bluuebunny/crossref_metadata_2025_split huggingface dataset:
New survival standards for advanced melanoma
Authors: Spain Lavinia , Larkin James , Turajlic Samra 
Published: February 2020

SummaryThe expectation for survival in patients with advanced melanoma now exceeds 50% at 5 years in patients treated with first-line combination ipilimumab and nivolumab, despite this regimen being associated with substantial toxicity. We discuss the latest updates from the Checkmate-067 study, framing the role of this combination in practice today.
Utility of microminipigs for evaluating liver-mediated gene expression in the presence of neutralizing antibody against vector capsid
Authors: Watano Ryota , Ohmori Tsukasa , Hishikawa Shuji , Sakata Asuka , Mizukami Hiroaki 
Published: February 2020

AbstractAdeno-associated virus (AAV) vectors can transduce hepatocytes efficiently in vivo in various animal species, including humans. Few reports, however, have examined the utility of pigs in gene therapy. Pigs are potentially useful in preclinical studies because of their anatomical and physiological similarity to humans. Here, we evaluated the utility of microminipigs for liver-targeted gene therapy. These pigs were intravenously inoculated with an AAV8 vector encoding the luciferase gene, and gene expression was assessed by an in vivo imaging system. Robust transgene expression was observed almost exclusively in the liver, even though the pig showed a low-titer of neutralizing antibody (NAb) against the AAV8 capsid. We assessed the action of NAbs against AAV, which interfere with AAV vector-mediated gene transfer by intravascular delivery. When a standard dose of vector was administered intravenously, transgene expression was observed in both NAb-negative and low-titer (14×)-positive subjects, whereas gene expression was not observed in animals with higher titers (56×). These results are compatible with our previous observations using nonhuman primates, indicating that pigs are useful in gene therapy experiments, and that the role of low-titer NAb in intravenous administration of the AAV vector shows similarities across species.
FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML
Authors: Sheng Yue , Yu Chunjie , Liu Yin , Hu Chao , Ma Rui , Lu Xinyan , Ji Peng , Chen Jianjun , Mizukawa Benjamin , Huang Yong , Licht Jonathan D. , Qian Zhijian 
Published: February 2020

AbstractFOXM1, a known transcription factor, promotes cell proliferation in a variety of cancer cells. Here we show that Foxm1 is required for survival, quiescence and self-renewal of MLL-AF9 (MA9)-transformed leukemia stem cells (LSCs) in vivo. Mechanistically, Foxm1 upregulation activates the Wnt/β-catenin signaling pathways by directly binding to β-catenin and stabilizing β-catenin protein through inhibiting its degradation, thereby preserving LSC quiescence, and promoting LSC self-renewal in MLL-rearranged AML. More importantly, inhibition of FOXM1 markedly suppresses leukemogenic potential and induces apoptosis of primary LSCs from MLL-rearranged AML patients in vitro and in vivo in xenograft mice. Thus, our study shows a critical role and mechanisms of Foxm1 in MA9-LSCs, and indicates that FOXM1 is a potential therapeutic target for selectively eliminating LSCs in MLL-rearranged AML.
Noise-tolerant single photon sensitive three-dimensional imager
Authors: Rehain Patrick , Sua Yong Meng , Zhu Shenyu , Dickson Ivan , Muthuswamy Bharathwaj , Ramanathan Jeevanandha , Shahverdi Amin , Huang Yu-Ping 
Published: February 2020

AbstractActive imagers capable of reconstructing 3-dimensional (3D) scenes in the presence of strong background noise are highly desirable for many sensing and imaging applications. A key to this capability is the time-resolving photon detection that distinguishes true signal photons from the noise. To this end, quantum parametric mode sorting (QPMS) can achieve signal to noise exceeding by far what is possible with typical linear optics filters, with outstanding performance in isolating temporally and spectrally overlapping noise. Here, we report a QPMS-based 3D imager with exceptional detection sensitivity and noise tolerance. With only 0.0006 detected signal photons per pulse, we reliably reconstruct the 3D profile of an obscured scene, despite 34-fold spectral-temporally overlapping noise photons, within the 6 ps detection window (amounting to 113,000 times noise per 20 ns detection period). Our results highlight a viable approach to suppress background noise and measurement errors of single photon imager operation in high-noise environments.
Prefrontal attentional saccades explore space rhythmically
Authors: Gaillard Corentin , Ben Hadj Hassen Sameh , Di Bello Fabio , Bihan-Poudec Yann , VanRullen Rufin , Ben Hamed Suliann 
Published: February 2020

