bluuebunny/crossref_metadata_2025 huggingface dataset:
Accelerating the Adoption of eSource in Clinical Research: A Transcelerate Point of View
Authors: Parab Abhijit A. , Mehta Prasann , Vattikola Arundhati , Denney Christine K. , Cherry Michele , Maniar Rakesh M. , Kjaer Jesper
Published: March 2020

For almost a decade, regulators and pharmaceutical industry groups have been interested in electronic source (eSource) in clinical trials (Nordo et al. in Learn Health Syst 3:e10076, 2019). eSource may provide efficiencies and value; however, eSource adoption is fragmented and slow. Acceleration of eSource adoption is a critical step in modernizing the conduct of clinical trials. The desired future state is one in which all source data, acquired through any context (e.g., healthcare delivery, chronic disease management) and actor (e.g., healthcare professional, patient, caregiver), are completely electronic, adequate in quality, and fully acceptable in clinical trial submissions by regulators worldwide. Achieving this desired future state requires transformative change management to foster adoption and minimize the burden of implementing eSource. Realizing this vision requires collaborative and dedicated efforts from multiple stakeholders, including patients, clinical trial participants, sites, technology vendors, standards organizations, regulators, payers, and sponsors. Stakeholders should align upon guidance to promote data integrity, data privacy, data security, and interoperability. The eSource revolution requires open dialogue, inclusive of shared learnings among stakeholders, to collectively and rapidly advance adoption. Adoption of eSource will optimize clinical research by enabling faster access to research data and more rapid decision-making, increasing clinical trial efficiency. Furthermore, adoption of eSource will improve data integrity by allowing direct data flow from the source to the sponsor’s system, with minimal or no human intervention. This paper provides the TransCelerate point of view (POV) and recommendations to achieve the future state vision of complete utilization of eSource data in clinical trials and builds on previous TransCelerate eSource publications.
Preventing Covert Brain Infarct-Related Cognitive Impairment and Dementia
Authors: Durrani Romella , Hill Michael D. , Smith Eric E.
Published: March 2020

Covert brain infarcts (CBIs) are five times more prevalent than symptomatic brain infarcts. CBIs are associated with cognitive impairment and therefore may be a target for preventing cognitive decline and dementia. This review focuses on strategies for preventing CBI-related cognitive impairment, either by preventing incident or recurrent CBI or by enhancing cognitive reserve. CBIs begin to become prevalent during midlife and are highly prevalent in later life. The distribution of vascular pathologies of CBI differs from those that cause symptomatic stroke; therefore, preventive treatments may need to differ as well. Only a few randomized clinical trials have provided data on CBI prevention, without conclusive results. Limited data suggest that higher early-life education, hypothesized to enhance cognitive reserve, can protect the brain from effects of CBI.
Fructose and irritable bowel syndrome
Authors: Melchior Chloé , Douard Véronique , Coëffier Moïse , Gourcerol Guillaume
Published: March 2020

Irritable bowel syndrome (IBS) is a chronic disorder characterised by recurrent abdominal pain or discomfort and transit disturbances with heterogeneous pathophysiological mechanisms. The link between food and gastrointestinal (GI) symptoms is often reported by patients with IBS and the role of fructose has recently been highlighted. Fructose malabsorption can easily be assessed by hydrogen and/or methane breath test in response to 25 g fructose; and its prevalence is about 22 % in patients with IBS. The mechanism of fructose-related symptoms is incompletely understood. Osmotic load, fermentation and visceral hypersensitivity are likely to participate in GI symptoms in the IBS population and may be triggered or worsened by fructose. A low-fructose diet could be integrated in the overall treatment strategy, but its role and implication in the improvement of IBS symptoms should be evaluated. In the present review, we discuss fructose malabsorption in adult patients with IBS and the interest of a low-fructose diet in order to underline the important role of fructose in IBS.
The Connection Project: Changing the peer environment to improve outcomes for marginalized adolescents
Authors: Allen Joseph P. , Narr Rachel K. , Nagel Alison G. , Costello Meghan A. , Guskin Karen
Published: March 2020

This study evaluated a school-based intervention to enhance adolescent peer relationships and improve functional outcomes, building upon Ed Zigler’s seminal contribution in recognizing the potential of academic contexts to enhance social and emotional development. Adolescents (N = 610) primarily from economically or racially/ethnically marginalized groups were assessed preintervention, postintervention, and at 4-month follow-up in a randomized controlled trial. At program completion, intervention participants reported significantly increased quality of peer relationships; by 4-month follow-up, this increased quality was also observable by peers outside of the program, and program participants also displayed higher levels of academic engagement and lower levels of depressive symptoms. These latter effects appear to have potentially been mediated via participants’ increased use of social support. The potential of the Connection Project intervention specifically, and of broader efforts to activate adolescent peer relationships as potent sources of social support and growth more generally within the secondary school context, is discussed.
The common origin of family and non-family asteroids: Implications
Authors: Dermott Stanley F. , Christou Apostolos , Li Dan
Published: March 2020

Because the number of asteroids in the IMB with absolute magnitude H<16.5 is effectively complete, the distributions of the sizes and the orbital elements of these asteroids must be devoid of observational selection effects. This allows us to state that the observed size-frequency distributions (SFDs) of the five major asteroid families in the IMB, defined by Nesvorný (2015) using the Hierarchical Clustering Method (Zappala et al. 1990), are distinctly different and deviate significantly from the linear log-log relation described by Dohnanyi (1969). The existence of these differences in the SFDs, and the fact that the precursor bodies of the major families have distinctly different eccentricities and inclinations, provides a simple explanation for the observations that the mean sizes of the family asteroids, taken as a whole, are correlated with their mean proper eccentricities and anti-correlated with their mean proper inclinations. While the latter observations do have a simple explanation, we observe that the mean sizes of the non-family asteroids in the IMB are also correlated with their mean proper eccentricities and anti-correlated with their mean proper inclinations. We deduce from this, and from the fact that the SFDs of the non-family and the family asteroids (again taken as a whole) are almost identical, that the family and most of the non-family and asteroids have a common origin. We estimate that ~85% of all the asteroids in the IMB with H<16.5 originate from the Flora, Vesta, Nysa, Polana and Eulalia families with the remaining ~15% originating from either the same families or, more likely, a few ghost families (Dermott et al. 2018).
Fragmentation of a Filamentary Cloud Threaded by Perpendicular Magnetic Field
Authors: Hanawa Tomoyuki , Kudoh Takahiro , Tomisaka Kohji
Published: March 2020

Filamentary molecular clouds are thought to fragment to form clumps and cores. However, the fragmentation may be suppressed by magnetic force if the magnetic fields run perpendicularly to the cloud axis. We evaluate the effect using a simple model. Our model cloud is assumed to have a Plummer like radial density distribution,
$\rho = {\rho _{\rm{c}}}{\left[ {1 + {r^2}/(2p{H^2})} \right]^{2p}}$
, where r and H denote the radial distance from the cloud axis and the scale length, respectively. The symbols, ρc and p denote the density on the axis and radial density index, respectively. The initial magnetic field is assumed to be uniform and perpendicular to the cloud axis. The model cloud is assumed to be supported against the self gravity by gas pressure and turbulence. We have obtained the growth rate of the fragmentation instability as a function of the wavelength, according to the method of Hanawa, Kudoh & Tomisaka (2017). The instability depends crucially on the outer boundary. If the displacement vanishes in regions very far from the cloud axis, cloud fragmentation is suppressed by a moderate magnetic field. If the displacement is constant along the magnetic field in regions very far from the cloud, the cloud is unstable even when the magnetic field is infinitely strong. The wavelength of the most unstable mode is longer for smaller index, p.
The role of the magnetic field in a translucent molecular cloud
Authors: Panopoulou Georgia
Published: March 2020

Translucent molecular clouds represent a vastly underexplored regime of cloud evolution in terms of the effect of the magnetic field. Their pristine nature renders them ideal for investigating the initial properties of the magnetic field, prior to the onset of star formation. Using starlight polarimetry, we map the plane-of-sky magnetic field orientation throughout 10 sq. degrees of the Polaris Flare translucent molecular cloud. We provide the first quantitative estimate of the magnetic field strength in this type of system. By combining our measurements with the high-resolution Herschel dust emission map, we find a preferred alignment between filaments and the observed magnetic field. Our results support the presence of a strong magnetic field in this system (Panopoulou et al. 2016).
Near-IR imaging polarimetry of the RCW 106 cloud complex
Authors: Tamaoki Shohei , Sugitani Koji , Kusune Takayoshi
Published: March 2020

We have carried out near-IR imaging polarimetry toward RCW 106 with the JHKs-simultaneous imaging polarimeter SIRPOL mounted on the IRSF 1.4m telescope at SAAO, in March and May, 2017 and January, 2018. We have observed 29 fields and covered mostly the southern part of the giant molecular cloud complex associated with the
${{\rm{H}}_\mathbb{I}}$
region RCW 106, which is located at a distance of 3.5 kpc (Moises etal 2011) and is elongated approximately in the north-south direction with a size of ∼70×15 pc. Our preliminary analysis indicates that the magnetic field seems to globally run along the complex elongation, unlike many other elongated clouds that are often reported to have their global elongations perpendicular to the magnetic fields. The RCW 106 complex consists of many small filaments or clumps. Some of such filaments seem to parallel to the magnetic fields, but some others perpendicular. Around the central part of the
${{\rm{H}}_\mathbb{I}}$
region RCW 106, the magnetic field appears to be influenced by the expansion of this
${{\rm{H}}_\mathbb{I}}$
region. Here, we present our preliminary results by comparing with the archival molecular line and far- to mid-IR data.
Ambiguity, Scope, and Significance: Difficulties in Interpreting Celestial Phenomena in Chinese Records
Authors: Chapman J. J.
Published: March 2020

