bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating the Spread in Future Fine Dust Concentrations in the Southwest United States
Authors: Brey Steven J. , Pierce Jeffrey R. , Barnes Elizabeth A. , Fischer Emily V. 
Published: October 2020

AbstractThis work examines how environmental variables previously shown to be correlated with dust emissions (temperature, vapor pressure deficit, relative humidity, precipitation, soil moisture, wind speed, and leaf area index [LAI]) explain historical variability in observed fine dust concentrations in the southwestern United States. We quantify fine dust concentrations in the U.S. Southwest dust season, March through July 1995 through 2015, using fine iron measurements from the Interagency Monitoring of Protected Visual Environments network as a dust proxy. We use Coupled Model Intercomparison Project Phase 5 (CMIP5) output to estimate how environmental variables that drive dust concentrations may change in the future. The majority of CMIP5 models that simulate LAI, a quantity anticorrelated with dust concentrations, show increasing LAI in the Southwest United States in the 21st century. Based on linear estimates of how dust concentrations respond to changes in LAI, increases in LAI could result in reduced dust concentrations in the future. However, when environmental variables are selected objectively using lasso regression, LAI is not selected in favor of other variables. When using a linear combination of objectively selected environmental variables, we estimate that future Southwest dust season concentrations will increase by 0.24 μg m−3 (12%) by the end of the 21st century for RCP 8.5. This estimated increase in fine dust concentration is driven by decreases in relative humidity, precipitation, and soil moisture and buffered by decreased wind speeds.
Slow Slip and Inter‐transient Locking on the Nicoya Megathrust in the Late and Early Stages of an Earthquake Cycle
Authors: Xie Surui , Dixon Timothy H. , Malservisi Rocco , Jiang Yan , Protti Marino , Muller Cyril 
Published: October 2020

AbstractWe analyzed continuous GPS data collected from 2002–2020 to characterize slow slip events (SSEs) in and near the Nicoya Peninsula, Costa Rica. These data are bisected by the 5 September 2012 Mw 7.6 earthquake. The displacement time series contain multiple signals, including plate convergence, plate interface locking, coseismic and postseismic deformation, seasonal oscillations, SSEs, and noise. GPS‐measured coseismic and postseismic displacements associated with the Mw 7.6 earthquake are modeled and removed by a step function plus multiple timescale relaxation processes with four characteristic times: 11, 94, 470, and 1,865 days. Seasonal oscillations are eliminated using a multichannel singular spectrum analysis (M‐SSA). Ten major SSEs (Mw > 6.6) are observed in the remaining time series, with a constant recurrence interval of 21.7 ± 2.6 months. SSEs occur in both shallow (~10 km) and deep (~35 km) portions of the plate interface, but the latter last longer and have larger magnitudes. There is minimum to no slow slip in the Mw 7.6 seismic rupture area and a persistent slow slip patch beneath the Nicoya Gulf entrance. Despite strong earthquake‐related stress perturbations, the inter‐SSE locking status on the megathrust is very similar between the late and early stages of the earthquake cycle and includes locked patches that ruptured in the 2012 earthquake or continue to rupture via SSEs. Some locked patches offshore south of the Nicoya Peninsula did not rupture in 2012, do not participate in SSEs, and may be indicative of supercycle behavior, that is, strain accumulation over several seismic cycles. These areas warrant heightened monitoring.
Epigenome-wide analysis reveals functional modulators of drug sensitivity and post-treatment survival in chronic lymphocytic leukaemia
Authors: Barrow Timothy M. , Nakjang Sirintra , Lafta Fadhel , Bilotkach Kateryna , Woodhouse Laura , Junge Gesa , Tudhope Susan J. , Wallis Jonathan P. , Marr Helen , Marshall Scott , Bown Nick , Willmore Elaine , Strathdee Gordon 
Published: October 2020

Abstract
Background
Chronic lymphocytic leukaemia (CLL) patients display a highly variable clinical course, with progressive acquisition of drug resistance. We sought to identify aberrant epigenetic traits that are enriched following exposure to treatment that could impact patient response to therapy.

