bluuebunny/crossref_metadata_2025 huggingface dataset:
Time‐dependent uptake and trafficking of vesicles capturing extracellular S100B in cultured rat astrocytes
Authors: Lasič Eva , Galland Fabiana , Vardjan Nina , Šribar Jernej , Križaj Igor , Leite Marina Concli , Zorec Robert , Stenovec Matjaž
Published: August 2016

Astrocytes, the most heterogeneous glial cells in the central nervous system, contribute to brain homeostasis, by regulating a myriad of functions, including the clearance of extracellular debris. When cells are damaged, cytoplasmic proteins may exit into the extracellular space. One such protein is S100B, which may exert toxic effects on neighboring cells unless it is removed from the extracellular space, but the mechanisms of this clearance are poorly understood. By using time‐lapse confocal microscopy and fluorescently labeled S100B (S100B‐Alexa488) and fluorescent dextran (Dextran546), a fluid phase uptake marker, we examined the uptake of fluorescently labeled S100B‐Alexa488 from extracellular space and monitored trafficking of vesicles that internalized S100B‐Alexa488. Initially, S100B‐Alexa488 and Dextran546 internalized with distinct rates into different endocytotic vesicles; S100B‐Alexa488 internalized into smaller vesicles than Dextran546. At a later stage, S100B‐Alexa488‐positive vesicles substantially co‐localized with Dextran546‐positive endolysosomes and with acidic LysoTracker‐positive vesicles. Cell treatment with anti‐receptor for advanced glycation end products (RAGE) antibody, which binds to RAGE, a ‘scavenger receptor’, partially inhibited uptake of S100B‐Alexa488, but not of Dextran546. The dynamin inhibitor dynole 34‐2 inhibited internalization of both fluorescent probes. Directional mobility of S100B‐Alexa488‐positive vesicles increased over time and was inhibited by ATP stimulation, an agent that increases cytosolic free calcium concentration ([Ca2+]i). We conclude that astrocytes exhibit RAGE‐ and dynamin‐dependent vesicular mechanism to efficiently remove S100B from the extracellular space. If a similar process occurs in vivo, astroglia may mitigate the toxic effects of extracellular S100B by this process under pathophysiologic conditions.

image

This study reveals the vesicular clearance mechanism of extracellular S100B in astrocytes. Initially, fluorescent S100B internalizes into smaller endocytotic vesicles than dextran molecules. At a later stage, both probes co‐localize within endolysosomes. S100B internalization is both dynamin‐ and RAGE‐dependent, whereas dextran internalization is dependent on dynamin. Vesicle internalization likely mitigates the toxic effects of extracellular S100B and other waste products.
Five‐day study to judge the short‐term effect of a benzoyl peroxide 3% gel on acne lesions
Authors: Draelos Zoe Diana , Ertel Keith , Rom Dror
Published: August 2016

Introduction

Acne is a common, chronic skin disease that has both physical and psychological consequences. Over‐the‐counter products are a treatment option frequently chosen by dermatologists and acne sufferers for reasons of cost or convenience. There are reports that such products can effect rapid resolution in certain lesion parameters.

Aims

To evaluate the short‐term effect of a benzoyl peroxide 3% gel on acne lesions.

Methods

A 5‐day, double‐blind, randomized clinical trial was conducted among subjects with mild‐to‐moderate acne. Subjects applied the benzoyl peroxide 3% gel, a salicylic acid 2% gel, or a vehicle gel under supervision once daily for 4 days. Target lesion parameters of swelling, diameter, and erythema were evaluated at various times after the first and subsequent applications.

Results

Although target lesion parameters showed overall improvement from baseline, the effects of the active treatment gels were not significantly different from those of the vehicle gel at any evaluation. The assessed parameters showed marked variability in target lesion behavior at the subject level over the course of the study.

Conclusions

The results of this study illustrate the unpredictability of individual acne lesion's responses to therapy and the challenge associated with using these responses to judge short‐term treatment efficacy. While rapid acne resolution is desired by patients and consumers, setting realistic expectations for treatment response is critical to encourage compliance and avoid disappointment.
Valuation Risk and Asset Pricing
Authors: ALBUQUERQUE RUI , EICHENBAUM MARTIN , LUO VICTOR XI , REBELO SERGIO
Published: August 2016

Standard representative‐agent models fail to account for the weak correlation between stock returns and measurable fundamentals, such as consumption and output growth. This failing, which underlies virtually all modern asset pricing puzzles, arises because these models load all uncertainty onto the supply side of the economy. We propose a simple theory of asset pricing in which demand shocks play a central role. These shocks give rise to valuation risk that allows the model to account for key asset pricing moments, such as the equity premium, the bond term premium, and the weak correlation between stock returns and fundamentals.
Self‐management in temporomandibular disorders: a systematic review of behavioural components
Authors: Story W. P. , Durham J. , Al‐Baghdadi M. , Steele J. , Araujo‐Soares V.
Published: August 2016

