Reversal of a full-length mutant huntingtin neuronal cell phenotypeby chemical inhibitors of polyglutamine-mediated aggregation

Background: Huntington's disease (HD) is an inherited neurodegenerative disorder triggered by an expanded polyglutamine tract in huntingtin that is thought to confer a new conformational property on this large protein. The propensity of small amino-terminal fragments with mutant, but not wild-type, glutamine tracts to self-aggregate is consistent with an altered conformation but such fragments occur relatively late in the disease process in human patients and mouse models expressing full-length mutant protein. This suggests that the altered conformational property may act within the full-length mutant huntingtin to initially trigger pathogenesis. Indeed, genotypephenotype studies in HD have defined genetic criteria for the disease initiating mechanism, and these are all fulfilled by phenotypes associated with expression of full-length mutant huntingtin, but not amino-terminal fragment, in mouse models. As the in vitro aggregation of amino-terminal mutant huntingtin fragment offers a ready assay to identify small compounds that interfere with the conformation of the polyglutamine tract, we have identified a number of aggregation inhibitors, and tested whether these are also capable of reversing a phenotype caused by endogenous expressionof mutant huntingtin in a striatal cell line from the HdhQ111/Q111 knock-in mouse. Results: We screened the NINDS Custom Collection of 1,040 FDA approved drugs and bioactive compounds for their ability to prevent in vitro aggregation of Q58-htn 1¿171 amino terminal fragment. Ten compounds were identified that inhibited aggregation with IC50 < 15 ¿M, including gossypol, gambogic acid, juglone, celastrol, sanguinarine and anthralin. Of these, both juglone and celastrol were effective in reversing the abnormal cellular localization of full-length mutant huntingtin observed in mutant HdhQ111/Q111 striatal cells. Conclusions: At least some compounds identified as aggregation inhibitors also prevent a neuronal cellular phenotype caused by full-length mutant huntingtin, suggesting that in vitro fragment aggregation can act as a proxy for monitoring the disease-producing conformational property in HD. Thus, identification and testing of compounds that alter in vitro aggregation is a viable approach for defining potential therapeutic compounds that may act on the deleterious conformational property of full-length mutant huntingtin.

Fondaparinux in the initial and long-term treatment of venous thromboembolism.

BACKGROUND: Even in the absence of evidence on its long-term efficacy and safety, a number of patients with venous thromboembolism (VTE) receive long-term therapy with fondaparinux alone in everyday practice. METHODS: We used the Registro Informatizado de Enfermedad Tromboembólica (RIETE) registry to compare the rate of VTE recurrences and major bleeding at 10 and 90 days in patients with and without cancer. For long-term therapy, fondaparinux was compared with vitamin K antagonists (VKA) in patients without cancer and with low-molecular-weight heparin (LMWH) in those with cancer. RESULTS: Of 47,378 patients recruited, 46,513 were initially treated with heparin, 865 with fondaparinux. Then, 263 patients (78 with cancer) were treated for at least 3 months with fondaparinux. After propensity-score matching, there were no differences between patients receiving initial therapy with heparin or fondaparinux. Among patients with cancer, there were no differences between fondaparinux and LMWH. Among patients without cancer, the long-term use of fondaparinux was associated with an increased risk of major bleeding (3.24 % vs. 0.95 %, p<0.05). CONCLUSIONS: An unexpected high rate of major bleeding was observed in non-cancer patients treated with long-term fondaparinux. Our small sample does not allow to derive relevant conclusions on the use of fondaparinux in cancer patients.

Reciprocal preening and food sharing in colour-polymorphic nestling barn owls.

