Miracle-dz/UniFAR-FTUs huggingface dataset:
Analysis of the Structural Properties of cAMP-responsive Element-binding Protein (CREB) and Phosphorylated CREB*

The transcription factor CREB (AMP esponsive lement inding protein) is activated by protein kinase A (PKA) phosphorylation of a single serine residue. To investigate possible mechanisms of CREB regulation by phosphorylation, we initiated a structural and biophysical characterization of the full-length, wild-type CREB protein, an altered CREB protein (CREB/SER) in which the three cysteine residues in the DNA-binding domain were replaced with serine residues and a truncated protein (ACT265) which encompasses the entire activation domain of CREB. Circular dichroism (CD) reveals that CREB and CREB/SER have identical secondary structures and contain approximately 20% α-helix, 9% β-strand, 34% β-turn, and 37% random coil structures. PKA phosphorylation does not alter the CD spectra, and therefore the secondary structure, of CREB or of CREB bound to DNA. Protease cleavage patterns indicate that PKA phosphorylation does not induce a global conformational change in CREB. Furthermore, PKA phosphorylation does not change the DNA binding affinity of CREB for either canonical or non-canonical CRE sequences as measured by a fluorescence anisotropy DNA binding assay. Since PKA phosphorylation of CREB results in its specific binding to the transcriptional co-activators CREB-binding protein and p300, we suggest that the PKA activation of CREB occurs by the production of specific, complementary interactions with these proteins, rather than through the previously proposed mechanisms of a phosphorylation-dependent conformational change or increased DNA binding affinity.
Latency Correction Explains the Classical Geometrical Illusions

There is a significant delay between the time when light hits the retina and the time of the consequent percept. It has been hypothesized that the visual system attempts to correct for this latency by generating a percept representative of the way the world probably is at the time the percept is elicited, rather than a percept of the recent past. Here we show that such a ‘perceiving the present’ hypothesis explains a number of classical geometrical illusions: the Hering, Orbison, Müller-Lyer, Double Judd, Poggendorff, Corner, and Upside-down-T illusions. Each stimulus is perceived as it would project in the next moment were the observer moving through the scene the stimulus probably represents. We also examine one general class of predictions made by the hypothesis, and report psychophysical experiments confirming the predictions.
Tumor response and toxicity with multiple infusions of high dose 131I‐MIBG for refractory neuroblastoma

131I Metaiodobenzylguanidine (131I‐MIBG) is an effective targeted radiotherapeutic for neuroblastoma with response rates greater than 30% in refractory disease. Toxicity is mainly limited to myelosuppression. The aim of this study was to determine the response rate and hematologic toxicity of multiple infusions of 131I‐MIBG.
The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines

Suberoylanilide hydroxamic acid (SAHA) is a hydroxamic acid-containing hybrid polar molecule; SAHA specifically binds to and inhibits the activity of histone deacetylase. Although SAHA, like other inhibitors of histone deacetylase, exhibits antitumor effects by increasing expression of genes regulating tumor survival, we found that SAHA reduces the production of proinflammatory cytokines in vivo and in vitro. A single oral administration of SAHA to mice dose-dependently reduced circulating TNF-α, IL-1-β, IL-6, and IFN-γ induced by lipopolysaccharide (LPS). Administration of SAHA also reduced hepatic cellular injury in mice following i.v. injection of Con A. SAHA inhibited nitric oxide release in mouse macrophages stimulated by the combination of TNF-α plus IFN-γ. Human peripheral blood mononuclear cells stimulated with LPS in the presence of SAHA released less TNF-α, IL-1-β, IL-12, and IFN-γ (50% reduction at 100–200 nM). The production of IFN-γ stimulated by IL-18 plus IL-12 was also inhibited by SAHA (85% at 200 nM). However, SAHA did not affect LPS-induced synthesis of the IL-1-β precursor, the IL-1 receptor antagonist, or the chemokine IL-8. In addition, IFN-γ induced by anti-CD3 was not suppressed by SAHA. Steady-state mRNA levels for LPS-induced TNF-α and IFN-γ in peripheral blood mononuclear cells were markedly decreased, whereas IL-8 and IL-1-β mRNA levels were unaffected. Because SAHA exhibits antiinflammatory properties in vivo and in vitro, inhibitors of histone deacetylase may stimulate the expression of genes that control the synthesis of cytokines and nitric oxide or hyperacetylate other targets.
Antioxidants as Adjuvant Therapy in Rheumatoid Disease

