Strain-Promoted Thiol-Mediated Cellular Uptake of Giant Substrates: Liposomes and Polymersomes

Simple cyclic disulfides under high tension mediate the uptake of giant substrates, that is, liposomes and polymersomes with diameters of up to 400 nm, into HeLa Kyoto cells. To place them at the surface of the vesicles, the strained disulfides were attached to the head-group of cationic amphiphiles. Bell-shaped dose response curves revealed self-activation of the strained amphiphiles by self-assembly into microdomains at low concentrations and self-inhibition by micelle formation at high concentrations. Poor colocalization of internalized vesicles with endosomes, lysosomes, and mitochondria indicate substantial release into the cytosol. The increasing activity with disulfide ring tension, inhibition with Ellman`s reagent, and inactivity of maleimide and guanidinium controls outline a distinct mode of action that deserves further investigation and is promising for practical applications

Analysis of Somatic Copy Number Gains in Pancreatic Ductal Adenocarcinoma Implicates ECT2 as a Candidate Therapeutic Target

This study presents an integrated analysis of pancreatic ductal adenocarcinomas (PDACs) for identification of putative cancer driver genes in somatic copy number gains (SCNGs). SCNG data on 60 PDAC genomes was extracted to identify 756 genes, mapping to 20 genomic loci that are recurrently gained. Through copy number and gene expression analysis on a panel of 29 human pancreatic cancer cell lines, this gene catalogue was refined to 34 PDAC high-confidence candidate genes. The performance of these genes was assessed in pooled shRNA screens and only ECT2 showed significant essentiality to cell viability in specific PDAC cell lines with genomic gains at the 3q26.3 locus that harbor this gene. Targeted shRNA-mediated interference of ECT2, as well as pharmacological inhibition, are supportive of the pooled shRNA screen findings. These results favor ECT2 as a candidate target gene for further evaluation in the subset of PDACs presenting with 3q26 somatic copy number gains.MAS

Genetic and Epigenetic Crosstalk Define TP53-mediated Human Cancer Susceptibility

Deregulation of epigenetic programming is crucial to tumorigenesis, yet the extent to which epigenetics plays a role in cancer susceptibility remains unclear. This work details systematic molecular investigations of the familial cancer predisposition syndrome, Li-Fraumeni Syndrome (LFS), to garner a better understanding of the role of epigenetics in cancer susceptibility in humans. LFS is a prototypical cancer susceptibility syndrome characterized by a 73-100% lifetime incidence of developing at least one malignancy in affected individuals. The majority of LFS cases are associated with inherited or de novo mutations in the TP53 gene, encoding the tumor suppressor protein, p53. This work reports the first genome-wide survey of DNA methylation in peripheral blood leukocytes from carriers of germline TP53 mutations, and reveals that TP53 mutation carriers harbor a distinct DNA methylation profile relative to non-carriers overall, and in subgroup analyses stratified by cancer diagnosis. Many TP53 mutation-associated differential methylation marks occur at previously characterized p53 transcription factor binding sites. In particular, striking hypomethylation of the miR-34A promoter, a known tumor suppressor in the p53 regulatory network, is detected in leukocytes from LFS patients in two independent cohorts. By contrast, miR-34A promoter hypermethylation is a recurrent epigenetic event in primary LFS tumors of various histologies and correlates with poor clinical outcome in patients with choroid plexus carcinomas. These findings suggest a role for miR-34A as an important tumor suppressor in LFS, and demonstrate that loss of miR-34A by somatic epimutation may comprise a step in neoplastic progression in this clinical context. Detailed molecular investigations to better understand the functional role of miR-34A in the background of mutant TP53 reveal that miR-34A is essential for cell viability and regulates a network of noncoding RNAs, including components of the minor spliceosome, as well as various long non-coding RNAs. The function of miR-34A in cell cycle states may be mediated by these transcriptional changes. Collectively, this work provides the first insights into the mechanisms by which germline TP53 mutations may confer cancer predisposition and implicates a novel gene, miR-34A, in the pathogenesis of TP53-associated human cancer susceptibility.Ph.D

New rhombiferan blastozoans (Echinodermata) from the Late Ordovician of Morocco

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Scientific overview: CSCI-CITAC Annual General Meeting and Young Investigators’ Forum 2014

