SNAI1 and SNAI2 Are Asymmetrically Expressed at the 2-Cell Stage and Become Segregated to the TE in the Mouse Blastocyst

SNAI1 and SNAI2 are transcription factors that initiate Epithelial-to-Mesenchymal cell transitions throughout development and in cancer metastasis. Here we show novel expression of SNAI1 and SNAI2 throughout mouse preimplantation development revealing asymmetrical localization of both SNAI1 and SNAI2 in individual blastomeres beginning at the 2-cell stage through to the 8-cell stage where SNAI1 and SNAI2 are then only detected in outer cells and not inner cells of the blastocyst. This study implicates SNAI1 and SNAI2 in the lineage segregation of the trophectoderm and inner cell mass, and provides new insight into these oncogenes

A Profile Likelihood Analysis of the Constrained MSSM with Genetic Algorithms

The Constrained Minimal Supersymmetric Standard Model (CMSSM) is one of the simplest and most widely-studied supersymmetric extensions to the standard model of particle physics. Nevertheless, current data do not sufficiently constrain the model parameters in a way completely independent of priors, statistical measures and scanning techniques. We present a new technique for scanning supersymmetric parameter spaces, optimised for frequentist profile likelihood analyses and based on Genetic Algorithms. We apply this technique to the CMSSM, taking into account existing collider and cosmological data in our global fit. We compare our method to the MultiNest algorithm, an efficient Bayesian technique, paying particular attention to the best-fit points and implications for particle masses at the LHC and dark matter searches. Our global best-fit point lies in the focus point region. We find many high-likelihood points in both the stau co-annihilation and focus point regions, including a previously neglected section of the co-annihilation region at large m_0. We show that there are many high-likelihood points in the CMSSM parameter space commonly missed by existing scanning techniques, especially at high masses. This has a significant influence on the derived confidence regions for parameters and observables, and can dramatically change the entire statistical inference of such scans.Comment: 47 pages, 8 figures; Fig. 8, Table 7 and more discussions added to Sec. 3.4.2 in response to referee's comments; accepted for publication in JHE

Murine Models for Trypanosoma brucei gambiense Disease Progression—From Silent to Chronic Infections and Early Brain Tropism

Trypanosoma brucei gambiense is responsible for more than 90% of reported cases of human African trypanosomosis (HAT). Infection can last for months or even years without major signs or symptoms of infection, but if left untreated, sleeping sickness is always fatal. In the present study, different T. b. gambiense field isolates from the cerebrospinal fluid of patients with HAT were adapted to growth in vitro. These isolates belong to the homogeneous Group 1 of T. b. gambiense, which is known to induce a chronic infection in humans. In spite of this, these isolates induced infections ranging from chronic to silent in mice, with variations in parasitaemia, mouse lifespan, their ability to invade the CNS and to elicit specific immune responses. In addition, during infection, an unexpected early tropism for the brain as well as the spleen and lungs was observed using bioluminescence analysis. The murine models presented in this work provide new insights into our understanding of HAT and allow further studies of parasite tropism during infection, which will be very useful for the treatment and the diagnosis of the disease

Bioluminescent Imaging of Trypanosoma brucei Shows Preferential Testis Dissemination Which May Hamper Drug Efficacy in Sleeping Sickness

Monitoring Trypanosoma spread using real-time imaging in vivo provides a fast method to evaluate parasite distribution especially in immunoprivileged locations. Here, we generated monomorphic and pleomorphic recombinant Trypanosoma brucei expressing the Renilla luciferase. In vitro luciferase activity measurements confirmed the uptake of the coelenterazine substrate by live parasites and light emission. We further validated the use of Renilla luciferase-tagged trypanosomes for real-time bioluminescent in vivo analysis. Interestingly, a preferential testis tropism was observed with both the monomorphic and pleomorphic recombinants. This is of importance when considering trypanocidal drug development, since parasites might be protected from many drugs by the blood-testis barrier. This hypothesis was supported by our final study of the efficacy of treatment with trypanocidal drugs in T. brucei-infected mice. We showed that parasites located in the testis, as compared to those located in the abdominal cavity, were not readily cleared by the drugs

