Proinflammatory activity of cell-wall constituents from gram-positive bacteria.

Innate immunity reacts to conserved bacterial molecules. The outermost lipopolysaccharide (LPS) of Gram-negative organisms is highly inflammatory. It activates responsive cells via specific CD14 and toll-like receptor-4 (TLR4) surface receptor and co-receptors. Gram-positive bacteria do not contain LPS, but carry surface teichoic acids, lipoteichoic acids and peptidoglycan instead. Among these, the thick peptidoglycan is the most conserved. It also triggers cytokine release via CD14, but uses the TLR2 co-receptor instead of TLR4 used by LPS. Moreover, whole peptidoglycan is 1000-fold less active than LPS in a weight-to-weight ratio. This suggests either that it is not important for inflammation, or that only part of it is reactive while the rest acts as ballast. Biochemical dissection of Staphylococcus aureus and Streptococcus pneumoniae cell walls indicates that the second assumption is correct. Long, soluble peptidoglycan chains (approximately 125 kDa) are poorly active. Hydrolysing these chains to their minimal unit (2 sugars and a stem peptide) completely abrogates inflammation. Enzymatic dissection of the pneumococcal wall generated a mixture of highly active fragments, constituted of trimeric stem peptides, and poorly active fragments, constituted of simple monomers and dimers or highly polymerized structures. Hence, the optimal constraint for activation might be 3 cross-linked stem peptides. The importance of structural constraint was demonstrated in additional studies. For example, replacing the first L-alanine in the stem peptide with a D-alanine totally abrogated inflammation in experimental meningitis. Likewise, modifying the D-alanine decorations of lipoteichoic acids with L-alanine, or deacylating them from their diacylglycerol lipid anchor also decreased the inflammatory response. Thus, although considered as a broad-spectrum pattern-recognizing system, innate immunity can detect very subtle differences in Gram-positive walls. This high specificity underlines the importance of using well-characterized microbial material in investigating the system.

Attachment of Combination Rails to Concrete Parapets Utilizing Epoxy Adhesive Anchors, RPFP-IOWA-1, 2015

The Iowa Department of Transportation (IaDOT) was interested in investigating the use of epoxy adhesive anchorages for the attachment of posts used in the BR27C combination bridge rail system. Alternative anchorage concepts were developed using a modified version of the ACI 318-11 procedures for embedded anchor design. Four design concepts were developed for review by IaDOT, including: (1) a four-bolt square anchorage, (2) a four-bolt spread anchorage, (3) a twobolt centered anchorage, and (4) a two-bolt offset anchorage. IaDOT representatives selected the four-bolt spread anchorage and the two-bolt offset anchorage as the preferred designs for evaluation. In addition to these two proposed configurations, IaDOT also requested that the researchers evaluate a third option that had been previously installed on the US-20 bridge near Hardin, IA. The proposed alternative anchorages and the original cast-in-place anchorage for the BR27C combination bridge rail were evaluated through dynamic component testing. The test of the original cast-in-place anchorage was used a baseline for comparison with the alternative designs. Test no. IBP-1 of the original cast-in-place anchorage developed a peak load of 22.9 kips (101.9 kN) at a deflection of 1.5 in. (38 mm). All three of the tested alternative anchorages provided greater load capacity than the original cast-in-place design and were deemed acceptable surrogates. Of the three alternative designs, the two-bolt offset design was deemed the best option.

Hepatitis C virus RNA replication requires a conserved structural motif within the transmembrane domain of the NS5B RNA-dependent RNA polymerase.

Hepatitis C virus (HCV) nonstructural protein 5B (NS5B), the viral RNA-dependent RNA polymerase (RdRp), is a tail-anchored protein with a highly conserved C-terminal transmembrane domain (TMD) that is required for the assembly of a functional replication complex. Here, we report that the TMD of the HCV RdRp can be functionally replaced by a newly identified analogous membrane anchor of the GB virus B (GBV-B) NS5B RdRp. Replicons with a chimeric RdRp consisting of the HCV catalytic domain and the GBV-B membrane anchor replicated with reduced efficiency. Compensatory amino acid changes at defined positions within the TMD improved the replication efficiency of these chimeras. These observations highlight a conserved structural motif within the TMD of the HCV NS5B RdRp that is required for RNA replication.

