Effect of RGD Peptide-Coated TiO 2

The purpose of this research was to characterize an Arg-Gly-Asp (RGD) peptide immobilized on TiO2 nanotubes. In addition, we investigated the effects of the RGD peptide-coated TiO2 nanotubes on the cellular response, proliferation, and functionality of osteogenic-induced human mesenchymal stem cells (hMSCs), which are osteoclasts that have been induced by bone marrow macrophages. The RGD peptide was grafted covalently onto the surface of TiO2 nanotubes based on the results of SEM, FT-IR, and XPS. Furthermore, the RGD peptide promoted the initial attachment and proliferation of the hMSCs, regardless of the size of the TiO2 nanotubes. However, the RGD peptide did not prominently affect the osteogenic functionality of the hMSCs because the peptide suppressed hMSC motility associated with osteogenic differentiation. The result of an in vitro osteoclast test showed that the RGD peptide accelerated the initial attachment of preosteoclasts and the formation of mature osteoclasts, which could resorb the bone matrix. Therefore, we believe that an RGD coating on TiO2 nanotubes synthesized on Ti implants might not offer significant acceleration of bone formation in vivo because osteoblasts and osteoclasts reside in the same compartment

Novel Pyrrolopyrimidine-Based α-Helix Mimetics: Cell- Permeable Inhibitors of Protein-Protein Interactions

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ja108230s.There is considerable interest in developing nonpeptidic, small molecule α-helix mimetics to disrupt α-helix-mediated protein-protein interactions. Herein, we report the design of a novel pyrrolopyrimidine-based scaffold for such α-helix mimetics with increased conformational rigidity. We also developed a facile solid phase synthetic route, which is amenable to divergent synthesis of a large library. Using a fluorescence polarization-based assay, we identified cell permeable, dual MDMX/MDM2 inhibitors, demonstrating that the designed molecules can act as α-helix mimetics

THE EFFECTS OF WHEELCHAIR CAMBER AND HANDRIM SIZE IN WHEELCHAIR BASKETBALL MOVEMENT

Improving the wheelchair design can be an important determinant of high performance in the wheelchair basketball. Researchers have focused on increasing the efficiency of the wheelchair, looking at the factors such as the seat position, handrim size, and wheel camber. Most handrim and wheel chamber studies, however, have focused only on the propulsive phase. Quick turn as well as fast propulsion is essential to the success in a wheelchair basketball game and the energy efficiency becomes particularly important in a prolonged wheelchair use. The purpose of this study was to investigate the effects of wheelchair camber and handrim size on the linear propulsion, turn velocity, and efficiency

Electric field control of nonvolatile four-state magnetization at room temperature

We find the realization of large converse magnetoelectric (ME) effects at room temperature in a multiferroic hexaferrite Ba$_{0.52}$Sr$_{2.48}$Co$_{2}$Fe$_{24}$O$_{41}$ single crystal, in which rapid change of electric polarization in low magnetic fields (about 5 mT) is coined to a large ME susceptibility of 3200 ps/m. The modulation of magnetization then reaches up to 0.62 $\mu$$_{B}$/f.u. in an electric field of 1.14 MV/m. We find further that four ME states induced by different ME poling exhibit unique, nonvolatile magnetization versus electric field curves, which can be approximately described by an effective free energy with a distinct set of ME coefficients

Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assist or prevent certain protein-protein assemblies. These activities are being exploited for the development of treatments for diseases caused by protein instability and/or aberrant protein-protein interactions, such as those found in certain forms of cancers and neurodegenerative diseases. However, designing or discovering pharmacological chaperones for specific targets is challenging because of the relatively featureless protein target surfaces, the lack of suitable chemical libraries, and the shortage of efficient high-throughput screening methods. In this study, we attempted to address all these challenges by synthesizing a diverse library of small molecules that mimic protein α-helical secondary structures commonly found in protein-protein interaction surfaces. This was accompanied by establishing a facile "on-bead" high-throughput screening method that allows for rapid and efficient discovery of potential pharmacological chaperones and for identifying novel chaperones/inhibitors against a cancer-associated protein, myeloid cell leukemia 1 (MCL-1), and a Parkinson disease-associated protein, α-synuclein. Our data suggest that the compounds and methods described here will be useful tools for the development of pharmaceuticals for complex-disease targets that are traditionally deemed "undruggable.

High-Grade Hydronephrosis Predicts Poor Outcomes After Radical Cystectomy in Patients with Bladder Cancer

We examined whether the presence and severity of preoperative hydronephrosis have prognostic significance in patients who underwent radical cystectomy for transitional cell carcinoma of the bladder. The medical records of 457 patients who underwent radical cystectomy for bladder cancer between 1986 and 2005 were retrospectively reviewed. Following the Society for Fetal Urology grading system, patients were divided into low-, and high-grade hydronephrosis groups. Clinicopathologic factors associated with preoperative hydronephrosis and survival were evaluated. Of a total of 406 patients, unilateral hydronephrosis was found in 74 (18.2%), bilateral hydronephrosis in 11 (2.7%), and no hydronephoris in 321 (79.1%). Low-grade hydronephrosis was found in 57 (12.2%) patients and high-grade hydronephrosis in 28 (6%). Preoperative hydronephrosis was related to higher pT stage and lymph node invasion. In univariate analysis, the presence of hydronephrosis, hydronephrosis grade, age, pT and pN stage, tumor grade, surgical margin, number of retrieved nodes, carcinoma in situ, and lymphovascular invasion were significant prognostic factors for cancer-specific survival. In multivariate analysis, bilateral hydronephrosis and high-grade hydronephrosis remained significant predictors for decreased survival. The presence of preoperative hydronephrosis, and high-grade hydronephrosis are significant prognostic factors in patients with bladder cancer after radical cystectomy

