bluuebunny/crossref_metadata_2025_split huggingface dataset:
Economic control of next generation aerospace fleets
Authors: Montana Felipe , Jacobs Will , Pontika Evangelia , Laskaridis Panagiotis , Griffiths Matthew , Beecroft Peter , Wall Derek , Kadirkamanathan Visakan , Mills Andrew R 
Published: December 2024

Abstract
Engineering machines are becoming increasingly complex and possess more control variables, increasing the complexity and versatility of the control systems. Different configurations of the control system, named a policy, can result in similar output behavior but with different resource or component life usage. There is therefore an opportunity to find optimal policies with respect to economic decisions. While many solutions have been proposed to find such economic policy decisions at the asset level, we consider this problem at the fleet level. In this case, the optimal operation of each asset is affected by the state of all other assets in the fleet. Challenges introduced by considering multiple assets include the construction of economic multi-objective optimization criteria, handling rare events such as failures, application of fleet-level constraints, and scalability. The proposed solution presents a framework for economic fleet optimization. The framework is demonstrated for economic criteria relating to resource usage, component lifing, and maintenance scheduling, but is generically extensible. Direct optimization of lifetime distributions is considered in order to avoid the computational burden of discrete event simulation of rare events. Results are provided for a real-world case study targeting the optimal economic operation of a fleet of aerospace gas turbine engines.
Observed Influences of Subpolar Front in the Japan/East Sea on Winter and Spring North Pacific Storm Track Activity
Authors: Yu Peilong , Chen Shiyao , Wang Huijun , Lin Xiaopei , Duan Mingkeng , Zhang Chao 
Published: December 2024

AbstractThis study investigated the response of the North Pacific storm track (NPST) activity to the meridional shift of the Japan/East Sea subpolar front during the cold season using a statistical method called generalized equilibrium feedback analysis. Results showed that the NPST response exhibits a basin‐wide anomaly in winter but a north‐south dipole in spring. Synoptic eddy temperature variance budget was employed to explore possible mechanisms from the perspective of eddy available potential energy (EAPE) generation. In winter, the baroclinic conversion directly induced by baroclinicity changes drives EAPE generation, and then, the positive eddy feedback reinforces this EAPE generation, giving rise to an intensified NPST. In spring, poleward‐shifted baroclinicity drives a displaced EAPE generation, leading to the poleward displacement of NPST. The shifted baroclinicity is caused by a basin‐scale warm air temperature anomaly, which is coherent with the anticyclone anomaly induced by the divergence of synoptic eddy heat and vorticity fluxes.
Present‐Day Shortening Accommodated by Folding, Thrusting and Strike‐Slip Faulting in the Enriquillo Basin of Southern Central Hispaniola: Implications for the Regional Seismic Hazard
Authors: Escuder‐Viruete J. , Fernández F. J. , Valera F. Pérez , Medialdea A. , Castillo‐Carrión M. 
Published: December 2024

AbstractHispaniola accommodates a significant portion of the present‐day convergence between Caribbean and North American plates. Located in southern Hispaniola, the Neogene Enriquillo basin is bounded by the Neiba and Bahoruco mountain ranges. The role of active individual faults and fault systems in this basin is not well understood, particularly their geometry and kinematics, slip rates and seismic activity. Knowing this information is important to characterize the active deformation pattern in southern Hispaniola, but it is also crucial to estimate the regional seismic hazard. Here, we analyze GPS geodetic data and seismicity and present the results of fault mapping of the Enriquillo basin based on tectonic field observations, radiocarbon and luminescence dating, remote sensing and regional magnetic data. These observations indicate that WNW to NW‐trending thrust faults and associate large‐scale folds, as well as minor strike‐slip and normal faults, have been active both in the Tertiary rocks within the mountain ranges and in the basin margins along the Quaternary. Inversion of fault‐slip data establishes that a NE‐directed shortening has controlled the formation of these structures. We propose a regional kinematic model in which the present‐day kinematics of each main fault depend strongly on its orientation with respect to the regional stress tensor. Computed seismic hazard defines a map pattern for the peak ground acceleration elongated to the main seismotectonic fault zones. Regions around the southwest Sierra de Neiba, the western Enriquillo basin and the northwest Sierra de Bahoruco, where peak ground acceleration exceed 500 cm/s2, have a high seismic hazard.
Mitophagy in ischemic heart disease: molecular mechanisms and clinical management
Authors: Xu Shujuan , Wang Zihan , Guo Fan , Zhang Yehao , Peng Han , Zhang Huiyu , Liu Zixin , Cao Ce , Xin Gaojie , Chen Yuan Yuan , Fu Jianhua 
Published: December 2024

