Targeting lentiviral vectors to antigen-specific immunoglobulins

Gene transfer into B cells by lentivectors can provide an alternative approach to managing B lymphocyte malignancies and autoreactive B cell-mediated autoimmune diseases. These pathogenic B cell Populations can be distinguished by their surface expression of monospecific immunoglobulin. Development of a novel vector system to deliver genes to these specific B cells could improve the safety and efficacy of gene therapy. We have developed an efficient rnethod to target lentivectors to monospecific immunoglobulin-expressing cells in vitro and hi vivo. We were able to incorporate a model antigen CD20 and a fusogenic protein derived from the Sindbis virus as two distinct molecules into the lentiviral Surface. This engineered vector could specifically bind to cells expressing Surface immunoglobulin recognizing CD20 (αCD20), resulting in efficient transduction of target cells in a cognate antigen-dependent manner in vitro, and in vivo in a xenografted tumor model. Tumor suppression was observed in vivo, using the engineered lentivector to deliver a suicide gene to a xenografted tumor expressing αCD20. These results show the feasibility of engineering lentivectors to target immunoglobulin-specific cells to deliver a therapeutic effect. Such targeting lentivectors also Could potentially be used to genetically mark antigen-specific B cells in vivo to study their B cell biology

Energy Dissipation and Regularity for a Coupled Navier-Stokes and Q-Tensor System

We study a complex non-newtonian fluid that models the flow of nematic liquid crystals. The fluid is described by a system that couples a forced Navier-Stokes system with a parabolic-type system. We prove the existence of global weak solutions in dimensions two and three. We show the existence of a Lyapunov functional for the smooth solutions of the coupled system and use the cancellations that allow its existence to prove higher global regularity, in dimension two. We also show the weak-strong uniqueness in dimension two

Punctuated equilibria and 1/f noise in a biological coevolution model with individual-based dynamics

We present a study by linear stability analysis and large-scale Monte Carlo simulations of a simple model of biological coevolution. Selection is provided through a reproduction probability that contains quenched, random interspecies interactions, while genetic variation is provided through a low mutation rate. Both selection and mutation act on individual organisms. Consistent with some current theories of macroevolutionary dynamics, the model displays intermittent, statistically self-similar behavior with punctuated equilibria. The probability density for the lifetimes of ecological communities is well approximated by a power law with exponent near -2, and the corresponding power spectral densities show 1/f noise (flicker noise) over several decades. The long-lived communities (quasi-steady states) consist of a relatively small number of mutualistically interacting species, and they are surrounded by a ``protection zone'' of closely related genotypes that have a very low probability of invading the resident community. The extent of the protection zone affects the stability of the community in a way analogous to the height of the free-energy barrier surrounding a metastable state in a physical system. Measures of biological diversity are on average stationary with no discernible trends, even over our very long simulation runs of approximately 3.4x10^7 generations.Comment: 20 pages RevTex. Minor revisions consistent with published versio

Insights into the mode of action of a putative zinc transporter CzrB in thermus thermophilus

peer-reviewedThis paper was obtained through PEER (Publishing and the Ecology of European Research) http://www.peerproject.euThe crystal structures of the cytoplasmic domain of the putative zinc transporter CzrB in the apoand zinc-bound forms reported herein are consistent with the protein functioning in vivo as a homodimer. NMR, X-ray scattering and size exclusion chromatography provide support for dimer formation. Full-length variants of CzrB in the apo and zinc-loaded states were generated by homology modelling with the Zn2+ / H+ antiporter YiiP. The model suggests a way in which zinc binding to the cytoplasmic fragment creates a docking site to which a metallochaperone can bind for delivery and transport of its zinc cargo. Since the cytoplasmic domain may exist in the cell as an independent, soluble protein a proposal is advanced that it functions as a metallochaperone and that it regulates the zinc-transporting activity of the full-length protein. The latter requires that zinc binding becomes uncoupled from the creation of a metallochaperone-docking site on CzrB

Asymptotic Behavior for a Nematic Liquid Crystal Model with Different Kinematic Transport Properties

We study the asymptotic behavior of global solutions to hydrodynamical systems modeling the nematic liquid crystal flows under kinematic transports for molecules of different shapes. The coupling system consists of Navier-Stokes equations and kinematic transport equations for the molecular orientations. We prove the convergence of global strong solutions to single steady states as time tends to infinity as well as estimates on the convergence rate both in 2D for arbitrary regular initial data and in 3D for certain particular cases