Methods
Epigenome-wide analysis of DNA methylation was performed for 20 patients at two timepoints during treatment. The prognostic significance of differentially methylated regions (DMRs) was assessed in independent cohorts of 139 and 163 patients. Their functional role in drug sensitivity was assessed in vitro.

Results
We identified 490 DMRs following exposure to therapy, of which 31 were CLL-specific and independent of changes occurring in normal B-cell development. Seventeen DMR-associated genes were identified as differentially expressed following treatment in an independent cohort. Methylation of the HOXA4, MAFB and SLCO3A1 DMRs was associated with post-treatment patient survival, with HOXA4 displaying the strongest association. Re-expression of HOXA4 in cell lines and primary CLL cells significantly increased apoptosis in response to treatment with fludarabine, ibrutinib and idelalisib.

Conclusion
Our study demonstrates enrichment for multiple CLL-specific epigenetic traits in response to chemotherapy that predict patient outcomes, and particularly implicate epigenetic silencing of HOXA4 in reducing the sensitivity of CLL cells to therapy.
Impaired autophagy increases susceptibility to endotoxin-induced chronic pancreatitis
Authors: Xia L. , Xu Z. , Zhou X. , Bergmann F. , Grabe N. , Büchler M. W. , Neoptolemos J. P. , Hackert T. , Kroemer G. , Fortunato F. 
Published: October 2020

AbstractChronic pancreatitis (CP) is associated with elevated plasma levels of bacterial lipopolysaccharide (LPS) and we have demonstrated reduced acinar cell autophagy in human CP tissue. Therefore, we investigated the role of autophagy in experimental endotoxin-induced pancreatic injury and aimed to identify LPS in human CP tissue. Pancreatic Atg7-deficient mice were injected with a single sub-lethal dose of LPS. Expression of autophagy, apoptosis, necroptosis, and inflammatory markers was determined 3 and 24 h later utilizing immunoblotting and immunofluorescence. The presence of LPS in pancreatic tissue from mice and from patients and healthy controls was determined using immunohistochemistry, immunoblots, and chromogenic assay. Mice lacking pancreatic autophagy exhibited local signs of inflammation and were particularly sensitive to the toxic effect of LPS injection as compared to control mice. In response to LPS, Atg7Δpan mice exhibited enhanced vacuolization of pancreatic acinar cells, increase in TLR4 expression coupled to enhanced expression of NF-κΒ, JNK, and pro-inflammatory cytokines by acinar cells and enhanced infiltration by myeloid cells (but not Atg7F/F controls). Cell death was enhanced in Atg7Δpan pancreata, but only necroptosis and trypsin activation was further amplified following LPS injection along with elevated pancreatic LPS. The presence of LPS was identified in the pancreata from all 14 CP patients examined but was absent in the pancreata from all 10 normal controls. Altogether, these results support a potential role for metabolic endotoxemia in the pathogenesis of CP. Moreover, the evidence also supports the notion that autophagy plays a major cytoprotective and anti-inflammatory role in the pancreas, and blunting metabolic endotoxemia-induced CP.
Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis
Authors: Choi So Yoen , Lee Ju-Hyun , Chung Ah-Young , Jo Youhwa , Shin Joo-ho , Park Hae-Chul , Kim Hyun , Lopez-Gonzalez Rodrigo , Ryu Jae Ryun , Sun Woong 
Published: October 2020

