One billion years of bZIP transcription factor evolution: conservation and change in dimerization and DNA-binding site specificity.

The genomic era has revealed that the large repertoire of observed animal phenotypes is dependent on changes in the expression patterns of a finite number of genes, which are mediated by a plethora of transcription factors (TFs) with distinct specificities. The dimerization of TFs can also increase the complexity of a genetic regulatory network manifold, by combining a small number of monomers into dimers with distinct functions. Therefore, studying the evolution of these dimerizing TFs is vital for understanding how complexity increased during animal evolution. We focus on the second largest family of dimerizing TFs, the basic-region leucine zipper (bZIP), and infer when it expanded and how bZIP DNA-binding and dimerization functions evolved during the major phases of animal evolution. Specifically, we classify the metazoan bZIPs into 19 families and confirm the ancient nature of at least 13 of these families, predating the split of the cnidaria. We observe fixation of a core dimerization network in the last common ancestor of protostomes-deuterostomes. This was followed by an expansion of the number of proteins in the network, but no major dimerization changes in interaction partners, during the emergence of vertebrates. In conclusion, the bZIPs are an excellent model with which to understand how DNA binding and protein interactions of TFs evolved during animal evolution.

Trail pheromones: an integrative view of their role in social insect colony organization.

Trail pheromones do more than simply guide social insect workers from point A to point B. Recent research has revealed additional ways in which they help to regulate colony foraging, often via positive and negative feedback processes that influence the exploitation of the different resources that a colony has knowledge of. Trail pheromones are often complementary or synergistic with other information sources, such as individual memory. Pheromone trails can be composed of two or more pheromones with different functions, and information may be embedded in the trail network geometry. These findings indicate remarkable sophistication in how trail pheromones are used to regulate colony-level behavior, and how trail pheromones are used and deployed at the individual level.

Origins, evolution, and phenotypic impact of new genes.

Ever since the pre-molecular era, the birth of new genes with novel functions has been considered to be a major contributor to adaptive evolutionary innovation. Here, I review the origin and evolution of new genes and their functions in eukaryotes, an area of research that has made rapid progress in the past decade thanks to the genomics revolution. Indeed, recent work has provided initial whole-genome views of the different types of new genes for a large number of different organisms. The array of mechanisms underlying the origin of new genes is compelling, extending way beyond the traditionally well-studied source of gene duplication. Thus, it was shown that novel genes also regularly arose from messenger RNAs of ancestral genes, protein-coding genes metamorphosed into new RNA genes, genomic parasites were co-opted as new genes, and that both protein and RNA genes were composed from scratch (i.e., from previously nonfunctional sequences). These mechanisms then also contributed to the formation of numerous novel chimeric gene structures. Detailed functional investigations uncovered different evolutionary pathways that led to the emergence of novel functions from these newly minted sequences and, with respect to animals, attributed a potentially important role to one specific tissue--the testis--in the process of gene birth. Remarkably, these studies also demonstrated that novel genes of the various types significantly impacted the evolution of cellular, physiological, morphological, behavioral, and reproductive phenotypic traits. Consequently, it is now firmly established that new genes have indeed been major contributors to the origin of adaptive evolutionary novelties.

Dynamic impacts of the inhibition of the molecular chaperone hsp90 on the T-cell proteome have implications for anti-cancer therapy.

The molecular chaperone Hsp90-dependent proteome represents a complex protein network of critical biological and medical relevance. Known to associate with proteins with a broad variety of functions termed clients, Hsp90 maintains key essential and oncogenic signalling pathways. Consequently, Hsp90 inhibitors are being tested as anti-cancer drugs. Using an integrated systematic approach to analyse the effects of Hsp90 inhibition in T-cells, we quantified differential changes in the Hsp90-dependent proteome, Hsp90 interactome, and a selection of the transcriptome. Kinetic behaviours in the Hsp90-dependent proteome were assessed using a novel pulse-chase strategy (Fierro-Monti et al., accompanying article), detecting effects on both protein stability and synthesis. Global and specific dynamic impacts, including proteostatic responses, are due to direct inhibition of Hsp90 as well as indirect effects. As a result, a decrease was detected in most proteins that changed their levels, including known Hsp90 clients. Most likely, consequences of the role of Hsp90 in gene expression determined a global reduction in net de novo protein synthesis. This decrease appeared to be greater in magnitude than a concomitantly observed global increase in protein decay rates. Several novel putative Hsp90 clients were validated, and interestingly, protein families with critical functions, particularly the Hsp90 family and cofactors themselves as well as protein kinases, displayed strongly increased decay rates due to Hsp90 inhibitor treatment. Remarkably, an upsurge in survival pathways, involving molecular chaperones and several oncoproteins, and decreased levels of some tumour suppressors, have implications for anti-cancer therapy with Hsp90 inhibitors. The diversity of global effects may represent a paradigm of mechanisms that are operating to shield cells from proteotoxic stress, by promoting pro-survival and anti-proliferative functions. Data are available via ProteomeXchange with identifier PXD000537.

