对抗感染 动物有高招

<正>人类在一刻不停地与疾病作战。我们朝细菌发射抗生素导弹,向病毒投掷疫苗形状的手雷,把抗菌肥皂和洗手液做成的炸弹扔到所有能扔到的东西上。人类和寄生物(这是个涵盖了病毒、细菌以及大得多的寄生生物的统称)之间的斗争有着古老的根源。和猎食者、干旱或者饥荒一样,这种斗争对演化施加着强大的力量。其他物种当然也面临着类似的威胁,一说起人     

Near-isothermal conditions in the middle and lower crust induced by melt migration

The thermal structure of the crust strongly influences deformation, metamorphism and plutonism. Models for the geothermal gradient in stable crust predict a steady increase of temperature with depth. This thermal structure, however, is incompatible with observations from high-temperature metamorphic terranes exhumed in orogens. Global compilations of peak conditions in high-temperature metamorphic terranes define relatively narrow ranges of peak temperatures over a wide range in pressure, for both isothermal decompression and isobaric cooling paths. Here we develop simple one-dimensional thermal models that include the effects of melt migration. These models show that long-lived plutonism results in a quasi-steady-state geotherm with a rapid temperature increase in the upper crust and nearly isothermal conditions in the middle and lower crust. The models also predict that the upward advection of heat by melt generates granulite facies metamorphism, and widespread andalusite-sillimanite metamorphism in the upper crust. Once the quasi-steady-state thermal profile is reached, the middle and lower crust are greatly weakened due to high temperatures and anatectic conditions, thus setting the stage for gravitational collapse, exhumation and isothermal decompression after the onset of plutonism. Near-isothermal conditions in the middle and lower crust result from the thermal buffering effect of dehydration melting reactions that, in part, control the shape of the geotherm.     

A stem batrachian from the Early Permian of Texas and the origin of frogs and salamanders

The origin of extant amphibians (Lissamphibia: frogs, salamanders and caecilians) is one of the most controversial questions in vertebrate evolution, owing to large morphological and temporal gaps in the fossil record. Current discussions focus on three competing hypotheses: a monophyletic origin within either Temnospondyli or Lepospondyli, or a polyphyletic origin with frogs and salamanders arising among temnospondyls and caecilians among the lepospondyls. Recent molecular analyses are also controversial, with estimations for the batrachian (frog-salamander) divergence significantly older than the palaeontological evidence supports. Here we report the discovery of an amphibamid temnospondyl from the Early Permian of Texas that bridges the gap between other Palaeozoic amphibians and the earliest known salientians and caudatans from the Mesozoic. The presence of a mosaic of salientian and caudatan characters in this small fossil makes it a key taxon close to the batrachian (frog and salamander) divergence. Phylogenetic analysis suggests that the batrachian divergence occurred in the Middle Permian, rather than the late Carboniferous as recently estimated using molecular clocks, but the divergence with caecilians corresponds to the deep split between temnospondyls and lepospondyls, which is congruent with the molecular estimates.     

Template-directed synthesis of a genetic polymer in a model protocell

Contemporary phospholipid-based cell membranes are formidable barriers to the uptake of polar and charged molecules ranging from metal ions to complex nutrients. Modern cells therefore require sophisticated protein channels and pumps to mediate the exchange of molecules with their environment. The strong barrier function of membranes has made it difficult to understand the origin of cellular life and has been thought to preclude a heterotrophic lifestyle for primitive cells. Although nucleotides can cross dimyristoyl phosphatidylcholine membranes through defects formed at the gel-to-liquid transition temperature, phospholipid membranes lack the dynamic properties required for membrane growth. Fatty acids and their corresponding alcohols and glycerol monoesters are attractive candidates for the components of protocell membranes because they are simple amphiphiles that form bilayer membrane vesicles that retain encapsulated oligonucleotides and are capable of growth and division. Here we show that such membranes allow the passage of charged molecules such as nucleotides, so that activated nucleotides added to the outside of a model protocell spontaneously cross the membrane and take part in efficient template copying in the protocell interior. The permeability properties of prebiotically plausible membranes suggest that primitive protocells could have acquired complex nutrients from their environment in the absence of any macromolecular transport machinery; that is, they could have been obligate heterotrophs.     

Structure and mechanism of the M2 proton channel of influenza A virus

The integral membrane protein M2 of influenza virus forms pH-gated proton channels in the viral lipid envelope. The low pH of an endosome activates the M2 channel before haemagglutinin-mediated fusion. Conductance of protons acidifies the viral interior and thereby facilitates dissociation of the matrix protein from the viral nucleoproteins--a required process for unpacking of the viral genome. In addition to its role in release of viral nucleoproteins, M2 in the trans-Golgi network (TGN) membrane prevents premature conformational rearrangement of newly synthesized haemagglutinin during transport to the cell surface by equilibrating the pH of the TGN with that of the host cell cytoplasm. Inhibiting the proton conductance of M2 using the anti-viral drug amantadine or rimantadine inhibits viral replication. Here we present the structure of the tetrameric M2 channel in complex with rimantadine, determined by NMR. In the closed state, four tightly packed transmembrane helices define a narrow channel, in which a 'tryptophan gate' is locked by intermolecular interactions with aspartic acid. A carboxy-terminal, amphipathic helix oriented nearly perpendicular to the transmembrane helix forms an inward-facing base. Lowering the pH destabilizes the transmembrane helical packing and unlocks the gate, admitting water to conduct protons, whereas the C-terminal base remains intact, preventing dissociation of the tetramer. Rimantadine binds at four equivalent sites near the gate on the lipid-facing side of the channel and stabilizes the closed conformation of the pore. Drug-resistance mutations are predicted to counter the effect of drug binding by either increasing the hydrophilicity of the pore or weakening helix-helix packing, thus facilitating channel opening.     

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.     

Enantioselective silyl protection of alcohols catalysed by an amino-acid-based small molecule

Reliable, selective and environmentally friendly chemical transformations are crucial to the development of new therapeutics and the design of novel materials. Chiral catalysts that can be easily prepared and used to obtain organic molecules of high enantiomeric purity are critical to modern chemical synthesis. The development of protecting groups that shield reactive functionalities has also proved indispensable in the preparation of complex biologically active molecules. Here we present a chiral catalyst that promotes the enantioselective protection of a secondary alcohol as one of the most commonly used protected forms of an alcohol: a silyl ether. The catalyst is a small, simple molecule that can be prepared in three steps from commercial materials without the need for rigorously controlled conditions. Enantioselective silylations are performed with commercial silyl chlorides and produce yields of up to 96 per cent at an enantiomeric ratio of up to 98:2. Chiral catalysts for selective formation of commonly used protecting groups such as silyl ethers should significantly enhance the ability of chemical synthesis to deliver, in a more practical and efficient manner, important organic molecules.     

Kemp elimination catalysts by computational enzyme design

The design of new enzymes for reactions not catalysed by naturally occurring biocatalysts is a challenge for protein engineering and is a critical test of our understanding of enzyme catalysis. Here we describe the computational design of eight enzymes that use two different catalytic motifs to catalyse the Kemp elimination-a model reaction for proton transfer from carbon-with measured rate enhancements of up to 10(5) and multiple turnovers. Mutational analysis confirms that catalysis depends on the computationally designed active sites, and a high-resolution crystal structure suggests that the designs have close to atomic accuracy. Application of in vitro evolution to enhance the computational designs produced a >200-fold increase in k(cat)/K(m) (k(cat)/K(m) of 2,600 M(-1)s(-1) and k(cat)/k(uncat) of >10(6)). These results demonstrate the power of combining computational protein design with directed evolution for creating new enzymes, and we anticipate the creation of a wide range of useful new catalysts in the future.