bluuebunny/crossref_metadata_2025 huggingface dataset:
Charles Darwin and the scientific mind
Authors: STACK DAVID
Published: January 2019

Although often presented as an essential, ahistorical or innate psychological entity, the notion of a ‘scientific mind’ is ripe for historical analysis. The growing historical interest in the self-fashioning of masculine identities, and more particularly the self-fashioning of the nineteenth-century scientist, has opened up a space in which to probe what was understood by someone being said to possess a ‘scientific mind’. This task is made all the more urgent by the recently revived interest of some psychologists in the concept and the highly gendered and culturally conditioned understanding of the scientific mind displayed in some contemporary debates. This article contributes to that task, and fills a rare gap in Darwin studies by making the first detailed exploration of Charles Darwin's understanding of the scientific mind, as revealed in the psychological self-analysis he undertook in his ‘Recollections of the development of my mind and character’ (1876), and supplemented in hisLife of Erasmus Darwin(1879). Drawing upon a broad range of Darwin's published and unpublished works, this article argues that Darwin's understanding of the scientific mind was rooted in his earliest notebooks, and was far more central to his thought than is usually acknowledged. The article further delineates the differences between Darwin's understanding and that of his half-cousin Francis Galton, situates his understanding in relation to his reading of William Whewell and Auguste Comte, and considers what Darwin's view of the scientific mind tells us about his perspective on questions of religion and gender. Throughout, the article seeks to show that the ‘scientific mind’ is always an agglomeration of historically specific prejudices and presumptions, and concludes that this study of Darwin points to the need for a similarly historical approach to the question of the scientific mind today.
ON NONLOCAL NONLINEAR ELLIPTIC PROBLEMS WITH THE FRACTIONAL LAPLACIAN
Authors: MA LI
Published: January 2019

In this paper, we study the existence of positive solutions to a semilinear nonlocal elliptic problem with the fractional α-Laplacian on Rn, 0 < α < n. We show that the problem has infinitely many positive solutions in $ {C^\tau}({R^n})\bigcap H_{loc}^{\alpha /2}({R^n}) $. Moreover, each of these solutions tends to some positive constant limit at infinity. We can extend our previous result about sub-elliptic problem to the nonlocal problem on Rn. We also show for α ∊ (0, 2) that in some cases, by the use of Hardy’s inequality, there is a nontrivial non-negative $ H_{loc}^{\alpha /2}({R^n}) $ weak solution to the problem
$$ {( - \Delta )^{\alpha /2}}u(x) = K(x){u^p} \quad {\rm{ in}} \ {R^n}, $$
where K(x) = K(|x|) is a non-negative non-increasing continuous radial function in Rn and p > 1.
OPTIMAL ENERGY DISTRIBUTION WITH ENERGY PACKET NETWORKS
Authors: Zhang Yunxiao
Published: January 2019

We use the Energy Packet Network (EPN) to investigate an optimal energy distribution problem for the computer-communication system which is powered by intermittent renewable energy sources. The objective is to find an optimal energy distribution to minimize the proposed cost function which computes penalty costs caused by the overall average response time of jobs and the energy loss. In this EPN system, we consider the energy can be lost through storage leakages, or due to empty workstations which will consume energy even no job needs to be processed. Related numerical examples with different sets of parameter values are presented in the paper to evaluate the system performance and to examine the obtained analytical solution. Then a special case is considered to study the optimal system performance when the total energy harvesting rate is sufficiently large.
High accuracy measurement of gravitational wave back-reaction in the OJ287 black hole binary
Authors: Valtonen Mauri J. , Dey L. , Hudec R. , Zola S. , Gopakumar A. , Mikkola S. , Ciprini S. , Matsumoto K. , Sadakane K. , Kidger M. , Gazeas K. , Nilsson K. , Berdyugin A. , Piirola V. , Jermak H. , Baliyan K.S. , Reichart D. E. , Caton D. B. , Haque S. ,   the OJ287-15/16 Collaboration
Published: January 2019

Blazar OJ287 exhibits large thermal flares at least twice every 12 years. The times of these flares have been predicted successfully using the model of a quasi-Keplerian eccentric black hole binary where the secondary impacts the accretion disk of the primary, creating the thermal flares. New measurements of the historical light curve have been combined with the observations of the 2015 November/December flare to identify the impact record since year 1886, and to constrain the orbit of the binary. The orbital solution shows that the binary period, now 12.062 years, is decreasing at the rate of 36 days per century. This corresponds to an energy loss to gravitational waves that is 6.5 ± 4 % less than the rate predicted by the standard quadrupolar gravitational wave (GW) emission. We show that the difference is due to higher order gravitational radiation reaction terms that include the dominant order tail contributions.
GW170817: Swift UV detection of a blue kilonova, and improving the search in O3
Authors: Tohuvavohu Aaron , Kennea Jamie A. ,   the  gravitational wave follow-up group
Published: January 2019