The aim of this qualitative systematic review was to identify the behaviour change techniques most frequently employed in published temporomandibular disorder (TMD) self‐management (SM) programmes. The reviewers matched the components of SM programmes into the relevant behaviour change technique domains according to the definitions of the behaviour change taxonomy (version 1). Electronic databases were searched for randomised controlled trials assessing an SM programme for TMD. Manual searches were also conducted for potentially important journals. Eligibility criteria for the review included: the type of study, the participants, the intervention utilised and the comparators/control. Fifteen randomised controlled trials with 554 patients were included in this review. The review concludes a minority of the available behaviour change techniques are currently employed in SM programmes. Other behaviour change techniques should be examined to see whether there is a theoretical underpinning that might support their inclusion in self‐management programmes in TMD. Further trials are required to conclude that SM programmes are more effective than no treatment at all and or placebo. With more structured SM programmes, greater therapeutic benefits might be achieved, and certainly if SM programmes published in the literature define their components through use of the behaviour change taxonomy, it would be easier for clinicians to replicate efficacious programmes.
Monetary and Fiscal Policy in Times of Crisis: A New Keynesian Perspective in Continuous Time
Authors: Förster Britta , Hayo Bernd
Published: August 2016

To analyse the interdependence between monetary and fiscal policy during a financial crisis, we develop an open‐economy DSGE model with monetary and fiscal policy, as well as financial markets, in a continuous‐time framework based on stochastic differential equations. Monetary policy is modelled using both a standard and a modified Taylor rule and fiscal policy is modelled as either expansionary or austere. In addition, we differentiate between open economies and monetary union members. We find evidence that the modified Taylor rule notably reduces the likelihood that the financial market crisis affects the real economy. However, if we assume that households are averse to outstanding government debt, we find that a combination of expansionary monetary policy and austerity‐oriented fiscal policy does a better job of stabilising both domestic and foreign economies in regard to both output and inflation. In the case of a monetary union, we find that stabilization of output in the country where the financial shock originated is no longer as easy and, in terms of prices, there is now deflation in that country and a positive inflation rate in the other member country of the monetary union.
Petrology and geochemistry of feldspathic impact‐melt breccia Abar al' Uj 012, the first lunar meteorite from Saudi Arabia
Authors: Mészáros Marianna , Hofmann Beda A. , Lanari Pierre , Korotev Randy L. , Gnos Edwin , Greber Nicolas D. , Leya Ingo , Greenwood Richard C. , Jull A. J. Timothy , Al‐Wagdani Khalid , Mahjoub Ayman , Al‐Solami Abdulaziz A. , Habibullah Siddiq N.
Published: August 2016

Abar al' Uj (AaU) 012 is a clast‐rich, vesicular impact‐melt (IM) breccia, composed of lithic and mineral clasts set in a very fine‐grained and well‐crystallized matrix. It is a typical feldspathic lunar meteorite, most likely originating from the lunar farside. Bulk composition (31.0 wt% Al2O3, 3.85 wt% FeO) is close to the mean of feldspathic lunar meteorites and Apollo FAN‐suite rocks. The low concentration of incompatible trace elements (0.39 ppm Th, 0.13 ppm U) reflects the absence of a significant KREEP component. Plagioclase is highly anorthitic with a mean of An96.9Ab3.0Or0.1. Bulk rock Mg# is 63 and molar FeO/MnO is 76. The terrestrial age of the meteorite is 33.4 ± 5.2 kyr. AaU 012 contains a ~1.4 × 1.5 mm2 exotic clast different from the lithic clast population which is dominated by clasts of anorthosite breccias. Bulk composition and presence of relatively large vesicles indicate that the clast was most probably formed by an impact into a precursor having nonmare igneous origin most likely related to the rare alkali‐suite rocks. The IM clast is mainly composed of clinopyroxenes, contains a significant amount of cristobalite (9.0 vol%), and has a microcrystalline mesostasis. Although the clast shows similarities in texture and modal mineral abundances with some Apollo pigeonite basalts, it has lower FeO and higher SiO2 than any mare basalt. It also has higher FeO and lower Al2O3 than rocks from the FAN‐ or Mg‐suite. Its lower Mg# (59) compared to Mg‐suite rocks also excludes a relationship with these types of lunar material.
The roles of AtxA orthologs in virulence of anthrax‐like Bacillus cereus G9241
Authors: Scarff Jennifer M. , Raynor Malik J. , Seldina Yuliya I. , Ventura Christy L. , Koehler Theresa M. , O'Brien Alison D.
Published: August 2016

AtxA is a critical transcriptional regulator of plasmid‐encoded virulence genes in Bacillus anthracis. Bacillus cereus G9241, which caused an anthrax‐like infection, has two virulence plasmids, pBCXO1 and pBC210, that each harbor toxin genes and a capsule locus. G9241 also produces two orthologs of AtxA: AtxA1, encoded on pBCXO1, and AtxA2, encoded on pBC210. The amino acid sequence of AtxA1 is identical to that of AtxA from B. anthracis, while the sequences of AtxA1 and AtxA2 are 79% identical and 91% similar to one another. We found by qRT‐PCR that AtxA1 and AtxA2 function as positive regulators of toxin (AtxA1) and capsule operon (both) transcription in G9241 and that a ΔatxA1 mutant produced lower levels of the anthrax toxins and no hyaluronic acid capsule. Deletion of atxA1 or atxA2 decreased the virulence of spores administered intranasally or subcutaneously to C57BL/6 mice but not to A/J mice, and deletion of both genes rendered spores avirulent in A/J mice. In addition, unlike AtxA1, AtxA2 did not form stable homomultimers in vitro, although AtxA1 and AtxA2 formed heterodimers. Our data show that AtxA1 is the primary regulator of G9241 virulence factor expression and that AtxA1 and AtxA2 are both required for full virulence.
Moving Towards Estimating Sons' Lifetime Intergenerational Economic Mobility in the UK
Authors: Gregg Paul , Macmillan Lindsey , Vittori Claudia
Published: August 2016

