Response profiles of murine spiral ganglion neurons on multi-electrode arrays.

OBJECTIVE Cochlear implants (CIs) have become the gold standard treatment for deafness. These neuroprosthetic devices feature a linear electrode array, surgically inserted into the cochlea, and function by directly stimulating the auditory neurons located within the spiral ganglion, bypassing lost or not-functioning hair cells. Despite their success, some limitations still remain, including poor frequency resolution and high-energy consumption. In both cases, the anatomical gap between the electrode array and the spiral ganglion neurons (SGNs) is believed to be an important limiting factor. The final goal of the study is to characterize response profiles of SGNs growing in intimate contact with an electrode array, in view of designing novel CI devices and stimulation protocols, featuring a gapless interface with auditory neurons. APPROACH We have characterized SGN responses to extracellular stimulation using multi-electrode arrays (MEAs). This setup allows, in our view, to optimize in vitro many of the limiting interface aspects between CIs and SGNs. MAIN RESULTS Early postnatal mouse SGN explants were analyzed after 6-18 days in culture. Different stimulation protocols were compared with the aim to lower the stimulation threshold and the energy needed to elicit a response. In the best case, a four-fold reduction of the energy was obtained by lengthening the biphasic stimulus from 40 μs to 160 μs. Similarly, quasi monophasic pulses were more effective than biphasic pulses and the insertion of an interphase gap moderately improved efficiency. Finally, the stimulation with an external electrode mounted on a micromanipulator showed that the energy needed to elicit a response could be reduced by a factor of five with decreasing its distance from 40 μm to 0 μm from the auditory neurons. SIGNIFICANCE This study is the first to show electrical activity of SGNs on MEAs. Our findings may help to improve stimulation by and to reduce energy consumption of CIs and thereby contribute to the development of fully implantable devices with better auditory resolution in the future.

Functional interplay of SP family members and nuclear factor Y is essential for transcriptional activation of the human Calreticulin gene

Calreticulin (CALR) is a highly conserved, multifunctional protein involved in a variety of cellular processes including the maintenance of intracellular calcium homeostasis, proper protein folding, differentiation and immunogenic cell death. More recently, a crucial role for CALR in the pathogenesis of certain hematologic malignancies was discovered: in clinical subgroups of acute myeloid leukemia, CALR overexpression mediates a block in differentiation, while somatic mutations have been found in the majority of patients with myeloproliferative neoplasms with nonmutated Janus kinase 2 gene (JAK2) or thrombopoietin receptor gene (MPL). However, the mechanisms underlying CALR promoter activation have insufficiently been investigated so far. By dissecting the core promoter region, we could identify a functional TATA-box relevant for transcriptional activation. In addition, we characterized two evolutionary highly conserved cis-regulatory modules (CRMs) within the proximal promoter each composed of one binding site for the transcription factors SP1 and SP3 as well as for the nuclear transcription factor Y (NFY) and we verified binding of these factors to their cognate sites in vitro and in vivo.

A multi-level stakeholder approach to sustainable land management

Soils provide us with over 90% of all human food, livestock feed, fibre and fuel on Earth. Soils, however, have more than just productive functions. The key challenge in coming years will be to address the diverse and potentially conflicting demands now being made by human societies and other forms of life, while ensuring that future generations have the same potential to use soils and land of comparable quality. In a multi-level stakeholder approach, down-to-earth action will have to be supplemented with measures at various levels, from households to communities, and from national policies to international conventions. Knowledge systems, both indigenous and scientific, and related research and learning processes must play a central role. Ongoing action can be enhanced through a critical assessment of the impact of past achievements, and through better cooperation between people and institutions.

