bluuebunny/crossref_metadata_2025_split huggingface dataset:
A network toxicology approach for mechanistic modelling of nanomaterial hazard and adverse outcomes
Authors: del Giudice Giusy , Serra Angela , Pavel Alisa , Maia Marcella Torres , Saarimäki Laura Aliisa , Fratello Michele , Federico Antonio , Alenius Harri , Fadeel Bengt , Greco Dario 
Published: January 2024

AbstractHazard assessment is the first step in evaluating the potential adverse effects of chemicals. Traditionally, toxicological assessment has focused on the exposure, overlooking the impact of the exposed system on the observed toxicity. However, systems toxicology emphasises how system properties significantly contribute to the observed response. Hence, systems theory states that interactions store more information than individual elements, leading to the adoption of network based models to represent complex systems in many fields of life sciences. Here, we developed a network-based approach to characterise toxicological responses in the context of a biological system, inferring biological system specific networks. We directly linked molecular alterations to the adverse outcome pathway (AOP) framework, establishing connections with toxicologically relevant phenotypic events. We applied this framework on a dataset including 31 engineered nanomaterials with different physicochemical properties in two differentin vitroand onein vivomodels and demonstrated how the biological system is the driving force of the observed response. This work highlights the potential of network-based methods to significantly improve our understanding of toxicological mechanisms from a systems biology perspective, guiding the hazard assessment of nanomaterials and other advanced materials.
The Subcortical Atlas of the Marmoset (“SAM”) monkey based on high-resolution MRI and histology
Authors: Saleem Kadharbatcha S , Avram Alexandru V , Glen Daniel , Schram Vincent , Basser Peter J 
Published: January 2024

AbstractA comprehensive three-dimensional digital brain atlas of cortical and subcortical regions based on MRI and histology has a broad array of applications for anatomical, functional, and clinical studies. We first generated aSubcorticalAtlas of theMarmoset, called the “SAM,” from 251 delineated subcortical regions (e.g., thalamic subregions, etc.) derived from the high-resolution MAP-MRI, T2W, and MTR imagesex vivo. We then confirmed the location and borders of these segmented regions in MRI data using matched histological sections with multiple stains obtained from the same specimen. Finally, we estimated and confirmed the atlas-based areal boundaries of subcortical regions by registering thisex vivoatlas template toin vivoT1- or T2W MRI datasets of different age groups (single vs. multisubject population-based marmoset control adults) using a novel pipeline developed within AFNI. Tracing and validating these important deep brain structures in 3D improves neurosurgical planning, anatomical tract tracer injections, navigation of deep brain stimulation probes, fMRI and brain connectivity studies, and our understanding of brain structure-function relationships. This newex vivotemplate and atlas are available as volumes in standard NIFTI and GIFTI file formats and are intended for use as a reference standard for marmoset brain research.
A Dimerization-dependent Allosteric Activation for Receptor-like Kinase in Plants
Authors: Chen Jia , Cai Dan , Zhang Yunxuan , Chen Lin , Yu Feng 
Published: January 2024

ABSTRACTReceptor-like kinases (RLKs) are essential in plants and phosphorylation is a critical step for their function. Interestingly, RLKs have many non-catalytic kinases/ pseudokinases and the biochemical basis for these pseudokinases remains unclear. FERONIA (FER) is an RLK with kinase activity, but the necessity of its kinase activity for genetic functions has been debated. Here, we uncovered that the kinase-deficient variant FERK565Rcan activate kinase activity in FER and its homologous through homo/heterodimerization-dependent allosteric activation. We further showed that reactive oxygen species (ROS) significantly promote the dimerization of FER family members. Next, we revealed that mutating the FER P740 within the αG-αH loop reduces FER dimerization and disrupts its allosteric activation, thus attenuating FER’s transphosphorylation for its substrate. This disruption in allosteric activation abolishes the genetic function of FERK565R, impacting ROS production and ABA-mediated stomatal movements. Additionally, we found that MEDOS1 (MDS1), a member of the FER family, is incapable of catalyzing phosphotransfer, but can boost the kinase activity of FER and HERK1 through allosteric activation. These findings settle the debate on FER’s inactivated forms, and reveal a new mechanism for allosteric activation of RLKs via redox signaling, enhancing our understanding of pseudokinases in plants.One-sentence summaryFER activates kinase activity of homologous family members through allosteric activation.
CAP peptide artificially induces insect gall
Authors: Hirano Tomoko , Sakamoto Tomoaki , Kimura Seisuke , Nakayama Takumi , Sato Mitsuhiko P. , Shirasawa Kenta , Sato Masa H. 
Published: January 2024

AbstractGalls caused by gall-inducing insects in their host plants clearly illustrate the concept of ‘extended phenotype’, which refers to traits expressed in a host organism when manipulated by a parasite. Candidate effector molecules involved in gall formation, such as phytohormones, amino acids, and proteins, have been reported in numerous studies. However, to date, no attempts to artificially regenerate gall structures using effector candidates have been reported. In this study, we tested the peptide fromCysteine-rich secretory proteins,Antigen 5, andPathogenesis-related 1 proteins, CAP peptide as a gall-inducing effector candidate obtained from transcripts isolated from the horned gall aphid, (Schlechtendalia chinensis) through in silico screening and the Arabidopsis-based gall-forming assay, which is a bioassay system for analysing the molecular mechanisms of gall formation. Furthermore, we succeeded in generating an artificial gall in the host plantVeronica peregrina,without any insect parasitism, using three minimal effector elements: CAP peptide, auxin, and cytokinin. Given the strong similarities observed in organ structure with a central cavity and three types of tissue and gene expression patterns between the native and artificial galls, we concluded that CAP peptide is a general gall-inducing effector peptide secreted by gall-inducing insects.
Activation of Polycystin-1 Signaling by Binding of Stalk-derived Peptide Agonists
Authors: Pawnikar Shristi , Magenheimer Brenda S. , Joshi Keya , Munoz Ericka Nevarez , Haldane Allan , Maser Robin L. , Miao Yinglong 
Published: January 2024

ABSTRACTPolycystin-1 (PC1) is the membrane protein product of the PKD1 gene whose mutation is responsible for 85% of the cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is primarily characterized by the formation of renal cysts and potential kidney failure. PC1 is an atypical G protein-coupled receptor (GPCR) consisting of 11 transmembrane helices and an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal (NTF) and membrane-embedded C-terminal (CTF) fragments. Recently, signaling activation of the PC1 CTF was shown to be regulated by a stalk tethered agonist (TA), a distinct mechanism observed in the adhesion GPCR family. A novel allosteric activation pathway was elucidated for the PC1 CTF through a combination of Gaussian accelerated molecular dynamics (GaMD), mutagenesis and cellular signaling experiments. Here, we show that synthetic, soluble peptides with 7 to 21 residues derived from the stalk TA, in particular, peptides including the first 9 residues (p9), 17 residues (p17) and 21 residues (p21) exhibited the ability to re-activate signaling by a stalkless PC1 CTF mutant in cellular assays. To reveal molecular mechanisms of stalk peptide-mediated signaling activation, we have applied a novel Peptide GaMD (Pep-GaMD) algorithm to elucidate binding conformations of selected stalk peptide agonists p9, p17 and p21 to the stalkless PC1 CTF. The simulations revealed multiple specific binding regions of the stalk peptide agonists to the PC1 protein including an “intermediate” bound yet inactive state. Our Pep-GaMD simulation findings were consistent with the cellular assay experimental data. Binding of peptide agonists to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of the PC1 CTF signaling activation mechanism. Using sequence covariation analysis of PC1 homologs, we further showed that the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. Therefore, structural dynamic insights into the mechanisms of PC1 activation by stalk-derived peptide agonists have enabled an in-depth understanding of PC1 signaling. They will form a foundation for development of PC1 as a therapeutic target for the treatment of ADPKD.
Unbiased identification of cell identity in dense mixed neural cultures
Authors: De Beuckeleer Sarah , Van De Looverbosch Tim , Van Den Daele Johanna , Ponsaerts Peter , De Vos Winnok H. 
Published: January 2024

AbstractInduced pluripotent stem cell (iPSC) technology is revolutionizing cell biology. However, the variability between individual iPSC lines and the lack of efficient technology to comprehensively characterize iPSC-derived cell types hinder its adoption in routine preclinical screening settings. To facilitate the validation of iPSC-derived cell culture composition, we have implemented an imaging assay based on cell painting and convolutional neural networks to recognize cell types in dense and mixed cultures with high fidelity. We have benchmarked our approach using pure and mixed cultures of neuroblastoma and astrocytoma cell lines and attained a classification accuracy above 96%. Through iterative data erosion we found that inputs containing the nuclear region of interest and its close environment, allow achieving equally high classification accuracy as inputs containing the whole cell for semi-confluent cultures and preserved prediction accuracy even in very dense cultures. We then applied this regionally restricted cell profiling approach to evaluate the differentiation status of iPSC-derived neural cultures, by determining the ratio of postmitotic neurons and neural progenitors. We found that the cell-based prediction significantly outperformed an approach in which the time in culture was used as classification criterion (96%vs.86%, resp.). In mixed iPSC-derived neuronal cultures, microglia could be unequivocally discriminated from neurons, regardless of their reactivity state. A tiered strategy, allowed for discriminating microglial cell states as well, albeit with lower accuracy. Thus, morphological single cell profiling provides a means to quantify cell composition in complex mixed neural cultures and holds promise for use in quality control of iPSC-derived cell culture models.
Negative allosteric modulation of cannabinoid CB1receptor signaling suppresses opioid-mediated tolerance and withdrawal without blocking opioid antinociception
Authors: Iyer Vishakh , Saberi Shahin A. , Pacheco Romario , Sizemore Emily Fender , Stockman Sarah , Kulkarni Abhijit , Cantwell Lucas , Thakur Ganesh A. , Hohmann Andrea G. 
Published: January 2024

AbstractThe direct blockade of CB1cannabinoid receptors produces therapeutic effects as well as adverse side-effects that limit their clinical potential. CB1negative allosteric modulators (NAMs) represent an indirect approach to decrease the affinity and/or efficacy of orthosteric cannabinoid ligands or endocannabinoids at CB1. We recently reported that GAT358, a CB1-NAM, blocked opioid-induced mesocorticolimbic dopamine release and reward via a CB1-allosteric mechanism of action. Whether a CB1-NAM dampens opioid-mediated therapeutic effects such as analgesia or alters other unwanted side-effects of opioids remain unknown. Here, we characterized the effects of GAT358 on nociceptive behaviors in the presence and absence of morphine. We examined the impact of GAT358 on formalin-evoked pain behavior and Fos protein expression, a marker of neuronal activation, in the lumbar dorsal horn. We also assessed the impact of GAT358 on morphine-induced slowing of colonic transit, tolerance, and withdrawal behaviors. GAT358 attenuated morphine antinociceptive tolerance without blocking acute antinociception. GAT358 also reduced morphine-induced slowing of colonic motility without impacting fecal boli production. GAT358 produced antinociception in the presence and absence of morphine in the formalin model of inflammatory nociception and reduced the number of formalin-evoked Fos protein-like immunoreactive cells in the lumbar spinal dorsal horn. Finally, GAT358 mitigated the somatic signs of naloxone-precipitated, but not spontaneous, opioid withdrawal following chronic morphine dosing in mice. Our results support the therapeutic potential of CB1-NAMs as novel drug candidates aimed at preserving opioid-mediated analgesia while preventing their unwanted side-effects. Our studies also uncover previously unrecognized antinociceptive properties associated with an arrestin-biased CB1-NAMs.HighlightsCB1negative allosteric modulator (NAM) GAT358 attenuated morphine toleranceGAT358 reduced morphine-induced slowing of colonic motility but not fecal productionGAT358 was antinociceptive for formalin pain alone and when combined with morphineGAT358 reduced formalin-evoked Fos protein expression in the lumbar spinal cordGAT358 mitigated naloxone precipitated withdrawal after chronic morphine dosing
Poor decision making and sociability impairment following central serotonin reduction in inducible TPH2-knockdown rats
Authors: Alonso Lucille , Peeva Polina , Fernández del valle Alquicira Tania , Erdelyi Narda , Gil-Nolskog Ángel , Bader Michael , Winter York , Alenina Natalia , Rivalan Marion 
Published: January 2024

AbstractSerotonin is an essential neuromodulator for mental health and animals’ socio-cognitive abilities. However, we previously found that a constitutive depletion of central serotonin did not impair rat cognitive abilities in stand-alone tests. Here we investigated how a mild and acute decrease of brain serotonin would affect rats’ cognitive abilities. Using a novel rat model of inducible serotonin depletion via the genetic knock-down of tryptophan hydroxylase 2 (TPH2), we achieved 20% decrease of serotonin levels in the hypothalamus after three weeks of non-invasive oral doxycycline administration. Decision making in the Rat Gambling Task and the Probability Discounting Task, cognitive flexibility and social recognition memory were tested in low-serotonin (Tph2-kd) and control rats. Our results showed that the Tph2-kd rats were more prone to choose disadvantageously on the long term (poor decision making) and that only the low-serotonin poor decision makers were more sensitive to probabilistic discounting and had poorer social recognition memory than other low-serotonin and control individuals. Flexibility was unaffected by the acute brain serotonin reduction. Poor social recognition memory was the most central characteristic of the behavioral network of low-serotonin poor decision makers, suggesting a key role of social recognition in expression of their profile. The acute decrease of brain serotonin appeared to specifically amplify cognitive impairments of the subgroup of individuals also identified as poor decision makers in the population. This study highlights the great opportunity Tph2-kd rat model offers to study inter-individual susceptibilities to develop cognitive impairment following mild variations of brain serotonin in otherwise healthy individuals. These transgenic and differential approaches together could be critical for the identification of translational markers and vulnerabilities in the development of mental disorders.
Leveraging engineeredPseudomonas putidaminicells for bioconversion of organic acids into short-chain methyl ketones
Authors: Kozaeva Ekaterina , Nieto-Domínguez Manuel , Tang Kent Kang Yong , Nikel Pablo Iván 
Published: January 2024

ABSTRACTMethyl ketones, key building-blocks widely used in diverse industrial applications, largely depend on oil-derived chemical methods for their production. Here, we investigated bio-based production alternatives for short-chain ketones, adapting the solvent-tolerant soil bacteriumPseudomonas putidaas a host for ketone biosynthesis either by whole-cell biocatalysis or using engineered minicells, chromosome-free bacterial vesicles. Organic acids (acetate, propanoate and butyrate) were selected as the main carbon substrate to drive the biosynthesis of acetone, 2-butanone and 2-pentanone. Pathway optimization identified efficient enzyme variants fromClostridium acetobutylicumandEscherichia coli, which were tested under both constitutive and inducible expression of the cognate genes. By implementing these optimized pathways inP.putidaminicells, which can be prepared through a simple 3-step purification protocol, the feedstock was converted into the target short-chain methyl ketones, remaining catalytically functional for >4 months. These results highlight the value of combining morphology and pathway engineering of non-canonical bacterial hosts to establish alternative bioprocesses for toxic chemicals that are difficult to produce by conventional approaches.GRAPHICAL ABSTRACT
Comparison of urine proteome between obese people and normal weight people
Authors: Wang Haitong , Wei Lilong , Zhou Yun , Cao Yongtong , Gao Youhe 
Published: January 2024

AbstractObjectiveTo explore whether urine proteome can reflect the difference between obese and normal weight people.MethodsUrine samples from obese and normal weight people were collected and identified by non-label quantitative proteomics using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The difference proteins of urine proteome between obese and normal weight people were screened for protein function and biological pathway analysis. The urine proteome of obese individuals was compared with that of normal weight people, and the common differential proteins were counted to analyze the protein function and biological pathways. Reported biomarkers of obesity were searched in the urine proteome of obese individuals.Results38 different proteins can be identified in the urine proteome of obese people compared with normal weight people, some of which have been reported to be related to metabolism and obesity, and the biological processes of differential proteins are also related to metabolism and other processes. 8 common differential proteins in the urine proteome of obese individuals and normal weight people, among which some proteins have been reported to be related to metabolism and obesity, and the biological processes of differential proteins are also related to metabolism and other processes. Among the differential proteins in the urine proteome of obese individuals compared with the normal weight people, the reported obesity biomarkers can be matched.ConclusionsThe urine proteome can distinguish the obese people from the normal weight people, and the differential proteins in the urine proteome have key proteins that are known to be related to obesity and metabolism, and the biological processes of differential proteins also related biological processes such as nutrition and metabolism. Urine proteome has the potential to explore the pathogenesis of obesity and provide personalized treatment.
Dynamic cytoophidia duringDrosophilalate oogenesis
Authors: Zhang Shi-Qi , Liu Ji-Long 
Published: January 2024

ABSTRACTCTP synthase (CTPS) catalyzes the final step of de novo synthesis of CTP. CTPS was first discovered to form filamentous structures termed cytoophidia inDrosophilaovarian cells. Subsequent studies have shown that cytoophidia are widely present in cells of three life domains. In theDrosophilaovary model, our previous studies mainly focused on the early and middle stages, with less involvement in the later stages. In this work, we focus on the later stages of female germline cells inDrosophila. We use live cell imaging to capture the continuous dynamics of cytoophidia in Stages 10-12. We notice the heterogeneity of cytoophidia in the two types of germline cells (nurse cells and oocytes), manifested in significant differences in morphology, distribution, and dynamics. Surprisingly, we also find that neighboring nurse cells in the same egg chamber exhibit multiple dynamic patterns of cytoophidia over time. Our observation provides a systematic understanding of the dynamics of cytoophidia duringDrosophilalate oogenesis.
WITHDRAWN: BBB recovery after stroke by self-replenishing E-pericytes transdifferentiated from local endothelial cells
Authors: Li Tingbo , Tu Jiaqi , Gao Qingzhu , Li Xuzhao , Zhu Zhu , Jin Yuxiao , Zhang Yiyi , Xie Jiongfang , Zhu Peiran , Zhao Bingrui , Jia Jie-Min 
Published: January 2024

Withdrawal statementThe authors have withdrawn this manuscript due to a duplicate posting of manuscript number BIORXIV/2023/570712. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The correct preprint can be found at doi: 10.1101/2023.12.07.570712.
Spatial transcriptomic analysis drives PET imaging of tight junction protein expression in pancreatic cancer theranostics
Authors: Wang James , Seo Jai Woong , Kare Aris J. , Schneider Martin , Tumbale Spencer K. , Wu Bo , Raie Marina N. , Pandrala Mallesh , Iagaru Andrei , Brunsing Ryan L. , Charville Gregory W. , Park Walter G. , Ferrara Katherine W. 
Published: January 2024

AbstractWe apply spatial transcriptomics and proteomics to select pancreatic cancer surface receptor targets for molecular imaging and theranostics using an approach that can be applied to many cancers. Selected cancer surfaceome epithelial markers were spatially correlated and provided specific cancer localization, whereas the spatial correlation between cancer markers and immune- cell or fibroblast markers was low. While molecular imaging of cancer-associated fibroblasts and integrins has been proposed for pancreatic cancer, our data point to the tight junction protein claudin-4 as a theranostic target. Claudin-4 expression increased ∼16 fold in cancer as compared with normal pancreas, and the tight junction localization conferred low background for imaging in normal tissue. We developed a peptide-based molecular imaging agent targeted to claudin-4 with accumulation to ∼25% injected activity per cc (IA/cc) in metastases and ∼18% IA/cc in tumors. Our work motivates a new approach for data-driven selection of molecular targets.
AXOLOTL: an accurate method for detecting aberrant gene expression in rare diseases using coexpression constraints
Authors: Leng Fei , Liu Yang , Zhang Jianzhao , Shen Yansheng , Liu Xiangfu , Wang Yi , Xu Wenjian 
Published: January 2024

AbstractBackgroundThe assessment of aberrant transcription events in patients with rare diseases holds promise for significantly enhancing the prioritization of causative genes, a practice already widely employed in clinical settings to increase diagnostic accuracy. Nevertheless, the entangled correlation between genes presents a substantial challenge for accurate identification of causal genes in clinical diagnostic scenarios. Currently, none of the existing methods are capable of effectively modeling gene correlation.MethodsWe propose a novel unsupervised method, AXOLOTL, to identify aberrant gene expression events in an RNA expression matrix. AXOLOTL effectively addresses biological confounders by incorporating coexpression constraints.ResultsWe demonstrated the superior performance of AXOLOTL on representative RNA-seq datasets, including those from the GTEx healthy cohort, mitochondrial disease cohort and Collagen VI-related dystrophy cohort. Furthermore, we applied AXOLOTL to real case studies and demonstrated its ability to accurately identify aberrant gene expression and facilitate the prioritization of pathogenic variants.