Inhibition by warfarin of prothrombin synthesis and of lipid-saccharide synthesis in rat liver

In vivo and in vitro studies using [³H]glucosamine incorporation into prothrombin and into glycolipids were conducted in rat liver to determine the role of lipid-saccharides in the biosynthesis of prothrombin.In vivo studies demonstrated that 10 mg warfarin/kg inhibited the incorporation of radiolabeled glucosamine into liver prothrombin and glycolipids. This inhibition was similar to the kinetics of inhibition of prothrombin synthesis in the liver.In vitro studies demonstrated a time-dependent increase in the incorporation of radiolabeled glucosamine into lipid-saccharides and prothrombin. This incorporation was inhibited 50% by 5 · 10^?4 M warfarin. Warfarin also inhibited the incorporation of radiolabeled glucosamine into glycolipids in a dose-related manner.In all studies, vitamin K-1 reversed the inhibition of glucosamine incorporation into glycolipids and into prothrombin.     

Development of a system for simultaneous dissolution studies and magnetic resonance imaging of water transport in hydrodynamically balanced systems: A technical note

Summary and Conclusions  Without disturbing the observed processes, the MRI methods combined with the dissolution studies provide insight into the phenomena occurring when the dosage form comes into contact with aqueous fluids. The MR images allow one to observe the solvent penetration into the hydrophilic matrix and the hydrogel formation. The data obtained in the MRI studies complement information obtained from the dissolution studies. The analysis of MR images may support the explanation of differences in the drug-releasing or floating properties of HBS. Published: February 23, 2007     

The Synthesis of Ribosomes in E. coli: IV. The Synthesis of Ribosomal Protein and the Assembly of Ribosomes

The incorporation of C¹⁴ leucine into the protein moiety of ribosomes has been studied as a sequel to the studies of ribosomal RNA synthesis. In contrast to the latter studies, labeled leucine is incorporated directly into 50S and 30S ribosomes without measurable delay by precursor stages. There is, however, evidence of some transfer of radioactivity from the 43S group of particles to the 50S. The inhibition of protein synthesis by chloramphenicol results in the accumulation of material similar to the eosome—the primary precursor in ribosome synthesis. There is also evidence for the synthesis of some neosome. The results of the studies of ribosomal RNA and protein synthesis are combined into a model of ribosome synthesis. Finally, consideration is made of the significance of these studies of ribosome synthesis for general problems of protein synthesis and information transfer.     

Nucleotide excision repair in chromatin: the shape of things to come

Much of our mechanistic understanding of nucleotide excision repair (NER) has been derived from biochemical studies that have analysed the reaction as it occurs on DNA substrates that are not representative of DNA as it exists in the living cell. These studies have been extremely useful in deciphering the core mechanism of the NER reaction, but efforts to understand how NER operates in chromatin have been hampered in part because assembling DNA into nucleosomes, the first level of chromatin compaction, is inhibitory to NER in vitro. However, recent research using biochemical, genetic and cell-based studies is now providing us with the first insights into the molecular mechanism of NER as it occurs in the cellular context. A number of recent studies have provided glimpses of a chromatin--NER connection. Here I review this literature and evaluate how it might aid our understanding, and shape our future research into NER.     

Kallmann syndrome: adhesion,afferents, and anosmia

Three new studies into the function of human anosmin-1 and related proteins in C. elegans and rodents show that these influence axon branching and axon targeting. The rodent anosmin appears to work at two stages of development, initially promoting axon outgrowth from the olfactory bulb and then stimulating branching from axons into the olfactory cortex. CeKal-1 further influences morphogenesis, and, as the human and nematode anosmins are functionally conserved, these studies provide insights into the pathogenesis of Kallmann syndrome (KS).     

Enzymes with extra talents: moonlighting functions and catalytic promiscuity

Recent studies of moonlighting functions and catalytic promiscuity provide insights into the structural and mechanistic bases of these phenomena. Moonlighting proteins that are highlighted include gephyrin, the Neurospora crassa tyrosyl tRNA synthetase, phosphoglucose isomerase, and cytochrome c. New insights into catalytic promiscuity are provided by studies of aminoglycoside kinase (3') type IIIa, tetrachlorohydroquinone dehalogenase, and aldolase antibody 38C2.     

Altered gravity effects on mothers and offspring: the importance of maternal behavior

In this paper, I review and discuss recent studies of pregnant, parturient and lactating rat mothers and neonates exposed to hypo- and hypergravity. These studies are revealing new insights into how deviations form Earth-normal gravity may affect fundamental reproductive and ontogenetic processes in mammals. By way of background, I will first briefly summarize the spaceflights that have carried mammalian mothers and their offspring into space.     

造礁石珊瑚群落结构研究的概况,问题和前景

造礁石珊瑚作为珊瑚礁生态系统中的关键生物类群,其群落结构是珊瑚礁系统研究中的一个重 要方面。本文回顾了20余年以来世界各国对造礁石珊瑚群落结构研究所取得的主要进展和认识,指出了目前研究中存在的问题并分析了不同空间范围研究结论之间的缺乏一致性和中等干扰假说的不足。 最后,结合珊瑚礁生态系统基础理论和应用发展的需求,本文探讨了造礁石珊瑚群落结构研究的前景。     

成体干细胞可塑性的事实、质疑和展望

成体干细胞的可塑性是指存在于成年组织或器官中的不成熟细胞跨胚层分化的一种能力。近年来相关研究很多,有人认为成体干细胞具有可塑性,如造血干细胞可以分化为神经外胚层细胞和内胚层细胞：有人对其持怀疑态度,认为成年造血干细胞发育可塑性证据不足,成体干细胞不能跨胚层分化。由于分离纯化、检测手段等的局限,大多数研究均存在这样或那样的不足和误区,彻底研究清楚还有很长的路要走。     

Liposome encapsulated tetracaine lowers blood glucose

Tetracaine, a local anesthetic, was previously shown to block hormonal stimulation of gluconeogenesis and glycogenolysis ( Friedmann , N. and Rasmussen, H. (1970) Biochim. Biophys. Acta 222, 41-52). In the present studies tetracaine incorporated into liposomes (phospholipid vesicles) was injected into intact rats and epinephrine was administered an hour later. Liposomal tetracaine blocked 50% of the hyperglycemic response. When tetracaine, incorporated into liposomes, was injected into diabetic rats it reduced transiently, but significantly, blood glucose levels. Equivalent doses of free tetracaine were toxic. These studies indicate that liposomal drug administration might be developed into a tool to influence hepatic metabolism and, consequently, blood glucose levels.     

The combined effects of delay and probability in discounting

Human discounting studies have frequently observed hyperbolic discounting of rewards that are delayed or probabilistic. However, no studies have systematically combined delay and probability in a single discounting procedure. Indifference points of hypothetical money rewards that are both delayed and probabilistic were determined. Probabilities were converted into comparable delays according to the h/k constant of proportionality determined by , and discounting rates were calculated. These data provided a very good fit to the hyperbolic model of discounting, suggesting that delay and probability can be combined into a single metric in studies of discounting. The inclusion of a magnitude condition found the Magnitude Effect commonly found in studies of temporal discounting. A temporal resolution of uncertainty condition found no effect. The present paper offers a novel statistical method, within an established framework, for the analysis of data from studies of discounting that combine delay and probability.     

Entry pathways of herpes simplex virus type 1 into human keratinocytes are dynamin- and cholesterol-dependent

Herpes simplex virus type 1 (HSV-1) can enter cells via endocytic pathways or direct fusion at the plasma membrane depending on the cell line and receptor(s). Most studies into virus entry have used cultured fibroblasts but since keratinocytes represent the primary entry site for HSV-1 infection in its human host, we initiated studies to characterize the entry pathway of HSV-1 into human keratinocytes. Electron microscopy studies visualized free capsids in the cytoplasm and enveloped virus particles in vesicles suggesting viral uptake both by direct fusion at the plasma membrane and by endocytic vesicles. The ratio of the two entry modes differed in primary human keratinocytes and in the keratinocyte cell line HaCaT. Inhibitor studies further support a role for endocytosis during HSV-1 entry. Infection was inhibited by the cholesterol-sequestering drug methyl-β-cyclodextrin, which demonstrates the requirement for host cholesterol during virus entry. Since the dynamin-specific inhibitor dynasore and overexpression of a dominant-negative dynamin mutant blocked infection, we conclude that the entry pathways into keratinocytes are dynamin-mediated. Electron microscopy studies confirmed that virus uptake is completely blocked when the GTPase activity of dynamin is inhibited. Ex vivo infection of murine epidermis that was treated with dynasore further supports the essential role of dynamin during entry into the epithelium. Thus, we conclude that HSV-1 can enter human keratinocytes by alternative entry pathways that require dynamin and host cholesterol.     

Transposable elements as introns: evolutionary connections

Recent molecular genetic studies demonstrate that many transposable elements, when inserted into nuclear genes, can behave as introns and create novel intron processing patterns. These studies point to possible mechanisms by which transposable element insertions participate in the evolutionary diversification of gene structure, the rise of alternative splicing patterns and the production of novel regulatory interactions. Moreover, they provide us with fresh insights into the evolutionary dynamics of these mobile sequences.     

Natural history collections as windows on evolutionary processes

Natural history collections provide an immense record of biodiversity on Earth. These repositories have traditionally been used to address fundamental questions in biogeography, systematics and conservation. However, they also hold the potential for studying evolution directly. While some of the best direct observations of evolution have come from long‐term field studies or from experimental studies in the laboratory, natural history collections are providing new insights into evolutionary change in natural populations. By comparing phenotypic and genotypic changes in populations through time, natural history collections provide a window into evolutionary processes. Recent studies utilizing this approach have revealed some dramatic instances of phenotypic change over short timescales in response to presumably strong selective pressures. In some instances, evolutionary change can be paired with environmental change, providing a context for potential selective forces. Moreover, in a few cases, the genetic basis of phenotypic change is well understood, allowing for insight into adaptive change at multiple levels. These kinds of studies open the door to a wide range of previously intractable questions by enabling the study of evolution through time, analogous to experimental studies in the laboratory, but amenable to a diversity of species over longer timescales in natural populations.     

WHO research agenda for radiofrequency fields

The World Health Organization (WHO) has recently published a new research agenda for radiofrequency fields. The document lists high priority and other research needs for health effects research, subdivided into epidemiology, human studies, animal studies, cellular studies and mechanisms, and for social science research.     

BR-squared: a practical solution to the winner’s curse in genome-wide scans

The detrimental effects of the winner’s curse, including overestimation of the genetic effects of associated variants and underestimation of sufficient sample sizes for replication studies are well-recognized in genome-wide association studies (GWAS). These effects can be expected to worsen as the field moves from GWAS into whole genome sequencing. To date, few studies have reported statistical adjustments to the naive estimates, due to the lack of suitable statistical methods and computational tools. We have developed an efficient genome-wide non-parametric method that explicitly accounts for the threshold, ranking, and allele frequency effects in whole genome scans. Here, we implement the method to provide bias-reduced estimates via bootstrap re-sampling (BR-squared) for association studies of both disease status and quantitative traits, and we report the results of applying BR-squared to GWAS of psoriasis and HbA1c. We observed over 50% reduction in the genetic effect size estimation for many associated SNPs. This translates into a greater than fourfold increase in sample size requirements for successful replication studies, which in part explains some of the apparent failures in replicating the original signals. Our analysis suggests that adjusting for the winner’s curse is critical for interpreting findings from whole genome scans and planning replication and meta-GWAS studies, as well as in attempts to translate findings into the clinical setting.