Estimates of intergenerational economic mobility that use point in time measures of income and earnings suffer from lifecycle and attenuation bias. They also suffer from sample selection issues and further bias driven by spells out of work. We consider these issues together for UK data, the National Child Development Study and British Cohort Study, for the first time. When all three biases are considered, our best estimate of lifetime intergenerational economic persistence in the UK is 0.43 for children born in 1970. Whilst we argue that this is the best available estimate to date, we discuss why there is good reason to believe that this is still a lower bound, owing to residual attenuation bias.
Development of a neurofeedback protocol targeting the frontal pole using near‐infrared spectroscopy
Authors: Kinoshita Akihide , Takizawa Ryu , Yahata Noriaki , Homae Fumitaka , Hashimoto Ryuichiro , Sakakibara Eisuke , Kawasaki Shingo , Nishimura Yukika , Koike Shinsuke , Kasai Kiyoto
Published: August 2016

Aim

Neurofeedback has been studied with the aim of controlling cerebral activity. Near‐infrared spectroscopy is a non‐invasive neuroimaging technique used for measuring hemoglobin concentration changes in cortical surface areas with high temporal resolution. Thus, near‐infrared spectroscopy may be useful for neurofeedback, which requires real‐time feedback of repeated brain activation measurements. However, no study has specifically targeted neurofeedback, using near‐infrared spectroscopy, in the frontal pole cortex.

Methods

We developed an original near‐infrared spectroscopy neurofeedback system targeting the frontal pole cortex. Over a single day of testing, each healthy participant (n = 24) received either correct or incorrect (Sham) feedback from near‐infrared spectroscopy signals, based on a crossover design.

Results

Under correct feedback conditions, significant activation was observed in the frontal pole cortex (P = 0.000073). Additionally, self‐evaluation of control and metacognitive beliefs were associated with near‐infrared spectroscopy signals (P = 0.006).

Conclusion

The neurofeedback system developed in this study might be useful for developing control of frontal pole cortex activation.
Cultural influences on suicide in Japan
Authors: Russell Roxanne , Metraux Daniel , Tohen Mauricio
Published: August 2016

Following the economic crash of the late 1990s, the suicide rate in Japan increased to a rate of over 30 000 people per year and has been one of the highest in the world. Cultural factors have influenced this high suicide rate, such as a tradition of honorable suicide as well as permissive attitudes towards suicide that remain in modern times. Additionally, the economic downturn, particularly the trend of unemployment in middle‐aged men, also played a significant role in the high suicide rate. The suicide rate has started to decrease in recent years perhaps in part due to suicide prevention measures undertaken by the government.
Disproportionality and Resource‐Based Environmental Inequality: An Analysis of Neighborhood Proximity to Coal Impoundments in Appalachia
Authors: Greenberg Pierce
Published: August 2016

Environmental hazards created by resource extraction impose numerous risks on rural populations, but have been understudied in quantitative analyses of environmental inequality. This study fills that gap by examining whether neighborhoods with socioeconomic disadvantages are disproportionately proximate to coal impoundments in Appalachia. Coal impoundments are large, hazardous dams that hold billions of gallons of wastewater and slurry, a sludge‐like by‐product of processing coal. I ground this study in William Freudenburg's double diversion framework, which highlights “disproportionality”—the unequal trade‐off between economic benefits and environmental costs of certain industries. Disproportionality is evident in Appalachia, where coal mining makes up a small percentage of the region's jobs, but threatens local communities through the creation of environmental hazards. Spatial regression results indicate that neighborhoods closest to impoundments are slightly more likely to have higher rates of poverty and unemployment, even after controlling for rurality, mining‐related variables, and spatial dependence. The findings also suggest that a neighborhood's proximity to past mining activity is a stronger predictor of impoundment proximity than current levels of mining employment. This article lays the groundwork for future research on resource‐based environmental inequality that considers the uneven spatial distribution of hazards created by resource extraction.
Coupled ‘storm‐flood’ depositional model: Application to the Miocene–Modern Baram Delta Province, north‐west Borneo
Authors: Collins Daniel S. , Johnson Howard D. , Allison Peter A. , Guilpain Pierre , Damit Abdul Razak
Published: August 2016

The Miocene to Modern Baram Delta Province is a highly efficient source to sink system that has accumulated 9 to 12 km of coastal–deltaic to shelf sediments over the past 15 Myr. Facies analysis based on ca 1 km of total vertical outcrop stratigraphy, combined with subsurface geology and sedimentary processes in the present‐day Baram Delta Province, suggests a ‘storm‐flood’ depositional model comprising two distinct periods: (i) fair‐weather periods are dominated by alongshore sediment reworking and coastal sand accumulation; and (ii) monsoon‐driven storm periods are characterized by increased wave‐energy and offshore‐directed downwelling storm flow that occur simultaneously with peak fluvial discharge caused by storm precipitation (‘storm‐floods’). The modern equivalent environment has the following characteristics: (i) humid‐tropical monsoonal climate; (ii) narrow (ca <100 km) and steep (ca 1°), densely vegetated, coastal plain; (iii) deep tropical weathering of a mudstone‐dominated hinterland; (iv) multiple independent, small to moderate‐sized (102 to 105 km2) drainage basins; (v) predominance of river‐mouth bypassing; and (vi) supply‐dominated shelf. The ancient, proximal part of this system (the onshore Belait Formation) is dominated by strongly cyclical sandier‐upward successions (metre to decametre‐scale) comprising (from bottom to top): (i) finely laminated mudstone with millimetre‐scale silty laminae; (ii) heterolithic sandstone–mudstone alternations (centimetre to metre‐scale); and (iii) sharp‐based, swaley cross‐stratified sandstone beds and bedsets (metre to decimetre‐scale). Gutter casts (decimetre to metre‐scale) are widespread, they are filled with swaley cross‐stratified sandstone and their long axes are oriented perpendicular to the palaeo‐shoreline. The gutter casts and other associated waning‐flow event beds suggest that erosion and deposition was controlled by high‐energy, offshore‐directed, oscillatory‐dominated, sediment‐laden combined flows within a shoreface to delta front setting. The presence of multiple river mouths and exceptionally high rates of accommodation creation (characteristic of the Neogene to Recent Baram Delta Province; up to 3000 m Ma−1), in a ‘storm‐flood’‐dominated environment, resulted in a highly efficient and effective offshore‐directed sediment transport system.
First report of the isolation of Lactococcus garvieae from a platelet concentrate in Japan
Authors: Kozakai Moe , Matsumoto Mami , Matsumoto Chieko , Uchida Shigeharu , Nagai Tadashi , Satake Masahiro , Tadokoro Kenji
Published: August 2016