AbstractRecent studies suggest that attention samples space rhythmically through oscillatory interactions in the frontoparietal network. How these attentional fluctuations coincide with spatial exploration/displacement and exploitation/selection by a dynamic attentional spotlight under top-down control is unclear. Here, we show a direct contribution of prefrontal attention selection mechanisms to a continuous space exploration. Specifically, we provide a direct high spatio-temporal resolution prefrontal population decoding of the covert attentional spotlight. We show that it continuously explores space at a 7–12 Hz rhythm. Sensory encoding and behavioral reports are increased at a specific optimal phase w/ to this rhythm. We propose that this prefrontal neuronal rhythm reflects an alpha-clocked sampling of the visual environment in the absence of eye movements. These attentional explorations are highly flexible, how they spatially unfold depending both on within-trial and across-task contingencies. These results are discussed in the context of exploration-exploitation strategies and prefrontal top-down attentional control.
A solvent-assisted ligand exchange approach enables metal-organic frameworks with diverse and complex architectures
Authors: Yu Dongbo , Shao Qi , Song Qingjing , Cui Jiewu , Zhang Yongli , Wu Bin , Ge Liang , Wang Yan , Zhang Yong , Qin Yongqiang , Vajtai Robert , Ajayan Pulickel M. , Wang Huanting , Xu Tongwen , Wu Yucheng 
Published: February 2020

AbstractUnlike inorganic crystals, metal-organic frameworks do not have a well-developed nanostructure library, and establishing their appropriately diverse and complex architectures remains a major challenge. Here, we demonstrate a general route to control metal-organic framework structure by a solvent-assisted ligand exchange approach. Thirteen different types of metal-organic framework structures have been prepared successfully. To demonstrate a proof of concept application, we used the obtained metal-organic framework materials as precursors for synthesizing nanoporous carbons and investigated their electrochemical Na+storage properties. Due to the unique architecture, the one-dimensional nanoporous carbon derived from double-shelled ZnCo bimetallic zeolitic imidazolate framework nanotubes exhibits high specific capacity as well as superior rate capability and cycling stability. Our study offers an avenue for the controllable preparation of well-designed meta-organic framework structures and their derivatives, which would further broaden the application opportunities of metal-organic framework materials.
The kinase polypharmacology landscape of clinical PARP inhibitors
Authors: Antolin Albert A. , Ameratunga Malaka , Banerji Udai , Clarke Paul A. , Workman Paul , Al-Lazikani Bissan 
Published: February 2020

AbstractPolypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.
Rare events in generalized Lévy Walks and the Big Jump principle
Authors: Vezzani Alessandro , Barkai Eli , Burioni Raffaella 
Published: February 2020

AbstractThe prediction and control of rare events is an important task in disciplines that range from physics and biology, to economics and social science. The Big Jump principle deals with a peculiar aspect of the mechanism that drives rare events. According to the principle, in heavy-tailed processes a rare huge fluctuation is caused by a single event and not by the usual coherent accumulation of small deviations. We consider generalized Lévy walks, a class of stochastic processes with power law distributed step durations and with complex microscopic dynamics in the single stretch. We derive the bulk of the probability distribution and using the big jump principle, the exact form of the tails that describes rare events. We show that the tails of the distribution present non-universal and non-analytic behaviors, which depend crucially on the dynamics of the single step. The big jump estimate also provides a physical explanation of the processes driving the rare events, opening new possibilities for their correct prediction.
Experimental observation of drumhead surface states in SrAs3
Authors: Hosen M. Mofazzel , Dhakal Gyanendra , Wang Baokai , Poudel Narayan , Dimitri Klauss , Kabir Firoza , Sims Christopher , Regmi Sabin , Gofryk Krzysztof , Kaczorowski Dariusz , Bansil Arun , Neupane Madhab 
Published: February 2020

AbstractThe topological nodal-line semimetal (TNS) is a unique class of materials with a one dimensional line node accompanied by a nearly dispersionless two-dimensional surface state. However, a direct observation of the so called drumhead surface state within current nodal-line materials is still elusive. Here, using high-resolution angle-resolved photoemission spectroscopy (ARPES) along with first-principles calculations, we report the observation of a topological nodal-loop (TNL) in SrAs3, whereas CaAs3 exhibits a topologically trivial state. Our data reveal that surface projections of the bulk nodal-points are connected by clear drumhead surface states in SrAs3. Furthermore, our magneto-transport and magnetization data clearly suggest the presence (absence) of surface states in SrAs3 (CaAs3). Notably, the observed topological states in SrAs3 are well separated from other bands in the vicinity of the Fermi level. RAs3 where R = Ca, Sr, thus, offers a unique opportunity to realize an archetype nodal-loop semimetal and establish a platform for obtaining a deeper understanding of the quantum phase transitions.
Role of Early PET/CT Imaging with 68Ga-PSMA in Staging and Restaging of Prostate Cancer
Authors: Barakat Andrew , Yacoub Basel , Homsi Maria El , Saad Aldine Amro , El Hajj Albert , Haidar Mohamad B. 
Published: February 2020

AbstractGa-68 Prostate-Specific Membrane Antigen PET/CT is a new tool for the assessment of prostate cancer. Standard imaging time is 60 minutes post injection of radiotracer. At 60 minutes, there is physiologic accumulation of radiotracer in the urinary bladder which may cause some lesions in its vicinity to be obscured. Our aim is to determine if early imaging at 3 minutes in addition to standard imaging at 60 minutes can improve the detection of PSMA-avid lesions. A retrospective review of 167 consecutive patients was conducted. Overall, 115 patients (68.9%) were ruled to have prostate cancer based on imaging as seen on early or standard PET/CT images. In 106/115 (64%), the lesions were detected on both early and standard imaging; in 8/115 (6.9%), the lesions were only detected on early imaging; in 1/115 (0.6%) the lesion was detected only on standard imaging. The addition of early imaging significantly improved the overall detection rate of PSMA-avid lesions (p = 0.039). The ratio of patients with lesions detected on early imaging but not on standard imaging in restaging group was 7/88 and was higher than that in staging group 1/79 (p = 0.043). We recommend early imaging in addition to the standard imaging in Ga-68 PSMA PET/CT, particularly in patients presenting for restaging of prostate cancer.
A co-culture nanofibre scaffold model of neural cell degeneration in relevance to Parkinson’s disease
Authors: Chemmarappally Joseph M. , Pegram Henry C. N. , Abeywickrama Neranga , Fornari Enzo , Hargreaves Alan J. , De Girolamo Luigi A. , Stevens Bob 
Published: February 2020

AbstractCurrent therapeutic strategies for Parkinson’s disease (PD) aim to delay progression or replace damaged neurons by restoring the original neuronal structures. The poor regenerative capacity of neural tissue highlights the need for the development of cellular environments to model the pathogenesis of PD. In the current work, we have characterised the growth, survival and response to PD mimetics of human SH-SY5Y neuroblastoma and U-87MG glioblastoma cell lines cultured on polyacrylonitrile (PAN) and Jeffamine® doped polyacrylonitrile (PJ) nano-scaffolds. Differentiation induced by a range of agents was evaluated by immunoassays of neural protein biomarkers. PAN and PJ nanofibre scaffolds provided suitable three-dimensional (3D) environment to support the growth, differentiation and network formation of dopaminergic neuron- and astrocyte-like cell populations, respectively. The scaffolds selectively supported the survival and differentiation of both cell populations with prolonged neuronal survival when exposed to PD mimetics in the presence of astrocytes in a co-culture model. Such 3D nanoscaffold-based assays could aid our understanding of the molecular basis of PD mimetic-induced Parkinsonism and the discovery of neuroprotective agents.
Revealing Plasma-Surface Interaction at Atmospheric Pressure: Imaging of Electric Field and Temperature inside the Targeted Material
Authors: Slikboer Elmar , Acharya Kishor , Sobota Ana , Garcia-Caurel Enric , Guaitella Olivier 
Published: February 2020

AbstractThe plasma-surface interaction is studied for a low temperature helium plasma jet generated at atmospheric pressure using Mueller polarimetry on an electro-optic target. The influence of the AC kHz operating frequency is examined by simultaneously obtaining images of the induced electric field and temperature of the target. The technique offers high sensitivity in the determination of the temperature variation on the level of single degrees. Simultaneously, the evolution of the electric field in the target caused by plasma-driven charge accumulation can be measured with the threshold of the order of 105 V/m. Even though a specific electro-optic crystal is used to obtain the results, they are generally applicable to dielectric targets under exposure of a plasma jet when they are of 0.5 mm thickness, have a dielectric constant greater than 4 and are at floating potential. Other techniques to examine the induced electric field in a target do not exist to the best of our knowledge, making this technique unique and necessary. The influence of the AC kHz operating frequency is important because many plasma jet designs used throughout the world operate at different frequency which changes the time between the ionization waves and hence the leftover species densities and stability of the plasma. Results for our jet show a linear operating regime between 20 and 50 kHz where the ionization waves are stable and the temperature increases linearly by 25 K. The charge deposition and induced electric fields do not increase significantly but the surface area does increase due to an extended surface propagation. Additionally, temperature mapping using a 100 μm GaAs probe of the plasma plume area has revealed a mild heat exchange causing a heating of several degrees of the helium core while the surrounding air slightly cools. This peculiarity is also observed without plasma in the gas plume.
Screening of inmates transferred to Spain reveals a Peruvian prison as a reservoir of persistent Mycobacterium tuberculosis MDR strains and mixed infections
Authors: Abascal Estefanía , Herranz Marta , Acosta Fermín , Agapito Juan , Cabibbe Andrea M. , Monteserin Johana , Ruiz Serrano María Jesús , Gijón Paloma , Fernández-González Francisco , Lozano Nuria , Chiner-Oms Álvaro , Cáceres Tatiana , Pintado Pilar Gómez , Acín Enrique , Valencia Eddy , Muñoz Patricia , Comas Iñaki , Cirillo Daniela M. , Ritacco Viviana , Gotuzzo Eduardo , García de Viedma Darío 
Published: February 2020

