Dyrk1A (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A) is a serine/ threonine kinase essential for brain development and function, and its excessive activity is considered a pathogenic factor in Down syndrome. The development of potent, selective inhibitors of Dyrk1A would help to elucidate the molecular mechanisms of normal and diseased brains, and may provide a new lead compound for molecular-targeted drug discovery. Here, we report a novel Dyrk1A inhibitor, InDY, a benzothiazole derivative showing a potent ATPcompetitive inhibitory effect with IC 50 and K i values of 0.24 and 0.18 µm, respectively. X-ray crystallography of the Dyrk1A/InDY complex revealed the binding of InDY in the ATP pocket of the enzyme. InDY effectively reversed the aberrant tau-phosphorylation and rescued the repressed nFAT (nuclear factor of activated T cell) signalling induced by Dyrk1A overexpression. Importantly, proInDY, a prodrug of InDY, effectively recovered Xenopus embryos from head malformation induced by Dyrk1A overexpression, resulting in normally developed embryos and demonstrating the utility of proInDY in vivo.
The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for
Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative of
the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan
(JSTP) and North America (STP) to develop an internationally accepted nomenclature for
proliferative and nonproliferative lesions in laboratory animals. The purpose of this
publication is to provide a standardized nomenclature for classifying microscopic lesions
observed in the female reproductive tract of laboratory rats and mice, with color
photomicrographs illustrating examples of some lesions. The standardized nomenclature
presented in this document is also available electronically on the internet
(http://www.goreni.org/). Sources of material included histopathology databases from
government, academia, and industrial laboratories throughout the world. Content includes
spontaneous and aging lesions as well as lesions induced by exposure to test materials.
There is also a section on normal cyclical changes observed in the ovary, uterus, cervix
and vagina to compare normal physiological changes with pathological lesions. A widely
accepted and utilized international harmonization of nomenclature for female reproductive
tract lesions in laboratory animals will decrease confusion among regulatory and
scientific research organizations in different countries and provide a common language to
increase and enrich international exchanges of information among toxicologists and
pathologists.
The LT50 values and soluble carbohydrate levels in wheat (Triticum aestivum L.) crowns and leaves were monitored throughout autumn and winter in cultivars varying in freezing tolerance and snow mold resistance during 1993/1994 and 1994/1995 in the field at Sapporo, Japan. During the first stage of hardening, from sowing to mid‐November, the pattern of accumulation of mono‐ and disaccharides was similar for all cultivars. During the second stage of cold hardening, from mid‐November to mid‐December, the greatest accumulation of mono‐ and disaccharides, without a corresponding increase in fructan, was observed among the freezing‐tolerant cultivars; and levels of simple saccharides rapidly decreased under snow cover. Conversely, levels of mono‐ and disaccharides in snow mold‐resistant cultivars were less than 70% of those in freezing‐tolerant cultivars before snow cover and maintained low levels throughout winter, while polysaccharide levels in snow mold‐resistant cultivars were about 120% of those in freezing‐tolerant cultivars in December. Sugar metabolism during the winter was examined using 18 cultivars in 1994/1995. LT50 values were correlated to the greatest extent with total mono‐ and disaccharide and fructan content among wheat cultivars excluding snow mold‐resistant cultivars in December. Snow mold‐resistant cultivars tended to metabolize carbohydrates more slowly until the end of the snow cover period. This result suggested that the enzymatic metabolism of the synthesis of sugars and the conversion of fructan to cryoprotective sugars in response to low temperatures, especially subzero ones, might be different between the two contrasting types in resistance to winter stress.
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