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PubMedDate not supplied

[Is the implantation of hinged knee joint prostheses still justifiable today? 15 years' experience using the Blauth knee joint prosthesis].

In objection to knee hinge prostheses there is often mentioned a higher complication rate. An increased load impact on the bone-cement interface results from the close connection of tibial and femoral components. This is assumed to cause bad results, as reported from early artificial knee joint replacements, characterised by weight bearing axes and direct contact metal to metal. These are contrasted to long term results of the Blauth hinge prosthesis. The Blauth prosthesis is constructed according to the low friction principle without a weightbearing axis. A prospective multicentric long term follow-up study reports on 556 prostheses. 463 (83%) were controlled between 1 and 15 years after operation (average: 43 months). Aseptic loosenings had to be confirmed in 1.3% of the patients, deep infections in 2.6%. The survival analysis did not show an erratic deterioration in dependence of the observation period. After 10 years there is still a probability of 89% that a prosthesis does not show a deep infection or loosening. The efficiency of artificial knee joint replacement by hinge joints should therefore not be judged on the results of the first generation of these models.

Adult↗
PubMed1998

Time scales and heterogeneous structure in geodynamic earth models

Computer models of mantle convection constrained by the history of Cenozoic and Mesozoic plate motions explain some deep-mantle structural heterogeneity imaged by seismic tomography, especially those related to subduction. They also reveal a 150-million-year time scale for generating thermal heterogeneity in the mantle, comparable to the record of plate motion reconstructions, so that the problem of unknown initial conditions can be overcome. The pattern of lowermost mantle structure at the core-mantle boundary is controlled by subduction history, although seismic tomography reveals intense large-scale hot (low-velocity) upwelling features not explicitly predicted by the models.

Journal Article↗
PubMed2025

Deep learning guided programmable design of Escherichia coli core promoters from sequence architecture to strength control.

Core promoters are essential regulatory elements that control transcription initiation, but accurately predicting and designing their strength remains challenging due to complex sequence-function relationships and the limited generalizability of existing AI-based approaches. To address this, we developed a modular platform integrating rational library design, predictive modelling, and generative optimization into a closed-loop workflow for end-to-end core promoter engineering. Conserved and spacer region of core promoters exert distinct effects on transcriptional strength, with the former driving large-scale variation and the latter enabling finer gradation. Based on this insight, Mutation-Barcoding-Reverse Sequencing approach was used and constructed a synthetic promoter library comprising 112 955 variants with minimal redundancy and a 16 226-fold expression range. A Transformer-based model trained on this dataset achieved a Pearson correlation of 0.87 with experimentally measured promoter strengths. When combined with a conditional diffusion model, the system enabled de novo generation of promoter sequences with defined strengths, achieving a design-to-measurement correlation of 0.95 and maintaining high accuracy (R = 0.93) across varied sequence contexts. The designed promoters consistently preserved their intended strength gradients, demonstrating robust plug-and-play functionality. This work establishes a scalable and extensible platform (www.yudenglab.com) for deep learning-guided programmable design of Escherichia coli core promoters, enabling precise transcriptional control.

Promoter Regions, Genetic↗
PubMed2026

Peptide-phosphorodiamidate morpholino oligomer therapy for dysferlinopathy induces pseudoexon skipping and restoration of functional protein.

