bluuebunny/crossref_metadata_2025_split huggingface dataset:
T-cells in chronic lymphocytic leukemia: Guardians or drivers of disease?
Authors: Roessner Philipp M. , Seiffert Martina 
Published: May 2020

SummaryChronic lymphocytic leukemia (CLL) is a B-cell malignancy, which is associated with profound alterations and defects in the immune system and a prevalent dependency on the microenvironmental niche. An abnormal T-cell compartment in the blood of CLL patients was already reported 40 years ago. Since then, our knowledge of T-cell characteristics in CLL has grown steadily, but the question of whether T-cells act as pro-tumoral bystander cells or possess anti-tumoral activity is still under debate. Increased numbers of CD4+ T-helper cell subsets are present in the blood of CLL patients, and T-helper cell cytokines have been shown to stimulate CLL cell survival and proliferation in vitro. In line with this, survival and growth of CLL cells in murine xenograft models have been shown to rely on activated CD4+ T-cells. This led to the hypothesis that T-cells are tumor-supportive in CLL. In recent years, evidence for an enrichment of antigen-experienced CD8+ T-cells in CLL has accumulated, and these cells have been shown to control leukemia in a CLL mouse model. Based on this, it was suggested that CD8+ T-cells recognize CLL-specific antigens and exert an anti-leukemia function. As described for other cancer entities, T-cells in CLL express multiple inhibitory receptors, such as PD-1, and lose their functional capacity, leading to an exhaustion phenotype which has been shown to be more severe in T-cells from secondary lymphoid organs compared with peripheral blood. This exhausted phenotype has been suggested to be causative for the poor response of CLL patients to CAR T-cell therapies. In addition, T-cells have been shown to be affected by drugs that are used to treat CLL, which likely impacts therapy response. This review provides an overview of the current knowledge about alterations of T-cells in CLL, including their distribution, function, and exhaustion state in blood and lymphoid organs, and touches also on the topic of how CLL drugs impact on the T-cell compartment and recent results of T-cell-based immunotherapy. We will discuss potential pathological roles of T-cell subsets in CLL and address the question of whether they foster progression or control of disease.
Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis
Authors: Bugallo Ricardo , Marlin Elías , Baltanás Ana , Toledo Estefanía , Ferrero Roberto , Vinueza-Gavilanes Rodrigo , Larrea Laura , Arrasate Montserrat , Aragón Tomás 
Published: May 2020

AbstractLoss of protein folding homeostasis features many of the most prevalent neurodegenerative disorders. As coping mechanism to folding stress within the endoplasmic reticulum (ER), the unfolded protein response (UPR) comprises a set of signaling mechanisms that initiate a gene expression program to restore proteostasis, or when stress is chronic or overwhelming promote neuronal death. This fate-defining capacity of the UPR has been proposed to play a key role in amyotrophic lateral sclerosis (ALS). However, the several genetic or pharmacological attempts to explore the therapeutic potential of UPR modulation have produced conflicting observations. In order to establish the precise relationship between UPR signaling and neuronal death in ALS, we have developed a neuronal model where the toxicity of a familial ALS-causing allele (mutant G93A SOD1) and UPR activation can be longitudinally monitored in single neurons over the process of neurodegeneration by automated microscopy. Using fluorescent UPR reporters we established the temporal and causal relationship between UPR and neuronal death by Cox regression models. Pharmacological inhibition of discrete UPR processes allowed us to establish the contribution of PERK (PKR-like ER kinase) and IRE1 (inositol-requiring enzyme-1) mechanisms to neuronal fate. Importantly, inhibition of PERK signaling with its downstream inhibitor ISRIB, but not with the direct PERK kinase inhibitor GSK2606414, significantly enhanced the survival of G93A SOD1-expressing neurons. Characterization of the inhibitory properties of both drugs under ER stress revealed that in neurons (but not in glial cells) ISRIB overruled only part of the translational program imposed by PERK, relieving the general inhibition of translation, but maintaining the privileged translation of ATF4 (activating transcription factor 4) messenger RNA. Surprisingly, the fine-tuning of the PERK output in G93A SOD1-expressing neurons led to a reduction of IRE1-dependent signaling. Together, our findings identify ISRIB-mediated translational reprogramming as a new potential ALS therapy.
P2Y14 receptor has a critical role in acute gouty arthritis by regulating pyroptosis of macrophages
Authors: Li Hanwen , Jiang Wenjiao , Ye Shumin , Zhou Mengze , Liu Chunxiao , Yang Xiping , Hao Kun , Hu Qinghua 
Published: May 2020

