Differential Roles of PRDM16 Isoforms in Normal and Malignant Hematopoiesis

PRDM16 is a transcriptional co-regulator that is highly expressed in HSCs and required for their maintenance. It is also involved in translocations in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and T-cell acute lymphoblastic leukemia. Prdm16 is expressed as both full-length (f Prdm16) and short-length (s-Prdm16) isoforms, the latter lacking an N-terminal PR domain homologous to SET methyltransferase domains. The roles of both isoforms in normal and malignant hematopoiesis are unclear. In chromosomal rearrangements involving PRDM16, the PR domain is deleted. Furthermore, overexpression of s-Prdm16, but not f-Prdm16, can cause leukemia in a p53-/- background predisposed to malignancy. Based on this, s-Prdm16 has been proposed as an oncogene whereas f-Prdm16 has been suggested to possess tumor suppressor activity. The aim of this thesis was to more clearly elucidate the role of each Prdm16 isoform in normal and malignant hematopoiesis. We first showed that Prdm16 is essential for adult HSC maintenance using a conditional deletion mouse model specific for hematopoietic cells, as previous findings using an embryonic-lethal global Prdm16-/- mouse demonstrated this only in fetal liver. We then found, using a specific f-Prdm16-/- mouse model, that full-length Prdm16 is essential for HSC maintenance and induces multiple genes involved in GTPase signaling and represses inflammation. Based on a comparison of Prdm16-/- HSCs lacking both isoforms, and f-Prdm16-/- HSCs which express s-Prdm16, we were able to infer some hematopoietic properties of s-Prdm16 – namely that this isoform induces inflammatory gene expression and supports development of a Lineage-Sca1+cKit- lymphoid progenitor distinct from CLPs which predominantly differentiates into marginal zone B cells. s-Prdm16 expression alone, however, was not sufficient to maintain HSCs. We used a mouse model of human MLL-AF9 leukemia and found that leukemia derived from Prdm16-deficient HSCs had extended latency, although expression of Prdm16 decreases during MLL-AF9 transformation and is undetectable in ex vivo leukemic cells. Forced expression of f-Prdm16 in these cells further extended leukemic latency, while forced expression of s-Prdm16 shortened latency. Gene expression profiling using RNAseq indicated that forced expression of f-Prdm16 resulted in altered respiratory metabolism of MLL-AF9 cells, whereas expression of s-Prdm16 induced a strong inflammatory gene signature, comparable to that seen in HSCs expressing only s-Prdm16. Several inflammatory cytokines and chemokines induced by s-Prdm16 are associated with MDS and with a worse prognosis in human AML. Furthermore, leukemia expressing s-Prdm16 had an elevated number of cells with abnormal nuclei, characteristic of dysplasia. Finally, we performed an analysis of PRDM16 in human AML from the publically-available Cancer Genome Atlas dataset, containing clinical and gene expression data for 179 cases of AML. PRDM16 expression negatively correlated with overall survival, both in the entire dataset and in the NPM1 mutated and MLL¬-rearranged subsets, and s-PRDM16 exhibited a stronger correlation than f-PRDM16. HOX gene expression correlated with PRDM16 expression, suggesting that HOX genes may positively regulate PRDM16 expression in AML. In NPM1-mutant and MLL-rearranged subsets of AML, we also found that high PRDM16 expression correlated with an inflammatory gene signature, thus corroborating our findings in mouse MLL-AF9. Our findings demonstrate distinct roles for Prdm16 isoforms in both normal hematopoiesis and AML, and identify s-Prdm16 as one of the drivers of prognostically-adverse inflammatory gene expression in leukemia

A comparison of substance use stigma and health stigma in a population of veterans with co-occurring mental health and substance use disorders

