Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle.

Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contraction-induced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contraction-induced injury was not accompanied by increased necrosis, excitation-contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions.

Refinement and Validation of the Student Perceptions of Physician-Pharmacist Interprofessional Clinical Education Instrument.

Objective. To refine the Student Perceptions of Physician-Pharmacist Interprofessional Clinical Education (SPICE) instrument to address deficiencies observed in previous studies and to demonstrate external validity and reliability of the refined instrument in a broad population of medical and pharmacy students. Methods. The original SPICE instrument plus four pilot items generated via cognitive interviewing of students was administered to 1708 medical and pharmacy students at five academic institutions. Exploratory factor analysis was used to identify candidate model structures and evaluate their psychometric properties. Results. An improved version of the instrument was created (SPICE 2) by incorporating three pilot items and removing three original items. Validity and reliability were demonstrated. Conclusion. The SPICE 2 instrument addresses the limitations observed to date in model structure while increasing its utility. The authors recommend use of the SPICE 2 instrument moving forward.

"Off-on" aggregation-based fluorescent sensor for the detection of chloride in water.

Receptors selective for anions in aqueous media are a crucial component in the detection of anions for biological and environmental applications. Recent sensor designs have taken advantage of systems known to aggregate in solution, eliciting a fluorescent response. Herein, we demonstrate a chloride-selective fluorescent response of receptor 1(+), based on our well-established class of 2,6-bis(2-anilinoethynyl)pyridine bisureas. The fluorescence intensity ratio of 1(+)·Cl(->) aggregates in water is four times larger than the next most fluorescent anion complex, 1(+)·ClO4(->). In addition, (1)H NMR spectroscopic titrations demonstrate 1(+) binds chloride more strongly than other biologically relevant anions in solutions of both DMSO-d6 and 50/50 DMSO-d6/MeCN-d3.

Synthesis and solid-state structures of a macrocyclic receptor based on the 2,6-bis(2-anilinoethynyl)pyridine scaffold.

A fluorescent macrocyclic anion receptor based on the 2,6-bis(2-anilinoethynyl)pyridine scaffold has been synthesized to investigate the mechanism of fluorescence quenching in this class of compounds. X-ray crystallography reveals that the binding pocket of the receptor is a natural host to both H2O and HCl, accommodating either molecule in nearly identical environments. Our studies show that protonation, not collisional quenching, is responsible for the observed fluorescence quenching response.

Recommendations for a national agenda to substantially reduce cervical cancer.

PURPOSE: Prophylactic human papillomavirus (HPV) vaccines and new HPV screening tests, combined with traditional Pap test screening, provide an unprecedented opportunity to greatly reduce cervical cancer in the USA. Despite these advances, thousands of women continue to be diagnosed with and die of this highly preventable disease each year. This paper describes the initiatives and recommendations of national cervical cancer experts toward preventing and possibly eliminating this disease. METHODS: In May 2011, Cervical Cancer-Free America, a national initiative, convened a cervical cancer summit in Washington, DC. Over 120 experts from the public and private sector met to develop a national agenda for reducing cervical cancer morbidity and mortality in the USA. RESULTS: Summit participants evaluated four broad challenges to reducing cervical cancer: (1) low use of HPV vaccines, (2) low use of cervical cancer screening, (3) screening errors, and (4) lack of continuity of care for women diagnosed with cervical cancer. The summit offered 12 concrete recommendations to guide future national and local efforts toward this goal. CONCLUSIONS: Cervical cancer incidence and mortality can be greatly reduced by better deploying existing methods and systems. The challenge lies in ensuring that the array of available prevention options are accessible and utilized by all age-appropriate women-particularly minority and underserved women who are disproportionately affected by this disease. The consensus was that cervical cancer can be greatly reduced and that prevention efforts can lead the way towards a dramatic reduction in this preventable disease in our country.

Synthesis and optoelectronic properties of 2,6-bis(2-anilinoethynyl)pyridine scaffolds.

A series of sixteen bisphenylureas based on a 2,6-bis(2-anilinoethynyl)pyridine scaffold have been synthesized for use as potential anion sensors. Prior work with one of these receptors revealed a distinct fluorescence response in the presence of a suitable anion source with specificity towards chloride anion. This study demonstrates that the fluorescent properties of these receptors can be tuned through the systematic variation of the pendant functional groups.

Molecular Self Assembly: Solvent Guests Tune the Conformation of a Series of 2,6-Bis(2-anilinoethynyl)pyridine-Based Ureas.

The conformations of 2,6-bis(2-anilinoethynyl)pyridine-based urea receptors were studied by single crystal X-ray diffraction methods and revealed a rich conformational flexibility influenced by solvents. Whereas receptor L(1) in DMSO prefers an "S" conformation, receptor L(1) crystallizes in an "O" conformation from DMSO/CH(3)OH binary solvent system, and a "W" conformation in the ternary solvent mixture DMSO/toluene/1,4-dioxane. In the case of L(2), the molecule adopts an "S" conformation where water molecules are sandwiched between two molecules of L(2) to form a dimer. Similar to L(2), L(3) also forms a dimer where water molecules are sandwiched between L(3) molecules, which are capped with two molecules of DMSO. Such a capping DMSO solvate is lacking in the case of L(2). Taken together, these results demonstrate that the conformation of 2,6-bis(2-anilinoethynyl) pyridine-based urea receptors can be dramatically manipulated and tuned by the choice of crystallization solvents.

Synthesis and biological evaluation of RON-neoglycosides as tumor cytotoxins.

Cardenolides such as digitoxin have been shown to inhibit cancer cell growth, to reduce cancer metastasis, and to induce apoptosis in tumor cells. Among the most potent digitoxin-based cytotoxins identified to date are MeON-neoglycosides generated via oxyamine neoglycosylation. Here, we report our studies of oxyamine neoglycosylation aimed at facilitating the elucidation of linkage-diversified digitoxin neoglycoside structure-activity relationships. We identified conditions suitable for the convenient synthesis of digitoxin neoglycosides and found that sugar structure, rather than RON-glycosidic linkage, exerts the strongest influence on neoglycoside yield and stereochemistry. We synthesized a library of digitoxin neoglycosides and assessed their cytotoxicity against eight human cancer cell lines. Consistent with previous findings, our data show that the structure of RON-neoglycosidic linkages influences both the potency and selectivity of digitoxin neoglycosides.