bluuebunny/crossref_metadata_2025 huggingface dataset:
Respiratory medium and circulatory anatomy constrain size evolution in marine macrofauna
Authors: Heim Noel A. , Bakshi Saket H. , Buu Loc , Chen Stephanie , Heh Shannon , Jain Ashli , Noll Christopher , Patkar Ameya , Rizk Noah , Sundararajan Sriram , Villante Isabella , Knope Matthew L. , Payne Jonathan L.
Published: May 2020

The typical marine animal has increased in biovolume by more than two orders of magnitude since the beginning of the Cambrian, but the causes of this trend remain unknown. We test the hypothesis that the efficiency of intra-organism oxygen delivery is a major constraint on body-size evolution in marine animals. To test this hypothesis, we compiled a dataset comprising 13,723 marine animal genera spanning the Phanerozoic. We coded each genus according to its respiratory medium, circulatory anatomy, and feeding mode. In extant genera, we find that respiratory medium and circulatory anatomy explain more of the difference in size than feeding modes. Likewise, we find that most of the Phanerozoic increase in mean biovolume is accounted for by size increase in taxa that accomplish oxygen delivery through closed circulatory systems. During the Cambrian, water-breathing animals with closed circulatory systems were smaller, on average, than contemporaries with open circulatory systems. However, genera with closed circulatory systems superseded in size genera with open circulatory systems by the Middle Ordovician, as part of their Phanerozoic-long trend of increasing size. In a regression analysis, respiratory and circulatory anatomy explain far more size variation in the living fauna than do feeding modes, even after accounting for taxonomic affinity at the class level. These findings suggest that ecological and environmental drivers of the Phanerozoic increase in the mean size of marine animals operated within strong, anatomically determined constraints.
Option-Based Estimation of the Price of Coskewness and Cokurtosis Risk
Authors: Christoffersen Peter , Fournier Mathieu , Jacobs Kris , Karoui Mehdi
Published: May 2020

We show that the prices of risk for factors that are nonlinear in the market return can be obtained using index option prices. The price of coskewness risk corresponds to the market variance risk premium, and the price of cokurtosis risk corresponds to the market skewness risk premium. Option-based estimates of the prices of risk lead to reasonable values of the associated risk premia. An analysis of factor models with coskewness risk indicates that the new estimates of the price of risk improve the models’ performance compared with regression-based estimates.
Second language learning of phonological alternations with and without orthographic input: Evidence from the acquisition of a German-like voicing alternation
Authors: Barrios Shannon L. , Hayes-Harb Rachel
Published: May 2020

While a growing body of research investigates the influence of orthographic input on the acquisition of second language (L2) segmental contrasts, few studies have examined its influence on the acquisition of L2 phonological processes. Hayes-Harb, Brown, and Smith (2018) showed that exposure to words’ written forms caused native English speakers to misremember the voicing of final obstruents in German-like words exemplifying voicing neutralization. However, they did not examine participants’ acquisition of the final devoicing process. To address this gap, we conducted two experiments wherein native English speakers (assigned to Orthography or No Orthography groups) learned German-like words in suffixed and unsuffixed forms, and later completed a picture naming test. Experiment 1 investigated learners’ knowledge of the surface voicing of obstruents in both final and nonfinal position, and revealed that while all participants produced underlyingly voiced obstruents as voiceless more often in final than nonfinal position, the difference was only significant for No Orthography participants. Experiment 2 investigated participants’ ability to apply the devoicing process to new words, and provided no evidence of generalization. Together these findings shed light on the acquisition of final devoicing by naïve adult learners, as well as the influence of orthographic input in the acquisition of a phonological alternation.
A social history of serious mental illness
Authors: Daugherty Brendan , Warburton Katherine , Stahl Stephen M.
Published: May 2020

Despite medical, technological, and humanitarian advances, the criminalization of those with serious mental illness continues. This is not an isolated phenomenon. The benefits of treatment reform and innovation are difficult to maintain or sometimes outright harmful. Across time and geography, the care of those with serious mental illness tends towards maltreatment, be it criminalization or other forms of harm. We present a social history of serious mental illness, along with the idea that the treatment of serious mental illness is a Sisyphean task—perpetually pushing a boulder up a hill, only for it to roll down and start again. The history is provided as a basis for deeper reflection of treatment, and treatment reform, of those with serious mental illnesses.
Tipo de antipsicótico y correlatos de la interrupción del tratamiento de antipsicóticos en el tratamiento ambulatorio de la esquizofrenia
Authors: María Haro Joseph , Novick Diego , Belger Mark , Jones Peter B. ,   Junta Consultiva SOHO
Published: May 2020

