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Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8α+ DC correlates with unresponsiveness to imidazoquinolines
No full textToll-like receptors (TLR) recognize microbial and viral patterns and activate dendritic cells (DC). TLR distribution among human DC subsets is heterogeneous: plasmacytoid DC (PDC) express TLR1, 7 and 9, while other DC types do not express TLR9 but express other TLR. Here, we report that mRNA for most TLR is expressed at similar levels by murine splenic DC sub-types, including PDC, but that TLR3 is preferentially expressed by CD8α+ DC while TLR5 and TLR7 are selectively absent from the same subset. Consistent with the latter, TLR7 ligand activates CD8α– DC and PDC, but not CD8α+ DC as measured by survival ex vivo, up-regulation of surface markers and production of IL-12p40. These data suggest that the dichotomy in TLR expression between plasmacytoid and non-plasmacytoid DC is not conserved between species. However, lack of TLR7 expression could restrict the involvement of CD8α+ DC in recognition of certain mouse pathogens
Regulation of dendritic cell function by Dectin-1.
No full textInnate pattern recognition receptors (PRRs) expressed on dendritic cells (DC) link direct recognition of pathogens to initiation of T cell responses. Here I describe evidence that Dectin-1 is a novel pattern recognition receptor involved the activation of dendritic cells by the yeast cell wall preparation, zymosan. Zymosan contains ligands for the known PRR Toll-like Receptor-2 (TLR2). Interestingly, recent work in macrophages has implicated the p-glucan receptor Dectin-1 in zymosan recognition. This thesis demonstrates that Dectin-1 can function as a PRR independently of the Toll-like Receptor system to induce DC cytokine production (IL-2, IL-10) and Notch-ligand upregulation (Jagged-1). My work has helped determine that Dectin-1 can signal via a novel HemlTAM motif to the tyrosine kinase Syk. DC stimulated with zymosan upregulate IL-10, IL-2 and Jagged-1 in a Syk-dependent manner. Indeed, IL-10 and Jagged-1 induction is independent of TLR-mediated recognition of zymosan. In addition, zymosan induced ERK activation is entirely dependent on signalling through Syk and is independent of TLR signalling. I demonstrate that this ERK activation is necessary for the induction of IL-2 and IL-10 in response to zymosan. Finally I present preliminary findings on how the unusual cytokine signature of zymosan-stimulated DCs may bias Thl and Thl7 differentiation induced in vitro
Comparative cellular analysis of motor cortex in human, marmoset and mouse
No full textThe primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch–seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.Author Correction: Comparative cellular analysis of motor cortex in human, marmoset and mouse Download PDF Author Correction Open Access Published: 22 March 2022 Author Correction: Comparative cellular analysis of motor cortex in human, marmoset and mouse Trygve E. Bakken, Nikolas L. Jorstad, …Ed S. Lein Nature (2022)Cite this article 399 Accesses 1 Altmetric Metrics details The Original Article was published on 06 October 2021 Correction to: Nature https://doi-org.tudelft.idm.oclc.org/10.1038/s41586-021-03465-8 Published online 6 October 2021 In the version of this article initially published, the Acknowledgements section was incomplete and has now been amended to include the following: “NIH BRAIN Initiative awards U01 MH121282 to J.R.E and M.M.B, U19 MH114831 to J.R.E. and E.M.C., U19 MH114830 to H.Z., U01 MH114819 to G.F., 1U01MH114828 to K.Z. and J.C., RF1MH123220 to M.H. and R.H.S., and U19 MH114821. NIH awards R01DC019370 to R.H., R24MH114815 to R.H. and O.R.W., and R24 MH114788 to O.R.W. Nancy and Buster Alvord Endowment to C.D.K.” The changes have been made to the HTML and PDF versions of the articleComputer Graphics and VisualisationPattern Recognition and Bioinformatic
Cyclical DNA Methyltransferase 3a Expression Is a Seasonal and Estrus Timer in Reproductive Tissues
