Forward and Inverse Energy Cascade in Fluid Turbulence Adhere to Kolmogorov's Refined Similarity Hypothesis.

We study fluctuations of the local energy cascade rate Φ_{ℓ} in turbulent flows at scales (ℓ) in the inertial range. According to the Kolmogorov refined similarity hypothesis (KRSH), relevant statistical properties of Φ_{ℓ} should depend on ε_{ℓ}, the viscous dissipation rate locally averaged over a sphere of size ℓ, rather than on the global average dissipation. However, the validity of KRSH applied to Φ_{ℓ} has not yet been tested from data. Conditional averages such as ⟨Φ_{ℓ}|ε_{ℓ}⟩ as well as of higher-order moments are measured from direct numerical simulations data, and results clearly adhere to the predictions from KRSH. Remarkably, the same is true when considering forward (Φ_{ℓ}>0) and inverse (Φ_{ℓ}<0) cascade events separately. Measured ratios of forward and inverse cascade probability densities conditioned on ε_{ℓ} also confirm the applicability of the KRSH to analysis of the fluctuation relation from nonequilibrium thermodynamics.

Oscillations Modulating Power Law Exponents in Isotropic Turbulence: Comparison of Experiments with Simulations.

Inertial-range features of turbulence are investigated using data from experimental measurements of grid turbulence and direct numerical simulations of isotropic turbulence simulated in a periodic box, both at the Taylor-scale Reynolds number R_{λ}∼1000. In particular, oscillations modulating the power-law scaling in the inertial range are examined for structure functions up to sixth-order moments. The oscillations in exponent ratios decrease with increasing sample size in simulations, although in experiments they survive at a low value of 4 parts in 1000 even after massive averaging. The two datasets are consistent in their intermittent character but differ in small but observable respects. Neither the scaling exponents themselves nor all the viscous effects are consistently reproduced by existing models of intermittency.

Turbulence is an Ineffective Mixer when Schmidt Numbers Are Large.

We solve the advection-diffusion equation for a stochastically stationary passive scalar θ, in conjunction with forced 3D Navier-Stokes equations, using direct numerical simulations in periodic domains of various sizes, the largest being 8192^{3}. The Taylor-scale Reynolds number varies in the range 140-650 and the Schmidt number Sc≡ν/D in the range 1-512, where ν is the kinematic viscosity of the fluid and D is the molecular diffusivity of θ. Our results show that turbulence becomes an ineffective mixer when Sc is large. First, the mean scalar dissipation rate ⟨χ⟩=2D⟨|∇θ|^{2}⟩, when suitably nondimensionalized, decreases as 1/logSc. Second, 1D cuts through the scalar field indicate increasing density of sharp fronts on larger scales, oscillating with large excursions leading to reduced mixing, and additionally suggesting weakening of scalar variance flux across the scales. The scaling exponents of the scalar structure functions in the inertial-convective range appear to saturate with respect to the moment order and the saturation exponent approaches unity as Sc increases, qualitatively consistent with 1D cuts of the scalar.

Small-Scale Isotropy and Ramp-Cliff Structures in Scalar Turbulence.

Passive scalars advected by three-dimensional Navier-Stokes turbulence exhibit a fundamental anomaly in odd-order moments because of the characteristic ramp-cliff structures, violating small-scale isotropy. We use data from direct numerical simulations with grid resolution of up to 8192^{3} at high Péclet numbers to understand this anomaly as the scalar diffusivity, D, diminishes, or as the Schmidt number, Sc=ν/D, increases; here ν is the kinematic viscosity of the fluid. The microscale Reynolds number varies from 140 to 650 and Sc varies from 1 to 512. A simple model for the ramp-cliff structures is developed and shown to characterize the scalar derivative statistics very well. It accurately captures how the small-scale isotropy is restored in the large-Sc limit, and additionally suggests a possible correction to the Batchelor length scale as the relevant smallest scale in the scalar field.

Cancellation exponents in isotropic turbulence and magnetohydrodynamic turbulence.

