bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis
Authors: Illouz Tomer , Nicola Raneen , Ben-Shuhan Linoy , Madar Ravit , Biragyn Arya , Okun Eitan 
Published: September 2020

AbstractDown Syndrome (DS) features a life-long overexpression of theAPPandDYRK1Agenes, leading to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation. As DS can be diagnosed in utero, maternally transferred anti-Aβ antibodies might promote removal of early accumulation of Aβ from the CNS. A DNA-vaccine expressing Aβ1-11was delivered to wild-type female mice, followed by mating with 5xFAD males, which exhibit early Aβ plaque formation, similar to individuals with DS. Maternal Aβ-specific antibodies provided transgenic offspring with passive immunization against Aβ via the placental and subsequently lactation. Maternal antibodies reduced cortical Aβ levels 4 months after antibodies were undetectable, along with alleviating short-term memory deficits and activation of the FcγR1/Syk/Cofilin pathway in microglia. Sera from immunized dams facilitated Aβ clearance by microglia in a Syk-dependent manner. These data suggest that maternal anti-Aβ immunization is a potential strategy to alleviate cognitive decline in individuals with DS.
RNA-sequencing manifests the intrinsic role of MAPKAPK2 in facilitating molecular crosstalk during HNSCC pathogenesis
Authors: Soni Sourabh , Anand Prince , Swarnkar Mohit Kumar , Patial Vikram , Tirpude Narendra V. , Padwad Yogendra S. 
Published: September 2020

AbstractBackgroundTranscriptome profiling has been pivotal in better comprehending the convoluted biology of tumors including head and neck squamous cell carcinoma (HNSCC). Recently, growing evidence has implicated the role of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in many human diseases including tumors. MK2 has been recently reported as a critical regulator of HNSCC that functionsviamodulating the transcript turnover of crucial genes involved in its pathogenesis. Comprehensive MK2-centric transcriptomic analyses could help the scientific community to delve deeper into MK2-pathway driven mechanisms of tumor progression, but such studies have not yet been reported. Consequently, to delineate the biological relevance of MK2 and its intricate crosstalk in the tumor milieu, an extensive transcriptome analysis of HNSCC was conceptualized and effectuated with MK2 at the nexus.MethodsIn the current study, comprehensive next-generation sequencing-based transcriptome profiling was accomplished to ascertain global patterns of mRNA expression profiles in bothin vitroandin vivomodels of the HNSCC microenvironment. The findings of the RNA-sequencing analysis were cross-validatedviarobust validation using nCounter gene expression assays, immunohistochemistry, and real-time quantitative polymerase chain reaction (RT–qPCR).ResultsTranscriptomic characterization followed by annotation and differential gene expression analyses identified certain MK2-regulated candidate genes constitutively involved in regulating HNSCC pathogenesis, and the biological significance of these genes was established by pathway enrichment analysis. Additionally, advanced gene expression assays through the nCounter system in conjunction with immunohistochemical analysis validated the transcriptome profiling outcomes quite robustly. Furthermore, the results obtained from immunohistochemistry and transcript stability analysis indicated the crucial role of MK2 in the modulation of the expression pattern of these genes in HNSCC tumors and cells.ConclusionsConclusively, the findings have paved the way toward the identification of new effective tumor markers and potential molecular targets for HNSCC management. The results have accentuated the importance of certain differentially expressed MK2-regulated genes that are constitutively involved in HNSCC pathogenesis to potentially serve as putative candidates for future endeavors pertaining to diagnosis and therapeutic interventions for HNSCC.
Genes on Different Strands Mark Boundaries Associated with Co-regulation Domains
Authors: Baguette Audrey , Bilodeau Steve , Bourque Guillaume 
Published: September 2020

