bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposing anthelmintic agents to eradicate resistant leukemia
Authors: Mezzatesta Caterina , Abduli Liridon , Guinot Anna , Eckert Cornelia , Schewe Denis , Zaliova Marketa , Vinti Luciana , Marovca Blerim , Tsai Yi-Chien , Jenni Silvia , Aguade-Gorgorio Julia , von Stackelberg Arend , Schrappe Martin , Locatelli Franco , Stanulla Martin , Cario Gunnar , Bourquin Jean-Pierre , Bornhauser Beat C. 
Published: June 2020

AbstractDespite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC50 values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.
Cetuximab-induced natural killer cell cytotoxicity in head and neck squamous cell carcinoma cell lines: investigation of the role of cetuximab sensitivity and HPV status
Authors: Baysal Hasan , De Pauw Ines , Zaryouh Hannah , De Waele Jorrit , Peeters Marc , Pauwels Patrick , Vermorken Jan Baptist , Smits Evelien , Lardon Filip , Jacobs Julie , Wouters An 
Published: June 2020

Abstract
Background
The epidermal growth factor receptor (EGFR) is overexpressed by 80–90% of squamous cell carcinoma of head and neck (HNSCC). In addition to inhibiting EGFR signal transduction, cetuximab, a monoclonal antibody targeting EGFR can also bind to fragment crystallisable domain of immunoglobulins G1 present on natural killer (NK), causing antibody-dependent cellular cytotoxicity (ADCC). However, presence of cetuximab resistance limits effective clinical management of HNSCC.

Methods
In this study, differences in induction of ADCC were investigated in a panel of ten HNSCC cell lines. Tumour cells were co-cultured with NK cells and monitored using the xCELLigence RTCA.

Results
While ADCC was not influenced by HPV status, hypoxia and cetuximab resistance did affect ADCC differentially. Intrinsic cetuximab-resistant cell lines showed an increased ADCC induction, whereas exposure to hypoxia reduced ADCC. Baseline EGFR expression was not correlated with ADCC. In contrast, EGFR internalisation following cetuximab treatment was positively correlated with ADCC.

Conclusion
These findings support the possibility that resistance against cetuximab can be overcome by NK cell-based immune reactions. As such, it provides an incentive to combine cetuximab with immunotherapeutic approaches, thereby possibly enhancing the anti-tumoural immune responses and achieving greater clinical effectiveness of EGFR-targeting agents.
Twelve-year clinical trajectories of multimorbidity in a population of older adults
Authors: Vetrano Davide L. , Roso-Llorach Albert , Fernández Sergio , Guisado-Clavero Marina , Violán Concepción , Onder Graziano , Fratiglioni Laura , Calderón-Larrañaga Amaia , Marengoni Alessandra 
Published: June 2020

AbstractMultimorbidity—the co-occurrence of multiple diseases—is associated to poor prognosis, but the scarce knowledge of its development over time hampers the effectiveness of clinical interventions. Here we identify multimorbidity clusters, trace their evolution in older adults, and detect the clinical trajectories and mortality of single individuals as they move among clusters over 12 years. By means of a fuzzy c-means cluster algorithm, we group 2931 people ≥60 years in five clinically meaningful multimorbidity clusters (52%). The remaining 48% are part of an unspecific cluster (i.e. none of the diseases are overrepresented), which greatly fuels other clusters at follow-ups. Clusters contribute differentially to the longitudinal development of other clusters and to mortality. We report that multimorbidity clusters and their trajectories may help identifying homogeneous groups of people with similar needs and prognosis, and assisting clinicians and health care systems in the personalization of clinical interventions and preventive strategies.
Kinetics of motile solitons in nematic liquid crystals
Authors: Aya Satoshi , Araoka Fumito 
Published: June 2020

