bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr)
Authors: Ramirez Aguilar Laura , Acosta‐Uribe Juliana , Giraldo Margarita M. , Moreno Sonia , Baena Ana , Alzate Diana , Cuastumal Rosario , Aguillón David , Madrigal Lucía , Saldarriaga Amanda , Navarro Alexander , Garcia Gloria P. , Aguirre‐Acevedo Daniel C. , Geier Ethan G. , Cochran J. Nicholas , Quiroz Yakeel T. , Myers Richard M. , Yokoyama Jennifer S. , Kosik Kenneth S. , Lopera Francisco
Published: February 2019

Introduction

A small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1.

Methods

We performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole‐genome sequencing.

Results

Genetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03).

Discussion

Ile416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a “mini‐population bottleneck” and subsequent emergence of a rare dominant mutation.
Viscoplastic water entry
Authors: Jalaal Maziyar , Kemper Dave , Lohse Detlef
Published: February 2019

The impact of viscoplastic droplets on a free surface of water is studied. The droplet undergoes an elasto-plastic deformation at the early stages of water entry. At large time, the yield stress dominates; therefore, the droplet solidifies and reaches an equilibrium shape. Depending on the impact velocity and the rheology of the droplet, the final morphologies vary from pear-shaped to capsules that contain bubbles. We perform an analysis of the orders of magnitude of the forces and introduce the relevant dimensionless groups. Furthermore, we categorize the final shapes in a phase diagram and analyse their geometrical properties. The process presents a method of making non-spherical beads and capsules with tunable shapes and provides information on the general problem of the impact of highly deformable objects on a liquid surface.
The cell-free layer in simulated microvascular networks
Authors: Balogh Peter , Bagchi Prosenjit
Published: February 2019

In the microcirculation, a plasma layer forms near the vessel walls that is free of red blood cells (RBCs). This region, often termed as the cell-free layer (CFL), plays important haemorheological and biophysical roles, and has been the subject of extensive research. Many previous studies have considered the CFL development in single, isolated vessels that are straight tubes or channels, as well as in isolated bifurcations and mergers. In the body, blood vessels are typically winding and sequentially bifurcate into smaller vessels or merge to form larger vessels. Because of this geometric complexity, the CFL in vivo is three-dimensional (3D) and asymmetric, unlike in fully developed flow in straight tubes. The three-dimensionality of the CFL as it develops in a vascular network, and the underlying hydrodynamic mechanisms, are not well understood. Using a high-fidelity model of cellular-scale blood flow in microvascular networks with in vivo-like topologies, we present a detailed analysis of the fully 3D and asymmetric nature of the CFL in such networks. We show that the CFL significantly varies over different aspects of the networks. Along the vessel lengths, such variations are predominantly non-monotonic, which indicates that the CFL profiles do not simply become more symmetric over the length as they would in straight vessels. We show that vessel tortuosity causes the CFL to become more asymmetric along the length. We specifically identify a curvature-induced migration of the RBCs as the underlying mechanism of increased asymmetry in curved vessels. The vascular bifurcations and mergers are also seen to change the CFL profiles, and in the majority of them the CFL becomes more asymmetric. For most bifurcations, this is generally observed to occur such that the CFL downstream narrows on the side of the vessel nearest the upstream bifurcation, and widens on the other side. The 3D aspects of such behaviour are elucidated. For many bifurcations, a discrepancy exists between the CFL in the daughter vessels, which arises from a disproportionate partitioning between the flow rate and RBC flux. For most mergers, the downstream CFL narrows in the plane of the merger, but widens away from this plane. The dominant mechanism by which such changes occur is identified as the geometric focusing of the two merging streams. To our knowledge, this work provides the first simulation-based analysis of the 3D CFL structure in complex in vivo-like microvascular networks, including the hydrodynamic origins of the observed behaviour.
Upstream vortex and elastic wave in the viscoelastic flow around a confined cylinder
Authors: Qin Boyang , Salipante Paul F. , Hudson Steven D. , Arratia Paulo E.
Published: February 2019

Viscoelastic flow past a cylinder is a classic benchmark problem that is not completely understood. Using novel three-dimensional (3D) holographic particle velocimetry, we report three main discoveries of the elastic instability upstream of a single cylinder in viscoelastic channel flow. First, we observe that upstream vortices initiate at the corner between the cylinder and the wall, and grow with increasing flow rate. Second, beyond a critical Weissenberg number, the flow upstream becomes unsteady and switches between two bistable configurations, leading to symmetry breaking in the cylinder axis direction that is highly 3D in nature. Lastly, we find that the disturbance of the elastic instability propagates relatively far upstream via an elastic wave, and is weakly correlated with that in the cylinder wake. The wave speed and the extent of the instability increase with Weissenberg number, indicating an absolute instability in viscoelastic fluids.
BASIS THEOREMS FOR -SETS
Authors: CHONG CHI TAT , WU LIUZHEN , YU LIANG
Published: February 2019

We prove the following two basis theorems for ${\rm{\Sigma }}_2^1$-sets of reals:

(1)

Every nonthin ${\rm{\Sigma }}_2^1$-set has a perfect ${\rm{\Delta }}_2^1$-subset if and only if it has a nonthin ${\rm{\Delta }}_2^1$-subset, and this is equivalent to the statement that there is a nonconstructible real.

