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At least 199 records · Page 11Linked to original sources
PubMed1993

Beta-blockers and thimidine-3H captation in the human foetal heart.

In the present research the effects that the beta-blockers may express on the development of foetal myocardium have been studied "in vivo" and "in vitro". On the basis of previous researches (7), the beta-blocker effects have been observed by utilizing low doses in comparison with the therapeutic levels. Wistar rats affected by a surgically elicited renal hypertension and "in vitro" cultivated human heart buds, represent the two models utilized for our research. In the first model the low dose of beta-blocker, able to reduce the plasmatic renin activity (PRA) but unable to determine normal conditions of blood pressure, evokes an eccentric dilation of ventricular room and severe alterations of the myofilament pattern. Also in human heart buds cultivated in presence of beta-blocker at low levels of concentration in the cultural media, deep changes in the structural and ultrastructural pictures of the myocardium can be observed; the major changes consist in a particular and constant accumulation of glycogen in the cytoplasm of the myoblasts whose organules are pushed to the periphery of the cells. At electron microscopic level, disorders affecting the myofilaments and their genesis are present, while the intercellular junctions seem to be blocked in their ability to transfer into functional contacts; in fact, they appear only as mechanical junctions. Utilizing an autoradiographic technique the above described alterations seem to derive from a different degree of captation of thimidine-methyl-3H that appears to be higher in the specimens exposed to high dose of beta-blocker. Finally, all the results obtained seem to indicate the negative influence that the studied drugs can express on the histogenesis and the metabolism of myocardial cells.

Actin Cytoskeleton↗
PubMed1982

Nonlinear feedback model of neuronal populations in hippocampal CAl region.

1. A lumped-circuit model is proposed for the local interactions within the hippocampal CAl region. Each neuronal population is represented by a linear differential equation or a linear transfer function in the Laplace domain. Interactions between neuronal populations are represented by gain factors. Recurrent inhibition of pyramidal cells by the inhibitory interneurons is the important interaction represented by an asymmetric, bidirectionally saturating gain curve. The inputs to the model are orthodromic or antidromic inputs to the pyramidal cells and a tonic input from the brain stem. The outputs are the response ot pyramidal cells and interneurons. 2. The model is evaluated by data of intracellular and extracellular recordings from the hippocampus. Extracellular recordings consist of the average evoked potentials (AEPs), unitary poststimulus time histograms (PSTHs), and the spontaneous electroencephalogram (EEG). On account of the regular structure of the hippocampus, extracellular potentials are expected to correspond to the average intracellular potential among a local neuronal population. 3. Under deep anesthesia, all neuronal responses evoked by an electrical shock to the hippocampal afferents end in a prolonged inhibition of pyramidal cells. The model further predicts that the duration of inhibition increases with stimulus intensity, which is verified experimentally. 4. In the awake rat, especially during behaviors accompanied by a hippocampal theta rhythm (e.g., walking), the AEPs evoked by stimulation of afferent input to the CAl region were oscillatory with a frequency of 20-50 cycles/s. In the model an excitatory bias from the brain stem is assumed to linearize the local circuits, resulting in oscillatory responses similar to those obtained experimentally. 5. As observed by spectral analysis, the hippocampal EEG of the frequency 40-70 Hz varied in power and resonance during various behaviors of the rat. Except for the theta rhythm, analysis of the output(s) of the model given a Gaussian white-noise input showed similar power spectra as the EEG in vivo. The increase in power of the 40-70 Hz EEG in some behaviors, e.g., walking, is reproduced by assuming that during such behaviors a modulating bias from the brain stem linearizes the local CAl circuits. This latter circumstances underlies the generation of oscillatory AEPs and the high-frequency EEG. 6. When recurrent excitatory-inhibitory feedback is very large, the model produces a limit cycle of 50-65 cycles/s. The limit cycle is suggested to be the cause of a particular type of high-frequency (50-65 cycles/s) hippocampal afterdischarge that occurs after tetanization of the input pathways. The amplitude, frequency, and waveform of the model generated and experimental data are similar. 7. In conclusion, a nonlinear recurrent excitatory-inhibitory feedback model of the hippocampus explains and integrates various existing experimental data. The model further predicts results that can be experimentally tested.

