bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial
Authors: Eiger Daniel , Pondé Noam F. , Agbor-Tarh Dominique , Moreno-Aspitia Alvaro , Piccart Martine , Hilbers Florentine S. , Werner Olena , Chumsri Saranya , Dueck Amylou , Kroep Judith R. , Gomez Henry , Láng István , Rodeheffer Richard J. , Ewer Michael S. , Suter Thomas , de Azambuja Evandro 
Published: March 2020

Abstract
Background
Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting.

Methods
This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm.

Results
With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68–1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4–11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54–6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25–2.75]), BMI > 30 kg/m2 (vs < 25 mg/kg2, OR 2.21 [95% CI 1.40–3.49]), cumulative dose of doxorubicin ≥240 mg/m2 (OR 1.36 [95% CI 1.01–1.82]) and of epirubicin≥ 480 mg/m2 (OR 2.33 [95% CI 1.55–3.51]).

Conclusions
Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial.

Trial registration number
ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006–000562–36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2–06 /EGF106708/N063D.
Chiral twisting in a bacterial cytoskeletal polymer affects filament size and orientation
Authors: Shi Handuo , Quint David A. , Grason Gregory M. , Gopinathan Ajay , Huang Kerwyn Casey 
Published: March 2020

AbstractIn many rod-shaped bacteria, the actin homolog MreB directs cell-wall insertion and maintains cell shape, but it remains unclear how structural changes to MreB affect its organization in vivo. Here, we perform molecular dynamics simulations for Caulobacter crescentus MreB to extract mechanical parameters for inputs into a coarse-grained biophysical polymer model that successfully predicts MreB filament properties in vivo. Our analyses indicate that MreB double protofilaments can exhibit left-handed twisting that is dependent on the bound nucleotide and membrane binding; the degree of twisting correlates with the length and orientation of MreB filaments observed in vitro and in vivo. Our molecular dynamics simulations also suggest that membrane binding of MreB double protofilaments induces a stable membrane curvature of similar magnitude to that observed in vivo. Thus, our multiscale modeling correlates cytoskeletal filament size with conformational changes inferred from molecular dynamics simulations, providing a paradigm for connecting protein filament structure and mechanics to cellular organization and function.
Synergistic electroreduction of carbon dioxide to carbon monoxide on bimetallic layered conjugated metal-organic frameworks
Authors: Zhong Haixia , Ghorbani-Asl Mahdi , Ly Khoa Hoang , Zhang Jichao , Ge Jin , Wang Mingchao , Liao Zhongquan , Makarov Denys , Zschech Ehrenfried , Brunner Eike , Weidinger Inez M. , Zhang Jian , Krasheninnikov Arkady V. , Kaskel Stefan , Dong Renhao , Feng Xinliang 
Published: March 2020

AbstractHighly effective electrocatalysts promoting CO2 reduction reaction (CO2RR) is extremely desirable to produce value-added chemicals/fuels while addressing current environmental challenges. Herein, we develop a layer-stacked, bimetallic two-dimensional conjugated metal-organic framework (2D c-MOF) with copper-phthalocyanine as ligand (CuN4) and zinc-bis(dihydroxy) complex (ZnO4) as linkage (PcCu-O8-Zn). The PcCu-O8-Zn exhibits high CO selectivity of 88%, turnover frequency of 0.39 s−1 and long-term durability (>10 h), surpassing thus by far reported MOF-based electrocatalysts. The molar H2/CO ratio (1:7 to 4:1) can be tuned by varying metal centers and applied potential, making 2D c-MOFs highly relevant for syngas industry applications. The contrast experiments combined with operando spectroelectrochemistry and theoretical calculation unveil a synergistic catalytic mechanism; ZnO4 complexes act as CO2RR catalytic sites while CuN4 centers promote the protonation of adsorbed CO2 during CO2RR. This work offers a strategy on developing bimetallic MOF electrocatalysts for synergistically catalyzing CO2RR toward syngas synthesis.
Observation of an antiferromagnetic quantum critical point in high-purity LaNiO3
Authors: Liu Changjiang , Humbert Vincent F. C. , Bretz-Sullivan Terence M. , Wang Gensheng , Hong Deshun , Wrobel Friederike , Zhang Jianjie , Hoffman Jason D. , Pearson John E. , Jiang J. Samuel , Chang Clarence , Suslov Alexey , Mason Nadya , Norman M. R. , Bhattacharya Anand 
Published: March 2020

