XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome

The homeostasis of the immune response requires tight regulation of the proliferation and apoptosis of activated lymphocytes. In humans, defects in immune homeostasis result in lymphoproliferation disorders including autoimmunity, haemophagocytic lymphohystiocytosis and lymphomas. The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency that is characterized by lymphohystiocytosis, hypogammaglobulinaemia and lymphomas, and that usually develops in response to infection with Epstein-Barr virus (EBV). Mutations in the signalling lymphocyte activation molecule (SLAM)-associated protein SAP, a signalling adaptor molecule, underlie 60% of cases of familial XLP. Here, we identify mutations in the gene that encodes the X-linked inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from three families without mutations in SAP. These mutations lead to defective expression of XIAP. We show that apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli including the T-cell antigen receptor (TCR)-CD3 complex, the death receptor CD95 (also termed Fas or Apo-1) and the TNF-associated apoptosis-inducing ligand receptor (TRAIL-R). We also found that XIAP-deficient patients, like SAP-deficient patients, have low numbers of natural killer T-lymphocytes (NKT cells), indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP-deficiency and SAP-deficiency are both associated with a defect in NKT cells strengthens the hypothesis that NKT cells have a key role in the immune response to EBV. Furthermore, by identifying an XLP immunodeficiency that is caused by mutations in XIAP, we show that XIAP is a potent regulator of lymphocyte homeostasis in vivo.     

Gene therapy: X-SCID transgene leukaemogenicity

Gene therapy has been remarkably effective for the immunological reconstitution of patients with severe combined immune deficiency, but the occurrence of leukaemia in a few patients has stimulated debate about the safety of the procedure and the mechanisms of leukaemogenesis. Woods et al. forced high expression of the corrective therapeutic gene IL2RG, which encodes the gamma-chain of the interleukin-2 receptor, in a mouse model of the disease and found that tumours appeared in a proportion of cases. Here we show that transgenic IL2RG does not necessarily have potent intrinsic oncogenic properties, and argue that the interpretation of this observation with respect to human trials is overstated.     

Approximate analysis of variance of spatially autocorrelated regional data

The classical method for analysis of variance of data divided in geographic regions is impaired if the data are spatially autocorrelated within regions, because the condition of independence of the observations is not met. Positive autocorrelation reduces within-group variability, thus artificially increasing the relative amount of among-group variance. Negative autocorrelation may produce the opposite effect. This difficulty can be viewed as a loss of an unknown number of degrees of freedom. Such problems can be found in population genetics, in ecology and in other branches of biology, as well as in economics, epidemiology, geography, geology, marketing, political science, and sociology. A computer-intensive method has been developed to overcome this problem in certain cases. It is based on the computation of pooled within-group sums of squares for sampled permutations of internally connected areas on a map. The paper presents the theory, the algorithms, and results obtained using this method. A computer program, written in PASCAL, is available.This work was supported by NSERC grant no. A7738 to Pierre Legendre and by grant BSR 8614384 from the National Science Foundation to Robert R. Sokal. This is contribution No. 366 of the Groupe d'Ecologie des Eaux Douces, Université de Montréal, and contribution No. 727 in Ecology and Evolution from the State University of New York at Stony Brook.     

A new hominid from the Upper Miocene of Chad,Central Africa

The search for the earliest fossil evidence of the human lineage has been concentrated in East Africa. Here we report the discovery of six hominid specimens from Chad, central Africa, 2,500 km from the East African Rift Valley. The fossils include a nearly complete cranium and fragmentary lower jaws. The associated fauna suggest the fossils are between 6 and 7 million years old. The fossils display a unique mosaic of primitive and derived characters, and constitute a new genus and species of hominid. The distance from the Rift Valley, and the great antiquity of the fossils, suggest that the earliest members of the hominid clade were more widely distributed than has been thought, and that the divergence between the human and chimpanzee lineages was earlier than indicated by most molecular studies.     

IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice

Studies in invertebrates have led to the identification of a number of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signalling pathways. Examples include the related tyrosine kinase receptors InR (Drosophila melanogaster) and DAF-2 (Caenorhabditis elegans) that are homologues of the mammalian insulin-like growth factor type 1 receptor (IGF-1R). To investigate whether IGF-1R also controls longevity in mammals, we inactivated the IGF-1R gene in mice (Igf1r). Here, using heterozygous knockout mice because null mutants are not viable, we report that Igf1r(+/-) mice live on average 26% longer than their wild-type littermates (P < 0.02). Female Igf1r(+/-) mice live 33% longer than wild-type females (P < 0.001), whereas the equivalent male mice show an increase in lifespan of 16%, which is not statistically significant. Long-lived Igf1r(+/-) mice do not develop dwarfism, their energy metabolism is normal, and their nutrient uptake, physical activity, fertility and reproduction are unaffected. The Igf1r(+/-) mice display greater resistance to oxidative stress, a known determinant of ageing. These results indicate that the IGF-1 receptor may be a central regulator of mammalian lifespan.     

5-羟色胺在F344大鼠下丘脑释放及其免疫调节作用

在F344雄性大鼠腹腔注射血蓝蛋白(KLH),研究T 细胞依赖抗原初始免疫反应对中枢神经系统5 羟色胺(5 HT)代谢的影响。当免疫刺激大鼠4天后,其下丘脑匀浆5 羟色胺水平出现降低,同时应用在体脑微透析技术研究发现清醒大鼠腹腔注射血蓝蛋白4天后,其下丘脑前叶细胞外液的5 羟色胺水平增加。为了评价在免疫反应中大鼠下丘脑5 羟色胺释放效应,本文应用氯苯丙胺(PCA)选择性预先耗竭5 羟色胺释放,并测定这些动物在注射血蓝蛋白后抗体产生情况。结果显示在应用氯苯丙胺预处理的血蓝蛋白免疫动物特异抗体IgM和IgG与未用氯苯丙胺预处理的动物比较均有明显增加(P<0.01)。上述资料表明,对于T 细胞依赖抗原,其初始抗体产生的量是由位于下丘脑5 羟色胺神经终端抑制性递质释放所调节。     

Palaeogeography: Devonian tetrapod from western Europe

Several discoveries of Late Devonian tetrapods (limbed vertebrates) have been made during the past two decades, but each has been confined to one locality. Here we describe a tetrapod jaw of about 365 million years (Myr) old from the Famennian of Belgium, which is the first from western continental Europe. The jaw closely resembles that of Ichthyostega, a Famennian tetrapod hitherto known only from Greenland. The environment of this fossil provides information about the conditions that prevailed just before the virtual disappearance of tetrapods from the fossil record for 20 Myr.     

The Metric Bridge Partition Problem: Partitioning of a Metric Space into Two Subspaces Linked by an Edge in Any Optimal Realization

Let G = (V,E,w) be a graph with vertex and edge sets V and E, respectively, and w:E → R ⁺ a function which assigns a positive weight or length to each edge of G. G is called a realization of a finite metric space (M,d), with M = { 1,...,n} if and only if { 1,...,n} ⫅ V and d(i,j) is equal to the length of the shortest chain linking i and j in G ∀ i,j = 1,...,n. A realization G of (M,d), is said optimal if the sum of its weights is minimal among all the realizations of (M,d). Consider a partition of M into two nonempty subsets K and L, and let e be an edge in a realization G of (M,d); we say that e is a bridge linking K with L if e belongs to all chains in G linking a vertex of K with a vertex of L. The Metric Bridge Partition Problem is to determine if the elements of a finite metric space (M,d) can be partitioned into two nonempty subsets K and L such that all optimal realizations of (M,d) contain a bridge linking K with L. We prove in this paper that this problem is polynomially solvable. We also describe an algorithm that constructs an optimal realization of (M,d) from optimal realizations of (K,d|_K) and (L,d|_L).     

Redox evolution of a degassing magma rising to the surface

Volatiles carried by magmas, either dissolved or exsolved, have a fundamental effect on a variety of geological phenomena, such as magma dynamics and the composition of the Earth's atmosphere. In particular, the redox state of volcanic gases emanating at the Earth's surface is widely believed to mirror that of the magma source, and is thought to have exerted a first-order control on the secular evolution of atmospheric oxygen. Oxygen fugacity (f(O2) estimated from lava or related gas chemistry, however, may vary by as much as one log unit, and the reason for such differences remains obscure. Here we use a coupled chemical-physical model of conduit flow to show that the redox state evolution of an ascending magma, and thus of its coexisting gas phase, is strongly dependent on both the composition and the amount of gas in the reservoir. Magmas with no sulphur show a systematic f(O2) increase during ascent, by as much as 2 log units. Magmas with sulphur show also a change of redox state during ascent, but the direction of change depends on the initial f(O2) in the reservoir. Our calculations closely reproduce the H2S/SO2 ratios of volcanic gases observed at convergent settings, yet the difference between f(O2) in the reservoir and that at the exit of the volcanic conduit may be as much as 1.5 log units. Thus, the redox state of erupted magmas is not necessarily a good proxy of the redox state of the gases they emit. Our findings may require re-evaluation of models aimed at quantifying the role of magmatic volatiles in geological processes.