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Results for “Deep generative models”

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PubMed2001

Matrix metalloproteinases and aggrecanases cleave aggrecan in different zones of normal cartilage but colocalize in the development of osteoarthritic lesions in STR/ort mice.

OBJECTIVE: To map aggrecan cleavage by matrix metalloproteinases (MMPs) and aggrecanases in normal murine tibial articular cartilage (CBA strain) and in the development of spontaneous osteoarthritis (OA) in the STR/ort mouse and to assess the influence of sex hormone status on these conditions in gonadectomized STR/ort mice. METHODS: The distributions of neoepitopes of aggrecan generated by MMP (VDIPEN) and aggrecanase (NITEGE) cleavage were investigated by immunohistochemistry. RESULTS: VDIPEN neoepitope was detected mainly in the pericellular matrix of deep-zone chondrocytes in normal tibial cartilage from STR/ort and CBA mice. In early OA, VDIPEN immunostaining also localized to the pericellular matrix of chondrocytes at the site of the lesion. With increasing severity of OA lesions, VDIPEN immunostaining was also detected in the interterritorial matrix, close to the site of the lesion. In contrast, NITEGE mapped most strongly to the pericellular matrix of upper-zone chondrocytes in normal tibial cartilage. As with VDIPEN, NITEGE was strongly expressed in the pericellular matrix at the site of early OA lesions. With advancing OA, NITEGE colocalized with VDIPEN in both the pericellular and interterritorial matrices of chondrocytes adjacent to OA lesions and in those of the deep zones. Hormone status did not appear to influence the development of OA or the distribution of aggrecan neoepitopes in STR/ort mice. CONCLUSION: MMP- and aggrecanase-generated neoepitopes map predominantly to different regions in normal murine tibial cartilage. However, both groups of enzymes generate increased amounts of neoepitopes in pericellular and interterritorial matrix adjacent to histopathologic lesions of OA. Aggrecan degradation and the development of OA appear to be independent of sex hormone status in this model.

Aggrecans↗

PubMed1994

Development of a model of the premotor potential.

This study explored the sensory nature of the small negative premotor potential (PMP) that is often seen preceding the compound muscle action potential. We developed a model of the PMP, using the ulnar and superficial radial sensory (SRS) nerves. Standard conduction studies of the deep ulnar motor nerve recording over the first dorsal interosseous manus (FDIM) and of the SRS nerve recording over the same site were done separately, then simultaneously, on 20 normal hands. In all subjects, there was no FDIM PMP, but with simultaneous stimulation of both nerves, there was a potential in all subjects that appeared similar to their median thenar and ulnar hypothenar PMPs. Reference data for the median thenar, ulnar hypothenar, and model PMP were generated. Findings from this study are discussed and appear to support the concept of the PMP being either a sensory potential or a junctional potential.

Action Potentials↗

PubMed2026

Single-organ proteomics in Drosophila melanogaster larva.

The combination of genetic accessibility, organ complexity, evolutionary conservation, and cost-efficiency makes Drosophila melanogaster (Dm) a well-known model system for biomedical and fundamental biological research. Proteomic analysis of single organs enables the identification and quantification of proteins expressed in specific organs. This will help to uncover specific biological functions and unique protein profiles that are not detectable in whole-organism analyses. In this study we have isolated single organs form Dm larvae, and we have performed a deep proteomics mapping by following a minimal manipulation preparation procedure. The combined dataset across all organs comprised 9132 identified proteins. As anticipated, principal component analysis (PCA) revealed clear separation between the proteomes of most organs, confirming distinct protein profiles. These findings demonstrate the applicability of the sample preparation strategy for high-resolution proteomic characterization of individual organs in Drosophila. Given the extensive genetic tools available for this model organism, our approach has the potential to open new avenues for proteomic studies in Drosophila melanogaster and any other biological systems where the sample amount is limiting. SIGNIFICANCE STATEMENT: Drosophila melanogaster is a well-known model system for biomedical and fundamental biological research that serves as a valuable in vivo model organism due to its high degree of evolutionary conservation with higher vertebrates, tractable genetics, and logistical efficiency. However, the proteome of Drosophila at single organ level has been elusive to date, due to several factors like low sensitivity of previous generation mass spectrometers and sample preparation procedures, difficult isolation of some organs. In this study we have applied a compilation of advanced methods including minimal sample manipulation together with simple, straightforward and efficient protein extraction and digestion methods. Obtained peptides were minimally handled to be analyzed by applying specific and sensitive nLC methods coupled on-line to state-of-the-art MS/MS system. Altogether, the applied strategy allowed us to get the first single organ study to date for this animal. These datasets represent a significative resource for future genomic, transcriptomic and proteomic studies in Drosophila, as multi-omic integration requires deep proteomics to translate data into functional biochemistry, and serves as a critical bridge and an indispensable standalone resource across the genomic, transcriptomic, and proteomic landscapes.

Animals↗

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↗

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↗

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

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↗

PubMed2026

Profiler: an open web platform for multi-omics analysis.

MOTIVATION: High-throughput multi-omics technologies produce increasingly large and heterogeneous datasets that are difficult to analyze without advanced computational expertise. Existing bioinformatics tools are often fragmented or limited to specific omics types, hindering reproducibility and accessibility. There is a critical need for an integrated, user-friendly, and scalable platform capable of supporting multi-omics analyses across different data modalities. RESULTS: We present Profiler, an open-source, modular platform that unifies data import, quality control, preprocessing, statistical testing, machine and deep learning, biomarker discovery, pathway and drug-target enrichment, and survival modeling within a single reproducible environment. Built in Python with Streamlit, Profiler is available as both a web-based platform deployed on high-performance computing and a desktop version for local execution, enabling flexible usage across computational infrastructures. Profiler supports diverse omics modalities, including proteomics, transcriptomics, lipidomics, and electroencephalogram data. Through applications to glioblastoma proteomic, pancancer, and multi-omics datasets, Profiler reproduced known molecular subtypes, revealed potential therapeutic targets, and generated fully traceable analysis reports within minutes. By integrating advanced analytics behind an intuitive interface, Profiler democratizes multi-omics analysis and provides a robust, scalable foundation for systems biology and precision medicine research. AVAILABILITY AND IMPLEMENTATION: Profiler is open-source and freely available via its web platform (https://prism-profiler.univ-lille.fr) and GitHub (web version: https://github.com/yanisZirem/Profiler_v1_requests_datatests, desktop version: https://github.com/yanisZirem/prism-profiler), and archived on Zenodo (DOI: https://doi.org/10.5281/zenodo.17478158).

Software↗

PubMed2002

The clinical course of deep vein thrombosis in patients with gynecologic cancer.

OBJECTIVE: The aim of this study was to evaluate the survival of gynecologic cancer patients diagnosed with deep vein thrombosis. METHODS: We retrospectively reviewed the charts of patients admitted to our institution with gynecologic malignancy who were diagnosed with deep vein thrombosis (DVT) between 1984 and 1995. Data were collected regarding site, stage, histology, treatment, and proximity of DVT to treatment with surgery, chemotherapy, and radiotherapy. This study was limited to cases of ovarian, uterine, and cervical cancer. Descriptive statistics were generated and the survival of patients from the time of DVT was calculated using the Kaplan and Meier method. Cases were then matched by site, stage, histology, and age to controls without DVT to evaluate the effect of DVT on survival. A Cox regression model was used to assess the effect of multiple variables on survival. RESULTS: A total of 74 cases were identified. Ovarian, uterine, and cervical cancer accounted for 45, 27, and 28% of cases, respectively. Approximately 64% of patients had stage III or greater disease. The median survival of all patients from the time of DVT diagnosis was 7.8 months, with only about 20% of patients surviving at 5 years. Patients with cervical cancer or patients who had radiation therapy within 3 months of DVT diagnosis had significantly lessened survival (P < 0.01) than other patients with DVT. The survival of patients from the time of cancer diagnosis with venous thrombosis was significantly worse than a matched control group without DVT (P < 0.001). On multivariate analysis, there was a twofold greater risk of dying in those patients with gynecologic cancer and DVT. CONCLUSION: The development of DVT in conjunction with a gynecologic malignancy connotes a poor prognosis, especially in patients with cervical cancer. It is possible that this poor prognosis is related to the pathophysiology that results in venous thrombosis and not just the presence of cancer.

