bluuebunny/crossref_metadata_2025_split huggingface dataset:
PI3 kinase inhibitor PI828 uncouples aminergic GPCRs and Ca2+mobilization irrespectively of its primary target
Authors: Kotova Polina D. , Dymova Ekaterina A. , Lyamin Oleg O. , Rogachevskaja Olga A. , Kolesnikov Stanislav S. 
Published: January 2024

ABSTRACTThe phosphoinositide 3-kinase (PI3K) is involved in regulation of multiple intracellular processes. Although the inhibitory analysis is generally employed for validating a physiological role of PI3K, increasing body of evidence suggests that PI3K inhibitors can exhibit PI3K-unrelated activity as well. Here we studied Ca2+signaling initiated by aminergic agonists in a variety of different cells and analyzed effects of the PI3K inhibitor PI828 on cell responsiveness. It turned out that PI828 inhibited Ca2+transients elicited by acetylcholine (ACh), histamine, and serotonin, but did not affect Ca2+responses to norepinephrine and ATP. Another PI3K inhibitor wortmannin negligibly affected Ca2+signaling initiated by any one of the tested agonists. Using the genetically encoded PIP3sensor PH(Akt)-Venus, we confirmed that both PI828 and wortmannin effectively inhibited PI3K and ascertained that this kinase negligibly contributed to ACh transduction. These findings suggested that PI828 inhibited Ca2+responses to aminergic agonists tested, involving an unknown cellular mechanism unrelated to the PI3K inhibition. Complementary physiological experiments provided evidence that PI828 could inhibit Ca2+signals induced by certain agonists, by acting extracellularly, presumably, through their surface receptors. For the muscarinic M3 receptor, this possibility was verified with molecular docking and molecular dynamics. As demonstrated with these tools, wortmannin could be bound in the extracellular vestibule at the muscarinic M3 receptor but this did not preclude binding of ACh to the M3 receptor followed by its activation. In contrast, PI828 could sterically block the passage of ACh into the allosteric site, preventing activation of the muscarinic M3 receptor.
Acute exercise increases systemic kynurenine pathway metabolites and activates the AHR in human PBMCs
Authors: Joisten Niklas , Walzik David , Schenk Alexander , Metcalfe Alan J , Belen Sergen , Schaaf Kirill , Gehlert Sebastian , Spiliopoulou Polyxeni , Garzinsky Ann-Marie , Thevis Mario , Rappelt Ludwig , Donath Lars , Meuth Sven G , Bloch Wilhelm , Zimmer Philipp 
Published: January 2024

AbstractThe kynurenine pathway of tryptophan degradation generates several metabolites such as kynurenine or kynurenic acid that serve as endogenous ligands of the aryl hydrocarbon receptor (AHR). Due to its distinct biological roles particularly modulating the immune system, the AHR is a current therapeutic target across different inflammation-related diseases. Here, we show an exercise-induced increase in AHR ligand availability on a systemic level and a kynurenine pathway activation in peripheral mononuclear blood cells (PBMCs). Concurrently, the AHR is activated in PBMCs following acute exercise, with effects being dependent on exercise intensity. In conclusion, these data indicate a novel mechanistic link how exercise modulates the immune system through the kynurenine pathway-AHR axis, potentially underlying exercise-induced benefits in various chronic diseases.
cis-MoO2(BHAN)2Complex: Its Role in the Protection of Radiation-Induced DNA Damage
Authors: Deb Priyangana 
Published: January 2024

AbstractThe synthesized molybdenum complex, [cis-MoO2(BHAN)2] (BHAN=β-hydroxy-α-naphthaldehyde), exhibits remarkable efficacy in safeguarding DNA against radiation-induced damage. Comparative studies reveal that the complex offers superior protection to radiolysed DNA compared to the ligand (BHAN). Notably, at a concentration of 2 mM, the complex demonstrates the capability to shield 90% of damaged plasmid DNA from a 20 Gy radiation exposure. Additionally, it also affords significant protection against radiation-induced damage to cellular DNA (CTDNA) from gamma rays. These findings underscore the significant potential of cis-MoO2(BHAN)2as an effective radioprotector for normal tissues in the context of radiotherapy. The results of this study contribute valuable insights into the advancement of radioprotective strategies, presenting a noteworthy breakthrough with implications for future medical advancements.
Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein (FABP1) and FABP1 Binding Alters Drug Metabolism
Authors: Yabut King Clyde B. , Martynova Alice , Nath Abhinav , Zercher Benjamin P. , Bush Matthew F. , Isoherranen Nina 
Published: January 2024

