Human subtelomeric WASH genes encode a new subclass of the WASP family

Subtelomeres are duplication-rich, structurally variable regions of the human genome situated just proximal of telomeres. We report here that the most terminally located human subtelomeric genes encode a previously unrecognized third subclass of the Wiskott-Aldrich Syndrome Protein family, whose known members reorganize the actin cytoskeleton in response to extracellular stimuli. This new subclass, which we call WASH, is evolutionarily conserved in species as diverged as Entamoeba. We demonstrate that WASH is essential in Drosophila. WASH is widely expressed in human tissues, and human WASH protein colocalizes with actin in filopodia and lamellipodia. The VCA domain of human WASH promotes actin polymerization by the Arp2/3 complex in vitro. WASH duplicated to multiple chromosomal ends during primate evolution, with highest copy number reached in humans, whose WASH repertoires vary. Thus, human subtelomeres are not genetic junkyards, and WASH's location in these dynamic regions could have advantageous as well as pathologic consequences.     

Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: evidence for the critical period hypothesis

Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women. This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger (ages 50-62) and older (ages 70-81) postmenopausal women. Twenty-two postmenopausal women were randomly and blindly placed on 1 mg of 17-beta estradiol orally for 1 month then 2 mg for 2 months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory and attention were assessed. Subjects were administered either the antimuscarinic drug scopolamine (SCOP), the antinicotinic drug mecamylamine (MECA), or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another 3 months and repeated the challenges. Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory (the Buschke Selective Reminding Task) for the younger group only, while estradiol treatment impaired performance of the older group. The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects, supporting the concept of a critical period for postmenopausal estrogen use.     

Controlling the hydration of covalently immobilised penicillin G amidase in low-water medium: properties and use of Celite R-640

The study describes how Celite R-640 adsorbs liquid water in toluene and vapour water from a gas phase. In toluene, Celite R-640 is able to maintain the water activity (a_w) constant within broad ranges of water concentrations. The a_w values are strongly related to the original hydration of the Celite batches, but prolonged drying confers comparable and reproducible properties to the different batches. The use of Celite R-640 in controlling the hydration and activity of covalently immobilised PGA in toluene is reported.     

Assessing pedometer accuracy while walking, skipping, galloping, sliding, and hopping

The purpose of this study was to determine the accuracy of the pedometer when walking, skipping, galloping, sliding, and hopping. One hundred-two college students were fitted with a pedometer (Walk4Life LS-7010) at mid-thigh on the right and left of the hip. Participants then performed the randomly assigned movements for the length (26 m) of a hardwood court playing surface, during which time the investigator tallied the steps with a hand counter. Each step with the lead foot elicited a tally on the counter. Participants were instructed to perform the movement at a brisk pace, to jump-stop at the end of the court, and to remain still until after the pedometer reading was recorded. Repeated measure ANOVAs using the Bonferroni technique were used to compare differences between pedometer counts and hand counts. Significant differences were evident between the hand tally counts and readings from the right and left pedometers during all five locomotor movements (P < .01). Mean error was lowest between the hand tally and the average of the right and left pedometers while walking (-1.35 +/- 1.60) and hopping (-2.94 +/- 2.33), and increased while sliding (-6.42 +/- 4.78), galloping (-8.22 +/- 4.63), and skipping (-8.30 +/- 4.45). Results indicate the pedometer may not consistently register the vertical force produced by the trail foot contact, the lead foot contact, or a combination of the two while skipping, galloping, and sliding. Though the pedometer is a valid instrument when estimating physical activity levels, caution is urged when interpreting movements other than walking.     

The effect of psychosis associated CACNA1C,and its epistasis with ZNF804A,on brain function

CACNA1C‐rs1006737 and ZNF804A‐rs1344706 polymorphisms are among the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction)—to better understand how they might induce risk. We recently reported effects on functional VF‐related (for ZNF804A‐rs1344706) and structural (for both) connectivity. We genotyped and fMRI‐scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C‐rs1006737, and its interaction with ZNF804A‐rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions—PPI). Using public data, we reported effects of CACNA1C‐rs1006737 and diagnosis on brain expression. The CACNA1C‐rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto‐temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up‐regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole‐brain, voxel‐wise, and familywise‐error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis—which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets.     

Simvastatin Ameliorates Matrix Stiffness-Mediated Endothelial Monolayer Disruption

Arterial stiffening accompanies both aging and atherosclerosis, and age-related stiffening of the arterial intima increases RhoA activity and cell contractility contributing to increased endothelium permeability. Notably, statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors whose pleiotropic effects include disrupting small GTPase activity; therefore, we hypothesized the statin simvastatin could be used to attenuate RhoA activity and inhibit the deleterious effects of increased age-related matrix stiffness on endothelial barrier function. Using polyacrylamide gels with stiffnesses of 2.5, 5, and 10 kPa to mimic the physiological stiffness of young and aged arteries, endothelial cells were grown to confluence and treated with simvastatin. Our data indicate that RhoA and phosphorylated myosin light chain activity increase with matrix stiffness but are attenuated when treated with the statin. Increases in cell contractility, cell-cell junction size, and indirect measurements of intercellular tension that increase with matrix stiffness, and are correlated with matrix stiffness-dependent increases in monolayer permeability, also decrease with statin treatment. Furthermore, we report that simvastatin increases activated Rac1 levels that contribute to endothelial barrier enhancing cytoskeletal reorganization. Simvastatin, which is prescribed clinically due to its ability to lower cholesterol, alters the endothelial cell response to increased matrix stiffness to restore endothelial monolayer barrier function, and therefore, presents a possible therapeutic intervention to prevent atherogenesis initiated by age-related arterial stiffening.     

PRIMARY PRODUCTION OF EDAPHIC ALGAL COMMUNITIES IN A MISSISSIPPI SALT MARSH1

Primary production rates of edaphic algae associated with the sediments beneath four monospecific canopies of vascular plants were determined over an annual cycle in a Mississippi salt marsh. The edaphic algal flora was dominated by small, motile pennate diatoms. Algal production (as measured by ¹⁴C uptake) was generally highest in spring-early summer and lowest in fall. Hourly rates ranged from a low of 1.4 mg C/m² in Juncus roemerianus Scheele to a high of 163 mg C/m² beneath the Scirpus olneyi gray canopy. Stepwise multiple regressions identified a soil moisture index and chlorophyll a as the best environmental predictors of hourly production; light energy reaching the marsh surface and sediment and air temperature proved of little value. Adding the relative abundances of 33 diatom taxa to the set of independent variables only slightly increased R²; however, virtually all variables selected were diatom taxa. R² was only 0.38 for the Spartina alterniflora Loisel. habitat but ranged from 0.70 to 0.87 for the remaining three vascular plant zones. Annual rates of algal production (g C/m²) were estimated as follows: Juncus (28), Spartina (57), Distichlis spicata (L.) Greene (88), and Scirpus (151). The ratio of annual edaphic algal production to vascular plant net aerial production (EAP / VPP) was 10–12% for the first three habitats and 61% for Scirpus. Chlorophyll a concentrations, annual algal production rates, and EAP / VPP values were comparable to those determined in Texas, Delaware, and Massachusetts salt marshes but lower than those reported for Georgia and particularly California marshes.