bluuebunny/crossref_metadata_2025_split huggingface dataset:
ENNGene: an Easy Neural Network model building tool for Genomics
Authors: Chalupová Eliška , Vaculík Ondřej , Poláček Jakub , Jozefov Filip , Majtner Tomáš , Alexiou Panagiotis 
Published: November 2021

AbstractBackgroundThe recent big data revolution in Genomics, coupled with the emergence of Deep Learning as a set of powerful machine learning methods, has shifted the standard practices of machine learning for Genomics. Even though Deep Learning methods such as Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNNs) are becoming widespread in Genomics, developing and training such models is outside the ability of most researchers in the field.ResultsHere we present ENNGene - Easy Neural Network model building tool for Genomics. This tool simplifies training of custom CNN or hybrid CNN-RNN models on genomic data via an easy-to-use Graphical User Interface. ENNGene allows multiple input branches, including sequence, evolutionary conservation, and secondary structure, and performs all the necessary preprocessing steps, allowing simple input such as genomic coordinates. The network architecture is selected and fully customized by the user, from the number and types of the layers to each layer's precise set-up. ENNGene then deals with all steps of training and evaluation of the model, exporting valuable metrics such as multi-class ROC and precision-recall curve plots or TensorBoard log files. To facilitate interpretation of the predicted results, we deploy Integrated Gradients, providing the user with a graphical representation of an attribution level of each input position. To showcase the usage of ENNGene, we train multiple models on the RBP24 dataset, quickly reaching the state of the art while improving the performance on more than half of the proteins by including the evolutionary conservation score and tuning the network per protein.ConclusionsAs the role of DL in big data analysis in the near future is indisputable, it is important to make it available for a broader range of researchers. We believe that an easy-to-use tool such as ENNGene can allow Genomics researchers without a background in Computational Sciences to harness the power of DL to gain better insights into and extract important information from the large amounts of data available in the field.Contactpanagiotis.alexiou@ceitec.muni.cz
Multiparametric quantitative phase imaging for real-time, single cell, drug screening in breast cancer
Authors: Polanco Edward R. , Moustafa Tarek E. , Butterfield Andrew , Scherer Sandra D. , Cortes-Sanchez Emilio , Bodily Tyler , Spike Benjamin T. , Welm Bryan E. , Bernard Philip S. , Zangle Thomas A. 
Published: November 2021

AbstractQuantitative phase imaging (QPI) measures the growth rate of individual cells by quantifying changes in mass versus time. Here, we use the breast cancer cell lines MCF-7, BT-474, and MDA-MB-231 to validate QPI as a multiparametric approach for determining response to single-agent therapies. Our method allows for rapid determination of drug sensitivity, cytotoxicity, heterogeneity, and time of response for up to 100,000 individual cells or small clusters in a single experiment. We find that QPI EC50values are concordant with CellTiter-Glo (CTG), a gold standard metabolic endpoint assay. In addition, we apply multiparametric QPI to characterize cytostatic/cytotoxic and rapid/slow responses and track the emergence of resistant subpopulations. Thus, QPI reveals dynamic changes in response heterogeneity in addition to average population responses, a key advantage over endpoint viability or metabolic assays. Overall, multiparametric QPI reveals a rich picture of cell growth by capturing the dynamics of single-cell responses to candidate therapies.
Layer 1 of somatosensory cortex: An important site for input to a tiny cortical compartment
Authors: Ledderose Julia MT , Zolnik Timothy A , Toumazou Maria , Trimbuch Thorsten , Rosenmund Christian , Eickholt Britta J , Jaeger Dieter , Larkum Matthew E , Sachdev Robert NS 
Published: November 2021

