bluuebunny/crossref_metadata_2025 huggingface dataset:
VALIDATING DSGE MODELS WITH SVARS AND HIGH-DIMENSIONAL DYNAMIC FACTOR MODELS
Authors: Lippi Marco
Published: December 2021

A popular validation procedure for Dynamic Stochastic General Equilibrium (DSGE) models consists in comparing the structural shocks and impulse-response functions obtained by estimation-calibration of the DSGE with those obtained in an Structural Vector Autoregressions (SVAR) identified by means of some of the DSGE restrictions. I show that this practice can be seriously misleading when the variables used in the SVAR contain measurement errors. If this is the case, for generic values of the parameters of the DSGE, the shocks estimated in the SVAR are not “made of” the corresponding structural shocks plus measurement error. Rather, each of the SVAR shocks is contaminated by noncorresponding structural shocks. We argue that High-Dimensional Dynamic Factor Models are free from this drawback and are the natural model to use in validation procedures for DSGEs.
Childhood temperament as a predictor of adolescent nonsuicidal self-injury
Authors: Dale Kristina , Case Julia A.C. , Dyson Margaret W. , Klein Daniel N. , Olino Thomas M.
Published: December 2021

Previous cross-sectional work has consistently found associations between neuroticism and impulsivity and nonsuicidal self-injury (NSSI). However, there are few longitudinal studies of personality risk factors for NSSI. In this study, we examined associations between individual differences in temperament at age 3 and NSSI from ages 9 to 15. At age 3, 559 preschool-aged children (54% male; Mage = 42.2 months [SD = 3.10]) completed laboratory assessments of temperament. Parents also completed questionnaires about their child’s temperament. Children completed a diagnostic interview assessing NSSI engagement at ages 9, 12, and 15. By the age 15 assessment, 12.4% of adolescents reported engaging in NSSI. In univariate models, we found that higher levels of observed sadness and maternal-reported sadness and anger were associated with increased risk for NSSI. In multivariate models, female sex and maternal-reported anger were significantly associated with greater likelihood of NSSI. Laboratory observed sadness and impulsivity were associated with a higher likelihood of NSSI. This work extends the literature on personality risk factors associated with NSSI by finding longitudinal associations between early childhood negative affect and later NSSI engagement during adolescence.
Harpy Eagle Harpia harpyja nest activity patterns: Potential ecotourism and conservation opportunities in the Amazon Forest
Authors: MIRANDA EVERTON B. P. , KENUP CAIO F. , MUNN CHARLES A. , HUIZINGA NIKI , LORMAND NICKOLAS , DOWNS COLLEEN T.
Published: December 2021

Tourism can be a powerful tool for wildlife conservation if well controlled and responsibly managed. Apex predators constitute particularly attractive subjects for tourism, but simultaneously they may generate conflict with local communities. Harpy Eagles Harpia harpyja are the largest eagle species and are highly sought-after by ecotourists. The last stronghold of the Harpy Eagle is the Amazon Forest, which is being deforested for cattle ranching. We tested methods for developing Harpy Eagle ecotourism as a potential tool to harmonize these issues. Using camera traps, we collected data on timing of Harpy Eagle visits to their nests, as well as on probabilities of viewing an eagle. Harpy Eagles can only be seen predictably during the first 12 of the 30–36 month nest cycle. In nests with nestlings (up to 5–7 months), adults are visible on a daily basis, and this period lasts 16.6% of the nesting cycle, demanding a minimum of 13, 17, and 26 nests to have at least one nest with a nestling on 90%, 95% and 99% of the days. After this 5–7 month window, we found that two and 4.16 days spent at nests afforded high probabilities of sighting a fledgling or adult eagle, respectively. Harpy Eagles were mainly active at the beginning and the end of the day. Activity core lasted 6.5 decimal hours for adults, peaking at 10h00, and 7.45 decimal hours for fledged eagles, peaking at 15h00. Our results demonstrate that Harpy Eagles fit several criteria for a viable wildlife attraction: predictable in activity and location, viewable, and diurnal, even though at the same time they are considered a rarity. In a broader perspective, Harpy Eagle tourism shows every indication of being a significant tool for more robust rainforest conservation.
Silver coins, wooden tallies and parchment rolls in Henry III's Exchequer
Authors: Cassidy Richard
Published: December 2021

In the mid thirteenth century, England used only a single coin, the silver penny. The flow of coins into and out of the government's treasury was recorded in the rolls of the Exchequer of Receipt. These receipt and issue rolls have been largely ignored, compared to the pipe rolls, which were records of audit. Some more obscure records, the memoranda of issue, help to show how the daily operations of government finance worked, when cash was the only medium available. They indicate something surprising: the receipt and issue rolls do not necessarily record transactions which took place during the periods they nominally cover. They also show that the Exchequer was experimenting with other forms of payment, using tally sticks, several decades earlier than was previously known. The rolls and the tallies indicate that the objectives of the Exchequer were not, as we would now expect, concerned with balancing income and expenditure, drawing up a budget, or even recording cash flows within a particular year. These concepts were as yet unknown. Instead, the Exchequer's aim was to ensure the accountability of officials, its own and those in other branches of government, by allocating financial responsibility to individuals rather than institutions.
The role of psychological distress in the relationship between lifestyle and compulsivity: An analysis of independent, bi-national samples
Authors: Brierley Mary-Ellen E. , Albertella Lucy , Rotaru Kristian , Destree Louise , Thompson Emma M. , Liu Chang , Christensen Erynn , Lowe Amelia , Segrave Rebecca A. , Richardson Karyn E. , Kayayan Edouard , Chamberlain Samuel R. , Grant Jon E. , Lee Rico S. C. , Hughes Sam , Yücel Murat , Fontenelle Leonardo F.
Published: December 2021

