bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective inhibition of somatostatin-positive dentate hilar interneurons induces age-related cellular changes and cognitive dysfunction
Authors: Lyu Jinrui , Nagarajan Rajasekar , Kambali Maltesh , Wang Muxiao , Rudolph Uwe 
Published: October 2022

ABSTRACTThe cellular basis of age-related impairments of hippocampal function is not fully understood. In order to evaluate the role of somatostatin-positive (Sst+) interneurons in the dentate gyrus hilus in this process, we chemogenetically inhibited Sst+interneurons in the dentate gyrus (DG) hilus. Chronic chemogenetic inhibition (CCI) of these neurons resulted in increased c-Fos staining in the DG hilus, a decrease in the percentage of Gad67- and of Sst-expressing interneurons in the DG, and increased microglial activation in DG, CA3, and CA1. Total dendritic length and spine density were reduced in DG and CA1, suggesting reduced dendritic complexity. Behaviorally, the recognition index in an object recognition task and the percentage of spontaneous alternations in the Y maze were decreased, while in both initial and reversal learning in the Morris water maze the latencies to find the hidden platform were increased, suggesting cognitive dysfunction. Our findings establish a causal role for a reduced function of Sst+interneurons in the DG hilus for cognitive decline and suggest that this reduced function may contribute to age-related impairments of learning and memory. Furthermore, our CCI mice may represent a cellularly defined model of hippocampal aging.SIGNIFICANCE STATEMENTNeuronal circuits and cellular processes underlying age-related cognitive dysfunction are not well understood. We observed that chronic chemogenetic inhibition of a defined cell type, somatostatin-positive interneurons in the dentate gyrus hilus, which have previously been found to be associated with cognitive dysfunction in aged rodents, is necessary and sufficient to elicit changes in expression of interneuronal markers, an increase in the activity of dentate gyrus granule cells, increased microglial activation across the entire hippocampus and an impairment of learning and memory-related tasks. Thus, inhibition of somatostatin-positive interneurons in the dentate gyrus hilus replicates changes that are also seen with normal aging, representing a novel cellularly defined animal model of hippocampal aging.
Neural representational geometries correlate with behavioral differences in monkeys and recurrent neural networks
Authors: Fascianelli Valeria , Battista Aldo , Stefanini Fabio , Tsujimoto Satoshi , Genovesio Aldo , Fusi Stefano 
Published: October 2022

AbstractAnimals likely use a variety of strategies to solve laboratory tasks. Traditionally, combined analysis of behavioral and neural recording data across subjects employing different strategies may obscure important signals and give confusing results. Hence, it is essential to develop techniques that can infer strategy at the single-subject level. We analyzed an experiment in which two monkeys performed a visually cued rule-based task. The analysis of their performance shows no indication that they used a different strategy. However, when we examined the geometry of stimulus representations in the state space of the neural activities recorded in dorsolateral prefrontal cortex, we found striking differences between the two monkeys. Our purely neural results induced us to reanalyze the behavior. The new analysis showed that the differences in representational geometry correlate with differences in the reaction times, revealing behavioral differences we were unaware of. All these analyses indicate that the monkeys are using different strategies. Finally, using recurrent neural network models trained to perform the same task, we show that these strategies correlate with the amount of training, suggesting a possible explanation for the observed neural and behavioral differences.
Alternative designs lead to similar performance when traits and performance vary on different axes
Authors: Nolting Kristen M. , Holsinger Kent E. 
Published: October 2022