AbstractLiver fatty acid binding protein (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and homeostasis of endogenous lipids in the liver. Drugs have also been shown to bind to rat FABP1, but limited data is available for human FABP1 (hFABP1). FABP1 has a large binding pocket and multiple fatty acids can bind to FABP1 simultaneously. We hypothesized that drug binding to hFABP1 results in formation of ternary complexes and that FABP1 binding alters drug metabolism. To test these hypotheses native protein mass spectrometry (MS) and fluorescent 11-(dansylamino)undecanoic acid (DAUDA) displacement assays were used to characterize drug binding to hFABP1 and diclofenac oxidation by cytochrome P450 2C9 (CYP2C9) was studied in the presence and absence of hFABP1. DAUDA binding to hFABP1 involved high (Kd,1=0.2 µM) and low affinity (Kd,2>10 µM) binding sites. Nine drugs bound to hFABP1 with Kdvalues ranging from 1 to 20 µM. None of the tested drugs completely displaced DAUDA from hFABP1 and fluorescence spectra showed evidence of ternary complex formation. Formation of DAUDA-diclofenac-hFABP1 ternary complex was verified with native MS. Docking placed diclofenac in the portal region of FABP1 with DAUDA in the binding cavity. Presence of hFABP1 decreased the kcatand Km,uof diclofenac with CYP2C9 by ∼50% suggesting that hFABP1 binding in the liver will alter drug metabolism and clearance. Together, these results suggest that drugs form ternary complexes with hFABP1 and that hFABP1 interacts with CYP2C9.Significance statementMany commonly prescribed drugs bind FABP1 forming ternary complexes with FABP1 and the fluorescent fatty acid DAUDA. This suggests that in the human liver drugs will bind to apo-FABP1 and fatty acid bound FABP1. The high expression of FABP1 in the liver and binding of drugs to FABP1 will alter rates of drug metabolism in the liver.
Neutrophil immune profile controls spinal cord regeneration in zebrafish
Authors: de Sena-Tomás Carmen , Lameira Leonor Rebola , Taborda Patrícia Naique , Laborde Alexandre , Orger Michael , de Oliveira Sofia , Saúde Leonor 
Published: January 2024

ABSTRACTSpinal cord injury triggers a strong innate inflammatory response in both non-regenerative mammals and regenerative zebrafish. Neutrophils are the first immune population to be recruited to the injury site. Yet, their role in the repair process, particularly in a regenerative context, remains largely unknown. Here, we show that, following rapid recruitment to the injured spinal cord, neutrophils mostly reverse migrate throughout the zebrafish body. In addition, promoting neutrophil inflammation resolution by inhibiting Cxcr4 boosts cellular and functional regeneration. Neutrophil-specific RNA-seq analysis reveals an enhanced activation state that correlates with a transient increase intnf-αexpression in macrophage/microglia populations. Conversely, blocking neutrophil recruitment through Cxcr1/2 inhibition diminishes the presence of macrophage/microglia at the injury site and impairs spinal cord regeneration. Altogether, these findings provide new insights into the role of neutrophils in spinal cord regeneration, emphasizing the significant impact of their immune profile on the outcome of the repair process.Graphical Abstract
Efficient 3D cone trajectory design for improved combined angiographic and perfusion imaging using arterial spin labeling
Authors: Shen Qijia , Wu Wenchuan , Chiew Mark , Ji Yang , Woods Joseph , Okell Thomas W 
Published: January 2024

