NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina.

We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting, dehydration, and elevated transaminases. They had frequent infections, hypogammaglobulinemia, reduced natural killer cells, and the Pelger-Huët anomaly of their granulocytes. Their facial features were similar with a pointed chin and proptosis; loose skin and reduced subcutaneous fat gave them a progeroid appearance. Skeletal features included short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, and small C1-C2 vertebrae causing cervical instability and myelopathy. Retinal dystrophy and optic atrophy were present in one patient. NBAS is a component of the synthaxin-18 complex and is involved in nonsense-mediated mRNA decay control. Putative loss-of-function mutations in NBAS are already known to cause disease in humans. A specific founder mutation has been associated with short stature, optic nerve atrophy and Pelger-Huët anomaly of granulocytes (SOPH) in the Siberian Yakut population. A more recent report associates NBAS mutations with recurrent acute liver failure in infancy in a group of patients of European descent. Our observations indicate that the phenotypic spectrum of NBAS deficiency is wider than previously known and includes skeletal, hepatic, metabolic, and immunologic aspects. Early recognition of the skeletal phenotype is important for preventive management of cervical instability. © 2015 Wiley Periodicals, Inc.

Tgfbi/Bigh3 silencing activates ERK in mouse retina.

BIGH3 is a secreted protein, part of the extracellular matrix where it interacts with collagen and integrins on the cell surface. BIGH3 can play opposing roles in cancer, acting as either tumor suppressor or promoter, and its mutations lead to different forms of corneal dystrophy. Although many studies have been carried out, little is known about the physiological role of BIGH3. Using the cre-loxP system, we generated a mouse model with disruption of the Bigh3 genomic locus. Bigh3 silencing did not result in any apparent phenotype modifications, the mice remained viable and fertile. We were able to determine the presence of BIGH3 in the retinal pigment epithelium (RPE). In the absence of BIGH3, a transient decrease in the apoptotic process involved in retina maturation was observed, leading to a transient increase in the INL thickness at P15. This phenomenon was accompanied by an increased activity of the pro-survival ERK pathway.

Corticosteroids and the retina: a role for the mineralocorticoid receptor.

PURPOSE OF REVIEW: Long-lasting devices releasing steroids have been approved recently for macular edema of various origins. Identification of the retina as a novel mineralo-sensitive tissue also raises new therapeutic options. RECENT FINDINGS: Recently, the over activation of the mineralocorticoid receptor (MR) pathway has been shown to cause fluid accumulation in the retina, choroidal vasodilation, and to promote retinal neovascularization in hypoxic conditions. These findings indicate that MR antagonists could have beneficial effects in the treatment of retinal diseases. Central serous chorioretinopathy is a retinal disease associated with choroidal vasodilation and subretinal fluid that affects mostly men with type A personality and occurrence has been associated with steroid intake. In several independent studies, MR antagonists have shown beneficial effects, significantly reducing subretinal fluid in eyes of chronic central serous chorioretinopathy patients. SUMMARY: The role of MR in retinal disorder is emerging and the potential association with psychological traits is considered. The place of MR antagonists for retinal diseases treatment is discussed.

Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner.

Upon infection, antigen-specific naive CD8 T cells are activated and differentiate into short-lived effector cells (SLECs) and memory precursor cells (MPECs). The underlying signaling pathways remain largely unresolved. We show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2), regulates SLEC and MPEC commitment. Rictor deficiency favors memory formation and increases IL-2 secretion capacity without dampening effector functions. Moreover, mTORC2-deficient memory T cells mount more potent recall responses. Enhanced memory formation in the absence of mTORC2 was associated with Eomes and Tcf-1 upregulation, repression of T-bet, enhanced mitochondrial spare respiratory capacity, and fatty acid oxidation. This transcriptional and metabolic reprogramming is mainly driven by nuclear stabilization of Foxo1. Silencing of Foxo1 reversed the increased MPEC differentiation and IL-2 production and led to an impaired recall response of Rictor KO memory T cells. Therefore, mTORC2 is a critical regulator of CD8 T cell differentiation and may be an important target for immunotherapy interventions.

