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Results for “Deep generative models”

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PubMed2004

A separation-of-timescales approach to the coalescent in a continuous population.

This article presents an analysis of a model of isolation by distance in a continuous, two-dimensional habitat. An approximate expression is derived for the distribution of coalescence times for a pair of sequences sampled from specific locations in a rectangular habitat. Results are qualitatively similar to previous analyses of isolation by distance, but account explicitly for the location of samples relative to the habitat boundaries. A separation-of-timescales approach takes advantage of the fact that the sampling locations affect only the recent coalescent behavior. When the population size is larger than the number of generations required for a lineage to cross the habitat range, the long-term genealogical process is reasonably well described by Kingman's coalescent with time rescaled by the effective population size. This long-term effective population size is affected by the local dispersal behavior as well as the geometry of the habitat. When the population size is smaller than the time required to cross the habitat, deep branches in the genealogy are longer than would be expected under the standard neutral coalescent, similar to the pattern expected for a panmictic population whose population size was larger in the past.

Data Interpretation, Statistical↗

PubMed1984

Flow through a venous valve and its implication for thrombus formation.

To elucidate the possible connection between the flow patterns in the pockets of venous valves and thrombus formation, detailed studies of the behavior of model particles and red cells flowing through a venous valve have been carried out using isolated transparent dog saphenous veins containing two-leaflet valves, and cinemicrographic techniques. It was found that large paired vortices, located symmetrically on both sides of the bisector plane of the valve leaflets, were present in each valve pocket under physiological flow conditions. Particles continually entered the valve pockets from the mainstream, spending long periods of time describing a series of spiral orbits of decreasing diameter, while moving away from the bisector plane, and eventually left the vortex, rejoining the mainstream. With concentrated suspensions of red cells, it was found that another smaller counter-rotating secondary vortex, driven by the large primary vortex existed deep in each valve pocket. The concentration of red cells in this secondary vortex remained appreciably lower than that in the mainstream. In such regions, fluid circulated with extremely low velocities, thus creating a very low shear field which allowed red cells to form aggregates. The results suggest that in some pathological states, the valve-pocket vortices could act as automatic traps and generators of thrombi in a fashion similar to that previously demonstrated in an annular vortex formed downstream from a sudden tubular expansion.

Animals↗

PubMed2003

Whole-mantle convection and the transition-zone water filter.

Because of their distinct chemical signatures, ocean-island and mid-ocean-ridge basalts are traditionally inferred to arise from separate, isolated reservoirs in the Earth's mantle. Such mantle reservoir models, however, typically satisfy geochemical constraints, but not geophysical observations. Here we propose an alternative hypothesis that, rather than being divided into isolated reservoirs, the mantle is filtered at the 410-km-deep discontinuity. We propose that, as the ascending ambient mantle (forced up by the downward flux of subducting slabs) rises out of the high-water-solubility transition zone (between the 660 km and 410 km discontinuities) into the low-solubility upper mantle above 410 km, it undergoes dehydration-induced partial melting that filters out incompatible elements. The filtered, dry and depleted solid phase continues to rise to become the source material for mid-ocean-ridge basalts. The wet, enriched melt residue may be denser than the surrounding solid and accordingly trapped at the 410 km boundary until slab entrainment returns it to the deeper mantle. The filter could be suppressed for both mantle plumes (which therefore generate wetter and more enriched ocean-island basalts) as well as the hotter Archaean mantle (thereby allowing for early production of enriched continental crust). We propose that the transition-zone water-filter model can explain many geochemical observations while avoiding the major pitfalls of invoking isolated mantle reservoirs.

Journal Article↗

PubMed2003

Functional imaging of airway narrowing.

The report will focus on studies that illustrate how high resolution computed tomography can be used to provide new insights into airway and lung function, that cannot be obtained with any other methodology in humans or animal models. In one series of experiments, we have clearly demonstrated that even large cartilaginous airways are capable of complete closure in vivo. These unequivocal in vivo results invalidate the ubiquitous concept that there is a limit to airway narrowing in normal subjects. In another series of experiments, we have investigated potential reasons why asthmatic subjects might show airway constriction following deep inspiration instead of the normal dilation. Experimental results show that a constrictor response to deep inspiration can be generated in normal airways simply by minimizing tidal stresses. The absence of these normal rhythmic stresses alters the smooth muscle throughout the airway tree, such that subsequent large stresses lead to a further constriction. These results also offer a possible mechanism by which the response to deep inspiration is altered in asthmatic subjects. By allowing accurate measurement of the size of individual airways, computed tomography with modern commercially available scanners thus provides a unique opportunity to evaluate specific hypotheses regarding mechanisms underlying lung disease.

