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At least 217 records · Page 12Linked to original sources
PubMed2025

Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons.

Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection via WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.

Humans↗
PubMed2005

Wavelet-based Poisson solver for use in particle-in-cell simulations.

We report on a successful implementation of a wavelet-based Poisson solver for use in three-dimensional particle-in-cell simulations. Our method harnesses advantages afforded by the wavelet formulation, such as sparsity of operators and data sets, existence of effective preconditioners, and the ability simultaneously to remove numerical noise and additional compression of relevant data sets. We present and discuss preliminary results relating to the application of the new solver to test problems in accelerator physics and astrophysics.

Journal Article↗
PubMed2006

Dynamic tables: an architecture for managing evolving, heterogeneous biomedical data in relational database management systems.

Data sparsity and schema evolution issues affecting clinical informatics and bioinformatics communities have led to the adoption of vertical or object-attribute-value-based database schemas to overcome limitations posed when using conventional relational database technology. This paper explores these issues and discusses why biomedical data are difficult to model using conventional relational techniques. The authors propose a solution to these obstacles based on a relational database engine using a sparse, column-store architecture. The authors provide benchmarks comparing the performance of queries and schema-modification operations using three different strategies: (1) the standard conventional relational design; (2) past approaches used by biomedical informatics researchers; and (3) their sparse, column-store architecture. The performance results show that their architecture is a promising technique for storing and processing many types of data that are not handled well by the other two semantic data models.

Computational Biology↗
PubMed1995

Novel associations among gonadotropin-releasing hormone neurons.

GnRH is secreted in bursts into the hypophyseal portal vasculature by a small dispersed population of neurons. The means by which the activity of these intrinsically pulsatile cells is coordinated are unknown. This study was initiated as a continuation of our examination of the synaptic input to these cells and their anatomical relationships. Brain tissue from female rhesus monkeys and male and female rats was prepared for the immunocytochemical demonstration of GnRH. At the light microscopic level, GnRH neurons were occasionally found to be in close apposition. Such pairs (or small groups) were randomly distributed throughout the population of GnRH neurons from the diagonal band of Broca through the anterior hypothalamic area in rats and monkeys and in the medial basal hypothalamus in monkeys. The percentage of neurons found in such associations was small (2-7% in rats and 3-15% in monkeys) and was independent of the hormonal condition of the animal. GnRH neurons, either singly or in pairs, were serially sectioned for electron microscopic examination. The sparsity of synaptic input to the cell body that we had reported earlier on the basis of random sampling was confirmed. No soma had more than a dozen synapses, but none totally lacked innervation. The most significant result of serial reconstruction was the discovery of intercellular bridges or passageways between contiguous pairs of GnRH neurons. These were formed by the fusion of processes extending from the two cells or by fusion and opening of passageways in the membranes along regions of contiguity between the two cells. They were found in four of seven pairs of neurons examined in the rat and in four of eight pairs in the monkey. This syncytial arrangement along with GnRH-GnRH synaptic interactions could contribute to the coordination of dispersed influences on these neurons and the propagation of coordinated pulsatile release of GnRH.

Animals↗
PubMed1990

Hyperbaric nitrous oxide as a sole anesthetic agent in humans.

Nitrous oxide (N2O) has been used to produce analgesia and anesthesia for more than 100 yr. However, because of its high MAC value (1.04), general anesthesia with N2O can usually be attained only in a hyperbaric environment. Because of the sparsity of documentation for human physiologic responses to hyperbaric N2O, we studied eight male volunteers at 2 ATA (1520 mm Hg) anesthetized with N2O only for periods of 2-4 h. N2O partial pressures ranged from 836 to 1368 mm Hg. The anesthetic state was associated with tachypnea, tachycardia, increases in systemic blood pressure, mydriasis, diaphoresis, and at times, clonus and opisthotonus. A stable level of physiologic activity was difficult to maintain.

Adult↗
PubMed2003

Order-N sparse minimum-variance open-loop reconstructor for extreme adaptive optics.

A scalable sparse minimum-variance open-loop wave-front reconstructor for extreme adaptive optics (ExAO) systems is presented. The reconstructor is based on Ellerbroek's sparse approximation of the wave-front inverse covariance matrix [J. Opt. Soc. Am. A 19, 1803 (2002)]. The baseline of the numerical approach is an iterative conjugate gradient (CG) algorithm for reconstructing a spatially sampled wave front at N grid points on a computational domain of size equal to the telescope's primary mirror's diameter D that uses a multigrid (MG) accelerator to speed up convergence efficiently and enhance its robustness. The combined MGCG scheme is order N and requires only two CG iterations to converge to the asymptotic average Strehl ratio (SR) and root-mean-square reconstruction error. The SR and reconstruction squared error are within standard deviation with figures obtained from a previously proposed MGCG fast-Fourier-transform based minimum-variance reconstructor that incorporates the exact wave-front inverse covariance matrix on a computational domain of size equal to 2D. A cost comparison between the present sparse MGCG algorithm and a Cholesky factorization based algorithm that uses a reordering scheme to preserve sparsity indicates that the latter method is still competitive for real-time ExAO wave-front reconstruction for systems with up to N approximately equal to 10(4) degrees of freedom because the update rate of the Cholesky factor is typically several orders of magnitude lower than the temporal sampling rate.

