bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the insulin-like growth factor-1 receptor in MTAP-deficient renal cell carcinoma
Authors: Xu Jihao , Chang Wen-Hsin , Fong Lon Wolf R. , Weiss Robert H. , Yu Sung-Liang , Chen Ching-Hsien 
Published: January 2019

AbstractRenal cell carcinoma (RCC) has emerged as a metabolic disease characterized by dysregulated expression of metabolic enzymes. Patients with metastatic RCC have an unusually poor prognosis and near-universal resistance to all current therapies. To improve RCC treatment and the survival rate of patients with RCC, there is an urgent need to reveal the mechanisms by which metabolic reprogramming regulates aberrant signaling and oncogenic progression. Through an integrated analysis of RCC metabolic pathways, we showed that methylthioadenosine phosphorylase (MTAP) and its substrate methylthioadenosine (MTA) are dysregulated in aggressive RCC. A decrease in MTAP expression was observed in RCC tissues and correlated with higher tumor grade and shorter overall survival. Genetic manipulation of MTAP demonstrated that MTAP expression inhibits the epithelial-mesenchymal transition, invasion and migration of RCC cells. Interestingly, we found a decrease in the protein methylation level with a concomitant increase in tyrosine phosphorylation after MTAP knockout. A phospho-kinase array screen identified the type 1 insulin-like growth factor-1 receptor (IGF1R) as the candidate with the highest upregulation in tyrosine phosphorylation in response to MTAP loss. We further demonstrated that IGF1R phosphorylation acts upstream of Src and STAT3 signaling in MTAP-knockout RCC cells. IGF1R suppression by a selective inhibitor of IGF1R, linsitinib, impaired the cell migration and invasion capability of MTAP-deleted cells. Surprisingly, an increase in linsitinib-mediated cytotoxicity occurred in RCC cells with MTAP deficiency. Our data suggest that IGF1R signaling is a driver pathway that contributes to the aggressive nature of MTAP-deleted RCC.
Demonstration of a two-dimensional $${\cal P}{\cal T}$$-symmetric crystal
Authors: Kremer Mark , Biesenthal Tobias , Maczewsky Lukas J. , Heinrich Matthias , Thomale Ronny , Szameit Alexander 
Published: January 2019

AbstractWith the discovery of $${\cal P}{\cal T}$$
P
T
-symmetric quantum mechanics, it was shown that even non-Hermitian systems may exhibit entirely real eigenvalue spectra. This finding did not only change the perception of quantum mechanics itself, it also significantly influenced the field of photonics. By appropriately designing one-dimensional distributions of gain and loss, it was possible to experimentally verify some of the hallmark features of $${\cal P}{\cal T}$$
P
T
-symmetry using electromagnetic waves. Nevertheless, an experimental platform to study the impact of $${\cal P}{\cal T}$$
P
T
-symmetry in two spatial dimensions has so far remained elusive. We break new grounds by devising a two-dimensional $${\cal P}{\cal T}$$
P
T
-symmetric system based on photonic waveguide lattices with judiciously designed refractive index landscape and alternating loss. With this system at hand, we demonstrate a non-Hermitian two-dimensional topological phase transition that is closely linked to the emergence of topological mid-gap edge states.
AAV2.7m8 is a powerful viral vector for inner ear gene therapy
Authors: Isgrig Kevin , McDougald Devin S. , Zhu Jianliang , Wang Hong Jun , Bennett Jean , Chien Wade W. 
Published: January 2019

AbstractAdeno-associated virus (AAV) has been successfully used to deliver gene therapy to improve auditory function in mouse models of hereditary hearing loss. Many forms of hereditary hearing loss have mutations which affect the cochlear hair cells, the mechanosensory cells which allow for sound detection and processing. While most conventional AAVs infect inner hair cells (IHCs) with various efficiencies, they infect outer hair cells (OHCs) and supporting cells at lower levels in the cochlea. Here we examine the infection patterns of two synthetic AAVs (AAV2.7m8 and AAV8BP2) in the mouse inner ear. AAV2.7m8 infects both IHCs and OHCs with high efficiency. In addition, AAV2.7m8 infects inner pillar cells and inner phalangeal cells with high efficiency. Our results suggest that AAV2.7m8 is an excellent viral vector for inner ear gene therapy targeting cochlear hair cells and supporting cells, and it will likely greatly expand the potential applications for inner ear gene therapy.
Light- and bias-induced structural variations in metal halide perovskites
Authors: Kim Dohyung , Yun Jae Sung , Sharma Pankaj , Lee Da Seul , Kim Jincheol , Soufiani Arman M. , Huang Shujuan , Green Martin A. , Ho-Baillie Anita W. Y. , Seidel Jan 
Published: January 2019

AbstractOrganic–inorganic metal halide perovskites have gained considerable attention for next-generation photovoltaic cells due to rapid improvement in power conversion efficiencies. However, fundamental understanding of underlying mechanisms related to light- and bias-induced effects at the nanoscale is still required. Here, structural variations of the perovskites induced by light and bias are systematically investigated using scanning probe microscopy techniques. We show that periodically striped ferroelastic domains, spacing between 40 to 350 nm, exist within grains and can be modulated significantly under illumination as well as by electric bias. Williamson-Hall analysis of X-ray diffraction results shows that strain disorder is induced by these applied external stimuli. We show evidence that the structural emergence of domains can provide transfer pathways for holes to a hole transport layer with positive bias. Our findings point to potential origins of I–V hysteresis in halide perovskite solar cells.
The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma
Authors: Bhaskaran Vivek , Nowicki Michal O. , Idriss Mahmoud , Jimenez Miguel A. , Lugli Gianmarco , Hayes Josie L. , Mahmoud Ahmad Bakur , Zane Rachel E. , Passaro Carmela , Ligon Keith L. , Haas-Kogan Daphne , Bronisz Agnieszka , Godlewski Jakub , Lawler Sean E. , Chiocca E. Antonio , Peruzzi Pierpaolo 
Published: January 2019

AbstractMicroRNA deregulation is a consistent feature of glioblastoma, yet the biological effect of each single gene is generally modest, and therapeutically negligible. Here we describe a module of microRNAs, constituted by miR-124, miR-128 and miR-137, which are co-expressed during neuronal differentiation and simultaneously lost in gliomagenesis. Each one of these miRs targets several transcriptional regulators, including the oncogenic chromatin repressors EZH2, BMI1 and LSD1, which are functionally interdependent and involved in glioblastoma recurrence after therapeutic chemoradiation. Synchronizing the expression of these three microRNAs in a gene therapy approach displays significant anticancer synergism, abrogates this epigenetic-mediated, multi-protein tumor survival mechanism and results in a 5-fold increase in survival when combined with chemotherapy in murine glioblastoma models. These transgenic microRNA clusters display intercellular propagation in vivo, via extracellular vesicles, extending their biological effect throughout the whole tumor. Our results support the rationale and feasibility of combinatorial microRNA strategies for anticancer therapies.
Isolation and characterization of Sphingomonadaceae from fouled membranes
Authors: de Vries Hendrik J. , Beyer Florian , Jarzembowska Monika , Lipińska Joanna , van den Brink Paula , Zwijnenburg Arie , Timmers Peer H. A. , Stams Alfons J. M. , Plugge Caroline M. 
Published: January 2019

AbstractMembrane filtration systems are widely applied for the production of clean drinking water. However, the accumulation of particles on synthetic membranes leads to fouling. Biological fouling (i.e., biofouling) of reverse osmosis and nanofiltration membranes is difficult to control by existing cleaning procedures. Improved strategies are therefore needed. The bacterial diversity on fouled membranes has been studied, especially to identify bacteria with specialized functions and to develop targeted approaches against these microbes. Previous studies have shown that Sphingomonadaceae are initial membrane colonizers that remain dominant while the biofilm develops. Here, we characterized 21 Sphingomonadaceae isolates, obtained from six different fouled membranes, to determine which physiological traits could contribute to colonization of membrane surfaces. Their growth conditions ranged from temperatures between 8 and 42 oC, salinity between 0.0 and 5.0% w/v NaCl, pH from 4 and 10, and all isolates were able to metabolize a wide range of substrates. The results presented here show that Sphingomonadaceae membrane isolates share many features that are uncommon for other members of the Sphingomonadaceae family: all membrane isolates are motile and their tolerance for different temperatures, salt concentrations, and pH is high. Although relative abundance is an indicator of fitness for a whole group, for the Sphingomonadaceae it does not reveal the specific physiological traits that are required for membrane colonization. This study, therefore, adds to more fundamental insights in membrane biofouling.
Single dose of a rVSV-based vaccine elicits complete protection against severe fever with thrombocytopenia syndrome virus
Authors: Dong Fangfang , Li Dandan , Wen Dan , Li Suhua , Zhao Chaoyue , Qi Yue , Jangra Rohit K. , Wu Cuiping , Xia Dequan , Zhang Xing , Deng Fei , Chandran Kartik , Zou Zhen , Yuan Fei , Zheng Aihua 
Published: January 2019

AbstractSevere fever with thrombocytopenia virus (SFTSV) is an emerging tick-borne phlebovirus that causes lethal human disease, for which there are no licensed antiviral vaccines or therapies. Herein, we developed a live attenuated recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate expressing the SFTSV Gn/Gc glycoproteins (rVSV-SFTSV/AH12-GP). High titers of cross-protective, broadly neutralizing antibodies were elicited by a single dose of rVSV-SFTSV/AH12-GP in both immunocompetent and immunocompromised mice against multiple strains of SFTSV and the related but distinct phlebovirus Heartland virus (HRTV). Remarkably, complete protection against lethal challenge with SFTSV was conferred in young and old immunocompromised mice irrespective of any pre-existing vector-specific immunity. Collectively, these results suggest that a rVSV vector expressing SFTSV glycoproteins is a promising candidate vaccine against two emerging phleboviruses associated with severe human diseases.
Effective CRISPR/Cas9-mediated correction of a Fanconi anemia defect by error-prone end joining or templated repair
Authors: van de Vrugt Henri J. , Harmsen Tim , Riepsaame Joey , Alexantya Georgina , van Mil Saskia E. , de Vries Yne , Bin Ali Rahmen , Huijbers Ivo J. , Dorsman Josephine C. , Wolthuis Rob M. F. , te Riele Hein 
Published: January 2019

AbstractFanconi anemia (FA) is a cancer predisposition syndrome characterized by congenital abnormalities, bone marrow failure, and hypersensitivity to aldehydes and crosslinking agents. For FA patients, gene editing holds promise for therapeutic applications aimed at functionally restoring mutated genes in hematopoietic stem cells. However, intrinsic FA DNA repair defects may obstruct gene editing feasibility. Here, we report on the CRISPR/Cas9-mediated correction of a disruptive mutation in Fancf. Our experiments revealed that gene editing could effectively restore Fancf function via error-prone end joining resulting in a 27% increased survival in the presence of mitomycin C. In addition, templated gene correction could be achieved after double strand or single strand break formation. Although templated gene editing efficiencies were low (≤6%), FA corrected embryonic stem cells acquired a strong proliferative advantage over non-corrected cells, even without imposing genotoxic stress. Notably, Cas9 nickase activity resulted in mono-allelic gene editing and avoidance of undesired mutagenesis. In conclusion: DNA repair defects associated with FANCF deficiency do not prohibit CRISPR/Cas9 gene correction. Our data provide a solid basis for the application of pre-clinical models to further explore the potential of gene editing against FA, with the eventual aim to obtain therapeutic strategies against bone marrow failure.
External ballistics of Pleistocene hand-thrown spears: experimental performance data and implications for human evolution
Authors: Milks Annemieke , Parker David , Pope Matt 
Published: January 2019

AbstractThe appearance of weaponry - technology designed to kill - is a critical but poorly established threshold in human evolution. It is an important behavioural marker representing evolutionary changes in ecology, cognition, language and social behaviours. While the earliest weapons are often considered to be hand-held and consequently short-ranged, the subsequent appearance of distance weapons is a crucial development. Projectiles are seen as an improvement over contact weapons, and are considered by some to have originated only with our own species in the Middle Stone Age and Upper Palaeolithic. Despite the importance of distance weapons in the emergence of full behavioral modernity, systematic experimentation using trained throwers to evaluate the ballistics of thrown spears during flight and at impact is lacking. This paper addresses this by presenting results from a trial of trained javelin athletes, providing new estimates for key performance parameters. Overlaps in distances and impact energies between hand-thrown spears and spearthrowers are evidenced, and skill emerges as a significant factor in successful use. The results show that distance hunting was likely within the repertoire of hunting strategies of Neanderthals, and the resulting behavioural flexibility closely mirrors that of our own species.
Selective control of molecule charge state on graphene using tip-induced electric field and nitrogen doping
Authors: Pham Van Dong , Ghosh Sukanya , Joucken Frédéric , Pelaez-Fernandez Mario , Repain Vincent , Chacon Cyril , Bellec Amandine , Girard Yann , Sporken Robert , Rousset Sylvie , Dappe Yannick J. , Narasimhan Shobhana , Lagoute Jérôme 
Published: January 2019

