bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted therapy for capillary-venous malformations
Authors: Zerbib Lola , Ladraa Sophia , Fraissenon Antoine , Bayard Charles , Firpion Marina , Venot Quitterie , Protic Sanela , Hoguin Clément , Thomas Amandine , Fraitag Sylvie , Duong Jean-Paul , Kaltenbach Sophie , Balducci Estelle , Lefevre Coline , Villarese Patrick , Asnafi Vahid , Broissand Christine , Goudin Nicolas , Nemazanyy Ivan , Autret Gwennhael , Tavitian Bertrand , Legendre Christophe , Arzouk Nadia , Minard-Colin Veronique , Chopinet Caroline , Dussiot Michael , Adams Denise M. , Mirault Tristan , Guibaud Laurent , Isenring Paul , Canaud Guillaume 
Published: June 2024

AbstractSporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations’ occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.
DNA of neutrophil extracellular traps promote NF-κB-dependent autoimmunity via cGAS/TLR9 in chronic obstructive pulmonary disease
Authors: Chen Jun , Wang Tao , Li Xiaoou , Gao Lijuan , Wang Ke , Cheng Mengxin , Zeng Zijian , Chen Lei , Shen Yongchun , Wen Fuqiang 
Published: June 2024

AbstractChronic obstructive pulmonary disease (COPD) is characterised by persistent airway inflammation even after cigarette smoking cessation. Neutrophil extracellular traps (NETs) have been implicated in COPD severity and acute airway inflammation induced by short-term cigarette smoke (CS). However, whether and how NETs contribute to sustained airway inflammation in COPD remain unclear. This study aimed to elucidate the immunoregulatory mechanism of NETs in COPD, employing human neutrophils, airway epithelial cells (AECs), dendritic cells (DCs), and a long-term CS-induced COPD mouse model, alongside cyclic guanosine monophosphate-adenosine monophosphate synthase and toll-like receptor 9 knockout mice (cGAS-−/−, TLR9−/−); Additionally, bronchoalveolar lavage fluid (BALF) of COPD patients was examined. Neutrophils from COPD patients released greater cigarette smoke extract (CSE)-induced NETs (CSE-NETs) due to mitochondrial respiratory chain dysfunction. These CSE-NETs, containing oxidatively-damaged DNA (NETs-DNA), promoted AECs proliferation, nuclear factor kappa B (NF-κB) activation, NF-κB-dependent cytokines and type-I interferons production, and DC maturation, which were ameliorated/reversed by silencing/inhibition of cGAS/TLR9. In the COPD mouse model, blocking NETs-DNA-sensing via cGAS−/− and TLR9−/− mice, inhibiting NETosis using mitoTEMPO, and degrading NETs-DNA with DNase-I, respectively, reduced NETs infiltrations, airway inflammation, NF-κB activation and NF-κB-dependent cytokines, but not type-I interferons due to IFN-α/β receptor degradation. Elevated NETs components (myeloperoxidase and neutrophil elastase activity) in BALF of COPD smokers correlated with disease severity and NF-κB-dependent cytokine levels, but not type-I interferon levels. In conclusion, NETs-DNA promotes NF-κB-dependent autoimmunity via cGAS/TLR9 in long-term CS exposure-induced COPD. Therefore, targeting NETs-DNA and cGAS/TLR9 emerges as a potential strategy to alleviate persistent airway inflammation in COPD.
Randomised, double-blind, placebo-controlled, parallel-group, multicentric, phase IIA clinical trial for evaluating the safety, tolerability, and therapeutic efficacy of daily oral administration of NFX88 to treat neuropathic pain in individuals with spinal cord injury
Authors: Escribá Pablo V. , Gil-Agudo Ángel M. , Vidal Samsó Joan , Sánchez-Raya Judith , Salvador-de la Barrera Sebastián , Soto-León Vanesa , León-Álvarez Natacha , Méndez Ferrer Bosco , Membrilla-Mesa Miguel David , Redondo Galán Carolina , Benito-Penalva Jesús , Montoto-Marqués Antonio , Medel Rebollo Javier , Palazón García Ramiro , Gutiérrez Henares Francisco , Miralles Marc , Torres Manuel , Nieto-Librero Ana B. , García Marco David , Gómez Carmela , Jimeno David , Oliviero Antonio 
Published: June 2024

Abstract
Study design
Double-blind, randomized, placebo-controlled, parallel-group multicentric phase IIA clinical trial.

Objective
To assess the safety and tolerability of oral administration of NFX-88 in subjects with chronic spinal cord injury (SCI) and explore its efficacy in pain control.

Setting
A total of 7 spinal cord injury rehabilitation units in Spain.

Methods
A total of 61 adult with traumatic complete or incomplete spinal cord injury (C4-T12 level), were randomised 1:1:1:1 to a placebo, NFX88 1.05 g, 2.1 g, 4.2 g/day for up to 12 weeks. The placebo or NFX-88 was administered as add-on therapy to pre-existing pregabalin (150–300 mg per day). Safety and tolerability were evaluated, and the Visual Analogue Scale (VAS) was the primary measure to explore the efficacy of NFX-88 in pain control.

Results
No severe treatment-related adverse effects were reported for any of the four study groups. 44 SCI individuals completed the study and were analysed. The data obtained from the VAS analysis and the PainDETECT Questionnaire (PD-Q) suggested that the combination of NFX88 with pregabalin is more effective than pregabalin with placebo at reducing neuropathic pain (NP) in individuals with SCI and that the dose 2.10 g/day causes the most dramatic pain relief.

Conclusions
NFX88 treatment was found to be highly safe and well tolerated, with the dose of 2.10 g/day being the most effective at causing pain relief. Thus, the promising efficacy of this first-in-class lipid mediator deserves further consideration in future clinical trials.
Temporal turnover of viral biodiversity and functional potential in intertidal wetlands
Authors: Ji Mengzhi , Li Yan , Zhou Jiayin , Song Wen , Zhou Yuqi , Ma Kai , Wang Mengqi , Liu Xia , Li Yueyue , Gong Xiaofan , Tu Qichao 
Published: June 2024

AbstractAs the central members of the microbiome networks, viruses regulate the composition of microbial communities and drive the nutrient cycles of ecosystems by lysing host cells. Therefore, uncovering the dynamic patterns and the underlying ecological mechanisms mediating the tiniest viral communities across space and through time in natural ecosystems is of crucial importance for better understanding the complex microbial world. Here, the temporal dynamics of intertidal viral communities were investigated via a time-series sampling effort. A total of 1911 viral operational taxonomic units were recovered from 36 bimonthly collected shotgun metagenomes. Functionally important auxiliary metabolic genes involved in carbohydrate, sulfur, and phosphorus metabolism were detected, some of which (e.g., cysH gene) were stably present within viral genomes over time. Over the sampling period, strong and comparable temporal turnovers were observed for intertidal viromes and their host microbes. Winter was determined as the pivotal point for the shifts in viral diversity patterns. Notably, the viral micro-diversity covaried with the macro-diversity, following similar temporal patterns. The relative abundances of viral taxa also covaried with their host prokaryotes. Meanwhile, the virus–host relationships at the whole community level were relatively stable. Further statistical analyses demonstrated that the dynamic patterns of viral communities were highly deterministic, for which temperature was the major driver. This study provided valuable mechanistic insights into the temporal turnover of viral communities in complex ecosystems such as intertidal wetlands.
A novel approach to identify critical knowledge gaps for food safety in circular food systems
Authors: van Leeuwen Stefan P. J. , Verschoor A. M. , van der Fels-Klerx H. J. , van de Schans M. G. M. , Berendsen B. J. A. 
Published: June 2024

AbstractThe transition from linear production towards a circular agro-food system is an important step towards increasing Europe’s sustainability. This requires re-designing the food production systems, which inevitably comes with challenges as regards controlling the safety of our food, animals and the ecosystem. Where in current food production systems many food safety hazards are understood and well-managed, it is anticipated that with the transition towards circular food production systems, known hazards may re-emerge and new hazards will appear or accumulate, leading to new -and less understood- food safety risks. In this perspective paper, we present a simple, yet effective approach, to identify knowledge gaps with regard to food safety in the transition to a circular food system. An approach with five questions is proposed, derived from current food safety management approaches like HACCP. Applying this to two cases shows that risk assessment and management should emphasize more on the exposure to unexpected (with regards to its nature and its origin) hazards, as hazards might circulate and accumulate in the food production system. Five knowledge gaps became apparent: there’s a need for (1) risk assessment and management to focus more on unknown hazards and mixtures of hazards, (2) more data on the occurrence of hazards in by-products, (3) better understanding the fate of hazards in the circular food production system, (4) the development of models to adequately perform risk assessments for a broad range of hazards and (5) new ways of valorization of co-products in which a safe-by-design approach should be adopted.
Framework for evaluation of food safety in the circular food system
Authors: van der Fels-Klerx H. J. , van Asselt E. D. , Berendsen B. , Focker M. F. 
Published: June 2024