Professionalisation of sport federations – A multi-level framework for analysing forms, causes and consequences

Research question: International and national sport federations as well as their member organisations are key actors within the sport system and have a wide range of relationships outside the sport system (e.g. with the state, sponsors, and the media). They are currently facing major challenges such as growing competition in top-level sports, democratisation of sports with ‘sports for all’ and sports as the answer to social problems. In this context, professionalising sport organisations seems to be an appropriate strategy to face these challenges and current problems. We define the professionalisation of sport organisations as an organisational process of transformation leading towards organisational rationalisation, efficiency and business-like management. This has led to a profound organisational change, particularly within sport federations, characterised by the strengthening of institutional management (managerialism) and the implementation of efficiency-based management instruments and paid staff. Research methods: The goal of this article is to review the current international literature and establish a global understanding of and theoretical framework for analysing why and how sport organisations professionalise and what consequences this may have. Results and findings: Our multi-level approach based on the social theory of action integrates the current concepts for analysing professionalisation in sport federations. We specify the framework for the following research perspectives: (1) forms, (2) causes and (3) consequences, and discuss the reciprocal relations between sport federations and their member organisations in this context. Implications: Finally, we work out a research agenda and derive general methodological consequences for the investigation of professionalisation processes in sport organisations.

Professionalisation of sports federations – A multi-level framework for analysing forms, causes and consequences

Introduction: International and national sports federations as well as their member organisations (usually sports clubs) are key actors within the sports system and have a wide range of relationships outside the sports system (e.g. with the state, sponsors, and the media). They are currently facing major challenges such as growing competition in top-­‐level sports, democratisation of sports with “sports for all” and sports as the answer to social problems (integration, education, health, unemployment, etc.). In this context, professionalising sports organisations seems to be an appropriate strategy to face these challenges and solve current problems. This has led to a profound organisational change, particularly within sports federations, characterised by the strengthening of institutional management (managerialism) and the implementation of efficiency-­‐based management instruments and paid staff. In this context the questions arise how sports organisations professionalise and what consequences this may have. Theoretical framework: The goal of our presentation is to review the international literature and develop an appropriate concept of professionalisation in sport federations. Our multi-­‐level approach based on social theory of action integrates the current concepts and perspectives for analysing professionalisation in sports federations. We specify the framework for the following research perspectives: (1) forms, (2) causes and mechanisms, (3) consequences and (4) dynamics, and discuss the reciprocal relations between sports federations and their member organisations in this context. When analysing these different research perspectives, it is important to select or elaborate appropriate theoretical concepts to match the general multi-­‐level framework Discussion: The elaborated multi-­‐level framework for analysing professionalisation in sports federations is able to integrate most of the existing theoretical concepts and therefore, the broad range of endogenous as well as exogenous factors that might influence the professionalisation of sports organisations. Based on the theoretical framework, we can identify several consequences for the methodological design of studies intending to analyse the different perspectives of professionalisation in sports organisations: Data have to be collected on the different levels. Not only the forms of professionalisation and relevant structures of the organisations should be taken into account but also important characteristics of the environment (macro level) as well as members or member organisations, particularly key actors who might play a crucial role in gaining an understanding of professionalisation processes in sports organisations. In order to carry out a complex organisational research design, it seems necessary to focus on case studies – an approach that has become increasingly important in organisational research. Different strategies and methods of data collection have to be used within the case studies (e.g. interviews with experts within the organisations, questionnaire for selected people in the organisation, document analysis). Therefore, qualitative and quantitative research strategies have to be combined.

Elucidating underlying processes of psychometric intelligence: A comparison of behavioral response latency and P3 latency in a modified Hick reaction time paradigm

The mental speed approach explains individual differences in intelligence by faster information processing in individuals with higher compared to lower intelligence - especially in elementary cognitive tasks (ECTs). One of the most examined ECTs is the Hick paradigm. The present study aimed to contrast reaction time (RT) and P3 latency in a Hick task as predictors of intelligence. Although both, RT and P3 latency, are commonly used as indicators of mental speed, it is also known that they measure different aspects of information processing. Participants were 113 female students. RT and P3 latency were measured while participants completed the Hick task with four levels of complexity. Intelligence was assessed with Cattell's Culture Fair Test. A RT factor and a P3 factor were extracted by employing a PCA across complexity levels. There was no significant correlation between the factors. Commonality analysis was used to determine the proportions of unique and shared variance in intelligence explained by the RT and P3 latency factors. RT and P3 latency explained 5.5% and 5% of unique variance in intelligence. However, the two speed factors did not explain a significant portion of shared variance. This result suggests that RT and P3 latency in the Hick paradigm are measuring different aspects of information processing that explain different parts of variance in intelligence.

siRNA mediated knockdown of tissue factor expression in pigs for xenotransplantation.

