Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology

Spatial variability of physical attributes of an alfisol under different hillslope curvatures Variabilidade espacial de atributos físicos de um argissolo sob diferentes curvaturas do relevo

The influence of relief forms has been studied by several authors and explains the variability in the soil attributes of a landscape. Soil physical attributes depend on relief forms, and their assessment is important in mechanized agricultural systems, such as of sugarcane. This study aimed to characterize the spatial variability in the physical soil attributes and their relationship to the hillslope curvatures in an Alfisol developed from sandstone and growing sugarcane. Grids of 100 x 100 m were delimited in a convex and a concave area. The grids had a regular spacing of 10 x 10 m, and the crossing points of this spacing determined a total of 121 georeferenced sampling points. Samples were collected to determine the physical attributes related to soil aggregates, porosity, bulk density, resistance to penetration and moisture within the 0-0.2 and 0.2-0.4 m depth. Statistical analyses, geostatistics and Student's t-tests were performed with the means of the areas. All attributes, except aggregates > 2 mm in the 0-0.2 m depth and macroporosity at both depths, showed significant differences between the hillslope curvatures. The convex area showed the highest values of the mean weighted diameter, mean geometric diameter, aggregates > 2 mm, 1-2 mm aggregates, total porosity and moisture and lower values of bulk density and resistance to penetration in both depth compared to the concave area. The number of soil attributes with greater spatial variability was higher in the concave area.<br>A influência das formas do relevo tem sido estudada por diversos autores e explica a variabilidade dos atributos do solo na paisagem. Os atributos físicos do solo são dependentes das formas do relevo, e a avaliação desses atributos é importante em sistemas mecanizados como o da cultura de cana-de-açúcar. O presente estudo teve como objetivo caracterizar a variabilidade espacial dos atributos físicos de Argissolos desenvolvidos de arenito e cultivados com cana-de-açúcar bem como a relação desses com as curvaturas do relevo. Uma malha de dimensão de 100 x 100 m foi delimitada em uma área caracterizada pela forma convexa e outra em uma área caracterizada pela forma côncava. As malhas tinham espaçamento regular de 10 x 10 m, e os pontos de cruzamento desse espaçamento determinaram os pontos de coleta das amostras, num total de 121 pontos amostrais georreferenciados. Amostras foram coletadas para determinação dos atributos físicos: agregados, porosidade, densidade do solo, resistência à penetração e umidade nas profundidades 0,00-0,20 e 0,20-0,40 m. Foram realizadas análises estatísticas e geoestatísticas. Todos os atributos, com exceção dos agregados > 2 mm na profundidade de 0,00-0,20 m e dos macroporos nas duas profundidades, apresentaram diferença significativa entre as curvaturas. A área convexa apresentou os maiores valores de diâmetro médio ponderado, diâmetro médio geométrico, agregados > 2 mm, agregados de 2-1 mm, volume total de poros e umidade e os menores valores de densidade do solo e resistência à penetração nas duas profundidades estudadas, em relação à área côncava. A área côncava apresentou maior número de atributos do solo com maior variabilidade espacial