bluuebunny/crossref_metadata_2025_split huggingface dataset:
HDAC-6 inhibition ameliorates the early neuropathology in a mouse model of Krabbe disease
Authors: Braz Sandra O. , Morgado Marlene M. , Pereira Marta I. , Monteiro Ana C. , Golonzhka Olga , Jarpe Matthew , Brites Pedro , Sousa Monica M. , Nogueira-Rodrigues Joana 
Published: May 2023

AbstractIn Krabbe disease (KD), mutations in β-galactosylceramidase (GALC), a lysosomal enzyme responsible for the catabolism of galactolipids, lead to the accumulation of its substrates galactocerebroside and psychosine. This neurologic condition is characterized by a severe and progressive demyelination together with neuron-autonomous defects and degeneration. Twitcher mice mimic the infantile form of KD, which is the most common form of the human disease. The Twitcher CNS and PNS present demyelination, axonal loss and neuronal defects including decreased levels of acetylated tubulin, decreased microtubule stability and impaired axonal transport. Here, we tested whether inhibiting the α-tubulin deacetylase HDAC6 with a specific inhibitor, ACY-738, was able to counteract the early neuropathology and neuronal defects of Twitcher mice. Our data show that delivery of ACY-738 corrects the low levels of acetylated tubulin in the Twitcher nervous system. Furthermore, it reverts the loss myelinated axons in the sciatic nerve and in the optic nerve when administered from birth to postnatal day 9, suggesting that the drug holds neuroprotective properties. The extended delivery of ACY-738 to Twitcher mice delayed axonal degeneration in the CNS and ameliorated the general presentation of the disease. ACY-738 was effective in rescuing neuronal defects of Twitcher neurons, stabilizing microtubule dynamics and increasing the axonal transport of mitochondria. Overall, our results support that ACY-738 has a neuroprotective effect in KD and should be considered as an add-on therapy combined with strategies targeting metabolic correction.
Optimisation of asymmetric field pulses for transcranial magnetic stimulation
Authors: Ma Ke , Goetz Stephan M. 
Published: May 2023

AbstractTranscranial magnetic stimulation (TMS) is a widely-used noninvasive brain stimulation technique through electromagnetic induction. Nowadays commercial TMS devices routinely use conventional biphasic pulses for repetitive TMS protocols and monophasic pulses for single-pulse stimulation. They respectively generate underdamped or damped cosinusoidal electric field pulses that have been proven to be power-inefficient. Recently, symmetric field pulses with near-rectangular electric fields show great potential in terms of energy loss and coil heating, but only limited studies have investigated asymmetric field pulses with different asymmetry levels for the induced electric field waveforms. Thus, this paper optimises and searches a wide range of potential current waveforms with the goal of minimising energy loss and coil heating. The optimised results demonstrated that asymmetric field pulses with near-rectangular electric fields have significantly lower power consumption than conventional ones. These optimised waveforms commonly consist of an initial falling phase followed by rapidly rising and falling phases, trailed by a slow decay to zero. Interestingly, the initial phase has a decay time constant around 260 µs and introduces a pulse-duration-dependent negative bias for the current baseline to minimise the energy loss and coil heating. Thus, it is possible to directly design asymmetric field pulses with various asymmetry ratios by using several prediction equations rather than running optimisation. These results also suggest that introducing such an initial current phase could likely significantly reduce the coil heating of most TMS pulse shapes to improve their power efficiencies.
Meta-learning in head fixed mice navigating in virtual reality: A Behavioral Analysis
Authors: Zhao Xinyu , Gattoni Rachel , Kozlosky Andrea , Jacobs Angela , Morrow Colin , Lindo Sarah , Spruston Nelson 
Published: May 2023

AbstractAnimals can learn general task structures and use them to solve new problems with novel sensory specifics. This capacity of ‘learning to learn’, or meta-learning, is difficult to achieve in artificial systems, and the mechanisms by which it is achieved in animals are unknown. As a step toward enabling mechanistic studies, we developed a behavioral paradigm that demonstrates meta-learning in head-fixed mice. We trained mice to perform a two-alternative forced-choice task in virtual reality (VR), and successively changed the visual cues that signaled reward location. Mice showed increased learning speed in both cue generalization and serial reversal tasks. During reversal learning, behavior exhibited sharp transitions, with the transition occurring earlier in each successive reversal. Analysis of motor patterns revealed that animals utilized similar motor programs to execute the same actions in response to different cues but modified the motor programs during reversal learning. Our study demonstrates that mice can perform meta-learning tasks in VR, thus opening up opportunities for future mechanistic studies.
Characterization of an evolutionarily distinct bacterial ceramide kinase fromCaulobacter crescentus
Authors: Dhakephalkar Tanisha , Stukey Geordan , Guan Ziqiang , Carman George M. , Klein Eric A. 
Published: May 2023

AbstractA common feature among nearly all Gram-negative bacteria is the requirement for lipopolysaccharide (LPS) in the outer leaflet of the outer membrane. LPS provides structural integrity to the bacterial membrane which aids bacteria in maintaining their shape and acts as a barrier from environmental stress and harmful substances such as detergents and antibiotics. Recent work has demonstrated thatCaulobacter crescentuscan survive without LPS due to the presence of the anionic sphingolipid ceramide-phosphoglycerate. Based on genetic evidence, we predicted that protein CpgB functions as a ceramide kinase and performs the first step in generating the phosphoglycerate head group. Here, we characterized the kinase activity of recombinantly expressed CpgB and demonstrated that it can phosphorylate ceramide to form ceramide 1-phosphate. The pH optimum for CpgB was 7.5, and the enzyme required Mg2+as a cofactor. Mn2+, but not other divalent cations, could substitute for Mg2+. Under these conditions, the enzyme exhibited typical Michaelis-Menten kinetics with respect to NBD-C6-ceramide (Km,app=19.2 ± 5.5 μM; Vmax,app=2586.29 ± 231.99 pmol/min/mg enzyme) and ATP (Km,app=0.29 ± 0.07 mM; Vmax,app=10067.57 ± 996.85 pmol/min/mg enzyme). Phylogenetic analysis of CpgB revealed that CpgB belongs to a new class of ceramide kinases which is distinct from its eukaryotic counterpart; furthermore, the pharmacological inhibitor of human ceramide kinase (NVP-231) had no effect on CpgB. The characterization of a new bacterial ceramide kinase opens avenues for understanding the structure and function of the various microbial phosphorylated sphingolipids.
CWHM-974 is a fluphenazine derivative with improved antifungal activity againstCandida albicansdue to reduced susceptibility to multidrug transporter-mediated resistance mechanisms
Authors: Miron-Ocampo Aracely , Beattie Sarah R. , Guin Soumitra , Conway Thomas , Meyers Marvin J. , Moye-Rowley W. Scott , Krysan Damian J. 
Published: May 2023

AbstractMultidrug resistance (MDR) transporters such as ATP Binding Cassette (ABC) and Major Facilitator Superfamily (MFS) proteins are important mediators of antifungal drug resistance, particularly with respect to azole class drugs. Consequently, identifying molecules that are not susceptible to this mechanism of resistance is an important goal for new antifungal drug discovery. As part of a project to optimize the antifungal activity of clinically used phenothiazines, we synthesized a fluphenazine derivative (CWHM-974) with 8-fold higher activity againstCandidaspp. compared to the fluphenazine and with activity againstCandidaspp. with reduced fluconazole susceptibility due to increased multidrug resistance transporters. Here, we show that the improvedC. albicansactivity is because fluphenazine induces its own resistance by triggering expression of CDR transporters while CWHM-974 induces expression but does not appear to be a substrate for the transporters or is insensitive to their effects through other mechanisms. We also found that fluphenazine and CWHM-974 are antagonistic with fluconazole inC. albicansbut not inC. glabrata, despite inducingCDR1expression to high levels. Overall, CWHM-974 represents a unique example of a medicinal chemistry-based conversion of chemical scaffold from MDR-sensitive to MDR-resistant and, hence, active against fungi that have developed resistance to clinically used antifungals such as the azoles.
The landscape of tolerated genetic variation in humans and primates
Authors: Gao Hong , Hamp Tobias , Ede Jeffrey , Schraiber Joshua G. , McRae Jeremy , Singer-Berk Moriel , Yang Yanshen , Dietrich Anastasia , Fiziev Petko , Kuderna Lukas , Sundaram Laksshman , Wu Yibing , Adhikari Aashish , Field Yair , Chen Chen , Batzoglou Serafim , Aguet Francois , Lemire Gabrielle , Reimers Rebecca , Balick Daniel , Janiak Mareike C. , Kuhlwilm Martin , Orkin Joseph D. , Manu Shivakumara , Valenzuela Alejandro , Bergman Juraj , Rouselle Marjolaine , Silva Felipe Ennes , Agueda Lidia , Blanc Julie , Gut Marta , Vries Dorien de , Goodhead Ian , Harris R. Alan , Raveendran Muthuswamy , Jensen Axel , Chuma Idriss S. , Horvath Julie , Hvilsom Christina , Juan David , Frandsen Peter , Melo Fabiano R. de , Bertuol Fabricio , Byrne Hazel , Sampaio Iracilda , Farias Izeni , Valsecchi do Amaral João , Messias Mariluce , Silva Maria N. F. da , Trivedi Mihir , Rossi Rogerio , Hrbek Tomas , Andriaholinirina Nicole , Rabarivola Clément J. , Zaramody Alphonse , Jolly Clifford J. , Phillips-Conroy Jane , Wilkerson Gregory , Abee Christian , Simmons Joe H. , Fernandez-Duque Eduardo , Kanthaswamy ee , Shiferaw Fekadu , Wu Dongdong , Zhou Long , Shao Yong , Zhang Guojie , Keyyu Julius D. , Knauf Sascha , Le Minh D. , Lizano Esther , Merker Stefan , Navarro Arcadi , Batallion Thomas , Nadler Tilo , Khor Chiea Chuen , Lee Jessica , Tan Patrick , Lim Weng Khong , Kitchener Andrew C. , Zinner Dietmar , Gut Ivo , Melin Amanda , Guschanski Katerina , Schierup Mikkel Heide , Beck Robin M. D. , Umapathy Govindhaswamy , Roos Christian , Boubli Jean P. , Lek Monkol , Sunyaev Shamil , O’Donnell Anne , Rehm Heidi , Xu Jinbo , Rogers Jeffrey , Marques-Bonet Tomas , Farh Kyle Kai-How 
Published: May 2023

AbstractPersonalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human. We show that these variants can be inferred to have non-deleterious effects in human based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.One Sentence SummaryDeep learning classifier trained on 4.3 million common primate missense variants predicts variant pathogenicity in humans.
Quantifying marine larval dispersal to assess MPA network connectivity and inform future national and transboundary planning efforts
Authors: Cristiani John , Rubidge Emily M. , Thompson Patrick L. , Robb Carrie , Lewis Margot Hessing- , O’Connor Mary I. 
Published: May 2023

AbstractA Marine Protected Area (MPA) network, in which multiple reserves are designated in a region, can promote the protection of biodiversity across space. To be effective as a network, the design must consider whether MPAs are likely to be connected through the movement of individuals of species of interest. Additionally, network design may explicitly incorporate design features that promote biodiversity in unprotected habitats through the dispersal or spillover of multiple species. Patterns of dispersal and the ability of MPAs to function as an interacting network, however, are difficult to estimate at broad and transboundary spatial scales, and therefore connectivity is often not fully integrated in the design and assessment of MPA networks. Here, we model the dispersal of multiple nearshore species to estimate the potential connectivity of the existing MPAs in British Columbia, Canada, including connections to MPAs in the United States by simulating dispersal using a biophysical model with regional oceanographic currents. We found that MPAs in BC potentially meet connectivity design criteria for nearshore invertebrate species: the majority of MPAs (65-90%) are likely to exchange individuals (i.e. functional connectivity) and support persistent metapopulations, and more than half the unprotected coast (55-85%) receives a large proportion of the larvae produced in MPAs. Furthermore, we found that species’ dispersal abilities and the level of exposure of an MPA to open ocean can predict dispersal distance when we account for the random effects of dispersal location and season. Therefore, future predictions of connectivity are possible based on these core biological and physical attributes, without running new simulations. Together, these analyses provide a robust and novel assessment of multi-species connectivity that can support the design of new MPAs with transboundary connectivity on the northwest coast of North America.
Susceptibility-induced internal gradients reveal axon morphology and cause anisotropic effects in the dMRI signal
Authors: Winther S. , Lundell H. , Rafael-Patiño J. , Andersson M. , Thiran J-P. , Dyrby T. B. 
Published: May 2023

AbstractDiffusion-weighted MRI is our most promising method for estimating microscopic tissue morphology in vivo. The signal acquisition is based on scanner-generatedexternal magnetic gradients. However, it will also be affected by susceptibility-inducedinternal magnetic gradients caused by interaction between the tissue and the static magnetic field of the scanner. With 3D in silico experiments, we show how internal gradients cause morphology-, compartment-, and orientation-dependence of spin-echo and pulsed-gradient spin-echo experiments in myelinated axons. These effects are unseen in previous 2D modelling. For an ex vivo monkey brain, we observe the orientation-dependency generated only when including non-circular cross-sections in the in silico morphological configurations, and find orientation-dependent deviation of up to 17% for diffusion tensor metrics. Our findings underline the importance of accounting for realistic 3D axon morphology in modelling. Interestingly, the morphology-specific orientation-dependency trends show potential for a novel sensitivity to morphology, which is not attainable by the theoretical diffusion-weighted MRI signal itself.
A 2D convolutional neural network for taxonomic classification applied to viruses in the phylumCressdnaviricota
Authors: Gomes Ruither A. L. , Zerbini F. Murilo 
Published: May 2023

ABSTRACTTaxonomy, defined as the classification of different objects/organisms into defined stable hierarchical categories (taxa), is fundamental for proper scientific communication. In virology, taxonomic assignments based on sequence alone are now possible and their use may contribute to a more precise and comprehensive framework. The current major challenge is to develop tools for the automated classification of the millions of putative new viruses discovered in metagenomic studies. Among the many tools that have been proposed, those applying machine learning (ML), mainly in the deep learning branch, stand out with highly accurate results. One ML tool recently released that uses k-mers, VirusTaxo, was the first one to be applied with success, 93% average accuracy, to all types of viruses. Nevertheless, there is a demand for new tools that are less computationally intensive. Viruses classified in the phylumCressdnaviricota, with their small and compact genomes, are good subjects for testing these new tools. Here we tested the usage of 2D convolutional neural networks for the taxonomic classification of cressdnaviricots, also testing the effect of data imbalance and two augmentation techniques by benchmarking against VirusTaxo. We were able to get perfect classification during k-fold test evaluations for balanced taxas, and more than 98% accuracy in the final pipeline tested for imbalanced datasets. The mixture of augmentation on more imbalanced groups and no augmentation for more balanced ones achieved the best score in the final test. These results indicate that these architectures can classify DNA sequences with high precision.
Towards Preclinical Validation of Arbaclofen (R-baclofen) Treatment for 16p11.2 Deletion Syndrome
Authors: Gundersen Brigitta B. , O’Brien William T. , Schaffler Melanie D. , Schultz Maria N. , Tsukahara Tatsuya , Lorenzo Sandra Martin , Nalesso Valerie , Luo Clayton Alice H. , Abel Ted , Crawley Jacqueline N. , Datta Sandeep Robert , Herault Yann 
Published: May 2023

AbstractA microdeletion on human chromosome 16p11.2 is one of the most common copy number variants associated with autism spectrum disorder and other neurodevelopmental disabilities. Arbaclofen, a GABA(B) receptor agonist, is a component of racemic baclofen, which is FDA-approved for treating spasticity, and has been shown to alleviate behavioral phenotypes, including recognition memory deficits, in animal models of 16p11.2 deletion. Given the lack of reproducibility sometimes observed in mouse behavioral studies, we brought together a consortium of four laboratories to study the effects of arbaclofen on behavior in three different mouse lines with deletions in the mouse region syntenic to human 16p11.2 to test the robustness of these findings. Arbaclofen rescued cognitive deficits seen in two 16p11.2 deletion mouse lines in traditional recognition memory paradigms. Using an unsupervised machine-learning approach to analyze behavior, one lab found that arbaclofen also rescued differences in exploratory behavior in the open field in 16p11.2 deletion mice. Arbaclofen was not sedating and had modest off-target behavioral effects at the doses tested. Our studies show that arbaclofen consistently rescues behavioral phenotypes in 16p11.2 deletion mice, providing support for clinical trials of arbaclofen in humans with this deletion.One sentence summaryExperiments across four laboratories found that arbaclofen rescued cognitive deficits in mouse models of 16p11.2 deletion, without sedation or significant off-target behavioral effects.
Synergistic effects of predation and parasitism on competition between edible and inedible phytoplankton
Authors: Kasada Minoru , Thongthaisong Patch , Wollrab Sabine , Van den Wyngaert Silke , Kiel Christine , Berger Stella A. , Grossart Hans-Peter 
Published: May 2023

