bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans
Authors: Gualtieri Angelica , Kyprianou Nikolina , Gregory Louise C. , Vignola Maria Lillina , Nicholson James G. , Tan Rachael , Inoue Shin-ichi , Scagliotti Valeria , Casado Pedro , Blackburn James , Abollo-Jimenez Fernando , Marinelli Eugenia , Besser Rachael E. J. , Högler Wolfgang , Karen Temple I. , Davies Justin H. , Gagunashvili Andrey , Robinson Iain C.A.F. , Camper Sally A. , Davis Shannon W. , Cutillas Pedro R. , Gevers Evelien F. , Aoki Yoko , Dattani Mehul T. , Gaston-Massuet Carles 
Published: April 2021

AbstractGermline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.
A Hierarchical Attractor Network Model of perceptual versus intentional decision updates
Authors: Löffler Anne , Sylaidi Anastasia , Fountas Zafeirios , Haggard Patrick 
Published: April 2021

AbstractChanges of Mind are a striking example of our ability to flexibly reverse decisions and change our own actions. Previous studies largely focused on Changes of Mind in decisions about perceptual information. Here we report reversals of decisions that require integrating multiple classes of information: 1) Perceptual evidence, 2) higher-order, voluntary intentions, and 3) motor costs. In an adapted version of the random-dot motion task, participants moved to a target that matched both the external (exogenous) evidence about dot-motion direction and a preceding internally-generated (endogenous) intention about which colour to paint the dots. Movement trajectories revealed whether and when participants changed their mind about the dot-motion direction, or additionally changed their mind about which colour to choose. Our results show that decision reversals about colour intentions are less frequent in participants with stronger intentions (Exp. 1) and when motor costs of intention pursuit are lower (Exp. 2). We further show that these findings can be explained by a hierarchical, multimodal Attractor Network Model that continuously integrates higher-order voluntary intentions with perceptual evidence and motor costs. Our model thus provides a unifying framework in which voluntary actions emerge from a dynamic combination of internal action tendencies and external environmental factors, each of which can be subject to Change of Mind.
Presence of complete murine viral genome sequences in patient-derived xenografts
Authors: Yuan Zihao , Fan Xuejun , Zhu Jay-Jiguang , Fu Tong-Ming , Wu Jiaqian , Xu Hua , Zhang Ningyan , An Zhiqiang , Zheng W. Jim 
Published: April 2021

AbstractPatient-derived xenografts are crucial for drug development but their use is challenged by issues such as murine viral infection. We evaluate the scope of viral infection and its impact on patient-derived xenografts by taking an unbiased data-driven approach to analyze unmapped RNA-Seq reads from 184 experiments. We find and experimentally validate the extensive presence of murine viral sequence reads covering entire viral genomes in patient-derived xenografts. The existence of viral sequences inside tumor cells is further confirmed by single cell sequencing data. Extensive chimeric reads containing both viral and human sequences are also observed. Furthermore, we find significantly changed expression levels of many cancer-, immune-, and drug metabolism-related genes in samples with high virus load. Our analyses indicate a need to carefully evaluate the impact of viral infection on patient-derived xenografts for drug development. They also point to a need for attention to quality control of patient-derived xenograft experiments.
Axial localization and tracking of self-interference nanoparticles by lateral point spread functions
Authors: Liu Yongtao , Zhou Zhiguang , Wang Fan , Kewes Günter , Wen Shihui , Burger Sven , Ebrahimi Wakiani Majid , Xi Peng , Yang Jiong , Yang Xusan , Benson Oliver , Jin Dayong 
Published: April 2021