No full textAcknowledgments We thank Gerald Lincoln for his critical feedback on a previous version of this manuscript. Author contributions included the following: T.J.S. conceived the project, designed the experiments, analyzed the data, and wrote the manuscript. E.W.J.L. conducted the experiments and analyzed the data. C.S.C. conducted the immunocytochemistry. M.L. conducted the HEK293 cell culture assays. E.M.C. and A.S.B. provided technical assistance. This work was supported by the University of Aberdeen College of Life Sciences and Medicine grant (to T.J.S.). E.W.J.L. was supported by a Society for Reproduction and Fertility undergraduate scholarship. Disclosure Summary: The authors have nothing to disclose.Peer reviewe
Heat transfer from wall to dense packing structures of spheres, cylinders and Raschig rings
No full textThis paper investigates the validity of azimuthal averaging of 3D temperature fields in the analysis of lateral heat transfer in dense particle packings. This is conducted by synthetic generation of 3D packing surrogates of spheres, cylinders and Raschig rings with tube-to-pellet diameter ratio, 3 < N < 6, using an in-house Rigid Body Dynamics packing algorithm, followed by detailed discrete pellet CFD simulations of heat transfer from wall to bed for laminar, transient and turbulent flow regimes. The CFD results of hydrodynamics and temperature fields are benchmarked against empirical correlations for pressure drop and interphase heat transfer Nusselt number, Nu, offering the best fits with correlations proposed by Eisfeld and Schnitzlein (for cylinders and spheres) and Nemec and Levec (for rings) for pressure drop, and by Gunn and Sun and coworkers for the prediction of Nu. The CFD results demonstrate that fluctuations in local temperature are completely neglected by azimuthal-averaging of 3D temperature fields over the bed volume, leading to more than 150 °C deviations from the local temperature data. Furthermore, it is found that deviations between azimuthally-averaged axial velocity profile and true local velocities are in an analogous fashion transmitted to the temperature field. This is evidenced by the coincidence of the peaks in the deviation profiles of azimuthally-averaged temperature and velocity from the local data over the bed radius. This is due to thermal disequilibrium between fluid and pellet phases which is partially omitted by the azimuthal-averaging of the 3D temperature field and basically neglected in pseudo-homogenous ker-hw models.Mechanical EngineeringComplex Fluid Processin
On generalized Kneser hypergraph colorings
No full textIn Ziegler (2002), the second author presented a lower bound for the chromatic numbers of hypergraphs KGr sS, “generalized r-uniform Kneser hypergraphs with intersection multiplicities s. ” It generalized previous lower bounds by Kˇríˇz (1992/2000) for the case s = (1,...,1) without intersection multiplicities, and by Sarkaria (1990) for S = � [n] � k. Here we discuss subtleties and difficulties that arise for intersection multiplicities si> 1: 1. In the presence of intersection multiplicities, there are two different versions of a “Kneser hypergraph,”depending on whether one admits hypergraph edges that are multisets rather than sets. We show that the chromatic numbers are substantially different for the two concepts of hypergraphs. The lower bounds of Sarkaria (1990) and Ziegler (2002) apply only to the multiset version. 2. The reductions to the case of prime r in the proofs by Sarkaria and by Ziegler work only if the intersection multiplicities are strictly smaller than the largest prime factor of r. Currently we have no valid proof for the lower bound result in the other cases. We also show that all uniform hypergraphs without multiset edges can be represented as generalized Kneser hypergraphs
Dosimetric benefits and preclinical performance of steerable needles in HDR prostate brachytherapy
No full textProstate cancer patients with an enlarged prostate and/or excessive pubic arch interference (PAI) are generally considered non-eligible for high-dose-rate (HDR) brachytherapy (BT). Steerable needles have been developed to make these patients eligible again. This study aims to validate the dosimetric impact and performance of steerable needles within the conventional clinical setting. HDR BT treatment plans were generated, needle implantations were performed in a prostate phantom, with prostate volume > 55 cm3 and excessive PAI of 10 mm, and pre- and post-implant dosimetry were compared considering the dosimetric constraints: prostate V100 > 95 % (13.50 Gy), urethra D0.1cm3 < 115 % (15.53 Gy) and rectum D1cm3 < 75 % (10.13 Gy). The inclusion of steerable needles resulted in a notable enhancement of the dose