BACKGROUND

Bacterial contamination of platelet concentrates (PCs) remains a serious problem in transfusion. We have been conducting sterility tests on all PCs rejected by blood centers or hospitals due to abnormal appearances. We recently experienced a case in which discrepant results were obtained between the methods used to identify a bacterial species isolated from a PC, requiring further analyses.

STUDY DESIGN AND METHODS

Bacteria were isolated from a PC using the BacT/ALERT system and plate culture. The species was identified using biochemical tests and molecular analysis. Phylogenetic trees were constructed using sequences of the 16S ribosomal RNA (rRNA) and superoxide dismutase (sodA) genes from the bacterial isolate and related species. In addition, the isolate was cultured at temperatures of 10°C and below to determine its growth activity at low temperatures.

RESULTS

Biochemical tests determined that the isolate was Streptococcus alactolyticus, whereas molecular analysis determined that it was Lactococcus garvieae. These two species belonged to different clusters on the phylogenetic tree. Similar to L. garvieae, the isolate could grow at 10°C.

CONCLUSIONS

We conclude that the isolate was L. garvieae according to molecular identification and its growth characteristic at 10°C. Molecular analysis enabled the identification of this species, which was difficult to classify by biochemical tests. Blood facilities need to be prepared with multiple techniques, including genetic analysis techniques, for identifying contaminating bacterial species. L. garvieae can grow at 10°C and can contaminate both red blood cell concentrates and PCs; thus, this species should be listed as a cryophilic bacterium that could threaten blood safety.
Optical constants, band gap, and infrared-active phonons of (LaAlO3)0.3(Sr2AlTaO6)0.35 (LSAT) from spectroscopic ellipsometry
Authors: Nunley Timothy Nathan , Willett-Gies Travis I. , Cooke Jacqueline A. , Manciu Felicia S. , Marsik Premysl , Bernhard Christian , Zollner Stefan
Published: August 2016

Using spectroscopic ellipsometry, the authors determined the optical constants (complex dielectric function) for (LaAlO3)0.3(Sr2AlTaO6)0.35 (LSAT) from 0.01 to 6.5 eV. Above 0.5 eV, the data were described with a sum of two Tauc-Lorentz oscillators and two poles. A direct gap of 5.8 ± 0.1 eV was found. An Urbach tail extends to even lower photon energies and makes the crystal opaque above 4.8 eV. Using Fourier-transform infrared ellipsometry, the lattice dynamics was studied. Nine pairs of transverse/longitudinal phonons were found and attributed to disorder in the La/Sr sublattice, ordering in the Al/Ta sublattice, and two-phonon absorption.
Use of local noise power spectrum and wavelet analysis in quantitative image quality assurance for EPIDs
Authors: Lee Soyoung , Yan Guanghua , Bassett Philip , Gopal Arun , Samant Sanjiv
Published: August 2016

Purpose:

To investigate the use of local noise power spectrum (NPS) to characterize image noise and wavelet analysis to isolate defective pixels and inter‐subpanel flat‐fielding artifacts for quantitative quality assurance (QA) of electronic portal imaging devices (EPIDs).

Methods:

A total of 93 image sets including custom‐made bar‐pattern images and open exposure images were collected from four iViewGT a‐Si EPID systems over three years. Global quantitative metrics such as modulation transform function (MTF), NPS, and detective quantum efficiency (DQE) were computed for each image set. Local NPS was also calculated for individual subpanels by sampling region of interests within each subpanel of the EPID. The 1D NPS, obtained by radially averaging the 2D NPS, was fitted to a power‐law function. The r‐square value of the linear regression analysis was used as a singular metric to characterize the noise properties of individual subpanels of the EPID. The sensitivity of the local NPS was first compared with the global quantitative metrics using historical image sets. It was then compared with two commonly used commercial QA systems with images collected after applying two different EPID calibration methods (single‐level gain and multilevel gain). To detect isolated defective pixels and inter‐subpanel flat‐fielding artifacts, Haar wavelet transform was applied on the images.

Results:

Global quantitative metrics including MTF, NPS, and DQE showed little change over the period of data collection. On the contrary, a strong correlation between the local NPS (r‐square values) and the variation of the EPID noise condition was observed. The local NPS analysis indicated image quality improvement with the r‐square values increased from 0.80 ± 0.03 (before calibration) to 0.85 ± 0.03 (after single‐level gain calibration) and to 0.96 ± 0.03 (after multilevel gain calibration), while the commercial QA systems failed to distinguish the image quality improvement between the two calibration methods. With wavelet analysis, defective pixels and inter‐subpanel flat‐fielding artifacts were clearly identified as spikes after thresholding the inversely transformed images.

Conclusions:

The proposed local NPS (r‐square values) showed superior sensitivity to the noise level variations of individual subpanels compared with global quantitative metrics such as MTF, NPS, and DQE. Wavelet analysis was effective in detecting isolated defective pixels and inter‐subpanel flat‐fielding artifacts. The proposed methods are promising for the early detection of imaging artifacts of EPIDs.
Microfluidic device for the formation of optically excitable, three-dimensional, compartmentalized motor units
Authors: Uzel Sebastien G. M. , Platt Randall J. , Subramanian Vidya , Pearl Taylor M. , Rowlands Christopher J. , Chan Vincent , Boyer Laurie A. , So Peter T. C. , Kamm Roger D.
Published: August 2016

Microfluidics and optogenetics enable the formation of light-excitable motor units in a compartmentalized and 3D environment.
Analysis of neural crest–derived clones reveals novel aspects of facial development
Authors: Kaucka Marketa , Ivashkin Evgeny , Gyllborg Daniel , Zikmund Tomas , Tesarova Marketa , Kaiser Jozef , Xie Meng , Petersen Julian , Pachnis Vassilis , Nicolis Silvia K. , Yu Tian , Sharpe Paul , Arenas Ernest , Brismar Hjalmar , Blom Hans , Clevers Hans , Suter Ueli , Chagin Andrei S. , Fried Kaj , Hellander Andreas , Adameyko Igor
Published: August 2016

Facial shaping results from oriented divisions and crowd movements of ectomesenchymal cells during morphogenetic events.
Synchrotron aims to bridge divides in the Middle East
Authors: Stokstad Erik
Published: August 2016

Light source in Jordan is just about ready to start shining.
The long road to LIGO
Authors: Cho Adrian
Published: August 2016

During its early years, the megaproject suffered from legendary infighting.
RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS
Authors: Ito Yasushi , Ofengeim Dimitry , Najafov Ayaz , Das Sudeshna , Saberi Shahram , Li Ying , Hitomi Junichi , Zhu Hong , Chen Hongbo , Mayo Lior , Geng Jiefei , Amin Palak , DeWitt Judy Park , Mookhtiar Adnan Kasim , Florez Marcus , Ouchida Amanda Tomie , Fan Jian-bing , Pasparakis Manolis , Kelliher Michelle A. , Ravits John , Yuan Junying
Published: August 2016

Axonal pathology and necroptosis in ALS

Necroptosis, a non–caspase-dependent form of cell death, can be reduced in disease states by inhibiting a kinase called RIPK1. Until now, no human mutations have been linked to necroptosis. Ito
et al.
show that loss of optineurin, which is encoded by a gene that has been implicated in the human neurodegenerative disorder ALS (amyotrophic lateral sclerosis), results in sensitivity to necroptosis and axonal degeneration. When RIPK1-kinase dependent signaling is disrupted in mice that lack optineurin, necroptosis is inhibited and axonal pathology is reversed.

Science
, this issue p.
603
The inhibition mechanism of human 20
S
proteasomes enables next-generation inhibitor design
Authors: Schrader Jil , Henneberg Fabian , Mata Ricardo A. , Tittmann Kai , Schneider Thomas R. , Stark Holger , Bourenkov Gleb , Chari Ashwin
Published: August 2016

Insights into proteasome inhibition

Proteasomes are large protein complexes that degrade and remove proteins to maintain proper cellular physiology and growth. Proteasomes are a validated target for anticancer therapy, but drug design has been hampered by poor understanding of how inhibitors interact with the active site. Schrader
et al.
succeeded in crystallizing various proteasome-inhibitor complexes. They subsequently obtained crystal structures for the native human proteasome and eight different inhibitor complexes at resolutions between 1.9 and 2.1 Å. The inhibitors sampled include drugs that are approved or in trial for cancer treatment.

Science
, this issue p.
594
The FDA is prohibited from going germline
Authors: Cohen I. Glenn , Adashi Eli Y.
Published: August 2016

Full stop: U.S. Congress precludes human germline modification
Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease
Authors: Kozak Robert , He Shihua , Kroeker Andrea , de La Vega Marc-Antoine , Audet Jonathan , Wong Gary , Urfano Chantel , Antonation Kym , Embury-Hyatt Carissa , Kobinger Gary P. , Qiu Xiangguo
Published: August 2016

Bundibugyo virus (BDBV) is the etiological agent of a severe hemorrhagic fever in humans with a case-fatality rate ranging from 25 to 36%. Despite having been known to the scientific and medical communities for almost 1 decade, there is a dearth of studies on this pathogen due to the lack of a small animal model. Domestic ferrets are commonly used to study other RNA viruses, including members of the order
Mononegavirales
. To investigate whether ferrets were susceptible to filovirus infections, ferrets were challenged with a clinical isolate of BDBV. Animals became viremic within 4 days and succumbed to infection between 8 and 9 days, and a petechial rash was observed with moribund ferrets. Furthermore, several hallmarks of human filoviral disease were recapitulated in the ferret model, including substantial decreases in lymphocyte and platelet counts and dysregulation of key biochemical markers related to hepatic/renal function, as well as coagulation abnormalities. Virological, histopathological, and immunohistochemical analyses confirmed uncontrolled BDBV replication in the major organs. Ferrets were also infected with Ebola virus (EBOV) to confirm their susceptibility to another filovirus species and to potentially establish a virus transmission model. Similar to what was seen with BDBV, important hallmarks of human filoviral disease were observed in EBOV-infected ferrets. This study demonstrates the potential of this small animal model for studying BDBV and EBOV using wild-type isolates and will accelerate efforts to understand filovirus pathogenesis and transmission as well as the development of specific vaccines and antivirals.

