Design of protease-resistant myelin basic protein-derived peptides by cleavage site directed amino acid substitutions

Multiple Sclerosis (MS) is considered to be a T cell-mediated autoimmune disease. An attractive strategy to prevent activation of autoaggressive T cells in MS, is the use of altered peptide ligands (APL), which bind to major histocompatibility complex class II (MHC II) molecules. To be of clinical use, APL must be capable of resisting hostile environments including the proteolytic machinery of antigen presenting cells (APC). The current design of APL relies on cost- and labour-intensive strategies. To overcome these major drawbacks, we used a deductive approach which involved modifying proteolytic cleavage sites in APL. Cleavage site-directed amino acid substitution of the autoantigen myelin basic protein (MBP) resulted in lysosomal protease-resistant, high-affinity binding peptides. In addition, these peptides mitigated T cell activation in a similar fashion as conventional APL. The strategy outlined allows the development of protease-resistant APL and provides a universal design strategy to improve peptide-based immunotherapeutics

The type 2 cannabinoid receptor regulates susceptibility to osteoarthritis in mice

SummaryObjectiveCannabinoid receptors and their ligands have been implicated in the regulation of various physiological processes but their role in osteoarthritis has not been investigated. The aim of this study was to evaluate the role of the type 2 cannabinoid receptor (Cnr2) in regulating susceptibility to osteoarthritis in mice.MethodsWe analysed the severity of knee osteoarthritis as assessed by the Osteoarthritis Research Society International (OARSI) scoring system in mice with targeted deletion of Cnr2 (Cnr2−/−) and wild type (WT) littermates. Studies were conducted in mice subjected to surgical destabilisation of the medial meniscus (DMM) and in those with spontaneous age-related osteoarthritis (OA).ResultsOsteoarthritis was more severe following DMM in the medial compartment of the knee in Cnr2−/− compared with WT mice (mean ± sem score = 4.9 ± 0.5 vs 3.6 ± 0.3; P = 0.017). Treatment of WT mice with the CB2-selective agonist HU308 following DMM reduced the severity of OA in the whole joint (HU308 = 8.4 ± 0.2 vs vehicle = 10.4 ± 0.6; P = 0.007). Spontaneous age related osteoarthritis was also more severe in the medial compartment of the knee in 12-month old Cnr2−/− mice compared with WT (5.6 ± 0.5 vs 3.5 ± 0.3, P = 0.008). Cultured articular chondrocytes from Cnr2−/− mice produced less proteoglycans in vitro than wild type chondrocytes.ConclusionThese studies demonstrate that the Cnr2 pathway plays a role in the pathophysiology of osteoarthritis in mice and shows that pharmacological activation of CB2 has a protective effect. Further studies of the role of cannabinoid receptors in the pathogenesis of osteoarthritis in man are warranted

Solar Intranetwork Magnetic Elements: bipolar flux appearance

The current study aims to quantify characteristic features of bipolar flux appearance of solar intranetwork (IN) magnetic elements. To attack such a problem, we use the Narrow-band Filter Imager (NFI) magnetograms from the Solar Optical Telescope (SOT) on board \emph{Hinode}; these data are from quiet and an enhanced network areas. Cluster emergence of mixed polarities and IN ephemeral regions (ERs) are the most conspicuous forms of bipolar flux appearance within the network. Each of the clusters is characterized by a few well-developed ERs that are partially or fully co-aligned in magnetic axis orientation. On average, the sampled IN ERs have total maximum unsigned flux of several 10^{17} Mx, separation of 3-4 arcsec, and a lifetime of 10-15 minutes. The smallest IN ERs have a maximum unsigned flux of several 10^{16} Mx, separations less than 1 arcsec, and lifetimes as short as 5 minutes. Most IN ERs exhibit a rotation of their magnetic axis of more than 10 degrees during flux emergence. Peculiar flux appearance, e.g., bipole shrinkage followed by growth or the reverse, is not unusual. A few examples show repeated shrinkage-growth or growth-shrinkage, like magnetic floats in the dynamic photosphere. The observed bipolar behavior seems to carry rich information on magneto-convection in the sub-photospheric layer.Comment: 26 pages, 14 figure

