bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of potential mechanisms of non-carbapenemase mediated carbapenem resistance inAcinetobacter baumannii
Authors: Höfken Lisa-Marie , Gatermann Sören G. , Pfennigwerth Niels 
Published: January 2025

AbstractObjectivesAcinetobacter baumanniiis a Gram-negative nosocomial pathogen that plays an important role in the context of bacterial multidrug-resistance. Increasing resistance to carbapenems in particular is of high therapeutic relevance, as in this case only a few antibiotics remain for treatment. The mechanisms of carbapenem resistance inA. baumanniiare mainly based upon carbapenemases and the mechanisms such as porin loss, efflux pumps and altered PBPs have been poorly studied to date.MethodsTheA. baumanniireference strain ATCC 17978 was artificially mutated by selection pressure with increasing meropenem concentrations until carbapenem resistance was achieved. Growth analyses were carried out with the mutants and MICs for relevant antibiotics were determined. In addition, the mutants were whole genome sequenced, and the sequences were compared with the wild type. As various mutagenesis attempts for targeted construction of these respective mutants were unfortunately not successful, the strain collection of the NRC was screened for isolates that showed carbapenem resistance without a detectable carbapenemase. These isolates were sequenced and analysed for abnormalities in PBPs and porins in comparison to the sequence of the reference strain ATCC 17978 and were compared to other strains that possessed a carbapenemase.ResultsIn three of the resulting ATCC 17978 mutants, a mutation of PBP2 was observed (W366L). Theses mutants were carbapenem resistant and were not affected by avibactam in contrast to the wild type ATCC 17978. Growth experiments indicated a fitness loss compared to the wild type.As W366L was not found in the clinical isolates, we looked for other abnormalities in various genes associated with carbapenem resistance. Mutations were primarily found in the PBPs, with a mutation in PBP3 (A515V) occurring particularly often.ConclusionThe results of this work support the prevailing thesis that PBP mutations inA. baumanniican lead to carbapenem resistance. Since there are hardly any studies on this hypothesis and for the most part only using outdated methods, these results are of particular relevance and further studies on this topic are recommended.
A common neuronal basis for Pavlovian and instrumental learning in amygdala circuits
Authors: Riffault Coline , Bitterman Yael , Müller Sigrid , Lüthi Andreas , Courtin Julien 
Published: January 2025

SUMMARYReward-predictive Pavlovian cues can selectively invigorate instrumental behaviors. Accumulating evidence pinpoints the basolateral amygdala (BLA) as a key brain structure to assign outcome-specific motivational significance to Pavlovian cues or Instrumental actions. However, whether neuronal representations of Pavlovian and Instrumental learnings are processed in different BLA circuits and how the resulting memories interact is unknown. Here, we used calcium imaging and optogenetic manipulation of the BLA neurons in mice that acquired and expressed Pavlovian and Instrumental behaviors in a multi-phase behavioral task called specific Pavlovian to Instrumental Transfer (sPIT). We first confirmed that Pavlovian cues selectively invigorate instrumental actions and showed that this effect, referred as the sPIT effect, depends on BLA activity. Then, by tracking the activity of single BLA neurons across days, we found that BLA neurons integrate common reward-anticipation information relevant for Pavlovian and instrumental learning. Interestingly, this reward-anticipation information re-emerged during subsequent memory transfer and covaried with sPIT effect. These findings reveal that the BLA encodes an outcome-specific motivational state that generalizes across Pavlovian and instrumental behaviors to promote and guide reward-seeking behavior.
Chloroform release from ageing cells andDrosophilaDJ-1 mutants
Authors: Issitt Theo , Johnston Timothy , Ugbode Chris , Grumulaityte Juste , Harmens Amy , Brackenbury William J , Sweeney Sean T , Redeker Kelly R 
Published: January 2025

