bluuebunny/crossref_metadata_2025 huggingface dataset:
Metathesis of aspiration as the source of anticipatory voicelessness in Basque
Authors: Egurtzegi Ander
Published: July 2019

In Basque, there is evidence, especially in early loans from Latin, that a sequence #DV(R)T… where D is a voiced stop and T is a voiceless (aspirated) stop was optionally produced with devoicing of the first of these stops. An additional particularity of this sound pattern is that the devoiced word-initial stop typically surfaces with aspiration, while the previously aspirated stop loses it: #DV(R)T(h)… > #T(h)V(R)T… This typologically uncommon sound pattern has been described as assimilation of voicelessness in the literature, or spread of [-voiced]. I propose that this sound pattern is triggered by aspiration, not voicelessness, and that it is a case of metathesis, not assimilation. Under the proposed analysis, aspiration of the second stop in the word is reanalysed as originating in the first stop, an instance of perceptual metathesis. This approach accounts for the distribution of aspirated stops before and after the optional change, and the failure of post-sibilant stops to trigger. This account also has implications for the chronology of aspiration-loss in Western dialects: at the time the earliest Latin loans were borrowed, all Basque dialects still maintained a historical series of aspirated stops. Only later, after this process of optional metathesis, did the Western dialects lose *h and stop aspiration.
Heart failure in primary care: prevalence related to age and
comorbidity
Authors: Bosch Lieke , Assmann Patricia , de Grauw Wim J. C. , Schalk Bianca W. M. , Biermans Marion C. J.
Published: July 2019

Background

Diagnosing heart failure (HF) in primary care can be challenging, especially
in elderly patients with comorbidities. Insight in the prevalence, age,
comorbidity and routine practice of diagnosing HF in general practice may
improve the process of diagnosing HF.

Aim

To examine the prevalence of HF in relation to ageing and comorbidities, and
routine practice of diagnosing HF in general practice.

Methods

A retrospective cohort study was performed using data from electronic health
records of 56 320 adult patients of 11 general practices. HF patients were
compared with patients without HF using descriptive analyses and
χ2 tests. The following comorbidities were considered: chronic
obstructive pulmonary disorder (COPD), diabetes mellitus (DM), hypertension,
anaemia and renal function disorder (RFD). Separate analyses were performed
for men and women.

Findings

The point prevalence of HF was 1.2% (95% confidence interval
1.13–1.33) and increased with each age category from 0.04%
(18–44 years) to 20.9% (⩾85 years). All studied
comorbidities were significantly (P<0.001) more
common in HF patients than in patients without HF: COPD (24.1% versus
3.1%), DM (34.7% versus 6.5%), hypertension
(52.7% versus 16.0%), anaemia (10.9% versus
2.3%) and RFD (61.8% versus 7.5%). N-terminal pro-BNP
(NT-proBNP) was recorded in 38.1% of HF patients.

Conclusions

HF is highly associated with ageing and comorbidities. Diagnostic use of
NT-proBNP in routine primary care seems underutilized. Instruction of GPs to
determine NT-proBNP in patients suspected of HF is recommended, especially
In elderly patients with comorbidities.
Fullerton Virtual Twin Project: Overview and 2019 Update
Authors: Segal Nancy L. , Niculae Francisca J.
Published: July 2019

Virtual twins (VTs) are defined as same-age unrelated siblings raised together from early infancy. This special class of adoptive siblings replays the rearing situation of twins, absent genetic relatedness. The first such pair was identified and studied in 1990 at the University of Minnesota, leading to the creation of the Fullerton Virtual Twin Study (FVTS) at California State University, Fullerton (CSUF) the following year. The registry currently includes 169 VT pairs, mostly children, with new pairs identified on a regular basis. These sibling sets provide a direct estimate of environmental influences on developmental traits and, as such, offer informative comparisons with ordinary monozygotic and dizygotic twins, full siblings and adoptive brothers and sisters. The sample characteristics, assessment battery and findings to date are summarized in this 2019 update.
Local Time Variation in the Large‐Scale Structure of Saturn's Magnetosphere
Authors: Sorba A. M. , Achilleos N. A. , Sergis N. , Guio P. , Arridge C. S. , Dougherty M. K.
Published: July 2019

The large‐scale structure of Saturn's magnetosphere is determined by internal and external factors, including the rapid planetary rotation rate, significant internal hot and cold plasma sources, and varying solar wind pressure. Under certain conditions the dayside magnetospheric magnetic field changes from a dipolar to more disk‐like structure, due to global force balance being approximately maintained during the reconfiguration. However, it is still not fully understood which factors dominantly influence this behavior, and in particular how it varies with local time. We explore this in detail using a 2‐D force‐balance model of Saturn's magnetodisk to describe the magnetosphere at different local time sectors. For model inputs, we use recent observational results that suggest a significant local time asymmetry in the pressure of the hot (>3 keV) plasma population, and magnetopause location. We make calculations under different solar wind conditions, in order to investigate how these local time asymmetries influence magnetospheric structure for different system sizes. We find significant day/night asymmetries in the model magnetic field, consistent with recent empirical studies based on Cassini magnetometer observations. We also find dawn‐dusk asymmetries in equatorial current sheet thickness, with the varying hot plasma content and magnetodisk radius having comparable influence on overall structure, depending on external conditions. We also find significant variations in magnetic mapping between the ionosphere and equatorial disk, and ring current intensity, with substantial enhancements in the night and dusk sectors. These results have consequences for interpreting many magnetospheric phenomena that vary with local time, such as reconnection events and auroral observations.
Bottom and Intermediate Nepheloid Layer Induced by Shoaling Internal Solitary Waves: Impacts of the Angle of the Wave Group Velocity Vector and Slope Gradients
Authors: Tian Zhuangcai , Jia Yonggang , Zhang Shaotong , Zhang Xiaojiang , Li Yang , Guo Xiujun
Published: July 2019