Small-scale characteristics of turbulence such as velocity gradients and vorticity fluctuate rapidly in magnitude and oscillate in sign. Much work exists on the characterization of magnitude variations, but far less on sign oscillations. While in homogeneous turbulence averages performed on large scales tend to zero because of the oscillatory character, those performed on increasingly smaller scales will vary with the averaging scale in some characteristic way. This characteristic variation at high Reynolds numbers is captured by the so-called cancellation exponent, which measures how local averages tend to cancel out as the averaging scale increases, in space or time. Past experimental work suggests that the exponents in turbulence depend on whether one considers quantities in full three-dimensional (3D) space or uses their one- or two-dimensional cuts. We compute cancellation exponents of vorticity and longitudinal as well as transverse velocity gradients in isotropic turbulence at Taylor-scale Reynolds numbers up to 1300 on 8192^{3} grids. The 2D cuts yield the same exponents as those for full 3D, while the 1D cuts yield smaller numbers, suggesting that the results in higher dimensions are more reliable. We make the case that the presence of vortical filaments in isotropic turbulence leads to this conclusion. This effect is particularly conspicuous in magnetohydrodynamic turbulence, where an increased degree of spatial coherence develops along the direction of an imposed magnetic field.

Steep Cliffs and Saturated Exponents in Three-Dimensional Scalar Turbulence.

The intermittency of a passive scalar advected by three-dimensional Navier-Stokes turbulence at a Taylor-scale Reynolds number of 650 is studied using direct numerical simulations on a 4096^{3} grid; the Schmidt number is unity. By measuring scalar increment moments of high orders, while ensuring statistical convergence, we provide unambiguous evidence that the scaling exponents saturate to 1.2 for moment orders beyond about 12, indicating that scalar intermittency is dominated by the most singular shocklike cliffs in the scalar field. We show that the fractal dimension of the spatial support of steep cliffs is about 1.8, whose sum with the saturation exponent value of 1.2 adds up to the space dimension of 3, thus demonstrating a deep connection between the geometry and statistics in turbulent scalar mixing. The anomaly for the fourth and sixth order moments is comparable to that in the Kraichnan model for the roughness exponent of 4/3.

Reynolds number scaling of velocity increments in isotropic turbulence.

Using the largest database of isotropic turbulence available to date, generated by the direct numerical simulation (DNS) of the Navier-Stokes equations on an 8192^{3} periodic box, we show that the longitudinal and transverse velocity increments scale identically in the inertial range. By examining the DNS data at several Reynolds numbers, we infer that the contradictory results of the past on the inertial-range universality are artifacts of low Reynolds number and residual anisotropy. We further show that both longitudinal and transverse velocity increments scale on locally averaged dissipation rate, just as postulated by Kolmogorov's refined similarity hypothesis, and that, in isotropic turbulence, a single independent scaling adequately describes fluid turbulence in the inertial range.

Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac.

Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1(-/-)) or Epac2 (Epac2(-/-)) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2(-/-) mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2(-/-) mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2(-/-) mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis.

Abnormalities in left inferior frontal gyral thickness and parahippocampal gyral volume in young people at high genetic risk for bipolar disorder.

BACKGROUND: Fronto-limbic structural brain abnormalities have been reported in patients with bipolar disorder (BD), but findings in individuals at increased genetic risk of developing BD have been inconsistent. We conducted a study in adolescents and young adults (12-30 years) comparing measures of fronto-limbic cortical and subcortical brain structure between individuals at increased familial risk of BD (at risk; AR), subjects with BD and controls (CON). We separately examined cortical volume, thickness and surface area as these have distinct neurodevelopmental origins and thus may reflect differential effects of genetic risk. METHOD: We compared fronto-limbic measures of grey and white matter volume, cortical thickness and surface area in 72 unaffected-risk individuals with at least one first-degree relative with bipolar disorder (AR), 38 BD subjects and 72 participants with no family history of mental illness (CON). RESULTS: The AR group had significantly reduced cortical thickness in the left pars orbitalis of the inferior frontal gyrus (IFG) compared with the CON group, and significantly increased left parahippocampal gyral volume compared with those with BD. CONCLUSIONS: The finding of reduced cortical thickness of the left pars orbitalis in AR subjects is consistent with other evidence supporting the IFG as a key region associated with genetic liability for BD. The greater volume of the left parahippocampal gyrus in those at high risk is in line with some prior reports of regional increases in grey matter volume in at-risk subjects. Assessing multiple complementary morphometric measures may assist in the better understanding of abnormal developmental processes in BD.

