bluuebunny/crossref_metadata_2025 huggingface dataset:
Introducing a Crystallography-Mediated Reconstruction (CMR) Approach to Atom Probe Tomography
Authors: Day Alec C. , Ceguerra Anna V. , Ringer Simon P.
Published: February 2019

Current approaches to reconstruction in atom probe tomography produce results that exhibit substantial distortions throughout the analysis depth. This is largely because of the need to apply a multitude of assumptions when estimating the evolution of the tip shape, and other pseudo-empirical reconstruction factors, which vary both across the face of the tip and throughout the analysis depth. We introduce a new crystallography-mediated reconstruction to improve the spatial accuracy and dramatically reduce these in-depth variations. To achieve this, we developed a barycentric transform to directly relate atomic positions in detector space to real space. This is mediated by novel crystallographic analysis techniques, including: (1) calculating the orientation of a crystal directly from the field evaporation map, (2) tracking pole locations throughout the evaporation sequence, and (3) accounting for the evolving tip radius in a manner that removes the dependence on the geometric field factor. By improving the in-depth spatial accuracy of the atom probe reconstruction, a greater accuracy of the atomic neighborhood relationships is available. This is critical in modern materials science and engineering, where an understanding of the solid solution architecture, precipitate dispersions, and descriptions of the interfaces between phases or grains are key inputs to microstructure–property relationships.
A Micro-Analytical Study of the Scarabs of the Necropolis of Vinha das Caliças (Portugal)
Authors: Costa Mafalda , Arruda Ana Margarida , Barbosa Rui , Barrulas Pedro , Vandenabeele Peter , Mirão José
Published: January 2019

Five scarabs and one scaraboid found in Vinha das Caliças 4 (Beja, Portugal) were analyzed using a micro-analytical methodology in order to determine their mineralogical and chemical composition. Microstructural characterization and chemical analysis revealed that all were composed of a white body of crushed feldspathic sand covered by a lead-rich, alkaline-depleted silicate blue-green glaze showing evident signs of glass deterioration. Variable pressure scanning electron microscopy with X-ray energy dispersive spectrometry, handheld X-ray fluorescence spectroscopy, and micro X-ray diffraction results show that blue-green color of the glaze was produced by using copper ions (Cu2+) in conjunction with the lead antimonate bindheimite, a yellow-colored opacifier. The introduction of small amounts of tin in the structure of bindheimite enabled the production of a ternary Pb–Sb–Sn oxide. Tin, which was most likely added with the copper source (bronze scrapings), is known to facilitate the crystallization of bindheimite. The results are consistent with the five scarabs and one scaraboid being manufactured in Egypt. This study, the first archeometric study of scarabs found in the Iberian peninsula, has greatly contributed to the understanding of the influence of the Eastern and Central Mediterranean world in the Southwestern Iberia during the first millennium B.C.
Structure and Sense Organs of Ovipositors of an Endoparasitoid Aprostocetus causalis and an Ectoparasitoid Quadrastichus mendeli in Leptocybe spp.
Authors: Huang Zong-You , Li Si-Yan , Lu Wen , Zheng Xia-Lin
Published: February 2019

Little is known of the olfactory mechanisms of host detection in the ovipositors of endoparasitoids and ectoparasitoids. An endoparasitoid Aprostocetus causalis La Salle & Wu (Hymenoptera: Eulophidae) and an ectoparasitoid Quadrastichus mendeli Kim & La Salle (Hymenoptera: Eulophidae: Tetrastichinae) are the two parasitoids of the eucalyptus gall wasp Leptocybe spp. Structures and sense organs of ovipositors of A. causalis and Q. mendeli were studied using scanning and transmission electron microscopy, which provided essential information for exploring the mechanism of host detection by endoparasitoid and ectoparasitoid. The ovipositors of two parasitoids consisted of the first and second valvulae and ended in a pointed tip. There were three types of microtrichia, two types of sensilla chaetica, and one type of sensilla campaniformia on the ovipositors of A. causalis and Q. mendeli. However, Q. mendeli has the fourth type of microtrichia on the ovipositor. The morphology, types, distribution, length, and width of these sensilla and microtrichia were described, and their possible functions are discussed in conjunction with the stinging, oviposition, and the host selection process.
Mineralization of Sialoliths Investigated by Ex Vivo and In Vivo X-ray Computed Tomography
Authors: Nolasco Pedro , Coelho Paulo V. , Coelho Carla , Angelo David F. , Dias J. R. , Alves Nuno M. , Maurício António , Pereira Manuel F.C. , Alves de Matos António P. , Martins Raul C. , Carvalho Patrícia A.
Published: February 2019

The fraction of organic matter present affects the fragmentation behavior of sialoliths; thus, pretherapeutic information on the degree of mineralization is relevant for a correct selection of lithotripsy procedures. This work proposes a methodology for in vivo characterization of salivary calculi in the pretherapeutic context. Sialoliths were characterized in detail by X-ray computed microtomography (μCT) in combination with atomic emission spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. Correlative analysis of the same specimens was performed by in vivo and ex vivo helical computed tomography (HCT) and ex vivo μCT. The mineral matter in the sialoliths consisted essentially of apatite (89 vol%) and whitlockite (11 vol%) with average density of 1.8 g/cm3. In hydrated conditions, the mineral mass prevailed with 53 ± 13 wt%, whereas the organic matter, with a density of 1.2 g/cm3, occupied 65 ± 10% of the sialoliths’ volume. A quantitative relation between sialoliths mineral density and X-ray attenuation is proposed for both HCT and μCT.
The Gender Gap in Brazilian Politics and the Role of the Electoral Court
Authors: Ramos Luciana de Oliveira , da Silva Virgílio Afonso
Published: February 2019