Se analizó el mantenimiento de la medicación antipsicótica y los factores que influyen en él utilizando datos del estudio SOHO, un gran estudio observacional de la evolucion del tratamiento de antipsicóticos para la esquizofrenia en Europa. Se analizó a un total de 7.186 pacientes adultos en el entorno ambulatorio en los que se inició o cambió la medicación antipsicótica y a quienes se prescribió sólo un antipsicótico después de la vísita de linea de base. El mantenimiento de la medicación a los 12 meses variaba con el tipo de antipsicótico prescrito, siendo más alto con la clozapina (79,5%) y la olanzapina (77%) y más bajo con la quetiapina (51,4%) y la amisulprida (58,2%). El análisis de regresión logística mύltiple demostró que el tipo de antipsicótico prescrito en la línea de base era el predictor más importante del mantenimiento de la medicación. La dependencia de alcohol, el consumo de estabilizadores del estado de ánimo, el ingreso obligatorio o la detención en los 6 meses anteriores, la mayor gravedad clínica y el cambio de la medicación antipsicótica debido a falta de eficacia en la línea de base predecían una frecuencia mayor de interrupción de la medicación en los 12 meses posteriores. Por contraste, el mantenimiento de la medicación era más alto entre los pacientes que no habían recibido ningύn tratamiento en la línea de base, eran activos socialmente o habían perdido la líbido en la linea de base. Los hallazgos de este estudio se deben interpretar conservadoramente a causa de su diseño observacional no distribuido al azar. © 2005 Elsevier SAS. Todos los derechos reservados.
Spatial Distribution of Heterochromatin Bodies in the Nuclei of Triatoma infestans (Klug)
Authors: Imperador Carlos Henrique L. , Bardella Vanessa B. , dos Anjos Eli Heber M. , Rodrigues Vera L.C.C. , Cabral-de-Mello Diogo C. , Mello Maria Luiza S.
Published: May 2020

Constitutive heterochromatin typically exhibits low gene density and is commonly found adjacent or close to the nuclear periphery, in contrast to transcriptionally active genes concentrated in the innermost nuclear region. In Triatoma infestans cells, conspicuous constitutive heterochromatin forms deeply stained structures named chromocenters. However, to the best of our knowledge, no information exists regarding whether these chromocenters acquire a precise topology in the cell nuclei or whether their 18S rDNA, which is important for ribosome function, faces the nuclear center preferentially. In this work, the spatial distribution of fluorescent Feulgen-stained chromocenters and the distribution of their 18S rDNA was analyzed in Malpighian tubule cells of T. infestans using confocal microscopy. The chromocenters were shown to be spatially positioned relatively close to the nuclear periphery, though not adjacent to it. The variable distance between the chromocenters and the nuclear periphery suggests mobility of these bodies within the cell nuclei. The distribution of 18S rDNA at the edge of the chromocenters was not found to face the nuclear interior exclusively. Because the genome regions containing 18S rDNA in the chromocenters also face the nuclear periphery, the proximity of the chromocenters to this nuclear region is not assumed to be associated with overall gene silencing.
Microanalysis of Fish Ovarian Follicular Atresia: A Possible Synergic Action of Somatic and Immune Cells
Authors: Mokhtar Doaa M. , Hussein Marwa M.
Published: May 2020

The present study describes in detail the morphological characteristics of the process of ovarian follicular atresia in Redbelly tilapia (Coptodon zillii) during the nonbreeding season using light and electron microscopy and immunohistochemistry. The follicular regression process was initiated with shrinkage and disintegration of the nuclear membrane of oocytes resulting in dispersing of chromatin within the ooplasm, followed by marked hyperplasia and hypertrophy of follicular and granulosa cells, which exhibited a strong phagocytic activity to engulf the liquefied yolk particles. Rodlet cells and granulocytes were recorded on the follicular wall and invaded the regressed follicles. Rodlet cells expressed a strong immunoreactivity to matrix metalloperoxidase (MMP-9) and α-smooth muscle actin, while neutrophils expressed a strong reactivity to Myeloperoxidase-3 (MPO). In the advanced stage of follicular atresia, the yolk was almost phagocytized and resorbed and the regressed follicle lost its integrity and appeared to be formed of a cellular mass of phagocytic cells. Transmission electron microscopy revealed the presence of neutrophils, eosinophils, and dendritic cells within the atretic follicle in between these phagocytic cells. Moreover, numerous lysosomes, granules, and phagosomes were observed within the cytoplasm of both phagocytic cells and granulocytes. Telocytes were also demonstrated within the highly thickened richly vascularized theca layer during the late stages of follicular atresia. Immunohistochemical staining for caspase-3 established the participation of apoptosis in the advanced stages of follicular regression. Immune cells, rodlet cells, and telocytes in combination with follicular cells play an essential role in follicular atresia. In conclusion, the present study provides a new evidence on the role of both somatic and immune cells in the phenomenon of ovarian follicular atresia in Redbelly tilapia (Coptodon zillii) during the nonbreeding season.
Making visible, rendering obscure: reading the plastic crisis through contemporary artistic visual representations
Authors: Chertkovskaya Ekaterina , Holmberg Karl , Petersén Moa , Stripple Johannes , Ullström Sara
Published: May 2020

Non-technical summary

Modern society without plastics is difficult to imagine. Yet the global plastic system is linked to a multitude of problems of a scope that is hard to grasp and address. In short, we are facing a plastic crisis. This article explores the role of art in stimulating critical reflection about plastics and analyses how it contributes to making the plastic crisis increasingly visible. Plastic-related artworks mostly focus on ocean pollution and do not pay due attention to other aspects of the plastic crisis. At the same time, they creatively communicate clear and emotionally charged messages. Art has the potential to play an important role in coming to grips with the plastic crisis if it succeeds in adopting a broader understanding of the problem.
Ameliorating soil acidity–reduced growth of rigid ryegrass (Lolium rigidum) in wheat
Authors: Borger Catherine P. D. , Azam Gaus , Gazey Chris , van Burgel Andrew , Scanlan Craig A.
Published: May 2020

