bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise, heat shock proteins and insulin resistance
Authors: Archer Ashley E. , Von Schulze Alex T. , Geiger Paige C. 
Published: December 2017

Best known as chaperones, heat shock proteins (HSPs) also have roles in cell signalling and regulation of metabolism. Rodent studies demonstrate that heat treatment, transgenic overexpression and pharmacological induction of HSP72 prevent high-fat diet-induced glucose intolerance and skeletal muscle insulin resistance. Overexpression of skeletal muscle HSP72 in mice has been shown to increase endurance running capacity nearly twofold and increase mitochondrial content by 50%. A positive correlation between HSP72 mRNA expression and mitochondrial enzyme activity has been observed in human skeletal muscle, and HSP72 expression is markedly decreased in skeletal muscle of insulin resistant and type 2 diabetic patients. In addition, decreased levels of HSP72 correlate with insulin resistance and non-alcoholic fatty liver disease progression in livers from obese patients. These data suggest the targeted induction of HSPs could be a therapeutic approach for preventing metabolic disease by maintaining the body's natural stress response. Exercise elicits a number of metabolic adaptations and is a powerful tool in the prevention and treatment of insulin resistance. Exercise training is also a stimulus for increased HSP expression. Although the underlying mechanism(s) for exercise-induced HSP expression are currently unknown, the HSP response may be critical for the beneficial metabolic effects of exercise. Exercise-induced extracellular HSP release may also contribute to metabolic homeostasis by actively restoring HSP72 content in insulin resistant tissues containing low endogenous levels of HSPs.
This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.
The role of heat shock proteins and co-chaperones in heart failure
Authors: Ranek Mark J. , Stachowski Marisa J. , Kirk Jonathan A. , Willis Monte S. 
Published: December 2017

The ongoing contractile and metabolic demands of the heart require a tight control over protein quality control, including the maintenance of protein folding, turnover and synthesis. In heart disease, increases in mechanical and oxidative stresses, post-translational modifications (e.g., phosphorylation), for example, decrease protein stability to favour misfolding in myocardial infarction, heart failure or ageing. These misfolded proteins are toxic to cardiomyocytes, directly contributing to the common accumulation found in human heart failure. One of the critical class of proteins involved in protecting the heart against these threats are molecular chaperones, including the heat shock protein70 (HSP70), HSP90 and co-chaperones CHIP (carboxy terminus of Hsp70-interacting protein, encoded by theStub1gene) and BAG-3 (BCL2-associated athanogene 3). Here, we review their emerging roles in the maintenance of cardiomyocytes in human and experimental models of heart failure, including their roles in facilitating the removal of misfolded and degraded proteins, inhibiting apoptosis and maintaining the structural integrity of the sarcomere and regulation of nuclear receptors. Furthermore, we discuss emerging evidence of increased expression of extracellular HSP70, HSP90 and BAG-3 in heart failure, with complementary independent roles from intracellular functions with important therapeutic and diagnostic considerations. While our understanding of these major HSPs in heart failure is incomplete, there is a clear potential role for therapeutic modulation of HSPs in heart failure with important contextual considerations to counteract the imbalance of protein damage and endogenous protein quality control systems.This article is part of the theme issue ‘Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective’.
The hydrophobin-like OmSSP1 may be an effector in the ericoid mycorrhizal symbiosis
Authors: Casarrubia Salvatore , Daghino Stefania , Kohler Annegret , Morin Emmanuelle , Khouja Hassine-Radhouane , Daguerre Yohann , Veneault-Fourrey Claire , Martin Francis M. , Perotto Silvia , Martino Elena 
Published: December 2017

