6 research outputs found
Towards Learned Emulation of Interannual Water Isotopologue Variations in General Circulation Models
Simulating abundances of stable water isotopologues, i.e. molecules differing
in their isotopic composition, within climate models allows for comparisons
with proxy data and, thus, for testing hypotheses about past climate and
validating climate models under varying climatic conditions. However, many
models are run without explicitly simulating water isotopologues. We
investigate the possibility to replace the explicit physics-based simulation of
oxygen isotopic composition in precipitation using machine learning methods.
These methods estimate isotopic composition at each time step for given fields
of surface temperature and precipitation amount. We implement convolutional
neural networks (CNNs) based on the successful UNet architecture and test
whether a spherical network architecture outperforms the naive approach of
treating Earth's latitude-longitude grid as a flat image. Conducting a case
study on a last millennium run with the iHadCM3 climate model, we find that
roughly 40\% of the temporal variance in the isotopic composition is explained
by the emulations on interannual and monthly timescale, with spatially varying
emulation quality. A modified version of the standard UNet architecture for
flat images yields results that are equally good as the predictions by the
spherical CNN. We test generalization to last millennium runs of other climate
models and find that while the tested deep learning methods yield the best
results on iHadCM3 data, the performance drops when predicting on other models
and is comparable to simple pixel-wise linear regression. An extended choice of
predictor variables and improving the robustness of learned climate--oxygen
isotope relationships should be explored in future work
Parkinsonâs disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures
Sequence variants at or near the leucine-rich repeat kinase 2 (LRRK2) locus have been associated with susceptibility to three human conditions: Parkinson disease (PD), Crohnâs disease and leprosy. Because all three disorders represent complex diseases with evidence of inflammation, we hypothesized a role for LRRK2 in immune cell functions. Here, we report that full-length Lrrk2 is a relatively common constituent of human peripheral blood mononuclear cells (PBMC) including affinity-isolated, CD14+ monocytes, CD19+ B-cells, and CD4+ as well as CD8+ T-cells. Up to 25% of PBMC from healthy donors and up to 43% of CD14+ monocytes were stained by anti-Lrrk2 antibodies using cell sorting. PBMC lysates contained full-length (>260 kDa) and higher molecular weight Lrrk2 species. The expression of LRRK2 in circulating leukocytes was confirmed by microscopy of human blood smears and in sections from normal midbrain and distal ileum. Lrrk2 reactivity was also detected in mesenteric lymph nodes and spleen (including in dendritic cells), but was absent in splenic mononuclear cells from lrrk2-null mice, as expected. In cultured bone marrow-derived macrophages (BMDM) from mice we made three observations: (i) a predominance of higher molecular weight lrrk2; (ii) the reduction of autophagy marker LC3-II in (R1441C)lrrk2-mutant cells (â„31%); and (iii) a significant up-regulation of lrrk2 mRNA (>4-fold) and protein after exposure to microbial structures including bacterial lipopolysaccharide and to lentiviral particles. We conclude that Lrrk2 is a constituent of many cell types in the immune system. Following the recognition of microbial structures, stimulated macrophages respond with increased lrrk2 gene expression. In the same cells, lrrk2 appears to co-regulate autophagy, which is reduced in (R1441C)lrrk2-mutant mice. A pattern recognition receptor-type function for LRRK2 could explain the locus association with Crohnâs disease and leprosy risk. We speculate that the role of Lrrk2 in immune cells may also be of relevance for the susceptibility to develop PD or its propagation
Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy
International audienceBACKGROUND Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2: 1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (>= 3 points), an outcome that indicates improvement in at least two motor skills. RESULTS In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P< 0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P< 0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). CONCLUSIONS Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials. gov number, NCT02292537.