bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluorofenidone attenuates pulmonary inflammation and fibrosis via inhibiting the activation of NALP3 inflammasome and IL‐1β/IL‐1R1/MyD88/NF‐κB pathway
Authors: Song Cheng , He Lujuan , Zhang Jin , Ma Hong , Yuan Xiangning , Hu Gaoyun , Tao Lijian , Zhang Jian , Meng Jie
Published: June 2016

Interleukin (IL)‐1β plays an important role in the pathogenesis of idiopathic pulmonary fibrosis. The production of IL‐1β is dependent upon caspase‐1‐containing multiprotein complexes called inflammasomes and IL‐1R1/MyD88/NF‐κB pathway. In this study, we explored whether a potential anti‐fibrotic agent fluorofenidone (FD) exerts its anti‐inflammatory and anti‐fibrotic effects through suppressing activation of NACHT, LRR and PYD domains‐containing protein 3 (NALP3) inflammasome and the IL‐1β/IL‐1R1/MyD88/NF‐κB pathway in vivo and in vitro. Male C57BL/6J mice were intratracheally injected with Bleomycin (BLM) or saline. Fluorofenidone was administered throughout the course of the experiment. Lung tissue sections were stained with haemotoxylin and eosin and Masson's trichrome. Cytokines were measured by ELISA, and α‐smooth muscle actin (α‐SMA), fibronectin, collagen I, caspase‐1, IL‐1R1, MyD88 were measured by Western blot and/or RT‐PCR. The human actue monocytic leukaemia cell line (THP‐1) were incubated with monosodium urate (MSU), with or without FD pre‐treatment. The expression of caspase‐1, IL‐1β, NALP3, apoptosis‐associated speck‐like protein containing (ASC) and pro‐caspase‐1 were measured by Western blot, the reactive oxygen species (ROS) generation was detected using the Flow Cytometry, and the interaction of NALP3 inflammasome‐associated molecules were measured by Co‐immunoprecipitation. RLE‐6TN (rat lung epithelial‐T‐antigen negative) cells were incubated with IL‐1β, with or without FD pre‐treatment. The expression of nuclear protein p65 was measured by Western blot. Results showed that FD markedly reduced the expressions of IL‐1β, IL‐6, monocyte chemotactic protein‐1 (MCP‐1), myeloperoxidase (MPO), α‐SMA, fibronectin, collagen I, caspase‐1, IL‐1R1 and MyD88 in mice lung tissues. And FD inhibited MSU‐induced the accumulation of ROS, blocked the interaction of NALP3 inflammasome‐associated molecules, decreased the level of caspase‐1 and IL‐1β in THP‐1 cells. Besides, FD inhibited IL‐1β‐induced the expression of nuclear protein p65. This study demonstrated that FD, attenuates BLM‐induced pulmonary inflammation and fibrosis in mice via inhibiting the activation of NALP3 inflammasome and the IL‐1β/IL‐1R1/MyD88/ NF‐κB pathway.
Mapping the structural organization of the brain in conduct disorder: replication of findings in two independent samples
Authors: Fairchild Graeme , Toschi Nicola , Sully Kate , Sonuga‐Barke Edmund J.S. , Hagan Cindy C. , Diciotti Stefano , Goodyer Ian M. , Calder Andrew J. , Passamonti Luca
Published: June 2016

Background

Neuroimaging methods that allow researchers to investigate structural covariance between brain regions are increasingly being used to study psychiatric disorders. Structural covariance analyses are particularly well suited for studying disorders with putative neurodevelopmental origins as they appear sensitive to changes in the synchronized maturation of different brain regions. We assessed interregional correlations in cortical thickness as a measure of structural covariance, and applied this method to investigate the coordinated development of different brain regions in conduct disorder (CD). We also assessed whether structural covariance measures could differentiate between the childhood‐onset (CO‐CD) and adolescence‐onset (AO‐CD) subtypes of CD, which may differ in terms of etiology and adult outcomes.

Methods

We examined interregional correlations in cortical thickness in male youths with CO‐CD or AO‐CD relative to healthy controls (HCs) in two independent datasets. The age range in the Cambridge sample was 16–21 years (mean: 18.0), whereas the age range of the Southampton sample was 13–18 years (mean: 16.7). We used FreeSurfer to perform segmentations and applied structural covariance methods to the resulting parcellations.

Results

In both samples, CO‐CD participants displayed a strikingly higher number of significant cross‐cortical correlations compared to HC or AO‐CD participants, whereas AO‐CD participants presented fewer significant correlations than HCs. Group differences in the strength of the interregional correlations were observed in both samples, and each set of results remained significant when controlling for IQ and comorbid attention‐deficit/hyperactivity disorder symptoms.

Conclusions

This study provides new evidence for quantitative differences in structural brain organization between the CO‐CD and AO‐CD subtypes, and supports the hypothesis that both subtypes of CD have neurodevelopmental origins.
PCR and real‐time PCR approaches to the identification of Arthroderma otae species Microsporum canis and Microsporum audouinii/Microsporum ferrugineum
Authors: Kobylak N. , Bykowska B. , Kurzyk E. , Nowicki R. , Brillowska‐Dąbrowska A.
Published: June 2016

Objectives

The identification of species in the Arthroderma otae complex is essential to determine the origin of infection and to eliminate the risk of transmission. Microsporum canis is a zoophilic species, whereas Microsporum audouinii and Microsporum ferrugineum are anthropophilic species. In this paper, we propose alternative methods that permit species‐specific identification of both anthropophilic and zoophilic members of the A. otae complex

Methods

Two PCR assays were designed based on differences in the DNA fragment encoding β‐tubulin and were applied in both traditional and real‐time PCR using DNA isolated by rapid method from culture.