AbstractVolatile Organic Compounds (VOCs) offer potential for non-invasive diagnosis as biomarkers of disease and metabolism. In complex biological matrices, such as breath however, identifying useful biomarkers from hundreds, or even thousands of VOCs can be challenging. Models of disease, such as cellular or animal models, offer a means to elucidate VOC metabolisms, for accurate targeted studies in patient samples. Neurodegenerative conditions, such as parkinsons have been associated with changed VOCs, offering a potential for early diagnostics and interventions improving treatments and outcomes for patients. Here, three separate models including; human HEK-293t cells, isolated primary rat glial cells,Drosophilaflies (wild type and a mutant of the parkinson’s associated gene, DJ-1) were grown for an extended period and levels of the VOC chloroform (CHCl3) investigated using custom static headspace sampling chambers. Samples were analysed using targeted gas chromatography mass spectroscopy over time to generate metabolic flux values and chloroform shown to dramatically increase in all models as they aged. HEK-293t cells revealed a 60-fold increase after 10 weeks, glial cells revealed a 10-fold increase after 3 to 4 weeks and DJ-1 mutant flies revealed significant increases compared to control flies at 4 weeks. These results, taken together, indicate that chloroform release is related to ageing in these models and may provide a target for neurodegenerative studies moving forward. We present here the first evidence of chloroform being actively produced by human and rat cells and the first observation of volatile metabolisms inDrosophila.
Two Transport Routes for Fetuin-A-based Mineral Complexes in Osteogenic Matrix Mineralization
Authors: Schaart Judith M. , Rutten Luco , To Shaina V. , Shah Alisha A. , Martens Martijn , Macías-Sánchez Elena , Jahnen-Dechent Willi , Sommerdijk Nico , Akiva Anat 
Published: January 2025

AbstractFetuin-A is an abundant serum glycoprotein that prevents ectopic calcification. It has a high binding capacity for calcium phosphate and forms calciprotein monomers (CPM) and particles (CPP) upon binding. While it is also an abundant non-collagenous protein in bone, it’s role in bone matrix mineralization remains unclear. Using DLS and liquid-phase TEM, we identified a two-phase assembly process of primary CPPs, in which small and transient particles (tCPPs) are formed initially, after which larger, stable CPPs form. Using cell-free and osteoblast-based mineralization experiments, we found that CPMs and tCPPs can directly mineralize collagen fibrils, while CPPs are only a suitable mineral source after endocytosis and processing by matrix-producing osteoblasts. This indicates the existence of two potential transport routes for Fetuin-A/mineral complexes during bone matrix formation.
Deciphering Brain Organoids Heterogeneity by Identifying Key Quality Determinants
Authors: Kachkin Daniil , Zagha Naime , Boerstler Tom , Furlanetto Federica , Nayebzade Negar , Zappia Luke , Boisvert Michelle , Farrell Michaela , Ploetz Sonja , Regensburger Martin , Günther Claudia , Winkler Juergen , Gupta Pooja , Theis Fabian , Karow Marisa , Falk Sven , Winner Beate , Krach Florian 
Published: January 2025

AbstractBrain organoids derived from human pluripotent stem cells (hPSCs) hold immense potential for modeling neurodevelopmental processes and disorders. However, their experimental variability and undefined organoid selection criteria for analysis hinder reproducibility. As part of the Bavarian ForInter consortium, we generated 72 brain organoids from distinct hPSC lines. We conducted a comprehensive analysis of their morphological and cellular characteristics at an early stage of their development. In our assessment, the Feret diameter emerged as a reliable, single parameter that characterizes brain organoid quality. Transcriptomic analysis further confirmed the reliability of this marker and identified a negative impact of mesenchymal cells on the abundance of organoid formation. High-quality organoids consistently displayed a lower mesenchymal cell presence. These findings offer a framework for enhancing brain organoid standardization and reproducibility, underscoring the need for morphological quality controls and the consideration of mesenchymal cell influence on organoid-based modeling.Graphical Abstract
Combinatorial phosphorylation on CTD of RNA polymerase II selectively controls transcription and export of protein-coding mRNAs
Authors: Panina Svetlana B. , Irani Seema , Hardtke Haley A. , Stephenson Renee , Floyd Brendan M. , Moreno Rosamaria Y. , Marcotte Edward M. , Zhang Qian , Zhang Y. Jessie 
Published: January 2025