Journal Article↗
PubMed2025

A generalized higher-order correlation analysis framework for multi-omics network inference.

Multiple -omics (genomics, proteomics, etc.) profiles are commonly generated to gain insight into a disease or physiological system. Constructing multi-omics networks with respect to the trait(s) of interest provides an opportunity to understand relationships between molecular features but integration is challenging due to multiple data sets with high dimensionality. One approach is to use canonical correlation to integrate one or two omics types and a single trait of interest. However, these types of methods may be limited due to (1) not accounting for higher-order correlations existing among features, (2) computational inefficiency when extending to more than two omics data when using a penalty term-based sparsity method, and (3) lack of flexibility for focusing on specific correlations (e.g., omics-to-phenotype correlation versus omics-to-omics correlations). In this work, we have developed a novel multi-omics network analysis pipeline called Sparse Generalized Tensor Canonical Correlation Analysis Network Inference (SGTCCA-Net) that can effectively overcome these limitations. We also introduce an implementation to improve the summarization of networks for downstream analyses. Simulation and real-data experiments demonstrate the effectiveness of our novel method for inferring omics networks and features of interest.

Genomics↗
PubMed2025

Gene regulatory network structure informs the distribution of perturbation effects.

Gene regulatory networks (GRNs) govern many core developmental and biological processes underlying human complex traits. Even with broad-scale efforts to characterize the effects of molecular perturbations and interpret gene coexpression, it remains challenging to infer the architecture of gene regulation in a precise and efficient manner. Key properties of GRNs, like hierarchical structure, modular organization, and sparsity, provide both challenges and opportunities for this objective. Here, we seek to better understand properties of GRNs using a new approach to simulate their structure and model their function. We produce realistic network structures with a novel generating algorithm based on insights from small-world network theory, and we model gene expression regulation using stochastic differential equations formulated to accommodate modeling molecular perturbations. With these tools, we systematically describe the effects of gene knockouts within and across GRNs, finding a subset of networks that recapitulate features of a recent genome-scale perturbation study. With deeper analysis of these exemplar networks, we consider future avenues to map the architecture of gene expression regulation using data from cells in perturbed and unperturbed states, finding that while perturbation data are critical to discover specific regulatory interactions, data from unperturbed cells may be sufficient to reveal regulatory programs.

Gene Regulatory Networks↗
PubMed1980

Foreign body aspiration of grass inflorescences as a cause of hemoptysis.

Although the sparsity of reports in the literature suggest aspiration of grass inflorescence is rare, in certain areas of the southern United States, aspiration of this type of foreign body is not so uncommon. Four cases of aspiration of Hordeum pusillium, often referred to as "cheat grass" are reported: three of the four patients had hemoptysis. The highest incidence of inhaled foreign bodies usually occur in young children, but all our four patients were older children or adolescents. The clinical manifestations of grass inflorescence are of the following two types: (1) the "lodging" type in which inflorescences remain in the respiratory passages causing bronchial obstruction with pneumonitis; and (2) the "extrusive type" in which the inflorescences migrate into the periphery of the lung and through the chest wall.

Adolescent↗
PubMed1999

Systematic review and guide to selection of selective serotonin reuptake inhibitors.