Result

The two assays presented in this study enable the identification of M. canis and M. audouinii/M. ferrugineum with 100% sensitivity and specificity by both traditional and real‐time PCR.

Conclusion

We developed a new diagnostic assay using specific primers and both traditional and real‐time PCR reactions that can be applied in routine laboratory praxis as well as in epidemiological studies to detect M. canis and M. audouinii/M. ferrugineum DNA from a pure culture.
Changes in neurosyphilis presentation: a survey on 286 patients
Authors: Drago F. , Merlo G. , Ciccarese G. , Agnoletti A.F. , Cozzani E. , Rebora A. , Parodi A.
Published: June 2016

Although neurosyphilis (NS) keeps plaguing worldwide, often with oligosymptomatic and atypical manifestations, the most recent reports fail to provide useful information, like details of the clinical history and even of the previous early therapy. We conducted a survey of the literature of the last 5 years on the clinical presentation of NS, recording the aforementioned inaccuracies. One hundred and thirty‐seven articles were collected, reporting on 286 patients. General paresis was the commonest form (49%), often manifesting with cognitive impairment and psychiatric symptoms. Syphilitic meningitis was found in 63 patients (22%), mainly with ocular or auditory involvement. Meningovascular and tabetic form were both found in 12% of cases. Gummatous and epileptic manifestations were rare. Perusal of the literature confirms that NS prevalence is increasing, often with manifestations that are atypical for timing and type of lesions. Unfortunately, many articles are lacking of critical information, like an accurate clinical history and timing of the therapy making difficult to assess the effectiveness of penicillin in preventing NS.
Effects of Blanching and Hot Air Drying Conditions on the Physicochemical and Technological Properties of Yellow Passion Fruit (Passiflora edulis Var. Flavicarpa) by‐Products
Authors: Duarte Y. , Chaux A. , Lopez N. , Largo E. , Ramírez C. , Nuñez H. , Simpson R. , Vega O.
Published: June 2016

Passion fruit peel constitutes 50% of the whole fruit; therefore, a method to transform it to an active ingredient would be useful. Hot air drying is the most common process applied to extend the shelf life by reducing water activity. However, the processing conditions must be carefully selected to retain bioactive compounds. The goal of this study was to investigate the effects of blanching, temperature and airflow rate during hot air drying on the physicochemical and technological properties of passion fruit peel. A 32 experimental design with replicates in the central point was used. Three temperatures (50–55–60°C) and three airflow rates (2.4–2.7–3.0 m/s) were used, and the drying curves were analyzed to estimate the effective diffusion (Deff) and drying time. The dried peels were milled and their physicochemical properties (total fiber content and total polyphenol content), and technological properties (water holding capacity, the swelling capacity and the oil holding capacity) were measured. The results showed that the shortest drying time (∼2.5 h) was obtained at 60°C and 2.7 m/s for both control and blanched fruits. The physicochemical and technological properties were not affected by the drying conditions, because the temperatures used were not high enough to be detrimental. In addition, Deff and the physicochemical and technological properties were not affected by blanching due to preserve the samples a slower freezing process (freezing rate <1 cm/h) was performed, which can produce severe damage at the cellular level facilitating water diffusion and therefore can be considered such as pretreatment.

Practical Applications

Considering that Passion fruit waste constitutes 50% of the whole fruit and that has a high potential, primarily because it is rich in bioactive compounds, such as vitamins, minerals, polyphenolic compounds with a high antioxidant capacity and dietary fiber it is important study an adequate process to allow stabilize and store the passion fruit by‐products. Therefore, the passion fruit by‐product can be used as active ingredient in the formulation of different kind of foods, specially bakery and pastry products.
Comparison of Frailty Phenotypes for Prediction of Mortality, Incident Falls, and Hip Fracture in Older Women
Authors: Zaslavsky Oleg , Zelber‐Sagi Shira , Gray Shelly L. , LaCroix Andrea Z. , Brunner Robert L. , Wallace Robert B. , O'Sullivan Mary J. , Cochrane Barbara , Woods Nancy F.
Published: June 2016

Objectives

To compare the ability of the commonly used Women's Health Initiative (WHI) and Cardiovascular Health Study (CHS) frailty phenotypes to predict falls, hip fracture, and death in WHI Clinical Trial participants aged 65 and older.

Design

Longitudinal cohort study.

Setting

WHI Clinical Trial.

Participants

Participants with data for WHI and CHS frailty phenotypes (N = 3,558).

Measurements

Frailty was operationally defined in the CHS as the presence of three or more of weight loss, poor energy, weakness, slowness, and low physical activity. WHI operationalized frailty similarly but with the RAND‐36 physical function scale substituted for slowness and weakness (RAND‐36 physical function scale score <13 = 2 points, 13–78 = 1 point, >78 = 0 points). Frailty was defined as a summary score of 3 or greater, prefrailty as a score of 2 or 1, and nonfrailty as a score of 0. Outcomes were modeled using Cox regression. Harrell C‐statistics were compared for models containing alternative instruments.