IMPORTANCE
The 2013-2016 outbreak of Ebola virus in West Africa has highlighted the threat posed by filoviruses to global public health. Bundibugyo virus (BDBV) is a member of the genus
Ebolavirus
and has caused outbreaks in the past but is relatively understudied, likely due to the lack of a suitable small animal model. Such a model for BDBV is crucial to evaluating vaccines and therapies and potentially understanding transmission. To address this, we demonstrated that ferrets are susceptible models to BDBV infection as well as to Ebola virus infection and that no virus adaptation is required. Moreover, these animals develop a disease that is similar to that seen in humans and nonhuman primates. We believe that this will improve the ability to study BDBV and provide a platform to test vaccines and therapeutics.
ITCH E3 Ubiquitin Ligase Interacts with Ebola Virus VP40 To Regulate Budding
Authors: Han Ziying , Sagum Cari A. , Bedford Mark T. , Sidhu Sachdev S. , Sudol Marius , Harty Ronald N.
Published: August 2016

Ebola virus (EBOV) and Marburg virus (MARV) belong to the
Filoviridae
family and can cause outbreaks of severe hemorrhagic fever, with high mortality rates in humans. The EBOV VP40 (eVP40) and MARV VP40 (mVP40) matrix proteins play a central role in virion assembly and egress, such that independent expression of VP40 leads to the production and egress of virus-like particles (VLPs) that accurately mimic the budding of infectious virus. Late (L) budding domains of eVP40 recruit host proteins (e.g., Tsg101, Nedd4, and Alix) that are important for efficient virus egress and spread. For example, the PPxY-type L domain of eVP40 and mVP40 recruits the host Nedd4 E3 ubiquitin ligase via its WW domains to facilitate budding. Here we sought to identify additional WW domain host interactors and demonstrate that the PPxY L domain motif of eVP40 interacts specifically with the WW domain of the host E3 ubiquitin ligase ITCH. ITCH, like Nedd4, is a member of the HECT class of E3 ubiquitin ligases, and the resultant physical and functional interaction with eVP40 facilitates VLP and virus budding. Identification of this novel eVP40 interactor highlights the functional interplay between cellular E3 ligases, ubiquitination, and regulation of VP40-mediated egress.

IMPORTANCE
The unprecedented magnitude and scope of the recent 2014-2015 EBOV outbreak in West Africa and its emergence here in the United States and other countries underscore the critical need for a better understanding of the biology and pathogenesis of this emerging pathogen. We have identified a novel and functional EBOV VP40 interactor, ITCH, that regulates VP40-mediated egress. This virus-host interaction may represent a new target for our previously identified small-molecule inhibitors of virus egress.
Flexibility of the Head-Stalk Linker Domain of Paramyxovirus HN Glycoprotein Is Essential for Triggering Virus Fusion
Authors: Adu-Gyamfi Emmanuel , Kim Lori S. , Jardetzky Theodore S. , Lamb Robert A.
Published: August 2016

The
Paramyxoviridae
comprise a large family of enveloped, negative-sense, single-stranded RNA viruses with significant economic and public health implications. For nearly all paramyxoviruses, infection is initiated by fusion of the viral and host cell plasma membranes in a pH-independent fashion. Fusion is orchestrated by the receptor binding protein hemagglutinin-neuraminidase (HN; also called H or G depending on the virus type) protein and a fusion (F) protein, the latter undergoing a major refolding process to merge the two membranes. Mechanistic details regarding the coupling of receptor binding to F activation are not fully understood. Here, we have identified the flexible loop region connecting the bulky enzymatically active head and the four-helix bundle stalk to be essential for fusion promotion. Proline substitution in this region of HN of parainfluenza virus 5 (PIV5) and Newcastle disease virus HN abolishes cell-cell fusion, whereas HN retains receptor binding and neuraminidase activity. By using reverse genetics, we engineered recombinant PIV5-EGFP viruses with mutations in the head-stalk linker region of HN. Mutations in this region abolished virus recovery and infectivity. In sum, our data suggest that the loop region acts as a “hinge” around which the bulky head of HN swings to-and-fro to facilitate timely HN-mediate F-triggering, a notion consistent with the stalk-mediated activation model of paramyxovirus fusion.