The Canadian Society of Clinician Investigators (CSCI) and Clinical Investigator Trainee Association of Canada/Association des cliniciens-chercheurs en formation du Canada (CITAC/ACCFC) annual general meeting (AGM) was held in Toronto during November 21-24, 2015 for the first time in conjunction with the University of Toronto Clinician-Investigator Program Research Day. The overall theme for this year’s meeting was the role of mentorship in career development, with presentations from Dr. Chaim Bell (University of Toronto), Dr. Shurjeel Choudhri (Bayer Healthcare), Dr. Ken Croitoru (University of Toronto), Dr. Astrid Guttman (University of Toronto), Dr. Prabhat Jha (University of Toronto) and Dr. Sheila Singh (McMaster University). The keynote speakers of the 2014 AGM included Dr. Qutayba Hamid, who was presented with the Distinguished Scientist Award, Dr. Ravi Retnakaran, who was presented with the Joe Doupe Award, and Dr. Lorne Babiuk, who was the CSCI-RCPSC Henry Friesen Award winner. The highlight of the conference was, once again, the outstanding scientific presentations from the numerous clinician investigator (CI) trainees from across the country who presented at the Young Investigators’ Forum. Their research topics spanned the diverse fields of science and medicine, ranging from basic science to cutting-edge translational research, and their work has been summarized in this review. Over 120 abstracts were presented at this year’s meeting. This work was presented during two poster sessions, with the six most outstanding submitted abstracts presented in the form of oral presentations during the President’s Forum

The Cambrian edrioasteroid Stromatocystites (Echinodermata): Systematics, palaeogeography, and palaeoecology

International audienceThe Cambrian edrioasteroid Stromatocystites is reported and described from Spain, Sweden and Turkey. All previously known occurrences of the genus are critically reviewed, and S.flexibilis is reinterpreted as a junior synonym of S. pentangularis. Stromatocystites was biogeographically widespread and colonized different areas of Baltica, Gondwana (Arabian, eastern and western margins) and Laurentia (western Newfoundland). Stratigraphically, it ranges from Cambrian Series 2, Stage 4 to Cambrian Series 3, Drumian. Stromatocystites lived in quiet water environments with stabilized substrates. It was attached directly to the substrate by its aboral surface. As these environments were widespread throughout Baltica, Gondwana and Laurentia, availability of suitable substrates for larval settlement and oceanic palaeocurrents led to the successful development of Stromatocystites colonies. (C) 2015 Elsevier Masson SAS. All rights reserved

Effect of MacroRAFT Copolymer Adsorption on the Colloidal Stability of Layered Double Hydroxide Nanoparticles.

International audienceThe colloidal behavior of layered double hydroxide nanoparticles containing Mg2+ and Al3+ ions as intralayer cations and nitrates as counterions (MgAl-NO3-LDH) was studied in the presence of a short statistical copolymer of acrylic acid (AA) and butyl acrylate (BA) terminated with 4-cyano-4-thiothiopropylsulfanyl pentanoic acid (CTPPA) (P(AA7.5-stat-BA7.5)-CTPPA) synthesized by reversible addition–fragmentation chain-transfer (RAFT) polymerization. Surface charge properties and aggregation of the particles were investigated by electrophoresis and dynamic light scattering (DLS), respectively. The negatively charged P(AA7.5-stat-BA7.5)-CTPPA adsorbed strongly on the oppositely charged particles, leading to charge neutralization at the isoelectric point (IEP) and charge reversal at higher copolymer concentrations. The dispersions were unstable, i.e., fast aggregation of the MgAl-NO3-LDH occurred near the IEP while high stability was achieved at higher P(AA7.5-stat-BA7.5)-CTPPA concentrations. Atomic force (AFM) and transmission electron (TEM) microscopy imaging revealed that the platelets preferentially adopted a face-to-face orientation in the aggregates. While the stability of the bare particles was very sensitive to ionic strength, the P(AA7.5-stat-BA7.5)-CTPPA copolymer-coated particles were extremely stable even at high salt levels. Accordingly, the limited colloidal stability of bare MgAl-NO3-LDH dispersions was significantly improved by adding an appropriate amount of P(AA7.5-stat-BA7.5)-CTPPA to the suspension

Palaeobiogeographic implications of exceptionally preserved Late Ordovician echinoderm assemblages from the Tafilalt area, Morocco

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