Silencing disease genes in the laboratory and the clinic

Synthetic nucleic acids are commonly used laboratory tools for modulating gene expression and have the potential to be widely used in the clinic. Progress towards nucleic acid drugs, however, has been slow and many challenges remain to be overcome before their full impact on patient care can be understood. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the two most widely used strategies for silencing gene expression. We first describe these two approaches and contrast their relative strengths and weaknesses for laboratory applications. We then review the choices faced during development of clinical candidates and the current state of clinical trials. Attitudes towards clinical development of nucleic acid silencing strategies have repeatedly swung from optimism to depression during the past 20 years. Our goal is to provide the information needed to design robust studies with oligonucleotides, making use of the strengths of each oligonucleotide technology

Teachers and Careers: The role of school teachers in delivering career and employability learning

Teach Firs

Immediate versus water-storage performance of Class V flowable composite restoratives

Objectives The aims of this investigation were to clarify the effects of 24 h water-storage and finishing time on mechanical properties and marginal adaptation to a Class V cavity of eight modern flowable resin-composites. Methods Eight flowable composites, plus two controls (one microfilled and one hybrid composite), were investigated with specimen sub-groups (n = 10) for each property measured. The principal series of experiments was conducted in model Class V cavities with interfacial polishing either immediately (3 min) after setting or after 24 h water-storage. After the finishing procedure, each tooth was sectioned in a buccolingual direction through the center of the restoration, and the presence or absence of marginal-gaps was measured (and then summed for each cavity) at 14 points (each 0.5 mm apart) along the cavity restoration interface (n = 10 per group; total points measured = 140). The shear bond-strengths to enamel and to dentin, and flexural strengths and moduli data were also measured at 3 min and after 24 h water-storage. Results For all flowable composites, polished immediately after setting, 14–30 summed gaps were observed (controls: 64 and 42). For specimens polished after 24 h, a significantly (p &#60; 0.05) reduced number of 8–17 summed gaps occurred for only 3 flowable composites; whereas for 5 flowable composites there were non-significantly-different (p &#62; 0.05) numbers (11–17) of summed gaps (controls: 28 and 22). After 24 h storage, shear bond-strengths to enamel and to dentin, flexural strengths and moduli increased highly significantly (p &#60; 0.001) for all materials, except Silux Plus. Significance A post-cure interval of 24 h resulted in enhanced mechanical and adhesive properties of flowable dental composites. In a minority of cases there was also a reduced incidence of marginal-gap formation. However the latter effect may be partly attributed to 24 h delayed polishing, even though such a delay is not usual clinical practice.</p

Drug and Alcohol Abuse Prevention: Defining the Need in Organizations

This paper outlines initial interventions to prevent drug and alcohol abuse in organizations.Grounded in sociological theory, the first intervention is to define the natureof the problem through data gathering and analysis, particularly self-reports of drugand alcohol use by the organization\u27s members. The self-report data, when comparedwith national data, provide a base of information from which direct interventions canbe designed. Student, faculty, administration, and staff survey results from a universityand their applications are reported as a case study. Interventions which centeron peer prevention are briefly discussed. Self-report survey data of drug and alcoholabuse define the problem and the types of interventions that are likely to be successful

Evolutionary descent of prion genes from a ZIP metal ion transport ancestor

In the more than 20 years since its discovery, both the phylogenetic origin and cellular function of the prion protein (PrP) have remained enigmatic. Insights into the function of PrP may be obtained through a characterization of its molecular neighborhood. Quantitative interactome data revealed the spatial proximity of a subset of metal ion transporters of the ZIP family to mammalian prion proteins. A subsequent bioinformatic analysis revealed the presence of a prion-like protein sequence within the N-terminal, extracellular domain of a phylogenetic branch of ZIPs. Additional structural threading and ortholog sequence alignment analyses consolidated the conclusion that the prion protein gene family is phylogenetically derived from a ZIP-like ancestor molecule. Our data explain structural and functional features found within mammalian prion proteins as elements of an ancient involvement in the transmembrane transport of divalent cations. The connection to ZIP proteins is expected to open new avenues to elucidate the biology of the prion protein in health and disease