Synthesis and pharmacological evaluation of 8α-estradiol derivatives

A number of 2- and 16-alkyl 8α-estradiol derivatives were synthesized and pharmacologically characterized with respect to estrogenic/antiestrogenic activities.     

No Spillover Effect of the Foreclosure Crisis on Weight Change: The Diabetes Study of Northern California (DISTANCE)

The emerging body of research suggests the unprecedented increase in housing foreclosures and unemployment between 2007 and 2009 had detrimental effects on health. Using data from electronic health records of 105,919 patients with diabetes in Northern California, this study examined how increases in foreclosure rates from 2006 to 2010 affected weight change. We anticipated that two of the pathways that explain how the spike in foreclosure rates affects weight gain—increasing stress and declining salutary health behaviors- would be acute in a population with diabetes because of metabolic sensitivity to stressors and health behaviors. Controlling for unemployment, housing prices, temporal trends, and time-invariant confounders with individual fixed effects, we found no evidence of an association between the foreclosure rate in each patient''s census block of residence and body mass index. Our results suggest, although more than half of the population was exposed to at least one foreclosure within their census block, the foreclosure crisis did not independently impact weight change.     

Occurrence of Aflatoxins and Aflatoxin-Producing Strains of Aspergillus spp. in Soybeans

Above average rainfall in Maryland during August, September, and October 1971 resulted in heavy mold growth in soybeans while still in the field. Of 28 samples of soybean seed, aflatoxins were found in 14, 2 of which had been used in poultry feed. Aflatoxins were identified by thin-layer chromatography, spectrophotometry, and chicken embryo bioassay. Aspergillus spp. were isolated from 11 samples, and 5 of these isolates produced aflatoxins when grown in liquid culture.     

Membrane filter technique for the quantification of stressed fecal coliforms in the aquatic environment.

A two-layer membrane filtration (MF) medium (injury-mitigating MF [IM-MF]) and a procedure for the enumeration of injured fecal coliforms are described. These procedures included the addition of glycerol and acetate plus reducing agents to both layers of a two-layer medium and rinsing of the filter with a rich resuscitation medium. Some changes in incubation time and temperatures were used. This method was compared with the multiple-tube fermentation most-probable-number procedure and the one-step M-FC agar-membrane filter method (direct M-FC) in terms of fecal coliform recovery from various aquatic environments that cause bacterial injury. With chlorinated sewage effluents, results of the IM-MF technique were equal to or greater than the most probable number in 9 of 18 trials and were 1.3 to 19 times greater than the M-FC method. When sewage samples were chlorinated in the laboratory, fecal coliform counts with IM-MF equaled or exceeded the most probable number in 7 of 15 trials and always exceeded the M-FC. M-FC was exceeded by IM-MF in 30 of 33 trials with clean mountain stream water. Fecal coliform bacteria that were exposed to low levels of an iodophore in the laboratory produced IM-MF counts 3 to 10 times greater than those with M-FC. A biochemical rationale for the formation of the IM-MF medium is discussed.     

Bacterial Survival in Laundered Fabrics

Bacterial survival was determined in linens (i) inoculated with Staphylococcus aureus (ii), taken from hospital isolation patients' beds, and (iii) used by students in their homes. Two different washers using temperatures of 38, 49, 54 and 60 C, respectively, for different times were employed along with a commercial tumbler dryer. Findings, after macerating the linens in a Waring blender and enumerating on nonselective media, indicate that acceptable levels of survivors can be achieved in motel and hotel linens by an 8- to 10-min wash cycle at 54 C followed by adequate drying. However, it is recommended that a wash cycle with 60 C for 10 to 13 min be employed for linens in health care factilities. The microbial significance of various laundering practices is discussed.     

Paradoxical attenuation of β2-AR function in airway smooth muscle by Gi-mediated counterregulation in transgenic mice overexpressing type 5 adenylyl cyclase

The limiting component within the receptor-G protein-effector complex in airway smooth muscle (ASM) for β(2)-adrenergic receptor (β(2)-AR)-mediated relaxation is unknown. In cardiomyocytes, adenylyl cyclase (AC) is considered the "bottleneck" for β-AR signaling, and gene therapy trials are underway to increase inotropy by increasing cardiac AC expression. We hypothesized that increasing AC in ASM would increase relaxation from β-agonists, thereby providing a strategy for asthma therapy. Transgenic (TG) mice were generated with approximately two- to threefold overexpression of type 5 AC (AC5) in ASM. cAMP and airway relaxation in response to direct activation of AC by forskolin were increased in AC5-TG. Counter to our hypothesis, isoproterenol-mediated airway relaxation was significantly attenuated (～50%) in AC5-TG, as was cAMP production, suggesting compensatory regulatory events limiting β(2)-AR signaling when AC expression is increased. In contrast, acetylcholine-mediated contraction was preserved. G(αi) expression and ERK1/2 activation were markedly increased in AC5-TG (5- and 8-fold, respectively), and β-AR expression was decreased by ～40%. Other G proteins, G protein-coupled receptor kinases, and β-arrestins were unaffected. β-agonist-mediated airway relaxation of AC5-TG was normalized to that of nontransgenic mice by pertussis toxin, implicating β(2)-AR coupling to the increased G(i) as a mechanism of depressed agonist-promoted relaxation in these mice. The decrease in β(2)-AR may account for additional relaxation impairment, given that there is no enhancement over nontransgenic after pertussis toxin, despite AC5 overexpression. ERK1/2 inhibition had no effect on the phenotype. Thus perturbing the ratio of β(2)-AR to AC in ASM by increasing AC fails to improve (and actually decreases) β-agonist efficacy due to counterregulatory events.     

Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression,but non-specifically enhanced on induction of Tax expression

Background

Immunogenetic evidence indicates that cytotoxic T lymphocytes (CTLs) specific for the weak CTL antigen HBZ limit HTLV-1 proviral load in vivo, whereas there is no clear relationship between the proviral load and the frequency of CTLs specific for the immunodominant antigen Tax. In vivo, circulating HTLV-1-infected cells express HBZ mRNA in contrast, Tax expression is typically low or undetectable. To elucidate the virus-suppressing potential of CTLs targeting HBZ, we compared the ability of HBZ- and Tax-specific CTLs to lyse naturally-infected cells, by co-incubating HBZ- and Tax-specific CTL clones with primary CD4⁺ T cells from HLA-matched HTLV-1-infected donors. We quantified lysis of infected cells, and tested whether specific virus-induced host cell surface molecules determine the susceptibility of infected cells to CTL-mediated lysis.

Results

Primary infected cells upregulated HLA-A*02, ICAM-1, Fas and TRAIL-R1/2 in concert with Tax expression, forming efficient targets for both HTLV-1-specific CTLs and CTLs specific for an unrelated virus. We detected expression of HBZ mRNA (spliced isoform) in both Tax-expressing and non-expressing infected cells, and the HBZ_26–34 epitope was processed and presented by cells transfected with an HBZ expression plasmid. However, when coincubated with primary cells, a high-avidity HBZ-specific CTL clone killed significantly fewer infected cells than were killed by a Tax-specific CTL clone. Finally, incubation with Tax- or HBZ-specific CTLs resulted in a significant decrease in the frequency of cells expressing high levels of HLA-A*02.

Conclusions

HTLV-1 gene expression in primary CD4⁺ T cells non-specifically increases susceptibility to CTL lysis. Despite the presence of HBZ spliced-isoform mRNA, HBZ epitope presentation by primary cells is significantly less efficient than that of Tax.

     

Considering the Role of Time Budgets on Copy-Error Rates in Material Culture Traditions: An Experimental Assessment

Ethnographic research highlights that there are constraints placed on the time available to produce cultural artefacts in differing circumstances. Given that copying error, or cultural ‘mutation’, can have important implications for the evolutionary processes involved in material culture change, it is essential to explore empirically how such ‘time constraints’ affect patterns of artefactual variation. Here, we report an experiment that systematically tests whether, and how, varying time constraints affect shape copying error rates. A total of 90 participants copied the shape of a 3D ‘target handaxe form’ using a standardized foam block and a plastic knife. Three distinct ‘time conditions’ were examined, whereupon participants had either 20, 15, or 10 minutes to complete the task. One aim of this study was to determine whether reducing production time produced a proportional increase in copy error rates across all conditions, or whether the concept of a task specific ‘threshold’ might be a more appropriate manner to model the effect of time budgets on copy-error rates. We found that mean levels of shape copying error increased when production time was reduced. However, there were no statistically significant differences between the 20 minute and 15 minute conditions. Significant differences were only obtained between conditions when production time was reduced to 10 minutes. Hence, our results more strongly support the hypothesis that the effects of time constraints on copying error are best modelled according to a ‘threshold’ effect, below which mutation rates increase more markedly. Our results also suggest that ‘time budgets’ available in the past will have generated varying patterns of shape variation, potentially affecting spatial and temporal trends seen in the archaeological record. Hence, ‘time-budgeting’ factors need to be given greater consideration in evolutionary models of material culture change.