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons (MNs) and subsequent muscle weakness. These pathological features are associated with numerous cellular changes, including alteration in mitochondrial morphology and function. However, the molecular mechanisms associating mitochondrial structure with ALS pathology are poorly understood. In this study, we found that Dynamin-related protein 1 (Drp1) was dephosphorylated in several ALS models, including those with SOD1 and TDP-43 mutations, and the dephosphorylation was mediated by the pathological induction of protein phosphatase 1 (PP1) activity in these models. Suppression of the PP1-Drp1 cascade effectively prevented ALS-related symptoms, including mitochondrial fragmentation, mitochondrial complex I impairment, axonal degeneration, and cell death, in primary neuronal culture models, iPSC-derived human MNs, and zebrafish models in vivo. These results suggest that modulation of PP1-Drp1 activity may be a therapeutic target for multiple pathological features of ALS.
The GEF Trio controls endothelial cell size and arterial remodeling downstream of Vegf signaling in both zebrafish and cell models
Authors: Klems Alina , van Rijssel Jos , Ramms Anne S. , Wild Raphael , Hammer Julia , Merkel Melanie , Derenbach Laura , Préau Laetitia , Hinkel Rabea , Suarez-Martinez Irina , Schulte-Merker Stefan , Vidal Ramon , Sauer Sascha , Kivelä Riikka , Alitalo Kari , Kupatt Christian , van Buul Jaap D. , le Noble Ferdinand 
Published: October 2020

AbstractArterial networks enlarge in response to increase in tissue metabolism to facilitate flow and nutrient delivery. Typically, the transition of a growing artery with a small diameter into a large caliber artery with a sizeable diameter occurs upon the blood flow driven change in number and shape of endothelial cells lining the arterial lumen. Here, using zebrafish embryos and endothelial cell models, we describe an alternative, flow independent model, involving enlargement of arterial endothelial cells, which results in the formation of large diameter arteries. Endothelial enlargement requires the GEF1 domain of the guanine nucleotide exchange factor Trio and activation of Rho-GTPases Rac1 and RhoG in the cell periphery, inducing F-actin cytoskeleton remodeling, myosin based tension at junction regions and focal adhesions. Activation of Trio in developing arteries in vivo involves precise titration of the Vegf signaling strength in the arterial wall, which is controlled by the soluble Vegf receptor Flt1.
Sensitivity enhancement of homonuclear multidimensional NMR correlations for labile sites in proteins, polysaccharides, and nucleic acids
Authors: Novakovic Mihajlo , Kupče Ēriks , Oxenfarth Andreas , Battistel Marcos D. , Freedberg Darón I. , Schwalbe Harald , Frydman Lucio 
Published: October 2020

AbstractMultidimensional TOCSY and NOESY are central experiments in chemical and biophysical NMR. Limited efficiencies are an intrinsic downside of these methods, particularly when targeting labile sites. This study demonstrates that the decoherence imparted on these protons through solvent exchanges can, when suitably manipulated, lead to dramatic sensitivity gains per unit time in the acquisition of these experiments. To achieve this, a priori selected frequencies are encoded according to Hadamard recipes, while concurrently subject to looped selective inversion or selective saturation procedures. Suitable processing then leads to protein, oligosaccharide and nucleic acid cross-peak enhancements of ≈200–1000% per scan, in measurements that are ≈10-fold faster than conventional counterparts. The extent of these gains will depend on the solvent exchange and relaxation rates of the targeted sites; these gains also benefit considerably from the spectral resolution provided by ultrahigh fields, as corroborated by NMR experiments at 600 MHz and 1 GHz. The mechanisms underlying these experiments’ enhanced efficiencies are analyzed on the basis of three-way polarization transfer interplays between the water, labile and non-labile protons, and the experimental results are rationalized using both analytical and numerical derivations. Limitations as well as further extensions of the proposed methods, are also discussed.
An all-photonic focal-plane wavefront sensor
Authors: Norris Barnaby R. M. , Wei Jin , Betters Christopher H. , Wong Alison , Leon-Saval Sergio G. 
Published: October 2020