The widely recognized global phenomena of bottom nepheloid layer (BNL) and intermediate nepheloid layer (INL) are ubiquitous in the ocean. These phenomena are induced by shoaling internal solitary waves (ISWs), as observed in many studies. In this study, we analyzed the BNLs and INLs induced by shoaling ISWs and their detailed processes using flume experiments and field observations. ISWs suspended seabed sediment by the horizontal velocity in the vortex, and the near‐bottom vertical velocity lifted sediment into the water column to create a BNL, which detached from the slope and diffused along the isopycnals, forming more than one INL. Considering the results of previous researchers, we found that the numbers of BNLs and INLs were principally determined by the relationship between the angle of the ISW group velocity vector (α) relative to horizontal and the slope gradients (γ). In transmissive regions (γ/α < 1), one BNL and more than one INL were formed. In critical regions (γ/α~1), only one BNL and less than one INL were observed. In reflective regions (γ/α > 1), less than one BNL was formed and no INL. The BNL in the critical regions should be the thickest where the sediment resuspension was the greatest. The concentrations and thicknesses of BNLs and INLs were related to the energy and amplitude of ISW and the sediment condition. The results in the transmissive regions were proved by field observation. Our research will help to predict the number and magnitude of transport channels formed by shoaling ISWs from the ocean margin to the ocean interior.
A Transient Coupled Ice Flow‐Damage Model to Simulate Iceberg Calving From Tidewater Outlet Glaciers
Authors: Mercenier R. , Lüthi M. P. , Vieli A.
Published: July 2019

Iceberg calving, the detachment of an ice block at the glacier front, is the main process responsible for the dynamic mass loss from the ice sheets to the ocean. Understanding this process is essential to accurately predict ice sheet response to the future climate. We present a transient multiphysics finite‐element model to simulate iceberg break‐off and geometry evolution of a marine‐terminating glacier. The model solves the coupled equations of ice flow, damage mechanics, oceanic melt, and geometry evolution on the same Lagrangian computational grid. A modeling sensitivity analysis shows that the choice of stress measure used for damage evolution strongly influences the resulting calving front geometries. Our analysis suggests that the von Mises stress measures produce the most realistic calving front geometry evolutions for tidewater glaciers. Submarine frontal melt is shown to have a strong impact on the calving front geometry. The presented multiphysics model includes all processes thus far shown to be relevant for the evolution of tidewater glaciers and can be readily adapted for 3‐D and arbitrary bedrock geometries.
River Bathymetry Estimate and Discharge Assessment from Remote Sensing
Authors: Moramarco Tommaso , Barbetta Silvia , Bjerklie David M. , Fulton John W. , Tarpanelli Angelica
Published: July 2019

The NASA Surface Water Ocean Topography (SWOT) mission and ESA Sentinel‐1, inter‐alia, propose to monitor inland waters from satellites. The radar altimeter and the microwave radiometer can be used to monitor water surface level and assess the cross‐sectional mean flow velocity, respectively. However, for most river sites bathymetric data are lacking, preventing the direct computation of discharge. In this context, a new methodology for simulating the bathymetry and estimating the discharge is proposed. The approach is based on entropy theory and can be applied using ground and satellite observations. Four parameters are needed and include channel roughness, water surface slope, channel bottom elevation, and an entropy parameter of flow depth. These parameters are estimated using a genetic algorithm by minimizing the error in the observed maximum surface velocity. Parameter uncertainty is considered through 1,000 random realizations based on different initial values. Eighteen streamflow measurements recorded from three different gauged river sites are used to benchmark the ground observations. The method included ENVISAT altimetry and Moderate Resolution Imaging Spectroradiometer (MODIS) data (2002‐2010) at one river site. Relative to ground measurements, the method provides good results with an error in channel area and discharge that, on average, does not exceed 10% on the 50th percentile. Relative to satellite measurements, channel area is well simulated with an error, on average, lower than 9%; discharge is less well simulated and represented by an error greater than 30% on the 50th percentile.
Simulated Arctic Ocean Response to Doubling of Riverine Carbon and Nutrient Delivery
Authors: Terhaar J. , Orr J. C. , Ethé C. , Regnier P. , Bopp L.
Published: July 2019

