bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amino‐terminally elongated Aβ peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease brains
Authors: Wirths Oliver , Lehnen Christina , Fricke Merle , Talucci Ivan , Klafki Hans‐Wolfgang , Morgado Barbara , Lehmann Sandra , Münch Carolina , Liepold Thomas , Wiltfang Jens , Rostagno Agueda , Ghiso Jorge , Maric Hans Michael , Jahn Olaf , Weggen Sascha 
Published: June 2024

AbstractAimsThe aggregation and deposition of amyloid‐β (Aβ) peptides in the brain is thought to be the initial driver in the pathogenesis of Alzheimer's disease (AD). Aside from full‐length Aβ peptides starting with an aspartate residue in position 1, both N‐terminally truncated and elongated Aβ peptides are produced by various proteases from the amyloid precursor protein (APP) and have been detected in brain tissues and body fluids. Recently, we demonstrated that the particularly abundant N‐terminally truncated Aβ4–x peptides are generated by ADAMTS4, a secreted metalloprotease that is exclusively expressed in the oligodendrocyte cell population. In this study, we investigated whether ADAMTS4 might also be involved in the generation of N‐terminally elongated Aβ peptides.MethodsWe used cell‐free and cell‐based assays in combination with matrix‐assisted laser desorption/ionisation time‐of‐flight mass spectrometry (MALDI‐TOF) and electrochemiluminescence sandwich immunoassays to identify and quantify N‐terminally elongated Aβ peptide variants. Antibodies against these Aβ variants were characterised by peptide microarrays and employed for the immunohistochemical analyses of human brain samples.ResultsIn this study, we discovered additional ADAMTS4 cleavage sites in APP. These were located N‐terminal to Asp‐(1) in the Aβ peptide sequence between residues Glu‐(‐7) and Ile‐(‐6) as well as Glu‐(‐4) and Val‐(‐3), resulting in the release of N‐terminally elongated Aβ‐6‐x and Aβ‐3‐x peptides, of which the latter serve as a component in a promising Aβ‐based plasma biomarker. Aβ‐6/‐3‐40 peptides were detected in supernatants of various cell lines and in the cerebrospinal fluid (CSF), and ADAMTS4 enzyme activity promoted the release of Aβ‐6/‐3‐x peptides. Furthermore, by immunohistochemistry, a subset of AD cases displayed evidence of extracellular and vascular localization of N‐terminally elongated Aβ‐6/‐3‐x peptides.DiscussionThe current findings implicate ADAMTS4 in both the pathological process of Aβ peptide aggregation and in the early detection of amyloid pathology in AD.
Enhancing PDT efficacy in NMIBC: Efflux inhibitor mediated improvement of PpIX levels and efficacy of the combination of PpIX‐PDT and SO‐cleavable prodrugs
Authors: Kumbham Soniya , Rahman Kazi Md Mahabubur , Bosmajian Caroline , Bist Ganesh , Foster Barbara A. , Woo Sukyung , You Youngjae 
Published: June 2024

AbstractProtoporphyrin IX (PpIX)‐based photodynamic therapy (PDT) has shown limited efficacy in nonmuscle‐invasive bladder cancer (NMIBC). To improve PDT efficacy, we developed singlet oxygen‐cleavable prodrugs. These prodrugs, when combined with PpIX‐PDT, induce cancer cell death through both PDT and drug release mechanisms. Inhibition of PpIX efflux was reported to be an effective strategy to improve PpIX‐PDT in certain cancer cells. Our main goal was to investigate whether adding an efflux inhibitor to the combination of PpIX and prodrugs can improve the PpIX levels in bladder cancer cells and the release of active drugs, thus improving the overall efficacy of the treatment. We treated bladder cancer cell lines with lapatinib and evaluated intracellular PpIX fluorescence, finding significantly increased accumulation. Combining lapatinib with prodrugs led to significantly reduced cell viability compared to prodrugs or PpIX‐PDT alone. The effect of lapatinib depended on the expression level of the efflux pump in bladder cancer cells. Interestingly, lapatinib increased paclitaxel (PTX) prodrug uptake by threefold compared to prodrug alone. Adding an efflux inhibitor (e.g., lapatinib) into bladder instillation solutions could be a straightforward and effective strategy for NMIBC treatment, particularly in tumors expressing efflux pumps, with the potential for clinical translation.
Experimental Characterisation of GATOR Morphing Aircraft Skins Under Combined In-Plane and Out-of-Plane Loading
Authors: Heeb Rafael Martin , Woods Benjamin King Sutton 
Published: June 2024

Abstract
This work introduces a novel method of conducting differential pressure testing on 3D printed Geometrically Anisostrpopic TermOplastic Rubber (GATOR) morphing aircraft skins to explore their response under the combined in-plane stretching and out-of-plane pressure loading that they would experience on an aircraft wing surface, without the complexity of a full wind tunnel test. An airtight, four-sided GATOR skin specimen is tested up to an in-plain stretch ratio of 1.6 and a differential pressure of 0.028 MPa, with force and displacement data supplemented with stereo Digital image Correlation (DIC) measurements of skin strains. The results have produced high-quality data showcasing that this is a feasible method to test the static differential pressure behaviour of GATOR morphing skins. More importantly, though, it has highlighted that at low stretch ratios, there are small local out-of-plane deformations, and at higher stretch ratios, a more even skin deformation can be observed.
Machine Learning and Artificial Intelligence-Enhanced Image Processing and Feature Extraction for Microstructure and Metallurgical Characterization
Authors: Sherwood Benjamin , Billings Christopher , Hall Joshua , Nimmo Caylin , Siddique Zahed , Liu Yingtao 
Published: June 2024

Abstract
Scanning Electron Microscopy (SEM) image processing and metallurgical analysis are critical for gaining a deep understanding of the structures, properties, and performance of metals. Since metals exhibit complex microstructures composed of grains, phases, and defects that significantly influence their mechanical properties, it is important for researchers to visualize and characterize these intricate structures at a microscopic level, providing valuable insights into the material’s behavior. Although advanced SEM platforms and tools have been widely applied for research and development of novel materials, novel algorithms and image processing techniques are needed to automatically and efficiently analyze a large number of SEM images.
This research paper presents the development of machine learning (ML) and artificial intelligence (AI)-enhanced SEM image processing techniques for the characterization of microstructures in metals. Our long-term goal is to establish an adaptive, data-driven framework for extracting optimal information from individual SEM images, ultimately working towards the creation of a fully automated image processing and analysis methodology. Various data preparation processes, such as image filtering and quality assessment methods, will be investigated for feature identification, extraction, and localization in the SEM images. Then, the extracted information will be used to identify and quantify targeted physical properties and deposition attributes by denoising and image segmentation techniques. Our approach encompasses a comprehensive range of AI/ML techniques, including deep learning, data analytics, and pattern recognition, amalgamated to streamline the image processing workflow. The developed algorithm and software will be able to automatically analyze images and delve into the intricate aspects of physical properties, microstructures, and grain structures, thereby facilitating comprehensive property characterization. The research outcomes will be beneficial for the characterization of 3D printed metals, such as stainless steels, and will be further extended to other alloys in the future.
Nanoscale Property Characterization of Composite Adhesive Bonding Systems With Long-Term Environmental Exposures
Authors: Olander Rita , Tracey Ashley , Grace William , Flinn Brian 
Published: June 2024

Abstract
This preliminary research was directed toward understanding the fundamental science behind polymer matrix-adhesive interactions in adhesively bonded composite aircraft materials throughout the product’s lifecycle. Nanoindentation were used to characterize various regions of adhesively bonded carbon fiber/epoxy composite samples including the matrix resin, adhesive, and bondline mixing zones (interface/interphase). Since bondlines are heterogeneous in nature and are composed of multiple micron-scale subregions, subtle interactions and variations at the bond interface/interphase region can influence the performance of the bonded joint. Characterizing these regions may provide more understanding of process dependent variables, as well as potentially expand the operating limits for these bonded systems. For this study, adhesive bonded composite materials from carbon fiber specimens with long-term on-aircraft time temperature and stress exposures (scrapped parts) as well as specimens with on-ground, outdoor environmental exposures were compared to lab-produced baseline samples. The materials were evaluated using nanomechanical testing to understand the differences between initial interface and/or interphase development and the adhesive interface/interphase after on-aircraft time temperature and stress exposures (scrapped parts) and environmental exposure conditions. Previous studies using standard mechanical property characterization methods have not been able to isolate the adhesive/adherend interphase, due to the micron-sized scale of these regions. Nanomechanical test methods can be used to measure the adhesive/adherend interphase specific properties. Future work is to further understand how these nanoscale properties can be related to bond quality and performance.
Optimal Cable-Stayed Configurations for Pretensioned Space Structures
Authors: Daye Jacob G. , Lee Andrew J. , Griffee Cody , Scalice Niccoli 
Published: June 2024

Abstract
To improve the deployed stiffness and mass efficiency of pre-tensioned spacecraft structures, the efficacy of cable-stayed configurations is analyzed in this paper. The reference structure is a deployable array wing that supports a series of RF panels for space-based antenna applications, and it is designed to be z-folded under stowage. Due to the significant mass of the panels and the large span of the array wing, the entire structure is susceptible to low frequency excitation. Lightweight pretensioned cables that elastically support and stiffen the array along its span are found to drastically raise its fundamental frequency and critical buckling load. An analytical model that is validated by finite element simulations is used to predict the vibration and buckling modes of the constituent structures for both the reference and cable-stayed architectures. A parametric analysis then optimizes the cross-section of the load-bearing members, cable attachment points, and the number of cables to maximize the fundamental frequency for the structural systems. These optimal cable-stayed forms are compared against the reference design, and their effectiveness is demonstrated with a 157% and 255% increase in fundamental frequency for one and two cables, respectively.
Ancient nitrogenases are ATP dependent
Authors: Harris Derek F. , Rucker Holly R. , Garcia Amanda K. , Yang Zhi-Yong , Chang Scott D. , Feinsilber Hannah , Kaçar Betül , Seefeldt Lance C. 
Published: June 2024

ABSTRACT

Life depends on a conserved set of chemical energy currencies that are relics of early biochemistry. One of these is ATP, a molecule that, when paired with a divalent metal ion such as Mg
2+
, can be hydrolyzed to support numerous cellular and molecular processes. Despite its centrality to extant biochemistry, it is unclear whether ATP supported the function of ancient enzymes. We investigate the evolutionary necessity of ATP by experimentally reconstructing an ancestral variant of the N
2
-reducing enzyme nitrogenase. The Proterozoic ancestor is predicted to be ~540–2,300 million years old, post-dating the Great Oxidation Event. Growth rates under nitrogen-fixing conditions are ~80% of those of wild type in
Azotobacter vinelandii
. In the extant enzyme, the hydrolysis of two MgATP is coupled to electron transfer to support substrate reduction. The ancestor has a strict requirement for ATP with no other nucleotide triphosphate analogs (GTP, ITP, and UTP) supporting activity. Alternative divalent metal ions (Fe
2+
, Co
2+
, and Mn
2+
) support activity with ATP but with diminished activities compared to Mg
2+
, similar to the extant enzyme. Additionally, it is shown that the ancestor has an identical efficiency in ATP hydrolyzed per electron transferred to the extant of two. Our results provide direct laboratory evidence of ATP usage by an ancient enzyme.

IMPORTANCE
Life depends on energy-carrying molecules to power many sustaining processes. There is evidence that these molecules may predate the rise of life on Earth, but how and when these dependencies formed is unknown. The resurrection of ancient enzymes provides a unique tool to probe the enzyme’s function and usage of energy-carrying molecules, shedding light on their biochemical origins. Through experimental reconstruction, this research investigates the ancestral dependence of a nitrogen-fixing enzyme on the energy carrier ATP, a requirement for function in the modern enzyme. We show that the resurrected ancestor does not have generalist nucleotide specificity. Rather, the ancestor has a strict requirement for ATP, like the modern enzyme, with similar function and efficiency. The findings elucidate the early-evolved necessity of energy-yielding molecules, delineating their role in ancient biochemical processes. Ultimately, these insights contribute to unraveling the intricate tapestry of evolutionary biology and the origins of life-sustaining dependencies.
Radio Occultation Modeling Experiment (ROMEX): Determining the Impact of Radio Occultation Observations on Numerical Weather Prediction
Authors: Anthes Richard A. , Marquardt Christian , Ruston Benjamin , Shao Hui 
Published: June 2024

Abstract
The international radio occultation (RO) community is conducting a collaborative effort to explore the impact of a large number of RO observations on numerical weather prediction (NWP). This effort, the Radio Occultation Modeling Experiment (ROMEX), has been endorsed by the International Radio Occultation Working Group, a scientific working group under the auspices of the Coordination Group for Meteorological Satellites (CGMS). ROMEX seeks to inform strategies for future RO missions and acquisitions. ROMEX is planned to consist of at least one 3-month period during which all available RO data are collected, processed, archived, and made available to the global community free of charge for research and testing. Although the primary purpose is to test the impact of varying numbers of RO observations on NWP, the 3 months of RO observations during the first ROMEX period (ROMEX-1, September–November 2022) will be a rich dataset for research on many atmospheric phenomena. The RO data providers have sent their data to EUMETSAT for processing. The total number of RO profiles averages between 30 000 and 40 000 per day for ROMEX-1. The processed data (phase, bending angle, refractivity, temperature, and water vapor) will be distributed to ROMEX participants by the Radio Occultation Meteorology Satellite Application Facility (ROM SAF). The data will also be processed independently by the UCAR COSMIC Data Analysis and Archive Center (CDAAC) and available via ROM SAF. The data are freely available to all participants who agree to the conditions that the providers be acknowledged, and the data are not used for commercial or operational purposes.
A novel PH1/pE27HGFK1 nanoparticles for orthotopic glioblastoma therapy
Authors: zhang Jian , Li Tao , Liu Ling , Chen Zhenpu , Li Li , Yao Xiaoxuan , Cheng Jiaxing , Hu Xiaoyuan , Guo Jiyin , Li Ruilei , Ge Chunlei , Ling Eng-Ang , Yao Hong 
Published: June 2024

Abstract
Background
The therapeutic resistance to ionizing radiation (IR) and angiogenesis inhibitors is a great challenge for clinicians in the treatment of glioblastoma, which is associated with Hepatocyte growth factor (HGF)/MET, VEGF/VEGFR signaling pathway, and the crosstalk between them. In this study, we developed a novel recombinant fusion protein, rE27HGFK1, via HGFK1 tandem with 27 N-terminal residues of Endostatin (E27) and produced a polymeric nanoparticle formed by the co-polymer of PEGylated H1 cationic polymer (PH1) with a plasmid encoding the secreted rE27HGFK1 protein (PH1/pE27HGFK1). We further investigated the anti-tumor effects of rE27HGFK1 and PH1/pE27HGFK1 nanoparticles both in vivo and in vitro.

Methods
We expressed and purified the rE27HGFK1 protein via E. coli. Then, we performed cellular experiments to determine the antitumoral effects and IR radio-sensitivities of the rE27HGFK1 protein in vitro. Finally, we performed animal studies to determine the tumor-targeted abilities and antitumoral activities of the polymeric nanoparticles, PH1/pE27HGFK1, in an orthotopic U118-Luc-bearing xenografted mouse model.

Results
We showed that rE27HGFK1 inhibited the proliferation and the angiogenesis and enhanced the senescence and radiosensitivity of GBM via both MET and VEFGR2 signaling mediated-p16 over-expression and the down-regulation of cyclin D1-CDK4-Rb axis activities in vitro. Next, we displayed that systemic administration of the PEGylated H1 cationic polymer (PH1) effectively delivered the reporter genes to the brain tumor of an orthotopic U118-bearing xenografted mouse model. Finally, we showed that PH1/pE27HGFK1 significantly produced antitumor effects with radiosensitivity in the orthotopic U118-Luc-bearing xenografted Blab/c mouse model through inhibiting angiogenesis and tumor cell proliferation, as well as inducing the necrosis of tumor cells in vivo.

Conclusions
The PH1/pE27HGFK1 nano-drug combined with radiotherapy can be used as a potentially effective therapeutic strategy for Glioblastoma multiforme.
Colonization of the ocean floor by jawless vertebrates across three mass extinctions
Authors: Brownstein Chase Doran , Near Thomas J 
Published: June 2024

Abstract
Background
The deep (> 200 m) ocean floor is often considered to be a refugium of biodiversity; many benthic marine animals appear to share ancient common ancestry with nearshore and terrestrial relatives. Whether this pattern holds for vertebrates is obscured by a poor understanding of the evolutionary history of the oldest marine vertebrate clades. Hagfishes are jawless vertebrates that are either the living sister to all vertebrates or form a clade with lampreys, the only other surviving jawless fishes.

Results
We use the hagfish fossil record and molecular data for all recognized genera to construct a novel hypothesis for hagfish relationships and diversification. We find that crown hagfishes persisted through three mass extinctions after appearing in the Permian ~ 275 Ma, making them one of the oldest living vertebrate lineages. In contrast to most other deep marine vertebrates, we consistently infer a deep origin of continental slope occupation by hagfishes that dates to the Paleozoic.

Conclusion
Our results establish hagfishes as ancient members of demersal continental slope faunas and suggest a prolonged accumulation of deep sea jawless vertebrate biodiversity.
The radiation of New Zealand’s skinks and geckos is associated with distinct viromes
Authors: Waller Stephanie J. , Butcher Richelle G. , Lim Lauren , McInnes Kate , Holmes Edward C. , Geoghegan Jemma L. 
Published: June 2024

Abstract
Background
New Zealand is home to over 120 native endemic species of skinks and geckos that radiated over the last 20–40 million years, likely driven by the exploitation of diverse habitats formed during the Miocene. The recent radiation of animal hosts may facilitate cross-species virus transmission, likely reflecting their close genetic relationships and therefore relatively low barriers for viruses to emerge in new hosts. Conversely, as animal hosts adapt to new niches, even within specific geographic locations, so too could their viruses. Consequently, animals that have niche-specialised following radiations may be expected to harbour genetically distinct viruses. Through a metatranscriptomic analysis of eight of New Zealand’s native skink and gecko species, as well as the only introduced lizard species, the rainbow skink (Lampropholis delicata), we aimed to reveal the diversity of viruses in these hosts and determine whether and how the radiation of skinks and geckos in New Zealand has impacted virus diversity and evolution.

Results
We identified a total of 15 novel reptilian viruses spanning 11 different viral families, across seven of the nine species sampled. Notably, we detected no viral host-switching among the native animals analysed, even between those sampled from the same geographic location. This is compatible with the idea that host speciation has likely resulted in isolated, niche-constrained viral populations that have prevented cross-species transmission. Using a protein structural similarity-based approach, we further identified a highly divergent bunya-like virus that potentially formed a new family within the Bunyavirales.

Conclusions
This study has broadened our understanding of reptilian viruses within New Zealand and illustrates how niche adaptation may limit viral-host interactions.