The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal–Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.

Background: Laparoendoscopic single-site surgery (LESS) has gained popularity in urology over the last few years. Objective: To report a large multi-institutional worldwide series of LESS in urology. Design, Setting, And Participants: Consecutive cases of LESS done between August 2007 and November 2010 at 18 participating institutions were included in this retrospective analysis. Intervention: Each group performed a variety of LESS procedures according to its own protocols, entry criteria, and techniques. Measurements: Demographic data, main perioperative outcome parameters, and information related to the surgical technique were gathered and analyzed. Conversions to reduced-port laparoscopy, conventional laparoscopy, or open surgery were evaluated, as were intraoperative and postoperative complications. Results and Limitations: Overall, 1076 patients were included in the analysis. The most common procedures were extirpative or ablative operations in the upper urinary tract. The da Vinci robot was used to operate on 143 patients (13%). A single-port technique was most commonly used and the umbilicus represented the most common access site. Overall, operative time was 160 ± 93 min. and estimated blood loss was 148 ± 234 mL. Skin incision length at closure was 3.5 ± 1.5cm. Mean hospital stay was 3.6 ± 2.7 d with a visual analog pain score at discharge of 1.5 ± 1.4. An additional port was used in 23% of cases. The overall conversion rate was 20.8%; 15.8% of patients were converted to reduced-port laparoscopy, 4% to conventional laparoscopy/ robotic surgery, and 1% to open surgery. The intraoperative complication rate was 3.3%. Postoperative complications, mostly low grade, were encountered in 9.5% of cases. Conclusions: This study provides a global view of the evolution of LESS in the field of minimally invasive urologic surgery. A broad range of procedures have been effectively performed, primarily in the academic setting, within diverse health care systems around the world. Since LESS is performed by experienced laparoscopic surgeons, the risk of complications remains low when stringent patient-selection criteria are applied.

Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand–peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer’s disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, our in vitro and in vivo studies of DMPD toward Aβ with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.