Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease.

C9ORF72 mutations are found in a significant fraction of patients suffering from amyotrophic lateral sclerosis and frontotemporal dementia, yet the function of the C9ORF72 gene product remains poorly understood. We show that mice harboring loss-of-function mutations in the ortholog of C9ORF72 develop splenomegaly, neutrophilia, thrombocytopenia, increased expression of inflammatory cytokines, and severe autoimmunity, ultimately leading to a high mortality rate. Transplantation of mutant mouse bone marrow into wild-type recipients was sufficient to recapitulate the phenotypes observed in the mutant animals, including autoimmunity and premature mortality. Reciprocally, transplantation of wild-type mouse bone marrow into mutant mice improved their phenotype. We conclude that C9ORF72 serves an important function within the hematopoietic system to restrict inflammation and the development of autoimmunity

Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease.

C9ORF72 mutations are found in a significant fraction of patients suffering from amyotrophic lateral sclerosis and frontotemporal dementia, yet the function of the C9ORF72 gene product remains poorly understood. We show that mice harboring loss-of-function mutations in the ortholog of C9ORF72 develop splenomegaly, neutrophilia, thrombocytopenia, increased expression of inflammatory cytokines, and severe autoimmunity, ultimately leading to a high mortality rate. Transplantation of mutant mouse bone marrow into wild-type recipients was sufficient to recapitulate the phenotypes observed in the mutant animals, including autoimmunity and premature mortality. Reciprocally, transplantation of wild-type mouse bone marrow into mutant mice improved their phenotype. We conclude that C9ORF72 serves an important function within the hematopoietic system to restrict inflammation and the development of autoimmunity. Sci Transl Med 2016 Jul 13; 8(347):347ra93

Monitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging

The study of amyotrophic lateral sclerosis (ALS) and potential interventions would be facilitated if motor axon degeneration could be more readily visualized. Here we demonstrate that stimulated Raman scattering (SRS) microscopy could be used to sensitively monitor peripheral nerve degeneration in ALS mouse models and ALS autopsy materials. Three-dimensional imaging of pre-symptomatic SOD1 mouse models and data processing by a correlation-based algorithm revealed that significant degeneration of peripheral nerves could be detected coincidentally with the earliest detectable signs of muscle denervation and preceded physiologically measurable motor function decline. We also found that peripheral degeneration was an early event in FUS as well as C9ORF72 repeat expansion models of ALS, and that serial imaging allowed long-term observation of disease progression and drug effects in living animals. Our study demonstrates that SRS imaging is a sensitive and quantitative means of measuring disease progression, greatly facilitating future studies of disease mechanisms and candidate therapeutics

Iron distributions in the water column of the Japan Basin and Yamato Basin (Japan Sea)

In the Japan and Yamato basins (Japan Sea), dissolved Fe ([D-Fe], <0.22 μm fraction) was characterized by surface depletion, mid-depth maxima, then a slight decrease with depth in deep water and uniform concentration in bottom waters because of biological uptake in the surface water and release by microbial decomposition of sinking organic matter in mid-depth waters. Total Fe concentrations ([T-Fe]) in the surface water of the Japan Sea were 1-4 nM, a little higher than those in the surface waters of the nutrient-deficient subtropical western North Pacific and extremely higher than the nutrient-rich subarctic western North Pacific and the nutrient-deficient subtropical central North Pacific, resulting from high atmospheric Fe input to nutrient-depleted surface water of the Japan Sea. In the Japan Basin, the [T-Fe] in bottom water were lower than those in deep water, resulting from (1) the injection of new bottom water with the lower [T-Fe] into the Japan Basin bottom water, (2) the particulate Fe removal by particle scavenging during the bottom water circulation of the Japan Basin, or (3) the injection of deep water with the higher [T-Fe] into the Japan Basin deep water. On the other hand, the [T-Fe] in deep water of the Yamato Basin and the slope regions were variable with different [T-Fe] levels among stations and depths. We found a significant relationship between [T-Fe] and water transmittance in deep water, probably resulting from the iron supply into the deep water because of the lateral transport of resuspended sediment from the slope

Mass Spectrometry Based Glycoproteomics—From a Proteomics Perspective*

Glycosylation is one of the most important and common forms of protein post-translational modification that is involved in many physiological functions and biological pathways. Altered glycosylation has been associated with a variety of diseases, including cancer, inflammatory and degenerative diseases. Glycoproteins are becoming important targets for the development of biomarkers for disease diagnosis, prognosis, and therapeutic response to drugs. The emerging technology of glycoproteomics, which focuses on glycoproteome analysis, is increasingly becoming an important tool for biomarker discovery. An in-depth, comprehensive identification of aberrant glycoproteins, and further, quantitative detection of specific glycosylation abnormalities in a complex environment require a concerted approach drawing from a variety of techniques. This report provides an overview of the recent advances in mass spectrometry based glycoproteomic methods and technology, in the context of biomarker discovery and clinical application