Like many other countries, Brazil has adopted gender quotas in elections for legislatures at all levels of the federation. However, Brazilian gender quotas have been ineffective at increasing women's participation in politics. Authors usually point to reasons related to the electoral system and party structure. This article analyzes a variable that is rarely considered: the role of the Electoral Court. We argue that the quality and intensity of the control exercised by an electoral court, when called upon to decide on the enforcement of the gender quota law, can influence the efficacy of this policy. We show that, in general, the Brazilian Superior Electoral Court tends to foster the participation of women in politics. However, based on two divides—between easy and difficult cases and between cases with low and high impact—we argue that in the realm of gender quotas, this court takes a rather restrained stance in those cases considered both difficult and with high impact.
Do attackers have a legal duty of care? Limits to the ‘individualization of war’
Authors: Dill Janina
Published: February 2019

Does International Humanitarian Law (IHL) impose a duty of care on the attacker? From a moral point of view, should it? This article argues that the legal situation is contestable, and the moral value of a legal duty of care in attack is ambivalent. This is because a duty of care is both a condition for and an obstacle to the ‘individualization of war’. The individualization of war denotes an observable multi-dimensional norm shift in international relations. Norms for the regulation of war that focus on the interests, rights, and duties of the individual have gained in importance compared to those that focus on the interests, rights, and duties of the state. As the individual, not the state, is the ultimate locus of moral value, this norm shift in international relations, and the corresponding developments in international law, are morally desirable. When it comes to IHL, the goal of protecting the interests of the individual creates strong reasons both for and against imposing a legal duty of care on the attacker. The enquiry into whether IHL does and should impose a legal duty of care therefore reveals that the extent to which war can be individualized is limited.
On the efficient computation of range and Doppler data in noise radar
Authors: Wasserzier Christoph , Galati Gaspare
Published: February 2019

In noise radar, digital signal processing algorithms for implementing the computation of the Cross Ambiguity Function through range correlation and Doppler compensation call for optimized solutions. In fact, to achieve a high coherent processing gain, they often compute a large amount of data beyond the maximum range and/or the maximum radial velocity of interest, adding useless information. A novel, efficient algorithm, called Range Filter Bank, is proposed to implement a scope-tailored computation of range/Doppler data in continuous emission noise radar. Downstream its theoretical analysis, the algorithm has been applied to a real-life case study based on dedicated field experiments, in which good quality kinematic data of a car moving at various speeds have been extracted.
Exposure to maternal depressive symptoms in childhood and adolescent suicide-related thoughts and attempts: mediation by child psychiatric symptoms
Authors: Goodday S. M. , Bondy S. , Brown H. K. , Sutradhar R. , Rhodes A.
Published: February 2019

Aims

The nature of the association between child psychiatric symptoms and adolescent suicide-related thoughts (SRT) and attempts (SA) remains unclear. Our objective was to assess whether child psychiatric symptoms from 6 to 10 years of age mediate the association between exposure to maternal depressive symptoms in childhood and offspring SRT and SA in adolescence.

Methods

A population-based cohort study was constructed by linking all eight cycles from the National Longitudinal Survey of Children and Youth (NLSCY), a nationally representative Canadian panel survey conducted from 1994 to 2009. Self-reported maternal depressive symptoms were measured when offspring were between 0 and 5 years. Maternal-reported child psychiatric symptoms and psychiatric comorbid symptoms were measured from 6 to 10 years, and offspring self-reported SRT and SA were measured between 11 and 19 years. Indirect effects, the effect proportion mediated and their corresponding bootstrapped 95% confidence intervals (CI) were estimated.

Results

Hyperactivity and inattention significantly mediated the association between maternal depressive symptoms in childhood and risk of both SRT and SA from 11 to 19 years, where approximately 60% (SRT 95% CI 23–94%; SA 95% CI 27–95%) of this association was explained by hyperactivity and inattention. Psychiatric comorbid symptoms also significantly mediated this relationship and accounted for 50% (95% CI 18–81%) of this association with SA.

Conclusions

Targeting hyperactivity and inattention, and co-occurring psychiatric symptoms in offspring of depressed mothers could reduce risk of SRT, eventual SA and halt progression towards suicide. However, further understanding of comorbid psychiatric symptoms in childhood that most strongly predict adolescent SA is needed.
Dressing the Myanmar Migrant Body: (In-)Visibility and Empowerment in Thailand
Authors: Gruß Inga
Published: January 2019

The invisibility of migrants has been widely analysed in relation to states’ policies and practices. I argue in this article that emphasising the role of states and institutions in marginalising vulnerable populations by rendering them invisible throws a shadow over the multifaceted ways in which migrants interpret and relate to invisibility. Among Myanmar migrants in Thailand, as we shall see here, the notion that invisibility provides a protective shield to migrant bodies is in fact widespread. While invisibility is at times perceived as a threat to the future of these people, conceiving of invisibility solely as a tool of domination precludes us from fully understanding the complexity of Myanmar migrants’ experiences in Thailand and, more specifically, the many forms of empowerment that shape these experiences. Privileging the discourses and practices of Myanmar migrants in Thailand about their sartorial choices reveals that migrants appreciate invisibility for its capacity to create control over their own bodies. Further, it reveals the complexities of negotiating and expressing diasporic sartorial conventions.
The Protective Effect of Thiamine Pryophosphate Against Sugar-Induced Retinal Neovascularisation in Rats
Authors: Cinici Emine , Mammadov Renad , Findik Huseyin , Suleyman Bahadir , Cetin Nihal , Calik Ilknur , Balta Hilal , Hakki Tas Ismail , Sener Ebru , Altuner Durdu
Published: February 2019

