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We present a novel high-resolution inverse modelling system (“FLEXVAR”) based on FLEXPART-COSMO back trajectories driven by COSMO meteorological fields at 7 km×7 km resolution over the European COSMO-7 domain and the four-dimensional variational (4DVAR) data assimilation technique. FLEXVAR is coupled offline with the global inverse modelling system TM5-4DVAR to provide background mole fractions (“baselines”) consistent with the global observations assimilated in TM5-4DVAR. We have applied the FLEXVAR system for the inverse modelling of European CH4 emissions in 2018 using 24 stations with in situ measurements, complemented with data from five stations with discrete air sampling (and additional stations outside the European COSMO-7 domain used for the global TM5-4DVAR inversions). The sensitivity of the FLEXVAR inversions to different approaches to calculate the baselines, different parameterizations of the model representation error, different settings of the prior error covariance parameters, different prior inventories, and different observation data sets are investigated in detail. Furthermore, the FLEXVAR inversions are compared to inversions with the FLEXPART extended Kalman filter (“FLExKF”) system and with TM5-4DVAR inversions at 1∘×1∘ resolution over Europe. The three inverse modelling systems show overall good consistency of the major spatial patterns of the derived inversion increments and in general only relatively small differences in the derived annual total emissions of larger country regions. At the same time, the FLEXVAR inversions at 7 km×7 km resolution allow the observations to be better reproduced than the TM5-4DVAR simulations at 1∘×1∘. The three inverse models derive higher annual total CH4 emissions in 2018 for Germany, France, and BENELUX compared to the sum of anthropogenic emissions reported to UNFCCC and natural emissions estimated from the Global Carbon Project CH4 inventory, but the uncertainty ranges of top-down and bottom-up total emission estimates overlap for all three country regions. In contrast, the top-down estimates for the sum of emissions from the UK and Ireland agree relatively well with the total of anthropogenic and natural bottom-up inventories.

The outer membrane (OM) of Gram-negative bacteria efficiently protects from harmful environmental stresses such as antibiotics, disinfectants, or dryness. The main constituents of the OM are integral OM β-barrel proteins (OMPs). In Gram-negative bacteria such as Escherichia coli, Yersinia enterocolitica, and Pseudomonas aeruginosa, the insertion of OMPs depends on a sophisticated biogenesis pathway. This comprises the SecYEG translocon, which enables inner membrane (IM) passage; the chaperones SurA, Skp, and DegP, which facilitate the passage of β-barrel OMPs through the periplasm; and the β-barrel assembly machinery (BAM), which facilitates insertion into the OM. In E. coli, Y. enterocolitica, and P. aeruginosa, the deletion of SurA is particularly detrimental and leads to a loss of OM integrity, sensitization to antibiotic treatment, and reduced virulence. In search of targets that could be exploited to develop compounds that interfere with OM integrity in Acinetobacter baumannii, we employed the multidrug-resistant strain AB5075 to generate single gene knockout strains lacking individual periplasmic chaperones. In contrast to E. coli, Y. enterocolitica, and P. aeruginosa, AB5075 tolerates the lack of SurA, Skp, or DegP with only weak mutant phenotypes. While the double knockout strains ΔisurA/iΔiskp/iand ΔisurA/iΔidegP/iare conditionally lethal in E. coli, all double deletions were well tolerated by AB5075. Strikingly, even a triple-knockout strain of AB5075, lackingisurA/i,iskp/i, andidegP/i, was viable.bIMPORTANCE/bAcinetobacter baumannii is a major threat to human health due to its ability to persist in the hospital environment, resistance to antibiotic treatment, and ability to deploy multiple and redundant virulence factors. In a rising number of cases, infections with multidrug-resistant A. baumannii end up fatally, because all antibiotic treatment options fail. Thus, novel targets have to be identified and alternative therapeutics have to be developed. The knockout of periplasmic chaperones has previously proven to significantly reduce virulence and even break antibiotic resistance in other Gram-negative pathogens. Our study in A. baumannii demonstrates how variable the importance of the periplasmic chaperones SurA, Skp, and DegP can be and suggests the existence of mechanisms allowing A. baumannii to cope with the lack of the three periplasmic chaperones.

