Miracle-dz/UniFAR-FTUs huggingface dataset:
Modulation of GSK-3β/β-Catenin Signaling Contributes to Learning and Memory Impairment in a Rat Model of Depression

Abstract Background It is widely accepted that cognitive processes, such as learning and memory, are affected in depression, but the molecular mechanisms underlying the interactions of these 2 disorders are not clearly understood. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signaling was shown to play an important role in the regulation of learning and memory. Methods The present study used a rat model of depression, chronic unpredictable stress, to determine whether hippocampal GSK-3β/β-catenin signaling was involved in learning and memory alterations. Results Our results demonstrated that chronic unpredictable stress had a dramatic influence on spatial cognitive performance in the Morris water maze task and reduced the phosphorylation of Ser9 of GSK-3β as well as the total and nuclear levels of β-catenin in the hippocampus. Inhibition of GSK3β by SB216763 significantly ameliorated the cognitive deficits induced by chronic unpredictable stress, while overexpression of GSK3β by AAV-mediated gene transfer significantly decreased cognitive performance in adult rats. In addition, chronic unpredictable stress exposure increased the expression of the canonical Wnt antagonist Dkk-1. Furthermore, chronic administration of corticosterone significantly increased Dkk-1 expression, decreased the phosphorylation of Ser9 of GSK-3β, and resulted in the impairment of hippocampal learning and memory. Conclusions Our results indicate that impairment of learning and memory in response to chronic unpredictable stress may be attributed to the dysfunction of GSK-3β/β-catenin signaling mediated by increased glucocorticoid signaling via Dkk-1.
Nerve Injury, Axonal Degeneration and Neural Regeneration: Basic Insights

Axotomy or crush of a peripheral nerve leads to degeneration of the distal nerve stump referred to as Wallerian degeneration (WD). During WD a microen‐vironment is created that allows successful regrowth of nerve fibres from the proximal nerve segment. Schwann cells respond to loss of axons by extrusion of their myelin sheaths, downregulation of myelin genes, dedifferentiation and proliferation. They finally aline in tubes (Büngner bands) and express surface molecules that guide regenerating fibres. Hematogenous macrophages are rapidly recruited to the distal stump and remove the vast majority of myelin debris. Molecular changes in the distal stump include upregulation of neurotrophins, neural cell adhesion molecules, cytokines and other soluble factors and their corresponding receptors. Axonal injury not only induces muscle weakness and loss of sensation but also leads to adaptive responses and neuropathic pain. Regrowth of nerve fibres occurs with high specificity with formerly motor fibres preferentially reinnervating muscle. This involves recognition molecules of the L2/HNK‐1 family. Nerve regeneration occurs at a rate of 3–4 mm/day after crush and 2–3 mm/day after sectioning a nerve. Nerve regeneration can be fostered pharmacologically. Upon reestablishment of axonal contact Schwann cells remyelinate nerve sprouts and downregulate surface molecules characteristic for precursor/premyelinating or nonmyelinating Schwann cells. At present it is unclear whether axonal regeneration after nerve injury is impeded in neuropathies.
Recurrent abdominal liposarcoma: analysis of 19 cases and prognostic factors.

AIM To evaluate the clinical outcome of re-operation for recurrent abdominal liposarcoma following multidisciplinary team cooperation. METHODS Nineteen consecutive patients who had recurrent abdominal liposarcoma underwent re-operation by the retroperitoneal sarcoma team at our institution from May 2009 to January 2012. Patient demographic and clinical data were reviewed retrospectively. Multidisciplinary team discussions were held prior to treatment, and re-operation was deemed the best treatment. The categories of the extent of resection were as follows: gross total resection (GTR), palliative resection and partial resection. Surgical techniques were divided into discrete lesion resection and combined contiguous multivisceral resection (CMR). Tumor size was determined as the largest diameter of the specimen. Patients were followed up at approximately 3-monthly intervals. For survival analysis, a univariate analysis was performed using the Kaplan-Meier method, and a multivariate analysis was performed using the Cox proportional hazards model. RESULTS Nineteen patients with recurrent abdominal liposarcoma (RAL) underwent 32 re-operations at our institute. A total of 51 operations were reviewed with a total follow-up time ranging from 4 to 120 (47.4 ± 34.2) mo. The GTR rate in the CMR group was higher than that in the non-CMR group (P = 0.034). CMR was positively correlated with intra-operative bleeding (correlation coefficient = 0.514, P = 0.010). Six cases with severe postoperative complications were recorded. Patients with tumor sizes greater than 20 cm carried a significant risk of profuse intra-operative bleeding (P = 0.009). The ratio of a highly malignant subtype (dedifferentiated or pleomorphic) in recurrent cases was higher compared to primary cases (P = 0.027). Both single-factor survival using the Kaplan-Meier model and multivariate analysis using the Cox proportional hazards model showed that overall survival was correlated with resection extent and pathological subtype (P < 0.001 and P = 0.02), however, relapse-free interval (RFI) was only correlated with resection extent (P = 0.002). CONCLUSION Close follow-up should be conducted in patients with RAL. Early re-operation for relapse is preferred and gross resection most likely prolongs the RFI.
A Replication of Pindyck's Willingness to Pay: On the Sacrifice Needed to Obtain Results

