DISC1-related signaling pathways in adult neurogenesis of the hippocampus

Disrupted-in-schizophrenia 1 (DISC1) is a multifunctional scaffold protein which plays an important role in neurogenesis and neural development in the adult brain, especially in the dentate gyrus (DG) of the hippocampus. Accumulated research has unveiled the role of DISC1 in several aspects of neural development and neurogenesis, such as neuronal maturation, proliferation, migration, positioning, differentiation, dendritic growth, axonal outgrowth, and synaptic plasticity. Studies on the function of this protein have explored multiple facets, including variants and missense mutants in genetics, proteins interactivity and signaling pathways in molecular biology, and pathogenesis and treatment targets of major mental illness, and more. In this review, we present several signaling pathways discussed in recent research, such as the AKT signaling pathway, GABA signaling pathway, GSK3β signaling pathway, Wnt signaling pathway, and NMDA-R signaling pathway. DISC1 interacts, directly or indirectly, with these signaling pathways and they co-regulate the process of adult neurogenesis in the hippocampus.     

Sex differences in oxytocin receptor binding in forebrain regions: Correlations with social interest in brain region- and sex- specific ways

Social interest reflects the motivation to approach a conspecific for the assessment of social cues and is measured in rats by the amount of time spent investigating conspecifics. Virgin female rats show lower social interest towards unfamiliar juvenile conspecifics than virgin male rats. We hypothesized that the neuropeptide oxytocin (OT) may modulate sex differences in social interest because of the involvement of OT in pro-social behaviors. We determined whether there are sex differences in OT system parameters in the brain and whether these parameters would correlate with social interest. We also determined whether estrus phase or maternal experience would alter low social interest and whether this would correlate with changes in OT system parameters. Our results show that regardless of estrus phase, females have significantly lower OT receptor (OTR) binding densities than males in the majority of forebrain regions analyzed, including the nucleus accumbens, caudate putamen, lateral septum, bed nucleus of the stria terminalis, medial amygdala, and ventromedial hypothalamus. Interestingly, male social interest correlated positively with OTR binding densities in the medial amygdala, while female social interest correlated negatively with OTR binding densities in the central amygdala. Proestrus/estrus females showed similar social interest to non-estrus females despite increased OTR binding densities in several forebrain areas. Maternal experience had no immediate or long-lasting effects on social interest or OT brain parameters except for higher OTR binding in the medial amygdala in primiparous females. Together, these findings demonstrate that there are robust sex differences in OTR binding densities in multiple forebrain regions of rats and that OTR binding densities correlate with social interest in brain region- and sex-specific ways.     

Synthesis of novel acridine and bis acridine sulfonamides with effective inhibitory activity against the cytosolic carbonic anhydrase isoforms II and VII

4-Amino-N-(4-sulfamoylphenyl)benzamide was synthesized by reduction of 4-nitro-N-(4-sulfamoylphenyl)benzamide and used to synthesize novel acridine sulfonamide compounds, by a coupling reaction with cyclic-1,3-diketones and aromatic aldehydes. The new compounds were investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), and more precisely the cytosolic isoforms hCA I, II and VII. hCA I was inhibited in the micromolar range by the new compounds (K_Is of 0.16–9.64 μM) whereas hCA II and VII showed higher affinity for these compounds, with K_Is in the range of 15–96 nM for hCA II, and of 4–498 nM for hCA VII. The structure–activity relationships for the inhibition of these isoforms with the acridine–sulfonamides reported here were also elucidated.     

Nucleostemin基因在卵巢上皮性肿瘤的表达及与病理分型的关系

目的：研究核干细胞因子Nucleostemin（NS）基因在卵巢上皮性肿瘤中的表达,探讨其与肿瘤病理分型的关系。方法：采用RT-PCR及Western blot检测36例卵巢癌组织手术标本,32例卵巢良性上皮肿瘤组织手术标本,12例正常卵巢组织标本中Nu-cleostemin基因及相应蛋白的表达,采用分组对照的方法对比3组样本中NS基因及蛋白的表达情况,并进行相对定量研究。采用统计学方法检测NS基因的表达是否与临床病理分级及血清CA125存在关联。结果：①卵巢癌组织中NS的阳性表达率显著高于良性肿瘤组织及正常卵巢组织;②卵巢癌组织中,淋巴结转移组NS的表达水平高于未转移组;③临床分期Ⅲ期组的表达水平高于ⅠB期组;④中、低分化组的表达水平高于高分化组。结论：卵巢癌组织中存在NS基因的高表达,其表达量与组织类型无关,而与临床TNM分期及组织分级正相关。     

地高辛对老年慢性心衰患者血清CA125，BNP及MMP-9 水平的影响

目的:探讨地高辛片对老年慢性心力衰竭患者血清血清糖类抗原(CA125)、心钠肽(ANP)、脑钠肽(BNP)、基质金属蛋白酶9(MMP-9)及金属蛋白酶组织抑制剂(TIMP-1)水平的影响。方法:收集我院老年慢性心力衰竭患者100例,随机分为对照组和实验组,每组各50例,对照组患者给予常规治疗,实验组患者在对照组的基础上给予地高辛片。比较治疗前后两组患者血清糖类抗原(CA125)、心钠肽(ANP)、脑钠肽(BNP)、基质金属蛋白酶9(MMP-9)及金属蛋白酶组织抑制剂(TIMP-1)水平。结果:与治疗前相比,两组患者血清CA125、ANP、BNP及MMP-9水平降低,TIMP-1水平升高(P0.05);治疗后与对照组相比,实验组CA125水平(34.05±4.63)较低,ANP水平较低(216.98±27.65),BNP水平较低(437.62±45.26),MMP-9水平较低(550.17±65.15),TIMP-1水平较高(182.32±21.78)(P0.05)。结论:地高辛片能够改善老年慢性心力衰竭患者心肌功能,推测其机制可能与降低血清CA125、ANP、BNP、MMP-9水平,升高TIMP-1水平有关。     

Conveying Advanced Li‐ion Battery Materials into Practice The Impact of Electrode Slurry Preparation Skills

Li‐ion batteries (LIB's) are of the greatest practical utility for portable electronics and electric vehicles (EV's). LIB energy, power and cycle life performances depend on cathode and anode compositions and morphology, electrolyte composition and the overall cell design. Electrode morphology is influenced by the shape and size of the active material (AM), conductive additive (CA) particles, the polymeric binder properties, and also on the AM/CA/binder mass ratio. At the same time, it also substantially depends on the electrode preparation process. This process is usually comprised of mixing a solvent, a binder, AM and CA powders, and casting the resulting slurry onto a current collector foil followed by a drying process. Whereas the problems of electrode morphology and their influence on the LIB‐electrode performance always receive a proper attention, the influence of slurry properties and slurry preparation techniques on the electrode morphology is often overlooked or at least underrated. The present work summarizes the current state‐of‐the‐art in the field of LIB‐electrode precursor slurries preparation, characterized by multicomponent compounds and large variations in sizes and shapes of the solid components. Approaches to LIB‐electrode slurry preparation are outlined and discussed in the context of the ultimate LIB‐electrode morphology and performance.     

The Tau/A152T mutation,a risk factor for frontotemporal‐spectrum disorders,leads to NR2B receptor‐mediated excitotoxicity

We report on a novel transgenic mouse model expressing human full‐length Tau with the Tau mutation A152T (hTau^AT), a risk factor for FTD‐spectrum disorders including PSP and CBD. Brain neurons reveal pathological Tau conformation, hyperphosphorylation, mis‐sorting, aggregation, neuronal degeneration, and progressive loss, most prominently in area CA3 of the hippocampus. The mossy fiber pathway shows enhanced basal synaptic transmission without changes in short‐ or long‐term plasticity. In organotypic hippocampal slices, extracellular glutamate increases early above control levels, followed by a rise in neurotoxicity. These changes are normalized by inhibiting neurotransmitter release or by blocking voltage‐gated sodium channels. CA3 neurons show elevated intracellular calcium during rest and after activity induction which is sensitive to NR2B antagonizing drugs, demonstrating a pivotal role of extrasynaptic NMDA receptors. Slices show pronounced epileptiform activity and axonal sprouting of mossy fibers. Excitotoxic neuronal death is ameliorated by ceftriaxone, which stimulates astrocytic glutamate uptake via the transporter EAAT2/GLT1. In summary, hTau^AT causes excitotoxicity mediated by NR2B‐containing NMDA receptors due to enhanced extracellular glutamate.     

Kinetic and in silico studies of hydroxy-based inhibitors of carbonic anhydrase isoforms I and II

A series of hydroxy and phenolic compounds have been assayed for the inhibition of two physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II. The investigated molecules showed inhibition constants in the range of 1.07–4003 and 0.09–31.5?μM at the hCA I and hCA II enzymes, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico studies were also applied. Molecular docking scores of the studied compounds are compared using three different scoring algorithms, namely Glide/SP, Glide/XP and Glide/IFD. In addition, different ADME (absorption, distribution, metabolism and excretion) analysis was performed. All the examined compounds were found within the acceptable range of pharmacokinetic profiles.