bluuebunny/crossref_metadata_2025_split huggingface dataset:
Water Transport in the Mars Northern Winter Polar Atmosphere: Observations and Simulations
Authors: Gillespie H. E. , McCleese D. J. , Kleinböhl A. , Kass D. M. , Greybush S. J. , Wilson R. J. 
Published: May 2024

AbstractThis study involving both observations and simulations furthers our understanding of water transport in the Martian northern polar region, a critical component of the global water cycle, and explores strengths and weaknesses in simulations of the polar atmosphere. Observations of the northern polar winter by the Mars Climate Sounder (MCS) onboard the Mars Reconnaissance Orbiter show extensive water ice clouds over the polar ice cap throughout the 300–3 Pa (∼10–50 km) vertical column within the vortex during the entire winter season. The observations also indicate that the vortex evolves throughout its depth on a broad range of timescales, from sub‐diurnal to seasonal. Time sequences of these data together with results from a Mars global circulation model and Ensemble Mars Atmosphere Reanalysis System reanalysis (EMARS) are used to study the evolution of the winter polar atmosphere and to examine dynamic mechanisms for transporting water across the vortex boundary. Model simulations and reanalysis show a similar temperature structure to observations, although they struggle to reproduce some of the detailed features such as the extent of polar warming above the vortex and the magnitude of the temperature minima inside the vortex. The free run simulation also fails to capture the vertically distributed water ice cloud due to a general absence of transport across the vortex boundary. EMARS results, with assimilated MCS temperatures, show a greater amount of water entering the vortex at pressures below 200 Pa, leading to a more vertically extended cloud within the vortex and improving agreement with observations.
Global Flash Droughts Characteristics: Onset, Duration, and Extent at Watershed Scales
Authors: Neelam Maheshwari , Hain Christopher 
Published: May 2024

AbstractAddressing impacts of flash droughts (FDs) on the water‐food nexus requires a understanding of FD mechanisms and drivers at the watershed level. Examining climatic drivers, dry and wet spell lengths from 1980 to 2019, we analyzed FD spatial and temporal characteristics, emphasizing areal extent, onset time, and duration. Our findings reveal substantial variations in FDs among different watersheds. Notably, watersheds in the Southern Hemisphere are witnessing expanding, faster‐developing, and longer‐lasting FDs, aligning with climate variations in precipitation and temperature. Additionally, at the watershed scale, the onset and duration of FDs are more influenced by the intensity (magnitude and variability) of climatic drivers than the average length of wet and dry periods. FD‐extents, however, correlate with both climatic conditions and wet and dry periods, underscoring watershed connectivity. Ultimately, our results underscore the necessity for research to comprehend the interplay between FDs and watershed characteristics and how it manifests in overall water resource management.
Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results
Authors: Cortes Jorge E. , Sasaki Koji , Kim Dong-Wook , Hughes Timothy P. , Etienne Gabriel , Mauro Michael J. , Hochhaus Andreas , Lang Fabian , Heinrich Michael C. , Breccia Massimo , Deininger Michael , Goh Yeow Tee , Janssen Jeroen J.W.M. , Talpaz Moshe , de Soria Valle Gomez Garcia , le Coutre Philipp , DeAngelo Daniel J. , Damon Andrea , Cacciatore Silvia , Polydoros Fotis , Agrawal Nithya , Rea Delphine 
Published: May 2024

AbstractAsciminib targets the BCR::ABL1 myristoyl pocket, maintaining activity against BCR::ABL1T315I, which is resistant to most approved adenosine triphosphate–competitive tyrosine kinase inhibitors. We report updated phase I results (NCT02081378) assessing safety/tolerability and antileukemic activity of asciminib monotherapy 200 mg twice daily in 48 heavily pretreated patients with T315I-mutated chronic-phase chronic myeloid leukemia (CML-CP; data cutoff: January 6, 2021). With 2 years’ median exposure, 56.3% of patients continued receiving asciminib. Overall, 62.2% of evaluable patients achieved BCR::ABL1 ≤1% on the International Scale (IS); 47.6% and 81.3% of ponatinib-pretreated and -naive patients, respectively, achieved BCR::ABL1IS ≤1%. Of 45 evaluable patients, 48.9% achieved a major molecular response (MMR, BCR::ABL1IS ≤0.1%), including 34.6% and 68.4% of ponatinib-pretreated and -naive patients, respectively. MMR was maintained until data cutoff in 19 of 22 patients who achieved it. The most common grade ≥3 adverse events (AEs) included increased lipase level (18.8%) and thrombocytopenia (14.6%). Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib’s effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.
E3 ubiquitin ligase UBR5 promotes gemcitabine resistance in pancreatic cancer by inducing O-GlcNAcylation-mediated EMT via destabilization of OGA
Authors: Du Yunyan , Yang Zhangjian , Shi Hao , Chen Zhihan , Chen Rong , Zhou Fan , Peng Xiaogang , Hong Tao , Jiang Liping 
Published: May 2024

