bluuebunny/crossref_metadata_2025 huggingface dataset:
Low Energy, Low Angle, Large Area Ion Polishing for Improved EBSD Indexing
Authors: Walck SD , Porter JR , Yang H-W , Dheda SS
Published: May 2018

Good sample preparation is essential for acquiring successful electron backscattered diffraction (EBSD) patterns in the SEM. Mechanical polishing to obtain the required surface quality with minimal sub-surface defects and deformation that does not interfere with the quality of the diffraction data is, more often than not, an art form. Special polishing techniques, such as low force lapping fixtures, electrochemical-mechanical polishing, and vibratory polishing, have been used to minimize the sub-surface damage, but have not eliminated it. Ion polishing has been used to reduce the damage layer further. However, the commercially available ion systems suffer several drawbacks, including: 1) small area treatment (≤ 1 cm) 2) decreasing beam current density with accelerating voltages, and 3) the inability to process non-conducting samples. Barna and Pecz have shown that at 3 keV with an incident angle of 5° relative to the surface, approximately 25 nm of ion damage occurs in Si and GaAs, but at 250 eV, there is less than 1 nm of amorphization of the surface. They also showed that a glancing angle across the surface is essential for removing topographic features. The ion guns that have been available for ion polishing and ion etching of SEM samples typically cannot operate effectively below 3 keV because of the low current density.
Toward Robust High Resolution Chemical Imaging
Authors: Barrios Carlos A , Malkovskiy Andrey V , Kisliuk Alexander , Sokolov Alexei P , Foster Mark D
Published: May 2018

Resonant plasmon excitations at the surface of noble metals can localize and amplify an electromagnetic field in a very small volume and are the enabling element of surface enhanced optical microscopies. Tip enhanced Raman spectroscopy (TERS) combines scanning probe microscopy (SPM) with Raman spectroscopy, taking advantage of this enhancing mechanism. So far a 20 nm lateral resolution in chemical imaging of a surface has been achieved. So far a 20 nm lateral resolution in chemical imaging of a surface has been achieved.
Pioneers in Optics: Alhazen and Roger Bacon
Authors: Davidson Michael W
Published: May 2018

Born in Iraq as Abu Ali Hasan Ibn al–Haitham, the great Arab physicist is more often known by the Latinized version of his first name, Alhazen. Although he was to eventually become a profound intellectual specializing in mathematics and optics, Alhazen's early education was geared towards religion and prepared him for a career as a minister. However, apparently unhappy in his religious pursuits, Alhazen later decided to devote himself to the study of science and became particularly intrigued by Aristotle.
On the Sub-Nanometer Resolution of Scanning Electron and Helium Ion Microscopes
Authors: Vladár András E , Postek Michael T , Ming Bin
Published: May 2018

All forms of microscopy are being pushed to the limit by nanotechnology. This is especially true for high-resolution scanning electron and helium ion microscopes, which are proving to be extremely useful for nanometer-scale imaging, characterization, and dimensional measurements. Excellent resolution is essential for imaging nanomaterials. Hence, there is a relentless quest to achieve better and better resolution with various electron and ion microscopes and to monitor and maintain these instruments to achieve the best possible performance levels.

The ability to resolve fine details with a microscope has greatly improved over the past 20 years. The resolution achievable with the newest scanning electron microscopes (SEMs) can now be at or below 0.4 nm and for the scanning helium ion microscope (HeIM), 0.24 nm has been reported. To put this into perspective, the {111} crystal plane in silicon (Si) has 0.32 nm lattice spacing, so one cubic nanometer in the Si crystal contains only a few atoms. Therefore, an instrument must be performing at the highest level possible to resolve routinely the finest structures. Clearly, the instrument operator must also be functioning at a high level as well to achieve the best resolution and to prove that the instrument is capable of doing the work.
Dip Pen Nanolithography: A Desktop Nanofabrication Approach Using High-Throughput Flexible Nanopatterning
Authors: Haaheim Jason , Nafday Omkar A
Published: May 2018

Dip Pen Nanolithography (DPN) is a scanning probe lithography technique where an atomic force microscope tip is used to transfer molecules to a surface via a solvent meniscus. This technique allows surface patterning on scales of under 100 nanometres. DPN is the nanotechnology analog of the dip pen (also called the quill pen), where the tip of an atomic force microscope cantilever acts as a “pen,” which is coated with a chemical compound or mixture acting as an “ink,” and put in contact with a substrate, the “paper.”

DPN enables direct deposition of nanoscale materials onto a substrate in a flexible manner. The vehicle for deposition can include pyramidal scanning probe microscope tips, hollow tips, and even tips on thermally actuated cantilevers. Recent advances have demonstrated massively parallel patterning using two-dimensional arrays of 55,000 tips, depicted below. Applications of this technology currently range through chemistry, materials science, and the life sciences, and include such work as ultra high density biological nanoarrays, additive photomask repair, and brand protection for pharmaceuticals.
Manufacturer Training of Electron Microscopy and Analysis Techniques
Authors: Rowlands Neil
Published: May 2018

Training by an instrument manufacturer is provided at various levels, ranging from basic operation requirements of instrumentation to high level courses for specific advanced level applications and integrated solutions.

Initial training usually is in the form of an initial familiarization performed by the installation engineer, and subsequent training is given at training courses at the instrument company laboratory or, in some instances, at the customer site. Manufacturer training can be required on different levels from initiation to basic techniques and operation of the instrumentation to advanced courses for specific applications. Although basic theory is present at the start of a course, the overall aim is to provide practical expertise on an operational level. It is encouraged that customers who are new to the techniques presented may avail themselves of more theoretically orientated courses available at universities and other private institutes.
SEM Short Courses for Industry: the Lehigh Microscopy School as an example
Authors: Lyman Charles E
Published: May 2018

Short courses in scanning electron microscopy (SEM) can quickly sharpen practical skills for industrial microscopists. The SEM and the energy-dispersive X-ray spectrometer (EDS) together constitute one of the most powerful and versatile instruments available for solving industrial problems, but interpreting images and spectra is not quite as simple as acquiring them. Applications of SEM span many disciplines, and each application may require knowledge of different aspects of the microscope, and of the industrial problem at hand, to successfully interpret the images and data obtained. Regardless of the problem, whether transistors or trachea cells, the interpretation of SEM images relies upon the microscopist's understanding the fundamentals of image formation as well as the practical aspects of specimen preparation and microscope operation. Many people using SEMs today have not taken any courses beyond the on-site and demo-lab instruction provided by SEM vendors. Equipment manufacturers provide excellent training on how to use the knobs and menus on the SEM to produce useful images and data via the embedded software functions. Since there are many options and setup procedures, these instrument-specific courses are valuable for the novice and expert alike.
THE LOGIC OF RESOURCES AND CAPABILITIES
Authors: BÍLKOVÁ MARTA , GRECO GIUSEPPE , PALMIGIANO ALESSANDRA , TZIMOULIS APOSTOLOS , WIJNBERG NACHOEM
Published: May 2018

We introduce the logic LRC, designed to describe and reason about agents’ abilities and capabilities in using resources. The proposed framework bridges two—up to now—mutually independent strands of literature: the one on logics of abilities and capabilities, developed within the theory of agency, and the one on logics of resources, motivated by program semantics. The logic LRC is suitable to describe and reason about key aspects of social behaviour in organizations. We prove a number of properties enjoyed by LRC (soundness, completeness, canonicity, and disjunction property) and its associated analytic calculus (conservativity, cut elimination, and subformula property). These results lay at the intersection of the algebraic theory of unified correspondence and the theory of multitype calculi in structural proof theory. Case studies are discussed which showcase several ways in which this framework can be extended and enriched while retaining its basic properties, so as to model an array of issues, both practically and theoretically relevant, spanning from planning problems to the logical foundations of the theory of organizations.
Specificities and challenges of responding to internal displacement in urban settings
Authors: Cotroneo Angela
Published: May 2018

The world is rapidly urbanizing, and so is internal displacement. However, knowledge about the specific situation of internally displaced persons (IDPs) in urban settings and how it differs from, and impacts on, their host communities is still limited, and responses continue to be inadequate. This article analyzes the particular needs of urban IDPs by taking into account how the various contexts and patterns of urban internal displacement contribute to shaping people's experience. It discusses three key challenges that humanitarian actors are faced with in developing effective responses: identifying and reaching IDPs in urban settings, addressing their urgent protection concerns, and supporting their local integration. It concludes by pointing out the need for methodological and operational guidance on how to bring together area-based approaches that account for the impact of displacement on entire urban communities, and tailored approaches addressing IDPs’ specific needs in urban settings. The need for stocktaking exercises and more effective sharing of experiences among practitioners, municipal authorities and policy-makers is also underlined.
Obligations of transit countries under refugee law: A Western Balkans case study
Authors: Kilibarda Pavle
Published: May 2018

A significant increase in the number of arrivals of refugees and migrants in Europe along the Western Balkans route brought several Balkan countries into the spotlight of international refugee protection in 2015 and 2016. Out of hundreds of thousands of refugees and migrants recorded entering the former Yugoslav Republic of Macedonia and Serbia, only a handful remained to seek asylum from their authorities. Under the circumstances, the applicability of the 1951 Refugee Convention with respect to refugees refraining from seeking asylum was brought into question, as well as the extent of transit countries’ legal obligations under refugee law. Based on the Western Balkans experience, the present article seeks to re-examine the relationship between the concept of asylum and the regime of the 1951 Refugee Convention, the Convention's scope of application in “transit countries”, and minimal standards stemming from positive law regarding the treatment of refugees and migrants in a transit context.
Seasonal Variability of the Midlatitude Traveling Ionospheric Disturbances From Wallops Island, VA, Dynasonde Data: Evidence of a Semiannual Variation
Authors: Negrea Catalin , Zabotin Nikolay , Bullett Terence
Published: May 2018

