Free D- and L-amino acids in ventricular cerebrospinal fluid from Alzheimer and normal subjects

Summary Free D-Ser, D-Asp and total D-amino acids were significantly higher (p < 0.05) in Alzheimer (AD) ventricular CSF than in normal CSF. There was no significant difference in the total L-amino acids between AD and normal CSF, but L-Gln and L-His were significantly higher (p < 0.05) in ADCSF. The higher concentrations of these D- and L-amino acids in AD ventricular CSF could reflect the degenerative process that occurs in Alzheimer's brain since ventricular CSF is the repository of amino acids from the brain.     

Concepts of nematode-fungus associations in plant disease complexes: a review

Plant parasitic nematodes interact with fungi in a variety of ways to cause plant disease complexes. Even some nonplant parasitic nematodes are able to carry fungal spores internally which not only increases their mobility, but also protects them from fungicides. Plant parasitic nematodes frequently wound plants in the process of penetration and feeding. These wounds become subject to infection by fungal pathogens that require aid in penetrating their host. Other nematodes modify plant tissue in such a way that it becomes a better substrate for the fungus and thus increases their growth and reproduction to the detriment of the host. Quantitative and qualitative changes in root exudate which are induced by certain nematodes stimulate the germination, growth, and reproduction of fungal propagules in the rhizosphere. These exudates may also indirectly inhibit components of the rhizosphere microflora (e.g., actinomycetes) which are antagonistic to some plant pathogens. Depending on the species of nematode and fungus, concomitant infections may stimulate nematode reproduction (Pratylenchus-Verticillium) or inhibit reproduction (Heterodera-Fusarium).     

Frequent genes in rare diseases: panel‐based next generation sequencing to disclose causal mutations in hereditary neuropathies

Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot‐Marie‐Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X‐linked inheritance. The most frequently affected genes were PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 with a declining frequency. Thirty‐four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC2. One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time‐ and cost‐effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations.

     

Phenanthridin-6-one derivatives as the first class of non-steroidal pharmacological chaperones for Niemann-Pick disease type C1 protein

Niemann-Pick disease type C is a fatal, progressive neurodegenerative disease mostly caused by mutations in Nieamnn-Pick type C1 (NPC1), a late endosomal membrane protein that is essential for intracellular cholesterol transport. The most prevalent mutation, I1061T (Ile to Thr), interferes with the protein folding process. Consequently, mutated but intrinsically functional NPC1 proteins are prematurely degraded via proteasome, leading to loss of NPC1 function. Previously, we reported sterol derivatives as pharmacological chaperones for NPC1, and showed that these derivatives can normalize folding-defective phenotypes of I1061T NPC1 mutant by directly binding to, and stabilizing, the protein. Here, we report a series of compounds containing a phenanthridin-6-one scaffold as the first class of non-steroidal pharmacological chaperones for NPC1. We also examined their structure-activity relationships.     

Mitochondrial Dysfunction and Oxidative Stress in Parkinson’s Disease

Environmental toxins, genetic predisposition and old age are major risk factors for Parkinson’s disease (PD). Although the mechanism(s) underlying selective dopaminergic (DA) neurodegeneration remain unclear, molecular studies in both toxin based models and genetic based models of the disease suggest a major etiologic role for mitochondrial dysfunction in the pathogenesis of PD. Further, recent studies have presented clear evidence for a high burden of mtDNA deletions within the substantia nigra neurons in individuals with PD. Ultimately, an understanding of the molecular events which precipitate DA neurodegeneration in idiopathic PD will enable the development of targeted and effective therapeutic strategies. We review recent advances and current understanding of the genetic factors, molecular mechanisms and animal models of PD.     