We present a novel high-resolution inverse modelling system ("FLEXVAR") based on FLEXPART-COSMO back trajectories driven by COSMO meteorological fields at 7 km × 7 km resolution over the European COSMO-7 domain and the four-dimensional variational (4DVAR) data assimilation technique. FLEXVAR is coupled offline with the global inverse modelling system TM5-4DVAR to provide background mole fractions ("baselines") consistent with the global observations assimilated in TM5-4DVAR. We have applied the FLEXVAR system for the inverse modelling of European emissions in 2018 using 24 stations with in situ measurements, complemented with data from five stations with discrete air sampling (and additional stations outside the European COSMO-7 domain used for the global TM5-4DVAR inversions). The sensitivity of the FLEXVAR inversions to different approaches to calculate the baselines, different parameterizations of the model representation error, different settings of the prior error covariance parameters, different prior inventories and different observation data sets are investigated in detail. Furthermore, the FLEXVAR inversions are compared to inversions with the FLEXPART extended Kalman filter ("FLExKF") system and with TM5-4DVAR inversions at 1° × 1° resolution over Europe. The three inverse modelling systems show overall good consistency of the major spatial patterns of the derived inversion increments and in general only relatively small differences in the derived annual total emissions of larger country regions. At the same time, the FLEXVAR inversions at 7 km × 7 km resolution allow to better reproduce the observations than the TM5 4DVAR simulations at 1° × 1°. The three inverse models derive higher annual total CH4 emissions in 2018 for Germany, France and BENELUX compared to the sum of anthropogenic emissions reported to UNFCCC and natural emissions estimated from the Global Carbon Project CH4 inventory, but the uncertainty ranges of top-down and bottom-up total emission estimates overlap for all three country regions. In contrast, the top-down estimates for the sum of emissions from the United Kingdom and Ireland agree relatively well with the total of anthropogenic and natural bottom-up inventories.

A series of derivatives of the substrate amino acid l-tryptophan have been investigated for inhibition of the L-type amino acid transporter LAT1 (SLC7A5), which is an emerging target in anticancer drug discovery. Of the four isomeric 4-, 5-, 6-, or 7-benzyloxy-l-tryptophans, the 5-substituted derivative was the most potent, with an IC50 of 19 mu M for inhibition of [H-3]-l-leucine uptake into HT-29 human colon carcinoma cells. The replacement of the carboxy group in 5-benzyloxy-l-tryptophan by a bioisosteric tetrazole moiety led to a complete loss in potency. Likewise, the corresponding tetrazolide derived from l-tryptophan itself was found to be neither a substrate nor an inhibitor of the transporter. Increasing the steric bulk at the 5-position, while reasonably well tolerated in some cases, did not result in an improvement in potency. At the same time, none of these derivatives was found to be a substrate for LAT1-mediated transport., ChemMedChem, 17 (17), ISSN:1860-7179, ISSN:1860-7187

Menschen mit Migrationshintergrund stosen im Gesundheitswesen haufig auf eine Vielzahl von Barrieren, wodurch die medizinische Versorgung nachteilig beeinflusst werden kann. Auch die Augenheilkunde sieht sich in ihrem klinischen Alltag vermehrt mit dieser Diversitatsthematik konfrontiert. Die unterschiedlichen Aspekte der Diversitat und ihre Relevanz fur die Patientenversorgung in der Augenheilkunde sollen dargestellt werden. Der Beitrag bietet eine Literaturubersicht aus PubMed und eigene Erfahrungen. Fur die optimale Umsetzung interkultureller Kompetenz muss das Bewusstsein uber die eigenen Wertevorstellungen und Normen vorhanden sein, um dieses wiederum optimal zu den Normen und Werten der Migranten in Beziehung setzen zu konnen. Das Ziel von Diversitat in der Medizin ist, jeden Patienten als Ganzes zu betrachten. Ausschlaggebend ist hierbei, eine empathische Haltung gegenuber der Individualitat und der kulturellen Lebenseinstellung der Patienten einzunehmen. Ein gestarktes Wohlbefinden der Patienten geht einher mit der Bereitschaft, kulturelle Besonderheiten und religiose Normen und Werte im Rahmen einer guten Beziehung zwischen Arzten, Pflegepersonal und Patienten mit in die Behandlung einfliesen zu lassen. Hierdurch wird letztendlich die positive Grundeinstellung erhoht und eine aktive Heilung, auch in der Augenheilkunde unterstutzt. Das Bewusstsein und die Akzeptanz der Bedeutung von Diversitat erleichtern die klinische Patientenversorgung in der Augenheilkunde.

We present a statistical framework to identify regional signals in station-based CO2 time series with minimal local influence. A curve-fitting function is first applied to the detrended time series to derive a harmonic describing the annual CO2 cycle. We then combine a polynomial fit to the data with a short-term residual filter to estimate the smoothed cycle and define a seasonally adjusted noise component, equal to 2 standard deviations of the smoothed cycle about the annual cycle. Spikes in the smoothed daily data which surpass this ±2σ threshold are classified as anomalies. Examining patterns of anomalous behavior across multiple sites allows us to quantify the impacts of synoptic-scale atmospheric transport events and better understand the regional carbon cycling implications of extreme seasonal occurrences such as droughts.

