A Plug-and-Play Approach for the De Novo Generation of Dually Functionalized Bispecifics

Diseases are multifactorial, with redundancies and synergies between various pathways. However, most of the antibody-based therapeutics on the market interact with only one target, thus limiting their efficacy. The targeting of multiple epitopes could improve the therapeutic index of treatment and counteract mechanisms of resistance. To this effect, a new class of therapeutics has emerged: bispecific antibodies. Bispecific formation using chemical methods is rare and low-yielding and/or requires a large excess of one of the two proteins to avoid homodimerization and heterogeneity. In order for chemically prepared bispecifics to deliver their full potential, high-yielding, modular, and reliable cross-linking technologies are required. Herein, we describe a novel approach not only for the rapid and high-yielding chemical generation of bispecific antibodies from native antibody fragments, but also for the site-specific dual functionalization of the resulting bioconjugates. Based on orthogonal clickable functional groups, this strategy enables the assembly of functionalized bispecifics with controlled loading in a modular and convergent manner

Tricritical Points in the Sherrington-Kirkpatrick Model in the Presence of Discrete Random Fields

The infinite-range-interaction Ising spin glass is considered in the presence of an external random magnetic field following a trimodal (three-peak) distribution. The model is studied through the replica method and phase diagrams are obtained within the replica-symmetry approximation. It is shown that the border of the ferromagnetic phase may present first-order phase transitions, as well as tricritical points at finite temperatures. Analogous to what happens for the Ising ferromagnet under a trimodal random field, it is verified that the first-order phase transitions are directly related to the dilution in the fields (represented by $p_{0}$). The ferromagnetic boundary at zero temperature also exhibits an interesting behavior: for $0<p_{0}<p_{0}^{*} \approx 0.30856$, a single tricritical point occurs, whereas if $p_{0}>p_{0}^{*}$ the critical frontier is completely continuous; however, for $p_{0}=p_{0}^{*}$, a fourth-order critical point appears. The stability analysis of the replica-symmetric solution is performed and the regions of validity of such a solution are identified; in particular, the Almeida-Thouless line in the plane field versus temperature is shown to depend on the weight $p_{0}$.Comment: 23pages, 7 ps figure

Production of scalar and pseudo-scalar Higgs bosons to next-to-next-to-leading order at hadron colliders

We consider the production of intermediate-mass CP-even and CP-odd Higgs bosons in proton-proton and proton-anti-proton collisions. We extend the recently published results for the complete next-to-next-to-leading order calculation for a scalar Higgs boson to the pseudo-scalar case and present details of the calculation that might be useful for similar future investigations. The result is based on an expansion in the limit of a heavy top quark mass and a subsequent matching to the expression obtained in the limit of infinite energy. For a Higgs boson mass of 120 GeV the deviation from the infinite-top quark mass result is small. For 300 GeV, however, the next-to-next-to-leading order corrections for a scalar Higgs boson exceed the effective-theory result by about 9% which increases to 22% in the pseudo-scalar case. Thus in this mass range the effect on the total cross section amounts to about 2% and 6%, respectively, which may be relevant in future precision studies.Comment: 29 page

Anomalous dimensions and phase transitions in superconductors

The anomalous scaling in the Ginzburg-Landau model for the superconducting phase transition is studied. It is argued that the negative sign of the $\eta$ exponent is a consequence of a special singular behavior in momentum space. The negative sign of $\eta$ comes from the divergence of the critical correlation function at finite distances. This behavior implies the existence of a Lifshitz point in the phase diagram. The anomalous scaling of the vector potential is also discussed. It is shown that the anomalous dimension of the vector potential $\eta_A=4-d$ has important consequences for the critical dynamics in superconductors. The frequency-dependent conductivity is shown to obey the scaling $\sigma(\omega)\sim\xi^{z-2}$. The prediction $z\approx 3.7$ is obtained from existing Monte Carlo data.Comment: RevTex, 20 pages, no figures; small changes; version accepted in PR

Ising spin glass under continuous-distribution random magnetic fields: Tricritical points and instability lines

