Supramolecular Assembly of Aminoethylene‐Lipopeptide PMO Conjugates into RNA Splice‐Switching Nanomicelles

Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile.     

The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

Using an integrated process of data and modeling in HRA

The paper describes an approach taken to estimate the probabilities of failure associated with various railroad tasks to prevent accidents (principally collisions and derailments). These probabilities were estimated using an expert elicitation process that used partially relevant data available from a variety of databases and that were filtered and scaled to make them more directly relevant to the analyses being performed. Extensive qualitative studies were performed prior to the elicitation process to identify relevant contexts under which the tasks can be performed.     

Epoxy paint failure in B-52 fuel tanks: Part II. Influence of DIEGME concentration in the fuel on the failure process

A model has been proposed to explain the failure of the original BMS10-39 epoxy paint on upper vertical surfaces in B-52 fuel tanks. The model involves interaction of the paint with DIEGME, a fuel system ice inhibitor (FSII) in jet fuel, that is distilled from the liquid fuel. In this communication, distillation experiments used to support the model are refined to better match the mass transfer of vapor from fuel in a B-52 fuel tank at close to room temperature. The interaction of these lower temperature distillates with the paint affirms the earlier model. On the basis of these experiments it is proposed that paint failure may be controlled or eliminated by reducing the level of DIEGME in the fuel. Proposed changes in military jet fuel composition are detailed.     

Halo effects in grading student projects.

Halo effects in rating specific pieces of work, as in educational grading, have received little attention. Grades awarded by 2 independent graders to undergraduate projects were analyzed with a correlated uniqueness model. Grades showed substantial halo despite being awarded by expert assessors at the time of reading the work. There was greater halo between different grades applying to the same section of the project than between grades applying to different sections. Supervisors who had regular contact with the student whose work they were grading showed no more halo than other graders. More reliable graders showed less within-section halo than graders of lower reliability but equal between-sections halo. The halo effects observed cannot be entirely attributable to a unitary general impression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Is evidence-based practice diverse enough? Philosophy of science considerations.

In its policy rationale for evidence-based practice in psychology (EBPP), the APA Presidential Task Force on Evidence-Based Practice (see record 2006-05893-001) claims to have constituted itself with "scientists and practitioners from a wide range of perspectives and traditions, reflecting the diverse perspectives within the field" (p. 273). We applaud this attention to diversity but contend that an entire perspective of the debate was omitted in the Task Force's newly approved policy and its underlying report. The failure to consider a philosophy of science perspective led the Task Force to make a number of epistemological assumptions that are not based on evidence or rationale and that thus violate the very spirit of evidence-based decision making. In this comment, we reveal a few of these assumptions and discuss their detrimental consequences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Free-Edge and Ply Cracking Effect in Angle-Ply Laminated Composites Subjected to In-Plane Loads

This paper presents a semianalytical method for the prediction of interlaminar stresses and displacements near the free edges and ply cracks in general angle-ply laminates subjected to biaxial extensions and/or in plane shear deformation. The method is based on a state space representation of the three-dimensional equations of elasticity. Numerical solutions are obtained by using layer refinement in the through thickness direction and Fourier series expansion in the other directions. By this approach, an angle-ply laminate may be composed of an arbitrary number of monoclinic layers and each layer may have different material property and thickness. This method guarantees continuous fields of all interlaminar stresses across interfaces between material layers. Numerical results are compared with those obtained from other methods. It is found that the theory provides a satisfactory approximation to the stress singularities near the free edges and ply cracks. Numerical solutions for antisymmetric laminates under extension and general laminates under shearing are new in the literature and can be used as benchmarks for validating new models.     

History of depression and smoking cessation outcome: A meta-analysis.

The authors conducted a meta-analysis of published studies to (a) evaluate the premise that a history of major depression is associated with failure to quit smoking and (b) identify factors that moderate the relationship between history of depression and cessation outcome. Fifteen studies met the selection requirements and were coded for various study methodology and treatment characteristics. DSTAT was used to calculate individual study effect sizes, determine the mean effect size across studies. and test for moderator effects. No differences in either short-term (≤ 3 months) or long-term abstinence rates (≥ 6 months) were observed between smokers positive versus negative for history of depression. Lifetime history of major depression does not appear to be an independent risk factor for cessation failure in smoking cessation treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hyperhomocysteinemia: detection, risk assessment, and treatment

OBJECTIVE: The aim of this study was to evaluate both the importance of the screening strategy and the familial aggregation characteristics of families with hypercholesterolemic children. PATIENTS AND METHODS: Ninety-one families (369 subjects) with one hypercholesterolemic child were studied. In addition to clinical and general biochemical evaluation, lipids including apo A-I and B-100 were examined. LDL was quantified under ultracentrifugation. RESULTS: Among the 91 children studied, 10 (10.99%) suffered heterozygous hypercholesterolemia, while 81 (89.01%) suffered polygenic hypercholesterolemia. Following a diet, polygenic children exhibited normal lipid parameters. In heterozygous children a decrease of 19% for total cholesterol, 19.9% for LDL-cholesterol and 16.3% for apo B were observed. When starting the study, 77.5% of the family members thought that they had normal serum lipid values. At the end of the study it was confirmed that only 28% were really normolipemic, indicating that 49.4% of the individual did not know that they were suffering dyslipemia. The study also showed that fathers exhibited the highest incidence of hypercholesterolemia (80.2%) followed by brothers (65.6%) and mothers (61.5%). Therefore, 69.4% of the individuals studied exhibited dyslipemia. CONCLUSIONS: The screening strategy allows one to diagnose a high percentage (almost 50%) of individuals suffering hypercholesterolemia in families with a child previously diagnosed of this pathology. Moreover, in these families there is a high degree of familiar aggregation of dyslipemia.