AbstractPurposeTo improve the spatial resolution and repeatability of a non-contrast MRI technique for simultaneous time resolved 3D angiography and perfusion imaging by developing an efficient 3D cone trajectory design.MethodsA novel parameterized 3D cone trajectory design incorporating the 3D Golden Angle was integrated into 4D combined angiography and perfusion using radial imaging and arterial spin labeling (CAPRIA) to achieve higher spatial resolution and sampling efficiency for both dynamic angiography and perfusion imaging with flexible spatiotemporal resolution. Numerical simulations and physical phantom scanning were used to optimize the cone design. Eight healthy volunteers were scanned to compare the original radial trajectory in 4D CAPRIA with our newly designed cone trajectory. A locally low rank reconstruction method was used to leverage the complementary k-space sampling across time.ResultsThe improved sampling in the periphery of k-space obtained with the optimized 3D cone trajectory resulted in improved spatial resolution compared with the radial trajectory in phantom scans. Improved vessel sharpness and perfusion visualization were also achieved in vivo. Less dephasing was observed in the angiograms due to the short echo time of our cone trajectory and the improved k-space sampling efficiency also resulted in higher repeatability compared to the original radial approach.ConclusionThe proposed 3D cone trajectory combined with 3D Golden Angle ordering resulted in improved spatial resolution and image quality for both angiography and perfusion imaging and could potentially benefit other applications that require an efficient sampling scheme with flexible spatial and temporal resolution.
Spatially targeted inhibitory rhythms differentially affect neuronal integration
Authors: Headley Drew B. , Latimer Benjamin , Aberbach Adin , Nair Satish S. 
Published: January 2024

ABSTRACTPyramidal neurons form dense recurrently connected networks with multiple types of inhibitory interneurons. A major differentiator between interneuron subtypes is whether they synapse onto perisomatic or dendritic regions. They can also engender local inhibitory rhythms, beta (12-35 Hz) and gamma (40-80 Hz). The interaction between the rhythmicity of inhibition and its spatial targeting on the neuron may determine how it regulates neuronal integration. Thus, we sought to understand how rhythmic perisomatic and distal dendritic inhibition impacted integration in a layer 5 pyramidal neuron model with elaborate dendrites and Na+, NMDA, and Ca2+dendritic spikes. We found that inhibition regulated the coupling between dendritic spikes and action potentials in a location and rhythm-dependent manner. Perisomatic inhibition principally regulated action potential generation, while distal dendritic inhibition regulated the incidence of dendritic spikes and their temporal coupling with action potentials. Perisomatic inhibition was most effective when provided at gamma frequencies, while distal dendritic inhibition functioned best at beta. Moreover, beta modulated responsiveness to apical inputs in a phase-dependent manner, while gamma did so for basal inputs. These results may provide a functional interpretation for the reported association of soma-targeting parvalbumin positive interneurons with gamma, and dendrite-targeting somatostatin interneurons with beta.
Plastid phylogenomics and cytonuclear discordance in Rubioideae, Rubiaceae
Authors: Thureborn Olle , Wikström Niklas , Razafimandimbison Sylvain G. , Rydin Catarina 
Published: January 2024

AbstractIn this study of evolutionary relationships in the subfamily Rubioideae (Rubiaceae), we take advantage of the off-target proportion of reads generated via previous target capture sequencing projects based on nuclear genomic data to build a plastome phylogeny and investigate cytonuclear discordance. The assembly of off-target reads resulted in a comprehensive plastome dataset and robust inference of phylogenetic relationships, where most intratribal and intertribal relationships are resolved with strong support. While the phylogenetic results were mostly in agreement with previous studies based on plastome data, novel relationships in the plastid perspective were also detected. For example, our analyses of plastome data provide strong support for the SCOUT clade and its sister relationship to the remaining members of the subfamily, which differs from previous results based on plastid data but agrees with recent results based on nuclear genomic data. However, several instances of highly supported cytonuclear discordance were identified across the Rubioideae phylogeny. Coalescent simulation analysis indicates that while ILS could, by itself, explain the majority of the discordant relationships, plastome introgression may be the better explanation in some cases. Our study further indicates that plastomes across the Rubioideae are, with few exceptions, highly conserved and mainly conform to the structure, gene content, and gene order present in the majority of the flowering plants.
Structural Insights into the DNA-Binding Mechanism of BCL11A: The Integral Role of ZnF6
Authors: Viennet Thibault , Yin Maolu , Jayaraj Abhilash , Kim Woojin , Sun Zhen-Yu J. , Fujiwara Yuko , Zhang Kevin , Seruggia Davide , Seo Hyuk-Soo , Dhe-Paganon Sirano , Orkin Stuart H. , Arthanari Haribabu 
Published: January 2024