AbstractThe generation of spatially localized, soliton-like hydrodynamic disturbances in microscale fluidic systems is an intriguing challenge. Herein, we introduce nonequilibrium solitons in nematic liquid crystals stimulated by an electric field. These dynamic solitons are robust as long as the electric field is maintained. Interestingly, their kinetic behaviours depend on the field condition—Tuning of the amplitude and frequency of the applied electric field alters the solitons to self-assemble into lattice ordering like physical particles or to command them to various dynamic states. Our key property to the realisation is the electrohydrodynamic instability due to the coupling between the fluid elasticity and the background convection. This paper describes a new mechanism for realising dynamic solitons in fluid systems on the basis of the electrohydrodynamic phenomena.
Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex
Authors: Watanabe Hidenori , Sano Hiromi , Chiken Satomi , Kobayashi Kenta , Fukata Yuko , Fukata Masaki , Mushiake Hajime , Nambu Atsushi 
Published: June 2020

AbstractOptogenetics has become an indispensable tool for investigating brain functions. Although non-human primates are particularly useful models for understanding the functions and dysfunctions of the human brain, application of optogenetics to non-human primates is still limited. In the present study, we generate an effective adeno-associated viral vector serotype DJ to express channelrhodopsin-2 (ChR2) under the control of a strong ubiquitous CAG promoter and inject into the somatotopically identified forelimb region of the primary motor cortex in macaque monkeys. ChR2 is strongly expressed around the injection sites, and optogenetic intracortical microstimulation (oICMS) through a homemade optrode induces prominent cortical activity: Even single-pulse, short-duration oICMS evokes long-lasting repetitive firings of cortical neurons. In addition, oICMS elicits distinct forelimb movements and muscle activity, which are comparable to those elicited by conventional electrical ICMS. The present study removes obstacles to optogenetic manipulation of neuronal activity and behaviors in non-human primates.
NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation
Authors: Miao Kai , Lei Josh Haipeng , Valecha Monica Vishnu , Zhang Aiping , Xu Jun , Wang Lijian , Lyu Xueying , Chen Si , Miao Zhengqiang , Zhang Xin , Su Sek Man , Shao Fangyuan , Rajendran Barani Kumar , Bao Jiaolin , Zeng Jianming , Sun Heng , Chen Ping , Tan Kaeling , Chen Qiang , Wong Koon Ho , Xu Xiaoling , Deng Chu-Xia 
Published: June 2020

AbstractBRCA1 mutation carriers have a higher risk of developing triple-negative breast cancer (TNBC), which is a refractory disease due to its non-responsiveness to current clinical targeted therapies. Using the Sleeping Beauty transposon system in Brca1-deficient mice, we identified 169 putative cancer drivers, among which Notch1 is a top candidate for accelerating TNBC by promoting the epithelial-mesenchymal transition (EMT) and regulating the cell cycle. Activation of NOTCH1 suppresses mitotic catastrophe caused by BRCA1 deficiency by restoring S/G2 and G2/M cell cycle checkpoints, which may through activation of ATR-CHK1 signalling pathway. Consistently, analysis of human breast cancer tissue demonstrates NOTCH1 is highly expressed in TNBCs, and the activated form of NOTCH1 correlates positively with increased phosphorylation of ATR. Additionally, we demonstrate that inhibition of the NOTCH1-ATR-CHK1 cascade together with cisplatin synergistically kills TNBC by targeting the cell cycle checkpoint, DNA damage and EMT, providing a potent clinical option for this fatal disease.
Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons
Authors: Silva M. Catarina , Nandi Ghata A. , Tentarelli Sharon , Gurrell Ian K. , Jamier Tanguy , Lucente Diane , Dickerson Bradford C. , Brown Dean G. , Brandon Nicholas J. , Haggarty Stephen J. 
Published: June 2020

