Membrane Recruitment of Scaffold Proteins Drives Specific Signaling

Cells must give the right response to each stimulus they receive. Scaffolding, a signaling process mediated by scaffold proteins, participates in the decoding of the cues by specifically directing signal transduction. The aim of this paper is to describe the molecular mechanisms of scaffolding, i.e. the principles by which scaffold proteins drive a specific response of the cell. Since similar scaffold proteins are found in many species, they evolved according to the purpose of each organism. This means they require adaptability. In the usual description of the mechanisms of scaffolding, scaffold proteins are considered as reactors where molecules involved in a cascade of reactions are simultaneously bound with the right orientation to meet and interact. This description is not realistic: (i) it is not verified by experiments and (ii) timing and orientation constraints make it complex which seems to contradict the required adaptability. A scaffold protein, Ste5, is used in the MAPK pathway of Saccharomyces Cerevisiae for the cell to provide a specific response to stimuli. The massive amount of data available for this pathway makes it ideal to investigate the actual mechanisms of scaffolding. Here, a complete treatment of the chemical reactions allows the computation of the distributions of all the proteins involved in the MAPK pathway when the cell receives various cues. These distributions are compared to several experimental results. It turns out that the molecular mechanisms of scaffolding are much simpler and more adaptable than previously thought in the reactor model. Scaffold proteins bind only one molecule at a time. Then, their membrane recruitment automatically drives specific, amplified and localized signal transductions. The mechanisms presented here, which explain how the membrane recruitment of a protein can produce a drastic change in the activity of cells, are generic and may be commonly used in many biological processes

Single-cell analysis tools for drug discovery and development

The genetic, functional or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development. Such heterogeneity hinders the design of accurate disease models and can confound the interpretation of biomarker levels and of patient responses to specific therapies. The complex nature of virtually all tissues has motivated the development of tools for single-cell genomic, transcriptomic and multiplex proteomic analyses. Here, we review these tools and assess their advantages and limitations. Emerging applications of single cell analysis tools in drug discovery and development, particularly in the field of oncology, are discussed

Observation of Two New Excited Ξb0 States Decaying to Λb0 K-π+

Two narrow resonant states are observed in the Λb0K-π+ mass spectrum using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the LHCb experiment and corresponding to an integrated luminosity of 6 fb-1. The minimal quark content of the Λb0K-π+ system indicates that these are excited Ξb0 baryons. The masses of the Ξb(6327)0 and Ξb(6333)0 states are m[Ξb(6327)0]=6327.28-0.21+0.23±0.12±0.24 and m[Ξb(6333)0]=6332.69-0.18+0.17±0.03±0.22 MeV, respectively, with a mass splitting of Δm=5.41-0.27+0.26±0.12 MeV, where the uncertainties are statistical, systematic, and due to the Λb0 mass measurement. The measured natural widths of these states are consistent with zero, with upper limits of Γ[Ξb(6327)0]<2.20(2.56) and Γ[Ξb(6333)0]<1.60(1.92) MeV at a 90% (95%) credibility level. The significance of the two-peak hypothesis is larger than nine (five) Gaussian standard deviations compared to the no-peak (one-peak) hypothesis. The masses, widths, and resonant structure of the new states are in good agreement with the expectations for a doublet of 1D Ξb0 resonances

Implementation of complex biological logic circuits using spatially distributed multicellular consortia

Engineered synthetic biological devices have been designed to perform a variety of functions from sensing molecules and bioremediation to energy production and biomedicine. Notwithstanding, a major limitation of in vivo circuit implementation is the constraint associated to the use of standard methodologies for circuit design. Thus, future success of these devices depends on obtaining circuits with scalable complexity and reusable parts. Here we show how to build complex computational devices using multicellular consortia and space as key computational elements. This spatial modular design grants scalability since its general architecture is independent of the circuit's complexity, minimizes wiring requirements and allows component reusability with minimal genetic engineering. The potential use of this approach is demonstrated by implementation of complex logical functions with up to six inputs, thus demonstrating the scalability and flexibility of this method. The potential implications of our results are outlined.This work was supported by an ERC Advanced Grant Number 294294 from the EU seventh framework program (SYNCOM) to RS and FP, and the Santa Fe Institute to RS. FP and RS laboratories are also supported by Fundación Botín, by Banco Santander through its Santander Universities Global Division. The laboratory of FP and EdN is supported by grants from the Spanish Government (BFU2012-33503/ BFU2015-64437 P and FEDER to FP; BFU2014-52333-P and FEDER to EdN) and the Catalan Government (2014 SGR 599). The research leading to these results has received funding from “la Caixa” Foundation in collaboration with “Centre per a la Innovació de la Diabetis Infantil Sant Joan de Déu (CIDI)”. FP and EdN are recipients of an ICREA Acadèmia (Generalitat de Catalunya). RM was a former EMBO postdoctoral fellow. AU is a recipient of a “La Caixa” fellowship

First Observation of the Decay B 0 s → K − μ + ν μ and a Measurement of | V u b | / | V c b |

The first observation of the suppressed semileptonic Bs0→K-μ+νμ decay is reported. Using a data sample recorded in pp collisions in 2012 with the LHCb detector, corresponding to an integrated luminosity of 2 fb-1, the branching fraction B(Bs0→K-μ+νμ) is measured to be [1.06±0.05(stat)±0.08(syst)]×10-4, where the first uncertainty is statistical and the second one represents the combined systematic uncertainties. The decay Bs0→Ds-μ+νμ, where Ds- is reconstructed in the final state K+K-π-, is used as a normalization channel to minimize the experimental systematic uncertainty. Theoretical calculations on the form factors of the Bs0→K- and Bs0→Ds- transitions are employed to determine the ratio of the Cabibbo-Kobayashi-Maskawa matrix elements |Vub|/|Vcb| at low and high Bs0→K- momentum transfer

Tests of Lepton Universality Using B-0 -> K(S)(0)l(+) l(-) and B+ -> K*(+)l(+)l(-) Decays

Tests of lepton universality in B-0 -> K(S)(0)l(+)l(-) and B+ -> K*(+)l(+)l(-) decays where l is either an electron or a muon are presented. The differential branching fractions of B-0 -> K(S)(0)e(+)e(-) and B+ -> K*(+)e(+)e(-) decays are measured in intervals of the dilepton invariant mass squared. The measurements are performed using proton-proton collision data recorded by the LHCb experiment, corresponding to an integrated luminosity of 9 fb(-1). The results are consistent with the standard model and previous tests of lepton universality in related decay modes. The first observation of B-0 -> K(S)(0)e(+)e(-) and B+ -> K*(+)e(+)e(-) decays is reported