AbstractMutualistic and pathogenic plant-colonizing fungi use effector molecules to manipulate the host cell metabolism to allow plant tissue invasion. Some small secreted proteins (SSPs) have been identified as fungal effectors in both ectomycorrhizal and arbuscular mycorrhizal fungi, but it is currently unknown whether SSPs also play a role as effectors in other mycorrhizal associations. Ericoid mycorrhiza is a specific endomycorrhizal type that involves symbiotic fungi mostly belonging to the Leotiomycetes (Ascomycetes) and plants in the family Ericaceae. Genomic and RNASeq data from the ericoid mycorrhizal fungus Oidiodendron maius led to the identification of several symbiosis-upregulated genes encoding putative SSPs. OmSSP1, the most highly symbiosis up-regulated SSP, was found to share some features with fungal hydrophobins, even though it lacks the Pfam hydrophobin domain. Sequence alignment with other hydrophobins and hydrophobin-like fungal proteins placed OmSSP1 within Class I hydrophobins. However, the predicted features of OmSSP1 may suggest a distinct type of hydrophobin-like proteins. The presence of a predicted signal peptide and a yeast-based signal sequence trap assay demonstrate that OmSSP1 is secreted during symbiosis. OmSSP1 null-mutants showed a reduced capacity to form ericoid mycorrhiza with Vaccinium myrtillus roots, suggesting a role as effectors in the ericoid mycorrhizal interaction.
The promiscuous estrogen receptor: evolution of physiological estrogens and response to phytochemicals and endocrine disruptors
Authors: Baker Michael E. , Lathe Richard 
Published: December 2017

ABSTRACTMany actions of estradiol (E2), the principal physiological estrogen in vertebrates, are mediated by estrogen receptor-α (ERα) and ERβ. An important physiological feature of vertebrate ERs is their promiscuous response to several physiological steroids, including estradiol (E2), Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol. A novel structural characteristic of Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol is the presence of a C19 methyl group, which precludes the presence of an aromatic A ring with a C3 phenolic group that is a defining property of E2. The structural diversity of these estrogens can explain the response of the ER to synthetic chemicals such as bisphenol A and DDT, which disrupt estrogen physiology in vertebrates, and the estrogenic activity of a variety of plant-derived chemicals such as genistein, coumestrol, and resveratrol. Diversity in the A ring of physiological estrogens also expands potential structures of industrial chemicals that can act as endocrine disruptors. Compared to E2, synthesis of 27-hydroxycholesterol and Δ5-androstenediol is simpler, leading us, based on parsimony, to propose that one or both of these steroids or a related metabolite was a physiological estrogen early in the evolution of the ER, with E2 assuming this role later as the canonical estrogen. In addition to the well-studied role of the ER in reproductive physiology, the ER also is an important transcription factor in non-reproductive tissues such as the cardiovascular system, kidney, bone, and brain. Some of these ER actions in non-reproductive tissues appeared early in vertebrate evolution, long before mammals evolved.
Testing Equality of Curves after Covariate Adjustment
Authors: Pal Choudhury Parichoy , Kundu Prosenjit , Xue Qian-Li , Westbrook Reyhan , Crainiceanu Ciprian M. 
Published: December 2017

SummaryThis paper is concerned with providing simple methodological approaches for global and local tests of difference between the mean of treatment and control groups when the measured outcome is a function. The added complexity is that for every subject we have repeated samples for the same curve and additional covariates of interest. We propose a permutation based approach to test for a global difference between the averages of two functional processes after covariate adjustment. The within group averages are estimated by modeling the relationship of the functional outcome on the covariate using functional regression methods and then averaging with respect to the covariate distribution in each group. The test statistic is the L2 area under the squared difference curve. We also test for the localized differences between the two average curves using a nonparametric bootstrap of subjects to obtain the 95% pointwise and joint confidence intervals for the estimated covariate-adjusted difference curve. Extensive simulation studies illustrate that the proposed tests preserve the type one error and are highly sensitive to detecting departures from the null assumption. We illustrate our method by studying the differences in time varying oxygen consumption between the frail Interleukin 10tm1Cgn (IL10tm) mice and the wildtype mice after adjusting for body composition measures.
CONFOLD2: Improved contact-driven ab initio protein structure modeling
Authors: Adhikari Badri , Cheng Jianlin 
Published: December 2017

AbstractBackgroundContact-guided protein structure prediction methods are becoming more and more successful because of the latest advances in residue-residue contact prediction. To support the contact-driven structure prediction, effective tools that can quickly build tertiary structural models of good quality from predicted contacts need to be developed.ResultsWe develop an improved contact-driven protein modeling method, CONFOLD2, and study how it may be effectively used for ab initio protein structure prediction with predicted contacts as input. It builds models using various subsets of input contacts to explore the fold space under the guidance of a soft square energy function, and then clusters the models to obtain top five models. CONFOLD2 is benchmarked on various datasets including CASP11 and 12 datasets with publicly available predicted contacts and yields better performance than the popular CONFOLD method.ConclusionCONFOLD2 allows to quickly generate top five structural models for a protein sequence, when its secondary structures and contacts predictions at hand. CONFOLD2 is publicly available athttps://github.com/multicom-toolbox/CONFOLD2/.
Transcription activation domains of the yeast factors Met4 and Ino2: tandem activation domains with properties similar to the yeast Gcn4 activator
Authors: Pacheco Derek , warfield Linda , Brajcich Michelle , Robbins Hannah , Luo Jie , Ranish jeff , Hahn Steven 
Published: December 2017

AbstractEukaryotic transcription activation domains (ADs) are intrinsically disordered polypeptides that typically interact with coactivator complexes, leading to stimulation of transcription initiation, elongation and chromatin modifications. Here we examine the properties of two strong and conserved yeast ADs: Met4 and Ino2. Both factors have tandem ADs that were identified by conserved sequence and functional studies. While AD function from both factors depends on hydrophobic residues, Ino2 further requires key conserved acidic and polar residues for optimal function. Binding studies show that the ADs bind multiple Med15 activator binding domains (ABDs) with a similar order of micromolar affinity, and similar but distinct thermodynamic properties. Protein crosslinking shows that no unique complex is formed upon Met4-Med15 binding. Rather, we observed heterogeneous AD-ABD contacts with nearly every possible AD-ABD combination. Many of these properties are similar to those observed with the yeast activator Gcn4, which forms a large heterogeneous, dynamic, and fuzzy complex with Med15. We suggest that this molecular behavior is common among eukaryotic activators.
Non-blocking modulation as the major mechanism of sodium channel inhibition by riluzole
Authors: Szabo AK , Pesti K , Lukacs P , Földi MC , Gerevich Z , Sperlagh B , Mike A 
Published: December 2017

ABSTRACTModulated- or guarded receptor hypothesis; Channel block or modulation; “Voltage-sensor block” or “lipophilic block” are some of the questions that arise when drug effects on sodium channels are investigated. Understanding the exact mechanism of action for individual drugs is essential, because it is one of the major factors that determine their therapeutic applicability.In this study we created a kinetic model of sodium channels, which can help us understand the modes of action for individual drugs in the context of these hypotheses. The model was constructed so that it could integrate the above hypotheses.In particular we aimed to understand the mode of action of riluzole, a neuroprotective drug with a peculiar state-dependent inhibition. In experiments the inhibition by 100μM riluzole was full within the first two milliseconds, but it was almost completely removed between 2 and 20 ms post-depolarization. This abrupt loss of inhibition could not be explained by dissociation, which was proceeding with a time constant of ~300 ms. We propose that for sodium channel inhibitors binding without blocking is possible, and riluzole predominantly inhibits by non-blocking modulation. We used lidocaine as a reference compound, and found that non-blocking modulation, although less prominent, also may play a role in its mechanism of inhibition. Non-blocking modulation may selectively inhibit cells with pathological activity patterns, therefore this property may be a good trait to investigate in the development of sodium channel inhibitor drugs.SUMMARYAlthough never actually proven, presence of sodium channel inhibitors at their binding site is assumed to prevent ion conduction. Authors provide evidence from experiments and kinetic simulations that bound riluzole permits conduction and exerts its inhibitory effect almost entirely by modulation.
Competition and niche construction in a model of cancer metastasis
Authors: Qian Jimmy J. , Akçay Erol 
Published: December 2017