AbstractThe influence of the mitochondrial control system on ischemic heart disease has become a major focus of current research. Mitophagy, as a very crucial part of the mitochondrial control system, plays a special role in ischemic heart disease, unlike mitochondrial dynamics. The published reviews have not explored in detail the unique function of mitophagy in ischemic heart disease, therefore, the aim of this paper is to summarize how mitophagy regulates the progression of ischemic heart disease. We conclude that mitophagy affects ischemic heart disease by promoting cardiomyocyte hypertrophy and fibrosis, the progression of oxidative stress, the development of inflammation, and cardiomyocyte death, and that the specific mechanisms of mitophagy are worthy of further investigation.
Combining genomics and epidemiology to investigate a zoonotic outbreak of rabies in Romblon Province, Philippines
Authors: Yuson Mirava , Bautista Criselda T. , Rees Eleanor M. , Bogaardt Carlijn , Cruz Van Denn D. , Durrant Rowan , Formstone Anna , Manalo Daria L. , Manzanilla Duane R. , Kundergorski Mikolaj , Nacion Leilanie , Aloyon Hannaniah , Bolivar Jude Karlo , Bondoc Jeromir , Cobbold Christina , Panganiban Efraim , Telmo Shynie Vee. M. , Maestro Jobin , Miranda Mary Elizabeth G. , Chng Nai Rui , Brunker Kirstyn , Hampson Katie 
Published: December 2024

AbstractRabies is a viral zoonosis that kills thousands of people annually in low- and middle-income countries across Africa and Asia where domestic dogs are the reservoir. ‘Zero by 30’, the global strategy to end dog-mediated human rabies, promotes a One Health approach underpinned by mass dog vaccination, post-exposure vaccination of bite victims, robust surveillance and community engagement. Using Integrated Bite Case Management (IBCM) and whole genome sequencing (WGS), we enhanced rabies surveillance to detect an outbreak in a formerly rabies-free island province in the Philippines. We inferred that the outbreak was seeded by at least three independent human-mediated introductions that were identified as coming from neighbouring rabies-endemic provinces. Considerable local transmission went undetected, and two human deaths occurred within 6 months of outbreak detection. Suspension of routine dog vaccination due to COVID-19 restrictions likely facilitated rabies spread from these introductions. Emergency response, consisting of awareness measures, and ring vaccination, were performed, but swifter and more widespread implementation is needed to contain and eliminate the outbreak and to secure rabies freedom. We conclude that strengthened surveillance making use of new tools such as IBCM, WGS, and rapid diagnostic tests can support One Health in action and progress towards the ‘Zero by 30’ goal.
Antibodies to the RBD of SARS-CoV-2 spike mediate productive infection of primary human macrophages
Authors: Pickering Suzanne , Wilson Harry , Bravo Enrico , Perera Marianne R. , Seow Jeffrey , Graham Carl , Almeida Nathalia , Fotopoulos Lazaros , Williams Thomas , Moitra Atlanta , Winstone Helena , Nissen Tinne A. D. , Galão Rui Pedro , Snell Luke B. , Doores Katie J. , Malim Michael H. , Neil Stuart J. D. 
Published: December 2024

AbstractThe role of myeloid cells in the pathogenesis of SARS-CoV-2 is well established, in particular as drivers of cytokine production and systemic inflammation characteristic of severe COVID-19. However, the potential for myeloid cells to act as bona fide targets of productive SARS-CoV-2 infection, and the specifics of entry, remain unclear. Using a panel of anti-SARS-CoV-2 monoclonal antibodies (mAbs) we performed a detailed assessment of antibody-mediated infection of monocytes/macrophages. mAbs with the most consistent potential to mediate infection were those targeting a conserved region of the receptor binding domain (RBD; group 1/class 4). Infection was closely related to the neutralising concentration of the mAbs, with peak infection occurring below the IC50, while pre-treating cells with remdesivir or FcγRI-blocking antibodies inhibited infection. Studies performed in primary macrophages demonstrated high-level and productive infection, with infected macrophages appearing multinucleated and syncytial. Infection was not seen in the absence of antibody with the same quantity of virus. Addition of ruxolitinib significantly increased infection, indicating restraint of infection through innate immune mechanisms rather than entry. High-level production of pro-inflammatory cytokines directly correlated with macrophage infection levels. We hypothesise that infection via antibody-FcR interactions could contribute to pathogenesis in primary infection, systemic virus spread or persistent infection.
NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression
Authors: Reddy Tejaswini , Puri Akshjot , Guzman-Rojas Liliana , Thomas Christoforos , Qian Wei , Zhou Jianying , Zhao Hong , Mahboubi Bijan , Oo Adrian , Cho Young-Jae , Kim Baek , Thaiparambil Jose , Rosato Roberto , Martinez Karina Ortega , Chervo Maria Florencia , Ayerbe Camila , Giese Noah , Wink David , Lockett Stephen , Wong Stephen , Chang Jeffrey , Krishnamurthy Savitri , Yam Clinton , Moulder Stacy , Piwnica-Worms Helen , Meric-Bernstam Funda , Chang Jenny 
Published: December 2024

AbstractMetaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH2-terminal kinase (JNK)/c-Jun complex to repress its transcriptional output, leading to enhanced tumor differentiation and associated chemosensitivity. As a result, combined NOS and PI3K inhibition with taxane targets MpBC stem cells and improves survival in patient-derived xenograft models relative to single-/dual-agent therapy. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed a post-treatment reversal of epithelial-to-mesenchymal transition and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a unique strategy to decrease chemoresistance and improve clinical outcomes in MpBC.
Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice
Authors: Zallar Lia J. , Rivera-Irizarry Jean K. , Hamor Peter U. , Pigulevskiy Irena , Rico Rozo Ana-Sofia , Mehanna Hajar , Liu Dezhi , Welday Jacqueline P. , Bender Rebecca , Asfouri Joseph J. , Levine Olivia B. , Skelly Mary Jane , Hadley Colleen K. , Fecteau Kristopher M. , Nelson Scottie , Miller John , Ghazal Pasha , Bellotti Peter , Singh Ashna , Hollmer Lauren V. , Erikson David W. , Geri Jacob , Pleil Kristen E. 
Published: December 2024

AbstractOvarian-derived estrogen can signal non-canonically at membrane-associated receptors in the brain to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high estrogen levels, but a causal role for estrogen in driving alcohol drinking has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance when estrogen was high during the estrous cycle than when it was low. The pro-drinking, but not anxiolytic, effect of high endogenous estrogen occurred via rapid signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis, which promoted synaptic excitation of corticotropin-releasing factor neurons and facilitated their activity during alcohol drinking. Thus, this study demonstrates a rapid, nongenomic signaling mechanism for ovarian-derived estrogen in the brain controlling behavior in gonadally intact females.
Reconstitution of pluripotency from mouse fibroblast through Sall4 overexpression
Authors: Xiao Lizhan , Huang Zifen , Wu Zixuan , Yang Yongzheng , Zhang Zhen , Kumar Manish , Wu Haokaifeng , Mao Huiping , Lin Lihui , Lin Runxia , Long Jingxian , Zeng Lihua , Guo Jing , Luo Rongping , Li Yi , Zhu Ping , Liao Baojian , Wang Luqin , Liu Jing 
Published: December 2024

AbstractSomatic cells can be reprogrammed into pluripotent stem cells (iPSCs) by overexpressing defined transcription factors. Specifically, overexpression of OCT4 alone has been demonstrated to reprogram mouse fibroblasts into iPSCs. However, it remains unclear whether any other single factor can induce iPSCs formation. Here, we report that SALL4 alone, under an optimized reprogramming medium iCD4, is capable of reprogramming mouse fibroblasts into iPSCs. Mechanistically, SALL4 facilitates reprogramming by inhibiting somatic genes and activating pluripotent genes, such as Esrrb and Tfap2c. Furthermore, we demonstrate that co-overexpressing SALL4 and OCT4 synergistically enhances reprogramming efficiency. Specifically, the activation of Rsk1/Esrrb/Tfap2c by SALL4, alongside OCT4’s activation of Sox2 and the suppression of Mndal by SALL4 and Sbsn by OCT4, cooperate to facilitate SALL4+OCT4-mediated reprogramming. Overall, our study not only establishes an efficient method for iPSCs induction using the SALL4 single factor but also provides insights into the synergistic effects of SALL4 and OCT4 in reprogramming.
Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release
Authors: Bose Dipayan , Bera Manindra , Norman Christopher A. , Timofeeva Yulia , Volynski Kirill E. , Krishnakumar Shyam S. 
Published: December 2024

AbstractNeurotransmitters are released from synaptic vesicles with remarkable precision in response to presynaptic calcium influx but exhibit significant heterogeneity in exocytosis timing and efficacy based on the recent history of activity. This heterogeneity is critical for information transfer in the brain, yet its molecular basis remains poorly understood. Here, we employ a biochemically-defined fusion assay under physiologically relevant conditions to delineate the minimal protein machinery sufficient to account for various modes of calcium-triggered vesicle fusion dynamics. We find that Synaptotagmin-1, Synaptotagmin-7, and Complexin synergistically restrain SNARE complex assembly, thus preserving vesicles in a stably docked state at rest. Upon calcium activation, Synaptotagmin-1 induces rapid vesicle fusion, while Synaptotagmin-7 mediates delayed fusion. Competitive binding of Synaptotagmin-1 and Synaptotagmin-7 to the same SNAREs, coupled with differential rates of calcium-triggered fusion clamp reversal, govern the overall kinetics of vesicular fusion. Under conditions mimicking sustained neuronal activity, the Synaptotagmin-7 fusion clamp is destabilized by the elevated basal calcium concentration, thereby enhancing the synchronous component of fusion. These findings provide a direct demonstration that a small set of proteins is sufficient to account for how nerve terminals adapt and regulate the calcium-evoked neurotransmitter exocytosis process to support their specialized functions in the nervous system.
Anti-CTLA4 treatment reduces lymphedema risk potentially through a systemic expansion of the FOXP3+ Treg population
Authors: Wolf Stefan , Madanchi Matiar , Turko Patrick , Hollmén Maija , Tugues Sonia , von Atzigen Julia , Giovanoli Pietro , Dummer Reinhard , Lindenblatt Nicole , Halin Cornelia , Detmar Michael , Levesque Mitchell , Gousopoulos Epameinondas 
Published: December 2024

AbstractSecondary lymphedema is a common sequel of oncologic surgery and presents a global health burden still lacking pharmacological treatment. The infiltration of the lymphedematous extremities with CD4+T cells influences lymphedema onset and emerges as a promising therapy target. Here, we show that the modulation of CD4+FOXP3+CD25+regulatory T (Treg) cells upon anti-CTLA4 treatment protects against lymphedema development in patients with melanoma and in a mouse lymphedema model. A retrospective evaluation of a melanoma patient registry reveals that anti-CTLA4 reduces lymphedema risk; in parallel, anti-CTLA4 reduces edema and improves lymphatic function in a mouse-tail lymphedema model. This protective effect of anti-CTLA4 correlates with a systemic expansion of Tregs, both in the animal model and in patients with melanoma. Our data thus show that anti-CTLA4 with its lymphedema-protective and anti-tumor properties is a promising candidate for more diverse application in the clinics.
Integrative determination of atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington disease
Authors: Bagherpoor Helabad Mahdi , Matlahov Irina , Kumar Raj , Daldrop Jan O. , Jain Greeshma , Weingarth Markus , van der Wel Patrick C. A. , Miettinen Markus S. 
Published: December 2024

AbstractNeurodegeneration in Huntington’s disease (HD) is accompanied by the aggregation of fragments of the mutant huntingtin protein, a biomarker of disease progression. A particular pathogenic role has been attributed to the aggregation-prone huntingtin exon 1 (HTTex1), generated by aberrant splicing or proteolysis, and containing the expanded polyglutamine (polyQ) segment. Unlike amyloid fibrils from Parkinson’s and Alzheimer’s diseases, the atomic-level structure of HTTex1 fibrils has remained unknown, limiting diagnostic and treatment efforts. We present and analyze the structure of fibrils formed by polyQ peptides and polyQ-expanded HTTex1 in vitro. Atomic-resolution perspectives are enabled by an integrative analysis and unrestrained all-atom molecular dynamics (MD) simulations incorporating experimental data from electron microscopy (EM), solid-state NMR, and other techniques. Alongside the use of prior data, we report magic angle spinning NMR studies of glutamine residues of the polyQ fibril core and surface, distinguished via hydrogen-deuterium exchange (HDX). Our study provides a molecular understanding of the structure of the core as well as surface of aggregated HTTex1, including the fuzzy coat and polyQ–water interface. The obtained data are discussed in context of their implications for understanding the detection of such aggregates (diagnostics) as well as known biological properties of the fibrils.
Laser scribed proton exchange membranes for enhanced fuel cell performance and stability
Authors: Chen Jianuo , Lu Xuekun , Wang Lingtao , Du Wenjia , Guo Hengyi , Rimmer Max , Zhai Heng , Liu Yuhan , Shearing Paul R. , Haigh Sarah J. , Holmes Stuart M. , Miller Thomas S. 
Published: December 2024

AbstractHigh-temperature proton exchange membrane fuel cells (HT-PEMFCs) offer solutions to challenges intrinsic to low-temperature PEMFCs, such as complex water management, fuel inflexibility, and thermal integration. However, they are hindered by phosphoric acid (PA) leaching and catalyst migration, which destabilize the critical three-phase interface within the membrane electrode assembly (MEA). This study presents an innovative approach to enhance HT-PEMFC performance through membrane modification using picosecond laser scribing, which optimises the three-phase interface by forming a graphene-like structure that mitigates PA leaching. Our results demonstrate that laser-induced modification of PA-doped membranes, particularly on the cathode side, significantly enhances the performance and durability of HT-PEMFCs, achieving a peak power density of 817.2 mW cm⁻² after accelerated stress testing, representing a notable 58.2% increase compared to untreated membranes. Furthermore, a comprehensive three-dimensional multi-physics model, based on X-ray micro-computed tomography data, was employed to visualise and quantify the impact of this laser treatment on the dynamic electrochemical processes within the MEA. Hence, this work provides both a scalable methodology to stabilise an important future membrane technology, and a clear mechanistic understanding of how this targeted laser modification acts to optimise the three-phase interface of HT-PEMFCs, which can have impact across a wide array of applications.
Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility
Authors: Ibrahim Amy , Mohring Franziska , Manko Emilia , van Schalkwyk Donelly A. , Phelan Jody E. , Nolder Debbie , Borrmann Steffen , Adegnika Ayola A. , Di Santi Silvia Maria , Alam Mohammad Shafiul , Mondal Dinesh , Nosten Francois , Sutherland Colin J. , Moon Robert W. , Clark Taane G. , Campino Susana 
Published: December 2024

AbstractPlasmodium malariae parasites are widely observed across the tropics and sub-tropics. This slow-growing species, known to maintain chronic asymptomatic infections, has been associated with reduced antimalarial susceptibility. We analyse 251 P. malariae genomes from 28 countries, and leveraging 131,601 high-quality SNPs, demonstrate segregation of African and Asian isolates. Signals of recent evolutionary selection were identified in genes encoding putative surface proteins (pmmsp1) and putative erythrocyte invasion proteins (pmdpap3, pmrbp2, pmnif4). Amino acid substitutions were identified in orthologs of genes associated with antimalarial susceptibility including 2 amino acid substitutions in pmdhfr aligning with pyrimethamine resistance mutations in P. falciparum. Additionally, we characterise pmdhfr mutation F57L and demonstrate its involvement in reduced susceptibility to pyrimethamine in an in vitro parasite assay. We validate CRISPR-Cas9 mediated ortholog replacement in P. knowlesi parasites to determine the function of pmdhfr mutations and demonstrate that circulating pmdhfr genotypes are less susceptible to pyrimethamine.