Extreme events in computational turbulence.

We have performed direct numerical simulations of homogeneous and isotropic turbulence in a periodic box with 8,192(3) grid points. These are the largest simulations performed, to date, aimed at improving our understanding of turbulence small-scale structure. We present some basic statistical results and focus on "extreme" events (whose magnitudes are several tens of thousands the mean value). The structure of these extreme events is quite different from that of moderately large events (of the order of 10 times the mean value). In particular, intense vorticity occurs primarily in the form of tubes for moderately large events whereas it is much more "chunky" for extreme events (though probably overlaid on the traditional vortex tubes). We track the temporal evolution of extreme events and find that they are generally short-lived. Extreme magnitudes of energy dissipation rate and enstrophy occur simultaneously in space and remain nearly colocated during their evolution.

Refined similarity hypothesis using three-dimensional local averages.

The refined similarity hypotheses of Kolmogorov, regarded as an important ingredient of intermittent turbulence, has been tested in the past using one-dimensional data and plausible surrogates of energy dissipation. We employ data from direct numerical simulations, at the microscale Reynolds number R(λ)∼650, on a periodic box of 4096(3) grid points to test the hypotheses using three-dimensional averages. In particular, we study the small-scale properties of the stochastic variable V=Δu(r)/(rε(r))(1/3), where Δu(r) is the longitudinal velocity increment and ε(r) is the dissipation rate averaged over a three-dimensional volume of linear size r. We show that V is universal in the inertial subrange. In the dissipation range, the statistics of V are shown to depend solely on a local Reynolds number.

Universal intermittent properties of particle trajectories in highly turbulent flows.

We present a collection of eight data sets from state-of-the-art experiments and numerical simulations on turbulent velocity statistics along particle trajectories obtained in different flows with Reynolds numbers in the range R{lambda}in[120:740]. Lagrangian structure functions from all data sets are found to collapse onto each other on a wide range of time lags, pointing towards the existence of a universal behavior, within present statistical convergence, and calling for a unified theoretical description. Parisi-Frisch multifractal theory, suitably extended to the dissipative scales and to the Lagrangian domain, is found to capture the intermittency of velocity statistics over the whole three decades of temporal scales investigated here.

Inhibition of cell proliferation by mechanical agitation involves transient cell cycle arrest at G1 phase in dinoflagellates.

Cell proliferation of dinoflagellates is negatively affected by mechanical agitation and red tides caused by members of the group have been correlated with periods of calm sea conditions. The mechanism involved in the mechanically transduced inhibition of cell proliferation is thought to involve the disruption of the cell division apparatus. In this study, we used highly synchronized cells and flow cytometry to study the effects of mechanical agitation on cell cycle progression. We observed that mechanical agitation induced transient cell cycle arrest at G(1) phase, in both the heterotrophic dinoflagellate Crypthecodinium cohniiand the photosynthetic dinoflagellate Heteroscapsa triquetra.

VEGF-2 (St Elizabeth's Medical Center).

St Elizabeth's Medical Center of Boston is developing VEGF gene therapy for the potential treatment of angina and diabetic neuropathy. The center is studying three isoforms of VEGF, although the expression of phVEGF165 has yielded the most positive results [312563]. VEGF-2 gene therapy augments perfusion of ischemic myocardium that contributes to improved clinical outcomes in patients with chronic myocardial ischemia as assessed by NOGA electromechanical mapping [390786]. Phase I trials demonstrated that gene transfer directly into the heart of the patient facilitates blood flow to the primary muscles of the heart, providing relief of angina [348564]. Reduced angina was reported by 28 out of 30 patients and tolerance of exercise increased from 240 to 410 s up to 180 days post-therapy [348632].

Effect of administration route and length of exposure on pharmacokinetics and metabolism of diltiazem in dogs.