AbstractAdaptive optics (AO) is critical in astronomy, optical communications and remote sensing to deal with the rapid blurring caused by the Earth’s turbulent atmosphere. But current AO systems are limited by their wavefront sensors, which need to be in an optical plane non-common to the science image and are insensitive to certain wavefront-error modes. Here we present a wavefront sensor based on a photonic lantern fibre-mode-converter and deep learning, which can be placed at the same focal plane as the science image, and is optimal for single-mode fibre injection. By measuring the intensities of an array of single-mode outputs, both phase and amplitude information on the incident wavefront can be reconstructed. We demonstrate the concept with simulations and an experimental realisation wherein Zernike wavefront errors are recovered from focal-plane measurements to a precision of 5.1 × 10−3 π radians root-mean-squared-error.
Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics
Authors: Morita Kiyomi , Wang Feng , Jahn Katharina , Hu Tianyuan , Tanaka Tomoyuki , Sasaki Yuya , Kuipers Jack , Loghavi Sanam , Wang Sa A. , Yan Yuanqing , Furudate Ken , Matthews Jairo , Little Latasha , Gumbs Curtis , Zhang Jianhua , Song Xingzhi , Thompson Erika , Patel Keyur P. , Bueso-Ramos Carlos E. , DiNardo Courtney D. , Ravandi Farhad , Jabbour Elias , Andreeff Michael , Cortes Jorge , Bhalla Kapil , Garcia-Manero Guillermo , Kantarjian Hagop , Konopleva Marina , Nakada Daisuke , Navin Nicholas , Beerenwinkel Niko , Futreal P. Andrew , Takahashi Koichi 
Published: October 2020

AbstractClonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.
Synaptic vesicle traffic is supported by transient actin filaments and regulated by PKA and NO
Authors: Chenouard Nicolas , Xuan Feng , Tsien Richard W. 
Published: October 2020

AbstractSynaptic vesicles (SVs) can be pooled across multiple synapses, prompting questions about their dynamic allocation for neurotransmission and plasticity. We find that the axonal traffic of recycling vesicles is not supported by ubiquitous microtubule-based motility but relies on actin instead. Vesicles freed from synaptic clusters undergo ~1 µm bouts of active transport, initiated by nearby elongation of actin filaments. Long distance translocation arises when successive bouts of active transport were linked by periods of free diffusion. The availability of SVs for active transport can be promptly increased by protein kinase A, a key player in neuromodulation. Vesicle motion is in turn impeded by shutting off axonal actin polymerization, mediated by nitric oxide-cyclic GMP signaling leading to inhibition of RhoA. These findings provide a potential framework for coordinating post-and pre-synaptic strength, using retrograde regulation of axonal actin dynamics to mobilize and recruit presynaptic SV resources.
Single-cell derived tumor organoids display diversity in HLA class I peptide presentation
Authors: Demmers Laura C. , Kretzschmar Kai , Van Hoeck Arne , Bar-Epraïm Yotam E. , van den Toorn Henk W. P. , Koomen Mandy , van Son Gijs , van Gorp Joost , Pronk Apollo , Smakman Niels , Cuppen Edwin , Clevers Hans , Heck Albert J. R. , Wu Wei 
Published: October 2020

AbstractTumor heterogeneity is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug-resistant cells, where tumor-specific human leukocyte antigen (HLA) peptide ligands are promising leads to invoke targeted anti-tumor responses. Here, we investigate the variability in HLA class I peptide presentation between different clonal cells of the same colorectal cancer patient, using an organoid system. While clone-specific differences in HLA peptide presentation were observed, broad inter-clone variability was even more prevalent (15–25%). By coupling organoid proteomics and HLA peptide ligandomics, we also found that tumor-specific ligands from DNA damage control and tumor suppressor source proteins were prominently presented by tumor cells, coinciding likely with the silencing of such cytoprotective functions. Collectively, these data illustrate the heterogeneous HLA peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.
Antibody-mediated disruption of the SARS-CoV-2 spike glycoprotein
Authors: Wrobel Antoni G. , Benton Donald J. , Hussain Saira , Harvey Ruth , Martin Stephen R. , Roustan Chloë , Rosenthal Peter B. , Skehel John J. , Gamblin Steven J. 
Published: October 2020

AbstractThe CR3022 antibody, selected from a group of SARS-CoV monoclonal antibodies for its ability to cross-react with SARS-CoV-2, has been examined for its ability to bind to the ectodomain of the SARS-CoV-2 spike glycoprotein. Using cryo-electron microscopy we show that antibody binding requires rearrangements in the S1 domain that result in dissociation of the spike.
Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia
Authors: Jiang Lei , Park Ji-Sun , Yin Ling , Laureano Rodrigo , Jacquinet Eric , Yang Jinsong , Liang Shi , Frassetto Andrea , Zhuo Jenny , Yan Xinhua , Zhu Xuling , Fortucci Steven , Hoar Kara , Mihai Cosmin , Tunkey Christopher , Presnyak Vlad , Benenato Kerry E. , Lukacs Christine M. , Martini Paolo G. V. , Guey Lin T. 
Published: October 2020

AbstractPropionic acidemia/aciduria (PA) is an ultra-rare, life-threatening, inherited metabolic disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC) composed of six alpha (PCCA) and six beta (PCCB) subunits. We herein report an enzyme replacement approach to treat PA using a combination of two messenger RNAs (mRNAs) (dual mRNAs) encoding both human PCCA (hPCCA) and PCCB (hPCCB) encapsulated in biodegradable lipid nanoparticles (LNPs) to produce functional PCC enzyme in liver. In patient fibroblasts, dual mRNAs encoded proteins localize in mitochondria and produce higher PCC enzyme activity vs. single (PCCA or PCCB) mRNA alone. In a hypomorphic murine model of PA, dual mRNAs normalize ammonia similarly to carglumic acid, a drug approved in Europe for the treatment of hyperammonemia due to PA. Dual mRNAs additionally restore functional PCC enzyme in liver and thus reduce primary disease-associated toxins in a dose-dependent manner in long-term 3- and 6-month repeat-dose studies in PA mice. Dual mRNAs are well-tolerated in these studies with no adverse findings. These studies demonstrate the potential of mRNA technology to chronically administer multiple mRNAs to produce large complex enzymes, with applicability to other genetic disorders.
5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation
Authors: Cho Yong-Hee , Ro Eun Ji , Yoon Jeong-Su , Mizutani Tomohiro , Kang Dong-Woo , Park Jong-Chan , Il Kim Tae , Clevers Hans , Choi Kang-Yell 
Published: October 2020

Abstract5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.
Decarboxylative thiolation of redox-active esters to free thiols and further diversification
Authors: Cao Tianpeng , Xu Tianxiao , Xu Ruting , Shu Xianli , Liao Saihu 
Published: October 2020

AbstractThiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. In view of the versatile reactivity of free thiols, here we report the development of a visible light-mediated direct decarboxylative thiolation reaction of alkyl redox-active esters to free thiols based on the abundant carboxylic acid feedstock. This transformation is applicable to various carboxylic acids, including primary, secondary, and tertiary acids as well as natural products and drugs, forging a general and facile access to free thiols with diverse structures. Moreover, the direct access to free thiols affords an advantage of rapid in situ diversification with high efficiency to other important thiol derivatives such as sulfide, disulfide, thiocyanide, thioselenide, etc.
Completing asthma action plans by screen-sharing in video-consultations: practical insights from a feasibility assessment
Authors: Hamour Omer , Smyth Eve , Pinnock Hilary 
Published: October 2020

AbstractSupported self-management is a vital component of routine asthma care. Completion of an agreed personalised asthma action plan is integral to implementation of this care, and traditionally this requires a face-to-face consultation. We aimed to assess the practical feasibility and potential utility of using screen-sharing technologies to complete asthma action plans remotely. Assisted by people with diverse technological ability and using a range of devices, we tested the technological feasibility of completing action plans in remote consultations using two leading video-conference systems. We used a semi-structured topic guide to check functionality and lead feedback discussions. Themes were interpreted using the Model for ASsessment of Telemedicine applications (MAST). Discussions with ten participants (age 20–74 years) revealed that screen-sharing was practical on most devices. Joint editing of an action plan (as was possible with Zoom) was considered to encourage participation and improve communication. Attend Anywhere had less functionality than Zoom, but the NHS badging was reassuring. Most participants appreciated the screen-sharing and considered it enabled a meaningful discussion about their action plan. Online shared completion of action plans is feasible with only a few (potentially remediable) practical problems. These findings suggest this may be a fruitful approach for further study—made more urgent by the imperative to develop remote consultations in the face of a global pandemic.