AbstractAmongst the rare-earth perovskite nickelates, LaNiO3 (LNO) is an exception. While the former have insulating and antiferromagnetic ground states, LNO remains metallic and non-magnetic down to the lowest temperatures. It is believed that LNO is a strange metal, on the verge of an antiferromagnetic instability. Our work suggests that LNO is a quantum critical metal, close to an antiferromagnetic quantum critical point (QCP). The QCP behavior in LNO is manifested in epitaxial thin films with unprecedented high purities. We find that the temperature and magnetic field dependences of the resistivity of LNO at low temperatures are consistent with scatterings of charge carriers from weak disorder and quantum fluctuations of an antiferromagnetic nature. Furthermore, we find that the introduction of a small concentration of magnetic impurities qualitatively changes the magnetotransport properties of LNO, resembling that found in some heavy-fermion Kondo lattice systems in the vicinity of an antiferromagnetic QCP.
Impact of functional synapse clusters on neuronal response selectivity
Authors: Ujfalussy Balázs B. , Makara Judit K. 
Published: March 2020

AbstractClustering of functionally similar synapses in dendrites is thought to affect neuronal input-output transformation by triggering local nonlinearities. However, neither the in vivo impact of synaptic clusters on somatic membrane potential (sVm), nor the rules of cluster formation are elucidated. We develop a computational approach to measure the effect of functional synaptic clusters on sVm response of biophysical model CA1 and L2/3 pyramidal neurons to in vivo-like inputs. We demonstrate that small synaptic clusters appearing with random connectivity do not influence sVm. With structured connectivity, ~10–20 synapses/cluster are optimal for clustering-based tuning via state-dependent mechanisms, but larger selectivity is achieved by 2-fold potentiation of the same synapses. We further show that without nonlinear amplification of the effect of random clusters, action potential-based, global plasticity rules cannot generate functional clustering. Our results suggest that clusters likely form via local synaptic interactions, and have to be moderately large to impact sVm responses.
Causal networks for climate model evaluation and constrained projections
Authors: Nowack Peer , Runge Jakob , Eyring Veronika , Haigh Joanna D. 
Published: March 2020

AbstractGlobal climate models are central tools for understanding past and future climate change. The assessment of model skill, in turn, can benefit from modern data science approaches. Here we apply causal discovery algorithms to sea level pressure data from a large set of climate model simulations and, as a proxy for observations, meteorological reanalyses. We demonstrate how the resulting causal networks (fingerprints) offer an objective pathway for process-oriented model evaluation. Models with fingerprints closer to observations better reproduce important precipitation patterns over highly populated areas such as the Indian subcontinent, Africa, East Asia, Europe and North America. We further identify expected model interdependencies due to shared development backgrounds. Finally, our network metrics provide stronger relationships for constraining precipitation projections under climate change as compared to traditional evaluation metrics for storm tracks or precipitation itself. Such emergent relationships highlight the potential of causal networks to constrain longstanding uncertainties in climate change projections.
Parallel evolution of dominant pistil-side self-incompatibility suppressors in Arabidopsis
Authors: Fujii Sota , Shimosato-Asano Hiroko , Kakita Mitsuru , Kitanishi Takashi , Iwano Megumi , Takayama Seiji 
Published: March 2020

