[Opposite Effects of Histone H1 and HMGN5 Protein on Distant Interactions in Chromatin].

Transcriptional enhancers in the cell nuclei typically interact with the target promoters in cis over long stretches of chromatin, but the mechanism of this communication remains unknown. Previously we have developed a defined in vitro system for quantitative analysis of the rate of distant enhancer-promoter communication (EPC) and have shown that the chromatin fibers maintain efficient distant EPC in cis. Here we investigate the roles of linker histone H1 and HMGN5 protein in EPC. A considerable negative effect of histone H1 on EPC depending on its C- and N-tails was shown. Protein HMGN5 that affects chromatin compaction and is associated with active chromatin counteracts EPC inhibition by H1. The data suggest that the efficiency of the interaction between the enhancer and the promoter depends on the structure and dynamics of the chromatin fiber localized between them and can be regulated by proteins associated with chromatin.

Treating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement.

Acute allergic symptoms are caused by allergen-induced crosslinking of allergen-specific immunoglobulin E (IgE) bound to Fc-epsilon receptors on effector cells. Desensitization with allergen-specific immunotherapy (SIT) has been used for over a century, but the dominant protective mechanism remains unclear. One consistent observation is increased allergen-specific IgG, thought to competitively block allergen binding to IgE. Here we show that the blocking potency of the IgG response to Cat-SIT is heterogeneous. Next, using two potent, pre-selected allergen-blocking monoclonal IgG antibodies against the immunodominant cat allergen Fel d 1, we demonstrate that increasing the IgG/IgE ratio reduces the allergic response in mice and in cat-allergic patients: a single dose of blocking IgG reduces clinical symptoms in response to nasal provocation (ANCOVA, p = 0.0003), with a magnitude observed at day 8 similar to that reported with years of conventional SIT. This study suggests that simply augmenting the blocking IgG/IgE ratio may reverse allergy.

The microwave properties of simulated melting precipitation particles: sensitivity to initial melting.

A simplified approach is presented for assessing the microwave response to the initial melting of realistically-shaped ice particles. This paper is divided into two parts: (1) a description of the Single Particle Melting Model (SPMM): a heuristic melting simulation for ice-phase precipitation particles of any shape or size. SPMM is applied to two simulated aggregate snow particles, simulating melting up to 0.15 melt fraction by mass; and (2) the computation of the single-particle microwave scattering and extinction properties these hydrometeors, using the discrete dipole approximation (via DDSCAT), at the following selected frequencies: 13.4, 35.6, 94.0 GHz for radar applications; and 89, 165.0 and 183.31 GHz for radiometer applications. These selected frequencies are consistent with current microwave remote sensing platforms, such as CloudSat and the Global Precipitation Measurement (GPM) mission. Comparisons with calculations using variable-density spheres indicate significant deviations in scattering and extinction properties throughout the initial range of melting (liquid volume fractions less than 0.15). Integration of the single-particle properties over an exponential particle-size distribution provides additional insight into idealized radar reflectivity and passive microwave brightness temperature sensitivity to variations in size/mass, shape, melt fraction, and particle orientation.

Silicon micromachined ultrasonic scalpel for the dissection and coagulation of tissue.

This work presents a planar, longitudinal mode ultrasonic scalpel microfabricated from monocrystalline silicon wafers. Silicon was selected as the material for the ultrasonic horn due to its high speed of sound and thermal conductivity as well as its low density compared to commonly used titanium based alloys. Combined with a relatively high Young's modulus, a lighter, more efficient design for the ultrasonic scalpel can be implemented which, due to silicon batch manufacturing, can be fabricated at a lower cost. Transverse displacement of the piezoelectric actuators is coupled into the planar silicon structure and amplified by its horn-like geometry. Using finite element modeling and experimental displacement and velocity data as well as cutting tests, key design parameters have been identified that directly influence the power efficiency and robustness of the device as well as its ease of controllability when driven in resonance. Designs in which the full- and half-wave transverse modes of the transducer are matched or not matched to the natural frequencies of the piezoelectric actuators have been evaluated. The performance of the Si micromachined scalpels has been found to be comparable to existing commercial titanium based ultrasonic scalpels used in surgical operations for efficient dissection of tissue as well as coaptation and coagulation of tissue for hemostasis. Tip displacements (peak-to-peak) of the scalpels in the range of 10-50 µm with velocities ranging from 4 to 11 m/s have been achieved. The frequency of operation is in the range of 50-100 kHz depending on the transverse operating mode and the length of the scalpel. The cutting ability of the micromachined scalpels has been successfully demonstrated on chicken tissue.