The dysferlinopathies are a spectrum of autosomal recessive muscle diseases caused by mutations in the dysferlin gene (DYSF). Clinical manifestations vary from asymptomatic hyperCKemia to severe muscle pathology and loss of muscle function. These are designated as limb-girdle muscular dystrophy type 2R (LGMDR2; formerly LGMD2B or Miyoshi myopathy). Among other functions, dysferlin is crucial for plasma membrane repair and maintenance of intracellular calcium homeostasis. In previous studies, we identified 2 independent point mutations deep within introns that cause aberrant DYSF mRNA splicing and the inclusion of pseudoexons within transcripts that diminish protein expression. In this study, we generated and characterized a mouse model for 1 of these mutations (within DYSF intron 44). In these mice, a segment of human DYSF DNA containing the mutant intronic sequence flanked by surrounding human exon sequences replaced the normal homologous mouse DNA. These mice exhibited aberrant Dysf pre-mRNA splicing, pseudoexon inclusion, loss of DYSF protein expression, and muscle pathology similar to that observed in patients. Using this model, we identified antisense oligonucleotides and a peptide-phosphorodiamidate morpholino oligomer that blocks the mouse Dysf pre-mRNA splicing complexes from binding the mutant pre-mRNA, thereby restoring nearly normal muscle pathology and function.

Animals↗
PubMed1998

Experimentally induced muscle pain induces hypoalgesia in heterotopic deep tissues, but not in homotopic deep tissues.

The ability of muscle pain to generate somatosensory sensibility changes is controversial. Thus, in the present study, tonic infusion of hypertonic saline (5%, 7.1 ml administered over 15 min) into the tibialis anterior (TA) muscle was used as an experimental model to induce local and referred pain. The sensibility to high-intensity pressure stimuli applied to the local pain area, referred pain area and an arm was assessed in 14 healthy volunteers. Infusion of isotonic (0.9%) saline into the other leg served as control. The subject continuously scored the pain intensity on an electronic visual analogue scale (VAS). Pressure pain threshold (PPT) was determined on the TA muscle (2 cm and 10 cm from the infusion site), at the frontal aspect of the ankle (area of referred pain) and on the arm. To minimise the skin component of the PPT, the skin covering the assessment sites was anaesthetised with an anaesthetic creme. The PPTs were obtained before and after cutaneous analgesia, 1 min and 10 min after infusion start and 10 min after the pain had disappeared. Infusion of hypertonic saline caused significantly (P<0. 05) higher VAS scores than infusion of isotonic saline. A significant (P<0.04) increase of the PPT (i.e., decreased sensibility) was found at the ankle and on the arm during muscle pain compared to the control condition. No significant differences in PPTs on the TA muscle were found during saline-induced muscle pain compared to the infusion of isotonic saline. The decrease in deep sensibility at the heterotopic sites (referred pain area and arm), but not at homotopic sites (TA muscle), probably reflected the phenomenon of diffuse noxious inhibitory control (DNIC). The inhibitory mechanism during muscle pain was shown to be effective for the deep tissue sensibility in healthy subjects. Thus, a pathologically disturbed inhibitory mechanism may result in widespread deep hyperalgesia in muscle pain patients.

Adult↗
PubMed1989

Creation of realistic appearing simulated patient cases using the INTERNIST-1/QMR knowledge base and interrelationship properties of manifestations.

The Internist-1/Quick Medical Reference (QMR) knowledge base (KB) describes the clinical manifestations of some 600 diseases in the domain of internal medicine. This KB, while not representing deep causal modelling of disease processes, is nonetheless effective in providing medical diagnostic assistance through the QMR medical decision support system. One potential application of this extensive KB is the generation of simulated patient cases for use in educating health professionals. However, the "flat" KB is not adequate for this because the clinical manifestations used in the disease descriptions are not mutually independent. While it is theoretically possible to construct disease descriptions which embody pathophysiologic mechanisms of disease causality, it is not practical from the standpoint of resource utilization. Short of constructing a causal knowledge base, the authors herein describe the generation of realistic appearing simulated patient case data using existing information in the knowledge base. This existing information in the KB is in the form of properties which represent a shallow form of interrelationships of the manifestations. The authors conclude that this ability to generate simulated cases represents another view in which to look at an extensive knowledge base, as well as having application to constructing intelligent tutoring systems for health professionals in training.

Artificial Intelligence↗
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↗
PubMed1986

Architecture of the masticatory apparatus in eastern raccoons (Procyon lotor lotor).