Summary The aim of the present study was to assess the therapeutic value of adding a high dose of vitamin E or an antioxidant combination to the treatment regimen of the rheumatoid disease. The study was carried out on 30 patients with rheumatoid disease diagnosed according to the criteria of American Rheumatism Association (ARA), subvided into three equal groups. Patients in group I received a standard treatment of intramuscular me-thotrexate (CAS 59-05-2; 12.5 mg/week), oral sulphasalazine (CAS 599-79-1; 0.5 g b.i.d.) and indometacin (CAS 53-86-1; 100 mg suppository at bed-time). In group II the patients received the standard treatment plus a combination of anti-oxidants. Patients in group III received a high dose of vitamin E (400 mg t.i.d.) in addition to the standard treatment. The disease state was evaluated using Ritchie’s articular score index and the duration of morning stiffness. Laboratory evaluations included the rheumatoid factor, erythrocyte sedimentation rate (ESR), plasma levels of vitamin E and ma-lonedialdehyde (MDA), and the activity of glutathione peroxidase (GPx). In the group receiving the standard regimen, the patients started to feel tangible improvement by the end of the second month. With adjuvant therapy of either the antioxidant combination or a high dose of vitamin E the symptoms of arthritis were better controlled from the first month. By the end of the second month, the values of the three monitoring tests were significantly decreased indicating better control of the disease. The percentage increase in the activity of GPx was highest in patients taking the antioxidant combination and least in those taking the standard treatment. The decrease in plasma MDA followed the same pattern. With adjuvant therapy, the vitamin E level in plasma increased with the duration of treatment. The results obtained in the present study are encouraging. The clinical improvement and the shift in the disease indices towards normal make the use of antioxidants as adjuvant therapy in rheumatoid disease worth pursuing.
Sorting in the Labor Market

This review surveys the literature on sorting in the labor market. There are inherent differences in worker ability and across-firm productivity. Two fundamental questions are whether the exact composition of skills of workers and productivity of firms affects output and how this composition determines the equilibrium allocation of workers within a firm and between firms. There has been a surge of research investigating the causes and consequences of the process of allocation of heterogeneous workers to firms. The focus in this review is on theory that sheds light on open questions in macroeconomics, labor, and industrial organization, with a particular emphasis on the role of firm size. Those models allow us to infer from the observed sorting patterns (who matches with whom) what the underlying technological determinants are and how they have evolved in recent decades. Furthermore, they help us understand the technological origins of important labor market trends, such as the increase in wage inequality and the change in labor market and firm dynamics.
Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in The Bethesda System for Reporting Thyroid Cytopathology

Recent discussions have focused on redefining noninvasive follicular variant of papillary thyroid carcinoma (NI‐FVPTC) as a neoplasm rather than a carcinoma. This study assesses the potential impact of such a reclassification on the implied risk of malignancy (ROM) for the diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).
Passive water and urea permeability of a human Na+–glutamate cotransporter expressed in Xenopus oocytes

The human Na+‐glutamate transporter (EAAT1) was expressed in Xenopus laevis oocytes. The passive water permeability, Lp, was derived from volume changes of the oocyte induced by changes in the external osmolarity. Oocytes were subjected to two‐electrode voltage clamp. In the presence of Na+, the EAAT1‐specific (defined in Discussion) Lp increased linearly with positive clamp potentials, the Lp being around 23 % larger at +50 mV than at –50 mV. l‐Glutamate increased the EAAT1‐specific Lp by up to 40 %. The K0.5 for the glutamate‐dependent increase was 20 ± 6 μm, which is similar to the K0.5 value for glutamate activation of transport. The specific inhibitor dl‐threo‐β‐benzyloxyaspartate (TBOA) reduced the EAAT1‐specific Lp to 72 %. EAAT1 supported passive fluxes of [14C]urea and [14C]glycerol. The [14C]urea flux was increased in the presence of glutamate. The data suggest that the permeability depends on the conformational equilibrium of the EAAT1. At positive potentials and in the presence of Na+ and glutamate, the pore is enlarged and water and urea penetrate more readily. The Lp was larger when measured with urea or glycerol as osmolytes as compared with mannitol. Apparently, the properties of the pore are not uniform along its length. The outer section may accommodate urea and glycerol in an osmotically active form, giving rise to larger water fluxes. The physiological role of EAAT1 for water homeostasis in the central nervous system is discussed.
Earnings Responses to Disability Benefit Cuts

Using Dutch administrative data, we assess the work and earnings capacity of disability insurance (DI) recipients by estimating employment and earnings responses to benefit cuts. Reassessment of DI entitlement under more stringent criteria removed 14.4 percent of recipients from the program and reduced benefits by 20 percent, on average. In response, employment increased by 6.7 points and earnings rose by 18 percent. Recipients were able to increase earnings by €0.64 for each €1 of DI income lost. Female and younger recipients, as well as those with more subjectively defined disabilities, were able to increase earnings most. The earnings response declined as claim duration lengthened, suggesting that earnings capacity deteriorates while on DI. The deterioration was steepest for male, younger and fully disabled recipients. Working while claiming partial disability benefits appears to slow the deterioration of earnings capacity.
Immunity Provided by an Outer Membrane Vesicle Cholera Vaccine Is Due to O-Antigen-Specific Antibodies Inhibiting Bacterial Motility

ABSTRACT An outer membrane vesicle (OMV)-based cholera vaccine is highly efficacious in preventing intestinal colonization in the suckling mouse model. Immunity from OMVs comes from immunoglobulin (Ig), particularly IgG, in the milk of mucosally immunized dams. Anti-OMV IgG renders Vibrio cholerae organisms immotile, thus they pass through the small intestine without colonizing. However, the importance of motility inhibition for protection and the mechanism by which motility is inhibited remain unclear. By using both in vitro and in vivo experiments, we found that IgG inhibits motility by specifically binding to the O-antigen of V. cholerae. We demonstrate that the bivalent structure of IgG, although not required for binding to the O-antigen, is required for motility inhibition. Finally, we show using competition assays in suckling mice that inhibition of motility appears to be responsible for most, if not all, of the protection engendered by OMV vaccination, thus providing insight into the mechanism of immune protection.
Ultrastructural and ultracytochemical differences between transient myeloproliferative disorder and megakaryoblastic leukaemia in Down's syndrome

Ultrastructural and ultracytochemical studies were performed on blast cells from 12 Down's syndrome neonates with transient myeloproliferative disorder (TMD) and 13 Down's syndrome patients with megakaryoblastic leukaemia (MKL), in order to clarify the cytological characteristics of these cells. Average platelet peroxidase‐positivity in blast cells of TMD patients was similar to that found in cases of MKL. Blast cells from subjects with TMD contained a number of different granules, namely, alpha granules, those that were myeloperoxidase (MPO)‐positive, electron‐lucent or basophil‐like, and those containing membrane components or ferritin particles. On the other hand, granules found in the blast cells of MKL patients with Down's syndrome included the electron‐lucent variety, those with membrane components and a few that were basophil‐like, but not alpha and MPO‐positive granules nor those containing ferritin particles. A demarcation membrane system was observed in blasts from the TMD group, but not in the MKL group.
Is a Potent and Selective Antagonist at Rat and Human Native 7 Nicotinic Acetylcholine Receptors

A recently developed -conotoxin, -conotoxin Arenatus IB[V11L,V16D] ( -CtxArIB[V11L,V16D]), is a potent and selective competitive antagonist at rat recombinant 7 nicotinic acetylcholine receptors (nAChRs), making it an attractive probe for this receptor subtype. 7 nAChRs are potential therapeutic targets that are widely expressed in both neuronal and nonneuronal tissues, where they are implicated in a variety of functions. In this study, we evaluate this toxin at rat and human native nAChRs. Functional 7 nAChR responses were evoked by choline plus the allosteric potentiator PNU-120596 [1-(5chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea] in rat PC12 cells and human SH-SY5Y cells loaded with calcium indicators. -CtxArIB[V11L,V16D] specifically inhibited 7 nAChR-mediated increases in Ca in PC12 cells. Responses to other stimuli, 5-I-A-85380 [5-iodo-3-(2(S)azetidinylmethoxy)pyridine dihydrochloride], nicotine, or KCl, that did not activate 7 nAChRs were unaffected. Human 7 nAChRs were also sensitive to -CtxArIB[V11L, V16D]; acetylcholine-evoked currents in Xenopus laevis oocytes expressing human 7 nAChRs were inhibited by -CtxArIB[V11L,V16D] (IC50, 3.4 nM) in a slowly reversible manner, with full recovery taking 15 min. This is consistent with the time course of recovery from blockade of rat 7 nAChRs in PC12 cells. -CtxArIB[V11L,V16D] inhibited human native 7 nAChRs in SHSY5Y cells, activated by either choline or AR-R17779 [(2)-spiro[1-azabicyclo[2.2. 2]octane3,59-oxazolidin]-29-one] plus PNU-120596. Rat brain 7 nAChRs contribute to dopamine release from striatal minces; -CtxArIB[V11L,V16D] (300 nM) selectively inhibited cholineevoked dopamine release without affecting responses evoked by nicotine that activates heteromeric nAChRs. This study establishes that -CtxArIB[V11L,V16D] selectively inhibits human and rat native 7 nAChRs with comparable potency, making this a potentially useful antagonist for investigating 7 nAChR functions. The 7 subtype of nicotinic acetylcholine receptors (nAChRs) is currently attracting considerable interest for its roles in brain function, including synaptic plasticity (McKay et al., 2007) and attentional aspects of cognitive performance (Levin et al., 2006). Consequently, 7 nAChRs are therapeutic targets for cognitive impairments in Alzheimer’s disease, schizophrenia, and attention deficit hyperactivity disorder (Mazurov et al., 2006; Chiamulera and Fumagalli, 2007; Wilens and Decker, 2007). 7 nAChRs also have therapeutic potential in several other processes, including pain, inflammation, and wound healing (Decker and Meyer, 1999; de Jonge and Ulloa, 2007). Selective antagonists are essential research tools for elucidating and clarifying the molecular and cellular mechanisms that under-
Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists

Rivaroxaban is a new oral anticoagulant (NOAC) that can be prescribed in a fixed dose, making regular monitoring and dose adjustments unnecessary. It has been proven to be safe and effective in comparison with enoxaparin/vitamin K antagonists (LMWH/VKA) for the (extended) treatment of venous thromboembolism in the EINSTEIN studies. Nevertheless, there is a need for information regarding the clinical impact of (major) bleeding events with NOACs such as rivaroxaban.
Domo Arigato Gozaimasu: Economic Spillovers of Regional Tourism in Japan

A growing body of literature investigates the relationship between tourism and economic growth (Brida et al. 2016); even if sub-national studies are deemed relevant in order to analyze the issue (Pablo-Romero and Molina, 2013), these are rare: thus, we aim to provide a first analysis of the bi-univocal relationship between tourism and economic growth for Japanese regions and prefectures, using multiple Granger Causality tests in a Bayesian VAR model, from 2007 to 2014. We find that either (or both) tourism-led growth hypothesis and economic-led tourism hypothesis are supported empirically in 4 out of 8 regions and in 19 out of 47 prefectures, in univocal or bi-univocal direction, proving that sub-national territories do not always display the behaviour found on the national level. Our findings suggest the use of tourism as a policy instrument able to stimulate economic growth on sub-national level, even if some regional discrepancies are to be expected.
Brimonidine Tartrate–Eudragit Long-Acting Nanoparticles: Formulation, Optimization, In Vitro and In Vivo Evaluation

In the present study, an effort was made to design prolonged release Eudragit nanoparticles of brimonidine tartrate by double emulsion–solvent evaporation technique for the treatment of open-angle glaucoma. The effect of various formulation variables like initial drug amount, lecithin proportion, phase volume and pH, secondary emulsifier and polymer proportion were studied. Various process variables like energy and duration of emulsification, lyophilization on the characteristics of nanoparticles and in vitro drug release profile were studied. The selected formulations were subjected to in vivo intraocular pressure-lowering efficacy studies by administering aqueous dispersion of nanoparticles into the lower cul de sac of glaucomatous rabbits. The prepared Eudragit-based nanoparticles were found to have narrow particle size range and improved drug loading. The investigated process and formulation variables found to have significant effect on the particle size, drug loading and entrapment efficiency, and in vitro drug release profile of nanoparticles. The selected formulations upon in vivo ocular irritability and tolerability tests were found to be well tolerated with no signs of irritation. In vivo pharmacodynamic efficacy studies revealed that the selected nanoparticle formulations significantly improved the therapy as area under the ∆IOP vs. time curve [AUC(∆IOP vs.t)] showed several fold increase in intensity and duration of intraocular pressure (IOP) decrease. All the selected nanoparticle formulations were found to prolong the drug release in vitro and prolong IOP reduction efficacy in vivo, thus rendering them as a potential carrier in developing improved drug delivery systems for the treatment of glaucoma.
IL MODELLO SUD-EUROPEO Dl WELFARE STATE