A meta-analysis of 20 short term comparative studies of 5 selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) has shown no difference in efficacy between individual compounds but a slower onset of action of fluoxetine. There were suggestions that fluoxetine caused more agitation, weight loss and dermatological reactions than the other SSRIs. More patients discontinued fluvoxamine and fewer patients stopped sertraline because of adverse effects than their comparator SSRIs. The most common adverse reactions to the SSRIs were gastrointestinal (especially nausea) and neuropsychiatric (particularly headache and tremor). Data from the Committee on Safety of Medicines showed more reports of suspected reactions (including discontinuation reactions) to paroxetine, and of gastrointestinal reactions to fluvoxamine and paroxetine, than the other SSRIs during their first 2 years of marketing. Prescription-event monitoring revealed a higher incidence of adverse events related to fluvoxamine than its comparators. There were higher incidences of gastrointestinal symptoms, malaise, sedation and tremor during treatment with fluvoxamine and of sedation, tremor, sweating, sexual dysfunction and discontinuation reactions with paroxetine. Fluoxetine was not associated with a higher incidence of suicidal, aggressive and related events than the other SSRIs. Patients have survived large overdoses of each of the compounds, but concern has been expressed over 6 fatalities following overdoses of citalopram. Drug interactions mediated by cytochrome P450 enzymes are theoretically less likely to occur during treatment with citalopram and sertraline, but there is a sparsity of clinical data to support this. Methodological difficulties and price changes do not allow choice for recommendations on the choice of SSRI based on pharmacoeconomic data. Taking into account the strengths and weaknesses of the methods used to compare drugs, guidelines to the selection of individual SSRIs in clinical practice are proposed. Citalopram should be avoided in patients likely to take overdoses. Fluoxetine may not be the drug of first choice for patients in whom a rapid antidepressant effect is important or for those who are agitated, but it may have advantages over other SSRIs in patients who are poorly compliant with treatment and those who have previously had troublesome discontinuation symptoms. Fluvoxamine, and possibly paroxetine, should not be used as first choice in patients especially prone to SSRI-related adverse reactions, while paroxetine should be avoided if previous discontinuation of treatment was troublesome. When in doubt about the risks of drug interactions, citalopram or sertraline should be considered given the lower theoretical risk of interactions.

Humans↗
PubMed1984

Adapting to old age in rural Britain.

The data on which this article is based were collected to inform and guide policy for rural social service provision. Over 500 elderly persons were interviewed in their own homes using a questionnaire schedule. Over the last two decades, the availability and support of the family for the elderly has remained in debate, some writers suggesting that urbanization and industrialization have led to the weakening of family support, others claiming that the family still functions well. At the same time, the ability of the elderly to change and adapt has been questioned. In rural and less developed regions concern has been expressed that the impact of reductions in or lack of services fall hardest on the elderly. This article looks at ways in which the elderly in a remote rural area of Britain adapt to the problems of sparsity, lack of adequate public transportation, migration in and out of the region and the reality of increasing age. It shows that the elderly are capable of adaptation and have a tolerance for isolation, and that changes in residence, household composition, and methods of access are made over time. The article presents evidence of commitment on the part of others towards the elderly and creative adaptations on the part of the elderly to provide necessary support.

Adaptation, Psychological↗
PubMed1979

Muscle spindles in the human anterior digastric muscle.

The occurrence of muscle spindles in the anterior digastric muscle in man was investigated and the fibre calibre spectrum of the corresponding nerve was determined. After removal at autopsy from five individuals of both sexes (aged 23--73), the muscles were stained with Weigert's iron hematoxylin-van Gieson stain and the nerves according to the Alzheimer - Mann - Häggqvist method. Altogether 12 spindles were found in five out of ten muscles. Only muscles from one individual were devoid of spindles. This sparsity or absence was supported by analyses of fibre calibre spectra. The small number of spindles and the fact that they do not occur in all muscles or in all individuals, suggest that they are not an essential source of sensory information.

Adult↗
PubMed1982

Tracheopathia osteoplastica: report of four cases.

We describe 4 florid examples of tracheopathia osteoplastica (TPO) discovered incidentally at autopsy. The sparsity of previously reported cases of TPO from Australia possibly reflects a lack of awareness of this entity rather than its true incidence. The more recent literature concerning the etiopathogenesis, pathology and clinical complications of this uncommon condition is reviewed. In our view TPO is a distinct entity and does not represent a late stage of diffuse tracheal amyloidosis.

Aged↗
PubMed1976

The relative effectiveness of a medical hospitalization program vs a feedback-behavior modification program in treating alcohol and drug abusers.

There is a sparsity of studies specifying the relative effectiveness of different types of treatment programs in treating a similar target population of drug and alcohol abusers in the same locale. In this paper, two drug and alcohol rehabilitation programs are described and their relative effectiveness compared in treating similar target populations. The first treatment program evaluated is a medically oriented hospitalization program and the second is a short-term therapeutic community program, called "Feedback" because it is structured on the basis of a collection of feedback and behavior modification principles and techniques. Both programs were implemented by basically the same staff and both treated similar target populations of multiple drug abusers and alcohol abusers during comparable time periods. The results indicated that the feedback program was significantly more effective in rehabilitating multiple drug abusers (nonheroin abusers) than the hospitalization program with regard to three criteria (return to work for 60 days, perform effectively according to the supervisor, and control drug or alcohol problems). But both programs were equally effective in rehabilitating alcohol abusers (problem drinkers and alcoholics).

Alcoholism↗
PubMedDate not supplied

Hypoechoic rim of chronically inflamed prostate, as seen at TRUS: histopathologic findings.

