Functional genomics of brain aging and Alzheimer's disease: focus on selective neuronal vulnerability

Pivotal brain functions, such as neurotransmission, cognition, and memory, decline with advancing age and, especially, in neurodegenerative conditions associated with aging, such as Alzheimer's disease (AD). Yet, deterioration in structure and function of the nervous system during aging or in AD is not uniform throughout the brain. Selective neuronal vulnerability (SNV) is a general but sometimes overlooked characteristic of brain aging and AD. There is little known at the molecular level to account for the phenomenon of SNV. Functional genomic analyses, through unbiased whole genome expression studies, could lead to new insights into a complex process such as SNV. Genomic data generated using both human brain tissue and brains from animal models of aging and AD were analyzed in this review. Convergent trends that have emerged from these data sets were considered in identifying possible molecular and cellular pathways involved in SNV. It appears that during normal brain aging and in AD, neurons vulnerable to injury or cell death are characterized by significant decreases in the expression of genes related to mitochondrial metabolism and energy production. In AD, vulnerable neurons also exhibit down-regulation of genes related to synaptic neurotransmission and vesicular transport, cytoskeletal structure and function, and neurotrophic factor activity. A prominent category of genes that are up-regulated in AD are those related to inflammatory response and some components of calcium signaling. These genomic differences between sensitive and resistant neurons can now be used to explore the molecular underpinnings of previously suggested mechanisms of cell injury in aging and AD.     

手术室术前访视应用ipad对访视效果影响的研究

目的：探讨术前访视应用ipad在术前访视中对手术患者心理状态的影响。方法：将300例择期手术患者随机分为对照组（150例）和实验组（150例）,对照组采用常规术前访视方案;实验组在此基础上结合ipad展示围术期相关信息,采用焦虑自量表评估两组病人入院时和入手术室时的焦虑状况及血压、心率等指标,并且进行术后并发症和满意度的调查。结果：改良术前访视后焦虑评分、收缩压、舒张压、心率实验组明显低于对照组。结论：术前访视应用ipad可明显减轻手术病人术前的焦虑。     

Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)

The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX₁R/OX₂R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.     

弥散张量成像对脑室周围白质软化患儿术后脑白质恢复的评估作用

目的:研究弥散张量成像(DTI)对脑室周围白质软化(PVL)患儿选择性脊神经后根切除术(SPR)后脑白质恢复的评估价值。方法:选取从2014年1月至2015年8月在新疆医科大学二附院脑瘫中心择期行SPR手术治疗的PVL患儿40例作为观察组,另选同期磁共振成像(MRI)检查正常儿童40例作为对照组,两组分别在手术前后进行DTI检查,比较两组不同部位的部分各向异性值(FA)及表观弥散系数(ADC)。结果:术前观察组不同部位的FA值均显著低于对照组,胼胝体压部的ADC值显著高于对照组,差异均有统计学意义(P0.05)。与术前比较,术后观察组不同部位的FA值均上升,胼胝体压部的ADC值下降,差异均有统计学意义(P0.05),且与对照组之间的差异无统计学意义(P0.05)。结论:SPR术能够明显控制PVL患儿的病情,且采用DTI成像技术能够客观地反应PVL患儿SPR术后脑白质恢复情况,对辅助临床治疗和预后评估具有重要作用。     

A quantitative analysis of behavioral selectivity for pulse rise-time in the gray treefrog, Hyla versicolor

The selectivity of female phonotactic responses to synthetic advertisement calls was tested in choice situations. Preferences based on differences in the linear rise-time of synthetic pulses depended on intensity and carrier frequency. When the carrier frequency was 1.1 kHz, simulating the low-frequency peak in the advertisement call, females preferred alternatives with slower rise-time pulses that differed by 5 ms at playback levels of 75 dB SPL and higher. A rise-time difference of 10 ms was discriminated at 65 dB SPL. When the carrier frequency was 2.2 kHz, simulating the high-frequency peak in the call, females discriminated a 5-ms difference in rise-time only at 85 dB SPL. Females showed no preference when the difference was 10 ms at lower playback levels. The difference in the thresholds (about 15–20 dB) for discriminating differences in rise-time at the two carrier frequencies was greater than the difference in behavioral thresholds for these two frequencies (about 10 dB). This result suggests that rise-time discrimination can be mediated solely by the neural channel mainly tuned to the low-frequency peak in the call. Females probably assess differences in rise-time by comparing the first few pulses of each call rather than by averaging over the entire call. Accepted: 30 March 1999     

Directional mutation pressure,mutator mutations,and dynamics of molecular evolution