Abstarct

Several problems contribute to difficulties in interpreting transient celestial phenomena as described in Chinese records. Frameworks are an overarching problem.Tianwen, the modern Chinese term for astronomy, in pre-modern times included meteorological phenonemena and was concerned with omenology. Manuscripts that include star charts and comets but also meteorological phenomena and omen reading texts were routinely reframed in modern scholarship to appear as if they included only astronomical content. The scope of pre-moderntianwen, however, was broader than its modern sense. Pre-modern celestial phenomena had political and religious significance. Apparent ambiguity arises from the presence of both meteorological and astronomical phenomena in a single category and from features of the classical Chinese language. Accounting for these problems is essential for research into transient phenomena using historical archives.
Angular Momentum Accretion onto Disc Galaxies
Authors: Fraternali Filippo , Pezzulli Gabriele
Published: March 2020

Throughout the Hubble time, gas makes its way from the intergalactic medium into galaxies fuelling their star formation and promoting their growth. One of the key properties of the accreting gas is its angular momentum, which has profound implications for the evolution of, in particular, disc galaxies. Here, we discuss how to infer the angular momentum of the accreting gas using observations of present-day galaxy discs. We first summarize evidence forongoinginside-out growth of star forming discs. We then focus on the chemistry of the discs and show how the observed metallicity gradients can be explained if gas accretes onto a disc rotating with a velocity 20 – 30% lower than the local circular speed. We also show that these gradients are incompatible with accretion occurring at the edge of the discs and flowing radially inward. Finally, we investigate gas accretion from a hot corona with a cosmological angular momentum distribution and describe how simple models of rotating coronae guarantee the inside-out growth of disc galaxies.
Radial metallicity gradients with Galactic nebular probes
Authors: García-Rojas Jorge
Published: March 2020

The study of radial metallicity gradients in the disc of the Milky Way is a powerful tool to understand the mechamisms that have been acting in the formation and evolution of the Galactic disc. In this proceeding, I will put the eye on some problems that should be carefully addressed to obtain precise determinations of the metallicity gradients.
Time-series photometry of a new set of candidate faint spectrophotometric standard DA white dwarfs
Authors: Calamida Annalisa
Published: March 2020

Future facilities and deep surveys such as LSST, JWST and WFIRST, will require a network of standards faint enough to avoid saturation and homogenously distributed in both hemispheres. DA white dwarfs have almost pure hydrogen atmospheres and they are the simplest stars to model. The opacities are known from first principles, and for temperatures higher than ∼ 20,000 K, their photospheres are purely radiative and should be photometrically stable. DA white dwarfs are then the best candidates to establish a network of faint spectrophotometric standards. In order to provide standards in the dynamic range of large aperture (d > 4m) telescopes, we collected Hubble Space Telescope WFC3 images and ground-based spectroscopy for 23 DA white dwarfs fainter than r ∼ 16.5 mag, distributed at equatorial and northern latitudes (see Saha et al. in these conference proceedings).
The Quality Lighting Teaching Kit: Utilizing Problem-Based Learning in Classrooms
Authors: Walker Constance E. , Pompea Stephen M.
Published: March 2020

Abstarct

The U.S. National Optical Astronomy Observatory’s Education and Public Outreach group has produced a Quality Lighting Teaching Kit. The kits are designed around problem-based learning scenarios. The kit’s six activities allow students to address real lighting problems that relate to wildlife, sky glow, aging eyes, energy consumption, safety, and light trespass. The activities are optimized for 11-16 year olds. As part of the IAU100 celebration, the kits will be manufactured and made available to observatories and communities around the world.
Ocean Warming Pattern Effect On Global And Regional Climate Change
Authors: Xie Shang‐Ping
Published: March 2020

Anthropogenic emissions of greenhouse gases cause the planet to warm, and the ocean uptake of anthropogenic heat slows the warming, preventing the climate system from equilibrating with the increasing radiative forcing. The uneven ocean surface warming affects regional changes in tropical rainfall, El Niño, and the global climate sensitivity. Thus, the study of ocean warming patterns bridges the ocean‐atmospheric dynamics community focusing on spatial patterns on one hand and the climate change community with a traditional emphasis on the planetary energy budget and radiative feedback on the other.
Springtime Export of Arctic Sea Ice Influences Phytoplankton Production in the Greenland Sea
Authors: Mayot N. , Matrai P. A. , Arjona A. , Bélanger S. , Marchese C. , Jaegler T. , Ardyna M. , Steele M.
Published: March 2020