ABSTRACTC-terminal domain (CTD) of RNA polymerase II is crucial for recruiting transcription regulators via specific post-translational modifications (PTM), especially phosphorylation. The hypothesis of combination of PTMs, or ‘CTD code’, that can allow precise and dynamic recruitment of transcription machinery is highly attractive, yet the experimental evidence to support this hypothesis has been scarce. Here, despite lacking specific antibodies for combinatorial CTD phosphorylation, we developed an innovative approach that detects double phosphorylation patterns on the CTD in a whole-genomic fashion by leveraging the antibody masking effect with selectively removing the flanking interference. Using this method, we detected pT4pS5 double phosphosites occurring exclusively during the transcription of protein-coding genes. Furthermore, we showed that pT4pS5 marks recruit the Transcription and Export complex (TREX), which specifically facilitates mRNA processing and nucleocytoplasmic export of protein-coding mRNAs. The recruitment of TREX by pT4pS5 phosphosites is particularly important for the processing of lengthy neurogenesis-related genes. Our results provide experimental support for the notion that CTD coding system can function combinatorially and in a gene-specific manner, which encodes an exact information about the transcription of specific gene clusters. This method can be broadly applied to map all combinatorial PTM patterns on RNA polymerase II, paving the way for a deeper understanding of gene-specific transcription regulation at the molecular level.
Functional characterization of eicosanoid signaling inDrosophiladevelopment
Authors: Fujinaga Daiki , Nolan Cebrina , Yamanaka Naoki 
Published: January 2025

Abstract20-carbon fatty acid-derived eicosanoids are versatile signaling oxylipins in mammals. In particular, a group of eicosanoids termed prostanoids are involved in multiple physiological processes, such as reproduction and immune responses. Although some eicosanoids such as prostaglandin E2 (PGE2) have been detected in some insect species, molecular mechanisms of eicosanoid synthesis and signal transduction in insects have been poorly investigated. Our phylogenetic analysis indicated that, in clear contrast to the presence of numerous receptors for oxylipins and other lipid mediators in humans, theDrosophilagenome only possesses a single ortholog of such receptors, which is homologous to human prostanoid receptors. This G protein-coupled receptor, named Prostaglandin Receptor or PGR, is activated by PGE2 and its isomer PGD2 inDrosophilaS2 cells.PGRmutant flies die as pharate adults with insufficient tracheal development, which can be rescued by supplying high oxygen. Consistent with this, through a comprehensive mutagenesis approach, we identified aDrosophilaPGE synthase whose mutants show similar pharate adult lethality with hypoxia responses.Drosophilathus has a highly simplified eicosanoid signaling pathway as compared to humans, and it may provide an ideal model system for investigating evolutionarily conserved aspects of eicosanoid signaling.Author SummaryThere are numerous bioactive lipids that control animal physiology, and some of them are commonly observed in both humans and insects. Well-studied insects such as fruit flies can therefore be an excellent gateway to learn about lipid molecules that have common functions in various animal species. In this study, we analyzed the fruit fly genome to look for genes that encode sensors (or receptors) for such lipid molecules called lipid mediators and found that the fruit fly only has one such receptor, as compared to ∼50 receptors in humans. Interestingly, the fly receptor we found was similar to human receptors for lipid molecules called prostanoids. Our work on the fruit fly prostanoid receptor further revealed that it is important for development of the fly respiratory system, and we showed that flies can also synthesize prostanoids in their body just like humans. Prostanoids are clinically important due to their pro-inflammatory functions, and some widely used drugs such as ibuprofen target enzymes that synthesize prostanoids. Our study on fruit fly prostanoids therefore provides a solid basis for using this simple organism to reveal common prostanoid functions in animals, which may provide important insights into animal health in general.
In vitro reconstitution defines the mechanistic basis of HSET motor activity regulation by IntraFlagellar Transport proteins
Authors: Guesdon Audrey , Simon Valérie , Van Dijk Juliette , Delaval Bénédicte , Vitre Benjamin 
Published: January 2025

AbstractHSET is a mitotic kinesin essential for centrosome clustering in cells harboring supernumerary centrosomes. Workin cellulorevealed that IntraFlagellar Transport proteins (IFT) interact with the kinesin HSET to promote efficient extra centrosome clustering and subsequent cancer cell proliferation. However, whether and how IFT proteins regulate HSET activity is unknown. Using a reconstitutedin vitrosystem combining purified HSET and IFT proteins coupled to TIRF microscopy approaches, we identified a minimal subcomplex made of IFT52/IFT70 directly binding to HSET. We demonstrate that this binding induces HSET oligomerization allowing its activation and the formation of processive HSET complexes. We also show that HSET activation by IFT proteins accounts for an increased ability to slide microtubules and to organize dynamic microtubule networksin vitro. Overall, this work shows that IFT proteins can directly activate a mitotic kinesin and provides mechanistic explanation for the contribution of IFT proteins to efficient centrosome clustering.
Frontoparietal activity related to neuropsychological assessment of working memory
Authors: Jurva August , Singh Balbir , Qian Helen , Wang Zhengyang , Jacobs Monica L. , Dhima Kaltra , Englot Dario J. , Roberson Shawniqua Williams , Bick Sarah K. , Constantinidis Christos 
Published: January 2025

