bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein Acetylation Induced by Dichloroacetate (DCA) Treatment is Associated with Decreased Respiration in Cultured Hepatocytes: Preliminary Results
Authors: Meyer Jesse G. 
Published: June 2019

AbstractProtein post-translational modification (PTM) by acetylation at the ε-amine on lysine residues in proteins regulates various cellular processes including transcription and metabolism. Several metabolic and genetic perturbations are known to increase acetylation of various proteins. Hyper-acetylation can also be induced using deacetylase inhibitors. While there is much interest in discovering drugs that can reverse protein acetylation, pharmacological tools that increase non-enzymatic protein acetylation are needed in order to understand the physiological role of excess protein acetylation. In this study, I assessed whether inhibition of pyruvate dehydrogenase kinase (PDHK) could cause protein hyper-acetylation due to excess production of acetyl-CoA by pyruvate dehydrogenase (PDH). Western blot of total protein from dichloroacetate (DCA) treated hepatocytes with anti-acetyl-lysine antibody showed increased protein acetylation, and seahorse respirometry of DCA pretreated hepatocytes indicated a subtle decrease in basal and maximal respiratory capacity.
Multi-omic analyses reveal antibody-dependent natural killer cell-mediated cytotoxicity in autoimmune thyroid diseases
Authors: Martin Tiphaine C. , Illieva Kristina M. , Visconti Alessia , Beaumont Michelle , Kiddle Steven J. , Dobson Richard J.B. , Mangino Massimo , Lim Ee Mun , Pezer Marija , Steves Claire J. , Bell Jordana T. , Wilson Scott G. , Lauc Gordan , Roederer Mario , Walsh John P. , Spector Tim D. , Karagiannis Sophia N. 
Published: June 2019

AbstractThe pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation of peripheral blood mononuclear cells in AITD, correlated with thyroid peroxidase antibody (TPOAb) levels. We hypothesized that deficiency in IgG core fucose enhances antibody-dependent cell-mediated cytotoxicity of thyrocytes by TPOAb, contributing to thyroid autoimmunity. Multi-omic evaluations in 622 individuals (172 with AITD) from the TwinsUK cohort showed decreased IgG core fucosylation levels associated with a subpopulation of natural killer (NK) cells featuring CD335, CD314, and CD158b immunoreceptors, and increased levels of apoptosis-associated Caspase-2 and Interleukin-1α, positively associated with AITD. AITD-associated genetic variants rs1521 and rs3094228 alter expression of thyrocyte ligands of the CD314 and CD158b immunoreceptors on NK cells. The combination of low-core fucose IgG associated with an NK cell subpopulation and genetic variant-promoted ligand activation in thyrocytes may promote antibody-dependent NK cell-mediated cytotoxicity of thyrocytes in AITD.
The emergent Yo-yo movement of nuclei driven by collective cytoskeletal remodeling in pseudo-synchronous mitotic cycles
Authors: Lv Zhiyi , Rosenbaum Jan , Mohr Stephan , Zhang Xiaozhu , Kong Deqing , Preiß Helen , Kruss Sebastian , Alim Karen , Aspelmeier Timo , Großhans Jörg 
Published: June 2019

AbstractMany aspects in tissue morphogenesis are attributed to the collective behavior of the participating cells. Yet, the mechanism for emergence of dynamic tissue behavior is not understood completely. Here we report the “yo-yo”-like nuclear drift movement in Drosophila syncytial embryo displays typical emergent feature of collective behavior, which is associated with pseudo-synchronous nuclear division cycle. We uncover the direct correlation between the degree of asynchrony of mitosis and the nuclear collective movement. Based on experimental manipulations and numerical simulations, we find the ensemble of spindle elongation, rather than a nucleus’ own spindle, is the main driving force for its drift movement. The cortical F-actin acts as viscoelastic medium to dampen the movements and plays a critical role in restoring the nuclear positions after a mitosis cycle. Our study provides insights into how the interactions between cytoskeleton as individual elements leads to collective movement of the nuclear array on a macroscopic scale.
Antigen-Specific Immune Decoys Intercept and Exhaust Autoimmunity to Prevent Disease
Authors: Griffin J. Daniel , Song Jimmy Y. , Huang Aric , Sedlacek Alexander R. , Flannagan Kaitlin L. , Berkland Cory J. 
Published: June 2019

