragment sequencing (SLAF-seq) technology, and 76 markers displayed different polymorphism among rye Kustro, Imperial, and King II. A total of 427 and 387 markers were, respectively, located on individual chromosomes and chromosome arms of Kustro by using a set of wheat–rye monosomic addition lines and 13 monotelosomic addition lines, which were derived from T. aestivum L. ‘Mianyang11’ × S. cereale L. ‘Kustro’. In addition, two sets of wheat–rye disomic addition lines, which were derived from T. aestivum L. var. Chinese Spring × S. cereale L. var. Imperial and T. aestivum L. ‘Holdfast’ × S. cereale L. var. King II, were used to test the chromosomal specificity of the 427 markers. The chromosomal locations of 281 markers were consistent among the three sets of wheat–rye addition lines. The markers developed in this study can be used to identify a given segment of rye chromosomes in wheat background and accelerate the utilization of elite genes on rye chromosomes in wheat breeding programs.
Seamless Outdoors-Indoors Localization Solutions on Smartphones
Authors: Maghdid Halgurd S. , Lami Ihsan Alshahib , Ghafoor Kayhan Zrar , Lloret Jaime
Published: February 2016

The demand for more sophisticated Location-Based Services (LBS) in terms of applications variety and accuracy is tripling every year since the emergence of the smartphone a few years ago. Equally, smartphone manufacturers are mounting several wireless communication and localization technologies, inertial sensors as well as powerful processing capability, to cater to such LBS applications. A hybrid of wireless technologies is needed to provide seamless localization solutions and to improve accuracy, to reduce time to fix, and to reduce power consumption. The review of localization techniques/technologies of this emerging field is therefore important. This article reviews the recent research-oriented and commercial localization solutions on smartphones. The focus of this article is on the implementation challenges associated with utilizing these positioning solutions on Android-based smartphones. Furthermore, the taxonomy of smartphone-location techniques is highlighted with a special focus on the detail of each technique and its hybridization. The article compares the indoor localization techniques based on accuracy, utilized wireless technology, overhead, and localization technique used. The pursuit of achieving ubiquitous localization outdoors and indoors for critical LBS applications such as security and safety shall dominate future research efforts.