We present a verification, an extension and a reanalysis of “Uncertain outcomes and climate change policy”, R. Pindyck, Journal of Environmental Economics and Management, 2012. As far as verification is concerned, we are able to reproduce the results provided in Pindyck’s work in many cases and convincingly confirm the quality of the work. Some discrepancies are present, they are due to rounding or related to specific sets of parametric values and do not change the economic interpretation or significance of the results. The re-estimation of the model with more recent data on climate change made available in 2014 shows that temperature increments are now deemed to be higher in mean but less dispersed. As a consequence, the willingness to pay doesn’t vary much with respect to the original paper. We also modify the functional form describing the impact of temperature increase on the growth rate of consumption and obtain much bigger and potentially problematic increments of the willingness to pay. Finally, the paper demonstrates that the numerical results are sensitive to a variety of technical settings used in the computations and suggests that great care is needed in obtaining estimates and employing results in policy discussions.
BRG1 interacts with SOX10 to establish the melanocyte lineage and to promote differentiation

Abstract Mutations in SOX10 cause neurocristopathies which display varying degrees of hypopigmentation. Using a sensitized mutagenesis screen, we identified Smarca4 as a modifier gene that exacerbates the phenotypic severity of Sox10 haplo-insufficient mice. Conditional deletion of Smarca4 in SOX10 expressing cells resulted in reduced numbers of cranial and ventral trunk melanoblasts. To define the requirement for the Smarca4 -encoded BRG1 subunit of the SWI/SNF chromatin remodeling complex, we employed in vitro models of melanocyte differentiation in which induction of melanocyte-specific gene expression is closely linked to chromatin alterations. We found that BRG1 was required for expression of Dct, Tyrp1 and Tyr, genes that are regulated by SOX10 and MITF and for chromatin remodeling at distal and proximal regulatory sites. SOX10 was found to physically interact with BRG1 in differentiating melanocytes and binding of SOX10 to the Tyrp1 distal enhancer temporally coincided with recruitment of BRG1. Our data show that SOX10 cooperates with MITF to facilitate BRG1 binding to distal enhancers of melanocyte-specific genes. Thus, BRG1 is a SOX10 co-activator, required to establish the melanocyte lineage and promote expression of genes important for melanocyte function.
Selection for Chaperone-Like Mediated Genetic Robustness at Low Mutation Rate: Impact of Drift, Epistasis and Complexity

Genetic robustness is defined as the constancy of a phenotype in the face of deleterious mutations. Overexpression of chaperones, to assist the folding of proteins carrying deleterious mutations, is so far one of the most accepted molecular mechanisms enhancing genetic robustness. Most theories on the evolution of robustness have focused on the implications of high mutation rate. Here we show that genetic drift, which is modulated by population size, organism complexity, and epistasis, can be a sufficient force to select for chaperone-mediated genetic robustness. Using an exact analytical solution, we also show that selection for costly genetic robustness leads to a paradox: the decrease of population fitness on long timescales and the long-term dependency on robustness mechanisms. We suggest that selection for genetic robustness could be universal and not restricted to high mutation rate organisms such as RNA viruses. The evolution of the endosymbiont Buchnera illustrates this selection mechanism and its paradox: the increased dependency on chaperones mediating genetic robustness. Our model explains why most chaperones might have become essential even in optimal growth conditions.
Economic analysis of injury prevention –  applying results and methodologies from cost-of-injury studies

Injuries pose an economic problem of immense proportion to communities in every society. The economic burden from injuries can be quantified through cost-of-injury studies, using techniques adopted from cost-of-illness research. This study explores the feasibility of applying results and methodologies from existing cost-of-injury studies in economic analyses of injury prevention interventions and programmes. The literature on cost-of-injury studies and economic appraisals of injury prevention efforts was examined to elicit studies that calculated injury costs. Studies were accepted for inclusion if they included an analysis of the costs of all injuries occurring in a geographical area (community, region or country) during a specific time period, employed a societal perspective and an incidence-based costing approach and were conducted in industrialized countries. There were 12 studies that met the inclusion criteria. The average total cost per injury case was US$3536, while the average share of indirect to total cost per injury case was 71%. However, the cost figures showed wide variation across the studies. Based on the limited similarity of findings from the studies, it was concluded that it is not feasible to apply results and methodologies from existing cost-of-injury studies. The cost estimators described in this study could possibly be adapted for use as reference points in economic analyses of existing programmes, but any other uses should be approached with caution. Locally obtained data are needed for reliable economic analyses of injury prevention interventions and programmes.
Winners and Losers of the Ballot: Electronic vs. Traditional Paper Voting Systems in Brazil