AbstractPancreatic cancer (PC) is among the deadliest malignancies, with an extremely poor diagnosis and prognosis. Gemcitabine (GEM) remains the first-line drug for treating PC; however, only a small percentage of patients benefit from current immunotherapies or targeted therapies. Resistance to GEM is prevalent and affects long-term survival. We found that ubiquitin-protein ligase E3 module N-recognition 5 (UBR5) is a therapeutic target against GEM resistance. UBR5 was markedly upregulated in clinical GEM-resistant PC samples and GEM-resistant PC cells. UBR5 knockdown markedly increased GEM sensitivity in GEM-resistant PC cell lines. UBR5-mediated GEM resistance was accompanied by activation of epithelial-mesenchymal transition (EMT) and could be mitigated by inhibiting EMT. Further analysis revealed that UBR5 promoted GEM resistance in PC cells by enhancing O-GlcNAcylation-mediated EMT. In addition, UBR5 knockdown resulted in increased O-GlcNAase (OGA) levels, an essential negatively regulated enzyme in the O-GlcNAcylation process. We identified a negative association between OGA and UBR5 levels, which further supported the hypothesis that O-GlcNAcylation-mediated GEM resistance induced by UBR5 is OGA-dependent in PC cells. Mechanistic studies revealed that UBR5 acts as an E3 ubiquitin ligase of OGA and regulates O-GlcNAcylation by binding and modulating OGA, facilitating its degradation and ubiquitination. Additionally, high-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified a Food and Drug Administration drug, Y-39983 dihydrochloride, as a potent GEM sensitiser and UBR5 inhibitor. The combination of Y-39983 dihydrochloride and GEM attenuated tumour growth in a mouse xenograft tumour model. Collectively, these data demonstrated that UBR5 plays a pivotal role in the sensitisation of PC to GEM and provides a potential therapeutic strategy to overcome GEM resistance.
Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes
Authors: Binder Moritz , Szalat Raphael E. , Talluri Srikanth , Fulciniti Mariateresa , Avet-Loiseau Hervé , Parmigiani Giovanni , Samur Mehmet K. , Munshi Nikhil C. 
Published: May 2024

AbstractThe natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches.
Physiological basis for atmospheric methane oxidation and methanotrophic growth on air
Authors: Schmider Tilman , Hestnes Anne Grethe , Brzykcy Julia , Schmidt Hannes , Schintlmeister Arno , Roller Benjamin R. K. , Teran Ezequiel Jesús , Söllinger Andrea , Schmidt Oliver , Polz Martin F. , Richter Andreas , Svenning Mette M. , Tveit Alexander T. 
Published: May 2024

AbstractAtmospheric methane oxidizing bacteria (atmMOB) constitute the sole biological sink for atmospheric methane. Still, the physiological basis allowing atmMOB to grow on air is not well understood. Here we assess the ability and strategies of seven methanotrophic species to grow with air as sole energy, carbon, and nitrogen source. Four species, including three outside the canonical atmMOB group USCα, enduringly oxidized atmospheric methane, carbon monoxide, and hydrogen during 12 months of growth on air. These four species exhibited distinct substrate preferences implying the existence of multiple metabolic strategies to grow on air. The estimated energy yields of the atmMOB were substantially lower than previously assumed necessary for cellular maintenance in atmMOB and other aerobic microorganisms. Moreover, the atmMOB also covered their nitrogen requirements from air. During growth on air, the atmMOB decreased investments in biosynthesis while increasing investments in trace gas oxidation. Furthermore, we confirm that a high apparent specific affinity for methane is a key characteristic of atmMOB. Our work shows that atmMOB grow on the trace concentrations of methane, carbon monoxide, and hydrogen present in air and outlines the metabolic strategies that enable atmMOB to mitigate greenhouse gases.
Direct conversion of cardiac fibroblasts into endothelial-like cells using Sox17 and Erg
Authors: Farber Gregory , Dong Yanhan , Wang Qiaozi , Rathod Mitesh , Wang Haofei , Dixit Michelle , Keepers Benjamin , Xie Yifang , Butz Kendall , Polacheck William J. , Liu Jiandong , Qian Li 
Published: May 2024

AbstractEndothelial cells are a heterogeneous population with various organ-specific and conserved functions that are critical to organ development, function, and regeneration. Here we report a Sox17-Erg direct reprogramming approach that uses cardiac fibroblasts to create differentiated endothelial cells that demonstrate endothelial-like molecular and physiological functions in vitro and in vivo. Injection of these induced endothelial cells into myocardial infarct sites after injury results in improved vascular perfusion of the scar region. Furthermore, we use genomic analyses to illustrate that Sox17-Erg reprogramming instructs cardiac fibroblasts toward an arterial-like identity. This results in a more efficient direct conversion of fibroblasts into endothelial-like cells when compared to traditional Etv2-based reprogramming. Overall, this Sox17-Erg direct reprogramming strategy offers a robust tool to generate endothelial cells both in vitro and in vivo, and has the potential to be used in repairing injured tissue.
TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression
Authors: Garcia-Montojo Marta , Fathi Saeed , Rastegar Cyrus , Simula Elena Rita , Doucet-O’Hare Tara , Cheng Y. H. Hank , Abrams Rachel P. M. , Pasternack Nicholas , Malik Nasir , Bachani Muzna , Disanza Brianna , Maric Dragan , Lee Myoung-Hwa , Wang Herui , Santamaria Ulisses , Li Wenxue , Sampson Kevon , Lorenzo Juan Ramiro , Sanchez Ignacio E. , Mezghrani Alexandre , Li Yan , Sechi Leonardo Antonio , Pineda Sebastian , Heiman Myriam , Kellis Manolis , Steiner Joseph , Nath Avindra 
Published: May 2024

AbstractTAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology.
Systematic review and meta-analysis of ex-post evaluations on the effectiveness of carbon pricing
Authors: Döbbeling-Hildebrandt Niklas , Miersch Klaas , Khanna Tarun M. , Bachelet Marion , Bruns Stephan B. , Callaghan Max , Edenhofer Ottmar , Flachsland Christian , Forster Piers M. , Kalkuhl Matthias , Koch Nicolas , Lamb William F. , Ohlendorf Nils , Steckel Jan Christoph , Minx Jan C. 
Published: May 2024

AbstractToday, more than 70 carbon pricing schemes have been implemented around the globe, but their contributions to emissions reductions remains a subject of heated debate in science and policy. Here we assess the effectiveness of carbon pricing in reducing emissions using a rigorous, machine-learning assisted systematic review and meta-analysis. Based on 483 effect sizes extracted from 80 causal ex-post evaluations across 21 carbon pricing schemes, we find that introducing a carbon price has yielded immediate and substantial emission reductions for at least 17 of these policies, despite the low level of prices in most instances. Statistically significant emissions reductions range between –5% to –21% across the schemes (–4% to –15% after correcting for publication bias). Our study highlights critical evidence gaps with regard to dozens of unevaluated carbon pricing schemes and the price elasticity of emissions reductions. More rigorous synthesis of carbon pricing and other climate policies is required across a range of outcomes to advance our understanding of “what works” and accelerate learning on climate solutions in science and policy.
The vacuolar fusion regulated by HOPS complex promotes hyphal initiation and penetration in Candida albicans
Authors: Liu Yu , Wang Ruina , Liu Jiacun , Fan Mengting , Ye Zi , Hao Yumeng , Xie Fei , Wang Ting , Jiang Yuanying , Liu Ningning , Cui Xiaoyan , Lv Quanzhen , Yan Lan 
Published: May 2024

AbstractThe transition between yeast and hyphae is crucial for regulating the commensalism and pathogenicity inCandida albicans. The mechanisms that affect the invasion of hyphae in solid media, whose deficiency is more related to the pathogenicity ofC. albicans, have not been elucidated. Here, we found that the disruption ofVAM6orVPS41which are components of the homotypic vacuolar fusion and protein sorting (HOPS) complex, or the Rab GTPaseYPT72, all responsible for vacuole fusion, led to defects in hyphal growth in both liquid and solid media, but more pronounced on solid agar. The phenotypes ofvac8Δ/Δ andGTR1OE-vam6Δ/Δ mutants indicated that these deficiencies are mainly caused by the reduced mechanical forces that drive agar and organs penetration, and confirmed that large vacuoles are required for hyphal mechanical penetration. In summary, our study revealed that large vacuoles generated by vacuolar fusion support hyphal penetration and provided a perspective to refocus attention on the role of solid agar in evaluatingC. albicansinvasion.
High-performance piezoelectric energy harvesting in amorphous perovskite thin films deposited directly on a plastic substrate
Authors: Han Ju , Park Sung Hyun , Jung Ye Seul , Cho Yong Soo 
Published: May 2024

