Phenobarbital and SKF-525A on vinblastine and vincristine toxicity in mice

Summary The effect of SKF-525A and phenobarbirtal on the LD₅₀ values of vinblastine and vincristine suggests that the toxicity of these agents in mice does not arise from a toxic metabolite.This work was supported by PHS Grant No. GM 15956. The author wishes to thankMary-Lucille Mantz for her valuable technical assistance and the Eli Lilly Company for graciously providing generous samples of VLB and VCR. The ample gift of SKF-525A from Smith, Kline and French Laboratories is also gratefully acknowledged.     

Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1

The crystal structure of the protease of the human immunodeficiency virus type (HIV-1), which releases structural proteins and enzymes from viral polyprotein products, has been determined to 3 A resolution. Large regions of the protease dimer, including the active site, have structural homology to the family of microbial aspartyl proteases. The structure suggests a mechanism for the autoproteolytic release of protease and a role in the control of virus maturation.     

Pliocene eclogite exhumation at plate tectonic rates in eastern Papua New Guinea

As lithospheric plates are subducted, rocks are metamorphosed under high-pressure and ultrahigh-pressure conditions to produce eclogites and eclogite facies metamorphic rocks. Because chemical equilibrium is rarely fully achieved, eclogites may preserve in their distinctive mineral assemblages and textures a record of the pressures, temperatures and deformation the rock was subjected to during subduction and subsequent exhumation. Radioactive parent-daughter isotopic variations within minerals reveal the timing of these events. Here we present in situ zircon U/Pb ion microprobe data that dates the timing of eclogite facies metamorphism in eastern Papua New Guinea at 4.3 +/- 0.4 Myr ago, making this the youngest documented eclogite exposed at the Earth's surface. Eclogite exhumation from depths of approximately 75 km was extremely rapid and occurred at plate tectonic rates (cm yr(-1)). The eclogite was exhumed within a portion of the obliquely convergent Australian-Pacific plate boundary zone, in an extending region located west of the Woodlark basin sea floor spreading centre. Such rapid exhumation (> 1 cm yr(-1)) of high-pressure and, we infer, ultrahigh-pressure rocks is facilitated by extension within transient plate boundary zones associated with rapid oblique plate convergence.     

热轧带钢层流冷却设定模型的开发与实现

分析了热轧带钢层流冷却的传热过程,基于传热过程给出了冷却控制的空冷和水冷温降计算模型,该模型为线性回归模型,不同于理论的指数温降模型,回归数据取自于现场,更具有实用性,具有模型结构简单、精度高的特点·对层流冷却的设定计算(预设定和修正设定计算)的程序实现方法进行了详细描述,讨论了层流冷却系统中的组别划分,并给出了冷却控制系统的数据流程·本系统的冷却能力强,具有较宽的冷却速率调整范围,运行情况以及使用控制效果良好,能满足现场生产以及新品种开发的要求·     

NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1β and neuronal toxicity

Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1β has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1β upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K⁺, and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL-1 signaling pathway as the perspective target for the therapy of prion disease.     

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10?? and two loci with a combined P < 5 × 10??). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10??). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.     

Evolution Made to Order: Plant Breeding and Technological Innovation in Twentieth-Century America

The last charcoal iron blast furnace in the United States shut down in 1945. The most obvious reason for the extraordinary longevity of this industry was the almost unlimited supply of virgin timber in the United States. Although an obvious explanation, it is deceptive. The much more crucial reason for the longevity of the American charcoal iron industry was the technical difficulties involved in adapting coke- and coal-smelted iron to existing industrial processes. Until these technological problems could be overcome, charcoal iron was able to preserve a place for itself in the industrial environment of the late 19th and early 20th centuries. By concentrating their attention on the rapid advance of coke-smelted iron from 1870 onward, historians of the American iron industry have neglected this ability of the older iron technology to adapt to the new industrial conditions.