Action Potentials↗
PubMed2000

Fundamentals and prospects of passive thermoacoustic tomography.

The problems and possibilities of passive thermoacoustical tomography are discussed. Algorithms for reconstruction of internal temperature in the human body are proposed. These algorithms take into account heat transfer and blood circulation and the absorption factor, obtained previously. The results of reconstruction of deep temperature in the human hand in simulations with the medium with a heated object are reported. These results support the possibility of the correlation measurements of the thermal acoustic radiation. Such measurements allow the information on ultrasound absorption by the object under study to be obtained and open the way to the development of a passive acoustic tomography system using a priori information on the absorption factor.

Algorithms↗
PubMed2025

OpenSpliceAI: An efficient, modular implementation of SpliceAI enabling easy retraining on non-human species.

The SpliceAI deep learning system is currently one of the most accurate methods for identifying splicing signals directly from DNA sequences. However, its utility is limited by its reliance on older software frameworks and human-centric training data. Here we introduce OpenSpliceAI, a trainable, open-source version of SpliceAI implemented in PyTorch to address these challenges. OpenSpliceAI supports both training from scratch and transfer learning, enabling seamless retraining on species-specific datasets and mitigating human-centric biases. Our experiments show that it achieves faster processing speeds and lower memory usage than the original SpliceAI code, allowing large-scale analyses of extensive genomic regions on a single GPU. Additionally, OpenSpliceAI's flexible architecture makes for easier integration with established machine learning ecosystems, simplifying the development of custom splicing models for different species and applications. We demonstrate that OpenSpliceAI's output is highly concordant with SpliceAI. In silico mutagenesis (ISM) analyses confirm that both models rely on similar sequence features, and calibration experiments demonstrate similar score probability estimates.

Journal Article↗
PubMed2006

Deep diving mammals: Dive behavior and circulatory adjustments contribute to bends avoidance.

A mathematical model was created that predicted blood and tissue N(2) tension (P(N2)) during breath-hold diving. Measured muscle P(N2) from the bottlenose dolphin after diving repeatedly to 100 m (Tursiops truncatus [Ridgway and Howard, 1979, Science, 4423, 1182-1183]) was compared with predictions from the model. Lung collapse was modelled as a 100% pulmonary shunt which yielded tissue P(N2) similar to those reported for the dolphin. On the other hand, predicted muscle P(N2) for an animal with a dive response, reducing cardiac output by 66% from surface values (20.5 to 6.8l x min(-1)), also agreed well with observed values in the absence of lung collapse. In fact, modelling indicated that both cardiovascular adjustments and dive behaviour are important in reducing N2 uptake during diving and enhancing safe transfer of tissue and blood N2 back to the lung immediately before coming to the surface. In particular, diving bradycardia during the descent and bottom phase together with a reduced ascent rate and increase in heart rate reduced mixed venous P(N2) upon return to the surface by as much as 45%. This has important implications as small reductions in inert gas load (approximately 5%) can substantially reduce decompression sickness (DCS) risk by as much as 50% (Fahlman et al., 2001, J. Appl. Physiol. 91, 2720-2729).

Acclimatization↗
PubMedDate not supplied

Thermodynamics of movable inductively heated seeds for the treatment of brain tumors.