Quantifying stratospheric biases and identifying their potential sources in subseasonal forecast systems

The stratosphere can be a source of predictability for surface weather on timescales of several weeks to months. However, the potential predictive skill gained from stratospheric variability can be limited by biases in the representation of stratospheric processes and the coupling of the stratosphere with surface climate in forecast systems. This study provides a first systematic identification of model biases in the stratosphere across a wide range of subseasonal forecast systems. It is found that many of the forecast systems considered exhibit warm global-mean temperature biases from the lower to middle stratosphere, too strong/cold wintertime polar vortices, and too cold extratropical upper-troposphere/lowerstratosphere regions. Furthermore, tropical stratospheric anomalies associated with the Quasi-Biennial Oscillation tend to decay toward each system¿s climatology with lead time. In the Northern Hemisphere (NH), most systems do not capture the seasonal cycle of extreme-vortex-event probabilities, with an underestimation of sudden stratospheric warming events and an overestimation of strong vortex events in January. In the Southern Hemisphere (SH), springtime interannual variability in the polar vortex is generally underestimated, but the timing of the final breakdown of the polar vortex often happens too early in many of the prediction systems. These stratospheric biases tend to be considerably worse in systems with lower model lid heights. In both hemispheres, most systems with low-top atmospheric models also consistently underestimate the upward wave driving that affects the strength of the stratospheric polar vortex. We expect that the biases identified here will help guide model development for subseasonal-to-seasonal forecast systems and further our understanding of the role of the stratosphere in predictive skill in the troposphere.This work uses S2S Project data. S2S is a joint initiative of the World Weather Research Programme (WWRP) and the World Climate Research Programme (WCRP). This work was initiated by the Stratospheric Network for the Assessment of Predictability (SNAP), a joint activity of SPARC (WCRP) and the S2S Project (WWRP–WCRP). The work of Rachel W.-Y. Wu is funded through ETH grant ETH-05 19-1. Support from the Swiss National Science Foundation through projects PP00P2_170523 and PP00P2_198896 to Daniela I. V. Domeisen is gratefully acknowledged. Chaim I. Garfinkel and Chen Schwartz are supported by the ISF–NSFC joint research program (grant no. 3259/19). The work of Marisol Osman was supported by UBACyT20020170100428BA and PICT-2018-03046 projects. The work of Alvaro de la Cámara is funded by the Spanish Ministry of Science and Innovation through project PID2019-109107GB-I00. Blanca Ayarzagüena and Natalia Calvo acknowledge the support of the Spanish Ministry of Science and Innovation through the JeDiS (RTI2018-096402-B-I00) project. Froila M. Palmeiro and Javier García-Serrano have been partially supported by the Spanish ATLANTE project (PID2019-110234RB-C21) and Ramón y Cajal program (RYC-2016-21181), respectively. Neil P. Hindley and Corwin J. Wright are supported by UK Natural Environment Research Council (NERC), grant number NE/S00985X/1. Corwin J. Wright is also supported by a Royal Society University Research Fellowship UF160545. Seok-Woo Son and Hera Kim are supported by the Basic Science Research Program through the National Research Foundation of Korea (2017R1E1A1A01074889). This material is based upon work supported by the US Department of Energy, Office of Science, Office of Biological and Environmental Research (BER), Regional and Global Model Analysis (RGMA) component of the Earth and Environmental System Modeling program under award no. DE-SC0022070 and National Science Foundation (NSF) IA 1947282. This work was also supported by the National Center for Atmospheric Research (NCAR), which is a major facility sponsored by the NSF under cooperative agreement no. 1852977. Pu Lin is supported by award NA18OAR4320123 from the National Oceanic and Atmospheric Administration (NOAA), U.S. Department of Commerce. Zachary D. Lawrence was partially supported under NOAA award NA20NWS4680051; Zachary D. Lawrence and Judith Perlwitz also acknowledge support from US federally appropriated funds