AbstractNiche construction theory states that not only does the environment act on populations to generate Darwinian selection, but organisms reciprocally modify the environment and the sources of natural selection. Cancer cells participate in niche construction as they alter their microenvironments and create pre-metastatic niches; in fact, metastasis is a product of niche construction. Here, we present a mathematical model of niche construction and metastasis. Our model contains producers, which pay a cost to contribute to niche construction that benefits all tumor cells, and cheaters, which reap the benefits without paying the cost. We derive expressions for the conditions necessary for metastasis, showing that the establishment of a mutant lineage that promotes metastasis depends on niche construction specificity and strength of interclonal competition. We identify a tension between the arrival and invasion of metastasis-promoting mutants, where tumors composed only of cheaters remain small but are susceptible to invasion whereas larger tumors containing producers may be unable to facilitate metastasis depending on the level of niche construction specificity. Our results indicate that even if metastatic subclones arise through mutation, metastasis may be hindered by interclonal competition, providing a potential explanation for recent surprising findings that most metastases are derived from early mutants in primary tumors.
Neural Computations Underlying Causal Structure Learning
Authors: Tomov Momchil S. , Dorfman Hayley M. , Gershman Samuel J. 
Published: December 2017

AbstractBehavioral evidence suggests that beliefs about causal structure constrain associative learning, determining which stimuli can enter into association, as well as the functional form of that association. Bayesian learning theory provides one mechanism by which structural beliefs can be acquired from experience, but the neural basis of this mechanism is unknown. A recent study (Gershman, 2017) proposed a unified account of the elusive role of “context” in animal learning based on Bayesian updating of beliefs about the structure of causal relationships between contexts and cues in the environment. The model predicts that the computations which arbitrate between these abstract causal structures are distinct from the computations which learn the associations between particular stimuli under a given structure. In this study, we used fMRI with male and female human subjects to interrogate the neural correlates of these two distinct forms of learning. We show that structure learning signals are encoded in rostrolateral prefrontal cortex and the angular gyrus, anatomically distinct from correlates of associative learning. Within-subject variability in the encoding of these learning signals predicted variability in behavioral performance. Moreover, representational similarity analysis suggests that some regions involved in both forms of learning, such as parts of the inferior frontal gyrus, may also encode the full probability distribution over causal structures. These results provide evidence for a neural architecture in which structure learning guides the formation of associations.Significance StatementAnimals are able to infer the hidden structure behind causal relations between stimuli in the environment, allowing them to generalize this knowledge to stimuli they have never experienced before. A recently published computational model based on this idea provided a parsimonious account of a wide range of phenomena reported in the animal learning literature, suggesting that the neural mechanisms dedicated to learning this hidden structure are distinct from those dedicated to acquiring particular associations between stimuli. Here we validate this model by measuring brain activity during a task which dissociates structure learning from associative learning. We show that different brain networks underlie the two forms of learning and that the neural signal corresponding to structure learning predicts future behavioral performance.
Histone modifications and active gene expression are associated with enhanced CRISPR activity in de-silenced chromatin
Authors: Daer René , Barrett Cassandra M. , Haynes Karmella A 
Published: December 2017

