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Biomedical subjects

Matthew Clark

Publications and source records attributed to Matthew Clark.

18 recordsLinked to original sources
PubMed2026

Incidence of invasive group A streptococcal infections and comparison of emm types from invasive infections, pharyngitis, and throat carriage in American Indian communities in the Southwest United States.

BACKGROUND: American Indian/Alaska Native (AI/AN) communities in the US have high rates of group A streptococcal (GAS) infections. We determined the incidence of invasive infections in AI communities in the Southwest and compared emm types from invasive infections, pharyngitis, and throat carriage. METHODS: Activities conducted in the White Mountain Apache Tribal lands (WMA) and Navajo Nation (NN) included active, laboratory-based surveillance for invasive GAS infections (WMA: 2019─2024; NN: 2023─2024; all ages); surveillance for GAS pharyngitis (2023-2024; children 0─17 years); and culture for GAS from oropharyngeal carriage samples (2019 and 2022─2023; children 0─14 years). Emm types were determined by whole-genome sequencing. Annual incidence rates were calculated using Poisson regression. RESULTS: In WMA, age-standardized rates of invasive infections ranged from 80-270/100,000 persons between 2019-2024. Predominant emm types varied (n=74 isolates): 91 (59%) and 49 (32%) in 2019-2020, and 43 (40%) and 53 (30%) in 2023. In NN, rates were 40-60/100,000 persons in 2023-2024; common emm types (n=51) were 53 (28%), 101 (18%), and 12 (16%). In WMA and NN, emm types 1, 12, and 53 predominated in pharyngitis (n=190), and 1, 12, and 91 in throat carriage (n=119). CONCLUSIONS: Rates of invasive GAS infections in these communities were 3-35 times higher than the national US average (12.2/100,000 in 2024). Emm types varied over time with limited overlap in strains from throat carriage or pharyngitis isolates and those from invasive infections. Findings support continuing GAS surveillance and engaging AI/AN communities throughout vaccine development and evaluation.

Indigenous health↗
PubMed2022

A Multitrait Locus Regulates Sarbecovirus Pathogenesis.

Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6, that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2, and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species. IMPORTANCE Host genetic variation is an important determinant that predicts disease outcomes following infection. In the setting of highly pathogenic coronavirus infections genetic determinants underlying host susceptibility and mortality remain unclear. To elucidate the role of host genetic variation on sarbecovirus pathogenesis and disease outcomes, we utilized the Collaborative Cross (CC) mouse genetic reference population as a model to identify susceptibility alleles to SARS-CoV and SARS-CoV-2 infections. Our findings reveal that a multitrait loci found in chromosome 9 is an important regulator of sarbecovirus pathogenesis in mice. Within this locus, we identified and validated CCR9 and CXCR6 as important regulators of host disease outcomes. Specifically, both CCR9 and CXCR6 are protective against severe SARS-CoV, SARS-CoV-2, and SARS-related HKU3 virus disease in mice. This chromosome 9 multitrait locus may be important to help identify genes that regulate coronavirus disease outcomes in humans.

Animals↗
PubMed2005

A novel modelling approach for spatial and temporal variations in nitrate concentrations in an N-impacted UK small upland river basin.

Monthly data for 11 moorland streams displaying marked seasonality and spatial variation in nitrate concentrations have been used with readily available catchment characteristics to develop a method for predicting stream water nitrate concentrations throughout an upland river network in the Lake District, UK. Over a 12-month period, a simple asymmetric truncated cosine function of day number is used to describe seasonality effects on stream water nitrate concentrations. This is then adjusted to compensate for differences in seasonality effects with catchment elevation. Occurrence of greater proportions of steeper slopes (>20 degrees -40 degrees ) in individual catchments facilitated nitrate leaching, as did increased extent of occurrence of outcropping rocks. It is shown that the spatial and temporal variation in nitrate concentration through the river network studied may therefore be effectively represented by an equation which is a function of day number, % outcropping rock and % of catchment area with a >20 degrees -40 degrees slope.

Environmental Monitoring↗
PubMed2005

Disability associated with headaches occurring inside and outside the menstrual period in those with migraine: a general practice study.

OBJECTIVES: This study investigated the disability of females who have migraine and other headache attacks occurring during and outside the menstrual period. METHODS: One thousand four hundred and thirty-four of 3470 female patients (41.3%) aged 14 to 50 years registered at a UK general practice completed two questionnaires. The first questionnaire assessed the prevalence of headache, depression, and bodily pain in the total population. The second questionnaire assessed the disability of all headaches over a 2-month period (to capture a complete menstrual cycle) for patients reporting migraine who were still menstruating. Disability was assessed as the time lost and time spent at less than 50% productivity in normal activities due to headache, and analyzed as rank sums using the Mann-Whitney U-test. RESULTS: The first part of the study showed that the prevalence of headache (66.1%), depression (55.4%), and bodily pain (40.6%) were high in this population of women. Thirty migraine patients who were still menstruating reported 89 migraine and 114 nonmigraine headache episodes in the second part of the study. For migraine, the rank order of time at less than 50% productivity was greater for attacks taking place inside the menstrual period than for those occurring outside the menstrual period. The comparison was significant for time at less than 50% productivity (P=.01). For nonmigraine headaches, the rank order of time lost was greater for attacks taking place outside the menstrual period than for those occurring inside the menstrual period. The comparison was not significant for time lost (P= .06). CONCLUSIONS: For those with migraine, migraine attacks that took place during the menstrual period tended to be slightly more disabling than those taking place outside the menstrual period, but the opposite was true for nonmigraine headache.