Results

Approximately 5% of participants were frail based on the CHS or WHI phenotype. The WHI frailty phenotype was associated with higher rates of falls (hazard ratio (HR) = 1.48, P = .003), hip fracture (HR = 1.87, P = .04), and death (HR = 2.32, P < .001). Comparable HRs in CHS‐phenotype frail women were 1.32 (P = .04), 1.08 (P = .83), and 1.91 (P < .001), respectively. Harrell C‐statistics revealed marked but insignificant differences in predicting abilities between CHS and WHI phenotype models (P > .50 for all).

Conclusion

The WHI phenotype, which does not require direct measurements of physical performance, might offer a practical advantage for epidemiological and clinical needs.
Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies
Authors: Mackenzie Ian R. A. , Neumann Manuela
Published: June 2016

Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The past decade has seen the discovery of several new FTD‐causing genetic mutations and the identification of many of the relevant pathological proteins. The current neuropathological classification is based on the predominant protein abnormality and allows most cases of FTD to be placed into one of three broad molecular subgroups; frontotemporal lobar degeneration with tau, TDP‐43 or FET protein accumulation. This review will describe our current understanding of the molecular basis of FTD, focusing on insights gained from the study of human postmortem tissue, as well as some of the current controversies.

image

Most cases of FTD can be subclassified into one of three broad molecular subgroups based on the predominant protein that accumulates as pathological cellular inclusions. Understanding the associated pathogenic mechanisms and recognizing these FTD molecular subtypes in vivo will likely be crucial for the development and use of targeted therapies.

This article is part of the Frontotemporal Dementia special issue.
Absence of neonatal intensive care units in secondary medical care zones is an independent risk factor of high perinatal mortality in Japan
Authors: Matsumoto Yoko , Nakai Akihito , Nishijima Yasuhiro , Kishita Eisaku , Hakuno Haruhiko , Sakoi Masami , Kusuda Satoshi , Unno Nobuya , Tamura Masanori , Fujii Tomoyuki
Published: June 2016

Aim

National medical projects are carried out according to medical care plans directed by the Medical Care Act of Japan. In order to improve Japanese perinatal medical care, it is necessary to determine the factors that might influence perinatal outcome.

Methods

Statistical data of births and perinatal deaths were obtained for all municipalities in Japan from 2008 to 2012 from the Portal Site of Official Statistics of Japan (e‐Stat). The perinatal mortality of all 349 Japanese secondary medical care zones was calculated. The number of neonatal intensive care units (NICUs), maternal‐fetal intensive care units (MFICUs), pediatricians and obstetricians in 2011 were also obtained from e‐Stat. Nine secondary medical care zones in two prefectures, Fukushima (7) and Miyagi (2) were excluded to eliminate the influence of the 2011 Great East Japan Earthquake.

Results

The 340 secondary medical care zones were divided into three groups according to population size and density: metropolis, provincial city, and depopulation. The number of secondary medical care zones in each group were 52, 168, and 120, respectively. The secondary medical care zones in the depopulation group had fewer pediatricians and significantly fewer NICUs and MFICUs than the metropolis group, but there was no significant difference in perinatal mortality. The only independent risk factor for high perinatal mortality, determined by multivariable analysis, was the absence of an NICU (P = 0.011).

Conclusions

To consider directions in perinatal medical care, planned arrangement and appropriate access to NICUs is indispensable.
Generic medications for hepatitis C
Authors: Jensen Donald M. , Sebhatu Phoebe , Reau Nancy S.
Published: June 2016

The recent development and approval of expensive but highly effective oral agents against hepatitis C has led to restrictions and access limitations in many countries with limited healthcare budgets. Generic formulations of many of these agents are available at a fraction of the retail price in several countries because of generic licensure agreements. The discounted alternatives are only accessible in developing countries and require manufacturing and distribution regulations to ensure the quality and bioequivalence of the new drug formulations. The continued medication access limitations have driven great interest in the practice of personal drug importation of the generic formulations. This review and debate will address the medical and legal issues involved in the purchase and importation of these medicines.
Mutations in the N‐terminal kinase‐like domain of the repressor of photomorphogenesis SPA1 severely impair SPA1 function but not light responsiveness in Arabidopsis
Authors: Holtkotte Xu , Dieterle Stefan , Kokkelink Leonie , Artz Oliver , Leson Lisa , Fittinghoff Kirsten , Hayama Ryosuke , Ahmad Margaret , Hoecker Ute
Published: June 2016

The COP1/SPA complex is an E3 ubiquitin ligase that acts as a key repressor of photomorphogenesis in dark‐grown plants. While both COP1 and the four SPA proteins contain coiled‐coil and WD‐repeat domains, SPA proteins differ from COP1 in carrying an N‐terminal kinase‐like domain that is not present in COP1. Here, we have analyzed the effects of deletions and missense mutations in the N‐terminus of SPA1 when expressed in a spa quadruple mutant background devoid of any other SPA proteins. Deletion of the large N‐terminus of SPA1 severely impaired SPA1 activity in transgenic plants with respect to seedling etiolation, leaf expansion and flowering time. This ΔN SPA1 protein showed a strongly reduced affinity for COP1 in vitro and in vivo, indicating that the N‐terminus contributes to COP1/SPA complex formation. Deletion of only the highly conserved 95 amino acids of the kinase‐like domain did not severely affect SPA1 function nor interactions with COP1 or cryptochromes. In contrast, missense mutations in this part of the kinase‐like domain severely abrogated SPA1 function, suggesting an overriding negative effect of these mutations on SPA1 activity. We therefore hypothesize that the sequence of the kinase‐like domain has been conserved during evolution because it carries structural information important for the activity of SPA1 in darkness. The N‐terminus of SPA1 was not essential for light responsiveness of seedlings, suggesting that photoreceptors can inhibit the COP1/SPA complex in the absence of the SPA1 N‐terminal domain. Together, these results uncover an important, but complex role of the SPA1 N‐terminus in the suppression of photomorphogenesis.
Comparative in vitro killing of canine strains of Staphylococcus pseudintermedius and Escherichia coli by cefovecin, cefazolin, doxycycline and pradofloxacin
Authors: Blondeau Joseph M. , Shebelski Shantelle D.
Published: June 2016