AbstractThe transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: α2γ2) to adult hemoglobin (HbA: α2β2) during development. BCL11A binds at a cognate recognition site (TGACCA) in the γ-globin gene promoter and represses its expression. DNA-binding is mediated by a triple zinc finger domain, designated ZnF456. Here, we report comprehensive investigation of ZnF456, leveraging X-ray crystallography and NMR to determine the structures in both the presence and absence of DNA. We delve into the dynamics and mode of interaction with DNA. Moreover, we discovered that the last zinc finger of BCL11A (ZnF6) plays a special role in DNA binding and γ-globin gene repression. Our findings help account for some rare γ-globin gene promoter mutations that perturb BCL11A binding and lead to increased HbF in adults (hereditary persistence of fetal hemoglobin). Comprehending the DNA binding mechanism of BCL11A opens avenues for the strategic, structure-based design of novel therapeutics targeting sickle cell disease and β-thalassemia.
Deep Learning Based Identification of Tissue of Origin for Carcinomas of Unknown Primary utilizing micro-RNA expression
Authors: Raghu Ananya , Raghu Anisha , Wise Jillian F. 
Published: January 2024

ABSTRACTCarcinoma of Unknown Primary (CUP) is a subset of metastatic cancers in which the primary tissue source, or origin, remains unidentified. CUP accounts for three to five percent of all malignancies [2]. Representing an exceptionally aggressive category of metastatic cancers, the median survival of those diagnosed with CUP is approximately three to six months [1]. The tissue in which a cancer arises plays a key role in our understanding of altered gene expression, altered cellular pathways, and sensitivities to various forms of cell death in cancer cells [3]. Thus, the lack of knowledge on tissue of origin makes it difficult to devise tailored treatments for patients with CUP [4]. Developing clinically implementable methods to identify the tissue of origin of the primary site is crucial in treating CUP patients [4]. In particular, the expression profiles of non-coding RNAs can provide insight into the tissue of origin for CUP. Non-coding RNAs provide a robust route to clinical implementation due to their resistance against chemical degradation [5].In this work, we investigate the potential of microRNAs as highly accurate biomarkers for detecting the tissue of origin for metastatic cancers. We further hypothesize that data driven approaches can identify specific microRNA biomarker targets. We used microRNA expression data from the Cancer Genome Atlas (TCGA) dataset [6] and assessed various machine learning approaches. Our results show that it is possible to design robust classifiers to detect the tissue of origin for metastatic samples on the TCGA dataset with an accuracy of up to 96%, which may be utilized in situations of CUP. As a validation of our classifiers, we evaluated the accuracy on a separate set of 194 primary tumor samples from the Sequence Read Archive (SRA) [7]. Our findings demonstrate that deep learning techniques enhance prediction accuracy. We progressed from an initial accuracy prediction of 62.5% with decision trees to 93.2% with logistic regression, finally achieving 96.1% accuracy using deep learning on metastatic samples. On the SRA validation set, a lower accuracy of 41.2% was achieved by decision tree, while deep learning achieved a higher accuracy of 81.2%. Notably, our feature importance analysis showed the top three important biomarkers for predicting tissue of origin to be mir-10b, mir-205, and mir-196b, which aligns with previous work [10]. Our findings highlight the potential of using machine learning techniques to devise tests for detecting tissue of origin for CUP. Since microRNAs are carried throughout the body via vesicles secreted from cells, they may serve as key biomarkers for liquid biopsy due to their presence in blood plasma [11]. Our work serves as a foundation towards developing blood-based cancer detection tests based on microRNA presence.
Differential Short-Term Facilitation Of Synaptic Inputs And Spike Transmission At The Retinocollicular SynapseIn Vivo
Authors: Teh Kai Lun , Dossi Elena , Rouach Nathalie , Sibille Jérémie , Kremkow Jens 
Published: January 2024