AbstractSub-diffraction limited localization of fluorescent emitters is a key goal of microscopy imaging. Here, we report that single upconversion nanoparticles, containing multiple emission centres with random orientations, can generate a series of unique, bright and position-sensitive patterns in the spatial domain when placed on top of a mirror. Supported by our numerical simulation, we attribute this effect to the sum of each single emitter’s interference with its own mirror image. As a result, this configuration generates a series of sophisticated far-field point spread functions (PSFs), e.g. in Gaussian, doughnut and archery target shapes, strongly dependent on the phase difference between the emitter and its image. In this way, the axial locations of nanoparticles are transferred into far-field patterns. We demonstrate a real-time distance sensing technology with a localization accuracy of 2.8 nm, according to the atomic force microscope (AFM) characterization values, smaller than 1/350 of the excitation wavelength.
Detecting local genetic correlations with scan statistics
Authors: Guo Hanmin , Li James J. , Lu Qiongshi , Hou Lin 
Published: April 2021

AbstractGenetic correlation analysis has quickly gained popularity in the past few years and provided insights into the genetic etiology of numerous complex diseases. However, existing approaches oversimplify the shared genetic architecture between different phenotypes and cannot effectively identify precise genetic regions contributing to the genetic correlation. In this work, we introduce LOGODetect, a powerful and efficient statistical method to identify small genome segments harboring local genetic correlation signals. LOGODetect automatically identifies genetic regions showing consistent associations with multiple phenotypes through a scan statistic approach. It uses summary association statistics from genome-wide association studies (GWAS) as input and is robust to sample overlap between studies. Applied to seven phenotypically distinct but genetically correlated neuropsychiatric traits, we identify 227 non-overlapping genome regions associated with multiple traits, including multiple hub regions showing concordant effects on five or more traits. Our method addresses critical limitations in existing analytic strategies and may have wide applications in post-GWAS analysis.
A KRAS-responsive long non-coding RNA controls microRNA processing
Authors: Shi Lei , Magee Peter , Fassan Matteo , Sahoo Sudhakar , Leong Hui Sun , Lee Dave , Sellers Robert , Brullé-Soumaré Laura , Cairo Stefano , Monteverde Tiziana , Volinia Stefano , Smith Duncan D. , Di Leva Gianpiero , Galuppini Francesca , Paliouras Athanasios R. , Zeng Kang , O’Keefe Raymond , Garofalo Michela 
Published: April 2021

AbstractWild-type KRAS (KRASWT) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. Nevertheless, the precise role of KRASWT overexpression in lung cancer progression is largely unexplored. Here, we identify and characterize a KRAS-responsive lncRNA, KIMAT1 (ENSG00000228709) and show that it correlates with KRAS levels both in cell lines and in lung cancer specimens. Mechanistically, KIMAT1 is a MYC target and drives lung tumorigenesis by promoting the processing of oncogenic microRNAs (miRNAs) through DHX9 and NPM1 stabilization while halting the biogenesis of miRNAs with tumor suppressor function via MYC-dependent silencing of p21, a component of the Microprocessor Complex. KIMAT1 knockdown suppresses not only KRAS expression but also KRAS downstream signaling, thereby arresting lung cancer growth in vitro and in vivo. Taken together, this study uncovers a role for KIMAT1 in maintaining a positive feedback loop that sustains KRAS signaling during lung cancer progression and provides a proof of principle that interfering with KIMAT1 could be a strategy to hamper KRAS-induced tumorigenesis.
Lead compounds for the development of SARS-CoV-2 3CL protease inhibitors
Authors: Iketani Sho , Forouhar Farhad , Liu Hengrui , Hong Seo Jung , Lin Fang-Yu , Nair Manoj S. , Zask Arie , Huang Yaoxing , Xing Li , Stockwell Brent R. , Chavez Alejandro , Ho David D. 
Published: April 2021

AbstractWe report the identification of three structurally diverse compounds – compound 4, GC376, and MAC-5576 – as inhibitors of the SARS-CoV-2 3CL protease. Structures of each of these compounds in complex with the protease revealed strategies for further development, as well as general principles for designing SARS-CoV-2 3CL protease inhibitors. These compounds may therefore serve as leads for the basis of building effective SARS-CoV-2 3CL protease inhibitors.
Activation of NF-κB signaling via cytosolic mitochondrial RNA sensing in kerotocytes with mitochondrial DNA common deletion
Authors: Zhou Xin , Backman Ludvig J. , Danielson Patrik 
Published: April 2021

AbstractScar formation as a result of corneal wound healing is a leading cause of blindness. It is a challenge to understand why scar formation is more likely to occur in the central part of the cornea as compared to the peripheral part. The purpose of this study was to unravel the underlying mechanisms. We applied RNA-seq to uncover the differences of expression profile in keratocytes in the central/peripheral part of the cornea. The relative quantity of mitochondrial RNA was measured by multiplex qPCR. The characterization of mitochondrial RNA in the cytoplasm was confirmed by immunofluoresence microscope and biochemical approach. Gene expression was analyzed by western blot and RT qPCR. We demonstrate that the occurrence of mitochondrial DNA common deletion is greater in keratocytes from the central cornea as compared to those of the peripheral part. The keratocytes with CD have elevated oxidative stress levels, which leads to the leakage of mitochondrial double-stranded RNA into the cytoplasm. The cytoplasmic mitochondrial double-stranded RNA is sensed by MDA5, which induces NF-κB activation. The NF-κB activation thereafter induces fibrosis-like extracellular matrix expressions and IL-8 mRNA transcription. These results provide a novel explanation of the different clinical outcome in different regions of the cornea during wound healing.
Outcomes of prostate cancer screening among men using antidiabetic medication
Authors: Vettenranta A. , Murtola T. J. , Talala K. , Taari K. , Stenman U.-H. , Tammela T. L. J. , Auvinen A. 
Published: April 2021

AbstractDiabetic men have decreased risk for prostate cancer (PCa) overall and lower PSA compared to non-diabetics. This may affect the outcomes of PSA-based screening. We investigated the effect of PSA-based screening at 4-year intervals on PCa incidence and mortality separately among users and non-users of antidiabetic medication with the hypothesis that screening would detect less low-grade cancer and more high-grade cancer in diabetic men. A cohort of 80,458 men from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) were linked to national prescription database to obtain information on antidiabetic medication purchases. PCa risk and mortality were compared between the FinRSPC screening arm (SA) and the control arm (CA) separately among users and non-users of antidiabetic medication. Among antidiabetic medication users median PSA was lower than in non-users (0.93 and 1.09 ng/ml, respectively, P for difference = 0.001). Screening increased overall PCa incidence compared to CA after the first screen both among medication users and non-users (HR 1.31, 95% CI 1.08–1.60 and HR 1.55, 95% CI 1.44–1.66, respectively). On the second and third screen the difference between SA and CA attenuated only among medication users. Detection of Gleason 6 tumors was lower among medication users, whereas no difference was observed in detection of Gleason 8–10 cancers. Concordantly, screening affected PCa mortality similarly regardless of antidiabetic medication use (HR 0.38, 95% CI 0.14–1.07 and HR 0.19, 95% CI 0.11–0.33 among users and non-users after three screens, respectively. P for difference = 0.18). Median PSA is lower in men using antidiabetic drugs than among non-users. Systematic PSA screening detects less low-risk tumors among medication users, whereas detection of high-risk tumors and mortality effects are similar regardless of medication use. This suggests that antidiabetic medication users may form a suitable target group for PCa screening, with less screening-related overdiagnosis of indolent tumors.
An efficient direct screening system for microorganisms that activate plant immune responses based on plant–microbe interactions using cultured plant cells
Authors: Kurokawa Mari , Nakano Masataka , Kitahata Nobutaka , Kuchitsu Kazuyuki , Furuya Toshiki 
Published: April 2021