Swift’s rapid slewing, flexible planning, and multi-wavelength instruments make it the most capable space-based follow-up engine for finding poorly localized sources. During O1 and O2 Swift successfully tiled hundreds of square-degrees of sky in the LVC localization regions, searching for, and identifying, possible X-ray and UV/O transients in the field. Swift made important contributions to the discovery and characterization of the kilonova AT 2017gfo, discovering the UV emission and providing the deepest X-ray upper limits in the first 24 hours after the trigger, strongly constraining the dynamics and geometry of the counterpart. Swift tiled 92% of the galaxy convolved error region down to average X-ray flux sensitivities of 10−12 erg cm−2 s−1, significantly increasing our confidence that AT 2017gfo is indeed the counterpart to GW 170817 and sGRB 170817. However, there remains significant room for improvement of Swift’s follow-up in preparation for O3. This will take the form of both revised observation strategy based on detailed analysis of the results from O2, and significant changes to Swift’s operational capabilities. These improvements are necessary both for maximizing the likelihood that Swift finds a counterpart, and minimizing the impact that follow-up activities have on other Swift science priorities. We outline areas of improvement to the observing strategy itself for optimal tiling of the LVC localization regions. We also discuss ongoing work on operational upgrades that will decrease latency in our response time, and minimize impact on pre-planned observations, while maintaining spacecraft health and safety.
Dating Clinopyroxene Phenocrysts in Submarine Basalts Using 40Ar/39Ar Geochronology
Authors: Konrad Kevin , Koppers Anthony A. P. , Balbas Andrea M. , Miggins Daniel P. , Heaton Daniel E.
Published: January 2019

Dating submarine basalts using 40Ar/39Ar geochronology is often hindered by a lack of potassium‐bearing phenocrystic phases and severe alteration in the groundmass. Clinopyroxene is a common phenocrystic phase in seafloor basalts and is highly resistive to low‐temperature alteration. Here we show that clinopyroxene phenocrysts separated from marine basalts are a viable phase for 40Ar/39Ar incremental heating age determinations. We provide results from a pilot study comprising 16 age experiments from nine clinopyroxene separates, five of which from samples with dated coeval phases. The clinopyroxene ages range from 11.5 to 112 Ma with relatively high uncertainties (ranging from 0.8% to 7.1%; median of 1.9%) compared to more traditional phases. The clinopyroxene age plateaus form at low to moderate temperature steps and are characterized by relatively elevated K/Ca of 0.002–0.4, suggesting that other K‐bearing phases hosted within the clinopyroxene are likely degassing to yield the 40Ar/39Ar age information. There are three possible origins for the K and corresponding 40Ar* including films of trapped melt/nanomineral inclusions along grain defects, secondary melt inclusion bands, or variations in degassing behaviors between lower and higher crystalline Ca pyroxene phases. Regardless of the source of the K, the age determinations are successful with 75% of the experiments producing long plateaus (>60% 39Ar released) with mean square of the weighted deviations ranging from 0.6 to 1.5 and probability of fit values >0.05. We conclude that clinopyroxene dating by the 40Ar/39Ar method has the potential to provide a wealth of information for previously undated, altered seafloor lithologies and continental equivalents.
Understanding the Dynamic Contribution to Future Changes in Tropical Precipitation From Low‐Level Convergence Lines
Authors: Weller Evan , Jakob Christian , Reeder Michael J.
Published: January 2019

Future precipitation changes include contributions from both thermodynamic and dynamic processes. Given that precipitation in the tropics is commonly associated with convergence lines, we construct a simple linear regression model relating the convergence line frequency and strength to precipitation at subdaily time scales, and use it to show that changes in the convergence lines are related to the dynamic change in the precipitation. Given GCM‐predicted convergence line changes, we predict precipitation changes using the regression model. The so‐predicted precipitation change is equivalent to the dynamic component of the precipitation change identified in earlier studies that used very different methods. The difference between the precipitation change in GCMs and that predicted from changes in convergence lines accounts for thermodynamic and other potentially important dynamic contributions. More accurate predictions of future precipitation therefore require the accurate simulations of the relatively short‐lived weather features responsible for convergence lines in the tropics in GCMs.
Soil Moisture Effects on Afternoon Precipitation Occurrence in Current Climate Models
Authors: Moon Heewon , Guillod Benoit P. , Gudmundsson Lukas , Seneviratne Sonia I.
Published: January 2019

Soil moisture‐precipitation feedbacks in a large ensemble of global climate model simulations are evaluated. A set of three metrics are used to assess the sensitivity of afternoon rainfall occurrence to morning soil moisture in terms of their spatial, temporal, and heterogeneity characteristics. Positive (negative) spatial feedback indicates that the afternoon rainfall occurs more frequently over wetter (drier) land surface than its surroundings. Positive (negative) temporal feedback indicates preference over temporally wetter (drier) conditions, and positive (negative) heterogeneity feedback indicates preference over more spatially heterogeneous (homogeneous) soil moisture conditions. We confirm previous results highlighting a dominantly positive spatial feedback in the models as opposed to observations. On average, models tend to agree better with observations for temporal and heterogeneity feedback characteristics, although intermodel variability is largest for these metrics. The collective influence of the three feedbacks suggests that they may lead to more localized precipitation persistence in models than in observations.
Recent Acceleration of Arabian Sea Warming Induced by the Atlantic‐Western Pacific Trans‐basin Multidecadal Variability
Authors: Sun Cheng , Li Jianping , Kucharski Fred , Kang In‐Sik , Jin Fei‐Fei , Wang Kaicun , Wang Chunzai , Ding Ruiqiang , Xie Fei
Published: January 2019

Arabian Sea (AS) warming has been significantly accelerated since the 1990s, in particular in the spring season. Here we link the AS warming changes to the Atlantic multidecadal oscillation (AMO). A set of Atlantic pacemaker experiments with a slab mixed‐layer ocean model successfully reproduces the AS spring multidecadal variability and its connection with the AMO. An atmospheric teleconnection from the Atlantic to the AS in the preceding winter and associated thermodynamic air‐sea feedback is found to be important. The teleconnection can be reestablished by the atmospheric model when the AMO sea surface temperature (SST) and its trans‐basin footprint over the western Pacific are prescribed simultaneously. The western Pacific SST warming associated with the AMO positive phase induces a Gill‐type Rossby wave over the AS, showing anomalously low pressures and converging southerlies that weaken winter northerlies. Thus, the wind‐evaporation‐SST feedback results in and maintains the AS warm SST anomalies to the subsequent spring.
Weakening of Upward Mass but Intensification of Upward Energy Transport in a Warming Climate
Authors: Wu Yutian , Lu Jian , Pauluis Olivier
Published: January 2019

How the atmospheric overturning circulation is projected to change is important for understanding changes in mass and energy budget. This study analyzes the overturning circulation by sorting the upward mass transport in terms of the moist static energy (MSE) of air parcels in an ensemble of coupled climate models. It is found that, in response to greenhouse gas increases, the upward transport of MSE increases in order to balance the increase in radiative cooling of the mass transport. At the same time, the overall mass transport decreases. The increase in energy transport and decrease in mass transport can be explained by the fact that the MSE of rising air parcels increases more rapidly than that of subsiding air, thus allowing for a weaker overturning circulation to transport more energy.
Universal Relationship Between Viscous and Inertial Permeability of Geologic Porous Media
Authors: Zhou Jia‐Qing , Chen Yi‐Feng , Wang Lichun , Cardenas M. Bayani
Published: January 2019

Fluid flow through geologic porous media is represented by Darcy's law and its inertial and nonlinear extension, the Forchheimer equation. These relationships equate the product of the driving potential gradient and phenomenological coefficients representing momentum resistance and dissipation to flux. From decades of research, the coefficient of viscous permeability (kv) in Darcy's law is largely predictable, but this is not the case for the coefficient of inertial permeability (ki) in the Forchheimer equation. Synthesizing results from thousands of laboratory and field flow tests and pore‐scale flow model results, we show that ki can be predicted from kv via the equation ki = 1010kv3/2 across 12 and 20 orders of magnitude in kv and ki, respectively. Since it is related with ki, kv is thus sufficient for predicting flow across viscous to inertial regimes for most geologic porous media.
Numerical Simulation of the Landslide and Tsunami Due to the 1741 Oshima‐Oshima Eruption in Hokkaido, Japan
Authors: Ioki Kei , Tanioka Yuichiro , Yanagisawa Hideaki , Kawakami Gentaro
Published: January 2019

Sector collapse during the 1741 eruption of Oshima‐Oshima volcano (southwestern Hokkaido, Japan) generated a large tsunami in the Japan Sea. The tsunami caused severe damage along the Oshima (Hokkaido) and Tsugaru (Honshu) peninsulas. Tsunami deposits due to the 1741 event were identified along the Okushiri and Hiyama coast in Hokkaido. In this study, we numerically simulated the landslide and tsunami generated by the 1741 Oshima‐Oshima eruption using an improved two‐layer model to explain the depositional area of the landslide, the tsunami heights written in historical records, and the distributions of tsunami deposits. Areas of erosion and deposition by the 1741 landslide were estimated from the bathymetric data on the northern slope of Oshima‐Oshima volcano. In addition, previous topography before the sector collapse was restored. From the bathymetry difference before and after the landslide, the volume of collapsed material was estimated at 2.2 km3. Based on those data, the landslide and tsunami were numerically simulated by solving equations of an improved two‐layer model that incorporates Manning's formula in the bottom friction terms of the lower layer. An apparent friction angle of 2.5 and a Manning's roughness coefficient of 0.15 were selected to explain the area of deposition estimated from the bathymetry analysis and distributions of tsunami deposits. The thickness distribution of the computed landslide mass fits relatively well with the depositional area. Computed tsunami heights match those from historical records along the Hiyama coast. Computed tsunami inundation areas cover most of the distributions of tsunami deposits identified along the coasts.
Microseismicity on Patches of Higher Compression During Larger‐Scale Earthquake Nucleation in a Rate‐and‐State Fault Model
Authors: Schaal Natalie , Lapusta Nadia
Published: January 2019

While many large earthquakes are preceded by observable foreshocks, the mechanism responsible for the occurrence of these smaller‐scale seismic events remains uncertain. One physical explanation of foreshocks with growing support is that they are produced by the interaction of slow slip with fault heterogeneity. Inspired by the suggestion from laboratory experiments that foreshocks occur on fault asperities (bumps), we explore rate‐and‐state fault models with patches of higher normal stress embedded in a larger seismogenic region by conducting 3‐D numerical simulations of their behavior over long‐term sequences of aseismic and seismic slips. The models do produce smaller‐scale seismicity during the aseismic nucleation of larger‐scale seismic events. These smaller‐scale events have reasonable stress drops, despite the highly elevated compression assigned to the source patches. We find that the two main factors contributing to the reasonable stress drops are the significant extent of the rupture into the region surrounding the patches and the aseismic stress release just prior to the seismic events. The smaller‐scale seismicity can only occur if a sufficient separation in nucleation scales between the foreshock‐like events and mainshocks is achieved. Our modeling provides insight into the conditions conducive for generating foreshocks on both natural and laboratory faults.
Exploring Aerosols Near Clouds With High‐Spatial‐Resolution Aircraft Remote Sensing During SEAC4RS
Authors: Spencer Robert S. , Levy Robert C. , Remer Lorraine A. , Mattoo Shana , Arnold George T. , Hlavka Dennis L. , Meyer Kerry G. , Marshak Alexander , Wilcox Eric M. , Platnick Steven E.
Published: January 2019

Since aerosols are important to our climate system, we seek to observe the variability of aerosol properties within cloud systems. When applied to the satellite‐borne Moderate‐resolution Imaging Spectroradiometer (MODIS), the Dark Target retrieval algorithm provides global aerosol optical depth (AOD; at 0.55 μm) in cloud‐free scenes. Since MODIS' resolution (500‐m pixels, 3‐ or 10‐km product) is too coarse for studying near‐cloud aerosol, we ported the Dark Target algorithm to the high‐resolution (~50‐m pixels) enhanced‐MODIS Airborne Simulator (eMAS), which flew on the high‐altitude ER‐2 during the Studies of Emissions, Atmospheric Composition, Clouds, and Climate Coupling by Regional Surveys Airborne Science Campaign over the United States in 2013. We find that even with aggressive cloud screening, the ~0.5‐km eMAS retrievals show enhanced AOD, especially within 6 km of a detected cloud. To determine the cause of the enhanced AOD, we analyze additional eMAS products (cloud retrievals and degraded‐resolution AOD), coregistered Cloud Physics Lidar profiles, MODIS aerosol retrievals, and ground‐based Aerosol Robotic Network observations. We also define spatial metrics to indicate local cloud distributions near each retrieval and then separate into near‐cloud and far‐from‐cloud environments. The comparisons show that low cloud masking is robust, and unscreened thin cirrus would have only a small impact on retrieved AOD. Some of the enhancement is consistent with clear‐cloud transition zone microphysics such as aerosol swelling. However, 3‐D radiation interaction between clouds and the surrounding clear air appears to be the primary cause of the high AOD near clouds.
New Insights on the Impact of Ozone‐Depleting Substances on the Brewer‐Dobson Circulation
Authors: Abalos Marta , Polvani Lorenzo , Calvo Natalia , Kinnison Douglas , Ploeger Felix , Randel William , Solomon Susan
Published: January 2019

It has recently been recognized that, in addition to greenhouse gases, anthropogenic emissions of ozone‐depleting substances (ODS) can induce long‐term trends in the Brewer‐Dobson circulation (BDC). Several studies have shown that a substantial fraction of the residual circulation acceleration over the last decades of the twentieth century can be attributed to increasing ODS. Here the mechanisms of this influence are examined, comparing model runs to reanalysis data and evaluating separately the residual circulation and mixing contributions to the mean age of air trends. The effects of ozone depletion in the Antarctic lower stratosphere are found to dominate the ODS impact on the BDC, while the direct radiative impact of these substances is negligible over the period of study. We find qualitative agreement in austral summer BDC trends between model and reanalysis data and show that ODS are the main driver of both residual circulation and isentropic mixing trends over the last decades of the twentieth century. Moreover, aging by isentropic mixing is shown to play a key role on ODS‐driven age of air trends.
Dependence of Vertical Alignment of Cloud and Precipitation Properties on Their Effective Fall Speeds
Authors: Ovchinnikov Mikhail , Giangrande Scott , Larson Vincent E. , Protat Alain , Williams Christopher R.
Published: January 2019

The vertical structure of clouds unresolved in large‐scale weather prediction and climate models is controlled by an overlap assumption. When a binary representation (cloud or no cloud) of subgrid horizontal variability is replaced by a probability density function (PDF) treatment of cloud‐related variables, a cloud occurrence overlap needs to be replaced by a PDF overlap. The PDF overlap can be quantified by a correlation length scale, z0, indicating how rapidly rank correlation of distributions at two levels diminishes with increasing level separation. In this study, we show that z0 varies widely for different properties (e.g., number and mass mixing ratios) and different hydrometeor types (cloud liquid and ice, rain, snow, and graupel) and that corresponding fall speed, Vf, is the primary factor controlling the degree of their vertical alignment, with vertical shear of the horizontal wind playing a smaller role. Linear and power law parametric relationships between z0 and Vf are derived using cloud‐resolving simulations of convection under midlatitude continental and tropical oceanic conditions, as well as observations from vertically pointing dual‐frequency radar profilers near Darwin, Australia. The functional form of z0‐Vf relationship is further examined using simple conceptual models that link variability in horizontal and vertical directions and provide insights into the role of Vf and wind shear. Being based on a physical property (i.e., fall speed) of hydrometeors rather than artificially defined and model‐specific hydrometeor types, the proposed parameterization of vertical PDF overlap can be applied to a wide range of microphysics treatments in regional and global models.
The Dependence of Radius on Relative Humidity and Solute Mass at High Relative Humidities Up to and Including 100%
Authors: Lewis Ernie R.
Published: January 2019