Estudi comparatiu: errors de les infermeres en la preparaci�� i l'administraci�� de la medicaci�� segons dos sistemes de distribuci��

Introducci��: Els errors de medicaci�� s��n definits com qualsevol incident prevenible que pot causar dany al pacient o donar lloc a una utilitzaci�� inapropiada dels medicaments, quan aquests estan sota el control dels professionals sanitaris o del pacient. Els errors en la preparaci�� i l���administraci�� de medicaci�� s��n els m��s comuns de l�����rea hospital��ria i, tot i la llarga cadena per la qual passa el f��rmac, el professional d���infermeria ��s el ��ltim responsable de l���acci��, tenint aix��, un paper molt important en la seguretat del pacient. Les infermeres dediquen el 40% del temps de la seva jornada laboral en tasques relacionades amb la medicaci��. Objectiu: Determinar si les infermeres produeixen m��s errors si treballen amb sistemes de distribuci�� de medicaci�� de stock o en sistemes de distribuci�� unidosis de medicaci��. Metodologia: Estudi quantitatiu, observacional i descriptiu, on la notificaci�� d���errors (o oportunitats d���error) realitzats per la infermera, en les fases de preparaci�� i administraci�� de medicaci��, es far�� mitjan��ant un q��estionari autoelaborat. Els elements a identificar seran: el tipus d���error, les causes que poden haver--���lo produ��t, la seva potencial gravetat i qui l���ha pogut evitar; aix�� com el tipus de professional que l���ha produ��t. Altres dades rellevants s��n: el medicament implicat junt amb la dosis i la via d���administraci�� i el sistema de distribuci�� utilitzat. Mostreig i mostra: El mostreig ser�� no probabil��stic i per conveni��ncia. S���escolliran aquelles infermeres que l���investigador consideri amb les caracter��stiques necess��ries per participar en l���estudi, aix�� que la mostra estar�� formada per les infermeres les quals treballen a la unitat 40 de l���Hospital del Mar i utilitzen un sistema de distribuci�� de medicaci�� de dosis unit��ries i les infermeres que treballen a urg��ncies (concretament a l�����rea de nivell dos) de l���Hospital del Mar les quals treballen amb un sistema de distribuci�� de medicaci�� de stock.

Les part��cules modals de la llengua alemanya i l���an��lisi del seu ��s comparant el llenguatge oral real i el fingit

Resum: El treball est�� enfocat en les anomenades ���part��cules modals��� de la llengua alemanya. La part te��rica inclou informaci�� extreta de diferents fonts bibliogr��fiques i a la part pr��ctica se n���analitza l�����s a partir d���un exercici elaborat amb fragments del gui�� de dues pel��l��cules (llenguatge oral fingit) i la col��laboraci�� d���estudiants de diferents parts d���Alemanya.

Emergence of novel domains in proteins

Proteins are composed of a combination of discrete, well-defined, sequence domains, associated with specific functions that have arisen at different times during evolutionary history. The emergence of novel domains is related to protein functional diversification and adaptation. But currently little is known about how novel domains arise and how they subsequently evolve. To gain insights into the impact of recently emerged domains in protein evolution we have identified all human young protein domains that have emerged in approximately the past 550 million years. We have classified them into vertebrate-specific and mammalian-specific groups, and compared them to older domains. We have found 426 different annotated young domains, totalling 995 domain occurrences, which represent about 12.3% of all human domains. We have observed that 61.3% of them arose in newly formed genes, while the remaining 38.7% are found combined with older domains, and have very likely emerged in the context of a previously existing protein. Young domains are preferentially located at the N-terminus of the protein, indicating that, at least in vertebrates, novel functional sequences often emerge there. Furthermore, young domains show significantly higher non-synonymous to synonymous substitution rates than older domains using human and mouse orthologous sequence comparisons. This is also true when we compare young and old domains located in the same protein, suggesting that recently arisen domains tend to evolve in a less constrained manner than older domains. We conclude that proteins tend to gain domains over time, becoming progressively longer. We show that many proteins are made of domains of different age, and that the fastest evolving parts correspond to the domains that have been acquired more recently.