ABSTRACTRelapsing-remitting patterns of many autoimmune diseases such as multiple sclerosis (MS) are perpetuated by a recurring circuit of adaptive immune cells that amplify in secondary lymphoid organs (SLOs) and traffic to compartments where antigen is abundant to elicit damage. Some of the most effective immunotherapies impede the migration of immune cells through this circuit, however, broadly suppressing immune cell migration can introduce life-threatening risks for patients. We developed antigen-specific immune decoys (ASIDs) to mimic tissues targeted in autoimmunity and selectively intercept autoimmune cells to preserve host tissue. Using Experimental Autoimmune Encephalomyelitis (EAE) as a model, we conjugated autoantigen PLP139-151 to a microporous collagen scaffold. By subcutaneously implanting ASIDs after induction but prior to the onset of symptoms, mice were protected from paralysis. ASID implants were rich with autoimmune cells, however, reactivity to cognate antigen was substantially diminished and apoptosis was prevalent. ASID-implanted mice consistently exhibited engorged spleens when disease normally peaked. In addition, splenocyte antigen-presenting cells were highly activated in response to PLP rechallenge, but CD3+ and CD19+ effector subsets were significantly decreased, suggesting exhaustion. ASID-implanted mice never developed EAE relapse symptoms even though the ASID material had long since degraded, suggesting exhausted autoimmune cells did not recover functionality. Together, data suggested ASIDs were able to sequester and exhaust immune cells in an antigen-specific fashion, thus offering a compelling approach to inhibit the migration circuit underlying autoimmunity.
A versatile method for circulating cell-free DNA methylome profiling by reduced representation bisulfite sequencing
Authors: De Koker A. , Van Paemel R. , De Wilde B. , De Preter K. , Callewaert N. 
Published: June 2019

AbstractThe methylation profile of circulating cell-free DNA (cfDNA) in blood can be exploited to detect and diagnose cancer and other tissue pathologies and is therefore of great diagnostic interest. There is an urgent need for a cost-effective genome-wide methylation profiling method that is simple, robust and automatable and that works on highly fragmented cfDNA. We report on a novel sample preparation method for reduced representation bisulfite sequencing (RRBS), rigorously designed and customized for minute amounts of highly fragmented DNA. Our method works in particular on cfDNA from blood plasma. It is a performant and cost-effective methodology (termed cf-RRBS) which enables clinical cfDNA epigenomics studies.
Nucleus Basalis links sensory stimuli with delayed reinforcement to support learning
Authors: Guo W. , Polley D.B. 
Published: June 2019

SummaryLinking stimuli with delayed reinforcement requires neural circuits that can bridge extended temporal gaps. Auditory cortex (ACx) circuits reorganize to support auditory fear learning, but only when afferent sensory inputs temporally overlap with cholinergic reinforcement signals. Here we show that mouse ACx neurons rapidly reorganize to support learning, even when sensory and reinforcement cues are separated by a long gap. We found that cholinergic basal forebrain neurons bypass the temporal delay through multiplexed, short-latency encoding of sensory and reinforcement cues. At the initiation of learning, cholinergic neurons in Nucleus Basalis increase responses to conditioned sound frequencies and increase functional connectivity with ACx. By rapidly scaling up responses to sounds that predict reinforcement, cholinergic inputs jump the gap to align with bottom-up sensory traces and support associative cortical plasticity.
Purinergic signaling is enhanced in the absence of UT-A1 and UT-A3
Authors: Himmel Nathaniel J. , Rogers Richard T. , Redd Sara K. , Wang Yirong , Blount Mitsi A. 
Published: June 2019