Barn owl (Tyto alba) siblings preen and offer food items to one another, behaviours that can be considered prosocial because they benefit a conspecific by relieving distress or need. In experimental broods, we analysed whether such behaviours were reciprocated, preferentially exchanged between specific phenotypes, performed to avoid harassment and food theft or signals of hierarchy status. Three of the results are consistent with the hypothesis of direct reciprocity. First, food sharing was reciprocated in three-chick broods but not in pairs of siblings, that is when nestlings could choose a partner with whom to develop a reciprocating interaction. Second, a nestling was more likely to give a prey item to its sibling if the latter individual had preened the former. Third, siblings matched their investment in preening each other. Manipulation of age hierarchy showed that food stealing was directed towards older siblings but was not performed to compensate for a low level of cooperation received. Social behaviours were related to melanin-based coloration, suggesting that animals may signal their propensity to interact socially. The most prosocial phenotype (darker reddish) was also the phenotype that stole more food, and the effect of coloration on prosocial behaviour depended upon rank and sex, suggesting that colour-related prosociality is state dependent.

Linking brain structure and activation in the temporoparietal junction to explain the neurobiology of human altruism

Human altruism shaped our evolutionary history and pervades social and political life. There are, however, enormous individual differences in altruism. Some people are almost completely selfish, while others display strong altruism, and the factors behind this heterogeneity are only poorly understood. We examine the neuroanatomical basis of these differences with voxel-based morphometry and show that gray matter (GM) volume in the right temporoparietal junction (TPJ) is strongly associated with both individuals' altruism and the individual-specific conditions under which this brain region is recruited during altruistic decision making. Thus, individual differences in GM volume in TPJ not only translate into individual differences in the general propensity to behave altruistically, but they also create a link between brain structure and brain function by indicating the conditions under which individuals are likely to recruit this region when they face a conflict between altruistic and selfish acts.

A territorial approach to R&D subsidies: Empirical evidence for Catalonian firms

Using a database of 2,263 responses to R&D public calls in Catalonia, during the period 2007–2010, this paper proceeds to analyse the potential interaction of the territorial and policy dimensions with the propensity to apply for, and be awarded, a public R&D subsidy. Controlling for characteristics at the firm and project level, we estimate models using a two-step procedure. In the first step, our results suggest that large firms which export and which belong to high-tech manufactures are more likely to participate in a public R&D call. Furthermore, both urban location and past experience of such calls have a positive effect. Our territorial proxy of information spillovers shows a positive sign, but this is only significant at intra-industry level. Membership of one of the sectors prioritized by the Catalan government, perhaps surprisingly, does not have a significant impact. In the second step, our results show that cooperative projects, SMEs or old firms shows a positive effect on the probability of obtaining a public subsidy. Finally, the cluster policy does not show a clear relationship with the public R&D call, suggesting that cluster policies and R&D subsidies follow different goals. Our results are in line with previous results in the literature, but they highlight the unequal territorial distribution of the firms which apply and the fact that policymakers should interlink the decision criteria for their public call with other policies. Keywords: Evaluation, R&D policies, territorial approach, clusters JEL Classifications: L53, L25, O38

Young Firms and R&D subsidies in Catalonia

Based on four different public R&D calls from the Catalan government, this article evaluates the propensity of entrants and young firms to apply for R&D public grants and, as compared to their counterparts, their capacity for obtaining subsides. This analysis is particularly relevant since entrants and young firms encounter greater market difficulties. Our sample contains 22,139 firms and corresponds to a merge of two databases: one from the Catalan agency responsible for promoting private innovation (ACC1Ó) and the other from the Mercantile Register. Merging these databases has two advantages. Firstly, participants and non-participants in the public R&D call (“InnoEmpresa”) are included and, secondly, it provides us with information at firm and project level. The period of observation is between 2006 and 2010, since some explanatory variables are lagged by one period. We apply a two-step methodology. Our results show that entrants and young firms show a lower propensity to apply for R&D subsidies and to obtain R&D public grants. Firm size, exports and participation in a previous call show a positive impact on the likelihood of applying, and firms located in the Barcelona metropolitan area have a greater propensity to apply. Additionally, project quality and R&D cooperative reports presented jointly with other partners have a positive impact on the likelihood of obtaining the R&D subsidy. Finally, firms that have previously obtained an R&D subsidy do not exhibit a greater propensity for obtaining subsequent grants. Keywords: R&D subsidies, entrants and young firms Classification JEL: L53, L25, O38

