bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liquid condensation drives telomere clustering during ALT
Authors: Zhang Huaiying , Liu Michel , Dilley Robert , Chenoweth David M. , Greenberg Roger A. , Lampson Michael A. 
Published: May 2019

AbstractTelomerase-free cancer cells employ a recombination-based alternative lengthening of telomeres (ALT) pathway that depends on ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs), whose function is unclear. We find that APBs behave as liquid condensates, suggesting two potential mechanisms to promote telomere elongation: condensation to enrich DNA repair factors for telomere synthesis and coalescence to cluster telomeres to provide repair templates. Using chemically-induced dimerization, we show that telomere sumoylation nucleates APB condensation via SUMO-SIM (SUMO interaction motif) interactions and clusters telomeres. The induced APBs lack DNA repair factors, indicating that these factors are clients recruited to the APB scaffold rather than components that drive condensation. Telomere clustering, however, relies only on liquid properties of the condensate, as an alternative condensation chemistry also induces clustering. Our results demonstrate how the material properties and chemical composition of APBs independently contribute to ALT, suggesting a general framework for how liquid condensates promote cellular functions.
Alpha/beta power decreases track the fidelity of stimulus-specific information
Authors: Griffiths Benjamin J. , Mayhew Stephen D. , Mullinger Karen J. , Jorge João , Charest Ian , Wimber Maria , Hanslmayr Simon 
Published: May 2019

AbstractMassed synchronised neuronal firing is detrimental to information processing. When networks of task-irrelevant neurons fire in unison, they mask the signal generated by task-critical neurons. On a macroscopic level, mass synchronisation of these neurons can contribute to the ubiquitous alpha/beta (8-30Hz) oscillations. Reductions in the amplitude of these oscillations, therefore, may reflect a boost in the processing of high-fidelity information within the cortex. Here, we test this hypothesis. Twenty-one participants completed an associative memory task while undergoing simultaneous EEG-fMRI recordings. Using representational similarity analysis, we quantified the amount of stimulus-specific information represented within the BOLD signal on every trial. When correlating this metric with concurrently-recorded alpha/beta power, we found a significant negative correlation which indicated that as alpha/beta power decreased, our metric of stimulus-specific information increased. This effect generalised across cognitive tasks, as the negative relationship could be observed during visual perception and episodic memory retrieval. Further analysis revealed that this effect could be better explained by alpha/beta power decreases providing favourable conditions for information processing, rather than directly representing stimulus-specific information. Together, these results indicate that alpha/beta power decreases parametrically track the fidelity of both externally-presented and internally-generated stimulus-specific information represented within the cortex.
Similarities between Borderline Personality Disorder and Post traumatic Stress Disorder: evidence from Resting-State Meta-Analysis
Authors: Amad Ali , Radua Joaquim , Vaiva Guillaume , Williams SCR , Fovet Thomas 
Published: May 2019

AbstractBorderline personality disorder (BPD) and post-traumatic stress disorder (PTSD) are common psychiatric disorders. The nature of the relationship between BPD and PTSD remains controversial, but it has been suggested that these disorders should brought closer because of their many similarities. We thus performed a quantitative meta-analysis of resting-state functional imaging to assess similarities in the brain activation across BPD and PTSD diagnostic groups.Overlap analyses revealed decreased activation in the left and right precuneus of both BPD and PTSD groups when compared to control subjects. BPD showed significant increased, but PTSD showed decreased activation, relative to control subjects, in the anterior cingulate/paracingulate gyri and in the left superior frontal gyrus. Complementary overlap analyses on a subgroup of studies with similar sex and age distribution partially confirmed the main results as the same pattern of functional activation in the anterior cingulate and in the left superior frontal gyrus were found.Our findings are in agreement with the hypothesis that BPD and PTSD share common neuropathological pathways.
Disentangling neuronal inhibition and inhibitory pathways in the lateral habenula
Authors: Webster Jack F. , Vroman Rozan , Balueva Kira , Wulff Peer , Sakata Shuzo , Wozny Christian 
Published: May 2019

