Miracle-dz/UniFAR-FTUs huggingface dataset:
-374 T/A RAGE Polymorphism Is Associated with Chronic Kidney Disease Progression in Subjects Affected by Nephrocardiovascular Disease

Background Chronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease. Methods 174 patients (119 males (68.4%) mean age 67.2±0.88 years; 55 females (31.6%): mean age 65.4±1.50 years) affected by mild to moderate nephrocardiovascular CKD were studied. Each subject was prospectively followed for 84 months, every 6–9 months. The primary endpoint of the study was a rise of serum creatinine concentrations above 50% of basal values or end stage renal disease. Results Carriers of the A/A and T/A genotype presented higher plasma levels of interleukin 6 (A/A 29.5±15.83; T/A 30.0±7.89, vs T/T 12.3±5.04 p = 0.01 for both) and Macrophages chemoattractant protein 1 (A/A 347.1±39.87; T/A 411.8±48.41, vs T/T 293.5±36.20, p = 0.04 for both) than T/T subjects. Carriers of the A allele presented a faster CKD progression than wild type patients (Log-Rank test: Chi square = 6.84, p = 0,03). Cox regression showed that -374 T/A RAGE polymorphism (p = 0.037), albuminuria (p = 0.01) and LDL cholesterol (p = 0.038) were directly associated with CKD progression. HDL cholesterol (p = 0.022) and BMI (p = 0.04) were inversely related to it. No relationship was found between circulating RAGE and renal function decline. Conclusions -374 T/A RAGE polymorphism could be associated with CKD progression and inflammation. Further studies should confirm this finding and address whether inhibiting RAGE downstream signalling would be beneficial for CKD progression.
The PGE2-Stat3 interaction in doxorubicin-induced myocardial apoptosis.

AIMS Both cyclooxygenase-2 (COX-2) and the transcription factor signal transducer and activator of transcription 3 (Stat3) are involved in adaptive growth and survival of cardiomyocytes. In ventricular cardiomyocytes, prostaglandin E(2) (PGE(2)), a major COX-2 product, leads to adaptive growth via Stat3 activation, but whether this transcription factor acts as a signalling molecule in PGE(2)-induced cell survival is unknown. Therefore, the purpose of this study was to determine whether PGE(2) counteracts cardiac apoptosis induced by doxorubicin (DOX), and if so, whether Stat3 plays a critical role in this cardioprotective effect. METHODS AND RESULTS Neonatal rat ventricular cardiomyocytes were incubated with DOX (0.5 microM) and/or PGE(2) (1 microM). Apoptosis was assessed by determining caspase3 activation and apoptotic DNA fragmentation. The role of Stat3 was evaluated in vitro and in vivo by transfecting cardiomyocytes with siRNA targeting rat Stat3 and by using cardiomyocyte-restricted Stat3 knockout (Stat3 KO) mice, respectively. Incubation of ventricular cardiomyocytes with PGE(2) led to a time-dependent decrease in the DOX-induced caspase3 activation, reaching a maximal inhibition of 70 +/- 5% after 4 h. Similarly, PGE(2) inhibited DOX-induced DNA fragmentation by 58 +/- 5% after 24 h. This antiapoptotic action of PGE(2) was strongly reduced by the ERK1/2 inhibitor, U0126, whereas the p38 MAP kinase inhibitor, SB203580, had no effect. Depleting Stat3 expression by 50-60% in isolated ventricular cardiomyocytes markedly reduced the protective effect of PGE(2) on DOX-induced caspase3 activation and DNA fragmentation. Likewise, the stable PGE(2) analogue, 16,16-dimethyl-PGE(2), was unable to counteract cardiac apoptosis induced by DOX in Stat3 KO mice. CONCLUSION Our results demonstrate that PGE(2) prevents myocardial apoptosis induced by DOX. This protection requires the activation of the prosurvival pathways of Stat3 and ERK1/2.
Individual Differences of How Attention is Allocated During Reading

The current study replicates a previous finding of how attention is allocated during reading and was expanded upon by controlling for individual differences between participants. An eye-tracking experiment was performed to determine how attention is allocated during reading, while individual differences between participants were recorded by measuring working memory capacity. In four tasks that increased in depth of processing, participants were instructed to correctly identify whether or not a target was presented in a series of 1-4 words. Results indicate a relationship between reaction time and working memory score in all but one task. This suggests that high-span individuals use parallel processing when detecting symbols or orthographic features, but use serial processing during tasks that require full semantic processing.
Improving ASR error detection with non-decoder based features

This study reports error detection experiments in large vocabulary automatic speech recognition (ASR) systems, by using statistical classifiers. We explored new features gathered from other knowledge sources than the decoder itself: a binary feature that compares outputs from two different ASR systems (word by word), a feature based on the number of hits of the hypothesized bigrams, obtained by queries entered into a very popular Web search engine, and finally a feature related to automatically infered topics at sentence and word levels. Experiments were conducted on a European Portuguese broadcast news corpus. The combination of baseline decoder-based features and two of these additional features led to significant improvements, from 13.87% to 12.16% classification error rate (CER) with a maximum entropy model, and from 14.01% to 12.39% CER with linear-chain conditional random fields, comparing to a baseline using only decoder-based features.
PINK1-Mediated Phosphorylation of Parkin Boosts Parkin Activity in Drosophila

Two genes linked to early onset Parkinson's disease, PINK1 and Parkin, encode a protein kinase and a ubiquitin-ligase, respectively. Both enzymes have been suggested to support mitochondrial quality control. We have reported that Parkin is phosphorylated at Ser65 within the ubiquitin-like domain by PINK1 in mammalian cultured cells. However, it remains unclear whether Parkin phosphorylation is involved in mitochondrial maintenance and activity of dopaminergic neurons in vivo. Here, we examined the effects of Parkin phosphorylation in Drosophila, in which the phosphorylation residue is conserved at Ser94. Morphological changes of mitochondria caused by the ectopic expression of wild-type Parkin in muscle tissue and brain dopaminergic neurons disappeared in the absence of PINK1. In contrast, phosphomimetic Parkin accelerated mitochondrial fragmentation or aggregation and the degradation of mitochondrial proteins regardless of PINK1 activity, suggesting that the phosphorylation of Parkin boosts its ubiquitin-ligase activity. A non-phosphorylated form of Parkin fully rescued the muscular mitochondrial degeneration due to the loss of PINK1 activity, whereas the introduction of the non-phosphorylated Parkin mutant in Parkin-null flies led to the emergence of abnormally fused mitochondria in the muscle tissue. Manipulating the Parkin phosphorylation status affected spontaneous dopamine release in the nerve terminals of dopaminergic neurons, the survivability of dopaminergic neurons and flight activity. Our data reveal that Parkin phosphorylation regulates not only mitochondrial function but also the neuronal activity of dopaminergic neurons in vivo, suggesting that the appropriate regulation of Parkin phosphorylation is important for muscular and dopaminergic functions.
Intravenous nicotine replacement suppresses nicotine intake from cigarette smoking.

Insofar as smokers regulate body levels of nicotine, nicotine replacement is expected to suppress the desire to smoke a cigarette. Our study was designed to test the hypothesis that i.v. replacement of nicotine will suppress daily intake of nicotine from ad libitum cigarette smoking and to compare the physiological effects of prolonged exposure to nicotine infused i.v. to the effect of smoking cigarettes throughout the day. Eight subjects received a 14-hr infusion of deuterium-labeled nicotine dosed to achieve levels of nicotine similar to those while smoking cigarettes for each individual (average, 33.1 mg; range, 17.7-49.9 mg) or saline (placebo). Cigarette smoking was permitted as desired. Nicotine infusion did not significantly affect the number of cigarettes smoked or the amount of tobacco burned, but nicotine intake from cigarette smoking was suppressed in all but one subject by an average of 24.6% (range, 4.0-51.2%). Down-regulation of levels of nicotine while smoking in response to infusion of nicotine was imprecise, which may be a result of psychosocial factors influencing smoking behavior along with the development of tolerance to toxic effects of nicotine as a consequence of prolonged exposure to nicotine. Intravenous nicotine and cigarette smoking increased average heart rate and blood pressure throughout the day and 24-hr urinary epinephrine excretion to a similar extent. Despite higher levels of nicotine when subjects smoked during infusion of nicotine, there were no additional nicotine-related effects. No adverse effects were noted; most subjects could not distinguish nicotine from saline. (ABSTRACT TRUNCATED AT 250 WORDS)
Correlation-based Intrinsic Evaluation of Word Vector Representations

We introduce QVEC-CCA--an intrinsic evaluation metric for word vector representations based on correlations of learned vectors with features extracted from linguistic resources. We show that QVEC-CCA scores are an effective proxy for a range of extrinsic semantic and syntactic tasks. We also show that the proposed evaluation obtains higher and more consistent correlations with downstream tasks, compared to existing approaches to intrinsic evaluation of word vectors that are based on word similarity.
Checkpoint modulation - A new way to direct the immune system against renal cell carcinoma

The introduction of targeted therapies like the tyrosine kinase (TKI) and mammalian target of rapamycin (mTOR) inhibitors has improved patients´ survival in general. Nevertheless the prognosis remains limited. Therapies with a new mode of action are urgently warranted, especially those who would provoke long-term responders or long-lasting complete remissions as observed with unspecific immunotherapy with the cytokines interleukin-2 and interferon-α. In the recent years a deeper understanding of the underlying immunology of T cell activation led to the development of checkpoint inhibitors, which are mainly monocloncal antibodies and which enhances the presence of the co-stimulatory signals needed for T cell activation or priming. This review discusses the clinical data and ongoing studies available for the inhibition of the PD-1 (CD279) and CTLA-4 (CD152) axis in mRCC. In addition, potential future immunological targets are discussed. This approach of T-cell activation or re-activation by immunological checkpoint inhibition holds the inherent promise to directly affect the tumor cell and thereby to potentially cure a subset of patients with mRCC.
Human reinforcement learning: Insights from intracranial recordings and stimulation

Reinforcement learning is the process by which individuals alter their decisions to maximize positive outcomes, and minimize negative outcomes. It is a cognitive process that is widely used in our daily lives and is often disrupted during psychiatric disease. Thus, a major goal of neuroscience is to characterize the neural underpinnings of reinforcement learning. Whereas animal studies have utilized invasive physiological methods to characterize several neural mechanisms that underlie reinforcement learning, human studies have largely relied on non-invasive techniques that have reduced physiological precision. Although ethical limitations preclude the use of invasive physiological methods in healthy human populations, patient populations undergoing certain neurosurgical interventions offer a rare opportunity to directly assay neural activity from the brain during human reinforcement learning. This dissertation presents early findings from this research effort. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Neuroscience First Advisor Michael J. Kahana
The European Regional Convergence Process, 1980-1995: Do Spatial Regimes and Spatial Dependence Matter?

The authors show that spatial dependence and spatial heterogeneity matter in the estimation of the β-convergence process among 138 European regions over the 1980 to 1995 period. Using spatial econometrics tools, the authors detect both spatial dependence and spatial heterogeneity in the form of structural instability across spatial convergence clubs. The estimation of the appropriate spatial regimes spatial error model shows that the convergence process is different across regimes. The authors also estimate a strongly significant spatial spillover effect: the average growth rate of per capita GDP of a given region is positively affected by the average growth rate of neighboring regions.
The Human Immunodeficiency Virus Type 1 Vif Protein Reduces Intracellular Expression and Inhibits Packaging of APOBEC3G (CEM15), a Cellular Inhibitor of Virus Infectivity

ABSTRACT Replication of human immunodeficiency virus type 1 (HIV-1) in most primary cells and some immortalized T-cell lines depends on the activity of the viral infectivity factor (Vif). Vif has the ability to counteract a cellular inhibitor, recently identified as CEM15, that blocks infectivity of Vif-defective HIV-1 variants. CEM15 is identical to APOBEC3G and belongs to a family of proteins involved in RNA and DNA deamination. We cloned APOBEC3G from a human kidney cDNA library and confirmed that the protein acts as a potent inhibitor of HIV replication and is sensitive to the activity of Vif. We found that wild-type Vif inhibits packaging of APOBEC3G into virus particles in a dose-dependent manner. In contrast, biologically inactive variants carrying in-frame deletions in various regions of Vif or mutation of two highly conserved cysteine residues did not inhibit packaging of APOBEC3G. Interestingly, expression of APOBEC3G in the presence of wild-type Vif not only affected viral packaging but also reduced its intracellular expression level. This effect was not seen in the presence of biologically inactive Vif variants. Pulse-chase analyses did not reveal a significant difference in the stability of APOBEC3G in the presence or absence of Vif. However, in the presence of Vif, the rate of synthesis of APOBEC3G was slightly reduced. The reduction of intracellular APOBEC3G in the presence of Vif does not fully account for the Vif-induced reduction of virus-associated APOBEC3G, suggesting that Vif may function at several levels to prevent packaging of APOBEC3G into virus particles.
Web Server Performance Evaluation in a Virtualisation Environment

Operational and investment costs are reduced by resource sharing in virtual machine (VM) environments, which also results in an overhead for hosted services. VM machine performance is important because of resource contention. If an application takes a long time to execute because of its CPU or network, it is considered to be a failure because if many VMs are running over a single hardware platform, there will be competition for shared resources, e.g., the CPU, network bandwidth, and memory. Therefore, this study focuses on measuring the performance of a web server under a virtual environment and comparing those results with that from a dedicated machine. We found that the difference between the two sets of results is largely negligible. However, in some areas, one approach performed better than the other.
Efficient Drug-Pathway Association Analysis via Integrative Penalized Matrix Decomposition

Traditional drug discovery practice usually follows the “one drug - one target” approach, seeking to identify drug molecules that act on individual targets, which ignores the systemic nature of human diseases. Pathway-based drug discovery recently emerged as an appealing approach to overcome this limitation. An important first step of such pathway-based drug discovery is to identify associations between drug molecules and biological pathways. This task has been made feasible by the accumulating data from high-throughput transcription and drug sensitivity profiling. In this paper, we developed “iPaD”, an integrative Penalized Matrix Decomposition method to identify drug-pathway associations through jointly modeling of such high-throughput transcription and drug sensitivity data. A scalable bi-convex optimization algorithm was implemented and gave iPaD tremendous advantage in computational efficiency over current state-of-the-art method, which allows it to handle the ever-growing large-scale data sets that current method cannot afford to. On two widely used real data sets, iPaD also significantly outperformed the current method in terms of the number of validated drug-pathway associations that were identified. The Matlab code of our algorithm publicly available at http://licong-jason. github.io/iPaD/
IQGAP1 Plays an Important Role in the Invasiveness of Thyroid Cancer

Purpose: This study was designed to explore the role of IQGAP1 in the invasiveness of thyroid cancer and its potential as a novel prognostic marker and therapeutic target in this cancer. Experimental Design: We examined IQGAP1 copy gain and its relationship with clinicopathologic outcomes of thyroid cancer and investigated its role in cell invasion and molecules involved in the process. Results: We found IQGAP1 copy number (CN) gain ≥3 in 1 of 30 (3%), 24 of 74 (32%), 44 of 107 (41%), 8 of 16 (50%), and 27 of 41 (66%) of benign thyroid tumor, follicular variant papillary thyroid cancer (FVPTC), follicular thyroid cancer (FTC), tall cell papillary thyroid cancer (PTC), and anaplastic thyroid cancer, respectively, in the increasing order of invasiveness of these tumors. A similar tumor distribution trend of CN ≥4 was also seen. IQGAP1 copy gain was positively correlated with IQGAP1 protein expression. It was significantly associated with extrathyroidal and vascular invasion of FVPTC and FTC and, remarkably, a 50%–60% rate of multifocality and recurrence of BRAF mutation–positive PTC (P = 0.01 and 0.02, respectively). The siRNA knockdown of IQGAP1 dramatically inhibited thyroid cancer cell invasion and colony formation. Coimmunoprecipitation assay showed direct interaction of IQGAP1 with E-cadherin, a known invasion-suppressing molecule, which was upregulated when IQGAP1 was knocked down. This provided a mechanism for the invasive role of IQGAP1 in thyroid cancer. In contrast, IQGAP3 lacked all these functions. Conclusions: IQGAP1, through genetic copy gain, plays an important role in the invasiveness of thyroid cancer and may represent a novel prognostic marker and therapeutic target for this cancer. Clin Cancer Res; 16(24); 6009–18. ©2010 AACR.
Designing and Delivering Neonatal Care in Single Rooms