The Arctic Ocean, more than any other ocean, is influenced by riverine input of carbon and nutrients. That riverine delivery is likely to change with climate change as runoff increases, permafrost thaws, and tree lines advance. But it is unknown to what extent these changes in riverine delivery will affect Arctic Ocean primary production, air‐to‐sea CO2 fluxes, and acidification. To test their sensitivity to changing riverine delivery, we made sensitivity tests using an ocean circulation model coupled to an ocean biogeochemical model. In separate idealized simulations, riverine inputs of dissolved inorganic carbon (CT), dissolved organic carbon (DOC), and nutrients were increased by 1%/year until doubling. Doubling riverine nutrient delivery increased primary production by 11% on average across the Arctic basin and by up to 34–35% locally. Doubling riverine DOC delivery resulted in 90% of that added carbon being lost to the atmosphere, partly because it was imposed that once delivered to the ocean, the riverine DOC is instantaneously remineralized to CT. That additional outgassing, when considered alone, reduced the net ingassing of natural CO2 into the Arctic Ocean by 25% while converting the Siberian shelf seas and the Beaufort Sea from net sinks to net sources of carbon to the atmosphere. The remaining 10% of DOC remained in the Arctic Ocean, but having been converted to CT, it enhanced acidification. Conversely, doubling riverine CT increased the Arctic Ocean's average surface pH by 0.02 because riverine total alkalinity delivery increased at the same rate as riverine CT delivery.
Shoreline Slope Breaks Revise Understanding of Hawaiian Shield Volcanoes Evolution
Authors: Taylor Brian
Published: July 2019

Slope gradient maps of swath bathymetry around the Hawaiian islands locate 12 shield slope breaks associated with former shorelines that are now submerged, ranging in age back to 5 Ma. The age of their drowning correlates with the waning of tholeiitic shield volcanism that ceases to repave the shoreline sometime between the beginning and the end of the late‐shield stage. Slope breaks on Mauna Loa's northeast and southwest rifts are consistent with it being in the waning stages of shield building. Superposition of shorebreaks shows that the Hualālai shield is older than Mauna Kea's. We find evidence for three volcanic shields forming Ka'ena Ridge, for a simultaneous waning of Maui‐Lāna'i‐Kaho'olawe shield building and the initiation of Kohala shield building by 1.3 Ma, and for Mahukona growing to just above sea level about 0.6 Ma. A contiguous shoreline slope break formed ~1.8 Ma at the end of the West Moloka'i late‐shield stage and the beginning of the East Moloka'i late‐shield stage. At its western end the shield dips obliquely away from, rather than toward, this slope break. Similarly, the short Hualālai slope break plunges north, which is opposite to that expected for volcanic loading to the south. Shields locally sloping away from paleoshorelines may be related to landslides causing flexural back tilting away from their unloaded footwall. The Nu'uanu and Wailau slides and Pololū slump were mostly shield flank events that cut marginally into their former shorelines, enough to preferentially nucleate headward erosion by streams.
Varying Sensitivity of East Asia Summer Monsoon Circulation to Temperature Change Since Last Glacial Maximum
Authors: Cheng Jun , Ma Wuyang , Liu Zhengyu , Wu Haibin
Published: July 2019

Proxy records of the East Asia summer monsoon (EASM) and temperature reveal an in‐phase relationship of the two since the Last Glacial Maximum (LGM), which is consistent with their expected physical relationship; but the response amplitude of EASM to temperature variation seemed larger over the Holocene than over the last deglaciation. Using a state‐of‐the‐art transient climate simulation, we confirm this proxy‐inferred phenomenon, and estimate the “sensitivity of EASM circulation to summer temperature over adjacent region” (defined as SMT here) is about five times over the Holocene of that over the last deglaciation. This varying SMT attributed to the diverse SMT under the solo forcing of orbital insolation and CO2 (eight times of the former vs. the latter), and their varying confounding effect along time. The results presented here should improve our understanding of the past change of EASM, and help project its variation magnitude under ongoing CO2‐forced global warming.
The Effects of Solar Wind Dynamic Pressure on the Structure of the Topside Ionosphere of Mars
Authors: Girazian Z. , Halekas J. , Morgan D. D. , Kopf A. J. , Gurnett D. A. , Chu F.
Published: July 2019

We use Mars Atmosphere and Volatile EvolutioN observations of the upstream solar wind, and Mars Express observations of ionospheric electron densities and magnetic fields, to study how the topside ionosphere (>320 km) of Mars is affected by variations in solar wind dynamic pressure. We find that high solar wind dynamic pressures result in the topside ionosphere being depleted of plasma at all solar zenith angles, coincident with increased induced magnetic field strengths. The depletion of topside plasma in response to high solar wind dynamic pressures is observed in both weak and strong crustal magnetic field regions. Taken together, our results suggest that high solar wind dynamic pressures lead to ionospheric compression, increased ion escape, and reduced day‐to‐night plasma transport in the high‐altitude nightside ionosphere.
Continent‐Wide, Interferometric SAR Phase, Mapping of Antarctic Ice Velocity
Authors: Mouginot J. , Rignot E. , Scheuchl B.
Published: July 2019

Surface ice velocity is a fundamental characteristic of glaciers and ice sheets that quantifies the transport of ice. Changes in ice dynamics have a major impact on ice sheet mass balance and its contribution to sea level rise. Prior comprehensive mappings employed speckle and feature tracking techniques, optimized for fast‐flow areas, with precision of 2‐5 m/year, hence limiting our ability to describe ice flow in the slow interior. We present a vector map of ice velocity using the interferometric phase from multiple satellite synthetic aperture radars resulting in 10 times higher precision in speed (20 cm/year) and direction (5°) over 80% of Antarctica. Precision mapping over areas of slow motion (<1 m/year) improves from 20 to 93%, which helps better constrain drainage boundaries, improve mass balance assessment, evaluate regional atmospheric climate models, reconstruct ice thickness, and inform ice sheet numerical models.
Western Mediterranean Climate Response to Dansgaard/Oeschger Events: New Insights From Speleothem Records
Authors: Budsky Alexander , Wassenburg Jasper A. , Mertz‐Kraus Regina , Spötl Christoph , Jochum Klaus Peter , Gibert Luis , Scholz Denis
Published: July 2019

