Perturbation of effector and regulatory T cell subsets in Myalgic EncephalomyelitisChronic Fatigue Syndrome (MECFS), bioRxiv, 2019-12-26

AbstractMyalgic encephalomyelitischronic fatigue syndrome (MECFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of MECFS patient or control blood samples for differences in T cell subset frequencies and functions. We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in MECFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in MECFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNγ, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in MECFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in MECFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the MECFS cohort as patients (93% true positive rate or sensitivity). In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in MECFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of MECFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.

biorxiv immunology 200-500-users 2019

Unconventional kinetochore kinases KKT2 and KKT3 have a unique zinc finger that promotes their kinetochore localization, bioRxiv, 2019-12-14

AbstractChromosome segregation in eukaryotes is driven by the kinetochore, a macromolecular protein complex that assembles onto centromeric DNA and binds spindle microtubules. Cells must tightly control the number and position of kinetochores so that all chromosomes assemble a single kinetochore. A central player in this process is the centromere-specific histone H3 variant CENP-A, which localizes specifically within centromeres and promotes kinetochore assembly. However, CENP-A is absent from several eukaryotic lineages including kinetoplastids, a group of evolutionarily divergent eukaryotes that have an unconventional set of kinetochore proteins. It remains unknown how kinetoplastids specify kinetochore positions or promote kinetochore assembly in the absence of CENP-A. Here we studied two homologous kinetoplastid kinases (KKT2 and KKT3) that localize constitutively at centromeres. KKT2 and KKT3 central domains were sufficient for centromere localization in Trypanosoma brucei. Crystal structures of the KKT2 central domain from two divergent kinetoplastids revealed a unique zinc finger domain, which promotes its kinetochore localization in T. brucei. Mutations in the equivalent zinc finger domain of KKT3 abolished its kinetochore localization and function. This study lays the foundation for understanding the mechanism of kinetochore specification and assembly in kinetoplastids.

biorxiv cell-biology 0-100-users 2019

Genomic evidence for global ocean plankton biogeography shaped by large-scale current systems, bioRxiv, 2019-12-07

AbstractBiogeographical studies have traditionally focused on readily visible organisms, but recent technological advances are enabling analyses of the large-scale distribution of microscopic organisms, whose biogeographical patterns have long been debated1,2. The most prominent global biogeography of marine plankton was derived by Longhurst3 based on parameters principally associated with photosynthetic plankton. Localized studies of selected plankton taxa or specific organismal sizes1,4–7 have mapped community structure and begun to assess the roles of environment and ocean current transport in shaping these patterns2,8. Here we assess global plankton biogeography and its relation to the biological, chemical and physical context of the ocean (the ‘seascape’) by analyzing 24 terabases of metagenomic sequence data and 739 million metabarcodes from the Tara Oceans expedition in light of environmental data and simulated ocean current transport. In addition to significant local heterogeneity, viral, prokaryotic and eukaryotic plankton communities all display near steady-state, large-scale, size-dependent biogeographical patterns. Correlation analyses between plankton transport time and metagenomic or environmental dissimilarity reveal the existence of basin-scale biological and environmental continua emerging within the main current systems. Across oceans, there is a measurable, continuous change within communities and environmental factors up to an average of 1.5 years of travel time. Modulation of plankton communities during transport varies with organismal size, such that the distribution of smaller plankton best matches Longhurst biogeochemical provinces, whereas larger plankton group into larger provinces. Together these findings provide an integrated framework to interpret plankton community organization in its physico-chemical context, paving the way to a better understanding of oceanic ecosystem functioning in a changing global environment.

biorxiv ecology 100-200-users 2019

 

Created with the audiences framework by Jedidiah Carlson

Powered by Hugo