Role of the naive and memory CD4+T-cell repertoire in transplantation

Purpose: The exact role of individual T cell-subsets in the development of rejection is not clearly defined. Given their distinct phenotypes, effector functions and trafficking patterns, na��ve (CD45RBhiCD44lo) and memory (CD45RBloCD44hi) T cells may play distinct roles in anti-donor immunity after transplantation. Furthermore, only the CD4+CD45RBlo population contains CD4+CD25+ T cells, a subset with suppressive functions playing a major role in the maintenance of peripheral tolerance. The aim of this work was to study the contribution of these individual subsets in alloresponses via the direct and indirect pathways using a murine experimental model. Methods and materials: Purified na��ve or memory CD4+ T cells were adoptively transferred into lymphopenic mice undergoing a skin allograft. Donor to recipient MHC combinations were chosen in order to study the direct and the indirect pathways of allorecognition separately. Graft survival and in vivo expansion, effector function and trafficking of the transferred T cells was assessed at different time points after transplantation. Results: We found that the cross-reactive CD4+CD45RBlo memory T-cell pool was heterogeneous and contained cells with regulatory potentials, both in the CD4+CD25+ and CD4+CD25-populations. CD4+ T cells capable of inducing strong primary alloreactive responses in vitro and rejection of a first allograft in vivo were mainly contained within the CD45RBhi na��ve CD4+ T-cell compartment. CD4+CD45RBlo T cells proliferated less abundantly to allogeneic stimulation than their na��ve counterparts both in vitro and in vivo, and allowed prolonged allograft survival even after the depletion of the CD4+CD25+ subset. Interestingly, CD4+CD25-CD45RBlo T cells were capable of prolonging allograft survival, mainly when the indirect pathway was the only mechanism of allorecognition. The indirect pathway response, which was shown to drive true chronic rejection and contribute to chronic allograft dysfunction, was predominantly mediated by na��ve CD4+ T cells. Conclusion: This work provides new insights into the mechanisms that drive allograft rejection and should help develop new clinical immunosuppressive protocols. In particular, our results highlight the importance of selectively targeting individual T-cell subsets to prevent graft rejection but at the same time maintain immune protective responses to common pathogens.

An��lisi de les eines TIC utilitzades a tres escoles bressol per a relacionar-se i comunicar-se amb les fam��lies i elaboraci�� d'una guia per a l'elecci�� d'eines TIC com a mitj�� de relaci��

A l���escola bressol el vincle entre equip educatiu i fam��lia ��s de gran import��ncia i, en la societat canviant en la que vivim, ��s important cercar noves vies de comunicaci��. Aquesta recerca ��s un estudi de casos de l�����s de les TIC com a mitj�� de comunicaci�� entre escola i fam��lia a tres escoles bressol. Amb l���objectiu de descriure i analitzar aquestes eines s���utilitzen entrevistes, q��estionaris i an��lisi de documents com a instruments de recollida de dades. Els resultats mostren que les eines m��s utilitzades s��n el blog i el correu electr��nic amb la funci�� d���informar a les fam��lies. Aquestes dades permeten identificar l�����s, la funci�� i els destinataris com a criteris necessaris per a escollir l���eina TIC m��s adient per a la relaci�� fam��lia-escola d���un centre, i per elaborar una guia per a l���elecci�� d���eines TIC com a mitj�� de relaci�� entre els dos agents educatius.

Post-switching beta synchronization reveals concomitant sensory reafferences and active inhibition processes

It is known that post-movement beta synchronization (PMBS) is involved both in active inhibition and in sensory reafferences processes. The aim of this study was examine the temporal and spatial dynamics of the PMBS involved during multi-limb coordination task. We investigated post-switching beta synchronization (assigned PMBS) using time-frequency and source estimations analyzes. Participants (n = 17) initiated an auditory-paced bimanual tapping. After a 1500 ms preparatory period, an imperative stimulus required to either selectively stop the left while maintaining the right unimanual tapping (Switch condition: SWIT) or to continue the bimanual tapping (Continue condition: CONT). PMBS significantly increased in SWIT compared to CONT with maximal difference within right central region in broad-band 14��euro"30 Hz and within left central region in restricted-band 22��euro"26 Hz. Source estimations localized these effects within right pre-frontal cortex and left parietal cortex, respectively. A negative correlation showed that participants with a low percentage of errors in SWIT had a large PMBS amplitude within right parietal and frontal cortices. This study shows for the first time simultaneous PMBS with distinct functions in different brain regions and frequency ranges. The left parietal PMBS restricted to 22��euro"26 Hz could reflect the sensory reafferences of the right hand tapping disrupted by the switching. In contrast, the right pre-frontal PMBS in a broad-band 14��euro"30 Hz is likely reflecting the active inhibition of the left hand stopped. Finally, correlations between behavioral performance and the magnitude of the PMBS suggest that beta oscillations can be viewed as a marker of successful active inhibition.

Gliotransmitters Travel in Time and Space.

The identification of the presence of active signaling between astrocytes and neurons in a process termed gliotransmission has caused a paradigm shift in our thinking about brain function. However, we are still in the early days of the conceptualization of how astrocytes influence synapses, neurons, networks, and ultimately behavior. In this Perspective, our goal is to identify emerging principles governing gliotransmission and consider the specific properties of this process that endow the astrocyte with unique functions in brain signal integration. We develop and present hypotheses aimed at reconciling confounding reports and define open questions to provide a conceptual framework for future studies. We propose that astrocytes mainly signal through high-affinity slowly desensitizing receptors to modulate neurons and perform integration in spatiotemporal domains complementary to those of neurons.

Materiaalitarpeen suunnitteluprosessin kehitt��minen ja varastonohjauksen parantaminen Elektroniikkalaitoksessa

Ty�� on tehty Puolustusvoimien Elektroniikkalaitoksella Riihim��ell��. Elektroniikkalaitos toimii yhten�� vastuuvarikkona ja vastaa omalta osaltaan elektroniikka-alan j��rjestelmien kunnossapidosta. Ty��n tarkoituksena on selvitt���� materiaalitarpeen suunnitteluprosessi, kehitt���� varastonohjausta ja tutustua SAP-toiminnallisuuksien hy��dynt��miseen. Materiaalitarpeen suunnittelemisella ja varastonohjauksen parantamisella pyrit����n kustannuss����st��ihin ja kunnossapitoprosessin kokonaisvaltaiseen tehostamiseen. Ty��ss�� k��sitell����n Elektroniikkalaitoksen materiaaliprosessia ja sen suhdetta kunnossapitoprosessiin sek�� selvitet����n materiaalitarpeen muodostumista ja kysynn��n ennustamistarpeita. Samalla esitet����n my��s varastonohjauksen parantamiskohteita. Materiaalitarpeen suunnitteluprosessista on luotu toimintamalli, jota on testattu pilottiprojektin avulla. Ty��ss��tarkastellaan SAP-toiminnallisuuksien hy��dynt��mist�� sek�� materiaalitarpeen suunnittelussa, ett�� varastonohjauksessa. Lis��ksi esitell����n kustannusarviolomake, joka on luotu osaksi materiaalitarpeen suunnitteluprosessia helpottamaan materiaalit��ydennysten kustannusarviointia.

Toimintaj��rjestelm��n rakentaminen laatu-, ymp��rist��- sek�� ty��terveys- ja ty��turvallisuusstandardien vaatimusten mukaisesti

Diplomity��n kohdeyritys on Lassila & Tikanoja Oyj:n (L&T) Vantaan j��tehuolto -yksikk��.Yrityksen yhten��iset toimintatavat ovat edellytyksen�� toiminnan tehostamiselle,jatkuvalle kehitt��miselle ja hallitulle laajentumiselle. Yrityksen toimintaj��rjestelm�� (johtamisj��rjestelm��) muodostuu laadun (ISO 9001), ymp��rist��n (ISO 14001) sek�� ty��terveyden ja ty��turvallisuuden (OHSAS 18001) hallintaj��rjestelmist��. Integroitu toimintaj��rjestelm�� muodostaa yritykselle tehokkaan ja kokonaisvaltaisen kehitt��misen ty��v��lineen.Diplomity��n tavoitteena on luoda teoreettinen perusta L&T:n Vantaan j��tehuolto -yksik��n sertifiointi -projektille. Diplomity��n teoriasis��lt�� muodostuu seuraavien asiakokonaisuuksien k��sittelyst��: kohdeyrityksen liiketoiminta-alan tunnuspiirteet, standardien sis��lt��vaatimukset, toimintaj��rjestelm�� yrityksen johtamisv��lineen�� sek�� suorituskyvyn mittaaminen ja analysointi. Diplomity�� kokoaa selke��t esitiedolliset l��ht��kohdat yksik��n sertifiointi -projektille.Diplomity��n muodostama teoreettinen perusta saavuttaa varsin onnistuneesti sille asetetut tavoitteet. Diplomity��n m����rittelemien l��ht��kohtien pohjalta rakentui yksik��n varsinainen toimintaj��rjestelm��. Diplomity�� tulee toimimaanhyv��n�� tukimateriaalina ty��n kohdeyritykselle jatkossakin; ty��st�� on helppo tarkastaa ja kerrata toimintaj��rjestelm����n liittyvi�� asiakokonaisuuksia.