AbstractMost reported thin-film piezoelectric energy harvesters have been based on cantilever-type crystalline ferroelectric oxide thin films deposited on rigid substrates, which utilize vibrational input sources. Herein, we introduce flexible amorphous thin-film energy harvesters based on perovskite CaCu3Ti4O12 (CCTO) thin films on a plastic substrate for highly competitive electromechanical energy harvesting. The room-temperature sputtering of CCTO thin films enable the use of plastic substrates to secure reliable flexibility, which has not been available thus far. Surprisingly, the resultant amorphous nature of the films results in an output voltage and power density of ~38.7 V and ~2.8 × 106 μW cm−3, respectively, which break the previously reported record for typical polycrystalline ferroelectric oxide thin-film cantilevers. The origin of this excellent electromechanical energy conversion is systematically explored as being related to the localized permanent dipoles of TiO6 octahedra and lowered dielectric constant in the amorphous state, depending on the stoichiometry and defect states. This is the leading example of a high-performance flexible piezoelectric energy harvester based on perovskite oxides not requiring a complex process for transferring films onto a plastic substrate.
Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity
Authors: Brunet-Ratnasingham Elsa , Morin Sacha , Randolph Haley E. , Labrecque Marjorie , Bélair Justin , Lima-Barbosa Raphaël , Pagliuzza Amélie , Marchitto Lorie , Hultström Michael , Niessl Julia , Cloutier Rose , Sreng Flores Alina M. , Brassard Nathalie , Benlarbi Mehdi , Prévost Jérémie , Ding Shilei , Anand Sai Priya , Sannier Gérémy , Marks Amanda , Wågsäter Dick , Bareke Eric , Zeberg Hugo , Lipcsey Miklos , Frithiof Robert , Larsson Anders , Zhou Sirui , Nakanishi Tomoko , Morrison David , Vezina Dani , Bourassa Catherine , Gendron-Lepage Gabrielle , Medjahed Halima , Point Floriane , Richard Jonathan , Larochelle Catherine , Prat Alexandre , Cunningham Janet L. , Arbour Nathalie , Durand Madeleine , Richards J. Brent , Moon Kevin , Chomont Nicolas , Finzi Andrés , Tétreault Martine , Barreiro Luis , Wolf Guy , Kaufmann Daniel E. 
Published: May 2024

AbstractPlasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the “Interferon paradox” previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity.
Correlative single molecule lattice light sheet imaging reveals the dynamic relationship between nucleosomes and the local chromatin environment
Authors: Daugird Timothy A. , Shi Yu , Holland Katie L. , Rostamian Hosein , Liu Zhe , Lavis Luke D. , Rodriguez Joseph , Strahl Brian D. , Legant Wesley R. 
Published: May 2024

AbstractIn the nucleus, biological processes are driven by proteins that diffuse through and bind to a meshwork of nucleic acid polymers. To better understand this interplay, we present an imaging platform to simultaneously visualize single protein dynamics together with the local chromatin environment in live cells. Together with super-resolution imaging, new fluorescent probes, and biophysical modeling, we demonstrate that nucleosomes display differential diffusion and packing arrangements as chromatin density increases whereas the viscoelastic properties and accessibility of the interchromatin space remain constant. Perturbing nuclear functions impacts nucleosome diffusive properties in a manner that is dependent both on local chromatin density and on relative location within the nucleus. Our results support a model wherein transcription locally stabilizes nucleosomes while simultaneously allowing for the free exchange of nuclear proteins. Additionally, they reveal that nuclear heterogeneity arises from both active and passive processes and highlight the need to account for different organizational principles when modeling different chromatin environments.
Serological evidence of zoonotic filovirus exposure among bushmeat hunters in Guinea
Authors: Akoi Boré Joseph , Timothy Joseph W. S. , Tipton Tom , Kekoura Ifono , Hall Yper , Hood Grace , Longet Stephanie , Fornace Kimberly , Lucien Millimono S. , Fehling Sarah Katarina , Koivogui Beatrice K. , Coggins Si’Ana A. , Laing Eric D. , Broder Christopher C. , Magassouba N’ Faly , Strecker Thomas , Rossman Jeremy , Konde Kader , Carroll Miles W. 
Published: May 2024

AbstractHuman Ebola virus (EBOV) outbreaks caused by persistent EBOV infection raises questions on the role of zoonotic spillover in filovirus epidemiology. To characterise filovirus zoonotic exposure, we collected cross-sectional serum samples from bushmeat hunters (n = 498) in Macenta Prefecture Guinea, adjacent to the index site of the 2013 EBOV-Makona spillover event. We identified distinct immune signatures (20/498, 4.0%) to multiple EBOV antigens (GP, NP, VP40) using stepwise ELISA and Western blot analysis and, live EBOV neutralisation (5/20; 25%). Using comparative serological data from PCR-confirmed survivors of the 2013-2016 EBOV outbreak, we demonstrated that most signatures (15/20) were not plausibly explained by prior EBOV-Makona exposure. Subsequent data-driven modelling of EBOV immunological outcomes to remote-sensing environmental data also revealed consistent associations with intact closed canopy forest. Together our findings suggest exposure to other closely related filoviruses prior to the 2013-2016 West Africa epidemic and highlight future surveillance priorities.