distribution and prostate V100 compared to treatment plans exclusively employing rigid needles to address PAI. Furthermore, the steerable needle plan demonstrated better agreement between pre- and post-implant dosimetry (prostate V100: 96.24 % vs. 93.74 %) compared to the rigid needle plans (79.13 % vs. 72.86 % and 87.70 % vs. 81.76 %), with no major changes in the clinical workflow and no changes in the clinical set-up. The steerable needle approach allows for more flexibility in needle positioning, ensuring a highly conformal dose distribution, and hence, HDR BT is a feasible treatment option again for prostate cancer patients with an enlarged prostate and/or excessive PAI.</p
Large-scale pathways-based association study in amyotrophic lateral sclerosis
No full textSporadic amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, most likely results from complex genetic and environmental interactions. Although a number of association studies have been performed in an effort to find genetic components of sporadic ALS, most of them resulted in inconsistent findings due to a small number of genes investigated in relatively small sample sizes, while the replication of results was rarely attempted. Defects in retrograde axonal transport, vesicle trafficking and xenobiotic metabolism have been implicated in neurodegeneration and motor neuron death both in human disease and animal models. To assess the role of common genetic variation in these pathways in susceptibility to sporadic ALS, we performed a pathway-based candidate gene case-control association study with replication. Furthermore, we determined reliability of whole genome amplified DNA in a large-scale association study. In the first stage of the study, 1277 putative functional and tagging SNPs in 134 genes spanning 8.7 Mb were genotyped in 822 British sporadic ALS patients and 872 controls using whole genome amplified DNA. To detect variants with modest effect size and discriminate among false positive findings 19 SNPs showing a trend of association in the initial screen were genotyped in a replication sample of 580 German sporadic ALS patients and 361 controls. We did not detect strong evidence of association with any of the genes investigated in the discovery sample (lowest uncorrected P-value 0.00037, lowest permutation corrected P-value 0.353). None of the suggestive associations was replicated in a second sample, further excluding variants with moderate effect size. We conclude that common variation in the investigated pathways is unlikely to have a major effect on susceptibility to sporadic ALS. The genotyping efficiency was only slightly decreased (∼1%) and genotyping quality was not affected using whole genome amplified DNA. It is reliable for large scale genotyping studies of diseases such as ALS, where DNA sample collections are limited because of low disease prevalence and short survival time. © 2007 The Author(s)
Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability
No full textThis work has been supported by: Motor Neurone Disease Association (G.B.M., S.C. and C.E.S.); Euan MacDonald Centre (G.B.M. and S.C.); European Research Council (L.V.); Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V.).Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which a greater understanding of early disease mechanisms is needed to reveal novel therapeutic targets. We report the use of human induced pluripotent stem cell (iPSC)-derived motoneurons (MNs) to study the pathophysiology of ALS. We demonstrate that MNs derived from iPSCs obtained from healthy individuals or patients harbouring TARDBP or C9ORF72 ALS-causing mutations are able to develop appropriate physiological properties. However, patient iPSC-derived MNs, independent of genotype, display an initial hyperexcitability followed by progressive loss of action potential output and synaptic activity. This loss of functional output reflects a progressive decrease in voltage-activated Na+ and K+ currents, which occurs in the absence of overt changes in cell viability. These data implicate early dysfunction or loss of ion channels as a convergent point that may contribute to the initiation of downstream degenerative pathways that ultimately lead to MN loss in ALS.Peer reviewe
Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia
No full textAn expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity. © 2013 The Author(s)