Background

Bacterial eradication is necessary for clinical cure of infections and antimicrobial agents are important adjunctive therapies for inhibiting the growth of or killing bacteria. Pre‐existing skin diseases predispose animals to infection by Staphylococcus pseudintermedius and, more rarely, by Gram‐negative bacilli. The property of rapid killing of bacteria may influence drug selection and duration of therapy in the setting of infection.

Objectives

To test the killing of canine isolates of S. pseudintermedius and Escherichia coli by cefazolin, cefovecin, doxycycline and pradofloxacin at the minimum inhibitory, mutant prevention, maximum serum and maximum tissue drug concentrations.

Methods

Under standard conditions, bacterial cells were exposed to clinically relevant drug concentrations in vitro and the log10 reduction (and % kill) of viable cells measured at 5, 10, 15, 20, 25, 30, 60, 120 and 180 min after drug exposure.

Results

Statistically significant differences were seen between killing efficiencies by pradofloxacin versus the other agents, whereby pradofloxacin killed cells more rapidly than the others. For example, against the S. pseudintermedius strains, significantly more cells were killed by pradofloxacin following 15 min of maximum tissue drug concentration exposure than for cefazolin (P = 0.0002), cefovecin (P = 0.0007) and doxycycline (P ≤ 0.0001).

Conclusion and clinical importance

The rank order of potency based on these kill experiments was pradofloxacin > cefazolin > cefovecin > doxycycline. Rapid killing of bacteria affects the speed of clinical resolution and may influence drug selection and duration of therapy for skin infections.
Agonist‐induced sensitisation of the irritant receptor ion channel TRPA1
Authors: Meents Jannis E. , Fischer Michael J. M. , McNaughton Peter A.
Published: June 2016

Key points

The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed in nociceptive neurons and its activation causes ongoing pain and inflammation; TRPA1 is thought to play an important role in inflammation in the airways.

TRPA1 is sensitised by repeated stimulation with chemical agonists in a calcium‐free environment and this sensitisation is very long lasting following agonist removal.

We show that agonist‐induced sensitisation is independent of the agonist's binding site and is also independent of ion channel trafficking or of other typical signalling pathways.

We find that sensitisation is intrinsic to the TRPA1 protein and is accompanied by a slowly developing shift in the voltage dependence of TRPA1 towards more negative membrane potentials.

Agonist‐induced sensitisation may provide an explanation for sensitisation following long‐term exposure to harmful irritants and pollutants, particularly in the airways.

The TRPA1 ion channel is expressed in nociceptive (pain‐sensitive) neurons and responds to a wide variety of chemical irritants, such as acrolein in smoke or isothiocyanates in mustard. Here we show that in the absence of extracellular calcium the current passing through TRPA1 gradually increases (sensitises) during prolonged application of agonists. Activation by an agonist is essential, because activation of TRPA1 by membrane depolarisation did not cause sensitisation. Sensitisation is independent of the site of action of the agonist, because covalent and non‐covalent agonists were equally effective, and is long lasting following agonist removal. Mutating N‐terminal cysteines, the target of covalent agonists, did not affect sensitisation by the non‐covalent agonist carvacrol, which activates by binding to a different site. Sensitisation is unaffected by agents blocking ion channel trafficking or by block of signalling pathways involving ATP, protein kinase A or the formation of lipid rafts, and does not require ion flux through the channel. Examination of the voltage dependence of TRPA1 activation shows that sensitisation is accompanied by a slowly developing shift in the voltage dependence of TRPA1 towards more negative membrane potentials, and is therefore intrinsic to the TRPA1 channel. Sensitisation may play a role in exacerbating the pain caused by prolonged activation of TRPA1.
Simplified Analysis for the Association of a Constrained Receptor to an Oscillating Ligand
Authors: Chen Xiaofeng , Chen Bin
Published: June 2016

The stability of a bond cluster upon oscillated loads under physiological conditions is strongly regulated by the kinetics of association and dissociation of a single bond, which can play critical roles in cell–matrix adhesion, cell–cell adhesion, etc. Here, we obtain a simplified analysis for the bond association process of a constrained receptor to an oscillating ligand due to its diffusion-independence, which can facilitate the potential multiscale studies in the future. Based on the analysis, our results indicate that the mean passage time for bond association intriguingly saturates at high oscillating frequencies, and there can also surprisingly exist optimal bond elasticity for bond association. This work can bring important insights into understanding of the behaviors of bond cluster under cyclic loads at the level of a single bond.
Double Overhung Disk and Parameter Effect on Rotordynamic Synchronous Instability—Morton Effect—Part II: Occurrence and Prevention
Authors: Tong Xiaomeng , Palazzolo Alan
Published: June 2016

This paper performs the parametric studies corresponding with the theoretical Morton effect (ME) model explained in Part I of this paper, where the fully nonlinear transient analysis based on the finite element method is introduced. Operating parameters, such as oil supply temperature, bearing clearance, oil viscosity, etc., are perturbed from the testing conditions to investigate the shifting of critical speeds and ME instability onset speed (IOS). The ME is significantly affected by the rotor bending mode with large overhung deflections, and operating parameters should be adjusted to increase the separation margin between the operating speed and the corresponding critical speed for ME mitigation. Reducing the carryover flow ratio and using the asymmetric bearing pivot offset are capable to suppress the ME by reducing both the average and differential journal temperature. The heat barrier sleeve with air or ceramic isolation is designed to prevent the heat flux into the journal and can successfully mitigate the ME based on the simulations.
An Experimental Investigation of Acoustic Black Hole Dynamics at Low, Mid, and High Frequencies
Authors: Feurtado Philip A. , Conlon Stephen C.
Published: June 2016

The acoustic black hole (ABH) has been developed in recent years as an effective, passive, and lightweight method for attenuating bending wave vibrations in beams and plates and reducing the sound radiation and structural-acoustic response of structures. The ABH effect utilizes a local change in the plate or beam thickness to reduce the bending wave speed and increase the transverse vibration amplitude. Attaching a viscoelastic damping layer to the ABH results in effective energy dissipation and vibration reduction. Surface-averaged mobility and radiated sound power measurements were performed on an aluminum plate containing an array of 20 two-dimensional ABHs with damping layers and compared to a similar uniform plate. Detailed laser vibrometer scans of an ABH cell (including the ABH and surrounding homogeneous plate) were also performed to analyze the vibratory characteristics of individual ABH cells and compared with mode shapes calculated using finite elements. The results showed that the surface-averaged mobility was reduced by up to 14 dB for the fully damped ABH plate compared to a uniform reference plate while also reducing the mass of the plate. The results demonstrated that the dynamics of plates with embedded ABHs can be characterized by low, mid, and high frequency ranges, with low-order local ABH modes contributing significantly to low frequency ABH performance. The effects of damping layer thickness and diameter were also investigated to assess ABH performance optimization. It was shown that the damping layer can have the added benefit of mass loading the ABH and enhancing low frequency performance. The results will be useful for designing the low frequency performance of future ABH systems and describing ABH performance in terms of design parameters.
Dynamic Analysis of a Geared Infinitely Variable Transmission
Authors: Wang X. F. , Li Z. R. , Zhu W. D.
Published: June 2016

Dynamic analysis of a geared infinitely variable transmission (IVT) that can generate a continuous output-to-input speed ratio from zero to a certain value is studied for vehicle and wind turbine applications. With the IVT considered as a multirigid-body system, the Lagrangian approach is used to analyze its speeds and accelerations, and the Newtonian approach is used to conduct force analysis of each part of the IVT. Instantaneous input and output speeds and accelerations of the IVT have variations in one rotation of its input shaft. This work shows that the instantaneous input speed has less variation than the instantaneous output speed when the inertia on the input side is larger than that on the output side and vice versa. The maximum torque on the output shaft that is a critical part of the IVT increases with the input speed.
Bio-Inspired Design and Iterative Feedback Tuning Control of a Wearable Ankle Rehabilitation Robot
Authors: Zhou Liang , Meng Wei , Lu Charles Z. , Liu Quan , Ai Qingsong , Xie Sheng Q.
Published: June 2016

Robotic rehabilitation for ankle injuries offers several advantages in terms of precision, force accuracy, and task-specific training. While the existing platform-based ankle rehabilitation robots tend to provide a rotation center that does not coincide with the actual ankle joint. In this paper, a novel bio-inspired ankle rehabilitation robot was designed, which is wearable and can keep the participant's shank be stationary. The robot is redundantly actuated by four motors in parallel to offer three ankle rotation degrees-of-freedom (DOFs) with sufficient range of motion (ROM) and force capacity. To control the robotic rehabilitation device operated in a repetitive trajectory training manner, a model-free robust control method in form of iterative feedback tuning (IFT) is proposed to tune the robot controller parameters. Experiments were performed on the parallel ankle rehabilitation platform to investigate the efficacy of the design and the robustness of the IFT technique under real-life rehabilitation scenarios.
Powder Mixed Electric Discharge Machining: An Innovative Surface Modification Technique to Enhance Fatigue Performance and Bioactivity of β-Ti Implant for Orthopedics Application
Authors: Prakash Chander , Kansal H. K. , Pabla B. S. , Puri Sanjeev
Published: June 2016

The development of surface modification technique has been the subject of the studies regarding the fatigue performance and biological characterization of the modified layers. In the present research work, powder mixed electric discharge machining (PMEDM) a novel nonconventional machining technique has been proposed for surface modification of β-Ti implant for orthopedics application. The surface topography and morphology like roughness, surface cracks, and recast layer thickness of each of the machined specimens were investigated using Mitutoyo surface roughness tester and field-emission scanning electron microscopy (FE-SEM), respectively. This study aims to investigate the effect of surface characteristics of PMEDM process on the fatigue performance and bioactivity of β-Ti implants and moreover a comparative analysis is made on the fatigue performance and biological activity of specimens machined with presently used machining methods like electric discharge machining (EDM) and mechanical polishing. The high cycle fatigue (HCF) performance of polished specimens was superior and had no adverse effect of microstructure on fatigue endurance. As expected, the fatigue behavior of β-Ti implant-based alloy, after undergoing EDM treatment, is poorly observed due to the microrough surface. The fatigue performance is dependent on microstructure and surface roughness of the specimens. Subsequent PMEDM process significantly improves the fatigue endurance of β-Ti implant-based alloy specimens. PMEDMed surface with micro-, sub-micro-, and nano-structured topography exhibited excellent bioactivity and improved biocompatibility. PMEDMed surface enabled better adhesion and growth of MG-63 when compared with the polished and EDMed substrate. Furthermore, the differentiation results indicated that a combination of nanoscale featured submicrorough PMEDMed surface promotes various osteoblast differentiation activities like alkaline phosphatase (ALP) activity, osteocalcin production, the local factor osteoprotegerin, which inhibits osteoclastogenesis.
Investigation of Deformation Behavior of SS304 and Pure Copper Subjected to Electrically Assisted Forming Process
Authors: Jiang Tianhao , Peng Linfa , Yi Peiyun , Lai Xinmin
Published: June 2016

Both electrically assisted tension (EAT) and thermally assisted tension (TAT) tests were performed on SS304 and pure copper to decouple the influence of elevated temperature from electric current on flow stress and ductility. It is found that the reduction on flow stress and ductility of SS304 are more dependent on the elevated temperature than electric current, but electric current has a stronger effect by 10% on reducing flow stress and ductility of pure copper than the elevated temperature does. As the flow stress and ductility of two metals are related to the dislocation evolution, a constitutive model considering both storage and annihilation process of dislocation was established to describe the effect of electric current and temperature on dislocation movement. It is found that electric current accelerated the annihilation process of dislocation in pure copper up to 20% in EAT compared with that in TAT, but such phenomenon was rarely observed in SS304. Furthermore, attempts have also been made to distinguish the influence of elevated temperature with that of electric current on microstructure evolution and it is also found that the formation of [111] crystals in pure copper is nearly 10% less in EAT than that in TAT.
Roughness generation during Si etching in Cl2 pulsed plasma
Authors: Mourey Odile , Petit-Etienne Camille , Cunge Gilles , Darnon Maxime , Despiau-Pujo Emilie , Brichon Paulin , Lattu-Romain Eddy , Pons Michel , Joubert Olivier
Published: June 2016

Pulsed plasmas are promising candidates to go beyond limitations of continuous waves' plasma. However, their interaction with surfaces remains poorly understood. The authors investigated the silicon etching mechanism in inductively coupled plasma (ICP) Cl2 operated either in an ICP-pulsed mode or in a bias-pulsed mode (in which only the bias power is pulsed). The authors observed systematically the development of an important surface roughness at a low duty cycle. By using plasma diagnostics, they show that the roughness is correlated to an anomalously large (Cl atoms flux)/(energetic ion flux) ratio in the pulsed mode. The rational is that the Cl atom flux is not modulated on the timescale of the plasma pulses although the ion fluxes and energy are modulated. As a result, a very strong surface chlorination occurs during the OFF period when the surface is not exposed to energetic ions. Therefore, each energetic ion in the ON period will bombard a heavily chlorinated silicon surface, leading to anomalously high etching yield. In the ICP pulsed mode (in which the ion energy is high), the authors report yields as high as 40, which mean that each individual ion impacts will generate a “crater” of about 2 nm depth at the surface. Since the ion flux is very small in the pulsed ICP mode, this process is stochastic and is responsible for the roughness initiation. The roughness expansion can then be attributed partly to the ion channeling effect and is probably enhanced by the formation of a SiClx reactive layer with nonhomogeneous thickness over the topography of the surface. This phenomenon could be a serious limitation of pulsed plasma processes.
Characterization of a synthetic single crystal diamond detector for dosimetry in spatially fractionated synchrotron x‐ray fields
Authors: Livingstone Jayde , Stevenson Andrew W. , Butler Duncan J. , Häusermann Daniel , Adam Jean‐François
Published: June 2016

Purpose:

Modern radiotherapy modalities often use small or nonstandard fields to ensure highly localized and precise dose delivery, challenging conventional clinical dosimetry protocols. The emergence of preclinical spatially fractionated synchrotron radiotherapies with high dose‐rate, sub‐millimetric parallel kilovoltage x‐ray beams, has pushed clinical dosimetry to its limit. A commercially available synthetic single crystal diamond detector designed for small field dosimetry has been characterized to assess its potential as a dosimeter for synchrotron microbeam and minibeam radiotherapy.

Methods:

Experiments were carried out using a synthetic diamond detector on the imaging and medical beamline (IMBL) at the Australian Synchrotron. The energy dependence of the detector was characterized by cross‐referencing with a calibrated ionization chamber in monoenergetic beams in the energy range 30–120 keV. The dose‐rate dependence was measured in the range 1–700 Gy/s. Dosimetric quantities were measured in filtered white beams, with a weighted mean energy of 95 keV, in broadbeam and spatially fractionated geometries, and compared to reference dosimeters.