OBJECTIVE: This pilot study examined whether substance use or mental illness was more stigmatizing among individuals with co-occurring mental health and substance abuse problems. METHODS: This study included 48 individuals with co-occurring substance use and mental health problems enrolled in a Substance Abuse and Mental Health Services funded treatment program. Subjects received a baseline assessment that included addiction, mental health, and stigma measures. RESULTS: The sample consisted primarily of White males with an average age of 38 years. Substance abuse was found to be more stigmatizing than mental illness, F(1, 47) = 14.213, p < .001, and stigma varied across four different levels of stigma (Aware, Agree, Apply, and Harm), F(2.099, 98.675) = 117.883, p < .001. The interaction between type and level of stigma was also significant, F(2.41, 113.284) = 20.250, p < .001, indicating that differences in reported stigma between types varied across levels of stigma. Post hoc tests found a significant difference between all levels of stigma except for the comparison between Apply and Harm. Reported stigma was significantly higher for substance abuse than mental illness at the Aware and Agree levels. In addition, pairwise comparisons found significant differences between all levels of stigma with the exception of the comparison between Apply and Harm, indicating a pattern whereby reported stigma generally decreased from the first level (Aware stage) to subsequent levels. CONCLUSIONS: These results have important implications for treatment, suggesting the need to incorporate anti-stigma interventions for individuals with co-occurring disorders with a greater focus on substance abuse

Moyal Brackets in M-Theory

The infinite limit of Matrix Theory in 4 and 10 dimensions is described in terms of Moyal Brackets. In those dimensions there exists a Bogomol'nyi bound to the Euclideanized version of these equations, which guarantees that solutions of the first order equations also solve the second order Matrix Theory equations. A general construction of such solutions in terms of a representation of the target space co-ordinates as non-local spinor bilinears, which are generalisations of the standard Wigner functions on phase space, is given.Comment: 10 pages, Latex, no figures. References altered, typos correcte

PIGEONS (Rock Doves)

Pigeons (Columbia livia) typically have a gray body with a whitish rump, two black bars on the secondary wing feathers, a broad black band on the tail, and red feet. Pigeons are found throughout the United States (including Hawaii), southern Canada, and Mexico. Pigeons are highly dependent on humans to provide them with food and sites for roosting, loafing, and nesting. Pigeons are primarily grain and seed eaters and will subsist on spilled or improperly stored grain. The common pigeon was introduced into the United States as a domesticated bird, but many escaped and formed feral populations. Pigeon droppings deface and accelerate the deterioration of buildings and increase the cost of maintenance. Feral pigeons are not protected by federal law and most states do not afford them protection

Estimating the Impact of Food and Drug Administration Regulation of Cigarette Package Warning Labels and the Potential Added Impact of Plain Packaging: Evidence From Experimental Auctions Among Adult Smokers

Objective: To estimate differences in demand for cigarette packages with different packaging and health warning label formats. Methods: Adult smokers (n=404) in four states participated in experimental auctions. Participants bid on two of four experimental conditions, each involving a different health warning label format but with the same warning message: 1. text on 50% of pack side; 2. text on 50% of the pack front and back; 3. text with a graphic picture on 50% of the pack front and back; and 4. same as previous format, but without brand imagery. Results: Mean bids decreased across conditions (1. $3.52; 2.$3.43; 3. $3.11; 4.$2.93). Bivariate and multivariate random effects models indicated that there was no statistically significant difference in demand for packs with either of the two text only warnings; however, demand was significantly lower for both packs with prominent pictorial warnings, with the lowest demand associated with the plain, unbranded pack. Conclusions: Results suggest that prominent health warnings with graphic pictures will reduce demand for cigarettes. Regulators should not only consider this type of warning label, but also plain packaging policies for tobacco products.experimental auctions, cigarette labels, grotesque images, Food Consumption/Nutrition/Food Safety, Health Economics and Policy, C93,

Neoarchean Mantle-derived Magmatism within the Repulse Bay Block, Melville Peninsula, Nunavut: Implications for Archean Crustal Extraction and Cratonization

