In Silico and In Vitro Investigations of the Mutability of Disease-Causing Missense Mutation Sites in Spermine Synthase

Spermine synthase (SMS) is a key enzyme controlling the concentration of spermidine and spermine in the cell. The importance of SMS is manifested by the fact that single missense mutations were found to cause Snyder-Robinson Syndrome (SRS). At the same time, currently there are no non-synonymous single nucleoside polymorphisms, nsSNPs (harmless mutations), found in SMS, which may imply that the SMS does not tolerate amino acid substitutions, i.e. is not mutable.To investigate the mutability of the SMS, we carried out in silico analysis and in vitro experiments of the effects of amino acid substitutions at the missense mutation sites (G56, V132 and I150) that have been shown to cause SRS. Our investigation showed that the mutation sites have different degree of mutability depending on their structural micro-environment and involvement in the function and structural integrity of the SMS. It was found that the I150 site does not tolerate any mutation, while V132, despite its key position at the interface of SMS dimer, is quite mutable. The G56 site is in the middle of the spectra, but still quite sensitive to charge residue replacement.The performed analysis showed that mutability depends on the detail of the structural and functional factors and cannot be predicted based on conservation of wild type properties alone. Also, harmless nsSNPs can be expected to occur even at sites at which missense mutations were found to cause diseases

Estimating the Extent of Vaccine-Derived Poliovirus Infection

BACKGROUND: Eight outbreaks of paralytic polio attributable to circulating vaccine-derived poliovirus (cVDPV) have highlighted the risks associated with oral poliovirus vaccine (OPV) use in areas of low vaccination coverage and poor hygiene. As the Polio Eradication Initiative enters its final stages, it is important to consider the extent to which these viruses spread under different conditions, so that appropriate strategies can be devised to prevent or respond to future cVDPV outbreaks. METHODS AND FINDINGS: This paper examines epidemiological (temporal, geographic, age, vaccine history, social group, ascertainment), and virological (type, genetic diversity, virulence) parameters in order to infer the numbers of individuals likely to have been infected in each of these cVDPV outbreaks, and in association with single acute flaccid paralysis (AFP) cases attributable to VDPVs. Although only 114 virologically-confirmed paralytic cases were identified in the eight cVDPV outbreaks, it is likely that a minimum of hundreds of thousands, and more likely several million individuals were infected during these events, and that many thousands more have been infected by VDPV lineages within outbreaks which have escaped detection. CONCLUSIONS: Our estimates of the extent of cVDPV circulation suggest widespread transmission in some countries, as might be expected from endemic wild poliovirus transmission in these same settings. These methods for inferring extent of infection will be useful in the context of identifying future surveillance needs, planning for OPV cessation and preparing outbreak response plans

From vineyards to feedlots: a fund-flow scanning of sociometabolic transition in the Vallès County (Catalonia) 1860-1956-1999

We analyse the changes to agricultural metabolism in four municipalities of Vallès County (Catalonia, Iberia) by accounting for their agroecosystemfunds and flows during the socioecological transition from organic to industrial farming between the late nineteenth and twentieth centuries. The choice of three different stages in this transition allows us to observe the transformation of its funds and flows over time, the links established between them and the effect on their energy profiles.We emphasize the relevance of the integration and consistency of agroecosystem funds for energy efficiency in agriculture and their role as underlying historical drivers of this socioecological transition. While readjustment to market conditions and availability and affordability of external inputs are considered the main drivers of the transition, we also highlight the role of societal energy and nutritional transitions. An analysis of advanced organic agriculture c. 1860 reveals the great effort required to reproduce soil fertility and livestock from the internal recirculation of biomass. Meanwhile, a balance between land produce and livestock densities enabled the integration of funds, with a positive impact on energy performance. The adoption of fossil fuels and synthetic fertilizers c. 1956 reduced somewhat the pressure exerted on the land by overcoming the former dependence on local biomass flows to reproduce the agroecosystem. Yet external inputs diminished sustainability. Partial dependence on external markets existed congruently with internal crop diversity and the predominance of organic over industrial farm management. A shift towards animal production and consumption led to a new specialization process c. 1999 that resulted in crop homogenization and agroecological landscape disintegration. The energy returns of this linear feed-food livestock bioconversion declined compared to earlier mixed farming. Huge energy flows driven by a globalized economy ran through this agroecosystem, provoking deep impacts at both a local and external scale

IL-21 Limits Peripheral Lymphocyte Numbers through T Cell Homeostatic Mechanisms

IL-21, a member of the common gamma-chain utilizing family of cytokines, participates in immune and inflammatory processes. In addition, the cytokine has been linked to autoimmunity in humans and rodents.To investigate the mechanism whereby IL-21 affects the immune system, we investigated its role in T cell homeostasis and autoimmunity in both non-autoimmune C57BL/6 and autoimmune NOD mice. Our data indicate that IL-21R knockout C57BL/6 and NOD mice show increased size of their lymphocyte population and decreased homeostatic proliferation. In addition, our experimental results demonstrate that IL-21 inhibits T cell survival. These data suggest that IL-21 acts to limit the size of the T cell pool. Furthermore, our data suggest IL-21 may contribute to the development of autoimmunity.Taken together, our results suggest that IL-21 plays a global role in regulating T cell homeostasis, promoting the continuous adaptation of the T cell lymphoid space

Acute Pain and a Motivational Pathway in Adult Rats: Influence of Early Life Pain Experience

The importance of neonatal experience upon behaviour in later life is increasingly recognised. The overlap between pain and reward pathways led us to hypothesise that neonatal pain experience influences reward-related pathways and behaviours in adulthood

PDZ domains and their binding partners: structure, specificity, and modification

PDZ domains are abundant protein interaction modules that often recognize short amino acid motifs at the C-termini of target proteins. They regulate multiple biological processes such as transport, ion channel signaling, and other signal transduction systems. This review discusses the structural characterization of PDZ domains and the use of recently emerging technologies such as proteomic arrays and peptide libraries to study the binding properties of PDZ-mediated interactions. Regulatory mechanisms responsible for PDZ-mediated interactions, such as phosphorylation in the PDZ ligands or PDZ domains, are also discussed. A better understanding of PDZ protein-protein interaction networks and regulatory mechanisms will improve our knowledge of many cellular and biological processes

Quantum simulation of the Hubbard model with dopant atoms in silicon

In quantum simulation, many-body phenomena are probed in controllable quantum systems. Recently, simulation of Bose-Hubbard Hamiltonians using cold atoms revealed previously hidden local correlations. However, fermionic many-body Hubbard phenomena such as unconventional superconductivity and spin liquids are more difficult to simulate using cold atoms. To date the required single-site measurements and cooling remain problematic, while only ensemble measurements have been achieved. Here we simulate a two-site Hubbard Hamiltonian at low effective temperatures with single-site resolution using subsurface dopants in silicon. We measure quasiparticle tunneling maps of spin-resolved states with atomic resolution, finding interference processes from which the entanglement entropy and Hubbard interactions are quantified. Entanglement, determined by spin and orbital degrees of freedom, increases with increasing covalent bond length. We find separation-tunable Hubbard interaction strengths that are suitable for simulating strongly correlated phenomena in larger arrays of dopants, establishing dopants as a platform for quantum simulation of the Hubbard model.Comment: 6 pages, 5 figures. Supplementary: 13 pages, 7 figures. New version with some additional discussion, accepted in Nature Communication