Prediction for serious bacterial infection in febrile children aged 3 years or younger: comparison of inflammatory markers, the Laboratory-score, and a new laboratory combined model

Purpose To compare the efficacy of inflammatory markers, the Laboratory-score, and a new laboratory combined model for predicting serious bacterial infection (SBI) in young febrile children. Methods The presence of SBI was reviewed in previously healthy children aged 3 years or younger with fever (> 38℃) who visited the emergency department from 2017 through 2018. Areas under the curves (AUCs) of the receiver operating characteristic curve for SBI were compared with individual inflammatory markers (white blood cells [WBC] count, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], procalcitonin [PCT], and urine WBC count), the Laboratory-score, and a laboratory combined model. The latter model was developed using logistic regression analysis including ESR, CRP, and PCT. Results Of the 203 enrolled children, SBI was diagnosed in 58 (28.6%). For SBI prediction, the Laboratory-score showed 51.7% sensitivity (95% confidence interval [CI], 38.2%-65.0%) and 83.5% specificity (95% CI, 76.4%-89.1%). The AUC of the Laboratory-score (0.76) was significantly superior to the values of all individual inflammatory markers (WBC, 0.59 [P = 0.032]; ESR, 0.69; and CRP, 0.74 [P < 0.001]) except that of PCT (0.77, [P < 0.001]). The AUC of the laboratory combined model (0.80) was superior to that of the Laboratory-score (0.76) (P < 0.001). Conclusion In this study, the new laboratory combined model showed good predictability for SBI. This finding suggests the usefulness of combining ESR, CRP, and PCT in predicting SBI

Structural and Biochemical Bases for the Inhibition of Autophagy and Apoptosis by Viral BCL-2 of Murine γ-Herpesvirus 68

All gammaherpesviruses express homologues of antiapoptotic B-cell lymphoma-2 (BCL-2) to counter the clearance of infected cells by host antiviral defense machineries. To gain insights into the action mechanisms of these viral BCL-2 proteins, we carried out structural and biochemical analyses on the interactions of M11, a viral BCL-2 of murine γ-herpesvirus 68, with a fragment of proautophagic Beclin1 and BCL-2 homology 3 (BH3) domain-containing peptides derived from an array of proapoptotic BCL-2 family proteins. Mainly through hydrophobic interactions, M11 bound the BH3-like domain of Beclin1 with a dissociation constant of 40 nanomole, a markedly tighter affinity compared to the 1.7 micromolar binding affinity between cellular BCL-2 and Beclin1. Consistently, M11 inhibited autophagy more efficiently than BCL-2 in NIH3T3 cells. M11 also interacted tightly with a BH3 domain peptide of BAK and those of the upstream BH3-only proteins BIM, BID, BMF, PUMA, and Noxa, but weakly with that of BAX. These results collectively suggest that M11 potently inhibits Beclin1 in addition to broadly neutralizing the proapoptotic BCL-2 family in a similar but distinctive way from cellular BCL-2, and that the Beclin1-mediated autophagy may be a main target of the virus

A standardized extract of Rhynchosia volubilis Lour. exerts a protective effect on benzalkonium chloride-induced mouse dry eye model

ETHNOPHARMACOLOGICAL RELEVANCE In contrast to other leguminous plants generally used as food, Rhynchosia volubilis Loureiro, a small soybean with a black seed coat, has been used as a traditional oriental remedy for various human diseases in Eastern Asia. In this study, we demonstrated the protective effect of R. volubilis against dry eye disease. AIM OF THE STUDY We aimed to investigate whether a standardized ethanol extract of R. volubilis (EERV) can protect the cornea in a benzalkonium chloride (BAC)-induced mouse dry eye model. MATERIALS AND METHODS Experimental dry eye was induced by the instillation of 0.2% BAC on mouse cornea. A standardized ethanol extract of R. volubilis (EERV) was orally administered following BAC treatment. The positive control group was treated with commercial eye drops. Fluorescein staining, tear break-up time (BUT), and hematoxylin and eosin staining were evaluated on the ocular surface. Squamous metaplasia and apoptosis in the corneal epithelial layer were detected by immunostaining. Furthermore, the protein expression of cytochrome c, Bcl-2, and Bax was determined. RESULTS EERV treatment significantly improved fluorescein scoring, BUT, and smoothness in the cornea compared to the vehicle group. In addition, EERV inhibited squamous metaplasia and apoptosis in the cornea. The expression of cytochrome c and Bax was upregulated, while that of Bcl-2 was downregulated in the vehicle group compared with that in the control group. However, EERV treatment inhibited the expression of cytochrome c and Bax, while that of Bcl-2 was improved. CONCLUSION Standardized EERV could be a beneficial candidate for the treatment of dry eye disease