Interleukin-1 beta-converting enzyme-like protease cleaves DNA-dependent protein kinase in cytotoxic T cell killing.

Cytotoxic T cells (CTL) represent the major defense mechanism against the spread of virus infection. It is believed that the pore-forming protein, perforin, facilitates the entry of a series of serine proteases (particularly granzyme B) into the target cell which ultimately leads to DNA fragmentation and apoptosis. We demonstrate here that during CTL-mediated cytolysis the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an enzyme implicated in the repair of double strand breaks in DNA, is specifically cleaved by an interleukin (IL)-1 beta-converting enzyme (ICE)-like protease. A serine protease inhibitor, 3,4-dichloroisocoumarin (DCl), which is known to block granzyme B activity, inhibited CTL-induced apoptosis and prevented the degradation of DNA-PKcs in cells but failed to prevent the degradation of purified DNA-PKcs by CTL extracts. However, Tyr-Val-Ala-Asp-CH2Cl (YVAD-CMK) and other cysteine protease inhibitors prevented the degradation of purified DNA-PKcs by CTL extracts. Furthermore, incubation of DNA-PKcs with granzyme B did not produce the same cleavage pattern observed in cells undergoing apoptosis and when this substrate was incubated with either CTL extracts or the ICE-like protease, CPP32. Sequence analysis revealed that the cleavage site in DNA-PKcs during CTL killing was the same as that when this substrate was exposed to CPP32. This study demonstrates for the first time that the cleavage of DNA-PKcs in this intact cell system is exclusively due to an ICE-like protease

Cross-Reactivity of Herpesvirus-Specific CD8 T Cell Lines Toward Allogeneic Class I MHC Molecules

Although association between persistent viral infection and allograft rejection is well characterized, few examples of T-cell cross-reactivity between self-MHC/viral and allogeneic HLA molecules have been documented so far. We appraised in this study the alloreactivity of CD8 T cell lines specific for immunodominant epitopes from human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). CD8 T cell lines were generated after sorting with immunomagnetic beads coated with either pp65495–503/A*0201, BMLF1259–267/A*0201, or BZLF154–64/B*3501 multimeric complexes. Alloreactivity of the CD8 T cell lines against allogeneic class I MHC alleles was assessed by screening of (i) TNF-α production against COS-7 cells transfected with as many as 39 individual HLA class I-encoding cDNA, and (ii) cytotoxicity activity toward a large panel of HLA-typed EBV-transformed B lymphoblastoid cell lines. We identified several cross-reactive pp65/A*0201-specific T cell lines toward allogeneic HLA-A*3001, A*3101, or A*3201. Moreover, we described here cross-recognition of HLA-Cw*0602 by BZLF1/B*3501-specific T cells. It is noteworthy that these alloreactive CD8 T cell lines showed efficient recognition of endothelial cells expressing the relevant HLA class I allele, with high level TNF-α production and cytotoxicity activity. Taken together, our data support the notion that herpes virus-specific T cells recognizing allo-HLA alleles may promote solid organ rejection

Primate modularity and evolution: first anatomical network analysis of primate head and neck musculoskeletal system

Network theory is increasingly being used to study morphological modularity and integration. Anatomical network analysis (AnNA) is a framework for quantitatively characterizing the topological organization of anatomical structures and providing an operational way to compare structural integration and modularity. Here we apply AnNA for the first time to study the macroevolution of the musculoskeletal system of the head and neck in primates and their closest living relatives, paying special attention to the evolution of structures associated with facial and vocal communication. We show that well-defined left and right facial modules are plesiomorphic for primates, while anthropoids consistently have asymmetrical facial modules that include structures of both sides, a change likely related to the ability to display more complex, asymmetrical facial expressions. However, no clear trends in network organization were found regarding the evolution of structures related to speech. Remarkably, the increase in the number of head and neck muscles – and thus of musculoskeletal structures – in human evolution led to a decrease in network density and complexity in humans

Relativistic ejecta from XRF 060218 and the rate of cosmic explosions

Over the last decade, long-duration gamma-ray bursts (GRBs) including the subclass of X-ray flashes (XRFs) have been revealed to be a rare variety of Type Ibc supernova (SN). While all these events result from the death of massive stars, the electromagnetic luminosities of GRBs and XRFs exceed those of ordinary Type Ibc SNe by many orders of magnitude. The essential physical process that causes a dying star to produce a GRB or XRF, and not just an SN, remains the crucial open question. Here we present radio and X-ray observations of XRF 060218 (associated with SN 2006aj), the second nearest GRB identified to-date, which allow us to measure its total energy and place it in the larger context of cosmic explosions. We show that this event is 100 times less energetic but ten times more common than cosmological GRBs. Moreover, it is distinguished from ordinary Type Ibc SNe by the presence of 10^48 erg coupled to mildly-relativistic ejecta, along with a central engine (an accretion-fed, rapidly rotating compact source) which produces X-rays for weeks after the explosion. This suggests that the production of relativistic ejecta is the key physical distinction between GRBs/XRFs and ordinary SNe, while the nature of the central engine (black hole or magnetar) may distinguish typical bursts from low-luminosity, spherical events like XRF 060218.Comment: To appear in Nature on August 31 2006 (15 pages, 3 figures, 1 table, including Supplementary Information

A meta-analysis of long-term effects of conservation agriculture on maize grain yield under rain-fed conditions

Conservation agriculture involves reduced tillage, permanent soil cover and crop rotations to enhance soil fertility and to supply food from a dwindling land resource. Recently, conservation agriculture has been promoted in Southern Africa, mainly for maize-based farming systems. However, maize yields under rain-fed conditions are often variable. There is therefore a need to identify factors that influence crop yield under conservation agriculture and rain-fed conditions. Here, we studied maize grain yield data from experiments lasting 5 years and more under rain-fed conditions. We assessed the effect of long-term tillage and residue retention on maize grain yield under contrasting soil textures, nitrogen input and climate. Yield variability was measured by stability analysis. Our results show an increase in maize yield over time with conservation agriculture practices that include rotation and high input use in low rainfall areas. But we observed no difference in system stability under those conditions. We observed a strong relationship between maize grain yield and annual rainfall. Our meta-analysis gave the following findings: (1) 92% of the data show that mulch cover in high rainfall areas leads to lower yields due to waterlogging; (2) 85% of data show that soil texture is important in the temporal development of conservation agriculture effects, improved yields are likely on well-drained soils; (3) 73% of the data show that conservation agriculture practices require high inputs especially N for improved yield; (4) 63% of data show that increased yields are obtained with rotation but calculations often do not include the variations in rainfall within and between seasons; (5) 56% of the data show that reduced tillage with no mulch cover leads to lower yields in semi-arid areas; and (6) when adequate fertiliser is available, rainfall is the most important determinant of yield in southern Africa. It is clear from our results that conservation agriculture needs to be targeted and adapted to specific biophysical conditions for improved impact

Geographical limits to species-range shifts are suggested by climate velocity

The reorganization of patterns of species diversity driven by anthropogenic climate change, and the consequences for humans, are not yet fully understood or appreciated. Nevertheless, changes in climate conditions are useful for predicting shifts in species distributions at global and local scales. Here we use the velocity of climate change to derive spatial trajectories for climatic niches from 1960 to 2009 (ref. 7) and from 2006 to 2100, and use the properties of these trajectories to infer changes in species distributions. Coastlines act as barriers and locally cooler areas act as attractors for trajectories, creating source and sink areas for local climatic conditions. Climate source areas indicate where locally novel conditions are not connected to areas where similar climates previously occurred, and are thereby inaccessible to climate migrants tracking isotherms: 16% of global surface area for 1960 to 2009, and 34% of ocean for the \u27business as usual\u27 climate scenario (representative concentration pathway (RCP) 8.5)8 representing continued use of fossil fuels without mitigation. Climate sink areas are where climate conditions locally disappear, potentially blocking the movement of climate migrants. Sink areas comprise 1.0% of ocean area and 3.6% of land and are prevalent on coasts and high ground. Using this approach to infer shifts in species distributions gives global and regional maps of the expected direction and rate of shifts of climate migrants, and suggests areas of potential loss of species richness

Plastic and Heritable Components of Phenotypic Variation in Nucella lapillus: An Assessment Using Reciprocal Transplant and Common Garden Experiments

Assessment of plastic and heritable components of phenotypic variation is crucial for understanding the evolution of adaptive character traits in heterogeneous environments. We assessed the above in relation to adaptive shell morphology of the rocky intertidal snail Nucella lapillus by reciprocal transplantation of snails between two shores differing in wave action and rearing snails of the same provenance in a common garden. Results were compared with those reported for similar experiments conducted elsewhere. Microsatellite variation indicated limited gene flow between the populations. Intrinsic growth rate was greater in exposed-site than sheltered-site snails, but the reverse was true of absolute growth rate, suggesting heritable compensation for reduced foraging opportunity at the exposed site. Shell morphology of reciprocal transplants partially converged through plasticity toward that of native snails. Shell morphology of F2s in the common garden partially retained characteristics of the P-generation, suggesting genetic control. A maternal effect was revealed by greater resemblance of F1s than F2s to the P-generation. The observed synergistic effects of plastic, maternal and genetic control of shell-shape may be expected to maximise fitness when environmental characteristics become unpredictable through dispersal

The Blood of Healthy Individuals Exhibits CD8 T Cells with a Highly Altered TCR Vb Repertoire but with an Unmodified Phenotype

CD8 T cell clonal expansions (TCE) have been observed in elderly, healthy individuals as well in old mice, and have been associated with the ageing process. Both chronic latent and non-persistent viral infections have been proposed to drive the development of distinct non-functional and functional TCE respectively. Biases in TCR Vβ repertoire diversity are also recurrently observed in patients that have undergone strong immune challenge, and are preferentially observed in the CD8 compartment. Healthy adults can also exhibit CD8 T cells with strong alterations of their CDR3 length distribution. Surprisingly, no specific investigations have been conducted to analyze the CD8 T cell repertoire in normal adults, to determine if such alterations in TCR Vβ repertoire share the features of TCE. In this study, we characterized the phenotype and function of the CD8 population in healthy individuals of 25–52 years of age. All but one of the EBV-positive HLA-B8 healthy volunteers that were studied were CMV-negative. Using a specific unsupervised statistical method, we identified Vβ families with altered CDR3 length distribution and increased TCR Vβ/HPRT transcript ratios in all individuals tested. The increase in TCR Vβ/HPRT transcript ratio was more frequently associated with an increase in the percentage of the corresponding Vβ+ T cells than with an absence of modification of their percentage. However, in contrast with the previously described TCE, these CD8+ T cells were not preferentially found in the memory CD8 subset, they exhibited normal effector functions (cytokine secretion and cytotoxic molecule expression) and they were not reactive to a pool of EBV/CMV/Flu virus peptides. Taken together, the combined analysis of transcripts and proteins of the TCR Vβ repertoire led to the identification of different types of CD8+ T cell clone expansion or contraction in healthy individuals, a situation that appears more complex than previously described in aged individuals