The beneficial effect of hydroxyapatite lasts: A randomized radiostereometric trial comparing hydroxyapatite-coated, uncoated, and cemented tibial components for up to 16 years

Analysis and Stochastic

Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia

Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR–ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR–ABL, which led to inhibition of the RAN–exportin-5–RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR–ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML

Toxoplasma Effector MAF1 Mediates Recruitment of Host Mitochondria and Impacts the Host Response

Recent information has revealed the functional diversity and importance of mitochondria in many cellular processes including orchestrating the innate immune response. Intriguingly, several infectious agents, such as Toxoplasma, Legionella, and Chlamydia, have been reported to grow within vacuoles surrounded by host mitochondria. Although many hypotheses have been proposed for the existence of host mitochondrial association (HMA), the causes and biological consequences of HMA have remained unanswered. Here we show that HMA is present in type I and III strains of Toxoplasma but missing in type II strains, both in vitro and in vivo. Analysis of F1 progeny from a type II×III cross revealed that HMA is a Mendelian trait that we could map. We use bioinformatics to select potential candidates and experimentally identify the polymorphic parasite protein involved, mitochondrial association factor 1 (MAF1). We show that introducing the type I (HMA+) MAF1 allele into type II (HMA-) parasites results in conversion to HMA+ and deletion of MAF1 in type I parasites results in a loss of HMA. We observe that the loss and gain of HMA are associated with alterations in the transcription of host cell immune genes and the in vivo cytokine response during murine infection. Lastly, we use exogenous expression of MAF1 to show that it binds host mitochondria and thus MAF1 is the parasite protein directly responsible for HMA. Our findings suggest that association with host mitochondria may represent a novel means by which Toxoplasma tachyzoites manipulate the host. The existence of naturally occurring HMA+ and HMA- strains of Toxoplasma, Legionella, and Chlamydia indicates the existence of evolutionary niches where HMA is either advantageous or disadvantageous, likely reflecting tradeoffs in metabolism, immune regulation, and other functions of mitochondria. © 2014 Pernas et al

A resting state network in the motor control circuit of the basal ganglia

<p>Abstract</p> <p>Background</p> <p>In the absence of overt stimuli, the brain shows correlated fluctuations in functionally related brain regions. Approximately ten largely independent resting state networks (RSNs) showing this behaviour have been documented to date. Recent studies have reported the existence of an RSN in the basal ganglia - albeit inconsistently and without the means to interpret its function. Using two large study groups with different resting state conditions and MR protocols, the reproducibility of the network across subjects, behavioural conditions and acquisition parameters is assessed. Independent Component Analysis (ICA), combined with novel analyses of temporal features, is applied to establish the basis of signal fluctuations in the network and its relation to other RSNs. Reference to prior probabilistic diffusion tractography work is used to identify the basal ganglia circuit to which these fluctuations correspond.</p> <p>Results</p> <p>An RSN is identified in the basal ganglia and thalamus, comprising the pallidum, putamen, subthalamic nucleus and substantia nigra, with a projection also to the supplementary motor area. Participating nuclei and thalamo-cortical connection probabilities allow this network to be identified as the motor control circuit of the basal ganglia. The network was reproducibly identified across subjects, behavioural conditions (fixation, eyes closed), field strength and echo-planar imaging parameters. It shows a frequency peak at 0.025 ± 0.007 Hz and is most similar in spectral composition to the Default Mode (DM), a network of regions that is more active at rest than during task processing. Frequency features allow the network to be classified as an RSN rather than a physiological artefact. Fluctuations in this RSN are correlated with those in the task-positive fronto-parietal network and anticorrelated with those in the DM, whose hemodynamic response it anticipates.</p> <p>Conclusion</p> <p>Although the basal ganglia RSN has not been reported in most ICA-based studies using a similar methodology, we demonstrate that it is reproducible across subjects, common resting state conditions and imaging parameters, and show that it corresponds with the motor control circuit. This characterisation of the basal ganglia network opens a potential means to investigate the motor-related neuropathologies in which the basal ganglia are involved.</p

Alteration of gene expression by alcohol exposure at early neurulation

<p>Abstract</p> <p>Background</p> <p>We have previously demonstrated that alcohol exposure at early neurulation induces growth retardation, neural tube abnormalities, and alteration of DNA methylation. To explore the global gene expression changes which may underline these developmental defects, microarray analyses were performed in a whole embryo mouse culture model that allows control over alcohol and embryonic variables.</p> <p>Result</p> <p>Alcohol caused teratogenesis in brain, heart, forelimb, and optic vesicle; a subset of the embryos also showed cranial neural tube defects. In microarray analysis (accession number GSM9545), adopting hypothesis-driven Gene Set Enrichment Analysis (GSEA) informatics and intersection analysis of two independent experiments, we found that there was a collective reduction in expression of neural specification genes (neurogenin, <it>Sox5, Bhlhe22</it>), neural growth factor genes [<it>Igf1, Efemp1</it>, <it>Klf10 </it>(<it>Tieg), and Edil3</it>], and alteration of genes involved in cell growth, apoptosis, histone variants, eye and heart development. There was also a reduction of retinol binding protein 1 (<it>Rbp1</it>), and <it>de novo </it>expression of aldehyde dehydrogenase 1B1 (<it>Aldh1B1</it>). Remarkably, four key hematopoiesis genes (glycophorin A, adducin 2, beta-2 microglobulin, and ceruloplasmin) were absent after alcohol treatment, and histone variant genes were reduced. The down-regulation of the neurospecification and the neurotrophic genes were further confirmed by quantitative RT-PCR. Furthermore, the gene expression profile demonstrated distinct subgroups which corresponded with two distinct alcohol-related neural tube phenotypes: an open (ALC-NTO) and a closed neural tube (ALC-NTC). Further, the epidermal growth factor signaling pathway and histone variants were specifically altered in ALC-NTO, and a greater number of neurotrophic/growth factor genes were down-regulated in the ALC-NTO than in the ALC-NTC embryos.</p> <p>Conclusion</p> <p>This study revealed a set of genes vulnerable to alcohol exposure and genes that were associated with neural tube defects during early neurulation.</p

New insights into the synergism of nucleoside analogs with radiotherapy

Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells