Spin and Chirality Effects in Antler-Topology Processes at High Energy e+e−e^+e^- Colliders

We perform a model-independent investigation of spin and chirality correlation effects in the antler-topology processes $e^+e^-\to\mathcal{P}^+\mathcal{P}^-\to (\ell^+ \mathcal{D}^0) (\ell^-\mathcal{\bar{D}}^0)$ at high energy $e^+e^-$ colliders with polarized beams. Generally the production process $e^+e^-\to\mathcal{P}^+\mathcal{P}^-$ can occur not only through the $s$-channel exchange of vector bosons, $\mathcal{V}^0$, including the neutral Standard Model (SM) gauge bosons, $\gamma$ and $Z$, but also through the $s$- and $t$-channel exchanges of new neutral states, $\mathcal{S}^0$ and $\mathcal{T}^0$, and the $u$-channel exchange of new doubly-charged states, $\mathcal{U}^{--}$. The general set of (non-chiral) three-point couplings of the new particles and leptons allowed in a renormalizable quantum field theory is considered. The general spin and chirality analysis is based on the threshold behavior of the excitation curves for $\mathcal{P}^+\mathcal{P}^-$ pair production in $e^+e^-$ collisions with longitudinal and transverse polarized beams, the angular distributions in the production process and also the production-decay angular correlations. In the first step, we present the observables in the helicity formalism. Subsequently, we show how a set of observables can be designed for determining the spins and chiral structures of the new particles without any model assumptions. Finally, taking into account a typical set of approximately chiral invariant scenarios, we demonstrate how the spin and chirality effects can be probed experimentally at a high energy $e^+e^-$ collider.Comment: 50 pages, 14 figures, 6 tables, matches version published in EPJ

Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach

Modeling the competition between lung metastases and the immune system using agents

<p>Abstract</p> <p>Background</p> <p>The Triplex cell vaccine is a cancer cellular vaccine that can prevent almost completely the mammary tumor onset in HER-2/neu transgenic mice. In a translational perspective, the activity of the Triplex vaccine was also investigated against lung metastases showing that the vaccine is an effective treatment also for the cure of metastases. A future human application of the Triplex vaccine should take into account several aspects of biological behavior of the involved entities to improve the efficacy of therapeutic treatment and to try to predict, for example, the outcomes of longer experiments in order to move faster towards clinical phase I trials. To help to address this problem, MetastaSim, a hybrid Agent Based - ODE model for the simulation of the vaccine-elicited immune system response against lung metastases in mice is presented. The model is used as in silico wet-lab. As a first application MetastaSim is used to find protocols capable of maximizing the total number of prevented metastases, minimizing the number of vaccine administrations.</p> <p>Results</p> <p>The model shows that it is possible to obtain "in silico" a 45% reduction in the number of vaccinations. The analysis of the results further suggests that any optimal protocol for preventing lung metastases formation should be composed by an initial massive vaccine dosage followed by few vaccine recalls.</p> <p>Conclusions</p> <p>Such a reduction may represent an important result from the point of view of translational medicine to humans, since a downsizing of the number of vaccinations is usually advisable in order to minimize undesirable effects. The suggested vaccination strategy also represents a notable outcome. Even if this strategy is commonly used for many infectious diseases such as tetanus and hepatitis-B, it can be in fact considered as a relevant result in the field of cancer-vaccines immunotherapy. These results can be then used and verified in future "in vivo" experiments, and their outcome can be used to further improve and refine the model.</p

Extreme genetic fragility of the HIV-1 capsid

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency &gt;3%, and were also present in the mutant library, had fitness levels that were &gt;40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies

Fecal Tests: From Blood to Molecular Markers

Detection of molecular markers for colorectal neoplasia in feces has the potential to improve performance of simple noninvasive screening tests for colorectal cancer. Most research has explored the value of DNA-based, RNA-based, and protein-based markers. In all cases there has been a trend to move from a single marker to a panel of markers to improve sensitivity. Unfortunately, no type of molecular marker has proved specific for neoplasia. DNA tests have been improved by combining mutation detection with assessment of DNA integrity plus epigenetic markers of neoplasia. RNA-based approaches are just beginning to explore the full power of transcriptomics. So far, no protein-based fecal test has proved better than fecal immunochemical tests for hemoglobin. Finally, no marker or panel of markers has yet been developed to the point where it has been evaluated in large unbiased population studies to assess performance across all stages of neoplasia and in all practical environments

Chasing Migration Genes: A Brain Expressed Sequence Tag Resource for Summer and Migratory Monarch Butterflies (Danaus plexippus)

North American monarch butterflies (Danaus plexippus) undergo a spectacular fall migration. In contrast to summer butterflies, migrants are juvenile hormone (JH) deficient, which leads to reproductive diapause and increased longevity. Migrants also utilize time-compensated sun compass orientation to help them navigate to their overwintering grounds. Here, we describe a brain expressed sequence tag (EST) resource to identify genes involved in migratory behaviors. A brain EST library was constructed from summer and migrating butterflies. Of 9,484 unique sequences, 6068 had positive hits with the non-redundant protein database; the EST database likely represents ∼52% of the gene-encoding potential of the monarch genome. The brain transcriptome was cataloged using Gene Ontology and compared to Drosophila. Monarch genes were well represented, including those implicated in behavior. Three genes involved in increased JH activity (allatotropin, juvenile hormone acid methyltransfersase, and takeout) were upregulated in summer butterflies, compared to migrants. The locomotion-relevant turtle gene was marginally upregulated in migrants, while the foraging and single-minded genes were not differentially regulated. Many of the genes important for the monarch circadian clock mechanism (involved in sun compass orientation) were in the EST resource, including the newly identified cryptochrome 2. The EST database also revealed a novel Na+/K+ ATPase allele predicted to be more resistant to the toxic effects of milkweed than that reported previously. Potential genetic markers were identified from 3,486 EST contigs and included 1599 double-hit single nucleotide polymorphisms (SNPs) and 98 microsatellite polymorphisms. These data provide a template of the brain transcriptome for the monarch butterfly. Our “snap-shot” analysis of the differential regulation of candidate genes between summer and migratory butterflies suggests that unbiased, comprehensive transcriptional profiling will inform the molecular basis of migration. The identified SNPs and microsatellite polymorphisms can be used as genetic markers to address questions of population and subspecies structure