AbstractMicroorganisms that activate plant immune responses have attracted considerable attention as potential biocontrol agents in agriculture because they could reduce agrochemical use. However, conventional methods to screen for such microorganisms using whole plants and pathogens are generally laborious and time consuming. Here, we describe a general strategy using cultured plant cells to identify microorganisms that activate plant defense responses based on plant–microbe interactions. Microbial cells were incubated with tobacco BY-2 cells, followed by treatment with cryptogein, a proteinaceous elicitor of tobacco immune responses secreted by an oomycete. Cryptogein-induced production of reactive oxygen species (ROS) in BY-2 cells served as a marker to evaluate the potential of microorganisms to activate plant defense responses. Twenty-nine bacterial strains isolated from the interior of Brassica rapa var. perviridis plants were screened, and 8 strains that enhanced cryptogein-induced ROS production in BY-2 cells were selected. Following application of these strains to the root tip of Arabidopsis seedlings, two strains, Delftia sp. BR1R-2 and Arthrobacter sp. BR2S-6, were found to induce whole-plant resistance to bacterial pathogens (Pseudomonas syringae pv. tomato DC3000 and Pectobacterium carotovora subsp. carotovora NBRC 14082). Pathogen-induced expression of plant defense-related genes (PR-1, PR-5, and PDF1.2) was enhanced by the pretreatment with strain BR1R-2. This cell–cell interaction-based platform is readily applicable to large-scale screening for microorganisms that enhance plant defense responses under various environmental conditions.
On the mechanisms governing the critical current reduction in Nb3Sn Rutherford cables under transverse stress
Authors: De Marzi Gianluca , Bordini Bernardo , Baffari Dario 
Published: April 2021

AbstractWithin the framework of the HiLumi-LHC project, CERN is currently manufacturing 11 T dipole and quadrupole accelerator magnets using state-of-the-art Nb3Sn Rutherford cables. Even higher magnetic fields are considered by the Hadron Future Circular Collider (FCC-hh) design study, which plans to develop 16 T Nb3Sn bending dipoles. In such high-field magnets, the design pre-stress can reach considerable values (150–200 MPa) and, since Nb3Sn is a brittle compound, this can constitute a technological difficult challenge. Due to the significant impact that a transverse load can have on the performances of a Nb3Sn magnet, CERN has launched a campaign of critical current measurements of reacted and impregnated Nb3Sn cables subjected to transverse pressure up to about 210 MPa. In this paper, results obtained on 18-strand 10-mm-wide cable sample based on a 1-mm-diameter powder-in-tube (PIT) wire are presented. The tests were carried out on a 2-m-long sample by using the FReSCa test station, at T = 4.3 K and background magnetic fields up to 9.6 T. For applied pressures below ≈ 130 MPa, only reversible reductions of the critical current, Ic, are observed. At higher pressures, a permanent Ic reduction occurs; such irreversible behaviour is due to the residual stresses generated by the plastic deformations of the copper stabilizer. This type of current reduction, whether reversible or not, is fully governed by the strain-induced variations of the upper critical field, Bc2. At higher pressures, estimated between 180 and 210 MPa, it is indeed plausible to believe that cracking of filaments occurs, with detrimental consequences for the Nb3Sn cable’s electrical performances. The complete set of critical current data here presented, collected at different pressures and as a function of the applied magnetic field, allows for the first time to investigate the evolution of superconducting parameters such as the upper critical field Bc2 in the irreversibility region, where both the effects of Cu matrix plasticization and/or cracking of filaments may occur. The experimental approach and data interpretation have a general value and can be applied to any typology of Rutherford cable.
Statistical shape modeling of the talocrural joint using a hybrid multi-articulation joint approach
Authors: Lenz Amy L. , Krähenbühl Nicola , Peterson Andrew C. , Lisonbee Rich J. , Hintermann Beat , Saltzman Charles L. , Barg Alexej , Anderson Andrew E. 
Published: April 2021

