Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity

Autoimmune diseases are thought to result from imbalances in normal immune physiology and regulation. Here, we show that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2). In order to test directly that an approximately twofold reduction in IL-2 underpins the Idd3-linked destabilization of immune homeostasis, we show that engineered haplodeficiency of Il2 gene expression not only reduces T cell IL-2 production by twofold but also mimics the autoimmune dysregulatory effects of the naturally occurring susceptibility alleles of Il2. Reduced IL-2 production achieved by either genetic mechanism correlates with reduced function of CD4(+) CD25(+) regulatory T cells, which are critical for maintaining immune homeostasis.     

Can urban coffee consumption help predict US inflation?

Motivated by the importance of coffee to Americans and the significance of the coffee subsector to the US economy, we pursue three notable innovations. First, we augment the traditional Phillips curve model with the coffee price as a predictor, and show that the resulting model outperforms the traditional variant in both in‐sample and out‐of‐sample predictability of US inflation. Second, we demonstrate the need to account for the inherent statistical features of predictors such as persistence, endogeneity, and conditional heteroskedasticity effects when dealing with US inflation. Consequently, we offer robust illustrations to show that the choice of estimator matters for improved US inflation forecasts. Third, the proposed augmented Phillips curve also outperforms time series models such as autoregressive integrated moving average and the fractionally integrated version for both in‐sample and out‐of‐sample forecasts. Our results show that augmenting the traditional Phillips curve with the urban coffee price will produce better forecast results for US inflation only when the statistical effects are captured in the estimation process. Our results are robust to alternative measures of inflation, different data frequencies, higher order moments, multiple data samples and multiple forecast horizons.     

Leadership and Learning: A Critical Reexamination of Senge’s Learning Organization

From its inception the concept of the learning organization has been identified with a particular type of organization or new forms of organizational learning. But it is often forgotten that Senge’s ‘system thinking’ formulation of the learning organization was inseparable from an attempt to reformulate a new way of thinking about change agency and leadership in organizations. Here it is argued that Senge’s learning organization can be re-conceptualised as a partial fusion of ‘systems thinking’ and learning theories that leads to a concept of organizational learning as a form of ‘distributed leadership’. However, the concept is critically flawed because it cannot theorise the organizing practices by which learning to lead and leading to learn are shared or distributed in organizations. It is concluded that Senge’s under-theorized focus on distributed leadership consistently neglects issues of practice and issues of power. As such his work does not provide an exploration of the possibilities for increasing the dispersal of human agency, power, knowledge and autonomy within the workplace.     

Oncogenically active MYD88 mutations in human lymphoma

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt's lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.     

Effects of prairie dog rodenticides on deer mice in western South Dakota

Mortality of nontarget small mammals was determined after application of three black-tailed prairie dog ( Cynomys ludovicianus ) rodenticide treatments (prebaited zinc phosphide, prebaited strychnine, and strychnine alone) in western South Dakota. Immediate (September 1983) and long-term (September 1983 through August 1984) impacts on deer mouse ( Peromyscus maniculatus ) relative densities were evaluated and the three rodenticide treatments were compared for efficacy. The three treatments had no significant (α < .10) immediate impacts on deer mouse relative densities, although zinc phosphide did lower them; that impact was not, however, long term. Long-term impacts of the two strychnine treatments were variable, with an increase in deer mouse densities with the strychnine only treatment. Overall, comparisons among the three treatments indicated that zinc phosphide was more effective than either strychnine treatment in reducing deer mouse densities.     

DISTORTIONAL PROPERTIES OF THE BIJECTIVE PATTERN MAP (PART I: DISTORTION IN LENGTH)

The Bijective Pattern Map maps the 3D surface patch to the 2D flat pattern. The bijection property has been proved. However, since the 3D Algebraic Mannequin is not developeable, meaning that it is not isometric to the 2D plane, the intrinsic geometry of the 3D surface patches is different from their images on the 2D plane. Consequently, distortion exists. The distortional property of the Bijective Pattern Map is discussed in this article.