The Adverse Effects of Air Pollution on the Nervous System

Exposure to ambient air pollution is a serious and common public health concern associated with growing morbidity and mortality worldwide. In the last decades, the adverse effects of air pollution on the pulmonary and cardiovascular systems have been well established in a series of major epidemiological and observational studies. In the recent past, air pollution has also been associated with diseases of the central nervous system (CNS), including stroke, Alzheimer’s disease, Parkinson’s disease, and neurodevelopmental disorders. It has been demonstrated that various components of air pollution, such as nanosized particles, can easily translocate to the CNS where they can activate innate immune responses. Furthermore, systemic inflammation arising from the pulmonary or cardiovascular system can affect CNS health. Despite intense studies on the health effects of ambient air pollution, the underlying molecular mechanisms of susceptibility and disease remain largely elusive. However, emerging evidence suggests that air pollution-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular dysfunction, and alterations in the blood-brain barrier contribute to CNS pathology. A better understanding of the mediators and mechanisms will enable the development of new strategies to protect individuals at risk and to reduce detrimental effects of air pollution on the nervous system and mental health

IL-13Rα2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis

Objective: Previous studies have shown that ulcerative colitis (UC) is associated with the presence of lamina propria non-invariant (Type II) NKT cells producing IL-13 and mediating epithelial cell cytotoxicity. Here we sought to define the antigen(s) stimulating the NKT cells and to quantitate these cells in the UC lamina propria. Design: Detection of Type II NKT cells in UC lamina propria mononuclear cells (LPMC) with lyso-sulfatide loaded tetramer and quantum dot-based flow cytometry and staining. Culture of UC LPMCs with lyso-sulfatide glycolipid to determine sulfatide induction of epithelial cell cytotoxicity, IL-13 production and IL-13Rα2 expression. Blinded quantum dot-based phenotypic analysis to assess UC LPMC expression of IL-13Rα2, CD161 and IL-13. Results: Approximately 36% of UC LPMC were lyso-sulfatide tetramer positive, whereas few, if any, control LPMCs were positive. When tested, the positive cells were also CD3 and IL-13Rα2 positive. Culture of UC LPMC with lyso-sulfatide glycolipid showed that sulfatide stimulates UC LPMC production of IL-13 and induces UC CD161 LPMC-mediated cytotoxicity of activated epithelial cells; additionally, lyso-sulfatide induces enhanced expression of IL-13Rα2. Finally, blinded phenotypic analysis of UC LP MC using multicolour quantum dot-staining technology showed that approximately 60% of the LPMC bear both IL-13Rα2 and CD161 and most of these cells also produce IL-13. Conclusions: These studies show that UC lamina propria is replete with Type II NKT cells responsive to lyso-sulfatide glycolipid and bearing IL-13Rα2. Since lyso-sulfatide is a self-antigen, these data suggest that an autoimmune response is involved in UC pathogenesis

Modulation of purinergic signaling by NPP-type ectophosphodiesterases

Extracellular nucleotides can elicit a wide array of cellular responses by binding to specific purinergic receptors. The level of ectonucleotides is dynamically controlled by their release from cells, synthesis by ectonucleoside diphosphokinases and ectoadenylate kinases, and hydrolysis by ectonucleotidases. One of the four structurally unrelated families of ectonucleotidases is represented by the NPP-type ectophosphodiesterases. Three of the seven members of the NPP family, namely NPP1–3, are known to hydrolyze nucleotides. The enzymatic action of NPP1–3 (in)directly results in the termination of nucleotide signaling, the salvage of nucleotides and/or the generation of new messengers like ADP, adenosine or pyrophosphate. NPP2 is unique in that it hydrolyzes both nucleotides and lysophospholipids and, thereby, generates products that could synergistically promote cell motility. We review here the enzymatic properties of NPPs and analyze current evidence that links their nucleotide-hydrolyzing capability to epithelial and neural functions, the immune response and cell motility

Aberrant Mucin Assembly in Mice Causes Endoplasmic Reticulum Stress and Spontaneous Inflammation Resembling Ulcerative Colitis

Michael McGuckin and colleagues identify two mutations that cause aberrant mucin oligomerization in mice. The resulting phenotype, including endoplasmic reticulum stress, resembles clinical and pathologic features of human ulcerative colitis

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Wnt/β-catenin signaling affects two modes of neurogenesis in the zebrafish olfactory epithelium

Olfactory sensory neurons undergo continuous turnover and the olfactory epithelium (OE) iscapable of efficient regeneration following traumatic injury. We have identified distinct progenitorcell populations in the zebrafish OE that selectively contribute to maintenance and repairneurogenesis. Gene expression analysis during OE regeneration suggests that canonicalWnt/β-catenin signaling contributes to the regulation of OE neurogenesis. To test thecontribution of Wnt signaling functionally, we pharmacologically manipulated the pathway in theintact OE and an experimental model of OE regeneration. Stimulation of the pathway resulted inan enhanced cell proliferation response that shares similarity with the pattern of neurogenesisthat can be observed in the damaged OE. Inhibitors of Wnt signaling suppressed both, the baserate of maintenance neurogenesis and damage-induced proliferation. Our results suggest thatWnt/β-catenin signaling is both necessary and sufficient to induce repair and maintenanceneurogenesis.Abstract selected by the committee for an oral presentationinfo:eu-repo/semantics/nonPublishe

Wnt/beta-catenin Signaling Affects Two Modes of Neurogenesis in the Zebrafish Olfactory Epithelium

Olfactory sensory neurons (OSNs) have a limited life span and need to be generated constantly by maintenance neurogenesis to prevent olfactory loss at old age. In addition, the olfactory epithelium (OE) is capable of mounting efficient regenerative responses to acute tissue damage. In zebrafish, non-identical progenitor pools with distinct tissue distribution contribute to OSN maintenance and OE repair, however, the signals that regulate these two modes of OSN neurogenesis are not well characterized. We have used gene expression profiling by RNA sequencing to identify molecular signaling pathways that are significantly upregulated in an experimental model of OE regeneration. We find that components of the canonical Wnt/β-catenin signaling pathway are strongly activated early after damage to the OE. In the intact OE, β-catenin-positive cells are restricted to regions of maintenance neurogenesis at the central and peripheral edge of the sensory tissue, while repair neurogenesis is induced in the sensory OE upon damage. To test the contribution to Wnt/β-catenin signaling to these two modes of OSN neurogenesis functionally, we manipulated Wnt activity pharmacologically in the intact and lesioned OE. Activation of the Wnt pathway promoted strong cell proliferation responses, including responses in the sensory OE that resembled the pattern of neurogenesis under damage conditions. Inhibitors of the pathway, on the other hand, suppressed, but did not abolish, maintenance neurogenesis and had a suppressive effect on damage-induced proliferation in the sensory OE. Our results suggest that Wnt/β-catenin signaling is necessary and sufficient to induce cell proliferation from two types of neuronal progenitor populations in the OE that selectively contribute to maintenance and repair neurogenesis.info:eu-repo/semantics/publishe

Rapid de- and Regeneration of The Zebrafish Olfactory System

The peripheral olfactory epithelium (OE) has an exceptionallyhigh regenerative capacity. We use an experimental injury model inzebrafish to study the cellular responses underlying OE regeneration.Nasal irrigation with the detergent Triton X-100 results in the loss ofup to 80% of the olfactory sensory neuron population within 24 h andnear complete recovery within 7 d. We use BrdU incorporation assaysand expression analysis of cell type-specific markers to describethe dynamics of the regeneration response and to identify relevantprogenitor populations contributing to OE regeneration. We identified abasally located cell population, which expresses the stem cell markerssox2, krt5, and tp63, which shows increased neurogenic activityupon injury and is distinct from cells that contribute to maintenanceneurogenesis. Using transcriptome analysis over the time course of de- and regeneration, we have identified candidate molecular pathwaysthat may be critical for the selective activation of repair neurogenesis.Supported by TUBİTAK 113T038.Award for the second Best Poster Presentationinfo:eu-repo/semantics/publishe