(2)

Every uncountable ${\rm{\Sigma }}_2^1$-set has an uncountable ${\rm{\Delta }}_2^1$-subset if and only if either every real is constructible or $\omega _1^L$ is countable.

We also apply the method that proves (2) to show that if there is a nonconstructible real, then there is a perfect ${\rm{\Pi }}_2^1$-set with no nonempty ${\rm{\Pi }}_2^1$-thin subset, strengthening a result of Harrington [4].
Inflammatory cytokines and mononuclear cells in sudden sensorineural hearing loss
Authors: Yoon S H , Kim M E , Kim H Y , Lee J S , Jang C H
Published: February 2019

Objective

This study evaluated tumour necrosis factor-α, interleukins 10 and 12, and interferon-γ levels, peripheral blood mononuclear cells, and clusters of differentiation 17c and 86 expression in unilateral sudden sensorineural hearing loss.

Methods

Twenty-four patients with unilateral sudden sensorineural hearing loss, and 24 individuals with normal hearing and no history of sudden sensorineural hearing loss (who were attending the clinic for other problems), were enrolled. Peripheral blood mononuclear cells, and clusters of differentiation 11c and 86 were isolated and analysed. Plasma and supernatant levels of tumour necrosis factor-α, interferon-γ, and interleukins 10 and 12 were measured.

Results

There were no significant differences with respect to age and gender. Monocyte population, mean tumour necrosis factor-α level and cluster of differentiation 86 expression were significantly increased in the study group compared to the control group. However, interferon-γ and interleukin 12 levels were significantly decreased. The difference in mean interleukin 10 level was not significant.

Conclusion

Increases in tumour necrosis factor-α level and monocyte population might play critical roles in sudden sensorineural hearing loss. This warrants detailed investigation and further studies on the role of dendritic cells in sudden sensorineural hearing loss.
Discrimination of colors by red–green color vision-deficient observers through digitally generated red filter
Authors: Sato Keiko , Inoue Takaaki , Tamura Shuto , Takimoto Hironori
Published: February 2019

Previous studies have shown that with the use of tinted lenses (or colored filters), individuals with red–green color vision deficiency (CVD) report an improvement in their performance on certain color vision tests. In this context, this study examines the effects of a digitally generated red-colored filter and identifies the mechanism mainly responsible for the changes in red–green CVD observers’ performance on a D-15 arrangement test performed using the filter. We simulate the red filter digitally with the spectral transmittance similar to that of the X-Chrom, which is a red-tinted lens. Fourteen red–green CVD subjects are subjected to the D-15 test on a computer monitor under four filter conditions, consisting of one condition without the filter and three conditions with the filter, corresponding to the opacity of the red filter. The results show that while the simulated red filter improves the performance of deutans to arrange the caps in the D-15 test, this is not the case for protans. In addition, considerations based on the human cone-contrast model enable us to identify that the improvement in deutan observers largely results from the increase in the luminance contrast between stimuli and a background. To summarize, the red filter simulated in this study induces different changes in the red–green CVD observer luminance contrast between the protan and deutan types, with the result that the performance of deuteranopes improves while that of protanopes deteriorates.
Inlining External Sources in Answer Set Programs
Authors: REDL CHRISTOPH
Published: February 2019

hex-programs are an extension of answer set programs (ASP) with external sources. To this end, external atoms provide a bidirectional interface between the program and an external source. The traditional evaluation algorithm for hex-programs is based on guessing truth values of external atoms and verifying them by explicit calls of the external source. The approach was optimized by techniques that reduce the number of necessary verification calls or speed them up, but the remaining external calls are still expensive. In this paper, we present an alternative evaluation approach based on inlining of external atoms, motivated by existing but less general approaches for specialized formalisms such as DL-programs. External atoms are then compiled away such that no verification calls are necessary. The approach is implemented in the dlvhex reasoner. Experiments show a significant performance gain. Besides performance improvements, we further exploit inlining for extending previous (semantic) characterizations of program equivalence from ASP to hex-programs, including those of strong equivalence, uniform equivalence, and $\langle\mathcal{H},\mathcal{B}\rangle$- equivalence. Finally, based on these equivalence criteria, we characterize also inconsistency of programs w.r.t. extensions. Since well-known ASP extensions (such as constraint ASP) are special cases of hex, the results are interesting beyond the particular formalism.
Transitions from career employment among public- and private-sector workers
Authors: Quinn Joseph F. , Cahill Kevin E. , Giandrea Michael D.
Published: February 2019

Do the retirement patterns of public-sector workers differ from those in the private sector? The latter typically face a retirement landscape with exposure to market uncertainties through defined-contribution pension plans and private saving. Public-sector workers, in contrast, are often covered by defined-benefit pension plans that encourage retirement at relatively young ages and offer financial security at older ages. We examine how private- and public-sector workers transition from full-time career employment, with a focus on the importance of gradual retirement. To our surprise, we find that the prevalence of continued work after career employment, predominantly on bridge jobs with new employers, is very similar in the two sectors, a result with important implications in a rapidly aging society.
Rapid Geodetic Analysis of Subduction Zone Earthquakes Leveraging a 3‐D Elastic Green's Function Library
Authors: Tung S. , Fielding E. J. , Bekaert D. P. S. , Masterlark T.
Published: February 2019