Nucleosome positioning and composition modulate in silico chromatin flexibility.

The dynamic organization of chromatin plays an essential role in the regulation of gene expression and in other fundamental cellular processes. The underlying physical basis of these activities lies in the sequential positioning, chemical composition, and intermolecular interactions of the nucleosomes-the familiar assemblies of ∼150 DNA base pairs and eight histone proteins-found on chromatin fibers. Here we introduce a mesoscale model of short nucleosomal arrays and a computational framework that make it possible to incorporate detailed structural features of DNA and histones in simulations of short chromatin constructs. We explore the effects of nucleosome positioning and the presence or absence of cationic N-terminal histone tails on the 'local' inter-nucleosomal interactions and the global deformations of the simulated chains. The correspondence between the predicted and observed effects of nucleosome composition and numbers on the long-range communication between the ends of designed nucleosome arrays lends credence to the model and to the molecular insights gleaned from the simulated structures. We also extract effective nucleosome-nucleosome potentials from the simulations and implement the potentials in a larger-scale computational treatment of regularly repeating chromatin fibers. Our results reveal a remarkable effect of nucleosome spacing on chromatin flexibility, with small changes in DNA linker length significantly altering the interactions of nucleosomes and the dimensions of the fiber as a whole. In addition, we find that these changes in nucleosome positioning influence the statistical properties of long chromatin constructs. That is, simulated chromatin fibers with the same number of nucleosomes exhibit polymeric behaviors ranging from Gaussian to worm-like, depending upon nucleosome spacing. These findings suggest that the physical and mechanical properties of chromatin can span a wide range of behaviors, depending on nucleosome positioning, and that care must be taken in the choice of models used to interpret the experimental properties of long chromatin fibers.

Prasugrel vs. clopidogrel in acute coronary syndrome patients treated with prasugrel.

WHAT IS KNOWN AND OBJECTIVE: Current guidelines recommend a combination of clopidogrel and aspirin for management of patients who have experienced an acute coronary syndrome (ACS). Additional antiplatelet agents have been recently approved. Few comparative effectiveness studies are available for these new agents. Accordingly, we evaluated effect on time to hospital admission and resource utilization (number of hospitalizations, ER visits and outpatient visits) of prasugrel vs. clopidogrel in prasugrel-treated patients as assessed in a matched cohort. METHODS: Based on the Truven Health Analytics MarketScan database from 01 January 2009 through 31 July 2012, a retrospective prasugrel-clopidogrel matched cohort was created. Inferences for average treatment effect over 1 and 12 months on time to hospitalization and resource utilization were performed by (i) frequentist Kaplan-Meier estimation with a Cox proportional hazard model and Lin's cost history method for censored resource utilization outcomes and (ii) Bayesian discrete-time hazard and negative binomial models. RESULTS AND DISCUSSION: The 10,963 matched pairs were well balanced on baseline characteristics. Frequentist analyses of time to hospital admission over 365 days and mean all-cause resource utilization over 30 and 365 days showed no statistical differences between prasugrel and clopidogrel (P-values > 0·05). Based on Bayesian analysis of time to admission over 12 months, there was positive evidence of equivalence (0·987 probability of equivalence at a 10% equivalence margin and a Bayes factor of 0·611). Although the frequentist analyses for number of all-cause hospitalizations showed a lack of a significant difference at Months 1 and 12, the Bayesian data analysis showed positive evidence of superiority of clopidogrel at Month 1 (Bayes factor: 5·369); however, at Month 12, there was little evidence of superiority of one treatment over the other (Bayes factor: 0·422). WHAT IS NEW AND CONCLUSION: Using frequentist and Bayesian data analyses, in prasugrel-treated patients, clopidogrel was equivalent to prasugrel for time to hospital admission over 12 months and there was positive evidence that it was superior to prasugrel for number of hospitalizations over the first month of treatment.

Comparative susceptibility among three stocks of yellow perch, Perca flavescens (Mitchill), to viral haemorrhagic septicaemia virus strain IVb from the Great Lakes.