Acute vascular rejection (AVR), in particular microvascular thrombosis, is an important barrier to successful pig-to-primate xenotransplantation. Here, we report the generation of pigs with decreased tissue factor (TF) levels induced by small interfering (si)RNA-mediated gene silencing. Porcine fibroblasts were transfected with TF-targeting small hairpin (sh)RNA and used for somatic cell nuclear transfer. Offspring were analyzed for siRNA, TF mRNA and TF protein level. Functionality of TF downregulation was investigated by a whole blood clotting test and a flow chamber assay. TF siRNA was expressed in all twelve liveborn piglets. TF mRNA expression was reduced by 94.1 ± 4.7% in TF knockdown (TFkd) fibroblasts compared to wild-type (WT). TF protein expression in PAEC stimulated with 50 ng/mL TNF-α was significantly lower in TFkd pigs (mean fluorescence intensity TFkd: 7136 ± 136 vs. WT: 13 038 ± 1672). TF downregulation significantly increased clotting time (TFkd: 73.3 ± 8.8 min, WT: 45.8 ± 7.7 min, p < 0.0001) and significantly decreased thrombus formation compared to WT (mean thrombus coverage per viewing field in %; WT: 23.5 ± 13.0, TFkd: 2.6 ± 3.7, p < 0.0001). Our data show that a functional knockdown of TF is compatible with normal development and survival of pigs. TF knockdown could be a valuable component in the generation of multi-transgenic pigs for xenotransplantation.

Comparing the factorial structure, invariance, and predictive validity of transtheoretical model constructs for alcohol use across restricted and unrestricted settings

With substance abuse treatment expanding in prisons and jails, understanding how behavior change interacts with a restricted setting becomes more essential. The Transtheoretical Model (TTM) has been used to understand intentional behavior change in unrestricted settings, however, evidence indicates restrictive settings can affect the measurement and structure of the TTM constructs. The present study examined data from problem drinkers at baseline and end-of-treatment from three studies: (1) Project CARE (n = 187) recruited inmates from a large county jail; (2) Project Check-In (n = 116) recruited inmates from a state prison; (3) Project MATCH, a large multi-site alcohol study had two recruitment arms, aftercare (n = 724 pre-treatment and 650 post-treatment) and outpatient (n = 912 pre-treatment and 844 post-treatment). The analyses were conducted using cross-sectional data to test for non-invariance of measures of the TTM constructs: readiness, confidence, temptation, and processes of change (Structural Equation Modeling, SEM) across restricted and unrestricted settings. Two restricted (jail and aftercare) and one unrestricted group (outpatient) entering treatment and one restricted (prison) and two unrestricted groups (aftercare and outpatient) at end-of-treatment were contrasted. In addition TTM end-of-treatment profiles were tested as predictors of 12 month drinking outcomes (Profile Analysis). Although SEM did not indicate structural differences in the overall TTM construct model across setting types, there were factor structure differences on the confidence and temptation constructs at pre-treatment and in the factor structure of the behavioral processes at the end-of-treatment. For pre-treatment temptation and confidence, differences were found in the social situations factor loadings and in the variance for the confidence and temptation latent factors. For the end-of-treatment behavioral processes, differences across the restricted and unrestricted settings were identified in the counter-conditioning and stimulus control factor loadings. The TTM end-of-treatment profiles were not predictive of drinking outcomes in the prison sample. Both pre and post-treatment differences in structure across setting types involved constructs operationalized with behaviors that are limited for those in restricted settings. These studies suggest the TTM is a viable model for explicating addictive behavior change in restricted settings but calls for modification of subscale items that refer to specific behaviors and caution in interpreting the mean differences across setting types for problem drinkers. ^