The structure and function of the masticatory apparatus of raccoons resemble those found in carnivores. In this study, the architecture of the skull, dentition, and masticatory apparatus is described, and a model is proposed that suggests a mechanism used by raccoons to reduce different foods. The model suggests that jaw movements are similar to those of cats, the posterior regions of the superficial and deep parts of the temporalis and the anterior region of the medial pterygoid generate horizontal jaw movements, and the anterior portions of the superficial and deep temporalis as well as portions of the masseteric complex generate vertical closing movement. The distributions of slow, fast fatigable, and fast fatigue-resistant fibers for the temporalis and masseteric complex are related to the possible actions of these muscles during mastication, as are the regional cross-sectional areas of the masticatory muscles.

Animals↗
PubMed2026

Unveiling tumor heterogeneity by single cell RNA-sequencing: From basic considerations to clinical applications.

Tumor heterogeneity-encompassing diverse cellular phenotypes, genomic alterations, and microenvironmental contexts-is a principal barrier to effective cancer therapy. Single-cell RNA sequencing (scRNA-seq) has transformed our ability to resolve this complexity by capturing transcriptomes at single-cell resolution. Here, we review the technical foundations required for high-quality scRNA-seq studies. We then trace the evolution of scRNA-seq platforms from manual micromanipulation to high-throughput systems, and describe the computational pipelines that enable reliable data interpretation. The application of scRNA-seq is exemplarily shown in the context of lung cancer, where single-cell profiling has revealed (i) the clonal and sub-clonal architecture of tumors, (ii) extensive remodeling of the immune microenvironment, iii) key mechanisms underlying resistance to targeted agents and immune-checkpoint blockade, and (iv) the dynamics of neo-antigen-specific T-cell responses. Integrating machine-learning techniques-such as deep-learning classifiers and graph-based models-with single-cell transcriptomic data has markedly sped up biomarker discovery, produced more accurate risk-stratification scores, and enabled the generation of patient-specific therapeutic predictions. We surveyed the major trial registry ClinicalTrials.gov and identified &#x223c;380&#xa0;ongoing or completed studies that explicitly incorporate scRNA-seq as a correlative or pharmacodynamic endpoint. Overall, the analysis shows that scRNA-seq becomes an increasingly important component of modern trials, providing high-resolution cellular and molecular readouts that complement conventional imaging and bulk-omics endpoints. While key challenges remain, ranging from costs, scalability and need for rigorous validation before routine clinical deployment, ongoing technological advances continue to expand the potential of scRNA-seq as a cornerstone of precision medicine.

Humans↗
PubMed1998

Ipsilateral dominance of human olfactory activated centers estimated from event-related magnetic fields measured by 122-channel whole-head neuromagnetometer using odorant stimuli synchronized with respirations.

The aim of this study was to measure and analyze olfactory event-related magnetic fields using a whole-cortex biomagnetometer (122-channel SQUID gradiometer). Amyl-acetate gas (approx. 1%) was administered for 300 msec into either the right or left nostril in synchronization with respiration using a mask and an optical fiber sensor. Clear olfactory event-related magnetic fields were asymmetrically obtained on both sides of the forehead in all six subjects. The generators of olfactory magnetic fields were estimated at two regions located fairly asymmetrivally near the bilateral frontal deep areas. The goodness-of-fit was better for the two-dipole model than the one-dipole model in all experiments. In almost all subjects the latency and intensity of ipsilateral olfactory magnetoencephalography (MEG) responses were shorter and larger than those of the contralateral responses, respectively. These results suggest that the olfactory MEG responses on the ipsilateral side are generally larger and more dominant than those on the contralateral side in the human olfactory system.

