CD18-dependent activation of the neutrophil NADPH oxidase during phagocytosis of Escherichia coli or Staphylococcus aureus is regulated by class III but not class I or II PI3Ks

Phagocytosis and activation of the NADPH oxidase are important mechanisms by which neutrophils and macrophages engulf and kill microbial pathogens. We investigated the role of PI3K signaling pathways in the regulation of the oxidase during phagocytosis of Staphylococcus aureus and Escherichia coli by mouse and human neutrophils, a mouse macrophage-like cell line and a human myeloid-like cell line. Phagocytosis of these bacteria was promoted by serum, independent of serum-derived antibodies, and effectively abolished in mouse neutrophils lacking the beta(2)-integrin common chain, CD18. A combination of PI3K isoform-selective inhibitors, mouse knock-outs, and RNA-interference indicated CD18-dependent activation of the oxidase was independent of class I and II PI3Ks, but substantially dependent on the single class III isoform (Vps34). Class III PI3K was responsible for the synthesis of PtdIns( 3) P on phagosomes containing either bacteria. The use of mouse neutrophils carrying an appropriate knock-in mutation indicated that PtdIns(3) P binding to the PX domain of their p40(phox) oxidase subunit is important for oxidase activation in response to both S aureus and E coli. This interaction does not, however, account for all the PI3K sensitivity of these responses, particularly the oxidase response to E coli, suggesting that additional mechanisms for PtdIns( 3) P-regulation of the oxidase must exist. ( Blood. 2008; 112: 5202-5211)

Langerin(+) Dermal Dendritic Cells Are Critical for CD8(+) T Cell Activation and IgH gamma-1 Class Switching in Response to Gene Gun Vaccines

The C-type lectin langerin/CD207 was originally discovered as a specific marker for epidermal Langerhans cells (LC). Recently, additional and distinct subsets of langerin(+) dendritic cells (DC) have been identified in lymph nodes and peripheral tissues of mice. Although the role of LC for immune activation or modulation is now being discussed controversially, other langerin(+) DC appear crucial for protective immunity in a growing set of infection and vaccination models. In knock-in mice that express the human diphtheria toxin receptor under control of the langerin promoter, injection of diphtheria toxin ablates LC for several weeks whereas other langerin(+) DC subsets are replenished within just a few days. Thus, by careful timing of diphtheria toxin injections selective states of deficiency in either LC only or all langerin(+) cells can be established. Taking advantage of this system, we found that, unlike selective LC deficiency, ablation of all langerin(+) DC abrogated the activation of IFN-gamma producing and cytolytic CD8(+) T cells after gene gun vaccination. Moreover, we identified migratory langerin(+) dermal DC as the subset that directly activated CD8(+) T cells in lymph nodes. Langerin(+) DC were also critical for IgG1 but not IgG2a Ab induction, suggesting differential polarization of CD4(+) T helper cells by langerin(+) or langerin-negative DC, respectively. In contrast, protein vaccines administered with various adjuvants induced IgG1 independently of langerin(+) DC. Taken together, these findings reflect a highly specialized division of labor between different DC subsets both with respect to Ag encounter as well as downstream processes of immune activation. The Journal of Immunology, 2011, 186: 1377-1383.

An Introduction to the Special issue - Housing in Hard Times: Marginality, Inequality and Class, with Kim McKee

‘Housing in Hard Times’ was the theme of the Housing Studies Association annual conference in April 2011. The papers featured in this special issue are drawn from that conference. They examine the uneven impact of economic change on housing policy and related areas, with reference to conceptual ideas pertaining to urban marginality, inequality and class. Whilst the empirical focus of the papers is the UK, their intellectual contribution represents an attempt to ‘bring class back in’ to the housing studies literature and encourage more critical, theoretically informed scholarship.

Interval timing and trajectory in unequal amplitude movements

The Wing-Kristofferson (WK) model of movement timing emphasises the separation of central timer and motor processes. Several studies of repetitive timing have shown that increase in variability at longer intervals is attributable to timer processes; however, relatively little is known about the way motor aspects of timing are affected by task movement constraints. In the present study, we examined timing variability in finger tapping with differences in interval to assess central timer effects, and with differences in movement amplitude to assess motor implementation effects. Then, we investigated whether effects of motor timing observed at the point of response (flexion offset/tap) are also evident in extension, which would suggest that both phases are subject to timing control. Eleven participants performed bimanual simultaneous tapping, at two target intervals (400, 600 ms) with the index finger of each hand performing movements of equal (3 or 6 cm) or unequal amplitude (left hand 3, right hand 6 cm and vice versa). As expected, timer variability increased with the mean interval but showed only small, non-systematic effects with changes in movement amplitude. Motor implementation variability was greater in unequal amplitude conditions. The same pattern of motor variability was observed both at flexion and extension phases of movement. These results suggest that intervals are generated by a central timer, triggering a series of events at the motor output level including flexion and the following extension, which are explicitly represented in the timing system.

Timing movements to interval durations specified by discrete or continuous sounds

Understanding how the timing of motor output is coupled to sensory temporal information is largely based on synchronisation of movements through small motion gaps (finger taps) to mostly empty sensory intervals (discrete beats). This study investigated synchronisation of movements between target barriers over larger motion gaps when closing time gaps of intervals were presented as either continuous, dynamic sounds, or discrete beats. Results showed that although synchronisation errors were smaller for discrete sounds, the variability of errors was lower for continuous sounds. Furthermore, finger movement between targets was found to be more sinusoidal when continuous sensory information was presented during intervals compared to discrete. When movements were made over larger amplitudes, synchronisation errors tended to be more positive and movements between barriers more sinusoidal, than for movements over shorter amplitudes. These results show that the temporal control of movement is not independent from the form of the sensory information that specifies time gaps or the magnitude of the movement required for synchronisation.

Interbirth interval is associated with childhood type 1 diabetes risk

Short interbirth interval has been associated with maternal complications and childhood autism and leukemia, possibly due to deficiencies in maternal micronutrients at conception or increased exposure to sibling infections. A possible association between interbirth interval and subsequent risk of childhood type 1 diabetes has not been investigated. A secondary analysis of 14 published observational studies of perinatal risk factors for type 1 diabetes was conducted. Risk estimates of diabetes by category of interbirth interval were calculated for each study. Random effects models were used to calculate pooled odds ratios (ORs) and investigate heterogeneity between studies. Overall, 2,787 children with type 1 diabetes were included. There was a reduction in the risk of childhood type 1 diabetes in children born to mothers after interbirth intervals <3 years compared with longer interbirth intervals (OR 0.82 [95% CI 0.72-0.93]). Adjustments for various potential confounders little altered this estimate. In conclusion, there was evidence of a 20% reduction in the risk of childhood diabetes in children born to mothers after interbirth intervals <3 years.

Transmission-Line Class-E Power Amplifier With Extended Maximum Operating Frequency

A novel Class-E power amplifier (PA) topology with transmission-line load network is presented in this brief. When compared with the classic Class-E topology, the new circuit can increase the maximum operating frequency up to 50% higher without trading the other Class-E figures of merit. Neither quarterwave line/massive radio-frequency choke for collector/drain biasing nor additional fundamental-frequency output matching circuit are needed in the proposed PA, thus resulting in a compact design. Closed-form formulations are derived and verified by simulations with practical design limitations carefully taken into consideration and good agreement achieved.

Multiple site dioxygenase-catalysed cis-dihydroxylation of polycyclic azaarenes to yield a new class of bis-cis-diol metabolites

The enhanced stability of new mono-cis-dihydrodiol bacterial metabolites of tricyclic azaarenes has facilitated the dioxygenase-catalysed formation and isolation of the corresponding bis-cis-dihydrodiols (cis-tetraols) and a three step chemoenzymatic route to the derived arene oxide mammalian metabolites.