Methionine Sulfoxides on Prion Protein Helix-3 Switch on the α-Fold Destabilization Required for Conversion

BACKGROUND: The conversion of the cellular prion protein (PrP(C)) into the infectious form (PrP(Sc)) is the key event in prion induced neurodegenerations. This process is believed to involve a multi-step conformational transition from an alpha-helical (PrP(C)) form to a beta-sheet-rich (PrP(Sc)) state. In addition to the conformational difference, PrP(Sc) exhibits as covalent signature the sulfoxidation of M213. To investigate whether such modification may play a role in the misfolding process we have studied the impact of methionine oxidation on the dynamics and energetics of the HuPrP(125-229) alpha-fold. METHODOLOGY/PRINCIPAL FINDINGS: Using molecular dynamics simulation, essential dynamics, correlated motions and signal propagation analysis, we have found that substitution of the sulfur atom of M213 by a sulfoxide group impacts on the stability of the native state increasing the flexibility of regions preceding the site of the modification and perturbing the network of stabilizing interactions. Together, these changes favor the population of alternative states which maybe essential in the productive pathway of the pathogenic conversion. These changes are also observed when the sulfoxidation is placed at M206 and at both, M206 and M213. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the sulfoxidation of Helix-3 methionines might be the switch for triggering the initial alpha-fold destabilization required for the productive pathogenic conversion

Modulating RNA structure and catalysis: lessons from small cleaving ribozymes

RNA is a key molecule in life, and comprehending its structure/function relationships is a crucial step towards a more complete understanding of molecular biology. Even though most of the information required for their correct folding is contained in their primary sequences, we are as yet unable to accurately predict both the folding pathways and active tertiary structures of RNA species. Ribozymes are interesting molecules to study when addressing these questions because any modifications in their structures are often reflected in their catalytic properties. The recent progress in the study of the structures, the folding pathways and the modulation of the small ribozymes derived from natural, self-cleaving, RNA motifs have significantly contributed to today’s knowledge in the field