ABSTRACTPlants differ from one another in size, architecture, water relations, and resource uptake, and these differences often lead to differences in performance. Yet within a community species that differ markedly in these traits often have similar performance. Here we use a simple model to show that when the major axes of trait covariation do not align with the axis of performance variation, large differences among species in structural traits may have similar performance, i.e., ‘alternative designs.’ We further illustrate this phenomenon using trait and performance data from co-occurringProteaspecies in the Cape Floristic Region, South Africa. Long-term coexistence of species within a community requires both similar levels of performance, so that some species are not excluded by competition, and niche differentiation, so that multiple species can coexist. Thus, misalignment between the axis of performance variation and the major axes of trait variation may be common, just as genetic variation may be maintained within a population when the selection gradient does not align with the major axes of the genetic variance-covariance matrix.
The prophylactic value of TNF-α inhibitors against retinal cell apoptosis and optic nerve axon loss after corneal surgery or trauma
Authors: Paschalis Eleftherios I. , Zhou Chengxin , Sharma Jyoti , Dohlman Thomas H. , Kim Sarah , Lei Fengyang , Chodosh James , Vavvas Demetrios , Urtti Arto , Papaliodis George , Dohlman Claes H. 
Published: October 2022

AbstractBackground and PurposeLate secondary glaucoma is an often-severe complication after acute events like anterior segment surgery, trauma, infection, etc. TNF-α is a major mediator that is rapidly upregulated, diffusing also to the retina and causes apoptosis of the ganglion cells and degeneration of their optic nerve axons (mediating steps to glaucomatous damage). Anti-TNF-α antibodies are in animals very effective in protecting the retinal cells and the optic nerve—and might therefore be useful prophylactically against secondary glaucoma in future such patients.Here we evaluate 1)toxicityand 2)efficacyof two TNF-α inhibitors (adalimumab and infliximab), in rabbits bysubconjunctivaladministration.MethodsFor drugtoxicity, animals withnormal, unburnedcorneas were injected with adalimumab (0.4, 4, or 40 mg), or infliximab (1, 10, or 100 mg). For drugefficacy, other animals were subjected to alkali burn before such injection, or steroids (for control). The rabbits were evaluated clinically with slit lamp and photography, electroretinography, optical coherence tomography, and intraocular pressure manometry. A sub-set of eyes were stainedex vivoafter 3 days for retinal cell apoptosis (TUNEL). In other experiments the optic nerves were evaluated by paraphenylenediamine staining after 50 or 90 days. Loss of retinal cells and optic nerve degeneration were quantified.ResultsSubconjunctival administration of 0.4 mg or 4.0 mg adalimumab were well tolerated, whereas 40.0 mg was toxic to the retina. 1, 10, or 100 mg infliximab were also well tolerated.Analysis of the optic nerve axons after 50 days confirmed the safety of 4.0 mg adalimumab and of 100 mg infliximab.Forefficacy, 4.0 mg adalimumab subconjunctivally in 0.08 mLprovided practically full protection against retinal cell apoptosis 3 days following alkali burn, and infliximab 100 mg only slightly less. At 90 days following burn injury, control optic nerves showed about 50% axon loss as compared to 8% in the adalimumab treatment group.ConclusionsSubconjunctival injection of 4.0 mg adalimumabin rabbits shows no eye toxicity and provides excellent neuroprotection, both short (3 days) and long-term (90 days).Ourtotal accumulated data from several of our studies, combined with the present paper, suggest that corneal injuries, including surgery, might benefit from routine administration of anti-TNF-α biologics to reduce inflammation and future secondary glaucoma.
Bridging the neural and algorithmic correlates of action-stopping
Authors: Jana Sumitash 
Published: October 2022

AbstractRapid stopping of actions is crucial for survival. The algorithm underlying action-stopping is often described using the independent race model, where the race between independent go- and stop-processes determines whether one is able to stop. However, it is unclear whether humans have neural correlates of these processes. Here, using scalp potentials from three studies, we show that the mu (8-13 Hz) desynchronization over the contralateral motor cortex follows the predictions of a go-process: the activity builds up till an action is made. We also show that the low beta (13-20 Hz) activity over the frontal areas follows the predictions of a stop-process: the activity builds up after the stop signal and prior to the stopping latency. Using these neural correlates, we observed that: 1) The failure to stop mostly results from a rapid go-process, 2) The go-process seems to be influenced by the stop-process during the late stages of action-stopping, 3) Intrinsic prefrontal beta activity has a retardive effect on movement, 4) Violations of independence assumption in the failed stop trials may result from the activity of the stop-process. Future studies may use these neural correlates to resolve the mimicry between models of action-stopping.
RNAcontacts, a pipeline for predicting contacts from RNA proximity ligation assays
Authors: Margasyuk Sergey , Vlasenok Mariia , Li Guo , Cao Changchang , Pervouchine Dmitri D. 
Published: October 2022

