Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics

Integrins are important adhesion receptors in all Metazoa that transmit conformational change bidirectionally across the membrane. Integrin alpha and beta subunits form a head and two long legs in the ectodomain and span the membrane. Here, we define with crystal structures the atomic basis for allosteric regulation of the conformation and affinity for ligand of the integrin ectodomain, and how fibrinogen-mimetic therapeutics bind to platelet integrin alpha(IIb)beta3. Allostery in the beta3 I domain alters three metal binding sites, associated loops and alpha1- and alpha7-helices. Piston-like displacement of the alpha7-helix causes a 62 degrees reorientation between the beta3 I and hybrid domains. Transmission through the rigidly connected plexin/semaphorin/integrin (PSI) domain in the upper beta3 leg causes a 70 A separation between the knees of the alpha and beta legs. Allostery in the head thus disrupts interaction between the legs in a previously described low-affinity bent integrin conformation, and leg extension positions the high-affinity head far above the cell surface.     

Environmental predictors of pre-European deforestation on Pacific islands

Some Pacific island societies, such as those of Easter Island and Mangareva, inadvertently contributed to their own collapse by causing massive deforestation. Others retained forest cover and survived. How can those fateful differences be explained? Although the answers undoubtedly involve both different cultural responses of peoples and different susceptibilities of environments, how can one determine which environmental factors predispose towards deforestation and which towards replacement of native trees with useful introduced tree species? Here we code European-contact conditions and nine environmental variables for 81 sites on 69 Pacific islands from Yap in the west to Easter in the east, and from Hawaii in the north to New Zealand in the south. We thereby detect statistical decreases in deforestation and/or forest replacement with island rainfall, elevation, area, volcanic ash fallout, Asian dust transport and makatea terrain (uplifted reef), and increases with latitude, age and isolation. Comparative analyses of deforestation therefore lend themselves to much more detailed interpretations than previously possible. These results might be relevant to similar deforestation-associated collapses (for example, Fertile Crescent, Maya and Anasazi) or the lack thereof (Japan and highland New Guinea) elsewhere in the world.     

Contrasting origins of the upper mantle revealed by hafnium and lead isotopes from the Southeast Indian Ridge

The origin of the isotopic signature of Indian mid-ocean ridge basalts has remained enigmatic, because the geochemical composition of these basalts is consistent either with pollution from recycled, ancient altered oceanic crust and sediments, or with ancient continental crust or lithosphere. The radiogenic isotopic signature may therefore be the result of contamination of the upper mantle by plumes containing recycled altered ancient oceanic crust and sediments, detachment and dispersal of continental material into the shallow mantle during rifting and breakup of Gondwana, or contamination of the upper mantle by ancient subduction processes. The identification of a process operating on a scale large enough to affect major portions of the Indian mid-ocean ridge basalt source region has been a long-standing problem. Here we present hafnium and lead isotope data from across the Indian-Pacific mantle boundary at the Australian-Antarctic discordance region of the Southeast Indian Ridge, which demonstrate that the Pacific and Indian upper mantle basalt source domains were each affected by different mechanisms. We infer that the Indian upper-mantle isotope signature in this region is affected mainly by lower continental crust entrained during Gondwana rifting, whereas the isotope signature of the Pacific upper mantle is influenced predominantly by ocean floor subduction-related processes.     

MYH9 is associated with nondiabetic end-stage renal disease in African Americans

As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.     

Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor

Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor. We explored their possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.     

基于科学思维的英语文学教学:跨学科的视角

本文阐述基于科学思维过程的英语文学教学策略,即英语文学作品以综合课程的形式应用于教学实践活动.其要点是从优秀文学作品中选取需要解决问题的情境,从跨学科的视角来审视作品中的矛盾和冲突.教师们通过分析这些问题情境教给学生科学的思维方法.其教学策略的重点在于提出问题和做出决策.这些用于跨学科教学策略的文学作品是关注真实世界的起点.生活中面临的两难问题通过基于科学思维的文学教学而获得理性的解释或合理的解决.     

Application of Teleonic Principles in the Search for Systemic Causes of Accidents in Anesthesia

Safety of patients in anesthesia has always been one of the major concerns of the anesthetist. It is clear from studies of safety in general that many accidents and critical incidents occur as the result of latent systemic failures to which a great number of factors contribute (Reason, 1990). An ideal way to approach this problem would be within a systemic framework, such as teleonics, developed by Járos and his co-workers (Cloete, 1999; Járos and Cloete, 1987, 1993). In this framework the events and procedures in anesthesia are considered to be part of a very complex network of process systems (teleons). It is postulated that teleonic uncertainty (telentropy) in this complex network is a factor that might lead to accidents. In a previous paper presented to the World Congress at Toronto in 2000, the principles of teleonics were described in a mathematico symbolic way (Horváth et al., 2000). This paper contains selected examples of application of these principles to the identification of possible systemic causes of accidents in anesthesia.     

Antibodies to a scrapie prion protein

Scrapie is a slow infection of the nervous system which progresses in the absence of any apparent immune response. The recent development of a large-scale purification protocol for scrapie prions made it possible to obtain substantial quantities of electrophoretically purified prion protein (PrP 27-30) and we report here on the successful production of a rabbit antiserum to PrP 27-30. The antiserum reacted with PrP 27-30 and several lower molecular weight proteins as shown by Western blots; it did not react with protein preparations from uninfected brains. Discrete structures in the subependymal region of scrapie-infected hamster brains were stained immunocytochemically. These same structures also stained with Congo red dye and showed green birefringence with polarized light, a characteristic of purified prion rods. This staining pattern suggests that they are amyloid plaques.