bluuebunny/crossref_metadata_2025_split huggingface dataset:
PEMEM Percentile: New Plasma Environment Specification Model for Surface Charging Risk Assessment
Authors: Dubyagin S. , Ganushkina N. , Sicard A. , Matéo‐Vélez J.‐C. , Monnin L. , Heynderickx D. , Jiggens P. , Deprez G. , Cipriani F. 
Published: February 2024

AbstractThe Plasma Environment Modeling in the Earth's Magnetosphere (PEMEM) is a European Space Agency activity supporting the development of a new specification model for the spacecraft surface charging risk assessment. This paper presents a description of the basic model version: the PEMEM percentile model. The model is intended to be used for space missions with near‐equatorial orbits. The model is based on the Van Allen Probes particle measurements inside the geostationary orbit. The model's primary input is a planned spacecraft trajectory. It outputs statistical characteristics of the plasma environment which are expected to be encountered during a mission lifetime. These characteristics include differential electron and proton flux percentiles for a set of energies (percentile spectra), and percentiles of the integrated electron flux. The model covers the energy range of 1–100 keV for electrons and 40 eV–51 keV for protons. Since extreme spacecraft charging usually occurs in the eclipse, the same characteristics can be separately output for the periods when the spacecraft is shadowed by the Earth.
Remote Estimates of Sea Surface Nitrate and Its Trends From Ocean Color in the Northwest Pacific
Authors: Chen Shuangling , Meng Yu , Shang Shaoling , Zheng Mei , Wang Yuntao , Chai Fei 
Published: February 2024

AbstractSea surface nitrate (SSN) plays an important role in assessing new production and phytoplankton growth in the ocean, yet it has been challenging to estimate SSN from satellites due to its complex and varying relationship with different environmental proxies. The different SSN trends in the northwest Pacific reported in previous studies call for more detailed research to examine the interannual variabilities in SSN. We addressed this problem by developing a stacking‐random‐forest based algorithm for Moderate Resolution Imaging Spectroradiometer (MODIS). It allows estimating SSN from daily sea surface temperature (SST) and Chlorophyll‐a concentration (Chl) at a spatial resolution of 4 km. For SSN ranging between 0.0005 and 25.88 μmol/kg (N = 3,452), the model had a root mean square difference of 1.34 μmol/kg (5.3%) and coefficient of determination of 0.92. Further independent validation and sensitivity tests demonstrated the validity of the algorithm in retrieving SSN. Using this novel data record, for the first time, we investigated the SSN interannual variabilities and trends from MODIS. Overall, the SSN showed a weak decreasing trend of −0.01 ± 0.007 μmol kg−1 yr−1 (p < 0.05) in the northwest Pacific in 2002–2020, associated with an increasing trend in SST (0.03 ± 0.01˚C yr−1 at p < 0.05) and insignificant trend (0.001 ± 0.001 mg m−3 yr−1 at p > 0.05) in Chl. The interannual variabilities of SSN were significantly correlated with the environmental proxies (SST, Chl) and the climate indices (Pacific Decadal Oscillation and North Pacific Gyre Oscillation). The SSN trends can be further restricted with more data available.
Observation of Near‐Inertial Waves Induced by Typhoon Lan in the Northwestern Pacific: Characteristics, Energy Fluxes and Impact on Diapycnal Mixing
Authors: Yuan Shengming , Yan Xiaomei , Zhang Linlin , Pang Chongguang , Hu Dunxin 
Published: February 2024

AbstractBased on mooring observations from October 10 to 5 November 2017 at four stations in the Northwestern Pacific, the characteristics of four strong near‐inertial wave (NIW) packets generated by the typhoon Lan were examined. The wave‐packet analysis revealed that for the NIWs with larger horizontal wavelengths, as their interactions with the background currents were weakened, the observed frequency was close to the intrinsic frequency. The near‐inertial kinetic energy (NIKE) between two cyclonic eddies penetrated deeper (∼620 m) than that in a negative vorticity region. A ray‐tracing model suggested that it was the strong positive vorticity to the north that caused the northward propagating NIWs to be reflected, and then the reflected NIWs were accelerated to propagate downward at ∼70 m depth where the stratification was strongest. In these two cases, furthermore, the efficiency of the downward propagation of NIKE was at a comparable level of 21%–25%. Energy budget analysis indicated that about 5%–25% of the near‐inertial wind work was injected into the upper 50–200 m, approximately 6%–25% of which could be further radiated to the deeper ocean. On average, after the passage of the typhoon Lan, the dissipation rate increased by 3–8 times, and for the enhanced diapycnal mixing, ∼42% of the energy was provided by the typhoon‐induced strong NIWs.
Understanding the Role of Sharp Edges in the Propagation of Surface Gravity Waves
Authors: Hitzegrad Jan , Köster Sebastian , Windt Christian , Goseberg Nils 
Published: February 2024

