Authors: Sliter DA, Martinez J, Hao L, Chen X, Sun N, Fischer TD, Burman JL, Li Y, Zhang Z, Narendra DP, Cai H, Borsche M, Klein C, Youle RJ
Journal: Nature. 2018 Aug 22. doi: 10.1038/s41586-018-0448-9. [Epub ahead of print]
Although serum from patients with Parkinson's disease contains elevated levels of numerous pro-inflammatory cytokines including IL-6, TNF, IL-1β, and IFNγ, whether inflammation contributes to or is a consequence of neuronal loss remains unknown. Mutations in parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onset Parkinson's disease. Both PINK1 and parkin function within the same biochemical pathway and remove damaged mitochondria from cells in culture and in animal models via mitophagy, a selective form of autophagy. The in vivo role of mitophagy, however, is unclear, partly because mice that lack either PINK1 or parkin have no substantial Parkinson's-disease-relevant phenotypes. Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity, suggesting that mitophagy may mitigate inflammation. Here we report a strong inflammatory phenotype in both Prkn-/- and Pink1-/- mice following exhaustive exercise and in Prkn-/-;mutator mice, which accumulate mutations in mitochondrial DNA (mtDNA). Inflammation resulting from either exhaustive exercise or mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I interferon response to cytosolic DNA. The loss of dopaminergic neurons from the substantia nigra pars compacta and the motor defect observed in aged Prkn-/-;mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic PRKN mutations also display elevated cytokines. These results support a role for PINK1- and parkin-mediated mitophagy in restraining innate immunity.
Authors: Pitcher MH, Von Korff M, Bushnell MC, Porter L
Journal: J Pain. 2018 Aug 7. doi: https://doi.org/10.1016/j.jpain.2018.07.006
The multidimensional nature of chronic pain is not reflected by definitions based solely on pain duration, resulting in high prevalence estimates limiting effective policy development. The newly proposed concept of High Impact Chronic Pain (HICP) incorporates both disability and pain duration to identify a more severely impacted portion of the chronic pain population, yet remains uncharacterized at the population level. As such, we used the 2011 National Health Interview Survey (NHIS; n=15,670) to (i) assess the likelihood of disability in the overall chronic pain population, (ii) to estimate the prevalence of HICP, and (iii) to characterize the disability, health status and health care use profile of this population in the United States. Overall, chronic pain, defined as pain experienced on most or every day in the last three months, was strongly associated with an increased risk of disability after controlling for other chronic health conditions (OR=4.43, CI=3.73-5.26), where disability was more likely in those with chronic pain than in those with stroke or kidney failure, among others. HICP affected 4.8% of the U.S. adult population, or approximately 10.6 million individuals in 2011. The HICP population reported more severe pain, mental health and cognitive impairments than persons with chronic pain without disability, and was also more likely to report worsening health, more difficulty with self-care and higher health care use. HICP clearly represents a more severely impacted portion of the chronic pain population. Understanding this heterogeneity will contribute to developing more effective legislation promoting safe and cost-effective approaches to prevention and treatment of chronic pain.
Authors: Dairaghi L, Flannery E, Giacobini P, Saglam A, Saadi H, Constantin S, Casoni F, Howell BW, Wray S
Journal: Front Cell Neurosci. 2018 Aug 3;12:228. doi: 10.3389/fncel.2018.00228.
One key signaling pathway known to influence neuronal migration involves the extracellular matrix protein Reelin. Typically, signaling of Reelin occurs via apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR), and the cytoplasmic adapter protein disabled 1 (Dab1). However, non-canonical Reelin signaling has been reported, though no receptors have yet been identified. Cariboni et al. (2005) indicated Dab1-independent Reelin signaling impacts gonadotropin releasing hormone-1 (GnRH) neuronal migration. GnRH cells are essential for reproduction. Prenatal migration of GnRH neurons from the nasal placode to the forebrain, juxtaposed to olfactory axons and olfactory ensheathing cells (OECs), has been well documented, and it is clear that alterations in migration of these cells can cause delayed or absent puberty. This study was initiated to delineate the non-canonical Reelin signaling pathways used by GnRH neurons. Chronic treatment of nasal explants with CR-50, an antibody known to interfere with Reelin homopolymerization and Dab1 phosphorylation, decreased the distance GnRH neurons and OECs migrated. Normal migration of these two cell types was observed when Reelin was co-applied with CR-50. Immunocytochemistry was performed to determine if OECs might transduce Reelin signals via the canonical pathway, and subsequently indirectly altering GnRH neuronal migration. We show that in mouse: (1) both OECs and GnRH cells express ApoER2, VLDLR and Dab1, and (2) GnRH neurons and OECs show a normal distribution in the brain of two mutant reeler lines. These results indicate that the canonical Reelin pathway is present in GnRH neurons and OECs, but that Reelin is not essential for development of these two systems in vivo.
