bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multinucleation resets human macrophages for specialized functions at the expense of mononuclear phagocyte identity
Authors: Ahmadzadeh Kourosh , Pereira Marie , Vanoppen Margot , Bernaerts Eline , Ko Jeong-Hun , Mitera Tania , Maksoudian Christy , Manshian Bella B , Soenen Stefaan , Rose Carlos D , Matthys Patrick , Wouters Carine , Behmoaras Jacques 
Published: August 2022

AbstractMacrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. While osteoclast multinucleation is a prerequisite for vertebrate bone homeostasis, the effector function resulting from LGC and FBGC multinucleation is less well-defined. More generally, how multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrated comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced down-regulation of mononuclear phagocyte identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, only B7-H3 (CD276)-expressing human LGCs can form granuloma-like clusters in vitro, suggesting that LGC multinucleation potentiates T cell activation. These findings demonstrate how cell-cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC-specific functionality.
Virtual drug screen reveals context-dependent inhibition of cardiomyocyte hypertrophy
Authors: Eggertsen Taylor G. , Saucerman Jeffrey J. 
Published: August 2022

ABSTRACTBackground and PurposePathological cardiomyocyte hypertrophy is a response to cardiac stress that typically leads to heart failure. Despite being a primary contributor to pathological cardiac remodeling, the therapeutic space that targets hypertrophy is limited. Here, we apply a network model to virtually screen for FDA-approved drugs that induce or suppress cardiomyocyte hypertrophy.Experimental ApproachA logic-based differential equation model of cardiomyocyte signaling was used to predict drugs that modulate hypertrophy. These predictions were validated against curated experiments from the prior literature. The actions of midostaurin were validated in new experiments using TGFβ- and NE-induced hypertrophy in neonatal rat cardiomyocytes.Key ResultsModel predictions were validated in 60 out of 70 independent experiments from the literature and identify 38 inhibitors of hypertrophy. We additionally predict that the efficacy of drugs that inhibit cardiomyocyte hypertrophy is often context dependent. We predicted that midostaurin inhibits cardiomyocyte hypertrophy induced by TGFβ, but not NE, exhibiting context dependence. We further validated this prediction byin vitroexperimentation. Network analysis predicted critical roles for the PI3K and RAS pathways in the activity of celecoxib and midostaurin, respectively. We further investigated the polypharmacology and combinatorial pharmacology of drugs. Brigatinib and irbesartan in combination were predicted to synergistically inhibit cardiomyocyte hypertrophy.Conclusion and ImplicationsThis study provides a well-validated platform for investigating the efficacy of drugs on cardiomyocyte hypertrophy, and identifies midostaurin for consideration as an antihypertrophic drug.‘What is already known’- Cardiac hypertrophy is a leading predictor of heart failure.- Cardiomyocyte hypertrophy is driven by intracellular signaling pathways that are not targeted by current drugs‘What this study adds’- Computational model integrates 69 unique drugs to predict cardiomyocyte hypertrophy- Drug-induced inhibition of cardiomyocyte hypertrophy is context-dependent- Midostaurin inhibits TGFβ-induced cardiomyocyte hypertrophy‘Clinical significance’- Midostaurin is identified as a candidate antihypertrophic drug- Several FDA approved drugs are predicted to inhibit cardiomyocyte hypertrophy either individually or in combination.
Photophysical studies at cryogenic temperature reveal a novel photoswitching mechanism of rsEGFP2
Authors: Mantovanelli Angela M. R. , Glushonkov Oleksandr , Adam Virgile , Wulffele Jip , Thédié Daniel , Byrdin Martin , Gregor Ingo , Nevskyi Oleksii , Enderlein Jörg , Bourgeois Dominique 
Published: August 2022

ABSTRACTSingle-molecule-localization-microscopy (SMLM) at cryogenic temperature opens new avenues to investigate intact biological samples at the nanoscale and perform cryo-correlative studies. Genetically encoded fluorescent proteins (FPs) are markers of choice for cryo-SMLM, but their reduced conformational flexibility below the glass transition temperature hampers efficient photoswitching at low temperature. We investigated cryo-switching of rsEGFP2, one of the most efficient reversibly switchable fluorescent protein at ambient temperature due to facile cis-trans isomerization of the chromophore. UV-visible microspectrophotometry and X-ray crystallography revealed a completely different switching mechanism at ∼110 K. At this cryogenic temperature, on-off photoswitching involves the formation of 2 dark states with blue shifted absorption relative to that of the trans protonated chromophore populated at ambient temperature. Only one of these dark states can be switched back to the fluorescent state by 405 nm light, while both of them are sensitive to UV light at 355 nm. The rsEGFP2 photoswitching mechanism discovered in this work adds to the panoply of known switching mechanisms in fluorescent proteins. It suggests that employing 355 nm light in cryo-SMLM experiments using rsEGFP2 or possibly other FPs could improve the achievable effective labeling efficiency in this technique.Table of Contents artwork
Visuomotor skill learning in young adults with Down syndrome
Authors: Munk Højberg Laurits , Lundbye-Jensen Jesper , Wienecke Jacob 
Published: August 2022

AbstractBackgroundIndividuals with Down syndrome (DS) have impaired general motor skills compared to typically developed (TD) individuals.AimsTo gain knowledge on how young adults with DS learn and retain new motor skills.Methods and ProceduresA DS-group (mean age = 23.9 ± 3 years, N = 11), and an age- matched TD-group (mean age 22.8 ± 1.8, N= 14) were recruited. The participants practiced a sequence visuomotor accuracy tracking task (VATT). Online and offline effects of practice were assessed in immediate and 7-day retention tests. Participants practiced the task in seven blocks (10.6 minutes).Outcomes and ResultsThe TD-group performed better than the DS-group in all blocks (all P < 0.001). Both groups improved VATT-performance online from baseline to immediate retention (all P < 0.001). The DS-groups’ performance at 7-day retention was at the same level as the immediate retention tests (ΔDS). An offline decrease in performance was found in the TD-group (ΔTD, P < 0.001). A between-group difference was observed in the offline effect on the sequence task (ΔTD - ΔDS, P = 0.04).Conclusions and ImplicationsThe motor performance of adults with DS is lower compared to their TD peers. However, adults with DS display significant online performance improvement during training, and offline consolidation following motor learning.What this paper addsLearning new motor skills is fundamental throughout our lifespan. Persons with Down syndrome have other prerequisites for learning new tasks, related to psychological, physiological, and anatomical factors imposed by the syndrome. This study is the first to investigate online and offline learning effects of a single motor skill training session in adults with DS. Our results show generally lower motor performance in DS individuals compared to the typically developed population, but with equal online learning effects. Both groups demonstrate retention, i.e., offline stabilisation but while TD demonstrate negative offline effects, this was not the case for DS. These results should be taken into consideration when planning training of motor and general life skills for adults with DS. This work lays the ground for further investigations of the trajectory of the early learning processes and the mechanisms involved when this target group acquires new skills.
Temporally multiplexed imaging of dynamic signaling networks in living cells
Authors: Qian Yong , Celiker Orhan T. , Wang Zeguan , Guner-Ataman Burcu , Boyden Edward S. 
Published: August 2022

AbstractMolecular signals interact to mediate diverse biological computations. Ideally one would be able to image many signals at once, in the same living cell, to reveal how they work together. Here we report temporally multiplexed imaging (TMI), which uses the clocklike properties of fluorescent proteins to enable different cellular signals to be represented by different temporal fluorescence codes. Using different photoswitchable fluorescent proteins to represent different cellular signals, we can linearly decompose a brief movie of the fluorescence fluctuations in a given cell, into a sum of the fluctuation traces of each individual fluorophore, each weighted by its respective signal amplitude. We demonstrate the power of TMI to report relationships amongst a diversity of second messenger, kinase, and cell cycle signals, using ordinary microscopes.One-Sentence SummaryImaging of many dynamic signals in a living cell is possible by using distinct clocklike fluorophores to represent the activity of each signal.
The Role of Objecthood and Animacy in Apparent Movement Processing
Authors: Cracco Emiel , Linthout Tilia , Orgs Guido 
Published: August 2022

AbstractMovement perception involves both motion and form processing. Previous research has shown that processing along the motion pathway requires a familiar but not necessarily a human shape. However, the role of objecthood and animacy in the form pathway is less clear. Here, we used EEG frequency tagging to study how objecthood and animacy influence both posture processing and the integration of postures into movements. Specifically, we measured brain responses to repeating sequences of well-defined or pixelated images (objecthood) of human or corkscrew agents (animacy) performing fluent or non-fluent movements (movement fluency). The results revealed that movement processing was sensitive to objecthood but not to animacy, whereas posture processing was sensitive to both. Thus, our results indicate that movement processing in the form pathway requires a familiar shape, but not necessarily a human shape. Instead, stimulus animacy appears to be relevant only for posture processing.
Dynamic applicability domain (dAD) for compound-target binding affinity prediction task with confidence guarantees
Authors: Oršolić Davor , Šmuc Tomislav 
Published: August 2022