Biological Characterization of Gene Response to Insulin-Induced Hypoglycemia in Mouse Retina.

Glucose is the most important metabolic substrate of the retina and maintenance of normoglycemia is an essential challenge for diabetic patients. Chronic, exaggerated, glycemic excursions could lead to cardiovascular diseases, nephropathy, neuropathy and retinopathy. We recently showed that hypoglycemia induced retinal cell death in mouse via caspase 3 activation and glutathione (GSH) decrease. Ex vivo experiments in 661W photoreceptor cells confirmed the low-glucose induction of death via superoxide production and activation of caspase 3, which was concomitant with a decrease of GSH content. We evaluate herein retinal gene expression 4 h and 48 h after insulin-induced hypoglycemia. Microarray analysis demonstrated clusters of genes whose expression was modified by hypoglycemia and we discuss the potential implication of those genes in retinal cell death. In addition, we identify by gene set enrichment analysis, three important pathways, including lysosomal function, GSH metabolism and apoptotic pathways. Then we tested the effect of recurrent hypoglycemia (three successive 4h periods of hypoglycemia spaced by 48 h recovery) on retinal cell death. Interestingly, exposure to multiple hypoglycemic events prevented GSH decrease and retinal cell death, or adapted the retina to external stress by restoring GSH level comparable to control situation. We hypothesize that scavenger GSH is a key compound in this apoptotic process, and maintaining "normal" GSH level, as well as a strict glycemic control, represents a therapeutic challenge in order to avoid side effects of diabetes, especially diabetic retinopathy.

The life history of retrocopies illuminates the evolution of new mammalian genes.

New genes contribute substantially to adaptive evolutionary innovation, but the functional evolution of new mammalian genes has been little explored at a broad scale. Previous work established mRNA-derived gene duplicates, known as retrocopies, as models for the study of new gene origination. Here we combine mammalian transcriptomic and epigenomic data to unveil the processes underlying the evolution of stripped-down retrocopies into complex new genes. We show that although some robustly expressed retrocopies are transcribed from preexisting promoters, most evolved new promoters from scratch or recruited proto-promoters in their genomic vicinity. In particular, many retrocopy promoters emerged from ancestral enhancers (or bivalent regulatory elements) or are located in CpG islands not associated with other genes. We detected 88-280 selectively preserved retrocopies per mammalian species, illustrating that these mechanisms facilitated the birth of many functional retrogenes during mammalian evolution. The regulatory evolution of originally monoexonic retrocopies was frequently accompanied by exon gain, which facilitated co-option of distant promoters and allowed expression of alternative isoforms. While young retrogenes are often initially expressed in the testis, increased regulatory and structural complexities allowed retrogenes to functionally diversify and evolve somatic organ functions, sometimes as complex as those of their parents. Thus, some retrogenes evolved the capacity to temporarily substitute for their parents during the process of male meiotic X inactivation, while others rendered parental functions superfluous, allowing for parental gene loss. Overall, our reconstruction of the "life history" of mammalian retrogenes highlights retroposition as a general model for understanding new gene birth and functional evolution.

A Virtual Laboratory Structure for Developing Programming Labs

Virtual Laboratories are an indispensablespace for developing practical activities in a Virtual Environment. In the field of Computer and Software Engineering different types of practical activities have tobe performed in order to obtain basic competences which are impossible to achieve by other means. This paper specifies an ontology for a general virtual laboratory.The proposed ontology provides a mechanism to select the best resources needed in a Virtual Laboratory once a specific practical activity has been defined and the maincompetences that students have to achieve in the learning process have been fixed. Furthermore, the proposed ontology can be used to develop an automatic and wizardtool that creates a Moodle Classroom using the practical activity specification and the related competences.

Suitability of human and mammalian cells of different origin for the assessment of genotoxicity of metal and polymeric engineered nanoparticles.

Nanogenotoxicity is a crucial endpoint in safety testing of nanomaterials as it addresses potential mutagenicity, which has implications for risks of both genetic disease and carcinogenesis. Within the NanoTEST project, we investigated the genotoxic potential of well-characterised nanoparticles (NPs): titanium dioxide (TiO2) NPs of nominal size 20 nm, iron oxide (8 nm) both uncoated (U-Fe3O4) and oleic acid coated (OC-Fe3O4), rhodamine-labelled amorphous silica 25 (Fl-25 SiO2) and 50 nm (Fl-50 SiO) and polylactic glycolic acid polyethylene oxide polymeric NPs - as well as Endorem® as a negative control for detection of strand breaks and oxidised DNA lesions with the alkaline comet assay. Using primary cells and cell lines derived from blood (human lymphocytes and lymphoblastoid TK6 cells), vascular/central nervous system (human endothelial human cerebral endothelial cells), liver (rat hepatocytes and Kupffer cells), kidney (monkey Cos-1 and human HEK293 cells), lung (human bronchial 16HBE14o cells) and placenta (human BeWo b30), we were interested in which in vitro cell model is sufficient to detect positive (genotoxic) and negative (non-genotoxic) responses. All in vitro studies were harmonized, i.e. NPs from the same batch, and identical dispersion protocols (for TiO2 NPs, two dispersions were used), exposure time, concentration range, culture conditions and time-courses were used. The results from the statistical evaluation show that OC-Fe3O4 and TiO2 NPs are genotoxic in the experimental conditions used. When all NPs were included in the analysis, no differences were seen among cell lines - demonstrating the usefulness of the assay in all cells to identify genotoxic and non-genotoxic NPs. The TK6 cells, human lymphocytes, BeWo b30 and kidney cells seem to be the most reliable for detecting a dose-response.

Developing a conceptual framework to analyse professionalisation in sport federations

Existing research on sport organisations is imprecise in the use of the concept 'professionalisation'. Furthermore, we do not know if analytical concepts of professionalisation correspond with the understanding in practice. This study explores the perceptions of practitioners and proposes a framework to analyse professionalisation in national sport federations. Expert interviews were conducted with six key people from Swiss national sport federations and then analysed these for characteristics of professionalisation using a hermeneutic approach. The characteristics were divided into three areas: (1) changed management philosophy, (2) functional differentiation and specialisation, and (3) application of management tools. However, professionalisation is primarily perceived to be a matter of 'professional' attitude that transforms into federation culture. The practitioners disclose an ambivalent view of professionalisation, e.g. business-like culture vs. voluntarism, for-profit vs. non-profit orientation, autonomy vs. control. A framework is developed that synthesises analytical concepts and practitioners' perceptions to support future comprehensive research into causes, forms and consequences of professionalisation in national sport federations.

CRM and higher education : developing a monitoring system to improve relationships in e-learning environments

Peer-reviewed

Developing of AC magnetometer and investigation of magnetic properties of LSMO

In this work AC magnetometer was developed and primary test measurements were performed for temperature range from 77 K up to 350 K in frequency range from 1 kHz up to 20 kHz. In the course of the present work dependencies of magnetization on temperature for Lao7Sr03Mni _yFeyO3 with y = 0.15, 0.20, 0.25 were obtained in DC magnetic field using SQUID magnetometer and in AC magnetic field using the developed AC magnetometer. Lai.XSrXMnO3 (LSMO) compounds belong to the class of Mn perovskites, which demonstrate very high degree of spin polarization. These materials are of great importance for nowadays applications in spintronics, where spin polarized electron transport is used. Spin glass like behavior was found as a characteristic feature of these solid solutions with the freezing temperature in the range 65 — 210 K.