AbstractNeocortical Layer (L) 1 has been proposed to be at the center for top-down and bottom-up integration. It is a locus for interactions between long-range inputs, L1 interneurons and apical tuft dendrites of pyramidal neurons. While input to L1 has been studied intensively, the level and effect of input to this layer has still not been completely characterized. Here we examined the input to L1 of mouse somatosensory cortex with retrograde tracing and optogenetics. Our assays reveal that local input to L1 is predominantly from L2/3 and L5 pyramidal neurons and interneurons, and that subtypes of local L5 and L6b neurons project to L1 with different probabilities. Long-range input from sensory-motor cortices to L1 of S1 arose predominantly from L2/3 neurons. Our optogenetic experiments showed that intra-telencephalic L5 pyramidal neurons drive L1 interneurons but have no effect locally on L5 apical tuft dendrites. Dual retrograde tracing revealed that a fraction of local and long-range neurons were both presynaptic to L5 neurons and projected to L1. Our work highlights the prominent role of local inputs to L1 and shows the potential for complex interactions between long-range and local inputs which are both in position to modify the output of somatosensory cortex.
Panton-Valentine leukocidin-induced neutrophil extracellular traps lack antimicrobial activity and are readily induced in patients with recurrent PVL+-Staphylococcus aureusinfections
Authors: Jhelum Hina , Čerina Dora , Harbort CJ , Lindner Andreas , Hanitsch Leif Gunnar , Leistner Rasmus , Schröder Jennyver-Tabea , von Bernuth Horst , Stegemann Miriam Songa , Schürmann Mariana , Zychlinsky Arturo , Krüger Renate , Marsman Gerben 
Published: November 2021

AbstractStaphylococcus aureus(S. aureus) strains that produce the toxin Panton-Valentine leukocidin (PVL; PVL-SA) frequently cause recurrent skin and soft tissue infections (SSTI). PVL binds to and kills human neutrophils, resulting in the formation of neutrophil extracellular traps, but the pathomechanism has not been extensively studied. Furthermore, it is unclear why some individuals colonized with PVL-SA suffer from recurring infections whereas others are asymptomatic. We thus aimed to (a) investigate how PVL exerts its pathogenicity on neutrophils and (b) identify factors that could help to explain the predisposition of patients with recurring infections.We provide genetic and pharmacological evidence that PVL-induced NET formation is independent of NADPH-oxidase and reactive oxygen species (ROS) production. Moreover, through NET proteome analysis we identified that the protein content of PVL-induced NETs is different from NETs induced by mitogen or the microbial toxin nigericin. The abundance of the proteins cathelicidin (CAMP), elastase (NE), and proteinase 3 (PRTN3) was lower on PVL-induced NETs, and as such they were unable to killS. aureus.Furthermore, we found that neutrophils from affected patients express higher levels of CD45, one of the PVL receptors, and are more susceptible to be killed at a low PVL concentration than control neutrophils. Neutrophils from patients that suffer from recurring PVL-positive infections may thus be more sensitive to PVL-induced NET formation, which might impair their ability to combat the infection.ImportanceIndividuals colonized byStaphylococcus aureusstrains that produce Panton-Valentine leukocidin (PVL-SA) often present with recurrent skin and soft-tissue infections, whilst other individuals remain asymptomatic. PVL is a toxin that kills neutrophils, which results in the formation of neutrophil extracellular traps. Traps induced by other stimuli are known to be toxic toS. aureus.We found however that NETs specifically induced by PVL are not toxic toS. aureus. Furthermore, we show that neutrophils from individuals that suffer from recurring PVL-SA infections are more sensitive to PVL-induced NET formation compared to healthy individuals. The significance of our work is in identifying a mechanism through which PVL-SA may actively counter the engagement of neutrophils. Moreover, we identified that patients with recuring PVL-SA infections may be more sensitive to this mechanism, which may help to explain their clinical condition and might provide avenues for future treatment development.
Increasing the Spatial Extent of Attention Strengthens Surround Suppression
Authors: Kiniklioglu Merve , Boyaci Huseyin 
Published: November 2021

AbstractHere we investigate how the extent of spatial attention affects center-surround interaction in visual motion processing. To do so, we measured motion direction discrimination thresholds in humans using drifting gratings and two attention conditions. Under the narrow attention condition, attention was limited to the central part of the visual stimulus, whereas under the wide attention condition, it was directed to both the center and surround of the stimulus. We found stronger surround suppression under the wide attention condition. The magnitude of the attention effect increased with the size of the surround when the stimulus had low contrast, but did not change when it had high contrast. Results also showed that attention had a weaker effect when the center and surround gratings drifted in opposite directions. Next, to establish a link between the behavioral results and the neuronal response characteristics, we performed computer simulations using the divisive normalization model. Our simulations showed that the model can successfully predict the observed behavioral results using parameters derived from the medial temporal (MT) area of the cortex. These findings reveal the critical role of spatial attention on surround suppression and establish a link between neuronal activity and behavior. Further, these results also suggest that the reduced surround suppression found in certain clinical disorders (e.g., schizophrenia and autism spectrum disorder) may be caused by abnormal attention mechanisms.
Quantitative evaluation of Mycobacterium abscessus clinical isolate virulence using a silkworm infection model
Authors: Matsumoto Yasuhiko , Fukano Hanako , Hasegawa Naoki , Hoshino Yoshihiko , Sugita Takashi 
Published: November 2021

AbstractMycobacterium abscessus causes chronic skin infections, lung diseases, and systemic or disseminated infections. Here we investigated whether the virulence of M. abscessus clinical isolates could be evaluated by calculating the median lethal dose (LD50) in a silkworm infection model. M. abscessus subsp. abscessus cells were injected into the silkworm hemolymph. When reared at 37°C, the silkworms died within 2 days post-infection with M. abscessus subsp. abscessus. Viable cell numbers of M. abscessus subsp. abscessus increased in the hemolymph of silkworms injected with M. abscessus subsp. abscessus. Silkworms were not killed by injections with heat-killed M. abscessus subsp. abscessus cells. The administration of clarithromycin, an antibacterial drug used to treat the infection, prolonged the survival time of silkworms injected with M. abscessus subsp. abscessus. The LD50 values of 7 clinical isolates were determined using the silkworm infection model and differed by up to 9-fold. The Mb-17 isolate, which was identified as a pathogenic strain in the silkworm infection model, induced more detachment of human THP-1-derived macrophages during infection than the Mb-10 isolate. These findings suggest that the silkworm M. abscessus infection model with can be used to quantitatively evaluate the virulence of M. abscessus clinical isolates in a short time period.
Reversible brain edema in experimental cerebral malaria is associated with transcellular blood-brain barrier disruption and delayed microhemorrhages
Authors: Jin Jessica , Ba Mame Aida , Wai Chi Ho , Mohanty Sanjib , Sahu Praveen K. , Pattnaik Rajyabardham , Pirpamer Lukas , Fischer Manuel , Heiland Sabine , Lanzer Michael , Frischknecht Friedrich , Mueller Ann-Kristin , Pfeil Johannes , Majhi Megharay , Cyrklaff Marek , Wassmer Samuel C. , Bendszus Martin , Hoffmann Angelika 
Published: November 2021

AbstractBrain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as investigations have been hampered by inadequate animal models. In this study, we show that reversible brain swelling in experimental murine cerebral malaria (ECM) can be induced reliably after single vaccination with radiation-attenuated sporozoites as revealed by in vivo high-field (9.4T) magnetic resonance imaging. Our results provide evidence that parenchymal fluid increase and consecutive brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In a cohort of 27 pediatric and adult CM patients (n=4 fatal, n=23 non-fatal) two out of four fatal CM patients (50%) and 8 out of 23 non-fatal CM patients (35%) showed microhemorrhages on MRI at clinical field strength of 1.5T, emphasizing the translational potential of the experimental model. Our data suggest that targeting transcellular BBBD may represent a promising adjunct therapeutic approach in cerebral brain swelling to reduce edema and may ultimately lead to a reduced permanent brain damage and a better longtime neurological outcome.Author summaryBrain swelling, which occurs in diseases such as cerebral malaria, is not necessarily fatal, and may reverse. Even upon reversal of brain swelling, neurological sequelae can still occur. The factors contributing to the reversibility of brain edema are not known, and treatment options remain therefore limited. Identifying the mechanisms leading to such reversibility could inform clinical management aimed at decreasing brain swelling and consecutive brain injury. Here we introduce a reproducible and simple animal model that allows comprehensive in vivo studies of reversible brain swelling in cerebral malaria at the peak of disease and upon recovery. We identify a specific type of blood-brain barrier disruption (BBBD) as a mechanism that occurs in brain swelling. We show that BBBD can reverse, but also highlight remaining brain damage in areas of most severe BBBD. As the ECM model introduced here bares crucial similarities to the CM in humans, our findings open strategies to study new therapeutic avenues and point to compounds that specifically target transcellular BBBD to reduce brain edema, and increase survival rates.
Curation, inference, and assessment of a globally reconstructed gene regulatory network forStreptomyces coelicolor
Authors: Zorro-Aranda Andrea , Escorcia-Rodríguez Juan Miguel , González-Kise José Kenyi , Freyre-González Julio Augusto 
Published: November 2021

AbstractStreptomyces coelicolorA3(2) is a model microorganism for the study of Streptomycetes, antibiotic production, and secondary metabolism in general. Even thoughS. coelicolorhas an outstanding variety of regulators among bacteria, little effort to globally study its transcription has been made. We manually curated 29 years of literature and databases to assemble a meta-curated experimentally-validated gene regulatory network (GRN) with 5386 genes and 9707 regulatory interactions (∼41% of the total expected interactions). This provides the most extensive and up-to-date reconstruction available for the regulatory circuitry of this organism. Only ∼6% (534/9707) are supported by experiments confirming the binding of the transcription factor to the upstream region of the target gene, the so-called “strong” evidence. While for the remaining interactions there is no confirmation of direct binding. To tackle network incompleteness, we performed network inference using several methods (including two proposed here) for motif identification in DNA sequences and GRN inference from transcriptomics. Further, we contrasted the structural properties and functional architecture of the networks to assess the reliability of the predictions, finding the inference from DNA sequence data to be the most trustworthy approach. Finally, we show two applications of the inferred and the curated networks. The inference allowed us to propose novel transcription factors for the keyStreptomycesantibiotic regulatory proteins (SARPs). The curated network allowed us to study the conservation of the system-level components betweenS. coelicolor and Corynebacterium glutamicum. There we identified the basal machinery as the common signature between the two organisms. The curated networks were deposited in Abasy Atlas (https://abasy.ccg.unam.mx/) while the inferences are available as Supplementary Material.
IL-37 expression reduces acute and chronic neuroinflammation and rescues cognitive impairment in an Alzheimer’s disease mouse model
Authors: Lonnemann Niklas , Hosseini Shirin , Ohm Melanie , Hiller Karsten , Dinarello Charles A. , Korte Martin 
Published: November 2021

AbstractThe anti-inflammatory cytokine interleukin-37 (IL-37) is a member of the IL-1 family but not expressed in mice. We used a human IL-37 (hIL-37tg) expressing mouse, which has been subjected to various models of local and systemic inflammation as well as immunological challenges. Those studies demonstrate an immune-modulatory role of IL-37 which can be characterized as an important suppressor of innate immunity. We investigated the functions of IL-37 in the CNS and explored the effects of IL-37 on neuronal architecture and function, microglia phenotype, cytokine production and behavior after inflammatory challenge by intraperitoneal LPS-injection. Reduced spine density, activated microglia phenotype and impaired long-term potentiation (LTP) were observed in wild-type mice after LPS injection, whereas hIL-37tg mice showed no impairment. In addition, we crossed the hIL-37tg mouse with an animal model of Alzheimer’s disease (APP/PS1) to investigate the anti-inflammatory properties of IL-37 under chronic neuroinflammatory conditions. Our results show that IL-37 is able to limit inflammation in the brain after acute inflammatory events and prevent the loss of cognitive abilities in a mouse model of AD.
Multi-State Modeling of G-protein Coupled Receptors at Experimental Accuracy
Authors: Heo Lim , Feig Michael 
Published: November 2021

