CRIPTO and its signaling partner GRP78 drive the metastatic phenotype in human osteotropic prostate cancer

CRIPTO (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of CRIPTO correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. CRIPTO and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDHhigh sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDHlow. Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced CRIPTO and GRP78 expression in cancer cells and increases the size of the ALDHhigh sub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDHhigh sub-population. CRIPTO knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for CRIPTO and GRP78 in PCa metastasis and suggest that targeting CRIPTO/GRP78 signaling may have significant therapeutic potential.Oncogene advance online publication, 10 April 2017; doi:10.1038/onc.2017.87

Clinical isolates of the modern Mycobacterium tuberculosis lineage 4 evade host defense in human macrophages through eluding IL-1\u3b2-induced autophagy article

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), has infected over 1.7 billion people worldwide and causes 1.4 million deaths annually. Recently, genome sequence analysis has allowed the reconstruction of Mycobacterium tuberculosis complex (MTBC) evolution, with the identification of seven phylogeographic lineages: four referred to as evolutionarily "ancient", and three "modern". The MTBC strains belonging to "modern" lineages appear to show enhanced virulence that may have warranted improved transmission in humans over ancient lineages through molecular mechanisms that remain to be fully characterized. To evaluate the impact of MTBC genetic diversity on the innate immune response, we analyzed intracellular bacterial replication, inflammatory cytokine levels, and autophagy response in human primary macrophages infected with MTBC clinical isolates belonging to the ancient lineages 1 and 5, and the modern lineage 4. We show that, when compared to ancient lineage 1 and 5, MTBC strains belonging to modern lineage 4 show a higher rate of replication, associated to a significant production of proinflammatory cytokines (IL-1\u3b2, IL-6, and TNF-\u3b1) and induction of a functional autophagy process. Interestingly, we found that the increased autophagic flux observed in macrophages infected with modern MTBC is due to an autocrine activity of the proinflammatory cytokine IL-1\u3b2, since autophagosome maturation is blocked by an interleukin-1 receptor antagonist. Unexpectedly, IL-1\u3b2-induced autophagy is not disadvantageous for the survival of modern Mtb strains, which reside within Rab5-positive phagosomal vesicles and avoid autophagosome engulfment. Altogether, these results suggest that autophagy triggered by inflammatory cytokines is compatible with a high rate of intracellular bacilli replication and may therefore contribute to the increased pathogenicity of the modern MTBC lineages

The Microcephalin Ancestral Allele in a Neanderthal Individual

Background: The high frequency (around 0.70 worlwide) and the relatively young age (between 14,000 and 62,000 years) of a derived group of haplotypes, haplogroup D, at the microcephalin (MCPH1) locus led to the proposal that haplogroup D originated in a human lineage that separated from modern humans.1 million years ago, evolved under strong positive selection, and passed into the human gene pool by an episode of admixture circa 37,000 years ago. The geographic distribution of haplogroup D, with marked differences between Africa and Eurasia, suggested that the archaic human form admixing with anatomically modern humans might have been Neanderthal. Methodology/Principal Findings: Here we report the first PCR amplification and high- throughput sequencing of nuclear DNA at the microcephalin (MCPH1) locus from Neanderthal individual from Mezzena Rockshelter (Monti Lessini, Italy). We show that a well-preserved Neanderthal fossil dated at approximately 50,000 years B.P., was homozygous for the ancestral, non-D, allele. The high yield of Neanderthal mtDNA sequences of the studied specimen, the pattern of nucleotide misincorporation among sequences consistent with post-mortem DNA damage and an accurate control of the MCPH

Cheek Tooth Morphology and Ancient Mitochondrial DNA of Late Pleistocene Horses from the Western Interior of North America: Implications for the Taxonomy of North American Late Pleistocene Equus