Abstract. The aim of this study was to investigate the effect of thiamine pyrophosphate (TPP), administered via sugar water, on retinal neovascularisation in rats. Animals were assigned to three groups, namely the TPP sugar-water group (TPSWG, n = 12), the control group (CG, n = 12) and the healthy group (HG, n = 12). The TPSWG was injected intraperitoneally with TPP once a day for 6 months. CG and HG rats were given distilled water in the same way. TPSWG and CG rats were left free to access an additional 0.292 mmol /ml of sugar water for 6 months. The fasting blood glucose (FBG) levels of the animals were measured monthly. After 6 months, biochemical, gene expression and histopathologic analyses were carried out in the retinal tissues removed from the animals after they were killed. The measured FBG levels were 6.96 ± 0.09 mmol/ml (p < 0.0001 vs. HG), 6.95 ± 0.06 mmol/ml (p < 0.0001 vs. HG) and 3.94 ± 0.10 mmol/ml in the CG, TPSWG and HG groups, respectively. The malondialdehyde (MDA) levels were found to be 2.82 ± 0.23 (p < 0.0001 vs. HG), 1.40 ± 0.32 (p < 0.0001 vs. HG) and 1.66 ± 0.17 in the CG, TPSWG and HG, respectively. Interleukin 1 beta (IL-1β) gene expression was increased (3.78 ± 0.29, p < 0.0001) and total glutathione (tGSH) was decreased (1.32 ± 0.25, p < 0.0001) in the retinal tissue of CG compared with TPSWG (1.92 ± 0.29 and 3.18 ± 0.46, respectively). Increased vascularisation and oedema were observed in the retinal tissue of CG, while the retinal tissues of TPSWG and HG rats had a normal histopathological appearance. A carbohydrate-rich diet may lead to pathological changes in the retina even in nondiabetics, but this may be overcome by TPP administration.
Zinc intake and status in Austria in the light of different reference values
Authors: Elmadfa Ibrahim , Meyer Alexa L. , Kuen Timo , Wagner Karin , Hasenegger Verena
Published: February 2019

Abstract. Zinc has been identified as a critical micronutrient also in high-income countries. There is still some uncertainty about the evaluation of zinc sufficiency due to divergent daily intake reference values. We wanted to exemplify this issue using data from the Austrian Study on Nutritional Status 2012. Plasma zinc concentrations were measured in a nationally representative sample of 872 persons aged 6–80 years (55.5 % female). Dietary zinc intake was estimated from two 24h dietary recalls. Additionally, parameters of the antioxidative status (plasma malondialdehyde (MDA), total antioxidative capacity) and activities of alkaline phosphatase (AP), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px)) were determined. Zinc status was marginal in schoolchildren (40 % of boys and 22 % of girls) and in elderly (28 % of men and 33 % of women). Dietary zinc intake was also unsatisfactory in these groups with 38 % of boys and 32 % of girls and 64.5 % of older men below the nationally recommended intake levels. However, the adequacy of zinc intake varied with different reference values. Adults were more likely to meet the D-A-CH reference values and those from the European Food Safety Authority than the recommendations of the International Zinc Nutrition Consultative Group (IZiNCG) and the Institute of Medicine, whereas children met the IZiNCG values best. Zinc status correlated weakly with AP activity (r = –0.298, p < 0.001) and some antioxidant status markers (CAT, MDA, GSH-PX, SOD), especially in the elderly (MDA: r = –0.527, p < 0.001, and SOD: r = –0.466, p = 0.002). Our results suggest a suboptimal zinc supply in Austria particularly among schoolchildren and older adults.
Vitamin D (FokI) Receptor Gene Polymorphism is associated with Vitamin D Deficiency and Chronic Musculoskeletal Pain. A meta-analysis
Authors: Abdurahman Ahmed Abdulahi , Khorrami-nezhad Leila , Mirzaei Khadijeh
Published: February 2019

Abstract. Background: Musculoskeletal pain is the most common chronic pain experienced by older adults. The aim of this study is to explore the associations between vitamin D (FOKI) receptor gene polymorphism (VDR) and vitamin D deficiency (VDD) and chronic musculoskeletal pain. Methods: Cross-sectional studies published in English from January 2000 to January 2015which reported prevalence of chronic pain (CP) and chronic musculoskeletal pain (CMP) were included in this systematic review and meta-analysis. A heat map was used to visualize and observe the correlation between VDR and CMP, CP and VDD. Results: 20 studies (N = 216,365) were included in the analysis, which showed an overall pooled prevalence estimate of CMP and CP as 30.6 per 100 (95 % CI: 30.59, 30.69) and 27.9 per 100 (95 % CI: 27.68, 28.24) respectively. The heat map clustering analysis visualizes the similarity between CP and CMP. Moreover, a direct correlation was observed between the three disease conditions (namely CMP, CP, and VDD) and FokI VDR polymorphism (FF). Spearman’s correlation analyses with adjusted r2 revealed that there is a statistically significant interaction effect of the FF genotype and VDD on CMP (r2 = 0.19, p = 0.03), a marginally significant interaction effect of the ff genotype and VDD on CMP (r2 = 0.11, p = 0.08). VDD was also associated with increased CMP (r2 = 0.19, p = 0.028). The pooled estimates of the prevalence of CMP in this review were found to be high. Conclusion: FokI VDR gene polymorphism (FF) plays an important role in the relationship between VDD and CMP.
Variations in Cascadia Low‐Frequency Earthquake Behavior With Downdip Distance
Authors: Sweet Justin R. , Creager Kenneth C. , Houston Heidi , Chestler Shelley R.
Published: February 2019