Adaptation, Physiological↗

PubMedDate not supplied

Multi-applicator hyperthermia system description using scattering parameters.

Hyperthermia systems using electromagnetic phased arrays have often been investigated from a SAR distribution point of view. One of the problems in these systems is that the achieved SAR distribution is different from the intended one because of changes in the generator signals due to mutual coupling between applications. The use of circuit theory and S-parameters in the description of an N-applicator phased array system is introduced in this paper, and a compact matrix equation giving excitation as a function of generator signals is derived. Measurement of the S-parameters is discussed using a phased array deep heating system (Danish Hyperthermia Foundation (DHF)) as an example. In a phantom experiment a significant improvement in the SAR distribution is demonstrated when the developed method is applied.

Electromagnetic Phenomena↗

PubMed2026

Translating functional molecular knowledge into crop-breeding success.

Historical plant breeding, which optimizes phenotypes through selective crossing guided by phenotypic evaluation and molecular markers, is limited by evolutionary constraints that hinder rapid crop improvement. A new paradigm, precision breeding, circumvents these limitations by targeting genetic variants through functional molecular knowledge. To generate this knowledge at scale, sequence-based deep learning leverages high-quality genome sequence data to predict variant effects at base-pair resolution. When linked to agronomically important traits, these predictions enable breeders to prioritize variants for precision selection or editing. Although it is still in the early stages of development, we foresee three key applications for this approach: introgressing genes from distant breeding pools, purging deleterious mutations and designing new plant ideotypes. Looking ahead, refined computational models will facilitate targeted editing and the systematic redesign of complex physiological processes to address emerging breeding goals under shifting environmental conditions.

Crops, Agricultural↗

PubMed2001

Cortical change in Alzheimer's disease detected with a disease-specific population-based brain atlas.

We report the first detailed population-based maps of cortical gray matter loss in Alzheimer's disease (AD), revealing prominent features of early structural change. New computational approaches were used to: (i) distinguish variations in gray matter distribution from variations in gyral patterns; (ii) encode these variations in a brain atlas (n = 46); (iii) create detailed maps localizing gray matter differences across groups. High resolution 3D magnetic resonance imaging (MRI) volumes were acquired from 26 subjects with mild to moderate AD (age 75.8+/-1.7 years, MMSE score 20.0+/-0.9) and 20 normal elderly controls (72.4+/-1.3 years) matched for age, sex, handedness and educational level. Image data were aligned into a standardized coordinate space specifically developed for an elderly population. Eighty-four anatomical models per brain, based on parametric surface meshes, were created for all 46 subjects. Structures modeled included: cortical surfaces, all major superficial and deep cortical sulci, callosal and hippocampal surfaces, 14 ventricular regions and 36 gyral boundaries. An elastic warping approach, driven by anatomical features, was then used to measure gyral pattern variations. Measures of gray matter distribution were made in corresponding regions of cortex across all 46 subjects. Statistical variations in cortical patterning, asymmetry, gray matter distribution and average gray matter loss were then encoded locally across the cortex. Maps of group differences were generated. Average maps revealed complex profiles of gray matter loss in disease. Greatest deficits (20-30% loss, P<0.001-0.0001) were mapped in the temporo-parietal cortices. The sensorimotor and occipital cortices were comparatively spared (0-5% loss, P>0.05). Gray matter loss was greater in the left hemisphere, with different patterns in the heteromodal and idiotypic cortex. Gyral pattern variability also differed in cortical regions appearing at different embryonic phases. 3D mapping revealed profiles of structural deficits consistent with the cognitive, metabolic and histological changes in early AD. These deficits can therefore be (i) charted in a living population and (ii) compared across individuals and groups, facilitating longitudinal, genetic and interventional studies of dementia.

Aged↗

PubMed1989

Flexibility plot of proteins.

The flexibility plot of a protein lies on the observation that amino acid residues with the highest turn potential, i.e. located in highly mobile regions of protein surface, also possess the smallest volumes as well as the lowest hydrophobicities. The plot is generated by shifting a five residue window along the protein sequence and calculating the value of the hydrophobicity-volume product for consecutive quintuplets of amino acid residues. The concomitant occurrence of small volumes and low hydrophobicities results in very deep minima. A threshold value has also been introduced in order to discriminate significant minima. To substantiate the interpretation that the selected minima actually indicate very flexible segments of a protein (loops, turns, etc.), we have compared plots obtained for model proteins (lysozyme, myoglobin, ribonuclease, trypsin, thermolysin and T4 lysozyme) with X-ray thermal factors profiles available for the same proteins. When compared to thermal profiles, the majority of flexible segments evidenced by our plots have been found to be in agreement with regions characterized by high thermal factors. Results have also been discussed in the light of local organization possessed by examined proteins.

Amino Acids↗

PubMed1998

Mice with an aspartylglucosaminuria mutation similar to humans replicate the pathophysiology in patients.

Aspartyglucosaminuria (AGU) is a lysosomal storage disease with autosomal recessive inheritance that is caused by deficient activity of aspartylglucosaminidase (AGA), a lysosomal enzyme belonging to the newly described enzyme family of N-terminal hydrolases. An AGU mouse model was generated by targeted disruption of the AGA gene designed to mimic closely one human disease mutation. These homozygous mutant mice have no detectable AGA activity and excrete aspartylglucosamine in their urine. Analogously to the human disease, the affected homozygous animals showed storage in lysosomes in all analyzed tissues, including the brain, liver, kidney and skin, and lysosomal storage was already detected in fetuses at 19 days gestation. Electron microscopic studies of brain tissue samples demonstrated lysosomal storage vacuoles in the neurons and glia of the neocortical and cortical regions. Magnetic resonance images (MRI) facilitating monitoring of the brains of living animals indicated cerebral atrophy and hypointensity of the deep gray matter structures of brain-findings similar to those observed in human patients. AGU mice are fertile, and up to 11 months of age their movement and behavior do not differ from their age-matched littermates. However, in the Morris water maze test, a slow worsening of performance could be seen with age. The phenotype mimics well AGU in humans, the patients characteristically showing only slowly progressive mental retardation and relatively mild skeletal abnormalities.

Acetylglucosamine↗

PubMed1979

Evaluation of electrofulguration in control of bleeding of experimental gastric ulcers.

The safety and efficacy of electrofulguration for control of bleeding from standard canine experimental gastric ulcers was studied. At settings of 2, 5, and 8 on a Valleylab SSE-3 generator, 0.5-sec applications provided effective hemostasis. However, a setting of 2 required an excessive number of applications. Settings of 5 and 8 showed deep injury to the muscularis externa when examined histologically. In an attempt to reduce the depth of injury, a more easily ionizable gas mixture of 50% argon gas and 50% CO2 was compared to CO2 alone. At a generator setting of 5 with 0.5-sec applications the argon-CO2 mixture produced slightly less deep injury than CO2 alone, but the difference was not significant. Although electrofulguration was effective in stopping bleeding in these experiments, the tissue injury was unpredictable and deep.

Animals↗

PubMed2026

Flexible use of conserved motifs constrains genome access in cell type evolution.

Cell types can be organized into related families, but the regulatory mechanisms that define and maintain these families across deep evolutionary time remain unknown. Here, combining single-nucleus multi-omic sequencing with deep learning to analyse the accessible genomes of two groups of vastly divergent animals including flatworms and vertebrates, we find that hundreds of accessibility-dictating sequence motifs partition into distinct yet conserved sets, or 'vocabularies', each associated with a specific cell type family. However, combinatorial relationships among these motifs preferred by individual cell types are largely species specific. Deep-learning models trained on one species accurately predict family-level chromatin accessibility in distantly related species, albeit frequently rely on different motifs from shared vocabularies to reach convergent predictions. By contrast, models trained on individual cell types within a family lose cross-species predictive power, indicating that the regulatory syntax governing cell type-level identity evolves rapidly. We propose a 'collective maintenance' model in which motif vocabularies defining cell type families are evolutionarily stable, while recombination of these motifs generates cell type-specific regulatory programmes. This suggests that family identity is maintained collectively by large, conserved pools of regulatory factors, analogous to the logic of developmental homology, where character identity persists through network-level conservation despite extensive rewiring.

Journal Article↗

PubMed2004

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency.

Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the large-conductance voltage- and Ca(2+)-activated K(+) channel (BK channel), a unique calcium, and voltage-activated potassium channel type have remained elusive. Here we report that mice lacking BK channels (BK(-/-)) show cerebellar dysfunction in the form of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK(-/-) mice showed a dramatic reduction in spontaneous activity of the BK(-/-) cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short-term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown roles of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a previously undescribed animal model of cerebellar ataxia.

Animals↗

PubMed2005

WZsGreen/+: a new green fluorescent protein knock-in mouse model for the study of KIT-expressing cells in gut and cerebellum.

In the small intestine, interstitial cells of Cajal (ICC) surrounding the myenteric plexus generate the pacemaking slow waves that are essential for an efficient intestinal transit. The underlying molecular mechanisms of the slow wave are poorly known. KIT is currently the sole practical marker for ICC. Attempts to purify living ICC have so far largely failed, due to the loss of the KIT epitope during enzymatic dissociation. Aiming to identify and isolate living ICC, we designed a knock-in strategy to express a fluorescent tag in KIT-expressing cells by inserting the sequence of the novel green fluorescent protein ZsGreen into the first exon of the c-Kit gene, creating a null allele called W(ZsGreen). In the gastrointestinal tract of heterozygous W(ZsGreen)/+ mice, tiny ZsGreen fluorescent dots were observed in all KIT-expressing ICC populations, with exception of ICC at the deep muscular plexus in small intestine. During development of the gastrointestinal tract, ZsGreen expression followed KIT expression in a spatiotemporal way. Stellate and basket KIT-expressing cells in the molecular layer of the cerebellum also exhibited ZsGreen dots, whereas no ZsGreen was detected in skin, testis, and bone marrow. ZsGreen dot-containing intestinal cells could be isolated from jejunum and maintained alive in culture for at least 3 days. ZsGreen is a suitable alternative to EGFP in transgenic animals. The novel W(ZsGreen)/+ model reported here appears to be a promising tool for live studies of KIT-expressing cells in the gastrointestinal tract and cerebellum and for the further analysis of pacemaker mechanisms.

Animals↗

PubMed1997

Use of in vitro reconstructed skin To cover skin flap donor site.

BACKGROUND: The skin flap technique is widely used in reconstructive surgery for the coverage of deep burns of the face, neck, and joints. Facial deformities and joint contractures are avoided by transplanting vascularized full-thickness skin on wounds. The major drawback of this technique is the injury inflicted upon the donor site, which corresponds to a third degree burn. The usual technique to cover the flap donor site is the transplantation of split-thickness autografts. In the case of patients with deep and extensive burns, the harvesting of good quality autografts is often difficult because of multiple scars. In order to avoid additional trauma to the patient by split-thickness skin harvesting, we have experimented the use of a new model of in vitro reconstructed skin graft for flap donor site coverage in a mouse model. MATERIALS AND METHODS: The reconstructed skin was grafted on the back of nude mice at the skin flap donor site, while flap was used to cover a wound generated on joint of the posterior leg. RESULTS: A 100% graft take was achieved (16 mice were used) and a limited contraction of the reconstructed skin was observed 30 days posttransplantation (78% of the initial surface area of the graft remained). Histological analysis of the graft demonstrated healing of a well differentiated epidermis laying on a dense dermis. CONCLUSIONS: Since this technique would prevent additional trauma to the patient while achieving a good healing of the wound, it may be a useful approach in the coverage of skin flap donor site in humans.

Animals↗

PubMedDate not supplied

Edge-element based finite element analysis of microwave hyperthermia treatments for superficial tumours on the chest wall.

Several three-dimensional hyperthermia treatment planning systems for deep regional hyperthermia have been successfully utilized for improving the performance of applicators such as the BSD Sigma 60. Treatment planning systems for superficial heating in contrast have been less utilized. This paper presents a study of the applicability of the finite element method that has been developed for modelling hyperthermia treatments of recurrent chest wall cancer using a patient geometry. The patient model was created by reconstructing the tissue geometry of a patient using a series of axial CT scans. Tetrahedral grids were generated from this geometry for use in finite element simulations of the SAR profile using edge-elements and in finite element simulations of the steady-state temperature profile using scalar elements. The predicted temperature profile was well correlated with thermometry readings taken after 30 min of heating during a hyperthermia treatment. The model predicted the presence of hot-spots in regions that were not monitored. Simulations also showed that the hot-spots can be manipulated by rotating the applicator by 90 degrees. This study demonstrates the ability of the model to provide detailed and accurate heating profiles in a patient specific model for superficial microwave hyperthermia of the chest wall.

Computer Simulation↗

PubMed2005

Long-wavelength adaptation reveals slow, spectrally opponent inputs to the human luminance pathway.

In addition to its expected fast, additive L- and M-cone inputs (L + M), the luminance pathway has slow, spectrally opponent inputs. We have previously shown that on long-wavelength fields, the dominant slow signals change from L-M at moderate intensity levels to M-L signals at high. Here, we focus on the transition between them, which we find is marked by substantial changes in temporal phase delay, and by large and unexpected shifts in flicker spectral sensitivity. At moderate temporal frequencies, counter to the selective adaptation caused by the field, spectral sensitivity changes from being M-cone-like to more L-cone-like. These changes can be accounted for by a change in the relative strengths of the slow spectrally opponent cone signals from L-M exceeding M-L below the transition to M-L exceeding L-M above it, and by the resulting changes in constructive and destructive interference between the dominant signal components. We speculate that the transition is caused by the deep-red field becoming equivalent, postreceptorally, to a green field at high bleaching levels. These results further challenge the dogma that there are separable psychophysical channels for the transmission and processing of color and luminance information. Although its output generates an achromatic percept, the luminance channel has spectrally opponent inputs.

Adaptation, Physiological↗

PubMedDate not supplied

Optimization of the intensity gain of multiple-focus phased-array heating patterns.

A new technique for enhancing the intensity gain at the focal points in multiple-focus patterns is introduced. The new technique is shown to be effective in reducing the interference typically associated with multiple-focus patterns. This reduction in interference patterns allows multiple-focus scanning to generate highly localized heating. Simulation results indicate that multiple-focus scanning not only provides an alternative to single-focus scanning, but also achieves better localization in the heating pattern. The maximization of intensity gain of multiple-focus heating patterns significantly reduces the pre-focal-depth high-temperature regions that can be caused by single-focus scanning. This is shown by computer simulation of a two-dimensional cylindrical-section array (CSA2D) as a heating applicator. Two series of simulations are presented in which different scan trajectories were used to therapeutically heat a small deep-seated target volume. In every case the heating pattern was generated using single-focus scanning and multiple-focus scanning (with and without intensity gain maximization). Multiple-focus scanning with gain maximization offers the best localization of heating to the target volume of the three methods.

Biophysical Phenomena↗

PubMed1996

Segmentation of 2-D and 3-D objects from MRI volume data using constrained elastic deformations of flexible Fourier contour and surface models.

This paper describes a new model-based segmentation technique combining desirable properties of physical models (snakes), shape representation by Fourier parametrization, and modelling of natural shape variability. Flexible parametric shape models are represented by a parameter vector describing the mean contour and by a set of eigenmodes of the parameters characterizing the shape variation. Usually the segmentation process is divided into an initial placement of the mean model and an elastic deformation restricted to the model variability. This, however leads to a separation of biological variation due to a global similarity transform from small-scale shape changes originating from elastic deformations of the normalized model contours only. The performance can be considerably improved by building shape models normalized with respect to a small set of stable landmarks (AC-PC in our application) and by explaining the remaining variability among a series of images with the model flexibility. This way the image interpretation is solved by a new coarse-to-fine segmentation procedure based on the set of deformation eigenmodes, making a separate initialization step unnecessary. Although straightforward, the extension to 3-D is severely impeded by difficulties arising during the generation of a proper surface parametrization for arbitrary objects with spherical topology. We apply a newly developed surface parametrization which achieves a uniform mapping between object surface and parameter space. The 3-D procedure is demonstrated by segmenting deep structures of the human brain from MR volume data.

Anatomy, Cross-Sectional↗