Results:

The detector exhibits an energy dependence; however, beam quality correction factors (kQ) have been measured for energies in the range 30–120 keV. The kQ factor for the weighted mean energy of the IMBL radiotherapy spectrum, 95 keV, is 1.05 ± 0.09. The detector response is independent of dose‐rate in the range 1–700 Gy/s. The percentage depth dose curves measured by the diamond detector were compared to ionization chambers and agreed to within 2%. Profile measurements of microbeam and minibeam arrays were performed. The beams are well resolved and the full width at halfmaximum agrees with the nominal width of the beams. The peak to valley dose ratio (PVDR) calculated from the profiles at various depths in water agrees within experimental error with PVDR calculations from Gafchromic film data.

Conclusions:

The synthetic diamond detector is now well characterized and will be used to develop an experimental dosimetry protocol for spatially fractionated synchrotron radiotherapy.
A peek at peer review helps young scientists
Authors: Mervis Jeffrey
Published: June 2016

Service on NIH study sections boosts success rates on grants but not diversity.
Translational control by 5′-untranslated regions of eukaryotic mRNAs
Authors: Hinnebusch Alan G. , Ivanov Ivaylo P. , Sonenberg Nahum
Published: June 2016

The eukaryotic 5′ untranslated region (UTR) is critical for ribosome recruitment to the messenger RNA (mRNA) and start codon choice and plays a major role in the control of translation efficiency and shaping the cellular proteome. The ribosomal initiation complex is assembled on the mRNA via a cap-dependent or cap-independent mechanism. We describe various mechanisms controlling ribosome scanning and initiation codon selection by 5′ upstream open reading frames, translation initiation factors, and primary and secondary structures of the 5′UTR, including particular sequence motifs. We also discuss translational control via phosphorylation of eukaryotic initiation factor 2, which is implicated in learning and memory, neurodegenerative diseases, and cancer.
Soil immune responses
Authors: Raaijmakers Jos M. , Mazzola Mark
Published: June 2016

Soil microbiomes may be harnessed for plant health
Northeastern North America as a potential refugium for boreal forests in a warming climate
Authors: D’Orangeville L. , Duchesne L. , Houle D. , Kneeshaw D. , Côté B. , Pederson N.
Published: June 2016

A future for boreal forests

Conservation under climate change presents the challenge of predicting where will be suitable for particular organisms and ecological communities in the future. D'Orangeville
et al.
assess the probable future range for boreal forests in eastern North America, which are expected to be subject to large temperature increases in their natural range. Using tree-ring data from many thousands of forest stands, they delineate the geographical extent of the region where tree growth responds favorably to higher temperatures and where the forest should persist at least until 2070.

Science
, this issue p.
1452
Form. Function. Fate
The Gene An Intimate History
Siddhartha Mukherjee
Scribner, 2016. 611 pp.
Authors: Goldman Michael A.
Published: June 2016

A rich history of genetics probes the social and ethical implications of human heredity
Seeing translation
Authors: Iwasaki Shintaro , Ingolia Nicholas T.
Published: June 2016

Monitoring individual messenger RNAs as they make protein reveals the tricks of translation
Human IgG1, IgG3, and IgG3 Hinge-Truncated Mutants Show Different Protection Capabilities against Meningococci Depending on the Target Antigen and Epitope Specificity
Authors: Giuntini S. , Granoff D. M. , Beernink P. T. , Ihle O. , Bratlie D. , Michaelsen T. E.
Published: June 2016

We compared the bactericidal activity of recombinant sets of chimeric IgG monoclonal antibodies against two important outer membrane meningococcal vaccine antigens: PorA and factor H binding protein (FHbp). The sets contained human Fc portions from IgG1, IgG3, and two IgG3 mutants (IgG3m15 and IgGm17) with hinge regions of 15 and 17 amino acids encoded by hinge exons h2 and h1, respectively (human IgG3 has a hinge region of 62 amino acids encoded by hinge exons h1, h2, h3, and h4, while human IgG1 has a hinge region of only 15 amino acids encoded by one hinge exon) and mouse V regions. IgG1 showed higher bactericidal activity than IgG3 when directed against PorA (an abundant antigen), while IgG3 was more bactericidal than IgG1 when directed against FHbp (a sparsely and variably distributed antigen). On the other hand, the IgG3 hinge-truncated antibodies IgG3m15 and IgGm17 showed higher bactericidal activity than both IgG1 and IgG3 regardless of the target antigen. Thus, the Fc region of IgG3 antibodies appears to have an enhanced complement-activating function, independent of their long hinge region, compared to IgG1 antibodies. The greater activity of the truncated IgG3 hinge mutants indicates that the long hinge of IgG3 seems to downregulate through an unknown mechanism the inherent increased complement-activating capability of IgG3 Fc when the antibody binds to a sparse antigen.
Development and Characterization of Monoclonal Antibodies to Yellow Fever Virus and Application in Antigen Detection and IgM Capture Enzyme-Linked Immunosorbent Assay
Authors: Adungo Ferdinard , Yu Fuxun , Kamau David , Inoue Shingo , Hayasaka Daisuke , Posadas-Herrera Guillermo , Sang Rosemary , Mwau Matilu , Morita Kouichi
Published: June 2016

