A 475 years-old founder effect involving IL12RB1: a highly prevalent mutation conferring Mendelian susceptibility to mycobacterial diseases in European descendants

Mutations in IFNGR1, IFNGR2, IL12RB1, IL12B, STAT1 and NEMO result in a common clinical phenotype known as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Interleukin-12 receptor 01 (IL12R beta 1) deficiency is the most common genetic etiology for MSMD. Known mutations affecting IL12RB1 are recessively inherited and are associated with null response to both IL-12 and IL-23. Mutation IL12RB1 1623_1624delinsTT was originally described in 5 families from European origin (2 from Germany: I from Cyprus, France and Belgium). Interestingly, this same mutation was found in an unexpectedly high prevalence among IL-12R beta 1 deficient patients in Argentina: 5-out-of-6 individuals born to unrelated families carried this particular change. To determine whether mutation 1623_1624delinsTT represents a DNA mutational hotspot or a founder effect, 34 polymorphic markers internal or proximal to IL12RB1 were studied in the Argentinean and the Belgian patients. A common haplotype spanning 1.45-3.51 Mb was shared by all chromosomes carrying mutation 1623_1624delinsTT, and was not detected on 100 control chromosomes. Applying a modified likelihood-based method the age of the most recent common ancestor carrying mutation 1623_1624delinsTT was estimated in 475 years (95% CI, 175-1275), which is the time when the Spaniards initiated the colonization of the Americas. Mutation 1623_1624delinsTT represents the first founder effect described on IL-12R beta 1, the most frequently affected gene in MSMD, and affecting patients with European ancestors. The reason(s) behind the persistency of this mutation across multiple generations, its relative high prevalence, and any potential selective advantage are yet to be established

Witten-Veneziano from Green-Schwarz

We consider the U(1) problem within the AdS/CFT framework. We explain how the Witten-Veneziano formula for the eta' mass is related to a generalized Green-Schwarz mechanism. The closed string mode, that cancels the anomaly of the gauged U(1) axial symmetry, is identified with the eta' meson. In a particular set-up of D3-branes on a C3/(Z3xZ3) orbifold singularity, the eta' meson is a twisted-sector R-R field.Comment: 10 pages, LaTex. 1 eps figure. v2: minor changes, refs. added, to appear in JHE

Numerical Study of the Lowest Energy Configurations for Global String-Antistring Pairs

We investigate the lowest energy configurations for string - antistring pairs at fixed separations by numerically minimizing the energy. We show that for separations smaller than a critical value, a region of false vacuum develops in the middle due to large gradient energy density. Consequently, well defined string - antistring pairs do not exist for such separations. We present an example of vortex - antivortex production by vacuum bubbles where this effect seems to play a dynamical role in the annihilation of the pair. We also study the dependence of the energy of an string-antistring pair on their separation and find deviations from a simple logarithmic dependence for small separations.Comment: 14 pages, in LATEX, 7 figures (not included

Wheat Yield Functions for Analysis of Land-Use Change in China

CERES-Wheat, a dynamic process crop growth model is specified and validated for eight sites in the major wheat-growing regions of China. Crop model results are then used to test functional forms for yield response to nitrogen fertilizer, irrigation water, temperature, and precipitation. The resulting functions are designed to be used in a linked biophysical-economic model of land-use and land-cover change. Variables explaining a significant proportion of simulated yield variance are nitrogen, irrigation water, and precipitation; temperature was not a significant component of yield variation within the range of observed year-to-year variability except at the warmest site. The Mitscherlich-Baule function is found to be more appropriate than the quadratic function at most sites. Crop model simulations with a generic soil with median characteristics of the eight sites were compared to simulations with site-specific soils, providing an initial test of the sensitivity of the functional forms to soil specification. The use of the generic soil does not affect the results significantly; thus, the functions may be considered representative of agriculturally productive regions with similar climate in China under intensifying management conditions

Topological String Defect Formation During the Chiral Phase Transition

We extend and generalize the seminal work of Brandenberger, Huang and Zhang on the formation of strings during chiral phase transitions(berger) and discuss the formation of abelian and non-abelian topological strings during such transitions in the early Universe and in the high energy heavy-ion collisions. Chiral symmetry as well as deconfinement are restored in the core of these defects. Formation of a dense network of string defects is likely to play an important role in the dynamics following the chiral phase transition. We speculate that such a network can give rise to non-azimuthal distribution of transverse energy in heavy-ion collisions.Comment: 10 pages, 4 figures, minor correction