AbstractIncreasing efforts are being made in the field of machine learning to advance the learning of robust and accurate models from experimentally measured data and enable more efficient drug discovery processes. The prediction of binding affinity is one of the most frequent tasks of compound bioactivity modelling. Learned models for binding affinity prediction are assessed by their average performance on unseen samples, but point predictions are typically not provided with a rigorous confidence assessment. Approaches such as conformal predictor framework equip conventional models with more rigorous assessment of confidence for individual point predictions. In this paper, we extend the inductive conformal prediction (ICP) framework for the dyadic data, such as compound-target binding affinity prediction task. The new framework is based on dynamically defined calibration sets that are specific for each testing interaction pair and provides prediction assessment in the context of calibration pairs from its compound-target neighbourhood, enabling improved guarantees based on local properties of the prediction model. The effectiveness of the approach is benchmarked on several publicly available datasets and through testing in more realistic scenarios with increasing levels of difficulty on a bespoke, complex compound-target binding affinity space. We demonstrate that in such scenarios, novel approach combining applicability domain paradigm with conformal prediction framework, produces superior confidence assessment with informative prediction regions compared to other state-of-the-art conformal prediction approaches.
Can growth in captivity alter the calcaneal microanatomy of a wild ungulate?
Authors: Cottereau Romain , Ortiz Katia , Locatelli Yann , Houssaye Alexandra , Cucchi Thomas 
Published: August 2022

AbstractReduced mobility associated with captivity induces changes in biomechanical stress on the skeleton of domesticated animals. Due to bone plasticity, bone’s morphology and internal structure can respond to these new biomechanical stresses over individuals’ lifetime. In a context where documenting early process of animal domestication is challenging, this study will test the hypothesis that change in mobility patterns during a wild ungulate’s life will alter the internal structure of its limb bones and provide a proof of concept for the application of this knowledge in Zooarchaeology. Using the calcaneus as a phenotypic marker through qualitative and quantitative 3D microanatomical analyses, we relied on a comparative study across wild boars (Sus scrofa) populations from controlled experimental conditions with different mobility patterns (natural habitat, large pen, and stall) and archaeological specimens collected from middle and late Mesolithic as surrogate for the norm of reaction in European wild boar phenotype before the spread of agriculture and domestic pigs. Results provide evidence for compressive and tensile forces as the main elements affecting the variation in the cortical thickness along the calcaneus. Furthermore, changes in the internal structure of the calcaneus between mobility patterns are observed but their intensity is not directly associated with the degree of mobility restriction and only weakly impacted by the size or weight of the individuals. Despite having greater bone volume, the calcaneus of the Mesolithic wild boars displays a very similar microanatomy compared to the present-day hunted or captive wild boars. These results suggest that calcaneal microanatomy is more affected by population differences than by locomotor variation. For all these reasons, this preliminary study doesn’t support the use of microanatomy of the calcaneus as an indicator of change in locomotor behaviour induced by captivity in the archaeological record.
Peripheral Myeloid-Derived Suppressor Cells are good biomarkers of the efficacy of Fingolimod in Multiple Sclerosis
Authors: Camacho-Toledano Celia , Machín-Díaz Isabel , Calahorra Leticia , Cabañas María , Otaegui David , Castillo-Triviño Tamara , Villar Luisa María , Costa-Frossard Lucienne , Comabella Manuel , Midaglia Luciana , García-Domínguez José Manuel , García-Arocha Jennifer , Ortega María Cristina , Clemente Diego 
Published: August 2022

AbstractThe increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition of inhibiting T cell egression from lymph nodes, fingolimod promotes the immunosuppressive activity of Myeloid-Derived Suppressor Cells (MDSCs), a cell type that can be used as a biomarker of disease severity, and of the degree of demyelination and extent of axonal damage in MS. In the present study, we have assessed whether the abundance of circulating monocytic-MDSCs (M-MDSCs) may represent a useful biomarker of fingolimod efficacy. As such, blood immune cells were analyzed at disease onset in the experimental autoimmune encephalomyelitis (EAE) MS mouse model. Fingolimod treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. The data obtained indicated that the M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e. patients who met at least two of the criteria used to define non-evidence of disease activity (NEDA-3) 12 months after treatment, providing relevant information of intention-to-treat MS patients. Collectively, our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.
16p11.2 locus decelerates subpallial maturation and limits variability in human iPSC-derived ventral telencephalic organoids
Authors: Fetit Rana , Theil Thomas , Pratt Thomas , Price David J. 
Published: August 2022

AbstractInhibitory interneurons regulate the activity of cortical circuitry, and their dysfunction has been implicated in Autism Spectrum Disorder (ASD). 16p11.2 microdeletions are genetically linked to 1% of ASD. However, there have been few studies of the effects of this microdeletion on interneuron development. Using ventral telencephalic organoids derived from human induced pluripotent stem cells, we investigated the effect of this microdeletion on organoid size, progenitor proliferation and organisation into neural rosettes, ganglionic eminence (GE) marker expression at early developmental timepoints and expression of the neuronal marker, NEUN at later stages. Early deletion organoids exhibited significantly greater variations in size with concomitant increases in relative neural rosette area and the expression of the ventral telencephalic marker, COUPTFII, with significantly increased variability in these properties. Cell cycle analysis revealed a significant increase in total cell cycle length caused primarily by an elongated G1-phase, the duration of which also varied significantly more than normal. Late deletion organoids increased their expression of the neuronal marker NEUN. We propose that 16p11.2 microdeletions increase developmental variability and may contribute to ASD aetiology by lengthening the cell cycle of ventral progenitors, promoting premature differentiation into interneurons.Summary StatementUsing 3D-region-specific organoids, we demonstrate that 16p11.2 deletion increases variability and prolongs the cell cycle of human subpallial progenitors by lengthening their G1 phase.
Predicting Dementia Severity by Merging Anatomical and Diffusion MRI with Deep 3D Convolutional Neural Networks
Authors: Chattopadhyay Tamoghna , Singh Amit , Joshy Neha Ann , Thomopoulos Sophia I. , Nir Talia M. , Zheng Hong , Nourollahimoghadam Elnaz , Gupta Umang , Steeg Greg Ver , Jahanshad Neda , Thompson Paul M. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2022

AbstractMachine learning methods have been used for over a decade for staging and subtyping a variety of brain diseases, offering fast and objective methods to classify neurodegenerative diseases such as Alzheimer’s disease (AD). Deep learning models based on convolutional neural networks (CNNs) have also been used to infer dementia severity and predict future clinical decline. Most CNN-based deep learning models use T1-weighted brain MRI scans to identify predictive features for these tasks. In contrast, we examine the added value of diffusion-weighted MRI (dMRI) - a variant of MRI, sensitive to microstructural tissue properties - as an additional input in CNN-based models of dementia severity. dMRI is sensitive to microstructural brain abnormalities not evident on standard anatomical MRI. By training CNNs on combined anatomical and diffusion MRI, we hypothesize that we could boost performance when predicting widely-used clinical assessments of dementia severity, such as individuals’ scores on the ADAS11, ADAS13, and MMSE (mini-mental state exam) clinical scales. For benchmarking, we evaluate CNNs that use T1-weighted MRI and dMRI to estimate “brain age” - the task of predicting a person’s chronological age from their neuroimaging data. To assess which dMRI-derived maps were most beneficial, we computed DWI-derived diffusion tensor imaging (DTI) maps of mean and radial diffusivity (MD/RD), axial diffusivity (AD) and fractional anisotropy (FA) for 1198 elderly subjects (age: 74.35 +/- 7.74 yrs.; 600 F/598 M, with a distribution of 636 CN/421 MCI/141 AD) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We tested both 2D Slice CNN and 3D CNN neural network models for the above predictive tasks. Our results suggest that for at least some deep learning architectures, diffusion-weighted MRI may enhance performance for several AD-relevant deep learning tasks relative to using T1-weighted images alone.
Protective effects of different doses of MitoQ separately and combined with trehalose on sperm function and antioxidative status of cryopreserved Markhoz goat semen
Authors: Rezaei Ako , Bahmani Hamid Reza , Mafakheri Shiva , Farshad Abbas , Nazari Parisa 
Published: August 2022

AbstractThe mitochondria-targeted antioxidant MitoQ has been regarded as an effective antioxidant agent against cryo-induced oxidative cellular damage. This study aimed to evaluate the use of different doses of MitoQ combined with trehalose to minimize mitochondrial impairment and oxidative stress during sperm cryopreservation of Markhoz goat. For this, semen collection was performed every 5 days from 5 bucks (10 ejaculates per buck). The ejaculates were pooled and then diluted in eight different Tris-based extenders as follows: no additives (control), 20, 200, 2000 nM of MitoQ (MT20, MT200, MT 2000, respectively), 150 mM of trehalose (Tr), MT20+Tr, MT200+Tr, MT2000+Tr. Each semen sample was frozen using a standard protocol, and sperm function and antioxidative status were evaluated after thawing. Results indicated higher total and progressive motility, acrosome and membrane integrity, superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and lower DNA fragmentation and malondialdehyde in MT200+Tr than for all other groups except MT200; meanwhile, MT200 was also greater in these parameters than in the control group (P < 0.05). Furthermore, MT200 and MT200+Tr showed higher (P < 0.05) percentages of live cryopreserved sperm with high membrane mitochondrial potential than other groups. However, abnormality percentage and catalase activity of frozen-thawed sperm were not affected by treatments (P > 0.05). To conclude, we have found that supplementation of 200 nM MitoQ alone or in combination with 150 mM trehalose to semen extender improves the quality of cryopreserved sperm in goats, which is associated with enhanced antioxidant enzymatic defense and mitochondrial activity and reduced DNA fragmentation.