AbstractThe combination of graphene with molecules offers promising opportunities to achieve new functionalities. In these hybrid structures, interfacial charge transfer plays a key role in the electronic properties and thus has to be understood and mastered. Using scanning tunneling microscopy and ab initio density functional theory calculations, we show that combining nitrogen doping of graphene with an electric field allows for a selective control of the charge state in a molecular layer on graphene. On pristine graphene, the local gating applied by the tip induces a shift of the molecular levels of adsorbed molecules and can be used to control their charge state. Ab initio calculations show that under the application of an electric field, the hybrid molecule/graphene system behaves like an electrostatic dipole with opposite charges in the molecule and graphene sub-units that are found to be proportional to the electric field amplitude, which thereby controls the charge transfer. When local gating is combined with nitrogen doping of graphene, the charging voltage of molecules on nitrogen is greatly lowered. Consequently, applying the proper electric field allows one to obtain a molecular layer with a mixed charge state, where a selective reduction is performed on single molecules at nitrogen sites.
Action and mechanism of the colistin resistance enzyme MCR-4
Authors: Zhang Huimin , Hou Mengyun , Xu Yongchang , Srinivas Swaminath , Huang Man , Liu Lizhang , Feng Youjun 
Published: January 2019

AbstractColistin is the last-resort antibiotic against lethal infections with multidrug-resistant bacterial pathogens. A rainbow coalition of mobile colistin resistance (mcr) genes raises global health concerns. Here, we describe the action and mechanism of colistin resistance imparted by MCR-4, a recently-identified member from the broader MCR family. We found that MCR-4 originates from the silenced variant of Shewanella frigidimarina via progressive evolution and forms a phylogenetically-distinct group from the well-studied MCR-1/2 family. Domain-swapping experiments further confirmed that MCR-1 and MCR-4 transmembrane and catalytic domains are not functionally-interchangeable. However, structural and functional analyses demonstrated that MCR-4 possesses a similar PE lipid substrate-recognizable cavity and exploits an almost-identical ping-pong catalysis mechanism. MCR-4 also can alleviate colistin-triggered accumulation of reactive oxygen species (ROS). Taken together, this finding constitutes a functional proof that MCR-4 proceeds in a distinct evolutionary path to fulfill a consistent molecular mechanism, resulting in phenotypic colistin resistance.
Time-resolved electrostatic force microscopy using tip-synchronized charge generation with pulsed laser excitation
Authors: Araki Kento , Ie Yutaka , Aso Yoshio , Ohoyama Hiroshi , Matsumoto Takuya 
Published: January 2019

AbstractNanoscale observation of charge distribution and electric polarization is crucial for understanding and controlling functional materials and devices. In particular, the importance of charge dynamics is well recognized, and direct methods to observe charge generation, transfer, and recombination processes are required. Here, we describe tip-synchronized time-resolved electrostatic force microscopy. Numerical modeling clarifies that the tip-synchronized method provides temporal resolution with the timescale of the cantilever oscillation cycle. This method enables us to resolve sub-microsecond charge migration on the surface. The recombination of photo-excited carriers in a bilayer organic photovoltaic thin film is observed as a movie with a 0.3 µs frame step time resolution. Analysis of the images shows that the carrier lifetime is 2.3 µs near the donor/acceptor interface. The tip-synchronized method increases the range of time-resolved electrostatic force microscopy, paving the way for studies of nanoscale charge dynamics.
Creating a potential diagnostic for prostate cancer risk stratification (InformMDx™) by translating novel scientific discoveries concerning cAMP degrading phosphodiesterase-4D7 (PDE4D7)
Authors: Henderson Dave J.P. , Houslay Miles D. , Bangma Chris H. , Hoffmann Ralf 
Published: January 2019

