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Heterogeneous ribonucleoprotein A1 (hnRNP A1) is an abundant nuclear protein that participates in RNA processing, alternative splicing, and chromosome maintenance. hnRNP A1 can be proteolyzed to unwinding protein (UP1), a 22.1-kDa protein that retains a high affinity for purine-rich single-stranded nucleic acids, including the human telomeric repeat (hTR) d(T-TAGGG) n . Using the structure of UP1 bound to hTR as a guide, we have incorporated the fluorescent guanine analog 6-MI at one of two positions within the DNA to facilitate binding studies. One is where 6-MI remains stacked with an adjacent purine, and another is where it becomes fully unstacked upon UP1 binding. The structures of both modified oligonucleotides complexed to UP1 were determined by x-ray crystallography to validate the efficacy of our design, and 6-MI has proven to be an excellent reporter molecule for single-stranded nucleic acid interactions in positions where there is a change in stacking environment upon complex formation. We have shown that UP1 affinity for d(TTAGGG) 2 is ϳ5 nM at 100 mM NaCl, pH 6.0, and our binding studies with d(TTAGG(6-MI)TTAGGG) show that binding is only modestly sensitive to salt and pH. UP1 also has a potent G-tetrad destabilizing activity that reduces the T m of the hTR sequence d(TAGGGT) 4 from 67.0°C to 36.1°C at physiological conditions (150 mM KCl, pH 7.0). Consistent with the structures determined by x-ray crystallography, UP1 is able to bind the hTR sequence in solution as a dimer and supports a model for hnRNP A1 binding to nucleic acids in arrays that may make a contiguous set of anti-parallel single-stranded nucleic acid binding clefts. These data suggest that seemingly disparate roles for hnRNP A1 in alternative splice site selection, RNA processing, RNA transport, and chromosome maintenance reflect its ability to bind a purine-rich consensus sequence (nYAGGn) and destabilize potentially deleterious G-tetrad structures.

Electronic messaging, whether in an office environment or for electronic commerce, is normally carried out in natural language, even when supported by information systems. For a variety of reasons, it would be useful if electronic messaging systems could have semantic access to, that is, access to the meanings and contents of, the messages they process. Given that natural language understanding is not a practicable alternative, there remain three approaches to delivering systems with semantic access: electronic data interchange (EDI), tagged messages, and the development of a formal language for business communication (FLBC). We favor the latter approach. In this article we compare and contrast these three approaches, present a theoretical basis for an FLBC (using speech act theory), and describe a prototype implementation.

After accounting for factors common to both periodontal disease and CAD, there was no significant association between periodontal disease and chronic CAD as assessed angiographically. Further investigations into the relationship between periodontal disease and CAD should clearly separate chronic CAD and acute coronary events.

Cardiogenic shock following an acute coronary syndrome (ACS) continues to be associated with significant mortality despite modern reperfusion strategies and inotropic support. There is mounting evidence that an acute inflammatory response accompanies the well documented decrement in left ventricular systolic function associated with cardiogenic shock and that this response may affect outcomes. In the past 2 decades it has also become apparent that nitric oxide (NO), a heteroatomic free radical has numerous biologic activities, among them the maintenance of vascular tone. The production of NO is mediated by three nitric oxide synthases (NOS); the transcription of one of these (NOS2 or inducible NOS [iNOS]) is induced by inflammatory stimuli. The iNOS gene product produces NO at very high and potentially pathologic levels. The up-regulation of iNOS transcription and overproduction of NO have been implicated in the pathogenesis of shock states where excess NO is thought to cause catecholamine resistant vasodilatation and reduced myocardial inotropy, resulting in hypotension and a fall in cardiac output. NO can also react with superoxide to produce peroxynitrate, a molecule directly toxic to the cells via modification of proteins and DNA. Inhibitors of NOS have long been utilized in the laboratory characterization of the NOS. More recently, attempts have been made to determine if the inhibition of NOS might have clinical utility in the setting of circulatory shock. With respect to septic shock, early animal studies and small trials in humans proved encouraging, but a larger trial was terminated early because of a trend toward harm among patients receiving the NO inhibitor. Studies have been undertaken in the setting of cardiogenic shock. Animal studies and small trials with humans again proved encouraging, but the large randomized TRIUMPH trial evaluating tilarginine (NG-monomethyl-L-arginine; L-NMMA) was recently terminated because of a lack of efficacy. These studies evaluated compounds with little selectivity for iNOS and their failure may have been due, in part, to the inhibition of the other NOS isoforms. In this review, we describe the biochemistry of NO synthesis, the regulation of NO production, and the clinical trials evaluating the efficacy of NOS inhibition with an eye to future trials with more selective inhibitors of iNOS.

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In this paper the author describes a formal language for communication based on linguistics-more specifically, a theory of natural language communication and models of natural language conversations. The language has a small number of general message types which are formally defined by their intended effects on the recipient. For each message type he defines a standard, automated method of responding that depends only on the message type and is independent of the message's content. For more complex conversations he provides methods for responding that do depend on the content. In this system, a message's sender-automated or human-constructs and sends a message knowing that he cannot know, but can only predict, how it will be interpreted. The agent receiving the message interprets it and then uses it as a basis for inferring how it should respond. The message interpretation mechanism for this language is reusable, modular and shared by all applications. The benefit of this communication system is that it makes the communication infrastructure more flexible, easier to modify, easier to expand, and more capable.