IMPORTANCE
Paramyxovirus fusion with the host cell plasma membrane is essential for virus infection. Membrane fusion is orchestrated via interaction of the receptor binding protein (HN, H, or G) with the viral fusion glycoprotein (F). Two distinct models have been suggested to describe the mechanism of fusion: these include “the clamp” and the “provocateur” model of activation. By using biochemical and reverse genetics tools, we have obtained strong evidence in favor of the HN stalk-mediated activation of paramyxovirus fusion. Specifically, our data strongly support the notion that the short linker between the head and stalk plays a role in “conformational switching” of the head group to facilitate F-HN interaction and triggering.
Inhibition of Human Metapneumovirus Binding to Heparan Sulfate Blocks Infection in Human Lung Cells and Airway Tissues
Authors: Klimyte Edita M. , Smith Stacy E. , Oreste Pasqua , Lembo David , Dutch Rebecca Ellis
Published: August 2016

Human metapneumovirus (HMPV), a recently discovered paramyxovirus, infects nearly 100% of the world population and causes severe respiratory disease in infants, the elderly, and immunocompromised patients. We previously showed that HMPV binds heparan sulfate proteoglycans (HSPGs) and that HMPV binding requires only the viral fusion (F) protein. To characterize the features of this interaction critical for HMPV binding and the role of this interaction in infection in relevant models, we utilized sulfated polysaccharides, heparan sulfate mimetics, and occluding compounds. Iota-carrageenan demonstrated potent anti-HMPV activity by inhibiting binding to lung cells mediated by the F protein. Furthermore, analysis of a minilibrary of variably sulfated derivatives ofEscherichia coliK5 polysaccharide mimicking the HS structure revealed that the highly O-sulfated K5 polysaccharides inhibited HMPV infection, identifying a potential feature of HS critical for HMPV binding. The peptide dendrimer SB105-A10, which binds HS, reduced binding and infection in an F-dependent manner, suggesting that occlusion of HS at the target cell surface is sufficient to prevent infection. HMPV infection was also inhibited by these compounds during apical infection of polarized airway tissues, suggesting that these interactions take place during HMPV infection in a physiologically relevant model. These results reveal key features of the interaction between HMPV and HS, supporting the hypothesis that apical HS in the airway serves as a binding factor during infection, and HS modulating compounds may serve as a platform for potential antiviral development.

IMPORTANCEHuman metapneumovirus (HMPV) is a paramyxovirus that causes respiratory disease worldwide. It has been previously shown that HMPV requires binding to heparan sulfate on the surfaces of target cells for attachment and infection. In this study, we characterize the key features of this binding interaction using heparan sulfate mimetics, identify an important sulfate modification, and demonstrate that these interactions occur at the apical surface of polarized airway tissues. These findings provide insights into the initial binding step of HMPV infection that has potential for antiviral development.
First Detection of Bat White-Nose Syndrome in Western North America
Authors: Lorch Jeffrey M. , Palmer Jonathan M. , Lindner Daniel L. , Ballmann Anne E. , George Kyle G. , Griffin Kathryn , Knowles Susan , Huckabee John R. , Haman Katherine H. , Anderson Christopher D. , Becker Penny A. , Buchanan Joseph B. , Foster Jeffrey T. , Blehert David S.
Published: August 2016

White-nose syndrome (WNS) represents one of the most consequential wildlife diseases of modern times. Since it was first documented in New York in 2006, the disease has killed millions of bats and threatens several formerly abundant species with extirpation or extinction. The spread of WNS in eastern North America has been relatively gradual, inducing optimism that disease mitigation strategies could be established in time to conserve bats susceptible to WNS in western North America. The recent detection of the fungus that causes WNS in the Pacific Northwest, far from its previous known distribution, increases the urgency for understanding the long-term impacts of this disease and for developing strategies to conserve imperiled bat species.
Protocol of the PLeural Effusion And Symptom Evaluation (PLEASE) study on the pathophysiology of breathlessness in patients with symptomatic pleural effusions
Authors: Thomas Rajesh , Azzopardi Maree , Muruganandan Sanjeevan , Read Catherine , Murray Kevin , Eastwood Peter , Jenkins Sue , Singh Bhajan , Lee Y C Gary
Published: August 2016

Introduction

Pleural effusion is a common clinical problem that can complicate many medical conditions. Breathlessness is the most common symptom of pleural effusion of any cause and the most common reason for pleural drainage. However, improvement in breathlessness following drainage of an effusion is variable; some patients experience either no benefit or a worsening of their breathlessness. The physiological mechanisms underlying breathlessness in patients with a pleural effusion are unclear and likely to be multifactorial with patient-related and effusion-related factors contributing. A comprehensive study of the physiological and symptom responses to drainage of pleural effusions may provide a clearer understanding of these mechanisms, and may identify predictors of benefit from drainage. The ability to identify those patients whose breathlessness will (or will not) improve after pleural fluid drainage can help avoid unnecessary pleural drainage procedures, their associated morbidities and costs. The PLeural Effusion And Symptom Evaluation (PLEASE) study is a prospective study to comprehensively evaluate factors contributing to pleural effusion-related breathlessness.

Methods and analysis

The PLEASE study is a single-centre prospective study of 150 patients with symptomatic pleural effusions that require therapeutic drainage. The study aims to identify key factors that underlie breathlessness in patients with pleural effusions and develop predictors of improvement in breathlessness following effusion drainage. Participants will undergo evaluation pre-effusion and post-effusion drainage to assess their level of breathlessness at rest and during exercise, respiratory and other physiological responses as well as respiratory muscle mechanics. Pre-drainage and post-drainage parameters will be collected and compared to identify the key factors and mechanisms that correlate with improvement in breathlessness.

Ethics and dissemination

Approved by the Sir Charles Gairdner Group Human Research Ethics Committee (HREC number 2014-079). Registered with the Australian New Zealand Clinical Trials Registry (ACTRN12616000820404). Results will be published in peer-reviewed journals and presented at scientific meetings.

