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Campbell Bruun posted an update 6 months ago
Rootletin is the main component of the ciliary rootlet and functions as a centriole linker connecting the two mother centrioles. Despite the functional importance of rootletin, the molecular architecture of the rootletin filament and its assembly mechanism are poorly understood. Here, we identify the coiled-coil domain 3 (CCD3) of rootletin as the key domain for its cellular function. The crystal structure of the CCD31108-1317 fragment containing 28 heptad repeats and one hendecad repeat reveals that it forms a parallel coiled-coil dimer spanning approximately 300 Å in length. Crosslinking experiments and biophysical analyses of the minimal functional region of CCD3 (CCD3-6) suggest that CCD3-6 is structurally dynamic and may be important for oligomer formation. We also show that oligomerization-defective CCD3 mutants fail in centrosomal localization and centriole linkage, suggesting that rootletin oligomerization may be important for its function. RNA polymerase transcribes certain genomic loci with higher errors rates. These Transcription Error-Enriched genomic Loci (TEELs) have implications in disease. Current deep-sequencing methods cannot distinguish TEELs from post-transcriptional modifications, stochastic transcription errors, and technical noise, impeding efforts to elucidate the mechanisms linking TEELs to disease. Here, we describe background Error Model-coupled Precision nuclear run-on Circular-sequencing (EmPC-seq) to discern genomic regions enriched for transcription misincorporations. EmPC-seq innovatively combines a nuclear run-on assay for capturing nascent RNA before post-transcriptional modifications, a circular-sequencing step that sequences the same nascent RNA molecules multiple times to improve accuracy, and a statistical model for distinguishing error-enriched regions amongst stochastic polymerase errors. Applying EmPC-seq to the ribosomal RNA transcriptome, we show that TEELs of RNA Polymerase I are not randomly distributed but clustered together, with higher error frequencies at nascent transcript 3′ ends. Our study establishes a reliable method of identifying TEELs with nucleotide precision, which can help elucidate their molecular origins. Despite the strong demand for orally-delivered fish vaccines and the deficient response of those currently available in the market, little is known about how teleost B cells differentiate to antibody secreting cells (ASCs) in response to antigens delivered to the intestinal mucosa. To fill this gap, in the current study, we have studied the dynamics of B cell differentiation in spleen and kidney of rainbow trout (Oncorhynchus mykiss) anally immunized with antigens catalogued in mammals as thymus dependent (TD) or thymus-independent (TI). Our results show that, in the absence of additional adjuvants, rainbow trout preferentially responded to a model TI antigen such as TNP-LPS (2,4,6-trinitrophenyl hapten conjugated to lipopolysaccharide). The anal administration of TNP-LPS elicited TNP-specific serum antibodies, and a significant increase in the number of total and TNP-specific ASCs in both spleen and kidney, being the kidney the site where most ASCs are found at later time points. In the spleen, a proliferative response of both IgM+ B and T cells was also clearly visible, while the proliferative response was weaker in the kidney. Finally, TNP-LPS also provoked a transcriptional regulation of some immune genes in the spleen and the intestine, including a decreased transcription of foxp3a and foxp3b in intestine that suggests a breach in tolerogenic responses in response to TI stimulation. These results contribute to a better understanding of how intestinal immunity is regulated in teleost and will aid in the future design of effective oral strategies for aquaculture. Regular physical activity (PA) offers positive effects on the human body. However, the effects of PA on cognition and in the brain are less clear. In this paper, we narratively review the relationship of PA with cognition and dementia, first from general perspective and then through genetically informed studies on the topic. Then we move on to imaging studies on exercise and brain anatomy first by presenting an overall picture of the topic and then discussing brain imaging studies addressing PA and brain structure in twins in more detailed way. Regarding PA and cognition or dementia, genetically informed studies are uncommon, even though the relationship between PA and cognitive ageing has been extensively studied. It is challenging to find twin pairs discordant for PA and dementia. Concerning brain imaging studies, among PA discordant young adult twin pairs, the more active co-twins showed larger gray matter volumes in striatal, prefrontal, and hippocampal regions and in electrophysiological studies automatic deviance-detection processes differed in brain regions involved with sensorimotor, visual and memory functions. Inflammation is a key factor in multiple diseases including primary immune-mediated inflammatory diseases e.g. rheumatoid arthritis but also, less obviously, in many other common conditions, e.g. this website cardiovascular disease and diabetes. Together, chronic inflammatory diseases contribute to the majority of global morbidity and mortality. However, our understanding of the underlying processes by which the immune response is activated and sustained is limited by a lack of cellular and molecular information obtained in situ. Molecular imaging is the visualization, detection and quantification of molecules in the body. The ability to reveal information on inflammatory biomarkers, pathways and cells can improve disease diagnosis, guide and monitor therapeutic intervention and identify new targets for research. The optimum molecular imaging modality will possess high sensitivity and high resolution and be capable of non-invasive quantitative imaging of multiple disease biomarkers while maintaining an acceptable safety profile. The mainstays of current clinical imaging are computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US) and nuclear imaging such as positron emission tomography (PET). However, none of these have yet progressed to routine clinical use in the molecular imaging of inflammation, therefore new approaches are required to meet this goal. This review sets out the respective merits and limitations of both established and emerging imaging modalities as clinically useful molecular imaging tools in addition to potential theranostic applications.
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