Correlation of blood rheology with vascular resistance in critically ill patients.

Blood rheologic measurements together with peripheral resistance determinations in vivo were made in 27 critically ill patients. Eighteen of these patients (group I) suffered from violent trauma or operative injury and the other 9 (group II) were patients with generalized sepsis. As a result of fluid therapy all patients underwent hemodilution, resulting in a decrease in blood viscosity. This drop in blood viscosity was counteracted to some extent by an increased plasma viscosity due to elevated fibrinogen levels and a decreased red cell deformability associated with massive transfusions of stored blood. The correlation of vivo hemodynamics with blood rheological data made it possible to separate the relative roles of vascular dimensions and blood viscosity in affecting the total peripheral resistance. This approach permitted us to distinguish varying degrees of vasoconstriction in nonseptic patients in low flow states (group I) and varying degrees of vasodilation in septic patients (group II). This type of analysis serves to elucidate the pathophysiology of hemodynamic alterations in disease and provides a rational basis for devising an effective therapeutic program.     

Phylogeny, evolution and systematics of Moehringia (Caryophyllaceae) as inferred from molecular and morphological data: a case of homology reassessment

The phylogeny of the genus Moehringia (Caryophyllaceae) is investigated by means of analyzing nuclear (ITS) and chloroplast (matK) sequence data in combination with morphological characters. Parsimony and Bayesian methods yield consistent results, and a common phylogenetic signal is shared by the nuclear and chloroplast data. Morphological characters are affected by a high level of homoplasy, but they provide valuable information when analyzed in combination with the molecular data. Moehringia is paraphyletic to Arenaria with the Iberian taxa belonging to Moehringia sect. Pseudomoehringia McNeill more closely related to Arenaria. This cladistic evidence led us to reinterpret the homology of the key character used in most, if not all, floras, to separate Moehringia from Arenaria, i.e., the seed strophiole. Thorough anatomical studies were carried out to elucidate the ontogeny of the strophiole, which proved different in Moehringia s. str. and the Iberian taxa. Within Moehringia s. str., two sister clades are recognized (i.e., Moehringia sect. Moehringia and M. sect. Latifoliae much as recognized by McNeill, whereas representatives of M. sect. Diversifoliae are assigned to either groups), and biogeographical events related to the Würm glaciation are considered to play a fundamental role in the evolution and present distribution of the genus. The variation of the strophiole is regarded as adaptability to ecological conditions and dispersal agents. We also propose two new combinations and two replacement names: Arenaria glochidisperma (J.M. Mont.) Fior et P.O. Karis, comb. nov., Arenaria tejedensis (Willk.) Fior et P.O. Karis, comb. nov., Arenaria suffruticosa Fior et P.O. Karis, nom. nov. for Moehringia intricata Willk., and Arenaria funiculata Fior et P.O. Karis, nom. nov. for Moehringia fontqueri Pau. © The Willi Hennig Society 2007.     

Transportins 1 and 2 are redundant nuclear import factors for hnRNP A1 and HuR

Several mRNA-binding proteins, including hnRNP A1 and HuR, contain bidirectional transport signals that mediate both their nuclear import and export. Previously, Transportin 1 (Trn1) was identified as a mediator of hnRNP A1 import, whereas the closely related protein Transportin 2 (Trn2) was shown to interact with HuR. Here we have investigated the subfamily of transportins that consists of Trn1 (or Kap beta2A) and two alternatively spliced Trn2 isoforms (Trn2a and Trn2b), also called Trn2 and Kap beta2B. The sequence differences among these proteins could alter either their cargo specificity or their response to RanGTP and thus their function as import or export receptors. Using in vitro binding assays, we show that hnRNP A1 preferentially binds Trn1 and Trn2b versus Trn2a. HuR interacts with all three transportins, as well as weakly with Imp beta. The hnRNP A1 and HuR shuttling domains, called M9 and HNS, respectively, are sufficient for these interactions. Despite small differences in the binding of HuR and hnRNP A1 to the three transportins, in vitro interaction studies performed in the presence and absence of RanQ69LGTP indicate that all three transportins most likely act as import factors for HuR and hnRNP A1. In digitonin-permeabilized HeLa cells, both M9 and HNS peptides compete for the import of recombinant hnRNP A1 and HuR, indicating that HuR and hnRNP A1 import pathways are at least partially overlapping. Possible nucleocytoplasmic shuttling mechanisms for hnRNP A1 and HuR are discussed.     

Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design

Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1’-S2’ FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1’-S2’ binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC₅₀ of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1’-S2’ binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.     

Beyond the senses: perception,the environment,and vision impairment

The ‘sensory turn’ in anthropology has generated a significant literature on sensory perception and experience. Whilst much of this literature is critical of the compartmentalization of particular ‘senses’, there has been limited exploration of how anthropologists might examine sensory perception beyond ‘the senses’. Based on ethnographic fieldwork with people who have impaired vision walking the South Downs landscape in England, this article develops such an approach. It suggests that the experiences of seeing in blindness challenge the conceptualization of ‘vision’ (and ‘non-vision’). In place of ‘vision’ (as a sense), the article explores ‘activities of seeing’ – an approach that contextualizes the visual to examine the biographically constituted and idiosyncratic nature of perception within an environment. Through an ethnography of seeing with anatomical eyes and ‘seeing in the mind's eye’, it articulates an approach that avoids associating perception with anatomy, or compartmentalizing experience into ‘senses’.