AbstractSelfing is a frequent evolutionary trend in angiosperms, and is a suitable model for studying the recurrent patterns underlying adaptive evolution. Many plants avoid self-fertilization by physiological processes referred to as self-incompatibility (SI). In the Brassicaceae, direct and specific interactions between the male ligand SP11/SCR and the female receptor kinase SRK are required for the SI response. Although Arabidopsis thaliana acquired autogamy through loss of these genes, molecular evolution contributed to the spread of self-compatibility alleles requires further investigation. We show here that in this species, dominant SRK silencing genes have evolved at least twice. Different inverted repeat sequences were found in the relic SRK region of the Col-0 and C24 strains. Both types of inverted repeats suppress the functional SRK sequence in a dominant fashion with different target specificities. It is possible that these dominant suppressors of SI contributed to the rapid fixation of self-compatibility in A. thaliana.
Dissecting the early steps of MLL induced leukaemogenic transformation using a mouse model of AML
Authors: Basilico Silvia , Wang Xiaonan , Kennedy Alison , Tzelepis Konstantinos , Giotopoulos George , Kinston Sarah J. , Quiros Pedro M. , Wong Kim , Adams David J. , Carnevalli Larissa S. , Huntly Brian J. P. , Vassiliou George S. , Calero-Nieto Fernando J. , Göttgens Berthold 
Published: March 2020

AbstractLeukaemogenic mutations commonly disrupt cellular differentiation and/or enhance proliferation, thus perturbing the regulatory programs that control self-renewal and differentiation of stem and progenitor cells. Translocations involving theMll1(Kmt2a) gene generate powerful oncogenic fusion proteins, predominantly affecting infant and paediatric AML and ALL patients. The early stages of leukaemogenic transformation are typically inaccessible from human patients and conventional mouse models. Here, we take advantage of cells conditionally blocked at the multipotent haematopoietic progenitor stage to develop a MLL-r model capturing early cellular and molecular consequences of MLL-ENL expression based on a clear clonal relationship between parental and leukaemic cells. Through a combination of scRNA-seq, ATAC-seq and genome-scale CRISPR-Cas9 screening, we identify pathways and genes likely to drive the early phases of leukaemogenesis. Finally, we demonstrate the broad utility of using matched parental and transformed cells for small molecule inhibitor studies by validating both previously known and other potential therapeutic targets.
Chromatin accessibility promotes hematopoietic and leukemia stem cell activity
Authors: Cabal-Hierro Lucia , van Galen Peter , Prado Miguel A. , Higby Kelly J. , Togami Katsuhiro , Mowery Cody T. , Paulo Joao A. , Xie Yingtian , Cejas Paloma , Furusawa Takashi , Bustin Michael , Long Henry W. , Sykes David B. , Gygi Steven P. , Finley Daniel , Bernstein Bradley E. , Lane Andrew A. 
Published: March 2020

AbstractChromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification is associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cells (HSCs) and leukemia, such as HoxA cluster genes. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs, and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.
Self-regulated spacing in a massive open online course is related to better learning
Authors: Carvalho Paulo F. , Sana Faria , Yan Veronica X. 
Published: March 2020

AbstractIn this study, we examined students’ natural studying behaviors in massive, open, online course (MOOC) on introductory psychology. We found that, overall, distributing study across multiple sessions—increasing spacing—was related to increased performance on end-of-unit quizzes, even when comparing the same student across different time-points in the course. Moreover, we found important variation on who is more likely to engage in spaced study and benefit from it. Students with higher ability and students who were more likely to complete course activities were more likely to space their study. Spacing benefits, however, were largest for the lower-ability students and for those students who were less likely to complete activities. These results suggest that spaced study might work as a buffer, improving performance for low ability students and those who do not engage in active practices. This study highlights the positive impact of spacing in real-world learning situations, but more importantly, the role of self-regulated learning decisions in shaping the impact of spaced practice.
Gadolinium labelled nanoliposomes as the platform for MRI theranostics: in vitro safety study in liver cells and macrophages
Authors: Šimečková Pavlína , Hubatka František , Kotouček Jan , Turánek Knötigová Pavlína , Mašek Josef , Slavík Josef , Kováč Ondrej , Neča Jiří , Kulich Pavel , Hrebík Dominik , Stráská Jana , Pěnčíková Kateřina , Procházková Jiřina , Diviš Pavel , Macaulay Stuart , Mikulík Robert , Raška Milan , Machala Miroslav , Turánek Jaroslav 
Published: March 2020

AbstractGadolinium (Gd)–based contrast agents are extensively used for magnetic resonance imaging (MRI). Liposomes are potential nanocarrier–based biocompatible platforms for development of new generations of MRI diagnostics. Liposomes with Gd–complexes (Gd–lip) co–encapsulated with thrombolytic agents can serve both for imaging and treatment of various pathological states including stroke. In this study, we evaluated nanosafety of Gd–lip containing PE-DTPA chelating Gd+3 prepared by lipid film hydration method. We detected no cytotoxicity of Gd–lip in human liver cells including cancer HepG2, progenitor (non–differentiated) HepaRG, and differentiated HepaRG cells. Furthermore, no potential side effects of Gd–lip were found using a complex system including general biomarkers of toxicity, such as induction of early response genes, oxidative, heat shock and endoplasmic reticulum stress, DNA damage responses, induction of xenobiotic metabolizing enzymes, and changes in sphingolipid metabolism in differentiated HepaRG. Moreover, Gd–lip did not show pro–inflammatory effects, as assessed in an assay based on activation of inflammasome NLRP3 in a model of human macrophages, and release of eicosanoids from HepaRG cells. In conclusion, this in vitro study indicates potential in vivo safety of Gd–lip with respect to hepatotoxicity and immunopathology caused by inflammation.
The atlas of StW 573 and the late emergence of human-like head mobility and brain metabolism
Authors: Beaudet Amélie , Clarke Ronald J. , Heaton Jason L. , Pickering Travis R. , Carlson Kristian J. , Crompton Robin H. , Jashashvili Tea , Bruxelles Laurent , Jakata Kudakwashe , Bam Lunga , Van Hoorebeke Luc , Kuman Kathleen , Stratford Dominic 
Published: March 2020

AbstractFunctional morphology of the atlas reflects multiple aspects of an organism’s biology. More specifically, its shape indicates patterns of head mobility, while the size of its vascular foramina reflects blood flow to the brain. Anatomy and function of the early hominin atlas, and thus, its evolutionary history, are poorly documented because of a paucity of fossilized material. Meticulous excavation, cleaning and high-resolution micro-CT scanning of the StW 573 (‘Little Foot’) skull has revealed the most complete early hominin atlas yet found, having been cemented by breccia in its displaced and flipped over position on the cranial base anterolateral to the foramen magnum. Description and landmark-free morphometric analyses of the StW 573 atlas, along with other less complete hominin atlases from Sterkfontein (StW 679) and Hadar (AL 333-83), confirm the presence of an arboreal component in the positional repertoire of Australopithecus. Finally, assessment of the cross-sectional areas of the transverse foramina of the atlas and the left carotid canal in StW 573 further suggests there may have been lower metabolic costs for cerebral tissues in this hominin than have been attributed to extant humans and may support the idea that blood perfusion of these tissues increased over the course of hominin evolution.
Integrative analysis of gut microbiome and metabolites revealed novel mechanisms of intestinal Salmonella carriage in chicken
Authors: Mon Khin K. Z. , Zhu Yuhua , Chanthavixay Ganrea , Kern Colin , Zhou Huaijun 
Published: March 2020