We identify and characterize four different low‐frequency earthquake (LFE) families (LFEs 1–4, ordered updip to downdip) that span the width of the transition zone in the Cascadia Subduction Zone beneath western Washington State. We find that LFE swarm duration, recurrence interval, and event size decrease systematically with increasing depth. LFE moments are observed to follow an exponential distribution rather than a power law distribution, allowing us to determine a characteristic event size for each family. Absolute locations of these LFE families place them very near the inferred Juan de Fuca‐North America plate interface. Relative relocation of individual LFEs within each family reveal elongation parallel to the plate convergence direction and narrow depth distributions with dips corresponding to plate interface models. We interpret the behavior of our LFE families as indicative of slow slip at those locations on the plate interface. The tidal response of LFE activity at LFEs 1, 2, and 3 during a large episodic tremor and slip (ETS) event follows a previously observed evolution, in which tidal response during the initial 1 to 2 days of slip at an LFE patch is much weaker than that during the next few days of slip. The brief bursts of activity at LFE4, although little affected by large episodic tremor and slip events, respond strongly to tidal stresses. Our observed along‐dip contrasts in recurrence behavior and tidal response provide evidence for stress transfer and increased frictional strength with position updip through the tremor zone.
Analyzing High‐Frequency Soil Respiration Using a Probabilistic Model in a Semiarid, Mediterranean Climate
Authors: Anjileli H. , Moftakhari H. R. , Mazdiyasni O. , Norouzi H. , Ashraf S. , Farahmand A. , Bowler P. , Azarderakhsh M. , Huxman Travis E. , AghaKouchak A.
Published: February 2019

High‐frequency (subhourly) changes in soil respiration (Rs), a critical component of the carbon cycle, are not well documented in semiarid ecosystems. We investigate the response of Rs to subhourly soil temperature (Tsoil) and soil volumetric water content (VWC) variation in a semiarid ecosystem across a year of highly variable weather. We propose a probabilistic model to estimate the likelihood of Rs exceeding its annual mean (1.2 μmol CO2/m2s), conditioned on different Tsoil and VWC values. The results show that Rs follows a Gaussian‐like pattern as Tsoil increases, where it follows an upward trend until ~18 °C, and then begins to decline. Rs remains constant at Tsoil beyond ~27 °C. Using our novel conditional probability model, we show both the increasing and decreasing response of Rs to rising Tsoil through two ranges (14–17 and 20–23 °C) where Rs observations show opposing responses. We demonstrate that an increase in Tsoil from 14 to 17 °C causes a rise in Rs by a factor of 1.4 relative to the mean. The proposed model also describes how Rs reduces as Tsoil continues to increase above ~18 °C. Considering VWC and Tsoil into the proposed model, we show that when Tsoil is low (e.g., 17 °C), a rise in VWC yields a decrease of Rs by a factor of 3.6. However, when Tsoil is high (e.g., 23 °C), Rs increases with increasing VWC by a factor of 2.5. Overall, the probabilistic model enables us to detect and characterize changes in Rs distribution in response to different environmental variables and thresholds.
Distribution and Preservation of Root‐ and Shoot‐Derived Carbon Components in Soils Across the Chinese‐Mongolian Grasslands
Authors: Ma Tian , Dai Guohua , Zhu Shanshan , Chen Dima , Chen Litong , Lü Xiaotao , Wang Xiaobo , Zhu Juntao , Zhang Yangjian , Ma Wenhong , He Jin‐Sheng , Bai Yongfei , Han Xingguo , Feng Xiaojuan
Published: February 2019

The relative contribution of roots versus shoots to soil organic carbon (SOC) is a long‐debated topic related to soil carbon formation and dynamics. However, the variation of root‐ and shoot‐derived carbon in natural soils remains poorly constrained due to limited tools to separate them. Here we overcome the difficulty by analyzing biomarkers for root (suberin) and shoot (cutin) in grassland soils spanning >7,000 km on the Qinghai‐Tibetan and Mongolian Plateaus. Coupled with a comprehensive list of climatic, edaphic, and vegetation variables, we assess their inputs, distribution, and preservation patterns. We find that while suberin was a root‐specific tracer, cutin biomarkers that occurred only in trace amount in roots also had a minor but nonnegligible contribution from belowground sources due to the massive root mass in the alpine grasslands. Both components had higher SOC‐normalized concentrations in the alpine than temperate grasslands, along with a higher preservation percentage against net primary productivity and a lower degradation parameter, suggesting a better preservation of these plant‐derived lipid components in the alpine region. Moreover, while cutin and suberin abundances were affected by plant inputs and other SOC constituents, the root mass normalized incorporation efficiency of suberin was only positively correlated to SOC in both regions with a steeper slope in the alpine grasslands and also negatively correlated to root mass in the alpine soils. These results imply that root carbon incorporation is sensitive to environmental variations in the cold region, suggesting potentially more dynamic alterations to root carbon sequestration with environmental changes.
Thermomechanical Implications of Sediment Transport for the Architecture and Evolution of Continental Rifts and Margins
Authors: Andrés‐Martínez Miguel , Pérez‐Gussinyé Marta , Armitage John , Morgan Jason P.
Published: February 2019

Erosion and deposition redistribute mass as a continental rift evolves, which modifies crustal loads and influences subsequent deformation. Surface processes therefore impact both the architecture and the evolution of passive margins. Here we use coupled numerical models to explore the interactions between the surface, crust, and lithosphere. This interaction is primarily sensitive to the efficiency of the surface processes in transporting mass from source to sink. If transport is efficient, there are two possible outcomes: (1) Faulting within the zone of extension is longer lived and has larger offsets. This implies a reduction of the number of faults and the width of the proximal domain. (2) Efficient transport of sediment leads to significant deposition and hence thermal blanketing. This will induce a switch from brittle to ductile deformation of the upper crust in the distal domains. The feedbacks between these two outcomes depend on the extension history, the underlying lithospheric rheology, and the influence of submarine deposition on sediment transport. High erosion/sedimentation during early faulting leads to abrupt crustal necking, while intermediate syntectonic sedimentation rates over distal deep submarine hotter crust leads to unstructured wide distal domains. In models where rheological conditions favor the formation of asymmetric conjugate margins, only subaerial transport of sediments into the distal domains can increase conjugate symmetry by plastic localization. These models suggest that passive margin architecture can be strongly shaped by the solid Earth structure, sea level, and climatic conditions during breakup.
Cobaviruses – a new globally distributed phage group infecting Rhodobacteraceae in marine ecosystems
Authors: Bischoff Vera , Bunk Boyke , Meier-Kolthoff Jan P , Spröer Cathrin , Poehlein Anja , Dogs Marco , Nguyen Mary , Petersen Jörn , Daniel Rolf , Overmann Jörg , Göker Markus , Simon Meinhard , Brinkhoff Thorsten , Moraru Cristina
Published: February 2019

Bacteriophages are widely considered to influence bacterial communities, however most phages are still unknown or not studied well enough to understand their ecological roles. We have isolated two phages infecting Lentibacter sp. SH36, affiliated with the marine Roseobacter group, and retrieved similar phage genomes from publicly available metagenomics databases. Phylogenetic analysis placed the new phages within the Cobavirus group, in the here newly proposed genus Siovirus and subfamily Riovirinae of the Podoviridae. Gene composition and presence of direct terminal repeats in cultivated cobaviruses point toward a genome replication and packaging strategy similar to the T7 phage. Investigation of the genomes suggests that viral lysis of the cell proceeds via the canonical holin-endolysin pathway. Cobaviral hosts include members of the genera Lentibacter, Sulfitobacter and Celeribacter of the Roseobacter group within the family Rhodobacteraceae (Alphaproteobacteria). Screening more than 5,000 marine metagenomes, we found cobaviruses worldwide from temperate to tropical waters, in the euphotic zone, mainly in bays and estuaries, but also in the open ocean. The presence of cobaviruses in protist metagenomes as well as the phylogenetic neighborhood of cobaviruses in glutaredoxin and ribonucleotide reductase trees suggest that cobaviruses could infect bacteria associated with phototrophic or grazing protists. With this study, we expand the understanding of the phylogeny, classification, genomic organization, biogeography and ecology of this phage group infecting marine Rhodobacteraceae.
Functional EEG connectivity in infants associates with later restricted and repetitive behaviours in autism; a replication study
Authors: Haartsen Rianne , Jones Emily J. H. , Orekhova Elena V. , Charman Tony , Johnson Mark H. ,   The BASIS team, Baron-Cohen S. , Bedford R. , Blasi A. , Bolton P. , Chandler S. , Cheung C. , Davies K. , Elsabbagh M. , Fernandes J. , Gammer I. , Garwood H. , Gliga T. , Guiraud J. , Hudry K. , Liew M. , Lloyd-Fox S. , Maris H. , O’Hara L. , Pasco G. , Pickles A. , Ribeiro H. , Salomone E. , Tucker L. , Volein A.
Published: February 2019

We conducted a replication study of our prior report that increased alpha EEG connectivity at 14-months associates with later autism spectrum disorder (ASD) diagnosis, and dimensional variation in restricted interests/repetitive behaviours. 143 infants at high and low familial risk for ASD watched dynamic videos of spinning toys and women singing nursery rhymes while high-density EEG was recorded. Alpha functional connectivity (7–8 Hz) was calculated using the debiased weighted phase lag index. The final sample with clean data included low-risk infants (N = 20), and high-risk infants who at 36 months showed either typical development (N = 47), atypical development (N = 21), or met criteria for ASD (N = 13). While we did not replicate the finding that global EEG connectivity associated with ASD diagnosis, we did replicate the association between higher functional connectivity at 14 months and greater severity of restricted and repetitive behaviours at 36 months in infants who met criteria for ASD. We further showed that this association is strongest for the circumscribed interests subdomain. We propose that structural and/or functional abnormalities in frontal-striatal circuits underlie the observed association. This is the first replicated infant neural predictor of dimensional variation in later ASD symptoms.
Neurodevelopmental heterogeneity and computational approaches for understanding autism
Authors: Jacob Suma , Wolff Jason J. , Steinbach Michael S. , Doyle Colleen B. , Kumar Vipan , Elison Jed T.
Published: February 2019

In recent years, the emerging field of computational psychiatry has impelled the use of machine learning models as a means to further understand the pathogenesis of multiple clinical disorders. In this paper, we discuss how autism spectrum disorder (ASD) was and continues to be diagnosed in the context of its complex neurodevelopmental heterogeneity. We review machine learning approaches to streamline ASD’s diagnostic methods, to discern similarities and differences from comorbid diagnoses, and to follow developmentally variable outcomes. Both supervised machine learning models for classification outcome and unsupervised approaches to identify new dimensions and subgroups are discussed. We provide an illustrative example of how computational analytic methods and a longitudinal design can improve our inferential ability to detect early dysfunctional behaviors that may or may not reach threshold levels for formal diagnoses. Specifically, an unsupervised machine learning approach of anomaly detection is used to illustrate how community samples may be utilized to investigate early autism risk, multidimensional features, and outcome variables. Because ASD symptoms and challenges are not static within individuals across development, computational approaches present a promising method to elucidate subgroups of etiological contributions to phenotype, alternative developmental courses, interactions with biomedical comorbidities, and to predict potential responses to therapeutic interventions.
Molecular underpinnings of clinical disparity patterns in African American vs. Caucasian American multiple myeloma patients
Authors: Kazandjian Dickran , Hill Elizabeth , Hultcrantz Malin , Rustad Evan H. , Yellapantula Venkata , Akhlaghi Theresia , Korde Neha , Mailankody Sham , Dew Alex , Papaemmanuil Elli , Maric Irina , Kwok Mary , Landgren Ola
Published: February 2019

Caucasian Americans (CA) compared with African Americans (AA) have a twofold increased incidence of multiple myeloma (MM) and have an earlier age of diagnosis. However, there is sparse information regarding underlying biological differences across racial/ethnic groups. We characterized genetic alterations using a targeted next-generation sequencing assay called myTYPE, developed at MSKCC, allowing capture of somatic mutations, IgH translocations, gains/losses, and hyperdiploidy. Samples were obtained from the NIH Plasma Cell Dyscrasia Racial Disparity Cohort. In total, 68 patient samples were successfully sequenced and manually curated based on well-established databases. Of the 68 patient samples (47 CA, 21 AA), 84% had at least one type of genomic alteration. Importantly, the IgH translocation, t(11;14), was observed more frequently in the AA group (0 vs. 29%, p = 0.001). Known oncogenic somatic non-synonymous mutations were found in 18 genes and indels in 2 genes. KRAS mutations were the most common mutation found in 16% of patients followed by NRAS and BRAF mutations. TP53 somatic mutations appeared to be more common in CA but lacked significance. This proof-of-principle study indicates the presence of varying underlying tumor biology between racial groups and supports the need of future prospective trials to capture these molecular characteristics.
Pro-oncogenic action of LOX-1 and its splice variant LOX-1Δ4 in breast cancer phenotypes
Authors: Pucci Sabina , Polidoro Chiara , Greggi Chiara , Amati Francesca , Morini Elena , Murdocca Michela , Biancolella Michela , Orlandi Augusto , Sangiuolo Federica , Novelli Giuseppe
Published: February 2019

The identification of new predictive biomarkers and therapeutic target for tailored therapy in breast cancer onset and progression is an interesting challenge. OLR-1 gene encodes the cell membrane receptor LOX-1 (lectin-like oxidized low-density lipoprotein receptor). We have recently identified a novel alternative OLR-1 isoform, LOX-1Δ4, whose expression and functions are still not clarified. In the present paper, we demonstrated that LOX-1 is overexpressed in 70% of human breast cancer (n = 47) and positively correlated to the tumor stage and grade (p < 0.01). Observations on LOX-1 and its splice variant Δ4 pointed out a different expression pattern correlated to breast cancer phenotypes. Overexpressing LOX-1 and LOX-1Δ4 in vitro, we obtained a strong enhancement of proliferative rate and a downregulation of cell death-related proteins. In addition, we observed a strong modulation of histone H4 acetylation and Ku70, the limiting factor of DNA double-strand breaks repair machinery implied in apoptosis inhibition and drug resistance acquisition. Moreover, LOX-1Δ4 overexpression is able to increase proliferation in a non-tumorigenic epithelial cell line, MCF12-F, acting as an oncogene. Altogether, these results suggest that LOX-1 may acts as a molecular link among metabolism, inflammation and cancer, indicating its potential role as biomarker and new molecular target, representing an attractive and concrete opportunity to improve current strategies for breast cancer tailored therapy.
CBX8 exhibits oncogenic properties and serves as a prognostic factor in hepatocellular carcinoma
Authors: Tang Bo , Tian Yu , Liao Yong , Li Zeming , Yu Shuiping , Su Huizhao , Zhong Fudi , Yuan Guandou , Wang Yan , Yu Hongping , Tomlinson Stephen , Qiu Xiaoqiang , He Songqing
Published: February 2019

Polycomb group family is a class of proteins that have important roles in both physiological and pathological processes, and its family member Chromobox homolog 8 (CBX8) regulates cell differentiation, aging, and cell cycle progression in numerous carcinomas; however, the effects and underlying mechanisms of CBX8 in hepatocellular carcinoma (HCC) are rarely reported. We found that CBX8 expression in clinical HCC specimens correlates inversely with patient survival. In HCC cells, we found that enforced overexpression of CBX8 induces epithelial–mesenchymal transition, invasive migration, and stem cell-like traits, which are associated with increased tumor growth and metastasis in mice. Conversely, CBX8 silencing inhibits the aggressive phenotype of HCC cells that have high CBX8 expression. Mechanistically, CBX8 modulates H3K27me3 in the gene promoter of bone morphogenetic protein 4 (BMP4), which is associated with active BMP4 transcription and, consequently, the activation of Smads and mitogen-activated protein kinases. BMP4 expression reverses the effects of CBX8 silencing in inhibiting epithelial–mesenchymal transition, stemness, and metastasis. Our results establish CBX8 as a critical driver of HCC stem cell-like and metastatic behaviors and characterize its role in modulating BMP4 expression. These findings have implications for the targeting of CBX8 as an approach to HCC prognosis and treatment.
miR-34a: a new player in the regulation of T cell function by modulation of NF-κB signaling
Authors: Hart Martin , Walch-Rückheim Barbara , Friedmann Kim S. , Rheinheimer Stefanie , Tänzer Tanja , Glombitza Birgit , Sester Martina , Lenhof Hans-Peter , Hoth Markus , Schwarz Eva C. , Keller Andreas , Meese Eckart
Published: February 2019

NF-κB functions as modulator of T cell receptor-mediated signaling and transcriptional regulator of miR-34a. Our in silico analysis revealed that miR-34a impacts the NF-κB signalosome with miR-34a binding sites in 14 key members of the NF-κB signaling pathway. Functional analysis identified five target genes of miR-34a including PLCG1, CD3E, PIK3CB, TAB2, and NFΚBIA. Overexpression of miR-34a in CD4+ and CD8+ T cells led to a significant decrease of NFΚBIA as the most downstream cytoplasmic NF-κB member, a reduced cell surface abundance of TCRA and CD3E, and to a reduction of T cell killing capacity. Inhibition of miR-34a caused an increase of NFΚBIA, TCRA, and CD3E. Notably, activation of CD4+ and CD8+ T cells entrails a gradual increase of miR-34a. Our results lend further support to a model with miR-34a as a central NF-κB regulator in T cells.
Sphingosine 1 phosphate receptor-1 (S1P1) promotes tumor-associated regulatory T cell expansion: leading to poor survival in bladder cancer
Authors: Liu Yi-Na , Zhang Han , Zhang Lin , Cai Ting-Ting , Huang Dai-Jia , He Jia , Ni Huan-He , Zhou Fang-Jian , Zhang Xiao-Shi , Li Jiang
Published: February 2019

Regulatory T cells (Tregs) represent an important contributor to cancer immune escape, but the molecular mechanism responsible for Treg expansion in tumors is heterogeneous and unclear. Here, we investigated the role of S1P1, a receptor of the bioactive lipid sphingosine 1-phosphate (S1P), in regulating the crosstalk between tumor cells and tumor-associated Tregs in bladder cancer (BC). We found that the frequency of CD4+Foxp3+ Tregs was increased in circulating and tumor-infiltrating lymphocytes from BC patients. S1P1 expression was upregulated in BC tissues compared with tumor-adjacent tissues and was positively correlated with the density of tumor-infiltrated Foxp3+ Tregs. Both S1P1 and Treg predicted poor overall survival in BC patients. The in vitro data paralleled the in vivo data and suggested that the activation or overexpression of S1P1 in BC cells promoted the generation of BC-induced (i)Tregs from CD4+CD25−cells, and the generation of these cells was reversed by treatment with anti-IL-10 or anti-TGF-β. Moreover, S1P1 promoted Treg migration mediated by BC cells. Mechanistically, S1P1 activated the TGF-β signaling pathway, leading to the secretion of TGF-β and IL-10 from BC cells. In total, our findings suggest that S1P1 induces tumor-derived Treg expansion in a cell-specific manner and serves as a potent prognostic biomarker and therapeutic target in BC.
Stress-induced precocious aging in PD-patient iPSC-derived NSCs may underlie the pathophysiology of Parkinson’s disease
Authors: Zhu Liang , Sun Chenxi , Ren Jie , Wang Guangming , Ma Rongjie , Sun Lixin , Yang Danjing , Gao Shane , Ning Ke , Wang Zhigang , Chen Xu , Chen Shengdi , Zhu Hongwen , Gao Zhengliang , Xu Jun
Published: February 2019

Parkinson’s disease (PD) is an aging-related degenerative disorder arisen from the loss of dopaminergic neurons in substantia nigra. Although many genetic mutations have been implicated to be genetically linked to PD, the low incidence of familial PD carried with mutations suggests that there must be other factors such as oxidative stress, mitochondrial dysfunction, accumulation of misfolded proteins, and enhanced inflammation, which are contributable to the pathophysiology of PD. The major efforts of current research have been devoted to unravel the toxic effect of multiple factors, which directly cause the degeneration of dopaminergic neurons in adulthood. Until recently, several studies have demonstrated that NSCs had compromised proliferation and differentiation capacity in PD animal models or PD patient-derived iPS models, suggesting that the pathology of PD may be rooted in some cellular aberrations at early developmental stage but the mechanism remains to be elusive. Based on the early-onset PD patient-specific iPSCs, we found that PD-patient iPSC-derived NSCs were more susceptible to stress and became functionally compromised by radiation or oxidative insults. We further unraveled that stress-induced SIRT1 downregulation leading to autophagic dysfunction, which were responsible for these deficits in PD-NSCs. Mechanistically, we demonstrated that stress-induced activation of p38 MAPK suppressed SIRT1 expression, which in turn augmented the acetylation of multiple ATG proteins of autophagic complex and eventually led to autophagic deficits. Our studies suggest that early developmental deficits may, at least partially, contribute to the pathology of PD and provide a new avenue for developing better therapeutic interventions to PD.
Ser46 phosphorylation of p53 is an essential event in prolyl-isomerase Pin1-mediated p53-independent apoptosis in response to heat stress
Authors: Li Li , Su Zijun , Zou Zhimin , Tan Hongping , Cai Daozhang , Su Lei , Gu Zhengtao
Published: February 2019

Heat stroke has increased in frequency worldwide in recent years and continues to have a high morbidity and mortality. Identification of the mechanisms mediating heat stoke is important and necessary. Our preliminary study revealed heat stress (HS)-induced apoptosis of vascular endothelial cells was associated with reactive oxygen species (ROS)-induced p53 translocation into mitochondria. Previous studies have suggested the prolyl-isomerase Pin1 regulates p53 functioning through specific binding to p53 phosphorylation sites. Based on these studies, we presumed Pin1 is a key intermediate in regulation of mitochondrial p53 translocation through a HS-induced ROS-p53 transcription-independent apoptosis pathway. In this context, we revealed p53 had a crucial role in a HS-induced mitochondrial apoptotic pathway, where p53 protein rapidly translocated into mitochondria in endothelial cells both in vitro and in vivo. In particular, HS caused an increase in p53 phosphorylation at Ser46 that facilitated interactions with phosphorylation-dependent prolyl-isomerase Pin1, which has a key role in promoting HS-induced localization of p53 to mitochondria. Furthermore, we also found ROS production was a critical mediator in HS-induced Pin1/p53 signaling and was involved in regulating mitochondrial apoptosis pathway activation. Therefore, we have contributed to our profound understanding of the mechanism underlying HS-induced endothelial dysfunction in an effort to reduce the mortality and morbidity of heat stroke.
Unfolded protein response is an early, non-critical event during hepatic stellate cell activation
Authors: Mannaerts Inge , Thoen Lien F. R. , Eysackers Nathalie , Cubero Francisco Javier , Batista Leite Sofia , Coldham Iain , Colle Isabelle , Trautwein Christian , van Grunsven Leo A.
Published: February 2019

Hepatic stellate cells activate upon liver injury and help at restoring damaged tissue by producing extracellular matrix proteins. A drastic increase in matrix proteins results in liver fibrosis and we hypothesize that this sudden increase leads to accumulation of proteins in the endoplasmic reticulum and its compensatory mechanism, the unfolded protein response. We indeed observe a very early, but transient induction of unfolded protein response genes during activation of primary mouse hepatic stellate cells in vitro and in vivo, prior to induction of classical stellate cell activation genes. This unfolded protein response does not seem sufficient to drive stellate cell activation on its own, as chemical induction of endoplasmic reticulum stress with tunicamycin in 3D cultured, quiescent stellate cells is not able to induce stellate cell activation. Inhibition of Jnk is important for the transduction of the unfolded protein response. Stellate cells isolated from Jnk knockout mice do not activate as much as their wild-type counterparts and do not have an induced expression of unfolded protein response genes. A timely termination of the unfolded protein response is essential to prevent endoplasmic reticulum stress-related apoptosis. A pathway known to be involved in this termination is the non-sense-mediated decay pathway. Non-sense-mediated decay inhibitors influence the unfolded protein response at early time points during stellate cell activation. Our data suggest that UPR in HSCs is differentially regulated between acute and chronic stages of the activation process. In conclusion, our data demonstrates that the unfolded protein response is a JNK1-dependent early event during hepatic stellate cell activation, which is counteracted by non-sense-mediated decay and is not sufficient to drive the stellate cell activation process. Therapeutic strategies based on UPR or NMD modulation might interfere with fibrosis, but will remain challenging because of the feedback mechanisms between the stress pathways.
CEMIP (KIAA1199) induces a fibrosis-like process in osteoarthritic chondrocytes
Authors: Deroyer Céline , Charlier Edith , Neuville Sophie , Malaise Olivier , Gillet Philippe , Kurth William , Chariot Alain , Malaise Michel , de Seny Dominique
Published: February 2019

CEMIP (for “Cell migration-inducing protein” also called KIAA1199 and Hybid for “Hyaluronan-binding protein”) expression is increased in cancers and described as a regulator of cell survival, growth and invasion. In rheumatoid arthritis, CEMIP is referred to as an angiogenic marker and participates in hyaluronic acid degradation. In this study, CEMIP expression is investigated in healthy and osteoarthritis (OA) cartilage from human and mouse. Its role in OA physiopathology is deciphered, specifically in chondrocytes proliferation and dedifferentiation and in the extracellular matrix remodeling. To this end, CEMIP, αSMA and types I and III collagen expressions were assessed in human OA and non-OA cartilage. CEMIP expression was also investigated in a mouse OA model. CEMIP expression was studied in vitro using a chondrocyte dedifferentiation model. High-throughput RNA sequencing was performed on chondrocytes after CEMIP silencing. Results showed that CEMIP was overexpressed in human and murine OA cartilage and along chondrocytes dedifferentiation. Most of genes deregulated in CEMIP-depleted cells were involved in cartilage turnover (e.g., collagens), mesenchymal transition and fibrosis. CEMIP regulated β-catenin protein level. Moreover, CEMIP was essential for chondrocytes proliferation and promoted αSMA expression, a fibrosis marker, and TGFβ signaling towards the p-Smad2/3 (Alk5/PAI-1) pathway. Interestingly, CEMIP was induced by the pSmad1/5 (Alk1) pathway. αSMA and type III collagen expressions were overexpressed in human OA cartilage and along chondrocytes dedifferentiation. Finally, CEMIP was co-expressed in situ with αSMA in all OA cartilage layers. In conclusion, CEMIP was sharply overexpressed in human and mouse OA cartilage and along chondrocytes dedifferentiation. CEMIP-regulated transdifferentiation of chondrocytes into “chondro-myo-fibroblasts” expressing α-SMA and type III collagen, two fibrosis markers. Moreover, these “chondro-myo-fibroblasts” were found in OA cartilage but not in healthy cartilage.