Addressing the needs of traumatic brain injury with clinical proteomics.

BackgroundNeurotrauma or injuries to the central nervous system (CNS) are a serious public health problem worldwide. Approximately 75% of all traumatic brain injuries (TBIs) are concussions or other mild TBI (mTBI) forms. Evaluation of concussion injury today is limited to an assessment of behavioral symptoms, often with delay and subject to motivation. Hence, there is an urgent need for an accurate chemical measure in biofluids to serve as a diagnostic tool for invisible brain wounds, to monitor severe patient trajectories, and to predict survival chances. Although a number of neurotrauma marker candidates have been reported, the broad spectrum of TBI limits the significance of small cohort studies. Specificity and sensitivity issues compound the development of a conclusive diagnostic assay, especially for concussion patients. Thus, the neurotrauma field currently has no diagnostic biofluid test in clinical use.ContentWe discuss the challenges of discovering new and validating identified neurotrauma marker candidates using proteomics-based strategies, including targeting, selection strategies and the application of mass spectrometry (MS) technologies and their potential impact to the neurotrauma field.SummaryMany studies use TBI marker candidates based on literature reports, yet progress in genomics and proteomics have started to provide neurotrauma protein profiles. Choosing meaningful marker candidates from such 'long lists' is still pending, as only few can be taken through the process of preclinical verification and large scale translational validation. Quantitative mass spectrometry targeting specific molecules rather than random sampling of the whole proteome, e.g., multiple reaction monitoring (MRM), offers an efficient and effective means to multiplex the measurement of several candidates in patient samples, thereby omitting the need for antibodies prior to clinical assay design. Sample preparation challenges specific to TBI are addressed. A tailored selection strategy combined with a multiplex screening approach is helping to arrive at diagnostically suitable candidates for clinical assay development. A surrogate marker test will be instrumental for critical decisions of TBI patient care and protection of concussion victims from repeated exposures that could result in lasting neurological deficits

Effects of street traffic noise in the night

The relationship between automobile traffic noise and the degree of disturbance experience experienced at night was explored through a random sample survey of 1600 individuals in rural and urban areas. The data obtained were used to establish threshold values

Studies on processing, particle formation, and immunogenicity of the HIV-1 gag gene product: a possible component of a HIV vaccine

Antigens in a particulate conformation were shown to be highly immunogenic in mammals. For this reason, the particle forming capacity of derivatives of the HIV-1 group specific core antigen p55 gag was assayed and compared dependent on various expression systems: recombinant bacteria, vaccinia- and baculoviruses were established encoding the entire core protein p55 either in its authentic sequence or lacking the myristylation consensus signal. Moreover, p55 gag was expressed in combination with the protease (p55-PR) or with the entire polymerase (p55-pol), respectively. Budding of 100-160 nm p55 core particles, resembling immature HIV-virions, was observed in the eucaryotic expression systems only. In comparison to the vaccinia virus driven expression of p55 in mammalian cells, considerably higher yields of particulate core antigen were obtained by infection of Spodoptera frugiperda (Sf9) insect cells with the recombinant Autographa californica nuclear polyhedrosis (AcMNPV) baculovirus. Mutation of the NH2-terminal myristylation signal sequence prevented budding of the immature core particles. Expression of the HIV p55-PR gene construct by recombinant baculovirus resulted in complete processing of the p55 gag precursor molecule in this system. The introduction of an artificial frameshift near the natural frameshift site resulted in constitutive expression of the viral protease and complete processing of p55, both in Escherichia coli and in vaccinia virus infected cells. Interestingly, significant processing of p55 resembling that of HIV infected H9 cells could also be achieved in the vaccinia system by fusing the entire pol gene to the gag gene. Moreover, processing was not found to be dependent on amino-terminal myristylation of the gag procursor molecule, which is in contrast to observations with type C and type D retrovirus. However, complete processing of p55 into p24, p17, p9 and p6 abolished particle formation. Purified immature HIV-virus like particles were highly immunogenic in rabbits, leading to a strong humoral immune response after immunization. Empty immature p55 gag particles represent a noninfectious and attractive candidate for a basic vaccine component

The role of working memory and contextual constraints in children's processing of relative clauses

An auditory sentence comprehension task investigated the extent to which the integration of contextual and structural cues was mediated by verbal memory span with 32 English-speaking 6- to 8-year old children. Spoken relative clause sentences were accompanied by visual context pictures which fully (depicting the actions described within the relative clause) or partially (depicting several referents) met the pragmatic assumptions of relativisation. Comprehension of the main and relative clauses of centre-embedded and right-branching structures was compared for each context. Pragmatically-appropriate contexts exerted a positive effect on relative clause comprehension, but children with higher memory spans demonstrated a further benefit for main clauses. Comprehension for centre-embedded main clauses was found to be very poor, independently of either context or memory span. The results suggest that children have access to adult-like linguistic processing mechanisms, and that sensitivity to extra-linguistic cues is evident in young children and develops as cognitive capacity increases

Increase of the mean inner Coulomb potential in Au clusters induced by surface tension and its implication for electron scattering

Electron holography in a transmission electron microscope was applied to measure the phase shift induced by Au clusters as a function of the cluster size. Large phase shifts Df observed for small Au clusters cannot be described by the well-known equation Df=C_E V_0 t (C_E: interaction constant, V_0: mean inner Coulomb potential (MIP) of bulk gold, t: cluster thickness). The rapid increase of the Au MIP with decreasing cluster size derived from Df, can be explained by the compressive strain of surface atoms in the cluster