Age Factors↗

PubMed1999

Normal tissue complication probabilities correlated with late effects in the rectum after prostate conformal radiotherapy.

PURPOSE: Radiation therapy of deep-sited tumours will always result in normal tissue doses to some extent. The aim of this study was to calculate different risk estimates of late effects in the rectum for a group of cancer prostate patients treated with conformal radiation therapy (CRT) and correlate these estimates with the occurrences of late effects. Since the rectum is a hollow organ, several ways of generating dose-volume distributions over the organ are possible, and we wanted to investigate two of them. METHODS AND MATERIALS: A mathematical model, known as the Lyman-Kutcher model, conventionally used to estimate normal tissue complication probabilities (NTCP) associated with radiation therapy, was applied to a material of 52 cancer prostate patients. The patients were treated with a four field box technique, with the rectum as organ at risk. Dose-volume histograms (DVH) were generated for the whole rectum (including the cavity) and of the rectum wall. One to two years after the treatment, the patients completed a questionnaire concerning bowel (rectum) related morbidity quantifying the extent of late effects. RESULTS: A correlation analysis using Spearman's rank correlation coefficient, for NTCP values calculated from the DVHs and the patients' scores, gave correlation coefficients which were not statistically significant at the p<0.01 level. The correlation coefficients based on histograms of the whole rectum were larger than those derived from histograms of the rectum wall. Also, simpler descriptive measures as Dmax, of the whole rectum, correlated better to observed late toxicity than Dmax derived from histograms of the rectum wall. Correlation coefficients from "high-dose" measures were larger than those calculated from the NTCP values. Accordingly, as the volume parameter of the Lyman-Kutcher model was reduced, raising the impact of small high-dose volumes on the NTCP values, the correlation between observed effects and NTCP values became significant at p<0.01 level. CONCLUSIONS: 1) High-dose levels corresponding to small volume fractions of the cumulative dose-volume histograms were best correlated with the occurrences of late effects in the rectum as measured with questionnaires. This is compatible with a more serial organisation of the rectal tissue architecture than previously reported. 2) Reducing the Lyman-Kutcher model's volume parameter, thus allowing small high-dose regions to determine the NTCP, improved the correlation, but not beyond that of high-dose levels corresponding to small volume fractions of the cumulative dose-volume histograms.

Diarrhea↗

PubMed1991

Source modelling of the rolandic focus.

In rolandic epilepsy, consideration of the stereotyped ictal symptomatology suggests that the epileptic zone is likely to be in the same cortical structure in different patients. Routine EEG tracings of the interictal spike activity suggests a deep Sylvian fissure location. On the basis of the predominantly tangential potential field at the peak spike negativity seen in this group of patients, the inferior bank of the Sylvian fissure appears to be a good candidate. Without invasive studies, little refinement to this rather imprecise localization can be made as there is neither neurologic deficit nor lesion to provide a marker on radiological imaging. However, the application of source modelling technique using a simple single-dipole spherical head model has resulted in improved understanding of the generator behaviour, and facilitated the generation of new ways of analyzing spikes (e.g., stability index). Review of newer quantitative approaches including matrix and singular value decomposition of the dataset, spatial-temporal constrained source estimates etc. suggest other fruitful approaches. At least in some patients with partial epilepsy, the source characteristics of interictal scalp spikes appear to contain information of the ictal generator. Under certain circumstances, such derived information which is not otherwise available from routine electrophysiology may influence clinical management and prognosis. This is an additional bonus to the primary objectives of quantification and data reduction.

Brain↗