Authors: Lee K, Famiglietti ML, McMahon A, Wei CH, MacArthur JAL, Poux S, Breuza L, Bridge A, Cunningham F, Xenarios I, Lu Z
Journal: PLoS Comput Biol. 2018 Aug 13;14(8):e1006390. doi: 10.1371/journal.pcbi.1006390. [Epub ahead of print]
Manually curating biomedical knowledge from publications is necessary to build a knowledge based service that provides highly precise and organized information to users. The process of retrieving relevant publications for curation, which is also known as document triage, is usually carried out by querying and reading articles in PubMed. However, this query-based method often obtains unsatisfactory precision and recall on the retrieved results, and it is difficult to manually generate optimal queries. To address this, we propose a machine-learning assisted triage method. We collect previously curated publications from two databases UniProtKB/Swiss-Prot and the NHGRI-EBI GWAS Catalog, and used them as a gold-standard dataset for training deep learning models based on convolutional neural networks. We then use the trained models to classify and rank new publications for curation. For evaluation, we apply our method to the real-world manual curation process of UniProtKB/Swiss-Prot and the GWAS Catalog. We demonstrate that our machine-assisted triage method outperforms the current query-based triage methods, improves efficiency, and enriches curated content. Our method achieves a precision 1.81 and 2.99 times higher than that obtained by the current query-based triage methods of UniProtKB/Swiss-Prot and the GWAS Catalog, respectively, without compromising recall. In fact, our method retrieves many additional relevant publications that the query-based method of UniProtKB/Swiss-Prot could not find. As these results show, our machine learning-based method can make the triage process more efficient and is being implemented in production so that human curators can focus on more challenging tasks to improve the quality of knowledge bases.
Authors: Haddad E, Logan BR, Griffith LM, Buckley RH, Parrott RE, Prockop SE, Small TN, Chaisson J, Dvorak CC, Murnane M, Kapoor N, Abdel-Azim H, Hanson IC, Martinez C, Bleesing JJH, Chandra S, Smith AR, Cavanaugh ME, Jyonouchi S, Sullivan KE, Burroughs L, Skoda-Smith S, Haight AE, Tumlin AG, Quigg TC, Taylor C, Dávila Saldaña BJ, Keller MD, Seroogy CM, Desantes KB, Petrovic A, Leiding JW, Shyr DC, Decaluwe H, Teira P, Gillio AP, Knutsen A, Moore TB, Kletzel M, Craddock JA, Aquino V, Davis JH, Yu LC, Cuvelier GDE, Bednarski JJ, Goldman FD, Kang EM, Shereck E, Porteus MH, Connelly JA, Fleisher TA, Malech HL, Shearer WT, Szabolcs P, Thakar MS, Vander Lugt MT, Heimall J, Yin Z, Pulsipher MA, Pai SY, Kohn DB, Puck JM, Cowan MJ, O'Reilly RJ, Notarangelo LD
Journal: Blood. 2018 Aug 28. pii: blood-2018-03-840702. doi: 10.1182/blood-2018-03-840702. [Epub ahead of print]
The Primary Immune Deficiency Treatment Consortium performed a retrospective analysis of 662 patients with Severe Combined Immunodeficiency (SCID) who received an Hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched sibling donors (MSD). Among recipients of non-MSD HCT, multivariate analysis showed that SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG or JAK3 defects, and was significantly better compared to patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced intensity or myeloablative conditioning had a lower incidence of treatment failure and better T and B cell reconstitution, but higher risk of graft versus host disease compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were each associated with improved survival. Typical SCID, leaky SCID and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.
