bluuebunny/crossref_metadata_2025 huggingface dataset:
A machine learning algorithm with subclonal sensitivity reveals widespread pan-cancer human leukocyte antigen loss of heterozygosity
Authors: Pyke Rachel Marty , Mellacheruvu Dattatreya , Dea Steven , Abbott Charles W. , McDaniel Lee , Bhave Devayani P. , Zhang Simo V. , Levy Eric , Bartha Gabor , West John , Snyder Michael P. , Chen Richard O. , Boyle Sean Michael
Published: April 2022

Human leukocyte antigen loss of heterozygosity (HLA LOH) allows cancer cells to escape immune recognition by deleting HLA alleles, causing the suppressed presentation of tumor neoantigens. Despite its importance in immunotherapy response, few methods exist to detect HLA LOH, and their accuracy is not well understood. Here, we develop DASH (Deletion of Allele-Specific HLAs), a machine learning-based algorithm to detect HLA LOH from paired tumor-normal sequencing data. With cell line mixtures, we demonstrate increased sensitivity compared to previously published tools. Moreover, our patient-specific digital PCR validation approach provides a sensitive, robust orthogonal approach that could be used for clinical validation. Using DASH on 610 patients across 15 tumor types, we find that 18% of patients have HLA LOH. Moreover, we show inflated HLA LOH rates compared to genome-wide LOH and correlations between CD274 (encodes PD-L1) expression and microsatellite instability status, suggesting the HLA LOH is a key immune resistance strategy.
ComFC mediates transport and handling of single-stranded DNA during natural transformation
Authors: Damke Prashant P. , Celma Louisa , Kondekar Sumedha M. , Di Guilmi Anne Marie , Marsin Stéphanie , Dépagne Jordane , Veaute Xavier , Legrand Pierre , Walbott Hélène , Vercruyssen Julien , Guérois Raphaël , Quevillon-Cheruel Sophie , Radicella J. Pablo
Published: April 2022

The ComFC protein is essential for natural transformation, a process that plays a major role in the spread of antibiotic resistance genes and virulence factors across bacteria. However, its role remains largely unknown. Here, we show that Helicobacter pylori ComFC is involved in DNA transport through the cell membrane, and is required for the handling of the single-stranded DNA once it is delivered into the cytoplasm. The crystal structure of ComFC includes a zinc-finger motif and a putative phosphoribosyl transferase domain, both necessary for the protein’s in vivo activity. Furthermore, we show that ComFC is a membrane-associated protein with affinity for single-stranded DNA. Our results suggest that ComFC provides the link between the transport of the transforming DNA into the cytoplasm and its handling by the recombination machinery.
Persistent COVID-19 symptoms in a community study of 606,434 people in England
Authors: Whitaker Matthew , Elliott Joshua , Chadeau-Hyam Marc , Riley Steven , Darzi Ara , Cooke Graham , Ward Helen , Elliott Paul
Published: April 2022

Long COVID remains a broadly defined syndrome, with estimates of prevalence and duration varying widely. We use data from rounds 3–5 of the REACT-2 study (n = 508,707; September 2020 – February 2021), a representative community survey of adults in England, and replication data from round 6 (n = 97,717; May 2021) to estimate the prevalence and identify predictors of persistent symptoms lasting 12 weeks or more; and unsupervised learning to cluster individuals by reported symptoms. At 12 weeks in rounds 3–5, 37.7% experienced at least one symptom, falling to 21.6% in round 6. Female sex, increasing age, obesity, smoking, vaping, hospitalisation with COVID-19, deprivation, and being a healthcare worker are associated with higher probability of persistent symptoms in rounds 3–5, and Asian ethnicity with lower probability. Clustering analysis identifies a subset of participants with predominantly respiratory symptoms. Managing the long-term sequelae of COVID-19 will remain a major challenge for affected individuals and their families and for health services.
Using high-resolution contact networks to evaluate SARS-CoV-2 transmission and control in large-scale multi-day events
Authors: Pung Rachael , Firth Josh A. , Spurgin Lewis G. ,   Singapore CruiseSafe working group, Chang Annie , Kong Jade , Wong Jazzy , Jin Ooi Jo , Selvaraj Deepa , Yong Dominique , Lang Jocelyn , Sivalingam Abilash ,   CMMID COVID-19 working group, Procter Simon R. , Flasche Stefan , Waites William , Prem Kiesha , Pearson Carl A. B. , Gibbs Hamish P. , Sherratt Katharine , Villabona-Arenas C. Julian , Wong Kerry L. M. , Liu Yang , Mee Paul , Chapman Lloyd A. C. , Atkins Katherine E. , Quaife Matthew , Munday James D. , Funk Sebastian , Eggo Rosalind M. , Huè Stèphane , Davies Nicholas G. , Hodgson David , Abbas Kaja , McCarthy Ciara V. , Hellewell Joel , Abbott Sam , Bosse Nikos I. , Brady Oliver , Barnard Rosanna C. , Jit Mark , Tully Damien C. , Medley Graham , Sun Fiona Yueqian , Jarvis Christopher I. , Lowev Rachel , O’Reilly Kathleen , Meakin Sophie R. , Endo Akira , Sandmann Frank G. , Edmunds W. John , Koltai Mihaly , Finch Emilie , Gimma Amy , Rosello Alicia , Quilty Billy J. , Jafari Yalda , Knight Gwenan M. , Clifford Samuel , Russell Timothy W. , Lee Vernon J. , Kucharski Adam J.
Published: April 2022