ABSTRACTExecutive functions, including working memory, are typically assessed clinically with neuropsychological instruments. In contrast, computerized tasks are used to test these cognitive functions in laboratory human and animal studies. Little is known of how neural activity captured by laboratory tasks relates to ability measured by clinical instruments and, by extension, clinical diagnoses of pathological conditions. We therefore sought to determine what aspects of neural activity elicited in laboratory tasks are predictive of performance in neuropsychological instruments. We recorded neural activity from intracranial electrodes implanted in human epilepsy patients as they performed laboratory working memory tasks. These patients had completed neuropsychological instruments preoperatively, including the Weschler Adult Intelligent Scale and the Wisconsin Card Sorting test. Our results revealed that increased high-gamma (70-150 Hz) power in the prefrontal and parietal cortex after presentation of visual stimuli to be remembered was indicative of lower performance in the neuropsychological tasks. On the other hand, we observed a positive correlation between high-frequency power amplitude in the delay period of the laboratory tasks and neuropsychological performance. Our results demonstrate how neural activity around task events relates to executive function and may be associated with clinical diagnosis of specific cognitive deficits.
Unveiling the Evolution of Antimicrobial Peptides in Gut Microbes via Foundation Model-Powered Framework
Authors: Li Wenhui , Huang Baicheng , Guo Menghao , Zeng Zihan , Cai Tao , Feng Linqing , Zhang Xinpeng , Guo Ling , Jiang Xianyue , Yin Yanbin , Wang Ercheng , Huang Xingxu , Zheng Jinfang 
Published: January 2025

AbstractAntimicrobial resistance poses a growing threat to public health, emphasizing the urgent need for novel therapeutic strategies. Antimicrobial peptides (AMPs), short peptide sequences with diverse mechanisms of action, offer a promising alternative due to their broad-spectrum activity against pathogens. Recent advances in protein language models (PLMs) have revolutionized protein structure prediction and functional annotation, highlighting their potential for AMP discovery and therapeutic development. In this context, we present AMP-SEMiner (Antimicrobial Peptide Structural Evolution Miner), an AI-driven framework designed to identify AMPs from metagenome-assembled genomes (MAGs). By integrating PLMs, structural clustering and evolutionary analysis into the framework, AMP-SEMiner can identify AMPs encoded by small open reading frames (smORFs) and encrypted peptides (EPs), significantly expanding the discovery space. Using this approach, we identified 1,670,600 AMP candidates from diverse habitats. Experimental validation of 29 candidates revealed antimicrobial activity in 18, with 13 surpassing antibiotics in effectiveness. Further analysis of AMPs from human gut microbiomes demonstrated both conserved and adaptive evolutionary strategies, ensuring their functional efficacy in the dynamic gut environment. These findings position AMP-SEMiner as a powerful tool for the discovery and characterization of novel AMPs, with significant potential to drive the development of new antimicrobial therapies.
Genomic insights into six clinical isolates ofStenotrophomonas maltophiliafrom Northern India
Authors: Gheewalla Nazneen , Jadhav Yuvraj , Jagannadham Jaisri , Tyagi Akansha , Budhiraja Sandeep , Tarai Bansidhar , Karve Shraddha 
Published: January 2025