AbstractFungi can affect aquatic ecosystems through syntrophic and parasitic interactions with other organisms and organic matter. In pelagic systems, fungal parasites on phytoplankton can control trophic interactions and food-web dynamics, e.g., zooplankton grazing on fungal parasite zoospores creates an alternative energy pathway (termed “mycoloop”) from otherwise inedible phytoplankton species. We aim to investigate how the mycoloop influences community dynamics in aquatic food-webs combining experimental and modelling approaches. We assembled an experimental system consisting of an inedible (host) phytoplankton species and its parasitic chytrid, an edible (non-host) phytoplankton species, and a zooplankton grazer. Chytrids parasitizing increased edible phytoplankton abundance, while zooplankton grazing decreased edible phytoplankton abundance. In the presence of zooplankton and chytrids, competition effects between edible and inedible phytoplankton species depended on nutrient levels. At high nutrient levels, competition was balanced by an indirect positive chytrid effect and negative zooplankton grazing effects on edible phytoplankton. In contrast, at low nutrient levels, we found chytrid had a negative impact on edible phytoplankton synergistically with zooplankton. Mathematical investigations suggest that the synergistic effect can be caused by the mycoloop. This indicates that the mycoloop substantially affects predator-prey interactions and phytoplankton competition with yet unknown ecological consequences.
Loss ofIRF5increases ribosome biogenesis leading to alterations in mammary gland architecture and metastasis
Authors: Brune Zarina , Li Dan , Song Su , Li Dan Iris , Castro Isabel , Rasquinha Rhea , Rice Matthew R. , Guo Qin , Kampta Kyle , Moss Matthew , Lallo Morgan , Pimenta Erica , Somerville Carter , Lapan Margaret , Nelson Victoria , dos Santos Camila O. , Blanc Lionel , Pruitt Kevin , Barnes Betsy J. 
Published: May 2023

SummaryDespite the progress made in identifying cellular factors and mechanisms that predict progression and metastasis, breast cancer remains the second leading cause of death for women in the US. Using The Cancer Genome Atlas and mouse models of spontaneous and invasive mammary tumorigenesis, we identified that loss of function of interferon regulatory factor 5 (IRF5) is a predictor of metastasis and survival. Histologic analysis ofIrf5-/-mammary glands revealed expansion of luminal and myoepithelial cells, loss of organized glandular structure, and altered terminal end budding and migration. RNA-seq and ChIP-seq analyses of primary mammary epithelial cells fromIrf5+/+andIrf5-/-littermate mice revealed IRF5-mediated transcriptional regulation of proteins involved in ribosomal biogenesis. Using an invasive model of breast cancer lackingIrf5, we demonstrate that IRF5 re-expression inhibits tumor growth and metastasis via increased trafficking of tumor infiltrating lymphocytes and altered tumor cell protein synthesis. These findings uncover a new function for IRF5 in the regulation of mammary tumorigenesis and metastasis.HighlightsLoss of IRF5 is a predictor of metastasis and survival in breast cancer.IRF5 contributes to the regulation of ribosome biogenesis in mammary epithelial cells.Loss of IRF5 function in mammary epithelial cells leads to increased protein translation.
Molecule-Morphology Contrastive Pretraining for Transferable Molecular Representation
Authors: Nguyen Cuong Q. , Pertusi Dante , Branson Kim M. 
Published: May 2023

AbstractImage-based profiling techniques have become increasingly popular over the past decade for their applications in target identification, mechanism-of-action inference, and assay development. These techniques have generated large datasets of cellular morphologies, which are typically used to investigate the effects of small molecule perturbagens. In this work, we extend the impact of such dataset to improving quantitative structure-activity relationship (QSAR) models by introducing Molecule-Morphology Contrastive Pretraining (MoCoP), a framework for learning multi-modal representation of molecular graphs and cellular morphologies. We scale MoCoP to approximately 100K molecules and 600K morphological profiles using data from the JUMP-CP Consortium and show that MoCoP consistently improves performances of graph neural networks (GNNs) on molecular property prediction tasks in ChEMBL20 across all dataset sizes. The pretrained GNNs are also evaluated on internal GSK pharmacokinetic data and show an average improvement of 2.6% and 6.3% in AUPRC for full and low data regimes, respectively. Our findings suggest that integrating cellular morphologies with molecular graphs using MoCoP can significantly improve the performance of QSAR models, ultimately expanding the deep learning toolbox available for QSAR applications.