bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Sensitivity of Atmospheric River Identification to Integrated Water Vapor Transport Threshold, Resolution, and Regridding Method
Authors: Reid Kimberley J. , King Andrew D. , Lane Todd P. , Short Ewan 
Published: October 2020

AbstractAtmospheric rivers (ARs) are elongated narrow bands of enhanced water vapor that can cause intense rainfall and flooding. ARs only appeared in the literature the last 30 years, and there has been much debate about how to define ARs and how to identify them. As a result, a wide range of AR identification algorithms have been produced with variations in the conditions required for an object to be classified as an AR and differences in the input data. One of the key conditions in most AR identification algorithms is a minimum threshold of water vapor flux, along with geometric criteria. The aim of this study is to explore uncertainties in global AR identification based on a single integrated water vapor transport (IVT)‐based identification method. We conduct a sensitivity analysis under one algorithmic framework to explore the effects of different IVT thresholds, input data resolutions, and regridding methods during the Years of Tropical Convection operational analysis (May 2008 to April 2010). We found that the resolution and regridding method affects the number of ARs identified but the seasonal cycle is maintained. AR identification is highly sensitive to the choice of IVT threshold; importantly, the commonly used 250 kg m−1 s−1 IVT threshold is not appropriate for global studies with detection methods that also include a restrictive geometric condition as this combination can lead to the strongest systems failing to be identified. The uncertainties within a single AR detection method and input data parameters may be as large as uncertainties across AR detection methodologies.
A multivariate neuromonitoring approach to neuroplasticity-based computerized cognitive training in recent onset psychosis
Authors: Haas Shalaila S. , Antonucci Linda A. , Wenzel Julian , Ruef Anne , Biagianti Bruno , Paolini Marco , Rauchmann Boris-Stephan , Weiske Johanna , Kambeitz Joseph , Borgwardt Stefan , Brambilla Paolo , Meisenzahl Eva , Salokangas Raimo K. R. , Upthegrove Rachel , Wood Stephen J. , Koutsouleris Nikolaos , Kambeitz-Ilankovic Lana 
Published: October 2020

AbstractTwo decades of studies suggest that computerized cognitive training (CCT) has an effect on cognitive improvement and the restoration of brain activity. Nevertheless, individual response to CCT remains heterogenous, and the predictive potential of neuroimaging in gauging response to CCT remains unknown. We employed multivariate pattern analysis (MVPA) on whole-brain resting-state functional connectivity (rsFC) to (neuro)monitor clinical outcome defined as psychosis-likeness change after 10-hours of CCT in recent onset psychosis (ROP) patients. Additionally, we investigated if sensory processing (SP) change during CCT is associated with individual psychosis-likeness change and cognitive gains after CCT. 26 ROP patients were divided into maintainers and improvers based on their SP change during CCT. A support vector machine (SVM) classifier separating 56 healthy controls (HC) from 35 ROP patients using rsFC (balanced accuracy of 65.5%,P < 0.01) was built in an independent sample to create a naturalistic model representing the HC-ROP hyperplane. This model was out-of-sample cross-validated in the ROP patients from the CCT trial to assess associations between rsFC pattern change, cognitive gains and SP during CCT. Patients with intact SP threshold at baseline showed improved attention despite psychosis status on the SVM hyperplane at follow-up (p < 0.05). Contrarily, the attentional gains occurred in the ROP patients who showed impaired SP at baseline only if rsfMRI diagnosis status shifted to the healthy-like side of the SVM continuum. Our results reveal the utility of MVPA for elucidating treatment response neuromarkers based on rsFC-SP change and pave the road to more personalized interventions.
Overview of current targeted therapy in gallbladder cancer
Authors: Song Xiaoling , Hu Yunping , Li Yongsheng , Shao Rong , Liu Fatao , Liu Yingbin 
Published: October 2020