Structure and Metal Binding Properties of ZnuA, a Periplasmic Zinc Transporter from \u3cem\u3eEscherichia coli\u3c/em\u3e

ZnuA is the periplasmic Zn2+-binding protein associated with the high-affinity ATP-binding cassette ZnuABC transporter from Escherichia coli. Although several structures of ZnuA and its homologs have been determined, details regarding metal ion stoichiometry, affinity, and specificity as well as the mechanism of metal uptake and transfer remain unclear. The crystal structures of E. coli ZnuA (Eco-ZnuA) in the apo, Zn2+-bound, and Co2+-bound forms have been determined. ZnZnuA binds at least two metal ions. The first, observed previously in other structures, is coordinated tetrahedrally by Glu59, His60, His143, and His207. Replacement of Zn2+ with Co2+ results in almost identical coordination geometry at this site. The second metal binding site involves His224 and several yet to be identified residues from the His-rich loop that is unique to Zn2+ periplasmic metal binding receptors. Electron paramagnetic resonance and X-ray absorption spectroscopic data on CoZnuA provide additional insight into possible residues involved in this second site. The second site is also detected by metal analysis and circular dichroism (CD) titrations. Eco-ZnuA binds Zn2+ (estimated K d \u3c 20 nM), Co2+, Ni2+, Cu2+, Cu+, and Cd2+, but not Mn2+. Finally, conformational changes upon metal binding observed in the crystal structures together with fluorescence and CD data indicate that only Zn2+ substantially stabilizes ZnuA and might facilitate recognition of ZnuB and subsequent metal transfer

Relating Dynamic Protein Interactions Of Metallochaperones With Metal Transfer At The Single-Molecule Level

Metallochaperones undertake specific interactions with their target proteins to deliver metal ions inside cells. Understanding how these protein interactions are coupled with the underlying metal transfer process is important, but challenging because they are weak and dynamic. Here we use a nanovesicle trapping scheme to enable single-molecule FRET measurements of the weak, dynamic interactions between the copper chaperone Hahl and the fourth metal binding domain (MBD4) of WDP. By monitoring the behaviors of single interacting pairs, we visualize their interactions in real time in both the absence and the presence of various equivalents of Cu(1+). Regardless of the proteins\u27 metallation state, we observe multiple, interconverting interaction complexes between Hah1 and MBD4. Within our experimental limit, the overall interaction geometries of these complexes appear invariable, but their stabilities are dependent on the proteins\u27 metallation state. In apo-holo Hah1-MBD4 interactions, the complexes are stabilized relative to that observed in the apo-apo interactions. This stabilization is indiscernible when Hah1\u27s Cu(1+)-binding is eliminated or when both proteins have Cu(1+) loaded. The nature of this Cu(1+)-induced complex stabilization and of the interaction complexes are discussed. These Cu(1+)-induced effects on the Hah1-MBD4 interactions provide a step toward understanding how the dynamic protein interactions of copper chaperones are coupled with their metal transfer function

Observation of Plasma Focusing of a 28.5 GeV Positron Beam

The observation of plasma focusing of a 28.5 GeV positron beam is reported. The plasma was formed by ionizing a nitrogen jet only 3 mm thick. Simultaneous focusing in both transverse dimensions was observed with effective focusing strengths of order Tesla per micron. The minimum area of the beam spot was reduced by a factor of 2.0 +/- 0.3 by the plasma. The longitudinal beam envelope was measured and compared with numerical calculations

Probing Gauge String Formation in a Superconducting Phase Transition

Superconductors are the only experimentally accessible systems with spontaneously broken gauge symmetries which support topologically nontrivial defects, namely string defects. We propose two experiments whose aim is the observation of the dense network of these strings thought to arise, via the Kibble mechanism, in the course of a spontaneous symmetry breaking phase transition. We suggest ways to estimate the order of magnitude of the density of flux tubes produced in the phase transition. This may provide an experimental check for the theories of the production of topological defects in a spontaneously broken gauge theory, such as those employed in the context of the early Universe.Comment: 16 pages (Latex), 4 figures included, change in title, some minor changes, published versio