Use of Remote Sensing for Collection of Data Elements for Linear Referencing Systems, 2001

This report evaluates the use of remotely sensed images in implementing the Iowa DOT LRS that is currently in the stages of system architecture. The Iowa Department of Transportation is investing a significant amount of time and resources into creation of a linear referencing system (LRS). A significant portion of the effort in implementing the system will be creation of a datum, which includes geographically locating anchor points and then measuring anchor section distances between those anchor points. Currently, system architecture and evaluation of different data collection methods to establish the LRS datum is being performed for the DOT by an outside consulting team.

Biochemical characterization of FANCD2 and FANCM in the Fanconi Anaemia pathway

Abstract : The maintenance of genome stability is a challenge for all living organisms. DNA is regularly subjected to chemical alterations by both endogenous and exogenous DNA damaging agents. If left unrepaired, these lesions will create mutations or lead to chromosomal instability. DNA crosslinking agents probably bring about the most toxic lesions. By linking covalently the two strands of DNA, crosslinking agents will impede essential cellular processes such as replication and transcription. Cells from Fanconi anaemia patients are extremely sensitive to these agents. Fanconi anaemia (FA) is a rare chromosomal instability disorder that leads to developmental defects, pancytopenia and cancer susceptibility. FA is a genetically heterogeneous disease with thirteen complementation groups identified. Proteins encoded by the FA genes work together in the FA pathway. Eight of these proteins form the FA core complex (FANC-A, B, C,E, F, G, L and -M), whose integrity is required to monoubiquitinate FANCD2 and FANCI in response to DNA damage. The hypersensitivity of FA cells to crosslinking agents, which perturb the progression of replication forks, has led to the hypothesis that FA proteins play a crucial role in the response to replication stress. However, at the molecular level, the functions of the FA pathway remain largely unknown. Our efforts were first focused on the characterization of FANCD2, "the key effector of the FA pathway". Using different substrates, we found that in vitro, purified hFANCD2 preferentially binds single strand DNA and double strand DNA extremities. Concomitantly, FANCM was identified as a new component of the FA core complex. Moreover FANCM was shown to have specific branch migration activities and probably a role as a "landing platform" on DNA for the other components of the core complex. By using FANCM mutants carrying deletions within the internal domain, we investigated the role of FANCM as a DNA anchor protein for the core complex. We observed that indeed, a specific part of the internal domain of FANCM interacts with components of the core complex. Finally, in collaboration with Weidong Wang's lab we characterized two new components of the FA pathway: FAAP10 and FAAP16. As a heterodimer these two proteins show affinity for dsDNA, and anneal complementary oligonucleotides in vitro. Moreover these proteins can associate with FANCM via a part of its internal domain. We find that FANCM, FAAP 10 and FAAP 16 can co-exist on the branch point of replication and recombination intermediates, and that FAAP10 and FAAP16 stimulate replication fork reversal by FANCM. These results suggest that FANCM may function as a landing platform for the core complex. After loading on DNA, the core complex can activate FANCD2 through monoubiquitination leading to its recruitment to the site of damage. Since ssDNA and double strand breaks are intermediates that are generated as a consequence of collapsed replication forks, FANCD2 by binding to ds DNA ends and ssDNA could protect such structures from the recombination repair machinery and prevent unscheduled recombination events. Alternatively, FANCD2 could avoid nucleases from gaining access to collapsed forks, preserving the DNA in state that can be used as a starting point for resumption of DNA synthesis. The overall comprehension