The Great Lakes strain of viral haemorrhagic septicaemia virus IVb (VHSV-IVb) is capable of infecting a wide number of naive species and has been associated with large fish kills in the Midwestern United States since its discovery in 2005. The yellow perch, Perca flavescens (Mitchill), a freshwater species commonly found throughout inland waters of the United States and prized for its high value in sport and commercial fisheries, is a species documented in several fish kills affiliated with VHS. In the present study, differences in survival after infection with VHSV IVb were observed among juvenile fish from three yellow perch broodstocks that were originally derived from distinct wild populations, suggesting innate differences in susceptibility due to genetic variance. While all three stocks were susceptible upon waterborne exposure to VHS virus infection, fish derived from the Midwest (Lake Winnebago, WI) showed significantly lower cumulative % survival compared with two perch stocks derived from the East Coast (Perquimans River, NC and Choptank River, MD) of the United States. However, despite differences in apparent susceptibility, clinical signs did not vary between stocks and included moderate-to-severe haemorrhages at the pelvic and pectoral fin bases and exophthalmia. After the 28-day challenge was complete, VHS virus was analysed in subsets of whole fish that had either survived or succumbed to the infection using both plaque assay and quantitative PCR methodologies. A direct correlation was identified between the two methods, suggesting the potential for both methods to be used to detect virus in a research setting.

In-hospital risk of venous thromboembolism and bleeding and associated costs for patients undergoing total hip or knee arthroplasty.

OBJECTIVE: Benefits of anti-coagulation for venous thromboembolism (VTE) prevention in total hip and knee arthroplasty (THA/TKA) may be offset by increased risk of bleeding. The aim was to assess in-hospital risk of VTE and bleeding after THA/TKA and quantify any increased costs. METHODS: Healthcare claims from the Premier Perspective(TM) Comparative Hospital Database (January 2000-September 2008) were selected for subjects ≥ 18 years with ≥ 1 diagnosis code for THA/TKA. VTE was defined as ≥ 1 code for deep vein thrombosis or pulmonary embolism. Bleeding was classified as major/non-major. Incremental in-hospital costs associated with VTE and bleeding were calculated as cost differences between inpatients with VTE or bleeding matched 1:1 with inpatients without VTE or bleeding. RESULTS: A total of 820,197 inpatient stays were identified: 8042 had a VTE event and 7401 a bleeding event (2740 major bleeding). The risks of VTE, any bleeding, and major bleeding were 0.98, 0.90, and 0.33/100 inpatient stays, respectively. Mean incremental in-hospital costs per inpatient were $2663 for VTE, $2028 for bleeding, and $3198 for major bleeding. LIMITATIONS: These included possible inaccuracies or omissions in procedures, diagnoses, or costs of claims data; no information on the amount of blood transfused or decreases in the hemoglobin level to evaluate bleeding event severity; and potential biases due to the observational design of the study. CONCLUSIONS: In-hospital risk and incremental all-cause costs with THA/TKA were higher for VTE than for bleeding. Despite higher costs, major bleeding occurred less frequently than VTE, suggesting a favorable benefit/risk profile for VTE prophylaxis in THA/TKA.

Estimating the economic impact of a half-day reduction in length of hospital stay among patients with community-acquired pneumonia in the US.

BACKGROUND: A recent study suggested that levofloxacin significantly reduces the hospital length of stay (LOS), by 0.5 days (p = 0.02), relative to moxifloxacin in patients with community-acquired pneumonia (CAP). The current analysis evaluated the potential economic impact of this half-day reduction in LOS. METHODS: A cost model was developed to estimate the impact of a half-day reduction in LOS for CAP hospitalizations in the US. CAP incidence, hospitalization rate, and costs were obtained from published studies in PubMed and from publicly available government sources. The average daily cost of hospitalization was estimated for fixed costs, which comprise 59% of total inpatient costs. Costs from prior years were inflated to 2007 US dollars using the consumer price index. A range of cost savings, calculated using inpatient CAP costs from several studies, was extrapolated to the US CAP population. RESULTS: Using the Centers for Disease Control National Hospital Discharge estimate of 5.3 days LOS for CAP, and an average cost (2007 $US) of $13,009 per CAP hospitalization, a daily fixed cost of $1448 was estimated. The resultant half-day reduction in costs associated with LOS was $724/hospitalization (range $457 to $846/hospitalization). When fixed and variable costs were considered, the estimated savings were $1227.27/episode. The incidence of CAP was estimated to be 1.9% (5.7 million cases/year based on current population census), and the estimated rate of CAP hospitalization was 19.6% (1.1 million annual hospitalizations). At $13,009/CAP-related hospitalization, total fixed inpatient costs of $8.6 billion annually were projected. The half-day reduction in LOS would therefore generate potential annual savings of approximately $813 million (range $513 million to $950 million). When total costs (fixed plus variable) were estimated, the mean savings for a half-day reduction would be approximately $1227/episode (range of $775 to $1434) or $1.37 billion annually in the US CAP population (range of $871 million to $1.6 billion). Limitations include the use of a single study for the estimation of fixed costs but a diversity of sources used for estimates of other variables, and lack of data with respect to the effects on costs of diagnostic-related groups, discounted contracts, and capitated payments. CONCLUSIONS: A relatively small decrease in LOS in CAP can have a substantial cost impact, with estimated savings of $457 to $846 per episode or $500-$900 million annually. Additional evaluation is warranted for interpreting these cost-savings in the context of current antibiotic prescribing patterns.

