bluuebunny/crossref_metadata_2025_split huggingface dataset:
An automated high-content synaptic phenotyping platform in human neurons and astrocytes reveals a role for BET proteins in synapse assembly
Authors: Berryer Martin H. , Rizki Gizem , Susco Sara G. , Lam Daisy , Messana Angelica , Trendafilova Darina , Nathanson Anna , Karhohs Kyle W. , Cimini Beth A. , Pfaff Kathleen , Carpenter Anne E. , Rubin Lee L. , Barrett Lindy E. 
Published: May 2022

ABSTRACTResolving fundamental molecular and functional processes underlying human synaptic development is crucial for understanding normal brain function as well as dysfunction in disease. Based upon increasing evidence of species divergent features of brain cell types, coupled with emerging studies of complex human disease genetics, we developed the first automated and quantitative high-content synaptic phenotyping platform using human neurons and astrocytes. To establish the robustness of our platform, we screened the effects of 376 small molecules on presynaptic density, neurite outgrowth and cell viability, validating six small molecules which specifically enhanced human presynaptic density in vitro. Astrocytes were essential for mediating the effects of all six small molecules, underscoring the relevance of non-cell autonomous factors in synapse assembly and their importance in synaptic screening applications. Bromodomain and extraterminal (BET) inhibitors emerged as the most prominent hit class and global transcriptional analyses using multiple BET inhibitors confirmed upregulation of synaptic gene expression programs. Through these analyses, we demonstrate the robustness of our automated screening platform for identifying potent synaptic modulators, which can be further leveraged for scaled analyses of human synaptic mechanisms and drug discovery efforts.
Integrative analysis ofHydrahead regeneration reveals actions of conserved signaling pathways and transposable elements
Authors: Macias-Muñoz Aide , Mesrop Lisa Y. , Liang Heidi Yahan , Mortazavi Ali 
Published: May 2022

AbstractThe extent to which animals can regenerate cells, tissues, or body parts varies largely.Hydrahas a remarkable ability to undergo full body regeneration. Bisected polyps can regenerate the head and foot, and whole polyps can form from aggregates of cells. This capability is made possible by a cluster of cells known as the head organizer. Previous studies have foundWnt3and other developmental genes associated with head organizer function. Yet, the genetic and molecular mechanisms of regeneratingHydraheads remain unresolved. In this study, we used bulk RNA-seq, bulk ATAC-seq, and single-cell RNA-seq from a regeneration time course to characterize the gene expression, gene regulation, molecular, and cellular features ofHydrahead regeneration. WGCNA modules andcis-regulation of candidate head organizer genes identified genes co-expressed withWnt3and transcription factors important for regeneration. At the single-cell level, we identified at least six distinct cell types in the regenerating head tissue and characterized the expression of candidate genes. With these combined data sets, we identify and clarify some of the interactions between JNK, Wnt3, and EGRF signaling duringHydrahead regeneration. Our study reveals coordination of early wound response, developmental transcription factors, and transposable elements duringHydratissue regeneration and provides insight into the evolution of regeneration programs.
Rab10 inactivation promotes AMPAR trafficking and spine enlargement during long-term potentiation
Authors: Wang Jie , Nishiyama Jun , Parra-Bueno Paula , Okaz Elwy , Oz Goksu , Liu Xiaodan , Watabe Tetsuya , Suponitsky-Kroyter Irena , McGraw Timothy E , Szatmari Erzsebet M. , Yasuda Ryohei 
Published: May 2022

SummaryRab-dependent membrane trafficking is critical for changing the structure and function of dendritic spines during synaptic plasticity. Here, we developed highly sensitive sensors to monitor Rab protein activity in single dendritic spines undergoing structural long-term potentiation (sLTP) in rodent organotypic hippocampal slices. During sLTP, Rab10 was persistently inactivated (>30 min) in the stimulated spines, whereas Rab4 was transiently activated over ∼5 min. Inhibiting or deleting Rab10 enhanced sLTP, electrophysiological LTP and AMPA receptor (AMPAR) trafficking during sLTP. In contrast, disrupting Rab4 impaired sLTP only in the first few minutes, and decreased AMPAR trafficking during sLTP. Thus, our results suggest that Rab10 and Rab4 oppositely regulate AMPAR trafficking during sLTP, and inactivation of Rab10 signaling facilitates the induction of LTP and associated spine structural plasticity.
The circadian clock mediates daily bursts of cell differentiation by periodically restricting cell differentiation commitment
Authors: Zhang Zhi-Bo , Sinha Joydeb , Bahrami-Nejad Zahra , Teruel Mary N. 
Published: May 2022

AbstractMost mammalian cells have an intrinsic circadian clock that coordinates their metabolic activity with the daily rest and wake cycle. In addition, the circadian clock is known to regulate cell differentiation, but how continuous daily oscillations of the internal clock control a much longer, multi-day differentiation process is not known. Here we simultaneously monitor the circadian clock and progression of adipocyte differentiation live in single cells. Strikingly, we find a bursting behavior in the cell population whereby individual preadipocytes commit to differentiate primarily during a 12-hour window each day corresponding to the time of rest. Daily gating of differentiation occurs because cells can irreversibly commit to differentiate within a few hours, which is faster than the rest phase and much faster than the overall multi-day differentiation process. We show that the daily bursts in differentiation are driven by a variable and slow increase in expression of PPARG, the master regulator of adipogenesis, combined with rapid, clock-driven expression of CEBPA, which is in a fast positive feedback relationship with PPARG. During each rest cycle, the increase in CEBPA causes a brief step increase in PPARG so that some cells can reach the threshold to irreversibly commit to differentiate, causing the consecutive daily bursts in cell differentiation at the population level. Our findings are broadly relevant given that most differentiating somatic cells are regulated by the circadian clock. Having a restricted time each day when differentiation occurs may open therapeutic strategies to use timed treatment relative to the clock to promote tissue regeneration.Significance StatementCells rely on a circadian clock that coordinates cellular activities with the day-night cycle. Defects in circadian clock genes dysregulate cell differentiation processes in immune, muscle, skin and fat cells. However, how a perpetual daily clock can regulate a multi-day long cell differentiation process was not understood. Here we show that the circadian clock controls a fast upregulation of the transcription factor CEBPA during each daily rest phase which in turn controls a fast irreversible step during the overall slow multi-day differentiation of fat cells, causing daily bursts of cell differentiation. Our finding opens potential therapeutic strategies to enhance tissue regeneration by timing when during the day drugs are administered.
X-ray imaging of 30 year old wine grape wood reveals cumulative impacts of rootstocks on scion secondary growth and harvest index
Authors: Migicovsky Zoë , Quigley Michelle Y. , Mullins Joey , Ali Tahira , Swift Joel F. , Agasaveeran Anita Rose , Dougherty Joseph D. , Grant Brendan Michael , Korkmaz Ilayda , Malpeddi Maneesh Reddy , McNichol Emily L. , Sharp Andrew W. , Harris Jackie L. , Hopkins Danielle R. , Jordan Lindsay M. , Kwasniewski Misha T. , Striegler R. Keith , Dowtin Asia L. , Stotts Stephanie , Cousins Peter , Chitwood Daniel H. 
Published: May 2022

SummaryAnnual rings from 30 year old vines in a California rootstock trial were measured to determine the effects of 15 different rootstocks on Chardonnay and Cabernet Sauvignon scions. Viticultural traits measuring vegetative growth, yield, berry quality, and nutrient uptake were collected at the beginning and end of the lifetime of the vineyard.X-ray Computed Tomography (CT) was used to measure ring widths in 103 vines. Ring width was modeled as a function of ring number using a negative exponential model. Early and late wood ring widths, cambium width, and scion trunk radius were correlated with 27 traits.Modeling of annual ring width shows that scions alter the width of the first rings but that rootstocks alter the decay thereafter, consistently shortening ring width throughout the lifetime of the vine. The ratio of yield to vegetative growth, juice pH, photosynthetic assimilation and transpiration rates, and stomatal conductance are correlated with scion trunk radius.Rootstocks modulate secondary growth over years, altering hydraulic conductance, physiology, and agronomic traits. Rootstocks act in similar but distinct ways from climate to modulate ring width, which borrowing techniques from dendrochronology, can be used to monitor both genetic and environmental effects in woody perennial crop species.
Impact of genus (Geotrigona,Melipona,Scaptotrigona) in the1H-NMR organic profile and authenticity test of honey processed in cerumen pots by stingless bees in Ecuador
Authors: Vit Patricia , van der Meulen Jane , Pedro Silvia RM , Esperança Isabelle , Zakaria Rahimah , Beckh Gudrun , Maza Favian 
Published: May 2022

AbstractThe biodiversity of Ecuadorian stingless bees is almost 200 species. Traditional pot-honey harvest in Ecuador is mostly done from nests of the three genera selected hereGeotrigonaMoure, 1942,Melipona, Illiger, 1806 andScaptotrigona, Moure 1943. The 20 pot-honey samples collected from cerumen pots and three ethnic honeys “abeja de tierra”, “bermejo”, and “cushillomishki” were analyzed for qualitative and quantitative1H-NMR honey profiling and for the Honey Authenticity Test by Interphase Emulsion (HATIE). Extensive data of targeted organic compounds (41 parameters) was identified, quantified and described. The three honey types were compared by ANOVA. Amino acids, ethanol, hydroxymethylfurfural, aliphatic organic acids, sugars, and markers of botanical or entomological origin. The number of phases observed with the HATIE was one inScaptotrigonaand three inGeotrigonaandMeliponahoneys. Acetic acid (19.60 ± 1.45 g/kg) and lactic acid (24.30 ± 1.65 g/kg) were particularly high inGeotrigonahoney (in contrast to 1.3 g/kg acetic acid and 1.6 g/kg lactic acid inMeliponaandScaptotrigona), with the lowest fructose + glucose (18.39 ± 1.68) g/100g honey compared toMelipona(52.87 ± 1.75) andScaptotrigona(52.17 ± 0.60). Three local honeys were tested using PCA (Principal Component Analysis), two were assigned with a correct declared bee origin, but “bermejo” was not aMeliponaand grouped with theScaptotrigonacluster. However, after HCA (Hierarchical Cluster Analysis), the three kinds of honey were positioned in theMelipona-Scaptotrigonacluster. This research supports the targeted NMR-based profiling in pot-honey metabolomics approach for multi-parameter visualization of organic compounds, descriptive and pertained multivariate statistics (Hierarchical Cluster Analysis HCA, and Principal Component Analysis PCA) to discriminate the stingless bee genus in a set ofGeotrigona,MeliponaandScaptotrigonahoney types. The NMR characterization of Ecuadorian honey produced by stingless bees is a contribution to the needed regulatory norms. A final note on searching stingless bee markers in pot-honey metabolites that may become nutritional trait candidates for phylogeny.Scaptotrigonahoney revealed biosurfactant activity in the HATIE, originating a fingerprint Honey Biosurfactant Test (HBT) for the genus in this set of pot-honeys.
Longitudinal white matter alterations in SIVmac239 infected rhesus monkeys with and without regular cART treatment
Authors: Liu Jiaojiao , Nguchu Benedictor Alexander , Liu Dan , Qi Yu , Alixire  , Han Shuai , Gao Yuxun , Wang Xiaoxiao , Qiao Hongwei , Cai Chao , Huang Xiaojie , Li Hongjun 
Published: May 2022

AbstractObjectiveWe use the SIV-mac239 infected Chinese rhesus monkeys to longitudinally investigate white matters alterations with and without regular combined antiretroviral therapy (cART) treatment, and its relationship with clinical tests.Material and methodsDiffusion tensor imaging (DTI), CD4 T cell counts, and CD4/CD8 were obtained at baseline, 10 days, 4th week,12th week, 24th week, and 36th week post virus inoculation. postinfection (wpi). Microstructural properties were examined within 76 white matter defined by DTI-WM atlas for rhesus macaques. Corrections for multiple comparisons were performed using a false discovery rate (p < 0.05, FDR). Correlation analyses between imaging markers and clinical measures (CD4 T-cell counts, CD4/CD8 ratio) were determined using Pearson’s correlations.ResultsIn our model, White matter alterations in SIV-infected macaques can be detected as soon as 4 weeks post inoculation in several brain regions. And with time proceeding, the cART can reverse, relieve, or even progressive effects. CD4 T-cell count is mainly associated with DTI metrics before the cART, whereas CD4/CD8 ratio was associated with white matter alteration with and without cART.ConclusionSIV-mac239 infection can be an idol modal to explore HIV induced HIV associated brain alterations, and the first group of white matter alterations was as soon as 4 weeks post inoculation in structure next to the periventricular area. As the time progressed, cART can bring different effect to each region, including reversed, relieved, and even progressive effects. In addition, these changes are closely linked to CD4/CD8 ratio even after cART.Importance
Phenol Sensing in Nature Modulated via a Conformational Switch Governed by Dynamic Allostery
Authors: Singh Jayanti , Sahil Mohammad , Ray Shamayeeta , Dcosta Criss , Panjikar Santosh , Krishnamoorthy G. , Mondal Jagannath , Anand Ruchi 
Published: May 2022

ABSTRACTNtrC family of proteins sense external stimuli and accordingly stimulate stress and virulence pathways via activation of associated σ54-dependent RNA polymerases. Here, we establish that MopR, an NtrC protein, harbors a dynamic bi-directional electrostatic network that connects the phenol pocket to two distal regions, namely the “G-hinge” and the “allo-steric-linker”. While G-hinge influences the entry of phenol, the allosteric-linker passes the signal to the downstream ATPase domain. Phenol binding induces a rewiring of the electrostatic connections by eliciting dynamic allostery, and it was demonstrated that perturbation of the core relay residues results in a complete loss of ATPase stimulation. A mutation of the G-hinge,∼20Å from the phenol pocket, demonstrated altered flexibility by shifting the pattern of conformational states accessed, leading to a protein with 7-fold enhanced phenol binding ability and enhanced transcriptional activation. A global analysis illustrates that dynamic allostery-driven conserved community networks are universal and evolutionarily conserved across species.
Increased CaMKK2 expression is an adaptive response that maintains the fitness of tumor-infiltrating natural killer cells
Authors: Juras Patrick K. , Racioppi Luigi , Mukherjee Debarati , Artham Sandeep , Gao Xia , D’Agostino Laura Akullian , Chang Ching-Yi , McDonnell Donald P. 
Published: May 2022

ABSTRACTCalcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been considerable interest in developing CaMKK2 inhibitors as potential cancer therapeutics. However, the roles of CaMKK2 in other cellular compartments within the tumor immune environment remain to be established, an impediment to the clinical development of these agents. We report that CaMKK2 is expressed at low basal levels in natural killer (NK) cells but is significantly upregulated in tumor-infiltrating NK cells where it suppresses apoptosis and promotes proliferation. It was further demonstrated that NK cell-intrinsic deletion of CaMKK2 increased metastatic progression across several murine models, establishing a critical role for this enzyme in NK cell tumor immunity. Interestingly, ablation of the CaMKK2 protein, but not inhibition of its kinase activity, resulted in decreased NK cell survival. These results indicate an important scaffold function for CaMKK2 in NK cells and suggest that competitive CaMKK2 inhibitors and ligand-directed degraders (LDDs) are likely to have distinct therapeutic utilities. Finally, we determined that intracellular lactic acid is a key driver of CaMKK2 expression, suggesting that upregulated expression of this enzyme is an adaptive mechanism by which tumor-infiltrating NK cells mitigate the deleterious effects of a lactate-rich tumor environment. The findings of this study should inform strategies to manipulate the CaMKK2 signaling axis as a therapeutic approach in cancer.
Midbrain-Hippocampus Structural Connectivity Selectively Predicts Motivated Memory Encoding
Authors: Elliott Blake L. , D’Ardenne Kimberlee , Murty Vishnu P. , Brewer Gene A. , McClure Samuel M. 
Published: May 2022

AbstractMotivation is a powerful driver of learning and memory. Functional MRI studies show that interactions between the dopaminergic midbrain (SN/VTA), hippocampus, and nucleus accumbens (NAc) are critical for motivated memory encoding. However, it is not known if these effects are transient and purely functional, or if individual differences in the structure of this circuit underlie motivated memory encoding. To quantify individual differences in structure, diffusion-weighted MRI and probabilistic tractography were used to quantify SN/VTA-striatum and SN/VTA-hippocampus pathways associated with motivated memory encoding in humans.Participants completed a motivated source memory paradigm. During encoding, words were randomly assigned to one of three conditions: reward ($1.00), control ($0.00), or punishment (-$1.00). During retrieval, participants were asked to retrieve item and source information of the previously studied words and were rewarded or penalized according to their performance. Source memory for words assigned to both reward and punishment conditions was greater than control words, while there were no differences in item memory based on value. Anatomically, probabilistic tractography results revealed a heterogeneous, topological arrangement of the SN/VTA. Tract density measures of SN/VTA-hippocampus pathways were positively correlated with individual differences in reward and punishment modulated memory performance, while density of SN/VTA-striatum pathways showed no association. This novel finding suggests that pathways emerging from the human SV/VTA are anatomically separable and functionally heterogeneous. Individual differences in structural connectivity of the dopaminergic hippocampus-VTA loop are selectively associated with motivated memory encoding.Significance StatementFunctional MRI studies show that interactions between the dopaminergic midbrain (SN/VTA), hippocampus, and nucleus accumbens (NAc) are critical for motivated memory encoding. This has led to competing theories that posit either SN/VTA-NAc reward prediction errors or SN/VTA-hippocampus signals underlie motivated memory encoding. Additionally, it is not known if these effects are transient and purely functional, or if individual differences in the structure of these circuits underlie motivated memory encoding. Using diffusion-weighted MRI and probabilistic tractography, we show that tract density measures of SN/VTA-hippocampus pathways are positively correlated with motivated memory performance, while density of SN/VTA-striatum pathways show no association. This finding suggests that anatomical individual differences of the dopaminergic hippocampus-VTA loop are selectively associated with motivated memory encoding.
Disruption of Smarce1, a component of the SWI/SNF chromatin remodeling complex, decreases nucleosome stability in mouse embryonic stem cells and impairs differentiation
Authors: Kashiwagi Katsunobu , Yoshida Junko , Kimura Hiroshi , Horie Kyoji 
Published: May 2022

AbstractThe SWI/SNF chromatin remodeling complex consists of more than 10 component proteins that form a large protein complex of > 1 MDa. The catalytic proteins Smarca4 or Smarca2 work in concert with the component proteins to form a chromatin platform suitable for transcriptional regulation. However, the mechanism by which each component protein works synergistically with the catalytic proteins remains largely unknown. Here, we report on the function of Smarce1, a component of the SWI/SNF complex, through the phenotypic analysis of homozygous mutant embryonic stem (ES) cells. Disruption of Smarce1 induced the dissociation of other complex components from the SWI/SNF complex. Histone binding to DNA was loosened in homozygous mutant ES cells, indicating that disruption of Smarce1 decreased nucleosome stability. Sucrose gradient sedimentation analysis suggested an ectopic genomic distribution of the SWI/SNF complex, accounting for the misregulation of chromatin conformations. Unstable nucleosomes remained during ES cell differentiation, impairing the heterochromatin formation that is characteristic of the differentiation process. These results suggest that Smarce1 guides the SWI/SNF complex to the appropriate genomic regions to generate chromatin structures adequate for transcriptional regulation.