ACAT inhibitors derived from hetero-Diels-Alder cycloadducts of thioaldehydes

Acyl-CoA:cholesterol acyltransferase (ACAT) is the enzyme largely responsible for intracellular cholesterol esterification. A systemic inhibitor of ACAT is believed to be able to slow or even reverse the atherosclerotic process. Towards that goal, a series of cyclic sulfides, derived from the hetero-Diels-Alder reaction of thioaldehydes with 1,3-dienes, and bearing carboxamide substituents, were prepared and evaluated for in vitro (in several tissues and species) and ex vivo ACAT inhibition. Minor changes in subsequent structure were found to have a significant effect in optimization of the biological activity of this series of compounds.     

Direct monitoring of the calcium concentration in the sarcoplasmic and endoplasmic reticulum of skeletal muscle myotubes

Direct monitoring of the free Ca2+ concentration in the sarcoplasmic reticulum (SR) was carried out in rat skeletal myotubes transfected with a specifically targeted aequorin chimera (srAEQ). Myotubes were also transfected with a chimeric aequorin (erAEQ) that we have demonstrated previously is retained in the endoplasmic reticulum (ER). Immunolocalization analysis showed that although both recombinant proteins are distributed in an endomembrane network identifiable with immature SR, the erAEQ protein was retained also in the perinuclear membrane. The difficulty of measuring [Ca2+] in 100-1000 microM range was overcome with the use of the synthetic coelenterazine analogue, coelenterazine n. We demonstrate that the steady state levels of [Ca2+] measured with srAEQ is around 300 microM, whereas that measured with erAEQ is significantly lower, i.e. around 200 microM. The effects of caffeine, high KCl, and nicotinic receptor stimulation, in the presence or absence of external calcium or after blockade of the Ca-ATPase, were investigated with both chimeras. The kinetics of [Ca2+] changes revealed by the erAEQ were similar, but not identical, neither quantitatively nor qualitatively, to those monitored with the srAEQ, indicating that at this stage of muscle development, differences exist between SR and ER in their mechanisms of Ca2+ handling. The functional implications of these findings are discussed.     

Efficacy of lonidamine combined with different DNA-damaging agents in the treatment of the MX-1 tumor xenograft

The a.c. conductivity of the proteins lysozyme and subtilisin, both in their active and inactive or inhibited forms were determined theoretically. For this, quantum mechanical calculations and a random walk theory were used. The conclusions are that these enzymatic proteins can easily transport electrons which is most probably important in their role as catalysators of biochemical reactions. The electron transport is sensitive to three-dimensional changes of the active sites of these enzymes which have more flexibility than the whole molecule. Therefore, the flexibility of the active sites of enzyme catalysts is not only important for the conformational fitting with the reactants, but also strongly influences the transport in biochemical reactions.     

Salvage chemotherapy with mitomycin, vindesine, and cisplatin (MiViP) in recurrent carcinoma of the cervix

We report two cases of metastatic non-functioning pancreatic endocrine tumour with very elevated plasma levels of alpha-fetoprotein. In these two cases, serial plasma levels of alpha-fetoprotein, initially normal, correlated well with hepatic tumour progression and were associated with fatal outcome. These results suggest that elevated plasma concentration of alpha-fetoprotein may be caused by metastatic pancreatic endocrine tumour and than alpha-fetoprotein serial measurement may be useful in prognostic evaluation.     

Fast acquisition clock and data recovery circuit with low jitter

This paper presents a half-rate clock and data recovery circuit (CDR)that combines the fast acquisition of a phase selection (PS) delay-locked loop (DLL) with the low jitter of a phase-locked loop (PLL). The PLL acquisition time improves considerably with use of a phase frequency magnitude detector(PFMD) that feeds back an estimate of the magnitude of the frequency difference in addition to the sign. Measurements in 0.5/spl mu/m CMOS technology show operation up to 700 Mb/s, a 7% acquisition range, an initial acquisition time of 8 bit times with jitter of 30% bit time, and jitter of 16 ps after the PLL acquires lock. With a phase frequency detector (PFD), the PLL locks in about 700 ns from an initial frequency difference of 7%. Measurements using a PFMD show the 700 ns PLL acquisition time is reduced on average by about a factor of 5 to 140 ns from an initial 7% frequency difference. The power dissipation is 300mW.     

Final Drying of Whole Milk Powder in Vibrated-Fluidized Beds

Vibro-fluidized beds are widely used in drying sticky powders and agglomerated materials as milk powder. Using a vibro-fluidized laboratory scale dryer, this work is aiming at analyzing preliminarily the effect of its operational variables on the drying kinetics and characteristics of whole milk powder. The full-factorial design technique with three replications at the central point has been employed to generate data and correlations to quantify the effect of inlet air temperature, air flow rate, and vibration bed amplitude on the drying curves and the milk powder properties related to its faster reconstitution in water (as tapped density, Hausner cohesion ratio, agglomerate size distribution, and internal pore concentration). Results obtained are analyzed and discussed to identify the adequate operation condition for final drying whole milk powder in vibro-fluidized beds, assuring a high product quality.     

The geometric nature of plasticity laws

This paper concerns the plasticity constitutive laws in small strain. In the thermodynamic approach developed here, the key concept is that of internal variables. The differential nature of plasticity law has been pointed out for a long time. If we unite the invariance condition of these laws in a state variable transformation, this involves, ultimately, that the natural mathematic frame of plasticity theory is Differential Geometry. The system state is defined as a point of a differentiable manifold. The state variable are the local coordinates of this point in a chart. The internal stresses are the components of a covariant vector of the cotangent bundle to internal state manifold and the elastic domain is a convex part of cotangent vector space. The plastic yield criteria such as von Mises condition define a Riemannian structure over the manifold. The metric element is identified with the internal dissipation element. Constitutive laws link the covariant derivatives of the thermodynamic stress with the state variable. Hardening modulus splits up in two parts, kinematic hardening and metric hardening. This last is defined by Christoffel connection coefficients. Applied to von Mises isotropic yield condition, the metric hardening is identified with isotropic hardening. The Baltov-Sawczuk model is also analysed. The use of appropriate polar coordinates simplifies significantly the computations. Generalization to a significant category of non-differentiable yield criteria, such as Tresca condition, is considered by introducting a metric tensor family. The adaptation of Drucker's postulate to the proposed model requires the introduction of parallel transport of the internal stress covector. Generally, this transport is different over distinctive paths joining two points. This fact expresses internal state manifold curvature. The Riemann-Christoffel tensor is computed for von Mises, Baltov-Sawczuk and Tresca models.     

On-body propagation velocity estimation using ultra-wideband frequency-domain spatial correlation analyses

On-body communications around the human torso are considered, using ultra-wideband transmissions. The velocity of the diffracted wave propagating around the body is extracted from frequency- domain spatial correlation analyses.