bluuebunny/crossref_metadata_2025_split huggingface dataset:
The vagus nerve mediates the suppressing effects of peripherally administered oxytocin on methamphetamine self-administration and seeking in rats
Authors: Everett Nicholas A. , Turner Anita J , Costa Priscila A , Baracz Sarah J. , Cornish Jennifer L. 
Published: December 2019

AbstractBackgroundThe neuropeptide oxytocin has emerged as a promising pharmacotherapy for methamphetamine (METH) addiction, and clinical trials of intranasal oxytocin are underway. However, there is debate as to how peripherally administered oxytocin alters brain signaling to modulate addiction processes. Interestingly, there is evidence for functional interactions between peripheral oxytocin administration and the vagus nerve. Therefore, this study investigated whether the effects of peripherally administered oxytocin require vagal signaling to reduce METH self-administration and reinstatement of METH-seeking behaviours.MethodsMale and female Sprague-Dawley rats underwent surgery for jugular catheterization and either subdiaphragmatic vagotomy (SDV) or a sham operation. Rats were trained to self-administer METH, and the effect of peripherally administered oxytocin on METH intake was assessed. Rats then underwent extinction, and effects of oxytocin were assessed on cue- and METH-induced reinstatement of METH-seeking.ResultsOxytocin treatment robustly attenuated METH intake in both sexes. Strikingly, SDV entirely prevented the suppressant effect of oxytocin (0.3 mg/kg) on METH intake, and partially prevented the effects of 1 mg/kg oxytocin in both sexes. After extinction, SDV impaired the suppressing effects of oxytocin on cue- and METH-primed reinstatement in males, but not females. SDV was functionally confirmed by measuring food intake following administration of the vagal dependent peptide, cholecyostokin-8.ConclusionOur data suggest that vagus nerve signaling is required for the anti-addiction effects of peripherally administered oxytocin, and that this vagal dependency is partially mediated by sex and drug withdrawal. This study has considerable implications for the applicability of oxytocin as a therapy for METH use disorder for both sexes.
Collective cell migration and residual stress accumulation: modeling consideration
Authors: Pajic-Lijakovic I. , Milivojevic M. 
Published: December 2019

AbstractStress generation during collective cell migration represents one of the key factors which influence the configuration of migrating cells, viscoelasticity of multicellular systems and their inter-relation. Local generation of stress (normal and shear) is significant even in 2D (up to ~100 − 150Pa). Compressive stress is primarily accumulated (1) within a core region of migrating cell clusters during their movement through the dense environment and (2) during the collisions of migrating cell clusters caused by uncorrelated motility. Shear stress can be significant within perturbed boundary layers around migrating clusters. Cells are more sensitive to the action of shear stress compared with compressive stress. Shear stress of a fewPasignificantly influences cell state. Deeper insight into cell strategy to minimize undesirable shear stress is a priority in order to understand various biological processes such as morphogenesis, wound healing and cancer invasion. We pointed out to cause-consequence relations of these complex phenomena based on rheological modeling consideration in order to stimulate further experimental work.Cell strategy should be connected with the type and distribution of adhesion contacts such as adherens junctions and tight junctions per migrating clusters in order to (1) reinforce the cluster structure perpendicular to the direction of cell migration and (2) ensure structural elasticity of cluster in the direction of migration. These conditions lead to the stiffness inhomogeneity per single migrating clusters. Cell strategy should also be related to the state of the perturbed boundary layer around the cluster in the context of its thickness and slip effects.Statement of SignificanceCollective cell migration induces a local generation of stress (normal and shear) significant even in 2D (up to100-150 Pa). Cells well tolerate compressive stress up to a fewkPa. However, shear stress of a fewPacan induce severe damage to vimentin and keratin intermediate filament networks during 1 h, while shear stress of ~60Pacan cause the inflammation in epithelial cells during 5.5 h. Deeper insight into cell strategy to minimize undesirable shear stress is a priority in order to understand various biological processes. Cell strategy should be connected with the type and distribution of adhesion contacts such as adherens junctions and tight junctions per migrating clusters and surrounding perturbed boundary layers.
ATM and PRDM9 Regulate SPO11-bound Recombination Intermediates During Meiosis
Authors: Paiano Jacob , Wu Wei , Yamada Shintaro , Sciascia Nicholas , Callen Elsa , Cotrim Ana Paola , Deshpande Rajashree A. , Maman Yaakov , Day Amanda , Paull Tanya T. , Nussenzweig André 
Published: December 2019

AbstractMeiotic recombination is initiated by genome-wide SPO11-induced double-strand breaks (DSBs) that are processed by MRE11-mediated release of SPO11. The DSB is then resected and loaded with DMC1/RAD51 filaments that invade homologous chromosome templates. In most mammals, DSB locations (“hotspots”) are determined by the DNA sequence specificity of PRDM9. Here, we demonstrate the first direct detection of meiotic DSBs and resection in vertebrates by performing END-seq on mouse spermatocytes using low sample input. We find that DMC1 limits both the minimum and maximum lengths of resected DNA, whereas 53BP1, BRCA1 and EXO1 play surprisingly minimal roles in meiotic resection. Through enzymatic modifications to the END-seq protocol that mimic thein vivoprocessing of SPO11, we identify a novel meiotic recombination intermediate (“SPO11-RI”) present at all hotspots. The SPO11-bound intermediate is dependent on PRDM9 and caps the 3’ resected end during engagement with the homologous template. We propose that SPO11-RI is generated because chromatin-bound PRDM9 asymmetrically blocks MRE11 from releasing SPO11. InAtm−/−spermatocytes, SPO11-RI is reduced while unresected DNA-bound SPO11 accumulate because of defective MRE11 initiation. Thus in addition to their global roles in governing SPO11 breakage, ATM and PRDM9 are critical local regulators of mammalian SPO11 processing.
Differential Correlation of Serum BDNF and microRNA Content in Rats with Rapid or Late Onset of Heavy Alcohol Use
Authors: Ehinger Yann , Phamluong Khanhky , Darevesky David , Welman Melanie , Moffat Jeffrey J. , Sakhai Samuel A. , Whiteley Ellanor L. , Berger Anthony L. , Laguesse Sophie , Farokhnia Mehdi , Leggio Lorenzo , Lordkipanidzé Marie , Ron Dorit 
Published: December 2019

AbstractHeavy alcohol use reduces the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents through the upregulation of microRNAs targetingBDNFmRNA. In humans, an inverse correlation exists between circulating blood levels of BDNF and the severity of psychiatric disorders including alcohol abuse. Here, we set out to determine whether a history of heavy alcohol use produces comparable alterations in the blood of rats. We used an intermittent access to 20% alcohol using the 2-bottle choice paradigm (IA20%2BC), and measured circulating levels of BDNF protein and microRNAs in the serum of Long-Evans rats before and after 8-weeks of excessive alcohol intake. We observed that the drinking profile of heavy alcohol users is not unified; Whereas 70% of the rats gradually escalate their alcohol intake (Late Onset), 30% of alcohol users exhibit a very Rapid Onset of drinking (Rapid Onset). We found that serum BDNF levels are negatively correlated with alcohol intake in both Rapid Onset and Late Onset rats. In contrast, increased expression of the microRNAs (miRs) targeting BDNF, miR30a-5p, miR-195-5p, miR191-5p and miR206-3p, was detected only in the Rapid Onset rats. Finally, we report that the alcohol-dependent molecular changes are not due to alterations in platelet number. Our data suggest that rats exhibit both Late and Rapid Onset of alcohol intake. We further show that heavy alcohol use produces comparable changes in BDNF protein levels in both groups. However, circulating microRNAs are responsive to alcohol only in the Rapid Onset rats.
Relaxation times of ligand-receptor complex formation control T cell activation
Authors: Teimouri Hamid , Kolomeisky Anatoly B. 
Published: December 2019

AbstractOne of the most important functions of immune T cells is to recognize the presence of the pathogen-derived ligands and to quickly respond to them while at the same time not to respond to its own ligands. This is known as an absolute discrimination, and it is one of the most challenging phenomena to explain. The effectiveness of pathogen detection by T cell receptor (TCR) is limited by the chemical similarity of foreign and self-peptides and very low concentrations of foreign ligands. We propose a new mechanism of the absolute discrimination by T cells. It is suggested that the decision to activate or not to activate the immune response is controlled by the time to reach the stationary concentration of the TCR-ligand activated complex, which transfers the signal to downstream cellular biochemical networks. Our theoretical method models T-cell receptor phosphorylation events as a sequence of stochastic transitions between discrete biochemical states, and this allows us to explicitly describe the dynamical properties of the system. It is found that the proposed criterion on the relaxation times is able to explain available experimental observations. In addition, our theoretical approach explicitly analyzes the relationships between speed, sensitivity and specificity of the T cell functioning, which are the main characteristics of the process. Thus, it clarifies the molecular picture of the T cell activation processes in immune response.
Estimating Sparse Neuronal Signal from Hemodynamic Response: the Mixture Components Inference Approach
Authors: Pidnebesna Anna , Fajnerová Iveta , Horáček Jiří , Hlinka Jaroslav 
Published: December 2019

AbstractThe approximate knowledge of the hemodynamic response to neuronal activity is widely used in statistical testing of effects of external stimulation, but has also been applied to estimate the neuronal activity directly from functional magnetic resonance data without knowing the stimulus timing. To this end, sparse linear regression methods have been previously used, including the well-known LASSO and the Dantzig selector. These methods generate a parametric family of solutions with different sparsity, among which a choice is finally based using some information criteria. As an alternative we propose a novel approach that instead utilizes the whole family of sparse regression solutions. Their ensemble provides a first approximation of probability of activation at each timepoint, and together with the conditional neuronal activity distributions estimated with the theory of mixtures with varying concentrations, they serve as the inputs to a Bayes classifier ultimately deciding between the true and false activations.As we show in extensive numerical simulations, the new method performs favourably in comparison with standard approaches in a range of realistic scenarios. This is mainly due to the avoidance of overfitting and underfitting that commonly plague the solutions based on sparse regression combined with model selection methods, including the corrected Akaike Information Criterion. This advantage is finally documented on fMRI task dataset.
Thermal cycling protects SH-SY5Y cells against hydrogen peroxide and β-amyloid-induced cell injury through stress response mechanisms involving Akt pathway
Authors: Chen Wei-Ting , Kuo Yu-Yi , Lin Guan-Bo , Lu Chueh-Hsuan , Hsu Hao-Ping , Sun Yi-Kun , Chao Chih-Yu 
Published: December 2019

AbstractNeurodegenerative diseases (NDDs) are becoming a major threat to public health, according to the World Health Organization (WHO). The most common form of NDDs is Alzheimer’s disease (AD), boasting 60-70% share. Although some debates still exist, excessive aggregation of β-amyloid protein (Aβ) and neurofibrillary tangles has been deemed one of the major causes for the pathogenesis of AD. A growing number of evidences from studies, however, have suggested that reactive oxygen species (ROS) also play a key role in the onset and progression of AD. Although scientists have had some understanding of the pathogenesis of AD, the disease still cannot be cured, with existing treatment only capable of providing a temporary relief at best, partly due to the obstacle of blood-brain barrier (BBB). The study was aimed to ascertain the neuroprotective effect of thermal cycle hyperthermia (TC-HT) against hydrogen peroxide (H2O2) and Aβ-induced cytotoxicity in SH-SY5Y cells. Treating cells with this physical stimulation beforehand significantly improved the cell viability and decreased the ROS content. The underlying mechanisms may be due to the activation of Akt pathway and the downstream antioxidant and prosurvival proteins. The findings manifest significant potential of TC-HT in neuroprotection, via inhibition of oxidative stress and cell apoptosis. It is believed that coupled with the use of drugs or natural compounds, this methodology can be even more effective in treating NDDs.
Where can a place cell put its fields? Let us count the ways
Authors: Yim Man Yi , Sadun Lorenzo A , Fiete Ila R , Taillefumier Thibaud 
Published: December 2019