Background

Poor mental health is a state of psychological distress that is influenced by lifestyle factors such as sleep, diet, and physical activity. Compulsivity is a transdiagnostic phenotype cutting across a range of mental illnesses including obsessive–compulsive disorder, substance-related and addictive disorders, and is also influenced by lifestyle. Yet, how lifestyle relates to compulsivity is presently unknown, but important to understand to gain insights into individual differences in mental health. We assessed (a) the relationships between compulsivity and diet quality, sleep quality, and physical activity, and (b) whether psychological distress statistically contributes to these relationships.

Methods

We collected harmonized data on compulsivity, psychological distress, and lifestyle from two independent samples (Australian n = 880 and US n = 829). We used mediation analyses to investigate bidirectional relationships between compulsivity and lifestyle factors, and the role of psychological distress.

Results

Higher compulsivity was significantly related to poorer diet and sleep. Psychological distress statistically mediated the relationship between poorer sleep quality and higher compulsivity, and partially statistically mediated the relationship between poorer diet and higher compulsivity.

Conclusions

Lifestyle interventions in compulsivity may target psychological distress in the first instance, followed by sleep and diet quality. As psychological distress links aspects of lifestyle and compulsivity, focusing on mitigating and managing distress may offer a useful therapeutic approach to improve physical and mental health. Future research may focus on the specific sleep and diet patterns which may alter compulsivity over time to inform lifestyle targets for prevention and treatment of functionally impairing compulsive behaviors.
Ichthyosaurs from the Upper Triassic (Carnian–Norian) of the New Siberian Islands, Russian Arctic, and their implications for the evolution of the ichthyosaurian basicranium and vertebral column
Authors: ZVERKOV Nikolay G. , GRIGORIEV Dmitry V. , WOLNIEWICZ Andrzej S. , KONSTANTINOV Alexey G. , SOBOLEV Evgeny S.
Published: December 2021

The first ichthyosaurian specimens discovered from the Upper Triassic of the Russian Arctic (Kotelny Island, New Siberian Islands) are described herein. They include the remains of large- to small-bodied ichthyosaurians originating from six stratigraphic levels spanning the lower Carnian to middle Norian. The material is mostly represented by isolated vertebrae and ribs, which are not possible to accurately diagnose, but also includes specimens comprising associated vertebrae and a fragmentary skeleton that preserves cranial remains (parabasisphenoid, fragmentary quadrate, partial mandible and hyoids). Based on vertebral and rib morphology, we identify the specimens as representatives of the following taxonomic groups: large-bodied shastasaurids, medium-sized indeterminate ichthyosaurians with a single rib facet in the presacral centra, and small euichthyosaurians with double rib facets present throughout the presacral vertebrae that likely represent toretocnemids and/or basal parvipelvians. In addition, the cranial and mandibular remains preserved in one of the specimens, ZIN PH 5/250, were studied using micro-computed tomography. Its mandible is highly similar to that of toretocnemids, whereas the parabasisphenoid demonstrates a peculiar combination of both plesiomorphic and derived character states, providing the first detailed data on this cranial element in a Late Triassic ichthyosaurian. Furthermore, the specimen also demonstrates a distinctive condition of rib articulation in the anteriormost presacral (cervical) vertebrae, which together with other features allows for the erection of a new taxon – Auroroborealia incognita gen. et sp. nov. Although the phylogenetic position of this taxon is uncertain due to its fragmentary nature, its anatomy, indicating toretocnemid or parvipelvian affinities, further supports the previously hypothesised sister-group relationships between these two clades. The morphology of the parabasisphenoid and vertebral column of the new taxon is discussed in broader contexts of the patterns of evolution of these skeletal regions in ichthyosaurs.
Authority and Power in Russia
Authors: Kharkhordin Oleg
Published: December 2021

Can classical political theories of mixed constitution from Polybius to Cicero help us shed new light on Russian politics? In order to so, this article first considers political structures of such non-parliamentary republics as medieval Novgorod and Venice, while choosing Constantinople as a basis for their comparison. Second, using Anthony Kaldellis's recent book that has reinterpreted Byzantium in terms of the classical theory of res publica, it analyzes the question of auctoritas in ancient republican Rome and then imperial Constantinople. Third, the author employs Giorgio Agamben's book on the state of exception, in order to see how mechanisms of power and authority that the Roman emperors had employed might help us interpret anew the phenomenon of tsardom, given that Ivan the Terrible was the first in Russia to be crowned as tsar, that is, Ceasar. This might have a lasting significance even for present day politics.
Czechoslovak Tariffs in the 1920s: An Example of Historical Specificity in Economic Policy
Authors: Krpec Oldřich , Hloušek Vít
Published: December 2021