Authors: Jiang X, Detera-Wadleigh SD, Akula N, Mallon BS, Hou L, Xiao T, Felsenfeld G, Gu X, McMahon FJ
Journal: Mol Psychiatry. 2018 Aug 22. doi: 10.1038/s41380-018-0207-1. [Epub ahead of print]
Biological characterization of genetic variants identified in genome-wide association studies (GWAS) remains a substantial challenge. Here we used human-induced pluripotent stem cells (iPSC) and their neural derivatives to characterize common variants on chromosome 3p22 that have been associated by GWAS with major mental illnesses. IPSC-derived neural progenitor cells carrying the risk allele of the single nucleotide polymorphism (SNP), rs9834970, displayed lower baseline TRANK1 expression that was rescued by chronic treatment with therapeutic dosages of valproic acid (VPA). VPA had the greatest effects on TRANK1 expression in iPSC, NPC, and astrocytes. Although rs9834970 has no known function, we demonstrated that a nearby SNP, rs906482, strongly affects binding by the transcription factor, CTCF, and that the high-affinity allele usually occurs on haplotypes carrying the rs9834970 risk allele. Decreased expression of TRANK1 perturbed expression of many genes involved in neural development and differentiation. These findings have important implications for the pathophysiology of major mental illnesses and the development of novel therapeutics.
Authors: Yin Y, Garcia MR, Novak AJ, Saunders AM, Ank RS, Nam AS, Fisher LW
Journal: PLoS Biol. 2018 Aug 7;16(8):e2005140. doi: 10.1371/journal.pbio.2005140. [Epub ahead of print]
Some secreted proteins that assemble into large complexes, such as extracellular matrices or hormones and enzymes in storage granules, must be kept at subaggregation concentrations during intracellular trafficking. We show surfeit locus protein 4 (Surf4) is the cargo receptor that establishes different steady-state concentrations for a variety of soluble cargo proteins within the endoplasmic reticulum (ER) through interaction with the amino-terminal tripeptides exposed after removal of leader sequences. We call this motif the ER-Exit by Soluble Cargo using Amino-terminal Peptide-Encoding motif (ER-ESCAPE motif). Proteins that most readily aggregate in the ER lumen (e.g., dentin sialophosphoprotein [DSPP] and amelogenin, X-linked [AMELX]) have strong ER-ESCAPE motifs to inhibit aggregate formation, while less susceptible cargo exhibits weaker motifs. Specific changes in a single amino acid of the tripeptide result in aggregate formation and failure to efficiently traffic cargo out of the ER. A logical subset of 8,000 possible tripeptides starting a model soluble cargo protein (growth hormone) established a continuum of steady-state ER concentrations ranging from low (i.e., high affinity for receptor) to the highest concentrations associated with bulk flow-limited trafficking observed for nonbinding motifs. Human cells lacking Surf4 no longer preferentially trafficked cargo expressing strong ER-ESCAPE motifs. Reexpression of Surf4 or expression of yeast's ortholog, ER-derived vesicles protein 29 (Erv29p), rescued enhanced ER trafficking in Surf4-null cells. Hence our work describes a new way of preferentially exporting soluble cargo out of the ER that maintains proteins below the concentrations at which they form damaging aggregates.
Authors: Lee JY, Kim GJ, Choi JK, Choi YA, Jeong NH, Park PH, Choi H, Kim SH
Journal: Front Pharmacol. 2018 Jul 20;9:726. doi: 10.3389/fphar.2018.00726. eCollection 2018.
Rheumatoid arthritis (RA) is a progressive autoimmune disease specific to synovial joints; it causes joint damage and other systemic abnormalities, thereby leading to physical disability and early mortality. Marine sponge-derived fungi, Pestalotiopsis sp., secrete immunosuppressive compounds in the culture broth. In the present study, we isolated 4-(hydroxymethyl)catechol (4-HMC) from these fungal species, and evaluated its anti-RA effects using a murine collagen-induced arthritis model and tumor necrosis factor-α-stimulated human RA synovial fibroblasts. Oral 4-HMC administration decreased the clinical arthritis score, paw thickness, histologic and radiologic changes, and serum IgG1 and IgG2a levels. It prevented the proliferation of helper T (Th) 1/Th17 CD4+ lymphocytes isolated from inguinal lymph nodes, thereby reducing inflammatory cytokine production in CIA mice. It decreased the expression of inflammatory mediators, including cytokines and matrix metalloproteinases (MMPs), both in vitro and in vivo. We observed that 4-HMC suppresses Th immune responses and MMP expression to inhibit inflammatory cytokine production in human RA synovial fibroblasts by modulating the PI3K/Akt/NF-κB pathway. These results verify the anti-RA potential of 4-HMC.