We investigate the ionospheric variability due to traveling ionospheric disturbances (TIDs) over Wallops Island, VA, using Dynasonde‐derived measurements of ionospheric tilts and vertical Doppler speed between May 2013 and August 2016, covering the bottomside ionospheric F layer. The mean power spectral density is determined separately for each month for both ionospheric tilts and for the Doppler speed, with a 2 km resolution in a broad altitude range. This is accomplished using a spectral analysis technique based on the Lomb‐Scargle and Welch methods, with an added filtering criterion. The analysis is performed separately for the daytime and nighttime data. By investigating the seasonal variability of the power spectral density integral, a semiannual variation is highlighted in the overall level of daytime TID activity, with increased activity during summer and winter seasons in the northern hemisphere. This result provides a more complete picture than other recent publications that only highlighted a winter peak in the same geographical sector. Finally, the relative amplitude of the two peaks in TID activity is shown to vary significantly during the three years investigated and also as a function of the altitude.
Multiple Exhumation Phases in the Central Pontides (N Turkey): New Temporal Constraints on Major Geodynamic Changes Associated With the Closure of the Neo‐Tethys Ocean
Authors: Ballato P. , Parra M. , Schildgen T. F. , Dunkl I. , Yıldırım C. , Özsayın E. , Sobel E. R. , Echtler H. , Strecker M. R.
Published: May 2018

The Central Pontides of N Turkey represents a mobile orogenic belt of the southern Eurasian margin that experienced several phases of exhumation associated with the consumption of different branches of the Neo‐Tethys Ocean and the amalgamation of continental domains. Our new low‐temperature thermochronology data help to constrain the timing of these episodes, providing new insights into associated geodynamic processes. In particular, our data suggest that exhumation occurred at (1) ~110 to 90 Ma, most likely during tectonic accretion and exhumation of metamorphic rocks from the subduction zone; (2) from ~60 to 40 Ma, during the collision of the Kirşehir and Anatolide‐Tauride microcontinental domains with the Eurasian margin; (3) from ~40 to 25 Ma, either during the early stages of the Arabia‐Eurasia collision (soft collision) when the Arabian passive margin reached the trench, implying 70 to 530 km of subduction of the Arabian passive margin, or during a phase of trench advance predating hard collision at ~20 Ma; and (4) ~11 Ma to the present, during transpression associated with the westward motion of Anatolia. Our findings document the punctuated nature of fault‐related exhumation, with episodes of fast cooling followed by periods of slow cooling or subsidence, the role of inverted normal faults in controlling the Paleogene exhumation pattern, and of the North Anatolian Fault in dictating the most recent pattern of exhumation.
Changing Seasonal Rainfall Distribution With Climate Directs Contrasting Impacts at Evapotranspiration and Water Yield in the Western Mediterranean Region
Authors: Montaldo Nicola , Oren Ram
Published: May 2018

Over the past century, climate change has been reflected in altered precipitation regimes worldwide. Because evapotranspiration is sensitive to both water availability and atmospheric demand for water vapor, it is essential to assess the likely consequences of future changes of these climate variables to evapotranspiration and, thus, runoff. We propose a simplified approach for annual evapotranspiration predictions, based on seasonal evapotranspiration estimates, accounting for the strong seasonality of meteorological conditions typical of Mediterranean climate, still holding the steady state assumption of basin water balance at mean annual scale. Sardinian runoff decreased over the 1975–2010 period by more than 40% compared to the preceding 1922–1974 period. Most of annual runoff in Sardinian basins is produced by winter precipitation, a wet season with relatively high evaporation rates. We derived linear seasonal evapotranspiration responses to seasonal precipitation, and, in turn, a relationship between the parameters of the linear functions and the seasonal vapor pressure deficit (D), accounting for residuals with basin properties. We then used these relationships to predict evapotranspiration and runoff using future Intergovernmental Panel on Climate Change climate scenarios, considering changing precipitation and D seasonality. We show that evapotranspiration is insensitive to D scenario changes. Although both evapotranspiration and runoff are sensitive to precipitation seasonality, future changes in runoff are related only to changes of winter precipitation, while evapotranspiration changes are related to those of spring and summer precipitation. Future scenario predicting further runoff decline is particularly alarming for the Sardinian water resources system, requiring new strategies and designs in water resources planning and management.
Cold Dense Ion Outflow Observed in the Martian‐Induced Magnetotail by MAVEN
Authors: Inui S. , Seki K. , Namekawa T. , Sakai S. , Brain D. A. , Hara T. , McFadden J. P. , Halekas J. S. , Mitchell D. L. , Mazelle C. , DiBraccio G. A. , Jakosky B. M.
Published: May 2018

Cold ion outflow is one of the candidate processes to cause significant atmospheric escape from Mars. We here report on the cold dense heavy ion outflow event observed in Martian‐induced magnetotail by Mars Atmosphere and Volatile EvolutioN (MAVEN) on 4 December 2014. In the outflow event, the cold dense heavy ion outflow was observed only in south dusk downward convection electric field (E) lobe. During the event, the strong crustal magnetic field was located on dayside of Mars. It suggests that combination of minimagnetosphere and downward E facilitates the cold dense heavy ion outflow. In order to estimate the CO2+ density, we adopted a fitting method of log‐normal distribution to the O2+ time of flight distributions to eliminate O2+ contamination in the CO2+ time of flight data. Contribution of O2+, O+, and CO2+ to the total heavy ions (~134 cm−3) is about 71%, 26%, and 3%, respectively. Average heavy ion flux was ~5.4 × 107 cm−2s−1, assuming the escape velocity at 2,000‐km altitude.
Predictions and Observations for the Oceanic Lithosphere FromS‐to‐PReceiver Functions andSSPrecursors
Authors: Rychert Catherine A. , Harmon Nick
Published: May 2018

The ocean lithosphere is classically described by the thermal half‐space cooling (HSC) or the plate models, both characterized by a gradual transition to the asthenosphere beneath. Scattered waves find sharp seismic discontinuities beneath the oceans, possibly from the base of the plate. Active source studies suggest sharp discontinuities from a melt channel. We calculate syntheticS‐to‐Preceiver functions andSSprecursors for the HSC and plate models and also for channels. We find that the HSC and plate model velocity gradients are too gradual to create interpretable scattered waves from the base of the plate. Subtle phases are predicted to follow a similar trend as observations, flattening at older ages. Therefore, the seismic discontinuities are probably caused by a thermally controlled process that can also explain their amplitude, such as melting. Melt may coalesce in channels, although channels >10 km thick should be resolvable by scattered wave imaging.
Why Do Aftershocks Occur Within the Rupture Area of a Large Earthquake?
Authors: Yabe Suguru , Ide Satoshi
Published: May 2018

The mainshock‐aftershock sequence is one of the fundamental characteristics of seismogenesis, yet the physical mechanism of aftershock generation remains poorly understood. The simple explanation that aftershocks are caused by the mainshock's redistribution of strain energy is not always applicable, especially for aftershocks within the mainshock slip area, where strain energy is released. Here we show that the genesis of aftershocks can be modeled using a frictionally heterogeneous fault system. We conducted quasi‐dynamic numerical simulations of fault rupture cycles on a finite fault governed by a rate‐ and state‐dependent friction law. Aftershocks are observed around and within the mainshock rupture area when the frictional heterogeneity varies significantly along the fault. On the other hand, aftershocks are not produced when along‐fault variations in the frictional heterogeneity are small, which mimics the observed lack of aftershocks for repeating earthquakes.
Heliospheric Conditions at Saturn During Cassini's Ring‐Grazing and Proximal Orbits
Authors: Roussos E. , Krupp N. , Paranicas C. , Kollmann P. , Mitchell D. G. , Krimigis S. M. , Palmaerts B. , Dialynas K. , Jackman C. M
Published: May 2018

We surveyed energetic charged particle measurements by Cassini between 2016 and the end of the mission in order to identify transients of solar energetic particles and galactic cosmic rays. Such transients offer hints about the state of the heliosphere and valuable context for interpreting space weather phenomena in Saturn's magnetosphere. The period studied includes the mission's Ring‐Grazing and Proximal orbits, which due to their week‐long periods are ideal for capturing short timescale dynamics in the planet's magnetosphere, including solar periodicities. We find that Saturn was exposed to corotating interaction regions for nearly all the 21 final months of Cassini and encountered just two interplanetary coronal mass ejections. Several independent studies report solar periodicities and storm‐time conditions in the magnetosphere at times, which coincide with the transients that we identify here.
ULF Wave‐Associated Density Irregularities and Scintillation at the Equator
Authors: Yizengaw E. , Zesta E. , Moldwin M. B. , Magoun M. , Tripathi N. K. , Surussavadee C. , Bamba Z.
Published: May 2018

This paper presents independent multi‐instrument observations that address the physical mechanisms of how ultralow‐frequency (ULF) wave‐associated electric fields initiate ionospheric density fluctuation and scintillation at the equator. Since the magnetic field at the equator is entirely embedded in a relatively high‐collision and high‐conductivity medium, the condition may not be possible for the geomagnetic field to fluctuate due to ULF wave activity. This implies that the fluctuating electric field at the equator may not be produced through equatorial dynamo action due to fluctuating magnetic fields. Instead, the electric field penetrates from high latitudes and produces fluctuating magnetic field as well as modulates the vertical drift and hence causes the density to fluctuate at the equatorial region. We demonstrate this by estimating the ULF associated fluctuating electric field at high latitudes and at the equatorial region by applying the appropriate attenuation factor as it penetrates to lower latitudes. The periodicity of both electric field and density fluctuations appears to be between 6 and 9 min, which is a typical period of ULF waves in the Pc5 range. Because of its large amplitude and long periods compared to other ULF wave frequency bands, the Pc5 wave‐associated electric field, which can even be estimated using magnetograms with low sensitivity and low sampling rate (e.g., 1 min), can easily penetrate to the lower latitude region and produce significant ionospheric density fluctuations that can be strong enough to create scintillation at the equatorial region.
Application of a Luminescence‐Based Sediment Transport Model
Authors: Gray Harrison J. , Tucker Gregory E. , Mahan Shannon A.
Published: May 2018