The 2018 M7.2 Pinotepa earthquake ruptured a shallow slab section along the Middle America subduction zone. We demonstrate how a geodetic Green's function (GF) library and efficient modeling algorithm can rapidly resolve earthquake slip and contribute to early warning systems. The source is characterized with InSAR data and a finite‐element model mimicking realistic slab geometry (Slab1.0) and velocity structures (CRUST2.0) that are not considered in the conventional homogeneous (HOM)‐ or layered(1‐D)‐crust solutions. The rupture is imaged 18 min after geodetic data are downloaded to a 16‐CPU‐thread workstation. Nearby Mw8.6‐megathrust scenarios are also studied with synthetic GPS data in the Guerrero/Oaxaca area. Our results show that earthquake slip solutions are sensitive to the materials of elastic‐modeling domains. Attaining smaller misfits or sums of squared errors, models by 3‐D GFs significantly better recover coseismic displacements than those estimated with 1‐D GFs or HOM GFs at 95% confidence.
Object‐Oriented Identification of Coherent Structures in Large Eddy Simulations: Importance of Downdrafts in Stratocumulus
Authors: Brient Florent , Couvreux Fleur , Villefranque Najda , Rio Catherine , Honnert Rachel
Published: February 2019

A novel methodology is proposed to characterize coherent structures in large eddy simulations. Based on two passive tracers emitted respectively at the surface and at cloud top, the object‐oriented framework allows individual characterization of coherent tridimensional plumes within the flow. Applying this method in a simulation of the diurnal cycle of a marine stratocumulus‐topped boundary layer shows that coherent updraft and downdraft structures contribute to most of the total transport of heat and moisture, although covering a small part of the domain volume. On average, downdrafts contribute equally compared to updrafts for moisture fluxes and more than updrafts for heat fluxes. The relative contribution of updraft and downdraft objects to heat transport exhibits a large diurnal cycle, which suggests cloud‐turbulence‐radiation interaction. Our results suggest that subgrid downdraft properties within stratocumulus‐topped boundary layers should be represented through nonlocal mass‐flux parameterization in climate models.
Chain‐Style Landslide Hazardous Process: Constraints From Seismic Signals Analysis of the 2017 Xinmo Landslide, SW China
Authors: Li Wei , Chen Yun , Liu Feng , Yang Hongfeng , Liu Jianli , Fu Bihong
Published: February 2019

Landslides generally involve rapid acceleration and deceleration of huge mass in just several minutes, and their unpredictability have made real‐time detections of their rapid processes difficult. Seismic signals generated by landslides provide an excellent opportunity to obtain the time‐dependent observations on landslide's processes. We invert the force‐time function by fitting long‐period seismic signals generated by Xinmo landslide on 23 June 2017, SW China, and determine three‐stage dynamic processes within 104‐s duration of this event. Constrained by the field observed runout distance, we deduce the landslide's mass of about 9 × 109 kg with corresponding maximum velocity and acceleration of 58.8 m/s and 4.38 m/s2, respectively. Combining dynamic parameters, apparent friction coefficient, and seismic signal features, we depict a dynamic landslide process initiated by high‐position rockslide, traveled by rapid long runout debris, and deposited over an old landslide's deposition fan. The rapid process of the landslide is affected by multiple preconditions such as the structure, topography, and meteorology of the site, which is characteristic of a typical chain‐style landslide hazard and could be helpful to recognize potential slope instabilities.
Velocity‐Density Systematics of Fe‐5wt%Si: Constraints on Si Content in the Earth's Inner Core
Authors: Edmund E. , Antonangeli D. , Decremps F. , Miozzi F. , Morard G. , Boulard E. , Clark A. N. , Ayrinhac S. , Gauthier M. , Morand M. , Mezouar M.
Published: February 2019

The elasticity of hcp‐Fe‐5wt%Si has been investigated by synchrotron X‐ray diffraction up to 110 GPa and 2,100 K and by picosecond acoustics measurements at ambient temperature up to 115 GPa. The established Pressure‐Volume‐Temperature equation of state shows that the density of the Earth's inner core can be matched by an Fe‐Si alloy with 5wt% Si for all reasonable core temperatures, but that its compressional and shear velocities remain too high with respect to seismological observations. On the other hand, Fe‐Si alloys whose velocities are expected to get close to seismological observations are too dense at relevant temperatures. Thus, based on these combined velocity‐density measurements, silicon is not likely to be the sole light element in the inner core.
Heat and Salt Flow in Subsea Permafrost Modeled with CryoGRID2
Authors: Angelopoulos Michael , Westermann Sebastian , Overduin Paul , Faguet Alexey , Olenchenko Vladimir , Grosse Guido , Grigoriev Mikhail N.
Published: February 2019