AbstractATP is an important paracrine regulator of renal tubular water and urea transport. The activity of P2Y2, the predominant P2Y receptor of the medullary collecting duct, is mediated by ATP, and modulates urinary concentration. To investigate the role of purinergic signaling in the absence of urea transport in the collecting duct, we housed wild-type (WT) and UT-A1/A3 null (UT-A1/A3 KO) mice in metabolic cages to monitor urine output, and collected tissue samples for analysis. We confirmed that UT-A1/A3 KO mice are polyuric, and concurrently observed lower levels of urinary cAMP as compared to WT, despite elevated serum vasopressin (AVP) levels. Because P2Y2inhibits AVP-stimulated transport by dampening cAMP synthesis, we suspected that, similar to other models of AVP-resistant polyuria, purinergic signaling is increased in UT-A1/A3 KO mice. In fact, we observed that both urinary ATP and purinergic-mediated prostanoid (PGE2) levels were elevated. Tissue analysis shows that P2Y2mRNA levels remain unchanged, while P2Y2protein levels are elevated in KO mice. Collectively, our data suggest that the reduction of medullary osmolality due to the lack of UT-A1 and UT-A3 induces an AVP-resistant polyuria that is possibly exacerbated by, or at least correlated with, enhanced purinergic signaling.Summary statementPhysiological analyses suggest that mice lacking urea transporters have increased renal purinergic signaling, perhaps contributing to previously observed vasopressin-resistant polyurias.
Effectiveness of treatments for firework fears in dogs
Authors: Riemer Stefanie 
Published: June 2019

AbstractAn online questionnaire survey investigated (1) management and (2) treatment methods for firework fears in dogs employed by dog owners and their (perceived) effectiveness. A PCA on data from 1225 respondents revealed four management strategies (i.e. interventions during firework exposure): the principal components “Environmental modification” (e.g. providing a hiding place, keeping windows and blinds closed, and playing music), “Feed/Play” (providing the dog with chews, play and food during fireworks in general, as well as contingent on loud bangs), “Alternative” (use of calming nutraceuticals, pheromones, herbal products, homeopathic products, Bach flowers, and essential oils) and “Interaction” (allowing body contact, petting and talking to the dog when loud bangs occurred). To explore possible effects of these management methods on fear development, the components were correlated with a score for fear progression. Of the four components, only “Feed/Play” was statistically associated with an improvement in fear responses to fireworks. To evaluate the effectiveness of various treatment strategies, owners were asked to select from a range of options which interventions they had used and whether they considered them as effective. With prescription medication (N=202), improvements were noted by 69% of owners, with high success rates reported for the most frequently prescribed drugs, alprazolam (91%) and Sileo® (74%). While individual products were not evaluated, the reported success rates for the categories “pheromones” (N=316), “herbal products” (N=282), “nutraceuticals” (N=211), “essential oils” (N=183), “homeopathic remedies” (N=250) and “Bach flowers” (N=281) were all in the range of 27-35%, which is not higher than would be expected based on a placebo effect. Pressure vests were deemed as effective by 44% of respondents (N=300). Counterconditioning (providing desirable stimuli after the occurrence of noises) was the most successful training technique according to the owners (N=694), with a reported effectiveness of over 70%. Relaxation training (N=433) was reported to be almost as successful at 69%, while noise CDs (N=377) were effective in 55% of cases. Thus, counterconditioning, relaxation training and anxiolytic medication appear to be the most effective strategies in the treatment of firework fears in dogs. On this basis it is recommended that ad-hoc counterconditioning and relaxation training should complement the standard behavioral technique of desensitization/ counterconditioning with noise recordings.HighlightsAn online survey on treatment options for firework fears in dogs was performedFeeding or playing with dogs during fireworks was associated with fear improvementSuccess was highest for ad-hoc counterconditioning, relaxation training and medicationSuccess was similar for pheromones, nutraceuticals and other alternative productsSuccess rates for these alternative products are consistent with a placebo effect
RHOA mediated mechanical force generation through Dectin-1
Authors: Choraghe Rohan P. , Kołodziej Tomasz , Buser Alan , Rajfur Zenon , Neumann Aaron K. 
Published: June 2019

ABSTRACTDectin-1 is an innate immune pattern recognition receptor which recognizes β-glucan on theCandida albicans(C. albicans) cell wall. Recognition of β-glucan by immune cells leads to phagocytosis, oxidative burst, cytokine and chemokine production. We looked for specific mechanisms that coordinate phagocytosis downstream of Dectin-1 leading to actin reorganization and internalization of fungus. We found that stimulation of Dectin-1 by soluble β-glucan leads to mechanical force generation and areal contraction in Dectin-1 transfected HEK-293 cells and M1 macrophages. With inhibitor studies, we found this force generation is a SYK-independent, SFK (SRC Family Kinase)-dependent process mediated through the RHOA-ROCK-MLC pathway. We confirmed activation of RHOA downstream of Dectin-1 using G-LISA and stress fiber formation. Through phagocytosis assays, we found direct evidence for importance of RHOA-ROCK-MLC pathway in process of phagocytosis ofC. albicans. In conclusion, we found evidence for RHOA-ROCK-MLC mediated mechanical force generation downstream of Dectin-1 forC. albicansphagocytosis.
Molecularly distinct cores coexist inside stress granules
Authors: Cirillo Luca , Cieren Adeline , Gotta Monica 
Published: June 2019