Authors: Ciftci-Yilmaz S, Au WC, Mishra PK, Eisenstatt JR, Chang J, Dawson AR, Zhu I, Rahman M, Bilke S, Costanzo M, Baryshnikova A, Myers CL, Meltzer PS, Landsman D, Baker RE, Boone C, Basrai MA
Journal: Genetics. 2018 Jul 16. pii: genetics.301305.2018. doi: 10.1534/genetics.118.301305. [Epub ahead of print]
Centromeric localization of the evolutionarily conserved centromere-specific histone H3 variant CENP-A (Cse4 in yeast) is essential for faithful chromosome segregation. Overexpression and mislocalization of CENP-A leads to chromosome segregation defects in yeast, flies, and human cells. Overexpression of CENP-A has been observed in human cancers; however, the molecular mechanisms preventing CENP-A mislocalization are not fully understood. Here, we used a genome-wide Synthetic Genetic Array (SGA) to identify gene deletions that exhibit synthetic dosage lethality (SDL) when Cse4 is overexpressed. Deletion for genes encoding the replication-independent histone chaperone HIR complex (HIR1, HIR2, HIR3, HPC2) and a Cse4-specific E3 ubiquitin ligase, PSH1, showed highest SDL. We defined a role for Hir2 in proteolysis of Cse4 that prevents mislocalization of Cse4 to non-centromeric regions for genome stability. Hir2 interacts with Cse4 in vivo and hir2Δ strains exhibit defects in Cse4 proteolysis, and stabilization of chromatin-bound Cse4. Mislocalization of Cse4 to non-centromeric regions with a preferential enrichment at promoter regions was observed in hir2Δ strains. We determined that Hir2 facilitates the interaction of Cse4 with Psh1 and that defects in Psh1-mediated proteolysis contribute to increased Cse4 stability and mislocalization of Cse4 in the hir2Δ strain. In summary, our genome-wide screen provides insights into pathways that regulate proteolysis of Cse4 and defines a novel role for the HIR complex in preventing mislocalization of Cse4 by facilitating proteolysis of Cse4 thereby promoting genome stability.
Authors: Han K, Nguyen A, Traba J, Yao X, Kaler M, Huffstutler RD, Levine SJ, Sack MN
Journal: J Immunol. 2018 Jul 18. pii: ji1800585. doi: 10.4049/jimmunol.1800585. [Epub ahead of print]
A fasting mimetic diet blunts inflammation, and intermittent fasting has shown ameliorative effects in obese asthmatics. To examine whether canonical inflammatory pathways linked with asthma are modulated by fasting, we designed a pilot study in mild asthmatic subjects to assess the effect of fasting on the NLRP3 inflammasome, Th2 cell activation, and airway epithelial cell cytokine production. Subjects with documented reversible airway obstruction and stable mild asthma were recruited into this study in which pulmonary function testing (PFT) and PBMCextraction was performed 24 h after fasting, with repeated PFT testing and blood draw 2.5 h after refeeding. PFTs were not changed by a prolonged fast. However, steroid-naive mild asthmatics showed fasting-dependent blunting of the NLRP3 inflammasome. Furthermore, PBMCs from these fasted asthmatics cocultured with human epithelial cells resulted in blunting of house dust mite-induced epithelial cell cytokine production and reduced CD4+ T cell Th2 activation compared with refed samples. This pilot study shows that prolonged fasting blunts the NLRP3 inflammasome and Th2 cell activation in steroid-naive asthmatics as well as diminishes airway epithelial cell cytokine production. This identifies a potential role for nutrient level-dependent regulation of inflammation in asthma. Our findings support the evaluation of this concept in a larger study as well as the potential development of caloric restriction interventions for the treatment of asthma.