Thawing of subsea permafrost can impact offshore infrastructure, affect coastal erosion, and release permafrost organic matter. Thawing is usually modeled as the result of heat transfer, although salt diffusion may play an important role in marine settings. To better quantify nearshore subsea permafrost thawing, we applied the CryoGRID2 heat diffusion model and coupled it to a salt diffusion model. We simulated coastline retreat and subsea permafrost evolution as it develops through successive stages of a thawing sequence at the Bykovsky Peninsula, Siberia. Sensitivity analyses for seawater salinity were performed to compare the results for the Bykovsky Peninsula with those of typical Arctic seawater. For the Bykovsky Peninsula, the modeled ice‐bearing permafrost table (IBPT) for ice‐rich sand and an erosion rate of 0.25 m/year was 16.7 m below the seabed 350 m offshore. The model outputs were compared to the IBPT depth estimated from coastline retreat and electrical resistivity surveys perpendicular to and crossing the shoreline of the Bykovsky Peninsula. The interpreted geoelectric data suggest that the IBPT dipped to 15–20 m below the seabed at 350 m offshore. Both results suggest that cold saline water forms beneath grounded ice and floating sea ice in shallow water, causing cryotic benthic temperatures. The freezing point depression produced by salt diffusion can delay or prevent ice formation in the sediment and enhance the IBPT degradation rate. Therefore, salt diffusion may facilitate the release of greenhouse gasses to the atmosphere and considerably affect the design of offshore and coastal infrastructure in subsea permafrost areas.
One Step at a Time: How Model Time Step Significantly Affects Convection‐Permitting Simulations
Authors: Barrett Andrew I. , Wellmann Constanze , Seifert Axel , Hoose Corinna , Vogel Bernhard , Kunz Michael
Published: February 2019

We show that there is a strong sensitivity of cloud microphysics to model time step in idealized convection‐permitting simulations using the COnsortium for Small‐scale MOdeling model. Specifically, we found a 53% reduction in precipitation when the time step is increased from 1 to 15 s, changes to the location of precipitation and hail reaching the surface, and changes to the vertical distribution of hydrometeors. The effect of cloud condensation nuclei perturbations on precipitation also changes both magnitude and sign with the changing model time step. The sensitivity arises because of the numerical implementation of processes in the model, specifically the so‐called “splitting” of the dynamics (e.g., advection and diffusion) and the parameterized physics (e.g., microphysics scheme). Calculating one step at a time (sequential‐update splitting) gives a significant time step dependence because large supersaturation with respect to liquid is generated in updraft regions, which strongly affect parameterized microphysical process rates—in particular, ice nucleation. In comparison, calculating both dynamics and microphysics using the same inputs of temperature and water vapor (hybrid parallel splitting) or adding an additional saturation adjustment within the dynamics reduces the time step sensitivity of surface precipitation by limiting the supersaturation seen by the microphysics, although sensitivity to time step remains for some processes.
Comparative cytology, physiology and transcriptomics of Burkholderia insecticola in symbiosis with the bean bug Riptortus pedestris and in culture
Authors: Ohbayashi Tsubasa , Futahashi Ryo , Terashima Mia , Barrière Quentin , Lamouche Florian , Takeshita Kazutaka , Meng Xian-Ying , Mitani Yasuo , Sone Teruo , Shigenobu Shuji , Fukatsu Takema , Mergaert Peter , Kikuchi Yoshitomo
Published: February 2019

In the symbiosis of the bean bug Riptortus pedestris with Burkholderia insecticola, the bacteria occupy an exclusive niche in the insect midgut and favor insect development and reproduction. In order to understand how the symbiotic bacteria stably colonize the midgut crypts and which services they provide to the host, we compared the cytology, physiology, and transcriptomics of free-living and midgut-colonizing B. insecticola. The analyses revealed that midgut-colonizing bacteria were smaller in size and had lower DNA content, they had increased stress sensitivity, lost motility, and an altered cell surface. Transcriptomics revealed what kinds of nutrients are provided by the bean bug to the Burkholderia symbiont. Transporters and metabolic pathways of diverse sugars such as rhamnose and ribose, and sulfur compounds like sulfate and taurine were upregulated in the midgut-colonizing symbionts. Moreover, pathways enabling the assimilation of insect nitrogen wastes, i.e. allantoin and urea, were also upregulated. The data further suggested that the midgut-colonizing symbionts produced all essential amino acids and B vitamins, some of which are scarce in the soybean food of the host insect. Together, these findings suggest that the Burkholderia symbiont is fed with specific nutrients and also recycles host metabolic wastes in the insect gut, and in return, the bacterial symbiont provides the host with essential nutrients limited in the insect food, contributing to the rapid growth and enhanced reproduction of the bean bug host.
Co-culture and biogeography of Prochlorococcus and SAR11
Authors: Becker Jamie W , Hogle Shane L , Rosendo Kali , Chisholm Sallie W
Published: February 2019

Prochlorococcus and SAR11 are among the smallest and most abundant organisms on Earth. With a combined global population of about 2.7 × 1028 cells, they numerically dominate bacterioplankton communities in oligotrophic ocean gyres and yet they have never been grown together in vitro. Here we describe co-cultures of Prochlorococcus and SAR11 isolates representing both high- and low-light adapted clades. We examined: (1) the influence of Prochlorococcus on the growth of SAR11 and vice-versa, (2) whether Prochlorococcus can meet specific nutrient requirements of SAR11, and (3) how co-culture dynamics vary when Prochlorococcus is grown with SAR11 compared with sympatric copiotrophic bacteria. SAR11 grew 15–70% faster in co-culture with Prochlorococcus, while the growth of the latter was unaffected. When Prochlorococcus populations entered stationary phase, this commensal relationship rapidly became amensal, as SAR11 abundances decreased dramatically. In parallel experiments with copiotrophic bacteria; however, the heterotrophic partner increased in abundance as Prochlorococcus densities leveled off. The presence of Prochlorococcus was able to meet SAR11’s central requirement for organic carbon, but not reduced sulfur. Prochlorococcus strain MIT9313, but not MED4, could meet the unique glycine requirement of SAR11, which could be due to the production and release of glycine betaine by MIT9313, as supported by comparative genomic evidence. Our findings also suggest, but do not confirm, that Prochlorococcus MIT9313 may compete with SAR11 for the uptake of 3-dimethylsulfoniopropionate (DMSP). To give our results an ecological context, we assessed the relative contribution of Prochlorococcus and SAR11 genome equivalents to those of identifiable bacteria and archaea in over 800 marine metagenomes. At many locations, more than half of the identifiable genome equivalents in the euphotic zone belonged to Prochlorococcus and SAR11 – highlighting the biogeochemical potential of these two groups.
Polyphosphate recovery by a native Bacillus cereus strain as a direct effect of glyphosate uptake
Authors: Acosta-Cortés Alejandra Guadalupe , Martinez-Ledezma Cesar , López-Chuken Ulrico Javier , Kaushik Garima , Nimesh Surendra , Villarreal-Chiu Juan Francisco
Published: February 2019

Seven bacterial strains isolated from a glyphosate-exposed orange plantation site were exposed to 1 mM N-(phosphonomethyl)glycine supplied as a phosphorus source. While some exhibited good biodegradation profiles, the strain 6 P, identified as Bacillus cereus, was the only strain capable of releasing inorganic phosphate to the culture supernatant, while accumulating polyphosphate intracellularly along the experimentation time. The composition and purity of the intracellular polyphosphate accumulated by the strain 6 P were confirmed by FTIR analysis. To date, the biological conversion of glyphosate into polyphosphate has not been reported. However, given the importance of this biopolymer in the survival of microorganisms, it can be expected that this process could represent an important ecological advantage for the adaptation of this strain to an ecological niche exposed to this herbicide. The polyphosphate production yield was calculated as 4 mg l−1, while the glyphosate biodegradation kinetic constant was calculated on 0.003 h−1 using the modified Hockey–Stick first-order kinetic model, with a half-life of 279 h. Our results suggest that B. cereus 6 P is a potential candidate for the generation of an innovative biotechnological process to produce polyphosphate through the biodegradation of the herbicide glyphosate.
Arctic marine fungi: biomass, functional genes, and putative ecological roles
Authors: Hassett B T , Borrego E J , Vonnahme T R , Rämä T , Kolomiets M V , Gradinger R
Published: February 2019

Recent molecular evidence suggests a global distribution of marine fungi; however, the ecological relevance and corresponding biological contributions of fungi to marine ecosystems remains largely unknown. We assessed fungal biomass from the open Arctic Ocean by applying novel biomass conversion factors from cultured isolates to environmental sterol and CARD-FISH data. We found an average of 16.54 nmol m−3 of ergosterol in sea ice and seawater, which corresponds to 1.74 mg C m−3 (444.56 mg C m−2 in seawater). Using Chytridiomycota-specific probes, we observed free-living and particulate-attached cells that averaged 34.07 µg C m−3 in sea ice and seawater (11.66 mg C m−2 in seawater). Summed CARD-FISH and ergosterol values approximate 1.77 mg C m−3 in sea ice and seawater (456.23 mg C m−2 in seawater), which is similar to biomass estimates of other marine taxa generally considered integral to marine food webs and ecosystem processes. Using the GeoChip microarray, we detected evidence for fungal viruses within the Partitiviridae in sediment, as well as fungal genes involved in the degradation of biomass and the assimilation of nitrate. To bridge our observations of fungi on particulate and the detection of degradative genes, we germinated fungal conidia in zooplankton fecal pellets and germinated fungal conidia after 8 months incubation in sterile seawater. Ultimately, these data suggest that fungi could be as important in oceanic ecosystems as they are in freshwater environments.
Visualizing the dynamics of soil aggregation as affected by arbuscular mycorrhizal fungi
Authors: Morris E K , Morris D J P , Vogt S , Gleber S-C , Bigalke M , Wilcke W , Rillig M C
Published: February 2019

Stable soils provide valuable ecosystem services and mechanical soil stability is enhanced by the presence of arbuscular mycorrhizal fungi (AMF). Soil aggregation, which is the major driver of mechanical soil stability, is often treated as a static phenomenon, even though aggregate turnover is continually ongoing. In fact, some breakdown of macroaggregates is necessary to allow new aggregate formation and inclusion of new organic matter into microaggregates. We determined how aggregate turnover times were affected by AMF by tracking movement of rare earth elements (REE), applied as their immobile oxides, between aggregate size classes, and using X-ray fluorescence microscopy to spatially localize REEs in a sample of aggregates. Here we show that AMF increased large macroaggregate formation and slowed down disintegration of large and small macroaggregates. Microaggregate turnover was increased in the presence of AMF. Internal aggregate organization suggested that although formation of microaggregates by accretion of soil to particulate organic matter is common, it is not the only mechanism in operation.
Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia
Authors: Gialluisi Alessandro , Andlauer Till F. M. , Mirza-Schreiber Nazanin , Moll Kristina , Becker Jessica , Hoffmann Per , Ludwig Kerstin U. , Czamara Darina , St Pourcain Beate , Brandler William , Honbolygó Ferenc , Tóth Dénes , Csépe Valéria , Huguet Guillaume , Morris Andrew P. , Hulslander Jacqueline , Willcutt Erik G. , DeFries John C. , Olson Richard K. , Smith Shelley D. , Pennington Bruce F. , Vaessen Anniek , Maurer Urs , Lyytinen Heikki , Peyrard-Janvid Myriam , Leppänen Paavo H. T. , Brandeis Daniel , Bonte Milene , Stein John F. , Talcott Joel B. , Fauchereau Fabien , Wilcke Arndt , Francks Clyde , Bourgeron Thomas , Monaco Anthony P. , Ramus Franck , Landerl Karin , Kere Juha , Scerri Thomas S. , Paracchini Silvia , Fisher Simon E. , Schumacher Johannes , Nöthen Markus M. , Müller-Myhsok Bertram , Schulte-Körne Gerd
Published: February 2019

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562–3468). We observed a genome-wide significant effect (p < 1 × 10−8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10−9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10−8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10−8) and with all the cognitive traits tested (p = 3.07 × 10−8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10−5–10−7]) and negatively associated with ADHD PRS (p ~ [10−8−10−17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
PET imaging of the mouse brain reveals a dynamic regulation of SERT density in a chronic stress model
Authors: Reisinger Sonali N. , Wanek Thomas , Langer Oliver , Pollak Daniela D.
Published: February 2019

The serotonin transporter (SERT, Slc6a4) plays an important role in the regulation of serotonergic neurotransmission and its aberrant expression has been linked to several psychiatric conditions. While SERT density has been proven to be amenable to in vivo quantitative evaluation by positron emission tomography (PET) in humans, this approach is in its infancy for rodents. Here we set out to evaluate the feasibility of using small-animal PET employing [11C]DASB ([11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) as a radiotracer to measure SERT density in designated areas of the mouse brain. Using Slc6a4+/+, Slc6a4+/−, and Slc6a4−/− mice as a genetic model of different SERT expression levels, we showed the feasibility of SERT imaging in the mouse brain with [11C]DASB-PET. The PET analysis was complemented by an evaluation of SERT protein expression using western blot, which revealed a highly significant correlation between in vivo and ex vivo measurements. [11C]DASB-PET was then applied to the examination of dynamic changes of SERT levels in different brain areas in the chronic corticosterone mouse model of chronic stress. The observed significant reduction in SERT density in corticosterone-treated mice was independently validated by and correlated with western blot analysis. This is the first demonstration of a quantitative in vivo evaluation of SERT density in subregions of the mouse brain using [11C]DASB-PET. The evidenced decrease in SERT density in response to chronic corticosterone treatment adds a new dimension to the complex involvement of SERT in the pathophysiology of stress-induced mental illnesses.
Identification of lenalidomide resistance pathways in myeloma and targeted resensitization using cereblon replacement, inhibition of STAT3 or targeting of IRF4
Authors: Zhu Yuan Xiao , Shi Chang-Xin , Bruins Laura A. , Wang Xuewei , Riggs Daniel L. , Porter Brooke , Ahmann Jonathan M. , de Campos Cecilia Bonolo , Braggio Esteban , Bergsagel P. Leif , Stewart A. Keith
Published: February 2019

To understand immunomodulatory drug (IMiD) resistance in multiple myeloma (MM), we created isogenic human multiple myeloma cell lines (HMCLs) sensitive and resistant to lenalidomide, respectively. Four HMCLs were demonstrated to be resistant to all IMiDs including lenalidomide, pomalidomide, and CC-220, but not to Bortezomib. In three HMLCs (MM.1.SLenRes, KMS11LenRes and OPM2LenRes), CRBN abnormalities were found, including chromosomal deletion, point mutation, and low CRBN expression. The remaining HMCL, XG1LenRes, showed no changes in CRBN but exhibited CD147 upregulation and impaired IRF4 downregulation after lenalidomide treatment. Depletion of CD147 in XG1LenRes and three additional HMCLs had no significant impact on MM viability and lenalidomide response. Further analysis of XG1LenRes demonstrated increased IL6 expression and constitutive STAT3 activation. Inhibition of STAT3 with a selective compound (PB-1-102) re-sensitized XG1LenRes to lenalidomide. Since XG1LenRes harbors a truncated IRF4 that is not downregulated by lenalidomide, we targeted IRF4/MYC axis with a selective inhibitor of the bromodomain of CBP/EP300 (SGC-CBP30), which restored lenalidomide response in XG1LenRes. This strategy also appeared to be more broadly applicable as SGC-CBP30 could re-sensitize two resistant HMCLs with low but detectable CRBN expression to lenalidomide, suggesting that targeting CBP/E300 is a promising approach to restore IMiD sensitivity in MM with detectable CRBN expression.
Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis
Authors: Liu Tangjingjun , Xia Lei , Yao Yao , Yan Chen , Fan Yanhua , Gajendran Babu , Yang Jue , Li You-Jun , Chen Juan , Filmus Jorge , Spaner David E , Zacksenhaus Eldad , Hao Xiaojiang , Ben-David Yaacov
Published: February 2019