Czechoslovakia was the first industrialized economy to substantially increase tariffs after the First World War. At that time, Czechoslovakia was highly export-oriented, with a large trade surplus in industrial goods. We argue that the introduction of tariffs was a consequence of the ethnically heterogeneous structure of the economy. German capital controlled the highly export-oriented light and consumer goods industries; Czech capital dominated in industries that were far less export-oriented or even import-competing, such as machinery, transportation equipment, and electrical goods. Trade and exchange-rate policy preferences of both groups clearly differed; however, the policy decision-making process (at least until 1926) was completely controlled by Czechoslovaks and Czech capital, explicitly committed to a nationalist takeover of Czechoslovakia's economy. This is why it was possible to implement an exchange rate and trade policy that ran contrary to theoretical expectations based on the general (national aggregate) indicators of the national economy.
Revisiting ENSO and IOD Contributions to Australian Precipitation
Authors: Liguori Giovanni , McGregor Shayne , Singh Martin , Arblaster Julie , Di Lorenzo Emanuele
Published: December 2021

Tropical modes of variability, such as El Niño–Southern Oscillation (ENSO) and the Indian Ocean Dipole (IOD), exert a strong influence on the interannual variability of Australian precipitation. Nevertheless, commonly used indices of ENSO and IOD variability display significant co‐variability that prevents a robust quantification of the independent contribution of each mode to precipitation anomalies. This co‐variability issue is often addressed by statistically removing ENSO or IOD variability from the precipitation field before calculating teleconnection patterns. However, by performing a suite of coupled and uncoupled modeling experiments in which either ENSO or IOD variability is physically removed, we show that ENSO‐only‐driven precipitation patterns computed by statistically removing the IOD influence significantly underestimate the impact of ENSO on Australian precipitation variability. Inspired by this, we propose a conceptual model that allows one to effectively separate the contribution of each mode to Australian precipitation variability.
Anomalous Behavior of Zirconium and Hafnium in Volcanic Fumarolic Fluids
Authors: Censi P. , Zuddas P. , Caracausi A. , Sortino F. , Cangemi M. , Piazzese D. , Censi V. , Falcone E.
Published: December 2021

The Zirconium and Hafnium concentrations in worldwide fumaroles fed by magmatic fluids reveal that the Zr/Hf ratio is inversely related to the temperature of emission. Lower Zr/Hf ratio values below the chondritic signature are found in fluids having the highest temperature while super‐chondritic Zr/Hf ratio values are found in lower temperatures. Sub‐chondritic values of the Zr/Hf ratio may be related to larger volatility of Hf‐chloride gas species with respect to Zr‐Cl gas species, while super‐chondritic ratios may correspond to fluid‐rock processes resulting from cooling of uprising magmatic fluids. We propose that sub‐chondritic Zr/Hf ratio values in fumaroles associated with high temperature may be an appropriate marker of fast magmatic rising representing a new sensitive tool for volcanic risks strategies.
The Importance of Electron Landau Damping for the Dissipation of Turbulent Energy in Terrestrial Magnetosheath Plasma
Authors: Afshari A. S. , Howes G. G. , Kletzing C. A. , Hartley D. P. , Boardsen S. A.
Published: December 2021

Heliospheric plasma turbulence plays a key role in transferring the energy of large‐scale magnetic field and plasma flow fluctuations to smaller scales where the energy can be dissipated, ultimately leading to plasma heating. High‐quality measurements of electromagnetic fields and electron velocity distributions by the Magnetospheric Multiscale (MMS) mission in Earth's magnetosheath present a unique opportunity to characterize plasma turbulence and to determine the mechanisms responsible for its dissipation. We apply the field‐particle correlation technique to a set of 20 MMS magnetosheath intervals to identify the dissipation mechanism and quantify the dissipation rate. It is found that 95% of the intervals have velocity‐space signatures of electron Landau damping that are quantitatively consistent with linear kinetic theory for the collisionless damping of kinetic Alfvén waves. About 75% of the intervals contain asymmetric signatures, indicating a local imbalance of kinetic Alfvén wave energy flux in one direction along the magnetic field than the other. About one‐third of the intervals have an electron energization rate with the same order‐of‐magnitude as the estimated turbulent cascade rate, suggesting that electron Landau damping plays a significant, and sometimes dominant, role in the dissipation of the turbulent energy in these magnetosheath intervals.
The Interaction Between Warm‐Core Rings and Submarine Canyons and Its Influence on the Onshore Transport of Offshore Waters
Authors: Li Xiaodan , Zhang Weifeng (Gordon) , Rong Zengrui
Published: December 2021

Gulf Stream warm‐core rings (WCRs) impinging onto the Mid‐Atlantic Bight (MAB) shelf edge can induce substantial water exchange between the shelf and slope seas. Combining satellite imagery and idealized ocean models, this study investigates the long‐neglected influence of submarine canyons on the WCR impingement process. Satellite images show onshore intrusion of the WCR water concentrated near the MAB shelf‐break canyons, indicating canyon‐induced enhancement of cross‐shelf exchange. Model simulations of the ring‐canyon interaction qualitatively reproduce the observed pattern and show greatly enhanced vertical motions and cross‐shelf transport in a canyon. The ring‐induced transient flow in a canyon resolved by the model is consistent with the three‐dimensional canyon circulation driven by ambient along‐slope steady flows as depicted in the literature. Cross‐isobath flows occur over both canyon slopes with a strong upwelling onshore flow over the slope upstream to the coastal‐trapped wave propagation (the upwave slope) and a weak downwelling offshore flow over the downwave slope. To conserve potential vorticity, a subsurface‐intensified cyclonic eddy is formed inside the canyon, which interacts with the sloping bottom and enhances the upwelling onshore flow over the upwave slope. The upwelled deep ring water is transported either back offshore by the ring‐edge current on the upwave side of the canyon or across the canyon onto the downwave shelf forming a localized bulge pattern. While the former is an ephemeral onshore transport process, the latter represents a more sustained onshore transport of the ring water, both of which have major implication for ecosystem dynamics at the shelf edge.
Origin of the Intra‐Oceanic Silverwood Block (New England Orogen, Australia): Evidence From Radiolarian Biostratigraphy and Detrital Zircon Petrochronology
Authors: Rosenbaum Gideon , Rogers Ashley , Gürer Derya , Andjić Goran , Allen Charlotte M.
Published: December 2021

