Solvent effects on the magnetic-field-dependent reaction yields of photogenerated radical ion pairs.

A pronounced solvent viscosity and polarity dependence of the magnetic field effect was found for polymethylene-linked radical ion pairs generated by photoinduced intramolecular electron transfer in compounds of the type pyrene-(CH2)n-N,N-dimethylaniline, with n = 7–16. This is interpreted in terms of the general radical pair mechanism, i.e. the nuclear hyperfine interaction mechanism including a spin-exchange interaction, modulated by the stochastic folding motion of the linking CH2 chain which leads to a “motional deformation” of the reaction yield spectra

Antimicrobial resistance and antimicrobial use animal monitoring policies in Europe: Where are we?

The World Health Organization has recognized antimicrobial resistance as one of the top three threats to human health. Any use of antibiotics in animals will ultimately affect humans and vice versa. Appropriate monitoring of antimicrobial use and resistance has been repeatedly emphasized along with the need for global policies. Under the auspices of the European Union research project, EFFORT, we mapped antimicrobial use and resistance monitoring programs in ten European countries. We then compared international and European guidelines and policies. In resistance monitoring, we did not find important differences between countries. Current resistance monitoring systems are focused on food animal species (using fecal samples). They ignore companion animals. The scenario is different for monitoring antibiotics use. Recently, countries have tried to harmonize methodologies, but reporting of antimicrobial use remains voluntary. We therefore identified a need for stronger policies

Modelling the species jump: towards assessing the risk of human infection from novel avian influenzas

The scientific understanding of the driving factors behind zoonotic and pandemic influenzas is hampered by complex interactions between viruses, animal hosts and humans. This complexity makes identifying influenza viruses of high zoonotic or pandemic risk, before they emerge from animal populations, extremely difficult and uncertain. As a first step towards assessing zoonotic risk of Influenza, we demonstrate a risk assessment framework to assess the relative likelihood of influenza A viruses, circulating in animal populations, making the species jump into humans. The intention is that such a risk assessment framework could assist decisionmakers to compare multiple influenza viruses for zoonotic potential and hence to develop appropriate strain-specific control measures. It also provides a first step towards showing proof of principle for an eventual pandemic risk model. We show that the spatial and temporal epidemiology is as important in assessing the risk of an influenza A species jump as understanding the innate molecular capability of the virus.We also demonstrate data deficiencies that need to be addressed in order to consistently combine both epidemiological and molecular virology data into a risk assessment framework

Simple and selective spectrophotometric assay of diethylcarbamazine citrate using 2,3-dichloro-5,6-dicyano-p-benzoquinone and 2,4-dinitro phenol

Two simple, rapid and inexpensive spectrophotometric methods are described for the determination of diethylcarbamazine citrate (DEC) in bulk drug and formulations. The methods are based on the charge-transfer (CT) complexation reaction involving DEC as the n- donor and 2,3-dichloro-5,6-dicyano-p-benzoquinone DDQ] (method A) and 2,4-dinitro phenol DNP] (method B) as pi-acceptors in chloroform. The absorbance of CT complexes was measured at 480 nm for method A, and 420 nm for method B. Under optimum conditions, Beer's law was obeyed over the concentration ranges 4-90 and 4-100 mu g mL(-1) for methods A and B, respectively

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies

Metastable Pluripotent States in NOD Mouse Derived ES Cells

Embryonic stem (ES) cells are isolated from the inner cell mass (ICM) of blastocysts, whereas epiblast stem cells (EpiSCs) are derived from the post-implantation epiblast and display a restricted developmental potential. Here we characterize pluripotent states in the non-obese diabetic (NOD) mouse strain, which prior to this study was considered “non-permissive” for ES cell derivation. We find that NOD stem cells can be stabilized by providing constitutive expression of Klf4 or c-Myc or small molecules that can replace these factors during in vitro reprogramming. The NOD ES and iPS cells appear “metastable”, as they acquire an alternative EpiSC-like identity after removal of the exogenous factors, while their reintroduction converts the cells back to ICM-like pluripotency. Our findings suggest that stem cells from different genetic backgrounds can assume distinct states of pluripotency in vitro, the stability of which is regulated by endogenous genetic determinants and can be modified by exogenous factors.National Institutes of Health (U.S.) (Grant RO1-HDO45022)National Institutes of Health (U.S.) (Grant R37-CA084198)National Institutes of Health (U.S.) (Grant RO1-CA087869

Effects of Clinically Relevant MPL Mutations in the Transmembrane Domain Revealed at the Atomic Level through Computational Modeling

BACKGROUND: Mutations in the thrombopoietin receptor (MPL) may activate relevant pathways and lead to chronic myeloproliferative neoplasms (MPNs). The mechanisms of MPL activation remain elusive because of a lack of experimental structures. Modern computational biology techniques were utilized to explore the mechanisms of MPL protein activation due to various mutations. RESULTS: Transmembrane (TM) domain predictions, homology modeling, ab initio protein structure prediction, and molecular dynamics (MD) simulations were used to build structural dynamic models of wild-type and four clinically observed mutants of MPL. The simulation results suggest that S505 and W515 are important in keeping the TM domain in its correct position within the membrane. Mutations at either of these two positions cause movement of the TM domain, altering the conformation of the nearby intracellular domain in unexpected ways, and may cause the unwanted constitutive activation of MPL's kinase partner, JAK2. CONCLUSIONS: Our findings represent the first full-scale molecular dynamics simulations of the wild-type and clinically observed mutants of the MPL protein, a critical element of the MPL-JAK2-STAT signaling pathway. In contrast to usual explanations for the activation mechanism that are based on the relative translational movement between rigid domains of MPL, our results suggest that mutations within the TM region could result in conformational changes including tilt and rotation (azimuthal) angles along the membrane axis. Such changes may significantly alter the conformation of the adjacent and intrinsically flexible intracellular domain. Hence, caution should be exercised when interpreting experimental evidence based on rigid models of cytokine receptors or similar systems