AbstractBackgroundHigh-throughput RNA proximity ligation assays are molecular methods that simultaneously analyze spatial proximity of many RNAs in living cells. Their principle is based on cross-linking, fragmentation, and consequent religation of RNAs followed by high-throughput sequencing. The generated fragments have two distinct types of splits, one resulting from pre-mRNA splicing, and the other resulting from ligating spatially close RNA strands.FindingsHere, we present RNAcontacts, a universal pipeline for detecting RNA-RNA contacts in high-throughput RNA proximity ligation assays. It circumvents the inherent problem of mapping sequences with two distinct split types using a two-pass alignment, in which splice junctions are inferred from a control RNA-seq experiment on the first pass and then provided to the aligner on the second pass as bona fide introns. This approach allows for a more sensitive detection of RNA contacts and has higher specificity with respect to splice junctions that are present in the biological sample in comparison to previously developed methods. RNAcontacts extracts contacts, clusters their ligation points, computes the read support, and generates tracks for the visualization through the UCSC Genome Browser. It is implemented in a reproducible and scalable workflow management system Snakemake that allows fast and uniform processing of multiple datasets.ConclusionsRNAcontacts represents a generic pipeline for the detection of RNA contacts that can be used with any proximity ligation method as long as one of the interacting partners is RNA.RNAcontacts is available via github at https://github.com/smargasyuk/RNAcontacts/
A Hybrid Learning Method with High Specificity for Excluding Non-chromosome Objects Problem
Authors: Kao E-Fong , Hsieh Ya-Ju , Ke Chien-Chih , Lin Wan-Chi , Yang Fang-Yu Ou , Wu Jain-Shing 
Published: October 2022

AbstractBackgroundFor automated analysis of metaphase chromosome images, the chromosome objects on the images need to be segmented in advance. However, the segmentation results often contain a lot of non-chromosome objects in the images. Hence, elimination of non-chromosome objects is an essential process in automated chromosome image analysis. This study aims to exclude non-chromosome objects and preserve as many chromosomes as possible. In this paper, we propose a hybrid deep learning method to exclude non-chromosome objects from metaphase chromosome images.MethodThe proposed method consists of two phases. In the first phase, two classification results are obtained from feature-based and image-based convolutional neural networks (CNN) separately (the feature-based CNN uses the features of the images as input; the image-based CNN uses the images as input directly). In the second phase, the prediction results from the above two CNNs are combined and resent to another CNN to obtain final classification results.ResultsThe proposed method uses 18,757 non-chromosome objects and 43,398 chromosomes (including single and multiple overlapped chromosomes) from 1038 chromosome images to evaluate the performance. The experimental results show that the proposed method can detect and exclude 99.61% (18,683/18,757) of the non-chromosome objects and preserve 99.95% (43,375/43,398) of the chromosomes for further analysis.ConclusionsThe proposed method has a high effectiveness on excluding non-chromosome objects and could be used as a preprocessing procedure for chromosome image analysis.Abstract FigureGraphic Abstract
The primordial knot: the deep-rooted origin of the disulfide-rich spider venom toxins
Authors: Shaikh Naeem Yusuf , Sunagar Kartik 
Published: October 2022