The project OPTIMAP is at the current stage a joint initiative of BGIC, GSSAC and DGFI-TUM. The development of an operational tool for ionospheric mapping and prediction is the main goal of the project.The ionosphere is a dispersive medium. Therefore, GNSS signals are refracted while they pass through the ionosphere. The magnitude of the refraction rate depends on the frequencies of the transmitted GNSS signals. The ionospheric disturbance on the GNSS signals paves the way of extracting Vertical Total Electron Content (VTEC) information of the ionosphere.In OPTIMAP, the representation of the global and regional VTEC signal is based on localizing B-spline basis functions. For global VTEC modeling, polynomial B-splines are employed to represent the latitudinal variations, whereas trigonometric B-splines are used for the longitudinal variations. The regional modeling in OPTIMAP relies on a polynomial B-spline representation for both latitude and longitude.The VTEC modeling in this study relies on both a global and a regional sequential estimator (Kalman filter) running in a parallel mode. The global VTEC estimator produces VTEC maps based on data from GNSS receiver stations which are mainly part of the global real-time IGS network. The global estimator relies on additional VTEC information obtained from a forecast procedure using ultra-rapid VTEC products. The regional estimator makes use of the VTEC product of the real-time global estimator as background information and generates high-resolution VTEC maps using real-time data from the EUREF Permanent GNSS Network. EUREF provides a network of very dense GNSS receivers distributed alongside Europe.Carrier phase observations acquired from GPS and GLONASS, which are transmitted in accordance with RTCM standard, are used for real-time regional VTEC modeling. After the acquisition of GNSS data, cycle slips for each satellite-receiver pair are detected, and ionosphere observations are constructed via the linear combination of carrier-phase observations in the data pre-processing step. The unknown B-spline coefficients, as well as the biases for each phase-continuous arc belonging to each receiver-satellite pair, are simultaneously estimated in the Kalman filter.Within this study, we compare the performance of regional and global VTEC products generated in real-time using the well-known dSTEC analysis.

The placenta supplies the foetus with critical nutrients such as essential amino acids (AA, eg leucine) for development and growth. It also represents a cellular barrier which is formed by a polarized, differentiated syncytiotrophoblast (STB) monolayer. Active Na+‐independent leucine transport across the placenta is mainly attributed to the System L transporters LAT1/SLC7A5 and LAT2/SLC7A8. This study explored the influence of trophoblast differentiation on the activity of LAT1/LAT2 and the relevance of LAT1/LAT2 in leucine uptake and transfer in trophoblasts by applying specific small molecule inhibitors (JPH203/JG336/JX009). L‐leucine uptake (total dose = 167 μmol/L) was sensitive to LAT1‐specific inhibition by JPH203 (EC50 = 2.55 µmol/L). The inhibition efficiency of JPH203 was increased by an additional methoxy group in the JPH203‐derivate JG336 (EC50 = 1.99 µmol/L). Interestingly, JX009 showed efficient System L inhibition (EC50 = 2.35 µmol/L) and was the most potent inhibitor of leucine uptake in trophoblasts. The application of JPH203 and JX009 in Transwell®‐based leucine transfer revealed LAT1 as the major accumulative transporter at the apical membrane, but other System L transporters such as LAT2 as rate‐limiting for leucine efflux across the basal membrane. Therefore, differential specificity of the applied inhibitors allowed for estimation of the contribution of LAT1 and LAT2 in materno‐foetal AA transfer and their potential impact in pregnancy diseases associated with impaired foetal growth.

Streptococcus pneumoniae is a major human pathogen, causing pneumonia and sepsis. Genetic components strongly influence host responses to pneumococcal infections, but the responsible loci are unknown. We have previously identified a locus on mouse chromosome 7 from a susceptible mouse strain, CBA/Ca, to be crucial for pneumococcal infection. Here we identify a responsible gene, Cd22, which carries a point mutation in the CBA/Ca strain, leading to loss of CD22 on B cells. CBA/Ca mice and gene-targeted CD22-deficient mice on a C57BL/6 background are both similarly susceptible to pneumococcal infection, as shown by bacterial replication in the lungs, high bacteremia and early death. After bacterial infections, CD22-deficient mice had strongly reduced B cell populations in the lung, including GM-CSF producing, IgM secreting innate response activator B cells, which are crucial for protection. This study provides striking evidence that CD22 is crucial for protection during invasive pneumococcal disease., Author summary Streptococcus pneumoniae (known as the pneumococcus) is a human bacterial pathogen responsible for diseases such as pneumonia and sepsis, that cause illness and death in millions of individuals. Susceptibility to pneumococcal infections is associated with genetic components that strongly influence how infected individuals respond to infection, but little is known about the causal gene(s) and the mechanisms of control of the infection. In previous studies we have found strong differences in susceptibility and resistance to pneumococcal infections between mouse strains. In this study we identified a gene, the Cd22 gene, that controls resistance to pneumococcal infection. Mice without the B-cell specific CD22 protein were much more susceptible to infection with S. pneumoniae. We could show that a protective population of B cells that migrates to the lung during pneumococcal infection is missing in Cd22-deficient mice. The study shows to a new role for CD22 and indicates a new potential target for treatment of pneumococcal infections.

