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At least 109 records · Page 6Linked to original sources
PubMed2001

Selection pressure for the factor-V-Leiden mutation and embryo implantation.

The factor-V-Leiden mutation is seen in high frequencies in white people, despite its contribution to second-trimester abortion, preterm birth, and deep-vein thrombosis. The reason for its high frequency is not known. We investigated 102 mother-child pairs who had had successful in-vitro fertilisation by intracytoplasmic sperm injection as a model for human implantation. In 90% (9 of 10) of mother-child pairs who carried factor-V-Leiden mutation, the first embryo transfer was successful, compared with 49% (45 of 92) in factor-V-Leiden negative pairs (p=0.018, Fisher's exact test). Furthermore, the median number of unsuccessful transfers was lower in pairs who were positive for the mutation (0, range 0-2) than those who were negative (1, 0-8) (p=0.02, Mann Whitney U test) suggesting that improved implantation rate is an important genetic advantage of the factor-V-Leiden mutation.

Adult↗
PubMed2006

Modeling interactions for resonant p-wave scattering.

In view of recent experiments on ultracold polarized fermions, the zero-range potential approach is generalized to situations where two-body scattering is resonant in the p-wave channel. We introduce a modified scalar product which reveals a deep relation between the geometry of the Hilbert space and the interaction. This formulation is used to obtain a simple interpretation for the transfer rates between atomic and molecular states within a two branches picture of the many-body system close to resonance. At resonance, the energy of the dilute gas is found to vary linearly with density.

Journal Article↗
PubMed2005

Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease.

Niemann-Pick type A disease is a lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously we showed that storage pathology in the ASM knockout (ASMKO) mouse brain can be corrected by adeno-associated virus serotype 2 (AAV2)-mediated gene transfer. The present experiment compared the relative therapeutic efficacy of different recombinant AAV serotype vectors (1, 2, 5, 7, and 8) using histological, biochemical, and behavioral endpoints. In addition, we evaluated the use of the deep cerebellar nuclei (DCN) as a site for injection to facilitate global distribution of the viral vector and enzyme. Seven-week-old ASM knockout mice were injected within the DCN with different AAV serotype vectors encoding human ASM (hASM) and then killed at either 14 or 20 weeks of age. Results showed that AAV1 was superior to serotypes 2, 5, 7, and 8 in its relative ability to express hASM, alleviate storage accumulation, and correct behavioral deficits. Expression of hASM was found not only within the DCN, but also throughout the cerebellum, brainstem, midbrain, and spinal cord. This finding demonstrates that targeting the DCN is an effective approach for achieving widespread enzyme distribution throughout the CNS. Our results support the continued development of AAV based vectors for gene therapy of the CNS manifestations in Niemann-Pick type A disease.

Animals↗
PubMed1988

[Vascularization of the skin of the limbs and surgical applications].

Skin flaps for coverage of skin defects in orthopaedic surgery have been more and more used in recent years. However all the authors are not in agreement concerning the pattern of vascularization of these flaps. Two problems should be studied separately: the vascularization of the skin in situ which is already rather well known and the vascularization and the pattern of vascularization of the flaps after transfer. Several models of flaps, that is axial, septal or musculo-cutaneous, are based on the origin of skin vascularization, that is by long running arteries, septal arterioles or indirectly by arteries coming from muscles. Therefore a flap must be determined by its type of vascularization, its shape and its composition. Surgical rules concerning skin incisions and deep structures approaches are recalled.

Extremities↗
PubMed2003

Electrostatic model of S4 motion in voltage-gated ion channels.

The S4 transmembrane domain of the family of voltage-gated ion channels is generally thought to be the voltage sensor, whose translocation by an applied electric field produces the gating current. Experiments on hSkMI Na(+) channels and both Shaker and EAG K(+) channels indicate which S4 residues cross the membrane-solution interface during activation gating. Using this structural information, we derive the steady-state properties of gating-charge transfer for wild-type and mutant Shaker K(+) channels. Assuming that the energetics of gating is dominated by electrostatic forces between S4 charges and countercharges on neighboring transmembrane domains, we calculate the total energy as a function of transmembrane displacement and twist of the S4 domain. The resulting electrostatic energy surface exhibits a series of deep energy minima, corresponding to the transition states of the gating process. The steady-state gating-charge distribution is then given by a Boltzmann distribution among the transition states. The resulting gating-charge distributions are compared to experimental results on wild-type and charge-neutralized mutants of the Shaker K(+) channel.

Amino Acid Sequence↗
PubMed1984

Theoretical temperature profiles for concentric coil induction heating devices in a two-dimensional, axi-asymmetric, inhomogeneous patient model.

In this paper we report on theoretical calculations for the temperature distributions produced by an rf magnetic induction device that is placed concentrically about the long axis of the patient. A two-dimensional, axi-asymmetric, inhomogeneous patient model was used in conjunction with a numerical moment method for calculating the electric fields in the tissues of the model and a numerical finite element method for calculating the resulting temperature distributions. The electric fields and the absorbed power per unit volume of tissue were calculated for both a thorax and viscera model, each of which included a tumor volume. The absorbed power values were input into the bioheat transfer equation and the temperature distributions were calculated for a wide range of blood flow rates. Based on the steady-state and transient results, our computer simulations predict poor therapeutic temperature profiles for tumors embedded deeply in the thorax and viscera. This heating technique appears to produce significant therapeutic volumes in superficial tumors located not greater than 7 cm in depth. These theoretical calculations should aid the clinician in the evaluation of induction heating devices for their effectiveness in heating deep-seated and superficial tumors.

Humans↗
PubMed2004

New model for a theoretical density functional theory investigation of the mechanism of the carbonic anhydrase: how does the internal bicarbonate rearrangement occur?

A theoretical density functional theory (DFT, B3LYP) investigation has been carried out on the catalytic cycle of the carbonic anhydrase. A model system including the Glu106 and Thr199 residues and the "deep" water molecule has been used. It has been found that the nucleophilic attack of the zinc-bound OH on the CO(2) molecule has a negligible barrier (only 1.2 kcal mol(-1)). This small value is due to a hydrogen-bond network involving Glu106, Thr199, and the deep water molecule. The two usually proposed mechanisms for the internal bicarbonate rearrangement have been carefully examined. In the presence of the two Glu106 and Thr199 residues, the direct proton transfer (Lipscomb mechanism) is a two-step process, which proceeds via a proton relay network characterized by two activation barriers of 4.4 and 9.0 kcal mol(-1). This pathway can effectively compete with a rotational mechanism (Lindskog mechanism), which has a barrier of 13.2 kcal mol(-1). The fast proton transfer found here is basically due to the effect of the Glu106 residue, which stabilizes an intermediate situation where the Glu106 fragment is protonated. In the absence of Glu106, the barrier for the proton transfer is much larger (32.3 kcal mol(-1)) and the Lindskog mechanism becomes favored.

Bicarbonates↗
PubMed1996

Dye transfer between cells of the lens.

Dye transfer between lens fiber cells and between lens epithelial cells and underlying fiber cells was studied using a wide dynamic range-cooled CCD camera, H2O immersion objectives and image analysis techniques. Each lens was decapsulated by a new technique which leaves the epithelial cells adherent to the lens fiber mass. Lucifer Yellow CH was injected into either single epithelial cells or single fiber cells using the standard whole cell configuration of the patch voltage clamp technique. The results demonstrate extensive dye communication between fiber cells at the lens posterior surface, anterior surface, and equatorial surface. Dye transfer between deep fiber cells was also observed. Dye transfer between approximately 10% of epithelial cells and their underlying fiber cells was apparent when care was taken to yield wide dynamic range images. This was required because the relatively high concentration of dye in the epithelial cell masks the presence of much lower dye concentrations in the underlying fiber cell. A mathematical model which includes dye concentration, time, and spatial spread suggests that those epithelial cells that are coupled to an underlying fiber cell are about as well dye coupled as the epithelial cells themselves. The relatively low dye concentration in a fiber cell is due to its larger volume and diffusion of the dye along the axis of the fiber away from the fiber/epithelial junction.

Animals↗
PubMed1993

Spatially localized neuronal cell lineages in the developing mammalian forebrain.

The role of cell lineage in the organization of the cerebral cortex and striatum of the developing rat forebrain was analysed using retroviral-mediated gene transfer to mark the progeny of individual progenitors. Injections around the onset of neurogenesis (embryonic day 14) produced neuronal- and glial-specific clones in the striatum and cortex. The majority of the neuronal clones were restricted to either the deep or superficial layers of the cortex and to either the striatal patch or matrix compartments of the striatum. Moreover, modeling the distributions of the neuronal clones in various ways revealed that grouping the clones into deep vs superficial cortical compartments and patch vs matrix striatal compartments best accounted for the clone distributions. These results suggest that at the onset of neurogenesis there is a heterogeneity of neuronal progenitors within the proliferative ventricular zone.

Animals↗
PubMed2026

Decoding TnsC Filament Assembly in CRISPR-Associated Transposons Using Interpretable Deep Learning and Molecular Simulations.

CRISPR-associated transposons (CASTs) enable programmable DNA integration, yet how the TnsC regulator forms processive filaments on DNA to coordinate RNA-guided transposition in type V-K CAST systems remains unknown. Here, we integrate large-scale molecular simulations, interpretable deep learning using graph attention networks (GATs), and causal inference analyses to define the molecular determinants of TnsC filament nucleation and elongation. We show that TnsC nucleates by inducing localized DNA deformation that propagates along extended filaments, with Granger causality revealing that TnsC motions precede and predict DNA deformation. Interpretable GAT models demonstrate that elongation is determined during early recognition between incoming and DNA-bound subunits, followed by structural reorganization that regenerates the recruitment interface and enables processive assembly. These results elucidate the molecular mechanism of processive TnsC filament assembly and explain why isolated TnsC filaments preferentially elongate in the 5' → 3' direction, while accessory transposition factors can reshape the interaction landscape and alter filament growth polarity. Together, these findings advance our understanding of CAST function and inform the engineering of programmable DNA integration platforms. Beyond CAST systems, this work introduces an interpretable GAT approach as a general and transferable deep learning strategy for uncovering molecular mechanisms in biological systems, while demonstrating the power of causal inference for dissecting directional relationships in molecular dynamics.

Deep Learning↗
PubMed1991

Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms.

Administration of the antiepileptic drug valproic acid (VPA) during early pregnancy can result in a 1-2% incidence of spina bifida aperta, a closure defect of the posterior neural tube in the human. The predominant defect produced by VPA in the mouse is exencephaly, a closure defect of the anterior neural tube. Recent experiments demonstrate that an appropriate dosing regimen (consecutive doses of VPA on day 9 of gestation) can also result in a low incidence of spina bifida aperta, and a high incidence of spina bifida occulta in the mouse as a potential animal model. Relatively high doses and concentrations of VPA are needed in the mouse to produce neural tube defects, the human appears to be more sensitive in this regard. Maximal concentrations and not AUC (area under the concentration-time curve) values correlate with the incidence of neural tube defects in the mouse which could in part be explained by saturation of plasma protein binding, increased free drug available for placental transfer and the embryonic neuroepithelium acting as a "deep compartment". It is likely that the parent drug and not a metabolite is the proximate teratogen. Structure-activity relationships show a strict structural requirement for high teratogenic potency: the molecule must contain an alpha-hydrogen atom, a carboxyl function, branching on carbon atom 2 with two chains containing 3 carbon atoms each for maximum activity. If these two carbon chains are different, then enantiomers are present such as the R- and S-enantiomers of 2-n-propyl-4-pentenoic acid (4-en-VPA), 2-n-propyl-4-pentynoic acid (4-yn-VPA) and 2-ethylhexanoic acid. These enantiomers were synthesized and shown to be significantly different in regard to teratogenic potency. Pharmacokinetic studies indicate that both enantiomers of each compound reach the embryo to the same degree. Therefore, the intrinsic teratogenic activity of the enantiomers differ, suggesting a stereoselective interaction between the drugs and a chiral structure within the embryo, is involved in the mechanism of action. In sharp contrast to the teratogenic effect, the anticonvulsant activity and neurotoxicity of this compound class show broad structural specificity, opening the possibility for development of novel antiepileptic agents with low teratogenic potency such as 2-n-propyl-2-pentenoic acid (2-en-VPA). The molecular mechanism of the teratogenicity of VPA is quite unknown; of the several hypothesis suggested, the interaction of VPA with embryonic folate metabolism is discussed here.

Abnormalities, Drug-Induced↗
PubMed1999

Envelope structure of deeply embedded young stellar objects in the Serpens Molecular Cloud.