AbstractSpider venoms are a complex concoction of enzymes, polyamines, inorganic salts and disulfide-rich peptides (DRPs). Although DRPs are widely distributed and abundant, their evolutionary origin has remained elusive. This knowledge gap stems from the extensive molecular divergence of DRPs and a lack of sequence and structural data from diverse lineages. By evaluating DRPs under a comprehensive phylogenetic, structural and evolutionary framework, we have not only identified over 70 novel spider toxin superfamilies but also provide the first evidence for their common origin. We trace the origin of these toxin superfamilies to a primordial knot - the ‘Adi Shakti’ - nearly ∼375 MYA in the common ancestor of Araneomorphae and Mygalomorphae. As these lineages constitute over 50% of the extant spiders, our findings provide fascinating insights into the early evolution and diversification of the spider venom arsenal. Reliance on a single molecular toxin scaffold by nearly all spiders is in complete contrast to most other venomous animals that have recruited into their venoms diverse toxins with independent origins. Moreover, by comparatively evaluating araneomorph and mygalomorph spiders that differentially depend on their ability to secrete silk for prey capture, we highlight the prominent role of predatory strategies in driving the evolution of spider venom.Significance StatementVenoms are concoctions of biochemicals that function in concert to incapacitate prey or predators of venom-producing animals. Most venomous animals secrete a complex venom cocktail, constituted by toxins with independent evolutionary origins. In complete contrast, we trace the origin of diverse toxin superfamilies in spiders to a single molecular scaffold. The common origin of these disulphide-rich peptides that constitute three-quarters of nearly all spider venoms, therefore, represents a unique scenario of weaponization, where a single motif was recruited and extensively diversified to generate a plethora of superfamilies with distinct activities. Remarkably, the evolution of spider venom was also found to be driven by prey capture (i.e., reliance on silk versus venom) and venom deployment (predation or self-defence) strategies.
Synthetically engineered IgG1 antibody Fc fragments presenting influenza A virus receptor sialic acid inhibit viral haemagglutination activity, but enhance virus replication in cultured A549 cells
Authors: Vrettou Christina , Blundell Patricia , Gaunt Eleanor R , Pleass Richard J 
Published: October 2022

AbstractMany clinically important viruses, including influenza A, SARS-CoV-1, adenoviruses, and DNA tumour viruses such as Kaposi’s sarcoma herpesvirus use multivalent binding to sialic acid (SA) to infect cells, or to modulate immune responses through interactions with sialylated attachment factors that facilitate virus infectivity and/or host survival. Molecular scaffolds rich in SA that bind virions with high avidity may therefore be useful as anti-infective medicines. We generated a panel of 12 of these molecules using fragment-crystallisable scaffolds in CHO-S cells that are rich in SA. The viral surface protein of influenza A virus (IAV), haemagglutinin, binds SA for cell entry, and so we tested the activity of these compounds against this virus. Two of the sialylated Fc-molecules reduced IAV haemagglutination activity by up to 64-fold. However, the same molecules enhanced virus infectivity of A549 cultured cells. To explain the increased viral titres, we postulated that sialylated Fcs may be anti-inflammatory. However, sialylated Fc multimers were instead pro-inflammatory; they induced chemokine/cytokine responses from differentiated human THP-1 derived macrophages, including raised IL-8 and MIP-1α/β, that mimicked responses driven by universal type I interferon. Steric targeting of SA to block virus entry may therefore have unexpected effects in target cells that currently preclude their use for medical intervention.
GLUT1 ablation in astrocytes paradoxically improves central and peripheral glucose metabolism via enhanced insulin-stimulated ATP release
Authors: Ardanaz Carlos G. , de la Cruz Aida , Elizalde-Horcada Marcos , Puerta Elena , Ramírez María J. , Ortega Jorge E. , Urbiola Ainhoa , Ederra Cristina , Ariz Mikel , Ortiz-de-Solórzano Carlos , Irigoyen Joaquín Fernández- , Santamaría Enrique , Karsenty Gerard , Brüning Jens C. , Solas Maite 
Published: October 2022

AbstractAstrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e. GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 ablation (GLUT11′GFAPmice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Importantly, GLUT11′GFAPmice did not present cognitive alterations. Mechanistically, we observed that GLUT1-ablated astrocytes exhibited increased insulin receptor-dependent ATP release, and both astrocyte insulin signalling and brain purinergic signalling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its ablation triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis and cognitive function.
Using SuperClomeleon to measure changes in intracellular chloride during development and after early life stress
Authors: Herstel L.J. , Peerboom C. , Uijtewaal S. , Selemangel D. , Karst H. , Wierenga C.J. 
Published: October 2022

AbstractIntraneuronal chloride concentrations ([Cl-]i) decrease during development resulting in a shift from depolarizing to hyperpolarizing y-aminobutyric acid (GABA) responses via chloride-permeable GABAAreceptors. This GABA shift plays a pivotal role in postnatal brain development, and can be strongly influenced by early life experience. Here, we assessed the applicability of the recently developed fluorescent SuperClomeleon (SClm) sensor to examine changes in [Cl-]iusing two-photon microscopy in brain slices. We used SClm mice of both sexes to monitor the developmental decrease in neuronal chloride levels in organotypic hippocampal cultures. We could discern a clear reduction in [Cl-]ibetween DIV3 and DIV9 (equivalent to the second postnatal weekin vivo)and a further decrease in some cells until DIV22. In addition, we assessed alterations in [Cl-]iin the medial prefrontal cortex (mPFC) of P9 male SClm mouse pups after early life stress (ELS). ELS was induced by limiting nesting material between P2 and P9. ELS induced a shift towards higher (i.e. immature) chloride levels in layer 2/3 cells in the mPFC. Although conversion from SClm fluorescence to absolute chloride concentrations proved difficult, our study underscores that the SClm sensor is a powerful tool to measure physiological changes in [Cl-]iin brain slices.Significance StatementThe reduction of intraneuronal chloride concentrations is crucial for brain development, as it ensures a shift from the initial excitatory action of the neurotransmitter GABA in immature neurons to the inhibitory GABA signaling in the adult brain. Despite the significance of chloride maturation, it has been difficult to study this phenomenon in experiments. Recent development of chloride sensors enable direct imaging of intracellular chloride signaling in neurons. Here we assessed the applicability of the SuperClomeleon chloride sensor to measure physiologically relevant changes in chloride levels using two-photon microscopy in cultured and acute brain slices. Although we also point out some limitations, we conclude that the SuperClomeleon sensor is a powerful tool to measure physiological changes in intracellular chloride.
The Neural Correlates of Continuous Feedback Processing
Authors: Hassall Cameron D. , Yan Yan , Hunt Laurence T. 
Published: October 2022

AbstractFeedback processing is commonly studied by analyzing the brain’s response to discrete rather than continuous events. Such studies have led to the hypothesis that rapid phasic midbrain dopaminergic activity tracks reward prediction errors (RPEs), the effects of which are measurable at the scalp via electroencephalography (EEG). Although studies using continuous feedback are sparse, recent animal work suggests that moment-to-moment changes in reward are tracked byslowly rampingmidbrain dopaminergic activity. Some have argued that these ramping signals index state values rather than RPEs. Our goal here was to develop an EEG measure of continuous feedback processing in humans, then test whether its behaviour could be accounted for by the RPE hypothesis. Participants completed a stimulus-response learning task in which a continuous reward cue gradually increased or decreased over time. A regression-based unmixing approach revealed EEG activity with a topography and timecourse consistent with the stimulus-preceding negativity (SPN), a scalp potential previously linked to reward anticipation and tonic dopamine release. Importantly, this reward-related activity depended on outcome expectancy: as predicted by the RPE hypothesis, activity for expected reward cues was reduced compared to unexpected reward cues. These results demonstrate the possibility of using human scalp-recorded potentials to track continuous feedback processing, and test candidate hypotheses of this activity.