AbstractThe lateral habenula (LHb) is hyperactive in depression, and thus potentiating inhibition of this structure makes an interesting target for future antidepressant therapies. However, the circuit mechanisms mediating inhibitory signalling within the LHb are not well-known. We addressed this issue by studying LHb neurons expressing either parvalbumin (PV), neuron-derived neurotrophic factor (Ndnf) or somatostatin (SOM), three markers of particular sub-classes of neocortical inhibitory neurons. While we report that Ndnf is not representative of any particular sub-population of LHb neuron, we find that both PV and SOM are expressed by physiologically distinct sub-classes. Furthermore, we describe multiple sources of inhibitory input to the LHb arising from both local PV-positive neurons, and from PV-positive neurons in the medial dorsal thalamic nucleus, and from SOM-positive neurons in the ventral pallidum. These findings hence provide new insight into inhibitory control within the LHb, and highlight that this structure is more neuronally diverse than previously thought.SummaryThe lateral habenula receives inhibitory input from three distinct sources: from local PV-positive neurons, from PV-positive neurons in the medial dorsal thalamic nucleus (MDT); and from SOM-positive neurons in the ventral pallidum (VP).Significance statementThe circuitry by which inhibitory signalling is processed within the lateral habenula is currently not well understood; yet this is an important topic as inhibition of the lateral habenula has been shown to have antidepressant efficacy. We therefore investigated inhibitory signalling mechanisms within the lateral habenula by studying input neurons expressing markers commonly associated with inhibitory identity. We identity sources of inhibitory input from both local neurons, and arising from neurons in the medial dorsal thalamic nucleus and ventral pallidum.ContributionsJ.F.W. performed the experiments. R.V. contributed to experiments. J.F.W. analysed the data. K.B. and P.W. designed and performed the in situ hybridisation experiments. C.W. designed and supervised the study, and helped J.F.W write the manuscript. R.V. and S.S. contributed to the manuscript and discussions.
Monocytes from Older Adults Maintain Capacity for Metabolic Compensation during Glucose Deprivation and Lipopolysaccharide Stimulation
Authors: Yarbro Johnathan R. , Pence Brandt D. 
Published: May 2019

ABSTRACTInflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism along with impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose deprivation as measured on a Seahorse XFp system. Additionally, aged monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged monocytes maintain effector and metabolic functions during glucose deprivation, at least in an ex vivo context.
Regulation of tau’s proline rich region by its N-terminal domain
Authors: McKibben Kristen , Rhoades Elizabeth 
Published: May 2019

AbstractTau is an intrinsically disordered, microtubule-associated protein with a role in regulating microtubule dynamics. Despite intensive research, the molecular mechanisms of taumediated microtubule polymerization are poorly understood. Here we use single molecule fluorescence to investigate the role of tau’s N-terminal domain (NTD) and proline rich region (PRR) in regulating interactions of tau with soluble tubulin. Both full-length tau isoforms and truncated variants are assayed for their ability to bind soluble tubulin and stimulate microtubule polymerization. We describe a novel role for tau’s PRR as an independent tubulin-binding domain with polymerization capacity. In contrast to the relatively weak tubulin interactions distributed throughout the microtubule binding repeats (MTBR), resulting in heterogeneous tau:tubulin complexes, the PRR binds tubulin tightly and stoichiometrically. Moreover, we demonstrate that interactions between the PRR and MTBR are reduced by the NTD through a conserved conformational ensemble. Based on our data, we propose that tau’s PRR can serve as a core tubulin-binding domain, while the MTBR enhances polymerization capacity by increasing the local tubulin concentration. The NTD negatively regulates tubulin-binding interactions of both of these domains. This study draws attention to the central role of the PRR in tau function, as well as providing mechanistic insight into tau-mediated polymerization of tubulin.Significance StatementTau is an intrinsically disordered, microtubule associated protein linked to a number of neurodegenerative disorders. Here we identify tau’s proline rich region as having autonomous tubulin binding and polymerization capacity, which is enhanced by the flanking microtubule binding repeats. Moreover, we demonstrate that tau’s N-terminal domain negatively regulates both binding and polymerization. We propose a novel model for tau-mediated polymerization whereby the proline rich region serves as a core tubulin-binding domain, while the microtubule binding repeats increase the local concentration. Our work draws attention to the importance of the proline rich region and N-terminal domain in tau function, and highlights the proline rich region as a putative target for the development of therapeutics.
Expression of genes in the16p11.2locus during human fetal cortical neurogenesis
Authors: Morson Sarah , Yang Yifei , Price David J. , Pratt Thomas 
Published: May 2019

AbstractThe 593 kbp16p11.2copy number variation (CNV) affects the gene dosage of 29 protein coding genes, with heterozygous16p11.2microduplication or microdeletion implicated in about 1% of autism spectrum disorder (ASD) cases. The16p11.2CNV is frequently associated with macrocephaly or microcephaly indicating early defects of neurogenesis may contribute to subsequent ASD symptoms, but it is unknown which16p11.2transcripts are expressed in progenitors and whose levels are likely, therefore, to influence neurogenesis. Analysis of human fetal gene expression data revealed that of all the16p11.2transcripts only two,ALDOAandKIF22, are significantly enriched in progenitors. To investigate the role ofALDOAandKIF22in human cerebral cortex development we used immunohistochemical staining to describe their expression in late first and early second trimester human cerebral cortex. KIF22 protein is restricted to proliferating cells with its levels increasing during the cell cycle and peaking at mitosis. ALDOA protein is expressed in all cell types and does not vary with cell-cycle phase. Our expression analysis suggests the hypothesis that the simultaneous changes in KIF22 and ALDOA dosage in cortical progenitors causes defects in neurogenesis that may contribute to ASD in16p11.2CNV patients.
Effect of Thrombospondin-4 on Pro-inflammatory Phenotype Differentiation and Apoptosis in Macrophages
Authors: Rahman Mohammed Tanjimur , Muppala Santoshi , Wu Jiahui , Krukovets Irene , Solovjev Dmitry , Verbovetskiy Dmitriy , Plow Edward F. , Stenina-Adognravi Olga 
Published: May 2019

AbstractThrombospondin-4 (TSP4) attracted a lot of attention recently as a result of new functions identified for this matricellular protein in cardiovascular, muscular, and nervous systems. We have previously reported that TSP4 promotes local vascular inflammation in mouse atherosclerosis model. A common variant of TSP4, P387-TSP4, was associated with increased cardiovascular disease risk in human population studies. In a mouse atherosclerosis model, TSP4 had profound effect on accumulation of macrophages in lesions, which prompted us to examine its effects on macrophages, more in detail in this report.We examined the effects of A387-TSP-4 and P387-TSP-4 on mouse macrophages in cell culture andin vivoin the model of LPS-induced peritonitis. In tissues and in cell culture, TSP4 expression was associated with inflammation: TSP4 expression was upregulated in peritoneal tissues in LPS-induced peritonitis, and pro-inflammatory signals, INFγ, GM-CSF, and LPS, induced TSP4 expression in macrophagesin vivoand in cell culture. Deficiency in TSP-4 in macrophages fromThbs4−/−mice reduced the expression of pro-inflammatory macrophage markers, suggesting that TSP-4 facilitates macrophage differentiation into pro-inflammatory phenotype. Expression of TSP4, especially more active P387-TSP4, was associated with higher cellular apoptosis. Cultured macrophages displayed increased adhesion to TSP4 and reduced migration in presence of TSP4, and these responses were further increased with P387 variant.We concluded that TSP4 expression in tissue macrophages and in cultured macrophages increases their accumulation in tissues during the acute inflammatory process and supports macrophage differentiation into a pro-inflammatory phenotype. In a model of acute inflammation, TSP4 supports pro-inflammatory macrophage apoptosis, a response that is closely related to their pro-inflammatory activity and release of pro-inflammatory signals. P387-TSP4 was found to be more active form of TSP4 in all examined functions.
Bubble Trouble: Conquering Microbubble Limitations in Contrast Enhanced Ultrasound Imaging by Nature-Inspired Ultrastable Echogenic Nanobubbles
Authors: de Leon Al , Perera Reshani , Hernandez Christopher , Cooley Michaela , Jung Olive , Jeganathan Selva , Abenojar Eric , Fishbein Grace , Sojahrood Amin Jafari , Emerson Corey C. , Stewart Phoebe L. , Kolios Michael C. , Exner Agata A. 
Published: May 2019

AbstractAdvancement of ultrasound molecular imaging applications requires not only a reduction in size of the ultrasound contrast agents (UCAs) but also a significant improvement in the in vivo stability of the shell-stabilized gas bubble. The transition from first generation to second generation UCAs was marked by an advancement in stability as air was replaced by a hydrophobic gas, such as perfluoropropane and sulfur hexafluoride. Further improvement can be realized by focusing on how well the UCAs shell can retain the encapsulated gas under extreme mechanical deformations. Here we report the next generation of UCAs for which we engineered the shell structure to impart much better stability under repeated prolonged oscillation due to ultrasound, and large changes in shear and turbulence as it circulates within the body. By adapting an architecture with two layers of contrasting elastic properties similar to bacterial cell envelopes, our ultrastable nanobubbles (NBs) withstand continuous in vitro exposure to ultrasound with minimal signal decay and have a significant delay on the onset of in vivo signal decay in kidney, liver, and tumor. Development of ultrastable NBs can potentially expand the role of ultrasound in molecular imaging, theranostics, and drug delivery.
MultiEditR: An easy validation method for detecting and quantifying RNA editing from Sanger sequencing
Authors: Kluesner Mitchell , Arnold Annette , Lerner Taga , Tasakis Rafail Nikolaos , Wüst Sandra , Binder Marco , Moriarity Branden S. , Pecori Riccardo 
Published: May 2019