of the FA pathway is far from been complete. Our results unravel new aspects of Fanconi Anaemia, which hopefully in the near future will address keys questions leading to a better understanding of the fascinating Fanconi Anaemia. Résumé : Le maintien de l'intégrité du génome est fondamentale chez tous les organismes vivants. L'ADN est constamment altéré par des composés aussi bien endogènes qu'exogènes. Si ces altérations ne sont pas réparées, elles peuvent conduire à l'apparition de mutations, ainsi qu'à une instabilité génomique accrue. Les lésions les plus sévères qui peuvent survenir sur l'ADN, sont les pontages inter caténaires. Des agents pontants en liant de façon covalente les deux brins d'ADN, vont empêcher le déroulement normal de processus cellulaires essentiels tels que la réplication ou la transcription. La compréhension des mécanismes permettant à la cellule de tolérer et réparer ces lésions est primordiale, notamment dans le cas des patients atteints de l'anémie de Fanconi qui présentent une très grande sensibilité à ces composés pontants. L'anémie de Fanconi est une maladie génétique rare appartenant à un groupe de pathologies associées à une grande instabilité chromosomique. Les patients atteints de l'anémie de Fanconi présentent des malformations du squelette, une pancytopénie et une forte propension à la survenue de cancer. L'anémie de Fanconi est génétiquement très hétérogène. À ce jour, 13 gènes codant pour 13 protéines FANC différentes ont été identifiés. Huit de ces protéines fonctionnent ensemble au sein d'un complexe (nommé le complexe FANC) ayant pour but de monoubiquitiner FANCD2 et FANCI en réponse à la formation de lésions sur l'ADN. L'extrême sensibilité des cellules de patients atteints de l'anémie de Fanconi à ces agents pontant l'ADN suggère l'implication des protéines FANC dans la réponse cellulaire suite à une stress réplicatif. Cependant, le rôle moléculaire exact de ces protéines demeure encore inconnu. Après purification, nous avons observé que FANCD2 était capable de lier l'ADN simple brin, ainsi que les extrémités d'ADN in vitro. Dans le même temps, FANCM fut identifié comme appartenant au complexe FANC. FANCM est décrit comme une translocase capable de promouvoir le déplacement de point de jonction dans des structures d'ADN spécifiques in vitro. De plus, en se liant à l'ADN, FANCM peut agir comme une plateforme pour les autres protéines FANC, leur permettant ainsi d'être adressées à l'ADN. En créant des protéines FANCM recombinantes ayant des délétions dans le domaine interne, nous avons pu observer que certaines protéines du complexe FANC se fixent à des sites spécifiques sur le domaine interne de FANCM. Enfin, au travers d'une collaboration, nous avons été amenés à caractériser deux nouvelles protéines appartenant au complexe FANC : FAAP 10 et FAAP16. Elles s'associent à FANCM par l'intermédiaire du domaine interne, et forment ainsi un hétérotrimére. La présence de FAAP10 et FAAP16 n'affecte pas la liaison de FANCM à l'ADN, mais semble potentialiser son activité de régression in vitro. FANCM semble donc fonctionner comme une plateforme pour les autres composants du complexe FANC. Ces derniers, une fois liés à l'ADN permettent la monoubiquitination de FANCD2 et son recrutement au site lésé de l'ADN. FANCD2 en se liant de façon préférentielle à l'ADN simple brin et aux extrémités d'ADN qui sont générés lors de l'arrêt et du démantèlement d'une fourche de réplication, pourrait protéger ces même fourches de réplication arrêtées, d'évènements de recombinaison aléatoires. Nos résultats apportent de nouveaux éléments concernant les mécanismes moléculaires de l'anémie de Fanconi. Enfin, l'étude de l'anémie de Fanconi permet aussi de mieux comprendre les mécanismes mis en place par la cellule pour tolérer des lésions survenant lors de la réplication.

Older Workers in Iowa, May 2006

A large wave of workers born during the Baby Boom of 1946 to 1964 will be leaving the workforce over the next few decades. A larger share than in past generations may “retire” to collect the pensions they earned over their work life and then continue working part-time or more flexible working arrangements.