The project OPTIMAP is at the current stage a joint initiative of BGIC, GSSAC and DGFI-TUM. The development of an operational tool for ionospheric mapping and prediction is the main goal of the project.The ionosphere is a dispersive medium. Therefore, GNSS signals are refracted while they pass through the ionosphere. The magnitude of the refraction rate depends on the frequencies of the transmitted GNSS signals. The ionospheric disturbance on the GNSS signals paves the way of extracting Vertical Total Electron Content (VTEC) information of the ionosphere.In OPTIMAP, the representation of the global and regional VTEC signal is based on localizing B-spline basis functions. For global VTEC modeling, polynomial B-splines are employed to represent the latitudinal variations, whereas trigonometric B-splines are used for the longitudinal variations. The regional modeling in OPTIMAP relies on a polynomial B-spline representation for both latitude and longitude.The VTEC modeling in this study relies on both a global and a regional sequential estimator (Kalman filter) running in a parallel mode. The global VTEC estimator produces VTEC maps based on data from GNSS receiver stations which are mainly part of the global real-time IGS network. The global estimator relies on additional VTEC information obtained from a forecast procedure using ultra-rapid VTEC products. The regional estimator makes use of the VTEC product of the real-time global estimator as background information and generates high-resolution VTEC maps using real-time data from the EUREF Permanent GNSS Network. EUREF provides a network of very dense GNSS receivers distributed alongside Europe.Carrier phase observations acquired from GPS, GLONASS and GALILEO constellations, which are transmitted in accordance with RTCM standard, are used for real-time regional VTEC modeling. After the acquisition of GNSS data, cycle slips for each satellite-receiver pair are detected, and ionosphere observations are constructed via the linear combination of carrier-phase observations in the data pre-processing step. The unknown B-spline coefficients, as well as the biases for each phase-continuous arc belonging to each receiver-satellite pair, are simultaneously estimated in the Kalman filter.Within this study, we compare the performance of regional and global VTEC products generated in real-time using the well-known dSTEC analysis.

Embodiment approaches to cognition and emotion have put forth the idea that the way we think and talk about affective events often recruits spatial information that stems, to some extent, from our bodily experiences. For example, metaphorical expressions such as “being someone’s right hand” or “leaving something bad behind” convey affectivity associated with the lateral and sagittal dimensions of space. Action tendencies associated with affect such as the directional fluency of hand movements (dominant right hand-side – positive; non-dominant left hand-side – negative) and approach-avoidance behaviors (forward – positive; backwards – negative) might be mechanisms supporting such associations. Against this background, experimental research has investigated whether positive and negative words are freely allocated into space (e.g., close or far from one’s body) or resonate with congruent (vs. incongruent) predefined manual actions usually performed by joysticks or button presses (e.g., positive – right; negative – left, or vice versa). However, to date, it is unclear how the processing of affective concepts resonate with directional actions of the whole body, the more if such actions are performed freely within a context enabling both, lateral and sagittal movements. Accordingly, 67 right-handed participants were to freely step on an 8-response pad (front, back, right, left, front-right, front-left, back-right, or back-left) after being presented in front of them valence-laden personal life-events submitted before the task (e.g., words or sentences such as “graduation” or “birth of a child”). The most revealing finding of this study indicates that approach-avoidance behaviors and space-valence associations across laterality are interwoven during whole body step actions: Positive events induced steps highly biased to front-right whereas negative events induced steps highly biased to back-left.