Climate model projections suggest a substantial decrease of sea ice export into the outflow areas of the Arctic Ocean over the 21st century. Fram Strait, located in the Greenland Sea sector, is the principal gateway for ice export from the Arctic Ocean. The consequences of lower sea ice flux through Fram Strait on ocean dynamics and primary production in the Greenland Sea remain unknown. By using the most recent 16 years (2003–2018) of satellite imagery available and hydrographic in situ observations, the role of exported Arctic sea ice on water column stratification and phytoplankton production in the Greenland Sea is evaluated. Years with high Arctic sea ice flux through Fram Strait resulted in high sea ice concentration in the Greenland Sea, stronger water column stratification, and an earlier spring phytoplankton bloom associated with high primary production levels. Similarly, years with low Fram Strait ice flux were associated with a weak water column stratification and a delayed phytoplankton spring bloom. This work emphasizes that sea ice and phytoplankton production in subarctic “outflow seas” can be strongly influenced by changes occurring in the Arctic Ocean.
Lithospheric Contraction on Mars: A 3D Model of the Amenthes Thrust Fault System
Authors: Herrero‐Gil A. , Ruiz J. , Romeo I.
Published: March 2020

Amenthes Rupes is the topographic expression of a main fault belonging to a thrust fault system located parallel to the martian dichotomy boundary. A 3D forward model has been applied to the Amenthes thrust fault system, constraining fault geometries at depth, variations of slip along strike, and structural parameters controlling the formation of fault propagation folds. Our results provide a complex 3D view of the tectonic framework of the area, with implications for tectonic evolution, regional shortening distribution, and the main mechanical discontinuities in the lithosphere. The modeled fault surfaces show planar morphologies combined with listric geometries at depth. The obtained depths of faulting for the major faults of this fault system suggest a depth of the brittle‐ductile transition (at the time of formation) of 20–24 km, somewhat shallower than previous estimates for this area. A possible mechanical discontinuity located at 9.5–13 km deep can be deduced from the faulting depths of the secondary faults. The listric geometries at depth imply that slip is transmitted from the decollement, which, together with the inclusion in the model of secondary and subsidiary faults, allow us to estimate the horizontal shortening recorded in this area ranging from 2–3 km up to ~5.5 km in the southeastern part of the fault system. This range increases the previous shortening estimates in this area between ~60% and ~200%. Consequently, global shortening estimates based on global fault maps are biased by the detail of mapping, and shortening would substantially increase if secondary faults were included.
Strategies for Determining Electron Yield Material Parameters for Spacecraft Charge Modeling
Authors: Lundgreen Phil , Dennison J. R.
Published: March 2020

Accurate modeling of spacecraft charging is essential to mitigate well‐known and all‐too‐common deleterious and costly effects on spacecraft resulting from charging induced by interactions with the space plasma environment. This paper addresses how limited availability of electron emission and transport properties of spacecraft materials—in particular, secondary electron yields—and the wide ranges measured for such properties pose a critical issue for modeling spacecraft charging. It describes a materials charging database for electron emission properties under development, which facilitates more accurate spacecraft charge modeling when used in concert with the strategies outlined herein. These data and techniques provide tools for more accurate material selection, increased confidence in charge models, and a concomitant decrease in mission risk. They also allow better customization of models in response to prolonged space environment exposure and specific mission requirements, which may evolve materials properties.
Comprehensive diagnostics of acute myeloid leukemia by whole transcriptome RNA sequencing
Authors: Arindrarto Wibowo , Borràs Daniel M. , de Groen Ruben A. L. , van den Berg Redmar R. , Locher Irene J. , van Diessen Saskia A. M. E. , van der Holst Rosalie , van der Meijden Edith D. , Honders M. Willy , de Leeuw Rick H. , Verlaat Wina , Jedema Inge , Kroes Wilma G. M. , Knijnenburg Jeroen , van Wezel Tom , Vermaat Joost S. P. , Valk Peter J. M. , Janssen Bart , de Knijff Peter , van Bergen Cornelis A. M. , van den Akker Erik B. , Hoen Peter A. C. ’t , Kiełbasa Szymon M. , Laros Jeroen F. J. , Griffioen Marieke , Veelken Hendrik
Published: March 2020

Acute myeloid leukemia (AML) is caused by genetic aberrations that also govern the prognosis of patients and guide risk-adapted and targeted therapy. Genetic aberrations in AML are structurally diverse and currently detected by different diagnostic assays. This study sought to establish whole transcriptome RNA sequencing as single, comprehensive, and flexible platform for AML diagnostics. We developed HAMLET (Human AML Expedited Transcriptomics) as bioinformatics pipeline for simultaneous detection of fusion genes, small variants, tandem duplications, and gene expression with all information assembled in an annotated, user-friendly output file. Whole transcriptome RNA sequencing was performed on 100 AML cases and HAMLET results were validated by reference assays and targeted resequencing. The data showed that HAMLET accurately detected all fusion genes and overexpression ofEVI1irrespective of 3q26 aberrations. In addition, small variants in 13 genes that are often mutated in AML were called with 99.2% sensitivity and 100% specificity, and tandem duplications inFLT3andKMT2Awere detected by a novel algorithm based on soft-clipped reads with 100% sensitivity and 97.1% specificity. In conclusion, HAMLET has the potential to provide accurate comprehensive diagnostic information relevant for AML classification, risk assessment and targeted therapy on a single technology platform.
European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia
Authors: Hochhaus A. , Baccarani M. , Silver R. T. , Schiffer C. , Apperley J. F. , Cervantes F. , Clark R. E. , Cortes J. E. , Deininger M. W. , Guilhot F. , Hjorth-Hansen H. , Hughes T. P. , Janssen J. J. W. M. , Kantarjian H. M. , Kim D. W. , Larson R. A. , Lipton J. H. , Mahon F. X. , Mayer J. , Nicolini F. , Niederwieser D. , Pane F. , Radich J. P. , Rea D. , Richter J. , Rosti G. , Rousselot P. , Saglio G. , Saußele S. , Soverini S. , Steegmann J. L. , Turkina A. , Zaritskey A. , Hehlmann R.
Published: March 2020