Developing a new service business model for an industrial supplier

Project business companies are moving towards solution offering in order to avoid discontinuity of project business and to gain other advantages. An option to implement solution business could be BOOT (Build-Own-Operate-Transfer) business model where a company is given the responsibilities to design, finance, build, own, operate and maintain for example production facilities of a client. The contract is made for 10-30 years, the client pays the solution during this period of time and after contract termination the facilities are transferred to the ownership of the client. The purpose of this study was to provide knowledge about BOOT business model for the company in question and its employees and to create a settlement of the advantages, disadvantages and risks of it. Furthermore, one of the main objectives was to create a description of the network needed to run a BOOT project. The objectives were met through a literature study and an explorative case study with appropriate interviews. Based on this study, the company should be able to evaluate the applicability of BOOT business model to their business environment better.

Developing a Service-Oriented Software Platform

Tehokkaasti toimiva sähköinen tiedonvälitys yrityksen omien sovellusten välillä sekä sen liikekumppaneiden kanssa on kasvanut merkittäväksi yrityksen kilpailukykyä lisääväksi tekijäksi. Yritysten erilaiset tietojärjestelmät asettavat haasteita tehokkaalle tiedonvälitykselle näiden järjestelmien välillä. Perinteiset EDI teknologioihin perustuvat sähköisen tiedonvälityksen ratkaisut eivät pysty mukautumaan nykyisin nopeasti muuttuviin markkinatilanteisiin. Palvelukeskeiseen arkkitehtuuriin ja Web-palveluihin perustuvat teknologiat mahdollistavat mukautumisen erilaisiin muutoksiin liiketoiminnassa nopeammin ja helpommin. Lisäksi ne nopeuttavat tiedon integrointia erilaisten tietojärjestelmien välillä, koska tiedonvälityksessä käytetään yleisesti hyväksyttyihin standardeihin perustuvia tiedonsiirtoprotokollia sekä tietoformaatteja. Diplomityössä esitellään keskeiset teknologiat ja menetelmät sähköisen tiedonvälityksen toteuttamiseen. Lisäksi työssä vertaillaan erilaisia vaihtoehtoja, joilla sähköinen tiedonvälitys voidaan toteuttaa. Vaihtoehtoina työssä ovat tiedonvälityspalveluiden ostaminen toiselta yritykseltä, olemassa olevan valmiin ohjelmiston hyödyntäminen, tai kokonaan uuden sovellusalustan kehittäminen. Työssä kuvaillaan palvelukeskeisen sovellusalustan toteutus, joka mahdollistaa tehokkaan sekä joustavan tiedonvälityksen sovellusten välillä. Alustan tarjoamien palveluiden päälle voidaan rakentaa erilaisia liiketoimintaa tukevia palveluita, jotka voivat hyödyntää sovellusalustan tarjoamia toiminnallisuuksia. Alustan toteutusta arvioidaan kolmen liiketoimintaskenaarion toteutuksesta saatujen kokemusten perusteella.

Developing the environmental marketing of an industrial company

The objective of this study was to examine how the customers of Larox Flowsys value environmental issues and how environmental issues affect their purchasing behaviour. A comparison between Larox peristaltic pumps and competing pump brands and types was also made in order to find out whether LPP pumps possess some more environmentally beneficial features that other pumps do not have. Finally, if the answers to the first two research questions show that a need for a new marketing message does exist, then the final stage is to select the most appropriate environmental arguments for Larox Flowsys. The empirical data in the study was collected from several different sources, but the main sources were the customer interviews and the outsourced market research. The data was analysed mainly by using content analysis, but theme formation and quantification were also utilized. The results showed that the customers do not consider environmental issues as a main purchasing criterion, but they may well be the criterion that differentiates the product from competing ones. The comparison proved that LPP pumps do possess some significant environmental benefits over competing pumps and therefore, the prerequisite for the use of environmental arguments exists. The final stage in the study was to select the proper environmental arguments for Larox Flowsys.