bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversible hydrogen control of antiferromagnetic anisotropy in α-Fe2O3
Authors: Jani Hariom , Linghu Jiajun , Hooda Sonu , Chopdekar Rajesh V. , Li Changjian , Omar Ganesh Ji , Prakash Saurav , Du Yonghua , Yang Ping , Banas Agnieszka , Banas Krzysztof , Ghosh Siddhartha , Ojha Sunil , Umapathy G. R. , Kanjilal Dinakar , Ariando A. , Pennycook Stephen J. , Arenholz Elke , Radaelli Paolo G. , Coey J. M. D. , Feng Yuan Ping , Venkatesan T. 
Published: March 2021

AbstractAntiferromagnetic insulators are a ubiquitous class of magnetic materials, holding the promise of low-dissipation spin-based computing devices that can display ultra-fast switching and are robust against stray fields. However, their imperviousness to magnetic fields also makes them difficult to control in a reversible and scalable manner. Here we demonstrate a novel proof-of-principle ionic approach to control the spin reorientation (Morin) transition reversibly in the common antiferromagnetic insulator α-Fe2O3 (haematite) – now an emerging spintronic material that hosts topological antiferromagnetic spin-textures and long magnon-diffusion lengths. We use a low-temperature catalytic-spillover process involving the post-growth incorporation or removal of hydrogen from α-Fe2O3 thin films. Hydrogenation drives pronounced changes in its magnetic anisotropy, Néel vector orientation and canted magnetism via electron injection and local distortions. We explain these effects with a detailed magnetic anisotropy model and first-principles calculations. Tailoring our work for future applications, we demonstrate reversible control of the room-temperature spin-state by doping/expelling hydrogen in Rh-substituted α-Fe2O3.
Pervasive cooperative mutational effects on multiple catalytic enzyme traits emerge via long-range conformational dynamics
Authors: Acevedo-Rocha Carlos G. , Li Aitao , D’Amore Lorenzo , Hoebenreich Sabrina , Sanchis Joaquin , Lubrano Paul , Ferla Matteo P. , Garcia-Borràs Marc , Osuna Sílvia , Reetz Manfred T. 
Published: March 2021

AbstractMultidimensional fitness landscapes provide insights into the molecular basis of laboratory and natural evolution. To date, such efforts usually focus on limited protein families and a single enzyme trait, with little concern about the relationship between protein epistasis and conformational dynamics. Here, we report a multiparametric fitness landscape for a cytochrome P450 monooxygenase that was engineered for the regio- and stereoselective hydroxylation of a steroid. We develop a computational program to automatically quantify non-additive effects among all possible mutational pathways, finding pervasive cooperative signs and magnitude epistasis on multiple catalytic traits. By using quantum mechanics and molecular dynamics simulations, we show that these effects are modulated by long-range interactions in loops, helices and β-strands that gate the substrate access channel allowing for optimal catalysis. Our work highlights the importance of conformational dynamics on epistasis in an enzyme involved in secondary metabolism and offers insights for engineering P450s.
Impact of equatorial Atlantic variability on ENSO predictive skill
Authors: Exarchou Eleftheria , Ortega Pablo , Rodríguez-Fonseca Belén , Losada Teresa , Polo Irene , Prodhomme Chloé 
Published: March 2021