AbstractTauopathies are neurodegenerative diseases associated with accumulation of abnormal tau protein in the brain. Patient iPSC-derived neuronal cell models replicate disease-relevant phenotypes ex vivo that can be pharmacologically targeted for drug discovery. Here, we explored autophagy as a mechanism to reduce tau burden in human neurons and, from a small-molecule screen, identify the mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds are more potent than rapamycin, and robustly downregulate phosphorylated and insoluble tau, consequently reducing tau-mediated neuronal stress vulnerability. MTORC1 inhibition and autophagy activity are directly linked to tau clearance. Notably, single-dose treatment followed by washout leads to a prolonged reduction of tau levels and toxicity for 12 days, which is mirrored by a sustained effect on mTORC1 inhibition and autophagy. This new insight into the pharmacodynamics of mTOR inhibitors in regulation of neuronal autophagy may contribute to development of therapies for tauopathies.
Coastal sedimentation across North America doubled in the 20th century despite river dams
Authors: Rodriguez A. B. , McKee B. A. , Miller C. B. , Bost M. C. , Atencio A. N. 
Published: June 2020

AbstractThe proliferation of dams since 1950 promoted sediment deposition in reservoirs, which is thought to be starving the coast of sediment and decreasing the resilience of communities to storms and sea-level rise. Diminished river loads measured upstream from the coast, however, should not be assumed to propagate seaward. Here, we show that century-long records of sediment mass accumulation rates (g cm−2 yr−1) and sediment accumulation rates (cm yr−1) more than doubled after 1950 in coastal depocenters around North America. Sediment sources downstream of dams compensate for the river-sediment lost to impoundments. Sediment is accumulating in coastal depocenters at a rate that matches or exceeds relative sea-level rise, apart from rapidly subsiding Texas and Louisiana where water depths are increasing and intertidal areas are disappearing. Assuming no feedbacks, accelerating global sea-level rise will eventually surpass current sediment accumulation rates, underscoring the need for including coastal-sediment management in habitat-restoration projects.
Structure and catalytic regulation of Plasmodium falciparum IMP specific nucleotidase
Authors: Carrique Loïc , Ballut Lionel , Shukla Arpit , Varma Neelakshi , Ravi Resmi , Violot Sébastien , Srinivasan Bharath , Ganeshappa Umesh Tippagondanahalli , Kulkarni Sonia , Balaram Hemalatha , Aghajari Nushin 
Published: June 2020

AbstractPlasmodium falciparum (Pf) relies solely on the salvage pathway for its purine nucleotide requirements, making this pathway indispensable to the parasite. Purine nucleotide levels are regulated by anabolic processes and by nucleotidases that hydrolyse these metabolites into nucleosides. Certain apicomplexan parasites, including Pf, have an IMP-specific-nucleotidase 1 (ISN1). Here we show, by comprehensive substrate screening, that PfISN1 catalyzes the dephosphorylation of inosine monophosphate (IMP) and is allosterically activated by ATP. Crystal structures of tetrameric PfISN1 reveal complex rearrangements of domain organization tightly associated with catalysis. Immunofluorescence microscopy and expression of GFP-fused protein indicate cytosolic localization of PfISN1 and expression in asexual and gametocyte stages of the parasite. With earlier evidence on isn1 upregulation in female gametocytes, the structures reported in this study may contribute to initiate the design for possible transmission-blocking agents.
Protein arginine deiminase 4 antagonizes methylglyoxal-induced histone glycation
Authors: Zheng Qingfei , Osunsade Adewola , David Yael 
Published: June 2020

AbstractProtein arginine deiminase 4 (PAD4) facilitates the post-translational citrullination of the core histones H3 and H4. While the precise epigenetic function of this modification has not been resolved, it has been shown to associate with general chromatin decompaction and compete with arginine methylation. Recently, we found that histones are subjected to methylglyoxal (MGO)-induced glycation on nucleophilic side chains, particularly arginines, under metabolic stress conditions. These non-enzymatic adducts change chromatin architecture and the epigenetic landscape by competing with enzymatic modifications, as well as changing the overall biophysical properties of the fiber. Here, we report that PAD4 antagonizes histone MGO-glycation by protecting the reactive arginine sites, as well as by converting already-glycated arginine residues into citrulline. Moreover, we show that similar to the deglycase DJ-1, PAD4 is overexpressed and histone citrullination is upregulated in breast cancer tumors, suggesting an additional mechanistic link to PAD4’s oncogenic properties.
Toward nanoscale molecular mass spectrometry imaging via physically constrained machine learning on co-registered multimodal data
Authors: Borodinov Nikolay , Lorenz Matthias , King Steven T. , Ievlev Anton V. , Ovchinnikova Olga S. 
Published: June 2020

AbstractMass spectrometry imaging (MSI) plays a pivotal role in investigating the chemical nature of complex systems that underly our understanding in biology and medicine. Multiple fields of life science such as proteomics, lipidomics and metabolomics benefit from the ability to simultaneously identify molecules and pinpoint their distribution across a sample. However, achieving the necessary submicron spatial resolution to distinguish chemical differences between individual cells and generating intact molecular spectra is still a challenge with any single imaging approach. Here, we developed an approach that combines two MSI techniques, matrix-assisted laser desorption/ionization (MALDI) and time-of-flight secondary ion mass spectrometry (ToF-SIMS), one with low spatial resolution but intact molecular spectra and the other with nanometer spatial resolution but fragmented molecular signatures, to predict molecular MSI spectra with submicron spatial resolution. The known relationships between the two MSI channels of information are enforced via a physically constrained machine-learning approach and directly incorporated in the data processing. We demonstrate the robustness of this method by generating intact molecular MALDI-type spectra and chemical maps at ToF-SIMS resolution when imaging mouse brain thin tissue sections. This approach can be readily adopted for other types of bioimaging where physical relationships between methods have to be considered to boost the confidence in the reconstruction product.
Two-dimensional hard-core Bose–Hubbard model with superconducting qubits
Authors: Yanay Yariv , Braumüller Jochen , Gustavsson Simon , Oliver William D. , Tahan Charles 
Published: June 2020

AbstractThe pursuit of superconducting-based quantum computers has advanced the fabrication of and experimentation with custom lattices of qubits and resonators. Here, we describe a roadmap to use present experimental capabilities to simulate an interacting many-body system of bosons and measure quantities that are exponentially difficult to calculate numerically. We focus on the two-dimensional hard-core Bose–Hubbard model implemented as an array of floating transmon qubits. We describe a control scheme for such a lattice that can perform individual qubit readout and show how the scheme enables the preparation of a highly excited many-body state, in contrast with atomic implementations restricted to the ground state or thermal equilibrium. We discuss what observables could be accessed and how they could be used to better understand the properties of many-body systems, including the observation of the transition of eigenstate entanglement entropy scaling from area-law behavior to volume-law behavior.
Resistance of Fritillaria imperialis to freezing stress through gene expression, osmotic adjustment and antioxidants
Authors: Hajihashemi Shokoofeh , Brestic Marian , Landi Marco , Skalicky Milan 
Published: June 2020

AbstractPlant survival in response to freezing stress depends on the efficient activation of tolerance mechanisms.Fritillaria imperialisexposure to freezing stress enhanced signalling molecules Ca2+and H2O2along with overexpression of Ca2+signalling proteins (Ca2+dependent protein kinases, CPK), followed by upregulation ofNHX1(Na+/H+antiporter),LEA(late embryogenesis abundant proteins) andP5CS(1-pyrroline-5-carboxylate synthetase). Overexpression ofOsCNGC6was responsible for high accumulation Ca2+, Na+and K+. The NHX1 gene product transported Na+to vacuoles and increased cytosolic K+content to re-establish ionic homeostasis under stress conditions. The reduced water potential of leaves was due to high accumulation of osmolytes and ions. No changes were observed in relative water content of leaves, which might be correlated with overexpression of theLEAgene, which protects against dehydration. High accumulation of H2O2under freezing stress was responsible for activation of antioxidant systems involving SOD, phenols, anthocyanins, catalase and ascorbate peroxidase. Photosynthesis, suppressed in freezing-stressed plants, returned to normal levels after termination of freezing stress. Taken together, our findings suggest that Fritillaria efficiently tolerated freezing stress through induction of signalling mechanisms and overexpression of cold stress-responsive genes, and prevention of cold-induced water stress, oxidative stress and photosynthetic damage.
Controller synthesis and clinical exploration of wearable gyroscopic actuators to support human balance
Authors: Lemus Daniel , Berry Andrew , Jabeen Saher , Jayaraman Chandrasekaran , Hohl Kristen , van der Helm Frans C. T. , Jayaraman Arun , Vallery Heike 
Published: June 2020

AbstractGyroscopic actuators are appealing for wearable applications due to their ability to provide overground balance support without obstructing the legs. Multiple wearable robots using this actuation principle have been proposed, but none has yet been evaluated with humans. Here we use the GyBAR, a backpack-like prototype portable robot, to investigate the hypothesis that the balance of both healthy and chronic stroke subjects can be augmented through moments applied to the upper body. We quantified balance performance in terms of each participant’s ability to walk or remain standing on a narrow support surface oriented to challenge stability in either the frontal or the sagittal plane. By comparing candidate balance controllers, it was found that effective assistance did not require regulation to a reference posture. A rotational viscous field increased the distance healthy participants could walk along a 30mm-wide beam by a factor of 2.0, compared to when the GyBAR was worn but inactive. The same controller enabled individuals with chronic stroke to remain standing for a factor of 2.5 longer on a narrow block. Due to its wearability and versatility of control, the GyBAR could enable new therapy interventions for training and rehabilitation.
Polarisation-insensitive generation of complex vector modes from a digital micromirror device
Authors: Rosales-Guzmán Carmelo , Hu Xiao-Bo , Selyem Adam , Moreno-Acosta Pedro , Franke-Arnold Sonja , Ramos-Garcia Ruben , Forbes Andrew 
Published: June 2020

AbstractIn recent time there has been an increasing amount of interest in developing novel techniques for the generation of complex vector light beams. Amongst these, digital holography stands out as one of the most flexible and versatile with almost unlimited freedom in the generation of scalar and complex vector light fields featuring arbitrary polarisation distributions and spatial profiles. In this manuscript we put forward a novel technique, which relies on the polarisation-insensitive attribute of Digital Micromirror Devices (DMDs). In a prior work where we outlined a new detection scheme based on Stokes projections we alluded to this technique. Here we outline the creation process in full, providing all the details for its experimental implementation. In addition, we fully characterise the performance of such technique, providing a quantitative analysis of the generated modes. To this end, we experimentally reconstruct the transverse polarisation distribution of arbitrary vector modes and compare the ellipticity and flatness of the polarisation ellipses with theoretical predictions. Further, we also generate vector modes with arbitrary degrees of non-separability and determine their degree of concurrence comparing this to theoretical predictions.
POE Immunoassay: Plate-based oligonucleotide electro-chemiluminescent immunoassay for the quantification of nucleic acids in biological matrices
Authors: Thayer Mai B. , Humphreys Sara C. , Chung Kyu S. , Lade Julie M. , Cook Kevin D. , Rock Brooke M. 
Published: June 2020

AbstractOligonucleotide therapeutics use short interfering RNA (siRNA) or antisense oligonucleotide (ASO) molecules to exploit endogenous systems—neutralizing target RNA to prevent subsequent protein translation. While the potential clinical application is vast, delivery efficiency and extrahepatic targeting is challenging. Bioanalytical assays are important in building understanding of these complex relationships. The literature currently lacks description of robust and sensitive methods to measure siRNA and ASOs in complex biological matrices. Described herein is a non-enzymatic hybridization-based immunoassay that enables quantification of individual siRNA strands (antisense or sense) in serum, urine, bile, and liver and kidney homogenates. Assay utility is also demonstrated in ASOs. The assay improves upon previous works by abolishing enzymatic steps and further incorporating Locked Nucleic Acid (LNA) nucleotide modifications to increase analyte hybridization affinity and improve sensitivity, specificity, and robustness. We report an assay with an ultrasensitive dynamic range of 0.3 to 16,700 pM for siRNA in serum. The assay was submitted to full qualification for accuracy and precision in both serum and tissue matrices and assay performance was assessed with single and mixed analytes. The reliable LNA-hybridization-based approach removes the need for matrix sample extraction, enrichment or amplification steps which may be impeded by more advanced chemical modifications.