Adolescent↗
PubMed2004

Rectal duplication cyst presenting as perianal sepsis: report of two cases and review of the literature.

INTRODUCTION: Recurrent perianal sepsis is a difficult problem to manage in colorectal surgical practice. One cause is rectal duplication cyst, a rare congenital lesion that is easily overlooked. Many cases have associated congenital defects, especially musculoskeletal anomalies, and may provide a clue to the underlying condition. Early diagnosis is important because these cysts do not resolve spontaneously and may undergo malignant change. METHODS: We present two cases of middle-aged females who presented with perianal sepsis secondary to rectal duplication cyst. The first case had numerous surgical procedures for a perianal fistula during a ten-year period. She had associated sacral anomalies consistent with Currarino syndrome. The second case presented with a perineal mass after a bout of perianal inflammation. Both cases had the entire cyst surgically excised. RESULTS: There were no complications postoperatively and no recurrence at follow-up. Histopathology revealed no malignancy in the cyst. CONCLUSIONS: Rectal duplication cyst is a rare cause of recurrent perianal sepsis that should be considered in difficult cases, especially in those with associated musculoskeletal anomalies. Complete surgical excision is the preferred treatment to prevent recurrence and the risk of malignant degeneration.

Abnormalities, Multiple↗
PubMed2004

Optimisation using measured Green's function for improving spatial coherence in acoustic measurements.

Aberrating materials can degrade acoustic measurements by distorting the acoustic wavefront and causing acoustic speckle (as opposed to speckle noise which is a manifestation of coherent backscatter). The amplitude and phase fluctuations associated with acoustic speckle can introduce considerable measurement uncertainty which is difficult to deal with. This paper demonstrates a new technique which optimises the spatial distribution of the generation of the ultrasound to compensate for the aberration. This technique uses experimentally measured Green's functions to allow the calculation of the field resulting from the generation wavefront during optimisation. The technique is used to improve the accuracy of velocity measurements in a steel sample using 82 MHz SAW waves. This is achieved by optimising for improved spatial coherence in the measurement region which suppresses the speckle noise. Experimental evidence of acoustic aberration arising from grain structure is shown for steel and aluminium and the measured Green's function optimisation technique is shown to overcome the resulting acoustic speckle. The technique was performed using the Adaptive Optical Scanning Acoustic Microscope (AOSAM) at Nottingham University, UK.

Journal Article↗
PubMed2004

Surface acoustic wavefront sensor using custom optics.

We have designed and had manufactured a custom surface acoustic wavefront sensor, using a standard CMOS process. Ultrasound propagating along the surface of an object perturbs the reflection of incident laser light, which has been focused onto the object using a cylindrical lens. These high-frequency angular perturbations of reflected light relate to the amplitude and phase of the ultrasound along a line on the surface of the object, and thus correspond to the acoustic wavefront. The reflected light is imaged onto a custom linear array of split photodiodes; these simultaneously detect the high-frequency perturbations at several discrete points along the line, forming an acoustic wavefront sensor. As well as a description of the device, its role within an adaptive optical scanning acoustic microscope is discussed. The sensor detects the distortions to the acoustic wavefront after it has propagated through an aberrating medium, such as a metal containing grains of random orientation. The information attained may then be used to alter the generation profile of the optical generation source of the acoustic waves, thus reducing the distortion caused by the aberration and increasing the resolution and accuracy of the system as a whole.

Journal Article↗
PubMed2004

Rapid and accurate analysis of surface and pseudo-surface waves using adaptive laser ultrasound techniques.

A method has been developed to measure the phase velocity of laser generated and detected surface acoustic waves. An optical grating produced by an electronically addressable spatial light modulator (SLM) was imaged onto the sample surface to generate surface acoustic waves whose frequency and wavefront was controlled by the SLM. When the grating period matched the surface acoustic wavelength, the surface wave was strongly excited, thus the wavelength and, thereby the phase velocity was determined. We present results with this method that allows the phase velocity and the angular dispersion of the generalized surface wave as well as the pseudo-surface wave on the (100) nickel to be measured. Measurements on (111) silicon single crystals are also presented. The measurement precision is approximately 0.2%. Methods to further improve the measurement precision are also discussed.

Journal Article↗
PubMed2003

Anxiety sensitivity, self-reported motives for alcohol and nicotine use, and level of consumption.