The climate of the western Mediterranean was characterized by a strong precipitation gradient during the Holocene driven by atmospheric circulation patterns. The scarcity of terrestrial paleoclimate archives has precluded exploring this hydroclimate pattern during Marine Isotope Stages 5 to 3. Here we present stable carbon and oxygen isotope records from three flowstones from southeast Iberia, which show that Dansgaard/Oeschger events were associated with more humid conditions. This is in agreement with other records from the Iberian Peninsula, the Mediterranean, and western Europe, which all responded in a similar way to millennial‐scale climate variability in Greenland. This general increase in precipitation during Dansgaard/Oeschger events cannot be explained by any present‐day or Holocene winter atmospheric circulation pattern. Instead, we suggest that changes in sea surface temperature played a dominant role in determining precipitation amounts in the western Mediterranean.
Spatially Extended Tests of a Neural Network Parametrization Trained by Coarse‐Graining
Authors: Brenowitz Noah D. , Bretherton Christopher S.
Published: July 2019

General circulation models (GCMs) typically have a grid size of 25–200 km. Parametrizations are used to represent diabatic processes such as radiative transfer and cloud microphysics and account for subgrid‐scale motions and variability. Unlike traditional approaches, neural networks (NNs) can readily exploit recent observational data sets and global cloud‐system resolving model (CRM) simulations to learn subgrid variability. This article describes an NN parametrization trained by coarse‐graining a near‐global CRM simulation with a 4‐km horizontal grid spacing. The NN predicts the residual heating and moistening averaged over (160 km)2 grid boxes as a function of the coarse‐resolution fields within the same atmospheric column. This NN is coupled to the dynamical core of a GCM with the same 160‐km resolution. A recent study described how to train such an NN to be stable when coupled to specified time‐evolving advective forcings in a single‐column model, but feedbacks between NN and GCM components cause spatially extended simulations to crash within a few days. Analyzing the linearized response of such an NN reveals that it learns to exploit a strong synchrony between precipitation and the atmospheric state above 10 km. Removing these variables from the NN's inputs stabilizes the coupled simulations, which predict the future state more accurately than a coarse‐resolution simulation without any parametrizations of subgrid‐scale variability, although the mean state slowly drifts.
Submesoscale Impacts on Mesoscale Agulhas Dynamics
Authors: Schubert R. , Schwarzkopf F. U. , Baschek B. , Biastoch A.
Published: July 2019

Mesoscale dynamics of the Agulhas Current system determine the exchange between the Indian and Atlantic oceans, thereby influencing the global overturning circulation. Using a series of ocean model experiments compared to observations, we show that the representation of mesoscale eddies in the Agulhas ring path improves with increasing resolution of submesoscale flows. Simulated submesoscale dynamics are validated with time‐mean horizontal‐wavenumber spectra from satellite sea surface temperature measurements and mesoscale dynamics with spectra from sea surface height. While the Agulhas ring path in a nonsubmesoscale‐resolving (1/20)° configuration is associated with too less power spectral densities on all scales and too steep spectral slopes, the representation of the mesoscale dynamics improves when the diffusion and the dissipation of the model are reduced and some small‐scale features are resolved. Realistic power spectral densities over all scales are achieved when additionally the horizontal resolution is increased to (1/60)° and a larger portion of the submesoscale spectrum is resolved. Results of an eddy detection algorithm applied to the model outputs as well as to a gridded sea surface height satellite product show that in particular strong cyclones are much better represented when submesoscale flows are resolved by the model. The validation of the submesoscale dynamics with sea surface temperature spectra provides guidance for the choice of advection schemes and explicit diffusion and dissipation as well as for further subgrid‐scale parameterizations. For the Agulhas ring path, the use of upstream biased advection schemes without explicit diffusion and dissipation is found to be associated with realistically simulated submesoscales.
Surface acoustic wave humidity sensors based on uniform and thickness controllable graphene oxide thin films formed by surface tension
Authors: Le Xianhao , Liu Yihan , Peng Li , Pang Jintao , Xu Zhen , Gao Chao , Xie Jin
Published: July 2019

