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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↗

PubMed2001

Estimating the time to the most recent common ancestor for the Y chromosome or mitochondrial DNA for a pair of individuals.

Bayesian posterior distributions are obtained for the time to the most recent common ancestor (MRCA) for a nonrecombining segment of DNA (such as the nonpseudoautosomal arm of the Y chromosome or the mitochondrial genome) for two individuals given that they match at k out of n scored markers. We argue that the distribution of the time t to the MRCA is the most natural measure of relatedness for such nonrecombining regions. Both an infinite-alleles (no recurring mutants) and stepwise mutation model are examined, and these agree well when n is moderate to large and k/n is close to one. As expected, the infinite alleles model underestimates t relative to the stepwise model. Using a modest number (20) of microsatellite markers is sufficient to obtain reasonably precise estimates of t for individuals separated by 200 or less generations. Hence, the multilocus haplotypes of two individuals can be used not only to date very deep ancestry but also rather recent ancestry as well. Finally, our results have forensic implications in that a complete match at all markers between a suspect and a sample excludes only a modest subset of the population unless a very large number of markers (>500 microsatellites) are used.

Alleles↗

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 ∼380 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 7598% 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↗

PubMedDate not supplied

A "next generation" ethics committee. St. Joseph Health system has integrated performance-improvement features into its ethics work.

Understanding the limitations that accompany the traditional model of ethics committees, St. Joseph Health System (SJHS), Orange, CA, has been working to integrate ethics expertise and quality-improvement methodology into its "Next Generation Model" (NG Model) for such committees. However, moving from a traditional structure to the NG Model (introduced to SJHS facilities in 1999) brought some challenges, not the least of which was a deep-rooted culture of resistance to change. Following a 2004 audit of how the NG model was working, some common challenges were identified. To deal with those challenges, SJHS developed some tools and techniques that have helped ease the ongoing transition. These tools have helped the system's ethics committees address such issues as collaboration for the sake of organizational integration, setting goals, and measuring performance of various ethics roles.

California↗

PubMed2004

Human phenylalanine hydroxylase is activated by H2O2: a novel mechanism for increasing the L-tyrosine supply for melanogenesis in melanocytes.

Epidermal phenylalanine hydroxylase (PAH) produces L-tyrosine from the essential amino acid L-phenylalanine supporting melanogenesis in human melanocytes. Those PAH activities increase linearly in the different skin phototypes I-VI (Fitzpatrick classification) and also increase up to 24h after UVB light with only one minimal erythemal dose. Since UVB generates also H(2)O(2), we here asked the question whether this reactive oxygen species could influence the activity of pure recombinant human PAH. Under saturating conditions with the substrate L-phenylalanine (1x10(-3)M), the V(max) for enzyme activity increased 4-fold by H(2)O(2) (>2.0x10(-3)M). Lineweaver-Burk analysis identified a mixed activation mechanism involving both the regulatory and catalytic domains of PAH. Hyperchem molecular modelling and Deep View analysis support oxidation of the single Trp(120) residue to 5-OH-Trp(120) by H(2)O(2) causing a conformational change in the regulatory domain. PAH was still activated by H(2)O(2) in the presence of the electron donor/cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin despite slow oxidation of this cofactor. In vivo FT-Raman spectroscopy confirmed decreased epidermal phenylalanine in association with increased tyrosine after UVB exposure. Hence, generation of H(2)O(2) by UVB can activate epidermal PAH leading to an increased L-tyrosine pool for melanogenesis.

Cell Division↗

PubMed1996

Nonuniformity of the constitutive law parameters for shear rupture and quasistatic nucleation to dynamic rupture: a physical model of earthquake generation processes.