The emergence of highly transmissible SARS-CoV-2 variants has created a need to reassess the risk posed by increasing social contacts as countries resume pre-pandemic activities, particularly in the context of resuming large-scale events over multiple days. To examine how social contacts formed in different activity settings influences interventions required to control Delta variant outbreaks, we collected high-resolution data on contacts among passengers and crew on cruise ships and combined the data with network transmission models. We found passengers had a median of 20 (IQR 10–36) unique close contacts per day, and over 60% of their contact episodes were made in dining or sports areas where mask wearing is typically limited. In simulated outbreaks, we found that vaccination coverage and rapid antigen tests had a larger effect than mask mandates alone, indicating the importance of combined interventions against Delta to reduce event risk in the vaccine era.
Therapeutic homology-independent targeted integration in retina and liver
Authors: Tornabene Patrizia , Ferla Rita , Llado-Santaeularia Manel , Centrulo Miriam , Dell’Anno Margherita , Esposito Federica , Marrocco Elena , Pone Emanuela , Minopoli Renato , Iodice Carolina , Nusco Edoardo , Rossi Settimio , Lyubenova Hristiana , Manfredi Anna , Di Filippo Lucio , Iuliano Antonella , Torella Annalaura , Piluso Giulio , Musacchia Francesco , Surace Enrico Maria , Cacchiarelli Davide , Nigro Vincenzo , Auricchio Alberto
Published: April 2022

Challenges to the widespread application of gene therapy with adeno-associated viral (AAV) vectors include dominant conditions due to gain-of-function mutations which require allele-specific knockout, as well as long-term transgene expression from proliferating tissues, which is hampered by AAV DNA episomal status. To overcome these challenges, we used CRISPR/Cas9-mediated homology-independent targeted integration (HITI) in retina and liver as paradigmatic target tissues. We show that AAV-HITI targets photoreceptors of both mouse and pig retina, and this results in significant improvements to retinal morphology and function in mice with autosomal dominant retinitis pigmentosa. In addition, we show that neonatal systemic AAV-HITI delivery achieves stable liver transgene expression and phenotypic improvement in a mouse model of a severe lysosomal storage disease. We also show that HITI applications predominantly result in on-target editing. These results lay the groundwork for the application of AAV-HITI for the treatment of diseases affecting various organs.
The crystal structure of iC3b-CR3 αI reveals a modular recognition of the main opsonin iC3b by the CR3 integrin receptor
Authors: Fernández Francisco J. , Santos-López Jorge , Martínez-Barricarte Rubén , Querol-García Javier , Martín-Merinero Héctor , Navas-Yuste Sergio , Savko Martin , Shepard William E. , Rodríguez de Córdoba Santiago , Vega M. Cristina
Published: April 2022

Complement activation on cell surfaces leads to the massive deposition of C3b, iC3b, and C3dg, the main complement opsonins. Recognition of iC3b by complement receptor type 3 (CR3) fosters pathogen opsonophagocytosis by macrophages and the stimulation of adaptive immunity by complement-opsonized antigens. Here, we present the crystallographic structure of the complex between human iC3b and the von Willebrand A inserted domain of the α chain of CR3 (αI). The crystal contains two composite interfaces for CR3 αI, encompassing distinct sets of contiguous macroglobulin (MG) domains on the C3c moiety, MG1-MG2 and MG6-MG7 domains. These composite binding sites define two iC3b-CR3 αI complexes characterized by specific rearrangements of the two semi-independent modules, C3c moiety and TED domain. Furthermore, we show the structure of iC3b in a physiologically-relevant extended conformation. Based on previously available data and novel insights reported herein, we propose an integrative model that reconciles conflicting facts about iC3b structure and function and explains the molecular basis for iC3b selective recognition by CR3 on opsonized surfaces.
SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes
Authors: Nikolov Vladislav N. , Malavia Dhara , Kubota Takashi
Published: April 2022

The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance. However, gene regulation of the PDR network is not well understood. Here, we show that the histone chaperone Rtt106 and the chromatin remodeller SWI/SNF control expression of the PDR network genes and confer drug resistance. In Saccharomyces cerevisiae, Rtt106 specifically localises to PDR network gene promoters dependent on transcription factor Pdr3, but not Pdr1, and is essential for Pdr3-mediated basal expression of the PDR network genes, while SWI/SNF is essential for both basal and drug-induced expression. Also in the pathogenic fungus Candida glabrata, Rtt106 and SWI/SNF regulate drug-induced PDR gene expression. Consistently, loss of Rtt106 or SWI/SNF sensitises drug-resistant S. cerevisiae mutants and C. glabrata to antifungal drugs. Since they cooperatively drive PDR network gene expression, Rtt106 and SWI/SNF represent potential therapeutic targets to combat antifungal resistance.
Anopheles mosquitoes reveal new principles of 3D genome organization in insects
Authors: Lukyanchikova Varvara , Nuriddinov Miroslav , Belokopytova Polina , Taskina Alena , Liang Jiangtao , Reijnders Maarten J. M. F. , Ruzzante Livio , Feron Romain , Waterhouse Robert M. , Wu Yang , Mao Chunhong , Tu Zhijian , Sharakhov Igor V. , Fishman Veniamin
Published: April 2022