Catalytic antibody response to the Staphylococcus aureus virulence factor Efb

Staphylococcus aureus is a globally prevalent pathogen that can cause a wide variety of acute and chronic diseases in both adults and children, in both immune susceptible populations and healthy individuals. Its ability to cause persistent infections has been linked to multiple immune evasion strategies, including Efb-mediated complement inhibition. As new multi-drug-resistant strains emerge, therapeutic alternatives to traditional antibiotics must be developed. These experiments assessed the ability of healthy patient immunoglobulin to cleave Efb and disable the complement-inhibitory properties of Efb in vitro. Levels of immunoglobulin-mediated Efb catalysis varied both between immunoglobulin isoform/isotype and between individuals. Serum IgG showed the strongest catalytic activity of the immunoglobulin isotypes tested. Additionally, IgG hydrolyzed the virulence factor in a way that enabled only minimal binding to the complement component C3b, effectively blocking Efb-mediated inhibition of complement lysis. Salivary IgA and serum IgM did not block Efb-mediated inhibition of complement. Catalytic IgG selectively cleaved Efb and showed no cleavage of a variety of other proteins tested. Catalytic activity of IgG was inhibited by serine protease inhibitors, but not by other protease inhibitors, suggesting a serine-protease mechanism of catalysis. It is proposed that varying concentrations and activity levels of catalytic IgG between healthy individuals and those with current or recurrent S. aureus infections in both adult and pediatric populations be studied in order to assess the potential effectiveness of passive immunization therapy with catalytic monoclonal IgG. ^

Ethnicity as a risk factor for diabetes incidence in a population of diagnosed hypertensives

Significant racial/ethnic differences exist in prevalence of hypertension (HTN) and non-insulin dependent diabetes mellitus (NIDDM). Hypertension is more common in diabetics than in non-diabetics, and an etiologic link between the two conditions has been proposed. Since there are few longitudinal studies of persons with both HTN and NIDDM, a retrospective cohort study was conducted to determine if ethnicity (Black, Hispanic (Mexican-American), and non-Hispanic White) was related to NIDDM incidence in a low-SES, multi-ethnic clinic population of diagnosed hypertensives. Two thousand nine hundred forty-one hypertensives free of NIDDM at baseline were followed for up to 10 years. Mean baseline age was 56 $\pm$ 12 years, M:F percent was 33:67, and Black:Hispanic:White percent was 63:17:20. There were 236 incident cases of NIDDM. In Cox proportional hazards analysis, the risk of developing NIDDM over 10 years was not related to ethnicity after controlling for significant covariates, including age, baseline blood glucose and body mass index (adjusted RR for Blacks compared to Whites =.82, 95 percent CI =.57-1.18; adjusted RR for Hispanics compared to Whites =.84, 95 percent CI =.51-1.38). This result contrasts with the increased risk of NIDDM among Blacks and Hispanics compared to Whites found in the general population. The study suggests that a diagnosis of hypertension equalizes the risk of developing NIDDM among the three ethnic groups. ^

A comparison between multi-proxy and historical data of drift-ice conditions on the East Greenland shelf

The reduction in sea ice along the SE Greenland coast during the last century has severely impacted ice-rafting to this area. In order to reconstruct ice-rafting and oceanographic conditions in the area of Denmark Strait during the last ~150 years, we conducted a multiproxy study on three short (20 cm) sediment cores from outer Kangerdlugssuaq Trough (~300 m water depth). The proxy-based data obtained have been compared with historical and instrumental data to gain a better understanding of the ice sheet-ocean interactions in the area. A robust chronology has been developed based on 210Pb and 137Cs measurements on core PO175GKC#9 (~66.2°N, 32°W) and expanded to the two adjacent cores based on correlations between calcite weight percent records. Our proxy records include sea-ice and phytoplankton biomarkers, and a variety of mineralogical determinations based on the <2 mm sediment fraction, including identification with quantitative x-ray diffraction, ice-rafted debris counts on the 63-150 µm sand fraction, and source identifications based on the composition of Fe oxides in the 45-250 µm fraction. A multivariate statistical analysis indicated significant correlations between our proxy records and historical data, especially with the mean annual temperature data from Stykkishólmur (Iceland) and the storis index (historical observations of sea-ice export via the East Greenland Current). In particular, the biological proxies (calcite weight percent, IP25, and total organic carbon %) showed significant linkage with the storis index. Our records show two distinct intervals in the recent history of the SE Greenland coast. The first of these (ad 1850-1910) shows predominantly perennial sea-ice conditions in the area, while the second (ad 1910-1990) shows more seasonally open water conditions.

(Table 1) Water column biogenic silica concentrations and Si isotopic composition during Marion Dufresne cruise MD166 off South Africa

Southern Ocean biogeochemical processes have an impact on global marine primary production and global elemental cycling, e.g. by likely controlling glacial-interglacial pCO2 variation. In this context, the natural silicon isotopic composition (d30Si) of sedimentary biogenic silica has been used to reconstruct past Si-consumption:supply ratios in the surface waters. We present a new dataset in the Southern Ocean from a IPY-GEOTRACES transect (Bonus-GoodHope) which includes for the first time summer d30Si signatures of suspended biogenic silica (i) for the whole water column at three stations and (ii) in the mixed layer at seven stations from the subtropical zone up to the Weddell Gyre. In general, the isotopic composition of biogenic opal exported to depth was comparable to the opal leaving the mixed layer and did not seem to be affected by any diagenetic processes during settling, even if an effect of biogenic silica dissolution cannot be ruled out in the northern part of the Weddell Gyre. We develop a mechanistic understanding of the processes involved in the modern Si-isotopic balance, by implementing a mixed layer model. We observe that the accumulated biogenic silica (sensu Rayleigh distillation) should satisfactorily describe the d30Si composition of biogenic silica exported out of the mixed layer, within the limit of the current analytical precision on the d30Si. The failures of previous models (Rayleigh and steady state) become apparent especially at the end of the productive period in the mixed layer, when biogenic silica production and export are low. This results from (1) a higher biogenic silica dissolution:production ratio imposing a lower net fractionation factor and (2) a higher Si-supply:Si-uptake ratio supplying light Si-isotopes into the mixed layer. The latter effect is especially expressed when the summer mixed layer becomes strongly Si-depleted, together with a large vertical silicic acid gradient, e.g. in the Polar Front Zone and at the Polar Front.

Determinación de la actividad de la óxido nítrico sintetasa endotelial y del factor NF-kB, en la piel del paciente con pseudoangiomatosis eruptiva : informe preliminar

La pseudoangiomatosis eruptiva se caracteriza por la aparición brusca de múltiples pápulas eritematosas, asintomáticas, rodeadas de un halo blanquecino, con remisión espontánea. Histológicamente se observa dilatación vascular con escaso infiltrado inflamatorio. Su etiología permanece incierta a pesar de ser relacionada con virus o picaduras de insectos. Basados en el compromiso vascular, el objetivo del trabajo fue investigar la actividad de la enzima endotelial oxido nítrico sintetasa (eNOS) y la expresión del factor NF-kB por inmunohistoquimica en un intento de esclarecer su patogenia. Material y métodos: Se estudiaron diez pacientes con diagnóstico clínico de pseudoangiomatosis eruptiva (PAE) que presentaron la dermatosis en forma epidémica. Se realizaron biopsias teñidas con Hematoxilina-Eosina y Tricrómico de Masson. Se efectuó estudio virológico de los pacientes Nª 4, 9 y 10 mediante determinaciones serológicas para echovirus, enterovirus, citomegalovirus, parvovirus B19 y hepatitis A, B y C. En cinco pacientes se obtuvo material para determinación de eNOS y NF-kB. Resultados: Todos los pacientes, 5 hombres y 5 mujeres presentaron pápulas eritematosas rodeadas por un halo blanquecino, especialmente en las extremidades, alrededor de las rodillas. Histológicamente mostraron vasos dilatados y células endoteliales prominentes con un infiltrado discreto perivascular. Todos los estudios serológicos fueron negativos. La actividad de eNOS fue significativamente menor comparada con la piel normal (p= 0,002) y la expresión de NF- ĸB fue fuertemente positiva en los vasos de la dermis papilar y reticular. Conclusiones: Todos los pacientes fueron afectados en verano, por lo que la picadura del mosquito debe ser considerada como un factor etiológico. La baja expresión de eNOS está relacionada con la vasodilatación y la expresión aumentada de NF-ĸB confirma que el proceso es de tipo inflamatorio.