AbstractGallbladder cancer (GBC) is rare, but is the most malignant type of biliary tract tumor. Unfortunately, only a small population of cancer patients is acceptable for the surgical resection, the current effective regimen; thus, the high mortality rate has been static for decades. To substantially circumvent the stagnant scenario, a number of therapeutic approaches owing to the creation of advanced technologic measures (e.g., next-generation sequencing, transcriptomics, proteomics) have been intensively innovated, which include targeted therapy, immunotherapy, and nanoparticle-based delivery systems. In the current review, we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC. Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease, ultimately improving the efficacy of treatment.
NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications
Authors: Ju Huai-Qiang , Lin Jin-Fei , Tian Tian , Xie Dan , Xu Rui-Hua 
Published: October 2020

AbstractNicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms, and provides the reducing power for anabolic reactions and redox balance. NADPH homeostasis is regulated by varied signaling pathways and several metabolic enzymes that undergo adaptive alteration in cancer cells. The metabolic reprogramming of NADPH renders cancer cells both highly dependent on this metabolic network for antioxidant capacity and more susceptible to oxidative stress. Modulating the unique NADPH homeostasis of cancer cells might be an effective strategy to eliminate these cells. In this review, we summarize the current existing literatures on NADPH homeostasis, including its biological functions, regulatory mechanisms and the corresponding therapeutic interventions in human cancers, providing insights into therapeutic implications of targeting NADPH metabolism and the associated mechanism for cancer therapy.
CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program
Authors: Guolo Fabio , Fianchi Luana , Minetto Paola , Clavio Marino , Gottardi Michele , Galimberti Sara , Rizzuto Giuliana , Rondoni Michela , Bertani Giambattista , Dargenio Michela , Bilio Atto , Scappini Barbara , Zappasodi Patrizia , Scattolin Anna Maria , Grimaldi Francesco , Pietrantuono Giuseppe , Musto Pellegrino , Cerrano Marco , D’Ardia Stefano , Audisio Ernesta , Cignetti Alessandro , Pasciolla Crescenza , Pavesi Francesca , Candoni Anna , Gurreri Carmela , Morselli Monica , Alati Caterina , Fracchiolla Nicola , Rossi Giovanni , Caizzi Manuela , Carnevale-Schianca Fabrizio , Tafuri Agostino , Rossi Giuseppe , Ferrara Felicetto , Pagano Livio , Lemoli Roberto Massimo 
Published: October 2020

AbstractSecondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT.
FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome
Authors: Schieber Michael , Marinaccio Christian , Bolanos Lyndsey C. , Haffey Wendy D. , Greis Kenneth D. , Starczynowski Daniel T. , Crispino John D. 
Published: October 2020

AbstractMyelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of transformation to secondary acute myeloid leukemia (sAML). A number of genetic abnormalities have been identified in MDS and sAML, but sensitive sequencing methods can detect these mutations in nearly all healthy individuals by 60 years of age. To discover novel cellular pathways that accelerate MDS and sAML, we performed a CRISPR/Cas9 screen in the human MDS-L cell line. We report here that loss of the F-Box protein FBXO11, a component of the SCF ubiquitin ligase complex, confers cytokine independent growth to MDS-L cells, suggesting a tumor suppressor role for FBXO11 in myeloid malignancies. Putative FBXO11 substrates are enriched for proteins with functions in RNA metabolism and, of note, spliceosome mutations that are commonly found in MDS/sAML are rare in patients with low FBXO11 expression. We also reveal that loss of FBXO11 leads to significant changes in transcriptional pathways influencing leukocyte proliferation, differentiation, and apoptosis. Last, we find that FBXO11 expression is reduced in patients with secondary AML. We conclude that loss of FBXO11 is a mechanism for disease transformation of MDS into AML, and may represent a future therapeutic target.
Salvage treatment with plerixafor in poor mobilizing allogeneic stem cell donors: results of a prospective phase II-trial
Authors: Hölig Kristina , Schmidt Helmuth , Hütter Gero , Kramer Michael , Teipel Raphael , Heidrich Katharina , Zimmer Kristin , Heidenreich Falk , Blechschmidt Matthias , Torosian Tigran , Ordemann Rainer , Kroschinsky Frank , Rücker-Braun Elke , Gopsca Laszlo , Wagner-Drouet Eva Maria , Oelschlaegel Uta , Schmidt Alexander H. , Bornhäuser Martin , Ehninger Gerhard , Schetelig Johannes 
Published: October 2020

AbstractWe conducted a prospective clinical trial to investigate the safety and efficacy of plerixafor (P) in allogeneic peripheral blood stem cells (PBSC) donors with poor mobilization response to standard-dose granulocyte colony-stimulating factor (G-CSF), defined by <2 × 106CD34 + cells/kg recipient body-weight (CD34+/kg RBW) after 1st apheresis. A single dose of 240 µg/kg P was injected subcutaneously at 10 p.m. on the day of the 1st apheresis. Thirty-seven allogeneic PBSC donors underwent study treatment. The median CD34+ count in peripheral blood was 15/µl on Day 1 after G-CSF alone, versus 44/µl on Day 2 after G-CSF plus P (p < 0.001). The median yield of CD34+ cells was 1.1 × 108on Day 1 and 2.8 × 108on Day 2. In contrast to a median yield of only 1.31 × 106CD CD34+/kg RBW on Day 1, triggering study inclusion, a median of 3.74 × 106CD CD34+/kg RBW were collected with G-CSF plus P on Day 2. Of 37 donors, 21 reached the target cell count of >4.5 × 106CD34+/kg RBW (57%, 95%CI 40–73%). No donor experienced a severe adverse event requiring treatment. In conclusion, P might be considered on a case-by-case basis for healthy allogeneic donors with very poor stem cell mobilization success after G-CSF.
Thymidylate synthase drives the phenotypes of epithelial-to-mesenchymal transition in non-small cell lung cancer
Authors: Siddiqui Mohammad Aarif , Gollavilli Paradesi Naidu , Ramesh Vignesh , Parma Beatrice , Schwab Annemarie , Vazakidou Maria Eleni , Natesan Ramakrishnan , Saatci Ozge , Rapa Ida , Bironzo Paolo , Schuhwerk Harald , Asangani Irfan Ahmed , Sahin Ozgur , Volante Marco , Ceppi Paolo 
Published: October 2020

Abstract
Background
Epithelial-to-mesenchymal transition (EMT) enhances motility, stemness, chemoresistance and metastasis. Little is known about how various pathways coordinate to elicit EMT’s different functional aspects in non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) has been previously correlated with EMT transcription factor ZEB1 in NSCLC and imparts resistance against anti-folate chemotherapy. In this study, we establish a functional correlation between TS, EMT, chemotherapy and metastasis and propose a network for TS mediated EMT.

Methods
Published datasets were analysed to evaluate the significance of TS in NSCLC fitness and prognosis. Promoter reporter assay was used to sort NSCLC cell lines in TSHIGH and TSLOW. Metastasis was assayed in a syngeneic mouse model.

Results
TS levels were prognostic and predicted chemotherapy response. Cell lines with higher TS promoter activity were more mesenchymal-like. RNA-seq identified EMT as one of the most differentially regulated pathways in connection to TS expression. EMT transcription factors HOXC6 and HMGA2 were identified as upstream regulator of TS, and AXL, SPARC and FOSL1 as downstream effectors. TS knock-down reduced the metastatic colonisation in vivo.

Conclusion
These results establish TS as a theranostic NSCLC marker integrating survival, chemo-resistance and EMT, and identifies a regulatory network that could be targeted in EMT-driven NSCLC.
Sequence-to-function deep learning frameworks for engineered riboregulators
Authors: Valeri Jacqueline A. , Collins Katherine M. , Ramesh Pradeep , Alcantar Miguel A. , Lepe Bianca A. , Lu Timothy K. , Camacho Diogo M. 
Published: October 2020

AbstractWhile synthetic biology has revolutionized our approaches to medicine, agriculture, and energy, the design of completely novel biological circuit components beyond naturally-derived templates remains challenging due to poorly understood design rules. Toehold switches, which are programmable nucleic acid sensors, face an analogous design bottleneck; our limited understanding of how sequence impacts functionality often necessitates expensive, time-consuming screens to identify effective switches. Here, we introduce Sequence-based Toehold Optimization and Redesign Model (STORM) and Nucleic-Acid Speech (NuSpeak), two orthogonal and synergistic deep learning architectures to characterize and optimize toeholds. Applying techniques from computer vision and natural language processing, we ‘un-box’ our models using convolutional filters, attention maps, and in silico mutagenesis. Through transfer-learning, we redesign sub-optimal toehold sensors, even with sparse training data, experimentally validating their improved performance. This work provides sequence-to-function deep learning frameworks for toehold selection and design, augmenting our ability to construct potent biological circuit components and precision diagnostics.
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
Authors: Douangamath Alice , Fearon Daren , Gehrtz Paul , Krojer Tobias , Lukacik Petra , Owen C. David , Resnick Efrat , Strain-Damerell Claire , Aimon Anthony , Ábrányi-Balogh Péter , Brandão-Neto José , Carbery Anna , Davison Gemma , Dias Alexandre , Downes Thomas D. , Dunnett Louise , Fairhead Michael , Firth James D. , Jones S. Paul , Keeley Aaron , Keserü György M. , Klein Hanna F. , Martin Mathew P. , Noble Martin E. M. , O’Brien Peter , Powell Ailsa , Reddi Rambabu N. , Skyner Rachael , Snee Matthew , Waring Michael J. , Wild Conor , London Nir , von Delft Frank , Walsh Martin A. 
Published: October 2020

AbstractCOVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.
Suppressing material loss in the visible and near-infrared range for functional nanophotonics using bandgap engineering
Authors: Wang Mingsong , Krasnok Alex , Lepeshov Sergey , Hu Guangwei , Jiang Taizhi , Fang Jie , Korgel Brian A. , Alù Andrea , Zheng Yuebing 
Published: October 2020

AbstractAll-dielectric nanostructures have recently opened exciting opportunities for functional nanophotonics, owing to their strong optical resonances along with low material loss in the near-infrared range. Pushing these concepts to the visible range is hindered by their larger absorption coefficient, thus encouraging the search for alternative dielectrics for nanophotonics. Here, we employ bandgap engineering to synthesize hydrogenated amorphous Si nanoparticles (a-Si:H NPs) offering ideal features for functional nanophotonics. We observe significant material loss suppression in a-Si:H NPs in the visible range caused by hydrogenation-induced bandgap renormalization, producing strong higher-order resonant modes in single NPs with Q factors up to ~100 in the visible and near-IR range. We also realize highly tunable all-dielectric meta-atoms by coupling a-Si:H NPs to photochromic spiropyran molecules. ~70% reversible all-optical tuning of light scattering at the higher-order resonant mode under a low incident light intensity is demonstrated. Our results promote the development of high-efficiency visible nanophotonic devices.
PilY1 and minor pilins form a complex priming the type IVa pilus in Myxococcus xanthus
Authors: Treuner-Lange Anke , Chang Yi-Wei , Glatter Timo , Herfurth Marco , Lindow Steffi , Chreifi Georges , Jensen Grant J. , Søgaard-Andersen Lotte 
Published: October 2020