A thermodynamic study is presented of temperature distributions created by an inductively heated 6-mm-diam Ni sphere imbedded in vivo and in vitro into porcine brain tissue. This study was performed in support of the development of a system that creates localized heat-induced lesions in deep-seated brain tumors. In this system, a magnetic "seed" will be remotely repositioned within the brain by an externally produced magnetic field. Convective effects of a hot moving seed will produce a different thermodynamic situation than that arising from an array of static implants. In this work, a study is presented of part of the expected change, in which a static sphere is heated to high temperature. Measurements were made of the temporal and spatial dependence of the temperature rise in the vicinity of the heated sphere, in vivo in four animals and in one that was euthanized immediately prior to experimentation. These results are used for parameter estimation with a theoretical model based on a point source solution to a form of the thermal diffusion equation, i.e., the "bioheat transfer equation." With this model thermal distributions from a power source of arbitrary geometry can be found using appropriate integration methods, and the method has widespread applicability. Estimates of blood flow rates, tissue thermal conductivity, and seed power absorption were found using the parameter estimation algorithm. The estimated blood perfusion exhibits a step increase following the first heating in multiple heating experiments. Thermal conductivity estimated using data from the nonperfused (in vitro) animal is 0.6 W/m degrees C. Seed power absorption is estimated correspondingly to be 0.9 W, a result confirmed independently with calorimetry. Statistical uncertainty is established for the radial decrease of the tissue temperature rise created by this method. This result allows estimation of a cell death boundary uncertainty of 0.6 mm, caused by fluctuations in power delivered to the seed, uncertainty in the temperature probe placements, and thermal properties such as blood perfusion and tissue thermal conductivity.

Animals↗
PubMed2002

Evolution of arginine deiminase (ADI) pathway genes.

We have analyzed the evolution of the three genes encoding structural enzymes of the arginine deiminase (ADI) pathway, arginine deiminase (ADI), ornithine transcarbamoylase (OTC), and carbamate kinase (CK) in a wide range of organisms, including Archaea, Bacteria, and Eukarya. This catabolic route was probably present in the last common ancestor to all the domains of life. The results obtained indicate that these genes have undergone a complex evolutionary history, including horizontal transfer events, duplications, and losses. Therefore, these genes are not adequate to infer organismal relationships at deep branching levels, but they provide an insight into how catabolic genes evolved and were assembled into metabolic pathways. Our results suggest that the three genes evolved independently and were later assembled into a single cluster with functional interdependence, thus, providing support for the gene recruitment hypothesis. Furthermore, the molecular phylogenetic analysis of OTC suggests a new classification of these genes into three subfamilies.

Amino Acid Sequence↗
PubMed1999

Solution structure of the catalytic domain of GCN5 histone acetyltransferase bound to coenzyme A.

Gene transcription requires the release of inactive DNA from its packaging of histone proteins. Following the discovery of the first transcription-associated histone acetyltransferase, tetrahymena GCN5, it was shown that yeast GCN5 is recruited to the promoter and causes hyper-acetylation of histones and transcriptional activation of target genes, establishing a direct connection between histone acetylation and transcriptional activation. Many other important transcription regulators have been found to have histone acetyltransferase activity, including TAFII230/250, p300/CBP and its associated factor PCAF. Here we present the solution structure of the catalytic domain of tGCN5 (residues 47-210) in complex with coenzyme A. The structure contains two domains; the amino-terminal domain is similar to those of other GCN5-related N-acetyltransferases but the carboxy-terminal domain is not. Coenzyme A binds in a deep hydrophobic pocket between the two domains. Chemical shift changes upon titration with histone H3 peptides indicate a binding site at the domain boundary opposite to the coenzyme A site. The structural data indicate a single-step acetyl-transfer reaction mechanism catalysed by a hydrogen bond to the backbone amide group of leucine 126 and the side-chain carboxyl group of a conserved acidic residue.

Acetyltransferases↗
PubMed1994

Risks of radiation cataracts from interplanetary space missions.

Recognition of the human risks from radiation exposure during manned missions in deep space has been fostered by international co-operation; interagency collaboration is facilitating their evaluation. Further co-operation can lead, perhaps by the end of this decade, to an evaluation of one of the three major risks, namely radiation cataractogenesis, sufficient for use in the planning of the manned mission to Mars.

Aluminum↗
PubMed2006

Universal mean moment rate profiles of earthquake ruptures.

Earthquake phenomenology exhibits a number of power law distributions including the Gutenberg-Richter frequency-size statistics and the Omori law for aftershock decay rates. In search for a basic model that renders correct predictions on long spatiotemporal scales, we discuss results associated with a heterogeneous fault with long-range stress-transfer interactions. To better understand earthquake dynamics we focus on faults with Gutenberg-Richter-like earthquake statistics and develop two universal scaling functions as a stronger test of the theory against observations than mere scaling exponents that have large error bars. Universal shape profiles contain crucial information on the underlying dynamics in a variety of systems. As in magnetic systems, we find that our analysis for earthquakes provides a good overall agreement between theory and observations, but with a potential discrepancy in one particular universal scaling function for moment rates. We primarily use mean field theory for the theoretical analysis, since it has been shown to be in the same universality class as the full three-dimensional version of the model (up to logarithmic corrections). The results point to the existence of deep connections between the physics of avalanches in different systems.