Horses were a dominant component of North American Pleistocene land mammal communities and their remains are well represented in the fossil record. Despite the abundant material available for study, there is still considerable disagreement over the number of species of Equus that inhabited the different regions of the continent and on their taxonomic nomenclature. In this study, we investigated cheek tooth morphology and ancient mtDNA of late Pleistocene Equus specimens from the Western Interior of North America, with the objective of clarifying the species that lived in this region prior to the end-Pleistocene extinction. Based on the morphological and molecular data analyzed, a caballine (Equus ferus) and a non-caballine (E. conversidens) species were identified from different localities across most of the Western Interior. A second non-caballine species (E. cedralensis) was recognized from southern localities based exclusively on the morphological analyses of the cheek teeth. Notably the separation into caballine and non-caballine species was observed in the Bayesian phylogenetic analysis of ancient mtDNA as well as in the geometric morphometric analyses of the upper and lower premolars. Teeth morphologically identified as E. conversidens that yielded ancient mtDNA fall within the New World stilt-legged clade recognized in previous studies and this is the name we apply to this group. Geographic variation in morphology in the caballine species is indicated by statistically different occlusal enamel patterns in the specimens from Bluefish Caves, Yukon Territory, relative to the specimens from the other geographic regions. Whether this represents ecomorphological variation and/or a certain degree of geographic and genetic isolation of these Arctic populations requires further study

Cianoacrilato na colagem de Bráquetes ortodônticos em resina acrílica: há maior adesão?

Pacientes em tratamento ortodôntico apresentam restaurações provisórias com frequência. No entanto, poucos estudos avaliam a influência dos adesivos na resistência ao cisalhamento dos bráquetes nessas superfícies. A resina acrílica é comumente indicada para colagem de bráquetes, porém o uso do cianoacrilato como adesivo ortodôntico é uma opção analisada. O objetivo do presente trabalho foi avaliar o desempenho do cianoacrilato associado aos materiais comumente utilizados para a fixação de bráquetes metálicos em restaurações provisórias de resina acrílica. Quarenta amostras em resina acrílica foram preparadas e as superfícies homogeinizadas com lixas de carboneto de silício (320 e 600). Em seguida, as amostras foram divididas aleatoriamente em quatro grupos (n=10) com base no tratamento de superfície e agente de união: G1 - bráquetes colados com resina acrílica; G2 - bráquetes colados com resina acrílica e aplicação de cianoacrilato; G3 - bráquetes colados com Transbond(tm) XT; G4 - bráquetes colados com Transbond(tm) XT e aplicação de cianoacrilato. Foram utilizados bráquetes ortodônticos de aço inoxidável, prescrição Roth, Kirium (3M/Abzil) para incisivos centrais superiores direitos, slot 022. Após colagem, as amostras foram submetidas ao teste de cisalhamento a uma velocidade de 0,5mm/min em uma máquina de ensaios universal (EMIC DL-1000). Os dados foram coletados e submetidos à análise estatística pelo teste ANOVA com nível de significância de 5%. A associação de resina acrílica ao cianoacrilato (G2) resultou na maior resistência ao cisalhamento (13,76 MPa), mas não significativa em comparação aos valores obtidos para a resina acrílica (G1= 7,76 MPa). O mesmo pôde ser observado para a associação Transbond(tm) XT e cianoacrilato (G4= 4,03 MPa) em relação a utilização da Transbond(tm) XT de forma isolada (G3= 3,87 MPa) e resina acrílica. O tratamento de superfície tem efeito significativo na resistência da união dos bráquetes colados aos materiais provisórios. A associação de cianoacrilato ao monômero de metilmetacrilato apresentou maior resistência ao cisalhamento, sendo mais indicada clinicamente

Application of fuzzy logic system for the pizza production processing optimisation

The main problem of industrial pizza production is process standardisation. This study focused on the individuation of single and interactive effects of processing variables that strongly influenced pizza's quality and aimed to propose a possible optimisation/standardisation of the production method through the fuzzy logic system. The decision tree derived from fuzzy inference and related to sensory properties of pizza highlighted the importance of oven ceiling temperature and dough hydration level to improve and standardise pizza quality made up with flour with poor quality. In particular, samples with low dough hydration levels (44%) and baked at medium oven ceiling temperature (350 °C) was the most appreciated by panellist (overall judgment >7). The validation on a wide scale of the algorithm used in this research could be helpful to design an easy-to-use application for both industrial and artisanal pizza production through management software or smartphones