AbstractA hippocampal place cell exhibits multiple firing fields within and across environments. What factors determine the configuration of these fields, and could they be set down in arbitrary locations? We conceptualize place cells as performing evidence combination across many inputs and selecting a threshold to fire. Thus, mathematically they are perceptrons, except that they act on geometrically organized inputs in the form of multiscale periodic grid-cell drive, and external cues. We analytically count which field arrangements a place cell can realize with structured grid inputs, to show that many more place-field arrangements are realizable with grid-like than one-hot coded inputs. However, the arrangements have a rigid structure, defining an underlying response scaffold. We show that the “separating capacity” or spatial range over which all potential field arrangements are realizable equals the rank of the grid-like input matrix, which in turn equals the sum of distinct grid periods, a small fraction of the unique grid-cell coding range. Learning different grid-to-place weights beyond this small range will alter previous arrangements, which could explain the volatility of the place code. However, compared to random inputs over the same range, grid-structured inputs generate larger margins, conferring relative robustness to place fields when grid input weights are fixed.Significance statementPlace cells encode cognitive maps of the world by combining external cues with an internal coordinate scaffold, but our ability to predict basic properties of the code, including where a place cell will exhibit fields without external cues (the scaffold), remains weak. Here we geometrically characterize the place cell scaffold, assuming it is derived from multiperiodic modular grid cell inputs, and provide exact combinatorial results on the space of permitted field arrangements. We show that the modular inputs permit a large number of place field arrangements, with robust fields, but also strongly constrain their geometry and thus predict a structured place scaffold.
Odor Modulates the Temporal Dynamics of Fear Memory Consolidation
Authors: Grella Stephanie L. , Fortin Amanda H. , McKissick Olivia , Leblanc Heloise , Ramirez Steve 
Published: December 2019

ABSTRACTSystems consolidation (SC) theory proposes that recent, contextually rich memories are stored in the hippocampus (HPC). As these memories become remote, they are believed to rely more heavily on cortical structures within the prefrontal cortex (PFC), where they lose much of their contextual detail and become schematized. Odor is a particularly evocative cue for intense remote memory recall and despite these memories being remote, they are highly contextual. In instances such as post-traumatic stress disorder (PTSD), intense remote memory recall can occur years after trauma, which seemingly contradicts SC. We hypothesized that odor may shift the organization of salient or fearful memories such that when paired with an odor at the time of encoding, they are delayed in the de-contextualization process that occurs across time, and retrieval may still rely on the HPC, where memories are imbued with contextually rich information, even at remote time points. We investigated this by tagging odor- and non-odor-associated fear memories in male c57BL/6 mice and assessed recall andc-Fosexpression in the dorsal CA1 (dCA1) and prelimbic cortex (PL) 1 d or 21 d later. In support of SC, our data showed that recent memories were more dCA1-dependent whereas remote memories were more PL-dependent. However, we also found that odor influenced this temporal dynamic biasing the memory system from the PL to the dCA1 when odor cues were present. Behaviorally, inhibiting the dCA1 with activity-dependent DREADDs had no effect on recall at 1 d and unexpectedly caused an increase in freezing at 21 d. Together, these findings demonstrate that odor can shift the organization of fear memories at the systems level.
mRNA with mammalian codon bias accumulates in yeast mutants with constitutive stress granules
Authors: Kozlova Natalia V. , Pichon Chantal , Rahmouni A. Rachid 
Published: December 2019

AbstractStress granules and P bodies are cytoplasmic structures assembled in response to various stress factors and represent sites of temporary storage or decay of mRNAs. Depending on the source of stress, the formation of these structures may be driven by distinct mechanisms, but several stresses were shown to stabilize mRNAs via inhibition of deadenylation. A recent study identified yeast gene deletion mutants with constitutive stress granules and elevated P bodies; however, the mechanisms which trigger its formation remain poorly understood. Here, we investigate the possibility of accumulating mRNA with mammalian codon bias, which we termed the model RNA, in these mutants. We found that the model RNA accumulates indcp2andxrn1mutants and in four mutants with constitutive stress granules overlapping with P bodies. However, in eight other mutants with constitutive stress granules the model RNA is downregulated, or its steady state levels vary. We further suggest that the accumulation of the model RNA is linked to its protection from the main mRNA surveillance path. However, there is no obvious targeting of the model RNA to stress granules or P bodies. Thus, accumulation of the model RNA and formation of constitutive stress granules occur independently and only some paths inducing formation of constitutive stress granules will stabilize mRNA as well.
Modeling of root nitrate responses suggests preferential foraging arises from the integration of demand, supply and local presence signals
Authors: Boer Meine D. , Teixeira Joana Santos , ten Tusscher Kirsten H. 
Published: December 2019

AbstractA plants’ fitness to a large extent depends on its capacity to adapt to spatio-temporally varying environmental conditions. One such environmental condition to which plants display extensive phenotypic plasticity is soil nitrate levels and patterns. In response to heterogeneous nitrate distribution, plants show a preferential foraging response, enhancing root growth in high nitrate patches and repressing root growth in low nitrate locations beyond a level that can be explained from local nitrate sensing. Although various molecular players involved in this preferential foraging behavior have been identified, how these together shape root system adaptation has remained unresolved. Here we use a simple modeling approach in which we incrementally incorporate the various known molecular pathways to investigate the combination of regulatory mechanisms that underly preferential root nitrate foraging. Our model suggests that instead of a thus far not discovered growth suppressing supply signal, growth reduction on the low nitrate side may simply arise from a reduced root foraging and increased competition for carbon. Additionally, our work suggests that the long distance CK signaling involved in root growth increase in high nitrate patches may represent a supply signal specifically functioning in modulating demand signaling strength. We illustrate how this integration of demand and supply signals prevents excessive preferential foraging under conditions in which demand is not met by sufficient supply and a more generic foraging in search of nitrate should be maintained.
Rapid method for generating designer algal mitochondrial genomes
Authors: Cochrane Ryan R. , Brumwell Stephanie L. , Soltysiak Maximillian P.M. , Hamadache Samir , Davis Jennifer G. , Wang Jiayi , Tholl Samuel Q. , Janakirama Preetam , Edgell David R. , Karas. Bogumil J. 
Published: December 2019

ABSTRACTWith synthetic biology, we can turn algae into bio-factories that produce high-value molecules (e.g. medicines or biofuels) or tackle global challenges (e.g. malnutrition and climate change). This realization has provoked rapid progress towards the creation of genetic tools for multiple algal species, notablyPhaeodactylum tricornutum.The power of synthetic biology to generate more useful or productive organisms is contingent on the ability to produce diverse DNA molecules and rapidly screen them for beneficial variants. However, it is still relatively expensive to synthesize DNA, and delivering large DNA (>50 kbp) to eukaryotic cellular compartments remains challenging. In this study, we establish a robust system for building algal mitochondrial genomes as a practical alternative to DNA synthesis. Our approach permits an inexpensive and rapid generation of mitochondrial derivatives designed for testing targeted DNA delivery. First, we cloned the mitochondrial genome ofP. tricornutuminto the eukaryotic host organismS. cerevisiaeusing two different techniques: transformation-associated recombination; and PCR-based cloning. Next, we analyzed the cloned genomes by multiplex PCR, and correct genomes were transferred to prokaryotic hostE. coli.Then these genomes were again analyzed by multiplex PCR, followed by diagnostic digest and complete-plasmid sequencing to evaluate the fidelity of each cloning method. Finally, we assessed the burden on eukaryotic and prokaryotic hosts to propagate the cloned genomes. We conclude that our system can reliably generate variants for genome-level engineering of algal mitochondria.HIGHLIGHTSTAR-cloned mitochondrial genome ofP. tricornutumin yeastDeveloped PCR-based cloning method to create designer algal mitochondrial genomesStably propagated algal mitochondrial genomes inS. cerevisiaeandE. colihosts