Quantifying the transport history of sand is a challenging but important goal in geomorphology. In this paper, we take a simple idea that luminescence is bleached during transport and regenerates during storage, and use this as a basis to re‐envision luminescence as a sediment tracer. We apply a mathematical model describing luminescence through an idealized channel and reservoir system and then compare this idealized model to real rivers to see if luminescence can reproduce known sediment transport data. We provide results from application of this luminescence method in three rivers from the mid‐Atlantic region of the United States. This method appears promising. However, as a river system diverges from idealized conditions of the mathematical model, the luminescence data diverge from model predictions. We suggest that spatial variation in the delivery of sediment from hillslopes can be reflected in the channel sediment luminescence and that luminescence acts as a function of landscape dynamics.
Midlatitude Ionospheric Irregularity Spectral Density as Determined by Ground‐Based GPS Receiver Networks
Authors: Lay Erin H. , Parker Peter A. , Light Max , Carrano Charles S. , Debchoudhury Shantanab , Haaser Robert A.
Published: May 2018

We present a new technique to experimentally measure the spatial spectrum of ionospheric disturbances in the spatial scale regime of 40–200 km. This technique produces a two‐dimensional (2‐D) spectrum for each time snapshot over two dense Global Positioning System (GPS) receiver networks (GPS Earth Observation Network in Japan and Plate Boundary Observatory in the Western United States). Because this technique created the spectrum from an instantaneous time snapshot, no assumptions are needed about the speed of ionospheric irregularities. We examine spectra from 3 days: one with an intense geomagnetic storm, one with significant lightning activity, and one quiet day. Radial slices along the 2‐D spectra provide one‐dimensional spectra that can be fit to a power law to quantify the steepness of the falloff in the spatial scale sizes. Continuous data of this type in a stationary location allow monitoring the variability in the 2‐D spectrum over the course of a day and comparing between days, as shown here, or even over a year or many years. We find that the spectra are highly variable over the course of a day and between the two selected regions of Japan and the Western United States. When strong traveling ionospheric disturbances (TIDs) are present, the 2‐D spectra provide information about the direction of propagation of the TIDs. We compare the TID propagation direction with horizontal wind directions from the Horizontal Wind Model. TID direction is correlated with the horizontal wind direction on all days, strongly indicating that the primary source of the TIDs measured by this technique is tropospheric.
SK channel activation is neuroprotective in conditions of enhanced ER–mitochondrial coupling
Authors: Honrath Birgit , Krabbendam Inge E. , IJsebaart Carmen , Pegoretti Valentina , Bendridi Nadia , Rieusset Jennifer , Schmidt Martina , Culmsee Carsten , Dolga Amalia M.
Published: May 2018

Alterations in the strength and interface area of contact sites between the endoplasmic reticulum (ER) and mitochondria contribute to calcium (Ca2+) dysregulation and neuronal cell death, and have been implicated in the pathology of several neurodegenerative diseases. Weakening this physical linkage may reduce Ca2+ uptake into mitochondria, while fortifying these organelle contact sites may promote mitochondrial Ca2+ overload and cell death. Small conductance Ca2+-activated K+ (SK) channels regulate mitochondrial respiration, and their activation attenuates mitochondrial damage in paradigms of oxidative stress. In the present study, we enhanced ER–mitochondrial coupling and investigated the impact of SK channels on survival of neuronal HT22 cells in conditions of oxidative stress. Using genetically encoded linkers, we show that mitochondrial respiration and the vulnerability of neuronal cells to oxidative stress was inversely linked to the strength of ER–mitochondrial contact points and the increase in mitochondrial Ca2+ uptake. Pharmacological activation of SK channels provided protection against glutamate-induced cell death and also in conditions of increased ER–mitochondrial coupling. Together, this study revealed that SK channel activation provided persistent neuroprotection in the paradigm of glutamate-induced oxytosis even in conditions where an increase in ER–mitochondrial coupling potentiated mitochondrial Ca2+ influx and impaired mitochondrial bioenergetics.
Proteasomal degradation of the histone acetyl transferase p300 contributes to beta-cell injury in a diabetes environment
Authors: Ruiz Lucie , Gurlo Tatyana , Ravier Magalie A. , Wojtusciszyn Anne , Mathieu Julia , Brown Matthew R. , Broca Christophe , Bertrand Gyslaine , Butler Peter C. , Matveyenko Aleksey V. , Dalle Stéphane , Costes Safia
Published: May 2018

In type 2 diabetes, amyloid oligomers, chronic hyperglycemia, lipotoxicity, and pro-inflammatory cytokines are detrimental to beta-cells, causing apoptosis and impaired insulin secretion. The histone acetyl transferase p300, involved in remodeling of chromatin structure by epigenetic mechanisms, is a key ubiquitous activator of the transcriptional machinery. In this study, we report that loss of p300 acetyl transferase activity and expression leads to beta-cell apoptosis, and most importantly, that stress situations known to be associated with diabetes alter p300 levels and functional integrity. We found that proteasomal degradation is the mechanism subserving p300 loss in beta-cells exposed to hyperglycemia or pro-inflammatory cytokines. We also report that melatonin, a hormone produced in the pineal gland and known to play key roles in beta-cell health, preserves p300 levels altered by these toxic conditions. Collectively, these data imply an important role for p300 in the pathophysiology of diabetes.
Endogenous authentic OCT4A proteins directly regulate FOS/AP-1 transcription in somatic cancer cells
Authors: Zhou Yanwen , Chen Xinyu , Kang Bo , She Shiqi , Zhang Xiaobing , Chen Cheng , Li Wenxin , Chen Wenjie , Dan Songsong , Pan Xiaoyun , Liu Xiaoli , He Jianqin , Zhao Qingwei , Zhu Chenggang , Peng Ling , Wang Haoyi , Yao Hangping , Cao Hongcui , Li Lanjuan , Herlyn Meenhard , Wang Ying-Jie
Published: May 2018