Diversity of Antibiotic-Active Bacteria Associated with the Brown Alga Laminaria saccharina from the Baltic Sea

Bacteria associated with the marine macroalga Laminaria saccharina, collected from the Kiel Fjord (Baltic Sea, Germany), were isolated and tested for antimicrobial activity. From a total of 210 isolates, 103 strains inhibited the growth of at least one microorganism from the test panel including Gram-negative and Gram-positive bacteria as well as a yeast. Most common profiles were the inhibition of Bacillus subtilis only (30%), B. subtilis and Staphylococcus lentus (25%), and B. subtilis, S. lentus, and Candida albicans (11%). In summary, the antibiotic-active isolates covered 15 different activity patterns suggesting various modes of action. On the basis of 16S rRNA gene sequence similarities >99%, 45 phylotypes were defined, which were classified into 21 genera belonging to Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria. Phylogenetic analysis of 16S rRNA gene sequences revealed that four isolates possibly represent novel species or even genera. In conclusion, L. saccharina represents a promising source for the isolation of new bacterial taxa and antimicrobially active bacteria

Identifiability and privacy in pluripotent stem cell research

Data sharing is an essential element of research; however, recent scientific and social developments have challenged conventional methods for protecting privacy. Here we provide guidance for determining data sharing thresholds for human pluripotent stem cell research aimed at a wide range of stakeholders, including research consortia, biorepositories, policy-makers, and funders.The International Stem Cell Forum and the Stem Cell Network of Canada

Theory and Phenomenology of mu in M theory

We consider a solution to the mu-problem within M theory on a G2-manifold. Our study is based upon the discrete symmetry proposed by Witten that forbids the mu-term and solves the doublet-triplet splitting problem. We point out that the symmetry must be broken by moduli stabilization, describing in detail how this can occur. The mu-term is generated via Kahler interactions after strong dynamics in the hidden sector generate a potential which stabilizes all moduli and breaks supersymmetry with m_{3/2} ~ 20 - 30 TeV. We show that mu is suppressed relative to the gravitino mass, by higher dimensional operators, mu ~ 0.1 m_{3/2} ~ 2-3 TeV. This necessarily gives a Higgsino component to the (mostly Wino) LSP, and a small but non-negligible LSP-nucleon scattering cross-section. The maximum, spin-independent cross-sections are not within reach of the current XENON100 experiment, but are within reach of upcoming runs and upgrades.Comment: 34 pages, 3 figure

Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia

Gas6 Downregulation Impaired Cytoplasmic Maturation and Pronuclear Formation Independent to the MPF Activity

Previously, we found that the growth arrest-specific gene 6 (Gas6) is more highly expressed in germinal vesicle (GV) oocytes than in metaphase II (MII) oocytes using annealing control primer (ACP)-PCR technology. The current study was undertaken to investigate the role of Gas6 in oocyte maturation and fertilization using RNA interference (RNAi). Interestingly, despite the specific and marked decrease in Gas6 mRNA and protein expression in GVs after Gas6 RNAi, nuclear maturation including spindle structures and chromosome segregation was not affected. The only discernible effect induced by Gas6 RNAi was a change in maturation promoting factor (MPF) activity. After parthenogenetic activation, Gas6 RNAi-treated oocytes at the MII stage had not developed further and arrested at MII (90.0%). After stimulation with Sr2+, Gas6-silenced MII oocytes had markedly reduced Ca2+ oscillation and exhibited no exocytosis of cortical granules. In these oocytes, sperm penetration occurred during fertilization but not pronucleus (PN) formation. By roscovitine and colcemid treatment, we found that the Gas6 knockdown affected cytoplasmic maturation directly, independent to the changed MPF activity. These results strongly suggest that 1) the Gas6 signaling itself is important to the cytoplasmic maturation, but not nuclear maturation, and 2) the decreased Gas6 expression and decreased MPF activity separately or mutually influence sperm head decondensation and PN formation