植物病媒昆虫的翅型分化

翅多型现象是昆虫非遗传多型性的一种表现,包括不具飞行能力的短翅型或无翅型,以及可以进行长距离迁飞的长翅型或有翅型。翅多型现象常发生在可以携带病原并将其传播给植物宿主的媒介昆虫中,对植物病害的时空分布与暴发有重要影响。本文从翅型分化的遗传规律、诱导因素、分子机制和伴随翅型分化的其他生理表现4个方面,对植物病原主要传播媒介蚜虫和飞虱的翅型分化研究进行综述和梳理。昆虫翅型分化的诱导因素主要包括温度、湿度和光周期等非生物因素以及虫口密度、宿主营养、病毒等生物因素;而其内在的分子机制大多是通过胰岛素/胰岛素样生长因子信号(IIS)通路、c-Jun氨基末端激酶(c-Jun NH₂-terminal kinase, JNK)信号通路、Wingless和嗅觉受体SaveOrco等调控。翅型分化的同时伴随着生理状态的变化,表现为短翅型具有更强的繁殖能力和长翅型含有更丰富的飞行肌结构成分。目前,昆虫翅型分化的研究尚不够完善,有许多需要解答的问题,如找到胰岛素/胰岛素样生长因子信号通路中真正发挥功能的靶基因,JNK如何调控翅型分化以及虫媒病毒影响媒介昆虫翅型的分子机理。本综述可为控制虫...     

粪菌移植对非酒精性脂肪肝大鼠肠黏膜的保护作用

目的探讨粪菌移植(fecal microbiota transplantation,FMT)对非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)大鼠肠黏膜屏障的保护作用。方法健康雄性SD大鼠30只,随机分为3组:正常对照组(control group,C组)10只,予正常饮食;高脂模型组(model group,M组)10只、粪菌移植治疗组(treatment group,T组)10只,M组和T组均予高脂饮食。T组予粪菌液灌胃2 mL/次,隔日1次,粪菌液灌胃的前一天晚上及当天早上均予奥美拉唑镁肠溶片灌胃;C组及M组同时予奥美拉唑及生理盐水灌胃。喂养12周后实验结束,测定血中TG、ALT、AST水平;苏丹黑B染色观察肝脏病理学变化;取回肠末端肠组织行HE染色及扫描电镜观察肠黏膜结构变化。结果与M组大鼠相比,T组血清TG、ALT、AST水平降低,差异有统计学意义(均P0.05)。T组大鼠肝脏苏丹黑B染色可见肝细胞内脂肪沉积明显减少,脂肪变性程度较M组减轻。T组大鼠肠组织HE染色肠绒毛轻度水肿,排列较整齐、紧密。扫描电镜中可见T组大鼠肠绒毛形态较饱满,排列比较紧密,微绒毛之间的间隙变小。结论粪菌移植能改善肝功能,减轻肝脏脂肪变,降低肠道通透性,改善肠黏膜屏障功能。     

Unchartered waters: Climate change likely to intensify infectious disease outbreaks causing mass mortality events in marine mammals

Infectious disease emergence has increased significantly over the last 30 years, with mass mortality events (MMEs) associated with epizootics becoming increasingly common. Factors influencing these events have been widely studied in terrestrial systems, but remain relatively unexplored in marine mammals. Infectious disease‐induced MMEs (ID MMEs) have not been reported ubiquitously among marine mammal species, indicating that intrinsic (host) and/or extrinsic (environmental) ecological factors may influence this heterogeneity. We assess the occurrence of ID MMEs (1955–2018) across extant marine mammals (n = 129) in relation to key life‐history characteristics (sociality, trophic level, habitat breadth) and environmental variables (season, sea surface temperature [SST] anomalies, El Niño occurrence). Our results show that ID MMEs have been reported in 14% of marine mammal species (95% CI 9%–21%), with 72% (n = 36; 95% CI 56%–84%) of these events caused predominantly by viruses, primarily morbillivirus and influenza A. Bacterial pathogens caused 25% (95% CI 14%–41%) of MMEs, with only one being the result of a protozoan pathogen. Overall, virus‐induced MMEs involved a greater number of fatalities per event compared to other pathogens. No association was detected between the occurrence of ID MMEs and host characteristics, such as sociality or trophic level, but ID MMEs did occur more frequently in semiaquatic species (pinnipeds) compared to obligate ocean dwellers (cetaceans; χ² = 9.6, p = .002). In contrast, extrinsic factors significantly influenced ID MMEs, with seasonality linked to frequency (χ² = 19.85, p = .0002) and severity of these events, and global yearly SST anomalies positively correlated with their temporal occurrence (Z = 3.43, p = 2.7e‐04). No significant association was identified between El Niño and ID MME occurrence (Z = 0.28, p = .81). With climate change forecasted to increase SSTs and the frequency of extreme seasonal weather events, epizootics causing MMEs are likely to intensify with significant consequences for marine mammal survival.