AbstractType IVa pili are ubiquitous and versatile bacterial cell surface filaments that undergo cycles of extension, adhesion and retraction powered by the cell-envelope spanning type IVa pilus machine (T4aPM). The overall architecture of the T4aPM and the location of 10 conserved core proteins within this architecture have been elucidated. Here, using genetics, cell biology, proteomics and cryo-electron tomography, we demonstrate that the PilY1 protein and four minor pilins, which are widely conserved in T4aP systems, are essential for pilus extension in Myxococcus xanthus and form a complex that is an integral part of the T4aPM. Moreover, these proteins are part of the extended pilus. Our data support a model whereby the PilY1/minor pilin complex functions as a priming complex in T4aPM for pilus extension, a tip complex in the extended pilus for adhesion, and a cork for terminating retraction to maintain a priming complex for the next round of extension.
A fluoride-responsive genetic circuit enables in vivo biofluorination in engineered Pseudomonas putida
Authors: Calero Patricia , Volke Daniel C. , Lowe Phillip T. , Gotfredsen Charlotte H. , O’Hagan David , Nikel Pablo I. 
Published: October 2020

AbstractFluorine is a key element in the synthesis of molecules broadly used in medicine, agriculture and materials. Addition of fluorine to organic structures represents a unique strategy for tuning molecular properties, yet this atom is rarely found in Nature and approaches to integrate fluorometabolites into the biochemistry of living cells are scarce. In this work, synthetic gene circuits for organofluorine biosynthesis are implemented in the platform bacterium Pseudomonas putida. By harnessing fluoride-responsive riboswitches and the orthogonal T7 RNA polymerase, biochemical reactions needed for in vivo biofluorination are wired to the presence of fluoride (i.e. circumventing the need of feeding expensive additives). Biosynthesis of fluoronucleotides and fluorosugars in engineered P. putida is demonstrated with mineral fluoride both as only fluorine source (i.e. substrate of the pathway) and as inducer of the synthetic circuit. This approach expands the chemical landscape of cell factories by providing alternative biosynthetic strategies towards fluorinated building-blocks.
Reconstructing lost BOLD signal in individual participants using deep machine learning
Authors: Yan Yuxiang , Dahmani Louisa , Ren Jianxun , Shen Lunhao , Peng Xiaolong , Wang Ruiqi , He Changgeng , Jiang Changqing , Gong Chen , Tian Ye , Zhang Jianguo , Guo Yi , Lin Yuanxiang , Li Shijun , Wang Meiyun , Li Luming , Hong Bo , Liu Hesheng 
Published: October 2020

AbstractSignal loss in blood oxygen level-dependent (BOLD) functional neuroimaging is common and can lead to misinterpretation of findings. Here, we reconstructed compromised fMRI signal using deep machine learning. We trained a model to learn principles governing BOLD activity in one dataset and reconstruct artificially compromised regions in an independent dataset, frame by frame. Intriguingly, BOLD time series extracted from reconstructed frames are correlated with the original time series, even though the frames do not independently carry any temporal information. Moreover, reconstructed functional connectivity maps exhibit good correspondence with the original connectivity maps, indicating that the model recovers functional relationships among brain regions. We replicated this result in two healthy datasets and in patients whose scans suffered signal loss due to intracortical electrodes. Critically, the reconstructions capture individual-specific information. Deep machine learning thus presents a unique opportunity to reconstruct compromised BOLD signal while capturing features of an individual’s own functional brain organization.
Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ
Authors: Barski Michał S. , Minnell Jordan J. , Hodakova Zuzana , Pye Valerie E. , Nans Andrea , Cherepanov Peter , Maertens Goedele N. 
Published: October 2020

AbstractHuman T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and the most oncogenic pathogen. Many of the ~20 million HTLV-1 infected people will develop severe leukaemia or an ALS-like motor disease, unless a therapy becomes available. A key step in the establishment of infection is the integration of viral genetic material into the host genome, catalysed by the retroviral integrase (IN) enzyme. Here, we use X-ray crystallography and single-particle cryo-electron microscopy to determine the structure of the functional deltaretroviral IN assembled on viral DNA ends and bound to the B56γ subunit of its human host factor, protein phosphatase 2 A. The structure reveals a tetrameric IN assembly bound to two molecules of the phosphatase via a conserved short linear motif. Insight into the deltaretroviral intasome and its interaction with the host will be crucial for understanding the pattern of integration events in infected individuals and therefore bears important clinical implications.