AbstractEl Niño-Southern Oscillation (ENSO) is a key mode of climate variability with worldwide climate impacts. Recent studies have highlighted the impact of other tropical oceans on its variability. In particular, observations have demonstrated that summer Atlantic Niños (Niñas) favor the development of Pacific Niñas (Niños) the following winter, but it is unclear how well climate models capture this teleconnection and its role in defining the seasonal predictive skill of ENSO. Here we use an ensemble of seasonal forecast systems to demonstrate that a better representation of equatorial Atlantic variability in summer and its lagged teleconnection mechanism with the Pacific relates to enhanced predictive capacity of autumn/winter ENSO. An additional sensitivity study further shows that correcting SST variability in equatorial Atlantic improves different aspects of forecast skill in the Tropical Pacific, boosting ENSO skill. This study thus emphasizes that new efforts to improve the representation of equatorial Atlantic variability, a region with long standing systematic model biases, can foster predictive skill in the region, the Tropical Pacific and beyond, through the global impacts of ENSO.
Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening
Authors: Baxley Ryan M. , Leung Wendy , Schmit Megan M. , Matson Jacob Peter , Yin Lulu , Oram Marissa K. , Wang Liangjun , Taylor John , Hedberg Jack , Rogers Colette B. , Harvey Adam J. , Basu Debashree , Taylor Jenny C. , Pagnamenta Alistair T. , Dreau Helene , Craft Jude , Ormondroyd Elizabeth , Watkins Hugh , Hendrickson Eric A. , Mace Emily M. , Orange Jordan S. , Aihara Hideki , Stewart Grant S. , Blair Edward , Cook Jeanette Gowen , Bielinsky Anja-Katrin 
Published: March 2021

AbstractMinichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.
Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer
Authors: Aissa Alexandre F. , Islam Abul B. M. M. K. , Ariss Majd M. , Go Cammille C. , Rader Alexandra E. , Conrardy Ryan D. , Gajda Alexa M. , Rubio-Perez Carlota , Valyi-Nagy Klara , Pasquinelli Mary , Feldman Lawrence E. , Green Stefan J. , Lopez-Bigas Nuria , Frolov Maxim V. , Benevolenskaya Elizaveta V. 
Published: March 2021

AbstractTyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabolism and cholesterol homeostasis. We show analysis of identified markers using the LINCS database to predict and functionally validate small molecules that target selected drug tolerant cell populations. In combination with EGFR inhibitors, crizotinib inhibits the emergence of a defined subset of EGFR inhibitor-tolerant clones. In this study, we describe the spectrum of changes associated with drug tolerance and inhibition of specific tolerant cell subpopulations with combination agents.
Plasmodium vivax infection compromises reticulocyte stability
Authors: Clark Martha A. , Kanjee Usheer , Rangel Gabriel W. , Chery Laura , Mascarenhas Anjali , Gomes Edwin , Rathod Pradipsinh K. , Brugnara Carlo , Ferreira Marcelo U. , Duraisingh Manoj T. 
Published: March 2021

AbstractThe structural integrity of the host red blood cell (RBC) is crucial for propagation of Plasmodium spp. during the disease-causing blood stage of malaria infection. To assess the stability of Plasmodium vivax-infected reticulocytes, we developed a flow cytometry-based assay to measure osmotic stability within characteristically heterogeneous reticulocyte and P. vivax-infected samples. We find that erythroid osmotic stability decreases during erythropoiesis and reticulocyte maturation. Of enucleated RBCs, young reticulocytes which are preferentially infected by P. vivax, are the most osmotically stable. P. vivax infection however decreases reticulocyte stability to levels close to those of RBC disorders that cause hemolytic anemia, and to a significantly greater degree than P. falciparum destabilizes normocytes. Finally, we find that P. vivax new permeability pathways contribute to the decreased osmotic stability of infected-reticulocytes. These results reveal a vulnerability of P. vivax-infected reticulocytes that could be manipulated to allow in vitro culture and develop novel therapeutics.
Human-interpretable image features derived from densely mapped cancer pathology slides predict diverse molecular phenotypes
Authors: Diao James A. , Wang Jason K. , Chui Wan Fung , Mountain Victoria , Gullapally Sai Chowdary , Srinivasan Ramprakash , Mitchell Richard N. , Glass Benjamin , Hoffman Sara , Rao Sudha K. , Maheshwari Chirag , Lahiri Abhik , Prakash Aaditya , McLoughlin Ryan , Kerner Jennifer K. , Resnick Murray B. , Montalto Michael C. , Khosla Aditya , Wapinski Ilan N. , Beck Andrew H. , Elliott Hunter L. , Taylor-Weiner Amaro 
Published: March 2021

AbstractComputational methods have made substantial progress in improving the accuracy and throughput of pathology workflows for diagnostic, prognostic, and genomic prediction. Still, lack of interpretability remains a significant barrier to clinical integration. We present an approach for predicting clinically-relevant molecular phenotypes from whole-slide histopathology images using human-interpretable image features (HIFs). Our method leverages >1.6 million annotations from board-certified pathologists across >5700 samples to train deep learning models for cell and tissue classification that can exhaustively map whole-slide images at two and four micron-resolution. Cell- and tissue-type model outputs are combined into 607 HIFs that quantify specific and biologically-relevant characteristics across five cancer types. We demonstrate that these HIFs correlate with well-known markers of the tumor microenvironment and can predict diverse molecular signatures (AUROC 0.601–0.864), including expression of four immune checkpoint proteins and homologous recombination deficiency, with performance comparable to ‘black-box’ methods. Our HIF-based approach provides a comprehensive, quantitative, and interpretable window into the composition and spatial architecture of the tumor microenvironment.
Model-based evaluation of school- and non-school-related measures to control the COVID-19 pandemic
Authors: Rozhnova Ganna , van Dorp Christiaan H. , Bruijning-Verhagen Patricia , Bootsma Martin C. J. , van de Wijgert Janneke H. H. M. , Bonten Marc J. M. , Kretzschmar Mirjam E. 
Published: March 2021

AbstractThe role of school-based contacts in the epidemiology of SARS-CoV-2 is incompletely understood. We use an age-structured transmission model fitted to age-specific seroprevalence and hospital admission data to assess the effects of school-based measures at different time points during the COVID-19 pandemic in the Netherlands. Our analyses suggest that the impact of measures reducing school-based contacts depends on the remaining opportunities to reduce non-school-based contacts. If opportunities to reduce the effective reproduction number (Re) with non-school-based measures are exhausted or undesired and Re is still close to 1, the additional benefit of school-based measures may be considerable, particularly among older school children. As two examples, we demonstrate that keeping schools closed after the summer holidays in 2020, in the absence of other measures, would not have prevented the second pandemic wave in autumn 2020 but closing schools in November 2020 could have reduced Re below 1, with unchanged non-school-based contacts.
Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase
Authors: Chen Bingyi , Luo Siting , Zhang Songxuan , Ju Yingchen , Gu Qiong , Xu Jun , Yang Xiang-Lei , Zhou Huihao 
Published: March 2021

AbstractThe polyketide natural product reveromycin A (RM-A) exhibits antifungal, anticancer, anti-bone metastasis, anti-periodontitis and anti-osteoporosis activities by selectively inhibiting eukaryotic cytoplasmic isoleucyl-tRNA synthetase (IleRS). Herein, a co-crystal structure suggests that the RM-A molecule occupies the substrate tRNAIle binding site of Saccharomyces cerevisiae IleRS (ScIleRS), by partially mimicking the binding of tRNAIle. RM-A binding is facilitated by the copurified intermediate product isoleucyl-adenylate (Ile-AMP). The binding assays confirm that RM-A competes with tRNAIle while binding synergistically with l-isoleucine or intermediate analogue Ile-AMS to the aminoacylation pocket of ScIleRS. This study highlights that the vast tRNA binding site of the Rossmann-fold catalytic domain of class I aminoacyl-tRNA synthetases could be targeted by a small molecule. This finding will inform future rational drug design.
On-surface preparation of coordinated lanthanide-transition-metal clusters
Authors: Liu Jing , Li Jie , Xu Zhen , Zhou Xiong , Xue Qiang , Wu Tianhao , Zhong Mingjun , Li Ruoning , Sun Rong , Shen Ziyong , Tang Hao , Gao Song , Wang Bingwu , Hou Shimin , Wang Yongfeng 
Published: March 2021

AbstractThe study of lanthanide (Ln)-transition-metal (TM) heterometallic clusters which play key roles in various high-tech applications is a rapid growing field of research. Despite the achievement of numerous Ln-TM cluster compounds comprising one Ln atom, the synthesis of Ln-TM clusters containing multiple Ln atoms remains challenging. Here, we present the preparation and self-assembly of a series of Au-bridged heterometallic clusters containing multiple cerium (Ce) atoms via on-surface coordination. By employing different pyridine and nitrile ligands, the ordered coordination assemblies of clusters containing 2, 3 and 4 Ce atoms bridged by Au adatoms are achieved on Au(111) and Au(100), as revealed by scanning tunneling microscopy. Density functional theory calculations uncover the indispensable role of the bridging Au adatoms in constructing the multi-Ce-containing clusters by connecting the Ce atoms via unsupported Ce-Au bonds. These findings demonstrate on-surface coordination as an efficient strategy for preparation and organization of the multi-Ln-containing heterometallic clusters.
Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43
Authors: Li Qiuye , Babinchak W. Michael , Surewicz Witold K. 
Published: March 2021

AbstractAmyotrophic lateral sclerosis and several other neurodegenerative diseases are associated with brain deposits of amyloid-like aggregates formed by the C-terminal fragments of TDP-43 that contain the low complexity domain of the protein. Here, we report the cryo-EM structure of amyloid formed from the entire TDP-43 low complexity domain in vitro at pH 4. This structure reveals single protofilament fibrils containing a large (139-residue), tightly packed core. While the C-terminal part of this core region is largely planar and characterized by a small proportion of hydrophobic amino acids, the N-terminal region contains numerous hydrophobic residues and has a non-planar backbone conformation, resulting in rugged surfaces of fibril ends. The structural features found in these fibrils differ from those previously found for fibrils generated from short protein fragments. The present atomic model for TDP-43 LCD fibrils provides insight into potential structural perturbations caused by phosphorylation and disease-related mutations.
Iron control of erythroid microtubule cytoskeleton as a potential target in treatment of iron-restricted anemia
Authors: Goldfarb Adam N. , Freeman Katie C. , Sahu Ranjit K. , Elagib Kamaleldin E. , Holy Maja , Arneja Abhinav , Polanowska-Grabowska Renata , Gru Alejandro A. , White Zollie , Khalil Shadi , Kerins Michael J. , Ooi Aikseng , Leitinger Norbert , Luckey Chance John , Delehanty Lorrie L. 
Published: March 2021

AbstractAnemias of chronic disease and inflammation (ACDI) result from restricted iron delivery to erythroid progenitors. The current studies reveal an organellar response in erythroid iron restriction consisting of disassembly of the microtubule cytoskeleton and associated Golgi disruption. Isocitrate supplementation, known to abrogate the erythroid iron restriction response, induces reassembly of microtubules and Golgi in iron deprived progenitors. Ferritin, based on proteomic profiles, regulation by iron and isocitrate, and putative interaction with microtubules, is assessed as a candidate mediator. Knockdown of ferritin heavy chain (FTH1) in iron replete progenitors induces microtubule collapse and erythropoietic blockade; conversely, enforced ferritin expression rescues erythroid differentiation under conditions of iron restriction. Fumarate, a known ferritin inducer, synergizes with isocitrate in reversing molecular and cellular defects of iron restriction and in oral remediation of murine anemia. These findings identify a cytoskeletal component of erythroid iron restriction and demonstrate potential for its therapeutic targeting in ACDI.
Dual Ni/photoredox-catalyzed asymmetric cross-coupling to access chiral benzylic boronic esters
Authors: Zheng Purui , Zhou Pan , Wang Dong , Xu Wenhao , Wang Hepan , XU Tao 
Published: March 2021

AbstractThe flourishing Ni/photoredox-catalyzed asymmetric couplings typically rely on redox-neutral reactions. In this work, we report a reductive cross-coupling of aryl iodides and α-chloroboranes under a dual catalytic regime to further enrich the metallaphotoredox chemistry. This approach proceeds under mild conditions (visible light, ambient temperature, no strong base) to access the versatile benzylic boronic esters with good functional group tolerance and excellent enantioselectivities.
Anatomy of subcritical submarine flows with a lutocline and an intermediate destruction layer
Authors: Salinas Jorge S. , Balachandar S. , Shringarpure M. , Fedele J. , Hoyal D. , Zuñiga S. , Cantero M. I. 
Published: March 2021

AbstractTurbidity currents are sediment-laden flows that travel over a sloping bed under a stagnant ambient fluid, driven by the density difference between the current and the ambient. Turbidity currents transport large amounts of carbon, nutrients and fresh water through oceans and play an important role in global geochemical cycling and seafloor ecosystems. Supercritical currents are observed in steeper slopes. Subcritical currents are observed in milder slopes, where the near-bed and interface layers are prevented from interacting across the velocity maximum. Past works show the existence of such a barrier to vertical momentum transfer is essential for the body of the subcritical current to extend over hundreds of kilometers in length without much increase in height. Here we observe the body of subcritical currents to have a three layer structure, where the turbulent near-bed layer and the non-turbulent interface layer are separated by an intermediate layer of negative turbulence production. We explain the mechanism by which this layer prevents the near-bed turbulent structures from penetrating into the interface layer by transferring energy back from turbulence to the mean flow.
A longitudinal, randomized experimental pilot study to investigate the effects of airborne ultrasound on human mental health, cognition, and brain structure
Authors: Ascone L. , Kling C. , Wieczorek J. , Koch C. , Kühn S. 
Published: March 2021

AbstractUltrasound-(US) emitting sources are highly present in modern human environments (e.g., movement sensors, electric transformers). US affecting humans or even posing a health hazard remains understudied. Hence, ultrasonic (22.4 kHz) vs. sham devices were installed in participants’ bedrooms, and active for 28 nights. Somatic and psychiatric symptoms, sound-sensitivity, sleep quality, executive function, and structural MRI were assessed pre-post. Somatization (possible nocebo) and phasic alertness increased significantly in sham, accuracy in a flexibility task decreased significantly in the verum condition (indicating hastier responses). Effects were not sustained after p-level adjustment. Exploratory voxel-based morphometry (VBM) revealed regional grey matter (rGMV) but no regional white matter volume changes in verum (relative to placebo). rGMV increased in bilateral cerebellum VIIb/Crus II and anterior cingulate (BA24). There were rGMV decreases in two bilateral frontal clusters: in the middle frontal gyri/opercular part of inferior frontal gyrus (BA46, 44), and the superior frontal gyri (BA4 ,6, 8). No brain-behavior-links were identified. Given the overall pattern of results, it is suggested that ultrasound may particularly induce regional gray matter decline in frontal areas, however with yet unclear behavioral consequences. Given the localization of clusters, candidate behavioral variables for follow-up investigation are complex motor control/coordination, stress regulation, speech processing, and inhibition tasks.Trial registration: The trial was registered at NIH www.clinicaltrials.gov, trial identifier: NCT03459183, trial name: SonicBrain01, full trial protocol available here: https://clinicaltrials.gov/ct2/show/NCT03459183.
Collective migration during a gap closure in a two-dimensional haptotactic model
Authors: Versaevel Marie , Alaimo Laura , Seveau Valentine , Luciano Marine , Mohammed Danahe , Bruyère Céline , Vercruysse Eléonore , Théodoly Olivier , Gabriele Sylvain 
Published: March 2021

AbstractThe ability of cells to respond to substrate-bound protein gradients is crucial for many physiological processes, such as immune response, neurogenesis and cancer cell migration. However, the difficulty to produce well-controlled protein gradients has long been a limitation to our understanding of collective cell migration in response to haptotaxis. Here we use a photopatterning technique to create circular, square and linear fibronectin (FN) gradients on two-dimensional (2D) culture substrates. We observed that epithelial cells spread preferentially on zones of higher FN density, creating rounded or elongated gaps within epithelial tissues over circular or linear FN gradients, respectively. Using time-lapse experiments, we demonstrated that the gap closure mechanism in a 2D haptotaxis model requires a significant increase of the leader cell area. In addition, we found that gap closures are slower on decreasing FN densities than on homogenous FN-coated substrate and that fresh closed gaps are characterized by a lower cell density. Interestingly, our results showed that cell proliferation increases in the closed gap region after maturation to restore the cell density, but that cell–cell adhesive junctions remain weaker in scarred epithelial zones. Taken together, our findings provide a better understanding of the wound healing process over protein gradients, which are reminiscent of haptotaxis.