Multiple structural states exist throughout the helical nucleation sequence of the intrinsically disordered protein stathmin, as reported by electron paramagnetic resonance spectroscopy.

The intrinsically disordered protein (IDP) stathmin plays an important regulatory role in cytoskeletal maintenance through its helical binding to tubulin and microtubules. However, it lacks a stable fold in the absence of its binding partner. Although stathmin has been a focus of research over the past two decades, the solution-phase conformational dynamics of this IDP are poorly understood. It has been reported that stathmin is purely monomeric in solution and that it bears a short helical region of persistent foldedness, which may act to nucleate helical folding in the C-terminal direction. Here we report a comprehensive study of the structural equilibria local to this region in stathmin that contradicts these two claims. Using the technique of electron paramagnetic resonance (EPR) spectroscopy on spin-labeled stathmin mutants in the solution-phase and when immobilized on Sepharose solid support, we show that all sites in the helical nucleation region of stathmin exhibit multiple spectral components that correspond to dynamic states of differing mobilities and stabilities. Importantly, a state with relatively low mobility dominates each spectrum with an average population greater than 50%, which we suggest corresponds to an oligomerized state of the protein. This is in contrast to a less populated, more mobile state, which likely represents a helically folded monomeric state of stathmin, and a highly mobile state, which we propose is the random coil conformer of the protein. Our interpretation of the EPR data is confirmed by further characterization of the protein using the techniques of native and SDS PAGE, gel filtration chromatography, and multiangle and dynamic light scattering, all of which show the presence of oligomeric stathmin in solution. Collectively, these data suggest that stathmin exists in a diverse equilibrium of states throughout the purported helical nucleation region and that this IDP exhibits a propensity toward oligomerization.

Chemoselective amide formation using O-(4-nitrophenyl)hydroxylamines and pyruvic acid derivatives.

A series of O-(4-nitrophenyl)hydroxylamines were synthesized from their respective oximes using a pulsed addition of excess NaBH(3)CN at pH 3 in 65-75% yield. Steric hindrance near the oxime functional group played a key role in both the ease by which the oxime could be reduced and the subsequent reactivity of the respective hydroxylamine. Reaction of the respective hydroxylamines with pyruvic acid derivatives generated the desired amides in good yields. A comparison of phenethylamine systems bearing different leaving groups revealed significant differences in the rates of these systems and suggested that the leaving group ability of the N-OR substituent plays an important role in determining their reactivity with pyruvic acid. Competition experiments (in 68% DMSO/phosphate buffered saline) using 1 equiv of N-phenethyl-O-(4-nitrophenyl)hydroxylamine and 2 equiv of pyruvic acid in the presence of other nucleophiles such as glycine, cysteine, phenol, hexanoic acid, and lysine demonstrated that significant chemoselectivity is present in this reaction. The results suggest that this chemoselective reaction can occur in the presence of excess α-amino acids, phenols, acids, thiols, and amines.

DERMS DO 5: A Proposed Curriculum for Dermatologic Training in 5 Osteopathic Competencies.

Dermatology programs seeking osteopathic recognition under the new single graduate medical education (GME) accreditation system are required to demonstrate osteopathic competencies within their teaching curriculum. Although the Accreditation Council for Graduate Medical Education has put forth guidelines to obtain osteopathic recognition, ambiguity lingers regarding specialty-specific content that would fulfill these requirements. To date, there are no set curriculum guidelines addressing osteopathic principles within the field of dermatology. In this article, we review the existing literature surrounding key competencies and propose a dermatology-focused educational model, "DERMS (Direct, Empathy, Restore, Mobilize, Senses) DO 5," to encourage the teaching of osteopathic competencies within GME training programs. Our proposed curriculum model addresses the 5 osteopathic care models and applications of osteopathic manipulative treatment within the realistic realm of dermatology.

Managing Mild-to-Moderate Psoriasis in Elderly Patients: Role of Topical Treatments.

The approach to managing mild-to-moderate psoriasis in the elderly (ages >65 years) should be no different to that in the younger population. Topical agents are frequently prescribed for elderly patients as first-line therapy because of their localized impact and minimal systemic effects. Although topical therapy remains the mainstay treatment of mild-to-moderate psoriasis, the elderly population may be at a higher risk of steroid-induced adverse events, including atrophy, purpura, telangiectasia, secondary skin infections, rebound phenomenon, and tachyphylaxis. In addition, offering photo- and systemic therapy to elderly patients with mild-to-moderate psoriasis may pose challenges due to the presence of comorbidities, patient adherence, and reduced physical functioning. Nonetheless, topical therapy remains first-line therapy for elderly and younger patients with mild-to-moderate psoriasis as standalone therapy or in combination with oral and biologic agents. Effective use of topical treatments should be prioritized to ensure elderly patients can be effectively managed prior to advancing to photo- or systemic treatment modalities.

Development of polyamine transport ligands with improved metabolic stability and selectivity against specific human cancers.

Polyamine homeostasis is critical for life and is accomplished via a balance of polyamine biosynthesis, degradation, and transport. Rapidly dividing cancer cells have been shown to have high polyamine transport activity compared to normal cells, likely due to their high requirement for polyamine metabolites. The polyamine transport system (PTS) is a therapeutically relevant target, as it can provide selective drug delivery to cancer cells. This report describes the synthesis and biological evaluation of multimeric polyamine derivatives as efficient PTS ligands. Arylmethyl-polyamine derivatives were synthesized to address two important concerns in PTS drug design: (a) PTS selectivity and (b) stability to amine oxidases. N(1),N(1')-[Naphthalene-1,4-diylbis(methylene)]bis{N(4)-[4-(methylamino)butyl])butane-1,4-diamine}, 3b, was found to have an optimal balance between these parameters and demonstrated excellent targeting of melanoma (e.g., MALME-3M) and breast cancer cells (e.g., T47D) over other cancer cell lines. These results provide a method to selectively target cancers via their intrinsic need for polyamine metabolites.