Brain Mapping↗
PubMed1997

Locomotion on the water surface: propulsive mechanisms of the fisher spider

Using kinematic and mechanical experiments, we have shown how fisher spiders, Dolomedes triton (Araneae, Pisauridae), can generate horizontal propulsive forces using their legs. This horizontal thrust is provided primarily by the drag of the leg and its associated dimple as both move across the water surface. Less important sources of resistance are surface tension and bow waves. The relative contributions of drag, surface tension and bow waves were examined in several different ways. In one experiment, we measured the forces acting on a leg segment as water flowed past it in non-turbulent flow; the bow wave was not present at leg relative velocities below 0.2ms-1 and thus cannot play a role in thrust production at low leg speeds. In a second experiment, we varied the surface tension by altering the concentration of ethanol from 0% to 9% in the experimental water tank. At a constant dimple depth, force varied little with changes in surface tension, a result consistent with the hypothesis that drag is the primary source of resistance. In addition, however, as surface tension decreased from 0.072 to 0.064Nm-1, the power exponent of the relationship between force and velocity (as measured by the exponent of the power function relating the two variables) increased; at lower surface tensions, down to 0.054Nm-1, the power exponent of the relationship between force and velocity decreased. These results suggest an influence of surface tension (albeit still secondary to drag) in generating horizontal resistance to leg movement. We also measured flow disturbance in the water downstream from a leg segment and confirmed that, even at velocities well below 0.2ms-1, the leg-cum-dimple transferred momentum to the water, which is a clear indication that drag is a contributor to the resistance encountered by a spider's leg. Finally, modeling the leg-cum-dimple as a circular cylinder generates values of drag that account for 75&shy;98% of the measured leg force when the dimple is 0 or 1mm deep. These results not only elucidate the primary mechanism of propulsion for D. triton and other similar-sized arthropods, such as adult water striders (Gerridae), but also suggest that the formerly enigmatic locomotion of very small water-walking organisms (e.g. first-instar water striders) can be understood in the same way.

Journal Article↗
PubMed2025

DiCARN-DNase: enhancing cell-to-cell Hi-C resolution using dilated cascading ResNet with self-attention and DNase-seq chromatin accessibility data.

MOTIVATION: The spatial organization of chromatin is fundamental to gene regulation and essential for proper cellular function. The Hi-C technique remains the leading method for unraveling 3D genome structures, but the limited availability of high-resolution (HR) Hi-C data poses significant challenges for comprehensive analysis. Deep learning models have been developed to predict HR Hi-C data from low-resolution counterparts. Early Convolutional Neural Network (CNN)-based models improved resolution but struggled with issues like blurring and capturing fine details. In contrast, Generative Adversarial Network (GAN)-based methods encountered difficulties in maintaining diversity and generalization. Additionally, most existing algorithms perform poorly in cross-cell line generalization, where a model trained on one cell type is used to enhance HR data in another cell type. RESULTS: In this work, we propose Dilated Cascading Residual Network (DiCARN) to overcome these challenges and improve Hi-C data resolution. DiCARN leverages dilated convolutions and cascading residuals to capture a broader context while preserving fine-grained genomic interactions. Additionally, we incorporate DNase-seq data into our model, providing a robust framework that demonstrates superior generalizability across cell lines in HR Hi-C data reconstruction. AVAILABILITY AND IMPLEMENTATION: DiCARN is publicly available at https://github.com/OluwadareLab/DiCARN.

Chromatin↗
PubMed1996

An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence.

It was demonstrated previously that abrupt transfer of vigorously aerated cultures of Mycobacterium tuberculosis to anaerobic conditions resulted in their rapid death, but gradual depletion of available O2 permitted expression of increased tolerance to anaerobiosis. Those studies used a model based on adaptation of unagitated bacilli as they settled through a self-generated O2 gradient, but the model did not permit examination of homogeneous populations of bacilli during discrete stages in that adaptation. The present report describes a model based on culture of tubercle bacilli in deep liquid medium with very gentle stirring that keeps them in uniform dispersion while controlling the rate at which O2 is depleted. In this model, at least two stages of nonreplicating persistence were seen. The shift into first stage, designated NRP stage 1, occurred abruptly at a point when the declining dissolved O2 level approached 1% saturation. This microaerophilic stage was characterized by a slow rate of increase in turbidity without a corresponding increase in numbers of CFU or synthesis of DNA. However, a high rate of production of glycine dehydrogenase was initiated and sustained while the bacilli were in this state, and a steady ATP concentration was maintained. When the dissolved O2 content of the culture dropped below about 0.06% saturation, the bacilli shifted down abruptly to an anaerobic stage, designated NRP stage 2, in which no further increase in turbidity was seen and the concentration of glycine dehydrogenase declined markedly. The ability of bacilli in NRP stage 2 to survive anaerobically was dependent in part on having spent sufficient transit time in NRP stage 1. The effects of four antimicrobial agents on the bacilli depended on which of the different physiologic stages the bacilli occupied at a given time and reflected the recognized modes of action of these agents. It is suggested that the ability to shift down into one or both of the two nonreplicating stages, corresponding to microaerophilic and anaerobic persistence, is responsible for the ability of tubercle bacilli to lie dormant in the host for long periods of time, with the capacity to revive and activate disease at a later time. The model described here holds promise as a tool to help clarify events at the molecular level that permit the bacilli to persist under adverse conditions and to resume growth when conditions become favorable. The culture model presented here is also useful for screening drugs for the ability to kill tubercle bacilli in their different stages of nonreplicating persistence.

Adenosine Triphosphate↗
PubMed1991

The influence of model parameter values on the prediction of skin surface temperature: II. Contact problems.

A model of heat transfer and temperature distribution in the skin and superficial tissues which is based on a finite difference numerical solution of the one-dimensional multilayer coupled bioheat equation is presented. The model is used to investigate the influence of the values chosen to represent the physiological and thermal properties of the tissues on the skin surface temperature after contact with an external medium. It was found that the skin blood flow and dermal conductivity were the main cutaneous parameters which influence the contact response, but in terms of normalized temperature the response was little influenced by cutaneous metabolic heat generation and deep dermal temperature. For contact with a good conductor, the transient behaviour was sensitive to the heat transfer coefficient on the outer surface and the thickness of the contact material, but insensitive to the conductivity of the material.

Humans↗
PubMed1995

Deep knowledge and computer-assisted instruction in cardiology.

In this paper, we describe a qualitative heart model that is part of a computing environment, CARDIOLAB, and whose role includes the diagnosis and Computer Assisted Instruction (CAI) in cardiology. The model is based on a "deep knowledge" approach to diagnosis. Deep knowledge representations model the inner works of complex physical systems. Explicit representations of system components, component functions, and behavior allow a principled form of reasoning that extends the classical rule-based, first-generation expert systems. One of the main advantage of model-based diagnosis resides in the possibility of providing explanations to observed facts or measured data. This feature can be incorporated into CAI programs with similar benefits.

Cardiology↗
PubMed2025

Caenorhabditis diversity on Pohnpei, Micronesia, provides evidence that the Elegans Supergroup has its roots in the Americas and diversified in the Pacific en route to Asia.

The microscopic nematode Caenorhabditis elegans stands unrivaled as a model for developmental biology, neurobiology, and genetics, but fundamental aspects of its ecology, biogeography, and natural history remain unknown. Leveraging recent findings that place its center of diversity in the cool, high-elevation forests of Hawaii, we performed an intensive survey of the Caenorhabditis fauna of Pohnpei, a high island in Micronesia that is home to the largest patch of high-elevation forest between Hawaii and East Asia. We found nine species of Caenorhabditis, five of them new, but not C. elegans. Most species were limited to the hot lowlands but three spanned the elevational range and one was found only in the cloudforest. Using the distribution of Caenorhabditis nematodes among habitat patches - individual rotting fruits or flowers - we parameterized simple models that capture key aspects of the population biology of these animals. We generated transcriptomes for the new species and inferred a phylogeny for 70 species of Caenorhabditis, based on 2955 genes. This phylogeny allowed us to perform the first quantitative biogeographic analysis for the group. Our analysis suggests that the deep ancestors of the Elegans Supergroup of species lived in the Americas, and that the Supergroup's subsequent diversification occurred in Remote Oceania. The ancestors of the Supergroup gave rise to a diverse Oceanian fauna and ultimately to multiple lineages that moved into Asia, Africa, Australasia, and back into the Americas. Though biogeographic inferences are limited by the lack of information from key regions of the southwest Pacific, the data are consistent with a model of trans-Pacific migration, with the islands of Oceania serving as sources rather than sinks for biodiversity.