People with an immigration background often encounter a multitude of barriers in the healthcare system, which may have negative impacts on medical care. Ophthalmology is also coming under ever-increasing pressure from this diversity issue in the clinical routine.This review outlines the different aspects of diversity and their significance for the patient care in ophthalmology.The study is based on a PubMed literature review and own experiences.Optimal implementation of intercultural expertise requires awareness of one's own values and norms in order to be able to relate these to the norms and values of migrants in an optimal manner. The goal of diversity in medicine includes a holistic approach to view each patient as a whole. It is crucial to adopt an empathetic attitude towards the individuality and cultural attitudes of patients. An enhanced well-being of the patients goes hand in hand with the willingness to incorporate cultural peculiarities as well as religious norms and values into the treatment within the framework of a good relationship between doctors, nursing staff and patients. This ultimately increases the positive basic attitude and supports active healing, also in the discipline of ophthalmology.Awareness and acceptance of the significance of diversity facilitate the clinical care of patients in ophthalmology.HINTERGRUND: Menschen mit Migrationshintergrund stoßen im Gesundheitswesen häufig auf eine Vielzahl von Barrieren, wodurch die medizinische Versorgung nachteilig beeinflusst werden kann. Auch die Augenheilkunde sieht sich in ihrem klinischen Alltag vermehrt mit dieser Diversitätsthematik konfrontiert.Die unterschiedlichen Aspekte der Diversität und ihre Relevanz für die Patientenversorgung in der Augenheilkunde sollen dargestellt werden.Der Beitrag bietet eine Literaturübersicht aus PubMed und eigene Erfahrungen.Für die optimale Umsetzung interkultureller Kompetenz muss das Bewusstsein über die eigenen Wertevorstellungen und Normen vorhanden sein, um dieses wiederum optimal zu den Normen und Werten der Migranten in Beziehung setzen zu können. Das Ziel von Diversität in der Medizin ist, jeden Patienten als Ganzes zu betrachten. Ausschlaggebend ist hierbei, eine empathische Haltung gegenüber der Individualität und der kulturellen Lebenseinstellung der Patienten einzunehmen. Ein gestärktes Wohlbefinden der Patienten geht einher mit der Bereitschaft, kulturelle Besonderheiten und religiöse Normen und Werte im Rahmen einer guten Beziehung zwischen Ärzten, Pflegepersonal und Patienten mit in die Behandlung einfließen zu lassen. Hierdurch wird letztendlich die positive Grundeinstellung erhöht und eine aktive Heilung, auch in der Augenheilkunde unterstützt.Das Bewusstsein und die Akzeptanz der Bedeutung von Diversität erleichtern die klinische Patientenversorgung in der Augenheilkunde.

Memory B cells are long-lived components of humoral immunological memory. Müller-Winkler et al. show that the survival of MBCs is critically dependent on signaling from the BCR, BAFF, BAFFR, and IKK2 kinase., Memory B cells (MBCs) are long-lived cells that form a critical part of immunological memory, providing rapid antibody responses to recurring infections. However, very little is known about signals controlling MBC survival. Previous work has shown that antigen is not required for MBC survival, but a requirement for the B cell antigen receptor (BCR) has not been tested. Other studies have shown that, unlike naive B cells, MBCs do not express BAFFR and their survival is independent of BAFF, the ligand for BAFFR. Here, using inducible genetic ablation, we show that survival of MBCs is critically dependent on the BCR and on signaling through the associated CD79A protein. Unexpectedly, we found that MBCs express BAFFR and that their survival requires BAFF and BAFFR; hence, loss of BAFF or BAFFR impairs recall responses. Finally, we show that MBC survival requires IKK2, a kinase that transduces BAFFR signals. Thus, MBC survival is critically dependent on signaling from BCR and BAFFR.

Menschen mit Migrationshintergrund stosen im Gesundheitswesen haufig auf eine Vielzahl von Barrieren, wodurch die medizinische Versorgung nachteilig beeinflusst werden kann. Auch die Augenheilkunde sieht sich in ihrem klinischen Alltag vermehrt mit dieser Diversitatsthematik konfrontiert. Die unterschiedlichen Aspekte der Diversitat und ihre Relevanz fur die Patientenversorgung in der Augenheilkunde sollen dargestellt werden. Der Beitrag bietet eine Literaturubersicht aus PubMed und eigene Erfahrungen. Fur die optimale Umsetzung interkultureller Kompetenz muss das Bewusstsein uber die eigenen Wertevorstellungen und Normen vorhanden sein, um dieses wiederum optimal zu den Normen und Werten der Migranten in Beziehung setzen zu konnen. Das Ziel von Diversitat in der Medizin ist, jeden Patienten als Ganzes zu betrachten. Ausschlaggebend ist hierbei, eine empathische Haltung gegenuber der Individualitat und der kulturellen Lebenseinstellung der Patienten einzunehmen. Ein gestarktes Wohlbefinden der Patienten geht einher mit der Bereitschaft, kulturelle Besonderheiten und religiose Normen und Werte im Rahmen einer guten Beziehung zwischen Arzten, Pflegepersonal und Patienten mit in die Behandlung einfliesen zu lassen. Hierdurch wird letztendlich die positive Grundeinstellung erhoht und eine aktive Heilung, auch in der Augenheilkunde unterstutzt. Das Bewusstsein und die Akzeptanz der Bedeutung von Diversitat erleichtern die klinische Patientenversorgung in der Augenheilkunde.