SummaryStress granules are membraneless organelles that form in eukaryotic cells after stress exposure. Stress granules are constituted by a stable core and a dynamic shell that establishes a liquid-liquid phase separation with the surrounding cytosol. The structure and assembly of stress granules and how different components contribute to their formation are not fully understood. Here, using super resolution and expansion microscopy, we find that the stress granule component UBAP2L and the core protein G3BP1 occupy different domains inside stress granules. Since UBAP2L displays typical properties of a core protein, our results indicate that different cores coexist inside the same granule. Consistent with a role as a core protein, UBAP2L is required for stress granule assembly in several stress conditions and reverse genetics show that it acts upstream of G3BP1. We propose a model in which UBAP2L is an essential stress granule nucleator that facilitates G3BP1 core formation and stress granule assembly and growth.
Long acyl chain ceramides govern cholesterol and cytoskeleton dependence of membrane outer leaflet dynamics
Authors: Gupta Anjali , Muralidharan Sneha , Torta Federico , Wenk Markus R. , Wohland Thorsten 
Published: June 2019

ABSTRACTThe cellular plasma membrane composition and organization is crucial for the regulation of biological processes. Based on our earlier work showing that the same lipid probe, DiI, exhibits different dynamics in CHO-K1 and RBL-2H3 cells, we investigate the molecular factors that govern these differences. First, we determined that the cytoskeleton-interacting Immunoglobulin E receptor (FcεRI), which is abundant in RBL-2H3 but not in CHO-K1 cells, is not responsible for the DiI confinement found in RBL-2H3 cells. Second, lipid mass spectrometry of the plasma membrane of the two cells indicated differences in ceramide content, especially with long and very long acyl chains (C16 to C24). We, therefore, measure membrane dynamics by imaging total internal reflection fluorescence correlation spectroscopy in dependence on these ceramides. Our results show that C24 and C16 saturated ceramides uniquely alter the membrane dynamics by promoting the formation of cholesterol-independent domains and by elevating inter-leaflet coupling.
A key interfacial residue identified with in-cell structure characterization of a class A GPCR dimer
Authors: Yang Ju , Gong Zhou , Lu Yun-Bi , Xu Chan-Juan , Wei Tao-Feng , Yang Men-Shi , Zhan Tian-Wei , Yang Yu-Hong , Lin Li , Liu Jian-Feng , Tang Chun , Zhang Wei-Ping 
Published: June 2019

AbstractG protein coupled receptors (GPCRs) have been shown homo-dimeric. Despite extensive studies, no single residue has been found essential for dimerization. Lacking an efficient method to shift the monomer-dimer equilibrium also makes functional relevance of GPCR dimer elusive. Here, using fluorescence lifetime-based imaging for distance measurements, we characterize the dimeric structure of GPR17, a class A GPCR, in cells. The structure reveals transmembrane helices 5 and 6 the dimer interface, and pinpoints F229 a key residue, mutations of which can render GPR17 monomeric or dimeric. Using the resulting mutants, we show that GPR17 dimer is coupled to both Gαi and Gαq signaling and is internalized, whereas GPR17 monomer is coupled to Gαi signaling only and is not internalized. We further show that residues equivalent to F229 of GPR17 in several other class A GPCRs are also important for dimerization. Our findings thus provide fresh insights into GPCR structure and function.
Use of solvent extraction–indigenous microbial degradation technology to repair soils contaminated by high concentrations of mechanical oil
Authors: Chen Guo , Yin Zhongyi , Liu Anping , Zheng Xuxu 
Published: June 2019

