Combined therapy with GABA and proinsulin/alum acts synergistically to restore long-term normoglycemia by modulating T-cell autoimmunity and promoting β-cell replication in newly diabetic NOD mice.

Antigen-based therapies (ABTs) fail to restore normoglycemia in newly diabetic NOD mice, perhaps because too few β-cells remain by the time that ABT-induced regulatory responses arise and spread. We hypothesized that combining a fast-acting anti-inflammatory agent with an ABT could limit pathogenic responses while ABT-induced regulatory responses arose and spread. γ-Aminobutyric acid (GABA) administration can inhibit inflammation, enhance regulatory T-cell (Treg) responses, and promote β-cell replication in mice. We examined the effect of combining a prototypic ABT, proinsulin/alum, with GABA treatment in newly diabetic NOD mice. Proinsulin/alum monotherapy failed to correct hyperglycemia, while GABA monotherapy restored normoglycemia for a short period. Combined treatment restored normoglycemia in the long term with apparent permanent remission in some mice. Proinsulin/alum monotherapy induced interleukin (IL)-4- and IL-10-secreting T-cell responses that spread to other β-cell autoantigens. GABA monotherapy induced moderate IL-10 (but not IL-4) responses to β-cell autoantigens. Combined treatment synergistically reduced spontaneous type 1 T-helper cell responses to autoantigens, ABT-induced IL-4 and humoral responses, and insulitis, but enhanced IL-10 and Treg responses and promoted β-cell replication in the islets. Thus, combining ABT with GABA can inhibit pathogenic T-cell responses, induce Treg responses, promote β-cell replication, and effectively restore normoglycemia in newly diabetic NOD mice. Since these treatments appear safe for humans, they hold promise for type 1 diabetes intervention

Analysis of parametric biological models with non-linear dynamics

In this paper we present recent results on parametric analysis of biological models. The underlying method is based on the algorithms for computing trajectory sets of hybrid systems with polynomial dynamics. The method is then applied to two case studies of biological systems: one is a cardiac cell model for studying the conditions for cardiac abnormalities, and the second is a model of insect nest-site choice.Comment: In Proceedings HSB 2012, arXiv:1208.315

Analysis of two pheromone-responsive conjugative multiresistance plasmids carrying the novel mobile optrA locus from Enterococcus faecalis

Background: The acquired optrA gene, which encodes a ribosomal protection protein of the ABC-F family, can confer cross-resistance to linezolid and florfenicol, posing a serious therapeutic challenge to both human and veterinary medicine. Purpose: The objective of this study was to investigate the two Enterococcus faecalis (E. faecalis) plasmids for their fine structure, their transferability and the presence of mobile antimicrobial resistance loci. Methods: To elucidate their fine structure, the two plasmids were completely sequenced and the sequences analysed. Besides conjugation experiments, inverse PCR assays were conducted to see whether minicircles are produced from the mobile antimicrobial resistance loci. Results: Two pheromone-responsive conjugative optrA-carrying plasmids from E. faecalis, pE211 and pE508 were identified, which can transfer with frequencies of 2.6 ×10−2 and 3.7 ×10−2 (transconjugant per donor), respectively. In both plasmids, optrA was located on the novel mobile optrA locus with different sizes (12,834 bp in pE211 and 7,561 bp in pE508, respectively), flanked by two copies of IS1216 genes in the same orientation. Inverse PCR revealed that circular forms can be generated, consisting of optrA and one copy of IS1216, indicating they are all active. The 77,562 bp plasmid pE211 also carried Tn558 and a mobile bcrABDR locus, and the 84,468 bp plasmid pE508 also harbored the genes fexA, tet(L), tet(O/W/32/O) and a mobile aac(A)-aph(D) locus. Conclusion: The presence of mobile genetic elements in these plasmids renders them flexible and these elements will aid to the persistence and dissemination of these plasmids among enterococci and potentially also other gram-positive bacteria

Kinetic study of the oxide-assisted catalyst-free synthesis of silicon nitride nanowires

The synthesis of Si3N4 nanowires from the reaction of silicon nanoparticles with N2 in the 1200-1440 C temperature range is reported. The nitridation conditions are such that the reaction with nitrogen is favoured by the presence of silicon oxide in the particles and by the active oxidation of silicon without a catalyst. It is shown that the Si to Si3N4 conversion rate depends on the amount of silicon particles used in the experiments and that, in general, the reaction slows down for greater amounts. This trend is explained by particle stacking, which restricts the exchange of gases between the furnace atmosphere and the atmosphere around the inner particles. In a first stage, local oxygen partial pressure increases around the inner particles and inhibits nitridation locally. If the amount of reactant Si nanoparticles is small enough, this extrinsic effect is avoided and the intrinsic nitridation kinetics can be measured. Experiments show that intrinsic kinetics does not depend on temperature

Relativistic Coulomb Sum Rules for (e,e′)(e,e^\prime)

A Coulomb sum rule is derived for the response of nuclei to $(e,e^\prime)$ scattering with large three-momentum transfers. Unlike the nonrelativistic formulation, the relativistic Coulomb sum is restricted to spacelike four-momenta for the most direct connection with experiments; an immediate consequence is that excitations involving antinucleons, e.g., $N{\bar N}$ pair production, are approximately eliminated from the sum rule. Relativistic recoil and Fermi motion of target nucleons are correctly incorporated. The sum rule decomposes into one- and two-body parts, with correlation information in the second. The one-body part requires information on the nucleon momentum distribution function, which is incorporated by a moment expansion method. The sum rule given through the second moment (RCSR-II) is tested in the Fermi gas model, and is shown to be sufficiently accurate for applications to data.Comment: 32 pages (LaTeX), 4 postscript figures available from the author