Formats radifònics "tot-notícies" a l'Estat Espanyol : naixement i consolidació de "Catalunya Informacio"(1992-1997)

Fa 20 anys que la ràdio española gaudeix de la libertad informativa que li va ser negada durant la dictadura. En aquests 20 anys, l’evolució del macro-gènere información ens ha portat des de l’anomenat “boom de la ràdio informativa” fins al naixement, al nostre país, de les primeres emissores dedicades íntegrament a la información, en primer lloc, Catalunya Informació, i més tard, Radio 5 Todo Noticias. El que pretenem amb aquest estudié s tractar del naixement i la consolidació del primer format radiofònic informatiu, un format sobre el qual no hi ha encara gaires referències bibliogràfiques.

Partial correlation : Network analysis

The final year project came to us as an opportunity to get involved in a topic which has appeared to be attractive during the learning process of majoring in economics: statistics and its application to the analysis of economic data, i.e. econometrics.Moreover, the combination of econometrics and computer science is a very hot topic nowadays, given the Information Technologies boom in the last decades and the consequent exponential increase in the amount of data collected and stored day by day. Data analysts able to deal with Big Data and to find useful results from it are verydemanded in these days and, according to our understanding, the work they do, although sometimes controversial in terms of ethics, is a clear source of value added both for private corporations and the public sector. For these reasons, the essence of this project is the study of a statistical instrument valid for the analysis of large datasets which is directly related to computer science: Partial Correlation Networks.The structure of the project has been determined by our objectives through the development of it. At first, the characteristics of the studied instrument are explained, from the basic ideas up to the features of the model behind it, with the final goal of presenting SPACE model as a tool for estimating interconnections in between elements in large data sets. Afterwards, an illustrated simulation is performed in order to show the power and efficiency of the model presented. And at last, the model is put into practice by analyzing a relatively large data set of real world data, with the objective of assessing whether the proposed statistical instrument is valid and useful when applied to a real multivariate time series. In short, our main goals are to present the model and evaluate if Partial Correlation Network Analysis is an effective, useful instrument and allows finding valuable results from Big Data.As a result, the findings all along this project suggest the Partial Correlation Estimation by Joint Sparse Regression Models approach presented by Peng et al. (2009) to work well under the assumption of sparsity of data. Moreover, partial correlation networks are shown to be a very valid tool to represent cross-sectional interconnections in between elements in large data sets.The scope of this project is however limited, as there are some sections in which deeper analysis would have been appropriate. Considering intertemporal connections in between elements, the choice of the tuning parameter lambda, or a deeper analysis of the results in the real data application are examples of aspects in which this project could be completed.To sum up, the analyzed statistical tool has been proved to be a very useful instrument to find relationships that connect the elements present in a large data set. And after all, partial correlation networks allow the owner of this set to observe and analyze the existing linkages that could have been omitted otherwise.

5

Die auJlerkörperliche Erfaltrung (AKE) hat in den letztenJahren Forscher vieler Fachrichtungen beschäftigt. Vor allem hat das Verständnis der Neurowissenschaften und experimentellen Psychologie zu diesem Boom entscheidend beigetragen. Um zu verdeutlichen, wie bereits wenige klinische Studien ein Feld verändern können, werden im Folgenden phänomenologische, neurologische, psychophysiologische, experimentelle und pharmakologische Studien zur AKE aufgefi:hrt, vor allem jene der Ietzten 20 Jahre. Von besonderer Bedeutung werden Hirnstimulationsstudien bei Patienten mit Epilepsie sein, da bei diesen Patienten das Hirn bei vollem Bewusstsein direk elektrisch stimuliert wird, Weiterhin werden Studien zur AKE vorgestellt, die Hirnströme bei Gesunden und Patienten messen; hinzu kommen Studien, mit denen versucht wird, den Ort einer Hirnschädigung mit dem Auftreten von AKE in Verbindung zu bringen, Die Schlussfolgerungen aus diesen Studien und aus experimentellen Verhaltensstudien sollen aufzeigen, dass man ein zuvor mystifiziertes Phänomen untersuchen kann, aber dass es einen genaueren Anhaltspunkt benötigt, anhand dessen man gezielt Studien planen und durchfi.rhren kann. Ebenfalls soll aufgezeigt werden, welche vielen Fragen zu diesem Phänomen noch immer offen sind und die Forschenden mindestens weitere 20 Jaltre beschäftigen werden.