AbstractUltra‐rough oceanic surfaces, such as oyster reefs, are characterized by densely‐packed, sharp‐edged roughness elements that induce high frictional resistance on the ambient flows. To effectively employ, for example, oyster reefs as a nature‐based solution in coastal protection, a detailed understanding of the frictional wave energy dissipation processes is necessary. This work reports on an experimental study in which six surrogates of very to ultra‐rough oceanic bed surfaces were subjected to regular waves. The influences of different sharpness' of roughness elements (bluntly‐shaped, sharp‐edged, and a combination thereof) and relative spacing between elements compared to the near‐bed horizontal excursion amplitude, λ/ab, on the wave attenuation have been investigated. Turbulence is 2–27 times larger for sharp‐edged surfaces and 1 to 18 times larger for mix surfaces than those of bluntly‐shaped surfaces. Maximum bed shear stresses, hydraulic roughness lengths, and wave friction factors are likewise significantly larger for sharp‐edged compared to bluntly‐shaped surfaces. These observations indicate that the sharp edges are crucial for frictional energy dissipation. Comparing the maximum bed shear stresses determined from wave height reductions to those determined from velocity measurements indicates that in addition to turbulent kinetic energy (TKE), periodic form‐induced stresses significantly contribute to the overall bed shear stresses. This study provides new insight into the frictional dissipation processes of oscillating flows encountering ultra‐rough surfaces.
Destratifying and Restratifying Instabilities During Down‐Front Wind Events: A Case Study in the Irminger Sea
Authors: Goldsworth F. W. , Johnson H. L. , Marshall D. P. , Le Bras I. A. 
Published: February 2024

AbstractObservations indicate that symmetric instability is active in the East Greenland Current during strong northerly wind events. Theoretical considerations suggest that mesoscale baroclinic instability may also be enhanced during these events. An ensemble of idealized numerical ocean models forced with northerly winds shows that the short time‐scale response (from 10 days to 3 weeks) to the increased baroclinicity of the flow is the excitation of symmetric instability, which sets the potential vorticity of the flow to zero. The high latitude of the current means that the zero potential vorticity state has low stratification, and symmetric instability destratifies the water column. On longer time scales (greater than 4 weeks), baroclinic instability is excited and the associated slumping of isopycnals restratifies the water column. Eddy‐resolving models that fail to resolve the submesoscale should consider using submesoscale parameterizations to prevent the formation of overly stratified frontal systems following down‐front wind events. The mixed layer in the current deepens at a rate proportional to the square root of the time‐integrated wind stress. Peak water mass transformation rates vary linearly with the time‐integrated wind stress. Mixing rates saturate at high wind stresses during wind events of a fixed duration which means increasing the peak wind stress in an event leads to no extra mixing. Using ERA5 reanalysis data we estimate that between 0.9 Sv and 1.0 Sv of East Greenland Coastal Current Waters are produced by mixing with lighter surface waters during wintertime due to down‐front wind events. Similar amounts of East Greenland‐Irminger Current water are produced.
Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence
Authors: Fabbrizi Maria Rita , Nickson Catherine M. , Hughes Jonathan R. , Robinson Emily A. , Vaidya Karthik , Rubbi Carlos P. , Kacperek Andrzej , Bryant Helen E. , Helleday Thomas , Parsons Jason L. 
Published: February 2024

AbstractComplex DNA damage (CDD), containing two or more DNA lesions within one or two DNA helical turns, is a signature of ionising radiation (IR) and contributes significantly to the therapeutic effect through cell killing. The levels and complexity of CDD increases with linear energy transfer (LET), however, the specific cellular response to this type of DNA damage and the critical proteins essential for repair of CDD is currently unclear. We performed an siRNA screen of ~240 DNA damage response proteins to identify those specifically involved in controlling cell survival in response to high-LET protons at the Bragg peak, compared to low-LET entrance dose protons which differ in the amount of CDD produced. From this, we subsequently validated that depletion of 8-oxoguanine DNA glycosylase (OGG1) and poly(ADP-ribose) glycohydrolase (PARG) in HeLa and head and neck cancer cells leads to significantly increased cellular radiosensitivity specifically following high-LET protons, whilst no effect was observed after low-LET protons and X-rays. We subsequently confirmed that OGG1 and PARG are both required for efficient CDD repair post-irradiation with high-LET protons. Importantly, these results were also recapitulated using specific inhibitors for OGG1 (TH5487) and PARG (PDD00017273). Our results suggest OGG1 and PARG play a fundamental role in the cellular response to CDD and indicate that targeting these enzymes could represent a promising therapeutic strategy for the treatment of head and neck cancers following high-LET radiation.
Periplogenin attenuates LPS-mediated inflammatory osteolysis through the suppression of osteoclastogenesis via reducing the NF-κB and MAPK signaling pathways
Authors: Gan Kai , Lian Haoyu , Yang Tao , Huang Jian , Chen Junchun , Su Yuangang , Zhao Jinmin , Xu Jiake , Liu Qian 
Published: February 2024