ABSTRACTGene regulation is influenced by chromatin conformation. Current models suggest that topologically associating domains (TADs) act as regulatory units, which could also include distinct co-expression domains (CODs) favouring correlated gene expression. We integrated publicly available RNA-seq, ChIP-seq and Hi-C data from A549 cells stimulated with the glucocorticoid dexamethasone to explore how differentially expressed genes are co-regulated among TADs and CODs. Interestingly, we found that gene position and orientation also impact co-regulation. Indeed, divergent and convergent pairs of genes we enriched at sub-TAD boundaries, forming distinct CODs. We also found that genes at COD boundaries were less likely to be separated by structural proteins such as Cohesin and CTCF. A complementary analysis of lung expression quantitative trait loci (eQTL) demonstrated that genes affected by the same variant were more likely to be found on the same strand while lacking a TAD boundary. Taken together, these results suggest a model where gene orientation can provide a boundary between CODs, at the sub-TAD level, thus affecting their likelihood of co-regulation.
A causal study of bumetanide on a marker of excitatory-inhibitory balance in the human brain
Authors: Botch Thomas L. , Spiegel Alina , Ricciardi Catherine , Robertson Caroline E. 
Published: September 2020

AbstractBumetanide has received much interest as a potential pharmacological modulator of the putative imbalance in excitatory/inhibitory (E/I) signaling that is thought to characterize autism spectrum conditions. Yet, currently, no studies of bumetanide efficacy have used an outcome measure that is modeled to depend on E/I balance in the brain. In this manuscript, we present the first causal study of the effect of bumetanide on an objective marker of E/I balance in the brain, binocular rivalry, which we have previously shown to be sensitive to pharmacological manipulation of GABA. Using a within-subjects placebo-control crossover design study, we show that, contrary to expectation, acute administration of bumetanide does not alter binocular rivalry dynamics in neurotypical adult individuals. Neither changes in response times nor response criteria can account for these results. These results raise important questions about the efficacy of acute bumetanide administration for altering E/I balance in the human brain, and highlight the importance of studies using objective markers of the underlying neural processes that drugs hope to target.
EEG Cross-Frequency Phase Synchronization as an Index of Memory Matching in Visual Search
Authors: Biel Anna Lena , Minarik Tamas , Sauseng Paul 
Published: September 2020

AbstractVisual perception is influenced by our expectancies about incoming sensory information. It is assumed that mental templates of expected sensory input are created and compared to actual input, which can be matching or not. When such mental templates are held in working memory, cross-frequency phase synchronization (CFS) between theta and gamma band activity has been proposed to serve matching processes between prediction and sensation. We investigated how this is affected by the number of activated templates that could be matched by comparing conditions where participants had to keep either one or multiple templates in mind for successful visual search. We found a transient CFS between EEG theta and gamma activity in an early time window around 150ms after search display presentation, in right hemispheric parietal cortex. Our results suggest that for single template conditions, stronger transient theta-gamma CFS at posterior sites contralateral to target presentation can be observed than for multiple templates. This can be interpreted as evidence to the idea of sequential attentional templates. But mainly, it is understood in line with previous theoretical accounts strongly arguing for transient synchronization between posterior theta and gamma phase as a neural correlate of matching incoming sensory information with contents from working memory and as evidence for limitations in memory matching during multiple template search.
Proneural genes define ground state rules to regulate neurogenic patterning and cortical folding
Authors: Han Sisu , Wilkinson Grey A , Okawa Satoshi , Adnani Lata , Dixit Rajiv , Faisal Imrul , Brooks Matthew , Cortay Veronique , Chinchalongporn Vorapin , Zinyk Dawn , Li Saiqun , Gao Jinghua , Malik Faizan , Touahri Yacine , Angarica Vladimir Espinosa , Oproescu Ana-Maria , Raharjo Eko , Ilnytskyy Yaroslav , Kim Jung-Woong , Wu Wei , Rahmani Waleed , Kovalchuk Igor , Chan Jennifer Ai-wen , Kurrasch Deborah , Castro Diogo S. , Dehay Colette , Swaroop Anand , Biernaskie Jeff , del Sol Antonio , Schuurmans Carol 
Published: September 2020