Based on the recent high-resolution laboratory experiments on propagating shear rupture, the constitutive law that governs shear rupture processes is discussed in view of the physical principles and constraints, and a specific constitutive law is proposed for shear rupture. It is demonstrated that nonuniform distributions of the constitutive law parameters on the fault are necessary for creating the nucleation process, which consists of two phases: (i) a stable, quasistatic phase, and (ii) the subsequent accelerating phase. Physical models of the breakdown zone and the nucleation zone are presented for shear rupture in the brittle regime. The constitutive law for shear rupture explicitly includes a scaling parameter Dc that enables one to give a common interpretation to both small scale rupture in the laboratory and large scale rupture as earthquake source in the Earth. Both the breakdown zone size Xc and the nucleation zone size L are prescribed and scaled by Dc, which in turn is prescribed by a characteristic length lambda c representing geometrical irregularities of the fault. The models presented here make it possible to understand the earthquake generation process from nucleation to unstable, dynamic rupture propagation in terms of physics. Since the nucleation process itself is an immediate earthquake precursor, deep understanding of the nucleation process in terms of physics is crucial for the short-term (or immediate) earthquake prediction.

Journal Article↗

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↗

PubMed2006

Antenna design for microwave hepatic ablation using an axisymmetric electromagnetic model.

BACKGROUND: An axisymmetric finite element method (FEM) model was employed to demonstrate important techniques used in the design of antennas for hepatic microwave ablation (MWA). To effectively treat deep-seated hepatic tumors, these antennas should produce a highly localized specific absorption rate (SAR) pattern and be efficient radiators at approved generator frequencies. METHODS AND RESULTS: As an example, a double slot choked antenna for hepatic MWA was designed and implemented using FEMLABtrade mark 3.0. DISCUSSION: This paper emphasizes the importance of factors that can affect simulation accuracy, which include boundary conditions, the dielectric properties of liver tissue, and mesh resolution.

Animals↗

PubMed2005

Study of the brightness of trumpet tones.

This study focuses on a particular attribute of trumpet tones, the brightness, and on the physical characteristics of the instrument thought to govern its magnitude. On the one hand, an objective study was carried out with input impedance measurements, and, on the other hand, a subjective study with hearing tests and a panel of subjects. To create a set of different trumpets a variable depth mouthpiece was developed whose depth can be easily and continuously adjusted from "deep" to "shallow." Using this mouthpiece and the same trumpet, several instruments were generated which may be played in three ways: (i) by a musician, (ii) by an artificial mouth, and (iii) using physical modeling simulations. The influence of the depth of the mouthpiece on the perception of the trumpet's tones was investigated, and the ability of a musician, the artificial mouth, or physical modeling simulations to demonstrate perceptively noticeable differences was assessed. Physical characteristics extracted from the impedance curves are finally proposed to explain the brightness of trumpet tones. As a result, the physical modeling simulations now seem to be mature enough to exhibit coherent and subtle perceptual differences between tones. This opens the door to virtual acoustics for instrument makers.

Acoustic Impedance Tests↗

PubMed2002

Data information and knowledge: the health informatics model and its role in evidence-based medicine.

The health informatics model consists of three essential parts: data, information and knowledge. These elements are arranged in a hierarchy, with data at the base of the model providing the basis for establishing information and leading in turn to the potential generation of knowledge. The informatics model converges closely with the principles, aims and tasks of evidence-based medicine (EBM), particularly as they relate to searching, appraising, reviewing and utilizing information and research. The development of health informatics today has its origins in the growth of statistics in the 18th and 19th centuries. As a new and growing discipline, statistics burgeoned amidst the challenge of measuring, monitoring and ultimately governing societies in the throes of massive change and expansion. The governance role embraced by statistics in the past resembles many aspects of the role ascribed to audit, quality assurance and EBM today. There are some deep-seated paradoxes within the field of health informatics. The informatics model posits an oversimplified and linear progression of data to information and knowledge. Health informatics may involve the spreading and dissemination of information but this should be seen as only a part, not the equivalent, of the complex process of generating knowledge.

Data Collection↗

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↗