bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of antibiotic resistance development ofE. coliin synthetic and real wastewater
Authors: Sutradhar Indorica , Gross Neila , Ching Carly , Nahum Yanina , Desai Darash , Bowes Devin A. , Zaman Muhammad H. 
Published: October 2024

AbstractAntimicrobial resistance (AMR) is a major threat to global health and resistant bacterial populations have been observed to develop and spread in and around wastewater. However,in vitrostudies on AMR development are typically conducted in ideal media conditions which can differ in composition and nutrient density from wastewater. In this study, we compare the growth and AMR development ofE. coliin standard LB broth to a synthetic wastewater recipe and autoclaved wastewater samples from the Massachusetts Water Resources Authority (MWRA). We found that synthetic wastewater and real wastewater samples both supported less bacterial growth compared to LB. Additionally, bacteria grown in synthetic wastewater and real wastewater samples had differing susceptibility to antibiotic pressure from Doxycycline, Ciprofloxacin, and Streptomycin. However, AMR development over time during continuous passaging under subinhibitory antibiotic pressure was similar in fold change across all media types. Thus, we find that while LB can act as a proxy for wastewater for AMR studies inE. coli, synthetic wastewater is a more accurate predictor of bothE.coligrowth and antibiotic resistance development. Moreover, we also show that antibiotic resistance can develop in real wastewater samples and components within wastewater likely have synergistic and antagonistic interactions with antibiotics.ImportanceAntimicrobial resistance (AMR) ranks among the leading global threats to public health and development. In 2019, bacterial AMR was estimated to have directly caused 1.27 million deaths worldwide and contributed to 4.95 million deaths overall (Murray, C. J., et al., (2022). Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis.The Lancet, 399(10325), 629–655.). With estimations of AMR only getting worse, it is imperative that we understand the complex dimensionalities that drive the genesis of antimicrobial resistance to where it begins–the environment. The paper investigates bacterial growth and AMR in real wastewater samples and highlights the importance of using a media that closely mimics real wastewater in AMR studies, compared to standard lab media like LB broth. This is crucial for understanding howE. coliand other bacteria develop AMR in environments similar to actual wastewater, which can inform more effective strategies to combat AMR in natural and engineered settings.
Statistical analysis of repertoire data demonstrates the influence of microhomology in V(D)J recombination
Authors: Russell Magdalena L , Trofimov Assya , Bradley Philip , Matsen Frederick A 
Published: October 2024

AbstractV(D)J recombination generates the diverse B and T cell receptors essential for recognizing a wide array of antigens. This diversity arises from the combinatorial assembly of V(D)J genes and the junctional deletion and insertion of nucleotides. While previousin vitrostudies have shown that microhomology—–short stretches of sequence homology between gene ends—–can bias the recombination process, the extent of microhomology’s impactin vivo, particularly in humans, remains unknown. In this paper, we assess how germline-encoded microhomology influences trimming and ligation during V(D)J recombination using statistical inference on previously-published high-throughput TCRαrepertoire sequencing data. We find that microhomology increases both trimming and ligation probabilities, making it an important predictor of recombination outcomes. These effects are consistent across different receptor loci and sequence types. Further, we demonstrate that accounting for microhomology effects significantly alters sequence annotation probabilities and rankings, highlighting its practical importance for accurately inferring the V(D)J recombination events that generated an observed sequence. Together, these results enhance our understanding of how microhomologous nucleotides shape the human V(D)J recombination process.Significance StatementHumans rely on diverse adaptive immune receptor repertoires to effectively defend against infections. The receptor generation process, known as V(D)J recombination, is designed to create this diversity by stochastically joining V(D)J gene segments and modifying their junctions through nucleotide deletions and insertions. Previous studies, conducted in vitro, have suggested that short stretches of homologous nucleotides between gene segments can bias these recombination steps. In this study, we explore the extent to which these homologous nucleotides influence V(D)J recombination in humans using statistical inference on large-scale receptor repertoire sequencing data. Our findings reveal that microhomology significantly biases several recombination steps, with important practical implications for the analysis, processing, and interpretation of receptor sequences.
Impact of mutations in theHEADING DATE 1gene on transcription and cell wall composition of rice
Authors: Biancucci Marco , Chirivì Daniele , Baldini Alessio , Badenhorst Eugene , Dobetti Fabio , Khahani Bahman , Formentin Elide , Eguen Tenai , Turck Franziska , Moore John P. , Tavakol Elahe , Wenkel Stephan , Schiavo Fiorella Lo , Ezquer Ignacio , Brambilla Vittoria , Horner David , Chiara Matteo , Perrella Giorgio , Betti Camilla , Fornara Fabio 
Published: October 2024