Graphene oxide (GO) is a promising candidate for humidity sensing, and the uniformity and thickness of GO films are important for the reproducibility and test signal strength of humidity sensors. In this paper, uniform and thickness-controllable GO films are first formed by the surface tension of different concentrations of GO solution and then transferred to surface acoustic wave (SAW) humidity sensors. This GO film formation and transfer process has very good repeatability and stability, as evidenced by the humidity response of the sensors. With the help of the uniform and highly oxidized GO film, the humidity sensors show a significantly high sensitivity (absolute sensitivity of 25.3 kHz/%RH and relative sensitivity of 111.7 p.p.m./%RH) in a wide test range from 10%RH to 90%RH with very little hysteresis (<1%RH). The sensors achieve good reversibility, excellent short-term repeatability and stability. Moreover, the humidity sensors also show a fast response and recovery time of <10 s.
Altered white matter microstructure in 22q11.2 deletion syndrome: a multisite diffusion tensor imaging study
Authors: Villalón-Reina Julio E. , Martínez Kenia , Qu Xiaoping , Ching Christopher R. K. , Nir Talia M. , Kothapalli Deydeep , Corbin Conor , Sun Daqiang , Lin Amy , Forsyth Jennifer K. , Kushan Leila , Vajdi Ariana , Jalbrzikowski Maria , Hansen Laura , Jonas Rachel K. , van Amelsvoort Therese , Bakker Geor , Kates Wendy R. , Antshel Kevin M. , Fremont Wanda , Campbell Linda E. , McCabe Kathryn L. , Daly Eileen , Gudbrandsen Maria , Murphy Clodagh M. , Murphy Declan , Craig Michael , Emanuel Beverly , McDonald-McGinn Donna M. , Vorstman Jacob A.S. , Fiksinski Ania M. , Koops Sanne , Ruparel Kosha , Roalf David , Gur Raquel E. , Eric Schmitt J. , Simon Tony J. , Goodrich-Hunsaker Naomi J. , Durdle Courtney A. , Doherty Joanne L. , Cunningham Adam C. , van den Bree Marianne , Linden David E. J. , Owen Michael , Moss Hayley , Kelly Sinead , Donohoe Gary , Murphy Kieran C. , Arango Celso , Jahanshad Neda , Thompson Paul M. , Bearden Carrie E.
Published: July 2019

22q11.2 deletion syndrome (22q11DS)—a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22—is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6–52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen’sd’s ranging from −0.9 to −1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.
Modifying PTEN recruitment promotes neuron survival, regeneration, and functional recovery after CNS injury
Authors: Shabanzadeh Alireza Pirsaraei , D’Onofrio Philippe Matteo , Magharious Mark , Choi Kyung An Brian , Monnier Philippe Patrick , Koeberle Paulo Dieter
Published: July 2019

Phosphatase and tensin homolog (PTEN) regulates apoptosis and axonal growth in the developing and adult central nervous system (CNS). Here, we show that human PTEN C-terminal PDZ interactions play a critical role in neuronal apoptosis and axon regeneration after traumatic CNS injury and stroke, highlighted by the findings that antagonizing the PDZ-motif interactions of PTEN has therapeutic applicability for these indications. Interestingly, the death-inducing function of PTEN following ischemic insult depends on a PDZ-domain interaction with MAGI-2 and MAST205, PDZ proteins that are known to recruit PTEN to the plasma membrane and stabilize its interaction with PIP3. Treatments with a human peptide that prevents PTEN association with MAGI-2 or MAST205 increased neuronal survival in multiple stroke models, in vitro. A pro-survival effect was also observed in models of retinal ischemia, optic nerve transection, and after middle cerebral artery occlusion (MCAO) in adult rats. The human PTEN peptide also improved axonal regeneration in the crushed optic nerve. Furthermore, human PTEN peptide therapy promoted functional improvement after MCAO or retinal ischemia induced via ophthalmic artery ligation. These findings show that the human peptide-based targeting of C-terminal PTEN PDZ interactions has therapeutic potential for insults of the CNS, including trauma and stroke.
Molecular movie of ultrafast coherent rotational dynamics of OCS
Authors: Karamatskos Evangelos T. , Raabe Sebastian , Mullins Terry , Trabattoni Andrea , Stammer Philipp , Goldsztejn Gildas , Johansen Rasmus R. , Długołecki Karol , Stapelfeldt Henrik , Vrakking Marc J. J. , Trippel Sebastian , Rouzée Arnaud , Küpper Jochen
Published: July 2019

Recording molecular movies on ultrafast timescales has been a longstanding goal for unravelling detailed information about molecular dynamics. Here we present the direct experimental recording of very-high-resolution and -fidelity molecular movies over more than one-and-a-half periods of the laser-induced rotational dynamics of carbonylsulfide (OCS) molecules. Utilising the combination of single quantum-state selection and an optimised two-pulse sequence to create a tailored rotational wavepacket, an unprecedented degree of field-free alignment, 〈cos2θ2D〉 = 0.96 (〈cos2θ〉 = 0.94) is achieved, exceeding the theoretical limit for single-pulse alignment. The very rich experimentally observed quantum dynamics is fully recovered by the angular probability distribution obtained from solutions of the time-dependent Schrödinger equation with parameters refined against the experiment. The populations and phases of rotational states in the retrieved time-dependent three-dimensional wavepacket rationalises the observed very high degree of alignment.
A plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity
Authors: Ooi Joshua D. , Jiang Jhih-Hang , Eggenhuizen Peter J. , Chua Ling L. , van Timmeren Mirjan , Loh Khai L. , O’Sullivan Kim M. , Gan Poh Y. , Zhong Yong , Tsyganov Kirill , Shochet Lani R. , Ryan Jessica , Stegeman Coen A. , Fugger Lars , Reid Hugh H. , Rossjohn Jamie , Heeringa Peter , Holdsworth Stephen R. , Peleg Anton Y. , Kitching A. Richard
Published: July 2019

Autoreactivity to myeloperoxidase (MPO) causes anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with rapidly progressive glomerulonephritis. Here, we show that a Staphylococcus aureus peptide, homologous to an immunodominant MPO T-cell epitope (MPO409–428), can induce anti-MPO autoimmunity. The peptide (6PGD391–410) is part of a plasmid-encoded 6-phosphogluconate dehydrogenase found in some S. aureus strains. It induces anti-MPO T-cell autoimmunity and MPO-ANCA in mice, whereas related sequences do not. Mice immunized with 6PGD391–410, or with S. aureus containing a plasmid expressing 6PGD391–410, develop glomerulonephritis when MPO is deposited in glomeruli. The peptide induces anti-MPO autoreactivity in the context of three MHC class II allomorphs. Furthermore, we show that 6PGD391–410 is immunogenic in humans, as healthy human and AAV patient sera contain anti-6PGD and anti-6PGD391–410 antibodies. Therefore, our results support the idea that bacterial plasmids might have a function in autoimmune disease.
Photothermal conversion triggered thermal asymmetric catalysis within metal nanoparticles loaded homochiral covalent organic framework
Authors: Ma Hui-Chao , Zhao Chen-Chen , Chen Gong-Jun , Dong Yu-Bin
Published: July 2019

For seeking high enantiopurity, the previously reported thermal asymmetric catalysis is usually carried out at low temperature sometimes with limited yield, that is, the high enantiomeric excess (ee) usually at the cost of high yield. Thus, the achieving both high stereoselectivity and yield is an enormous challenge. We report herein two metal nanoparticle (M NP)-loaded and porphyrin-containing homochiral covalent organic framework (CCOF)-based composite catalysts, and their application in the thermally-driven asymmetric one-pot Henry and A3-coupling reactions. All the reactions are conducted at elevated temperatures with both excellent stereoselectivity and yield which resulted from the synergy of CCOF confinement effect and M NP catalytic activation. Notably, the needed thermal energy for the asymmetric reactions herein is derived from the photothermal conversion via porphyrin-based CCOF upon irradiation with visible light. Remarkably, the CCOF confinement effect can be effectively maintained up to 100 °C for the asymmetric one-pot Henry and A3-coupling reactions herein.
Immunofluorescence can assess the efficacy of mTOR pathway therapeutic agent Everolimus in breast cancer models
Authors: Kuo Chun-Ting , Chen Chen-Lin , Li Chih-Chi , Huang Guan-Syuan , Ma Wei-Yuan , Hsu Wei-Fan , Lin Ching-Hung , Lu Yen-Shen , Wo Andrew M.
Published: July 2019

When breast cancer patients start to exhibit resistance to hormonal therapy or chemotherapy, the mTOR inhibitor everolimus can be considered as an alternative therapeutic agent. Everolimus can deregulate the PI3K/AKT/mTOR pathway and affect a range of cellular functions. In some patients, the agent does not exhibit the desired efficacy and, even worse, not without the associated side effects. This study assessed the use of immunofluorescence (IF) as a modality to fill this unmet need of predicting the efficacy of everolimus prior to administration. Cell viability and MTT assays based on IF intensities of pho-4EBP1 Thr37/46 and pho-S6K1 Ser424 on breast cancer cells (Hs578T, MCF7, BT474, MDA-MB-231) and patient-derived cell culture from metastatic sites (ABC-82T and ABC-16TX1) were interrogated. Results show that independent pho-4EBP1 Thr37/46 and pho-S6K1 Ser424 IF expressions can classify data into different groups: everolimus sensitive and resistant. The combined IF baseline intensity of these proteins is predictive of the efficacy of everolimus, and their intensities change dynamically when cells are resistant to everolimus. Furthermore, mTOR resistance is not only consequence of the AKT/mTOR pathway but also through the LKB1 or MAPK/ERK pathway. The LKB1 and pho-GSK3β may also be potential predictive markers for everolimus.
Enterotype-based Analysis of Gut Microbiota along the Conventional Adenoma-Carcinoma Colorectal Cancer Pathway
Authors: Yang Tzu-Wei , Lee Wei-Hsiang , Tu Siang-Jyun , Huang Wei-Chih , Chen Hui-Mei , Sun Ting-Hsuan , Tsai Ming-Chang , Wang Chi-Chih , Chen Hsuan-Yi , Huang Chi-Chou , Shiu Bei-Hao , Yang Tzu-Ling , Huang Hsin-Tzu , Chou Yu-Pao , Chou Chih-Hung , Huang Ya-Rong , Sun Yi-Run , Liang Chao , Lin Feng-Mao , Ho Shinn-Ying , Chen Wen-Liang , Yang Shun-Fa , Ueng Kwo-Chang , Huang Hsien-Da , Huang Chien-Ning , Jong Yuh-Jyh , Lin Chun-Che
Published: July 2019

The dysbiosis of human gut microbiota is strongly associated with the development of colorectal cancer (CRC). The dysbiotic features of the transition from advanced polyp to early-stage CRC are largely unknown. We performed a 16S rRNA gene sequencing and enterotype-based gut microbiota analysis study. In addition to Bacteroides- and Prevotella-dominated enterotypes, we identified an Escherichia-dominated enterotype. We found that the dysbiotic features of CRC were dissimilar in overall samples and especially Escherichia-dominated enterotype. Besides a higher abundance of Fusobacterium, Enterococcus, and Aeromonas in all CRC faecal microbiota, we found that the most notable characteristic of CRC faecal microbiota was a decreased abundance of potential beneficial butyrate-producing bacteria. Notably, Oscillospira was depleted in the transition from advanced adenoma to stage 0 CRC, whereas Haemophilus was depleted in the transition from stage 0 to early-stage CRC. We further identified 7 different CAGs by analysing bacterial clusters. The abundance of microbiota in cluster 3 significantly increased in the CRC group, whereas that of cluster 5 decreased. The abundance of both cluster 5 and cluster 7 decreased in the Escherichia-dominated enterotype of the CRC group. We present the first enterotype-based faecal microbiota analysis. The gut microbiota of colorectal neoplasms can be influenced by its enterotype.
Heterozygous mutations in valosin-containing protein (VCP) and resistance to VCP inhibitors
Authors: Bastola Prabhakar , Bilkis Rabeya , De Souza Cristabelle , Minn Kay , Chien Jeremy
Published: July 2019

