宇宙是一架时间机

时-空中存在环路，未来能够影响过去。物理学家马克·哈德利确信：宇宙正是这样工作的。本文作者（科学撰稿则对他作了专访。1992年，M·哈德利（MarkHadley）处在十字路口。他从事电子工业10多年，具有敏锐的商业感觉，因取得成就而闻名。他的发展纪录是独一无二的，成功鼓舞着他去组建自己的软件公司，前途无量。虽然如此，可另有一些奇怪的问题始终京回他的脑际。这些问题同他的公司前景无关。这类问题只有在大学里才值得让人们去思考：什么是电子？什么是光子？到底什么是位于？“奇怪的是”，哈德利说，“几乎没有哪个物理学家提出这…     

Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population

Objective： A study in a Caucasian population has identified two single-nucleotide polymorphisms （SNPs） in ZNF533, one in DOCK4, and two in IMMP2L, which were all significantly associated with autism. They are located in AUTS1 and AUTS5, which have been identified as autism susceptibility loci in several genome-wide screens. The present study aimed to investigate whether ZNF533, DOCK4, and IMMP2L genes are also associated with autism in a northeastern Chinese Han population. Methods： We performed a similar association study using families with three individuals （one autistic child and two unaffected parents）. A family-based transmission disequilibrium test （TDT） was used to analyze the results. Results： There were significant associations between autism and the two SNPs of ZNF533 gene （rs11885327： X^2=4.5200, P=0.0335; rs1964081 ：）（2=4.2610, P=0.0390） and the SNP of DOCK4 gene （rs2217262 X^2=5.3430, P=0.0208）. Conclusions： Our data suggest that ZNF533 and DOCK4 genes are linked to a predisposition to autism in the northeastern Chinese Han population.     

PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression

Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.     

Macro domains as metabolite sensors on chromatin

How metabolism and epigenetics are molecularly linked and regulate each other is poorly understood. In this review, we will discuss the role of direct metabolite-binding to chromatin components and modifiers as a possible regulatory mechanism. We will focus on globular macro domains, which are evolutionarily highly conserved protein folds that can recognize NAD⁺-derived metabolites. Macro domains are found in histone variants, histone modifiers, and a chromatin remodeler among other proteins. Here we summarize the macro domain-containing chromatin proteins and the enzymes that generate relevant metabolites. Focusing on the histone variant macroH2A, we further discuss possible implications of metabolite binding for chromatin function.     

Mast cells promote homeostasis by limiting endothelin-1-induced toxicity

Endothelin-1 (ET-1) is a 21-amino-acid peptide, derived from vascular endothelial cells, with potent vasoconstrictor activity. ET-1 has been implicated in diverse physiological or pathological processes, including the vascular changes associated with sepsis. However, the factors that regulate ET-1-associated toxicity during bacterial infections, or in other settings, are not fully understood. Both the pathology associated with certain allergic and autoimmune disorders, and optimal host defence against bacterial and parasitic infections are mediated by mast cells. In vitro, mast cells can produce ET-1 (ref. 11), undergo ET-1-dependent and endothelin-A receptor (ET(A))-dependent activation, and release proteases that degrade ET-1 (ref. 14). Although the potential relationships between mast cells and the ET-1 system thus may be complex, the importance of interactions between ET-1 and mast cells in vivo is obscure. Here we show that ET(A)-dependent mast-cell activation can diminish both ET-1 levels and ET-1-induced pathology in vivo, and also can contribute to optimal survival during acute bacterial peritonitis. These findings identify a new biological function for mast cells: promotion of homeostasis by limiting the toxicity associated with an endogenous mediator.     

Self-organization of dissolved organic matter to micelle-like microparticles in river water

In aquatic systems, the concept of the 'microbial loop' is invoked to describe the conversion of dissolved organic matter to particulate organic matter by bacteria. This process mediates the transfer of energy and matter from dissolved organic matter to higher trophic levels, and therefore controls (together with primary production) the productivity of aquatic systems. Here we report experiments on laboratory incubations of sterile filtered river water in which we find that up to 25% of the dissolved organic carbon (DOC) aggregates abiotically to particles of diameter 0.4-0.8 micrometres, at rates similar to bacterial growth. Diffusion drives aggregation of low- to high-molecular-mass DOC and further to larger micelle-like microparticles. The chemical composition of these microparticles suggests their potential use as food by planktonic bacterivores. This pathway is apparent from differences in the stable carbon isotope compositions of picoplankton and the microparticles. A large fraction of dissolved organic matter might therefore be channelled through microparticles directly to higher trophic levels--bypassing the microbial loop--suggesting that current concepts of carbon conversion in aquatic systems require revision.     

Spontaneous emergence of leaders and followers in foraging pairs

Animals that forage socially often stand to gain from coordination of their behaviour. Yet it is not known how group members reach a consensus on the timing of foraging bouts. Here we demonstrate a simple process by which this may occur. We develop a state-dependent, dynamic game model of foraging by a pair of animals, in which each individual chooses between resting or foraging during a series of consecutive periods, so as to maximize its own individual chances of survival. We find that, if there is an advantage to foraging together, the equilibrium behaviour of both individuals becomes highly synchronized. As a result of this synchronization, differences in the energetic reserves of the two players spontaneously develop, leading them to adopt different behavioural roles. The individual with lower reserves emerges as the 'pace-maker' who determines when the pair should forage, providing a straightforward resolution to the problem of group coordination. Moreover, the strategy that gives rise to this behaviour can be implemented by a simple 'rule of thumb' that requires no detailed knowledge of the state of other individuals.     

cdx4 mutants fail to specify blood progenitors and can be rescued by multiple hox genes

Organogenesis is dependent on the formation of distinct cell types within the embryo. Important to this process are the hox genes, which are believed to confer positional identities to cells along the anteroposterior axis. Here, we have identified the caudal-related gene cdx4 as the locus mutated in kugelig (kgg), a zebrafish mutant with an early defect in haematopoiesis that is associated with abnormal anteroposterior patterning and aberrant hox gene expression. The blood deficiency in kgg embryos can be rescued by overexpressing hoxb7a or hoxa9a but not hoxb8a, indicating that the haematopoietic defect results from perturbations in specific hox genes. Furthermore, the haematopoietic defect in kgg mutants is not rescued by scl overexpression, suggesting that cdx4 and hox genes act to make the posterior mesoderm competent for blood development. Overexpression of cdx4 during zebrafish development or in mouse embryonic stem cells induces blood formation and alters hox gene expression. Taken together, these findings demonstrate that cdx4 regulates hox genes and is necessary for the specification of haematopoietic cell fate during vertebrate embryogenesis.