AbstractPlants utilize environmental information to modify their developmental trajectories for optimal survival and reproduction. Over a century ago, day length (photoperiod) was identified as a major factor influencing developmental transitions, particularly the shift from vegetative to reproductive growth. In rice, exposure to day lengths shorter than a critical threshold accelerates flowering, while longer days inhibit this process. This response is mediated by HEADING DATE 1 (Hd1), a zinc finger transcription factor that is central in the photoperiodic flowering network. Hd1 acts as a repressor of flowering under long days but functions as a promoter of flowering under short days. However, the transcriptional organization of this dual function is still not fully understood. In this study, we utilized RNA-Seq to analyze the transcriptome ofhd1mutants under both long and short day conditions. We identified genes involved in the phenylpropanoid pathway that are deregulated under long days in the mutant. Quantitative profiling of cell wall components and abiotic stress assays suggest that Hd1 is involved in processes considered unrelated to flowering control. This indicates that day length perception and responses are intertwined with physiological processes beyond flowering.
Jasmonic acid signaling and glutathione coordinate plant recovery from high light stress
Authors: Kılıç Mehmet , Gollan Peter J. , Aro Eva-Mari , Rintamäki Eevi 
Published: October 2024

AbstractHigh light-induced chloroplast retrograde signaling originates from the photosynthetic apparatus and regulates nuclear gene expression to enhance photoprotection and coordination of cell metabolism. Here, we analyzed the transcript profiles and accumulation of ROS, stress hormones and small molecule antioxidants to investigate the signaling mechanisms operating under HL stress, and in particular during plant recovery under growth conditions. Exposure to high light for 15 min induced a number of1O2- and H2O2-responsive genes and accumulation of an oxidative form of glutathione and ascorbate, the hallmarks of oxidative stress in cells. Prolonged exposure to high light resulted in accumulation of transcripts encoding oxylipin biosynthesis enzymes, leading to accumulation of 12-oxo-phytodienoic acid and jasmonic acid. However, the expression of several jasmonic acid -responsive genes, already induced by HL, peaked during the recovery together with accumulation of jasmonic acid, reduced glutathione and ascorbate, highlighting the critical role of jasmonic acid signaling in restoring chloroplast redox balance following high light stress. The involvement of jasmonic acid signaling in recovery-sustained gene expression was further confirmed by conducting experiments with jasmonic acid receptor mutants. High light exposure of only two min was sufficient to induce some recovery-sustained genes, indicating rapid response of plants to changing light conditions. We propose that ROS production at high light induces the signaling cascade for early oxylipin biosynthesis and 12-oxo-phytodienoic acid accumulation, while increased accumulation of jasmonic acid in recovery-phase activates the genes that fully restore the glutathione metabolism, and ultimately allow recovery from short-term high light stress.
The combination of optogenetic-induced protein aggregation and proximity biotinylation assays strongly implicates endolysosomal proteins in the early stages of α-synuclein aggregation
Authors: Teixeira Maxime , Sheta Razan , Musiol Dylan , Ranjakasoa Vetso , Loehr Jérémy , Lambert Jean-Phillippe , Oueslati Abid 
Published: October 2024

SummaryAlpha-synuclein (α-syn) aggregation is a defining feature of Parkinson’s disease (PD) and related synucleinopathies. Despite significant research efforts focused on understanding α-syn aggregation mechanisms, the early stages of this process remain elusive, largely due to limitations in experimental tools that lack the temporal resolution to capture these dynamic events. Here, we introduce UltraID-LIPA, an innovative platform that combines the Light-Inducible Protein Aggregation (LIPA) system with the UltraID proximity-dependent biotinylation assay to identify α-syn-interacting proteins and uncover key mechanisms driving its oligomerization. UltraID-LIPA successfully identified 38 α-syn-interacting proteins, including both established and novel candidates, highlighting the accuracy and robustness of the approach. Notably, a strong interaction with endolysosomal and membrane-associated proteins was observed, supporting the hypothesis that interactions with membrane-bound organelles are pivotal in the early stages of α-syn aggregation. This powerful platform provides new insights into dynamic protein aggregation events, enhancing our understanding of synucleinopathies and other proteinopathies.
Federated deep learning enables cancer subtyping by proteomics
Authors: Cai Zhaoxiang , Boys Emma L , Noor Zainab , Aref Adel , Xavier Dylan , Lucas Natasha , Williams Steven G , Koh Jennifer M S , Poulos Rebecca C , Wu Yangxiu , Dausmann Michael , MacKenzie Karen L , Aguilar-Mahecha Adriana , Armengol Carolina , Barranco Maria M , Basik Mark , Bowman Elise D , Clifton-Bligh Roderick J , Connolly Elizabeth A , Cooper Wendy A , Dalal Bhavik , DeFazio Anna , Filipits Martin , Flynn Peter J , Graham J Dinny , George Jacob , Gill Anthony J , Gnant Michael , Habib Rosemary , Harris Curtis C , Harvey Kate , Horvath Lisa G , Jackson Christopher , Kohonen-Corish Maija R J , Lim Elgene , Liu Jia , Long Georgina , Lord Reginald V , Mann Graham J , McCaughan Geoffrey W , Morgan Lucy , Murphy Leigh C , Nagabushan Sumanth , Nagrial Adnan M , Navinés Jordi , Panizza Benedict J , Samra Jaswinder S , Scolyer Richard A , Souglakos Ioannis , Swarbrick Alexander , Thomas David M , Balleine Rosemary L , Hains Peter G , Robinson Phillip J , Zhong Qing , Reddel Roger R 
Published: October 2024

AbstractArtificial intelligence applications in biomedicine face major challenges from data privacy requirements. To address this issue for clinically annotated tissue proteomic data, we developed a Federated Deep Learning (FDL) approach (ProCanFDL), training local models on simulated sites containing data from a pan-cancer cohort (n=1,260) and 29 cohorts held behind private firewalls (n=6,265), representing 19,930 replicate data-independent acquisition mass spectrometry (DIA-MS) runs. Local parameter updates were aggregated to build the global model, achieving a 43% performance gain on the hold-out test set (n=625) in 14 cancer subtyping tasks compared to local models, and matching centralized model performance. The approach’s generalizability was demonstrated by retraining the global model with data from two external DIA-MS cohorts (n=55) and eight acquired by tandem mass tag (TMT) proteomics (n=832). ProCanFDL presents a solution for internationally collaborative machine learning initiatives using proteomic data, e.g., for discovering predictive biomarkers or treatment targets, while maintaining data privacy.Statement of SignificanceA federated deep learning approach applied to human proteomic data, acquired using two distinct proteomic technologies from 40 tumor cohorts from eight countries, enabled accurate cancer histopathological subtyping while preserving data privacy. This approach will enable privacy-compliant development of large-scale proteomic AI models, including foundation models, across institutions globally.
Noninvasive optical monitoring of cerebral hemodynamics in a preclinical model of neonatal intraventricular hemorrhage
Authors: Jethe Jyoti V. , Shen YuBing Y. , LaGamma Edmund F. , Vinukonda Govindaiah , Fisher Jonathan A. N. 
Published: October 2024

