What have dendritic cells ever done for adjuvant design? Cellular and molecular methods for the rational development of vaccine adjuvants

Our new molecular understanding of immune priming states that dendritic cell activation is absolutely pivotal for expansion and differentiation of naïve T lymphocytes, and it follows that understanding DC activation is essential to understand and design vaccine adjuvants. This chapter describes how dendritic cells can be used as a core tool to provide detailed quantitative and predictive immunomics information about how adjuvants function. The role of distinct antigen, costimulation, and differentiation signals from activated DC in priming is explained. Four categories of input signals which control DC activation – direct pathogen detection, sensing of injury or cell death, indirect activation via endogenous proinflammatory mediators, and feedback from activated T cells – are compared and contrasted. Practical methods for studying adjuvants using DC are summarised and the importance of DC subset choice, simulating T cell feedback, and use of knockout cells is highlighted. Finally, five case studies are examined that illustrate the benefit of DC activation analysis for understanding vaccine adjuvant function.

Conductance and relaxations of gelatin films in the glassy and rubbery states

The dielectric constant, epsilon', and the dielectric loss, epsilon'', for gelatin films were measured in the glassy and rubbery states over a frequency range from 20 Hz to 10 MHz; epsilon' and epsilon'' were transformed into M* formalism (M* = 1/(epsilon' - i epsilon'') = M' + iM''; i, the imaginary unit). The peak of epsilon'' was masked probably due to dc conduction, but the peak of M'', e.g. the conductivity relaxation, for the gelatin used was observed. By fitting the M'' data to the Havriliak-Negami type equation, the relaxation time, tauHN, was evaluated. The value of the activation energy, Etau, evaluated from an Arrhenius plot of 1/tauHN, agreed well with that of Esigma evaluated from the DC conductivity sigma0 both in the glassy and rubbery states, indicating that the conductivity relaxation observed for the gelatin films was ascribed to ionic conduction. The value of the activation energy in the glassy state was larger than that in the rubbery state.

Ageing impairs the T cell response to dendritic cells

Dendritic cells (DCs) are critical in priming adaptive T-cell responses, but the effects of ageing on interactions between DCs and T cells are unclear. This study investigated the influence of ageing on the maturation of and cytokine production by human blood-enriched DCs, and the impact on T cell responses in an allogeneic mixed leucocyte reaction (MLR). DCs from old subjects (65-75y) produced significantly less TNF-α and IFN-γ than young subjects (20-30y) in response to lipopolysaccharide (LPS), but expression of maturation markers and co-stimulatory molecules was preserved. In the MLR, DCs from older subjects induced significantly restricted proliferation of young T cells, activation of CD8+ T cells and expression of IL-12 and IFN-γ in T cells compared with young DCs. T cells from older subjects responded more weakly to DC stimulation compared with young T cells, regardless of whether the DCs were derived from young or older subjects. In conclusion, the capacity of DCs to induce T cell activation is significantly impaired by ageing.

Unconscious effects of grammatical gender during object categorisation

Does language modulate perception and categorisation of everyday objects? Here, we approach this question from the perspective of grammatical gender in bilinguals. We tested Spanish–English bilinguals and control native speakers of English in a semantic categorisation task on triplets of pictures in an all-in-English context while measuring event-related brain potentials (ERPs). Participants were asked to press a button when the third picture of a triplet belonged to the same semantic category as the first two, and another button when it belonged to a different category. Unbeknownst to them, in half of the trials, the gender of the third picture name in Spanish had the same gender as that of the first two, and the opposite gender in the other half. We found no priming in behavioural results of either semantic relatedness or gender consistency. In contrast, ERPs revealed not only the expected semantic priming effect in both groups, but also a negative modulation by gender inconsistency in Spanish–English bilinguals, exclusively. These results provide evidence for spontaneous and unconscious access to grammatical gender in participants functioning in a context requiring no access to such information, thereby providing support for linguistic relativity effects in the grammatical domain.