Chromosomes are hierarchically folded within cell nuclei into territories, domains and subdomains, but the functional importance and evolutionary dynamics of these hierarchies are poorly defined. Here, we comprehensively profile genome organizations of five Anopheles mosquito species and show how different levels of chromatin architecture influence each other. Patterns observed on Hi-C maps are associated with known cytological structures, epigenetic profiles, and gene expression levels. Evolutionary analysis reveals conservation of chromatin architecture within synteny blocks for tens of millions of years and enrichment of synteny breakpoints in regions with increased genomic insulation. However, in-depth analysis shows a confounding effect of gene density on both insulation and distribution of synteny breakpoints, suggesting limited causal relationship between breakpoints and regions with increased genomic insulation. At the level of individual loci, we identify specific, extremely long-ranged looping interactions, conserved for ~100 million years. We demonstrate that the mechanisms underlying these looping contacts differ from previously described Polycomb-dependent interactions and clustering of active chromatin.
Deforestation-induced climate change reduces carbon storage in remaining tropical forests
Authors: Li Yue , Brando Paulo M. , Morton Douglas C. , Lawrence David M. , Yang Hui , Randerson James T.
Published: April 2022

Biophysical effects from deforestation have the potential to amplify carbon losses but are often neglected in carbon accounting systems. Here we use both Earth system model simulations and satellite–derived estimates of aboveground biomass to assess losses of vegetation carbon caused by the influence of tropical deforestation on regional climate across different continents. In the Amazon, warming and drying arising from deforestation result in an additional 5.1 ± 3.7% loss of aboveground biomass. Biophysical effects also amplify carbon losses in the Congo (3.8 ± 2.5%) but do not lead to significant additional carbon losses in tropical Asia due to its high levels of annual mean precipitation. These findings indicate that tropical forests may be undervalued in carbon accounting systems that neglect climate feedbacks from surface biophysical changes and that the positive carbon–climate feedback from deforestation-driven climate change is higher than the feedback originating from fossil fuel emissions.
Trade-off between tree planting and wetland conservation in China
Authors: Xi Yi , Peng Shushi , Liu Gang , Ducharne Agnès , Ciais Philippe , Prigent Catherine , Li Xinyu , Tang Xutao
Published: April 2022

Trade-offs between tree planting programs and wetland conservation are unclear. Here, we employ satellite-derived inundation data and a process-based land surface model (ORCHIDEE-Hillslope) to investigate the impacts of tree planting on wetland dynamics in China for 2000–2016 and the potential impacts of near-term tree planting activities for 2017–2035. We find that 160,000–190,000 km2(25.3–25.6%) of historical tree planting over wetland grid cells has resulted in 1,300–1,500 km2(0.3–0.4%) net wetland loss. Compared to moist southern regions, the dry northern and western regions show a much higher sensitivity of wetland reduction to tree planting. With most protected wetlands in China located in the drier northern and western basins, continuing tree planting scenarios are projected to lead to a > 10% wetland loss relative to 2000 across 4–8 out of 38 national wetland nature reserves. Our work shows how spatial optimization can help the balance of tree planting and wetland conservation targets.
Lossless multi-scale constitutive elastic relations with artificial intelligence
Authors: Mianroodi Jaber Rezaei , Rezaei Shahed , Siboni Nima H. , Xu Bai-Xiang , Raabe Dierk
Published: April 2022

A seamless and lossless transition of the constitutive description of the elastic response of materials between atomic and continuum scales has been so far elusive. Here we show how this problem can be overcome by using artificial intelligence (AI). A convolutional neural network (CNN) model is trained, by taking the structure image of a nanoporous material as input and the corresponding elasticity tensor, calculated from molecular statics (MS), as output. Trained with the atomistic data, the CNN model captures the size- and pore-dependency of the material’s elastic properties which, on the physics side, derive from its intrinsic stiffness as well as from surface relaxation and non-local effects. To demonstrate the accuracy and the efficiency of the trained CNN model, a finite element method (FEM)-based result of an elastically deformed nanoporous beam equipped with the CNN as constitutive law is compared with that obtained by a full atomistic simulation. The trained CNN model predicts the elasticity tensor in the test dataset with a root-mean-square error of 2.4 GPa (3.0% of the bulk modulus) when compared to atomistic calculations. On the other hand, the CNN model is about 230 times faster than the MS calculation and does not require changing simulation methods between different scales. The efficiency of the CNN evaluation together with the preservation of important atomistic effects makes the trained model an effective atomistically informed constitutive model for macroscopic simulations of nanoporous materials, optimization of nanostructures, and the solution of inverse problems.
A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia
Authors: Miyagawa Taku , Tanaka Susumu , Shimada Mihoko , Sakai Noriaki , Tanida Kotomi , Kotorii Nozomu , Kotorii Tatayu , Ariyoshi Yu , Hashizume Yuji , Ogi Kimihiro , Hiejima Hiroshi , Kanbayashi Takashi , Imanishi Aya , Ikegami Azusa , Kamei Yuichi , Hida Akiko , Wada Yamato , Miyamoto Masayuki , Takami Masanori , Kondo Hideaki , Tamura Yoshiyuki , Taniyama Yukari , Omata Naoto , Mizuno Tomoyuki , Moriya Shunpei , Furuya Hirokazu , Kato Mitsuhiro , Kato Kayoko , Ishigooka Jun , Tsuruta Kazuhito , Chiba Shigeru , Yamada Naoto , Okawa Masako , Hirata Koichi , Kuroda Kenji , Kume Kazuhiko , Uchimura Naohisa , Kitada Masaaki , Kodama Tohru , Inoue Yuichi , Nishino Seiji , Mishima Kazuo , Tokunaga Katsushi , Honda Makoto
Published: April 2022

Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10−8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.
The corrosion behavior of EW75 magnesium alloy in the research vessel KEXUE during the ocean voyage
Authors: Jiang Quantong , Lu Dongzhu , Cheng Liren , Liu Nazhen , Yang Lihui , Hou Baorong
Published: April 2022

The corrosion behavior of EW75 magnesium alloy in the Research Vessel KEXUE (RV KEXUE) during the ocean voyage was researched. The weight loss, corrosion depths, corrosion morphologies, and corrosion products were all analyzed. The mean weight loss rate of EW75 alloy Extrusion Surface was 0.0672 mg cm−2 y−1 (0.0903 mm y−1) after exposure corrosion tests, whereas that of Cross-section Surface was 0.0938 mg cm−2 y−1 (0.1537 mm y−1). Both extrusion direction and transverse direction of magnesium alloy samples occurred the brittle fracture in the harsh marine environment, and the mechanical strength fell precipitously after the exposure tests. The corrosion resistance of EW75 magnesium alloys obviously showed the anisotropy, which was due to the texture of the magnesium alloy in the microstructure. High salinity and high humidity environment led to a severe corrosion of EW75 magnesium alloys during exposure in the RV KEXUE during the ocean voyage. This study will provide the effective data for the service of magnesium alloys in typical marine atmospheric environment.
Progressive changes in descriptive discourse in First Episode Schizophrenia: a longitudinal computational semantics study
Authors: Alonso-Sánchez Maria Francisca , Ford Sabrina D. , MacKinley Michael , Silva Angélica , Limongi Roberto , Palaniyappan Lena
Published: April 2022

Computational semantics, a branch of computational linguistics, involves automated meaning analysis that relies on how words occur together in natural language. This offers a promising tool to study schizophrenia. At present, we do not know if these word-level choices in speech are sensitive to the illness stage (i.e., acute untreated vs. stable established state), track cognitive deficits in major domains (e.g., cognitive control, processing speed) or relate to established dimensions of formal thought disorder. In this study, we collected samples of descriptive discourse in patients experiencing an untreated first episode of schizophrenia and healthy control subjects (246 samples of 1-minute speech; n = 82, FES = 46, HC = 36) and used a co-occurrence based vector embedding of words to quantify semantic similarity in speech. We obtained six-month follow-up data in a subsample (99 speech samples, n = 33, FES = 20, HC = 13). At baseline, semantic similarity was evidently higher in patients compared to healthy individuals, especially when social functioning was impaired; but this was not related to the severity of clinically ascertained thought disorder in patients. Across the study sample, higher semantic similarity at baseline was related to poorer Stroop performance and processing speed. Over time, while semantic similarity was stable in healthy subjects, it increased in patients, especially when they had an increasing burden of negative symptoms. Disruptions in word-level choices made by patients with schizophrenia during short 1-min descriptions are sensitive to interindividual differences in cognitive and social functioning at first presentation and persist over the early course of the illness.
Determination of acrolein generation pathways from linoleic acid and linolenic acid: increment by photo irradiation
Authors: Kato Shunji , Shimizu Naoki , Otoki Yurika , Ito Junya , Sakaino Masayoshi , Sano Takashi , Takeuchi Shigeo , Imagi Jun , Nakagawa Kiyotaka
Published: April 2022

2-Propenal (acrolein) is a toxic aldehyde generated from the thermal degradation of edible oils. While previous studies have suggested that linolenic acid (LnA) is the origin of acrolein formation in edible oils, these studies were performed under thermal conditions where only the fatty acid hydroperoxide (FAOOH) isomers derived from radical oxidation were formed. In this study, we reinvestigated the acrolein generation pathway through another oxidation mechanism involving singlet oxygen (1O2) oxidation (type II photo-oxidation). Standards of the main FAOOH isomers (oleic acid hydroperoxide, linoleic acid hydroperoxide (HpODE), and linolenic acid hydroperoxide (HpOTE)) found in edible oils were prepared, and their decomposition products, including those derived from1O2 oxidation (i.e., 10- and 12-HpODE) were analyzed by GC-EI-MS. We found that 1O2 oxidation products of linoleic acid (LA) and LnA but not OA, are significant sources of acrolein formation. The amount of acrolein formed from edible oils high in LA (e.g., rice bran oil) increased by photo irradiation. Further investigation into the mechanism of acrolein generation demonstrated that the amount of acrolein derived from 1O2 oxidation-specific HpOTE isomers (i.e., 10- and 15-HpOTE) was two times greater than that of other HpOTE isomers (i.e., 9-, 12-, 13-, and 16-HpOTE). The results of the present study provide a new pathway of acrolein formation from type II photo-oxidation. This information can be used to inform on oil storage and processing conditions to reduce exposure and dietary intake of acrolein.
Recent developments in hazardous pollutants removal from wastewater and water reuse within a circular economy
Authors: Ahmed Menatalla , Mavukkandy Musthafa O. , Giwa Adewale , Elektorowicz Maria , Katsou Evina , Khelifi Olfa , Naddeo Vincenzo , Hasan Shadi W.
Published: April 2022

