Friends or Foes? Emerging Impacts of Biological Toxins

Toxins are substances produced from biological sources (e.g., animal, plants, microorganisms) that have deleterious effects on a living organism. Despite the obvious health concerns of being exposed to toxins, they are having substantial positive impacts in a number of industrial sectors. Several toxin-derived products are approved for clinical, veterinary, or agrochemical uses. This review sets out the case for toxins as ‘friends’ that are providing the basis of novel medicines, insecticides, and even nucleic acid sequencing technologies. We also discuss emerging toxins (‘foes’) that are becoming increasingly prevalent in a range of contexts through climate change and the globalisation of food supply chains and that ultimately pose a risk to health

Constraining the primordial spectrum of metric perturbations from gravitino and moduli production

We consider the production of gravitinos and moduli fields from quantum vacuum fluctuations induced by the presence of scalar metric perturbations at the end of inflation. We obtain the corresponding occupation numbers, up to first order in perturbation theory, in terms of the power spectrum of the metric perturbations. We compute the limits imposed by nucleosynthesis on the spectral index $n_s$ for different models with constant $n_s$. The results show that, in certain cases, such limits can be as strong as $n_s<1.12$, which is more stringent than those coming from primordial black hole production.Comment: 16 pages, LaTeX, 5 figures. Corrected figures, new references included. Final version to appear in Phys. Rev.

Bjorken unpolarized and polarized sum rules: comparative analysis of large-N_F expansions

Analytical all-orders results are presented for the one-renormalon-chain contributions to the Bjorken unpolarized sum rule for the F_1 structure function of nu N deep-inelastic scattering in the large-N_F limit. The feasibility of estimating higher order perturbative QCD corrections, by the process of naive nonabelianization (NNA), is studied, in anticipation of measurement of this sum rule at a Neutrino Factory. A comparison is made with similar estimates obtained for the Bjorken polarized sum rule. Application of the NNA procedure to correlators of quark vector and scalar currents, in the euclidean region, is compared with recent analytical results for the O(alpha_s^4 N_F^2) terms.Comment: 9 page

Strong coupling constant from τ\tau decay within renormalization scheme invariant treatment

We extract a numerical value for the strong coupling constant \alpha_s from the \tau-lepton decay rate into nonstrange particles. A new feature of our procedure is the explicit use of renormalization scheme invariance in analytical form in order to perform the actual analysis in a particular renormalization scheme. For the reference coupling constant in the \MSsch-scheme we obtain \alpha_s(M_\tau)= 0.3184 \pm 0.0060_{exp} which corresponds to \al_s(M_Z)= 0.1184 \pm 0.0007_{exp} \pm 0.0006_{hq mass}. This new numerical value is smaller than the standard value from $\tau$-data quoted in the literature and is closer to \al_s(M_Z)-values obtained from high energy experiments.Comment: 8 page

Searching for TeV dark matter by atmospheric Cerenkov techniques

There is a growing interest in the possibility that dark matter could be formed of weakly interacting particles with a mass in the 100 GeV - 2 TeV range, and supersymmetric particles are favorite candidates. If they constitute the dark halo of our Galaxy, their mutual annihilations produce energetic gamma rays that could be detected using existing atmospheric \u{C}erenkov techniques.Comment: 10 pp, LaTex (3 figures available by e-mail) PAR-LPTHE 92X

Nonperturbative Effects from the Resummation of Perturbation Theory

Using the general argument in Borel resummation of perturbation theory that links the divergent perturbation theory to the nonperturbative effect we argue that the nonperturbative effect associated with the perturbation theory should have a branch cut only along the positive real axis in the complex coupling plane. The component in the weak coupling expansion of the nonperturbative amplitude, which usually includes the leading term in the weak coupling expansion, that gives rise to the branch cut can be calculated in principle from the perturbation theory combined with some exactly calculable properties of the nonperturbative effect. The realization of this mechanism is demonstrated in the double well potential and the two-dimensional O(N) nonlinear sigma model. In these models the leading term in weak coupling of the nonperturbative effect can be obtained with good accuracy from the first terms of the perturbation theory. Applying this mechanism to the infrared renormalon induced nonperturbative effect in QCD, we suggest some of the QCD condensate effects can be calculated in principle from the perturbation theory.Comment: 21 Pages, 1 Figure; To appear in Phys Rev

Separation of breast cancer and organ microenvironment transcriptomes in metastases

Background: The seed and soil hypothesis was proposed over a century ago to describe why cancer cells (seeds) grow in certain organs (soil). Since then, the genetic properties that define the cancer cells have been heavily investigated; however, genomic mediators within the organ microenvironment that mediate successful metastatic growth are less understood. These studies sought to identify cancer- and organ-specific genomic programs that mediate metastasis. Methods: In these studies, a set of 14 human breast cancer patient-derived xenograft (PDX) metastasis models was developed and then tested for metastatic tropism with two approaches: spontaneous metastases from mammary tumors and intravenous injection of PDX cells. The transcriptomes of the cancer cells when growing as tumors or metastases were separated from the transcriptomes of the microenvironment via species-specific separation of the genomes. Drug treatment of PDX spheroids was performed to determine if genes activated in metastases may identify targetable mediators of viability. Results: The experimental approaches that generated metastases in PDX models were identified. RNA sequencing of 134 tumors, metastases, and normal non-metastatic organs identified cancer- and organ-specific genomic properties that mediated metastasis. A common genomic response of the liver microenvironment was found to occur in reaction to the invading PDX cells. Genes within the cancer cells were found to be either transiently regulated by the microenvironment or permanently altered due to clonal selection of metastatic sublines. Gene Set Enrichment Analyses identified more than 400 gene signatures that were commonly activated in metastases across basal-like PDXs. A Src signaling signature was found to be extensively upregulated in metastases, and Src inhibitors were found to be cytotoxic to PDX spheroids. Conclusions: These studies identified that during the growth of breast cancer metastases, there were genomic changes that occurred within both the cancer cells and the organ microenvironment. We hypothesize that pathways upregulated in metastases are mediators of viability and that simultaneously targeting changes within different cancer cell pathways and/or different tissue compartments may be needed for inhibition of disease progression

A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424

BACKGROUND: Src is involved in cancer invasion and metastasis. AZD0424, an oral inhibitor of Src and ABL1, has shown evidence of anti-tumour activity in pre-clinical studies. METHODS: A phase Ia, dose escalation study was performed to assess the safety of continuous oral dosing with AZD0424 in advanced solid tumours. Secondary objectives included investigation of AZD0424 pharmacokinetics, effect on Src activity using markers of bone turnover, and anti-tumour activity. RESULTS: 41 patients were treated; 34 received AZD0424 once-daily at doses ranging from 5 mg to 150 mg, and 7 received 40 mg bi-daily 41.5% of patients experienced at least one AZD0424-related adverse event that was Grade 3-5 in severity, with patients treated at doses above 60 mg per day experiencing multiple treatment-related toxicities. The most commonly observed AZD0424-related adverse events were nausea, fatigue, anorexia and alopecia. Cmaxand AUC increased linearly with dose and the mean±standard deviation t1/2was 8.4±2.8 h. Clear evidence of Src target inhibition was seen at doses ⩾20 mg per day. No responses were observed and 7 patients (17.1%) achieved stable disease lasting 6 weeks or more. CONCLUSIONS: AZD0424 displayed no evidence of efficacy as monotherapy despite a clear pharmacodynamic effect. Further evaluation of AZD0424 monotherapy in patients with solid tumours is not recommended

Lymphocytes from rheumatoid arthritis patients have elevated levels of intracellular peroxiredoxin 2, and a greater frequency of cells with exofacial peroxiredoxin 2, compared with healthy human lymphocytes

AbstractPeroxiredoxin 2 has immune regulatory functions, but its expression in human peripheral blood lymphocytes and levels in extracellular fluid in healthy subjects and rheumatoid arthritis patients are poorly described. In the present study, the median intracellular peroxiredoxin 2 protein content of lymphocytes from rheumatoid arthritis patients was more than two-fold higher compared with healthy subjects’ lymphocytes. Intracellular peroxiredoxin 3 levels were similar in healthy and rheumatoid arthritis lymphocytes. Flow cytometry detected peroxiredoxin 2 on the surface of ca. 8% of T cells and ca. 56% of B cells (median % values) of all subjects analyzed. Exofacial thioredoxin-1 was also observed. In the total lymphocyte population from rheumatoid arthritis patients, few cells (median, 6%) displayed surface peroxiredoxin 2. In contrast, a significantly increased proportion of interleukin-17+ve lymphocytes were exofacially peroxiredoxin 2+ve (median, 39%). Prdx2 was also detected in human extracellular fluids. We suggest that crucial inflammatory cell subsets, i.e. interleukin-17+ve T cells, exhibit increased exofacial redox-regulating enzymes and that peroxiredoxin 2 may be involved in the persistence of pro-inflammatory cells in chronic inflammation

Brane oscillations and the cosmic coincidence problem

We show that, under general assumptions, in six-dimensional brane-world models with compactified large extra dimensions, the energy density of brane oscillations scales as that of cold dark matter and its present value is compatible with observations. Such value is obtained from the only dimensional scale in the theory, namely, the fundamental scale of gravity in six dimensions $M_6\sim 1$ TeV, without any fine-tuning or the introduction of additional mass scales apart from the large size of the extra dimensions. It has been suggested that the same kind of models could provide also the correct magnitude of the cosmological constant. This observation can be relevant for the resolution of the cosmic coincidence problem in the brane-world scenario.Comment: 5 pages, RevTeX. Comments on the renormalization of the branon mass included. Final version to appear in Phys.Rev.D (R