Un welfare del Sud? Con il ritorno della democrazia e l'ingresso nella Comunità europea di Spagna, Portogallo e Grecia la visibilità dell'Europa meridionale è costantemente cresciuta nel corso dell'ultimo decennio. L'approssimarsi delle scadenze previste per l'Unione economico-monetaria e il dibattito sulla cosiddetta «dimensione sociale» hanno a loro volta attirato l'attenzione dei policy makers nazionali e sovranazionali verso gli specifici problemi e le prospettive dei sistemi di welfare dei paesi latini. L'idea sottostante a questo nuovo interesse è che tali sistemi siano caratterizzati da una eredità comune e che si trovino oggi a fronteggiare sfide «regionali» anch'esse comuni nel nuovo contesto post-Maastricht.
Overexpression of Arabidopsis AGD7 Causes Relocation of Golgi-Localized Proteins to the Endoplasmic Reticulum and Inhibits Protein Trafficking in Plant Cells1[C][OA]

ADP ribosylation factor (Arf) GTPase-activating proteins (GAPs) promote the hydrolysis of GTP bound to Arfs to GDP, which plays a pivotal role in regulating Arfs by converting the active GTP-bound forms of these proteins into their inactive GDP-bound forms. Here, we investigated the biological role of AGD7, an Arf GAP homolog, in Arabidopsis (Arabidopsis thaliana). We show that AGD7 bears a highly conserved N-terminal region and a unique C-terminal region, interacts with Arf1 both in vitro and in vivo, and stimulates Arf1 GTPase activity in a phosphatidic acid-dependent manner in vitro. In plant cells, AGD7 localized to the Golgi complex, where its overexpression was found to inhibit the Golgi localization of γ-subunit of coat proteins and promote the relocation of Golgi proteins into the endoplasmic reticulum in both protoplasts and transgenic plants. Furthermore, overexpression of AGD7 inhibited anterograde trafficking of proteins from the endoplasmic reticulum. We propose that AGD7 functions as a GAP for Arf1 in the Golgi complex and plays a critical role in protein trafficking by controlling Arf1 activity.
NATO options and dilemmas for deterring Russia in the Baltic States

Abstract According to the NATO’s collective defence strategy and the principle of deterrence, “no one should doubt NATO’s resolve if the security of any of its members were to be threatened”. In this sense, credible deterrence acts as a guarantee for peace and stability in the Euro-Atlantic region. However, recent events in Ukraine and Georgia have revealed the potential weaknesses of the current deterrence models. Without any overt fear of retaliation, we have seen Russia’s aggressive steps towards its neighbours, which were planned and executed with great sophistication, initiative, agility and decisiveness. Although contrary to Ukraine and Georgia which are not the members of the Alliance, Estonia, Latvia and Lithuania are granted security guarantees in the NATO framework, the Baltic countries clearly constitute Russia’s point of contact with NATO and are, therefore, also subject to the interests of Russia to test mutual capabilities and commitment, and to send strategic messages to the Alliance. In this context, the article aims to assess how credible is the deterrence posture provided by NATO in avoiding potential aggression on the part of Russia against the Baltic countries.
Performance and availability modeling of hybrid storage systems

The need for performance has motivated the increasing adoption of solid-state drives (SSD) both in personal computers and data centers. However, the high cost per gigabyte and reduced lifetime hinder the thorough replacement of hard disk drives (HDD) with SSDs. To mitigate these issues, several architectures have been conceived based on hybrid storage systems, but performance and dependability models have not been proposed to better assess such different architectures. This paper presents an approach based on stochastic models for performance and availability modeling of hybrid storage systems, using stochastic Petri nets (SPN) and reliability block diagrams (RBD). A case study based on OpenStack Swift platform is adopted to demonstrate the feasibility of the proposed approach.