AbstractIntraventricular hemorrhage (IVH) is a common complication in premature infants and is associated with white matter injury and long-term neurodevelopmental disabilities. Standard diagnostic tools such as cranial ultrasound and MRI are widely used in both preclinical drug development and clinical practice to detect IVH. However, these methods only provide endpoint assessments of blood accumulation and lack real-time information about dynamic changes in ventricular blood flow. This limitation could potentially result in missed opportunities to advance drug candidates that may have protective effects against IVH. In this pilot study, we aimed to develop a noninvasive optical approach using diffuse correlation spectroscopy (DCS) to monitor real-time hemodynamic changes associated with hemorrhagic and sub-hemorrhagic events in a preclinical rabbit model of IVH. DCS measurements were conducted during the experimental induction of IVH, and results were compared with ultrasound and histological analysis to validate findings. Significant changes in hemodynamics were detected in all animals subjected to IVH-inducing procedures, including those that did not show clear positive results on ultrasound. The study revealed progressively elevated coefficients of variation in blood flow, particularly driven by increased oscillations within the 0.05-0.1 Hz frequency band. These hemodynamic changes were more pronounced in animals that developed IVH, as confirmed by ultrasound. Our findings suggest that real-time optical monitoring with DCS can provide critical insights into pathological blood flow changes, offering a more sensitive and informative tool for evaluating potential therapeutics in the context of IVH.
Virological characteristics of the SARS-CoV-2 XEC variant
Authors: Kaku Yu , Okumura Kaho , Kawakubo Shusuke , Uriu Keiya , Chen Luo , Kosugi Yusuke , Uwamino Yoshifumi , Begum MST Monira , Leong Sharee , Ikeda Terumasa , Sadamasu Kenji , Asakura Hiroyuki , Nagashima Mami , Yoshimura Kazuhisa ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ito Jumpei , Sato Kei 
Published: October 2024

AbstractThe SARS-CoV-2 JN.1 variant (BA.2.86.1.1), arising from BA.2.86.1 with spike protein (S) substitution S:L455S, outcompeted the previously predominant XBB lineages by the beginning of 2024. Subsequently, JN.1 subvariants including KP.2 (JN.1.11.1.2) and KP.3 (JN.1.11.1.3), which acquired additional S substitutions (e.g., S:R346T, S:F456L, and S:Q493E), have emerged concurrently. As of October 2024, KP.3.1.1 (JN.1.11.1.3.1.1), which acquired S:31del, outcompeted other JN.1 subvariants including KP.2 and KP.3 and is the most predominant SARS-CoV-2 variant in the world. Thereafter, XEC, a recombinant lineage of KS.1.1 (JN.13.1.1.1) and KP.3.3 (JN.1.11.1.3.3), was first identified in Germany on August 7, 2024. XEC acquired two S substitutions, S:T22N and S:F59S, compared with KP.3 through recombination, with a breakpoint at genomic position 21,738–22,599. We estimated the relative effective reproduction number (Re) of XEC using a Bayesian multinomial logistic model based on genome surveillance data from the USA, the United Kingdom, France, Canada, and Germany, where this variant has spread as of August 2024. In the USA, the Re of XEC is 1.13-fold higher than that of KP.3.1.1. Additionally, the other countries under investigation herein showed higher Re for XEC. These results suggest that XEC has the potential to outcompete the other major lineage including KP.3.1.1. We then assessed the virological properties of XEC using pseudoviruses. Pseudovirus infection assay showed that the infectivity of KP.3.1.1 and XEC was significantly higher than that of KP.3. Although S:T22N did not affect the infectivity of the pseudovirus based on KP.3, S:F59S significantly increased it. Neutralization assay was performed using three types of human sera: convalescent sera after breakthrough infection (BTI) with XBB.1.5 or KP.3.3, and convalescent sera after JN.1 infection. In all serum groups, XEC as well as KP.3.1.1 showed immune resistance when compared to KP.3 with statistically significant differences. In the cases of XBB.1.5 BTI sera and JN.1 infection sera, the 50% neutralization titers (NT50s) of XEC and KP.3.1.1 were comparable. However, we revealed that the NT50 of XEC was significantly (1.3-fold) lower than that of KP.3.1.1. Moreover, both S:T22N and S:F59S significantly (1.5-fold and 1.6-fold) increased the resistance to KP.3.3 BTI sera. Here we showed that XEC exhibited higher pseudovirus infectivity and higher immune evasion than KP.3. Particularly, XEC exhibited more robust immune resistance to KP.3.3 BTI sera than KP.3.1.1. Our data suggest that the higher Re of XEC than KP.3.1.1 is attributed to this property and XEC will be a predominant SARS-CoV-2 variant in the world in the near future.
Embryological cellular origins and hypoxia-mediated mechanisms inPIK3CA-Driven refractory vascular malformations
Authors: Torii Sota , Nagaharu Keiki , Nakanishi Nanako , Usui Hidehito , Hori Yumiko , Hirose Katsutoshi , Toyosawa Satoru , Morii Eiichi , Narushima Mitsunaga , Kubota Yoshiaki , Nakagawa Osamu , Imanaka-Yoshida Kyoko , Maruyama Kazuaki 
Published: October 2024