Journal Article↗
PubMed2004

Genome sequence of the deep-sea gamma-proteobacterium Idiomarina loihiensis reveals amino acid fermentation as a source of carbon and energy.

We report the complete genome sequence of the deep-sea gamma-proteobacterium, Idiomarina loihiensis, isolated recently from a hydrothermal vent at 1,300-m depth on the Loihi submarine volcano, Hawaii. The I. loihiensis genome comprises a single chromosome of 2,839,318 base pairs, encoding 2,640 proteins, four rRNA operons, and 56 tRNA genes. A comparison of I. loihiensis to the genomes of other gamma-proteobacteria reveals abundance of amino acid transport and degradation enzymes, but a loss of sugar transport systems and certain enzymes of sugar metabolism. This finding suggests that I. loihiensis relies primarily on amino acid catabolism, rather than on sugar fermentation, for carbon and energy. Enzymes for biosynthesis of purines, pyrimidines, the majority of amino acids, and coenzymes are encoded in the genome, but biosynthetic pathways for Leu, Ile, Val, Thr, and Met are incomplete. Auxotrophy for Val and Thr was confirmed by in vivo experiments. The I. loihiensis genome contains a cluster of 32 genes encoding enzymes for exopolysaccharide and capsular polysaccharide synthesis. It also encodes diverse peptidases, a variety of peptide and amino acid uptake systems, and versatile signal transduction machinery. We propose that the source of amino acids for I. loihiensis growth are the proteinaceous particles present in the deep sea hydrothermal vent waters. I. loihiensis would colonize these particles by using the secreted exopolysaccharide, digest these proteins, and metabolize the resulting peptides and amino acids. In summary, the I. loihiensis genome reveals an integrated mechanism of metabolic adaptation to the constantly changing deep-sea hydrothermal ecosystem.

Amino Acids↗
PubMed2001

Chimaeras and mosaics for dissecting complex mutant phenotypes.

Back at the first half of the 1980s, there was no mammalian experimental embryology in Hungary. One of us, AN, took up the challenge of establishing a small group in the field. In the absence of local information, AN and his former colleague, Andras Paldi (AP), used their tourist passport to visit several laboratories in Western Europe and collect information and advice. This is how AN and AP ended up one day sitting in Anne McLaren's office in the MRC Mammalian Development Unit at University College, London. They never forgot her endless enthusiasm and the way she clearly explained the important points of preimplantation embryo manipulation, chimaera making and embryo transfer. As well as the extremely useful suggestions, which were crucial to starting the lab in Hungary, they also took back her deep love for embryo development. They remember her telling them, 'never waste an embryo--there is always another unanswered question it can solve'. Many who have been lucky and experienced Anne's spirit and advice later realized how useful it was to generate 'new' ideas by following the 'not wasting' principle. Our views on chimaeras presented below definitely contain elements which grew out from this principle.

Animals↗
PubMed2003

A twelve-year analysis of disease and provider complications on an organized level I trauma service: as good as it gets?

BACKGROUND: The development of trauma systems reduces preventable mortality and the measurement of standardized complications creates further opportunity for improvement in morbidity. The annual incidence of complications in a trauma population has been previously reported but the frequency change over time in a single institution is not well studied. METHODS: All patients who were hospitalized for more than 24 hours, who died, were admitted to the Intensive Care Unit (ICU) or Intermediate Care Unit (IMU), or were inter-facility transfers prospectively evaluated for 12 consecutive years. A total of 13,382 patients were studied (range, 862-1234 patients per year). Complication events were collected using 135 standardized definitions including disease and provider outcomes. RESULTS: The overall incidence of complications has remained stable over time. Provider events, disease events, and patients developing three or more complications have remained unchanged as well. Specific disease complications including pneumonia, deep vein thrombosis (DVT), and small bowel obstruction have fallen over time. Improvements in provider errors have also occurred. CONCLUSION: This data suggests that most complications have a finite threshold despite the use of a stable trauma staff, implementation of standardized protocols, and emphasis on consistency of practice. Further reductions will require new research for disease-related treatment and new strategies for consistency and error reduction rather than our current models of continuous quality improvement.