OCT4A is well established as a master transcription factor for pluripotent stem cell (PSC) self-renewal and a pioneer factor for initiating somatic cell reprogramming, yet its presence and functionality in somatic cancer cells remain controversial and obscure. By combining the CRISPR-Cas9-based gene editing with highly specific PCR assays, highly sensitive immunoassays, and mass spectrometry, we provide unequivocal evidence here that full-length authentic OCT4A transcripts and proteins were both present in somatic cancer cells, and OCT4A proteins were heterogeneously expressed in the whole cell population and when expressed, they are predominantly localized in cell nucleus. Despite their extremely low abundance (approximately three orders of magnitude lower than in PSCs), OCT4A proteins bound to the promoter/enhancer regions of the AP-1 transcription factor subunit c-FOS gene and critically regulated its transcription. Knocking out OCT4A in somatic cancer cells led to dramatic reduction of the c-FOS protein level, aberrant AP-1 signaling, dampened self-renewal capacity, deficient cell migration that were associated with cell growth retardation in vitro and in vivo, and their enhanced sensitivity to anticancer drugs. Taken together, we resolve the long-standing controversy and uncertainty in the field, and reveal a fundamental role of OCT4A protein in regulating FOS/AP-1 signaling-centered genes that mediate the adhesion, migration, and propagation of somatic cancer cells.
Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS
Authors: Gibbs Katherine L. , Kalmar Bernadett , Rhymes Elena R. , Fellows Alexander D. , Ahmed Mahmood , Whiting Paul , Davies Ceri H. , Greensmith Linda , Schiavo Giampietro
Published: May 2018

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the degeneration of upper and lower motor neurons. Defects in axonal transport have been observed pre-symptomatically in the SOD1G93A mouse model of ALS, and have been proposed to play a role in motor neuron degeneration as well as in other pathologies of the nervous system, such as Alzheimer’s disease and hereditary neuropathies. In this study, we screen a library of small-molecule kinase inhibitors towards the identification of pharmacological enhancers of the axonal retrograde transport of signalling endosomes, which might be used to normalise the rate of this process in diseased neurons. Inhibitors of p38 mitogen-activated protein kinases (p38 MAPK) were identified in this screen and were found to correct deficits in axonal retrograde transport of signalling endosomes in cultured primary SOD1G93A motor neurons. In vitro knockdown experiments revealed that the alpha isoform of p38 MAPK (p38 MAPKα) was the sole isoform responsible for SOD1G93A-induced transport deficits. Furthermore, we found that acute treatment with p38 MAPKα inhibitors restored the physiological rate of axonal retrograde transport in vivo in early symptomatic SOD1G93A mice. Our findings demonstrate the pathogenic effect of p38 MAPKα on axonal retrograde transport and identify a potential therapeutic strategy for ALS.
YAP-dependent ubiquitination and degradation of β-catenin mediates inhibition of Wnt signalling induced by Physalin F in colorectal cancer
Authors: Chen Chen , Zhu Dongrong , Zhang Hao , Han Chao , Xue Guimin , Zhu Tianyu , Luo Jianguang , Kong Lingyi
Published: May 2018

Aberrant activation of Wnt/β-catenin signalling is critical in the progression of human cancers, especially colorectal cancer (CRC). Therefore, inhibition of Wnt/β-catenin signalling is a significant potential target for CRC therapy. Here, we identified for the first time that Physalin F (PF), a steroid derivative isolated from Physalis angulate, acts as an antagonist of Wnt/β-catenin signalling. In vitro, PF decreased Wnt3a-induced TOPFlash reporter activity in HEK293T cells and promoted the formation of the β-catenin destruction complex. Importantly, PF also inhibited Wnt/β-catenin signalling and accelerated the degradation of β-catenin in CRC cells. However, PF did not affect the stabilization of Axin or the interaction of β-catenin with E-cadherin. Interestingly, we further found that PF promoted YAP binding to the β-catenin destruction complex, which facilitated the ubiquitination and degradation of β-catenin. Silencing and pharmacological inhibition of YAP reversed the formation of the β-catenin destruction complex induced by PF, implying that YAP binding to the β-catenin destruction complex was responsible for PF-mediated inhibition of Wnt/β-catenin signalling. Furthermore, PF observably inhibited tumour growth by down-regulating β-catenin in tumour-bearing mice. Collectively, our findings indicated that PF inhibited Wnt/β-catenin signalling by accelerating the ubiquitination and degradation of β-catenin in a YAP-dependent manner and therefore PF could be a novel potential candidate for CRC therapy.
Enhancer of zeste homolog 2-catalysed H3K27 trimethylation plays a key role in acute-on-chronic liver failure via TNF-mediated pathway
Authors: Zhou Tianhui , Sun Ye , Li Ming , Ding Yongsen , Yin Rongkun , Li Ziqiang , Xie Qing , Bao Shisan , Cai Wei
Published: May 2018