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.
Ultrafast and broadband photodetectors based on a perovskite/organic bulk heterojunction for large-dynamic-range imaging
Authors: Li Chenglong , Wang Hailu , Wang Fang , Li Tengfei , Xu Mengjian , Wang Hao , Wang Zhen , Zhan Xiaowei , Hu Weida , Shen Liang
Published: March 2020

Organic-inorganic hybrid perovskite (OIHP) photodetectors that simultaneously achieve an ultrafast response and high sensitivity in the near-infrared (NIR) region are prerequisites for expanding current monitoring, imaging, and optical communication capbilities. Herein, we demonstrate photodetectors constructed by OIHP and an organic bulk heterojunction (BHJ) consisting of a low-bandgap nonfullerene and polymer, which achieve broadband response spectra up to 1 μm with a highest external quantum efficiency of approximately 54% at 850 nm, an ultrafast response speed of 5.6 ns and a linear dynamic range (LDR) of 191 dB. High sensitivity, ultrafast speed and a large LDR are preeminent prerequisites for the practical application of photodetectors. Encouragingly, due to the high-dynamic-range imaging capacity, high-quality visible-NIR actual imaging is achieved by employing the OIHP photodetectors. We believe that state-of-the-art OIHP photodetectors can accelerate the translation of solution-processed photodetector applications from the laboratory to the imaging market.
Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity
Authors: Hernandez Leanna M. , Lawrence Katherine E. , Padgaonkar N. Tanya , Inada Marisa , Hoekstra Jackson N. , Lowe Jennifer K. , Eilbott Jeffrey , Jack Allison , Aylward Elizabeth , Gaab Nadine , Van Horn John D. , Bernier Raphael A. , McPartland James C. , Webb Sara J. , Pelphrey Kevin A. , Green Shulamite A. , Geschwind Daniel H. , Bookheimer Susan Y. , Dapretto Mirella ,   On behalf of the GENDAAR Consortium
Published: March 2020

Autism spectrum disorder (ASD) is more prevalent in males than in females, but the neurobiological mechanisms that give rise to this sex-bias are poorly understood. The female protective hypothesis suggests that the manifestation of ASD in females requires higher cumulative genetic and environmental risk relative to males. Here, we test this hypothesis by assessing the additive impact of several ASD-associated OXTR variants on reward network resting-state functional connectivity in males and females with and without ASD, and explore how genotype, sex, and diagnosis relate to heterogeneity in neuroendophenotypes. Females with ASD who carried a greater number of ASD-associated risk alleles in the OXTR gene showed greater functional connectivity between the nucleus accumbens (NAcc; hub of the reward network) and subcortical brain areas important for motor learning. Relative to males with ASD, females with ASD and higher OXTR risk-allele-dosage showed increased connectivity between the NAcc, subcortical regions, and prefrontal brain areas involved in mentalizing. This increased connectivity between NAcc and prefrontal cortex mirrored the relationship between genetic risk and brain connectivity observed in neurotypical males showing that, under increased OXTR genetic risk load, females with ASD and neurotypical males displayed increased connectivity between reward-related brain regions and prefrontal cortex. These results indicate that females with ASD differentially modulate the effects of increased genetic risk on brain connectivity relative to males with ASD, providing new insights into the neurobiological mechanisms through which the female protective effect may manifest.
The neurochemical substrates of habitual and goal-directed control
Authors: Voon Valerie , Joutsa Juho , Majuri Joonas , Baek Kwangyeol , Nord Camilla L. , Arponen Eveliina , Forsback Sarita , Kaasinen Valtteri
Published: March 2020

Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [18F]FDOPA, [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [11C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations.
Variants of GRM7 as risk factor and response to antipsychotic therapy in schizophrenia
Authors: Liang Wei , Yu Hao , Su Yi , Lu Tianlan , Yan Hao , Yue Weihua , Zhang Dai
Published: March 2020

Genome-wide association study (GWAS) has determined the metabotropic glutamate receptor 7 (GRM7) gene as potential locus for schizophrenia risk variants; However, the relationship between the GRM7 variants and the risk of schizophrenia is still uncertain, and there are significant individual variations in response to the antipsychotic drugs. In order to identify susceptible gene and drug-response-related markers, 2413 subjects in our research were chosen for determining drug-response-related markers in schizophrenia. The rs1516569 variant (OR = 0.95, P < 3.47 × 10−4) was a significant risk factor, and a single-nucleotide polymorphism of GRM7 gene- rs9883258 (OR = 0.84, P = 2.18 × 10−3) has been determined as potential biomarkers for therapeutic responses of seven commonly used antipsychotic drugs (aripiprazole, haloperidol, olanzapine, perphenazine, quetiapine, risperidone and ziprasidone) in Chinese Han population; Significant associations with treatment response for several single-nucleotide polymorphisms in every antipsychotic drugs, such as rs779746 (OR = 1.39, P = 0.03), rs480409 (OR = 0.73, P = 0.04), rs78137319 (OR = 3.09, P = 0.04), rs1154370 (OR = 1.51, P = 0.006) have been identified in our study. Hence our research elucidates that GRM7 variants play the critical role of predicting the risk of schizophrenia and antipsychotic effect of seven common drugs.
Serum free light chain level at diagnosis in myeloma cast nephropathy—a multicentre study
Authors: Yadav Punit , Sathick Insara Jaffer , Leung Nelson , Brown Elizabeth E. , Cook Mark , Sanders Paul W. , Cockwell Paul
Published: March 2020

Myeloma cast nephropathy (MCN) is a common cause of severe renal impairment in multiple myeloma (MM). The level of free light chain (FLC) that causes MCN varies substantially and there is uncertainty about the threshold level that should be used to inform clinical practice. In a multicentre cohort study of 103 patients with a diagnosis of MM and biopsy-confirmed MCN made between 2002–2014, we report prospectively measured levels of serum FLC at diagnosis obtained using a single nephelometric assay (Freelite®) and we explore the relationship between serum FLC level at diagnosis with renal outcome and patient survival. Using a landmark approach, overall survival (OS) was compared between patients who achieved independence from dialysis compared to those who remained dialysis dependent at 3-month, 6-month, 9-month, and 12-month time points. The median serum FLC level at diagnosis was 7531 mg/L (range 107–114600). Serum creatinine was 535 μmol/L (range 168–2993) and eGFR 7 ml/min/1.73 m2 (range 1–34). Six patients (5.8%) had an FLC level <1500 mg/L, which is the International Myeloma Working Group threshold for MCN and two patients were below the International Kidney and Monoclonal Gammopathy working group threshold of 500 mg/L; one was hypercalcaemic, and one had high-normal serum calcium level and had received a non-steroidal anti-inflammatory agent. Sixty-nine (67%) patients required haemodialysis treatment of whom 36 (52.1%) recovered independent renal function. Sixty-six (64%) patients died with a median OS of 2.5 years (95% CI 1.8–3.3). A landmark analysis revealed that independence from dialysis was associated with improved survival at 3-months (P = 0.003), 6-months (P = 0.035) and 9-months (P = 0.014); there was no survival benefit observed beyond 12 months (P = 0.146). Serum FLC level at diagnosis was neither associated with renal function recovery nor with OS. This is the largest reported cohort of patients with biopsy-confirmed MCN and prospectively measured serum FLC levels. These results indicate that a serum monoclonal FLC > 500 mg/L should be considered the threshold level associated with the development of MCN.
Kea show three signatures of domain-general statistical inference
Authors: Bastos Amalia P. M. , Taylor Alex H.
Published: March 2020

One key aspect of domain-general thought is the ability to integrate information across different cognitive domains. Here, we tested whether kea (Nestor notabilis) can use relative quantities when predicting sampling outcomes, and then integrate both physical information about the presence of a barrier, and social information about the biased sampling of an experimenter, into their predictions. Our results show that kea exhibit three signatures of statistical inference, and therefore can integrate knowledge across different cognitive domains to flexibly adjust their predictions of sampling events. This result provides evidence that true statistical inference is found outside of the great apes, and that aspects of domain-general thinking can convergently evolve in brains with a highly different structure from primates. This has important implications not only for our understanding of how intelligence evolves, but also for research focused on how to create artificial domain-general thought processes.
Juvenile cleaner fish can socially learn the consequences of cheating
Authors: Truskanov Noa , Emery Yasmin , Bshary Redouan
Published: March 2020

Social learning is often proposed as an important driver of the evolution of human cooperation. In this view, cooperation in other species might be restricted because it mostly relies on individually learned or innate behaviours. Here, we show that juvenile cleaner fish (Labroides dimidiatus) can learn socially about cheating consequences in an experimental paradigm that mimics cleaners’ cooperative interactions with client fish. Juvenile cleaners that had observed adults interacting with model clients learned to (1) behave more cooperatively after observing clients fleeing in response to cheating; (2) prefer clients that were tolerant to cheating; but (3) did not copy adults’ arbitrary feeding preferences. These results confirm that social learning can play an active role in the development of cooperative strategies in a non-human animal. They further show that negative responses to cheating can potentially shape the reputation of cheated individuals, influencing cooperation dynamics in interaction networks.
Graph embedding and unsupervised learning predict genomic sub-compartments from HiC chromatin interaction data
Authors: Ashoor Haitham , Chen Xiaowen , Rosikiewicz Wojciech , Wang Jiahui , Cheng Albert , Wang Ping , Ruan Yijun , Li Sheng
Published: March 2020