The objective of this study was to systematically determine the pharmacokinetics and metabolism of diltiazem (DTZ) after a single i.v. dose, and after single and multiple oral (p.o.) doses. Four mongrel dogs (3 M, 1 F), aged 1-3 years, body weight 19-25 kg, were each given a single 30 mg dose of DTZ as a solution by i.v injection, the same dose orally from an immediate release tablet (Cardizem, Aventis Pharma, Canada, QC), and also t.i.d. for 10 doses. A 3-4 week washout period was allowed between each treatment. Blood samples (4 ml each) were obtained after each treatment from each animal via a cephalic vein at 0 (just before dosing), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, and 12.0 h post dose. Urine samples were collected for 24 h. The plasma samples were immediately separated by centrifugation and stored at -20 degrees C until analysis. The results showed that the bioavailability after a single p.o. dose of DTZ was 26+/-24%. Following a single i.v. dose, DTZ declined bi-exponentially with a terminal half-life (t1/2) of 4.2+/-1.7 h. N-Monodesmethyl DTZ (M(A)), deacetyl DTZ (M1), and deacetyl N-monodesmethyl DTZ (M2) were the major metabolites. Contrary to the results observed in clinical studies, there were no increase of plasma concentrations of DTZ after repeated doses (accumulation factor R = 0.94+/-0.51). Plasma concentrations of M1 decreased following repeated oral doses, accompanying by an increase of plasma concentrations of M2, although these changes were not statistically significant (p >0.05). This study cautions the use of mongrel dogs for direct extrapolation to humans, particularly for chronic pharmacokinetics studies of DTZ.

Determination of plasma concentrations of losartan in patients by HPLC using solid phase extraction and UV detection.

PURPOSE: To establish a HPLC assay for plasma losartan and its active metabolite EXP3174 to facilitate clinical pharmacokinetic studies. METHODS: the HPLC system consisted of a 250 x 2 mm i.d. C18 reversed phase column preceded by a 4 x 4 mm guard column, a UV detector set at 254 nm, and an integrator. The mobile phase was a mixture of 0.01 M ammonium phosphate: acetonitrile: methanol (6:3:1) containing 0.02 % sodium azide and 0.04% TEA, with pH adjusted to 3.2. The system was operated isocratically at ambient temperature at a flow rate of 0.3 ml/min. Losartan and its active metabolite EXP3174 were extracted from plasma using C2 bonded silica gel standard solid phase extraction. RESULTS: recoveries of losartan and EXP3174 from plasma were greater than 70%. Using 0.5 ml of plasma sample, standard curves were linear from 10 to 300 ng/ml (r2 = 0.996 and 0.997 for losartan and EXP 3174, respectively). Sensitivity of the assay was < 10 ng/ml. Intra-and inter-assay variations were < 10 and 15%. respectively. The assay has been successfully applied to measuring plasma concentrations of losartan and EXP3174 in patients receiving a daily dose of losartan (50-100 mg). CONCLUSION: The HPLC assay has adequate sensitivity, reproducibility, and specificity for clinical pharmacokinetic studies.

A simple high-performance liquid chromatography assay for simultaneous measurement of adenosine, guanosine, and the oxypurine metabolites in plasma.

To study the effect of pharmacologic agents on the biologic fate of adenosine, a reversed-phase high-performance liquid chromatography (HPLC) assay coupled with a solid-phase extraction (SPE) method was developed for simultaneous determination of plasma adenosine, hypoxanthine, xanthine, inosine, guanosine, and uric acid. The HPLC system consisted of a reversed phase C18 column, UV detector set at 254 nm, and a mobile phase composed of 0.01 M ammonium phosphate: methanol (9.5 : 0.5) vol/vol with the final pH adjusted to 3.9. The standard curves were linear between 0.1-2 microg/mL for all the analytes (except uric acid 50-400 microg/mL), with r2 > 0.99. The absolute recoveries were >60% and accuracy >85% in almost all cases. The limit of detection was <1 ng based on absolute injection of the analytes. The intraassay variations were <10% and interassay variations <15%. The presence of a wide range of medications in plasma samples did not interfere with the assay. The assay was applied successfully to measure plasma adenosine and the oxypurine metabolites in humans and rats. It was noted that plasma concentrations of adenosine and the oxypurine metabolites can vary considerably depending on the method of blood sample collection, and that species differences are apparent.