Acute-on-chronic liver failure is mainly due to host immunity self-destruction. The histone H3 lysine 27 (H3K27) trimethylating enzyme, enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing of gene expression and regulates immunity, also involves pathogenesis of several liver diseases. The current study was to determine the role of methyltransferase EZH2 and its catalysed H3K27 trimethylation (H3K27me3) in liver failure, and to further investigate the potential target for liver failure treatment. EZH2 and its catalysed H3K27me3 were determined in peripheral blood mononuclear cells (PBMC) from liver failure patients and Kupffer cells from experimental mice. Furthermore, GSK126 (an inhibitor for EZH2 trimethylation function) was applied in liver failure mice in vivo, and lipopolysaccharide-stimulated mononuclear cells in vitro. EZH2 and H3K27me3 were significantly upregulated in human PBMC from liver failure patients or murine Kupffer cells from the liver failure animals, respectively. GSK126 ameliorated disease severity in liver failure mice, which maybe attribute to down-regulate circulating and hepatic proinflammatory cytokines, especially TNF via reducing H3K27me3. In-depth chromatin immunoprecipitation analysis unravelled that decreased enrichment of H3K27me3 on Tnf promotor, resulting in TNF elevation in Kupffer cells from liver failure mice. Nuclear factor kappa B (NF-κB) and protein kinase B (Akt) signalling pathways were activated upon lipopolysaccharide stimulation, but attenuated by using GSK126, accompanied with decreased TNF in vitro. In conclusion, EZH2 and H3K27me3 contributed to the pathogenesis of liver failure via triggering TNF and other indispensable proinflammatory cytokines. EZH2 was to modify H3K27me3 enrichment, as well as, activation of the downstream NF-κB and Akt signalling pathways.
Epidermal glucocorticoid and mineralocorticoid receptors act cooperatively to regulate epidermal development and counteract skin inflammation
Authors: Bigas Judit , Sevilla Lisa M. , Carceller Elena , Boix Julia , Pérez Paloma
Published: May 2018

Endogenous and synthetic glucocorticoids (GCs) regulate epidermal development and combat skin inflammatory diseases. GC actions can be mediated through the GC receptor (GR) and/or the mineralocorticoid receptor (MR), highly homologous ligand-activated transcription factors. While the role of GR as a potent anti-inflammatory mediator is well known, that of MR is not as clear, nor is whether these receptors cooperate or antagonize each other in the epidermis. To address this, we generated mice with epidermal-specific loss of both receptors (double knockout, DKO), and analyzed the phenotypical and functional consequences relative to single KOs or controls (CO). At birth, DKO epidermis displayed a phenotype of defective differentiation and inflammation, which was more severe than in either single KO, featuring neutrophil-containing infiltrates, and gene dysregulation characteristic of human psoriatic lesions. This phenotype resolved spontaneously. However, in adulthood, single or combined loss of GC receptors increased susceptibility to inflammation and hyperproliferation triggered by phorbol ester which, different to CO, was not effectively counteracted by GC treatment. Also, DKOs were more susceptible to imiquimod-induced psoriasis than CO showing severe defective epidermal differentiation and microabcesses while single KOs showed an intermediate response. Immortalized DKO keratinocytes featured increased proliferation kinetics and reduced cell size, a unique phenotype relative to single KO cells. The lack of GR and MR in keratinocytes, individual or combined, caused constitutive increases in p38 and ERK activities, which were partially reversed upon reinsertion of receptors into DKO cells. DKO keratinocytes also displayed significant increases in AP-1 and NF-κB transcriptional activities, which were partially rescued by ERK and p38 inhibition, respectively. Reinsertion of GR and MR in DKO keratinocytes resulted in physical and cooperative functional interactions that restored the transcriptional response to GCs. In conclusion, our data have revealed that epidermal GR and MR act cooperatively to regulate epidermal development and counteract skin inflammation.
Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism
Authors: Yang Ying , Hsu Phillip J. , Chen Yu-Sheng , Yang Yun-Gui
Published: May 2018

N6-methyladenosine (m6A) is a chemical modification present in multiple RNA species, being most abundant in mRNAs. Studies on enzymes or factors that catalyze, recognize, and remove m6A have revealed its comprehensive roles in almost every aspect of mRNA metabolism, as well as in a variety of physiological processes. This review describes the current understanding of the m6A modification, particularly the functions of its writers, erasers, readers in RNA metabolism, with an emphasis on its role in regulating the isoform dosage of mRNAs.
Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation
Authors: Klammt Jürgen , Neumann David , Gevers Evelien F. , Andrew Shayne F. , Schwartz I. David , Rockstroh Denise , Colombo Roberto , Sanchez Marco A. , Vokurkova Doris , Kowalczyk Julia , Metherell Louise A. , Rosenfeld Ron G. , Pfäffle Roland , Dattani Mehul T. , Dauber Andrew , Hwa Vivian
Published: May 2018

Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.
Uranium(III)-carbon multiple bonding supported by arene δ-bonding in mixed-valence hexauranium nanometre-scale rings
Authors: Wooles Ashley J. , Mills David P. , Tuna Floriana , McInnes Eric J. L. , Law Gareth T. W. , Fuller Adam J. , Kremer Felipe , Ridgway Mark , Lewis William , Gagliardi Laura , Vlaisavljevich Bess , Liddle Stephen T.
Published: May 2018

Despite the fact that non-aqueous uranium chemistry is over 60 years old, most polarised-covalent uranium-element multiple bonds involve formal uranium oxidation states IV, V, and VI. The paucity of uranium(III) congeners is because, in common with metal-ligand multiple bonding generally, such linkages involve strongly donating, charge-loaded ligands that bind best to electron-poor metals and inherently promote disproportionation of uranium(III). Here, we report the synthesis of hexauranium-methanediide nanometre-scale rings. Combined experimental and computational studies suggest overall the presence of formal uranium(III) and (IV) ions, though electron delocalisation in this Kramers system cannot be definitively ruled out, and the resulting polarised-covalent U = C bonds are supported by iodide and δ-bonded arene bridges. The arenes provide reservoirs that accommodate charge, thus avoiding inter-electronic repulsion that would destabilise these low oxidation state metal-ligand multiple bonds. Using arenes as electronic buffers could constitute a general synthetic strategy by which to stabilise otherwise inherently unstable metal-ligand linkages.
Oxytocin and vasopressin flatten dominance hierarchy and enhance behavioral synchrony in part via anterior cingulate cortex
Authors: Jiang Yaoguang , Platt Michael L.
Published: May 2018

The neuropeptides oxytocin (OT) and arginine vasopressin (AVP) influence social functions in many mammals. In humans and rhesus macaques, OT delivered intranasally can promote prosocial behavior in certain contexts. Yet the precise neural mechanisms mediating these behavioral effects remain unclear. Here we show that treating a group of male macaque monkeys intranasally with aerosolized OT relaxes their spontaneous social interactions with other monkeys. OT reduces differences in social behavior between dominant and subordinate monkeys, thereby flattening the status hierarchy. OT also increases behavioral synchrony within a pair. Intranasal delivery of aerosolized AVP reproduces the effects of OT with greater efficacy. Remarkably, all behavioral effects are replicated when OT or AVP is injected focally into the anterior cingulate gyrus (ACCg), a brain area linked to empathy and other-regarding behavior. ACCg lacks OT receptors but is rich in AVP receptors, suggesting exogenous OT may shape social behavior, in part, via nonspecific binding. Notably, OT and AVP alter behaviors of both the treated monkey and his untreated partner, consistent with enhanced feedback through reciprocal social interactions. These findings bear important implications for use of OT in both basic research and as a therapy for social impairments in neurodevelopmental disorders.
Publisher Correction: Using high-amplitude and focused transcranial alternating current stimulation to entrain physiological tremor
Authors: Khatoun Ahmad , Breukers Jolien , Op de Beeck Sara , Nica Ioana Gabriela , Aerts Jean-Marie , Seynaeve Laura , Haeck Tom , Asamoah Boateng , Mc Laughlin Myles
Published: May 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Mechanisms responsible for increased circulating levels of galectin-3 in cardiomyopathy and heart failure
Authors: Nguyen My-Nhan , Su Yidan , Vizi Donna , Fang Lu , Ellims Andris H. , Zhao Wei-Bo , Kiriazis Helen , Gao Xiao-Ming , Sadoshima Junichi , Taylor Andrew J. , McMullen Julie R. , Dart Anthony M. , Kaye David M. , Du Xiao-Jun
Published: May 2018

Galectin-3 is a biomarker of heart disease. However, it remains unknown whether increase in galectin-3 levels is dependent on aetiology or disease-associated conditions and whether diseased heart releases galectin-3 into the circulation. We explored these questions in mouse models of heart disease and in patients with cardiomyopathy. All mouse models (dilated cardiomyopathy, DCM; fibrotic cardiomyopathy, ischemia-reperfusion, I/R; treatment with β-adrenergic agonist isoproterenol) showed multi-fold increases in cardiac galectin-3 expression and preserved renal function. In mice with fibrotic cardiomyopathy, I/R or isoproterenol treatment, plasma galectin-3 levels and density of cardiac inflammatory cells were elevated. These models also exhibited parallel changes in cardiac and plasma galectin-3 levels and presence of trans-cardiac galectin-3 gradient, indicating cardiac release of galectin-3. DCM mice showed no change in circulating galectin-3 levels nor trans-cardiac galectin-3 gradient or myocardial inflammatory infiltration despite a 50-fold increase in cardiac galectin-3 content. In patients with hypertrophic cardiomyopathy or DCM, plasma galectin-3 increased only in those with renal dysfunction and a trans-cardiac galectin-3 gradient was not present. Collectively, this study documents the aetiology-dependency and diverse mechanisms of increment in circulating galectin-3 levels. Our findings highlight cardiac inflammation and enhanced β-adrenoceptor activation in mediating elevated galectin-3 levels via cardiac release in the mechanism.