Trial registration number

ACTRN12616000820404; Pre-results.
Interventions to improve hospital patient satisfaction with healthcare providers and systems: a systematic review
Authors: Davidson Karina W , Shaffer Jonathan , Ye Siqin , Falzon Louise , Emeruwa Iheanacho O , Sundquist Kevin , Inneh Ifeoma A , Mascitelli Susan L , Manzano Wilhelmina M , Vawdrey David K , Ting Henry H
Published: August 2016

Background

Many hospital systems seek to improve patient satisfaction as assessed by the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys. A systematic review of the current experimental evidence could inform these efforts and does not yet exist.

Methods

We conducted a systematic review of the literature by searching electronic databases, including MEDLINE and EMBASE, the six databases of the Cochrane Library and grey literature databases. We included studies involving hospital patients with interventions targeting at least 1 of the 11 HCAHPS domains, and that met our quality filter score on the 27-item Downs and Black coding scale. We calculated post hoc power when appropriate.

Results

A total of 59 studies met inclusion criteria, out of these 44 did not meet the quality filter of 50% (average quality rating 27.8%±10.9%). Of the 15 studies that met the quality filter (average quality rating 67.3%±10.7%), 8 targeted the Communication with Doctors HCAHPS domain, 6 targeted Overall Hospital Rating, 5 targeted Communication with Nurses, 5 targeted Pain Management, 5 targeted Communication about Medicines, 5 targeted Recommend the Hospital, 3 targeted Quietness of the Hospital Environment, 3 targeted Cleanliness of the Hospital Environment and 3 targeted Discharge Information. Significant HCAHPS improvements were reported by eight interventions, but their generalisability may be limited by narrowly focused patient populations, heterogeneity of approach and other methodological concerns.

Conclusions

Although there are a few studies that show some improvement in HCAHPS score through various interventions, we conclude that more rigorous research is needed to identify effective and generalisable interventions to improve patient satisfaction.
Engaging older patients in cardiovascular research: observational analysis of the ICON-1 study
Authors: Sinclair Hannah , Batty Jonathan A , Qiu Weiliang , Kunadian Vijay
Published: August 2016

Background

As a consequence of population ageing, the number of older patients presenting with acute coronary syndrome (ACS) is increasing. The historical underrepresentation of older patients in many pivotal ACS clinical trials undermines the practice of evidence-based medicine in this high-risk cohort. This study evaluates the feasibility of recruitment of older patients to a longitudinal, clinical study.

Methods

The study to Improve Cardiovascular Outcomes in high-risk patieNts with ACS (ICON-1) is an observational, prospective cohort study investigating predictors of poor outcome in older patients with ACS. All patients aged ≥75 years, referred to a tertiary cardiovascular centre in the North East of England for coronary angiography with a view to urgent percutaneous coronary intervention, were screened for inclusion. A screening log was prospectively maintained, and a detailed analysis was performed to identify the factors associated with recruitment and non-recruitment to ICON-1.

Results

Of the 629 patients screened over 34 months, 457 (72.7%) satisfied the a priori-defined study inclusion/exclusion criteria. Of those eligible to participate, 300 (68.5%) provided informed consent and were recruited to the study; 59 (13.5%) were unable to consent due to a lack of capacity or limitations in communication, and 79 patients (18.0%) declined to participate in the study. Those lacking adequate capacity to consent were older than those able to provide informed consent (83.0±4.7 vs 81.0±4.7 years, p=0.002). Women were more likely to decline than men (25.1% vs 10.0%, p<0.001).

Conclusions

The recruitment of patients was robust, comparing favourably to previous longitudinal studies within this age group. Although enrolling older people to research remains challenging, this cohort is enthusiastic to participate. The contribution of older patients must not be ignored, particularly in the setting of an ever-ageing population, in whom cardiovascular disease burden is high.

Trial registration number

NCT01933581; Pre-results.
Timeliness of referral of children with new onset type 1 diabetes
Authors: Iyer Dhaara , Choudhary Deepak , Agwu Juliana Chizo
Published: August 2016

Introduction

Type 1 diabetes (T1D) is characterised by autoimmune destruction of pancreatic β cells leading to insulin deficiency. Prompt referral to a specialist paediatric diabetes team (PDT) for insulin initiation and further management is important to prevent diabetic ketoacidosis (DKA), which remains the most common cause of death in this condition.

Objective

The aim was to study the timeliness of referrals from general practitioners (GPs) to PDT, of children suspected of having TID.

Method

We carried out a survey of the practice of GPs when they suspect TID in a young person, to investigate whether they recognised the need for urgent referral to PDT. In addition, we carried out retrospective case notes review of children diagnosed with diabetes mellitus between January 2005 and December 2014.

Results

111/300 (37%) of GPs replied to survey. Of these, 73/111 (65.8%) would have referred promptly to the PDT in accordance with National Guidelines. However, 34.2% would have taken an action that would have led to delay in referral to PDT. 96 children were diagnosed with TID during the audit period. There was a delay in referral in 35 (36.5%) children. 19/35 (54.3%) of these children presented with DKA. Mean duration of delay in presentation to the PDT was 1.8 days. In both survey and audit, the most common reason for delayed referral was GP attempting to confirm the diagnosis by undertaking further diagnostic tests.

Conclusions

Our study has identified a modifiable reason for delayed referrals of children with TID.
Working in industry using skills learned in practice
Authors: Scott‐Morris Blaise
Published: August 2016

After qualifying, Blaise Scott‐Morris enjoyed working in small animal practice. In search of a new challenge, she joined Virbac where she is a technical adviser