ABSTRACTRNA editing is the base change that results from RNA deamination by two predominant classes of deaminases; the APOBEC family and the ADAR family. Respectively, deamination of nucleobases by these enzymes are responsible for endogenous editing of cytosine to uracil (C-to-U) and adenosine to inosine (A-to-I). RNA editing is known to play an essential role both in maintaining normal cellular function, as well as altered cellular physiology during oncogenesis and tumour progression. Analysis of RNA editing in these important processes, largely relies on RNA-seq technology for the detection and quantification of RNA editing sites. Despite the power of these technologies, multiple sources of error in detecting and measuring base editing still exist, therefore additional validation and quantification of editing through Sanger sequencing is still required for confirmation of editing. Depending on the number of RNA editing sites that are of interest, this validation step can be both expensive and time-consuming. To address this need we developed the tool MultiEditR which provides a simple, and cost-effective method of detecting and quantifying RNA editing form Sanger sequencing. We expect that MultiEditR will foster further discoveries in this rapidly expanding field.
An atlas of the catalytically active liver and spleen kinases in chicken identified by chemoproteomics
Authors: Nanduri Bindu , Gresham Cathy R. , Hui Winnie W. , Ou Mark , Bailey Richard H. , Edelmann Mariola J. 
Published: May 2019

AbstractChicken is the first agricultural animal to have a sequenced genome, but current kinase annotations of Gallus gallus are overwhelmingly limited to the predictions generated based on homology or isolated studies focused on specific kinases. Our approach used chemical probes consisting of ATP and ADP derivatives binding to specific lysine residues within the ATP-binding pocket of kinases. Collectively, we identified 188 chicken kinases and corresponding 267 peptides labeled with the ATP and ADP acyl derivatives in chicken spleen and liver. The kinases identified here are publicly available through the database, Chickspress genome browser (http://geneatlas.arl.arizona.edu/cgi-bin/GeneAtlas/chickspress_genes.cgii). Analysis of putative functions of these chicken kinases indicates that kinases identified in this study might regulate hematological system development, necrosis, apoptosis, epithelial neoplasm, and other processes. The identified tissue-specific expression atlas of active chicken kinases along with the ATP binding sites of kinases provide the basis for the development of specific drug targets for multiple chicken diseases as well as starting point for inhibitor selectivity studies in this agriculturally important species. Moreover, this study will support future studies focused on identifying the role of these kinases in chicken growth, metabolism, and disease.
Environmental, social, management and health factors associated with within- and between-individual variability in fecal glucocorticoid metabolite concentrations in zoo-housed Asian and African elephants
Authors: Brown Janine L. , Bray Jessica D. , Carlstead Kathy , Dickey David , Farin Charlotte , Heugten Kimberly Ange-van 
Published: May 2019

AbstractIdentifying links between environmental, social, management, and health factors as they relate to physiological stress in captive elephants is crucial for the improvement of welfare and husbandry practices in North American zoos. Studies have examined the effects of short-term and chronic elevations in glucocorticoids in small groups of elephants, but few have examined adrenal activity on a large scale. This study evaluated 106 Asian(Elephas maximus)and 131 African(Loxodonta africana)elephants housed at 64 accredited facilities across North America. Fecal samples were collected every other week for 12 months and analyzed for glucocorticoid metabolite (FGM) concentrations. Risk factors for mean and individual variability (CV) in FGM were subjected to univariate and multivariable analyses using epidemiological methods. Independent variables that included individual traits, social environment, housing and management factors were chosen based on their identification as risk factors in previously published models for the same North American population of elephants. Results indicate that African elephants are more responsive to social stressors than Asians, and that poor joint health is a stress-related welfare problem for Asian, but not African elephants. For both species, higher FGM concentrations were associated with zoos located at more northern latitudes and having free access to indoor/outdoor spaces, whereas spending more time in managed interactions with staff were associated with lower FGM concentrations. Also important for captive management, elephants having diverse enrichment options and belonging to compatible social groups exhibited lower mean and reduced intra-individual variability in FGM. Our findings show that aspects of the zoo environment can be potential sources of stress for captive elephants, and that there are management activities that can facilitate coping and adapting to zoo conditions. Given species differences in factors that affected FGM, targeted, species-specific management approaches likely are needed to ensure good welfare for all elephants.