AbstractNod-like receptor protein 3 (NLRP3)-mediated pyroptosis has a causal role in the pathogenesis of gout. P2Y14 receptor (P2Y14R) distributed in immune cells including macrophages is a Gi-coupled receptor that inhibits the synthesis of cAMP, which has been regarded as a potential regulator of inflammatory response. Nevertheless, the role of P2Y14R in MSU-induced pyroptosis of macrophages involved in acute gouty arthritis is still unclear. In our present study, P2Y14R knockout (P2Y14R-KO) disrupted MSU-induced histopathologic changes in rat synoviums, accompanied with a significant inhibition of pyroptotic cell death characterized by Caspase-1/PI double-positive and blockade of NLRP3 inflammasome activation in synovial tissues, which was consistent with that observed in in vitro studies. Owing to the interaction of NLRP3 inflammasome and cAMP, we then investigated the effect of adenylate cyclase activator (Forskolin) on macrophage pyroptosis and gout flare caused by MSU stimulation. The reversal effect of Forskolin verified the negative regulatory role of cAMP in MSU-induced pyroptosis. More importantly, adenylate cyclase inhibitor (SQ22536) intervention led to a reversal of protection attributed to P2Y14R deficiency. Findings in air pouch animal models also verified aforementioned experimental results. Our study first identified the role of P2Y14R/cAMP/NLRP3 signaling pathway in acute gouty arthritis, which provides a novel insight into the pathological mechanisms of pyroptosis-related diseases.
Novel LAMA2 variants identified in a patient with white matter abnormalities
Authors: Yamamoto-Shimojima Keiko , Ono Hiroaki , Imaizumi Taichi , Yamamoto Toshiyuki 
Published: May 2020

AbstractComprehensive genomic analysis was performed in a patient with mild psychomotor developmental delay, elevated creatine kinase, and white matter abnormalities. The results revealed biallelic pathogenic variants in the gene related to merosin-deficient congenital muscular dystrophy, NM_000426.3(LAMA2):c.1338_1339del [p.Gly447Phefs*7] and c.2749 + 2dup, which consist of compound heterozygous involvement with predicted loss-of-function and splicing abnormalities.
Light-switchable propulsion of active particles with reversible interactions
Authors: Vutukuri Hanumantha Rao , Lisicki Maciej , Lauga Eric , Vermant Jan 
Published: May 2020

AbstractActive systems such as microorganisms and self-propelled particles show a plethora of collective phenomena, including swarming, clustering, and phase separation. Control over the propulsion direction and switchability of the interactions between the individual self-propelled units may open new avenues in designing of materials from within. Here, we present a self-propelled particle system, consisting of half-gold-coated titania (TiO2) particles, in which we can quickly and on-demand reverse the propulsion direction, by exploiting the different photocatalytic activities on both sides. We demonstrate that the reversal in propulsion direction changes the nature of the hydrodynamic interaction from attractive to repulsive and can drive the particle assemblies to undergo both fusion and fission transitions. Moreover, we show these active colloids can act as nucleation sites, and switch rapidly the interactions between active and passive particles, leading to reconfigurable assembly and disassembly. Our experiments are qualitatively described by a minimal hydrodynamic model.
Sources of path integration error in young and aging humans
Authors: Stangl Matthias , Kanitscheider Ingmar , Riemer Martin , Fiete Ila , Wolbers Thomas 
Published: May 2020

AbstractPath integration plays a vital role in navigation: it enables the continuous tracking of one's position in space by integrating self-motion cues. Path integration abilities vary widely across individuals, and tend to deteriorate in old age. The specific causes of path integration errors, however, remain poorly characterized. Here, we combine tests of path integration performance in participants of different ages with an analysis based on the Langevin equation for diffusive dynamics, which allows us to decompose errors into distinct causes that can corrupt path integration computations. We show that, across age groups, the dominant error source is unbiased noise that accumulates with travel distance not elapsed time, suggesting that the noise originates in the velocity input rather than within the integrator. Age-related declines are primarily traced to a growth in this noise. These findings shed light on the contributors to path integration error and the mechanisms underlying age-related navigational deficits.
The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions
Authors: Littlejohns Thomas J. , Holliday Jo , Gibson Lorna M. , Garratt Steve , Oesingmann Niels , Alfaro-Almagro Fidel , Bell Jimmy D. , Boultwood Chris , Collins Rory , Conroy Megan C. , Crabtree Nicola , Doherty Nicola , Frangi Alejandro F. , Harvey Nicholas C. , Leeson Paul , Miller Karla L. , Neubauer Stefan , Petersen Steffen E. , Sellors Jonathan , Sheard Simon , Smith Stephen M. , Sudlow Cathie L. M. , Matthews Paul M. , Allen Naomi E. 
Published: May 2020

AbstractUK Biobank is a population-based cohort of half a million participants aged 40–69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world’s largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future directions.
Mode-resolved reciprocal space mapping of electron-phonon interaction in the Weyl semimetal candidate Td-WTe2
Authors: Hein Petra , Jauernik Stephan , Erk Hermann , Yang Lexian , Qi Yanpeng , Sun Yan , Felser Claudia , Bauer Michael 
Published: May 2020

AbstractThe excitation of coherent phonons provides unique capabilities to control fundamental properties of quantum materials on ultrafast time scales. Recently, it was predicted that a topologically protected Weyl semimetal phase in the transition metal dichalcogenide Td-WTe2 can be controlled and, ultimately, be destroyed upon the coherent excitation of an interlayer shear mode. By monitoring electronic structure changes with femtosecond resolution, we provide here direct experimental evidence that the shear mode acts on the electronic states near the phase-defining Weyl points. Furthermore, we observe a periodic reduction in the spin splitting of bands, a distinct electronic signature of the Weyl phase-stabilizing non-centrosymmetric Td ground state of WTe2. The comparison with higher-frequency coherent phonon modes finally proves the shear mode-selectivity of the observed changes in the electronic structure. Our real-time observations reveal direct experimental insights into electronic processes that are of vital importance for a coherent phonon-induced topological phase transition in Td-WTe2.
Single cell transcriptomics reveals opioid usage evokes widespread suppression of antiviral gene program
Authors: Karagiannis Tanya T. , Cleary John P. , Gok Busra , Henderson Andrew J. , Martin Nicholas G. , Yajima Masanao , Nelson Elliot C. , Cheng Christine S. 
Published: May 2020

AbstractChronic opioid usage not only causes addiction behavior through the central nervous system, but also modulates the peripheral immune system. However, how opioid impacts the immune system is still barely characterized systematically. In order to understand the immune modulatory effect of opioids in an unbiased way, here we perform single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from opioid-dependent individuals and controls to show that chronic opioid usage evokes widespread suppression of antiviral gene program in naive monocytes, as well as in multiple immune cell types upon stimulation with the pathogen component lipopolysaccharide. Furthermore, scRNA-seq reveals the same phenomenon after a short in vitro morphine treatment. These findings indicate that both acute and chronic opioid exposure may be harmful to our immune system by suppressing the antiviral gene program. Our results suggest that further characterization of the immune modulatory effects of opioid is critical to ensure the safety of clinical opioids.
Search and rescue at sea aided by hidden flow structures
Authors: Serra Mattia , Sathe Pratik , Rypina Irina , Kirincich Anthony , Ross Shane D. , Lermusiaux Pierre , Allen Arthur , Peacock Thomas , Haller George 
Published: May 2020

AbstractEvery year, hundreds of people die at sea because of vessel and airplane accidents. A key challenge in reducing the number of these fatalities is to make Search and Rescue (SAR) algorithms more efficient. Here, we address this challenge by uncovering hidden TRansient Attracting Profiles (TRAPs) in ocean-surface velocity data. Computable from a single velocity-field snapshot, TRAPs act as short-term attractors for all floating objects. In three different ocean field experiments, we show that TRAPs computed from measured as well as modeled velocities attract deployed drifters and manikins emulating people fallen in the water. TRAPs, which remain hidden to prior flow diagnostics, thus provide critical information for hazard responses, such as SAR and oil spill containment, and hence have the potential to save lives and limit environmental disasters.
Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure
Authors: Zhao Kun , Li Yaowang , Liu Zhenying , Long Houfang , Zhao Chunyu , Luo Feng , Sun Yunpeng , Tao Youqi , Su Xiao-dong , Li Dan , Li Xueming , Liu Cong 
Published: May 2020

AbstractAmyloid aggregation of α-synuclein (α-syn) is closely associated with Parkinson’s disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of α-syn have been identified causative to the early onset of familial PD. Here, we report the cryo-EM structure of an α-syn fibril formed by N-terminally acetylated E46K mutant α-syn (Ac-E46K). The fibril structure represents a distinct fold of α-syn, which demonstrates that the E46K mutation breaks the electrostatic interactions in the wild type (WT) α-syn fibril and thus triggers the rearrangement of the overall structure. Furthermore, we show that the Ac-E46K fibril is less resistant to harsh conditions and protease cleavage, and more prone to be fragmented with an enhanced seeding capability than that of the WT fibril. Our work provides a structural view to the severe pathology of the PD familial mutation E46K of α-syn and highlights the importance of electrostatic interactions in defining the fibril polymorphs.
CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer
Authors: Sanij Elaine , Hannan Katherine M. , Xuan Jiachen , Yan Shunfei , Ahern Jessica E. , Trigos Anna S. , Brajanovski Natalie , Son Jinbae , Chan Keefe T. , Kondrashova Olga , Lieschke Elizabeth , Wakefield Matthew J. , Frank Daniel , Ellis Sarah , Cullinane Carleen , Kang Jian , Poortinga Gretchen , Nag Purba , Deans Andrew J. , Khanna Kum Kum , Mileshkin Linda , McArthur Grant A. , Soong John , Berns Els M. J. J. , Hannan Ross D. , Scott Clare L. , Sheppard Karen E. , Pearson Richard B. 
Published: May 2020

AbstractAcquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.
UDP-glucosyltransferase regulates grain size and abiotic stress tolerance associated with metabolic flux redirection in rice
Authors: Dong Nai-Qian , Sun Yuwei , Guo Tao , Shi Chuan-Lin , Zhang Yi-Min , Kan Yi , Xiang You-Huang , Zhang Hai , Yang Yi-Bing , Li Ya-Chao , Zhao Huai-Yu , Yu Hong-Xiao , Lu Zi-Qi , Wang Yong , Ye Wang-Wei , Shan Jun-Xiang , Lin Hong-Xuan 
Published: May 2020

AbstractGrain size is an important component trait of grain yield, which is frequently threatened by abiotic stress. However, little is known about how grain yield and abiotic stress tolerance are regulated. Here, we characterize GSA1, a quantitative trait locus (QTL) regulating grain size and abiotic stress tolerance associated with metabolic flux redirection. GSA1 encodes a UDP-glucosyltransferase, which exhibits glucosyltransferase activity toward flavonoids and monolignols. GSA1 regulates grain size by modulating cell proliferation and expansion, which are regulated by flavonoid-mediated auxin levels and related gene expression. GSA1 is required for the redirection of metabolic flux from lignin biosynthesis to flavonoid biosynthesis under abiotic stress and the accumulation of flavonoid glycosides, which protect rice against abiotic stress. GSA1 overexpression results in larger grains and enhanced abiotic stress tolerance. Our findings provide insights into the regulation of grain size and abiotic stress tolerance associated with metabolic flux redirection and a potential means to improve crops.
Causal mechanism of injection-induced earthquakes through the Mw 5.5 Pohang earthquake case study
Authors: Yeo I. W. , Brown M. R. M. , Ge S. , Lee K. K. 
Published: May 2020

AbstractCausal mechanisms for fluid injection-induced earthquakes remain a challenge to identify. Past studies largely established spatiotemporal correlations. Here, we propose a multi-process causal mechanism for injection-induced earthquakes through a case study of the 2017 Mw 5.5 induced earthquake near Pohang Enhanced Geothermal System, Korea, where detailed hydraulic stimulation and on-site seismicity monitoring data provide an unprecedented opportunity. Pore pressure modeling reveals that pore pressure changes initiate seismicity on critically stressed faults and Coulomb static stress transfer modeling reveals that earthquake interactions promote continued seismicity, leading to larger events. On the basis of these results, we propose the following causal mechanism for induced seismicity: pore pressure increase and earthquake interactions lead to fault weakening and ultimately triggering larger earthquakes later in the process. We suggest that it is prudent that pore pressure change, initial seismicity locations, and Coulomb static stress transfer from seismicity earlier in the sequence are assessed in real-time.
Tuning molecular emission of organic emitters from fluorescence to phosphorescence through push-pull electronic effects
Authors: Feng Hai-Tao , Zeng Jiajie , Yin Ping-An , Wang Xue-Dong , Peng Qian , Zhao Zujin , Lam Jacky W. Y. , Tang Ben Zhong 
Published: May 2020

AbstractOrganic emitters with persistent phosphorescence have shown potential application in optoelectronic devices. However, rational design and phosphorescence tuning are still challenging. Here, a series of metal-free luminophores without heavy atoms and carbonyl groups from commercial/lab-synthesized carbazole and benzene were synthesized to realize tunable molecular emission from fluorescence to phosphorescence by simply substituent variation. All the molecules emit blue fluorescence in both solution and solid state. Upon removal of excitation source, the fluorinated luminophores show obvious phosphorescence. The lab-synthesized carbazole based molecules exhibit a huge lifetime difference to the commercially purchased ones due to the existence of isomer in the latter samples. The small energy gap between singlet and triplet state and low reorganization energy help enhance intersystem crossing to contribute to a more competitive radiative process from triplet to ground state. Blue and white organic light-emitting devices are fabricated by using fluorinated luminophore as emitting layer.
Electrical switching between exciton dissociation to exciton funneling in MoSe2/WS2 heterostructure
Authors: Meng Yuze , Wang Tianmeng , Jin Chenhao , Li Zhipeng , Miao Shengnan , Lian Zhen , Taniguchi Takashi , Watanabe Kenji , Song Fengqi , Shi Su-Fei 
Published: May 2020

AbstractThe heterostructure of monolayer transition metal dichalcogenides (TMDCs) provides a unique platform to manipulate exciton dynamics. The ultrafast carrier transfer across the van der Waals interface of the TMDC hetero-bilayer can efficiently separate electrons and holes in the intralayer excitons with a type II alignment, but it will funnel excitons into one layer with a type I alignment. In this work, we demonstrate the reversible switch from exciton dissociation to exciton funneling in a MoSe2/WS2 heterostructure, which manifests itself as the photoluminescence (PL) quenching to PL enhancement transition. This transition was realized through effectively controlling the quantum capacitance of both MoSe2 and WS2 layers with gating. PL excitation spectroscopy study unveils that PL enhancement arises from the blockage of the optically excited electron transfer from MoSe2 to WS2. Our work demonstrates electrical control of photoexcited carrier transfer across the van der Waals interface, the understanding of which promises applications in quantum optoelectronics.