Recent advances in wastewater treatment processes have resulted in high removal efficiencies for various hazardous pollutants. Nevertheless, some technologies are more suitable for targeting specific contaminants than others. We comprehensively reviewed the recent advances in removing hazardous pollutants from industrial wastewater through membrane technologies, adsorption, Fenton-based processes, advanced oxidation processes (AOP), and hybrid systems such as electrically-enhanced membrane bioreactors (eMBRs), and integrated eMBR-adsorption system. Each technology’s key features are compared, and recent modifications to the conventional treatment approaches and limitations of advanced treatment systems are highlighted. The removal of emerging contaminants such as pharmaceuticals from wastewater is also discussed.
China’s provincial process CO2 emissions from cement production during 1993–2019
Authors: Liao Shiming , Wang Dong , Xia Changyou , Tang Jie
Published: April 2022

Carbon dioxide (CO2) emissions from China’s cement production process have increased rapidly in recent decades, comprising the second-largest source of CO2 emissions in the country, next only to fossil fuel combustion. However, there used to lack high-quality data to estimate provincial process-related CO2 emissions from the cement industry of China. It has been recognised that many previous publications have adopted cement-based accounting methods or national average emission factors to estimate them. This study assembles fundamental provincial clinker production data and provincial clinker emission factors from multiple official statistics sources, following the Intergovernmental Panel on Climate Change (IPCC) methodology (A clinker-based estimation methodology), to develop a high-quality panel dataset of China’s provincial process-related cement emissions during 1993–2019. In 2019, the gross cement process emissions of China amounted to 818.2 Mt CO2, and the cumulative emissions between 1993–2019 were estimated to be approximately 12.5 Gt CO2. There are significant differences in provincial process-related CO2 emissions. The dataset is crucial to provincial cement process emission characterisation and emissions reduction policy-making in China.
Developing a large-scale dataset of flood fatalities for territories in the Euro-Mediterranean region, FFEM-DB
Authors: Papagiannaki Katerina , Petrucci Olga , Diakakis Michalis , Kotroni Vassiliki , Aceto Luigi , Bianchi Cinzia , Brázdil Rudolf , Gelabert Miquel Grimalt , Inbar Moshe , Kahraman Abdullah , Kılıç Özgenur , Krahn Astrid , Kreibich Heidi , Llasat Maria Carmen , Llasat-Botija Montserrat , Macdonald Neil , de Brito Mariana Madruga , Mercuri Michele , Pereira Susana , Řehoř Jan , Geli Joan Rossello , Salvati Paola , Vinet Freddy , Zêzere José Luis
Published: April 2022

This data paper describes the multinational Database of Flood Fatalities from the Euro-Mediterranean region FFEM-DB that hosts data of 2,875 flood fatalities from 12 territories (nine of which represent entire countries) in Europe and the broader Mediterranean region from 1980 to 2020. The FFEM-DB database provides data on fatalities’ profiles, location, and contributing circumstances, allowing researchers and flood risk managers to explore demographic, behavioral, and situational factors, as well as environmental features of flood-related mortality. The standardized data collection and classification methodology enable comparison between regions beyond administrative boundaries. The FFEM-DB is expandable, regularly updated, publicly available, and with anonymized data. The key advantages of the FFEM-DB compared to existing datasets containing flood fatalities are its high level of detail, data accuracy, record completeness, and the large sample size from an extended area.
Unique evidence of fluid alteration in the Kakowa (L6) ordinary chondrite
Authors: Baziotis I. P. , Ma C. , Guan Y. , Ferrière L. , Xydous S. , Hu J. , Kipp M. A. , Tissot F. L. H. , Asimow P. D.
Published: April 2022

Meteorites preserve evidence of processes on their parent bodies, including alteration, metamorphism, and shock events. Here we show that the Kakowa (L6) ordinary chondrite (OC) preserves both shock-melt veins and pockets of detrital grains from a brecciated and altered object, including corundum, albite, silica, fayalite, forsterite, and margarite in a Pb- and Fe-rich matrix. Preservation of the observed mineralogy and texture requires a sequence of at least two impacts: first, a high-velocity collision formed the shock melt veins containing the high-pressure minerals ringwoodite, wadsleyite, majorite, and albitic jadeite; later, a low-velocity impact formed fractures and filled them with the detrital material. Oxygen and Pb isotope ratios suggest an OC origin for these detrital minerals. Although fluid alteration is common in carbonaceous chondrites, the discovery of margarite with an OC oxygen isotopic signature is novel. Kakowa extends both the impact and alteration history of L6 ordinary chondrites in general.
Longitudinal in-vivo quantification of tumour microvascular heterogeneity by optical coherence angiography in pre-clinical radiation therapy
Authors: Allam Nader , Jeffrey Zabel W. , Demidov Valentin , Jones Blake , Flueraru Costel , Taylor Edward , Alex Vitkin I.
Published: April 2022

Stereotactic body radiotherapy (SBRT) is an emerging cancer treatment due to its logistical and potential therapeutic benefits as compared to conventional radiotherapy. However, its mechanism of action is yet to be fully understood, likely involving the ablation of tumour microvasculature by higher doses per fraction used in SBRT. In this study, we hypothesized that longitudinal imaging and quantification of the vascular architecture may elucidate the relationship between the microvasculature and tumour response kinetics. Pancreatic human tumour xenografts were thus irradiated with single doses of $$10$$

10

, $$20$$

20

and $$30$$

30

 Gy to simulate the first fraction of a SBRT protocol. Tumour microvascular changes were monitored with optical coherence angiography for up to $$8$$

8

weeks following irradiation. The temporal kinetics of two microvascular architectural metrics were studied as a function of time and dose: the diffusion-limited fraction, representing poorly vascularized tissue $$>150$$

>
150

μm from the nearest detected vessel, and the vascular distribution convexity index, a measure of vessel aggregation at short distances. These biological metrics allowed for dose dependent temporal evaluation of tissue (re)vascularization and vessel aggregation after radiotherapy, showing promise for determining the SBRT dose–response relationship.
QSAR analysis on a large and diverse set of potent phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors using MLR and ANN methods
Authors: Sadeghi Fereydoun , Afkhami Abbas , Madrakian Tayyebeh , Ghavami Raouf
Published: April 2022

Phosphorylation of PI3Kγ as a member of lipid kinases-enzymes, plays a crucial role in regulating immune cells through the generation of intracellular signals. Deregulation of this pathway is involved in several tumors. In this research, diverse sets of potent and selective isoform-specific PI3Kγ inhibitors whose drug-likeness was confirmed based on Lipinski’s rule of five were used in the modeling process. Genetic algorithm (GA)-based multivariate analysis was employed on the half-maximal inhibitory concentration (IC50) of them. In this way, multiple linear regression (MLR) and artificial neural network (ANN) algorithm, were used to QSAR models construction on 245 compounds with a wide range of pIC50 (5.23–9.32). The stability and robustness of the models have been evaluated by external and internal validation methods (R2 0.623–0.642, RMSE 0.464–0.473, F 40.114, Q2LOO 0.600, and R2y-random 0.011). External verification using a wide variety of structures out of the training and test sets show that ANN is superior to MLR. The descriptors entered into the model are in good agreement with the X-ray structures of target-ligand complexes; so the model is interpretable. Finally, Williams plot-based analysis was applied to simultaneously compare the inhibitory activity and structural similarity of training, test and validation sets.
Organic residue analysis reveals the function of bronze age metal daggers
Authors: Caricola Isabella , Charles Alasdair , Tirillò Jacopo , Charlton Fraser , Barton Huw , Breglia Francesco , Rossi Alberto , Deflorian Maria Chiara , De Marinis Anna Maria , Harris Susanna , Pellegrini Alessio , Scacchetti Federico , Boccuccia Paolo , Miari Monica , Dolfini Andrea
Published: April 2022

The article discusses results of organic residue analysis performed on ten copper-alloy daggers from Bronze Age Pragatto, Italy, c.1550–1250 BCE. Metal daggers are widespread in Chalcolithic and Bronze Age Europe, yet their social and practical roles are still hotly debated. Are they symbolic or functional? Are they tools or weapons? How were they used? For what tasks and on what materials? The research addresses these questions through a novel application of biochemical staining and SEM–EDX analysis. The method has proved successful in extracting and identifying animal residues located on cutting edges including bone, muscle, and tendons. These are interpreted as evidence of prehistoric carcass butchering and carving. Further residues were observed on blade faces and hafting plates or tangs; these are interpreted as remnants of bone handles and sheaths, the latter made of either wood fibers or processed hide and fur. The readings proposed in the article are validated by original experiments with replica daggers, as detailed in the Supplementary Materials. The analysis and experiments shed new light on Bronze Age metal daggers, showing that they were fully functional tools (and perhaps tool-weapons) primarily utilized for the processing of animal carcasses. This original research result contributes significant knowledge towards interpreting an under-studied, yet socially salient, prehistoric metal artifact.
A weakly supervised deep learning-based method for glioma subtype classification using WSI and mpMRIs
Authors: Hsu Wei-Wen , Guo Jing-Ming , Pei Linmin , Chiang Ling-An , Li Yao-Feng , Hsiao Jui-Chien , Colen Rivka , Liu Peizhong
Published: April 2022

Accurate glioma subtype classification is critical for the treatment management of patients with brain tumors. Developing an automatically computer-aided algorithm for glioma subtype classification is challenging due to many factors. One of the difficulties is the label constraint. Specifically, each case is simply labeled the glioma subtype without precise annotations of lesion regions information. In this paper, we propose a novel hybrid fully convolutional neural network (CNN)-based method for glioma subtype classification using both whole slide imaging (WSI) and multiparametric magnetic resonance imagings (mpMRIs). It is comprised of two methods: a WSI-based method and a mpMRIs-based method. For the WSI-based method, we categorize the glioma subtype using a 2D CNN on WSIs. To overcome the label constraint issue, we extract the truly representative patches for the glioma subtype classification in a weakly supervised fashion. For the mpMRIs-based method, we develop a 3D CNN-based method by analyzing the mpMRIs. The mpMRIs-based method consists of brain tumor segmentation and classification. Finally, to enhance the robustness of the predictions, we fuse the WSI-based and mpMRIs-based results guided by a confidence index. The experimental results on the validation dataset in the competition of CPM-RadPath 2020 show the comprehensive judgments from both two modalities can achieve better performance than the ones by solely using WSI or mpMRIs. Furthermore, our result using the proposed method ranks the third place in the CPM-RadPath 2020 in the testing phase. The proposed method demonstrates a competitive performance, which is creditable to the success of weakly supervised approach and the strategy of label agreement from multi-modality data.
Quantitative phase velocimetry measures bulk intracellular transport of cell mass during the cell cycle
Authors: Pradeep Soorya , Zangle Thomas A.
Published: April 2022

Transport of mass within cells helps maintain homeostasis and is disrupted by disease and stress. Here, we develop quantitative phase velocimetry (QPV) as a label-free approach to make the invisible flow of mass within cells visible and quantifiable. We benchmark our approach against alternative image registration methods, a theoretical error model, and synthetic data. Our method tracks not just individual labeled particles or molecules, but the entire flow of bulk material through the cell. This enables us to measure diffusivity within distinct cell compartments using a single approach, which we use here for direct comparison of nuclear and cytoplasmic diffusivity. As a label-free method, QPV can be used for long-term tracking to capture dynamics through the cell cycle.
Non-destructive crystallinity assessment of indomethacin in tablets made from smartFilms® using terahertz time-domain spectroscopy
Authors: Ornik Jan , Heidrich Lara , Schesny Robert , Castro-Camus Enrique , Keck Cornelia M. , Koch Martin
Published: April 2022

We use terahertz (THz) time-domain spectroscopy (TDS) to assess the crystalline state of indomethacin (IM) when loaded in smartFilms®. We found that smartFilms favour the amorphous IM (A-IM) for low loading concentrations. For higher concentrations, IM recrystallizes in its $$\alpha$$
α
- crystalline form and the amount of A-IM in the smartFilms reduces. Both, $$\alpha$$
α
- and A-IM are preferred over the more common $$\gamma$$
γ
- crystalline form, as they exhibit better water solubility, which can increase the oral bioavailability of the drug.
Porosity induced by dislocation dynamics in quartz-rich shear bands of granitic rocks
Authors: Précigout Jacques , Ledoux Estelle , Arbaret Laurent , Spriet Charlotte
Published: April 2022

The production of micro-pores is a driving mechanism for fluids to interact with deep environment and influence rock properties. Yet, such a porosity still remains misunderstood to occur in viscous rocks and may be attributed to either grain boundary sliding (GBS), dissolution effects or sub-grain rotation. Here we focus on quartz-rich shear bands across the Naxos western granite (Aegean Sea, Greece), where we document sub-micron pores at quartz boundaries. While most of these pores are observed along grain boundaries, some of them occur at intra-grain boundaries, which excludes dissolution or GBS to produce them, but instead involves the dynamic of dislocations. We then confirm that quartz is dominated by dislocation creep with evidence of a moderate to strong lattice-preferred orientation (LPO) and numerous tilt/twist boundaries, including at the pluton margin where rocks embrittled. These features coincide with (1) randomly oriented ‘inclusion’ quartz grains along tilt/twist boundaries and (2) a partial dependency of the LPO strength on grain size. Our findings suggest that pores arise from coalescing dislocations at boundaries of rotating sub-grains, providing nucleation sites for new grains to be precipitated during plastic flow. Fluid infiltration, rock embrittlement and related implications are also expected through pores accumulation with increasing strain.
3D visualization of microwave electric and magnetic fields by using a metasurface-based indicator
Authors: Baghdasaryan Zhirayr , Babajanyan Arsen , Parsamyan Henrik , Friedman Barry , Kim Seungwan , Lee Jung-Ha , Lee Kiejin
Published: April 2022

Visualizations of the microwave electric and magnetic near-field distributions of radio-frequency (RF) filters were performed using the technique of thermoelastic optical indicator microscopy (TEOIM). New optical indicators based on periodic dielectric-metal structures were designed for electric field visualization. Depending on the structure orientation, such metasurface-based indicators allow separately visualization of the Ex and Ey components of the in-plane electric field. Numerical simulations were conducted to examine the working principle of the designed indicator structures, and the results were compared to the experimental, showing good agreement. In addition, the 3D visualization of the microwave near-field distribution was built, to show the field intensity and distribution dependencies on the distance from the RF filter.
Crossed Andreev reflection in zigzag phosphorene nanoribbon based ferromagnet/superconductor/ferromagnet junctions
Authors: Li Ruigang , Chen Lei , Liu Jun-Feng , Wang Jun
Published: April 2022

We study the crossed Andreev reflection in zigzag phosphorene nanoribbon based ferromagnet/superconductor/ferromagnet junction. Only edge states, which are entirely detached from the bulk gap, involved in the transport processes. The perfect crossed Andreev reflection, with the maximal nonlocal conductance $$-2e^{2}/h$$

-
2

e
2

/
h

, is addressed by setting the electric potentials of the leads and device properly. At this situation, the local Andreev reflection and the electron tunneling are completely eliminated, the incoming electrons can only be reflected as electrons or transmitted as holes, corresponding to the electron reflection and the crossed Andreev reflection respectively.The nonlocal conductance oscillates periodically with the length and the electric potential of the superconductor. Our study shows that the phosphorene based junction can be used as the quantum device to generate entangled-electrons.
A comprehensive strategy for exploring corrosion in iron-based artefacts through advanced Multiscale X-ray Microscopy
Authors: Bernabale Martina , Cognigni Flavio , Nigro Lorenzo , Rossi Marco , de Caro Tilde , De Vito Caterina
Published: April 2022

The best strategy to tackle complexity when analyzing corrosion in iron artefacts is to combine different analytical methods. Traditional techniques provide effective means to identify the chemistry and mineralogy of corrosion products. Nevertheless, a further step is necessary to upgrade the understanding of the corrosion evolution in three dimensions. In this regard, Multiscale X-ray Microscopy (XRM) enables multi-length scale visualization of the whole object and provides the spatial distribution of corrosion phases. Herein, we propose an integrated workflow to explore corrosion mechanisms in an iron-nail from Motya (Italy) through destructive and non-destructive techniques, which permit the extraction of the maximum information with the minimum sampling. The results reveal the internal structure of the artefact and the structural discontinuities which lead the corrosion, highlighting the compositional differences between the tip and the head of the iron nail.
Barrier effect and wound healing activity of the medical device REF-FTP78 in the treatment of gastroesophageal reflux disease
Authors: Pecora Tiziana M. G. , Parisi Ortensia Ilaria , Bertin Walter , Ragazzo Barbara , Dattilo Marco , Scigliano Norma , Malivindi Rocco , Amone Fabio , Puoci Francesco
Published: April 2022

REF-FTP78 is a class IIb medical device present on the market with different trade names and developed for the treatment of gastroesophageal reflux disease (GERD). This medical device is based on polysaccharides from Aloe Barbadensis and fucoidans from brown seaweeds, such as Undaria pinnatifida and Fucus vesiculosus, and aims to exert a protective effect on the esophageal mucosa against the noxious components of refluxate. The present study reports on the efficacy of REF-FTP78 devoting a particular attention to the barrier effect and wound healing properties, combined with antioxidant and anti-inflammatory activities. Film-forming properties and barrier effect were investigated on in vitro reconstructed human esophageal epithelium, through TEER measurement and evaluation of caffeine and Lucifer yellow permeability, and in an ex vivo swine model of esophageal mucosa damage. Antioxidant and anti-inflammatory properties were evaluated in terms of scavenging activity towards DPPH, ABTS and NO radicals and a wound healing assay was carried out to study the influence of the product on cell migration. The obtained results highlighted a significant barrier effect, with a reduction in caffeine penetration equal to 65.3%, the ability to both repair and prevent the damage caused by an acid insult, confirmed by a good transepithelial resistance for the tissue treated with the tested item, and the capacity to promote wound healing. Furthermore, the tested product showed good antioxidant and anti-inflammatory properties in the performed radical scavenging assays. These findings support the use of REF-FTP78 in the treatment of GERD.
A high-generalizability machine learning framework for predicting the progression of Alzheimer’s disease using limited data
Authors: Wang Caihua , Li Yuanzhong , Tsuboshita Yukihiro , Sakurai Takuya , Goto Tsubasa , Yamaguchi Hiroyuki , Yamashita Yuichi , Sekiguchi Atsushi , Tachimori Hisateru ,   for the Alzheimer’s Disease Neuroimaging Initiative, Wang Caihua , Li Yuanzhong , Goto Tsubasa
Published: April 2022

Alzheimer’s disease is a neurodegenerative disease that imposes a substantial financial burden on society. A number of machine learning studies have been conducted to predict the speed of its progression, which varies widely among different individuals, for recruiting fast progressors in future clinical trials. However, because the data in this field are very limited, two problems have yet to be solved: the first is that models built on limited data tend to induce overfitting and have low generalizability, and the second is that no cross-cohort evaluations have been done. Here, to suppress the overfitting caused by limited data, we propose a hybrid machine learning framework consisting of multiple convolutional neural networks that automatically extract image features from the point of view of brain segments, which are relevant to cognitive decline according to clinical findings, and a linear support vector classifier that uses extracted image features together with non-image information to make robust final predictions. The experimental results indicate that our model achieves superior performance (accuracy: 0.88, area under the curve [AUC]: 0.95) compared with other state-of-the-art methods. Moreover, our framework demonstrates high generalizability as a result of evaluations using a completely different cohort dataset (accuracy: 0.84, AUC: 0.91) collected from a different population than that used for training.
Machine learning for medical imaging: methodological failures and recommendations for the future
Authors: Varoquaux Gaël , Cheplygina Veronika
Published: April 2022

Research in computer analysis of medical images bears many promises to improve patients’ health. However, a number of systematic challenges are slowing down the progress of the field, from limitations of the data, such as biases, to research incentives, such as optimizing for publication. In this paper we review roadblocks to developing and assessing methods. Building our analysis on evidence from the literature and data challenges, we show that at every step, potential biases can creep in. On a positive note, we also discuss on-going efforts to counteract these problems. Finally we provide recommendations on how to further address these problems in the future.