Estimates indicate that 30% of land surface globally is affected by soil acidity, influencing agricultural production. Application of lime increases soil pH and improves crop growth. We tested the hypothesis that liming will reduce rigid ryegrass (Lolium rigidum Gaudin) growth by improving the competitive ability of the crop. Experiments at Merredin and Wongan Hills in Western Australia indicated that application of lime in previous years reduced L. rigidum density, biomass, and seed production in wheat (Triticum aestivum L.) crops in 2018. At Merredin, L. rigidum seed production in 2018 was reduced from 9,390 to 2,820 seeds m−2, and wheat tiller number and yield was increased, following lime application of 0 to 6,000 kg ha−1 in 2016. At Wongan Hills, lime application of 4,000 kg ha−1 in 1994 reduced seed production in the 2018 wheat crop from 4,708 to 1,610 seeds m−2, and application of 3,000 kg ha−1 of lime in 2014 reduced seed production from 3,959 to 921 seeds m−2 in 2018. Again, lime increased wheat tiller number, but not yield. A screen house experiment (in controlled conditions) indicated that lime application increased the initial growth of both L. rigidum and wheat seedlings. This supports the conclusion that reduced L. rigidum growth and seed production in the field resulted from increased competitive ability of the crop, rather than any direct and detrimental impact of lime on L. rigidum growth. Incorporation of lime reduced initial emergence of L. rigidum in controlled conditions, with L. rigidum seeds at a uniform depth, and in the field experiments in situations of high weed density, with seeds buried by the incorporation process. Nationally, the revenue loss from residual L. rigidum in crop is A$93 million per year. The current research confirms that application of lime will increase the competitive ability of crops growing in regions with acidic soils.
Glufosinate enhances the activity of protoporphyrinogen oxidase inhibitors
Authors: Takano Hudson K , Beffa Roland , Preston Christopher , Westra Philip , Dayan Franck E
Published: May 2020

Glufosinate inhibits glutamine synthetase (GS), a key enzyme for amino acid metabolism and photorespiration. Protoporphyrinogen oxidase (PPO) inhibitors block chlorophyll biosynthesis and cause protoporphyrin accumulation, a highly photodynamic intermediate. Both herbicides ultimately lead to plant death by a massive accumulation of reactive oxygen species (ROS) through different mechanisms. We investigated a potential synergistic effect by the mixture of the two herbicide mechanisms of action (MoAs). The tank mix between a low rate of glufosinate (280 g ai ha−1) with an ultra-low dose of saflufenacil (1 g ha−1) provided enhanced herbicidal activity compared with the products applied individually on Palmer amaranth (Amaranthus palmeriS. Watson). The synergism between the two herbicides was also confirmed by isobole analysis and field trials. The herbicide combination provided high levels of efficacy when applied at low temperature and low humidity. Mechanistically, glufosinate caused a transient accumulation of glutamate, the building block for chlorophyll biosynthesis. Consequently, inhibition of both GS and PPO resulted in greater accumulation of protoporphyrin and ROS, forming the physiological basis for the synergism between glufosinate and PPO inhibitors. While the synergy between the two herbicide MoAs provided excellent efficacy on weeds, it caused low injury to PPO-resistant waterhemp [Amaranthus tuberculatus(Moq.) Sauer] and high injury to both glufosinate-resistant and glufosinate-susceptible soybean [Glycine max(L.) Merr.]. Glufosinate enhances the activity of PPO inhibitors through glutamate and protoporphyrin accumulation, leading to increased levels of ROS and lipid peroxidation. The synergism between the two herbicide MoAs can help to overcome environmental effects limiting the efficacy of glufosinate. Future research is needed to optimize the uses for this herbicidal composition across different cropping systems.
Does Object Size Matter With Regard to the Mental Simulation of Object Orientation?
Authors: Chen Sau-Chin , de Koning Bjorn B. , Zwaan Rolf A.
Published: May 2020

Abstract. Language comprehenders have been arguing to mentally represent the implied orientation of objects. However, compared to the effects of shape, size, and color, the effect of orientation is rather small. We examined a potential explanation for the relatively low magnitude of the orientation effect: Object size moderates the orientation effect. Theoretical considerations led us to predict a smaller orientation effect for small objects than for large objects in a sentence–picture verification task. We furthermore investigated whether this pattern generalizes across languages (Chinese, Dutch, and English) and tasks (picture-naming task). The results of the verification task show an orientation effect overall, which is not moderated by object size (contrary to our hypothesis) and language (consistent with our hypothesis). Meanwhile, the preregistered picture–picture verification task showed the predicted interaction between object size and orientation effect. We conducted exploratory analyses to address additional questions.
How Thermochemical Piles Can (Periodically) Generate Plumes at Their Edges
Authors: Heyn Björn H. , Conrad Clinton P. , Trønnes Reidar G.
Published: May 2020