AbstractCongenital vascular malformations, affecting 0.5% of the population, often occur in the head and neck, complicating treatment due to the critical functions in these regions. Our previous research identified distinct developmental origins for blood and lymphatic vessels in these areas, tracing them to the cardiopharyngeal mesoderm (CPM), which contributes to the development of the head, neck, and cardiovascular system in both mouse and human embryos.In this study, we investigated the pathogenesis of these malformations by expressing Pik3caH1047Rin the CPM. Mice expressing Pik3caH1047Rin the CPM developed vascular abnormalities restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3caH1047RupregulatesVegf-aexpression in endothelial cells through HIF-mediated hypoxia signaling. Human samples supported these findings, showing elevated HIF-1α and VEGF-A in malformed vessels. Notably, inhibition of HIF-1α and VEGF-A in the mouse model significantly reduced abnormal vasculature. These results highlight the role of embryonic origins and hypoxia-driven mechanisms in vascular malformations, providing a foundation for the development of therapies targeting these difficult-to-treat conditions.
Statins for Primary Prevention of Cardiovascular Disease in Germany: Benefits and Costs
Authors: Dressel Alexander , Fath Felix , Krämer Bernhard K. , Klose Gerald , März Winfried 
Published: October 2024

AbstractBackgroundThe reduction of LDL cholesterol lowers the risk of coronary and cerebrovascular events in individuals without manifest cardiovascular diseases. In Germany, statins may only be prescribed at the expense of statutory health insurance for patients with atherosclerosis-related diseases or those at high cardiovascular risk (over 20 percent event probability within the next 10 years, calculated using one of the “available risk calculators”). However, international guidelines recommend lower risk thresholds for the use of statins.MethodsThe health and economic impacts of different risk thresholds for statin use in primary prevention within the German population are estimated for thresholds of 7.5, 10, and 15 percent over 10 years, based on the USPooled Cohort Equation(PCE) which has been validated for Germany, using Markov models.FindingsCost-effectiveness increases with a rising risk threshold, while individual benefit decreases with age at the start of treatment. The use of statins at a risk of 7.5 percent or more is cost-effective at any age (cost per QALY between 410 and 2,100 euros). In none of the examined scenarios does the proportion of the population qualifying for statin therapy exceed 25 percent.InterpretationLowering the threshold for statin therapy based on age to a risk of 7.5 percent, estimated with the US PCE, aligns statin prescription with international standards. There is no urgent rationale for applying age-stratified risk thresholds using the SCORE2 proposed for Europe, which tends to underestimate actual risks.
Identification of undetected SARS-CoV-2 infections by clustering of Nucleocapsid antibody trajectories
Authors: Zwerwer Leslie R. , Peto Tim E. A. , Pouwels Koen B. , Walker Ann Sarah ,   the COVID-19 Infection Survey team
Published: October 2024

AbstractDuring the COVID-19 pandemic, numerous SARS-CoV-2 infections remained undetected. Serological testing could potentially aid their identification. We combined results from routine monthly nose and throat swabs, and self-reported positive swab tests, from a UK household survey, linked to national swab testing programme data from England and Wales, together with Nucleocapsid (N-) antibody trajectories clustered using a longitudinal variation of K-means to estimate the number of infections undetected by either approach (N=185,646). After combining N-antibody (hypothetical) infections with swab-positivity, we estimated that 7.4% of all true infections would have remained undetected, 25.8% by swab-positivity-only and 28.6% by trajectory-based N-antibody classifications only. Congruence with swab-positivity was much poorer using a fixed threshold to define N-antibody infections. Additionally, using multivariable logistic regression N-antibody seroconversion was more likely as age increased between 30 and 60 years, in non-white participants, those less (recently/frequently) vaccinated, for lower Ct values in the range above 30, in symptomatic and Delta (vs BA.1) infections. Comparing swab-positivity data sources showed that routine monthly swabs were not sufficient to detect infections by swab-positivity only and incorporating national testing programme/self-reported data substantially increased detection rates. Overall, whilst N-antibody serosurveillance can identify infections undetected by swab-positivity, optimal use requires trajectory-based analysis.