ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 7 (2017): 115, doi:10.1038/s41598-017-00091-1.Mutations in Fused in Sarcoma/Translocated in Liposarcoma (FUS) cause familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive axonal degeneration mainly affecting motor neurons. Evidence from transgenic mouse models suggests mutant forms of FUS exert an unknown gain-of-toxic function in motor neurons, but mechanisms underlying this effect remain unknown. Towards this end, we studied the effect of wild type FUS (FUS WT) and three ALS-linked variants (G230C, R521G and R495X) on fast axonal transport (FAT), a cellular process critical for appropriate maintenance of axonal connectivity. All ALS-FUS variants impaired anterograde and retrograde FAT in squid axoplasm, whereas FUS WT had no effect. Misfolding of mutant FUS is implicated in this process, as the molecular chaperone Hsp110 mitigated these toxic effects. Interestingly, mutant FUS-induced impairment of FAT in squid axoplasm and of axonal outgrowth in mammalian primary motor neurons involved aberrant activation of the p38 MAPK pathway, as also reported for ALS-linked forms of Cu, Zn superoxide dismutase (SOD1). Accordingly, increased levels of active p38 MAPK were detected in post-mortem human ALS-FUS brain tissues. These data provide evidence for a novel gain-of-toxic function for ALS-linked FUS involving p38 MAPK activation.We are grateful for funding from NIH/NINDS (R01 NS078145, R01 NS090352, and R21 NS091860 to D.A.B., R01 NS066942A and R21 NS096642 to G.M., R01NS023868 and R01NS041170 to S.T.B.), the ALS Therapy Alliance/CVS Pharmacy (to D.A.B. and G.M.) and the ALS Association (to C.F. and J.M.)

Adenocarcinoma arising at ileostomy sites: Two cases and a review of the literature

Total colectomy with ileostomy placement is a treatment for patients with inflammatory bowel disease or familial adenomatous polyposis (FAP). A rare and late complication of this treatment is carcinoma arising at the ileostomy site. We describe two such cases: a 78-year-old male 30 years after subtotal colectomy and ileostomy for FAP, and an 85-year-old male 50 years after colectomy and ileostomy for ulcerative colitis. The long latency period between creation of the ileostomies and development of carcinoma suggests a chronic metaplasia due to an irritating/inflammatory causative factor. Surgical excision of the mass and relocation of the stoma is the mainstay of therapy, with possible benefits from adjuvant chemotherapy. Newly developed lesions at stoma sites should be biopsied to rule out the possibility of this rare ileostomy complication

The Hilbert-Schmidt Theorem Formulation of the R-Matrix Theory

Using the Hilbert-Schmidt theorem, we reformulate the R-matrix theory in terms of a uniformly and absolutely convergent expansion. Term by term differentiation is possible with this expansion in the neighborhood of the surface. Methods for improving the convergence are discussed when the R-function series is truncated for practical applications.Comment: 16 pages, Late

Deuteron and antideuteron production in Au+Au collisions at sqrt(s_NN)=200 GeV

The production of deuterons and antideuterons in the transverse momentum range 1.1 < p_T < 4.3 GeV/c at mid-rapidity in Au + Au collisions at sqrt(s_NN)=200 GeV has been studied by the PHENIX experiment at RHIC. A coalescence analysis comparing the deuteron and antideuteron spectra with those of protons and antiprotons, has been performed. The coalescence probability is equal for both deuterons and antideuterons and increases as a function of p_T, which is consistent with an expanding collision zone. Comparing (anti)proton yields p_bar/p = 0.73 +/- 0.01, with (anti)deuteron yields: d_bar/d = 0.47 +/- 0.03, we estimate that n_bar/n = 0.64 +/- 0.04.Comment: 326 authors, 6 pages text, 5 figures, 1 Table. Submitted to PRL. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors

COMPOSITION AND FEATURES OF GEOGRAPHICAL DISTRIBUTION OF FAUNA OF ORIBATID MITES (ACARIFORMES, ORIBATIDA) IN THE TETHYS DESERT-STEPPE REGION

Aim. The aim is to identify the similarities and differences of fauna of oribatid mites (Acariformes, Oribatida) in the Tethys desert-steppe region and analyze geographic relationships of the studied area.Methods. For the research, we used the materials collected for 5 years (2008-13) by the members of the stuff of the Department of Biology and Biodiversity (Grikurova A.A.) in the territory of the Republic of Dagestan. In addition, we referred to personal collections and publications including" Catalogue of oribatid mites of the Caucasus" by Shtanchaeva U.Ya., Subias L.S. To analyze the similarities of fauna of the Tethys region we made a comprehensive analysis based on Jaccard similarity coefficient.Results. As a result of the research we gave the composition of fauna, held a brief overview on oribatid mites and their resettlement and migration. In Tethys region, we identified 381 genera of oribatid uniting 1506 species, one third of which is endemic (501 species). Despite the fact that the fauna of the oribatid in the Caucasus is studied unevenly, the greatest variety of species is observed here. The smallest amount of diversity compared with the Caucasian species is observed in the Mediterranean countries and Central Asia, which shows the peculiarities of the genesis and geographic distribution.Conclusion. The dendrogram of similarity of the oribatid mites genera in the Tethys region demonstrates the tremendous role of coastal and island ecosystems of the Tethys Ocean, followed by the enrichment of the diversity as well as independent species shaping

VOLUMES OF GENERA AND SPECIES COMPOSITION OF ORIBATIDA (ACARIFORMES, ORIBATIDA) OF THE INTERNAL MOUNTAIN DAGESTAN

This work is based on research and materials collected from 2000 to 2012, with the application of the method of selection of soil samples, according to the methodology of the quantitative survey. As a result of the conducted researches on the territory of the internal mountain Dagestan found 190 species of Oribatida belonging to 83 generations

Ethology of sea fish of the Caspian

The carrying capacity of the Caspian Sea is estimated in terms of bioresourses

The composition and geographical spreading of Carabidae flying in the light

The article is devoted the some species of insects and geographical spreading of Carabidae flying in the light under the condition of various high altitude belts of Dagestan