Deep‐rooted mantle plumes are thought to originate from the margins of the Large Low Shear Velocity Provinces (LLSVPs) at the base of the mantle. Visible in seismic tomography, the LLSVPs are usually interpreted to be intrinsically dense thermochemical piles in numerical models. Although piles deflect lateral mantle flow upward at their edges, the mechanism for localized plume formation is still not well understood. In this study, we develop numerical models that show plumes rising from the margin of a dense thermochemical pile, temporarily increasing its local thickness until material at the pile top cools and the pile starts to collapse back toward the core‐mantle boundary (CMB). This causes dense pile material to spread laterally along the CMB, locally thickening the lower thermal boundary layer on the CMB next to the pile, and initiating a new plume. The resulting plume cycle is reflected in both the thickness and lateral motion of the local pile margin within a few hundred km of the pile edge, while the overall thickness of the pile is not affected. The period of plume generation is mainly controlled by the rate at which slab material is transported to the CMB, and thus depends on the plate velocity and the sinking rate of slabs in the lower mantle. A pile collapse, with plumes forming along the edges of the pile's radially extending corner, may, for example, explain the observed clustering of Large Igneous Provinces (LIPs) in the southeastern corner of the African LLSVP around 95–155 Ma.
A Granular Physics‐Based View of Fault Friction Experiments
Authors: Ferdowsi Behrooz , Rubin Allan M.
Published: May 2020

Rate‐ and state‐dependent friction (RSF) equations are commonly used to describe the time‐dependent frictional response of fault gouge to perturbations in sliding velocity. Among the better‐known versions are the Aging and Slip laws for the evolution of state. Although the Slip law is more successful, neither can predict all the robust features of lab data. RSF laws are also empirical, and their micromechanical origin is a matter of much debate. Here we use a granular physics‐based model to explore the extent to which RSF behavior, as observed in rock and gouge friction experiments, can be explained by the response of a granular gouge layer with time‐independent properties at the contact scale. We examine slip histories for which abundant lab data are available and find that the granular model (1) mimics the Slip law for those loading protocols where the Slip law accurately models laboratory data (velocity‐step and slide‐hold tests) and (2) deviates from the Slip law under conditions where the Slip law fails to match laboratory data (the reslide portions of slide‐hold‐slide tests), in the proper sense to better match those data. The simulations also indicate that state is sometimes decoupled from porosity in a way that is inconsistent with traditional interpretations of “state” in RSF. Finally, if the “granular temperature” of the gouge is suitably normalized by the confining pressure, it produces an estimate of the direct velocity effect (the RSF parameter a) that is consistent with our simulations and in the ballpark of lab  data.
Pollution Spikes in Chile Tied to Soccer Fans’ Barbecuing
Authors: Kornei Katherine
Published: May 2020

In Santiago, mysterious pollution spikes—tenfold above normal levels—occur during televised soccer matches and are caused by tens of thousands of barbecues, new results reveal.
Near‐Future pCO2 During the Hot Miocene Climatic Optimum
Authors: Steinthorsdottir M. , Jardine P. E. , Rember W. C.
Published: May 2020

To improve future predictions of anthropogenic climate change, a better understanding of the relationship between global temperature and atmospheric concentrations of CO2 (pCO2), or climate sensitivity, is urgently required. Analyzing proxy data from climate change episodes in the past is necessary to achieve this goal, with certain geologic periods, such as the Miocene climatic optimum (MCO), a transient period of global warming with global temperatures up to ~7°C higher than today, increasingly viewed as good analogues to future climate under present emission scenarios. However, a problem remains that climate models cannot reproduce MCO temperatures with less than ~800 ppm pCO2, while most previously published proxies record pCO2 < 450 ppm. Here, we reconstructed MCO pCO2 with a multitaxon fossil leaf database from the well‐dated MCO Lagerstätte deposits of Clarkia, Idaho, USA, using four current methods of pCO2 reconstructions. The methods are principally based on either stomatal densities, carbon isotopes, or a combination of both—thus offering independent results. The total of six reconstructions mostly record pCO2 of ~450–550 ppm. Although slightly higher than previously reconstructed pCO2, the discrepancy with the ~800 ppm required by climate models remains. We conclude that climate sensitivity was heightened during MCO, indicating that highly elevated temperatures can occur at relatively moderate pCO2. Ever higher climate sensitivity with rising temperatures should be very seriously considered in future predictions of climate change.
SOX9 interacts with FOXC1 to activate MYC and regulate CDK7 inhibitor sensitivity in triple-negative breast cancer
Authors: Tang Lin , Jin Juan , Xu Kun , Wang Xin , Tang Jinhai , Guan Xiaoxiang
Published: May 2020

