Predictive Nature of Commitment Language in Relation to Outcome of Prolonged Exposure Therapy for Posttraumatic Stress Disorder

Sessions of prolonged exposure therapy, an extensively studied treatment for posttraumatic stress disorder, were coded for client verbalization in favor of maintaining or changing the focal behavior of the treatment. The frequency of client verbalization was used to attempt discrimination of group membership based on treatment completion and diagnosis remission. Client language was not predictive of group membership. However, for treatment completers, average frequency of verbalization against the status quo was twice as high as noncompleters when reviewing common reactions experienced following a trauma. Implications for treatment conceptualization and delivery are discussed

The curious case of the molecular catalysts that behaved like a dual-site catalyst

Semi-batch, solution copolymerizations of ethylene and 1-hexene were performed using both dichloride (Hf-Cl2) and dimethyl (Hf-Me2) analogues of the bis(n-propylcyclopentadienyl) hafnium precatalyst. Either tetrakis(pentafluorophenyl) borate dimethylanilinium salt ([B(C6F5)4]-[Me2NHPh]+) (B) or methyl aluminoxane (MAO) was employed as the activator, and tri-n-octylaluminum (TOA) was used as the scavenger for the borate-activated experiments. For the copolymerization study using Hf-Cl2/B/TOA, 1-hexene, borate and TOA concentrations were varied systematically. Crystallization analysis fractionation (CRYSTAF) or crystallization elution fractionation (CEF) profiles were used interchangeably to compare the chemical composition distributions (CCD) of the copolymers. Above a minimum threshold 1-hexene level, the CCD profiles of all the copolymers were bimodal and the areas under the peaks depended on the B/Hf-Cl2 and B/Al ratios. Decreasing the TOA concentration reduced the weight fraction of the higher crystallinity polymer component. Please download the file below for full content

Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity.

Falcipain-2 and falcipain-3 are critical hemoglobinases of Plasmodium falciparum, the most virulent human malaria parasite. We have determined the 2.9 A crystal structure of falcipain-2 in complex with the epoxysuccinate E64 and the 2.5 A crystal structure of falcipain-3 in complex with the aldehyde leupeptin. These complexes represent the first crystal structures of plasmodial cysteine proteases with small molecule inhibitors and the first reported crystal structure of falcipain-3. Our structural analyses indicate that the relative shape and flexibility of the S2 pocket are affected by a number of discrete amino acid substitutions. The cumulative effect of subtle differences, including those at "gatekeeper" positions, may explain the observed kinetic differences between these two closely related enzymes

In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi.

BackgroundCruzain, the major cysteine protease of Trypanosoma cruzi, is an essential enzyme for the parasite life cycle and has been validated as a viable target to treat Chagas' disease. As a proof-of-concept, K11777, a potent inhibitor of cruzain, was found to effectively eliminate T. cruzi infection and is currently a clinical candidate for treatment of Chagas' disease.Methodology/principal findingsWRR-483, an analog of K11777, was synthesized and evaluated as an inhibitor of cruzain and against T. cruzi proliferation in cell culture. This compound demonstrates good potency against cruzain with sensitivity to pH conditions and high efficacy in the cell culture assay. Furthermore, WRR-483 also eradicates parasite infection in a mouse model of acute Chagas' disease. To determine the atomic-level details of the inhibitor interacting with cruzain, a 1.5 A crystal structure of the protease in complex with WRR-483 was solved. The structure illustrates that WRR-483 binds covalently to the active site cysteine of the protease in a similar manner as other vinyl sulfone-based inhibitors. Details of the critical interactions within the specificity binding pocket are also reported.ConclusionsWe demonstrate that WRR-483 is an effective cysteine protease inhibitor with trypanocidal activity in cell culture and animal model with comparable efficacy to K11777. Crystallographic evidence confirms that the mode of action is by targeting the active site of cruzain. Taken together, these results suggest that WRR-483 has potential to be developed as a treatment for Chagas' disease

Structural and functional relationships in the virulence-associated cathepsin L proteases of the parasitic liver fluke, Fasciola hepatica

The helminth parasite Fasciola hepatica secretes cysteine proteases to facilitate tissue invasion, migration, and development within the mammalian host. The major proteases cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) were recombinantly produced and biochemically characterized. By using site-directed mutagenesis, we show that residues at position 67 and 205, which lie within the S2 pocket of the active site, are critical in determining the substrate and inhibitor specificity. FheCL1 exhibits a broader specificity and a higher substrate turnover rate compared with FheCL2. However, FheCL2 can efficiently cleave substrates with a Pro in the P2 position and degrade collagen within the triple helices at physiological pH, an activity that among cysteine proteases has only been reported forhuman cathepsin K. The 1.4-Å three-dimensional structure of the FheCL1 was determined by x-ray crystallography, and the three-dimensional structure of FheCL2 was constructed via homology-based modeling. Analysis and comparison of these structures and our biochemical data with those of human cathepsins L and Kprovided an interpretation of the substrate-recognition mechanisms of these major parasite proteases. Furthermore, our studies suggest that a configuration involving residue 67 and the "gatekeeper" residues 157 and 158 situated at the entrance of the active site pocket create a topology that endows FheCL2 with its unusual collagenolytic activity. The emergence of a specialized collagenolytic function in Fasciola likely contributes to the success of this tissue-invasive parasite. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc

Computational Identification of Uncharacterized Cruzain Binding Sites

Chagas disease, caused by the unicellular parasite Trypanosoma cruzi, claims 50,000 lives annually and is the leading cause of infectious myocarditis in the world. As current antichagastic therapies like nifurtimox and benznidazole are highly toxic, ineffective at parasite eradication, and subject to increasing resistance, novel therapeutics are urgently needed. Cruzain, the major cysteine protease of Trypanosoma cruzi, is one attractive drug target. In the current work, molecular dynamics simulations and a sequence alignment of a non-redundant, unbiased set of peptidase C1 family members are used to identify uncharacterized cruzain binding sites. The two sites identified may serve as targets for future pharmacological intervention

Nano-structured rhodium doped SrTiO3–Visible light activated photocatalyst for water decontamination

A modified hydrothermal synthesis, avoiding high temperature calcination, is used to produce nano-particulate rhodium doped strontium titanate in a single-step, maintaining the rhodium in the photocatalytically active +3 oxidation state as shown by X-ray spectroscopy. The photoactivity of the material is demonstrated through the decomposition of aqueous methyl orange and the killing of Escherichia coli in aqueous suspension, both under visible light activation. A sample of SrTiO3 containing 5 at% Rh completely decomposed a solution of methyl orange in less than 40 min and E. coli is deactivated within 6 h under visible light irradiation