In recent years, multiple studies including ours have reported on the mechanism of resistance towards valosin-containing protein (VCP) inhibitors. While all these studies reported target alterations via mutations in VCP as the primary mechanism of resistance, discrepancies persist to date regarding the zygosity of these mutations responsible for the resistance. In addition, the extent to which resistant cells harbor additional mutations in other genes is not well described. In this study, we performed global transcript analysis of the parental and previously reported VCP inhibitor (CB-5083) resistant cells and found additional mutations in the resistant cells. However, our CRISPR-Cas9 gene editing studies indicate that specific mutations in VCP are sufficient to produce resistance to CB-5083 suggesting the importance of on-target mutations in VCP for resistance. Strikingly, our analysis indicates a preexisting heterozygous frameshift mutation at codon 616 (N616fs*) in one of the VCP alleles in HCT116 cells, and we showed that this mutant allele is subjected to the nonsense-mediated decay (NMD). Accordingly, we identified a heterozygous mutation at codon 526 (L526S) in genomic DNA sequencing but a homozygous L526S mutation in complementary DNA sequencing in our independently generated CB-5083 resistant HCT116 cells, implying that the L526S mutation occurs in the allele that does not harbor the frameshift N616fs* mutation. Our results suggest the NMD as a possible mechanism for achieving the homozygosity of VCP mutant responsible for the resistance to VCP inhibitors while resolving the discrepancies among previous studies. Our results also underscore the importance of performing simultaneous genomic and complementary DNA sequencing when attributing mutational effects on the functionality particularly for an oligomer protein like VCP.
Dual dose-dependent effects of fingolimod in a mouse model of Alzheimer’s disease
Authors: Carreras Isabel , Aytan Nurgul , Choi Ji-Kyung , Tognoni Christina M. , Kowall Neil W. , Jenkins Bruce G. , Dedeoglu Alpaslan
Published: July 2019

Lipid metabolism is abnormal in Alzheimer’s disease (AD) brain leading to ceramide and sphingosine accumulation and reduced levels of brain sphingosine-1-phosphate (S1P). We hypothesize that changes in S1P signaling are central to the inflammatory and immune-pathogenesis of AD and the therapeutic benefits of fingolimod, a structural analog of sphingosine that is FDA approved for the treatment of multiple sclerosis. We recently reported that the neuroprotective effects of fingolimod in 5xFAD transgenic AD mice treated from 1–3 months of age were greater at 1 mg/kg/day than at 5 mg/kg/day. Here we performed a dose-response study using fingolimod from 0.03 to 1 mg/kg/day in 5xFAD mice treated from 1–8 months of age. At 1 mg/kg/day, fingolimod decreased both peripheral blood lymphocyte counts and brain Aβ levels, but at the lowest dose tested (0.03 mg/kg/day), we detected improved memory, decreased activation of brain microglia and astrocytes, and restored hippocampal levels of GABA and glycerophosphocholine with no effect on circulating lymphocyte counts. These findings suggests that, unlike the case in multiple sclerosis, fingolimod may potentially have therapeutic benefits in AD at low doses that do not affect peripheral lymphocyte function.
Elucidating the functional role of Mycobacterium smegmatis recX in stress response
Authors: Prasad Deepika , Arora Divya , Nandicoori Vinay Kumar , Muniyappa K.
Published: July 2019

The RecX protein has attracted considerable interest because therecXmutants exhibit multiple phenotypes associated with RecA functions. To further our understanding of the functional relationship betweenrecAandrecX, the effect of different stress treatments on their expression profiles, cell yield and viability were investigated. A significant correlation was found between the expression ofMycobacterium smegmatis recAandrecXgenes at different stages of growth, and in response to different stress treatments albeitrecXexhibiting lower transcript and protein abundance at the mid-log and stationary phases of the bacterial growth cycle. To ascertain their rolesin vivo, a targeted deletion of therecXandrecArecXwas performed inM.smegmatis. The growth kinetics of these mutant strains and their sensitivity patterns to different stress treatments were assessed relative to the wild-type strain. The deletion ofrecAaffected normal cell growth and survival, whilerecXdeletion showed no significant effect. Interestingly, deletion of bothrecXandrecAgenes results in a phenotype that is intermediate between the phenotypes of theΔrecAmutant and the wild-type strain. Collectively, these results reveal a previously unrecognized role forM.smegmatis recXand support the notion that it may regulate a subset of the yet unknown genes involved in normal cell growth and DNA-damage repair.
ORCA-SPOT: An Automatic Killer Whale Sound Detection Toolkit Using Deep Learning
Authors: Bergler Christian , Schröter Hendrik , Cheng Rachael Xi , Barth Volker , Weber Michael , Nöth Elmar , Hofer Heribert , Maier Andreas
Published: July 2019

Large bioacoustic archives of wild animals are an important source to identify reappearing communication patterns, which can then be related to recurring behavioral patterns to advance the current understanding of intra-specific communication of non-human animals. A main challenge remains that most large-scale bioacoustic archives contain only a small percentage of animal vocalizations and a large amount of environmental noise, which makes it extremely difficult to manually retrieve sufficient vocalizations for further analysis – particularly important for species with advanced social systems and complex vocalizations. In this study deep neural networks were trained on 11,509 killer whale (Orcinus orca) signals and 34,848 noise segments. The resulting toolkit ORCA-SPOT was tested on a large-scale bioacoustic repository – the Orchive – comprising roughly 19,000 hours of killer whale underwater recordings. An automated segmentation of the entire Orchive recordings (about 2.2 years) took approximately 8 days. It achieved a time-based precision or positive-predictive-value (PPV) of 93.2% and an area-under-the-curve (AUC) of 0.9523. This approach enables an automated annotation procedure of large bioacoustics databases to extract killer whale sounds, which are essential for subsequent identification of significant communication patterns. The code will be publicly available in October 2019 to support the application of deep learning to bioaoucstic research. ORCA-SPOT can be adapted to other animal species.
Altered transcriptional regulatory proteins in glioblastoma and YBX1 as a potential regulator of tumor invasion
Authors: Gupta Manoj Kumar , Polisetty Ravindra Varma , Sharma Rakesh , Ganesh Raksha A. , Gowda Harsha , Purohit Aniruddh K. , Ankathi Praveen , Prasad Komal , Mariswamappa Kiran , Lakshmikantha Akhila , Uppin Megha S. , Sundaram Challa , Gautam Poonam , Sirdeshmukh Ravi
Published: July 2019

We have studied differentially regulated nuclear proteome of the clinical tissue specimens of glioblastoma (GBM, WHO Grade IV) and lower grades of gliomas (Grade II and III) using high resolution mass spectrometry- based quantitative proteomics approach. The results showed altered expression of many regulatory proteins from the nucleus such as DNA binding proteins, transcription and post transcriptional processing factors and also included enrichment of nuclear proteins that are targets of granzyme signaling – an immune surveillance pathway. Protein - protein interaction network analysis using integrated proteomics and transcriptomics data of transcription factors and proteins for cell invasion process (drawn from another GBM dataset) revealed YBX1, a ubiquitous RNA and DNA-binding protein and a transcription factor, as a key interactor of major cell invasion-associated proteins from GBM. To verify the regulatory link between them, the co-expression of YBX1 and six of the interacting proteins (EGFR, MAPK1, CD44, SOX2, TNC and MMP13) involved in cell invasion network was examined by immunohistochemistry on tissue micro arrays. Our analysis suggests YBX1 as a potential regulator of these key molecules involved in tumor invasion and thus as a promising target for development of new therapeutic strategies for GBM.
A neural perspective on when and why trait greed comes at the expense of others
Authors: Mussel Patrick , Hewig Johannes
Published: July 2019

Depending on the point of view, conceptions of greed range from being a desirable and inevitable feature of a well-regulated, well-balanced economy to the root of all evil - radix omnium malorum avaritia (Tim 6.10). Regarding the latter, it has been proposed that greedy individuals strive for obtaining desired goods at all costs. Here, we show that trait greed predicts selfish economic decisions that come at the expense of others in a resource dilemma. This effect was amplified when individuals strived for obtaining real money, as compared to points, and when their revenue was at the expense of another person, as compared to a computer. On the neural level, we show that individuals high, compared to low in trait greed showed a characteristic signature in the EEG, a reduced P3 effect to positive, compared to negative feedback, indicating that they may have a lack of sensitivity to adjust behavior according to positive and negative stimuli from the environment. Brain-behavior relations further confirmed this lack of sensitivity to behavior adjustment as a potential underlying neuro-cognitive mechanism which explains selfish and reckless behavior that may come at the expense of others.
High-throughput identification of peptide agonists against GPCRs by co-culture of mammalian reporter cells and peptide-secreting yeast cells using droplet microfluidics
Authors: Yaginuma Kenshi , Aoki Wataru , Miura Natsuko , Ohtani Yuta , Aburaya Shunsuke , Kogawa Masato , Nishikawa Yohei , Hosokawa Masahito , Takeyama Haruko , Ueda Mitsuyoshi
Published: July 2019

Since G-protein coupled receptors (GPCRs) are linked to various diseases, screening of functional ligands against GPCRs is vital for drug discovery. In the present study, we developed a high-throughput functional cell-based assay by combining human culture cells producing a GPCR, yeast cells secreting randomized peptide ligands, and a droplet microfluidic device. We constructed a reporter human cell line that emits fluorescence in response to the activation of human glucagon-like peptide-1 receptor (hGLP1R). We then constructed a yeast library secreting an agonist of hGLP1R or randomized peptide ligands. We demonstrated that high-throughput identification of functional ligands against hGLP1R could be performed by co-culturing the reporter cells and the yeast cells in droplets. We identified functional ligands, one of which had higher activity than that of an original sequence. The result suggests that our system could facilitate the discovery of functional peptide ligands of GPCRs.