AbstractIt is relevant to evaluate MDR-tuberculosis in prisons and its impact on the global epidemiology of this disease. However, systematic molecular epidemiology programs in prisons are lacking. A health-screening program performed on arrival for inmates transferred from Peruvian prisons to Spain led to the diagnosis of five MDR-TB cases from one of the biggest prisons in Latin America. They grouped into two MIRU-VNTR–clusters (Callao-1 and Callao-2), suggesting a reservoir of two prevalent MDR strains. A high-rate of overexposure was deduced because one of the five cases was coinfected by a pansusceptible strain. Callao-1 strain was also identified in 2018 in a community case in Spain who had been in the same Peruvian prison in 2002–5. A strain-specific-PCR tailored from WGS data was implemented in Peru, allowing the confirmation that these strains were currently responsible for the majority of the MDR cases in that prison, including a new mixed infection.
Exome Sequencing in Individuals with Isolated Biliary Atresia
Authors: Rajagopalan Ramakrishnan , Tsai Ellen A. , Grochowski Christopher M. , Kelly Susan M. , Loomes Kathleen M. , Spinner Nancy B. , Devoto Marcella 
Published: February 2020

AbstractBiliary atresia (BA) is a severe pediatric liver disease resulting in necroinflammatory obliteration of the extrahepatic biliary tree. BA presents within the first few months of life as either an isolated finding or with additional syndromic features. The etiology of isolated BA is unknown, with evidence for infectious, environmental, and genetic risk factors described. However, to date, there are no definitive causal genes identified for isolated BA in humans, and the question of whether single gene defects play a major role remains open. We performed exome-sequencing in 101 North American patients of European descent with isolated BA (including 30 parent-child trios) and considered several experimental designs to identify potentially deleterious protein-altering variants that may be involved in the disease. In a case-only analysis, we did not identify genes with variants shared among more than two probands, and burden tests of rare variants using a case-case control design did not yield significant results. In the trio analysis of 30 simplex families (patient and parent trios), we identified 66 de novo variants in 66 genes including potentially deleterious variants in STIP1 and REV1. STIP1 is a co-chaperone for the heat-shock protein, HSP90, and has been shown to have diverse functions in yeast, flies and mammals, including stress-responses. REV1 is known to be a key player in DNA repair pathway and to interact with HSP90. In conclusion, our results do not support the hypothesis that a simple genetic model is responsible for the majority of cases of isolated BA. Our finding of de novo variants in genes linked to evolutionarily conserved stress responses (STIP1 and REV1) suggests that exploration of how genetic susceptibility and environmental exposure may interact to cause BA is warranted.
Elucidating the dual role of grain boundaries as dislocation sources and obstacles and its impact on toughness and brittle-to-ductile transition
Authors: Reiser Jens , Hartmaier Alexander 
Published: February 2020

AbstractIn this paper, we resolve the role of grain boundaries on toughness and the brittle-to-ductile transition. On the one hand, grain boundaries are obstacles for dislocation glide. On the other hand, the intersection points of grain boundaries with the crack front are assumed to be preferred dislocation nucleation sites. Here, we will show that the single contributions of grain boundaries (obstacles vs. source) on toughness and the brittle-to-ductile transition are contradicting, and we will weight the single contributions by performing carefully designed numerical experiments by means of two-dimensional discrete dislocation dynamics modelling. In our parameter studies, we vary the following parameters: (i) the mean free path for dislocation glide, δ, combined with (ii) the (obstacle) force of the grain boundary, ϕ, and (iii) the dislocation source spacing along the crack front, λ. Our results show that for materials or microstructures for which the mean distance of the intersection points of grain boundaries with the crack front is the relevant measure for λ, a decrease of grain size results in an increase of toughness. The positive impact of grain boundaries outweighs the negative consequences of dislocation blocking. Furthermore, our results explain the evolving anisotropy of toughness in cold-worked metals and give further insight into the question of why the grain-size-dependent fracture toughness passes through a minimum (and the brittle-to-ductile transition temperature passes through a maximum) at an intermediate grain size. Finally, a relation of the grain-size-dependence of fracture toughness in the form of K(dδ, dλ) = KIC + kdδ0.5/dλ is deduced.