The ETS transcription factor Fli-1 controls the expression of genes involved in hematopoiesis including cell proliferation, survival, and differentiation. Dysregulation of Fli-1 induces hematopoietic and solid tumors, rendering it an important target for therapeutic intervention. Through high content screens of a library of chemicals isolated from medicinal plants in China for inhibitors of a Fli-1 transcriptional reporter cells, we hereby report the identification of diterpenoid-like compounds that strongly inhibit Fli-1 transcriptional activity. These agents suppressed the growth of erythroleukemic cells by inducing apoptosis and differentiation. They also inhibited survival and proliferation of B-cell leukemic cell lines as well as primary B-cell lymphocytic leukemia (B-CLL) isolated from 7 patients. Moreover, these inhibitors blocked leukemogenesis in a mouse model of erythroleukemia, in which Fli-1 is the driver of tumor initiation. Computational docking analysis revealed that the diterpenoid-like compounds bind with high affinity to nucleotide residues in a pocket near the major groove within the DNA-binding sites of Fli-1. Functional inhibition of Fli-1 by these compounds triggered its further downregulation through miR-145, whose promoter is normally repressed by Fli-1. These results uncover the importance of Fli-1 in leukemogenesis, a Fli-1-miR145 autoregulatory loop and new anti-Fli-1 diterpenoid agents for the treatment of diverse hematological malignancies overexpressing this transcription factor.
Obesity-associated inflammation triggers an autophagy–lysosomal response in adipocytes and causes degradation of perilipin 1
Authors: Ju Liping , Han Junfeng , Zhang Xiaoyan , Deng Yujie , Yan Han , Wang Congrong , Li Xiaohua , Chen Shuqin , Alimujiang Miriayi , Li Xu , Fang Qichen , Yang Ying , Jia Weiping
Published: February 2019

In obesity, adipocytes exhibit high metabolic activity accompanied by an increase in lipid mobilization. Recent findings indicate that autophagy plays an important role in metabolic homeostasis. However, the role of this process in adipocytes remains controversial. Therefore, we performed an overall analysis of the expression profiles of 322 lysosomal/autophagic genes in the omental adipose tissue of lean and obese individuals, and found that among 35 significantly differentially expressed genes, 34 genes were upregulated. A large number of lysosomal/autophagic genes also were upregulated in murine 3T3-L1 adipocytes challenged with tumor necrosis factor α (TNFα) (within 24 h), which is in accordance with increased autophagy flux in adipocytes. SQSTM1/p62, a selective autophagy receptor that recognizes and binds specifically to ubiquitinated proteins, is transcriptionally upregulated upon TNFα stimulation as well. Perilipin 1 (PLIN1), a crucial lipid droplet protein, can be ubiquitinated and interacts with SQSTM1 directly. Thus, TNFα-induced autophagy is a more selective process that signals through SQSTM1 and can selectively degrade PLIN1. Our study indicates that local proinflammatory cytokines in obese adipose tissue impair triglyceride storage via autophagy induction.
Selective photocatalytic conversion of methane into carbon monoxide over zinc-heteropolyacid-titania nanocomposites
Authors: Yu Xiang , De Waele Vincent , Löfberg Axel , Ordomsky Vitaly , Khodakov Andrei Y.
Published: February 2019

Chemical utilization of vast fossil and renewable feedstocks of methane remains one of the most important challenges of modern chemistry. Herein, we report direct and selective methane photocatalytic oxidation at ambient conditions into carbon monoxide, which is an important chemical intermediate and a platform molecule. The composite catalysts on the basis of zinc, tungstophosphoric acid and titania exhibit exceptional performance in this reaction, high carbon monoxide selectivity and quantum efficiency of 7.1% at 362 nm. In-situ Fourier transform infrared and X-ray photoelectron spectroscopy suggest that the catalytic performance can be attributed to zinc species highly dispersed on tungstophosphoric acid /titania, which undergo reduction and oxidation cycles during the reaction according to the Mars–van Krevelen sequence. The reaction proceeds via intermediate formation of surface methyl carbonates.
Reversible fold-switching controls the functional cycle of the antitermination factor RfaH
Authors: Zuber Philipp Konrad , Schweimer Kristian , Rösch Paul , Artsimovitch Irina , Knauer Stefan H.
Published: February 2019

RfaH, member of the NusG/Spt5 family, activates virulence genes in Gram-negative pathogens. RfaH exists in two states, with its C-terminal domain (CTD) folded either as α-helical hairpin or β-barrel. In free RfaH, the α-helical CTD interacts with, and masks the RNA polymerase binding site on, the N-terminal domain, autoinhibiting RfaH and restricting its recruitment to opsDNA sequences. Upon activation, the domains separate and the CTD refolds into the β-barrel, which recruits a ribosome, activating translation. Using NMR spectroscopy, we show that only a complete ops-paused transcription elongation complex activates RfaH, probably via a transient encounter complex, allowing the refolded CTD to bind ribosomal protein S10. We also demonstrate that upon release from the elongation complex, the CTD transforms back into the autoinhibitory α-state, resetting the cycle. Transformation-coupled autoinhibition allows RfaH to achieve high specificity and potent activation of gene expression.
N-formyl-stabilizing quasi-catalytic species afford rapid and selective solvent-free amination of biomass-derived feedstocks
Authors: Li Hu , Guo Haixin , Su Yaqiong , Hiraga Yuya , Fang Zhen , Hensen Emiel J. M. , Watanabe Masaru , Smith Richard Lee
Published: February 2019

