Immune self-reactivity triggered by drug-modified HLA-peptide repertoire

Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T?cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs?6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.     

Understanding of the influence of process parameters on the heat transfer behavior at the metal/die interface in high pressure die casting process

The current paper focuses on the influence of the process parameters on the peak values of the interfacial heat transfer coefficient(IHTC)at metal/die interface during high pressure die casting(HPDC)process.A"step shape"casting and AM50 alloy were used during the experiment.The IHTC was determined by solving the inverse thermal problem based on the measured temperature inside the die.Results show that the initial die surface temperature(IDST,TDI)has a dominant influence while the casting pressure and fast shot velocity have a secondary influence on the IHTC peak values.By curve fitting,it was found that the IHTC peak value(hmax)changes as a function of the IDST in a manner of hmax=e αTγ DI .Such relationship between the IHTC peak value and the IDST can also be found when the casting alloy is ADC12,indicating that this phenomenon is a common characteristic in the HPDC process.     

De novo mutations revealed by whole-exome sequencing are strongly associated with autism

Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.     

Local to unity,long‐horizon forecasting thresholds for model selection in the AR(1)

This article introduces a novel framework for analysing long‐horizon forecasting of the near non‐stationary AR(1) model. Using the local to unity specification of the autoregressive parameter, I derive the asymptotic distributions of long‐horizon forecast errors both for the unrestricted AR(1), estimated using an ordinary least squares (OLS) regression, and for the random walk (RW). I then identify functions, relating local to unity ‘drift’ to forecast horizon, such that OLS and RW forecasts share the same expected square error. OLS forecasts are preferred on one side of these ‘forecasting thresholds’, while RW forecasts are preferred on the other. In addition to explaining the relative performance of forecasts from these two models, these thresholds prove useful in developing model selection criteria that help a forecaster reduce error. Copyright © 2004 John Wiley & Sons, Ltd.     

The green June beetle (Cotinis nitida) (Coleoptera: Scarabaeidae): local variation in the beetle’s major avian predators and in the competition for mates

The green June beetle (Cotinis nitida) was observed in northern Virginia for a second and third flight season. The study yielded some results that were consistent with earlier findings, namely that mate-locating beetles were vulnerable to attack by avian predators and matings occurred primarily early in the flight season. Novel findings included the following: (1) blue jays (Cyanocitta cristata) were the major predators, not common grackles (Quiscalus quiscala), (2) some jays appeared to selectively prey on female beetles, (3) competition for mates among male beetles could be so intense that some males attempted to copulate with already mated (unreceptive) females, and (4) the sex ratio of the beetle population feeding on wild blackberries remained near equality late in the flight season despite the fact that the sex ratio of the population of beetles at the emergence site became highly female-biased over time.     

Swimming and bipedal bottom-running in the pig-nosed turtle Carettochelys insculpta Ramsay, 1886

The pig-nosed freshwater turtle Carettochelys insculpta Ramsay, 1886 has paddle-shaped foreflippers that resemble those of sea turtles. These turtles exhibit a wide range of swimming capabilities. As well as swimming by the action of synchronized foreflippers alone, they sometimes used alternate hindlimb action at the same time. They could swim by ipsilaterally synchronized action of all four limbs, or by hindlimb action alone (combined with stabilizer/lift function of the foreflippers). The turtles also showed flexibility in bottom-walking. Besides the ipsilaterally synchronized quadrupedal action characteristic of other freshwater turtles, they exhibited a bipedal walking mechanism never previously described. Propelled by alternate action of the hindlimbs, the animals held the head and plastron above the substratum, with the large foreflippers acting to provide anterior lift and stability against roll and yaw. Because both hindlimbs were sometimes off the substratum simultaneously during bipedal locomotion, their duty factors were < 0.5, implying a bipedal run.