Regulation of Rat and Human T-cell Immune Response by Pharmacologically Modified Dendritic Cells.

BACKGROUND: The central function of dendritic cells (DC) in inducing and preventing immune responses makes them ideal therapeutic targets for the induction of immunologic tolerance. In a rat in vivo model, we showed that dexamethasone-treated DC (Dex-DC) induced indirect pathway-mediated regulation and that CD4+CD25+ T cells were involved in the observed effects. The aim of the present study was to investigate the mechanisms underlying the acquired immunoregulatory properties of Dex-DC in the rat and human experimental systems. METHODS: After treatment with dexamethasone (Dex), the immunogenicity of Dex-DC was analyzed in T-cell proliferation and two-step hyporesponsiveness induction assays. After carboxyfluorescein diacetate succinimidyl ester labeling, CD4+CD25+ regulatory T-cell expansion was analyzed by flow cytometry, and cytokine secretion was measured by ELISA. RESULTS: In this study, we demonstrate in vitro that rat Dex-DC induced selective expansion of CD4+CD25+ regulatory T cells, which were responsible for alloantigen-specific hyporesponsiveness. The induction of regulatory T-cell division by rat Dex-DC was due to secretion of interleukin (IL)-2 by DC. Similarly, in human studies, monocyte-derived Dex-DC were also poorly immunogenic, were able to induce T-cell anergy in vitro, and expand a population of T cells with regulatory functions. This was accompanied by a change in the cytokine profile in DC and T cells in favor of IL-10. CONCLUSION: These data suggest that Dex-DC induced tolerance by different mechanisms in the two systems studied. Both rat and human Dex-DC were able to induce and expand regulatory T cells, which occurred in an IL-2 dependent manner in the rat system.

Corporate governancen vaikutus osuustoiminnallisten yritysten riskienhallintaan

Tutkimuksen tarkoituksena on osallistua corporate governance -keskusteluun tuomalla esiin riskienhallinnan n��k��kulma osuustoiminnallisessa yritystoiminnassa. Tutkimuksen tavoitteena on kuvata corporate governancen vaikutuksia tuottajaosuustoiminnallisten yritysten riskienhallintaan, selvitt���� tuottajaosuustoiminnan riskienhallinnan tilaa ja toteutusta ja siihen vaikuttavia tekij��it�� sek�� tuoda esille n��k��kulmia riskienhallinnan kehitt��miseksi tuottajaosuustoiminnallisissa yrityksiss��. Tutkimus on luonteeltaan laadullinen tapaustutkimus. Tutkimuksen empiirinen aineisto ker��ttiin haastattelemalla kolmea osuustoiminnan asiantuntijaa ja seitsem���� riskienhallinnan ja hallinnon vastuuhenkil����. Haastattelut tehtiin vuoden 2006 kes��n ja alkusyksyn aikana. Tutkimuksen perusteella corporate governancen vaikutus organisaatioiden riskienhallintaan on ollut rajallinen. My��s riskienhallintaan sidoksissa olevien toimi- ja hallintoelinten osalta suosituksilla on ollut v��h��inen vaikutus. Huolimatta corporate governancen ja riskienhallinnan merkityksen lis����ntymisest�� tuottajaosuustoiminnallisissa yrityksiss��, konkreettisella tasolla riskienhallinta ei toteudu corporate governance -periaatteiden edellytt��m��ll�� tavalla niin, ett�� riskienhallintaa voisi kuvata kokonaisvaltaiseksi, periaatteiltaan m����ritellyksi ja suunnitelmalliseksi prosessiksi. Tutkimuksessa on my��s pyritty nostamaan esiin riskienhallinnan eroja eri organisaatiomallien v��lill��. Tarkastelussaolleiden perusosuuskuntien sek�� hybridimallien v��liset erot liittyv��t l��hinn�� yritysten resurssien ja koon vaikutuksista syntyviin eroihin riskienhallinnan toteutuksessa ja organisoinnissa. Merkitt��v����n rooliin tuottajaosuustoiminnallistenyritysten riskienhallinnassa nousee erillisen riskienhallintatoiminnon osaaminen ja sen hy��dynt��minen organisaatioiden riskienhallintaty��ss��.