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PubMedDate not supplied

Drug absorption evaluation in the presence of changes in clearance: an algorithm and computer program for deconvolution with exact clearance correction.

Most commonly drug absorption is evaluated with a reference dosing given on separate occasions. The assumption that no change in drug disposition is taking place between the drug administrations is often violated resulting in errors in the calculations. A novel deconvolution method is presented which exactly compensates for a change in drug clearance. The method is based on a model independent disposition decomposition-recomposition technique. The distribution function is obtained from an i.v. administration by disposition decomposition. This distribution function is assembled together with the elimination kinetics containing the perturbed clearance to construct the perturbed disposition function in the subsequent disposition recomposition operation. The perturbed absorption response is finally deconvolved using the corresponding perturbed disposition function. It is shown that the perturbed clearance can be obtained from the log-linear terminal disposition phase once the distribution function has been obtained from an i.v. administration. The proposed method is implemented in an algorithm and computer program DCONB and demonstrated using human cimetidine drug level data from an i.v. and oral administration. The usage of DCONB is identical to DECONV previously published. It requires only regular sums of exponentials to be fitted to drug level data. Such fittings are routinely done in pharmacokinetics thereby enabling DCONB to be implemented very simply.

Algorithms↗

PubMed1991

The regulation of myosin gene transcription in skeletal muscle: effects of altered functional demand.

Perturbations in the activity patterns of skeletal muscle have been used to probe adaptive mechanisms that occur when the function of a muscle is altered. A plethora of information is available concerning the phenotypic changes that occur in the skeletal muscle myosin patterns when the load placed on a muscle is changed. More recently, technological advances in molecular biology have facilitated investigations concerning how these changes at the protein level are mediated via transcription of the genome. The focus of this review will be the recent evidence concerning the regulation of transcription of the myosin isogenes in skeletal muscle. In addition, putative regulatory factors are discussed which may link an alteration in function to altered transcription of the genome.

Adaptation, Physiological↗

PubMed2000

A rab3 homolog in sea urchin functions in cell division.

Rabs are monomeric GTP binding proteins belonging to the ras superfamily that function throughout the secretory pathway. Members of the rab3 family function in the final steps of the secretory pathway, vesicle fusion with the plasma membrane. In contrast to mammalian systems with several rab3 isoforms (rab3A-D), a single family member homologue of rab3 is present in the rapidly dividing cleavage stage sea urchin embryo that localizes to numerous vesicles enriched at the cell cortex. We hypothesized that whereas the contents of these rab3-positive vesicles may contribute to the embryonic extracellular matrix, the membrane and its constituent proteins may be important for other aspects of cell division. We tested the function of rab3 in cell division by the microinjection of either antibodies or competing effector domain peptides to interfere with its function. We found that perturbing rab3 function results in cessation of cell division, whereas cells injected with either heat-inactivated antibodies or control scrambled peptides develop as normal. Moreover, neither endocytosis nor general membrane topology are affected by rab3 perturbation. Thus, we conclude that rab3-associated vesicles and/or their contents are critical for cell division.

Animals↗

PubMed2006

Ab initio correlation functionals from second-order perturbation theory.

Orbital-dependent exchange-correlation functionals are not limited by the explicit dependence on the density and present an attractive alternative to conventional functionals. With the successful implementation of the exact orbital-dependent exchange functional, the challenge lies in developing orbital-dependent approximations for the correlation functional. Ab initio many-body methods can provide such approximations. In particular, perturbation theory with the Kohn-Sham model as the reference [Görling and Levy, Phys. Rev. A 50, 196 (1994)] defines the exact correlation functional via an infinite perturbation series. The second-order term of these series gives the lowest-order approximation to the correlation functional. However, it has been suggested [Bartlett et al., J. Chem. Phys. 122, 034104 (2005)] that the Kohn-Sham Hamiltonian is not the optimal choice for the perturbation expansion and a different reference Hamiltonian may lead to an improved perturbation series and more accurate second-order approximation. Here, we demonstrate explicitly that the modified series can be used to define superior functional and potential. We present results of atomic and molecular calculations with both second-order functionals. Our results demonstrate that the modified functional offers a significantly improved description of the correlation effects as it does not suffer from convergence problems and results in energies and densities that are more accurate than those obtained with second-order Møller-Plesset perturbation theory or generalized-gradient approximation functionals.

Journal Article↗

PubMed2003

[Functional consequences of cutaneous lipid perturbation].

Epidermal lipids constitute an ultimate frontier between the organism and its environment. Their essential role consists of providing a barrier limiting both transepidermal water loss and penetration of external factors, such as irritants. Efficacy of the barrier depends on the physicochemical properties of the substance applied to the skin surface and the increase in transepidermal water loss, which may be quantified, is proportional to the provoked perturbation in the barrier function. In atopic dermatitis epidermis, a significant decrease in the ceramide content and abnormally low levels of omega-6 fatty acids correlate with an increased rate of water loss at the skin surface--a sign of an impaired barrier. However, similar signs are observed in the atrophic epidermis provoked by long term local corticotherapy. Epidermal lipid profiles are also seriously modified in various ichthyoses, and are partially responsible for the hyperkeratosis observed clinically, e.g.: the recessive X-linked form is provoked by a mutation of the steroid sulphatase gene and the resulting accumulation of unconverted precursor of cholesterol. Modification of the lipid composition in acne contributes to comedo formation, whereas UV improves barrier function (and may provoke hyperkeratosis) through an increase in the stratum corneum lipid content. Another source of lipids at the epidermal surface is sebaceous glands. Waxes present in the sebum increase friction coefficient of the skin surface. Sebum also influences (decreases) the rate of penetration of lipophilic substances applied on the skin. Its role in the skin biology appears to be less vital than that of the lipids constituting the permeability barrier of the stratum corneum.

Acne Vulgaris↗

PubMed2003

Specific effects of balance and gait exercises on physical function among the frail elderly.

OBJECTIVE: To evaluate the specific effects of balance and gait exercises among frail elderly individuals. DESIGN: A randomized three-group parallel controlled study. SETTING: Geriatric health services facility in Japan. SUBJECTS: Thirty-four frail elderly subjects attending the care facility were randomized into a control group, an exercise group with emphasis on balance or an exercise group with emphasis on gait re-education. INTERVENTIONS: The two exercise groups received balance or gait exercise for 40 minutes, 2-3 times weekly, for 12 weeks. MAIN OUTCOME MEASURES: One Leg Standing Test, Functional Reach Test, Manual Perturbation Test, Functional Balance Scale, Performance-Oriented Mobility Assessment, Timed 'Up and Go' Test and Stair Climbing/Descending Test. These assessments were performed before and after 12-week intervention. RESULTS: Comparison of the performance before and after intervention demonstrated significant improvement in One Leg Standing Test, Functional Reach Test and Functional Balance Scale in the balance exercise group, and Functional Balance Scale, Timed 'Up and Go' Test and Stair Descending Test showed improvement in the gait exercise group. All test items showed no significant differences in the control groups. Among the three groups, the balance exercise group showed more significant improvement in Functional Balance Scale, and the gait exercise group showed more significant improvement in Performance-Oriented Mobility Assessment than the control group. The balance exercise group showed greater improvement in performance in Functional Reach Test than the gait exercise group. CONCLUSIONS: Balance exercises led to improvements in static balance function, and gait exercises resulted in improvements to dynamic balance and gait functions in the very frail elderly.

Aged↗

PubMed1998

Overexpression of calreticulin fails to abolish its induction by perturbation of normal ER function.

Along with other endoplasmic reticulum (ER) Ca2+-binding proteins, notably the glucose-response proteins grp78 and grp94, expression of calreticulin is induced in response to perturbation of normal ER function. It has yet to be clearly defined how this stress is signaled from the ER to the nucleus in mammalian cells, particularly with regard to its initiation. Using a GFP-calreticulin fusion protein, we have generated and selected stably transfected HeLa cells that overexpress calreticulin to investigate whether the protein might be involved in signaling its own induction. Basal levels of endogenous calreticulin mRNA and protein were unaffected in these cells, indicating that overexpression alone does not induce a stress response. ER stress induced calreticulin expression in response to either thapsigargin or tunicamycin was equivalent in these cells to that seen in control, nontransfected cells, leading us to conclude that calreticulin is unlikely be involved in its own induction. Levels of the mRNA encoding the fusion protein were also increased by tunicamycin, but not thapsigargin, suggesting that, in agreement with our previous observations, inhibition of N-linked glycosylation may increase the stability of calreticulin mRNA. This indicates that in mammalian cells, there is more than one signaling pathway for the ER stress response.

Anti-Bacterial Agents↗

PubMed2006

Coupled-perturbed density-matrix functional theory equations. Application to static polarizabilities.

Starting from the variational equations for the natural occupation numbers and the recently proposed eigenequations for the natural spin-orbitals, we derive coupled-perturbed density-matrix equations that furnish a linear response of the one-electron reduced density matrix to a static perturbation when the total energy is a functional of the one-electron reduced density matrix. Cases when some occupation numbers achieve exactly 0 or 1 or when the total number of the particles in a system is not preserved are taken into consideration. The scheme is applied to computing static polarizabilities from two simple density-matrix functionals. The behavior of the functionals is erratic and they provide only little or no improvement over the coupled-perturbed Hartree-Fock results.

Journal Article↗

PubMed2005

Sexual dimorphism in cerebellar structure, function, and response to environmental perturbations.

Sexual dimorphism of CNS structure and function has been observed in humans and animals, but remains relatively unrecognized in the context of the cerebellum. Recent research in our laboratory has examined whether these gender differences extend to cerebellar structure and function, as well as the impact of environmental factors on the developing cerebellum. Perinatal exposure to both chemical and physical perturbations in the environment (in our experiments, PCBs or hypergravity) affects growth, neurodevelopment, and motor coordination differently in males and females. These neurodevelopmental and behavioral effects are accompanied by sex-related changes in cerebellar mass and cerebellar protein expression. Exposure to chemical toxins (PCBs) resulted in more dramatic neurodevelopmental and behavioral changes in male neonates. It is possible that gender-related differences in male and female cerebellar structure and function are related to sex-specific development of the cerebellum and sex-specific distribution of specific receptors, local synthesis of trophic factors, and maturation of the pituitary hypophesial axis. These sex-related differences may underlie the sex-specific preponderance of certain neuropsychiatric disorders, and must be incorporated in the design of future basic and clinical investigations.

Animals↗

PubMed2006

Technique for "tuning" vocal tract area functions based on acoustic sensitivity functions.

A technique for modifying vocal tract area functions is developed by using sum and difference combinations of acoustic sensitivity functions to perturb an initial vocal tract configuration. First, sensitivity functions [e.g., Fant and Pauli, Proc. Speech Comm. Sem. 74, 1975] are calculated for a given area function, at its specific formant frequencies. The sensitivity functions are then multiplied by scaling coefficients that are determined from the difference between a desired set of formant frequencies and those supported by the current area function. The scaled sensitivity functions are then summed together to generate a perturbation of the area function. This produces a new area function whose associated formant frequencies are closer to the desired values than the previous one. This process is repeated iteratively until the coefficients are equal to zero or are below a threshold value.

Glottis↗

PubMed2006

Inferring functional pathways from multi-perturbation data.

BACKGROUND: Recently, a conceptually new approach for analyzing gene networks, the Functional Influence Network (FIN) was presented. The FIN approach uses the measured performance of a given cellular function under different multi-perturbations, to identify the main functional pathways and interactions underlying its processing. Here we present and study an iterative, extended version of FIN, the Functional Influence Network Extractor (FINE), which is specifically geared towards the accurate analysis of sparse cellular systems. We employ it to study a conceptually fundamental question of practical importance--how well should we know the system studied (such that we can predict its performance) so that we can understand its workings (i.e., chart its underlying functional network)? RESULTS AND CONCLUSIONS: The performance of FINE is studied in both simulated and biological sparse systems. It successfully obtains an accurate and compact description of the underlying functional network even with limited data, and outperforms FIN. We show that prior estimates of a system's functional complexity are instrumental in determining how much predictive knowledge is required to accurately chart its underlying functional network. AVAILABILITY: The FINE software is available for download at http://www.cns.tau.ac.il/resc.html.

Algorithms↗

PubMed2006

Intermolecular potentials of the methane dimer calculated with Møller-Plesset perturbation theory and density functional theory.

We have calculated the intermolecular interaction potentials of the methane dimer at the minimum-energy D(3d) conformation using the Hartree-Fock (HF) self-consistent theory, the correlation-corrected second-order Møller-Plesset (MP2) perturbation theory, and the density functional theory (DFT) with the Perdew-Wang (PW91) functional as the exchange or the correlation part. The HF calculations yield unbound potentials largely due to the exchange-repulsion interaction. In the MP2 calculations, the basis set effects on the repulsion exponent, the equilibrium bond length, the binding energy, and the asymptotic behavior of the calculated intermolecular potentials have been thoroughly studied. We have employed basis sets from the Slater-type orbitals fitted with Gaussian functions (STO-nG) (n=3-6) [Quantum Theory of Molecular and Solids: The Self-Consistent Field for Molecular and Solids (McGraw-Hill, New York, 1974), Vol. 4], Pople's medium size basis sets of Krishnan et al. [J. Chem. Phys. 72, 650 (1980)] [up to 6-311++G(3df,3pd)] to Dunning's correlation consistent basis sets [J. Chem. Phys. 90, 1007 (1989)] (cc-pVXZ and aug-cc-pVXZ) (X=D, T, and Q). With increasing basis size, the repulsion exponent and the equilibrium bond length converge at the 6-31G** basis set and the 6-311++G(2d,2p) basis set, respectively, while a large basis set (aug-cc-pVTZ) is required to converge the binding energy at a chemical accuracy (approximately 0.01 kcal/mol). Up to the largest basis set used, the asymptotic dispersion coefficient has not converged to the destined C6 value from molecular polarizability calculations. The slow convergence could indicate the inefficacy of using the MP2 calculations with Gaussian-type functions to model the asymptotic behavior. Both the basis set superposition error (BSSE) corrected and uncorrected results are presented to emphasize the importance of including such corrections. Only the BSSE corrected results systematically converge to the destined potential curve with increasing basis size. The DFT calculations generate a wide range of interaction patterns, from purely unbound to strongly bound, underestimating or overestimating the binding energy. The binding energy calculated using the PW91PW91 functional and the equilibrium bond length calculated using the PW91VP86 functional are close to the MP2 results at the basis set limit.

Journal Article↗

PubMed2001

Functional postural responses after perturbations in multiple directions in a standing man: a principle of decoupled control.

The objective of this study was to assess functional postural responses by analyzing the net joint torques (NJT) in the ankles and the hips resulting from perturbations delivered in multiple directions to subjects standing quietly. A total of eight subjects were standing on two force platforms while an apparatus randomly delivered controlled perturbations at the level of the pelvis in eight directions: anterio-posterior (AP), medio-lateral (ML), and four combinations of these principal directions. Perturbations were repeated five times in each direction for six conditions (i.e., three different perturbation strengths and three different feet orientations). The comparison of the averaged ankle sum NJT (AP) responses showed that the time courses of the responses elicited by a perturbation acting only in the AP direction were identical to those elicited by a combination of two corresponding AP and ML perturbations. In contrast the observed averaged ankle NJT (ML) responses did not follow the same similarity. The comparison of the averaged ankle and hip sum NJT (ML) responses revealed that the time courses of the responses elicited by a perturbation acting only in the ML direction were identical to those elicited by a combination of two corresponding AP and ML perturbations. These findings were invariable of the experimental conditions and were consistent among all the eight subjects. Thereby, we conclude that the ankle sum NJT (AP) and the ankle and hip sum NJT (ML) are the global variables being controlled. This shows that CNS controls the recovery from the multiple direction perturbations of moderate strength by decoupling the AP-ML postural space into two orthogonal directions (AP and ML).

Adult↗

PubMed1990

Perturbation of pancreatic islet function in glucose-infused rats.

The secretory behavior of insulin- and glucagon-producing cells was found to be perturbed in isolated perfused pancreases removed from rats infused with hypertonic solutions of glucose for 48 hours. The anomalies included a high basal release of insulin and a paradoxical increase in insulin output and decrease in glucagon release in response to a fall in D-glucose concentration. Likewise, in isolated islets prepared from the glucose-infused rats, L-arginine or theophylline stimulated insulin release at a low ambient concentration of D-glucose, at variance with the situation found in islets removed from normal rats. These secretory perturbations could not be attributed to any obvious defect in either the transport of D-glucose into islet cells or its further utilization and oxidation, but coincided with the abnormal accumulation of glycogen in the B-cell. It is proposed that the latter anomaly may play a role in the altered dynamics of insulin release found in animals or patients with long-term hyperglycemia.

Animals↗

PubMed2006

DHFR and MSH3 co-amplification in childhood acute lymphoblastic leukaemia, in vitro and in vivo.

The MSH3 and dihydrofolate reductase (DHFR) genes, located on chromosome 5, share a common promoter but are divergently transcribed. Dysregulation of the mismatch repair (MMR) pathway has been found to occur in cell line models due to co-amplification of MSH3 as a coincident effect of DHFR amplification, acquired as a mechanism generating resistance to methotrexate (MTX). The increased levels of MSH3 perturbed MutSalpha function resulting in hypermutability and increased resistance to thiopurines, drugs whose cytotoxic effects are triggered by MutSalpha. The relevance of this phenomenon in clinical samples is unknown but is extremely pertinent in childhood acute lymphoblastic leukaemia (ALL) in which children are exposed for prolonged periods to both MTX and thiopurines such that a single amplification event involving both the DHFR and the MSH3 genes may cause chemotherapeutic resistance to both agents. Thus, we have generated a leukaemic cell line (PreB697) and a normal human lymphoblastoid cell line (TK6) that are resistant to a pharmacologically relevant dose of MTX and show that while increased DHFR levels result in MTX resistance, the associated increased levels of MSH3 are insufficient to perturb MutSalpha functionality, in terms of MMR capacity or 6-thioguanine sensitivity. In addition, we show that although low-level DHFR amplification occurs alone in a significant number of samples, both at disease onset and relapse, co-amplification of both MSH3 and DHFR is rarely found in primary ALL samples, even after prolonged MTX therapy and is not at a sufficiently high level to perturb MMR function.

Cell Line, Transformed↗

PubMed2003

Biochemical detection of adenosine and cytidine ionization within RNA by interference analysis.

Perturbation of active site functional group pKas is an important strategy employed by protein enzymes to achieve catalysis. There is increasing evidence to indicate that RNAs also utilize functional group pKa perturbation for folding and reactivity. The two best candidates for a functionally relevant pKa perturbation are the N3 of C (pKa 4.2) and the N1 of A (pKa 3.5), either of which could be sufficiently raised to allow protonation near physiological pH. Here we report the synthesis and use of a series of alpha-phosphorothioate tagged cytidine and adenosine analogs whose altered pKas make it possible to efficiently detect functionally relevant protonation events by Nucleotide Analog Interference Mapping. This approach has been used to detect ionization events in several catalytic RNAs, including the group I intron, the Hepatitis Delta Virus (HDV), the hairpin and the Varkud Satellite (VS) ribozymes. The active site residue of the VS ribozyme appears to be ionized in the course of the reaction pathway, which may be indicative of a general acid or base mechanism for catalysis by this RNA.

Adenosine↗

PubMed2007

Defects of immune regulation in the presenilin-1 mutant knockin mouse.

Mutations in the presenilin-1 (PS1) gene are causally linked to early-onset Alzheimer's disease (AD). Studies of neurons suggest that PS1 mutations result in a gain-of-function, which perturbs calcium regulation and increases cell vulnerability to apoptosis. Alterations in immune cell function have also been demonstrated in AD, and a role for PS1 in immune regulation has been suggested recently. We now report that splenocytes from PS1-mutant (M146V) knockin mice exhibit increased caspase activity, abnormal calcium regulation and aberrant mitochondrial function. Isolated splenic T cells from PS1-mutant mice respond poorly to proliferative signals and have downregulated cluster designation 3 and interleukin (IL)- 2-receptor expression necessary for a normal T-cell immune response. Thus, adverse effects of a mutation that causes AD on immune function that involves perturbed calcium regulation and cytokine signaling in lymphocytes, and associated sensitivity of lymphocytes to apoptosis are demonstrated. These findings suggest that abnormalities in immune function might play major roles in the pathogenesis of AD.

Alzheimer Disease↗

PubMed1989

Transepidermal water loss: the signal for recovery of barrier structure and function.

Previous studies have demonstrated that perturbations in barrier function stimulate epidermal lipid synthesis and that this increase can be prevented by occlusive membranes. These observations suggest that epidermal lipid synthesis might be related to barrier function and raised the question whether transcutaneous water flux might regulate epidermal lipogenesis. In the present study we first abrogated the barrier with acetone, and then compared the rate of repletion of stainable lipids, barrier recovery, and epidermal lipogenesis in animals covered with occlusive membranes or vapor-permeable membranes versus uncovered animals. Acetone treatment of hairless mice removed stainable neutral lipids from the stratum corneum, with repletion evident both biochemically and histochemically within 48 hr in uncovered animals. In contrast, when the animals were covered with an occlusive membrane, the usual return of stratum corneum lipids was aborted. Since application of vapor-permeable membranes allowed normal lipid repletion, occlusion alone is not responsible for the inhibition of lipid repletion. Acetone treatment also perturbed epidermal barrier function, which returned to normal in uncovered animals in parallel with the reappearance of stratum corneum lipid. However, when animals were covered with an occlusive membrane, barrier function did not recover normally. In contrast, occlusion with vapor-permeable membranes allowed barrier function to recover normally. Finally, whereas occlusive membranes prevented the characteristic increase in epidermal lipid synthesis that follows barrier perturbation, epidermal lipid synthesis was increased in animals covered with a vapor-permeable membrane. These results point to transepidermal water flux itself as the signal that regulates epidermal lipid synthesis, which is associated first with the redeposition of stratum corneum lipids and then the normalization of stratum corneum barrier function.

Acetone↗