ABSTRACTRecently we demonstrated that closed chromatin composed of Polycomb proteins and histone 3 lysine 27 trimethylation impedes CRISPR-mediated genome editing by blocking the accessibility of chromosomal DNA to spCas9/sgRNA. Editing efficiencies were higher in cells where the same reporter locus had not been repressed, thus we presume that silenced chromatin can be modified to generate a Cas9-accessible state. To test this idea, we exposed the locus to antagonists of Polycomb silencing: Gal4-p65, a targeted transcriptional activator, and UNC1999, a chemical inhibitor of the histone H3K27 methyltransferase EZH2. For both we observed loss of histone trimethylation. Only Gal4-p65 treatment increased target gene expression. Initial Gal4-p65 overexpression impedes Cas9 activity, while a 9-day recovery period leads to enhanced Cas9 efficiency up to 1000 bp from the Gal4 binding site. No enhancement was observed with UNC1999. These results demonstrate the strong influence of transcription-driven chromatin remodeling on CRISPR editing at closed chromatin.
Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog
Authors: Lukács P , Földi M C , Valánszki L , Casanova E.H , Biri-Kovács B , Nyitray L , Málnási-Csizmadia A , Mike A 
Published: December 2017

AbstractSodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their effects by a dual action: they obstruct ion flow ("block"), and they alter the energetics of channel opening and closing ("modulation"). Ideal drugs would be modulators without blocking effect, because modulation is inherently activity-dependent, therefore selective for pathological hyperactivity. Can block and modulation be separated? It has been difficult to tell, because the effect of modulation is obscured by confromation-dependent association/dissociation of the drug. To eliminate dynamic association/dissociation, we used a photoreactive riluzole analog which could be covalently bound to the channel; and found, unexpectedly, that drug-bound channels could still conduct ions, although with modulated gating. The finding that non-blocking modulation is possible, may open a novel avenue for drug development because non-blocking modulators could be more specific in treating hyperactivity-linked diseases.
A-to-I RNA editing uncovers hidden signals of adaptive genome evolution in animals
Authors: Popitsch Niko , Huber Christian D. , Buchumenski Ilana , Eisenberg Eli , Jantsch Michael , von Haeseler Arndt , Gallach Miguel 
Published: December 2017

AbstractIn animals, the most common type of RNA editing is the deamination of adenosines (A) into inosines (I). Because inosines base-pair with cytosines (C), they are interpreted as guanosines (G) by the cellular machinery and genomically encoded G alleles at edited sites mimic the function of edited RNAs. The contribution of this hardwiring effect on genome evolution remains obscure. We looked for population genomics signatures of adaptive evolution associated with A-to-I RNA edited sites in humans andDrosophila melanogaster. We found that single nucleotide polymorphisms at edited sites occur 3 (humans) to 15 times (Drosophila) more often than at unedited sites, the nucleotide G is virtually the unique alternative allele at edited sites and G alleles segregate at higher frequency at edited sites than at unedited sites. Our study reveals that coding synonymous and nonsynonymous as well as silent and intergenic A-to-I RNA editing sites are likely adaptive in the distantly related human andDrosophilalineages.
Targeted RNA knockdown by crRNA guided Csm in zebrafish
Authors: Fricke Thomas , Tamulaitis Gintautas , Smalakyte Dalia , Pastor Michal , Kolano Agnieszka , Siksnys Virginijus , Bochtler Matthias 
Published: December 2017

ABSTRACTRNA interference (RNAi) is a powerful experimental tool for RNA knockdown, but not all organisms are amenable. Here, we provide a “proof of principle” demonstration that CRISPR endoribonucleases can be used for programmable mRNA transcript degradation. Using zebrafish as the animal model and Csm(crRNA) complexes as the CRISPR endoribonucleases, we have targeted a transgenic EGFP transcript expressed from a variety of promoters. A drastic decrease of fluorescence was achieved in germ cells of the vasa:EGFP line. Weaker effects were also seen in fish lines that express EGFP zygotically. Knockdown was statistically significant in cmcl2:EGFP and fli1:EGFP zebrafish lines at 1 day post fertilization (dpf), but reduced to background levels at 2 dpf. The nkx2.5:EGFP fish line was least susceptible to Csm mediated EGFP knockdown. We conclude that at the present stage, Csm mediated knockdown is already efficient for maternal transcripts, and may compare favorably with morpholinos for such targets in zebrafish.