Do audible and ultrasonic sounds of intensities common in animal facilities affect the autonomic nervous system of rodents?

In animal facilities, noises, often poorly controlled, occur over a wide range of frequencies and intensities. Evidence demonstrates that audible noise and ultrasound have deleterious effects on rodent physiology, but it is not known how they affect the autonomic nervous system (ANS). This study exposed 3 unrestrained, male, Sprague-Dawley rats daily to a 15-min white noise regime (90 dB), a quiet regime, or a 15-min ultrasound regime (90 dB at 4 frequencies in the range 20 to 40 kHz)-each for several weeks—and used radiotelemetry to monitor their cardiovascular responses. Exposure to audible noise increased heart rate and mean arterial pressure. Spectral analysis of HR variability showed diminished stimulation of the parasympathetic nervous system, shifting the sympathovagal balance. However, ultrasound, at the frequencies used, did not reproducibly affect cardiovascular parameters. The preliminary data obtained from this study indicate that audible noise, but not ultrasound (delivered using the same protocol), affects the ANS. Because the cardiovascular, respiratory, renal, and gastrointestinal systems are under autonomic control, such noise could have wide-ranging effects on animal physiology.     

Predictors of belief that genetic test information about hemochromatosis should be shared with family members

We queried 101,951 white, Hispanic, black, Asian, American Indian (i.e., American Indian or Alaska Native in the United States and North American Indian, Metis, or Inuit in Canada) and Pacific Islander (including Native Hawaiian) adults who agreed to be genotypically and phenotypically screened for hemochromatosis as part of the Hemochromatosis and Iron Overload Screening (HEIRS) study about their views on sharing genetic test information with family members. Multiple logistic regression (adjusting for study site, age group, race/ethnicity, preferred language, gender, education group, income group, SF-36 General Health and Mental Health subscales, perceived benefits and limitations of genetic testing, and belief that genetic testing is a good idea) evaluated independent predictors of responding "Strongly Agree" or "Agree" versus "Disagree" or "Strongly Disagree" to the statement "Information about a person's genetic risk should be shared with family members". Agreement that genetic risk information should be shared with family members was high (93% in the overall sample of 78,952 who answered this question), but differed among racial/ethnic groups. Hispanics were significantly less likely to agree that genetic test information should be shared with family members (i.e., 88% versus 92% or more among all other ethnicities). The relationship of perceived limitations and benefits of testing, gender, and age group to the belief that information should be shared differed among racial/ethnic groups, with Spanish-preferring Hispanics being the most different from other subgroups.     

The structural basis of cooperative regulation at an alternate genetic switch

Bacteriophage lambda is a paradigm for understanding the role of cooperativity in gene regulation. Comparison of the regulatory regions of lambda and the unrelated temperate bacteriophage 186 provides insight into alternate ways to assemble functional genetic switches. The structure of the C-terminal domain of the 186 repressor, determined at 2.7 A resolution, reveals an unusual heptamer of dimers, consistent with presented genetic studies. In addition, the structure of a cooperativity mutant of the full-length 186 repressor, identified by genetic screens, was solved to 1.95 A resolution. These structures provide a molecular basis for understanding lysogenic regulation in 186. Whereas the overall fold of the 186 and lambda repressor monomers is remarkably similar, the way the two repressors cooperatively assemble is quite different and explains in part the differences in their regulatory activity.     

Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis

The Fc gamma receptors have been shown to play important roles in the initiation and regulation of many immunological and inflammatory processes and to amplify and refine the immune response to an infection. We have investigated the hypothesis that polymorphism within the FCGR genetic locus is associated with giant cell arteritis (GCA). Biallelic polymorphisms in FCGR2A, FCGR3A, FCGR3B and FCGR2B were examined for association with biopsy-proven GCA (n = 85) and healthy ethnically matched controls (n = 132) in a well-characterised cohort from Lugo, Spain. Haplotype frequencies and linkage disequilibrium (D') were estimated across the FCGR locus and a model-free analysis performed to determine association with GCA. There was a significant association between FCGR2A-131RR homozygosity (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.12 to 3.77, P = 0.02, compared with all others) and carriage of FCGR3A-158F (OR 3.09, 95% CI 1.10 to 8.64, P = 0.03, compared with non-carriers) with susceptibility to GCA. FCGR haplotypes were examined to refine the extent of the association. The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others). There was evidence of a multiplicative joint effect between homozygosity for FCGR2A-131R and HLA-DRB1*04 positivity, consistent with both of these two genetic factors contributing to the risk of disease. The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative. We have demonstrated that FCGR2A may contribute to the 'susceptibility' of GCA in this Spanish population. The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. These findings may ultimately provide new insights into disease pathogenesis.     