AbstractThe key target for treating inflammatory osteolysis is osteoclasts. In an inflammatory environment, osteoclast differentiation increases, and bone resorption is enhanced. Periplogenin (Ppg) is a traditional Chinese medicine. It has anti-inflammatory and antitumor effects, but its impact on inflammatory osteolysis is unknown. This study found that Ppg prevented LPS-induced skull osteolysis by inhibiting the expression of inflammatory cytokines and osteoclast production. In vitro, Ppg blocked the RANKL-induced generation of osteoclasts, the development of pseudopodia bands, and bone resorption. Ppg also attenuated the expression of NFATc1, c-Fos, CTSK, and Atp6v0d2 proteins by inhibiting the NFATc1 signaling pathway. In addition, Ppg inhibited the expression of osteoclast-specific genes, including NFATc1, c-Fos, CTSK, Atp6v0d2, and Mmp9. Moreover, Ppg also inhibited NF-κB and MAPK pathways. In vivo, Ppg reduced the number of osteoclasts on the surface of the bone and suppressed LPS-induced osteolysis of the skull. These outcomes suggest that Ppg can serve as a new alternative therapy for treating inflammatory osteolysis by inhibiting inflammation and osteoclasts.
COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase
Authors: Cummings Matthew J. , Bakamutumaho Barnabas , Lutwama Julius J. , Owor Nicholas , Che Xiaoyu , Astorkia Maider , Postler Thomas S. , Kayiwa John , Kiconco Jocelyn , Muwanga Moses , Nsereko Christopher , Rwamutwe Emmanuel , Nayiga Irene , Kyebambe Stephen , Haumba Mercy , Bosa Henry Kyobe , Ocom Felix , Watyaba Benjamin , Kikaire Bernard , Tomoiaga Alin S. , Kisaka Stevens , Kiwanuka Noah , Lipkin W. Ian , O’Donnell Max R. ,   Collaboration for Clinical and Laboratory Characterization of COVID-19 in Uganda, Watyaba Benjamin , Kikaire Bernard , O’Donnell Max R. 
Published: February 2024

AbstractLittle is known about the pathobiology of SARS-CoV-2 infection in sub-Saharan Africa, where severe COVID-19 fatality rates are among the highest in the world and the immunological landscape is unique. In a prospective cohort study of 306 adults encompassing the entire clinical spectrum of SARS-CoV-2 infection in Uganda, we profile the peripheral blood proteome and transcriptome to characterize the immunopathology of COVID-19 across multiple phases of the pandemic. Beyond the prognostic importance of myeloid cell-driven immune activation and lymphopenia, we show that multifaceted impairment of host protein synthesis and redox imbalance define core biological signatures of severe COVID-19, with central roles for IL-7, IL-15, and lymphotoxin-α in COVID-19 respiratory failure. While prognostic signatures are generally consistent in SARS-CoV-2/HIV-coinfection, type I interferon responses uniquely scale with COVID-19 severity in persons living with HIV. Throughout the pandemic, COVID-19 severity peaked during phases dominated by A.23/A.23.1 and Delta B.1.617.2/AY variants. Independent of clinical severity, Delta phase COVID-19 is distinguished by exaggerated pro-inflammatory myeloid cell and inflammasome activation, NK and CD8+ T cell depletion, and impaired host protein synthesis. Combining these analyses with a contemporary Ugandan cohort of adults hospitalized with influenza and other severe acute respiratory infections, we show that activation of epidermal and platelet-derived growth factor pathways are distinct features of COVID-19, deepening translational understanding of mechanisms potentially underlying SARS-CoV-2-associated pulmonary fibrosis. Collectively, our findings provide biological rationale for use of broad and targeted immunotherapies for severe COVID-19 in sub-Saharan Africa, illustrate the relevance of local viral and host factors to SARS-CoV-2 immunopathology, and highlight underemphasized yet therapeutically exploitable immune pathways driving COVID-19 severity.
Time-integrated BMP signaling determines fate in a stem cell model for early human development
Authors: Teague Seth , Primavera Gillian , Chen Bohan , Liu Zong-Yuan , Yao LiAng , Freeburne Emily , Khan Hina , Jo Kyoung , Johnson Craig , Heemskerk Idse 
Published: February 2024

AbstractHow paracrine signals are interpreted to yield multiple cell fate decisions in a dynamic context during human development in vivo and in vitro remains poorly understood. Here we report an automated tracking method to follow signaling histories linked to cell fate in large numbers of human pluripotent stem cells (hPSCs). Using an unbiased statistical approach, we discover that measured BMP signaling history correlates strongly with fate in individual cells. We find that BMP response in hPSCs varies more strongly in the duration of signaling than the level. However, both the level and duration of signaling activity control cell fate choices only by changing the time integral. Therefore, signaling duration and level are interchangeable in this context. In a stem cell model for patterning of the human embryo, we show that signaling histories predict the fate pattern and that the integral model correctly predicts changes in cell fate domains when signaling is perturbed. Our data suggest that mechanistically, BMP signaling is integrated by SOX2.
Genetic control of thermomorphogenesis in tomato inflorescences
Authors: Sun Shuai , Liu Zhiqiang , Wang Xiaotian , Song Jia , Fang Siyu , Kong Jisheng , Li Ren , Wang Huanzhong , Cui Xia 
Published: February 2024

AbstractUnderstanding how plants alter their development and architecture in response to ambient temperature is crucial for breeding resilient crops. Here, we identify the quantitative trait locus qMULTIPLE INFLORESCENCE BRANCH 2 (qMIB2), which modulates inflorescence branching in response to high ambient temperature in tomato (Solanum lycopersicum). The non-functional mib2 allele may have been selected in large-fruited varieties to ensure larger and more uniform fruits under varying temperatures. MIB2 gene encodes a homolog of the Arabidopsis thaliana transcription factor SPATULA; its expression is induced in meristems at high temperature. MIB2 directly binds to the promoter of its downstream gene CONSTANS-Like1 (SlCOL1) by recognizing the conserved G-box motif to activate SlCOL1 expression in reproductive meristems. Overexpressing SlCOL1 rescue the reduced inflorescence branching of mib2, suggesting how the MIB2–SlCOL1 module helps tomato inflorescences adapt to high temperature. Our findings reveal the molecular mechanism underlying inflorescence thermomorphogenesis and provide a target for breeding climate-resilient crops.
An alpha-helical lid guides the target DNA toward catalysis in CRISPR-Cas12a
Authors: Saha Aakash , Ahsan Mohd , Arantes Pablo R. , Schmitz Michael , Chanez Christelle , Jinek Martin , Palermo Giulia 
Published: February 2024

AbstractCRISPR-Cas12a is a powerful RNA-guided genome-editing system that generates double-strand DNA breaks using its single RuvC nuclease domain by a sequential mechanism in which initial cleavage of the non-target strand is followed by target strand cleavage. How the spatially distant DNA target strand traverses toward the RuvC catalytic core is presently not understood. Here, continuous tens of microsecond-long molecular dynamics and free-energy simulations reveal that an α-helical lid, located within the RuvC domain, plays a pivotal role in the traversal of the DNA target strand by anchoring the crRNA:target strand duplex and guiding the target strand toward the RuvC core, as also corroborated by DNA cleavage experiments. In this mechanism, the REC2 domain pushes the crRNA:target strand duplex toward the core of the enzyme, while the Nuc domain aids the bending and accommodation of the target strand within the RuvC core by bending inward. Understanding of this critical process underlying Cas12a activity will enrich fundamental knowledge and facilitate further engineering strategies for genome editing.
Domain-inlaid Nme2Cas9 adenine base editors with improved activity and targeting scope
Authors: Bamidele Nathan , Zhang Han , Dong Xiaolong , Cheng Haoyang , Gaston Nicholas , Feinzig Hailey , Cao Hanbing , Kelly Karen , Watts Jonathan K. , Xie Jun , Gao Guangping , Sontheimer Erik J. 
Published: February 2024

AbstractNme2Cas9 has been established as a genome editing platform with compact size, high accuracy, and broad targeting range, including single-AAV-deliverable adenine base editors. Here, we engineer Nme2Cas9 to further increase the activity and targeting scope of compact Nme2Cas9 base editors. We first use domain insertion to position the deaminase domain nearer the displaced DNA strand in the target-bound complex. These domain-inlaid Nme2Cas9 variants exhibit shifted editing windows and increased activity in comparison to the N-terminally fused Nme2-ABE. We next expand the editing scope by swapping the Nme2Cas9 PAM-interacting domain with that of SmuCas9, which we had previously defined as recognizing a single-cytidine PAM. We then use these enhancements to introduce therapeutically relevant edits in a variety of cell types. Finally, we validate domain-inlaid Nme2-ABEs for single-AAV delivery in vivo.
Spatiotemporal and direct capturing global substrates of lysine-modifying enzymes in living cells
Authors: Hu Hao , Hu Wei , Guo An-Di , Zhai Linhui , Ma Song , Nie Hui-Jun , Zhou Bin-Shan , Liu Tianxian , Jia Xinglong , Liu Xing , Yao Xuebiao , Tan Minjia , Chen Xiao-Hua 
Published: February 2024

AbstractProtein-modifying enzymes regulate the dynamics of myriad post-translational modification (PTM) substrates. Precise characterization of enzyme-substrate associations is essential for the molecular basis of cellular function and phenotype. Methods for direct capturing global substrates of protein-modifying enzymes in living cells are with many challenges, and yet largely unexplored. Here, we report a strategy to directly capture substrates of lysine-modifying enzymes via PTM-acceptor residue crosslinking in living cells, enabling global profiling of substrates of PTM-enzymes and validation of PTM-sites in a straightforward manner. By integrating enzymatic PTM-mechanisms, and genetically encoding residue-selective photo-crosslinker into PTM-enzymes, our strategy expands the substrate profiles of both bacterial and mammalian lysine acylation enzymes, including bacterial lysine acylases PatZ, YiaC, LplA, TmcA, and YjaB, as well as mammalian acyltransferases GCN5 and Tip60, leading to discovery of distinct yet functionally important substrates and acylation sites. The concept of direct capturing substrates of PTM-enzymes via residue crosslinking may extend to the other types of amino acid residues beyond lysine, which has the potential to facilitate the investigation of diverse types of PTMs and substrate-enzyme interactive proteomics.
Challenges and recent advancements in the synthesis of α,α-disubstituted α-amino acids
Authors: Zhang Yu , Vanderghinste Jaro , Wang Jinxin , Das Shoubhik 
Published: February 2024

Abstractα,α-Disubstituted α-amino acids (α-AAs) have improved properties compared to other types of amino acids. They serve as modifiers of peptide conformation and as precursors of bioactive compounds. Therefore, it has been a long-standing goal to construct this highly valuable scaffold efficiently in organic synthesis and drug discovery. However, access to α,α-disubstituted α-AAs is highly challenging and largely unexplored due to their steric constraints. To overcome these, remarkable advances have been made in the last decades. Emerging strategies such as synergistic enantioselective catalysis, visible-light-mediated photocatalysis, metal-free methodologies and CO2fixation offer new avenues to access the challenging synthesis of α,α-disubstituted α-AAs and continuously bring additional contributions to this field. This review article aims to provide an overview of the recent advancements since 2015 and discuss existing challenges for the synthesis of α,α-disubstituted α-AAs and their derivatives.
Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy
Authors: Li Fengwei , Liu Junjie , Liu Chao , Liu Ziyan , Peng Xiangda , Huang Yinyue , Chen Xiaoyu , Sun Xiangnan , Wang Sen , Chen Wei , Xiong Dan , Diao Xiaotong , Wang Sheng , Zhuang Jingjing , Wu Chuanliu , Wu Dalei 
Published: February 2024

AbstractOverexpressed pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL can render tumor cells malignant. Leukemia drug venetoclax is currently the only approved selective BCL-2 inhibitor. However, its application has led to an emergence of resistant mutations, calling for drugs with an innovative mechanism of action. Herein we present cyclic peptides (CPs) with nanomolar-level binding affinities to BCL-2 or BCL-XL, and further reveal the structural and functional mechanisms of how these CPs target two proteins in a fashion that is remarkably different from traditional small-molecule inhibitors. In addition, these CPs can bind to the venetoclax-resistant clinical BCL-2 mutants with similar affinities as to the wild-type protein. Furthermore, we identify a single-residue discrepancy between BCL-2 D111 and BCL-XL A104 as a molecular “switch” that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-XL by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics.