Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation

MASP-1 is a versatile serine protease that cleaves a number of substrates in human blood. In recent years it became evident that besides playing a crucial role in complement activation MASP-1 also triggers other cascade systems and even cells to mount a more powerful innate immune response. In this review we summarize the latest discoveries about the diverse functions of this multi-faceted protease. Recent studies revealed that among MBL-associated serine proteases, MASP-1 is the one responsible for triggering the lectin pathway via its ability to rapidly autoactivate then cleave MASP-2, and possibly MASP-3. The crystal structure of MASP-1 explains its more relaxed substrate specificity compared to the related complement enzymes. Due to the relaxed specificity, MASP-1 interacts with the coagulation cascade and the kinin generating system, and it can also activate endothelial cells eliciting pro-inflammatory signaling.

The research-action interface in sustainable land management in Kyrgyzstan and Tajikistan: Challenges and recommendations

International agencies and programmes introduced sustainable land management (SLM) to Central Asia after the former Soviet Republics became independent in 1991. An aim of early SLM initiatives was to address challenges linked to the transformation of the agricultural sector from a centrally planned economy to a decentralized market economy. This article analyses the knowledge–action interface in Kyrgyzstan and Tajikistan as it relates to SLM. The analysis focuses on the influence of underlying land management concepts by means of a literature review. Contemporary barriers at the research–action interface were identified using participatory appraisal. And a historically contextualized understanding of the effectiveness of interactions between researchers, policy makers and practitioners is based on an analysis of purposefully selected cases. The study concludes that knowledge of different stakeholder groups is often highly disconnected. Interdisciplinary and transdisciplinary studies are rare, and academic research on SLM has subsequently been ineffective at contributing to substantial benefits for society. Further, researchers, policy makers and practitioners in this context must recognize the differences between SLM and what is often referred to as the equivalent Soviet-era concept—rational use of land resources—and the resulting implications of these differences. The authors recommend the following: creating an enabling environment for SLM research through academic institutional reform removing structural constraints, making research outcomes more effective by applying systems approaches that produce evidence for policy makers on the multiple benefits of SLM, helping land users evaluate SLM strategies and investing in the establishment and maintenance of a multi-stakeholder SLM platform that allows dynamic exchange.

Development and Evaluation of a New Tablet Computer Application for the Therapy of Brain-Injured Patients with Aphasia

Introduction Language is the most important mean of communication and plays a central role in our everyday life. Brain damage (e.g. stroke) can lead to acquired disorders of lan- guage affecting the four linguistic modalities (i.e. reading, writing, speech production and comprehension) in different combinations and levels of severity. Every year, more than 5000 people (Aphasie Suisse) are affected by aphasia in Switzerland alone. Since aphasia is highly individual, the level of difficulty and the content of tasks have to be adapted continuously by the speech therapists. Computer-based assignments allow patients to train independently at home and thus increasing the frequency of ther- apy. Recent developments in tablet computers have opened new opportunities to use these devices for rehabilitation purposes. Especially older people, who have no prior experience with computers, can benefit from the new technologies. Methods The aim of this project was to develop an application that enables patients to train language related tasks autonomously and, on the other hand, allows speech therapists to assign exercises to the patients and to track their results online. Seven categories with various types of assignments were implemented. The application has two parts which are separated by a user management system into a patient interface and a therapist interface. Both interfaces were evaluated using the SUS (Subject Usability Scale). The patient interface was tested by 15 healthy controls and 5 patients. For the patients, we also collected tracking data for further analysis. The therapist interface was evaluated by 5 speech therapists. Results The SUS score are xpatients = 98 and xhealthy = 92.7 (median = 95, SD = 7, 95% CI [88.8, 96.6]) in case of the patient interface and xtherapists = 68 in case of the therapist interface. Conclusion Both, the patients and the healthy subjects, attested high SUS scores to the patient interface. These scores are considered as "best imaginable". The therapist interface got a lower SUS score compared to the patient interface, but is still considered as "good" and "usable". The user tracking system and the interviews revealed that there is room for improvements and inspired new ideas for future versions.