Using a general form of the directional mutation theory, this paper analyzes the effect of mutations in mutator genes on the G + C content of DNA, the frequency of substitution mutations, and evolutionary changes (cumulative mutations) under various degrees of selective constraints. Directional mutation theory predicts that when the mutational bias between A/T and G/C nucleotide pairs is equilibrated with the base composition of a neutral set of DNA nucleotides, the mutation frequency per gene will be much lower than the frequency immediately after the mutator mutation takes place. This prediction explains the wide variation of the DNA G + C content among unicellular organisms and possibly also the wide intragenomic heterogeneity of third codon positions for the genes of multicellular eukaryotes. The present analyses lead to several predictions that are not consistent with a number of the frequently held assumptions in the field of molecular evolution, including belief in a constant rate of evolution, symmetric branching of phylogenetic trees, the generality of higher mutation frequency for neutral sets of nucleotides, the notion that mutator mutations are generally deleterious because of their high mutation rates, and teleological explanations of DNA base composition. Presented at the NATO Advanced Research Workshop onGenome Organization and Evolution, Spetsai, Greece, 16–22 September 1992     

Genetic tools for selective labeling of proteins with α-15N-amino acids

Summary A collection of genetic tools that can be used to manipulate amino acid metabolism in Escherichia coli is described. The set comprises 21 strains of bacteria, each containing a different genetic defect that is closely linked to a selectable transposon marker. These tools can be used to construct strains of E. coli with ideal genotypes for residue-specific, selective labeling of proteins with nearly any ¹⁵N-amino acid. By using strains which have been modified to contain the appropriate genetic lesions to control amino acid biosynthesis, dilution of the isotope by endogenous amino acid biosynthesis and scrambling of the label to other types of residues can be avoided.Abbreviations ¹⁵N-amino acid -¹⁵N-amino acid - Cam^R chloramphenicol-resistant - DPA diaminopimelic acid - Hfr high-frequency recombinant - LB Luria broth - Kan^R kanamycin resistant - P1 bacteriophage P1 - pfu plaque-forming units - Str^R streptomycin-resistant - Tet^R tetracycline-resistant     

Seasonal selectivity of Magellanic horned owl (Bubo magellanicus) on rodents

This study examines prey selection by Magellanic horned owls (Bubo magellanicus) in an ecotonal steppe area of northwestern Argentine Patagonia, and analyzes morphological and behavioral traits of the owls main rodent prey. The owls diet was studied for two years, along with field estimates of rodent abundance. The frequency distribution of rodents was significantly different from that estimated from trapping, indicating that Magellanic horned owl behaved as a selective predator. Eligmodontia morgani and Abrothrix xanthorhinus, the smallest species inhabiting open areas, were consumed in lower proportion than their occurrence estimated from the trapped sample, whereas the larger Abrothrix longipilis and Oligoryzomys longicaudatus, which inhabited bushy habitats, were eaten in a greater proportion than their estimated abundance. It is suggested that distinctive morphological and behavioral characteristics among prey interacting with the owl hunting strategy, accounted for their differential vulnerability to predation.     

Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase

To develop potent and selective nNOS inhibitors, a new series of double-headed molecules with chiral linkers that derive from natural amino acid derivatives have been designed and synthesized. The new structures integrate a thiophenecarboximidamide head with two types of chiral linkers, presenting easy synthesis and good inhibitory properties. Inhibitor (S)-9b exhibits a potency of 14.7 nM against nNOS and is 1134 and 322-fold more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 9b and propionate A on the heme and tetrahydrobiopterin (H₄B) in nNOS, but not eNOS, contributes to its high selectivity. This work demonstrates the advantage of integrating known structures into structure optimization, and it should be possible to more readily develop compounds that incorporate bioavailability with these advanced features. Moreover, this integrative strategy is a general approach in new drug discovery.     

Studies on evolutionary and selective properties of hypercycles using a Monte Carlo method

Summary The most relevant properties of hypercycles were previously studied mainly from a theoretical point of view. We have developed a Monte Carlo method simulating hypercyclic organization to obtain information about the dynamics of this prebiotic organization. Nucleation, growth, and selective properties have been tested and the results obtained are in good agreement with those of the theoretical predictions. The influence of hypercyclic organization of the error threshold has also been studied. As a consequence of the emergence of a hypercycle, the value of this threshold decreases. The amount of this decrease depends on the population size. Moreover, for some interval of quality factor values, either the hypercycle organization or an error catastrophe can be produced, depending on the initial conditions. The influence of these phenomena on both the dynamic behavior and evolutionary advantages of the hypercycle, as well as their decisive roles on genome size, are discussed.Presented at the FEBS Symposium on Genome Organization and Evolution, held in Crete, Greece, September 1–5, 1986