Energy landscape of amyloidogenic peptide oligomerization by parallel-tempering molecular dynamics simulation: significant role of Asn ladder

Recent evidence suggests that amyloidogenic oligomers may be the toxic species in cell cultures. Thus, it is crucial to understand their structure and oligomerization mechanism in atomistic detail. By employing tens of fast central processing units and an advanced phase-space sampling algorithm, parallel-tempering molecular dynamics, we have explored the energy landscape of amyloidogenic peptide oligomerization in explicit water. A pentapeptide, DFNKF, derived from human calcitonin and its mutant, DFAKF, was simulated with a total simulation time of approximately 500 ns. The detailed oligomerization process of a DFNKF parallel beta-sheet formation at 300 K has been characterized. The assembly of a parallel beta-sheet from the amorphous state mainly occurs via a "bottleneck" channel where the interstrand Asn-Asn stacking is the major interaction. The interactions of Asn-Asn stacking include both backbone and side-chain hydrogen bonds. The Asn-Asn interactions work like "glue" by sticking the DFNKF strands together and assist the "on-pathway" oligomerization. The Asn-Asn stacking observed here is similar to the Asn ladder commonly found in globular beta-helix proteins. A control run shows that when Asn is mutated to Ala, the stability and population of the DFAKF parallel beta-sheet is decreased. Furthermore, our in vitro mutagenesis experiments show that the ability of DFAKF peptides to form amyloid fibrils is significantly reduced, in agreement with the simulations. Knowledge of the energy landscape of oligomerization may provide hints for rational drug design, preventing amyloid-associated diseases.     

Successful Management of Isolated Ventricular Inversion in an Adult

We report a case of isolated ventricular inversion in a 42-year-old woman. This rare congenital cardiac anomaly was corrected by an intraatrial baffle procedure. She also underwent left-sided double-chamber endocardial pacemaker implantation for postoperative tachycardia bradycardia syndrome.     

Congenital infiltrating lipomatosis of the face and neck

Congenital infiltrating lipomatosis is a rare clinicopathologic entity characterized by infiltrating lipomatous tumors which, although of benign nature, have a tendency to recur after surgery. This has a predilection for the extremities and the trunk and is seen as overgrowth of soft tissue and bone. It rarely affects the face and neck. We describe two cases of congenital infiltrating lipomatosis of face and neck depicting the bone and soft tissue changes seen on computed tomography, along with a review of the literature on the subject.     

Leukocyte(s) degranulation: therapeutic targets in [NTP]O and [NDP]O mediated leukocyte(s) degranulation

Extracellular nucleotide-induced stimulation and activation of peripheral blood leukocyte(s) and subsequent degranulation plays a critical role in immediate type hypersensitivity reaction and other inflammatory diseases. The extracellular nucleotides [NTP]O stimulate a P2Y receptor(s) on human PMN with the pharmacological profile similar to that of the P2Y2 receptor. Whereas, [NTP]O and [NDP]O, bind to P2Y2 and P2Y1 receptors on mononuclear leukocytes. Based on a recent proposal on the molecular mechanism of [NTP]O- and [NDP]O-induced leukocyte(s) degranulation, a scheme indicating the therapeutic targets with potential avenues for attenuating leukocyte(s) degranulation is suggested.     

Effect of a promotional campaign on heart-healthy menu choices in community restaurants

The research question examined in this study was: Does a promotional campaign impact the sales of heart-healthy menu items at community restaurants? The 8-week promotional campaign used professionally developed advertisements in daily and monthly print publications and posters and table tents in local restaurants. Nine restaurants tracked the sales of selected heart-healthy menu items and comparable menu items sold before and after a promotional campaign. The percentage of heart-healthy items sold after the campaign showed a trend toward a slight increase in heart-healthy menu item selections, although it was not statistically significant. This study and others indicate that dietetics professionals must continue to develop strategies to promote heart-healthy food choices in community restaurants.     

Therapeutic potential of monoisoamyl and monomethyl esters of meso 2,3-dimercaptosuccinic acid in gallium arsenide intoxicated rats

The dose dependent effects of monoisoamyl and monomethyl esters of meso 2,3-dimercaptosuccinic acid (DMSA) (0.1, 0.3 and 0.5 mmol kg(-1), intraperitoneally (i.p.) once daily for 5 days) to offset the characteristic biochemical, immunological, oxidative stress consequences and DNA damage (based on DNA fragmentation and comet assay) following sub-chronic administration of gallium arsenide and the mobilization of gallium and arsenic were examined. The effects of these chelators alone in normal animals too were examined on above-mentioned variables. Male Wistar rats were exposed to 10 mg kg(-1), GaAs, orally once daily for 12 weeks and were administered DMSA or two of its monoesters (monoisoamyl or monomethyl) for 5 consecutive days. DMSA was used as a positive control. DMSA and its derivatives, when given alone, generally have no adverse effects on various parameters. After 5 days of chelation therapy in GaAs pre-exposed rats, MiADMSA was most effective in the reduction of inhibited blood delta-aminolevulinic acid dehydratase (ALAD) activity and zinc protoporphyrin level while, all three chelators effectively reduced urinary ALA excretion, compared to GaAs alone exposed rats. MiADMSA was also effective, particularly at a dose of 0.3 mmol kg(-1), in enhancing the inhibited hepatic transaminase activities. Parameters indicative of oxidative stress responded less favorably to the chelation therapy, however, three chelators significantly restored the altered immunological variables. MiADMSA was relatively more effective than the other two chelators. GaAs produced significant DNA damage in the liver and kidneys and the chelation treatment had moderate but significant influence in reducing DNA damage. All three chelators significantly reduced arsenic concentration and, however, MiADMSA was more effective than the other two chelators in depleting arsenic concentration from blood and other soft tissues. A dose of 0.3 mmol kg(-1) was found to be relatively better than the other two doses examined. Gallium contents of blood and soft tissues remained uninfluenced by the chelation therapy. Significant loss of copper after MiADMSA administration, however, is of concern and requires further exploration. Additionally, further studies are required for the choice of appropriate dose, duration of treatment and possible toxic/side effects. Keeping in view the promising role of MiADMSA in the treatment of GaAs poisoning, these data will be needed for the registration of this chelating agent as licensed drug for the treatment of gallium arsenide intoxication.