AbstractHistorically, conventional radiographs have been the primary tool to morphometrically evaluate the talocrural joint, which is comprised of the distal tibia, distal fibula, and proximal talus. More recently, high-resolution volumetric imaging, including computed tomography (CT), has enabled the generation of three-dimensional (3D) reconstructions of the talocrural joint. Weightbearing cone-beam CT (WBCT) technology provides additional benefit to assess 3D spatial relationships and joint congruency while the patient is load bearing. In this study we applied statistical shape modeling, a computational morphometrics technique, to objectively quantify anatomical variation, joint level coverage, joint space distance, and congruency at the talocrural joint. Shape models were developed from segmented WBCT images and included the distal tibia, distal fibula, and full talus. Key anatomical variation across subjects included the fibular notch on the tibia, talar trochlea sagittal plane rate of curvature, tibial plafond curvature with medial malleolus prominence, and changes in the fibular shaft diameter. The shape analysis also revealed a highly congruent talocrural joint with minimal inter-individual morphometric differences at the articular regions. These data are helpful to improve understanding of ankle joint pathologies and to guide refinement of operative treatments.
Adsorption of bacteriophages on polypropylene labware affects the reproducibility of phage research
Authors: Richter Łukasz , Księżarczyk Karolina , Paszkowska Karolina , Janczuk-Richter Marta , Niedziółka-Jönsson Joanna , Gapiński Jacek , Łoś Marcin , Hołyst Robert , Paczesny Jan 
Published: April 2021

AbstractHydrophobicity is one of the most critical factors governing the adsorption of molecules and objects, such as virions, on surfaces. Even moderate change of wetting angle of plastic surfaces causes a drastic decrease ranging from 2 to 5 logs of the viruses (e.g., T4 phage) in the suspension due to adsorption on polymer vials' walls. The effect varies immensely in seemingly identical containers but purchased from different vendors. Comparison of glass, polyethylene, polypropylene, and polystyrene containers revealed a threshold in the wetting angle of around 95°: virions adsorb on the surface of more hydrophobic containers, while in more hydrophilic vials, phage suspensions are stable. The polypropylene surface of the Eppendorf-type and Falcon-type can accommodate from around 108 PFU/ml to around 1010 PFU/ml from the suspension. The adsorption onto the container’s wall might result in complete scavenging of virions from the bulk. We developed two methods to overcome this issue. The addition of surfactant Tween20 and/or plasma treatment provides a remedy by modulating surface wettability and inhibiting virions' adsorption. Plastic containers are essential consumables in the daily use of many bio-laboratories. Thus, this is important not only for phage-related research (e.g., the use of phage therapies as an alternative for antibiotics) but also for data comparison and reproducibility in the field of biochemistry and virology.
DNMT3.1 controls trade-offs between growth, reproduction, and life span under starved conditions in Daphnia magna
Authors: Nguyen Nhan Duc , Matsuura Tomoaki , Kato Yasuhiko , Watanabe Hajime 
Published: April 2021

AbstractThe cladoceran crustaceanDaphniahas long been a model of energy allocation studies due to its important position in the trophic cascade of freshwater ecosystems. However, the loci for controlling energy allocation between life history traits still remain unknown. Here, we report CRISPR/Cas-mediated target mutagenesis of DNA methyltransferase 3.1 (DNMT3.1) that is upregulated in response to caloric restriction inDaphnia magna. The resulting biallelic mutant is viable and did not show any change in growth rate, reproduction, and longevity under nutrient rich conditions. In contrast, under starved conditions, the growth rate of this DNMT3.1 mutant was increased but its reproduction was reciprocally reduced compared to the wild type when the growth and reproduction activities competed during a period from instar 4 to 8. The life span of this mutant was significantly shorter than that of the wild type. We also compared transcriptomes between DNMT3.1 mutant and wild type under nutrient-rich and starved conditions. Consistent with the DNMT3.1 mutant phenotypes, the starved condition led to changes in the transcriptomes of the mutant including differential expression of vitellogenin genes. In addition, we found upregulation of theI am not dead yet(INDY) ortholog, which has been known to shorten the life span inDrosophila, explaining the shorter life span of the DNMT3.1 mutant. These results establish DNMT3.1 as a key regulator for life span and energy allocation between growth and reproduction during caloric restriction. Our findings reveal how energy allocation is implemented by selective expression of a DNMT3 ortholog that is widely distributed among animals. We also infer a previously unidentified adaptation ofDaphniathat invests more energy for reproduction than growth under starved conditions.