bluuebunny/crossref_metadata_2025_split huggingface dataset:
A D‐Region Ionospheric Imaging Method Using Sferic‐Based Tomography
Authors: Richardson David K. , McCormick Jackson C. , Cohen Morris B. 
Published: August 2023

AbstractWe present a tomographic imaging technique for the D‐region electron density using a set of spatially distributed very low frequency (VLF) remote sensing measurements. The D‐region ionosphere plays a critical role in many long‐range and over‐the‐horizon communication systems; however, it is unreachable by most direct measurement techniques such as balloons and satellites. Fortunately, the D region, combined with Earth's surface, forms what is known as the Earth‐Ionosphere waveguide allowing VLF and low frequency (LF) radio waves to propagate to global distances. By measuring these signals, we can estimate a path measurement of the electron density, which we assume to be a path‐averaged electron density profile of the D region. In this work, we use path‐averaged inferences from lightning‐generated radio atmospherics (sferics) with a tomographic inversion to produce 3D models of electron density over the Southeastern United States and the Gulf of Mexico. The model begins with two‐dimensional great circle path observations, each of which is parameterized so it includes vertical profile information. The tomography is then solved in two dimensions (latitude and longitude) at arbitrarily many altitude slices to construct the 3D electron density. We examine the model's performance in the synthetic case and determine that we have an expected percent error better than 10% within our area of interest. We apply our model to the 2017 “Great American Solar Eclipse” and find a clear relationship between sunlight percentage and electron density at different altitudes.
Electron Lifetimes Measured at LEO: Comparison With RBSP Estimates and Pitch Angle Resolved Lifetimes
Authors: Shane A. D. , Marshall R. A. , Claudepierre S. G. , Pettit J. M. 
Published: August 2023

AbstractElectron lifetimes are important for understanding the dominant loss processes of radiation belt electrons to the atmosphere and for accurate radiation belt modeling. We estimate electron lifetimes from the precipitating population measured in Low Earth Orbit (LEO) from the Polar Orbiting Environmental Satellites (POES). We compare our estimates to previous estimates from the Radiation Belt Storm Probes (RBSP) by Claudepierre et al. (2020b, https://doi.org/10.1029/2019GL086053). We also present the first complete pitch angle resolved lifetimes in the radiation belts. Quasi‐linear theory predicts the pitch angle distribution decays uniformly, therefore if steady‐state decay is realized, POES and RBSP should measure similar lifetimes. Lifetime estimates from LEO are shown to be in good agreement with those from Van Allen Probes in the outer belt and pitch angle resolved lifetimes indicate that steady‐state decay is realized. However, a systematic slight overestimation of the POES lifetimes reveal that the POES instruments may suffer from bremsstrahlung contamination. At L = 2–3, no decay intervals were identified in the POES electron fluxes and the near loss cone RBSP electron fluxes. We show that at these L‐shells, where lifetimes are long, there is an apparent decoupling of the perpendicular and parallel flux. Large pitch angle anisotropy and processes that affect low pitch angle electrons are two explanations for this apparent decoupling. Electron lifetime models that use pitch angle independent lifetimes, derived from the equatorially mirroring electron flux, likely underestimate the amount of precipitating flux and may not capture the dynamics of low equatorial pitch angle electrons at L < 3.
Eddy Tracking From In Situ and Satellite Observations
Authors: Erickson Zachary K. , Fields Erik , Johnson Leah , Thompson Andrew F. , Dove Lilian A. , D’Asaro Eric , Siegel David A. 
Published: August 2023

AbstractMesoscale eddies are a dominant source of spatial variability in the surface ocean and play a major role in the biological marine carbon cycle. Satellite altimetry is often used to locate and track eddies, but this approach is rarely validated against in situ observations. Here we compare measurements of a small (under 25 km radius) mode water anticyclonic eddy over the Porcupine Abyssal Plain in the northeastern Atlantic Ocean using CTD and Acoustic Doppler Current Profiler (ADCP) measurements from three ships, two gliders, two profiling floats, and one Lagrangian float with those derived from sea level anomaly (SLA). In situ estimates of the eddy center were estimated from maps of the thickness of its central isopycnal layer, from ADCP velocities at a reference depth, and from the trajectory of the Lagrangian float. These were compared to three methods using altimetric SLA: one based on maximizing geostrophic rotation, one based on a constant SLA contour, and one which maximizes geostrophic velocity speed along the eddy boundary. All algorithms were used to select CTD profiles that were within the eddy. The in‐situ metrics agreed to 97%. The altimetry metrics showed only a small loss of accuracy, giving >90% agreement with the in situ results. This suggests that current satellite altimetry is adequate for understanding the spatial representation of even relatively small mesoscale eddies.
Wind Fields in Category 1–3 Tropical Cyclones Are Not Fully Represented in Wind Turbine Design Standards
Authors: Sanchez Gomez M. , Lundquist J. K. , Deskos G. , Arwade S. R. , Myers A. T. , Hajjar J. F. 
Published: August 2023

AbstractOffshore wind energy deployment in the U.S. is expected to increase in the years to come, with proposed wind farm sites located in regions with high risk for tropical cyclones. Yet, the wind turbine design criteria outlined by the International Electrotechnical Commission for extreme events may not account for wind field characteristics unique to tropical cyclones. To evaluate if current design standards capture the extreme conditions of these storms, we perform idealized large‐eddy simulations of three tropical cyclones (one Category 1, one Category 2, and one Category 3 storms) using the Weather Research and Forecasting model. Wind conditions near the eyewall of Cat‐1, Cat‐2, and Cat‐3 storms can exceed current design standards for offshore wind turbines. Winds at 90 m can be faster than outlined in the design criteria for Class I and Class T turbines for 50‐year recurrence periods. Wind speed shear across the turbine rotor layer is also larger than assumed in design specifications. Moreover, vertical variations in wind direction across the turbine rotor layer are large for tropical cyclones of all intensity levels, suggesting design standards should include veer, which can amplify loads in wind turbines. The existence of hurricane wind field characteristics that are not represented in design standards does not imply that damage or failure will certainly occur. Engineering safety factors incorporated in the design of the turbine's blades and structural components may prevent damage from occurring.
Genetic etiology of progressive pediatric neurological disorders
Authors: Aaltio Juho , Etula Anna , Ojanen Simo , Brilhante Virginia , Lönnqvist Tuula , Isohanni Pirjo , Suomalainen Anu 
Published: August 2023

Abstract
Background
The aim of the study was to characterize molecular diagnoses in patients with childhood-onset progressive neurological disorders of suspected genetic etiology.

Methods
We studied 48 probands (age range from newborn to 17 years old) with progressive neurological disorders of unknown etiology from the largest pediatric neurology clinic in Finland. Phenotypes included encephalopathy (54%), neuromuscular disorders (33%), movement disorders (11%), and one patient (2%) with hemiplegic migraine. All patients underwent whole-exome sequencing and disease-causing genes were analyzed.

Results
We found 20 (42%) of the patients to have variants in genes previously associated with disease. Of these, 12 were previously reported disease-causing variants, whereas eight patients had a novel variant on a disease-causing gene: ATP7A, CHD2, PURA, PYCR2, SLC1A4, SPAST, TRIT1, and UPF3B. Genetics also enabled us to define atypical clinical presentations of Rett syndrome (MECP2) and Menkes disease (ATP7A). Except for one deletion, all findings were single-nucleotide variants (missense 72%, truncating 22%, splice-site 6%). Nearly half of the variants were de novo.

Conclusions
The most common cause of childhood encephalopathies are de novo variants. Whole-exome sequencing, even singleton, proved to be an efficient tool to gain specific diagnoses and in finding de novo variants in a clinically heterogeneous group of childhood encephalopathies.

Impact

Whole-exome sequencing is useful in heterogeneous pediatric neurology cohorts.

Our article provides further evidence for and novel variants in several genes.