Asymmetric organocatalysis and the nitro group functionality

The nitro group is an exceptionally versatile functional group, not only because it is essentially a masked amine, but also because its chemistry can be exploited in a number of useful ways. Asymmetric organocatalysis in particular has capitalized on the use of the nitro group towards the synthesis of a variety of nitrogen- containing targets. Perhaps of greatest interest is that this functional group has been shown to be invaluable within the rapidly expanding field of organocatalytic domino reactions. This review features selected examples of nitro group reactivity in organocatalysis to demonstrate its dynamism and utility.

Morphological decomposition in Broca's aphasia

Background: Few studies have investigated how individuals diagnosed with post-stroke Broca’s aphasia decompose words into their constituent morphemes in real-time processing. Previous research has focused on morphologically complex words in non-time-constrained settings or in syntactic frames, but not in the lexicon. Aims: We examined real-time processing of morphologically complex words in a group of five Greek-speaking individuals with Broca’s aphasia to determine: (1) whether their morphological decomposition mechanisms are sensitive to lexical (orthography and frequency) vs. morphological (stem-suffix combinatory features) factors during visual word recognition, (2) whether these mechanisms are different in inflected vs. derived forms during lexical access, and (3) whether there is a preferred unit of lexical access (syllables vs. morphemes) for inflected vs. derived forms. Methods & Procedures: The study included two real-time experiments. The first was a semantic judgment task necessitating participants’ categorical judgments for high- and low-frequency inflected real words and pseudohomophones of the real words created by either an orthographic error at the stem or a homophonous (but incorrect) inflectional suffix. The second experiment was a letter-priming task at the syllabic or morphemic boundary of morphologically transparent inflected and derived words whose stems and suffixes were matched for length, lemma and surface frequency. Outcomes & Results: The majority of the individuals with Broca’s aphasia were sensitive to lexical frequency and stem orthography, while ignoring the morphological combinatory information encoded in the inflectional suffix that control participants were sensitive to. The letter-priming task, on the other hand, showed that individuals with aphasia—in contrast to controls—showed preferences with regard to the unit of lexical access, i.e., they were overall faster on syllabically than morphemically parsed words and their morphological decomposition mechanisms for inflected and derived forms were modulated by the unit of lexical access. Conclusions: Our results show that in morphological processing, Greek-speaking persons with aphasia rely mainly on stem access and thus are only sensitive to orthographic violations of the stem morphemes, but not to illegal morphological combinations of stems and suffixes. This possibly indicates an intact orthographic lexicon but deficient morphological decomposition mechanisms, possibly stemming from an underspecification of inflectional suffixes in the participants’ grammar. Syllabic information, however, appears to facilitate lexical access and elicits repair mechanisms that compensate for deviant morphological parsing procedures.

Validity of the ice shelf water plume concept beneath Filchner-Ronne Ice Shelf

In winter, brine rejection from sea ice formation and export in the Weddell Sea, offshore of Filchner-Ronne Ice Shelf (FRIS), leads to the formation of High Salinity Shelf Water (HSSW). This dense water mass enters the cavity beneath FRIS by sinking southward down the sloping continental shelf towards the grounding line. Melting occurs when the HSSW encounters the ice shelf, and the meltwater released cools and freshens the HSSW to form a water mass known as Ice Shelf Water (ISW). If this ISW rises, the ‘ice pump’ is initiated (Lewis and Perkin, 1986), whereby the ascending ISW becomes supercooled and deposits marine ice at shallower locations due to the pressure increase in the in-situ freezing temperature. Sandh¨ager et al. (2004) were able to infer the thickness patterns of marine ice deposits at the base of FRIS (figure 1), so the primary aim of this work is to try to understand the ocean flows that determine these patterns. The plume model we use to investigate ISW flow is described fully by Holland and Feltham (accepted) so only a relatively brief outline is presented here. The plume is simulated by combining a parameterisation of ice shelf basal interaction and a multiplesize- class frazil dynamics model with an unsteady, depth-averaged reduced-gravity plume model. In the model an active region of ISW evolves above and within an expanse of stagnant ambient fluid, which is considered to be ice-free and has fixed profiles of temperature and salinity. The two main assumptions of the model are that there is a well-mixed layer underneath the ice shelf and that the ambient fluid outside the plume is stagnant with fixed properties. The topography of the ice shelf that the plume flows beneath is set to the FRIS ice shelf draft calculated by Sandh¨ager et al. (2004) masked with the grounding line from the Antarctic Digital Database (ADD Consortium, 2002). To initiate the plumes, we assume that the intrusion of dense HSSW initially causes melting at the points on the grounding line where the glaciological tributaries feeding FRIS go afloat.