Quantification of water content across a cement-clay interface using high resolution neutron radiography

In many designs for radioactive waste repositories, cement and clay will come into direct contact. The geochemical contrast between cement and clay will lead to mass fluxes across the interface, which consequently results in alteration of structural and transport properties of both materials that may affect the performance of the multi-barrier system. We present an experimental approach to study cement-clay interactions with a cell to accommodate small samples of cement and clay. The cell design allows both in situ measurement of water content across the sample using neutron radiography and measurement of transport parameters using through-diffusion tracer experiments. The aim of the high- resolution neutron radiography experiments was to monitor changes in water content (porosity) and their spatial extent. Neutron radiographs of several evolving cement-clay interfaces delivered quantitative data which allow resolving local water contents within the sample domain. In the present work we explored the uncertainties of the derived water contents with regard to various input parameters and with regard to the applied image correction procedures. Temporal variation of measurement conditions created absolute uncertainty of the water content in the order of ±0.1 (m3/m3), which could not be fully accounted for by correction procedures. Smaller relative changes in water content between two images can be derived by specific calibrations to two sample regions with different, invariant water contents.

Polaronic metal state at the LaAlO₃/SrTiO₃ interface

Interplay of spin, charge, orbital and lattice degrees of freedom in oxide heterostructures results in a plethora of fascinating properties, which can be exploited in new generations of electronic devices with enhanced functionalities. The paradigm example is the interface between the two band insulators LaAlO3 and SrTiO3 that hosts a two-dimensional electron system. Apart from the mobile charge carriers, this system exhibits a range of intriguing properties such as field effect, superconductivity and ferromagnetism, whose fundamental origins are still debated. Here we use soft-X-ray angle-resolved photoelectron spectroscopy to penetrate through the LaAlO3 overlayer and access charge carriers at the buried interface. The experimental spectral function directly identifies the interface charge carriers as large polarons, emerging from coupling of charge and lattice degrees of freedom, and involving two phonons of different energy and thermal activity. This phenomenon fundamentally limits the carrier mobility and explains its puzzling drop at high temperatures.

Fetal programming and epigenetic mechanisms in arterial hypertension.

PURPOSE OF REVIEW To provide an overview of available evidence of the potential role of epigenetics in the pathogenesis of hypertension and vascular dysfunction. RECENT FINDINGS Arterial hypertension is a highly heritable condition. Surprisingly, however, genetic variants only explain a tiny fraction of the phenotypic variation and the term 'missing heritability' has been coined to describe this phenomenon. Recent evidence suggests that phenotypic alteration that is unrelated to changes in DNA sequence (thereby escaping detection by classic genetic methodology) offers a potential explanation. Here, we present some basic information on epigenetics and review recent work consistent with the hypothesis of epigenetically induced arterial hypertension. SUMMARY New technologies that enable the rigorous assessment of epigenetic changes and their phenotypic consequences may provide the basis for explaining the missing heritability of arterial hypertension and offer new possibilities for treatment and/or prevention.

SOMS: SurrOgate MultiStart algorithm for use with nonlinear programming for global optimization

SOMS is a general surrogate-based multistart algorithm, which is used in combination with any local optimizer to find global optima for computationally expensive functions with multiple local minima. SOMS differs from previous multistart methods in that a surrogate approximation is used by the multistart algorithm to help reduce the number of function evaluations necessary to identify the most promising points from which to start each nonlinear programming local search. SOMS’s numerical results are compared with four well-known methods, namely, Multi-Level Single Linkage (MLSL), MATLAB’s MultiStart, MATLAB’s GlobalSearch, and GLOBAL. In addition, we propose a class of wavy test functions that mimic the wavy nature of objective functions arising in many black-box simulations. Extensive comparisons of algorithms on the wavy testfunctions and on earlier standard global-optimization test functions are done for a total of 19 different test problems. The numerical results indicate that SOMS performs favorably in comparison to alternative methods and does especially well on wavy functions when the number of function evaluations allowed is limited.

A new fork for clinical application: Targeting forkhead transcription factors in cancer therapy

RAS-ERK-MAPK (Mitogen-activated protein kinase) pathway plays an essential role in proliferation, differentiation, and tumor progression. In this study, we showed that ERK downregulated FOXO3a through directly interacting with and phosphorylating FOXO3a at Serine 294, Serine 344, and Serine 425. ERK-phosphorylated FOXO3a was degraded by MDM2-mediated ubiquitin-proteosome pathway. FOXO3a phosphorylation and degradation consequently promoted cell proliferation and tumorigenesis. However, the non-phosphorylated FOXO3a mutant, which was resistant to the interaction and degradation by MDM2, resulted in inhibition of tumor formation. Forkhead O transcription factors (FOXOs) are important in the regulation of cellular functions including cell cycle arrest and cell death. Perturbation of FOXOs function leads to deregulated cell proliferation and cancer. Inactivation of FOXO proteins by activation of cell survival pathways, such as PI3K/AKT/IKK, is associated with tumorigenesis. Our study will further highlight FOXOs as new therapeutic targets in a broad spectrum of cancers. ^ Chemotherapeutic drug resistance is the most concerned problem in cancer therapy as resistance ultimately leads to treatment failure of cancer patients. In another study, we showed that blocking ERK activity with AZD6244, an established MEK1/2 inhibitor currently under human cancer clinical trials, enhances FOXO3a expression in various human cancer cell lines in vitro, and also in human colon cancer cell xenografts in vivo. Knocking down FOXO3a and its downstream gene Bim impaired AZD6244-induced growth suppression, whereas restoring activation of FOXO3a sensitized human cancer cell to AZD6244-induced growth arrest and apoptosis. More importantly, AZD6244-resistant cancer cells showed impaired endogenous FOXO3a nuclear translocation, reduced FOXO3a-Bim promoter association and significantly decreased Bim expression in response to AZD6244. AZD6244-resistant cancer cells can be sensitized to API-2 (an AKT inhibitor) and LY294002 (a PI3K inhibitor) in suppressing cell growth and colony formation, these inhibitors were known to enhance FOXO3a activity/nuclear translocation through inhibiting PI3K-AKT pathway. This study reveals novel molecular mechanism contributing to AZD6244-resistance through regulation of FOXO3a activity, further provides significant clinical implication of combining AZD6244 with PI3K/AKT inhibitors for sensitizing AZD6244-resistant cancer cells by activating FOXO3a. FOXO3a activation can be an essential pharmacological target and indicator to mediate and predict AZD6244 efficacy in clinical use. ^

Ethnographic and epidemiologic approaches for the programming of prenatal and birth services in Mesa los Hornos, Mexico

The investigator conducted an action-oriented investigation of pregnancy and birth among the women of Mesa los Hornos, an urban squatter slum in Mexico City. Three aims guided the project: (1) To obtain information for improving prenatal and maternity service utilization; (2) To examine the utility of rapid ethnographic and epidemiologic assessment methodologies; (3) To cultivate community involvement in health development.^ Viewing service utilization as a culturally-bound decision, the study included a qualitative phase to explore women's cognition of pregnancy and birth, their perceived needs during pregnancy, and their criteria of service acceptability. A probability-based community survey delineated parameters of service utilization and pregnancy health events, and probed reasons for decisions to use medical services, lay midwives, or other sources of prenatal and labor and delivery assistance. Qualitative survey of service providers at relevant clinics, hospitals, and practices contributed information on service availability and access, and on coordination among private, social security, and public assistance health service sectors. The ethnographic approach to exploring the rationale for use or non-use of services provided a necessary complement to conventional barrier-based assessment, to inform planning of culturally appropriate interventions.^ Information collection and interpretation was conducted under the aegis of an advisory committee of community residents and service agency representatives; the residents' committee formulated recommendations for action based on findings, and forwarded the mandate to governmental social and urban development offices. Recommendations were designed to inform and develop community participation in health care decision-making.^ Rapid research methods are powerful tools for achieving community-based empowerment toward investigation and resolution of local health problems. But while ethnography works well in synergy with quantitative assessment approaches to strengthen the validity and richness of short-term field work, the author strongly urges caution in application of Rapid Ethnographic Assessments. An ethnographic sensibility is essential to the research enterprise for the development of an active and cooperative community base, the design and use of quantitative instruments, the appropriate use of qualitative techniques, and the interpretation of culturally-oriented information. However, prescribed and standardized Rapid Ethnographic Assessment techniques are counter-productive if used as research short-cuts before locale- and subject-specific cultural understanding is achieved. ^

Las funcionalidades Web 2.0 en la interface de usuario de los OPACs Web de Latinoamérica