3DKL v1.0: creating the first 3D geological model of Kuala Lumpur

The objective of UN Sustainable Development Goal 11 is to make cities and human settlements inclusive, safe, resilient and sustainable. Geoscience can play a significant role in achieving targets within this goal by developing a better understanding of geological properties and processes within urban environments, and by ensuring that this understanding is integrated into urban development. A key step in this process will be enhancing awareness of urban geology among non-geoscience decision-makers, so that inherent subsurface risks and benefits are understood and accounted for during all phases of development. Three-dimensional geological models are an effective tool for geologists to communicate with stakeholders in government and industry during that process. They can also provide a framework to enable geological data and information to be integrated into Building and City Information Models, and thus facilitate more effective infrastructure and utility asset management. This paper describes the modelling workflow adopted by a consortium of geoscientists from government, industry and academia to deliver the first 3D geological model of Kuala Lumpur – 3DKL v1.0. The modelling workflow involved: digitising borehole logs from site investigation reports and storing them in a dedicated geospatially-enabled SQLite borehole database; viewing and interpreting that borehole data using QGIS software; generating multiple orthogonally oriented cross-section profiles across the modelled area using Groundhog Desktop software; and integrating the information derived from the interpreted boreholes, surface data and cross-section profiles to generate a 3D geological model in Leapfrog Geo software. 3DKL v1.0 has demonstrated proof-of-concept: we have developed a workflow, based largely on freely-available software, for transforming borehole information, previously captured in paper records, into a conceptual 3D model. The modelling process has also identified areas where geological knowledge and data need to be enhanced if 3DKL is to fulfil its potential to support more sustainable and resilient urban development in Kuala Lumpur

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters

Measurement of the Lambda(b) cross section and the anti-Lambda(b) to Lambda(b) ratio with Lambda(b) to J/Psi Lambda decays in pp collisions at sqrt(s) = 7 TeV

The Lambda(b) differential production cross section and the cross section ratio anti-Lambda(b)/Lambda(b) are measured as functions of transverse momentum pt(Lambda(b)) and rapidity abs(y(Lambda(b))) in pp collisions at sqrt(s) = 7 TeV using data collected by the CMS experiment at the LHC. The measurements are based on Lambda(b) decays reconstructed in the exclusive final state J/Psi Lambda, with the subsequent decays J/Psi to an opposite-sign muon pair and Lambda to proton pion, using a data sample corresponding to an integrated luminosity of 1.9 inverse femtobarns. The product of the cross section times the branching ratio for Lambda(b) to J/Psi Lambda versus pt(Lambda(b)) falls faster than that of b mesons. The measured value of the cross section times the branching ratio for pt(Lambda(b)) > 10 GeV and abs(y(Lambda(b))) < 2.0 is 1.06 +/- 0.06 +/- 0.12 nb, and the integrated cross section ratio for anti-Lambda(b)/Lambda(b) is 1.02 +/- 0.07 +/- 0.09, where the uncertainties are statistical and systematic, respectively.Comment: Submitted to Physics Letters

Search for new physics in events with opposite-sign leptons, jets, and missing transverse energy in pp collisions at sqrt(s) = 7 TeV

A search is presented for physics beyond the standard model (BSM) in final states with a pair of opposite-sign isolated leptons accompanied by jets and missing transverse energy. The search uses LHC data recorded at a center-of-mass energy sqrt(s) = 7 TeV with the CMS detector, corresponding to an integrated luminosity of approximately 5 inverse femtobarns. Two complementary search strategies are employed. The first probes models with a specific dilepton production mechanism that leads to a characteristic kinematic edge in the dilepton mass distribution. The second strategy probes models of dilepton production with heavy, colored objects that decay to final states including invisible particles, leading to very large hadronic activity and missing transverse energy. No evidence for an event yield in excess of the standard model expectations is found. Upper limits on the BSM contributions to the signal regions are deduced from the results, which are used to exclude a region of the parameter space of the constrained minimal supersymmetric extension of the standard model. Additional information related to detector efficiencies and response is provided to allow testing specific models of BSM physics not considered in this paper.Comment: Replaced with published version. Added journal reference and DO