AbstractRemediation of soils contaminated by mechanical oil has become a difficult problem worldwide. In this study, soil contaminated by mechanical oil was repaired by domestication and inoculation of microorganisms collected from the contaminated site, and soil quality and plant growth indexes were evaluated to verify the efficacy of our solvent extraction–indigenous microbial degradation technology. Solvent extraction of the contaminated soil removed 97.03% mechanical oil, increased soil water-holding capacity by 68.20%, and improved root activity and soluble sugar content of alfalfa plants. However, solvent extraction depleted 82.98% of the soil organic matter. Screening and domestication of strain TB-6 from the contaminated site revealed that it is anEnterobacterwith obvious degradation effects on petroleum hydrocarbons (C15–C28). After the solvent-extracted soil was inoculated with TB-6 for 30 days, the soil structure became loose; degradation rate of residual mechanical oil was 19.45%; and soil organic matter content, water-holding capacity, alfalfa root activity, and soluble sugar content increased by 35.00%, 9.01%, 44.60%, and 7.03%, respectively. These results indicate that TB-6 has a good repairing effect on the soil after solvent extraction, and the combined technology efficiently removed mechanical oil from the soil and reduced the damage caused by the solvent.
A machine learning algorithm predicts molecular subtypes in pancreatic ductal adenocarcinoma with differential response to gemcitabine-based versus FOLFIRINOX chemotherapy
Authors: Kaissis Georgios , Ziegelmayer Sebastian , Lohöfer Fabian , Steiger Katja , Algül Hana , Muckenhuber Alexander , Yen Hsi-Yu , Rummeny Ernst , Friess Helmut , Schmid Roland , Weichert Wilko , Siveke Jens T. , Braren Rickmer 
Published: June 2019

AbstractPurposeDevelopment of a supervised machine-learning model capable of predicting clinically relevant molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) from diffusion-weighted-imaging-derived radiomic features.MethodsThe retrospective observational study assessed 55 surgical PDAC patients. Molecular subtypes were defined by immunohistochemical staining of KRT81. Tumors were manually segmented and 1606 radiomic features were extracted withPyRadiomics. A gradient-boosted-tree algorithm (XGBoost) was trained on 70% of the patients (N=28) and tested on 30% (N=17) to predict KRT81+ vs. KRT81-tumor subtypes. The average sensitivity, specificity and ROC-AUC value were calculated. Chemotherapy response was assessed stratified by subtype. Radiomic feature importance was ranked.ResultsThe mean±STDEV sensitivity, specificity and ROC-AUC were 0.90±0.07, 0.92±0.11, and 0.93±0.07, respectively. Patients with a KRT81+ subtype experienced significantly diminished median overall survival compared to KRT81-patients (7.0 vs. 22.6 months, HR 1.44, log-rank-test P=<0.001) and a significantly improved response to gemcitabine-based chemotherapy over FOLFIRINOX (10.14 vs. 3.8 months median overall survival, HR 0.85, P=0.037) compared to KRT81-patients, who responded significantly better to FOLFIRINOX over gemcitabine-based treatment (30.8 vs. 13.4 months median overall survival, HR 0.88, P=0.027).ConclusionsThe machine-learning based analysis of radiomic features enables the prediction of subtypes of PDAC, which are highly relevant for overall patient survival and response to chemotherapy.
Focused attention meditation changes the boundary and configuration of functional networks in the brain
Authors: Kajimura Shogo , Masuda Naoki , Lau Johnny King , Murayama Kou 
Published: June 2019

AbstractResearch has shown that meditation not only improves our cognitive and motivational functioning (e.g., attention, mental health), it influences the way how our brain networks [e.g., default mode network (DMN), fronto-parietal network (FPN), and sensory-motor network (SMN)] function and operate. However, surprisingly little attention has been paid to the possibility that meditation alters the structure (composition) of these functional brain networks. Here, using a single-case experimental design with longitudinal intensive data, we examined the effect of mediation practice on intra-individual changes in the composition of whole-brain networks. The results showed that meditation (1) changed the community size (with a number of regions in the FPN being merged into the DMN after meditation), (2) changed the brain regions composing the SMN community without changing its size, and (3) led to instability in the community allegiance of the regions in the FPN. These results suggest that, in addition to altering specific functional connectivity, meditation leads to reconfiguration of whole-brain network structure. The reconfiguration of community structure in the brain provides fruitful information about the neural mechanisms of meditation.