AbstractStenotrophomonas maltophiliais a gram-negative opportunistic pathogen that causes respiratory, urinary and bloodstream infections. Due to rising prevalence of difficult to treatS. maltophiliainfections, it is considered as one of the important pathogens in many regions, including India. Despite its importance in public health, very few studies provide detailed characterization of the genomes of clinical isolates ofS. maltophilia. In this study, we sequence six isolates ofS. maltophiliafrom a tertiary healthcare centre in the Northern India. Along with the culture sensitivity, we report the genomic underpinnings of resistance and virulence in these isolates. In three out of six isolates, we identify a rare beta-lactamase genekbl-1that can confer resistance to variety of beta-lactam antibiotics. Though truncated in two isolates, an intact copy ofkbl-1is present in the third isolate. This intact copy ofkbl-1is flanked by insertion elements that are commonly found in several pathogenic species indicating high potential for horizontal gene transfer. To the best of our knowledge, this is a first report ofkbl-1inS. maltophiliafrom India.ImportanceAntimicrobial resistance (AMR) is one of the biggest global public health challenges. Tackling AMR gets complicated as diverse pathogenic species are involved and resistance is manifested against several different kinds of antibiotics. Genomic surveillance of the resistant pathogens is a key to fight this global threat and needs to extend to important emerging pathogens as well. Here we report genomic sequences and associated characteristics of sixStenotrophomonas maltophiliaisolates from Northern India. Along with several resistance and virulence genes we also discover a rare beta-lactamase,blaKBL-1, gene with a high potential of transfer to other species.blaKBL-1beta-lactamase confers resistance to several beta-lactam antibiotics like ampicillin, amoxicillin, penicillin G, piperacillin, ceftazidime and cefozopran. This is the first report of the presences of this beta-lactamase from India.
Prenatal and early childhood exposure to antibiotics or gastric acid inhibitors and increased risk of epilepsy: A nationwide population-based study
Authors: Gudnadottir Unnur , Wickström Ronny , Gunnerbeck Anna , Prast-Nielsen Stefanie , Brusselaers Nele 
Published: January 2025

AbstractOver 10 million children in the world have epilepsy, with unknown root cause in approximately half of cases. The gut microbiome has been associated with various neurological disorders, and certain drugs greatly disturb the microbiome. Our aim was to study the association of prenatal and childhood exposure (before the age of two) of antibiotics, proton pump inhibitors and histamine-2 receptor antagonists, and the risk of childhood epilepsy. Using population-based registers, we included all live singleton births in Sweden from 2006-2017. Exposure was considered prescription(s) to antibiotics, proton pump inhibitors or H2-receptor antagonists (separately) during pregnancy or the first two years of life.Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals.In total 708,903 mother-child dyads were included, and 0.5% of children were diagnosed with epilepsy. Average follow-up time was 3.8 years (IQR 1-6). Prenatal exposure to antibiotics (aHR 1.09, 95%CI 1.01-1.18) and proton pump inhibitors (aHR 1.38, 95%CI 1.17-1.65) were associated with an increased risk of epilepsy. Additionally, exposure to antibiotics (1.13, 95%CI 1.04-1.23), PPIs (3.82, 95%CI 2.83-5.16) and H2RAs (1.65, 95%CI 1.03-2.64) before the age of two was associated with an increased risk of epilepsy after the age of two.To conclude, our results support the hypothesis that microbiome modulating drugs are associated with an increased risk of epilepsy. This association needs to be further validated in other studies, ideally including the indications for drug use. Our results hopefully contribute to further studies or better prevention of childhood epilepsy.
Optimizing bioconvective heat transfer with MHD Eyring–Powell nanofluids containing motile microorganisms with viscosity variability and porous media in ciliated microchannels
Authors: Mehboob Junaid , Ellahi R. , Sait Sadiq M. , Akbar Noreen Sher 
Published: January 2025

Purpose
This paper aims to optimize bioconvective heat transfer for magnetohydrodynamics Eyring–Powell nanofluids containing motile microorganisms with variable viscosity and porous media in ciliated microchannels.

Design/methodology/approach
The flow problem is first modeled in the two-dimensional frame and then simplified under low Reynolds number and long wavelength approximations. The numerical method is used to examine the impact of thermal radiation, temperature-dependent viscosity, mixed convection, magnetic fields, Ohmic heating and porous media for velocity, temperature, concentration and motile microorganisms. Graphical results are presented to observe the impact of physical parameters on pressure rise, pressure gradient and streamlines.

Findings
It is observed that the temperature of nanofluid decreases with higher values of the viscosity parameter. It is absolutely in accordance with the physical expectation as the radiation parameter increases, the heat transfer rate at the boundary decreases. Nanoparticle concentration increases by increasing the values of bioconvection Rayleigh number. The density of motile microorganisms decreases when bioconvection Peclet number is increased. The velocity of the nanofluid decreases with higher value of Darcy number. With increase in the value of bioconvection parameter, the flow of nanofluid is increased.

Originality/value
The bioconvective peristaltic movement of magnetohydrodynamic nanofluid in ciliated media is proposed. The non-Newtonian behavior of the fluid is described by using an Eyring–Powell fluid model.