AbstractIn order to minimise food waste, side streams from feed and food production are increasingly being (re-) used in food supply chains. Such reuse contributes to the desire to implement circularity in food and agricultural systems. However, the reuse of side products in circular food systems may impact food safety, for instance, contaminant residues present at low levels in biomass may accumulate when reusing streams. In order to assess potential food safety issues related to circular food systems, a framework has been developed in this study. Based on this framework, appropriate actions can be taken to prevent from human health risks. The framework consists of three steps: 1. Describing the changes in the food supply chain as a result of the circularity transition; 2. Identifying potential food safety hazards related to the change; and 3. Prioritising food safety hazards related to the circularity transition. For the prioritisation, both the presence of the hazards in final foods and the effects of the hazards on human health need to be assessed. Persistence of the hazard in the environment and potential transfer from the environment to the final food product are relevant elements to include. The framework was tested in three case studies, showing that it allows for a prioritisation between hazards. Based on the case study results, circularity not so much influences the health effects of the hazards, but rather their presence depending on the persistence and transfer of food safety hazards in a circular system.
Detecting hallucinations in large language models using semantic entropy
Authors: Farquhar Sebastian , Kossen Jannik , Kuhn Lorenz , Gal Yarin 
Published: June 2024

AbstractLarge language model (LLM) systems, such as ChatGPT1or Gemini2, can show impressive reasoning and question-answering capabilities but often ‘hallucinate’ false outputs and unsubstantiated answers3,4. Answering unreliably or without the necessary information prevents adoption in diverse fields, with problems including fabrication of legal precedents5or untrue facts in news articles6and even posing a risk to human life in medical domains such as radiology7. Encouraging truthfulness through supervision or reinforcement has been only partially successful8. Researchers need a general method for detecting hallucinations in LLMs that works even with new and unseen questions to which humans might not know the answer. Here we develop new methods grounded in statistics, proposing entropy-based uncertainty estimators for LLMs to detect a subset of hallucinations—confabulations—which are arbitrary and incorrect generations. Our method addresses the fact that one idea can be expressed in many ways by computing uncertainty at the level of meaning rather than specific sequences of words. Our method works across datasets and tasks without a priori knowledge of the task, requires no task-specific data and robustly generalizes to new tasks not seen before. By detecting when a prompt is likely to produce a confabulation, our method helps users understand when they must take extra care with LLMs and opens up new possibilities for using LLMs that are otherwise prevented by their unreliability.
Control of proton transport and hydrogenation in double-gated graphene
Authors: Tong J. , Fu Y. , Domaretskiy D. , Della Pia F. , Dagar P. , Powell L. , Bahamon D. , Huang S. , Xin B. , Costa Filho R. N. , Vega L. F. , Grigorieva I. V. , Peeters F. M. , Michaelides A. , Lozada-Hidalgo M. 
Published: June 2024

AbstractThe basal plane of graphene can function as a selective barrier that is permeable to protons1,2 but impermeable to all ions3,4 and gases5,6, stimulating its use in applications such as membranes1,2,7,8, catalysis9,10 and isotope separation11,12. Protons can chemically adsorb on graphene and hydrogenate it13,14, inducing a conductor–insulator transition that has been explored intensively in graphene electronic devices13–17. However, both processes face energy barriers1,12,18 and various strategies have been proposed to accelerate proton transport, for example by introducing vacancies4,7,8, incorporating catalytic metals1,19 or chemically functionalizing the lattice18,20. But these techniques can compromise other properties, such as ion selectivity21,22 or mechanical stability23. Here we show that independent control of the electric field, E, at around 1 V nm−1, and charge-carrier density, n, at around 1 × 1014 cm−2, in double-gated graphene allows the decoupling of proton transport from lattice hydrogenation and can thereby accelerate proton transport such that it approaches the limiting electrolyte current for our devices. Proton transport and hydrogenation can be driven selectively with precision and robustness, enabling proton-based logic and memory graphene devices that have on–off ratios spanning orders of magnitude. Our results show that field effects can accelerate and decouple electrochemical processes in double-gated 2D crystals and demonstrate the possibility of mapping such processes as a function of E and n, which is a new technique for the study of 2D electrode–electrolyte interfaces.
The mechanism for directional hearing in fish
Authors: Veith Johannes , Chaigne Thomas , Svanidze Ana , Dressler Lena Elisa , Hoffmann Maximilian , Gerhardt Ben , Judkewitz Benjamin 
Published: June 2024

AbstractLocating sound sources such as prey or predators is critical for survival in many vertebrates. Terrestrial vertebrates locate sources by measuring the time delay and intensity difference of sound pressure at each ear1–5. Underwater, however, the physics of sound makes interaural cues very small, suggesting that directional hearing in fish should be nearly impossible6. Yet, directional hearing has been confirmed behaviourally, although the mechanisms have remained unknown for decades. Several hypotheses have been proposed to explain this remarkable ability, including the possibility that fish evolved an extreme sensitivity to minute interaural differences or that fish might compare sound pressure with particle motion signals7,8. However, experimental challenges have long hindered a definitive explanation. Here we empirically test these models in the transparent teleost Danionella cerebrum, one of the smallest vertebrates9,10. By selectively controlling pressure and particle motion, we dissect the sensory algorithm underlying directional acoustic startles. We find that both cues are indispensable for this behaviour and that their relative phase controls its direction. Using micro-computed tomography and optical vibrometry, we further show that D. cerebrum has the sensory structures to implement this mechanism. D. cerebrum shares these structures with more than 15% of living vertebrate species, suggesting a widespread mechanism for inferring sound direction.
dsRNA formation leads to preferential nuclear export and gene expression
Authors: Coban Ivo , Lamping Jan-Philipp , Hirsch Anna Greta , Wasilewski Sarah , Shomroni Orr , Giesbrecht Oliver , Salinas Gabriela , Krebber Heike 
Published: June 2024