Antibodies for HIV treatment and prevention: window of opportunity?

Monoclonal antibodies are routinely used as therapeutics in a number of disease settings and have thus also been explored as potential treatment for human immunodeficiency virus (HIV)-1 infection. Antibodies targeting viral antigens, and those directed to the cellular receptors, have been considered for use in prevention and therapy. For virus-targeted antibodies, attention has focused primarily on their neutralizing activity, but such antibodies also have the potential to exert antiviral effects via effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), opsonization, or complement activation. Anti-cell antibodies act through occlusion or down-modulation of the viral receptors with notable impact in vivo, as recent trials have shown. This review summarizes the diverse specificities and modes of action of therapeutic antibodies against HIV-1 infection. Successes, challenges, and future opportunities of harnessing antibodies for therapy of HIV-1 infection are discussed.

Time course of adverse events most commonly associated with topiramate for migraine prevention.

The efficacy, safety and tolerability of topiramate has been demonstrated in three large multicenter, randomized, double-blind, placebo-controlled trials. To characterize the time course of adverse events (AEs) that led to treatment discontinuation in >/=2% of patients who received topiramate 100 mg/day during three pivotal, multicenter, randomized, double-blind, placebo-controlled, and 26-week trials. The pooled population comprised all randomized patients who reported safety data during the double-blind phase (topiramate 100 mg/day, n = 386; placebo n = 372), which consisted of a 4-week titration period and a 22-week maintenance period. Incidence, time to onset, and cumulative mean rate of AEs were assessed. Overall, AEs led to treatment discontinuation in 24.9% of patients receiving topiramate 100 mg/day and 11.0% receiving placebo (P < 0.001). AEs leading to discontinuation during the double-blind phase in > or =2% of patients included paresthesia (8.0% discontinued), any cognitive symptoms (7.3% discontinued), fatigue (4.7% discontinued), insomnia (3.4% discontinued), nausea (2.3% discontinued), loss of appetite, anxiety, and dizziness (2.1% discontinued because each AE). Most AEs began during the titration period. Paresthesia, any cognitive symptoms, nausea, and loss of appetite occurred at a higher rate in the topiramate group than in the placebo group (P < 0.01). AEs leading to discontinuation of topiramate are probably to occur during dose titration. If a patient has not experienced one of these AEs within the first 6 weeks of initiating topiramate 100 mg/day, these AEs are unlikely to occur.

IL-12p70 and IL-18 gene-modified dendritic cells loaded with tumor antigen-derived peptides or recombinant protein effectively stimulate specific Type-1 CD4+ T-cell responses from normal donors and melanoma patients in vitro.

Although CD4(+) Type-1T helper (Th1) cells secreting interferon-gamma (IFN-gamma) appear to play an essential role in promoting durable antitumor immunity, we have previously shown that patients with cancer exhibit dysfunctional Th1-type responses against epitopes derived from tumor antigens, such as MAGE-A6. Here, we engineered human dendritic cells (DCs) to secrete high levels of the IFN-gamma-inducing cytokines, interleukin (IL)-12p70 and IL-18, via recombinant adenoviral infection to generate an in vitro stimulus capable of promoting previously deficient patient Th1-type responses. Dendritic cells co-infected with Ad.IL-12 and Ad.IL-18 (DC.IL-12/18) were more effective at stimulating MAGE-A6-specific Th1-type CD4(+) T-cell responses than DCs infected with either of the cytokine vectors alone, control Ad.Psi5 virus or uninfected DCs. Furthermore, we show that DC.IL-12/18 loaded with recombinant MAGE-A6 protein (rMAGE) and used as in vitro stimulators promote Th1-type immunity that is frequently directed against multiple MAGE-A6-derived epitopes. The superiority of DC.IL-12/18-based stimulations in melanoma patients was independent of disease stage or current disease status. Based on these results, we believe this modality may prove clinically useful as a vaccine platform to promote the recovery of tumor antigen-specific, Th1-type CD4(+) T-cell responses in patients with cancer.

Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study.

OBJECTIVE: The effects of long-term triphasic oral contraceptive administration on bone mineral density (BMD) were investigated in premenopausal women with hypothalamic amenorrhea (HA) and osteopenia. METHODS: After completing three 28-day cycles in the double-blind phase of a placebo-controlled trial, women (mean age, 26.7 years) who received norgestimate 180-250 microg/ethinyl estradiol 35 microg (NGM/EE, n = 15) or placebo (n = 12) in the double-blind phase were to receive open-label NGM/EE for 10 additional cycles. RESULTS: For subjects completing > or =10 NGM/EE treatment cycles, mean posteroanterior total lumbar spine BMD (L1-L4) increased from 0.881+/-0.0624 g/cm2 at baseline (last visit prior to NGM/EE) to 0.894+/-0.0654 g/cm2 at final visit (p = .043); no significant changes in hip BMD occurred. Decreases in N-telopeptide, osteocalcin, procollagen type I propeptide and bone-specific alkaline phosphatase levels indicated effects on bone metabolism. CONCLUSIONS: Long-term administration of triphasic NGM/EE to osteopenic women with HA may increase total lumbar spine BMD.

Effects of a triphasic combination oral contraceptive containing norgestimate/ethinyl estradiol on biochemical markers of bone metabolism in young women with osteopenia secondary to hypothalamic amenorrhea.

This multicenter, double-blind, placebo-controlled, randomized study of 45 patients evaluated the short-term effects of an oral contraceptive [Ortho Tri-Cyclen, 180-250 micro g of norgestimate (NGM) and 35 microg of ethinyl estradiol (EE)] on biochemical markers of bone resorption, formation, and osteoprotegerin in young women (mean age +/- SD, 26.5 +/- 6.3 yr) with hypothalamic amenorrhea and osteopenia. Body fat, endocrine, and cognitive function were evaluated as secondary endpoints. Biomarkers of bone metabolism were measured at baseline and after three cycles of NGM/EE or placebo. There were significant decreases in mean values of N-telopeptide [mean (SD), -13.4 (13.4) vs. 1.2 (23.8) nmol bone collagen equivalents (BCE)/mmol creatinine (Cr); P = 0.001] and deoxypyridinoline [-1.2 (2.9) vs. -0.5 (1.5) nmol deoxypyridinoline/mmol Cr; P = 0.021] as well as significant decreases in bone specific alkaline phosphatase [-5.1 (3.5) vs. 0.4 (3.1) ng/ml; P < 0.001], osteocalcin [-5.9 (3.6) vs. -2.9 (3.7); P = 0.016], and procollagen of type I propeptide [-35.2 (44.6) vs. -0.2 (30.0) ng/ml; P = 0.025], but not osteoprotegerin [0.39 (1.46) vs. -0.2 (0.49) pmol/liter; P = 0.397] in the NGM/EE vs. placebo group. There were no significant differences between groups with respect to changes in cognitive function, mood, body weight, body mass index, body fat, percentage of body fat, and all endocrine levels except FSH, [-3.7 (3.8) vs. -0.6 (2.1) IU/liter; P < 0.001, NGM/EE vs. placebo]. No serious adverse events were reported in either group. These results suggest that NGM/EE decreases bone turnover in osteopenic premenopausal women with hypothalamic amenorrhea. Further studies are needed to determine whether estrogen will increase bone density in this population.

Resistance to HIV-1 entry inhibitors.

Resistance-testing technology has been incorporated into the standard of care for human immunodeficiency virus type 1 (HIV-1) infection and therapy with protease and reverse transcriptase inhibitors. Inhibitors of HIV-1 entry represent an emerging mode of antiretroviral therapy, and HIV-1 entry inhibitors encompass three mechanistically distinct classes of agents known as attachment inhibitors, coreceptor inhibitors, and fusion inhibitors. Each class of agent has demonstrated promise in controlled clinical trials, and understanding the determinants and evolution of viral resistance will be critical for the optimal development and deployment of these new treatment classes. Advances in resistance-testing technologies have paralleled the development of HIV-1 entry inhibitor therapies, and the available data support the notion that attachment, coreceptor and fusion inhibitors offer complementary modes of therapy and distinct resistance profiles.