Abstract Scholars concur that free and fair elections are essential for proper democratic functioning, but our understanding of the political effects of democratic voting systems is incomplete. This article mitigates the gap by exploiting the gradual transformation of voting systems and ballot structures in Brazil’s 1998 executive elections to study the relationship between voting systems and viable and nonviable candidates’ vote shares, using regression discontinuity design. It finds that the introduction of electronic voting concentrated vote shares among viable candidates and thus exhibited electoral bias. We posit that this result occurred because viable candidates were better able to communicate the information that electronic voters needed to cast valid ballots than were their nonviable counterparts. The article uses survey data to demonstrate that electronic voters responded to changes in ballot design and internalized the information viable candidates made available to them.
Ligand-Specific Signaling Profiles and Resensitization Mechanisms of the Neuromedin U2 Receptor

The structurally related, but distinct neuropeptides, neuromedin U (NmU) and neuromedin S (NmS) are ligands of two G protein-coupled NmU receptors (NMU1 and NMU2). Hypothalamic NMU2 regulates feeding behavior and energy expenditure and has therapeutic potential as an anti-obesity target, making an understanding of its signaling and regulation of particular interest. NMU2 binds both NmU and NmS with high affinity, resulting in receptor-ligand co-internalization. We have investigated whether receptor trafficking events post-internalization are biased by the ligand bound and can therefore influence signaling function. Using recombinant cell lines expressing human NMU2, we demonstrate that acute Ca2+ signaling responses to NmU or NmS are indistinguishable and that restoration of responsiveness (resensitization) requires receptor internalization and endosomal acidification. The rate of NMU2 resensitization is faster following NmU compared with NmS exposure, but is similar if endothelin-converting enzyme-1 activity is inhibited or knocked down. Although acute activation of extracellular signal-regulated kinase (ERK) is also similar, activation by NMU2 is longer lasting if NmS is the ligand. Furthermore, when cells are briefly challenged before removal of free, but not receptor-bound ligand, activation of ERK and p38 mitogen-activated protein kinase by NmS is more sustained. However, only NmU responses are potentiated and extended by endothelin-converting enzyme-1 inhibition. These data indicate that differential intracellular ligand processing produces different signaling and receptor resensitization profiles and add to the findings of other studies demonstrating that intracellular ligand processing can shape receptor behavior and signal transduction.
5-Azacytidine treatment of HA-A melanoma cells induces Sp1 activity and concomitant transforming growth factor alpha expression

Evidence indicates DNA methylation as a part of the regulatory machinery controlling mammalian gene expression. The human melanoma cell line HA-A expresses low levels of transforming growth factor alpha (TGF-alpha). TGF-alpha mRNA accumulated, however, in response to DNA demethylation induced by a nucleoside analog, 5-azacytidine (5-azaC). The importance of DNA methylation in the TGF-alpha promoter region was examined by a transient transfection assay with luciferase reporter plasmids containing a portion of the TGF-alpha promoter. 5-azaC treatment of HA-A cells before the transfection caused a significant increase in the luciferase activity. Since input plasmids were confirmed to remain unmethylated, DNA demethylation of the TGF-alpha promoter itself does not account for the observed increase in TGF-alpha mRNA. Using an electrophoretic mobility shift assay, enhanced formation of protein-TGF-alpha promoter complex was detected in response to 5-azaC treatment. This 5-azaC-induced complex was shown to contain the transcription factor Sp1 by the following criteria: the protein-DNA complex formed on the TGF-alpha promoter contained immunoreactive Sp1; the mobility of the complex in an electrophoretic mobility shift assay was similar to that formed by recombinant Sp1; and DNase I footprinting analysis demonstrated that the 5-azaC-induced complex produced a footprint on the TGF-alpha promoter identical to that of authentic Sp1. These observations suggest that 5-azaC induces TGF-alpha expression by augmenting the Sp1 activity. However, neither the Sp1 mRNA nor its protein was induced by 5-azaC. These results suggest that in HA-A cells, TGF-alpha expression is down-modulated by DNA methylation. In addition, this process may involve the specific regulation of Sp1 activity without altering the amount of the transcription factor.
GENDER DIFFERENCES IN ACUTE RESPONSE TO TRAUMA-HEMORRHAGE

