Relations among whole blood serotonin and sex,age, diet,and social status in Macaca nemestrina

Whole blood serotonin (WBS) determinations were made in 56 pigtailed macaques (Macaca nemestrina) with approximately equal numbers in three age groups: young-adult (4–5 years), middle-aged (13–14 years), and old (over 18 years). The animals were housed in ten living groups with one female and male of each age group in each living group. Half of the groups were fed a diet high in lipid, cholesterol, simple sugars, and sodium; the other half received a restricted diet. Three determinations per animal showed WBS levels to be stable at two times of day and at a 1-week interval, and individual differences were stable over several months' time. The mean WBS concentrations in M. nemestrina were found to be considerably higher than those reported for other species. The mean levels in females were almost 25% higher than in males. No significant effects of age, diet, or dominance status were detected.     

Argentophilic papillae of Schistosomatium douthitti cercariae (Trematoda: Schistosomatidae).

Argentophilic papillae of cercariae of Schistosomatium douthitti were studied by light microscopy. The basic number of body papillae was 56, excluding 20 at the anterior tip. The average number of tail papillae was 18. Average locations and spatial ranges of body papillae indicate a rather constant pattern. Tail papillae showed greater variability in location. Twenty papillae (10 on each side) at the anterior tip of cercariae were associated with gland duct openings. Two types of papillae were recognized with light microscopy--uniciliated bulbs and pits. The papilla pattern of S. douthitti differs from those of other species of schistosomes derived to date, and its constancy supports the usefulness of papillae in systematic studies.     

cMyBPC phosphorylation alters response to heart failure drug

JGP study shows that the phosphorylation state of cMyBPC modulates the ability of omecamtiv mecarbil to enhance myocardial force generation.

The small molecule omecamtiv mecarbil (OM) is a cardiac-specific myosin activator that is currently undergoing clinical trials for the treatment of heart failure with reduced ejection fraction. In this issue of JGP, Mamidi et al. demonstrate that OM’s ability to increase cardiac force production is altered by the phosphorylation state of cardiac myosin-binding protein C (cMyBPC), a target of β-adrenergic signaling that is often dysregulated in late-stage heart failure patients (1).(Left to right) Ranganath Mamidi, Joshua Holmes, Julian Stelzer, and colleagues reveal that the effects of the heart failure drug OM are modulated by the phosphorylation state of the contractile protein cMyBPC. For example, OM’s ability to increase force generation is significantly blunted in mouse myocardial preparations expressing phosphoablated (SA) rather than WT cMyBPC due to changes in myosin cross-bridge kinetics.OM enhances myocardial force generation by increasing the number of strongly bound myosin cross-bridges (2), partly by slowing ADP release and cross-bridge detachment (3). Though the drug has progressed to phase 3 clinical trials, little is known about how its effects may be influenced by pathophysiological changes in other sarcomeric proteins, such as cMyBPC, that regulate myosin cross-bridges and force production.During exercise or other physiological stresses, adrenaline stimulates the phosphorylation of cMyBPC by PKA, thereby accelerating cross-bridge kinetics and myocardial contractility to meet the increased demand for cardiac output (4). In late-stage heart failure patients, however, β-adrenergic signaling is dysregulated and cMyBPC phosphorylation is greatly reduced. “We wanted to test how the phosphorylation state of cMyBPC would effect OM treatment,” explains Julian Stelzer, a professor at Case Western Reserve University.Stelzer’s team, including cofirst authors Ranganath Mamidi and Joshua Holmes, prepared myocardial tissue from both WT mice and mice expressing a cMyBPC mutant that lacks the three main PKA phosphorylation sites. The researchers treated the preparations with OM and found that the ablation of cMyBPC phosphorylation significantly blunted OM’s ability to increase force production (1).Dephosphorylated cMyBPC is thought to stabilize the super-relaxed state of myosin, in which the head domains are folded back toward the filament backbone and are less available to form active cross-bridges (5). Stelzer and colleagues have previously shown that ablating cMyBPC phosphorylation slows cross-bridge kinetics (6).“This is exacerbated by the addition of OM,” Stelzer says. “It creates an even slower system that limits cross-bridge recruitment, and those that are recruited can’t really be detached.” This may reduce the effectiveness of OM in end-stage heart failure patients with low levels of cMyBPC phosphorylation.In contrast, phosphorylation of cMyBPC by PKA usually accelerates myosin cross-bridge kinetics. However, when Stelzer and colleagues treated their myocardial preparations with both PKA and OM, mimicking the scenario of an early-stage heart failure patient exercising or experiencing stress, the effects of the drug dominated the effects of the kinase.“OM did not allow any acceleration and, in fact, slowed cross-bridge kinetics even further, completely negating the effect of PKA on contractility,” Stelzer says. This could mean that early-stage patients on OM are unable to increase their cardiac output during exercise, elevating the risk of ischemia.New iterations of OM are already being explored as potential next-generation treatments for heart failure. Stelzer says that it will be important to investigate how these drugs interact with cMyBPC and other components of the contractile machinery. In the meantime, Stelzer’s laboratory is focused on developing novel therapeutic approaches involving the direct manipulation of cMyBPC phosphorylation.     

Making parallel lines meet

There is currently great interest in the use of mesenchymal stem cells as a therapy for multiple sclerosis with potential to both ameliorate inflammatory processes as well as improve regeneration and repair. Although most clinical studies have used autologous bone marrow-derived mesenchymal stem cells, other sources such as allogeneic umbilical cord-derived cells may provide a more accessible and practical supply of cells for transplantation. In this case report we present the treatment of aggressive multiple sclerosis with multiple allogenic human umbilical cord-derived mesenchymal stem cell and autologous bone marrow-derived mesenchymal stem cells over a 4 y period. The treatments were tolerated well with no significant adverse events. Clinical and radiological disease appeared to be suppressed following the treatments and support the expansion of mesenchymal stem cell transplantation into clinical trials as a potential novel therapy for patients with aggressive multiple sclerosis.     

A method for the culture of tropical seagrasses

Three tropical seagrass species were planted into 1.5 m² culture tanks and grown under the same conditions for 2 years. New shoot production and vegetation growth of both Syringodium filiforme Kütz. and Halodule wrightii Aschers. resulted in complete cover in monoculture tanks within the first year. The vegetative spread of Thalassia testudinum Banks ex König was slower than that of the other species. The culture of seagrasses in open mesocosm systems was most successful when continuous current circulation was maintained, water column nutrients were kept low, and extreme high temperatures (> 36°C) were avoided. Seagrass colonized and grew equally well in Indian River mud substratum and in quartz sand.