Siglec-G, a member of the sialic acid–binding Ig-like lectin (Siglec) family, is expressed on B cell and dendritic cell surfaces. It acts as an inhibitory coreceptor and modulates B cell activation, especially on B1 cells, as Siglec-G–deficient mice show mainly a B1 cell–restricted phenotype resulting in increased B1 cell numbers. Although higher B1 cell numbers are discussed to be associated with autoimmunity, loss of Siglec-G does not result in autoimmune disease in BALB/c mice. However, there is evidence from Siglec-G × CD22 double-deficient mice and Siglec-G−/− mice on an autoimmune-prone MRL/lpr background that Siglec-G is important to maintain tolerance in B cells. In this study, we analyzed the role of Siglec-G in induction and maintenance of B cell tolerance on C57BL/6 background and in the FcγRIIb-deficient background. We find that aging Siglec-G–deficient and Siglec-G × FcγRIIb double-deficient mice develop an autoimmune phenotype with elevated autoantibody levels and mild glomerulonephritis. Aging Siglec-G–deficient mice have elevated numbers of plasma cells and germinal center B cells, as well as a higher number of activated CD4 T cells, which likely all contribute to autoantibody production. Additional loss of the inhibitory receptor FcγRIIb in Siglec-G−/− mice does not result in exacerbation of disease. These results indicate that Siglec-G is important to maintain tolerance in B cells and prevent autoimmunity.

Summary Background Friedreich's ataxia is a rare autosomal recessive neurodegenerative disorder. Here we report cross-sectional baseline data to establish the biological and clinical characteristics for a prospective, international, European Friedreich's ataxia database registry. Methods Within the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) framework, we assessed a cohort of patients with genetically confirmed Friedreich's ataxia. The primary outcome measure was the Scale for the Assessment and Rating of Ataxia (SARA) and secondary outcome measures were the Inventory of Non-Ataxia Signs (INAS), the performance-based coordination test Spinocerebellar Ataxia Functional Index (SCAFI), the neurocognitive phonemic verbal fluency test, and two quality-of-life measures: the activities of daily living (ADL) part of the Friedreich's Ataxia Rating Scale and EQ-5D. The Friedreich's ataxia cohort was subdivided into three groups: early disease onset (≤14 years), intermediate onset (15–24 years), and late onset (≥25 years), which were compared for clinical characteristics and outcome measures. We used linear regression analysis to estimate the annual decline of clinical outcome measures based on disease duration. This study is registered with ClinicalTrials.gov, number NCT02069509. Findings We enrolled 592 patients with genetically confirmed Friedreich's ataxia between Sept 15, 2010, and April 30, 2013, at 11 sites in seven European countries. Age of disease onset was inversely correlated with the number of GAA repeats in the frataxin ( FXN ) gene: every 100 GAA repeats on the smaller repeat allele was associated with a 2·3 year (SE 0·2) earlier onset. Regression analyses showed significant estimated annual worsening of SARA (regression coefficient 0·86 points [SE 0·05], INAS (0·14 points [0·01]), SCAFI Z scores (−0·09 [0·01]), verbal fluency (−0·34 words [0·07]), and ADL (0·64 points [0·04]) during the first 25 years of disease; the regression slope for health-related quality-of-life state from EQ-5D was not significant (−0·33 points [0·18]). For SARA, the predicted annual rate of worsening was significantly higher in early-onset patients (n=354; 1·04 points [0·13]) and intermediate-onset patients (n=137; 1·17 points [0·22]) than in late-onset patients (n=100; 0·56 points [0·10]). Interpretation The results of this cross-sectional baseline analysis of the EFACTS cohort suggest that earlier disease onset is associated with larger numbers of GAA repeats and more rapid disease progression. The differential estimated progression of ataxia symptoms related to age of onset have implications for the design of clinical trials in Friedreich's ataxia, for which SARA might be the most suitable measure to monitor disease progression. Funding European Commission.

This demo presents the multidisciplinary development of the enrichment program “Listening to Math: Kids compose with LEGO”, that aims at fostering the math and music skills of gifted primary school students. In this program LEGO bricks are used as tangible representation of music notes. The so called LEGO-Table, a tabletop computer, translates patterns made out of bricks into piano melodies. We will present the finished program, address our experiences made during the project, and we will also give some insights on the implementation and evaluation of the program. Functions of the LEGO-Table will be demonstrated interactively on a tablet.