Triple-negative breast cancer (TNBC) is particularly sensitive to cyclin-dependent kinase 7 inhibitor, THZ1, compared to hormone receptor (HR)+ breast cancer, but our data found that different TNBC cell lines had a wide range of IC50 values of THZ1, suggesting a possible heterogeneity in sensitivity to THZ1 in TNBC. To seek potential biomarkers of THZ1 sensitivity, we re-analyzed the mRNAs profile in breast cancer cells treated with THZ1 from the previous study and demonstrated that elevated expression of SOX9 was significantly associated with the sensitivity of THZ1 in TNBC. We also verified that SOX9 expression promoted cell proliferation, migration, stemness, and predicted poor prognosis. Moreover, based on the tissue array of 278 patients and over 900 samples from TCGA data, we found that SOX9 expression was significantly higher in TNBC than HR+ breast cancers. Furthermore, ChIP-sequencing indicated that SOX9 binding to enhancer near transcription factor FOXC1, was remarkably inhibited by THZ1. And we also demonstrated that SOX9 and FOXC1 interacted with each other, which might co-operate and co-regulate the MYC signaling pathway in TNBC. Mechanistically, SOX9 may sensitize TNBC cells to THZ1, in a FOXC1-related manner, suggesting that SOX9 could be as a predictive factor of THZ1.
Pairwise common variant meta-analyses of schizophrenia with other psychiatric disorders reveals shared and distinct gene and gene-set associations
Authors: Reay William R. , Cairns Murray J.
Published: May 2020

The complex aetiology of schizophrenia is postulated to share components with other psychiatric disorders. We investigated pleiotropy amongst the common variant genomics of schizophrenia and seven other psychiatric disorders using a multimarker association test. Transcriptomic imputation was then leveraged to investigate the functional significance of variation mapped to these genes, prioritising several interesting functional candidates. Gene-based analysis of common variation revealed 67 schizophrenia-associated genes shared with other psychiatric phenotypes, including bipolar disorder, major depressive disorder, ADHD and autism-spectrum disorder. In addition, we uncovered 78 genes significantly enriched with common variant associations for schizophrenia that were not linked to any of these seven disorders (P > 0.05). Multivariable gene-set association suggested that common variation enrichment within biologically constrained genes observed for schizophrenia also occurs across several psychiatric phenotypes. Pairwise meta-analysis of schizophrenia and each psychiatric phenotype was implemented and identified 330 significantly associated genes (PMeta < 2.7 × 10−6) that were only nominally associated with each disorder individually (P < 0.05). These analyses consolidate the overlap between the genomic architecture of schizophrenia and other psychiatric disorders, uncovering several candidate pleiotropic genes which warrant further investigation.
A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder
Authors: Martin Joanna , Hosking Grace , Wadon Megan , Agha Sharifah Shameem , Langley Kate , Rees Elliott , Owen Michael J. , O’Donovan Michael , Kirov George , Thapar Anita
Published: May 2020

Recent case–control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD. Children with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200 kb) CNVs and identified those calls that were present in the proband and absent in both biological parents. In 305 parent–offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at four genomic loci (15q13.1–13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case–control ADHD studies. Our study complements ADHD case–control genomic analyses and demonstrates the need for larger parent–offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.
Association of early-onset Alzheimer’s disease with germline-generated high affinity self-antigen load
Authors: Huang Poyin , Yang Yuan-Han , Chang Ya-Hsuan , Chang Shu-Ling , Chou Mei-Chuan , Lai Chiou-Lian , Liu Ching-Kuan , Chen Hsuan-Yu
Published: May 2020

Self-antigen presentation outside the central nervous system has crucial role regarding self-proteins tolerance and autoimmunity, leading to neuroinflammation. Self-antigen with strong-binding affinity is considered to be pathogenic. We aim to investigate whether strong-binding affinity self-antigen load is associated with early/late-onset Alzheimer’s disease (AD). A total of 54 AD samples (22 early-onset, 32 late-onset) underwent next-generation sequencing (NGS) for whole-exome sequencing. Genotypes of HLA class I genes and germline mutations were obtained for estimation of the binding affinity and number of self-antigens. For each patient, self-antigen load was estimated by adding up the number of self-antigens with strong-binding affinity. Self-antigen load of early-onset AD was significantly higher than late-onset AD (mean ± SD: 6115 ± 2430 vs 4373 ± 2492;p = 0.011). An appropriate cutoff value 2503 for dichotomizing self-antigen load was obtained by receiver operating characteristic (ROC) curve analysis. Patients were then dichotomized into high or low self-antigen load groups in the binary multivariate logistic regression analysis. Adjusted odds ratio of the high self-antigen load (>2503) was 14.22 (95% CI, 1.22–165.70;p = 0.034) after controlling other covariates including gender, education, ApoE status, and baseline CDR score. This is the first study using NGS to investigate germline mutations generated self-antigen load in AD. As strong-binding affinity self-antigen is considered to be pathogenic in neuroinflammation, our finding indicated that self-antigen load did have a role in the pathogenesis of AD owing to its association with neuroinflammation. This finding may also contribute to further research regarding disease mechanism and development of novel biomarkers or treatment.
Characteristics of gray matter alterations in never-treated and treated chronic schizophrenia patients
Authors: Liu Nian , Xiao Yuan , Zhang Wenjing , Tang Biqiu , Zeng Jiaxin , Hu Na , Chandan Shah , Gong Qiyong , Lui Su
Published: May 2020

Though gray matter deficits have been consistently revealed in chronic treated schizophrenia, it is still not clear whether there are different brain alterations between chronic never treated and treated patients. To explore the different patterns of gray matter alterations among chronic never treated patients and those treated with monotherapy, we recruited 35 never-treated chronic schizophrenia patients with illness durations ranging from 5 to 48 years, 20 illness duration-matched risperidone monotherapy and 20 clozapine monotherapy patients, and 55 healthy controls. GM (surface area, cortical thickness, and cortical volume) measures were extracted and compared using ANCOVA across the four groups followed by post hoc tests. Relative to controls, both treated and never-treated chronic schizophrenia patients showed reduced GM mainly involving the bilateral medial and rostral middle frontal, left banks superior temporal sulcus, left fusiform, and left pericalcarine cortex and increased in the left cuneus. Compared with the untreated patient group, the two treated groups showed reductions mainly in the bilateral prefrontal, temporal, and left inferior parietal lobules. The clozapine monotherapy patients demonstrated more severe decreases in the bilateral prefrontal cortex and left cuneus and less severe decreases in the left ventral temporal lobe than risperidone monotherapy patients. These findings provide new insights into the long-term effects of antipsychotic treatment on gray matter alterations in schizophrenia patients. Furthermore, the characteristic findings of reductions in the inferior parietal lobule might be specific for long-term antipsychotic treatment, which could be a possible target for medication development in the future.
Fermionic neural-network states for ab-initio electronic structure
Authors: Choo Kenny , Mezzacapo Antonio , Carleo Giuseppe
Published: May 2020

Neural-network quantum states have been successfully used to study a variety of lattice and continuous-space problems. Despite a great deal of general methodological developments, representing fermionic matter is however still early research activity. Here we present an extension of neural-network quantum states to model interacting fermionic problems. Borrowing techniques from quantum simulation, we directly map fermionic degrees of freedom to spin ones, and then use neural-network quantum states to perform electronic structure calculations. For several diatomic molecules in a minimal basis set, we benchmark our approach against widely used coupled cluster methods, as well as many-body variational states. On some test molecules, we systematically improve upon coupled cluster methods and Jastrow wave functions, reaching chemical accuracy or better. Finally, we discuss routes for future developments and improvements of the methods presented.
Dissociable neural correlates of uncertainty underlie different exploration strategies
Authors: Tomov Momchil S. , Truong Van Q. , Hundia Rohan A. , Gershman Samuel J.
Published: May 2020

Most real-world decisions involve a delicate balance between exploring unfamiliar alternatives and committing to the best known option. Previous work has shown that humans rely on different forms of uncertainty to negotiate this "explore-exploit” trade-off, yet the neural basis of the underlying computations remains unclear. Using fMRI (n = 31), we find that relative uncertainty is represented in right rostrolateral prefrontal cortex and drives directed exploration, while total uncertainty is represented in right dorsolateral prefrontal cortex and drives random exploration. The decision value signal combining relative and total uncertainty to compute choice is reflected in motor cortex activity. The variance of this signal scales with total uncertainty, consistent with a sampling mechanism for random exploration. Overall, these results are consistent with a hybrid computational architecture in which different uncertainty computations are performed separately and then combined by downstream decision circuits to compute choice.
Microplastics affect sedimentary microbial communities and nitrogen cycling
Authors: Seeley Meredith E. , Song Bongkeun , Passie Renia , Hale Robert C.
Published: May 2020

Microplastics are ubiquitous in estuarine, coastal, and deep sea sediments. The impacts of microplastics on sedimentary microbial ecosystems and biogeochemical carbon and nitrogen cycles, however, have not been well reported. To evaluate if microplastics influence the composition and function of sedimentary microbial communities, we conducted a microcosm experiment using salt marsh sediment amended with polyethylene (PE), polyvinyl chloride (PVC), polyurethane foam (PUF) or polylactic acid (PLA) microplastics. We report that the presence of microplastics alters sediment microbial community composition and nitrogen cycling processes. Compared to control sediments without microplastic, PUF- and PLA-amended sediments promote nitrification and denitrification, while PVC amendment inhibits both processes. These results indicate that nitrogen cycling processes in sediments can be significantly affected by different microplastics, which may serve as organic carbon substrates for microbial communities. Considering this evidence and increasing microplastic pollution, the impact of plastics on global ecosystems and biogeochemical cycling merits critical investigation.
Context-dependent regulation of endothelial cell metabolism: differential effects of the PPARβ/δ agonist GW0742 and VEGF-A
Authors: Faulkner Ashton , Lynam Eleanor , Purcell Robert , Jones Coleen , Lopez Colleen , Board Mary , Wagner Kay-Dietrich , Wagner Nicole , Carr Carolyn , Wheeler-Jones Caroline
Published: May 2020

Peroxisome proliferator activated receptor β/δ (PPARβ/δ) has pro-angiogenic functions, but whether PPARβ/δ modulates endothelial cell metabolism to support the dynamic phenotype remains to be established. This study characterised the metabolic response of HUVEC to the PPARβ/δ agonist, GW0742, and compared these effects with those induced by VEGF-A. In HUVEC monolayers, flux analysis revealed that VEGF-A promoted glycolysis at the expense of fatty acid oxidation (FAO), whereas GW0742 reduced both glycolysis and FAO. Only VEGF-A stimulated HUVEC migration and proliferation whereas both GW0742 and VEGF-A promoted tubulogenesis. Studies using inhibitors of PPARβ/δ or sirtuin-1 showed that the tubulogenic effect of GW0742, but not VEGF-A, was PPARβ/δ- and sirtuin-1-dependent. HUVEC were reliant on glycolysis and FAO, and inhibition of either pathway disrupted cell growth and proliferation. VEGF-A was a potent inducer of glycolysis in tubulogenic HUVEC, while FAO was maintained. In contrast, GW0742-induced tubulogenesis was associated with enhanced FAO and a modest increase in glycolysis. These novel data reveal a context-dependent regulation of endothelial metabolism by GW0742, where metabolic activity is reduced in monolayers but enhanced during tubulogenesis. These findings expand our understanding of PPARβ/δ in the endothelium and support the targeting of PPARβ/δ in regulating EC behaviour and boosting tissue maintenance and repair.
Arid1b haploinsufficiency in parvalbumin- or somatostatin-expressing interneurons leads to distinct ASD-like and ID-like behavior
Authors: Smith Amanda L. , Jung Eui-Man , Jeon Byeong Tak , Kim Woo-Yang
Published: May 2020

Inhibitory interneurons are essential for proper brain development and function. Dysfunction of interneurons is implicated in several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability (ID). We have previously shown that Arid1b haploinsufficiency interferes with interneuron development and leads to social, cognitive, and emotional impairments consistent with ASD and ID. It is unclear, however, whether interneurons play a major role for the behavioral deficits in Arid1b haploinsufficiency. Furthermore, it is critical to determine which interneuron subtypes contribute to distinct behavioral phenotypes. In the present study, we generated Arid1b haploinsufficient mice in which a copy of the Arid1b gene is deleted in either parvalbumin (PV) or somatostatin (SST) interneurons, and examined their ASD- and ID-like behaviors. We found that Arid1b haploinsufficiency in PV or SST interneurons resulted in distinct features that do not overlap with one another. Arid1b haploinsufficiency in PV neurons contributed to social and emotional impairments, while the gene deletion in the SST population caused stereotypies as well as learning and memory dysfunction. These findings demonstrate a critical role of interneurons in Arid1b haploinsufficient pathology and suggest that PV and SST interneurons may have distinct roles in modulating neurological phenotypes in Arid1b haploinsufficiency-induced ASD and ID.
Platform independent protein-based cell-of-origin subtyping of diffuse large B-cell lymphoma in formalin-fixed paraffin-embedded tissue
Authors: Reinders Jörg , Altenbuchinger Michael , Limm Katharina , Schwarzfischer Philipp , Scheidt Tamara , Strasser Lisa , Richter Julia , Szczepanowski Monika , Huber Christian G. , Klapper Wolfram , Spang Rainer , Oefner Peter J.
Published: May 2020

Diffuse large B-cell lymphoma (DLBCL) is commonly classified by gene expression profiling according to its cell of origin (COO) into activated B-cell (ABC)-like and germinal center B-cell (GCB)-like subgroups. Here we report the application of label-free nano-liquid chromatography - Sequential Window Acquisition of all THeoretical fragment-ion spectra – mass spectrometry (nanoLC-SWATH-MS) to the COO classification of DLBCL in formalin-fixed paraffin-embedded (FFPE) tissue. To generate a protein signature capable of predicting Affymetrix-based GCB scores, the summed log2-transformed fragment ion intensities of 780 proteins quantified in a training set of 42 DLBCL cases were used as independent variables in a penalized zero-sum elastic net regression model with variable selection. The eight-protein signature obtained showed an excellent correlation (r = 0.873) between predicted and true GCB scores and yielded only 9 (21.4%) minor discrepancies between the three classifications: ABC, GCB, and unclassified. The robustness of the model was validated successfully in two independent cohorts of 42 and 31 DLBCL cases, the latter cohort comprising only patients aged >75 years, with Pearson correlation coefficients of 0.846 and 0.815, respectively, between predicted and NanoString nCounter based GCB scores. We further show that the 8-protein signature is directly transferable to both a triple quadrupole and a Q Exactive quadrupole-Orbitrap mass spectrometer, thus obviating the need for proprietary instrumentation and reagents. This method may therefore be used for robust and competitive classification of DLBCLs on the protein level.
Identifying task-relevant spectral signatures of perceptual categorization in the human cortex
Authors: Kuzovkin Ilya , Vidal Juan R. , Perrone-Bertolotti Marcela , Kahane Philippe , Rheims Sylvain , Aru Jaan , Lachaux Jean-Philippe , Vicente Raul
Published: May 2020

Human brain has developed mechanisms to efficiently decode sensory information according to perceptual categories of high prevalence in the environment, such as faces, symbols, objects. Neural activity produced within localized brain networks has been associated with the process that integrates both sensory bottom-up and cognitive top-down information processing. Yet, how specifically the different types and components of neural responses reflect the local networks’ selectivity for categorical information processing is still unknown. In this work we train Random Forest classification models to decode eight perceptual categories from broad spectrum of human intracranial signals (4–150 Hz, 100 subjects) obtained during a visual perception task. We then analyze which of the spectral features the algorithm deemed relevant to the perceptual decoding and gain the insights into which parts of the recorded activity are actually characteristic of the visual categorization process in the human brain. We show that network selectivity for a single or multiple categories in sensory and non-sensory cortices is related to specific patterns of power increases and decreases in both low (4–50 Hz) and high (50–150 Hz) frequency bands. By focusing on task-relevant neural activity and separating it into dissociated anatomical and spectrotemporal groups we uncover spectral signatures that characterize neural mechanisms of visual category perception in human brain that have not yet been reported in the literature.
Effects of synchronised engine sound and vibration presentation on visually induced motion sickness
Authors: Sawada Yuki , Itaguchi Yoshihiro , Hayashi Masami , Aigo Kosuke , Miyagi Takuya , Miki Masayuki , Kimura Tetsuya , Miyazaki Makoto
Published: May 2020

Driving simulator usage is often accompanied by motion sickness, and techniques for its prevention are not yet established. To reduce visually induced motion sickness (VIMS), we investigated the effects of synchronised presentation of engine sounds and motorcycle vibration on VIMS. A total of 80 participants experienced a driving scene with a head-mounted display for 5 minutes with or without synchronised presentation of engine sound and vibration. The results showed that VIMS scores, as measured by the Fast Motion Sickness scale, were significantly lower in participants who experienced the driving scene with sounds and vibration than in those who experienced the scene with sounds only, vibration only, or neither. Multiple regression analyses revealed that susceptibility to VIMS consistently explained the severity of VIMS to some extent but not with perceived realism of the virtual reality (VR) scene, sex, and experiences about VR devices and vehicles. This study demonstrated that simultaneous presentation of engine sounds and vibration, which were synchronous to each other and tightly coupled with the visual flow speed, effectively reduces VIMS while experiencing motorcycling simulators. The findings not only improve practical knowledge for reducing VIMS in driving simulators but also provide evidence for understanding the mechanisms of VIMS.
Anomalous Decay of Quantum Resistance Oscillations of 2D Helical Electrons in Magnetic Field
Authors: Abedi S. , Vitkalov S. A. , Mikhailov N. N. , Kvon Z. D.
Published: May 2020

Shubnikov de Haas resistance oscillations of highly mobile two dimensional helical electrons propagating on a conducting surface of strained HgTe 3D topological insulator are studied in magnetic fields B tilted by angle θ from the normal to the conducting layer. Strong decrease of oscillation amplitude A is observed with the tilt: $${\boldsymbol{A}}\sim {\boldsymbol{e}}{\boldsymbol{x}}{\boldsymbol{p}}(\,-\,{\boldsymbol{\xi }}/{\boldsymbol{c}}{\boldsymbol{o}}{\boldsymbol{s}}({\boldsymbol{\theta }}))$$A∼exp(−ξ/cos(θ)), where ξ is a constant. Evolution of the oscillations with temperature T shows that the parameter $${\boldsymbol{\xi }}$$ξ contains two terms: $${\boldsymbol{\xi }}={{\boldsymbol{\xi }}}_{1}+{{\boldsymbol{\xi }}}_{2}{\boldsymbol{T}}$$ξ=ξ1+ξ2T. The temperature independent term, $${{\boldsymbol{\xi }}}_{{\bf{1}}}$$ξ1, signals possible reduction of electron mean free path $${l}_{q}$$lq and/or enhancement of in-homogeneous broadening of the oscillations in magnetic field B. The temperature dependent term, $${{\boldsymbol{\xi }}}_{{\bf{2}}}{\boldsymbol{T}}$$ξ2T, indicates increase of the reciprocal velocity of 2D helical electrons: $$\delta ({v}_{F}^{-1})\sim B$$δ(vF−1)∼B suggesting modification of the electron spectrum in magnetic fields. Results are found in good agreement with proposed phenomenological model.
Methotrexate elicits pro-respiratory and anti-growth effects by promoting AMPK signaling
Authors: Papadopoli David J. , Ma Eric H. , Roy Dominic , Russo Mariana , Bridon Gaëlle , Avizonis Daina , Jones Russell G. , St-Pierre Julie
Published: May 2020

One-carbon metabolism fuels the high demand of cancer cells for nucleotides and other building blocks needed for increased proliferation. Although inhibitors of this pathway are widely used to treat many cancers, their global impact on anabolic and catabolic processes remains unclear. Using a combination of real-time bioenergetics assays and metabolomics approaches, we investigated the global effects of methotrexate on cellular metabolism. We show that methotrexate treatment increases the intracellular concentration of the metabolite AICAR, resulting in AMPK activation. Methotrexate-induced AMPK activation leads to decreased one-carbon metabolism gene expression and cellular proliferation as well as increased global bioenergetic capacity. The anti-proliferative and pro-respiratory effects of methotrexate are AMPK-dependent, as cells with reduced AMPK activity are less affected by methotrexate treatment. Conversely, the combination of methotrexate with the AMPK activator, phenformin, potentiates its anti-proliferative activity in cancer cells. These data highlight a reciprocal effect of methotrexate on anabolic and catabolic processes and implicate AMPK activation as a metabolic determinant of methotrexate response.