Importance of the embedding environment on the strain within small rings in siliceous materials

The effect of the local environment on the energetic strain within small (SiO)N rings (with N=2,3) in silica materials is investigated via periodic model systems employing density functional calculations. Through comparison of the energies of various nonterminated systems containing small rings in strained and relatively unstrained environments, with alpha quartz, we demonstrate how small ring strain is affected by the nature of the embedding environment. We compare our findings with numerous previously reported calculations, often predicting significantly different small-ring strain energies, leading to a critical assessment of methods of calculating accurate localized ring energies. The results have relevance for estimates of the strain-induced response (e.g., chemical, photo, and radio) of small silica rings, and the propensity for them to form in bulk glasses, thin films, and nanoclusters.

Job losses, outsourcing and relocation: empirical evidence using microdata

Using microdata, we analyse the determinants of firm relocation and conventional outsourcing decisions as a way to reduce employment. The results for a sample of 32 countries show the relevance of factors not considered previously in the literature. Firms that are below average in quality or innovation have a higher propensity to externalise part of their production through outsourcing, while lower relative profitability and longer time to market for new products each imply a higher probability of relocation.

Decomposing differences in total factor productivity across firm size

This paper investigates the extent to which the gap in total factor productivity between small and large firms is due to differences in the endowment of factors determining productivity and to the returns associated with these factors. We place particular emphasis on the contribution of differences in the propensity to innovate and in the use of skilled labor across firms of different size. Empirical evidence from a representative sample of Spanish manufacturing firms corroborates that both differences in endowments and returns to innovation and skilled labor significantly contribute to the productivity gap between small and large firms. In addition, it is observed that the contribution of innovation to this gap is caused only by differences in quantity, while differences in returns have no effect; in the case of human capital, however, most of the effect can be attributed to increasing differences in returns between small and large firms.

Enzimas termoestáveis: fontes, produção e aplicação industrial

REVIEW: Living organisms encountered in hostile environments that are characterized by extreme temperatures rely on novel molecular mechanisms to enhance the thermal stability of their proteins, nucleic acids, lipids and cell membranes. Proteins isolated from thermophilic organisms usually exhibit higher intrinsic thermal stabilities than their counterparts isolated from mesophilic organisms. Although the molecular basis of protein thermostability is only partially understood, structural studies have suggested that the factors that may contribute to enhance protein thermostability mainly include hydrophobic packing, enhanced secondary structure propensity, helix dipole stabilization, absence of residues sensitive to oxidation or deamination, and increased electrostatic interactions. Thermostable enzymes such as amylases, xylanases and pectinases isolated from thermophilic organisms are potentially of interest in the optimization of industrial processes due to their enhanced stability. In the present review, an attempt is made to delineate the structural factors that increase enzyme thermostability and to document the research results in the production of these enzymes.

Treatment of oily wastewater by ultrafiltration: The effect of different operating and solution conditions