BackgroundSensitive outcome measures for clinical trials on cerebellar ataxias are lacking. Most cerebellar ataxias progress very slowly and quantitative measurements are required to evaluate cerebellar dysfunction.MethodsWe evaluated two scales for rating cerebellar ataxias: the Composite Cerebellar Functional Severity (CCFS) Scale and Scale for the Assessment and Rating of Ataxia (SARA), in patients with spinocerebellar ataxia (SCA) and controls. We evaluated these scales for different diseases and investigated the factors governing the scores obtained. All patients were recruited prospectively.ResultsThere were 383 patients with Friedreich’s ataxia (FRDA), 205 patients with SCA and 168 controls. In FRDA, 31% of the variance of cerebellar signs with the CCFS and 41% of that with SARA were explained by disease duration, age at onset and the shorter abnormal repeat in the FXN gene. Increases in CCFS and SARA scores per year were lower for FRDA than for SCA (CCFS index: 0.123±0.123 per year vs 0.163±0.179, PConclusionsCerebellar dysfunction, as measured with the CCFS and SARA scales, was more severe in FRDA than in patients with SCA, but with lower progression indexes, within the limits of these types of indexes. Ceiling effects may occur at late stages, for both scales. The CCFS scale is rater-independent and could be used in a multicentre context, as it is simple, rapid and fully automated.Trial registration numberClinicalTrials.gov: NCT02069509.

Signaling through the BCR can drive B cell activation and contribute to B cell differentiation into Ab-secreting plasma cells. The positive BCR signal is counterbalanced by a number of membrane-localized inhibitory receptors that limit B cell activation and plasma cell differentiation. Deficiencies in these negative signaling pathways may cause autoantibody generation and autoimmune disease in both animal models and human patients. We have previously shown that the transcription factor Ets1 can restrain B cell differentiation into plasma cells. In this study, we tested the roles of the BCR and inhibitory receptors in controlling the expression of Ets1 in mouse B cells. We found that Ets1 is downregulated in B cells by BCR or TLR signaling through a pathway dependent on PI3K, Btk, IKK2, and JNK. Deficiencies in inhibitory pathways, such as a loss of the tyrosine kinase Lyn, the phosphatase Src homology region 2 domain–containing phosphatase 1 (SHP1) or membrane receptors CD22 and/or Siglec-G, result in enhanced BCR signaling and decreased Ets1 expression. Restoring Ets1 expression in Lyn- or SHP1-deficient B cells inhibits their enhanced plasma cell differentiation. Our findings indicate that downregulation of Ets1 occurs in response to B cell activation via either BCR or TLR signaling, thereby allowing B cell differentiation and that the maintenance of Ets1 expression is an important function of the inhibitory Lyn → CD22/SiglecG → SHP1 pathway in B cells.

A high proportion of peripheral human B cells produce polyreactive or autoreactive antibodies, which indicates that they have escaped the elimination of self-reactive B cells in the bone marrow. CD22 and Siglec-G are two inhibitory receptors of the sialic-acid-binding immunoglobulin-like lectin (Siglec) family that inhibit the B-cell antigen receptor (BCR) signal. The ability of these two receptors to bind sialic acids is crucial for regulating inhibition and inducing tolerance to self-antigens. Sialylated glycans are usually absent on microbes (although several pathogenic microorganisms have evolved strategies to mimic self by decorating their surfaces with sialic acids) but abundant in higher vertebrates and might, therefore, provide an important tolerogenic signal. Combined Siglec-G deficiency and CD22 deficiency leads to spontaneous autoimmunity in mice, and mutations in an enzyme that modifies Siglec ligands are directly linked to several autoimmune diseases in humans. New data show that high-affinity ligands for CD22 and Siglec-G can be used to induce antigen-specific B-cell tolerance, which might be one strategy for the treatment of autoimmune diseases in the future.

Background Erythropoietin (EPO) derivatives have been found to increase frataxin levels in Friedreich's ataxia (FRDA) in vitro. This multicenter, double-blind, placebo-controlled, phase II clinical trial aimed to evaluate the safety and tolerability of Lu AA24493 (carbamylated EPO; CEPO). Methods Thirty-six ambulatory FRDA patients harboring >400 GAA repeats were 2:1 randomly assigned to either CEPO in a fixed dose (325 µg thrice-weekly) or placebo. Safety and tolerability were assessed up to 103 days after baseline. Secondary outcome measures of efficacy (exploration of biomarkers and ataxia ratings) were performed up to 43 days after baseline. Results All patients received six doses of study medication. Adverse events were equally distributed between CEPO and placebo. There was no evidence for immunogenicity of CEPO after multiple dosing. Biomarkers, such as frataxin, or measures for oxidative stress and ataxia ratings did not differ between CEPO and placebo. Conclusion CEPO was safe and well tolerated in a 2-week treatment phase. Secondary outcome measures remained without apparent difference between CEPO and placebo. © 2014 International Parkinson and Movement Disorder Society