Academic Medical Centers↗
PubMed2026

Refining a giant virus lineage: a novel order unifying Mamonoviridae and "Manesviridae," unveiled by the discovery of furtivovirus.

UNLABELLED: The evolutionary origins and taxonomic framework of giant viruses related to the family Mamonoviridae and its relative group, including clandestinovirus, remain unclassified due to gaps in genome size and host range between these two groups. This study aimed to address this gap by integrating our newly isolated virus with publicly available metagenome-assembled genomes (MAGs) to construct a more robust phylogenetic framework. Here, we report the isolation and characterization of a new giant virus, furtivovirus, using the unicellular amoeba Vermamoeba vermiformis as a host. Furtivovirus has a genome of approximately 560 kbp and shares key features with its closest relative, clandestinovirus. Ultrastructural analysis revealed a unique host-nucleus-dependent replication strategy characterized by the breakdown of the nuclear membrane and the packaging of nascent virions directly within the nucleoplasm, distinguishing it from canonical cytoplasmic virion factories. Comprehensive phylogenetic and comparative genomic analyses of shared orthologous groups and nucleocytovirus marker proteins revealed that furtivovirus, clandestinovirus, ushikuvirus, and usurpativirus form a distinct monophyletic clade, for which we propose a new family, "Manesviridae." Further analysis using amino acid-based similarity metrics of Nucleocytoviricota viral genomes, including established MAGs, demonstrated that this new family is robustly placed as a sister group to the family Mamonoviridae. This study elucidated the evolutionary relationships between viruses with large and small genomes that possess similar virion sizes within this lineage. Based on this cumulative evidence, we propose the establishment of a new order to unify these two families, thereby expanding their diversity and clarifying the evolutionary history of this branch within Nucleocytoviricota. IMPORTANCE: Giant viruses challenge our traditional understanding of viral evolution, raising the question of how a single related group can diverge to infect different hosts while evolving into vastly different genome sizes and replication strategies. The family Mamonoviridae and its relatives epitomize this evolutionary divergence: one group possesses massive genomes, whereas the other has genomes that are less than half their size. The discovery of furtivovirus and its unique nucleoplasm-dependent replication cycle provides a critical biological context for this genomic disparity. Through deep comparative genomic analysis, we demonstrated that these seemingly disparate lineages share a cohesive evolutionary origin that is distinct from other established orders. This finding highlights the complexity of genome evolution, demonstrating that giant viruses can expand their overall genome size to adapt to uncertain environments while reducing their core essential genes, thereby providing new insights into the evolutionary pressures that shape the diversity of the virosphere.

Giant Viruses↗
PubMed2006

Proton in the well and through the desolvation barrier.

The concept of the membrane proton well was suggested by Peter Mitchell to account for the energetic equivalence of the chemical (DeltapH) and electrical (Deltapsi) components of the proton-motive force. The proton well was defined as a proton-conducting crevice passing down into the membrane dielectric and able to accumulate protons in response to the generation either of Deltapsi or of DeltapH. In this review, the concept of proton well is contrasted to the desolvation penalty of > 500 meV for transferring protons into the membrane core. The magnitude of the desolvation penalty argues against deep proton wells in the energy-transducing enzymes. The shallow DeltapH- and Deltapsi-sensitive proton traps, mechanistically linked to the functional groups in the membrane interior, seem more realistic. In such constructs, the draw of a trapped proton into the membrane core can happen at the expense of some exergonic reaction, e.g., release of another proton from the membrane into the aqueous phase. It is argued that the proton transfer in the ATP synthase and the cytochrome bc complex could proceed in this way.

Biological Transport↗
PubMed2001

An investigation of 2 techniques for optimizing joint surface congruency using multiple cylindrical osteochondral autografts.

PURPOSE: To compare 2 techniques for optimizing joint congruency for miniature osteochondral autografting in the knee: intrinsic postoperative forces acting on overdrilled autografts protruding from the femur versus alignment by a surgeon at the time of grafting. TYPE OF STUDY: Controlled animal model experiment. METHODS: A full-thickness cartilage defect was created on the weight-bearing surface of the medial femoral condyle of 13 mature sheep. Three 4.5 x 10 mm cylindrical autografts were inserted into 14-mm deep recipient holes such that the grafts were held in place by side-wall friction alone. One treatment group received grafts that were delivered flush with the surrounding cartilage and the second group received grafts that were left 2-mm proud of the joint surface. RESULTS: Three months postoperatively, the proud grafts had been repositioned by weight bearing but perigraft fissuring and fibroplasia, and subchondral cavitations were serious complications. It is suspected that these complications were caused by excessive motion between the graft and recipient site in the proud grafts. CONCLUSIONS: Grafts should be delivered flush with the joint surface when performing osteochondral transfers to avoid graft micromotion and the consequent interference with graft integration and function.

Animals↗
PubMed2025

Deep learning-based cell-specific gene regulatory networks inferred from single-cell multiome data.

Gene regulatory networks (GRNs) provide a global representation of how genetic/genomic information is transferred in living systems and are a key component in understanding genome regulation. Single-cell multiome data provide unprecedented opportunities to reconstruct GRNs at fine-grained resolution. However, the inference of GRNs is hindered by insufficient single omic profiles due to the characteristic high loss rate of single-cell sequencing data. In this study, we developed scMultiomeGRN, a deep learning framework to infer transcription factor (TF) regulatory networks via unique integration of single-cell genomic (single-cell RNA sequencing) and epigenomic (single-cell ATAC sequencing) data. We create scMultiomeGRN to elucidate these networks by conceptualizing TF network graph structures. Specifically, we build modality-specific neighbor aggregators and cross-modal attention modules to learn latent representations of TFs from single-cell multi-omics. We demonstrate that scMultiomeGRN outperforms state-of-the-art models on multiple benchmark datasets involved in diseases and health. Via scMultiomeGRN, we identified Alzheimer's disease-relevant regulatory network of SPI1 and RUNX1 for microglia. In summary, scMultiomeGRN offers a deep learning framework to identify cell type-specific gene regulatory network from single-cell multiome data.

Deep Learning↗
PubMed2025

An updated compendium and reevaluation of the evidence for nuclear transcription factor occupancy over the mitochondrial genome.

In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that gave rise to modern mitochondria. Mitochondrial genomes are dramatically reduced in their gene content due to the process of endosymbiotic gene transfer to the nucleus; as a result most mitochondrial proteins are encoded in the nucleus and imported into mitochondria. This includes the components of the dedicated mitochondrial transcription and replication systems and regulatory factors, which are entirely distinct from the information processing systems in the nucleus. However, since the 1990s several nuclear transcription factors have been reported to act in mitochondria, and previously we identified 8 human and 3 mouse transcription factors (TFs) with strong localized enrichment over the mitochondrial genome using ChIP-seq (Chromatin Immunoprecipitation) datasets from the second phase of the ENCODE (Encyclopedia of DNA Elements) Project Consortium. Here, we analyze the greatly expanded in the intervening decade ENCODE compendium of TF ChIP-seq datasets (a total of 6,153 ChIP experiments for 942 proteins, of which 763 are sequence-specific TFs) combined with interpretative deep learning models of TF occupancy to create a comprehensive compendium of nuclear TFs that show evidence of association with the mitochondrial genome. We find some evidence for chrM occupancy for 50 nuclear TFs and two other proteins, with bZIP TFs emerging as most likely to be playing a role in mitochondria. However, we also observe that in cases where the same TF has been assayed with multiple antibodies and ChIP protocols, evidence for its chrM occupancy is not always reproducible. In the light of these findings, we discuss the evidential criteria for establishing chrM occupancy and reevaluate the overall compendium of putative mitochondrial-acting nuclear TFs.

Genome, Mitochondrial↗