A comparison of polymerase chain reaction with and without RNA extraction and virus isolation for detection of bovine viral diarrhea virus in young calves.

Previously, the authors described a multiplex reverse transcriptase-polymerase chain reaction (PCR) assay for detection and typing of bovine viral diarrhea virus (BVDV) from blood of persistently infected (PI) cattle that could be used with or without RNA extraction. In the present study, the PCR assay was evaluated for its ability to detect BVDV in young calves as a screening tool for detection of persistent infections. Both methods, PCR after RNA extraction (rPCR) and the direct method without RNA extraction (dPCR) were applied and compared with virus isolation (VI) with diagnostic specimens. From 450 whole blood samples from Ontario calves, 47 and 39 samples were positive by rPCR and VI, respectively. From the 47 samples positive by rPCR, 45 (96%) also were positive by dPCR when samples were tested both undiluted and diluted 1:10. In comparison to VI, the relative sensitivities of both PCR assays were 100%. Examination of the results indicates that both PCR assays can be used for screening calves for persistent infection with BVDV.

gp100/pmel17 and tyrosinase encode multiple epitopes recognized by Th1-type CD4+T cells.

CD4+ T cells modulate the magnitude and durability of CTL responses in vivo, and may serve as effector cells in the tumour microenvironment. In order to identify the tumour epitopes recognized by tumour-reactive human CD4+ T cells, we combined the use of an HLA-DR4/peptide binding algorithm with an IFN-gamma ELISPOT assay. Two known and three novel CD4+ T cell epitopes derived from the gp 100/pmel17 and tyrosinase melanocyte-associated antigens were confirmed or identified. Of major interest, we determined that freshly-isolated PBMC frequencies of Th1-type CD4+ T recognizing these peptides are frequently elevated in HLA-DR4+ melanoma patients (but not normal donors) that are currently disease-free as a result of therapeutic intervention. Epitope-specific CD4+ T cells from normal DR4+ donors could be induced, however, after in vitro stimulation with autologous dendritic cell pulsed with antigens (peptides or antigen-positive melanoma lysates) or infected with recombinant vaccinia virus encoding the relevant antigen. Peptide-reactive CD4+ T cells also recognized HLA-DR4+ melanoma cell lines that constitutively express the relevant antigen. Based on these data, these epitopes may serve as potent vaccine components to promote clinically-relevant Th1-type CD4+ T cell effector function in situ.

Management by consent in human-machine systems: when and why it breaks down.

This study examined the effects of conflict type, time pressure, and display design on operators' ability to make informed decisions about proposed machine goals and actions in a management-by-consent context. A group of 30 B757 pilots were asked to fly eight descent scenarios while responding to a series of air traffic control clearances. Each scenario presented pilots with a different conflict that arose from either incompatible goals contained in the clearance or inappropriate implementation of the clearance by automated flight deck systems. Pilots were often unable to detect these conflicts, especially under time pressure, and thus failed to disallow or intervene with proposed machine actions. Detection performance was particularly poor for conflicts related to clearance implementation. These conflicts were most likely to be missed when automated systems did more than the pilot expected of them. Performance and verbal protocol data indicate that the observed difficulties can be explained by a combination of poor system feedback and pilots' difficulties with generating expectations of future system behavior. Our results are discussed in terms of their implications for the choice and implementation of automation management strategies in general and, more specifically, with respect to risks involved in envisioned forms of digital air-ground communication in the future aviation system. Actual or potential applications of this research include the design of future data link systems and procedures, as well as the design of future automated systems in any domain that rely on operator consent as a mechanism for human-machine coordination.

Bridging the gap between developmental systems theory and evolutionary developmental biology.

Many scientists and philosophers of science are troubled by the relative isolation of developmental from evolutionary biology. Reconciling the science of development with the science of heredity preoccupied a minority of biologists for much of the twentieth century, but these efforts were not corporately successful. Mainly in the past fifteen years, however, these previously dispersed integrating programmes have been themselves synthesized and so reinvigorated. Two of these more recent synthesizing endeavours are evolutionary developmental biology (EDB, or "evo-devo") and developmental systems theory (DST). While the former is a bourgeoning and scientifically well-respected biological discipline, the same cannot be said of DST, which is virtually unknown among biologists. In this review, we provide overviews of DST and EDB, summarize their key tenets, examine how they relate to one another and to the study of epigenetics, and survey the impact that DST and EDB have had (and in future should have) on biological theory and practice.