AbstractIntestinal carriage of Salmonella Enteritidis (SE) in the chicken host serves as a reservoir for transmission of Salmonella to humans through the consumption of poultry products. The aim of the current study was to examine the three-way interaction that occurred between host metabolites, resident gut microbiota and Salmonella following inoculation of SE in two-week-old layer chicks. Our results revealed an overall alteration in gut microbiome and metabolites in association with SE infection. Enriched colonization by different microbial members throughout the course of experimental infection highlighted significant fluctuation in the intestinal microbial community in response to Salmonella infection. As changes in community membership occurred, there was also subsequent impact on differential regulation of interlinked predicted functional activities within the intestinal environment dictated by Salmonella-commensal interaction. Alteration in the overall microbial community following infection also has a ripple effect on the host regulation of cecum-associated metabolic networks. The findings showed that there was differential regulation in many of the metabolites in association with SE colonization in chickens. Perturbation in metabolic pathways related to arginine and proline metabolism as well as TCA cycle was most prominently detected. Taken together, the present findings provided a starting point in understanding the effect of intestinal Salmonella carriage on the microbiome and metabolome of developing young layer chicks.
An epilepsy-associated mutation in the nuclear import receptor KPNA7 reduces nuclear localization signal binding
Authors: Oostdyk Luke T. , Wang Zhenjia , Zang Chongzhi , Li Hui , McConnell Michael J. , Paschal Bryce M. 
Published: March 2020

AbstractKPNA7 is a member of the Importin-α family of nuclear import receptors. KPNA7 forms a complex with Importin-β and facilitates the translocation of signal-containing proteins from the cytoplasm to the nucleus. Exome sequencing of siblings with severe neurodevelopmental defects and clinical features of epilepsy identified two amino acid-altering mutations in KPNA7. Here, we show that the E344Q substitution reduces KPNA7 binding to nuclear localization signals, and that this limits KPNA7 nuclear import activity. The P339A substitution, by contrast, has little effect on KPNA7 binding to nuclear localization signals. Given the neuronal phenotype described in the two patients, we used SILAC labeling, affinity enrichment, and mass spectrometry to identify KPNA7-interacting proteins in human induced pluripotent stem cell-derived neurons. We identified heterogeneous nuclear ribonucleoproteins hnRNP R and hnRNP U as KPNA7-interacting proteins. The E344Q substitution reduced binding and KPNA7-mediated import of these cargoes. The c.1030G > C allele which generates E344Q is within a predicted CTCF binding site, and we found that it reduces CTCF binding by approximately 40-fold. Our data support a role for altered neuronal expression and activity of KPNA7 in a rare type of pediatric epilepsy.
Effect of row spacings on soil nematode communities and ecosystem multifunctionality at an aggregate scale
Authors: Zhang Guizong , Kou Xinchang , Zhang Xiaoke , Bai Wei , Liang Wenju 
Published: March 2020

AbstractEffect of crop row spacing on the belowground ecosystem, especially at an aggregate scale, remains unexplored. To explore how row spacing influenced nematode community and ecosystem function at the aggregate scale, four row spacings i.e. equidistant-row (ER, 50 cm-inter-row distance, 33 cm-intra-row between plants in each row) and non-equidistant-row including NR1 (100 cm + 50 cm row distance and 22 cm intra-row), NR2 (100 cm + 50 cm inter-row and 25 cm intra-row), and NR3 (60 cm + 40 cm inter-row and 33 cm intra-row) were compared, and four soil aggregate fractions i.e. >2 mm, 1–2 mm, 0.25–1 mm and <0.25 mm were separated. Row spacing did not impact C and N, but significantly influenced P. The regulation effect of acid phosphatase on soil available P was aggregate-scale dependent. Nematode faunal analysis indicated that NR3 within 0.25–1 mm was less disturbed or relatively undisturbed environments. Structural equation model showed row spacing pattern directly affected multifunctionality, while aggregate fractions indirectly contributed to multifunctionality mainly by regulating the richness of total nematodes and trophic groups. It was concluded that NR3 had potential to construct more stable food web, and therefore was possibly the suitable planting pattern.