Cambrian to Triassic subduction processes in eastern Australia produced a complex and highly contorted assembly of supra‐subduction units. However, regardless of the long history of oceanic subduction, relatively little evidence exists on oceanic terranes whose accretion onto the continental margin may have accompanied subduction processes. We present new radiolarian and petrochronological data from Devonian and Carboniferous rocks exposed in the middle of a tight orocline. Based on radiolarian biostratigraphy and U‐Pb dating of detrital zircon grains, we show that volcaniclastic rocks from the Silverwood Group and Alice Creek beds were deposited during the Late Devonian, which is later than previously thought. Trace‐element compositions of the Devonian zircons are characteristic of crystallization of magmas in an oceanic environment, thus supporting previous suggestions that the Silverwood Group was derived from an intra‐oceanic arc system. Carboniferous zircons from a nearby forearc basin unit (Mount Barney beds) exhibit a continental affinity, indicating that accretion of the Silverwood Block likely occurred before the establishment of this continental arc. A serpentinite belt that occurs adjacent to the Silverwood Block might represent a remnant ophiolitic suture of the now‐consumed oceanic domain, which once separated the Silverwood Block from the eastern Gondwanan margin. Based on the assumption that such an intervening ocean existed, we discuss alternative scenarios for the origin and accretion of the Silverwood Block. The most likely scenario involves intra‐oceanic magmatism in a marginal oceanic basin whose development was driven by trench retreat, and a subsequent accretion in response to trench advance and/or slab flattening.
Stochastic Inversion of Three‐Dimensional Discrete Fracture Network Structure With Hydraulic Tomography
Authors: Ringel Lisa Maria , Jalali Mohammadreza , Bayer Peter
Published: December 2021

We introduce an approach for the stochastic characterization of the geometric and hydraulic parameters of a three‐dimensional (3D) discrete fracture network (DFN) and for estimating their uncertainty based on data from hydraulic tomography experiments. The inversion approach relies on a Bayesian framework and the resulting posterior distribution is characterized by generating samples by Markov chain Monte Carlo (MCMC) methods. The inversion method is evaluated for four synthetic test cases related to the Grimsel test site in Switzerland. Comparison of original and reconstructed DFN models shows that the presented approach is suitable for identifying variable fracture locations and orientations. This is especially the case for those fractures that represent the preferential flow paths in the simulated experiments. It is also revealed that the Bayesian framework is useful to discriminate fractures based on the reliability of the inversion, which is illustrated by fracture probability maps taken as sections through the studied rock mass. Moreover, it is demonstrated that the hydraulic apertures can be calibrated together with the fracture geometries. A premise for applicability in practice, however, is that the hydraulic measurements are complemented by additional information to sufficiently constrain the value ranges of the geometric and hydraulic parameters to be inverted together. The presented work expands the applicability of a previously presented promising two‐dimensional procedure based on transdimensional inversion to field‐based 3D problems. The theoretical findings here open the door for highly flexible structural characterization in practice based on hydraulic tomography, as well as alternative or complementary tomographic methods.
Gab2 deficiency prevents Flt3-ITD driven acute myeloid leukemia in vivo
Authors: Spohr Corinna , Poggio Teresa , Andrieux Geoffroy , Schönberger Katharina , Cabezas-Wallscheid Nina , Boerries Melanie , Halbach Sebastian , Illert Anna L. , Brummer Tilman
Published: December 2021

Internal tandem duplications (ITD) of the FMS-like tyrosine kinase 3 (FLT3) predict poor prognosis in acute myeloid leukemia (AML) and often co-exist with inactivating DNMT3A mutations. In vitro studies implicated Grb2-associated binder 2 (GAB2) as FLT3-ITD effector. Utilizing a Flt3-ITD knock-in, Dnmt3a haploinsufficient mouse model, we demonstrate that Gab2 is essential for the development of Flt3-ITD driven AML in vivo, as Gab2 deficient mice displayed prolonged survival, presented with attenuated liver and spleen pathology and reduced blast counts. Furthermore, leukemic bone marrow from Gab2 deficient mice exhibited reduced colony-forming unit capacity and increased FLT3 inhibitor sensitivity. Using transcriptomics, we identify the genes encoding for Axl and the Ret co-receptor Gfra2 as targets of the Flt3-ITD/Gab2/Stat5 axis. We propose a pathomechanism in which Gab2 increases signaling of these receptors by inducing their expression and by serving as downstream effector. Thereby, Gab2 promotes AML aggressiveness and drug resistance as it incorporates these receptor tyrosine kinases into the Flt3-ITD signaling network. Consequently, our data identify GAB2 as a promising biomarker and therapeutic target in human AML.
Mammalian gut metabolomes mirror microbiome composition and host phylogeny
Authors: Gregor Rachel , Probst Maraike , Eyal Stav , Aksenov Alexander , Sasson Goor , Horovitz Igal , Dorrestein Pieter C , Meijler Michael M , Mizrahi Itzhak
Published: December 2021

