No abstract

A sequence within the E2 domain of soluble amyloid precursor protein (sAPP) stimulates iron efflux. This activity has been attributed to a ferroxidase activity suggested for this motif. We demonstrate that the stimulation of efflux supported by this peptide and by sAPPa is due to their stabilization of the ferrous iron exporter, ferroportin (Fpn), in the plasma membrane of human brain microvascular endothelial cells (hBMVEC). The peptide does not bind ferric iron explaining why it does not and thermodynamically cannot promote ferrous iron autoxidation. This peptide specifically pulls Fpn down from the plasma membrane of hBMVEC; based on these results, FTP, for ferroportin-targeting peptide, correctly identifies the function of this peptide. The data suggest that in stabilizing Fpn via the targeting due to the FTP sequence, sAPP will increase the flux of iron into the cerebral interstitium. This inference correlates with the observation of significant iron deposition in the amyloid plaques characteristic of Alzheimers disease.

[Purpose] The present study investigated the effect of an exercise program for posture correction on musculoskeletal pain. [Subjects] Between September 2, 2013 and November 3, 2013, an exercise program was performed in 88 students from S University in K city (male students, n = 34; female students, n = 54). [Methods] The exercise program for posture correction was performed for 20 minutes per session, 3 times a week for 8 weeks. Pain levels were measured using a pain scale, and pain levels before and after the exercise program were compared. [Results] Overall, pain levels of the participants were lower after the exercise program than before the program, and significant differences in pain levels were noted in the shoulders, middle back, and lower back. [Conclusion] In conclusion, shoulder pain, mid back pain, and low back pain were relieved with the exercise program for posture correction. Therefore, the findings of this study can be used to improve the work efficiency of students as well as people engaged in sedentary work.

Fluorescent indicators are widely used to visualize calcium dynamics downstream of membrane depolarization or G protein-coupled receptor activation, but are poorly suited for non-invasive imaging in mammals. Here, we report a bright calcium-modulated bioluminescent indicator named Orange CaMBI. Orange CaMBI reports calcium dynamics in single cells and, in the context of a transgenic mouse, reveals calcium oscillations in whole organs in an entirely noninvasive manner.

Background:The pyruvate dehydrogenase complex produces acetyl-CoA and NADH, utilizing three protein components whose structural interactions need elucidation. Results: The E3 structure and interaction loci between E2 and E3 were determined. Conclusion:The peripheral subunit-binding domain of E2 establishes key interactions with E1 and E3. Significance: The multifaceted approach used could help delineate interaction surfaces in other 2-oxoacid dehydrogenase complexes.

These results suggest that Korean ethnicity compared with US white ethnicity is an independent favorable prognostic factor for OS in NSCLC. In addition, greater survival benefit among Korean patients with NSCLC was noted in the postepidermal growth factor receptor tyrosine kinase inhibitor era (2002 and after) compared with US white ethnicity.

Mycobacterium tuberculosis (Mtb) remains the leading single cause of death from bacterial infection. Here we explored the possibility of species-selective inhibition of lipoamide dehydrogenase (Lpd), an enzyme central to Mtb's intermediary metabolism and antioxidant defense. High-throughput screening of combinatorial chemical libraries identified triazaspirodimethoxybenzoyls as highnanomolar inhibitors of Mtb's Lpd that were noncompetitive versus NADH, NAD + , and lipoamide and >100-fold selective compared to human Lpd. Efficacy required the dimethoxy and dichlorophenyl groups. The structure of an Lpd-inhibitor complex was resolved to 2.42 Å by X-ray crystallography, revealing that the inhibitor occupied a pocket adjacent to the Lpd NADH/NAD + binding site. The inhibitor did not overlap with the adenosine moiety of NADH/NAD + but did overlap with positions predicted to bind the nicotinamide rings in NADH and NAD + complexes. The dimethoxy ring occupied a deep pocket adjacent to the FAD flavin ring where it would block coordination of the NADH nicotinamide ring, while the dichlorophenyl group occupied a more exposed pocket predicted to coordinate the NAD + nicotinamide. Several residues that are not conserved between the bacterial enzyme and its human homolog were predicted to contribute both to inhibitor binding and species selectivity, as confirmed for 3 residues by analysis of the corresponding mutant Mtb Lpd proteins. Thus non-conservation of residues lining the electrontransfer tunnel in Mtb Lpd can be exploited for development of species-selective Lpd inhibitors.Most antibiotics with known mechanisms of action target bacterial synthesis of nucleic acids, protein, cell walls or folate (1). The practice of focusing antibiotic development almost solely on these targets may have contributed to a steep decline in the rate of introduction of new antiinfectives, while emergence of drug resistance has continued unabated (2,3). The need to † This work was supported by NIH grants AI064768 and DK080748, the Milstein Program in Chemical Biology of Infectious Diseases and the Milstein Chemistry Core Facility. # The atomic coordinates and structure factors have been deposited in the Protein Data Bank with the accession code 3II4. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript identify inhibitors of new bacterial targets is particularly acute in tuberculosis (TB) 1 . TB is second only to HIV as a leading cause of death from infectious disease, and is the leading cause of death in people infected with HIV (4). TB cases resistant to all approved anti-infectives have been reported in 55 countries (5). TB chemotherapy is particularly challenging because therapy is more prolonged than for almost any other bacterial infection. Prolonged therapy is required because some populations of Mtb are phenotypically tolerant to anti-infective agents that target pathways used by replicating Mtb to build biomass. Phenotypic tolerance is believed to arise when some of the bacteria persist in a non-replica...

This study was designed to determine the effect of an academic-workplace partnership intervention, "3,000 more steps," on improving physical activity (PA) and body composition of workers, and compare the characteristics of those workers who completed and did not complete the program. Participants were 70 sedentary office workers from an airline company. Pedometers determined their daily steps, and body composition was compared before and after the 8-week intervention; 39 of 70 (55.7%) participants completed the program. Daily steps increased from 5,811 to 9,240, and fat mass, waist-hip ratio, and body mass index (BMI) decreased for the completers. Non-completers had lower average PA and higher average fat mass at baseline than did completers. Overall, a workplace PA program could be successfully undertaken by occupational health nurses and a research team in partnership. However, to implement a cost-effective intervention program for inactive workers, further research is needed to ascertain why some workers do not complete the program.