Aperture-synthesis and single-dish (sub-) millimeter molecular-line and continuum observations reveal in great detail the envelope structure of deeply embedded young stellar objects (SMM 1 = FIRS 1, SMM 2, SMM 3, SMM 4) in the densely star-forming Serpens Molecular Cloud. SMM 1, 3, and 4 show partially resolved (>2" = 800 AU) continuum emission in the beam of the Owens Valley Millimeter Array at lambda = 3.4-1.4 mm. The continuum visibilities accurately constrain the density structure in the envelopes, which can be described by a radial power law with slope -2.0 +/- 0.5 on scales of 300 to 8000 AU. Inferred envelope masses within a radius of 8000 AU are 8.7, 3.0, and 5.3 Msolar for SMM 1, 3, and 4, respectively. A point source with 20%-30% of the total flux at 1.1 mm is required to fit the observations on long baselines, corresponding to warm envelope material within approximately 100 AU or a circumstellar disk. No continuum emission is detected interferometrically toward SMM 2, corresponding to an upper limit of 0.2 Msolar assuming Td = 24 K. The lack of any compact dust emission suggests that the SMM 2 core does not contain a central protostar. Aperture-synthesis observations of the 13CO, C18O, HCO+, H13CO+, HCN, H13CN, N2H+ 1-0, SiO 2-1, and SO 2(2)-1(1) transitions reveal compact emission toward SMM 1, 3, and 4. SMM 2 shows only a number of clumps scattered throughout the primary field of view, supporting the conclusion that this core does not contain a central star. The compact molecular emission around SMM 1, 3, and 4 traces 5"-10" (2000-4000 AU) diameter cores that correspond to the densest regions of the envelopes, as well as material directly associated with the molecular outflow. Especially prominent are the optically thick HCN and HCO+ lines that show up brightly along the walls of the outflow cavities. SO and SiO trace shocked material, where their abundances may be enhanced by 1-2 orders of magnitude over dark-cloud values. A total of 31 molecular transitions have been observed with the James Clerk Maxwell and Caltech Submillimeter telescopes in the 230, 345, 490, and 690 GHz atmospheric windows toward all four sources, containing, among others, lines of CO, HCO+, HCN, H2CO, SiO, SO, and their isotopomers. These lines show 20-30 km s-1 wide line wings, deep and narrow (1-2 km s-1) self-absorption, and 2-3 km s-1 FWHM line cores. The presence of highly excited lines like 12CO 4-3 and 6-5, 13CO 6-5, and several H2CO transitions indicates the presence of material with temperatures > or approximately 100 K. Monte Carlo calculations of the molecular excitation and line transfer show that the envelope model derived from the dust emission can successfully reproduce the observed line intensities. The depletion of CO in the cold gas is modest compared to values inferred in objects like NGC 1333 IRAS 4, suggesting that the phase of large depletions through the entire envelope is short lived and may be influenced by the local star formation density. Emission in high-excitation lines of CO and H2CO requires the presence of a small amount of approximately 100 K material, comprising less than 1% of the total envelope mass and probably associated with the outflow or the innermost region of the envelope. The derived molecular abundances in the warm (Tkin > 20 K) envelope are similar to those found toward other class 0 YSOs like IRAS 16293-2422, though some species appear enhanced toward SMM 1. Taken together, the presented observations and analysis provide the first comprehensive view of the physical and chemical structure of the envelopes of deeply embedded young stellar objects in a clustered environment on scales between 1000 and 10,000 AU.

Astronomy↗
PubMed1982

Carotid artery exteriorization for percutaneous catheterization in sheep and dogs.

Summary and reliable physiologic or pharmacologic investigation in animal models often requires arterial catheterization in awake animal subjects. This can be facilitated by surgical exteriorization of the carotid artery for subsequent percutaneous catheterization. A simplified surgical procedure is described that has been demonstrated to have limited morbidity and excellent applicability for multiple use, as well as to ensure high blood flow rates when needed. The surgical technique involves transfer of the carotid artery from a deep paratracheal position to a ventrolateral neck subcutaneous position, protected from the underlying mattress sutures by the sternomastoid muscle.

Animals↗
PubMed2001

What we can learn from heavy ion therapy for radioprotection in space.

A major problem in manned space flight is the impact of cosmic radiation, especially that of heavy charged particles since they have an elevated biological efficiency (RBE). The RBE estimation determines the potential exposure for man. It is one of the limiting factors for space flight and should be known very precisely. The same is true for heavy-ion tumor therapy where beams of carbon ions are used to treat deep-seated tumors. There, RBE values determine the dose distribution and are estimated using the Local Effect Model (LEM). The clinical results confirm the correctness of LEM and suggest to use the same theoretical approach to assess the impact of cosmic rays.

Carbon↗
PubMed1991

Food-chain and dose model, CALDOS, for assessing Canada's Nuclear Fuel Waste Management concept.

The food-chain and dose model, CALculation of DOSe (CALDOS), was developed for assessing Canada's concept for nuclear fuel waste disposal in a vault deep in crystalline rock of the Canadian Shield. The model is very general and based on the Shield as a whole. The critical group is totally self-sufficient and represented by ICRP (1975) Reference Man for dose prediction. CALDOS assumes steady-state conditions and deals with variation and uncertainty through Monte Carlo simulation techniques. Ingrowth of some radioactive daughters is considered during food-chain transfer. A limit is set on root uptake to avoid unrealistic plant concentrations. Integrated ingestion and inhalation rates of man are calculated in a unique way, based on energy needs. Soil ingestion by man and external exposure from building material are unique pathways considered. Tritium, 129I, and 222Rn are treated through special models, and 14C and 129I involve unique geosphere dose limits. All transfer coefficients are lognormally distributed, and the plant/soil concentration ratio is correlated with the soil partition coefficient. Animals' ingestion rates are normally distributed and correlated with each other. Comprehensive sets of internal and external dose conversion factors were calculated for CALDOS. Sample calculations show that dose distributions tend to be strongly right-skewed. Many features of CALDOS are relevant for environmental assessment in general.

Animals↗
PubMed1996

An inverse method to optimize heating conditions in RF-capacitive hyperthermia.

An inverse method to directly optimize the electrode configuration (positions, sizes, and driving voltages) for radio frequency (RF) capacitive hyperthermia was proposed. The main algorithm, based on the two-dimensional finite element method (2-D-FEM) solution of Laplace and bio-heat transfer equations, iteratively modified the individual boundary potentials around an object thereby making a calculated temperature distribution approach a target temperature distribution. A penalty function governed continuity and smoothness among the boundary potentials so that the optimized boundary potentials became attainable for two plate electrodes. Case simulations demonstrated the viability of the algorithm. For instance, in a computed tomography (CT)-based human abdomen model which had deep-and shallow-seated tumors, the optimized electrodes produced a temperature distribution suitable for heating the tumors; the average temperature differences between the tumors and normal tissues were 3.5 degree C for the deep-seated and 7.6 degree C for the shallow-seated tumors within 600 s of heating. A drawback with the present algorithm is that the choice of penalty coefficient and modification of the boundary potentials to coincide with the use of two plate electrodes are carried out manually. These procedures would be automated.

Algorithms↗
PubMed2026

Machine Learning in Hyperlipidaemia Research: Screening and Experimental Insights into Lipid Metabolism Modulators.

Hyperlipidemia, characterized by elevated blood lipid levels, represents a major global health concern due to its strong association with cardiovascular disease, diabetes, and metabolic syndrome. While current therapies - such as statins, fibrates, bile acid sequestrants, and PCSK9 inhibitors - are effective in controlling hyperlipidemia, they are often associated with adverse effects, potential drug resistance, and suboptimal efficacy in certain patient populations. All of the above underscore the urgent need for safer and more effective therapeutic alternatives. Among the major molecular targets involved in the regulation of lipid metabolism are HMG-CoA reductase, PCSK9, peroxisome proliferator-activated receptors (PPARs), cholesteryl ester transfer protein (CETP), and nuclear receptors, including the liver X receptor (LXR) and farnesoid X receptor (FXR), which are also targets for future antihyperlipidemic drug development. Recent advancements in artificial intelligence (AI) and machine learning (ML) have significantly transformed and accelerated drug discovery by enabling the processing of vast amounts of genomic, proteomic, and chemical data. Furthermore, ML tools such as quantitative structure-activity relationship (QSAR) modelling, deep learning, random forest, and support vector machines (SVM) have proven predictive and effective in identifying novel lipid metabolism modulators, thereby enhancing the efficacy and accuracy of virtual screening. Meanwhile, molecular docking has become an integral part of structure-based drug design (SBDD), and software such as AutoDock, Glide, and GOLD have proven effective in generating accurate ligand-target docking models. Molecular docking, together with ML-based approaches, enables the identification of potent and selective drug candidates. Overall, the combination of ML and molecular docking offers an efficient and accurate platform for antihyperlipidemic drug discovery, helping to overcome the limitations of currently available therapeutic strategies.

HMG-CoA reductase↗
PubMed1988

Dendritic anatomy and electrotonic transfer properties of cat superior colliculus neurons.

Detailed morphometrical and corresponding electrotonic characteristics on three classes of cat superior colliculus (SC) neurons have been derived. The sample of cells selected for analysis comprised ascending projection neurons (APNs), inter-layer neurons (ILNs) and tecto-reticulo-spinal neurons (TRSNs) recorded intracellularly and stained with HRP. Superficial SC neurons (APNs, ILNs) could be attached to the allo- and idiodendritic type while deep layer neurons (TRSNs) belong to the isodendritic type. For each neuron, the branching pattern, lengths and diameters of the dendritic trees were determined. These data served as input to the computer program "DENDRIT" from which electrotonic membrane and transfer properties were calculated. Both the morphometrical data and the electronic properties underline the contrasting features of superficial vs deep layer neurons in the SC. Our results support the hypothesis that on the neuron level a close relationship between dendritic pattern and neuron function might exist.

Animals↗