In the past decade, studies on the mammalian gut microbiome have revealed that different animal species have distinct gut microbial compositions. The functional ramifications of this variation in microbial composition remain unclear: do these taxonomic differences indicate microbial adaptations to host-specific functionality, or are these diverse microbial communities essentially functionally redundant, as has been indicated by previous metagenomics studies? Here, we examine the metabolic content of mammalian gut microbiomes as a direct window into ecosystem function, using an untargeted metabolomics platform to analyze 101 fecal samples from a range of 25 exotic mammalian species in collaboration with a zoological center. We find that mammalian metabolomes are chemically diverse and strongly linked to microbiome composition, and that metabolome composition is further correlated to the phylogeny of the mammalian host. Specific metabolites enriched in different animal species included modified and degraded host and dietary compounds such as bile acids and triterpenoids, as well as fermentation products such as lactate and short-chain fatty acids. Our results suggest that differences in microbial taxonomic composition are indeed translated to host-specific metabolism, indicating that taxonomically distant microbiomes are more functionally diverse than redundant.
Colonization of gut microbiota by plasmid-carrying bacteria is facilitated by evolutionary adaptation to antibiotic treatment
Authors: Zhang Peng , Mao Daqing , Gao Huihui , Zheng Liyang , Chen Zeyou , Gao Yuting , Duan Yitao , Guo Jianhua , Luo Yi , Ren Hongqiang
Published: December 2021

Multidrug-resistant plasmid-carrying bacteria are of particular clinical concern as they could transfer antibiotic resistance genes to other bacterial species. However, little is known whether evolutionary adaptation of plasmid-carrying bacteria after long-term antibiotic exposure could affect their subsequent colonization of the human gut. Herein, we combined a long-term evolutionary model based on Escherichia coli K-12 MG1655 and the multidrug-resistant plasmid RP4 with in vivo colonization experiments in mice. We found that the evolutionary adaptation of plasmid-carrying bacteria to antibiotic exposure facilitated colonization of the murine gut and subsequent plasmid transfer to gut bacteria. The evolved plasmid-carrying bacteria exhibited phenotypic alterations, including multidrug resistance, enhanced bacterial growth and biofilm formation capability and decreased plasmid fitness cost, which might be jointly caused by chromosomal mutations (SNPs in rpoC, proQ, and hcaT) and transcriptional modifications. The upregulated transcriptional genes, e.g., type 1 fimbrial-protein pilus (fimA and fimH) and the surface adhesin gene (flu) were likely responsible for the enhanced biofilm-forming capacity. The gene tnaA that encodes a tryptophanase-catalyzing indole formation was transcriptionally upregulated, and increased indole products participated in facilitating the maximum population density of the evolved strains. Furthermore, several chromosomal genes encoding efflux pumps (acriflavine resistance proteins A and B (acrA, acrB), outer-membrane protein (tolC), multidrug-resistance protein (mdtM), and macrolide export proteins A and B (macA, macB)) were transcriptionally upregulated, while most plasmid-harboring genes (conjugal transfer protein (traF) and (trbB), replication protein gene (trfA), beta-lactamase TEM precursor (blaTEM), aminoglycoside 3′-phosphotransferase (aphA) and tetracycline resistance protein A (tetA)) were downregulated. Collectively, these findings demonstrated that evolutionary adaptation of plasmid-carrying bacteria in an antibiotic-influenced environment facilitated colonization of the murine gut by the bacteria and plasmids.
Regional gray matter oligodendrocyte- and myelin-related measures are associated with differential susceptibility to stress-induced behavior in rats and humans
Authors: Long Kimberly L. P. , Chao Linda L. , Kazama Yurika , An Anjile , Hu Kelsey Y. , Peretz Lior , Muller Dyana C. Y. , Roan Vivian D. , Misra Rhea , Toth Claire E. , Breton Jocelyn M. , Casazza William , Mostafavi Sara , Huber Bertrand R. , Woodward Steven H. , Neylan Thomas C. , Kaufer Daniela
Published: December 2021

Individual reactions to traumatic stress vary dramatically, yet the biological basis of this variation remains poorly understood. Recent studies demonstrate the surprising plasticity of oligodendrocytes and myelin with stress and experience, providing a potential mechanism by which trauma induces aberrant structural and functional changes in the adult brain. In this study, we utilized a translational approach to test the hypothesis that gray matter oligodendrocytes contribute to traumatic-stress-induced behavioral variation in both rats and humans. We exposed adult, male rats to a single, severe stressor and used a multimodal approach to characterize avoidance, startle, and fear-learning behavior, as well as oligodendrocyte and myelin basic protein (MBP) content in multiple brain areas. We found that oligodendrocyte cell density and MBP were correlated with behavioral outcomes in a region-specific manner. Specifically, stress-induced avoidance positively correlated with hippocampal dentate gyrus oligodendrocytes and MBP. Viral overexpression of the oligodendrogenic factor Olig1 in the dentate gyrus was sufficient to induce an anxiety-like behavioral phenotype. In contrast, contextual fear learning positively correlated with MBP in the amygdala and spatial-processing regions of the hippocampus. In a group of trauma-exposed US veterans, T1-/T2-weighted magnetic resonance imaging estimates of hippocampal and amygdala myelin associated with symptom profiles in a region-specific manner that mirrored the findings in rats. These results demonstrate a species-independent relationship between region-specific, gray matter oligodendrocytes and differential behavioral phenotypes following traumatic stress exposure. This study suggests a novel mechanism for brain plasticity that underlies individual variance in sensitivity to traumatic stress.
Effects of escitalopram therapy on resting-state functional connectivity of subsystems of the default mode network in unmedicated patients with major depressive disorder
Authors: Cui Jian , Wang Yun , Liu Rui , Chen Xiongying , Zhang Zhifang , Feng Yuan , Zhou Jingjing , Zhou Yuan , Wang Gang
Published: December 2021

