镜像配基筛选:克服“酶屏障”的多肽、寡核苷酸药物研发技术

生物体内存在的酶屏障是功能性多肽和寡核苷酸成药的重要瓶颈.以镜像噬菌体展示技术(mirror-image phage display)和镜像适配体筛选技术(Spiegelmer technology)为代表的镜像配基筛选技术能有效地克服这一屏障,获得对靶点具有特异识别能力且在生理条件下高度稳定的D型多肽和L型寡核苷酸配基,有望成为多肽或寡核苷酸类特异性药物研发的有利工具.本文主要综述镜像配基筛选技术的原理及其在药学领域的研究进展.     

Unilateral Versus Bilateral Injections of Botulinum Toxin in Patients with Adductor Spasmodic Dysphonia

Both unilateral and bilateral thyroarytenoid muscle injections of Botox provide effective management of voice symptoms in patients with adductor spasmodic dysphonia; however, the preferred injection technique has not been established. In this study, 16 patients were treated with unilateral injections (72 injections total) and 33 patients were managed with bilateral injections (133 injections total). Individual assignments to injection type were based on treatment previously received and dose was adjusted according to the patient's previous treatment response. An optimal treatment included a benefit lasting 3 months or more with side effects lasting 2 weeks or less. Compared to patients receiving bilateral injections, those receiving unilateral injections more frequently noted a benefit of 3 months or more (p = 0.03), side effects of 2 weeks or less duration (p = 0.03), as well as both a 3-month benefit and a 2-week or less side effect (p = 0.0004). Injection type had no effect on optimal Botox dosing with repeat injections. Successive unilateral injections at the same dose were more likely (p = 0.012) than successive bilateral injections to produce the same or longer duration of benefit. We conclude that a unilateral injection routine has a more optimal and consistent treatment effect/side effect profile.     

The Relationship Between Cepstral Peak Prominence and Selected Parameters of Dysphonia

Traditional measures of dysphonia vary in their reliability and in their correlations with perceptions of grade. Measurements of cepstral peak prominence (CPP) have been shown to correlate well with perceptions of breathiness. Because it is a measure of periodicity, CPP should also predict roughness. The ability of CPP and other acoustic measures to predict overall dysphonia and the subcategories of breathiness and roughness in pathological voice samples is explored. Preoperative and postoperative speech samples from 19 patients with unilateral recurrent laryngeal nerve paralysis who underwent operative intervention were analyzed by trained listeners and by measures of smoothed CPP (CPPS), noise-to-harmonic ratio (NHR), amplitude perturbation quotient (APQ), relative average perturbation (RAP), and smoothed pitch perturbation quotient (sPPQ). The data were analyzed with bivariate Pearson correlation statistics. Grade of dysphonia and breathiness ratings correlated better with measurements of CPPS than with the other measures. CPPS from samples of connected speech (CPPS-s) best predicted overall dysphonia. None of the measures were useful in predicting roughness.     

Laryngeal and Other Otolaryngologic Manifestations of Crohn''s Disease

Laryngeal and other otolaryngologic manifestations of Crohn's disease are uncommon and may be subtle. Crohn's disease is a well-known inflammatory bowel disease of unknown etiology marked by relapsing and remitting granulomatous inflammation of the alimentary tract. Extraintestinal manifestations of Crohn's disease may appear anytime during the course of the disease process and may be the initial symptom. Findings are nonspecific, primarily edema and ulcerations, and may be confused with a multitude of other disease processes. Awareness of these manifestations in the head and neck will prevent misdiagnosis or a delay in diagnosis.     

Measurement of isomeric yield ratios for 93Nb(??,4n)89m,gNb and natMo(??,xn1p)95m,gNb reactions with 50-, 60-, and 70-MeV bremsstrahlung

We measured the isomeric yield ratios for the photonuclear reactions of ⁹³Nb(??,4n)^89m,gNb and ^natMo(??,xnp)^95m,gNb by using the activation method. The high-purity ⁹³Nb and ^natMo metallic foils in disc shape were irradiated with uncollimated bremsstrahlung beams of 50-, 60-, and 70-MeV generated from an electron linear accelerator in Pohang Accelerator Laboratory. The induced activities in the irradiated foils were measured by the high-resolution ??-ray spectrometry with a calibrated high-purity Germanium (HPGe) detector coupled to a PC-based 4?K multichannel analyzer. The reaction ⁹³Nb(??,4n)^89m,gNb was studied for the first time which has no comparable literature data. The result of ^95m,gNb isomeric pair was measured based on (??,p), (??,np), and (??,2np) reactions which is the first measurement at the intermediate energy region of 50?C70-MeV with a ^natMo target.     

EFFECT OF COMPOSITION AND PROCESSING CONDITION ON MICROSTRUCTURAL PROPERTIES AND DURABILITY OF FLUOROPOLYMER/ACRYLIC BLENDS

Fluoropolymer blends have been widely used as binders for exterior coatings because of their excellent resistance to ultra-violet (UV) radiation as well as to many corrosive chemical agents.It is known that the fluorinated component usually has a lower glass transition temperature and easily crystallizes in the final structure depending upon the blend composition and sample annealing condition.We investigated the effect of blend composition and annealing process (slow and fast cooling) on the surface mor...     

Observation of color-transparency in diffractive dissociation of pions

We have studied the diffractive dissociation into dijets of 500 GeV/c pions scattering coherently from carbon and platinum targets. Extrapolating to asymptotically high energies (where t(min)-->0), we find that when the per-nucleus cross section for this process is parametrized as sigma = sigma0Aalpha, alpha has values near 1.6, the exact result depending on jet transverse momentum. These values are in agreement with those predicted by theoretical calculations of color-transparency.     

Direct measurement of the pion valence-quark momentum distribution, the pion light-cone wave function squared

We present the first direct measurements of the pion valence-quark momentum distribution which is related to the square of the pion light-cone wave function. The measurements were carried out using data on diffractive dissociation of 500 GeV/c pi(-) into dijets from a platinum target at Fermilab experiment E791. The results show that the /q&q> light-cone asymptotic wave function describes the data well for Q2 approximately 10 (GeV/c)(2) or more. We also measured the transverse momentum distribution of the diffractive dijets.     

Understanding protease catalysed solid phase peptide synthesis

A protease (thermolysin) was used to directly synthesise a number of dipeptides from soluble Fmoc-amino acids onto a solid support (PEGA1900) in bulk aqueous media, often in very good yields. This shift in equilibrium toward synthesis is remarkable because for soluble dipeptides in aqueous solution hydrolysis rather than synthesis is observed. Three possible reasons for the equilibrium shift were considered: (i) using a solid support makes it easy to use an excess of reagents, so mass action contributes towards synthesis; (ii) reduction in the unfavourable hydrophobic hydration of the Fmoc group within the solid support compared with the free amino acid in solution and (iii) suppression of the ionization of amino groups linked to the solid phase due to mutual electrostatic repulsion. It was found that under the conditions studied the second effect was most important.