Nitrogen-containing compounds, especially primary amines, are vital building blocks in nature and industry. Herein, a protocol is developed that shows in situ formed N-formyl quasi-catalytic species afford highly selective synthesis of formamides or amines with controllable levels from a variety of aldehyde- and ketone-derived platform chemical substrates under solvent-free conditions. Up to 99% yields of mono-substituted formamides are obtained in 3 min. The C-N bond formation and N-formyl species are prevalent in the cascade reaction sequence. Kinetic and isotope labeling experiments explicitly demonstrate that the C-N bond is activated for subsequent hydrogenation, in which formic acid acts as acid catalyst, hydrogen donor and as N-formyl species source that stabilize amine intermediates elucidated with density functional theory. The protocol provides access to imides from aldehydes, ketones, carboxylic acids, and mixed-substrates, requires no special catalysts, solvents or techniques and provides new avenues for amination chemistry.
Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation
Authors: Cho Jonathan J. , Xu Zhiwei , Parthasarathy Upasana , Drashansky Theodore T. , Helm Eric Y. , Zuniga Ashley N. , Lorentsen Kyle J. , Mansouri Samira , Cho Joshua Y. , Edelmann Mariola J. , Duong Duc M. , Gehring Torben , Seeholzer Thomas , Krappmann Daniel , Uddin Mohammad N. , Califano Danielle , Wang Rejean L. , Jin Lei , Li Hongmin , Lv Dongwen , Zhou Daohong , Zhou Liang , Avram Dorina
Published: February 2019

Polyubiquitination promotes proteasomal degradation, or signaling and localization, of targeted proteins. Here we show that the E3 ubiquitin ligase Hectd3 is necessary for pathogenic Th17 cell generation in experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. Hectd3-deficient mice have lower EAE severity, reduced Th17 program and inefficient Th17 cell differentiation. However, Stat3, but not RORγt, has decreased polyubiquitination, as well as diminished tyrosine-705 activating phosphorylation. Additionally, non-degradative polyubiquitination of Malt1, critical for NF-κB activation and Th17 cell function, is reduced. Mechanistically, Hectd3 promotes K27-linked and K29-linked polyubiquitin chains on Malt1, and K27-linked polyubiquitin chains on Stat3. Moreover, Stat3 K180 and Malt1 K648 are targeted by Hectd3 for non-degradative polyubiquitination to mediate robust generation of RORγt+IL-17Ahi effector CD4+ T cells. Thus, our studies delineate a mechanism connecting signaling related polyubiquitination of Malt1 and Stat3, leading to NF-kB activation and RORγt expression, to pathogenic Th17 cell function in EAE.
Suppressed phase separation of mixed-halide perovskites confined in endotaxial matrices
Authors: Wang Xi , Ling Yichuan , Lian Xiujun , Xin Yan , Dhungana Kamal B. , Perez-Orive Fernando , Knox Javon , Chen Zhizhong , Zhou Yan , Beery Drake , Hanson Kenneth , Shi Jian , Lin Shangchao , Gao Hanwei
Published: February 2019

The functionality and performance of a semiconductor is determined by its bandgap. Alloying, as for instance in InxGa1-xN, has been a mainstream strategy for tuning the bandgap. Keeping the semiconductor alloys in the miscibility gap (being homogeneous), however, is non-trivial. This challenge is now being extended to halide perovskites – an emerging class of photovoltaic materials. While the bandgap can be conveniently tuned by mixing different halogen ions, as in CsPb(BrxI1-x)3, the so-called mixed-halide perovskites suffer from severe phase separation under illumination. Here, we discover that such phase separation can be highly suppressed by embedding nanocrystals of mixed-halide perovskites in an endotaxial matrix. The tuned bandgap remains remarkably stable under extremely intensive illumination. The agreement between the experiments and a nucleation model suggests that the size of the nanocrystals and the host-guest interfaces are critical for the photo-stability. The stabilized bandgap will be essential for the development of perovskite-based optoelectronics, such as tandem solar cells and full-color LEDs.
Japanese encephalitis virus neuropenetrance is driven by mast cell chymase
Authors: Hsieh Justin T. , Rathore Abhay P. S. , Soundarajan Gayathri , St. John Ashley L.
Published: February 2019

Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis. However, the mechanisms of JEV penetration of the blood-brain-barrier (BBB) remain poorly understood. Mast cells (MCs) are granulated innate immune sentinels located perivascularly, including at the BBB. Here we show that JEV activates MCs, leading to the release of granule-associated proteases in vivo. MC-deficient mice display reduced BBB permeability during JEV infection compared to congenic wild-type (WT) mice, indicating that enhanced vascular leakage in the brain during JEV infection is MC-dependent. Moreover, MCs promoted increased JEV infection in the central nervous system (CNS), enhanced neurological deficits, and reduced survival in vivo. Mechanistically, chymase, a MC-specific protease, enhances JEV-induced breakdown of the BBB and cleavage of tight-junction proteins. Chymase inhibition reversed BBB leakage, reduced brain infection and neurological deficits during JEV infection, and prolonged survival, suggesting chymase is a novel therapeutic target to prevent JEV encephalitis.