This manuscript presents a rigorous examination of the equilibrium radius ratio of hygroscopic aerosol particles that are solution drops of ideal and actual inorganic solutes for a range of solute masses in the relative humidity range 99–100%. Analysis is presented first for ideal solutes over a range of solute masses for different hygroscopicities, providing a theoretical framework for the subsequent analysis of actual solutes. Dimensionless quantities are used to reduce the Köhler equation to one with no free parameters and an approximate solution is presented. Next analysis is presented for three common inorganic solutes of atmospheric importance: sodium chloride, ammonium sulfate, and sulfuric acid, with a range of solute masses considered for each substance. The extent to which nonideality is important for these solutes over the ranges of relative humidities and solute masses considered is examined. A simple but accurate single‐parameter expression is presented for the equilibrium radius ratio as a function of relative humidity that contains the dependences on solute mass and composition for these solutes. The accuracy of this expression is quantified and factors that limit this accuracy are discussed. The expression is accurate to within 5% over most of the range of mass‐equivalent dry radii from 10 to 250 nm and relative humidities from below 99 up to 100%, over which the equilibrium radius ratio varies by more than a factor of 5, and it remains finite at 100% relative humidity. Finally, measurements of hygroscopic growth of aerosol particles in this relative humidity range are discussed.
Dynamics of Flow at Concordant Gravel Bed River Confluences: Effects of Junction Angle and Momentum Flux Ratio
Authors: Sukhodolov Alexander N. , Sukhodolova Tatiana A.
Published: January 2019

Although the dynamics of secondary flow at river confluences have received considerable attention, a lack of theoretical insight in exploratory field and experimental research has led to different conclusions about the mechanisms driving these dynamics. This study revisits the problem of secondary flow at confluences by examining responses of the flow to controllable variations in curvature of flow trajectories in a series of field‐based experiments. The experiments were performed in a physical model designed to eliminate the influence of bed morphology, while using a large width‐to‐depth ratio to enable proper identification of flow structures at different scales. The results show that no secondary flow is detectable in runs with parallel merging flows irrespective of the momentum ratio. In runs with converging channels the secondary flow is represented by large‐scale motions consisting either of a pair of counterrotating helixes or a single helix depending on the momentum ratio. Comparison of scaled measured and theoretically predicted vertical profiles of lateral velocity shows that the helical secondary flow is primarily driven by the curvature of flow trajectories. This study also indicates that small‐scale secondary motions that have the same sense of rotation as the large‐scale helixes may develop in the immediate margins of the mixing interface. Differing only slightly from the flow depth in size, they are manifested by local upwelling within the large‐scale secondary motions. Several reasons to believe that interactions of large‐scale motions with opposing sense of rotation drive these small‐scale secondary flow cells are discussed in the paper.
Stochastic Dynamics of Lagrangian Pore‐Scale Velocities in Three‐Dimensional Porous Media
Authors: Puyguiraud Alexandre , Gouze Philippe , Dentz Marco
Published: January 2019

Upscaling dispersion, mixing, and reaction processes from the pore to the Darcy scale is directly related to the understanding of the dynamics of pore‐scale particle velocities, which are at the origin of hydrodynamic dispersion and non‐Fickian transport behaviors. With the aim of deriving a framework for the systematic upscaling of these processes from the pore to the Darcy scale, we present a detailed analysis of the evolution of Lagrangian and Eulerian statistics and their dependence on the injection condition. The study is based on velocity data obtained from computational fluid dynamics simulations of Stokes flow and advective particle tracking in the three‐dimensional pore structure obtained from high‐resolution X‐ray microtomography of a Berea sandstone sample. While isochronously sampled velocity series show intermittent behavior, equidistant series vary in a regular random pattern. Both statistics evolve toward stationary states, which are related to the Eulerian velocity statistics. The equidistantly sampled Lagrangian velocity distribution converges on only a few pore lengths. These findings indicate that the equidistant velocity series can be represented by an ergodic Markov process. A stochastic Markov model for the equidistant velocity magnitude captures the evolution of the Lagrangian velocity statistics. The model is parameterized by the Eulerian velocity distribution and a relaxation length scale, which can be related to hydraulic properties and the medium geometry. These findings lay the basis for a predictive stochastic approach to upscale solute dispersion in complex porous media from the pore to the Darcy scale.
Stress dynamically regulates co-expression networks of glucocorticoid receptor-dependent MDD and SCZ risk genes
Authors: Zimmermann Christoph A. , Arloth Janine , Santarelli Sara , Löschner Anne , Weber Peter , Schmidt Mathias V. , Spengler Dietmar , Binder Elisabeth B.
Published: January 2019