To understand the pathogenesis of a disease, experimental models are needed. A good experimental model is the one that simulates responses observed in the clinical setting. In recent years, clinical studies have indicated that gender might be a factor that plays a significant role in the outcome of patients with shock, trauma, and sepsis. These observations are now being evaluated in experimental setting. Studies performed in a rodent model of trauma-hemorrhage have concluded that alterations in immune and cardiac functions after trauma-hemorrhage are more markedly depressed in adult males, and ovariectomized and aged females. However, both are maintained in castrated males and in proestrus females. Moreover, the survival rate of proestrus females subjected to sepsis after trauma-hemorrhage is significantly higher than age-matched males or ovariectomized females. Although these observations suggest gender-specific response after trauma-hemorrhage, the mechanisms responsible for gender specificity remain largely unknown. Furthermore, in other injuries such as burn, experimental studies dealing with sexual dimorphism are limited. Therefore, more studies in clinical and experimental settings are required to determine whether gender-specific responses are global across the injuries or are observed in specific injury situations. Studies are also needed to delineate underlying mechanisms responsible for differences between males and females after trauma-hemorrhage. The information gained from the experimental studies will help in designing innovative therapeutic approaches for the treatment of trauma patients.
Performance Bounds for Diversity Receptions Over Arbitrarily Correlated Nakagami-$m$ Fading Channels

Prior performance analyses of diversity receptions over arbitrarily correlated Nakagami-m fading channels use power correlation matrix to define correlation among branches. However, the power correlation matrix cannot uniquely determine the joint probability density function of the branch amplitudes as well as the system performance. In this paper, we derive asymptotically tight and closed-form upper and lower bounds for the error rates and the outage probabilities of maximum-ratio combining, equal-gain combining, and selection combining over arbitrarily correlated Nakagami-m fading channels. The correlation between the Nakagami-m random variables is defined through the correlation matrix of the accompanying Gaussian random variables, which can uniquely determine the joint probability density function of the Nakagami-m variables. Using the analytical results and Monte Carlo simulation, we show that the performance of diversity reception systems over Nakagami-m fading channels cannot be uniquely determined by the power correlation matrix of the branches. Furthermore, we also study the factors that determine the asymptotic performance of the diversity receptions.
Effects of isosorbide dinitrate on oxygen uptake kinetics in cardiac patients.

PURPOSE Although nitrates are known to improve indices of exercise capacity in patients with coronary artery disease, their effects on oxygen uptake kinetics during the onset of exercise have not been clarified. We evaluated the acute effects of isosorbide dinitrate on the kinetics of oxygen uptake during the onset of exercise at a constant work rate in patients with coronary artery disease. METHODS We studied 14 patients with coronary artery disease who performed 6 min of low-intensity exercise at a constant work rate on a cycle ergometer 30 min after oral administration of 10 mg of isosorbide dinitrate or placebo in a double-blind, crossover manner. Oxygen uptake was calculated from breath-by-breath analysis of respired gases. The time constant of oxygen uptake kinetics during the onset of exercise was determined by fitting a single exponential function to the oxygen uptake response. RESULTS Heart rate was significantly increased at rest, and systolic blood pressure was significantly decreased both at rest and during exercise after administration of isosorbide dinitrate. The time constant of oxygen uptake was significantly shorter (the kinetics were faster) after administration of isosorbide dinitrate (39.4+/-10.1 vs 44.5+/-10.5 s, P = 0.038). CONCLUSIONS Isosorbide dinitrate was found to speed the kinetics of the increase in oxygen uptake during constant work-rate exercise. The time constant of oxygen uptake, which reflects the rapidity of cardiovascular adaptation at the onset of exercise, seems to be a useful parameter of the effectiveness of therapy in patients with coronary artery disease.
Representing and comparing protein folds and fold families using three‐dimensional shape‐density representations

The question of how best to compare and classify the (three‐dimensional) structures of proteins is one of the most important unsolved problems in computational biology. To help tackle this problem, we have developed a novel shape‐density superposition algorithm called 3D‐Blast which represents and superposes the shapes of protein backbone folds using the spherical polar Fourier correlation technique originally developed by us for protein docking. The utility of this approach is compared with several well‐known protein structure alignment algorithms using receiver‐operator‐characteristic plots of queries against the “gold standard” CATH database. Despite being completely independent of protein sequences and using no information about the internal geometry of proteins, our results from searching the CATH database show that 3D‐Blast is highly competitive compared to current state‐of‐the‐art protein structure alignment algorithms. A novel and potentially very useful feature of our approach is that it allows an average or “consensus” fold to be calculated easily for a given group of protein structures. We find that using consensus shapes to represent entire fold families also gives very good database query performance. We propose that using the notion of consensus fold shapes could provide a powerful new way to index existing protein structure databases, and that it offers an objective way to cluster and classify all of the currently known folds in the protein universe. Proteins 2012. © 2011 Wiley Periodicals, Inc.