SUMMARYTransition from smooth, lissencephalic brains to highly-folded, gyrencephalic structures is associated with neuronal expansion and breaks in neurogenic symmetry. Here we show thatNeurog2andAscl1proneural genes regulate cortical progenitor cell differentiation through cross-repressive interactions to sustain neurogenic continuity in a lissencephalic rodent brain. Usingin vivolineage tracing, we found thatNeurog2andAscl1expression defines a lineage continuum of four progenitor pools, with ‘double+progenitors’ displaying several unique features (least lineage-restricted, complex gene regulatory network, G2pausing). Strikingly, selective killing of double+progenitors using split-Cre;Rosa-DTAtransgenics breaks neurogenic symmetry by locally disrupting Notch signaling, leading to cortical folding. Finally, consistent withNEUROG2andASCL1driving discontinuous neurogenesis and folding in gyrencephalic species, their transcripts are modular in folded macaque cortices and pseudo-folded human cerebral organoids.Neurog2/Ascl1double+progenitors are thus Notch-ligand expressing ‘niche’ cells that control neurogenic periodicity to determine cortical gyrification.HIGHLIGHTSNeurog2 and Ascl1 expression defines four distinct transitional progenitor statesDouble+NPCs are transcriptionally complex and mark a lineage branch pointDouble+NPCs control neurogenic patterning and cortical folding via Notch signalingNeurog2 and Ascl1 expression is modular in folded and not lissencephalic corticeseTOC BLURBEmergence of a gyrencephalic cortex is associated with a break in neurogenic continuity across the cortical germinal zone. Han et al. identify a pool of unbiased neural progenitors at a lineage bifurcation point that co-express Neurog2 and Ascl1 and produce Notch ligands to control neurogenic periodicity and cortical folding.
Mouse Single Islet β Cell Transcriptomics Reveal Sexually Dimorphic Transcriptomes and Type 2 Diabetes Genes
Authors: Liu Gang , Li Yana , Zhang Tengjiao , Li Mushan , Li Sheng , He Qing , Liu Shuxin , Xu Minglu , Xiao Tinghui , Shao Zhen , Shi Weiyang , Li Weida 
Published: September 2020

AbstractType 2 diabetes (T2D), characterized by malfunction of pancreatic β cells, is affected by multiple cues including sex differences. Nevertheless, mechanisms of sex differences in type 2 diabetes susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq) technology, we showed that sexual dimorphism of transcriptome exists in mouse β cells. Our analysis further revealed the existence of sex-dependent type 2 diabetes altered genes in high fat diet induced T2D model, suggesting divergences in pathological mechanisms of type 2 diabetes between sexes. Our results indicated that sex should be taken into consideration when treating diabetes, which was further validated by the sex-matched and sex-mismatched islet transplantation in mice. Compared to sex-matched transplants, sex-mismatched transplants showed downregulation of genes involved in the longevity regulating pathway in β cells and led to impaired glucose tolerance in diabetic mice. Taken together, our findings could advance current understanding of type 2 diabetes pathogenesis with sexually dimorphic perspectives and provide new insights to the development of precision medicine.
MarkerCapsule: Explainable Single Cell Typing using Capsule Networks
Authors: Ray Sumanta , Schönhuth Alexander 
Published: September 2020

ABSTRACTMany single cell typing methods require manual annotation which casts problems with respect to resolution of (sub-)types, manpower resources and bias towards existing human knowledge. The integration of heterogeneous data and biologically meaningful interpretation of results are further current key challenges. We introduceMarkerCapsule, which leverages the landmark advantages of capsule networks achieved in their original applications in single cell typing. Thereby, the small amount of labeled data required and the naturally arising, biologically meaningful interpretation of cell types in terms of characteristic gene activity patterns are exemplary strengths, beyond outperforming the state of the art in terms of basic typing accuracy. MarkerCapsule is available at:https://github.com/sumantaray/MarkerCapsule.
Programming effects of peripubertal stress on spatial learning
Authors: Tzanoulinou S. , Gantelet E. , Sandi C. , Marquez C. 
Published: September 2020

AbstractExposure to adversity during early life can have profound influences on brain function and behavior later in life. The peripubertal period is emerging as an important time-window of susceptibility to stress, with substantial evidence documenting long-term consequences in the emotional and social domains. However, little is known about how stress during this period impacts subsequent cognitive functioning. Here, we assessed potential long-term effects of peripubertal stress on spatial learning and memory using the water maze task. In addition, we interrogated whether individual differences in stress-induced behavioral and endocrine changes are related to the degree of adaptation of the corticosterone response to repeated stressor exposure during the peripubertal period. We found that, when tested at adulthood, peripubertally stressed animals displayed a slower learning rate. Strikingly, the level of spatial orientation in the water maze completed on the last training day was predicted by the degree of adaptation of the recovery -and not the peak-of the corticosterone response to stressor exposure (i.e., plasma levels at 60 min post-stressor) across the peripubertal stress period. In addition, peripubertal stress led to changes in emotional and glucocorticoid reactivity to novelty exposure, as well as in the expression levels of the plasticity molecule PSA-NCAM in the hippocampus. Importantly, by assessing the same endpoints in another peripubertally stressed cohort tested during adolescence, we show that the observed effects at adulthood are the result of a delayed programming manifested at adulthood and not protracted effects of stress. Altogether, our results support the view that the degree of stress-induced adaptation of the hypothalamus-pituitary-adrenal axis responsiveness at the important transitional period of puberty relates to the long-term programming of cognition, behavior and endocrine reactivity.
Antibiotics increase aggression behavior and aggression-related pheromones and receptors inDrosophila melanogaster
Authors: Grinberg Michal , Neuman Hadar , Ziv Oren , Turjeman Sondra , Nosenko Rita , Koren Omry 
Published: September 2020

AbstractAggression is a behavior common in most species; it is controlled by internal and external drivers, including hormones, environmental cues, and social interactions, and underlying pathways are understood in a broad range of species. To date, though, effects of gut microbiota on aggression in the context of gut-brain communication and social behavior have not been elucidated. We examine how manipulation ofDrosophila melanogastermicrobiota affect aggression as well as the pathways that underly the behavior in this species. Flies treated with antibiotics exhibited significantly more aggressive behaviors. Furthermore, they had higher levels of vCA and (Z)-9 Tricosene, pheromones associated with aggression in flies, as well as higher expression of the relevant pheromone receptors and transporters OR67d, OR83b, GR32a, and LUSH. These findings suggest that aggressive behavior is, at least in part, mediated by bacterial species in flies.
Neurocognitive Heterogeneity in Social Anxiety Disorder: The Role of Self-Referential Processing and Childhood Maltreatment
Authors: Talmon Anat , Dixon Matthew Luke , Goldin Philippe R. , Heimberg Richard G. , Gross James J. 
Published: September 2020

ABSTRACTSocial anxiety disorder (SAD) is characterized by negative self-beliefs and altered brain activation in the default mode network (DMN). However, the extent to which there is neurocognitive heterogeneity in SAD remains unclear. We had two independent samples of patients perform a self-referential encoding task, and complete self-reports of childhood maltreatment, subjective well-being, and emotion regulation. In the replication sample, we also measured DMN activation using functional magnetic resonance imaging. K-means clustering revealed two distinct sub-groups of SAD patients in the discovery sample. Cluster 1 demonstrated higher levels of negative and lower levels of positive self-referential trait endorsement, and significantly higher levels of childhood emotional maltreatment, lower subjective well-being, and altered emotion regulation strategy use. A similar pattern was observed in the replication sample, which further demonstrated higher DMN activation during negative trait judgments in cluster 1. These findings reveal neurocognitive heterogeneity in SAD and its relationship to emotional maltreatment.
A tale of two tails - efficient profiling of protein degraders by specific functional and target engagement readouts
Authors: Chernobrovkin Alexey L. , Cázares-Körner Cindy , Friman Tomas , Caballero Isabel Martin , Amadio Daniele , Molina Daniel Martinez 
Published: September 2020

AbstractTargeted protein degradation represents an area of great interest, potentially offering improvements with respect to dosing, side effects, drug resistance and reaching ‘undruggable’ proteins compared to traditional small molecule therapeutics. A major challenge in the design and characterization of degraders acting as molecular glues is that binding of the molecule to the protein of interest (PoI) is not needed for efficient and selective protein degradation, instead one needs to understand the interaction with the responsible ligase. Similarly, for proteasome targeting chimeras (PROTACs) understanding the binding characteristics of the PoI alone is not sufficient. Therefore, simultaneously assessing the binding to both PoI and the E3 ligase as well as the resulting degradation profile is of great value. The Cellular Thermal Shift Assay (CETSA) is an unbiased cell-based method, designed to investigate the interaction of compounds with their cellular protein targets by measuring compound-induced changes in protein thermal stability. In combination with mass spectrometry (MS) CETSA can simultaneously evaluate compound induced changes in the stability of thousands of proteins. We have used CETSA MS to profile a number of protein degraders, including molecular glues (e.g. IMiDs) and PROTACs to understand mode of action and to deconvolute off-target effects in intact cells. Within the same experiment we were able to monitor both target engagement by observing changes in protein thermal stability as well as efficacy by simultaneous assessment of protein abundances. This allowed us to correlate target engagement (i.e. binding to the PoI and ligases) and functional readout (i.e. degrader induced protein degradation).
A cell-autonomous PD-1/PD-L1 circuit promotes tumorigenicity of thyroid cancer cells by activating a SHP2/Ras/MAPK signalling cascade
Authors: Liotti Federica , Kumar Narender , Prevete Nella , Marotta Maria , Sorriento Daniela , Ieranò Caterina , Ronchi Andrea , Marino Federica Zito , Moretti Sonia , Colella Renato , Puxeddu Efiso , Paladino Simona , Kano Yoshihito , Ohh Michael , Scala Stefania , Melillo Rosa Marina 
Published: September 2020

AbstractThe programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2 are immune checkpoints. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their anti-cancer activity. Recently, PD-1 expression has been found in cancer cells. We analysed expression and functions of PD-1 in thyroid cancer (TC). Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 overexpression/stimulation promoted TC cell proliferation and migration in culture. PD-1 recruited the SHP2 phosphatase, potentiated its phosphatase activity thus enhancing Ras activation by dephosphorylation of inhibitory tyrosine 32 and triggering the MAPK cascade. PD-1 inhibition decreased, while PD-1 overexpression facilitated, TC cell xenograft growth by affecting cell proliferation. PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the Ras/MAPK pathway.
Structural Analysis of Simultaneous Activation and Inhibition of γ-Secretase Activity in Development of Drugs for Alzheimer’s disease
Authors: Svedružić Željko M. , Vrbnjak Katarina , Martinović Manuel , Miletić Vedran 
Published: September 2020

AbstractSignificanceThe majority of drugs that target membrane-embedded protease γ-secretase show unusual biphasic activation-inhibition dose-response in cells, model animals, and humans. Semagacestat and avagacestat are two biphasic-drugs that can facilitate cognitive decline in patients with Alzheimer’s disease. Initial mechanistic studies showed that the biphasic-drugs, and pathogenic mutations, can produce the same type of changes in γ-secretase activity.ResultsDAPT, semagacestat LY-411,575, and avagacestat are four drugs that show different binding constants, and biphasic activation-inhibition dose-response curves, for amyloid-β-40 products in SHSY-5 cells. Multiscale molecular dynamics studies showed that all four drugs bind to the most mobile parts in presenilin structure, at different ends of the 29 Å long active site tunnel. Combined results from structure-activity studies, showed that the biphasic dose-response curves are a result of modulation of γ-secretase activity by concurrent binding of multiple drug molecules at each end of the active site tunnel. The drugs activate γ-secretase by forcing the active site tunnel to open, when the rate-limiting step is the tunnel opening, and formation of the enzyme-substrate complex. The drugs inhibit γ-secretase as uncompetitive inhibitors, by binding next to the substrate to dynamic enzyme structures that regulate processive catalysis. The drugs can modulate the production of different amyloid-β catalytic intermediates, by penetrating into the active site tunnel to different depth with different binding affinity. The drugs and pathogenic mutations affect the same dynamic processes in γ-secretase structure.ConclusionsBiphasic-drugs like disease-causing mutations can reduce the catalytic capacity of γ-secretase and facilitate pathogenic changes in amyloid metabolism.