Early-life adversity is an important risk factor for major depressive disorder (MDD) and schizophrenia (SCZ) that interacts with genetic factors to confer disease risk through mechanisms that are still insufficiently understood. One downstream effect of early-life adversity is the activation of glucocorticoid receptor (GR)-dependent gene networks that drive acute and long-term adaptive behavioral and cellular responses to stress. We have previously shown that genetic variants that moderate GR-induced gene transcription (GR-response eSNPs) are significantly enriched among risk variants from genome-wide association studies (GWASs) for MDD and SCZ. Here, we show that the 63 transcripts regulated by these disease-associated functional genetic variants form a tight glucocorticoid-responsive co-expression network (termed GCN). We hypothesized that changes in the correlation structure of this GCN may contribute to early-life adversity-associated disease risk. Therefore, we analyzed the effects of different qualities of social support and stress throughout life on GCN formation across distinct brain regions using a translational mouse model. We observed that different qualities of social experience substantially affect GCN structure in a highly brain region-specific manner. GCN changes were predominantly found in two functionally interconnected regions, the ventral hippocampus and the hypothalamus, two brain regions previously shown to be of relevance for the stress response, as well as psychiatric disorders. Overall, our results support the hypothesis that a subset of genetic variants may contribute to risk for MDD and SCZ by altering circuit-level effects of early and adult social experiences on GCN formation and structure.
Peripheral and central levels of kynurenic acid in bipolar disorder subjects and healthy controls
Authors: Sellgren Carl M. , Gracias Jessica , Jungholm Oscar , Perlis Roy H. , Engberg Göran , Schwieler Lilly , Landen Mikael , Erhardt Sophie
Published: January 2019

Metabolites of the kynurenine pathway of tryptophan degradation, in particular, the N-Methyl-d-aspartic acid receptor antagonist kynurenic acid (KYNA), are increasingly recognized as primary pathophysiological promoters in several psychiatric diseases. Studies analyzing central KYNA levels from subjects with psychotic disorders have reported increased levels. However, sample sizes are limited and in contrast many larger studies examining this compound in blood from psychotic patients commonly report a decrease. A major question is to what extent peripheral KYNA levels reflect brain KYNA levels under physiological as well as pathophysiological conditions. Here we measured KYNA in plasma from a total of 277 subjects with detailed phenotypic data, including 163 BD subjects and 114 matched healthy controls (HCs), using an HPLC system. Among them, 94 BD subjects and 113 HCs also had CSF KYNA concentrations analyzed. We observe a selective increase of CSF KYNA in BD subjects with previous psychotic episodes although this group did not display altered plasma KYNA levels. In contrast, BD subjects with ongoing depressive symptoms displayed a tendency to decreased plasma KYNA concentrations but unchanged CSF KYNA levels. Sex and age displayed specific effects on KYNA concentrations depending on if measured centrally or in the periphery. These findings implicate brain-specific regulation of KYNA under physiological as well as under pathophysiological conditions and strengthen our previous observation of CSF KYNA as a biomarker in BD. In summary, biomarker and drug discovery studies should include central KYNA measurements for a more reliable estimation of brain KYNA levels.
S-nitrosylation of E3 ubiquitin-protein ligase RNF213 alters non-canonical Wnt/Ca+2 signaling in the P301S mouse model of tauopathy
Authors: Amal Haitham , Gong Guanyu , Gjoneska Elizabeta , Lewis Sarah M. , Wishnok John S. , Tsai Li-Huei , Tannenbaum Steven R.
Published: January 2019

Mutations in the MAPT gene, which encodes the tau protein, are associated with several neurodegenerative diseases, including frontotemporal dementia (FTD), dementia with epilepsy, and other types of dementia. The missense mutation in the Mapt gene in the P301S mouse model of FTD results in impaired synaptic function and microgliosis at three months of age, which are the earliest manifestations of disease. Here, we examined changes in the S-nitrosoproteome in 2-month-old transgenic P301S mice in order to detect molecular events corresponding to early stages of disease progression. S-nitrosylated (SNO) proteins were identified in two brain regions, cortex and hippocampus, in P301S and Wild Type (WT) littermate control mice. We found major changes in the S-nitrosoproteome between the groups in both regions. Several pathways converged to show that calcium regulation and non-canonical Wnt signaling are affected using GO and pathway analysis. Significant increase in 3-nitrotyrosine was found in the CA1 and entorhinal cortex regions, which indicates an elevation of oxidative stress and nitric oxide formation. There was evidence of increased Non-Canonical Wnt/Ca++ (NC-WCa) signaling in the cortex of the P301S mice; including increases in phosphorylated CaMKII, and S-nitrosylation of E3 ubiquitin-protein ligase RNF213 (RNF-213) leading to increased levels of nuclear factor of activated T-cells 1 (NFAT-1) and FILAMIN-A, which further amplify the NC-WCa and contribute to the pathology. These findings implicate activation of the NC-WCa pathway in tauopathy and provide novel insights into the contribution of S-nitrosylation to NC-WCa activation, and offer new potential drug targets for treatment of tauopathies.
Altered composition and function of intestinal microbiota in autism spectrum disorders: a systematic review
Authors: Liu Feitong , Li Jie , Wu Fan , Zheng Huimin , Peng Qiongling , Zhou Hongwei
Published: January 2019

At present, the pathophysiology of autism spectrum disorder (ASD) remains unclear. Increasing evidence suggested that gut microbiota plays a critical role in gastrointestinal symptoms and behavioral impairment in ASD patients. The primary aim of this systematic review is to investigate potential evidence for the characteristic dysbiosis of gut microbiota in ASD patients compared with healthy controls (HCs). The MEDLINE, EMBASE, Web of Science and Scopus were systematically searched before March 2018. Human studies that compared the composition of gut microbiota in ASD patients and HCs using culture-independent techniques were included. Independent data extraction and quality assessment of studies were conducted according to PRISMA statement and Newcastle-Ottawa Scale. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to infer biological functional changes of the shifted microbiota with the available data in four studies. Sixteen studies with a total sample size of 381 ASD patients and 283 HCs were included in this systematic review. The quality of the studies was evaluated as medium to high. The overall changing of gut bacterial community in terms of β-diversity was consistently observed in ASD patients compared with HCs. Furthermore, Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter were consistently decreased, while Lactobacillus, Bacteroides, Desulfovibrio, and Clostridium were increased in patients with ASD relative to HCs in certain studies. This systematic review demonstrated significant alterations of gut microbiota in ASD patients compared with HCs, strengthen the evidence that dysbiosis of gut microbiota may correlate with behavioral abnormality in ASD patients. However, results of inconsistent changing also existed and further big-sampled well-designed studies are needed. Generally, as a potential mediator of risk factors, the gut microbiota could be a novel target for ASD patients in the future.
Characterization of sulfur-compound metabolism underlying wax-ester fermentation in Euglena gracilis
Authors: Yamada Koji , Nitta Tomoaki , Atsuji Kohei , Shiroyama Maeka , Inoue Komaki , Higuchi Chieko , Nitta Nobuko , Oshiro Satoshi , Mochida Keiichi , Iwata Osamu , Ohtsu Iwao , Suzuki Kengo
Published: January 2019

Euglena gracilis is a microalga, which has been used as a model organism for decades. Recent technological advances have enabled mass cultivation of this species for industrial applications such as feedstock in nutritional foods and cosmetics. E. gracilis degrades its storage polysaccharide (paramylon) under hypoxic conditions for energy acquisition by an oxygen-independent process and accumulates high amount of wax-ester as a by-product. Using this sequence of reactions referred to as wax-ester fermentation, E. gracilis is studied for its application in biofuel production. Although the wax-ester production pathway is well characterized, little is known regarding the biochemical reactions underlying the main metabolic route, especially, the existence of an unknown sulfur-compound metabolism implied by the nasty odor generation accompanying the wax-ester fermentation. In this study, we show sulfur-metabolomics of E. gracilis in aerobic and hypoxic conditions, to reveal the biochemical reactions that occur during wax-ester synthesis. Our results helped us in identifying hydrogen sulfide (H2S) as the nasty odor-producing component in wax-ester fermentation. In addition, the results indicate that glutathione and protein degrades during hypoxia, whereas cysteine, methionine, and their metabolites increase in the cells. This indicates that this shift of abundance in sulfur compounds is the cause of H2S synthesis.
Diverse metabolic reactions activated during 58-hr fasting are revealed by non-targeted metabolomic analysis of human blood
Authors: Teruya Takayuki , Chaleckis Romanas , Takada Junko , Yanagida Mitsuhiro , Kondoh Hiroshi
Published: January 2019

During human fasting, metabolic markers, including butyrates, carnitines, and branched-chain amino acids, are upregulated for energy substitution through gluconeogenesis and use of stored lipids. We performed non-targeted, accurate semiquantitative metabolomic analysis of human whole blood, plasma, and red blood cells during 34–58 hr fasting of four volunteers. During this period, 44 of ~130 metabolites increased 1.5~60-fold. Consistently fourteen were previously reported. However, we identified another 30 elevated metabolites, implicating hitherto unrecognized metabolic mechanisms induced by fasting. Metabolites in pentose phosphate pathway are abundant, probably due to demand for antioxidants, NADPH, gluconeogenesis and anabolic metabolism. Global increases of TCA cycle-related compounds reflect enhanced mitochondrial activity in tissues during fasting. Enhanced purine/pyrimidine metabolites support RNA/protein synthesis and transcriptional reprogramming, which is promoted also by some fasting-related metabolites, possibly via epigenetic modulations. Thus diverse, pronounced metabolite increases result from greatly activated catabolism and anabolism stimulated by fasting. Anti-oxidation may be a principal response to fasting.
Caspase-4 disaggregates lipopolysaccharide micelles via LPS-CARD interaction
Authors: An Jinsu , Kim Seong Ho , Hwang Dohyeon , Lee Kyung Eun , Kim Min Jung , Yang Eun Gyeong , Kim So Yeon , Chung Hak Suk
Published: January 2019

Lipopolysaccharides (LPS) are a major component of the outer membrane of Gram-negative bacteria and are pathogen-associated molecular patterns recognized by the TLR4/MD2 complex that induces an inflammatory response. Recently, the cytosolic receptors caspase-4/-5/-11 that bind LPS inside the cell and trigger inflammasome activation or pyroptosis, have been identified. Despite the important roles of caspase-4 in human immune responses, few studies have investigated its biochemical characteristics and interactions with LPS. Since caspase-4 (C258A) purified from an Escherichia coli host forms aggregates, monomeric proteins including full-length caspase-4, caspase-4 (C258A), and the CARD domain of caspase-4 have been purified from the insect cell system. Here, we report the overexpression and purification of monomeric caspase-4 (C258A) and CARD domain from E. coli and demonstrate that purified caspase-4 (C258A) and CARD domain bind large LPS micelles and disaggregate them to small complexes. As the molar ratio of caspase-4 to LPS increases, the size of the caspase-4/LPS complex decreases. Our results present a new function of caspase-4 and set the stage for structural and biochemical studies, and drug discovery targeting LPS/caspase-4 interactions by establishing a facile purification method to obtain large quantities of purified caspase-4 (C258A) and the CARD domain.
Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling
Authors: Bartoli-Leonard F. , Wilkinson F. L. , Schiro A. , Inglott F. Serracino , Alexander M. Y. , Weston R.
Published: January 2019

Vascular calcification is associated with significant morbidity and mortality within diabetes, involving activation of osteogenic regulators and transcription factors. Recent evidence demonstrates the beneficial role of Sirtuin 1 (SIRT1), an NAD+ dependant deacetylase, in improved insulin sensitivity and glucose homeostasis, linking hyperglycaemia and SIRT1 downregulation. This study aimed to determine the role of SIRT1 in vascular smooth muscle cell (vSMC) calcification within the diabetic environment. An 80% reduction in SIRT1 levels was observed in patients with diabetes, both in serum and the arterial smooth muscle layer, whilst both RUNX2 and Osteocalcin levels were elevated. Human vSMCs exposed to hyperglycaemic conditions in vitro demonstrated enhanced calcification, which was positively associated with the induction of cellular senescence, verified by senescence-associated β-galactosidase activity and cell cycle markers p16 and p21. Activation of SIRT1 by SRT1720 reduced Alizarin red staining by a third, via inhibition of the RUNX2 pathway and prevention of senescence. Conversely, inhibition of SIRT1 via Sirtinol and siRNA increased RUNX2 by over 50%. These findings demonstrate the key role that SIRT1 plays in preventing calcification in a diabetic environment, through the inhibition of RUNX2 and senescence pathways, suggesting a downregulation of SIRT1 may be responsible for perpetuating vascular calcification in diabetes.
Dinoflagellate nucleus contains an extensive endomembrane network, the nuclear net
Authors: Gavelis Gregory S. , Herranz Maria , Wakeman Kevin C. , Ripken Christina , Mitarai Satoshi , Gile Gillian H. , Keeling Patrick J. , Leander Brian S.
Published: January 2019

Dinoflagellates are some of the most common eukaryotic cells in the ocean, but have very unusual nuclei. Many exhibit a form of closed mitosis (dinomitosis) wherein the nuclear envelope (NE) invaginates to form one or more trans-nuclear tunnels. Rather than contact spindles directly, the chromatids then bind to membrane-based kinetochores on the NE. To better understand these unique mitotic features, we reconstructed the nuclear architecture of Polykrikos kofoidii in 3D using focused ion beam scanning electron microscopy (FIB-SEM) in conjunction with high-pressure freezing, freeze-substitution, TEM, and confocal microscopy. We found that P. kofoidii possessed six nuclear tunnels, which were continuous with a reticulating network of membranes that has thus far gone unnoticed. These membranous extensions interconnect the six tunnels while ramifying throughout the nucleus to form a “nuclear net.” To our knowledge, the nuclear net is the most elaborate endomembrane structure described within a nucleus. Our findings demonstrate the utility of tomographic approaches for detecting 3D membrane networks and show that nuclear complexity has been underestimated in Polykrikos kofoidii and, potentially, in other dinoflagellates.
Evaluation of the effects on the QT-interval of 4 artemisinin-based combination therapies with a correction-free and heart rate-free method
Authors: Funck-Brentano Christian , Ouologuem Nouhoum , Duparc Stephan , Felices Mathieu , Sirima Sodiomon B. , Sagara Issaka , Soulama Issiaka , Ouedraogo Jean-Bosco , Beavogui Abdoul H. , Borghini-Fuhrer Isabelle , Khan Yasmin , Djimdé Abdoulaye A. , Voiriot Pascal
Published: January 2019

Several antimalarial drugs are known to prolong ventricular repolarization as evidenced by QT/QTc interval prolongation. This can lead to Torsades de Pointes, a potentially lethal ventricular arrhythmia. Whether this is the case with artemisinin-based combination therapies (ACTs) remains uncertain. Assessment of the extent of QTc prolongation with antimalarials is hampered by important variations of heart rate during malaria crises and previous studies have reported highly variable values of QTc prolongations with ACTs. We assessed QTc prolongation with four ACTs, using high quality ECG recording and measurement techniques, during the first episode of malaria in 2,091 African patients enrolled in the WANECAM study which also monitored clinical safety. Using an original and robust method of QTc assessment, independent from heart rate changes and from the method of QT correction, we were able to accurately assess the extent of mean maximum QTc prolongation with the four ACTs tested. There was no evidence of proarrhythmia with any treatment during the study although dihydroartemisinin-piperaquine, artesunate-amodiaquine and artemether-lumefantrine significantly prolonged QTc. The extent of prolongation of ventricular repolarization can be accurately assessed in studies where heart rate changes impede QTc assessment.