Chromatin interaction studies can reveal how the genome is organized into spatially confined sub-compartments in the nucleus. However, accurately identifying sub-compartments from chromatin interaction data remains a challenge in computational biology. Here, we present Sub-Compartment Identifier (SCI), an algorithm that uses graph embedding followed by unsupervised learning to predict sub-compartments using Hi-C chromatin interaction data. We find that the network topological centrality and clustering performance of SCI sub-compartment predictions are superior to those of hidden Markov model (HMM) sub-compartment predictions. Moreover, using orthogonal Chromatin Interaction Analysis by in-situ Paired-End Tag Sequencing (ChIA-PET) data, we confirmed that SCI sub-compartment prediction outperforms HMM. We show that SCI-predicted sub-compartments have distinct epigenetic marks, transcriptional activities, and transcription factor enrichment. Moreover, we present a deep neural network to predict sub-compartments using epigenome, replication timing, and sequence data. Our neural network predicts more accurate sub-compartment predictions when SCI-determined sub-compartments are used as labels for training.
Four European Salmonella Typhimurium datasets collected to develop WGS-based source attribution methods
Authors: Munck Nanna , Leekitcharoenphon Pimlapas , Litrup Eva , Kaas Rolf , Meinen Anika , Guillier Laurent , Tang Yue , Malorny Burkhard , Palma Federica , Borowiak Maria , Gourmelon Michèle , Simon Sandra , Banerji Sangeeta , Petrovska Liljana , Dallman Timothy J. , Hald Tine
Published: March 2020

Zoonotic Salmonella causes millions of human salmonellosis infections worldwide each year. Information about the source of the bacteria guides risk managers on control and preventive strategies. Source attribution is the effort to quantify the number of sporadic human cases of a specific illness to specific sources and animal reservoirs. Source attribution methods for Salmonella have so far been based on traditional wet-lab typing methods. With the change to whole genome sequencing there is a need to develop new methods for source attribution based on sequencing data. Four European datasets collected in Denmark (DK), Germany (DE), the United Kingdom (UK) and France (FR) are presented in this descriptor. The datasets contain sequenced samples of Salmonella Typhimurium and its monophasic variants isolated from human, food, animal and the environment. The objective of the datasets was either to attribute the human salmonellosis cases to animal reservoirs or to investigate contamination of the environment by attributing the environmental isolates to different animal reservoirs.
Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects
Authors: Sarmah Swapnalee , Srivastava Rajneesh , McClintick Jeanette N. , Janga Sarath C. , Edenberg Howard J. , Marrs James A.
Published: March 2020

Ethanol exposure during prenatal development causes fetal alcohol spectrum disorder (FASD), the most frequent preventable birth defect and neurodevelopmental disability syndrome. The molecular targets of ethanol toxicity during development are poorly understood. Developmental stages surrounding gastrulation are very sensitive to ethanol exposure. To understand the effects of ethanol on early transcripts during embryogenesis, we treated zebrafish embryos with ethanol during pre-gastrulation period and examined the transcripts by Affymetrix GeneChip microarray before gastrulation. We identified 521 significantly dysregulated genes, including 61 transcription factors in ethanol-exposed embryos. Sox2, the key regulator of pluripotency and early development was significantly reduced. Functional annotation analysis showed enrichment in transcription regulation, embryonic axes patterning, and signaling pathways, including Wnt, Notch and retinoic acid. We identified all potential genomic targets of 25 dysregulated transcription factors and compared their interactions with the ethanol-dysregulated genes. This analysis predicted that Sox2 targeted a large number of ethanol-dysregulated genes. A gene regulatory network analysis showed that many of the dysregulated genes are targeted by multiple transcription factors. Injection of sox2 mRNA partially rescued ethanol-induced gene expression, epiboly and gastrulation defects. Additional studies of this ethanol dysregulated network may identify therapeutic targets that coordinately regulate early development.
Dual dynamics of mitochondrial permeability transition pore opening
Authors: Wacquier Benjamin , Combettes Laurent , Dupont Geneviève
Published: March 2020