This article will outline the phases of the design process and describe the outcomes as related to a specific neonatal intensive care design project. The single-room concept allows for increased privacy and confidentiality, as well as decreased stress of family, staff, and especially patients. The improvement in family space facilitates improved opportunities for encouraging parent and sibling participation in care. Specific developmental and technological improvements have also been gained and are outlined throughout the article.
Inhibition of Ceramide De Novo Synthesis Ameliorates Diet Induced Skeletal Muscles Insulin Resistance

Nowadays wrong nutritional habits and lack of physical activity give a rich soil for the development of insulin resistance and obesity. Many researches indicate lipids, especially the one from the sphingolipids class, as the group of molecules heavily implicated in the progress of insulin resistance in skeletal muscle. Recently, scientists have focused their scrutiny on myriocin, a potent chemical compound that inhibits ceramide (i.e., central hub of sphingolipids signaling pathway) de novo synthesis. In the present research we evaluated the effects of myriocin application on type 2 diabetes mellitus in three different types of skeletal muscles: (1) slow-oxidative (red gastrocnemius), (2) oxidative-glycolytic (soleus), and (3) glycolytic (white gastrocnemius). For these reasons the animals were randomly divided into four groups: “control” (C), “myriocin” (M), “high fat diet” (HFD), “high fat diet” (HFD), and “high fat diet + myriocin” (HFD + M). Our in vivo study demonstrated that ceramide synthesis inhibition reduces intramuscular ceramide, its precursor sphinganine, and its derivatives sphingosine and sphingosine-1-phosphate concentrations. Moreover, FFA and TG contents were also decreased after myriocin treatment. Thus, myriocin presents potential therapeutic perspectives with respect to the treatment of insulin resistance and its serious consequences in obese patients.
Novel streptogramin antibiotics

Streptogramins represent a unique class of antibiotics remarkable for their antibacterial activity and their unique mechanism of action. These antibiotics are produced naturally as secondary metabolites by a number of Streptomyces species and have been classified into two main groups. They consist of at least two structurally unrelated compounds, group A or M (macrolactones) and group B or S (cyclic hexadepsipeptides). Both groups bind bacterial ribosomes and inhibit protein synthesis at the elongation step and they act synergistically in vitro against many microorganisms. Streptogramins A and B act synergistically in vivo; the mixture of the two compounds is more powerful than the individual components and their combined action is irreversible. The pharmacokinetic parameters of group A and B streptogramins in blood are similar. The major gap, limiting the therapeutic use of the natural compounds, was represented by the lack dissolution in water. The synthesis of water-soluble derivatives of pristinamycin IA and IIB has allowed the development of injectable, first represented by quinupristin/dalfopristin (Synercid™) and oral formulations, represented by RPR-106972, streptogramins with fixed compositions. Streptogramins have demonstrated activity against Gram-positive microorganisms in vitro and in vivo, including those with multi-drug resistance. Moreover, the absence of cross-resistance to macrolides in many of these microorganisms and the rarity of cross-resistance between the two groups of antibiotics associated with the rapid bacterial killing are the principal features of the streptogramins, offering the possibility for treating the rising number of infections that are caused by multi-resistant Gram-positive bacteria.