The spindle checkpoint in the dinoflagellate Crypthecodinium cohnii.

Dinoflagellates are a major group of organisms with an extranuclear spindle. As the purpose of the spindle checkpoint is to ensure proper alignment of the chromosomes on the spindle, dinoflagellate cell cycle control may be compromised to accomodate the extranuclear spindle. In the present study, we demonstrated that nocodazole reversibly prolonged the G2 + M phase of the dinoflagellate cell cycle, in both metaphase and anaphase. The regulation of the spindle checkpoint involves the activation and inhibition of the anaphase promoting complex (APC), which in turn degrades specific cell cycle regulators in the metaphase to anaphase transition. In Crypthecodinium cohnii, nocodazole was also able to induce a prolongation of the degradation of mitotic cyclins and a delay in the inactivation of p13(suc1)-associated histone kinase activities. In addition, cell extracts prepared from C. cohnii in G1 phase and G2/M phase (or nocodazole treated) were able to activate and inhibit, respectively, the degradation of exogenous human cyclin B1 in vitro. The present study thus demonstrated the presence of the spindle checkpoint and APC-mediated cyclin degradation in dinoflagellates. This is discussed in relation to a possible role of the nuclear membrane in mitosis in dinoflagellates.

Technology evaluation: transgenic antithrombin III (rhAT-III), Genzyme Transgenics.

AT-III LLC, a joint venture between Genzyme Transgenics (GTC) and Genzyme General, is developing transgenic recombinant human antithrombin III (rhAT-III) as a potential treatment for sepsis and other disorders involving thrombosis. It is in phase III clinical trials in the US and Europe as an anticoagulant in patients undergoing elective cardiac surgery such as cardiopulmonary bypass.

Transgenic antithrombin III (Genzyme).

ATIII LLC, a joint venture between Genzyme Transgenics (GTC) and Genzyme General, is developing transgenic recombinant human antithrombin III (rhAT-III) as a potential treatment for sepsis and other disorders involving thrombosis. It is in phase III clinical trials in the US and Europe as an anticoagulant in patients undergoing elective cardiac surgery requiring cardiopulmonary bypass (CPB). GTC has a license from Behringwerke (Hoechst Marion Roussel; now Aventis Pharma) to develop transgenic AT-III. Behringwerke retains exclusive worldwide marketing rights to the product, but has to purchase its entire supply of transgenic AT-III from GTC [156364]. In March 1997, GTC signed an agreement with SMIG, a joint venture formed by GTC and Sumitomo Metals, under which SMIG has the rights to develop rhAT-III in Asia in return for US dollar 4.4 million in additional funding for the continued transgenic development of rhAT-III. The dollar 4.4 million will be paid upon reaching certain milestones, which GTC expected to complete in 1997 [240202]. In December 1998, US-05843705 was issued covering rhAT-III production in transgenic goats [302263]. In January 2000, the results of the European phase III trial, which were significant in meeting the trial's primary endpoint of reduction in the use of fresh frozen plasma were reported. The trial was also significant in two of three secondary endpoints, maintenance of normal AT-III levels and changes in D-dimer and fibrin monomer [352041,353372]. Three phase III trials were initiated in the second quarter of 1998. Two identical trials, one in Europe and one in the US, evaluated the safety and efficacy of rhAT-III compared to placebo in restoring heparin sensitivity to heparin-resistant patients scheduled for elective cardiac surgery requiring CPB. The third trial, in both the US and Europe, will determine whether rhAT-III matches, at equivalent doses, the ability of plasma-derived AT-III to restore heparin sensitivity among heparin-resistant patients undergoing CPB [292235,292861]. Full enrollment onto the US trial was complete by the end of first quarter 2000 [363589], and the companies aim to complete trials and submit a filing by the end of 2000 [353372]. Clinical trials of the proteins in Japan were expected to begin in 1998 [286086].