Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2–5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis

The unfolded protein response in immunity and inflammation.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6

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Not AvailableTHE PAPER DESCRIBES HOW AREAS INFESTED WITH BROOM AND GORSE , EXOTIC SHRUBS , WHICH GROW WILD OVER LARGE AREAS IN THE NILGIRIS , CAN BE AFFORESTED WITH ECONOMIC SPECIES. IT WAS OBSERVED THAT THESE SHRUBS SERVE AS A GOOD NURSE CROP FOR THE EUCALYPTUS AND WATTLE SEEDLINGS. THE METHOD OF PLANTATIONS OF THESE SPECIES IN SUCH AREAS IS DESCRIBED IN DETAIL.Not Availabl

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Not AvailableTHE PAPER SUGGESTS THAT RAISING ACACIA MOLLISSIMA , EUCALYPTUS TERETICORNIS AND EUCALYPTUS CITRIODORA PLANTATIONS BY STUMP PLANTING, WILL SAVE CONSIDERABLE AMOUNT ON THE NURSERY COSTS, COSTS OF TRANSPORT OF PLANTING MATERIAL , COST OF FOREST COVERS ETC. THE STUMPS HAVE A GREAT ADVANTAGE OVER MOSSED SEEDLINGS NOT ONLY IN THE COST OF PLANTING STOCK BUT ALSO IN THE SURVIVAL DURING FORESTS SEASONS WITHOUT ANY FROST PROTECTION. RANGANATHAN (5) HAS POINTED OUT THAT FROST INJURY TO THE YOUNG SEEDLINGS IN THE NILGIRIS IS MAINLY DUE TO THE NON- AVAILABILITY OF SOIL MOISTURE FROM THE TOP LAYER OF ABOUT 12-15 cm AS A RESULT OF FROZEN SOIL WATER. IN THE CASE OF STUMPS THE TAP ROOT IS PLACED SUFFICIENTLY DEEP TO TAKE UP THE SOIL MOISTURE FROM DEEPER REVEALS. THIS PROBABLY EXPLAINS WHY THE PLANT DOES NOT SUFFER FROM FROST INJURY.Not Availabl

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Not AvailablePRESENTS RESULTS OF THE STUDIES ON THE SURFACE RUNOFF AND SOIL LOSS CONDUCTED IN SHOLA FORESTS AT OOTACAMUND . THE SIZE OF THE PLOTS WAS 0.09 ha (0.25 ACRE) EACH. RUNOFF WAS COLECTED FROM FOUR PLOTS FROM 1959 ON WARDS. THE MEAN MONTHLY RAINFALL AND RUNOFF DATA WERE COMPUTED FOR FIVE YEARS FROM FOUR PLOTS. CORRELATION STUDY ON MONTHLY MEAN RAINFALL AND RUNOFF SHOW THAT THE MEAN MONTHLY RAINFALL IS SIGNIFICANTLY CORRELATED WITH MEAN MONTHLY RUNOFF AT 0.01 LEVEL. MAXIMUM SURFACE RUNOFF WAS RECORDED IN SOUTH- WEST MONSOON ( JUNE- AUGUST) AS COMPARED TO NORTH- EAST MONSOON ( SEPTEMBER- NOVEMBER) AND PRE-MONSOON ( APRIL-MAY) . VERY LOW SURFACE RUNOFF AND NO SOIL LOSS CAN BE ATTRIBUTED TO GOOD TREE CANOPY AND DENSE UNDERGROWTH , DEPOSITION OF LEAFLITTER, HIGH HUMUS CONTENT OF THE SOIL AND HIGH INFILTRATION RATE.Not Availabl

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Not AvailableECOLOGICAL STUDIES CONDUCTED IN THE HIGH ALTITUDE GRASSLANDS OF THE NILGIRIS INDICATED THAT DICHANTHIUM POLYPTYCHUM ( STUED) , A CAMUS , REPRESENTS THE HIGHEST STAGE IN THESE GRASSLANDS AND CHRYSOPOGON ZEYLANICUS ( NEES) . THIS IS APPARENTLY STABLE STAGE IN RETROGRESSIVE SUCCESSION ON OVERGRAZED AND ERODED AREAS. ON THE BASIS OF PROGRESSIVE AND RETROGRESSIVE CHANGES IN THE HIGH ALTITUDE GRASSLANDS IN THE NILGIRIS , IT HAS BEEN SHOWN THAT THESE GRASSLANDS BELONG TO THE BROAD SEHIMA- DICHANTHIUM TYPE.Not Availabl

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Not AvailableTHE PAPER PRESENTS RESULTS OF THE RUNOFF STUDIES AT OOTACAMUND IN THE NILGIRIS . IT WAS OBSERVED THAT ARBORESCENT VEGETATION GAVE HIGH RUNOFF AS COMPARED TO SHRUB AND GRASS VEGETATION. PRACTICALLY NO RUNOFF WAS OBSERVED IN THE PROTECTED GRASSLANDS. SOIL LOSS WAS PRACTICALLY NEGLIGIBLE IN ALL THE TREATMENTS. IN PLANTATIONS AND IMMEDIATELY AFTER THINNING OPERATIONS.Not Availabl

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Not AvailableTHE NATURAL GROWTH OF BROOM AND GORSE , THE EXOTIC LEGUMINOUS , HAS BEEN SUCCESSFULLY UTILISED AS NURSE CROPS FRO AFFORESTING BLUEGUM AND BLACK WATTLE. THE AFFORESTATION HAS BEEN SUCCESSFULLY DONE IN 3 ( '0.0m) WIDE LINES 11' ( 3.4 m ) APART . 1 FOOT CUBE (0.09 m) PITS WERE DUG AT 11' X 10' ESPACEMENT AND MOSSED SEEDLINGS WERE PLANTED. THE DENSE BROOM AFFORDED PROTECTION TO THE SEEDLINGS AGAINST FROST, WIND ETC. THE GROWTH WAS BETTER UNDER BROOM THAN IN THE OPEN. THE BROOM GROWTH WAS REMOVED DURING THE MIDDLE OF THE SECOND YEAR. DURING THE FOURTH YEAR , BROOM FORMED A DENSE UNDERGROWTH DUE TO THE GROWTH OF COPPICE SHOOTS AND NATURAL REGENERATION BY SEED. THIS METHOD IS 30 TO 40 % CHEAPER THAN THE CONVENTIONAL CLEARING AND AFFORESTATION OF SUCH AREAS.Not Availabl