Use of secondary forests by understory birds in a fragmented landscape in central Amazonia

Rates of deforestation in the Brazilian Amazon have increased since 1991 and forecasts are not optimistic about the slowing of this process. Some authors believe that the Amazon may be experiencing a massive process of species extinction. However, the deforestation is accompanied by the expansion of secondary forests that are established in the abandoned areas. The trend is an increase in secondary forests cover, resulting in a mosaic of primary forest (FP) and fragments separated by an array of secondary forests (FS). In this scenario, the prediction of a massive extinction could be wrong if many species could survive in the secondary forests. To assess the importance of FS for the understory birds we sampled areas in regeneration and a continuous forest of a fragmented landscape. We conducted mist netting (24 nets/day) for six consecutive days/month, for 8 months (May-November) in 2009. Some forest species as do not seem to be adapted to the secondary forest environment and their occurrences are restricted to continuous forest environments. But most focal species showed no significant difference in apparent survival rates between the enviroments, suggesting that these species inhabit the secondary forest and the primary forest similarly. Because most of the matrix in fragmented landscapes are composed by secondary forests, such results highlights the conservation value that these habitats present in the long term. Thus, FS should be regarded as dynamic matrix that not only allows the movement of individuals but also function as habitat for many species typical of FP.Na Amazônia, as taxas de desmatamento crescem desde 1991 e as previsões não são otimistas quanto à desaceleração desse processo. A devastação da floresta é acompanhada de uma expansão de florestas secundárias (FS) que se estabelecem nas áreas abandonadas. A tendência é um aumento de florestas secundárias, resultando num mosaico de floresta contínua e fragmentos separados por uma matriz de FS. Nesse cenário, autores acreditam que a Amazônia pode passar por um processo massivo de extinção de espécies. Por outro lado, a previsão de um processo massivo de extinção pode ser equivocada, pois muitas espécies florestais poderiam sobreviver nas florestas secundárias. Para avaliar o valor das florestas secundárias para espécies florestais amostramos por oito meses com redes de neblina uma capoeira (FS) em regeneração e uma floresta primária (FP) de uma paisagem fragmentada. Algumas espécies não foram capturadas na capoeira e aparentemente evitam esse tipo de hábitat. No entanto, a maioria das espécies do grupo focal não apresentou diferença na sobrevivência aparente entre os ambientes, o que nos indica que estão habitando a capoeira e a floresta primária da mesma forma. Na realidade amazônica, onde grande parte da matriz é composta por floresta secundária, a matriz tem valor para conservação e deve ser analisada como um elemento dinâmico que não apenas permite a movimentação de indivíduos, mas também serve de hábitat para muitas espécies de floresta primária. Mas ressaltamos que é fundamental a preservação de áreas de floresta primária que servirão de fonte às florestas secundárias adjacentes

Identification of common genetic risk variants for autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.Peer reviewe

Search for gravitational waves from Scorpius X-1 in the second Advanced LIGO observing run with an improved hidden Markov model

We present results from a semicoherent search for continuous gravitational waves from the low-mass x-ray binary Scorpius X-1, using a hidden Markov model (HMM) to track spin wandering. This search improves on previous HMM-based searches of LIGO data by using an improved frequency domain matched filter, the J-statistic, and by analyzing data from Advanced LIGO's second observing run. In the frequency range searched, from 60 to 650 Hz, we find no evidence of gravitational radiation. At 194.6 Hz, the most sensitive search frequency, we report an upper limit on gravitational wave strain (at 95% confidence) of h095%=3.47×10-25 when marginalizing over source inclination angle. This is the most sensitive search for Scorpius X-1, to date, that is specifically designed to be robust in the presence of spin wandering. © 2019 American Physical Society