Multi-proxy analyses of sediment cores from the Pakistan continental margin

Late Holocene laminated sediments from a core transect centred in the oxygen minimum zone (OMZ) impinging at the continental slope off Pakistan indicate stable oxygen minimum conditions for the past 7000 calendar years. High SW-monsoon-controlled biological productivity and enhanced organic matter preservation during this period is reflected in high contents of total organic carbon (TOC) and redox-sensitive elements (Ni, V), as well as by a low-diversity, high-abundance benthic foraminiferal Buliminacea association and high abundance of the planktonic species Globigerina bulloides indicative of upwelling conditions. Surface-water productivity was strongest during SW monsoon maxima. Stable OMZ conditions (reflected by laminated sediments) were found also during warm interstadial events (Preboreal, Bølling-Allerød, and Dansgaard-Oeschger events), as well as during peak glacial times (17-22.5 ka, all ages in calendar years). Sediment mass accumulation rates were at a maximum during the Preboreal and Younger Dryas periods due to strong riverine input and mobilisation of fine-grained sediment coinciding with rapid deglacial sea-level rise, whereas eolian input generally decreased from glacial to interglacial times. In contrast, the occurrence of bioturbated intervals from 7 to 10.5 ka (early Holocene), in the Younger Dryas (11.7-13 ka), from 15 to 17 ka (Heinrich event 1) and from 22.5 to 25 ka (Heinrich event 2) suggests completely different conditions of oxygen-rich bottom waters, extremely low mass and organic carbon accumulation rates, a high-diversity benthic fauna, all indicating lowered surface-water productivity. During these intervals the OMZ was very poorly developed or absent and a sharp fall of the aragonite compensation depth favoured the preservation of pteropods. The abundance of lithogenic proxies suggests aridity and wind transport by northwesterly or northeasterly winds during these periods coinciding with the North Atlantic Heinrich events and dust peaks in the Tibetan Loess records. The correlation of the monsoon-driven OMZ variability in the Arabian Sea with the rapid climatic fluctuations in the high northern latitudes suggests a close coupling between the climates of the high and low latitudes at a global scale.

Multi-year high-frequency current and water quality in-situ observations at the Guadiana Estuary

High-frequency data collected continuously over a multiyear time frame are required for investigating the various agents that drive ecological and hydrodynamic processes in estuaries. Here, we present water quality and current in-situ observations from a fixed monitoring station operating from 2008 to 2014 in the lower Guadiana Estuary, southern Portugal (37°11.30' N, 7°24.67' W). The data were recorded by a multi-parametric probe providing hourly records (temperature, salinity, chlorophyll, dissolved oxygen, turbidity, and pH) at a water depth of ~1 m, and by a bottom-mounted acoustic Doppler current profiler measuring the pressure, near-bottom temperature, and flow velocity through the water column every 15 min. The time-series data, in particular the probe ones, present substantial gaps arising from equipment failure and maintenance, which are ineluctable with this type of observations in harsh environments. However, prolonged (months-long) periods of multi-parametric observations during contrasted external forcing conditions are available. The raw data are reported together with flags indicating the quality status of each record. River discharge data from two hydrographic stations located near the estuary head are also provided to support data analysis and interpretation.