Trichophyton rubrum secreted and membrane-associated carboxypeptidases

Dermatophytes are the most common agents of superficial mycoses, and exclusively infect stratum corneum, nails or hair. Therefore, secreted proteolytic activity is considered a virulence trait of these fungi. In a medium containing protein as a sole nitrogen and carbon source Trichophyton rubrum secretes a metallocarboxypeptidase (TruMcpA) of the M14 family according to the MEROPS proteolytic enzyme database. TruMcpA is homologous to human pancreatic carboxypeptidase A, and is synthesized as a precursor in a preproprotein form. The propeptide is removed to generate the mature active enzyme alternatively by either one of two subtilisins which are concomitantly secreted by the fungus. In addition, T. rubrum was shown to possess two genes (TruSCPA and TruSCPB) encoding serine carboxypeptidases of the S10 family which are homologues of the previously characterized Aspergillus and Penicillium secreted acid carboxypeptidases. However, in contrast to the Aspergillus and Penicillium homologues, TruScpA and TruScpB enzymes are not secreted into the environment, but are membrane-associated with a glycosylphosphatidylinositol (GPI) anchor. During infection, T. rubrum secreted and GPI-anchored carboxypeptidases may contribute to fungal virulence by cooperating with previously characterized endoproteases and aminopeptidases in the degradation of compact keratinized tissues into assimilable amino acids and short peptides.

Development of Rouble Exchange Rate in Russia

This 45th volume deals with the development of the Russian rouble, which suffered a severe depreciation crisis in 1998. In the aftermath of this event, a strong investment boom started in Russia. The new devalued rouble exchange rate gave price competitiveness to local industry. In addition to that, increasing export prices of Russian oil and natural gas deliveries have contributed to economic growth lately. Amid this boom period, inflationary pressure has remained high. Price increases have been higher than in the EU, Russia’s main trading partner. However, rouble/euro exchange rate has remained nominally rather stable in the current decade. This means, that rouble appreciates against euro in real terms, which is weakening Russia’s international competitiveness.

Puutavaranosturin teleskooppipuomin kehittäminen ultralujilla teräksillä toteutettavaksi

Diplomityössä on tutkittu ultralujien terästen käyttömahdollisuuksia puutavaranosturin puomirakenteissa. Työn tavoitteena on ollut suunnitella uusi puomikonstruktio, joka on kevyempi kuin aiemmat ratkaisut, mutta täyttää kuitenkin sovellettavien standardien asettamat vaatimukset väsymisen, staattisen kestävyyden ja stabiliteetin suhteen. Työ on tehty vertailemalla erilaisten uusien profiilien ja rakenneyksityiskohtien ominaisuuksia toisiinsa ja vanhaan rakenteeseen. Vertailukriteereinä on käytetty elastista taivutuskapasiteettia, kriittistä lommahduskuormaa, väsymislujuutta sekä hitsaus- ja materiaalikustannuksia. Työn lopputuloksena saatiin ehdotus uudeksi teleskooppipuomiksi, joka on noin 8 % kevyempi kuin nykyinen ratkaisu.

Nuevas profesiones periodísticas digitales

El present treball final de carrera té com a objecte analitzar el perfil i les condicions laborals de les noves professions periodístiques digitals, i fer una comparació d’aquestes amb les de les professions tradicionals en mitjans de comunicació i en comunicació corporativa mitjançant la realització d’enquestes a treballadors d’aquestes tres àrees. La finalitat es saber quin panorama es trobaran els llicenciats en periodisme en el futur, veure com han canviat aquestes feines respecte fa alguns anys en que el boom de les noves tecnologies i xarxes socials no era tan patent com és ara, i també veure com ha influït el context de crisi que travessa el país.