Mitochondria play an essential role in bioenergetics and cellular Ca$${}^{2+}$$2+ handling. The mitochondrial permeability transition pore (mPTP) is a non-specific channel located in the inner mitochondrial membrane. Long-lasting openings of the pore allow the rapid passage of ions and large molecules, which can result in cell death. The mPTP also exhibits transient, low conductance openings that contribute to Ca$${}^{2+}$$2+ homeostasis. Although many regulators of the pore have been identified, none of them uniquely governs the passage between the two operating modes, which thus probably relies on a still unidentified network of interactions. By developing a core computational model for mPTP opening under the control of mitochondrial voltage and Ca$${}^{2+}$$2+, we uncovered the existence of a positive feedback loop leading to bistability. The characteristics of the two stable steady-states correspond to those of the two opening states. When inserted in a full model of Ca$${}^{2+}$$2+ handling by mitochondria, our description of the pore reproduces observations in mitochondrial suspensions. Moreover, the model predicted the occurrence of hysteresis in the switching between the two modes, upon addition and removal of free Ca$${}^{2+}$$2+ in the extra-mitochondrial medium. Stochastic simulations then confirmed that the pore can undergo transient openings resembling those observed in intact cells.
Structure and mechanism of a redesigned multidrug transporter from the Major Facilitator Superfamily
Authors: Wu Hsin-Hui , Symersky Jindrich , Lu Min
Published: March 2020

The rapid increase of multidrug resistance poses urgent threats to human health. Multidrug transporters prompt multidrug resistance by exporting different therapeutics across cell membranes, often by utilizing the H+ electrochemical gradient. MdfA from Escherichia coli is a prototypical H+ -dependent multidrug transporter belonging to the Major Facilitator Superfamily. Prior studies revealed unusual flexibility in the coupling between multidrug binding and deprotonation in MdfA, but the mechanistic basis for this flexibility was obscure. Here we report the X-ray structures of a MdfA mutant E26T/D34M/A150E, wherein the multidrug-binding and protonation sites were revamped, separately bound to three different substrates at resolutions up to 2.0 Å. To validate the functional relevance of these structures, we conducted mutational and biochemical studies. Our data elucidated intermediate states during antibiotic recognition and suggested structural changes that accompany the substrate-evoked deprotonation of E26T/D34M/A150E. These findings help to explain the mechanistic flexibility in drug/H+ coupling observed in MdfA and may inspire therapeutic development to preempt efflux-mediated antimicrobial resistance.
Activation Complexity: A Cognitive Impairment Tool for Characterizing Neuro-isolation
Authors: Napoli Nicholas J. , Demas Matthew , Stephens Chad L. , Kennedy Kellie D. , Harrivel Angela R. , Barnes Laura E. , Pope Alan T.
Published: March 2020

Electroencephalography (EEG) is a method for recording electrical activity, indicative of cortical brain activity from the scalp. EEG has been used to diagnose neurological diseases and to characterize impaired cognitive states. When the electrical activity of neurons are temporally synchronized, the likelihood to reach their threshold potential for the signal to propagate to the next neuron, increases. This phenomenon is typically analyzed as the spectral intensity increasing from the summation of these neurons firing. Non-linear analysis methods (e.g., entropy) have been explored to characterize neuronal firings, but only analyze temporal information and not the frequency spectrum. By examining temporal and spectral entropic relationships simultaneously, we can better characterize how neurons are isolated, (the signal’s inability to propagate to adjacent neurons), an indicator of impairment. A novel time-frequency entropic analysis method, referred to as Activation Complexity (AC), was designed to quantify these dynamics from key EEG frequency bands. The data was collected during a cognitive impairment study at NASA Langley Research Center, involving hypoxia induction in 49 human test subjects. AC demonstrated significant changes in EEG firing patterns characterize within explanatory (p < 0.05) and predictive models (10% increase in accuracy). The proposed work sets the methodological foundation for quantifying neuronal isolation and introduces new potential technique to understand human cognitive impairment for a range of neurological diseases and insults.
Visuocortical tuning to a threat-related feature persists after extinction and consolidation of conditioned fear
Authors: Antov Martin I. , Plog Elena , Bierwirth Philipp , Keil Andreas , Stockhorst Ursula
Published: March 2020

Neurons in the visual cortex sharpen their orientation tuning as humans learn aversive contingencies. A stimulus orientation (CS+) that reliably predicts an aversive noise (unconditioned stimulus: US) is selectively enhanced in lower-tier visual cortex, while similar unpaired orientations (CS−) are inhibited. Here, we examine in male volunteers how sharpened visual processing is affected by fear extinction learning (where no US is presented), and how fear and extinction memory undergo consolidation one day after the original learning episode. Using steady-state visually evoked potentials from electroencephalography in a fear generalization task, we found that extinction learning prompted rapid changes in orientation tuning: Both conditioned visuocortical and skin conductance responses to the CS+ were strongly reduced. Next-day re-testing (delayed recall) revealed a brief but precise return-of-tuning to the CS+ in visual cortex accompanied by a brief, more generalized return-of-fear in skin conductance. Explorative analyses also showed persistent tuning to the threat cue in higher visual areas, 24 h after successful extinction, outlasting peripheral responding. Together, experience-based changes in the sensitivity of visual neurons show response patterns consistent with memory consolidation and spontaneous recovery, the hallmarks of long-term neural plasticity.