Se presenta el proyecto de investigación aprobado y subsidiado en el marco de la Programación Científica UBACYT 2011-2014 sobre la problemática de las interfaces de usuario de los catálogos en línea de acceso público (OPACs) en entorno web de las bibliotecas nacionales, universitarias, especializadas y públicas de Latinoamérica, a fin de examinar las funcionalidades propias de las áreas de control de operaciones, formulación de la búsqueda y puntos de acceso, control de salida y asistencia al usuario, así como también las funcionalidades Web 2.0. Se adopta una metodología cuantitativa. Se plantea aplicar a una muestra representada por 102 unidades, extraída por muestreo aleatorio simple (de una población compuesta por 846 casos), la lista de funcionalidades que proporciona Hildreth (1982) actualizada; comparar, mediante un diseño experimental de muestras relacionadas, las variaciones producidas en cuanto a presencia/ausencia de funcionalidades y tipo de software adoptado en relación con la situación existente ya verificada en investigaciones previas; identificar, a partir de la observación de las interfaces de los OPACs que constituyen la muestra, la presencia/ausencia de funcionalidades Web 2.0; utilizar para ello como instrumento de recolección la lista de funcionalidades deseables en los OPACs 2.0 confeccionada por Margaix-Arnal (2007); aplicar diferentes pruebas estadísticas para describir las características de la interface de usuario de los OPACs Web de la región a partir del supuesto de que ha aumentado el uso de Sistemas Integrados de Gestión Bibliotecaria y la presencia de funcionalidades en aquellas unidades que han adoptado estos sistemas, aunque carecen aún de funcionalidades 2.0.

Interface de recuperación para catálogos en línea con salidas ordenadas por probable relevancia

Se presenta el desarrollo de una interface de recuperación de información para catálogos en línea de acceso público (plataforma CDS/ISIS), basada en el concepto de similaridad para generar los resultados de una búsqueda ordenados por posible relevancia. Se expresan los fundamentos teóricos involucrados, para luego detallar la forma en que se efectuó su aplicación tecnológica, explícita a nivel de programación. Para finalizar se esbozan los problemas de implementación según el entorno

Interface de recuperación para catálogos en línea con salidas ordenadas por probable relevancia

Se presenta el desarrollo de una interface de recuperación de información para catálogos en línea de acceso público (plataforma CDS/ISIS), basada en el concepto de similaridad para generar los resultados de una búsqueda ordenados por posible relevancia. Se expresan los fundamentos teóricos involucrados, para luego detallar la forma en que se efectuó su aplicación tecnológica, explícita a nivel de programación. Para finalizar se esbozan los problemas de implementación según el entorno

Las funcionalidades Web 2.0 en la interface de usuario de los OPACs Web de Latinoamérica

Se presenta el proyecto de investigación aprobado y subsidiado en el marco de la Programación Científica UBACYT 2011-2014 sobre la problemática de las interfaces de usuario de los catálogos en línea de acceso público (OPACs) en entorno web de las bibliotecas nacionales, universitarias, especializadas y públicas de Latinoamérica, a fin de examinar las funcionalidades propias de las áreas de control de operaciones, formulación de la búsqueda y puntos de acceso, control de salida y asistencia al usuario, así como también las funcionalidades Web 2.0. Se adopta una metodología cuantitativa. Se plantea aplicar a una muestra representada por 102 unidades, extraída por muestreo aleatorio simple (de una población compuesta por 846 casos), la lista de funcionalidades que proporciona Hildreth (1982) actualizada; comparar, mediante un diseño experimental de muestras relacionadas, las variaciones producidas en cuanto a presencia/ausencia de funcionalidades y tipo de software adoptado en relación con la situación existente ya verificada en investigaciones previas; identificar, a partir de la observación de las interfaces de los OPACs que constituyen la muestra, la presencia/ausencia de funcionalidades Web 2.0; utilizar para ello como instrumento de recolección la lista de funcionalidades deseables en los OPACs 2.0 confeccionada por Margaix-Arnal (2007); aplicar diferentes pruebas estadísticas para describir las características de la interface de usuario de los OPACs Web de la región a partir del supuesto de que ha aumentado el uso de Sistemas Integrados de Gestión Bibliotecaria y la presencia de funcionalidades en aquellas unidades que han adoptado estos sistemas, aunque carecen aún de funcionalidades 2.0.