Testing Weak-Form Efficiency of the Chinese Stock Market

Tämän tutkielman tavoitteena on tarkastella Kiinan osakemarkkinoiden tehokkuutta ja random walk -hypoteesin voimassaoloa. Tavoitteena on myös selvittää esiintyykö viikonpäiväanomalia Kiinan osakemarkkinoilla. Tutkimusaineistona käytetään Shanghain osakepörssin A-sarjan,B-sarjan ja yhdistelmä-sarjan ja Shenzhenin yhdistelmä-sarjan indeksien päivittäisiä logaritmisoituja tuottoja ajalta 21.2.1992-30.12.2005 sekä Shenzhenin osakepörssin A-sarjan ja B-sarjan indeksien päivittäisiä logaritmisoituja tuottoja ajalta 5.10.1992-30.12.2005. Tutkimusmenetelminä käytetään neljä tilastollista menetelmää, mukaan lukien autokorrelaatiotestiä, epäparametrista runs-testiä, varianssisuhdetestiä sekä Augmented Dickey-Fullerin yksikköjuuritestiä. Viikonpäiväanomalian esiintymistä tutkitaan käyttämällä pienimmän neliösumman menetelmää (OLS). Testejä tehdään sekä koko aineistolla että kolmella erillisellä ajanjaksolla. Tämän tutkielman empiiriset tulokset tukevat aikaisempia tutkimuksia Kiinan osakemarkkinoiden tehottomuudesta. Lukuun ottamatta yksikköjuuritestien saatuja tuloksia, autokorrelaatio-, runs- ja varianssisuhdetestien perusteella random walk-hypoteesi hylättiin molempien Kiinan osakemarkkinoiden kohdalla. Tutkimustulokset osoittavat, että molemmilla osakepörssillä B-sarjan indeksien käyttäytyminenon ollut huomattavasti enemmän random walk -hypoteesin vastainen kuin A-sarjan indeksit. Paitsi B-sarjan markkinat, molempien Kiinan osakemarkkinoiden tehokkuus näytti myös paranevan vuoden 2001 markkinabuumin jälkeen. Tutkimustulokset osoittavat myös viikonpäiväanomalian esiintyvän Shanghain osakepörssillä, muttei kuitenkaan Shenzhenin osakepörssillä koko tarkasteluajanjaksolla.

Anchoring of both PKA and 14-3-3 inhibits the Rho-GEF activity of the AKAP-Lbc signaling complex.

A-kinase anchoring proteins (AKAPs) target the cAMP-regulated protein kinase (PKA) to its physiological substrates. We recently identified a novel anchoring protein, called AKAP-Lbc, which functions as a PKA-targeting protein as well as a guanine nucleotide exchange factor (GEF) for RhoA. We demonstrated that AKAP-Lbc Rho-GEF activity is stimulated by the alpha subunit of the heterotrimeric G protein G12. Here, we identified 14-3-3 as a novel regulatory protein interacting with AKAP-Lbc. Elevation of the cellular concentration of cAMP activates the PKA holoenzyme anchored to AKAP-Lbc, which phosphorylates the anchoring protein on the serine 1565. This phosphorylation event induces the recruitment of 14-3-3, which inhibits the Rho-GEF activity of AKAP-Lbc. AKAP-Lbc mutants that fail to interact with PKA or with 14-3-3 show a higher basal Rho-GEF activity as compared to the wild-type protein. This suggests that, under basal conditions, 14-3-3 maintains AKAP-Lbc in an inactive state. Therefore, while it is known that AKAP-Lbc activity can be stimulated by Galpha12, in this study we demonstrated that it is inhibited by the anchoring of both PKA and 14-3-3.