SUMMARYThe Repulse Bay block (RBb) of the southern Melville Peninsula, Nunavut, lies within the Rae craton and exposes a large (50,000 km2) area of middle to lower crust. The block is composed of ca. 2.86 Ga and 2.73–2.71 Ga tonalite-trondhjemite-granodiorite (TTG) and granitic gneiss that was derived from an older 3.25 and 3.10 Ga crustal substrate. This period of crustal generation was followed by the emplacement of ca. 2.69–2.66 Ga enderbite, charnockite, and granitoid intrusions with entrained websterite xenoliths. These voluminous batholith-scale bodies (dehydrated and hydrated intrusions), and the associated websterite xenoliths, have similar whole rock geochemical properties, including fractionated light rare earth element (LREE)–heavy (H)REE whole rock patterns and negative Nb, Ti, and Ta anomalies. Dehydrated intrusions and websterite xenoliths also contain similar mineralogy (two pyroxene, biotite, interstitial amphibole) and similar pyroxene trace element compositions. Based on geochemical and mineralogical properties, the two lithologies are interpreted to be related by fractional crystallization, and to be the product of a magmatic cumulate processes. Reworking of the crust in a ca. 2.72 Ga subduction zone setting was followed by ca. 2.69 Ga upwelling of the asthenospheric mantle and the intrusion of massif-type granitoid plutons. Based on a dramatic increase in FeO, Zr, Hf, and LREE content of the most evolved granitoid components from the 2.69–2.66 Ga cumulate intrusion, we propose that those granitoid plutons were in part derived from a metasomatized mantle source enriched by fluids from the subducting oceanic slab that underwent further hybridization (via assimilation) with the crust. Large-scale, mantle-derived Neoarchean sanukitoid-type magmatism played a role in the development of a depleted lower crust and residual sub-continental lithospheric mantle, a crucial element in the preservation of the RBb.RÉSUMÉLe bloc de Repulse Bay (RBb) dans le sud de la péninsule de Melville, au Nunavut, est situé dans le craton de Rae et expose une large zone (50 000 km2) de croûte moyenne à inférieur. Ce bloc est composé de tonalite-trondhjémite-granodiorite (TTG) daté à ca. 2,86 Ga et 2,73–2,71 Ga, et de gneiss granitique dérivé d’un substrat crustal plus ancien daté à 3,25 Ga et 3,10 Ga. Cette période de croissance crustale a été suivie par la mise en place entre ca. 2,69 et 2,66 Ga d’intrusions d’enderbite, charnockite et de granitoïde incluant des xénolites d’entraînement de websterite. Ces intrusions de taille batholitique (intrusions déshydratées et hydratées) ainsi que les xénolites d’entraînement de websterite associés, ont des propriétés géochimiques sur roche totale semblables notamment leurs profils de fractionnement des terres rares légers (LREE) et des terres rares lourds (HREE) ainsi que leurs anomalies négatives en Nb, Ti et Ta. Les intrusions déshydratées et les xénolites de websterite ont aussi des minéralogies similaires (deux pyroxènes, biotite, amphibole interstitielle) ainsi que des compositions semblables en éléments traces de leurs pyroxènes. Étant donné leurs propriétés géochimiques et minéralogiques, ces deux lithologies sont interprétées comme provenant d’une cristallisation fractionnée, et comme étant le produit de processus d'accumulations magmatiques. Le remaniement de la croûte dans un contexte de subduction vers ca. 2,72 Ga, a été suivi vers ca. 2,69 Ga d’une remontée du manteau asthénosphérique et de l’intrusion de granitoïdes de type massif. D'après l’importante augmentation en FeO, Zr, Hf et LREE dans les granitoïdes les plus évolués du magmatisme ayant pris place entre ca. 2,69 Ga et 2,66 Ga, nous proposons que ces plutons aient été en partie dérivés d’une source mantélique métasomatisée enrichies par des fluides d’une plaque océanique en subduction et qui a subi une hybridation supplémentaire (par assimilation) avec la croûte. Le magmatisme néo-archéen de type sanukitoïde, dérivé du manteau et de grande échelle, a joué un rôle dans le développement d’une croûte inférieure et d’un manteau lithosphérique continental résiduel appauvri, un élément déterminant pour la préservation du RBb

3D Object Recognition Based on Volumetric Representation Using Convolutional Neural Networks

Following the success of Convolutional Neural Networks on object recognition and image classification using 2D images; in this work the framework has been extended to process 3D data. However, many current systems require huge amount of computation cost for dealing with large amount of data. In this work, we introduce an efficient 3D volumetric representation for training and testing CNNs and we also build several datasets based on the volumetric representation of 3D digits, different rotations along the x, y and z axis are also taken into account. Unlike the normal volumetric representation, our datasets are much less memory usage. Finally, we introduce a model based on the combination of CNN models, the structure of the model is based on the classical LeNet. The accuracy result achieved is beyond the state of art and it can classify a 3D digit in around 9 ms