Yellow fever (YF) is an acute hemorrhagic viral infection transmitted by mosquitoes in Africa and South America. The major challenge in YF disease detection and confirmation of outbreaks in Africa is the limited availability of reference laboratories and the persistent lack of access to diagnostic tests. We used wild-type YF virus sequences to generate recombinant envelope protein in anEscherichia coliexpression system. Both the recombinant protein and sucrose gradient-purified YF vaccine virus 17D (YF-17D) were used to immunize BALB/c mice to generate monoclonal antibodies (MAbs). Eight MAbs were established and systematically characterized by indirect enzyme-linked immunosorbent assay (ELISA), Western blot analysis, and immunofluorescence assay (IFA). The established MAbs showed strong reactivity with wild-type YF virus and recombinant protein with no detectable cross-reactivity to dengue virus or Japanese encephalitis virus. Epitope mapping showed strong binding of three MAbs to amino acid positions 1 to 51, while two MAbs mapped to amino acid positions 52 to 135 of the envelope protein. The remaining three MAbs did not show reactivity to envelope fragments. The established MAbs exert no neutralization against wild-type YF and 17D viruses (titer of <10 for both strains). The applicability of MAbs 8H3 and 3F4 was further evaluated using IgM capture ELISA. A total of 49 serum samples were analyzed, among which 12 positive patient and vaccinee samples were correctly identified. Using serum samples that were 2-fold serially diluted, the IgM capture ELISA was able to detect all YF-positive samples. Furthermore, MAb-based antigen detection ELISA enabled the detection of virus in culture supernatants containing titers of about 1,000 focus-forming units.
Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway
Authors: Gardner Thomas J. , Tortorella Domenico
Published: June 2016

The prototypic herpesvirus human cytomegalovirus (CMV) exhibits the extraordinary ability to establish latency and maintain a chronic infection throughout the life of its human host. This is even more remarkable considering the robust adaptive immune response elicited by infection and reactivation from latency. In addition to the ability of CMV to exist in a quiescent latent state, its persistence is enabled by a large repertoire of viral proteins that subvert immune defense mechanisms, such as NK cell activation and major histocompatibility complex antigen presentation, within the cell. However, dissemination outside the cell presents a unique existential challenge to the CMV virion, which is studded with antigenic glycoprotein complexes targeted by a potent neutralizing antibody response. The CMV virion envelope proteins, which are critical mediators of cell attachment and entry, possess various characteristics that can mitigate the humoral immune response and prevent viral clearance. Here we review the CMV glycoprotein complexes crucial for cell attachment and entry and propose inherent properties of these proteins involved in evading the CMV humoral immune response. These include viral glycoprotein polymorphism, epitope competition, Fc receptor-mediated endocytosis, glycan shielding, and cell-to-cell spread. The consequences of CMV virion glycoprotein-mediated immune evasion have a major impact on persistence of the virus in the population, and a comprehensive understanding of these evasion strategies will assist in designing effective CMV biologics and vaccines to limit CMV-associated disease.
Potassium Uptake Modulates Staphylococcus aureus Metabolism
Authors: Gries Casey M. , Sadykov Marat R. , Bulock Logan L. , Chaudhari Sujata S. , Thomas Vinai C. , Bose Jeffrey L. , Bayles Kenneth W.
Published: June 2016

Previous studies describing mechanisms for K
+
uptake in
S. aureus
revealed that the Ktr-mediated K
+
transport system was required for normal growth under alkaline conditions but not under neutral or acidic conditions. This work focuses on the effect of K
+
uptake on
S. aureus
metabolism, including intracellular pH and carbon flux, and is the first to utilize a pH-dependent green fluorescent protein (GFP) to measure
S. aureus
cytoplasmic pH. These studies highlight the role of K
+
uptake in supporting proton efflux under alkaline conditions and uncover a critical role for K
+
uptake in establishing efficient carbon utilization.
Variable El Niño–Southern Oscillation influence on biofacies dynamics of eastern Pacific shallow-water carbonate systems
Authors: Humphreys Alexander F. , Halfar Jochen , Rivera Fernando , Manzello Derek , Reymond Claire E. , Westphal Hildegard , Riegl Bernhard
Published: June 2016

The El Niño–Southern Oscillation (ENSO) is a periodic climatic and oceanic event caused by sea-surface temperature and nutrient anomalies over the eastern tropical Pacific Ocean (ETP). Recurring ENSO events have a significant impact on climate and the ecosystems of the circum-Pacific region. In the marine realm, ENSO is known for altering temperature and nutrient patterns, affecting the pelagic food chain, and causing widespread bleaching of corals due to temperature stress. The potential impacts of ENSO on shallow benthic ecosystems as a whole, however, are poorly understood. Here, we compared biogenic sedimentary facies of ETP shallow-water carbonate systems in a strongly ENSO-influenced area (Galápagos Islands, Ecuador [GAL]) with similar systems in an area less strongly influenced by ENSO (Gulf of California, Mexico [GOC]). Carbonate assemblages in both study regions range from coral-algal–dominated (photozoan) to molluscan-dominated (heterozoan) assemblages. Linear statistical models, comparing the distribution of carbonates against prominent local oceanographic parameters, show that minimum chlorophyll-a and maximum sea-surface temperature (which are both strongly influenced by ENSO) are dominant drivers shaping carbonate sediment facies in the GAL. In contrast, GOC carbonates have a distinct mean chlorophyll-a signature that is the result of an upwelling-induced north-south nutrient gradient not significantly influenced by ENSO.