Abstract
Increased PSA-based screening for prostate cancer has resulted in a growing number of diagnosed cases. However, around half of these are ‘indolent’, neither metastasizing nor leading to disease specific death. Treating non-progressing tumours with invasive therapies is currently regarded as unnecessary over-treatment with patients being considered for conservative regimens, such as active surveillance (AS). However, this raises both compliance and protocol issues. Great clinical benefit could accrue from a biomarker able to predict long-term patient outcome accurately at the time of biopsy and initial diagnosis. Here we delineate the translation of a laboratory discovery through to the precision development of a clinically validated, novel prognostic biomarker assay (InformMDx™). This centres on determining transcript levels for phosphodiesterase-4D7 (PDE4D7), an enzyme that breaks down cyclic AMP, a signalling molecule intimately connected with proliferation and androgen receptor function. Quantifiable detection of PDE4D7 mRNA transcripts informs on the longitudinal outcome of post-surgical disease progression. The risk of post-surgical progression increases steeply for patients with very low ‘PDE4D7 scores’, while risk decreases markedly for those patients with very high ‘PDE4D7 scores’. Combining clinical risk variables, such as the Gleason or CAPRA (Cancer of the Prostate Risk Assessment) score, with the ‘PDE4D7 score’ further enhances the prognostic power of this personalized, precision assessment. Thus the ‘PDE4D7 score’ has the potential to define, more effectively, appropriate medical intervention/AS strategies for individual prostate cancer patients.
Aortic Aneurysm Eroding into the Spine
Authors: Rajab T. , Beyene Miriam , Yazdchi Farhang , Menard Matthew 
Published: January 2019

AbstractAortic aneurysms are usually asymptomatic until catastrophic rupture occurs. Ruptured abdominal aortic aneurysms classically present with acute back pain, shock, and a pulsatile abdominal mass. The natural history of some aortic aneurysms also includes a stage of contained rupture. This occurs when extravasation of blood from the ruptured aneurysm is contained by surrounding tissues. Here, the authors report the case of a chronic contained abdominal aortic aneurysm rupture that resulted in erosion of the spine.
Child Abuse or Bleeding Disorder—An Interdisciplinary Approach
Authors: Streif Werner , Watzer-Herberth Irmina , Hahn Gabriele , Schmidt Uwe , Knöfler Ralf 
Published: January 2019

AbstractChildren with an unexplained bleeding tendency are frequently referred to a haemostaseologist for further evaluation. Careful standardized history taking and clinical evaluation should allow for distinguishing bleeds after minor injury and trauma which are very common in all children. However, in two groups of children bleeding symptoms may be more significant than expected: those with an underlying coagulation disorder and those who have been subjected to physical child abuse. The coexistence of child abuse and a bleeding disorder must always be considered. An extended coagulation diagnostic is required if the morphology of bleedings is not clearly suspicious for child abuse and in the absence of typical concomitant injuries, e.g., bone fractures. An interdisciplinary approach involving a forensic pathologist and a paediatric haemostaseologist for assessment of bleeding symptoms, the explanation of the clinical findings, and the critical evaluation of laboratory results are essential in such cases. This review is focussed on symptoms in accidental and nonaccidental injuries in children assisting haemostaseologists in decision making in cases of child protection issues.
10.2 Product Class 2: Benzo[c]furan and Its Derivatives
Authors: Kwiecień H. 
Published: January 2019

AbstractThis chapter is a revision of the earlier Science of Synthesis contribution describing methods for the synthesis of benzo[c]furans (isobenzofurans), and has been expanded to include 1,3-dihydrobenzo[c]furan-1(3H)-ones [1,3-dihydroisobenzofuran-1(3H)-ones, phthalides]. Various methods for the in situ generation of the very reactive benzo[c]furans and their trapping with dienophiles through Diels–Alder reactions, as well as approaches to the preparation of stable 1,3-diarylbenzo[c]furans, are presented. Classical routes to 1,3-dihydrobenzo[c]furan-1(3H)-ones involve the disproportionation of 1,2-diacylbenzenes or formation of the lactone ring from 2-functionalized benzoic acid derivatives. More recent developments that involve other approaches are also included.
30.3.5.3 1,3-Dithiepanes (Update 2018)
Authors: Saikawa Y. , Nakata M. 
Published: January 2019

Abstract1,3-Dithiepanes are less common than 1,3-dithiolanes or 1,3-dithianes, but are also used in the thioacetalization of carbonyl compounds. This chapter covers methods published since 2007, including fused rings with hidden 1,3-dithiepane substructures.