Mäntsäläläisten pk-yritysten käyttämät B2B-palvelut

Suomalaisista yrityksistä valtaosa on kooltaan pieniä ja keskisuuria, eli pk-yrityksiä. Koska pk-yritysten asema työllistäjänä on kansantaloudellisesti merkittävä, on näiden yritysten toimintaympäristöön kiinnitettävä jatkuvasti enemmän huomiota. Yritysten toimintaympäristöjä kehittämässä ovat alueelliset elinkeinoyhtiöt, joiden tarkoituksena on huolehtia alueiden kilpailukyvyn kehittymisestä ja ylläpitämisestä. Kun paikalliset yritykset menestyvät, turvaa se alueen työllisyyttä ja näin myös lisää asukkaiden hyvinvointia. Tämä opinnäytetyö tehtiin toimeksiantona Mäntsälän Yrityskehitys Oy:lle. Tämä opinnäytetyö on luonteeltaan ostokäyttäytymistutkimus, jonka tarkoituksena oli tutkia Mäntsälässä toimivien pk-yritysten käyttämiä B2B-palveluita, sekä yritysten tyytyväisyyttä hankittuihin palveluihin. Tutkielmassa tutkittiin myös yritysten ostopäätösten taustoja, sekä ostopäätöksiin vaikuttavia tekijöitä. Yritysten ostopäätösten taustoja selvitettiin haastatteluiden avulla. Tutkielmassa selvitettiin myös, onko yrityksillä sellaisia palvelutarpeita, joihin Mäntsälästä ei nykyisellään löydy palveluntarjoajia, sekä mistä yritykset pääasiassa hankkivat tietoa suunnitellessaan uuden palvelun hankintaa. Vastauksia esitettyyn tutkimusongelmaan kerättiin kahden menetelmän avulla. Tutkielmaa varten tehtiin internetkysely, johon mäntsäläläisiä pk-yrityksiä kutsuttiin vastaamaan. Lisäksi täydentävänä aineistona käytettiin kolmea teemahaastattelua, jotka niin ikään on toteutettu yhteistyössä mäntsäläläisten yritysten kanssa. Tutkimustuloksista käy ilmi, että mäntsäläläiset pk-yritykset käyttävät B2B-palveluja laajasti ja hankkivat näitä palveluita sekä Mäntsälästä että muista kunnista. Yritykset ovat pääasiallisesti tyytyväisiä hankkimiinsa palveluihin. Yritysten ostopäätösten taustalla vaikuttaa merkittävästi hinnan lisäksi paikallisuus ja kumppanuus. Selkeänä tuloksena ilmeni, että paikalliset yritykset tekevät laitehankintansa pääasiassa muualta kuin Mäntsälästä. Erilaisia huoltopalveluja hankitaan paljon oman toimintaympäristön ulkopuolelta. Uutta palvelua hankittaessa merkittävimmät tiedonhankintakanavat ovat internetin omien hakujen lisäksi Mäntsälän Yrityskehityksen yritysrekisteri, sekä tästä rekisteristä johdettu Mäntsälän Nuorkauppakamarin palveluhakemisto. Suosittelut toisilta yrittäjiltä mainittiin tärkeäksi keinoksi saada tietoa uudesta palvelusta. Tutkielman avulla Mäntsälän Yrityskehitys Oy saa tietoa paikallisesti toimivista yrityksistä, sekä niiden palvelutarpeista. Tutkielma antaa tietoa siitä, mitkä palvelut ovat Mäntsälässä hyvin edustettuina ja minkälaisia palvelutarpeita kunnassa toimivilla yrityksillä on. Tutkielma tarjoaa paikallisesti toimiville yrittäjille katsauksen oman toimintaympäristönsä tilanteesta ja siitä, miten muut yritykset toteuttavat hankintojaan Mäntsälässä. Lisäksi tutkielmasta esille nouseva kumppanuuden merkitys ostopäätökseen vaikuttavana tekijänä saattaa kannustaa yrityksiä miettimään paikallisten hankintojensa osuuden lisäämistä.B2B-services used by small and medium sized enterprises in Mäntsälä The majority of Finnish companies are small and medium sized enterprises (SMEs). Because these companies have a significant status as employers, it is increasingly important to pay attention to the operating environment of these companies. These business environments are developed by municipal development companies, which aim to increase local competitiveness and to sustain it. When local companies can be successful in their own business environments, it secures municipal employment rate and also increases welfare. This thesis is an assignment from municipal development company Mäntsälän Yrityskehitys Oy. The nature of this thesis is a study about organizational buying behaviour and the aim of this thesis is to research SMEs that operates in Mäntsälä. The main focus is to study companies to see what kind of B2B-services these companies use, and how satisfied they are with their current services. In this thesis, research is also focused on factors affecting organizational buyer behaviour. These factors have been studied by interviewing local companies in Mäntsälä. The study also presents what kind of B2B-services local companies would like to acquire in Mäntsälä, instead of other municipal areas and where these companies search information about new services when they found a need of a new service. Answers to these presented questions have been sought with two different research methods. The first one was internet survey questionnaire, which was send to SMEs in Mäntsälä to answer. Also as a complementary material this thesis includes three theme interviews, which companies in Mäntsälä have been taken part in. In the results of this organizational buyer behaviour research it is seen how the use of B2B-services in Mäntsälä SMEs is widespread in most situations. These services are acquired both in Mäntsälä and other municipal areas. Majority of companies are satisfied with the services they use. The factors affecting buying decision were most commonly price related factors, but also locality and partnership factors rise from the results of this thesis. Another clear conclusion of this thesis was an observation about companies acquiring most of their devices and repair services from other municipal areas than Mäntsälä. When finding information about new services, the most common way to gather information is by internet. Another ways of gathering information of new services are mentioned to be company register maintained by Mäntsälän Yrityskehitys Oy. References and recommendations from another entrepreneurs were also a major way to gather information about new services. The goal of this assignment was to produce new information on Mäntsälä SMEs for the use of Mäntsälän Yrityskehitys Oy. With this new information Mäntsälän Yrityskehitys Oy can serve local companies better. This thesis also gives local entrepreneurs valuable information about their busi-ness environment and of the way other local companies are buying their B2B-services

Nash equilibrium strategy in the deregulated power industry and comparing its lost welfare with Iran wholesale electricity market

With the increasing use of different types of auctions in market designing, modeling of participants' behaviors to evaluate the market structure is one of the main discussions in the studies related to the deregulated power industries. In this article, we apply an approach of the optimal bidding behavior to the Iran wholesale electricity market as a restructured electric power industry and model how the participants of the market bid in the spot electricity market. The problem is formulated analytically using the Nash equilibrium concept composed of large numbers of players having discrete and very large strategy spaces. Then, we compute and draw supply curve of the competitive market in which all generators' proposed prices are equal to their marginal costs and supply curve of the real market in which the pricing mechanism is pay-as-bid. We finally calculate the lost welfare or inefficiency of the Nash equilibrium and the real market by comparing their supply curves with the competitive curve. We examine 3 cases on November 24 (2 cases) and July 24 (1 case), 2012. It is observed that in the Nash equilibrium on November 24 and demand of 23,487 MW, there are 212 allowed plants for the first case (plants are allowed to choose any quantity of generation except one of them that should be equal to maximum Power) and the economic efficiency or social welfare of Nash equilibrium is 2.77 times as much as the real market. In addition, there are 184 allowed plants for the second case (plants should offer their maximum power with different prices) and the efficiency or social welfare of Nash equilibrium is 3.6 times as much as the real market. On July 24 and demand of 42,421 MW, all 370 plants should generate maximum energy due to the high electricity demand that the economic efficiency or social welfare of the Nash equilibrium is about 2 times as much as the real market