ABSTRACTShort-term plasticity (STP) is important for understanding how neuronal circuits can perform different computations. The STP of a neuron pair can be measured directly using paired whole-cell recordings. Besides, the cross-correlation between the presynaptic and postsynaptic neuronal firing is usually used as a proxy for estimating the synaptic properties. However, the relationships between the synaptic inputs and the spiking properties of the postsynaptic neurons during the STPin vivostill remain unclear. Here, we characterized the STP of both synaptic input, measured by the postsynaptic field potential (PFP), and spike transmission at the retinocollicular pathway of mice. We found that the STP of the retinocollicular pathway is mainly facilitating, where the second presynaptic spike induces a larger PFP and higher postsynaptic firing rate than the first presynaptic spike. The facilitation in the postsynaptic firing rate is generally larger than the PFP facilitation. Interestingly, the last postsynaptic spike timing also has a large facilitating effect on the postsynaptic spiking upon receiving a presynaptic input spike. However, the PFP does not depend on the last postsynaptic spike timing, suggesting that there is an input-independent component of spike transmission in STP. Overall, our results indicate that the STP of the retinocollicular pathway is likely a two-stage process, where the spiking plasticity of the postsynaptic neuron could be independent of its inputs.HighlightsMeasure the short-term plasticity of the postsynaptic dendritic response and the spike transmission simultaneouslyThe retinocollicular pathway exhibits paired-spike facilitationSpike transmission facilitates more than postsynaptic dendritic responseShort last postsynaptic spike time facilitates spike transmission independent of the next presynaptic input
Genetic architecture of heritable leaf microbes
Authors: Boyle Julia A. , Frederickson Megan E. , Stinchcombe John R. 
Published: January 2024

AbstractAbstractHost-associated microbiomes are shaped by both their environment and host genetics, and often impact host performance. The scale of host genetic variation important to microbes is largely unknown, yet fundamental to the community assembly of host-associated microbiomes, and with implications for the eco-evolutionary dynamics of microbes and hosts. UsingIpomoea hederacea, Ivy-leaved morning glory, we generated matrilines differing in quantitative genetic variation and leaf shape, which is controlled by a single Mendelian locus. We then investigated the relative roles of Mendelian and quantitative genetic variation in structuring the leaf microbiome, and how these two sources of genetic variation contributed to microbe heritability. We found that despite large effects of the environment, both Mendelian and quantitative genetic host variation contribute to microbe heritability, and that the cumulative small effect genomic differences due to matriline explained as much or more microbial variation than a single large effect locus. Furthermore, our results are the first to suggest that leaf shape itself contributes to variation in the abundances of some phyllosphere microbes.ImportanceWe investigated how host genetic variation affected the assembly ofIpomoea hederacea’s natural microbiome. We found that the genetic architecture of leaf-associated microbiomes involves both quantitative genetic variation and Mendelian traits, with similar contributions to microbe heritability. The existence of Mendelian and quantitative genetic variation for host-associated microbes means that plant evolution at the leaf shape locus or other quantitative genetic loci has the potential to shape microbial abundance, and community composition.
RAN translation of C9orf72-related dipeptide repeat proteins in zebrafish recapitulates hallmarks of amyotrophic lateral sclerosis and identifies hypothermia as a therapeutic strategy
Authors: Burrows David J. , McGown Alexander , Abduljabbar Olfat , Castelli Lydia M. , Shaw Pamela J. , Hautbergue Guillaume M. , Ramesh Tennore M. 
Published: January 2024

ABSTRACTObjectiveHexanucleotide repeat expansions in theC9orf72gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates DPRs as one of the main drivers of neuronal injury in cell and animal models.MethodsA pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.ResultsHere we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.InterpretationThe transgenic model detailed in this paper provides a medium throughputin vivoresearch tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD.