bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-glycosylated IGF2 prohormones are more mitogenic than native IGF2
Authors: Potalitsyn Pavlo , Mrázková Lucie , Selicharová Irena , Tencerová Michaela , Ferenčáková Michaela , Chrudinová Martina , Brzozowski Andrzej Marek , Marek Aleš , Kaminský Jakub , Jiráček Jiří , Žáková Lenka 
Published: January 2023

AbstractInsulin-like Growth Factor-2 (IGF2) is important for the regulation of human embryonic growth and development, and for adults’ physiology. Incorrect processing of the IGF2 precursor, pro-IGF2(156), leads to the formation of two IGF2 proforms, big-IGF2(87) and big-IGF2(104). Unprocessed and mainly non-glycosylated IGF2 proforms are found at abnormally high levels in certain diseases, but their mode of action is still unclear. Here, we found that pro-IGF2(156) has the lowest ability to form its inactivating complexes with IGF-Binding Proteins and has higher proliferative properties in cells than IGF2 and other IGF prohormones. We also showed that big-IGF2(104) has a seven-fold higher binding affinity for the IGF2 receptor than IGF2, and that pro-IGF2(87) binds and activates specific receptors and stimulates cell growth similarly to the mature IGF2. The properties of these pro-IGF2 forms, especially of pro-IGF2(156) and big-IGF2(104), indicate them as hormones that may be associated with human diseases related to the accumulation of IGF-2 proforms in the circulation.
Dual Adversarial Deconfounding Autoencoder for joint batch-effects removal from multi-center and multi-scanner radiomics data
Authors: Cavinato Lara , Massi Michela Carlotta , Sollini Martina , Kirienko Margarita , Ieva Francesca 
Published: January 2023

AbstractMedical imaging represents the primary tool for investigating and monitoring several diseases, including cancer. The advances in quantitative image analysis have developed towards the extraction of biomarkers able to support clinical decisions. To produce robust results, multi-center studies are often set up. However, the imaging information must be denoised from confounding factors – known as batch-effect – like scanner-specific and center-specific influences. Moreover, in non-solid cancers, like lymphomas, effective biomarkers require an imaging-based representation of the disease that accounts for its multi-site spreading over the patient’s body. In this work, we address the dual-factor deconfusion problem and we propose a deconfusion algorithm to harmonize the imaging information of patients affected by Hodgkin Lymphoma in a multi-center setting. We show that the proposed model successfully denoises data from domain-specific variability while it coherently preserves the spatial relationship between imaging descriptions of peer lesions, which is a strong prognostic biomarker for tumor heterogeneity assessment. This harmonization step allows to significantly improve the performance in prognostic models, enabling building exhaustive patient representations and delivering more accurate analyses. This work lays the groundwork for performing large-scale and reproducible analyses on multi-center data that are urgently needed to convey the translation of imaging-based biomarkers into the clinical practice as effective prognostic tools. The code is available on GitHub at thislink
Sex differences in neurotransmitter levels in different brain regions after acute and chronic morphine treatment in mice
Authors: Gabel Florian , Hovhannisyan Volodya , Berkati Abdel-Karim , Andry Virginie , Goumon Yannick 
Published: January 2023

ABSTRACTBackground and PurposePain management is a major health burden. Pain results from the integration of the nociceptive message and neuronal communication relying on neurotransmitters such as glutamate, γ-aminobutyric acid (GABA), dopamine, noradrenaline and serotonin in brain regions including the periaqueductal gray (PAG), the nucleus accumbens (Nac), the caudate-putamen (Cpu) and the amygdala. Morphine remains the gold standard painkiller for severe painviathe activation of the mu opioid receptors. However, among side effects, morphine chronic treatment lead to antinociceptive tolerance. As antinociceptive tolerance might be linked to neurotransmission dysregulation, we have compared various neurotransmitter concentrations in acutevschronic morphine conditions in the amygdala, PAG, Cpu, and the Nac of male and female mice.Experimental approachSex differences in morphine antinociception and tolerance were assessed using the tail-immersion test. The behavioural effects of acute and chronic morphine treatments, as well as sex differences in the levels of dopamine, serotonin, noradrenaline, glutamate and GABA in the amygdala, PAG, Cpu, and the Nac were determined by an absolute quantification LC-MS/MS approach using the isotopic dilution method.Key resultsThis study indicates, as previously reported, that female mice are less sensitive to morphine and develop morphine antinociceptive tolerance earlier than males (ED50 of 5.5±0.24 daysvs1.54±0.11 days, respectively). However, the rate at which the tolerance developed did not differ between both sex. We have found major differences in dopamine, serotonin, noradrenaline, glutamate and GABA levels between female and male mice in the amygdala, PAG, Cpu, and the Nac. Finally, no major effect of anti-nociceptive tolerance induced by chronic morphine was observed compared to acute administration of morphine.ConclusionNeurotransmitter differences are attributable mainly to sex differences in pain-related CNS regions. However, the impacts of morphine anti-nociceptive tolerance on dopamine, serotonin, noradrenaline, glutamate and GABA contents appeared to be limited.
Volumetric refractive index measurement and quantitative density analysis of mouse brain tissue with sub-micrometer spatial resolution
Authors: Lee Ariel J. , Kim Young Seo , Kim Joon-Goon , Hugonnet Herve , Lee Moosung , Ku Taeyun , Park YongKeun 
Published: January 2023

AbstractHigh-resolution structural imaging of brain tissue is important for neuroscience research. However, conventional approaches have several limitations, such as the need for exogenous staining, limited accessibility to volumetric information, and qualitative analysis. Herein, we present high-resolution label-free volumetric imaging and analysis of mouse brain tissue using three-dimensional quantitative phase imaging. Measurement of the refractive index distribution of tissue enables direct imaging of the cellular and subcellular structures. Quantification of subcellular organelles is performed in the anatomical regions of the somatosensory cortex, corpus callosum, caudoputamen, and thalamus regions.
Mechanical models affecting beetle horn remodeling
Authors: Matsuda Keisuke , Adachi Haruhiko , Gotoh Hiroki , Inoue Yasuhiro , Kondo Shigeru 
Published: January 2023

AbstractClarifying the mechanisms of shape alteration by insect metamorphosis is important for comprehending exoskeletal morphogenesis. The large horn of the Japanese rhinoceros beetleTrypoxylus dichotomusis the result of drastic metamorphosis, wherein it appears as a rounded shape via pupation and then undergoes remodeling into an angular adult shape. However, the mechanical mechanisms of this remodeling process remain unknown. In this study, we investigated the remodeling mechanisms of the Japanese rhinoceros beetle horn by developing a physical simulation. We identified three factors contributing to remodeling by biological experiments—ventral adhesion, uneven shrinkage, and volume reduction—which were demonstrated to be crucial to the transformation by a physical simulation. We also corroborated our findings by applying the simulation to the stag beetle’s mandibular remodeling. These results indicate that the physical simulation is applicable to pupal remodeling in other beetles, and the morphogenic mechanisms could explain various exoskeletal shapes.Significance statementThe metamorphosis in insects is a mysterious process. By metamorphosis, insects sometimes change their shape dramatically. The head horn of the Japanese rhinoceros beetle is one of the most famous examples of metamorphosis. In larva-to-pupa molting, the horn appears suddenly, caused by the “furrow formation and unfolding” mechanism. The unfolding process makes the pupal horn rounded. However, pupa-to-adult molting transforms the rounded shape into an angular shape. In this paper, we investigated the mechanisms of the transformation. We extracted factors contributing to it through observations and experiments and developed a physical simulation. It could reproduce the adult shape from the pupal shape and could be a general model for the pupa-adult transformation of beetles.
MRI-assessed locus coeruleus contrast and functional response are not associated in young and late middle-aged individuals
Authors: Berger Alexandre , Koshmanova Ekaterina , Beckers Elise , Sharifpour Roya , Paparella Ilenia , Campbell Islay , Mortazavi Nasrin , Balda Fermin , Yi Yeo-Jin , Lamalle Laurent , Dricot Laurence , Phillips Christophe , Jacobs Heidi IL , Talwar Puneet , Tahry Riëm El , Sherif Siya , Vandewalle Gilles 
Published: January 2023

AbstractThe brainstem locus coeruleus (LC) influences a broad range of brain processes, including cognition. The so-called LC contrast is an accepted marker of the integrity of the LC that consists of a local hyperintensity on specific Magnetic Resonance Imaging (MRI) structural images. The small size of the LC has, however, rendered its functional characterization difficult in humans, including in aging. A full characterization of the structural and functional characteristics of the LC in healthy young and late middle-aged individuals is needed to determine to potential roles of the LC in different medical conditions. Here, we wanted to determine whether the activation of the LC in a mismatch negativity task changes in aging and whether the LC functional response was associated to the LC contrast. We used Ultra-High Field (UHF) 7-Tesla functional MRI (fMRI) to record brain response during an auditory oddball task in 53 healthy volunteers, including 34 younger (age: 22.15y ± 3.27; 29 women) and 19 late middle-aged (age: 61.05y ± 5.3; 14 women) individuals. Whole-brain analyses confirmed brain responses in the typical cortical and subcortical regions previously associated with mismatch negativity. When focusing on the brainstem, we found a significant response in the rostral part of the LC probability mask generated based on individual LC images. Although bilateral, the activation was more extensive in the left LC. Individual LC activity was not significantly different between young and late middle-aged individuals. Critically, while the LC contrast was higher in older individuals, the functional response of the LC was not associated with its contrast. These findings show that the age-related alterations of the LC structural integrity may not necessarily be related to changes in its functional response. The results further indicate that LC responses could remain stable in healthy individuals aged 20 to 70.
Modulatory Effect of Levodopa on the Basal Ganglia-Cerebellum Connectivity in Parkinson’s Disease
Authors: Abulikemu Subati , Tai Yen F , Haar Shlomi 
Published: January 2023

AbstractLevodopa has remained the mainstay of medical therapy for Parkinson’s disease since its development in the 1980s. However, long-term medication use is associated with declining clinical efficacy and the emergence of motor complications. Unveiling the effects of levodopa on brain functional reorganisation at a relatively early treatment phase is therefore imperative to inform the optimisation of Parkinson’s therapeutics. In this study, we comprehensively investigated levodopa’s modulation on the resting-state functional connectivity in the cortico- basal ganglia-cerebellum system at regional and network levels, with dual cross-sectional and longitudinal designs. The data was extracted from the Parkinson’s Progression Marker Initiative (PPMI) dataset. The cross-sectional patient groups comprised 17 Parkinson’s patients on stable levodopa medication and 15 drug-naïve patients, while the longitudinal set included 14 Parkinson’s patients measured at both drug-naïve and levodopa-medicated conditions. With nodes defined across cortical, basal ganglia, and cerebellar networks, we conducted univariate comparisons of the internodal connectivity strength between the medication conditions using nonparametric permutation. At the network level, we computed multivariate combinations of individual connections within and between the networks, followed by an assessment of their discriminative capabilities on patients’ medication classes using supervised machine learning. The univariate seed-based approach showed no statistically significant effect of levodopa in either dataset. However, the network connectivity pattern between basal ganglia and the cerebellum displayed a robust classification power in the longitudinal dataset and a similar trend was observed in the cross-sectional. The role of the cerebellum is often overlooked in previous functional integration investigations of Parkinson’s disease and levodopa effects. Considering the recent evidence suggesting the bidirectional communications between the cerebellum and basal ganglia networks, our study provides further insight into the importance of inter-network functional connectivity in Parkinson’s, as well as in the functional and plastic processes following levodopa medication.
G-quadruplex DNA structures mediate non-autonomous instruction of breast tumour microenvironments
Authors: Hunold Pascal , Hoehne Michaela N , Kiljan Martha , van Ray Olivia , Herter Jan , Herter-Sprie Grit S , Hänsel-Hertsch Robert 
Published: January 2023

AbstractBreast cancer is characterised by genetic and epigenetic alterations, such as G-quadruplex (G4) DNA secondary structures. Here, we uncover differentially enriched G4 structure-forming regions (∆G4Rs) and interlinked transcriptomes in the tumour microenvironment (TME) of breast cancer PDX modelsin vivo. We show that well-defined breast cancer cell models non-autonomously instruct ∆G4Rs and transcriptomes in the epigenomes of primary macrophagesin vitro. Mechanistically, we uncover that TNBC secretes, amongst other factors, glucocorticoids to promote G4-linked activation ofoctamer-binding transcription factor 1(OCT-1) and thereby reprogramme macrophages into an immunosuppressed and immunosuppressive state. This epigenetic mechanism is of clinical importance since instructed macrophages selectively associate with the triple-negative breast cancer (TNBC) basal-like 2 (BL2) subtype and with the distinct TNBC molecular signature derived from 2,000 primary breast cancer samples. Altogether, our data suggest that G4 formation is not only prevalent in breast cancer genomes but relevant in their TMEs as well, which is of clinical importance for cancer stratification and the discovery of novel actionable drivers.
VAP spatially stabilizes dendritic mitochondria to locally fuel synaptic plasticity
Authors: Bapat Ojasee , Purimetla Tejas , Kruessel Sarah , Thum Christina , Rupprecht Fiona , Shah Monil , Langer Julian D. , Rangaraju Vidhya 
Published: January 2023

AbstractSynapses are pivotal sites of memory formation and undergo plasticity in response to external inputs. Consequently, synapses are hotspots of energy consumption and are susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via cytoskeletal tethering and serve as local energy supplies to fuel synaptic plasticity. However, the mechanisms that tether and stabilize neuronal mitochondria for long durations and determine the spatial dendritic segment supported during synaptic plasticity are unknown. We identified a list of novel mitochondrial-cytoskeletal interactors in neurons using APEX-based proximity labeling. We narrowed down the protein candidates that exclusively tether mitochondria to actin near postsynaptic spines using high-resolution Airyscan confocal imaging. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in Amyotrophic Lateral Sclerosis and interacts with the endoplasmic reticulum, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we investigated individual spines stimulated by two-photon glutamate uncaging for spine plasticity induction and their adjacent spines. We find that, along with actin, VAP functions as a spatial stabilizer of mitochondrial compartments to sustain synaptic plasticity for up to ~60 min and as a spatial ruler that determines the ~30 μm length of the dendritic segment supporting synaptic plasticity.
QC-GN2oMS2: a Graph Neural Net for High Resolution Mass Spectra Prediction
Authors: Overstreet Richard , King Ethan , Nguyen Julia , Ciesielski Danielle 
Published: January 2023

AbstractPredicting the mass spectrum of a molecular ion is often accomplished via three generalized approaches: rules-based methods for bond breaking, deep learning, or quantum chemical (QC) modeling. Rules-based approaches are often limited by the conditions for different chemical subspaces and perform poorly under chemical regimes with few defined rules. Quantum chemical modeling is theoretically robust but requires significant amounts of computational time to produce a spectrum for a given target. Among deep learning techniques, graph neural networks (GNNs) have performed better than previous work with fingerprint-based neural networks in mass spectral prediction.1To explore this technique further, we investigate the effects of including quantum chemically derived features as edge features in the GNN to increase predictive accuracy. The models we investigated include categorical bond order, bond force constants derived from Extended Tight-Binding (xTB) quantum chemistry, and acyclic bond dissociation energies. We evaluated these models against a control GNN with no edge features in the input graphs. Bond dissociation enthalpies yielded the best improvement with a cosine similarity score of 0.462 relative to the baseline model (0.437). In this work we also apply dynamic graph attention which improves performance on benchmark problems and supports the inclusion of edge features. Between implementations, we investigate the nature of the molecular embedding for spectral prediction and discuss the recognition of fragment topographies in distinct chemistries for further development in tandem mass spectrometry prediction.
HuR modulation with tanshinone mimics impairs LPS response in murine macrophages
Authors: Bonomo Isabelle , Assoni Giulia , Pietra Valeria La , Canarutto Giulia , Facen Elisa , Donati Greta , Zucal Chiara , Genovese Silvia , Micaelli Mariachiara , Pérez-Ràfols Anna , Robbiati Sergio , Kontoyannis Dimitris L. , De Matteo Marilenia , Fragai Marco , Seneci Pierfausto , Marinelli Luciana , Arosio Daniela , Piazza Silvano , Provenzani Alessandro 
Published: January 2023

AbstractLipopolysaccharide exposure to macrophages induces an inflammatory response that is heavily regulated at the transcriptional and post-transcriptional levels. HuR (ELAVL1) is an RNA binding protein that binds and regulates the maturation and half-life of AU/U rich elements (ARE) containing cytokines and chemokines transcripts, mediating the LPS-induced response. Here we investigated how and to what extent small molecule tanshinone mimics (TMs) inhibiting HuR-RNA interaction counteract LPS stimulus in macrophages. We show TMs exist in solution in keto-enolic tautomerism and that, by molecular dynamic calculations, the orto quinone form is the bioactive species interacting with HuR and inhibiting its binding mode vs mRNA targets. A chemical blockage of the diphenolic, reduced form as a diacetate caused the loss of activity of TMsin vitrobut resulted to prodrug-like activityin vivo. The murine macrophage cell line RAW264.7 was treated with LPS and TMs, and the modulation of cellular LPS-induced response was monitored by RNA and Ribonucleoprotein immunoprecipitation sequencing. Correlation analyses indicated that LPS induced a strong coupling between differentially expressed genes and HuR-bound genes, and that TMs reduced such interactions. Functional annotation addressed a specific set of genes involved in chemotaxis and immune response, such asCxcl10, Il1b, Cd40, andFas, with a decreased association with HuR, a reduction of their expression and protein secretion. The same effect was observed in primary murine bone marrow-derived macrophages, andin vivoin an LPS induced peritonitis model, in which the serum level of Cxcl10 and Il1b was strongly reduced, endowing TMs such asTM7noxwith remarkable anti-inflammatory propertiesin vivo.
Apparent simplicity and emergent robustness in bacterial cell cycle control
Authors: Govers Sander K. , Campos Manuel , Tyagi Bhavyaa , Laloux Géraldine , Jacobs-Wagner Christine 
Published: January 2023

SummaryTo examine how bacteria achieve robust cell proliferation across diverse conditions, we developed a method that quantifies 77 cell morphological, cell cycle and growth phenotypes of a fluorescently-labeledEscherichia colistrain and >800 gene deletion derivatives under multiple nutrient conditions. This approach revealed extensive phenotypic plasticity and deviating mutant phenotypes were often found to be nutrient-dependent. From this broad phenotypic landscape emerged simple and robust unifying rules (laws) that connect DNA replication initiation, nucleoid segregation, FtsZ-ring formation, and cell constriction to specific aspects of cell size (volume, length, or added length). Furthermore, completion of cell division followed the initiation of cell constriction after a constant time delay across strains and nutrient conditions, identifying cell constriction as a key control point for cell size determination. Our work provides a systems-level understanding of the design principles by whichE. coliintegrates cell cycle processes and growth rate with cell size to achieve its robust proliferative capability.
Interactive computational and experimental approaches improve the sensitivity of periplasmic binding protein-based nicotine biosensors for measurements in biofluids
Authors: Haloi Nandan , Huang Shan , Nichols Aaron L. , Fine Eve J. , Friesenhahn Nicholas J. , Marotta Christopher B. , Dougherty Dennis A. , Lindahl Erik , Howard Rebecca J. , Mayo Stephen L. , Lester Henry A. 
Published: January 2023

AbstractWe developed fluorescent protein sensors for nicotine with improved sensitivity. For iNicSnFR12 at pH 7.4, the proportionality constant for ΔF/F0vs [nicotine] (δ-slope, 2.7 μM-1) is 6.1-fold higher than the previously reported iNicSnFR3a. The activated state of iNicSnFR12 has a fluorescence quantum yield of at least 0.6. We measured similar dose-response relations for the nicotine-induced absorbance increase and fluorescence increase, suggesting that the absorbance increase leads to the fluorescence increase via the previously described nicotine-induced conformational change, the “candle snuffer” mechanism. Molecular dynamics (MD) simulations identified a binding pose for nicotine, previously indeterminate from experimental data. MD simulations also showed that Helix 4 of the periplasmic binding protein (PBP) domain appears tilted in iNicSnFR12 relative to iNicSnFR3a, likely altering allosteric network(s) that link the ligand binding site to the fluorophore. In thermal melt experiments, nicotine stabilized the PBP of the tested iNicSnFR variants. iNicSnFR12 resolved nicotine in diluted mouse and human serum at 100 nM, the peak [nicotine] that occurs during smoking or vaping, and possibly at the decreasing levels during intervals between sessions. NicSnFR12 was also partially activated by unidentified endogenous ligand(s) in biofluids. Improved iNicSnFR12 variants could become the molecular sensors in continuous nicotine monitors for animal and human biofluids.