In many industries, such as petroleum production, and the petrochemical, metal, food and cosmetics industries, wastewaters containing an emulsion of oil in water are often produced. The emulsions consist of water (up to 90%), oils (mineral, animal, vegetable and synthetic), surfactants and other contaminates. In view of its toxic nature and its deleterious effects on the surrounding environment (soil, water) such wastewater needs to be treated before release into natural water ways. Membrane-based processes have successfully been applied in industrial applications and are considered as possible candidates for the treatment of oily wastewaters. Easy operation, lower cost, and in some cases, the ability to reduce contaminants below existing pollution limits are the main advantages of these systems. The main drawback of membranes is flux decline due tofouling and concentration polarisation. The complexity of oil-containing systems demands complementary studies on issues related to the mitigation of fouling and concentration polarisation in membranebased ultrafiltration. In this thesis the effect of different operating conditions (factors) on ultrafiltration of oily water is studied. Important factors are normally correlated and, therefore, their effect should be studied simultaneously. This work uses a novel approach to study different operating conditions, like pressure, flow velocity, and temperature, and solution properties, like oil concentration (cutting oil, diesel, kerosene), pH, and salt concentration (CaCl2 and NaCl)) in the ultrafiltration of oily water, simultaneously and in a systematic way using an experimental design approach. A hypothesis is developed to describe the interaction between the oil drops, salt and the membrane surface. The optimum conditions for ultrafiltration and the contribution of each factor in the ultrafiltration of oily water are evaluated. It is found that the effect on permeate flux of the various factors studied strongly depended on the type of oil, the type of membrane and the amount of salts. The thesis demonstrates that a system containing oil is very complex, and that fouling and flux decline can be observed even at very low pressures. This means that only the weak form of the critical flux exists for such systems. The cleaning of the fouled membranes and the influence of different parameters (flow velocity, temperature, time, pressure, and chemical concentration (SDS, NaOH)) were evaluated in this study. It was observed that fouling, and consequently cleaning, behaved differently for the studied membranes. Of the membranes studied, the membrane with the lowest propensity for fouling and the most easily cleaned was the regenerated cellulose membrane (C100H). In order to get more information about the interaction between the membrane and the components of the emulsion, a streaming potential study was performed on the membrane. The experiments were carried out at different pH and oil concentration. It was seen that oily water changed the surface charge of the membrane significantly. The surface charge and the streaming potential during different stages of filtration were measured and analysed being a new method for fouling of oil in this thesis. The surface charge varied in different stages of filtration. It was found that the surface charge of a cleaned membrane was not the same as initially; however, the permeability was equal to that of a virgin membrane. The effect of filtration mode was studied by performing the filtration in both cross-flow and deadend mode. The effect of salt on performance was considered in both studies. It was found that salt decreased the permeate flux even at low concentration. To test the effect of hydrophilicity change, the commercial membranes used in this thesis were modified by grafting (PNIPAAm) on their surfaces. A new technique (corona treatment) was used for this modification. The effect of modification on permeate flux and retention was evaluated. The modified membranes changed their pore size around 33oC resulting in different retention and permeability. The obtained results in this thesis can be applied to optimise the operation of a membrane plant under normal or shock conditions or to modify the process such that it becomes more efficient or effective.

Palvelutasopoikkeamariskin kustannusvaikutusten määrittäminen tietoliikennepalveluiden tuotannossa

Tutkimuksen päämääränä oli selvittää laadullisin menetelmin millaisia kustannusvaikutuksia laajavaikutteiset palvelutasopoikkeamat, eli erilaiset viat tai häiriöt tietoliikennepalveluissa aiheuttavat kohdeyrityksen tietoliikennepalveluiden tuotannossa. Tutkimus muistutti lähtökohdiltaan paljolti riskianalyysia, sillä sen tavoitteina oli tunnistaa merkittävimmät palvelutasopoikkeamien aiheuttajat, arvioida palvelutasopoikkeaman kustannusvaikutuksia ja pohtia millaisin toimin ja kustannuksin palvelutasopoikkeamia voitaisiin ehkäistä. Tutkimusongelmaa lähestyttiin jakamalla palvelutasopoikkeaman kustannusvaikutukset viankorjauksesta aiheutuviin välittömiin ja asiakasvaikutusten kautta mahdollisesti syntyviin välillisiin kustannuksiin. Välillisiä kustannuksia aiheuttaviksi ilmiöiksi tunnistettiin palvelukatkon aiheuttama liikennetulomenetys, nykyisten tai potentiaalisten asiakkaiden menettäminen ja nykyisten asiakkaiden alentunut ostohalukkuus. Yhteenvetona tutkimuksessa tehtyihin havaintoihin perustuen välilliset kustannukset eivät osoittautuneet niin merkittäviksi kuin tutkimuksen aloitusvaiheessa oletettiin, mutta lisätutkimus aiheesta voi olla perusteltua.

