General practitioners are the future intermediaries.

Rationale, Aims And Objectives: Technological changes will have a large influence on medical practice. This article discusses the influences of technology and innovation on the role of general practitioners.

Methods: This conceptual paper is based on a triangulation of expert discussions and literature studies.

Course of back pain across 5 years: a retrospective cohort study in the general population of Switzerland.

Study Design: A retrospective cohort study in the general population of Switzerland.

Objective: To investigate the course of back pain (BP) across 5 years and the impact of BP history on its incidence and recurrence.

Summary Of Background Data: Longitudinal studies on BP performed in the general population have reported varying prevalence and incidence rates.

Contrast improvement by selecting ballistic-photons using polarization gating.

In this paper a new approach to improve contrast in optical subsurface imaging is presented. The method is based on time-resolved reflectance and selection of ballistic photons using polarization gating. Numerical studies with a statistical Monte Carlo method also reveal that weakly scattered diffuse photons can be eliminated by employing a small aperture and that the contrast improvement strongly depends on the single-scattering phase function.

Th cells act via two synergistic pathways to promote antiviral CD8+ T cell responses.

The mechanisms of how Th cells promote CD8(+) T cell responses during viral infections are largely unknown. In this study, we unraveled the mechanisms of T cell help for CD8(+) T cell responses during vaccinia virus infection. Our results demonstrate that Th cells promote vaccinia virus-specific CD8(+) T cell responses via two interconnected synergistic pathways: First, CD40L expressed by activated CD4(+) T cells instructs dendritic cells to produce bioactive IL-12p70, which is directly sensed by Ag-specific CD8(+) T cells, resulting in increased IL-2Rα expression.

Stochastic modeling of polarized light scattering using a Monte Carlo based stencil method.

This paper deals with an efficient and accurate simulation algorithm to solve the vector Boltzmann equation for polarized light transport in scattering media. The approach is based on a stencil method, which was previously developed for unpolarized light scattering and proved to be much more efficient (speedup factors of up to 10 were reported) than the classical Monte Carlo while being equally accurate. To validate what we believe to be the new stencil method, a substrate composed of spherical non-absorbing particles embedded in a non-absorbing medium was considered.

No need to discriminate? Reproductive diploid males in a parasitoid with complementary sex determination.

Diploid males in hymenopterans are generally either inviable or sterile, thus imposing a severe genetic load on populations. In species with the widespread single locus complementary sex determination (sl-CSD), sex depends on the genotype at one single locus with multiple alleles. Haploid (hemizygous) individuals are always males.

Stochastic modeling of light scattering with fluorescence using a Monte Carlo-based multiscale approach.

This work deals with the efficient and accurate modeling of fluorescence in the context of stochastic Monte Carlo methods for which we propose a novel multiscale method. As in other approaches of this category, the transport theory is employed to describe the physics. The new framework was successfully applied for a quantitative assessment of halftone reflectance measurements with three different devices.

Rupture pathway of phosphatidylcholine liposomes on silicon dioxide.

We have investigated the pathway by which unilamellar POPC liposomes upon adsorption undergo rupture and form a supported lipid bilayer (SLB) on a SiO(2) surface. Biotinylated lipids were selectively incorporated in the outer monolayer of POPC liposomes to create liposomes with asymmetric lipid compositions in the outer and inner leaflets. The specific binding of neutravidin and anti-biotin to SLBs formed by liposome fusion, prior to and after equilibrated flip-flop between the upper and lower monolayers in the SLB, were then investigated.

An interaction network of the mammalian COP9 signalosome identifies Dda1 as a core subunit of multiple Cul4-based E3 ligases.

The COP9 signalosome (CSN) is an evolutionarily conserved macromolecular complex that interacts with cullin-RING E3 ligases (CRLs) and regulates their activity by hydrolyzing cullin-Nedd8 conjugates. The CSN sequesters inactive CRL4(Ddb2), which rapidly dissociates from the CSN upon DNA damage. Here we systematically define the protein interaction network of the mammalian CSN through mass spectrometric interrogation of the CSN subunits Csn1, Csn3, Csn4, Csn5, Csn6 and Csn7a.