Antidepressants are often the first-line medications prescribed for patients with major depressive disorder (MDD). Given the critical role of the default mode network (DMN) in the physiopathology of MDD, the current study aimed to investigate the effects of antidepressants on the resting-state functional connectivity (rsFC) within and between the DMN subsystems. We collected resting-state functional magnetic resonance imaging (rs-fMRI) data from 36 unmedicated MDD patients at baseline and after escitalopram treatment for 12 weeks. The rs-fMRI data were also collected from 61 matched healthy controls at the time point with the same interval. Then, we decomposed the DMN into three subsystems based on a template from previous studies and computed the rsFC within and between the three subsystems. Finally, repeated measures analysis of covariance was conducted to identify the main effect of group and time and their interaction effect. We found that the significantly reduced within-subsystem rsFC in the DMN core subsystem in patients with MDD at baseline was increased after escitalopram treatment and became comparable with that in the healthy controls, whereas the reduced within-subsystem rsFC persisted in the DMN dorsal medial prefrontal cortex (dMPFC) and medial temporal subsystems in patients with MDD following escitalopram treatment. In addition, the reduced between-subsystem rsFC between the core and dMPFC subsystem showed a similar trend of change after treatment in patients with MDD. Moreover, our main results were confirmed using the DMN regions from another brain atlas. In the current study, we found different effects of escitalopram on the rsFC of the DMN subsystems. These findings deepened our understanding of the neuronal basis of antidepressants’ effect on brain function in patients with MDD. The trial name: appropriate technology study of MDD diagnosis and treatment based on objective indicators and measurement. URL: http://www.chictr.org.cn/showproj.aspx?proj=21377. Registration number: ChiCTR-OOC-17012566.
Sex differences in the genetic regulation of the blood transcriptome response to glucocorticoid receptor activation
Authors: Moore Sarah R. , Halldorsdottir Thorhildur , Martins Jade , Lucae Susanne , Müller-Myhsok Bertram , Müller Nikola S. , Piechaczek Charlotte , Feldmann Lisa , Freisleder Franz Joseph , Greimel Ellen , Schulte-Körne Gerd , Binder Elisabeth B. , Arloth Janine
Published: December 2021

Substantial sex differences have been reported in the physiological response to stress at multiple levels, including the release of the stress hormone, cortisol. Here, we explore the genomic variants in 93 females and 196 males regulating the initial transcriptional response to cortisol via glucocorticoid receptor (GR) activation. Gene expression levels in peripheral blood were obtained before and after GR-stimulation with the selective GR agonist dexamethasone to identify differential expression following GR-activation. Sex stratified analyses revealed that while the transcripts responsive to GR-stimulation were mostly overlapping between males and females, the quantitative trait loci (eQTLs) regulation differential transcription to GR-stimulation was distinct. Sex-stratified eQTL SNPs (eSNPs) were located in different functional genomic elements and sex-stratified transcripts were enriched within postmortem brain transcriptional profiles associated with Major Depressive Disorder (MDD) specifically in males and females in the cingulate cortex. Female eSNPs were enriched among SNPs linked to MDD in genome-wide association studies. Finally, transcriptional sensitive genetic profile scores derived from sex-stratified eSNPS regulating differential transcription to GR-stimulation were predictive of depression status and depressive symptoms in a sex-concordant manner in a child and adolescent cohort (n = 584). These results suggest the potential of eQTLs regulating differential transcription to GR-stimulation as biomarkers of sex-specific biological risk for stress-related psychiatric disorders.
Faecal immunochemical test for patients with ‘high-risk’ bowel symptoms: a large prospective cohort study and updated literature review
Authors: Laszlo Helga E. , Seward Edward , Ayling Ruth M. , Lake Jennifer , Malhi Aman , Stephens Clare , Pritchard-Jones Kathy , Chung Donna , Hackshaw Allan , Machesney Michael
Published: December 2021

Background

We evaluated whether faecal immunochemical testing (FIT) can rule out colorectal cancer (CRC) among patients presenting with ‘high-risk’ symptoms requiring definitive investigation.

Methods

Three thousand five hundred and ninety-six symptomatic patients referred to the standard urgent CRC pathway were recruited in a multi-centre observational study. They completed FIT in addition to standard investigations. CRC miss rate (percentage of CRC cases with low quantitative faecal haemoglobin [f-Hb] measurement) and specificity (percentage of patients without cancer with low f-Hb) were calculated. We also provided an updated literature review.

Results

Ninety patients had CRC. At f-Hb < 10 µg/g, the miss rate was 16.7% (specificity 80.1%). At f-Hb < 4 µg/g, the miss rate was 12.2% (specificity 73%), which became 3.3% if low FIT plus the absence of anaemia and abdominal pain were considered (specificity 51%). Within meta-analyses of 9 UK studies, the pooled miss rate was 7.2% (specificity 74%) for f-Hb < 4 µg/g.

Discussion

FIT alone as a triage tool would miss an estimated 1 in 8 cases in our study (1 in 14 from meta-analysis), while many people without CRC could avoid investigations. FIT can focus secondary care diagnostic capacity on patients most at risk of CRC, but more work on safety netting is required before incorporating FIT triage into the urgent diagnostic pathway.
The BH3-only protein NOXA serves as an independent predictor of breast cancer patient survival and defines susceptibility to microtubule targeting agents
Authors: Karbon Gerlinde , Haschka Manuel D. , Hackl Hubert , Soratroi Claudia , Rocamora-Reverte Lourdes , Parson Walther , Fiegl Heidelinde , Villunger Andreas
Published: December 2021

Breast cancer (BC) treatment frequently involves microtubule-targeting agents (MTAs), such as paclitaxel, that arrest cells in mitosis. Sensitivity to MTAs is defined by a subset of pro- and anti-apoptotic BCL2 family proteins controlling mitochondrial apoptosis. Here, we aimed to determine their prognostic value in primary tumour samples from 92 BC patients. Our analysis identified high NOXA/PMAIP mRNA expression levels as an independent prognostic marker for improved relapse-free survival (RFS) and overall survival (OS) in multivariate analysis in BC patients, independent of their molecular subtype. Analysis of available TCGA datasets of 1060 BC patients confirmed our results and added a clear predictive value of NOXA mRNA levels for patients who received MTA-based therapy. In this TCGA cohort, 122 patients received MTA-treatment and high NOXA mRNA levels correlated with their progression-free interval (PFI) and OS. Our follow-up analyses in a panel of BC cell lines of different molecular subtypes identified NOXA protein expression as a key determinant of paclitaxel sensitivity in triple-negative breast cancer (TNBC) cells. Moreover, we noted highest additive effects between paclitaxel and chemical inhibition of BCLX, but not BCL2 or MCL1, documenting dependence of TNBC cells on BCLX for survival and paclitaxel sensitivity defined by NOXA expression levels.
Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases
Authors: Soriano-Teruel Paula M. , García‑Laínez Guillermo , Marco-Salvador María , Pardo Julián , Arias Maykel , DeFord Christian , Merfort Irmgard , Vicent María J. , Pelegrín Pablo , Sancho Mónica , Orzáez Mar
Published: December 2021

The ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) protein is an scaffold component of different inflammasomes, intracellular multiprotein platforms of the innate immune system that are activated in response to pathogens or intracellular damage. The formation of ASC specks, initiated by different inflammasome receptors, promotes the recruitment and activation of procaspase-1, thereby triggering pyroptotic inflammatory cell death and pro-inflammatory cytokine release. Here we describe MM01 as the first-in-class small-molecule inhibitor of ASC that interferes with ASC speck formation. MM01 inhibition of ASC oligomerization prevents activation of procaspase-1 in vitro and inhibits the activation of different ASC-dependent inflammasomes in cell lines and primary cultures. Furthermore, MM01 inhibits inflammation in vivo in a mouse model of inflammasome-induced peritonitis. Overall, we highlight MM01 as a novel broad-spectrum inflammasome inhibitor for the potential treatment of multifactorial diseases involving the dysregulation of multiple inflammasomes.
Natural history of NF1 c.2970_2972del p.(Met992del): confirmation of a low risk of complications in a longitudinal study
Authors: Forde Claire , Burkitt-Wright Emma , Turnpenny Peter D. , Haan Eric , Ealing John , Mansour Sahar , Holder Muriel , Lahiri Nayana , Dixit Abhijit , Procter Annie , Pacot Laurence , Vidaud Dominique , Capri Yline , Gerard Marion , Dollfus Hélène , Schaefer Elise , Quelin Chloé , Sigaudy Sabine , Busa Tiffany , Vera Gabriella , Damaj Lena , Messiaen Ludwine , Stevenson David A. , Davies Peter , Palmer-Smith Sheila , Callaway Alison , Wolkenstein Pierre , Pasmant Eric , Upadhyaya Meena
Published: December 2021

Individuals with the three base pair deletion NM_000267.3(NF1):c.2970_2972del p.(Met992del) have been recognised to present with a milder neurofibromatosis type 1 (NF1) phenotype characterised by café-au-lait macules (CALs) and intertriginous freckling, as well as a lack of cutaneous, subcutaneous and plexiform neurofibromas and other NF1-associated complications. Examining large cohorts of patients over time with this specific genotype is important to confirm the presentation and associated risks of this variant across the lifespan. Forty-one individuals with the in-frame NF1 deletion p.Met992del were identified from 31 families. Clinicians completed a standardised clinical questionnaire for each patient and the resulting data were collated and compared to published cohorts. Thirteen patients have been previously reported, and updated clinical information has been obtained for these individuals. Both CALs and intertriginous freckling were present in the majority of individuals (26/41, 63%) and the only confirmed features in 11 (27%). 34/41 (83%) of the cohort met NIH diagnostic criteria. There was a notable absence of all NF1-associated tumour types (neurofibroma and glioma). Neurofibroma were observed in only one individual—a subcutaneous lesion (confirmed histologically). Nineteen individuals were described as having a learning disability (46%). This study confirms that individuals with p.Met992del display a mild tumoural phenotype compared to those with ‘classical’, clinically diagnosed NF1, and this appears to be the case longitudinally through time as well as at presentation. Learning difficulties, however, appear to affect a significant proportion of NF1 subjects with this phenotype. Knowledge of this genotype–phenotype association is fundamental to accurate prognostication for families and caregivers.
Time-resolved cryo-EM visualizes ribosomal translocation with EF-G and GTP
Authors: Carbone Christine E. , Loveland Anna B. , Gamper Howard B. , Hou Ya-Ming , Demo Gabriel , Korostelev Andrei A.
Published: December 2021