A high proportion of human B cells carry B-cell receptors (BCRs) that are autoreactive. Inhibitory receptors such as CD22 can downmodulate autoreactive BCR responses. With its extracellular domain, CD22 binds to sialic acids in α2,6 linkages in cis , on the surface of the same B cell or in trans , on other cells. Sialic acids are self ligands, as they are abundant in vertebrates, but are usually not expressed by pathogens. We show that cis- ligand binding of CD22 is crucial for the regulation of B-cell Ca 2+ signaling by controlling the CD22 association to the BCR. Mice with a mutated CD22 ligand-binding domain of CD22 showed strongly reduced Ca 2+ signaling. In contrast, mice with mutated CD22 immunoreceptor tyrosine-based inhibition motifs have increased B-cell Ca 2+ responses, increased B-cell turnover, and impaired survival of the B cells. Thus, the CD22 ligand-binding domain has a crucial function in regulating BCR signaling, which is relevant for controlling autoimmunity.

Chorea-acanthocytosis (ChAc), a lethal disease caused by defective chorein, is characterized by neurodegeneration and erythrocyte acanthocytosis. The functional significance of chorein in other cell types remained ill-defined. The present study revealed chorein expression in blood platelets. As compared to platelets from healthy volunteers, platelets from patients with ChAc displayed a 47% increased globular/filamentous actin ratio, indicating actin depolymerization. Moreover, phosphoinositide-3-kinase subunit p85 phosphorylation, p21 protein-activated kinase (PAK1) phosphorylation, as well as vesicle-associated membrane protein 8 (VAMP8) expression were significantly reduced in platelets from patients with ChAc (by 17, 22, and 39%, respectively) and in megakaryocytic (MEG-01) cells following chorein silencing (by 16, 54, and 11%, respectively). Activation-induced platelet secretion from dense granules (ATP release) and α granules (P-selectin exposure) were significantly less (by 55% after stimulation with 1 μg/ml CRP and by 33% after stimulation with 5 μM TRAP, respectively) in ChAc platelets than in control platelets. Furthermore, platelet aggregation following stimulation with different platelet agonists was significantly impaired. These observations reveal a completely novel function of chorein, i.e., regulation of secretion and aggregation of blood platelets.

Long noncoding RNAs (lncRNAs) are potentially important regulators of cell differentiation and development, but little is known about their roles in B lymphocytes. Using RNA-seq and de novo transcript assembly, we identified 4516 lncRNAs expressed in 11 stages of B-cell development and activation. Most of these lncRNAs have not been previously detected, even in the closely related T-cell lineage. Comparison with lncRNAs previously described in human B cells identified 185 mouse lncRNAs that have human orthologs. Using chromatin immunoprecipitation-seq, we classified 20% of the lncRNAs as either enhancer-associated (eRNA) or promoter-associated RNAs. We identified 126 eRNAs whose expression closely correlated with the nearest coding gene, thereby indicating the likely location of numerous enhancers active in the B-cell lineage. Furthermore, using this catalog of newly discovered lncRNAs, we show that PAX5, a transcription factor required to specify the B-cell lineage, bound to and regulated the expression of 109 lncRNAs in pro-B and mature B cells and 184 lncRNAs in acute lymphoblastic leukemia.

With the frequent use of magnetic resonance imaging (MRI), patients with subtle and diffuse symptoms due to small syrinx cavities increasingly present to neurosurgical care. In this respect, a dilated central canal, hydromyelia, must be separated from patients with true syringomyelia with an underlying disorder, as they do not share clinical and radiological features. We hypothesize that a differentiation of these two entities with distinct diagnostic tools is possible. To describe the entity of hydromyelia, we excluded all patients from the syringomyelia database (n = 142) with any obvious cause of a syringomyelia, any objective neurological deficits on clinical examination, pathological results on electrophysiological monitoring (SSEP, MEP, silent periods) or a widening of the spinal cord cavity of more than 6 mm on MRI [routine acquisitions with FLAIR, T1/T2-weighted images, Cine and CISS (constructive interference in steady-state) studies]. Life quality was assessed through SF-36 questionnaires and an individualized questionnaire for the clinical history, pain and alternative therapies. Forty patients (15 males/25 females) matched the criteria of a hydromyelia. With a mean age of 36.7 years (range 11–62), they almost all presented with pain (79%) or dysaesthesia of the limbs, with some having been an incidental finding (10%). Over a follow-up time of 36.9 months (range 6–93) there was no neurological or radiological deterioration. Patients with a hydromyelia do not share clinical or radiological characteristics with patients harbouring a true syringomyelia. As hydromyelia does not represent a disease with an underlying pathology, no clinical or radiological progression has been seen. With sophisticated diagnostic tools to rule out any pathology this subset of patients can be identified.