Semantic self-knowledge and episodic self-knowledge: Independent or interrelated representations?

In this study of the structure of self-knowledge, we examined priming effects for the recall of personal episodes in order to investigate whether abstract trait knowledge and personal episodes are independent mental representations. We found that accessing similar abstract representations of traits facilitated a faster recall of related personal episodes than did accessing irrelevant abstract representations of traits (Experiments 1 and 2), reading a nonword prime (Experiments 2 and 3), accessing knowledge of one's mother (Experiment 3), or accessing semantic knowledge (Experiment 3). Contrary to previous findings, which indicated that abstract trait knowledge is represented independently of related personal episodes (e.g., Klein & Loftus, 1993, our results suggest that abstract trait knowledge is associated with personal episodes, and therefore that semantic self-knowledge is associated with episodic self-knowledge in long-term self-knowledge.

Distraction control processes in free recall: benefits and costs to performance

How is semantic memory influenced by individual differences under conditions of distraction? This question was addressed by observing how visual target words—drawn from a single category—were recalled whilst ignoring spoken distracter words that were either members of the same, or members of a different (single) category. Working memory capacity (WMC) was related to disruption only with synchronous, not asynchronous, presentation and distraction was greater when the words were presented synchronously. Subsequent experiments found greater negative priming of distracters amongst individuals with higher WMC but this may be dependent on targets and distracters being comparable category exemplars. With less dominant category members as distracters, target recall was impaired – relative to control – only amongst individuals with low WMC. The results highlight the role of cognitive control resources in target-distracter selection and the individual-specific cost implications of such cognitive control.

Impact of polysialylated CD56 on natural killer cell cytotoxicity

Background Siglec-7, a sialic acid binding inhibitory receptor expressed by NK cells is masked in vivo by a so far unknown ligand. It shows a strong binding prevalence for α-2,8-linked disialic acids in vitro. Results Here we describe the expression of PSA-NCAM (α-2,8-linked polysialic acid modified NCAM) on functional adult peripheral blood natural killer cells and examine its possible role in masking Siglec-7. Unmasking of Siglec-7 using Clostridium perfringens neuraminidase massively reduces NK cell cytotoxicity. By contrast a specific removal of PSA using Endo-NF does not lead to a reduction of NK cell cytotoxicity. Conclusion The results presented here therefore indicate that PSA-NCAM is not involved in masking Siglec-7.

The nature of impairments of memory in patients with end-stage renal disease (ESRD)

Possible impairments of memory in end-stage renal disease (ESRD) were investigated in two experiments. In Experiment 1, in which stimulus words were presented visually, participants were tested on conceptual or perceptual memory tasks, with retrieval being either explicit or implicit. Compared with healthy controls, ESRD patients were impaired when memory required conceptual but not when it required perceptual processing, regardless of whether retrieval was explicit or implicit. An impairment of conceptual implicit memory (priming) in the ESRD group represented a previously unreported deficit compared to healthy aging. There were no significant differences between pre- and immediate post-dialysis memory performance in ESRD patients on any of the tasks. In Experiment 2, in which presentation was auditory, patients again performed worse than controls on an explicit conceptual memory task. We conclude that the type of processing required by the task (conceptual vs. perceptual) is more important than the type of retrieval (explicit vs. implicit) in memory failures in ESRD patients, perhaps because temporal brain regions are more susceptible to the effects of the illness than are posterior regions.

A critical evaluation of the ability of the Spinning Enhanced Visible and Infrared Imager (SEVIRI) thermal infrared red-green-blue rendering to identify dust events: theoretical analysis

Using a combination of idealized radiative transfer simulations and a case study from the first field campaign of the Saharan Mineral Dust Experiment (SAMUM) in southern Morocco, this paper provides a systematic assessment of the limitations of the widely used Spinning Enhanced Visible and Infrared Imager (SEVIRI) red-green-blue (RGB) thermal infrared dust product. Both analyses indicate that the ability of the product to identify dust, via its characteristic pink coloring, is strongly dependent on the column water vapor, the lower tropospheric lapse rate, and dust altitude. In particular, when column water vapor exceeds ∼20–25 mm, dust presence, even for visible optical depths of the order 0.8, is effectively masked. Variability in dust optical properties also has a marked impact on the imagery, primarily as a result of variability in dust composition. There is a moderate sensitivity to the satellite viewing geometry, particularly in moist conditions. The underlying surface can act to confound the signal seen through variations in spectral emissivity, which are predominantly manifested in the 8.7μm SEVIRI channel. In addition, if a temperature inversion is present, typical of early morning conditions over the Sahara and Sahel, an increased dust loading can actually reduce the pink coloring of the RGB image compared to pristine conditions. Attempts to match specific SEVIRI observations to simulations using SAMUM measurements are challenging because of high uncertainties in surface skin temperature and emissivity. Recommendations concerning the use and interpretation of the SEVIRI RGB imagery are provided on the basis of these findings.

Designing a sampling scheme to reveal correlations between weeds and soil properties at multiple spatial scales

Weeds tend to aggregate in patches within fields and there is evidence that this is partly owing to variation in soil properties. Because the processes driving soil heterogeneity operate at different scales, the strength of the relationships between soil properties and weed density would also be expected to be scale-dependent. Quantifying these effects of scale on weed patch dynamics is essential to guide the design of discrete sampling protocols for mapping weed distribution. We have developed a general method that uses novel within-field nested sampling and residual maximum likelihood (REML) estimation to explore scale-dependent relationships between weeds and soil properties. We have validated the method using a case study of Alopecurus myosuroides in winter wheat. Using REML, we partitioned the variance and covariance into scale-specific components and estimated the correlations between the weed counts and soil properties at each scale. We used variograms to quantify the spatial structure in the data and to map variables by kriging. Our methodology successfully captured the effect of scale on a number of edaphic drivers of weed patchiness. The overall Pearson correlations between A. myosuroides and soil organic matter and clay content were weak and masked the stronger correlations at >50 m. Knowing how the variance was partitioned across the spatial scales we optimized the sampling design to focus sampling effort at those scales that contributed most to the total variance. The methods have the potential to guide patch spraying of weeds by identifying areas of the field that are vulnerable to weed establishment.

Investigation of the impact of anthropogenic heat flux within an urban land surface model and PILPS-urban

Results from the first international urban model comparison experiment (PILPS-Urban) suggested that models which neglected the anthropogenic heat flux within the surface energy balance performed at least as well as models that include the source term, but this could not be explained. The analyses undertaken show that the results from PILPS-Urban were masked by the signal from including vegetation, which was identified in PILPS-Urban as being important. Including the anthropogenic heat flux does give improved performance, but the benefit is small for the site studied given the relatively small magnitude of this flux relative to other terms in the surface energy balance. However, there is no further benefit from including temporal variations in the flux at this site. The importance is expected to increase at sites with a larger anthropogenic heat flux and greater temporal variations.

Assessing multilingual lexical incorporation hypotheses through a primed picture-naming task

The incorporation of new representations into the mental lexicon has raised numerous questions about the organisational principles that govern the process. A number of studies have argued that similarity between the new L3 items and existing representations in the L1 and L2 is the main incorporating force (Hall & Ecke, 2003; Herwig, 2001). Experimental evidence obtained through a primed picture-naming task with L1 Polish-L2 English learners of L3 Russian supports Hall and Ecke’s Parasitic Model of L3 vocabulary acquisition, displaying a significant main effect for both priming and proficiency. These results complement current models of vocabulary acquisition and lexical access in multilingual speakers.