OBJECTIVE: The purpose of this study is to correlate the findings of peripheral hypoechoic rim, seen at transrectal ultrasonography (TRUS) in chronic prostatitis patients, with the histopathologic findings. MATERIALS AND METHODS: Seven patients with pathologically proven chronic prostatitis were involved in this study. The conspicuity of the peripheral hypoechoic prostatic rim, seen at TRUS, was prominent and subtle, and to determine its histopathologic nature, the microscopic findings were reviewed. RESULTS: In five of seven cases (71%), TRUS demonstrated a prominent peripheral hypoechoic rim. Microscopic examination revealed that inflammatory cell infiltration of prostatic glandular tissue was severe in three cases (42.9%), moderate in two (28.6%), and minimal in two (28.6%). In all seven cases, the common histopathologic findings of peripheral hypoechoic rim on TRUS were loose stromal tissues, few prostatic glands, and sparse infiltration by inflammatory cells. CONCLUSION: The peripheral hypoechoic rim accompanying prostatic inflammation and revealed by TRUS reflects a sparsity of prostate glandular tissue and is thought to be an area in which inflammatory cell infiltration is minimal.

Aged↗
PubMed2026

Identifying Single-Cell Expression Quantitative Trait Loci Using a Bootstrap Penalized Hurdle Model.

BACKGROUND: Expression quantitative trait loci (eQTL) analysis links genetic variants to gene expression levels, helping to uncover how genetic variation contributes to gene regulation. While traditional eQTL analyses rely on bulk RNA-seq data, recent advances in single-cell RNA sequencing (scRNA-seq) have made it possible to detect cell-type-specific eQTLs. However, the inherent sparsity and heterogeneity of scRNA-seq data present major challenges for standard modeling approaches. METHODS: In this paper, we propose a novel statistical framework, Bootstrap Penalized Hurdle regression model (BPHurdle), designed specifically for scRNA-seq data. BPHurdle employs a hurdle modeling framework, where a logistic component accounts for the excess zeros in single-cell expression data, and a Poisson component jointly evaluates the effects of multiple SNPs on positive gene expression levels. RESULTS: Through simulation studies, we show that BPHurdle achieves high accuracy and robustness in identifying regulatory variants. We further demonstrate its utility on a real dataset through a case study focusing on a subset of differentially expressed genes, where it successfully identifies reliable cell-type-specific eQTLs. CONCLUSIONS: Overall, BPHurdle offers an advanced and flexible approach for single-cell eQTL mapping, providing deeper insight into the genetic regulation of gene expression at cellular resolution.

Quantitative Trait Loci↗
PubMed1993

Influences of closure, occlusion, and size on the perception of fragmented pictures.

Two experiments examined the ability to recognize a repeated figure in stimuli where only fragments of the figures were presented. Fragments were either closed or open regions presented either with or without an occluder that filled the spaces between the fragments (Experiment 1). Recognition performance was significantly better for open fragments, with or without an occluder, contrary to previous assertions that the occluder is the important factor for recognition. When stimulus size was varied, an occluder hindered recognition performance in the smallest size condition relative to unoccluded stimuli, which were equally easy to recognize across all size conditions (Experiment 2). The size results support the idea of size invariance in object naming. The difficulty in the smallest occluded condition is discussed in terms of differences in global and local processing depending on visual angle and sparsity.

Adult↗
PubMed2026

LAML-Pro: Joint Maximum Likelihood Inference of Cell Genotypes and Cell Lineage Trees.

MOTIVATION: Recent dynamic lineage tracing technologies use genome editing to induce heritable mutations, or edits, that accumulate across successive cell divisions. These edits are measured using single-cell sequencing or imaging, providing data to reconstruct cell lineages at single-cell resolution. Current computational approaches to infer cell lineage trees, or phylogenies, from these data perform two separate steps: (1) Identify each cell's edits (genotype) from the raw sequencing or imaging data; (2) Infer a cell lineage tree from the cell genotypes. However, genotyping cells is an inexact process and genotype errors can yield an inaccurate lineage tree. For example, using fluorescence based-imaging to measure edits results in a high fraction (≈ 25-50%) of uncertain or erroneous genotypes. RESULTS: We introduce Lineage Analysis via Maximum Likelihood with PRobabilistic Observations (LAML-Pro), an algorithm that jointly infers cell genotypes and a cell lineage tree. LAML-Pro is based on the Probabilistic Mixed-type Missing Observation (PMMO) model, which we derive to describe both the genome editing and genotype observation processes. LAML-Pro constructs lineage trees from thousands of cells in under an hour by leveraging the sparsity of transitions under the PMMO model. On simulated data, we demonstrate that LAML-Pro corrects genotype errors and infers substantially more accurate trees than existing methods which are vulnerable to genotype errors. Applied to data from two recent imaging-based lineage tracing systems, LAML-Pro reduces genotype errors by 5-fold and produces more spatially coherent lineage trees compared to existing methods. AVAILABILITY AND IMPLEMENTATION: LAML-Pro is freely available at: github.com/raphael-group/LAML-Pro.

Journal Article↗