ABSTRACTThe family of G-protein coupled receptors (GPCRs) is one of the largest protein families in the human genome. GPCRs transduct chemical signals from extracellular to intracellular regions via a conformational switch between active and inactive states upon ligand binding. While experimental structures of GPCRs remain limited, high-accuracy computational predictions are now possible with AlphaFold2. However, AlphaFold2 only predicts one state and is biased towards either the active or inactive conformation depending on the GPCR class. Here, a multi-state prediction protocol is introduced that extends AlphaFold2 to predict either active or inactive states at very high accuracy using state-annotated templated GPCR databases. The predicted models accurately capture the main structural changes upon activation of the GPCR at the atomic level. For most of the benchmarked GPCRs (10 out of 15), models in the active and inactive states were closer to their corresponding activation state structures. Median RMSDs of the transmembrane regions were 1.12 Å and 1.41 Å for the active and inactive state models, respectively. The models were more suitable for protein-ligand docking than the original AlphaFold2 models and template-based models. Finally, our prediction protocol predicted accurate GPCR structures and GPCR-peptide complex structures in GPCR Dock 2021, a blind GPCR-ligand complex modeling competition. We expect that high accuracy GPCR models in both activation states will promote understanding in GPCR activation mechanisms and drug discovery for GPCRs. At the time, the new protocol paves the way towards capturing the dynamics of proteins at high-accuracy via machine-learning methods.
The long and the short of it: Nanopore based eDNA metabarcoding of marine vertebrates works; sensitivity and specificity depend on amplicon lengths
Authors: Doorenspleet Karlijn , Jansen Lara , Oosterbroek Saskia , Kamermans Pauline , Bos Oscar , Wurz Erik , Murk Albertinka , Nijland Reindert 
Published: November 2021

AbstractTo monitor the effect of nature restoration projects in North Sea ecosystems, accurate and intensive biodiversity assessments are vital. DNA based techniques and especially environmental DNA (eDNA) metabarcoding is becoming a powerful monitoring tool. However, current approaches are based on genetic target regions <500 nucleotides, which offer limited taxonomic resolution. We developed a method for eDNA metabarcoding, based on nanopore sequencing of a longer amplicon, enabling improved identification of fish species. We designed a universal primer pair targeting a 2kb region of fish mitochondria, and compared it to the commonly used MiFish primer pair that targets only ∼170bp.In sillicoand mock community testing showed that the 2kb fragments improved the accurate identification of genetically closely related species. eDNA was amplified, and sequenced using the Oxford Nanopore MinION in combination with the sequence read processing pipeline Decona. Analyzing eDNA from a North Sea aquarium showed that sequences from both primer pairs could be assigned to most species, but both approaches also identified unique species in the aquarium eDNA. Next, both primer pairs were used on multiple eDNA samples from the North Sea. Here, similar location specific fish communities were obtained from both approaches. More species were identified through the MiFish approach in the field samples. Interestingly, this difference was not observed in the aquarium, suggesting that 2kb fragment based metabarcoding potentially detects more recent occurrences of animals. This new method has the potential to improve and expand the molecular toolbox for eDNA based monitoring approaches.
Timing is everything: event-related transcranial direct current stimulation improves motor adaptation
Authors: Weightman Matthew , Brittain John-Stuart , Hall Alison , Miall R. Chris , Jenkinson Ned 
Published: November 2021

AbstractBackgroundThere is a current discord between the foundational theories underpinning motor learning and how we currently apply transcranial direct current stimulation (TDCS): the former is dependent on tight coupling of events while the latter is conducted with very low temporal resolution.ObjectiveHere we aimed to investigate the temporal specificity of stimulation by applying TDCS in short epochs, and coincidentally with movement, during a motor adaptation task.MethodsParticipants simultaneously adapted a reaching movement to two opposing velocity-dependent force-fields (clockwise and counter-clockwise), distinguished by a contextual leftward or rightward shift in the task display and cursor location respectively. Brief bouts (< 3 second) of event-related TDCS (er-TDCS) were applied over M1 or the cerebellum during movements for only one of these learning contexts.ResultsWe show that when short duration stimulation is applied to the cerebellum and yoked to movement, only those reaching movements performed simultaneously with stimulation are selectively enhanced, whilst similar and interleaved movements are left unaffected. We found no evidence of improved adaptation following M1 er-TDCS, as participants displayed equivalent levels of error during both stimulated and unstimulated movements. Similarly, participants in the sham stimulation group adapted comparably during left and right-shift trials.ConclusionsIt is proposed that the coupling of cerebellar stimulation and movement influences timing-dependent (i.e., Hebbian-like) mechanisms of plasticity to facilitate enhanced learning in the stimulated context.