AbstractWhen mRNAs have been transcribed and processed in the nucleus, they are exported to the cytoplasm for translation. This export is mediated by the export receptor heterodimer Mex67–Mtr2 in the yeast Saccharomyces cerevisiae (TAP–p15 in humans)1,2. Interestingly, many long non-coding RNAs (lncRNAs) also leave the nucleus but it is currently unclear why they move to the cytoplasm3. Here we show that antisense RNAs (asRNAs) accelerate mRNA export by annealing with their sense counterparts through the helicase Dbp2. These double-stranded RNAs (dsRNAs) dominate export compared with single-stranded RNAs (ssRNAs) because they have a higher capacity and affinity for the export receptor Mex67. In this way, asRNAs boost gene expression, which is beneficial for cells. This is particularly important when the expression program changes. Consequently, the degradation of dsRNA, or the prevention of its formation, is toxic for cells. This mechanism illuminates the general cellular occurrence of asRNAs and explains their nuclear export.
Strain tracking in complex microbiomes using synteny analysis reveals per-species modes of evolution
Authors: Enav Hagay , Paz Inbal , Ley Ruth E. 
Published: June 2024

AbstractMicrobial species diversify into strains through single-nucleotide mutations and structural changes, such as recombination, insertions and deletions. Most strain-comparison methods quantify differences in single-nucleotide polymorphisms (SNPs) and are insensitive to structural changes. However, recombination is an important driver of phenotypic diversification in many species, including human pathogens. We introduce SynTracker, a tool that compares microbial strains using genome synteny—the order of sequence blocks in homologous genomic regions—in pairs of metagenomic assemblies or genomes. Genome synteny is a rich source of genomic information untapped by current strain-comparison tools. SynTracker has low sensitivity to SNPs, has no database requirement and is robust to sequencing errors. It outperforms existing tools when tracking strains in metagenomic data and is particularly suited for phages, plasmids and other low-data contexts. Applied to single-species datasets and human gut metagenomes, SynTracker, combined with an SNP-based tool, detects strains enriched in either point mutations or structural changes, providing insights into microbial evolution in situ.
Predicting histological grade in pediatric glioma using multiparametric radiomics and conventional MRI features
Authors: Zhou Tengfei , Qiao Baobao , Peng Bo , Liu Yuqi , Gong Zhenjia , Kang Mengfei , He Yu , Pang Chunying , Dai Yakang , Sheng Mao 
Published: June 2024

AbstractPrediction of glioma is crucial to provide a precise treatment plan to optimize the prognosis of children with glioma. However, studies on the grading of pediatric gliomas using radiomics are limited. Meanwhile, existing methods are mainly based on only radiomics features, ignoring intuitive information about tumor morphology on traditional imaging features. This study aims to utilize multiparametric magnetic resonance imaging (MRI) to identify high-grade and low-grade gliomas in children and establish a classification model based on radiomics features and clinical features. A total of 85 children with gliomas underwent tumor resection, and part of the tumor tissue was examined pathologically. Patients were categorized into high-grade and low-grade groups according to World Health Organization guidelines. Preoperative multiparametric MRI data, including contrast-enhanced T1-weighted imaging, T2-weighted imaging, T2-weighted fluid-attenuated inversion recovery, diffusion-weighted images, and apparent diffusion coefficient sequences, were obtained and labeled by two radiologists. The images were preprocessed, and radiomics features were extracted for each MRI sequence. Feature selection methods were used to select radiomics features, and statistically significant clinical features were identified using t-tests. The selected radiomics features and conventional MRI features were used to train the AutoGluon models. The improved model, based on radiomics features and conventional MRI features, achieved a balanced classification accuracy of 66.59%. The cross-validated areas under the receiver operating characteristic curve for the classifier of AutoGluon frame were 0.8071 on the test dataset. The results indicate that the performance of AutoGluon models can be improved by incorporating conventional MRI features, highlighting the importance of the experience of radiologists in accurately grading pediatric gliomas. This method can help predict the grade of pediatric glioma before pathological examination and assist in determining the appropriate treatment plan, including radiotherapy, chemotherapy, drugs, and gene surgery.