During translation, a conserved GTPase elongation factor—EF-G in bacteria or eEF2 in eukaryotes—translocates tRNA and mRNA through the ribosome. EF-G has been proposed to act as a flexible motor that propels tRNA and mRNA movement, as a rigid pawl that biases unidirectional translocation resulting from ribosome rearrangements, or by various combinations of motor- and pawl-like mechanisms. Using time-resolved cryo-EM, we visualized GTP-catalyzed translocation without inhibitors, capturing elusive structures of ribosome•EF-G intermediates at near-atomic resolution. Prior to translocation, EF-G binds near peptidyl-tRNA, while the rotated 30S subunit stabilizes the EF-G GTPase center. Reverse 30S rotation releases Pi and translocates peptidyl-tRNA and EF-G by ~20 Å. An additional 4-Å translocation initiates EF-G dissociation from a transient ribosome state with highly swiveled 30S head. The structures visualize how nearly rigid EF-G rectifies inherent and spontaneous ribosomal dynamics into tRNA-mRNA translocation, whereas GTP hydrolysis and Pi release drive EF-G dissociation.
Genomic analyses provide insights into spinach domestication and the genetic basis of agronomic traits
Authors: Cai Xiaofeng , Sun Xuepeng , Xu Chenxi , Sun Honghe , Wang Xiaoli , Ge Chenhui , Zhang Zhonghua , Wang Quanxi , Fei Zhangjun , Jiao Chen , Wang Quanhua
Published: December 2021

Spinach is a nutritious leafy vegetable belonging to the family Chenopodiaceae. Here we report a high-quality chromosome-scale reference genome assembly of spinach and genome resequencing of 305 cultivated and wild spinach accessions. Reconstruction of ancestral Chenopodiaceae karyotype indicates substantial genome rearrangements in spinach after its divergence from ancestral Chenopodiaceae, coinciding with high repeat content in the spinach genome. Population genomic analyses provide insights into spinach genetic diversity and population differentiation. Genome-wide association studies of 20 agronomical traits identify numerous significantly associated regions and candidate genes for these traits. Domestication sweeps in the spinach genome are identified, some of which are associated with important traits (e.g., leaf phenotype, bolting and flowering), demonstrating the role of artificial selection in shaping spinach phenotypic evolution. This study provides not only insights into the spinach evolution and domestication but also valuable resources for facilitating spinach breeding.
Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia
Authors: Benard Brooks A. , Leak Logan B. , Azizi Armon , Thomas Daniel , Gentles Andrew J. , Majeti Ravindra
Published: December 2021

The impact of clonal heterogeneity on disease behavior or drug response in acute myeloid leukemia remains poorly understood. Using a cohort of 2,829 patients, we identify features of clonality associated with clinical features and drug sensitivities. High variant allele frequency for 7 mutations (including NRAS and TET2) associate with dismal prognosis; elevated GATA2 variant allele frequency correlates with better outcomes. Clinical features such as white blood cell count and blast percentage correlate with the subclonal abundance of mutations such as TP53 and IDH1. Furthermore, patients with cohesin mutations occurring before NPM1, or transcription factor mutations occurring before splicing factor mutations, show shorter survival. Surprisingly, a branched pattern of clonal evolution is associated with superior clinical outcomes. Finally, several mutations (including NRAS and IDH1) predict drug sensitivity based on their subclonal abundance. Together, these results demonstrate the importance of assessing clonal heterogeneity with implications for prognosis and actionable biomarkers for therapy.
Seismic reflections from a lithospheric suture zone below the Archaean Yilgarn Craton
Authors: Calvert Andrew J. , Doublier Michael P. , Sellars Samantha E.
Published: December 2021

Seismic reflectors in the uppermost mantle, which can indicate past plate tectonic subduction, are exceedingly rare below Archaean cratons, and restricted to the Neoarchaean. Here we present reprocessed seismic reflection profiles from the northwest Archaean Yilgarn Craton and the Palaeoproterozoic Capricorn Orogen of western Australia that reveal the existence of a ~4 km thick south-dipping band of seismic reflectors that extends from the base of the Archaean crust to at least 60 km depth. We interpret these reflectors, which lie south of a ~50 km deep crustal root, as a relict suture zone within the lithosphere. We suggest that the mantle reflectors were created either by subduction of an oceanic plate along the northern edge of the Yilgarn Craton, which started in the Mesoarchaean and produced the rocks in northern Yilgarn greenstone belts that formed in a supra-subduction zone setting, or, alternatively, by underthrusting of continental crust deep into the lithosphere during the Palaeoproterozoic.