One-pot synthesis of pegylated ultrasmall iron-oxide nanoparticles and their in vivo evaluation as magnetic resonance imaging contrast agents

A well-defined copolymer poly(oligo(ethylene glycol) methacrylate-co-methacrylic acid) P(OEGMA-co-MAA) was studied as a novel water-soluble biocompatible coating for superparamagnetic iron oxide nanoparticles. This copolymer was prepared via a two-step procedure: a well-defined precursor poly(oligo(ethylene glycol) methacrylate-co-tert-butyl methacrylate), P(OEGMA-co-tBMA) (M(n) = 17300 g mol(-1); M(w)/M(n) = 1.22), was first synthesized by atom-transfer radical polymerization in the presence of the catalyst system copper(I) chloride/2,2'-bipyridyl and subsequently selectively hydrolyzed in acidic conditions. The resulting P(OEGMA-co-MAA) was directly utilized as a polymeric stabilizer in the nanoparticle synthesis. Four batches of ultrasmall PEGylated magnetite nanoparticles (i.e., with an average diameter below 30 nm) were prepared via aqueous coprecipitation of iron salts in the presence of variable amounts of P(OEGMA-co-MAA). The diameter of the nanoparticles could be easily tuned in the range 10-25 nm by varying the initial copolymer concentration. Moreover, the formed PEGylated ferrofluids exhibited a long-term colloidal stability in physiological buffer and could therefore be studied in vivo by magnetic resonance (MR) imaging. Intravenous injection into rats showed no detectable signal in the liver within the first 2 h. Maximum liver accumulation was found after 6 h, suggesting a prolongated circulation of the nanoparticles in the bloodstream as compared to conventional MR imaging contrast agents.     

Timing of events in mitosis

BACKGROUND: Regulation of the major transitions in the cell cycle, such as G1/S, G2/M, and metaphase to anaphase, are increasingly well understood. However, we have a poor understanding of the timing of events within each phase of the cell cycle, such as S phase or early mitosis. Two extreme models of regulation are possible. A "regulator-controlled model" in which the order of events is governed by the activation of a series of cytoplasmic regulators, such as kinases, phosphatases, or proteases; or a "substrate-controlled model" in which temporal regulation is determined by the differential responses of the cellular machinery to a common set of activators. RESULTS: We have tried to distinguish between these two models by examining the timing of both biochemical and morphological events in Xenopus egg extracts during mitosis. Several proteins respond with different delays to the activation of Cdc2. We have found that the timing of phosphorylation is largely unchanged when these proteins are exposed to extracts that have been in mitosis for various periods of time. Similarly, when Xenopus interphase nuclei are added to extracts at different times after the G2/M transition, they undergo all the expected morphological changes in the proper sequence and with very similar kinetics. CONCLUSIONS: Our results suggest that during early mitosis (from prophase to metaphase) the timing of biochemical events (such as phosphorylation) and morphological events (such as structural changes in the nucleus) is at least partly controlled by the responses of the substrates themselves to a common set of signals.     

Multivesicular bodies: a mechanism to package lytic and storage functions in one organelle?

Multivesicular bodies (MVBs) are endosomes or prevacuolar compartments. The lumens of their internal vesicles are thought to be topologically equivalent to cytoplasm and their membranes direct proteins and lipids for degradation. Here, we describe a new MVB function; in certain plant MVBs, the internal vesicles contain lytic enzymes and the surrounding 'soup' is a storage compartment. Separate vesicular pathways deliver proteins to the storage and lytic compartments. Recent data indicate that mammalian secretory lysosomes also have two compartments served by separate vesicular pathways. The formation of separate storage and lytic compartments within MVBs poses problems for membrane organization and topology that have not previously been considered in the literature. We offer a hypothetical model to address these problems.     

Age-associated biomarker profiles of human breast cancer

To explore the hypothesis that aging not only increases breast cancer incidence but also alters breast cancer biology, we correlated patient age and diagnosis with tumor histology, stage and biomarkers independently determined from two different tumor archives: an American collection of approximately 800 paraffin-embedded and immunohistochemically analyzed primary breast cancers, and an European collection of approximately 3000 cryobanked primary breast cancers analyzed by ligand-binding and enzyme immunoassay (EIA). The prognostic biomarkers chosen for comparison represented surrogate measures of tumor: (i). proliferation, growth and genetic instability (mitotic and apoptotic indices, Ki-67/MIB-1-positivity, nuclear grade, p53-positivity), (ii). endocrine-dependence (estrogen receptor (ER), progesterone receptors (PR), pS2, Bcl2), (iii). growth factor receptor-dependence (ErbB2, EGFR/ErbB1), and (iv). angiogenic, invasive and proteolytic potential (uPA, PAI-1, Cathepsin D, VEGF). No biomarker reflecting tumor angiogenic, invasive or proteolytic potential showed a significant correlation with patient age at diagnosis. In contrast, significant inverse correlations (|r|>0.1; P< or =0.05) were observed for all measures of tumor growth and genetic instability as well as growth factor receptor overexpression (ErbB2 or EGFR positivity). Only one marker of endocrine-dependence, ER expression, showed a significant positive correlation with patient age at diagnosis. In summary, these findings support the hypothesis that breast cancer biology is significantly affected by patient age. In particular, breast tumors arising in older patients have slower growth rates, are more likely to be ER-positive, and are less likely to be p53-positive, EGFR-positive or ErbB2-positive.