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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.

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.

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.

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.

Brain-computer interfaces (BCIs) are often based on the control of sensor motor processes, yet sensor motor processes are impaired in patients suffering from amyotrophic lateral sclerosis (ALS). We devised a new paradigm that targets higher level cognitive processes to transmit information from the user to the BCI. We instructed five ALS patients and eleven healthy subjects to either activate self-referential memories or to focus on processes without mnemonic content, while recording a high density electroencephalogram (EEG). Both tasks are likely to modulate activity in the default mode network (DMN) without involving sensor motor pathways. We find that the two tasks can be distinguished from band power modulations in the theta (3 -- 7 Hz) and alpha-range (8 -- 13 Hz) in fronto-parietal areas, consistent with modulation of neural activity in primary nodes of the DMN. Training a support vector machine (SVM) to discriminate the two tasks on theta- and alpha-power in the precuneus, as estimated by a beam forming procedure, resulted in above chance-level decoding accuracy after only one experimental session. Therefore, the presented work could serve as a basis for a novel tool which allows for simple, reliable communication with patients in late stages of ALS.

Summary Background The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich's ataxia. We used data from EFACTS to assess disease progression and the predictive value of disease-related factors on progression, and estimated sample sizes for interventional randomised clinical trials. Methods We enrolled patients with genetically confirmed Friedreich's ataxia from 11 European study sites in Austria, Belgium, France, Germany, Italy, Spain, and the UK. Patients were seen at three visits—baseline, 1 year, and 2 years. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. We estimated the yearly progression for each outcome with linear mixed-effect modelling. This study is registered with ClinicalTrials.gov, number NCT02069509, and follow-up assessments and recruitment of new patients are ongoing. Findings Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreich's ataxia. 546 patients (90%) contributed data with at least one follow-up visit. The progression rate on SARA was 0·77 points per year (SE 0·06) in the overall cohort. Deterioration in SARA was associated with younger age of onset (–0·02 points per year [0·01] per year of age) and lower SARA baseline scores (–0·07 points per year [0·01] per baseline point). Patients with more than 353 GAA repeats on the shorter allele of the FXN locus had a higher SARA progression rate (0·09 points per year [0·02] per additional 100 repeats) than did patients with fewer than 353 repeats. Annual worsening was 0·10 points per year (0·03) for INAS, −0·04 points per year (0·01) for SCAFI, 0·93 points per year (0·06) for ADL, and −0·02 points per year (0·004) for EQ-5D-3L. PVF performance improved by 0·99 words per year (0·14). To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial. Interpretation Our results show that SARA is a suitable clinical rating scale to detect deterioration of ataxia symptoms over time; ADL is an appropriate measure to monitor changes in daily self-care activities; and younger age at disease onset is a major predictor for faster disease progression. The results of the EFACTS longitudinal analysis provide suitable outcome measures and sample size calculations for the design of upcoming clinical trials of Friedreich's ataxia. Funding European Commission.

Altered progranulin levels play a major role in neurodegenerative diseases, like Alzheimer's dementia (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), even in the absence of GRN mutations. Increasing progranulin levels could hereby provide a novel treatment strategy. However, knowledge on progranulin regulation in neurodegenerative diseases remains limited. We here demonstrate that cerebrospinal fluid progranulin levels do not correlate with its serum levels in AD, FTD and ALS, indicating a differential regulation of its central and peripheral levels in neurodegeneration. Blood progranulin levels thus do not reliably predict central nervous progranulin levels and their response to future progranulin-increasing therapeutics.

Receptor organization and dynamics at the cell membrane are important factors of signal transduction regulation. Using super‐resolution microscopy and single‐particle tracking, we show how the negative coreceptor CD22 works with the cortical cytoskeleton in restraining BCR signalling. In naive B cells, we found endogenous CD22 to be highly mobile and organized into nanodomains. The landscape of CD22 and its lateral diffusion were perturbed either in the absence of CD45 or when the CD22 lectin domain was mutated. To understand how a relatively low number of CD22 molecules can keep BCR signalling in check, we generated Brownian dynamic simulations and supported them with ex vivo experiments. This combined approach suggests that the inhibitory function of CD22 is influenced by its nanoscale organization and is ensured by its fast diffusion enabling a “global BCR surveillance” at the plasma membrane.

Despite decades of research on EEG-based brain-computer interfaces (BCIs) in patients with amyotrophic lateral sclerosis (ALS), there is still little known about how the disease affects the electromagnetic field of the brain. This may be one reason for the present failure of EEG-based BCI paradigms for completely locked-in ALS patients. In order to help understand this failure, we have recorded resting state data from six ALS patients and thirty-two healthy controls to investigate for group differences. While similar studies have been attempted in the past, none have used high-density EEG or tried to distinguish between physiological and non-physiological sources of the EEG. We find an ALS-specific global increase in gamma power (30-90 Hz) that is not specific to the motor cortex, suggesting that the mechanism behind ALS affects non-motor cortical regions even in the absence of comorbid cognitive deficits.

Niemann–Pick disease type C (NP-C) is a rare autosomal-recessive neurodegenerative disease featuring pleiotropic neurological, psychiatric and visceral manifestations. Since many of the adult manifestations can be non-specific or missed, NP-C often goes undetected in adult-onset patients. Here we hypothesized that targeted high-throughput sequencing allows identifying NP-C patients among subjects with unexplained early-onset ataxia (EOA) and, moreover, that this population is enriched for NPC1 mutations. From 204 consecutive EOA patients, all 108 subjects with an established diagnosis were removed (including 4 NPC1 patients), yielding a target cohort of 96 subjects with unexplained EOA, but without primary suspicion of NP-C. This cohort was investigated for NPC1/NPC2 mutations using a high-coverage HaloPlex gene panel including 122 ataxia genes. Among 96 samples, we identified 4 known NPC1 mutations, 3 novel NPC1 missense variants of uncertain significance (VUS) and 1 novel NPC2 missense VUS. The total mutant allele frequency (8/192 = 4.17 %) was significantly enriched compared with control population data (1.57 %; p = 0.011). Two NPC1-positive patients were identified (both with non-specific incipient clinical features), giving a NPC1 patient frequency of 2/96 = 2.1 % in unexplained EOA and of 6/204 = 2.9 % in the total EOA series. NPC1 mutations are substantially enriched in unexplained EOA, demonstrating EOA as a risk-group for NP-C disease. Targeted high-throughput sequencing allows to identify also those NP-C patients with non-specific conditions where the diagnosis has initially been missed. This method does not require having considered NP-C during differential diagnosis, but allows identification of NP-C as part of the default analysis.

We evaluate the effect of discussion on the accuracy of collaborative judgments. In contrast to prior research, we show that discussion can either aid or impede accuracy relative to simple averaging of collaborators’ independent judgments, as a systematic function of task type and interaction process. On estimation tasks with a wide range of potential estimates, discussion aided accuracy by helping participants prevent and eliminate egregious errors. On estimation tasks with a naturally bounded range, discussion following independent estimates performed on par with averaging. Importantly, if participants did not first make independent estimates, discussion significantly harmed accuracy by limiting the range of considered estimates, independent of task type. Our research shows that discussion can be a powerful tool for error reduction, but only when structured appropriately: Decision-makers should form independent judgments in order to consider a wide range of possible answers, and then use discussion to eliminate extremely large errors.