Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity

Recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson’s disease. Nevertheless, it is currently unknown whether microglial activation constitutes a primary event in neurodegeneration. We generated a new mouse model by lentiviral-mediated selective α-synuclein (αSYN) accumulation in microglial cells. Surprisingly, these mice developed progressive degeneration of dopaminergic (DA) neurons without endogenous αSYN aggregation. Transcriptomics and functional assessment revealed that αSYN-accumulating microglial cells developed a strong reactive state with phagocytic exhaustion and excessive production of oxidative and proinflammatory molecules. This inflammatory state created a molecular feed-forward vicious cycle between microglia and IFNγ-secreting immune cells infiltrating the brain parenchyma. Pharmacological inhibition of oxidative and nitrosative molecule production was sufficient to attenuate neurodegeneration. These results suggest that αSYN accumulation in microglia induces selective DA neuronal degeneration by promoting phagocytic exhaustion, an excessively toxic environment and the selective recruitment of peripheral immune cells.

Stress-induced collective behavior leads to the formation of multicellular structures and the survival of the unicellular alga Chlamydomonas

Depending on their nature, living organisms use various strategies to adapt to environmental stress conditions. Multicellular organisms implement a set of reactions involving signaling and cooperation between different types of cells. Unicellular organisms on the other hand must activate defense systems, which involve collective behaviors between individual organisms. In the unicellular model alga Chlamydomonas reinhardtii, the existence and the function of collective behavior mechanisms in response to stress remain largely unknown. Here we report the discovery of a mechanism of abiotic stress response that Chlamydomonas can trigger to form large multicellular structures that can comprise several thousand cells. We show that these aggregates constitute an effective bulwark within which the cells are efficiently protected from the toxic environment. We have generated the first family of mutants that aggregate spontaneously, the socializer mutants (saz), of which we describe here in detail saz1. We took advantage of the saz mutants to implement a large scale multiomics approach that allowed us to show that aggregation is not the result of passive agglutination, but rather genetic reprogramming and substantial modification of the secretome. The reverse genetic analysis we conducted on some of the most promising candidates allowed us to identify the first positive and negative regulators of aggregation and to make hypotheses on how this process is controlled in Chlamydomonas.

Development of Polymer-Assisted Nanoparticles and Nanogels for Cancer Therapy: An Update

With cancer remaining as one of the main causes of deaths worldwide, many studies are undergoing the effort to look for a novel and potent anticancer drug. Nanoparticles (NPs) are one of the rising fields in research for anticancer drug development. One of the key advantages of using NPs for cancer therapy is its high flexibility for modification, hence additional properties can be added to the NPs in order to improve its anticancer action. Polymer has attracted considerable attention to be used as a material to enhance the bioactivity of the NPs. Nanogels, which are NPs cross-linked with hydrophilic polymer network have also exhibited benefits in anticancer application. The characteristics of these nanomaterials include non-toxic, environment-friendly, and variable physiochemical properties. Some other unique properties of polymers are also attributed by diverse methods of polymer synthesis. This then contributes to the unique properties of the nanodrugs. This review article provides an in-depth update on the development of polymer-assisted NPs and nanogels for cancer therapy. Topics such as the synthesis, usage, and properties of the nanomaterials are discussed along with their mechanisms and functions in anticancer application. The advantages and limitations are also discussed in this article.

Comparison of Fecal Microbiota of Horses Suffering from Atypical Myopathy and Healthy Co-Grazers

Equine atypical myopathy (AM) is caused by hypoglycin A (HGA) and methylenecyclopropylglycine (MCPG) intoxication resulting from the ingestion of seeds or seedlings of some Acer tree species. Interestingly, not all horses pasturing in the same toxic environment develop signs of the disease. In other species, it has been shown that the intestinal microbiota has an impact on digestion, metabolism, immune stimulation and protection from disease. The objective of this study was to characterize and compare fecal microbiota of horses suffering from AM and healthy co-grazers. Furthermore, potential differences in fecal microbiota regarding the outcome of diseased animals were assessed. This prospective observational study included 59 horses with AM (29 survivors and 30 non-survivors) referred to three Belgian equine hospitals and 26 clinically healthy co-grazers simultaneously sharing contaminated pastures during spring and autumn outbreak periods. Fresh fecal samples (rectal or within 30 min of defecation) were obtained from all horses and bacterial taxonomy profiling obtained by 16S amplicon sequencing was used to identify differentially distributed bacterial taxa between AM-affected horses and healthy co-grazers. Fecal microbial diversity and evenness were significantly (p < 0.001) higher in AM-affected horses as compared with their non-affected co-grazers. The relative abundance of families Ruminococcaceae, Christensenellaceae and Akkermansiaceae were higher (p ≤ 0.001) whereas those of the Lachnospiraceae (p = 0.0053), Bacteroidales (p < 0.0001) and Clostridiales (p = 0.0402) were lower in horses with AM, especially in those with a poor prognosis. While significant shifts were observed, it is still unclear whether they result from the disease or might be involved in the onset of disease pathogenesis.

NUCLEAR DEGENERATION AS A BY-PRODUCT OF AGING AND ENVIRONMENT

Background: The process of aging in the immediate toxic environment occurring in this Industrialized world is detrimental for human body. This is accelerating aging process and at the cellular level, the toxins present in environment are inducing chromosomal(micronuclei) and nuclear degenerative changes (karyorrhexis, karyolysis, pyknosis, condensed chromatin). The given study evaluates the effects of aging and environment on the chromosomal/nuclear degenerative changes, thus affecting the exfoliated cells collected from buccal mucosa. Methods: The sample included 86 healthy subjects divided into two groups according to age: 46 women aged above 60 years and 40 women of 20- 25 years of age. A questionnaire was prepared to retrieve all the data related to health and drug related history. Buccal smears were prepared and stained with both Papanicolaou and H&E stain. Hundred cells were counted from each slide to determine the number of micronuclei and other nuclear degenerative changes. Results: The number of micronuclei and other nuclear degenerative changes were signicantly higher among the elderly women (p<0.05) when compared with young women volunteers. Conclusion: Aging along with environmental factors appear to be detrimental in inducing mutagenic/ genotoxic effects at the cellular level. Cytological evaluation is clearly indicative of nuclear changes evident with aging.