The contribution of GABAergic dysfunction to neurodevelopmental disorders

GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter in the brain. The GABAergic system is indispensable for maintaining the balance between excitation and inhibition (E/I balance) required for normal neural circuit function. E/I imbalances that result from perturbations in the development of this system, ranging from the generation of inhibitory neurons to the formation of their synaptic connections, have been implicated in several neurodevelopmental disorders. In this review, we discuss how impairments at different stages in GABAergic development can lead to disease states. We also highlight recent studies which show that modulation of the GABAergic system can successfully reverse cognitive deficits in disease models and suggest that therapeutic strategies targeting the GABAergic system could be effective in treating neurodevelopmental disorders.     

Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism

Background

Clearance at the blood-brain barrier (BBB) plays an important role in removal of Alzheimer’s amyloid-β (Aβ) toxin from brain both in humans and animal models. Apolipoprotein E (apoE), the major genetic risk factor for AD, disrupts Aβ clearance at the BBB. The cellular and molecular mechanisms, however, still remain unclear, particularly whether the BBB-associated brain capillary pericytes can contribute to removal of aggregated Aβ from brain capillaries, and whether removal of Aβ aggregates by pericytes requires apoE, and if so, is Aβ clearance on pericytes apoE isoform-specific.

Methods

We performed immunostaining for Aβ and pericyte biomarkers on brain capillaries (<?6 μm in diameter) on tissue sections derived from AD patients and age-matched controls, and APP^Swe/0 mice and littermate controls. Human Cy3-Aβ42 uptake by pericytes was studied on freshly isolated brain slices from control mice, pericyte LRP1-deficient mice (Lrp^lox/lox;Cspg4-Cre) and littermate controls. Clearance of aggregated Aβ42 by mouse pericytes was studied on multi-spot glass slides under different experimental conditions including pharmacologic and/or genetic inhibition of the low density lipoprotein receptor related protein 1 (LRP1), an apoE receptor, and/or silencing mouse endogenous Apoe in the presence and absence of human astrocyte-derived lipidated apoE3 or apoE4. Student’s t-test and one-way ANOVA followed by Bonferroni's post-hoc test were used for statistical analysis.

Results

First, we found that 35% and 60% of brain capillary pericytes accumulate Aβ in AD patients and 8.5-month-old APP^Sw/0 mice, respectively, compared to negligible uptake in controls. Cy3-Aβ42 species were abundantly taken up by pericytes on cultured mouse brain slices via LRP1, as shown by both pharmacologic and genetic inhibition of LRP1 in pericytes. Mouse pericytes vigorously cleared aggregated Cy3-Aβ42 from multi-spot glass slides via LRP1, which was inhibited by pharmacologic and/or genetic knockdown of mouse endogenous apoE. Human astrocyte-derived lipidated apoE3, but not apoE4, normalized Aβ42 clearance by mouse pericytes with silenced mouse apoE.

Conclusions

Our data suggest that BBB-associated pericytes clear Aβ aggregates via an LRP1/apoE isoform-specific mechanism. These data support the role of LRP1/apoE interactions on pericytes as a potential therapeutic target for controlling Aβ clearance in AD.

     

国产合瓣花植物名称的后选模式指定——Ⅱ. 报春花科、龙胆科、马鞭草科、唇形科

在整理保存于中国科学院植物研究所中国国家植物标本馆（PE）的国产合瓣花植物模式标本时,根据《国际藻类、菌类、植物命名法规》（墨尔本法规）规则9.5,发现在报春花科中的小点地梅、羽叶点地梅和狭萼报春,龙胆科中的福建龙胆、云雾龙胆、大花深红龙胆、管花秦艽、五台山龙胆和四数獐牙菜,马鞭草科中的三花莸,唇形科中的白苞筋骨草、甘青青兰、血盆草和宽苞峨眉鼠尾草名称的模式为合模式。遵照规则8.1、9.11和9.12,以及辅则9A.3的精神,对这14个名称做出后选模式指定。     

Biodegradation of pyrazosulfuron-ethyl by <Emphasis Type="Italic">Acinetobacter</Emphasis> sp. CW17

The pyrazosulfuron-ethyl-degrading bacterium, designated as CW17, was isolated from contaminated soil near the warehouse of the factory producing pyrazosulfuron-ethyl in Changsha city, China. The strain CW17 was identified as Acinetobacter sp. based on analyses of 94 carbon source utilization or chemical sensitivity in Biolog microplates, conventional phenotypic characteristics, and 16S rRNA gene sequencing. When pyrazosulfuron-ethyl was provided as the sole carbon source, the effects of pyrazosulfuron-ethyl concentration, pH, and temperature on biodegradation were examined. The degradation rates of pyrazosulfuron-ethyl at initial concentrations of 5.0, 20.0, and 50.0 mg/L were 48.0%, 77.0%, and 32.6%, respectively, after inoculation for 7 days. The growth of the strain was inhibited at low pH buffers. The chemical degradation occurs much faster at low pH than at neutral and basic pH conditions. The degradation rate of pyrazosulfuron-ethyl at 30°C was faster than those at 20 and 37°C by CW17 strains. Two metabolites of degradation were analyzed by liquid chromatography–mass spectroscopy (LC/MS). Based on the identified products, strain CW17 seemed to be able to degrade pyrazosulfuron-ethyl by cleavage of the sulfonylurea bridge.     

An integrated model for simulating interactive thermal processes in human–clothing system

Stolwijk's multi-node model is modified by considering the sweat accumulation on the skin surface and is applied to simulate the human physiological regulatory response. This human model is interfaced with a coupled heat and moisture model of clothing materials that takes into consideration the adsorption of water vapor in the fibers. Furthermore, a multi-layer clothing system is developed and integrated with the human model. The result agrees well with the published experimental data.