Caenorhabditis↗
PubMed1987

Role of platelets in atherogenesis: relevance to coronary arterial restenosis after angioplasty.

There is now considerable evidence to suggest that some aspects of early lesion formation and later lesion growth are a reaction to injury. Hemodynamic factors are important in determining the site of injury and may produce injury directly. Injury can lead to atherogenesis in animal models as well as in humans. Superficial injury exposes the subendothelium, allowing platelet adhesion, which at high shear rates is dependent on vWF. Platelet adhesion and degranulation release PDGF, which stimulates smooth muscle cell proliferation, synthetic functions, and vasoconstriction. LDL stimulates smooth muscle cell growth as well as damages endothelium in some experimental systems. Thus, a link is provided between platelet and lipid involvement in atherosclerosis. Direct evidence for a role of platelets in atherogenesis comes from studies in which animals were treated to reduce platelet number or function or in which platelet function is genetically impaired (pigs with von Willebrand's disease). In these models, reduced platelet function is associated with less atherosclerosis. Deeper injury exposes collagen, with subsequent platelet aggregation, thrombin and fibrin generation. The role of reduced production of PGI2 and fibrinolytic agents following severe damage is unknown. Deep injury to the vessel occurs during plaque fissuring, the pathologic process underlying most cases of myocardial infarction, unstable angina, and some cases of sudden death. Angioplasty produces amelioration of many patients' symptoms and is safe. However, acute occlusion occurs occasionally, and restenosis in the first year occurs in some 30 percent of patients treated. Angioplasty damages the arterial wall, with endothelial denudation and intimal and medial splitting. Why does this, and plaque injury, by stimulating platelet deposition, not produce more restenosis? Changes in arterial anatomy are likely to be important: the increase in vessel diameter and in blood flow produce conditions less favorable for thrombotic or arteriosclerotic restenosis.

Angioplasty, Balloon↗
PubMed1993

Microcircuitry of posterior cingulate cortex in vitro: electrophysiology and laminar analysis using the current source density method.

We used current source density (CSD) analysis of a laminar profile of subicular stimulus-evoked field potentials recorded in cortical slices in vitro to characterize the interlaminar microcircuitry of posterior cingulate cortex. Neuroanatomic and electrophysiologic data indicate that subiculocingulate tract (SCT) afferents monosynaptically excite apical dendrites of deep laminae (V-VI) neurons, evoking pure EPSPs, while superficial laminae (II/III-IV) neurons are driven polysynaptically, evoking a mixture of longer latency EPSPs and IPSPs. Consistent with this model, CSD analysis of field potential laminar profiles supports the conclusion that activation of excitatory subicular afferent terminal fields in superficial laminae of cingulate cortex elicits primary monosynaptic activation of apical dendrites of deep lamina (V-VI) pyramids. Subsequent EPSP propagation to the somata of these pyramids generated synchronous action potential discharges which appeared to elicit delayed polysynaptic activation of superficial laminae pyramids and interneurons. Latency differences between SCT-stimulus-evoked EPSPs and action potentials in superficial and deep laminae were minimized by stimulus train frequencies of 5-8 Hz, indicating that the proposed microcircuitry can show functional tuning at frequencies characteristic of hippocampal neuronal activity (theta). Such tuning suggests that hippocampal output activity frequency and phase locked to theta rhythm will be preferentially gated through cingulate cortex.

Afferent Pathways↗