Alzheimer’s Disease Animal Models: Elucidation of Biomarkers and Therapeutic Approaches for Cognitive Impairment

Alzheimer’s disease (AD) is an age-related and progressive neurodegenerative disorder. It is widely accepted that AD is mainly caused by the accumulation of extracellular amyloid β (Aβ) and intracellular neurofibrillary tau tangles. Aβ begins to accumulate years before the onset of cognitive impairment, suggesting that the benefit of currently available interventions would be greater if they were initiated in the early phases of AD. To understand the mechanisms of AD pathogenesis, various transgenic mouse models with an accelerated accumulation of Aβ and tau tangles have been developed. However, none of these models exhibit all pathologies present in human AD. To overcome these undesirable phenotypes, APP knock-in mice, which were presented with touchscreen-based tasks, were developed to better evaluate the efficacy of candidate therapeutics in mouse models of early-stage AD. This review assesses several AD mouse models from the aspect of biomarkers and cognitive impairment and discusses their potential as tools to provide novel AD therapeutic approaches.     

An Engineered sgsh Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA

Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH) resulting in impaired catabolism of heparan sulfate glycosaminoglycan (HS GAG) and its accumulation in tissues. MPS IIIA represents a significant proportion of childhood dementias. This condition generally leads to patient death in the teenage years, yet no effective therapy exists for MPS IIIA and a complete understanding of the mechanisms of MPS IIIA pathogenesis is lacking. Here, we employ targeted CRISPR/Cas9 mutagenesis to generate a model of MPS IIIA in the zebrafish, a model organism with strong genetic tractability and amenity for high-throughput screening. The sgsh^Δex5−6 zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. sgsh^Δex5−6 zebrafish faithfully recapitulate diverse CNS-specific features of MPS IIIA, including neuronal lysosomal overabundance, complex behavioural phenotypes, and profound, lifelong neuroinflammation. We further demonstrate that neuroinflammation in sgsh^Δex5−6 zebrafish is largely dependent on interleukin-1β and can be attenuated via the pharmacological inhibition of Caspase-1, which partially rescues behavioural abnormalities in sgsh^Δex5−6 mutant larvae in a context-dependent manner. We expect the sgsh^Δex5−6 zebrafish mutant to be a valuable resource in gaining a better understanding of MPS IIIA pathobiology towards the development of timely and effective therapeutic interventions.     

Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair

Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies.     

包结拆分在手性药物分离中的机理与应用

对外消旋体药物进行分离拆分是获取手性药物的重要方法。探讨了环糊精体系包结拆分法的机理，并对运用其机理于手性药物分离中的应用作了探讨。     

拆坝对河流生态系统的影响及评估方法综述

为研究拆坝对河流生态系统造成的影响,从短期和长期两个时间尺度综合分析了河流水文情势、地形地貌、岸边带植物、鱼类和底栖动物等关键生态因子对拆坝的响应,并总结了目前拆坝对生态系统影响的两种主要评估方法。认为根据实际拆坝情况进行评估和基于数值模型进行预测两种评估方法中,实地观测是最直接、最有说服力的研究方法,但受成本和一些不可控因素限制;数值模拟具有速度快、费用低、无比尺影响等优点,可对拆坝影响进行预测,为管理者提供参考,但精度和准确性有待提高。指出后续研究中应综合考虑拆坝过程中各生态因子间的耦合效应,需对不同拆坝时机和分阶段拆坝方式对河流生态系统的影响进行深入研究。     

色谱技术在中药标准品制备中的应用

色谱技术是天然产物研究中重要的分离和纯化方法。本文介绍了色谱法，并综述了其在中药标准品制备中的应用，最后对此进行了展望。     

天然药物在现代医疗保健中的地位和作用

世界天然药物市场主要集中在美国、欧洲和亚洲三大区域,全球植物药市场的年销售额已达270亿美元。在过去的10年间,以植物制剂为主体的天然药物开始走俏西方。面对“回归自然”的世界潮流,采用现代科学技术,实现中药现代化和国际化,将为人类现代医疗保健做出重大贡献。     

The allelopathic mechanisms of dominance in bracken (Pteridium aquilinum) in Southern California

Bracken,Pteridium aquilinum, exerts a strong dominance over associated plants throughout much of its worldwide range. Associated plants are often severely inhibited or even excluded from dense stands of the fern. This study investigated the various aspects of herb suppression in bracken stands and assessed the contribution of the various forms of interference between plants to the establishment and maintenance of bracken dominance. It was shown that competition for soil moisture, light, and nutrients could not account for the lack of herbs in bracken stands. Further, uniformity of soil pH, texture, water-holding capacity, and organic matter content ruled out variability in physical factors as a cause. Baiting and trapping experiments showed that the higher concentration of animal activity inside the bracken stands contributed significantly to the pattern of herb suppression, but only against select species. The maintenance of this pattern in the animal-free Santa Cruz Island stands indicates the importance of another factor, allelopathy. It was found that phytotoxins leached from the dead, standing bracken fronds with the first few rains of the wet season were largely responsible for herb suppression. These toxins were isolated in raindrip and from soil inside the fern stands. Removal of the fronds from the stand before the rains could leach them resulted in reinvasion by the herbs after several seasons, and, conversely, placing fronds over the herbs in the grassland brought about herb inhibition. A number of known allelopathic chemicals were tentatively identified from bracken leachates. The importance of the interaction of allelopathy with other factors of plant interference is illustrated by bracken.     

Evaluation of methods of measurement of nitrogen in poultry and animal manures

Kjeldahl nitrogen (N), total N and forms of inorganic N (ammoniacal (NH₄)-N, nitrate (NO₃)-N and nitrite (NO₂)-N) were measured in a range of animal manures. The manures include fresh samples of poultry manure, sheep manure, horse manure, dairy slurry and pig slurry and composted poultry manure. Kjeldahl N was measured by standard micro-Kjeldahl digestion. For total N measurements, NO₃-N and NO₂-N were recovered during Kjeldahl digestion by pretreatments with various oxidizing and reducing agents. Inorganic forms of N were measured by extraction with 2M KCl solution.Kjeldahl digestion alone allowed measurement only of organic N and NH₄-N. Amongst various modifications to the Kjeldahl, pretreatment with either acidified (H₂SO₄) Zn-CrK(SO₄)₂ or acidified (H₂SO₄) reduced Fe achieved complete recovery of NO₃-N. Nitrite N was only recovered by first oxidising the NO ₂ ^- to NO ₃ ^- with KMnO₄ followed by reduction to NH₄-N with acidified (H₂SO₄) reduced Fe.More than 95% of the total N in fresh animal manure was present as organic N and NH₄-N which were recovered by the standard Kjeldahl digestion. In the case of fresh manures there was no difference between the amount of total N measured by the Kjeldahl digestion and its modified methods. However composting of poultry manure or drying of poultry manure, pig slurry and dairy slurry resulted in an increase in NO₃-N which was not recovered during Kjeldahl digestion alone. Under these conditions the total N could be measured by pretreating the samples with KMnO₄ and reduced Fe prior to Kjeldahl digestion.Drying of animal manures caused a decrease in organic N and NH₄-N, especially in poultry, pig and dairy manures. There was a slight increase in NO₃-N; but most of the decrease in N content with drying was attributed to the volatilization loss of ammonia (NH₃). Amongst various drying methods examined air drying caused maximum loss of N as NH₃ whereas freeze drying caused minimum loss of N. This suggests that fresh animal manures can be freeze dried for analysis of N which causes minimum loss of N.     

Synthesis of Organotin Polyamine Ethers Containing Acyclovir and their Preliminary Anticancer and Antiviral Activity

Organotin polyamine ethers containing acyclovir in their backbone were synthesized in moderate to high yield employing the aqueous interfacial polycondensation system. The products are high molecular weight polymers. Infrared spectroscopy of the products shows new bands characteristic of the formation of Sn–N and Sn–O bonds consistent with the proposed structure. MALDI-TOF MS below 2000 Da shows the presence of organotin and acyclovir units containing these two moieties. The products show moderate inhibition of a number of cancer cell lines and exhibit the ability to inhibit a number of viruses, particularly the herpes simplex virus-1 and varicella zoster virus that are responsible for herpes, chicken pox and shingles.