The effects of random magnetic fields are considered in an Ising spin-glass model defined in the limit of infinite-range interactions. The probability distribution for the random magnetic fields is a double Gaussian, which consists of two Gaussian distributions centered respectively, at $+H_{0}$ and $-H_{0}$, presenting the same width $\sigma$. It is argued that such a distribution is more appropriate for a theoretical description of real systems than its simpler particular two well-known limits, namely the single Gaussian distribution ($\sigma \gg H_{0}$), and the bimodal one ($\sigma = 0$). The model is investigated by means of the replica method, and phase diagrams are obtained within the replica-symmetric solution. Critical frontiers exhibiting tricritical points occur for different values of $\sigma$, with the possibility of two tricritical points along the same critical frontier. To our knowledge, it is the first time that such a behavior is verified for a spin-glass model in the presence of a continuous-distribution random field, which represents a typical situation of a real system. The stability of the replica-symmetric solution is analyzed, and the usual Almeida-Thouless instability is verified for low temperatures. It is verified that, the higher-temperature tricritical point always appears in the region of stability of the replica-symmetric solution; a condition involving the parameters $H_{0}$ and $\sigma$, for the occurrence of this tricritical point only, is obtained analytically. Some of our results are discussed in view of experimental measurements available in the literature.Comment: 23 pages, 8 figures, accept for publication in Phys. Rev.

Finite top quark mass effects in NNLO Higgs boson production at LHC

We present next-to-next-to-leading order corrections to the inclusive production of the Higgs bosons at the CERN Large Hadron Collider (LHC) including finite top quark mass effects. Expanding our analytic results for the partonic cross section around the soft limit we find agreement with a very recent publication by Harlander and Ozeren \cite{Harlander:2009mq}.Comment: 15 page

Composição e estrutura da ictiofauna demersal na Baía dos Pinheiros, Paraná

Between May of 2003 and April of 2004 the temporal changes were monitored in the structure of the demersal ichthyofauna of the Bay of Pinheiros (Paraná), through three bottom trawls accomplished monthly in each one of the four areas between the access bar and the most internal areas. In the 144 accomplished trawls 58 species belonging to 25 families were collected, totaling 18154 fishes. The families that presented larger wealth of species were Sciaenidae (15 species), Ariidae (5), Tetraodontidae (4), Engraulidae (4), Carangidae (4), Paralichthyidae (3) and Haemulidae (3). The species Stellifer rastrifer, Cathorops spixii, Chirocentrodon bleekerianus, Cynoscion leiarchus, Stellifer brasiliensis, Achirus lineatus and Micropogonias furnieri dominated in number of individuals, representing 91,4% of the total capture. Significantly, there was larger capture of number of fishes in April. Between the indexes of diversity of Shannon-Wiener and eveness of Pielou differences were not observed. Through the grouping analyses and ordination of the dominant species two groups were formed in the level of 70% of similarity. The first was composed by the dominant species S. rastrifer, C. spixii and C. leiarchus, and the second was formed by C. jamaicensis and P. harroweri, presents almost exclusively in the summer and autumn.Between May of 2003 and April of 2004 the temporal changes were monitored in the structure of the demersal ichthyofauna of the Bay of Pinheiros (Paraná), through three bottom trawls accomplished monthly in each one of the four areas between the access bar and the most internal areas. In the 144 accomplished trawls 58 species belonging to 25 families were collected, totaling 18154 fishes. The families that presented larger wealth of species were Sciaenidae (15 species), Ariidae (5), Tetraodontidae (4), Engraulidae (4), Carangidae (4), Paralichthyidae (3) and Haemulidae (3). The species Stellifer rastrifer, Cathorops spixii, Chirocentrodon bleekerianus, Cynoscion leiarchus, Stellifer brasiliensis, Achirus lineatus and Micropogonias furnieri dominated in number of individuals, representing 91,4% of the total capture. Significantly, there was larger capture of number of fishes in April. Between the indexes of diversity of Shannon-Wiener and eveness of Pielou differences were not observed. Through the grouping analyses and ordination of the dominant species two groups were formed in the level of 70% of similarity. The first was composed by the dominant species S. rastrifer, C. spixii and C. leiarchus, and the second was formed by C. jamaicensis and P. harroweri, presents almost exclusively in the summer and autumn