PASSIONS AND EVIL IN KANT'S PHILOSOPHY

In this paper, I aim at relating passions to evil in Kant's philosophy. I begin by explaining the difference between affects and passions in the textAnthropology from a Pragmatic Point of View. Kant claims that both affects and passions are illnesses of the mind, because both affect and passion hinder the sovereignty of reason. I show that passions are worse than affects for the purpose of pure reason. Second, I relate affects and passions to the degrees of the propensity to evil in theReligion. I analyze the idea of an ethical community as a way to overcome the evil, which goes beyond political and anthropological solutions suggested by Kant.

The effectiveness of vocationally oriented multidisciplinary rehabilitation (ASLAK®) amongst public sector employees

In Finland, vocationally oriented medical rehabilitation (ASLAK®) is a common preventive rehabilitation measure with the primary goal of preserving and improving work ability. The ASLAK® programme has been used for almost 30 years, although limited data exist on its effectiveness. The aims of this study were to determine whether the increased risk of work disability predicts the participants’ likelihood to be granted ASLAK® rehabilitation and to assess the effectiveness of the programme in decreasing the risk of work disability and modifying health-risk behaviours. This study is a part of the on-going Finnish Public Sector Study conducted by the Finnish Institute of Occupational Health. Data on 53 416 employees (81% women) were gathered from employers’ records, national health registers and repeated survey responses. During the 5-year follow-up, increased levels of the risk factors for work disability did not predict participation in the rehabilitation programme. During the 2.8-year followup (range 0.04–5.0 years), the risk of long-term work disability (sick leave >90 days or retirement) overall or, more specifically, due to musculoskeletal or mental diseases did not differ between the rehabilitants who participated in ASLAK® in 1997–2005 and their propensity score matched controls. There was no evidence of ASLAK® being effective in changing participants’ health-risk behaviours or in improving perceived general or mental health. The results suggest that potential participant recognition, mainly taking place in occupational health care, may fail to identify those with a higher risk of work disability. No evidence on the effectiveness of the programme was found in the study cohort when measured by the selected indicators.

Finnish cleantech SMEs in China: Challenges and solutions

The rapid economic growth in China has resulted in environmental challenges ranging from air pollution to water-related issues. Thus supporting clean technology, or cleantech, that encompasses industries that focus on alternative energy, pollution and recycling, power supplies and conservation has become one of the focal points in the Chinese economic policy for the next decade. Simultaneously, the Finnish government has initiated programs to support the internationalisation of domestic cleantech companies in an attempt to spiral the industry into one of the pillars of Finnish economic growth. This study concentrates on the conjunction of these two themes and studies the challenges faced by Finnish cleantech SMEs in the Chinese market. Consequently, the study answers the following sub questions: 1. What human and financial resource-based challenges do Finnish cleantech SMEs face in the Chinese market and what are their solutions? 2. What knowledge-based challenges do Finnish cleantech SMEs face in the Chinese market and how can these difficulties be resolved? 3. What network-based challenges do Finnish cleantech SMEs face in the Chinese market, how do they relate to the resource- and knowledge-based challenges, and how can these difficulties be resolved? This qualitative study is conducted by analysing four semi structured interviews collected from four Finnish SMEs that operate in China. The findings of the study indicate that in human resources the most important challenges are related to the hiring and retaining of employees. In contrast to extant academic literature results distinguish salary and social status as the main solutions to this challenge. Regarding financial resources it is discovered that cleantech companies enjoy a benign business environment in China and benefit from the Chinese government’s support for cleantech industry. Challenges related to knowledge resources can be grouped into categories with the most interesting knowledge flows being the stream of local market knowledge into to the foreign parent company and the outward flow of manufacturing and business practice information into the target venture. The challenge related to the first flow is gathering relevant information and the main solutions are clustering at the foreign location and hiring knowledge prior to internationalisation. Regarding the second flow the main challenge is related to intellectual property rights and the most interesting solution is the purposeful transformation of explicit knowledge into tacit knowledge. Finally, it is discovered that networks, called guanxi in China, greatly affect the business processes. Within the guanxi system there is the concept of face which was found to affect employee propensity to stay as well as, as a novel academic result, employees’ knowledge sharing intention.