De novo variants are an important cause of childhood encephalopathies.
Interspecific competition can drive plasmid loss from a focal species in a microbial community
Authors: Sünderhauf David , Klümper Uli , Gaze William H , Westra Edze R , van Houte Stineke 
Published: August 2023

Abstract
Plasmids are key disseminators of antimicrobial resistance genes and virulence factors, and it is therefore critical to predict and reduce plasmid spread within microbial communities. The cost of plasmid carriage is a key metric that can be used to predict plasmids’ ecological fate, and it is unclear whether plasmid costs are affected by growth partners in a microbial community. We carried out competition experiments and tracked plasmid maintenance using a model system consisting of a synthetic and stable five-species community and a broad host-range plasmid, engineered to carry different payloads. We report that both the cost of plasmid carriage and its long-term maintenance in a focal strain depended on the presence of competitors, and that these interactions were species specific. Addition of growth partners increased the cost of a high-payload plasmid to a focal strain, and accordingly, plasmid loss from the focal species occurred over a shorter time frame. We propose that the destabilising effect of interspecific competition on plasmid maintenance may be leveraged in clinical and natural environments to cure plasmids from focal strains.
B-type Plexins promote the GTPase activity of Ran to affect androgen receptor nuclear translocation in prostate cancer
Authors: Garg Ritu , Endzhievskaya Sofia , Williamson Magali 
Published: August 2023

AbstractResistance to anti-androgen therapy for metastatic prostate cancer is a major clinical problem. Sema3C promotes resistance to androgen withdrawal via its receptor, PlexinB1. Activation of PlexinB1 promotes the ligand-independent nuclear translocation of the androgen receptor (AR), which may contribute to resistance to androgen deprivation therapy. However, the mechanism by which PlexinB1 promotes nuclear translocation is unclear. We show here that PlexinB1 and B2 regulate nuclear import by acting as GTPase activating proteins (GAPs) for the small RasGTPase Ran, a key regulator of nuclear trafficking. Purified PlexinB1/B2 protein catalyses the hydrolysis of RanGTP, and mutations in the GAP domain of PlexinB1 inhibit this activity. Activation of PlexinB1/B2 with Sema4D decreases the levels of RanGTP, while PlexinB1 or B2 depletion increases the levels of activated Ran in the cell. Ran directly associates with B-type plexins in a GTP-dependent manner. Sema4D is internalised by endocytosis, and PlexinB1 and Ran display overlapping patterns of expression. Furthermore, Sema4D/PlexinB1-induced AR nuclear translocation is dependent on the GAP domain of PlexinB1 and is blocked by the expression of non-functional Ran mutants. Depletion of PlexinB1 decreases the nuclear/cytoplasmic ratio of Ran, indicative of a higher RanGTP/GDP ratio. Plexins may promote the growth of androgen-independent prostate cancer through their activity as RanGAPs.
Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis
Authors: Zheng Kang , Hao Fengjie , Medrano-Garcia Sandra , Chen Chaobo , Guo Feifei , Morán-Blanco Laura , Rodríguez-Perales Sandra , Torres-Ruiz Raúl , Peligros María Isabel , Vaquero Javier , Bañares Rafael , Gómez del Moral Manuel , Regueiro José R. , Martínez-Naves Eduardo , Mohamed Mohamed Ramadan , Gallego-Durán Rocío , Maya Douglas , Ampuero Javier , Romero-Gómez Manuel , Gilbert-Ramos Albert , Guixé-Muntet Sergi , Fernández-Iglesias Anabel , Gracia-Sancho Jordi , Coll Mar , Graupera Isabel , Ginès Pere , Ciudin Andreea , Rivera-Esteban Jesús , Pericàs Juan M. , Frutos María Dolores , Ramos Molina Bruno , Herranz José María , Ávila Matías A. , Nevzorova Yulia A. , Fernández-Malavé Edgar , Cubero Francisco Javier 
Published: August 2023

AbstractProgressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.
Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice
Authors: Rosenberg Ayelet M. , Saggar Manish , Monzel Anna S. , Devine Jack , Rogu Peter , Limoges Aaron , Junker Alex , Sandi Carmen , Mosharov Eugene V. , Dumitriu Dani , Anacker Christoph , Picard Martin 
Published: August 2023

AbstractThe brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied at a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in male mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity, and exhibited distinct molecular mitochondrial phenotype signatures. This work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the male mouse brain.
Dimeric G-quadruplex motifs-induced NFRs determine strong replication origins in vertebrates
Authors: Poulet-Benedetti Jérémy , Tonnerre-Doncarli Caroline , Valton Anne-Laure , Laurent Marc , Gérard Marie , Barinova Natalja , Parisis Nikolaos , Massip Florian , Picard Franck , Prioleau Marie-Noëlle 
Published: August 2023

AbstractReplication of vertebrate genomes is tightly regulated to ensure accurate duplication, but our understanding of the interplay between genetic and epigenetic factors in this regulation remains incomplete. Here, we investigated the involvement of three elements enriched at gene promoters and replication origins: guanine-rich motifs potentially forming G-quadruplexes (pG4s), nucleosome-free regions (NFRs), and the histone variant H2A.Z, in the firing of origins of replication in vertebrates. We show that two pG4s on the same DNA strand (dimeric pG4s) are sufficient to induce the assembly of an efficient minimal replication origin without inducing transcription in avian DT40 cells. Dimeric pG4s in replication origins are associated with formation of an NFR next to precisely-positioned nucleosomes enriched in H2A.Z on this minimal origin and genome-wide. Thus, our data suggest that dimeric pG4s are important for the organization and duplication of vertebrate genomes. It supports the hypothesis that a nucleosome close to an NFR is a shared signal for the formation of replication origins in eukaryotes.
Structural basis of agonist specificity of α1A-adrenergic receptor
Authors: Su Minfei , Wang Jinan , Xiang Guoqing , Do Hung Nguyen , Levitz Joshua , Miao Yinglong , Huang Xin-Yun 
Published: August 2023

Abstractα1-adrenergic receptors (α1-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α1 subtypes has limited our understanding of the physiological roles of different α1-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α1A-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α1A-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α1A-AR and α1B-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α1A-AR mutants that are not responsive to A61603, and α1B-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α1-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.
Decision making for implementing non-traditional water sources: a review of challenges and potential solutions
Authors: Quon Hunter , Jiang Sunny 
Published: August 2023

AbstractThe effects of climate change, population growth, and future hydrologic uncertainties necessitate increased water conservation, new water resources, and a shift towards sustainable urban water supply portfolios. Diversifying water portfolios with non-traditional water sources can play a key role. Rooftop harvested rainwater (RHRW), atmospheric and condensate harvesting, stormwater, recycled wastewater and greywater, and desalinated seawater and brackish water are all currently utilized and rapidly emerging non-traditional water sources. This review explores the status and trends around these non-traditional water sources, and reviews approaches and models for prioritizing, predicting, and quantifying metrics of concern. The analysis presented here suggests that understanding the challenges of location specific scenarios, socioeconomic knowledge gaps, water supply technologies, and/or water management structure is the crucial first step in establishing a model or framework approach to provide a strategy for improvement going forward. The findings of this study also suggest that clear policy guidance and onsite maintenance is necessary for variable water quality concerns of non-traditional sources like harvested rainwater and greywater. In addition, use of stormwater or reuse of wastewater raises public health concerns due to unknown risks and pathogen levels, thus rapid monitoring technologies and transparent reporting systems can facilitate their adoption. Finally, cost structure of desalination varies significantly around the world, largely due to regulatory requirements and local policies. Further reduction of its capital cost and energy consumption is identified as a hurdle for implementation. Overall, models and process analyses highlight the strength of comparative assessments across scenarios and water supply options.
First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial
Authors: Thibaudin Marion , Fumet Jean-David , Chibaudel Benoist , Bennouna Jaafar , Borg Christophe , Martin-Babau Jerome , Cohen Romain , Fonck Marianne , Taieb Julien , Limagne Emeric , Blanc Julie , Ballot Elise , Hampe Léa , Bon Marjorie , Daumoine Susy , Peroz Morgane , Mananet Hugo , Derangère Valentin , Boidot Romain , Michaud Henri-Alexandre , Laheurte Caroline , Adotevi Olivier , Bertaut Aurélie , Truntzer Caroline , Ghiringhelli François 
Published: August 2023

AbstractAlthough patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable metastatic CRC. Safety was the primary objective of phase Ib; no safety issue was observed. The phase 2 primary objective of efficacy in terms of 3-month progression-free survival (PFS) in patients with MSS tumors was met, with 3-month PFS of 90.7% (95% confidence interval (CI): 79.2–96%). For secondary objectives, response rate was 64.5%; median PFS was 8.2 months (95% CI: 5.9–8.6); and overall survival was not reached in patients with MSS tumors. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial–mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor-specific T cell response associated with better PFS. The combination of durvalumab–tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758.