Function and regulation of protein neddylation. 'Protein modifications: beyond the usual suspects' review series.

Neddylation is the post-translational protein modification that is most closely related to ubiquitination. However, ubiquitination is known to regulate a myriad of processes in eukaryotic cells, whereas only a limited number of neddylation substrates have been described to date. Here, we review the principles of protein neddylation and highlight the mechanisms that ensure the specificity of neddylation over ubiquitination.

Rtt101 and Mms1 in budding yeast form a CUL4(DDB1)-like ubiquitin ligase that promotes replication through damaged DNA.

In budding yeast the cullin Rtt101 promotes replication fork progression through natural pause sites and areas of DNA damage, but its relevant subunits and molecular mechanism remain poorly understood. Here, we show that in budding yeast Mms1 and Mms22 are functional subunits of an Rtt101-based ubiquitin ligase that associates with the conjugating-enzyme Cdc34. Replication forks in mms1Delta, mms22Delta and rtt101Delta cells are sensitive to collisions with drug-induced DNA lesions, but not to transient pausing induced by nucleotide depletion.

Formation of supported bacterial lipid membrane mimics.

In recent years, a large effort has been spent on advancing the understanding of how surface-supported membranes are formed through vesicle fusion. The aim is to find simple model systems for investigating biophysical and biochemical interactions between constituents of cell membranes and, for example, drugs and toxins altering membrane function. Designing and controlling the self-assembly of model membranes onto sensor substrates thus constitutes an important field of research, enabling applications in, e.

How force might activate talin's vinculin binding sites: SMD reveals a structural mechanism.

Upon cell adhesion, talin physically couples the cytoskeleton via integrins to the extracellular matrix, and subsequent vinculin recruitment is enhanced by locally applied tensile force. Since the vinculin binding (VB) sites are buried in the talin rod under equilibrium conditions, the structural mechanism of how vinculin binding to talin is force-activated remains unknown. Taken together with experimental data, a biphasic vinculin binding model, as derived from steered molecular dynamics, provides high resolution structural insights how tensile mechanical force applied to the talin rod fragment (residues 486-889 constituting helices H1-H12) might activate the VB sites.

On the Calculation of Atomic Forces in Classical Simulation Using the Charge-on-Spring Method To Explicitly Treat Electronic Polarization.

An expression for the atomic forces in simulations using the charge-on-spring (COS) polarizable model is rederived. In previous implementations of COS-based models, contributions arising from the dependence of the induced dipoles (i.e.

Fiber and lignin analysis in concentrate, forage, and feces: detergent versus enzymatic-chemical method.

Hemicelluloses, cellulose, and lignin contents of contrasting feeds, with emphasis on concentrate ingredients and complete concentrates, were analyzed using the Van Soest detergent procedure (analyzing neutral detergent fiber, acid detergent fiber, and acid detergent lignin) and the enzymatic-chemical procedure (analyzing cellulose, soluble and insoluble noncellulosic polysaccharides, and Klason lignin). Also, feces from cows fed concentrates differing in carbohydrate composition were analyzed by the 2 procedures. The correlation between acid detergent lignin and Klason lignin was significant, but not as close as the one between individual structural polysaccharides measured with the 2 procedures.

The cullin Rtt101p promotes replication fork progression through damaged DNA and natural pause sites.

Accurate and complete DNA replication is fundamental to maintain genome integrity. While the mechanisms and underlying machinery required to duplicate bulk genomic DNA are beginning to emerge, little is known about how cells replicate through damaged areas and special chromosomal regions such as telomeres, centromeres, and highly transcribed loci . Here, we have investigated the role of the yeast cullin Rtt101p in this process.

Pharmacologic transgene control systems for gene therapy.

Pharmacologic transgene-expression dosing is considered essential for future gene therapy scenarios. Genetic interventions require precise transcription or translation fine-tuning of therapeutic transgenes to enable their titration into the therapeutic window, to adapt them to daily changing dosing regimes of the patient, to integrate them seamlessly into the patient's transcriptome orchestra, and to terminate their expression after successful therapy. In recent years, decisive progress has been achieved in designing high-precision trigger-inducible mammalian transgene control modalities responsive to clinically licensed and inert heterologous molecules or to endogenous physiologic signals.

BicAT: a biclustering analysis toolbox.

Summary: Besides classical clustering methods such as hierarchical clustering, in recent years biclustering has become a popular approach to analyze biological data sets, e.g. gene expression data.

The cell penetrating peptides pVEC and W2-pVEC induce transformation of gel phase domains in phospholipid bilayers without affecting their integrity.

The cell penetrating peptide (CPP) pVEC has been shown to translocate efficiently the plasma membrane of different mammalian cell lines by a receptor-independent mechanism without exhibiting cellular toxicity. This ability renders CPPs of broad interest in cell biology, biotechnology, and drug delivery. To gain insight into the interaction of CPPs with biomembranes, we studied the interaction of pVEC and W2-pVEC, an Ile --> Trp modification of the former, with phase-separated supported phospholipid bilayers (SPB) by atomic force microscopy (AFM).

Development and evaluation of a standard method for the quantitative determination of elements in float glass samples by LA-ICP-MS.

Forensic analysis of glass samples was performed in different laboratories within the NITE-CRIME (Natural Isotopes and Trace Elements in Criminalistics and Environmental Forensics) European Network, using a variety of Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) systems. The main objective of the interlaboratory tests was to cross-validate the different combinations of laser ablation systems with different ICP-MS instruments. A first study using widely available samples, such as the NIST SRM 610 and NIST SRM 612 reference glasses, led to deviations in the determined concentrations for trace elements amongst the laboratories up to 60%.

Membrane surface-associated helices promote lipid interactions and cellular uptake of human calcitonin-derived cell penetrating peptides.

hCT(9-32) is a human calcitonin (hCT)-derived cell-penetrating peptide that has been shown to translocate the plasma membrane of mammalian cells. It has been suggested as a cellular carrier for drugs, green fluorescent protein, and plasmid DNA. Because of its temperature-dependent cellular translocation resulting in punctuated cytoplasmatic distribution, its uptake is likely to follow an endocytic pathway.

The Bud14p-Glc7p complex functions as a cortical regulator of dynein in budding yeast.

Regulated interactions between microtubules (MTs) and the cell cortex control MT dynamics and position the mitotic spindle. In eukaryotic cells, the adenomatous polyposis coli/Kar9p and dynein/dynactin pathways are involved in guiding MT plus ends and MT sliding along the cortex, respectively. Here we identify Bud14p as a novel cortical activator of the dynein/dynactin complex in budding yeast.

Insulin-like growth factor I-releasing alginate-tricalciumphosphate composites for bone regeneration.

Purpose: Development and characterization of an in situ-forming, osteoconductive, and growth factor-releasing bone implant.

Methods: Injectable in situ-forming scaffolds were prepared from a 2% (m/v) alginate solution, tricalciumphosphate (TCP) granules, and poly(lactide-co-glycolide) microspheres (MS), loaded with the osteoinductive growth factor insulin-like growth factor I (IGF-I). Scaffolds were prepared by mixing the components followed by hydrogel formation through calcium carbonate-induced physical cross-linking of the alginate at slightly acidic pH.

A new in situ method to analyze mineral particle reactions in soils.

We developed a simple method to monitorthe transformation of particles in soils under in situ conditions. The particles were fixed on small polymer supports (2 cm x 2 cm) with a thin film of epoxy resin. Attached to these carriers, the particles could be put into close contact with soil at a chosen site and easily recovered after extended periods of time.

Bilayer interaction and localization of cell penetrating peptides with model membranes: a comparative study of a human calcitonin (hCT)-derived peptide with pVEC and pAntp(43-58).

Cell-penetrating peptides (CPPs) are able to translocate problematic therapeutic cargoes across cellular membranes. The exact mechanisms of translocation are still under investigation. However, evidence for endocytic uptake is increasing.