We examined the relationship between anxiety sensitivity, alcohol and nicotine use, and drinking and smoking motives in a nonclinical university population. Participants (n=293) completed the 16-item Anxiety Sensitivity (AS) Index and a drinking and smoking history questionnaire. Sixty percent of participants completed the Drinking Motives Questionnaire and 29% completed the Smoking Motives Questionnaire. Level of alcohol and cigarette consumption was not related to AS but was related to motives. AS was directly related to coping-related drinking and moderated the relationship between level of smoking and mood-related smoking motives. Although AS may be more predictive of coping-related drinking motives than of level of alcohol consumption, given the relationship between these types of drinking motives and abusive drinking, high AS individuals might be an at-risk group due to their reasons for drinking. In addition, striking differences were found between drinkers who smoke and those who do not smoke, suggesting that this subgroup may also represent an at-risk group of drinkers.

Adaptation, Psychological↗
PubMed2002

Simulation of DNA array hybridization experiments and evaluation of critical parameters during subsequent image and data analysis.

BACKGROUND: Gene expression analyses based on complex hybridization measurements have increased rapidly in recent years and have given rise to a huge amount of bioinformatic tools such as image analyses and cluster analyses. However, the amount of work done to integrate and evaluate these tools and the corresponding experimental procedures is not high. Although complex hybridization experiments are based on a data production pipeline that incorporates a significant amount of error parameters, the evaluation of these parameters has not been studied yet in sufficient detail. RESULTS: In this paper we present simulation studies on several error parameters arising in complex hybridization experiments. A general tool was developed that allows the design of exactly defined hybridization data incorporating, for example, variations of spot shapes, spot positions and local and global background noise. The simulation environment was used to judge the influence of these parameters on subsequent data analysis, for example image analysis and the detection of differentially expressed genes. As a guide for simulating expression data real experimental data were used and model parameters were adapted to these data. Our results show how measurement error can be balanced by the analysis tools. CONCLUSIONS: We describe an implemented model for the simulation of DNA-array experiments. This tool was used to judge the influence of critical parameters on the subsequent image analysis and differential expression analysis. Furthermore the tool can be used to guide future experiments and to improve performance by better experimental design. Series of simulated images varying specific parameters can be downloaded from our web-site: http://www.molgen.mpg.de/~lh_bioinf/projects/simulation/biotech/

Algorithms↗
PubMed2002

Rainbow trout (Oncorhynchus mykiss) can eliminate chiral organochlorine compounds enantioselectively.

Dietary accumulation of four chiral organochlorine compounds--alpha-hexachlorocyclohexane (alpha-HCH), trans-chlordane, and chlorobiphenyls (CBs) 95 and 136-by immature rainbow trout (Oncorhynchus mykiss) was studied to determine if fish can accumulate and eliminate these compounds enantioselectively. Fish rapidly accumulated all four compounds from food spiked at micrograms per gram concentrations during a 40-d feeding period. Depuration half-lives were from 13 d for (+/-)-alpha-HCH to 375 d for (+/-)-CB 136. Fish preferentially eliminated (-)-trans-chlordane and (+)-CB 136, with significant nonracemic residues observed after 20 d. These results are consistent with field measurements of these compounds in fish as well as known metabolic pathways. Enantiomeric fractions (EFs) for these two compounds changed significantly over the course of the experiment, suggesting that trout were enantioselectively biotransforming the compounds during the 238-d depuration phase. CB 95 and alpha-HCH residues were racemic throughout the experiment. High biomagnification factors for CB 95 suggest that it was not metabolized. Minimum values for metabolic elimination rates calculated from EF suggest that at least 58% of the trans-chlordane depuration rate can be attributed to metabolism, and all of the CB 136 depuration rate can be attributed to it. This study highlights the potential of chiral analysis as a tracer of in vivo biotransformation processes of xenobiotic compounds.

Animals↗
PubMed2002

Effects of the mGlu2/3 receptor agonist LY379268 on motor activity in phencyclidine-sensitized rats.

Previous work has shown that mGlu2/3 receptor agonists such as LY379268 inhibit motor responses to acutely administered phencyclidine (PCP) in rats. However, it has not been determined whether mGlu2/3 receptor agonists will reverse the enhanced effects of repeatedly administered PCP (so called PCP sensitization). In these studies, rats were administered daily PCP and monitored for the number of ambulations, fine movements, time at rest and rears using an automated activity system. At Day 10, when compared the first (Day 1) response, PCP-treated animals showed enhanced responses to all measures tested. Augmentations of these PCP-induced behaviors generally peaked between the third and tenth day after PCP administration had begun. Acute administration of LY379268 effectively suppressed PCP-evoked motor behaviors in rats sensitized to PCP. However, daily administrations of LY379268 (for 9 days), along with PCP, did not prevent the expression of the enhanced PCP response on Day 10. Thus, LY379268 administration can suppress PCP responses after either acute or chronic exposure to PCP. However, the underlying plasticity that leads to PCP sensitization was not affected by this treatment.

Amino Acids↗
PubMed2002

Expression of the helix-loop-helix gene id3 in the zebrafish embryo.

Proteins of the Extramacrochaetae and Id subfamily of Helix-Loop-Helix (HLH) proteins are negative regulators of bHLH transcription factors. We cloned a cDNA from zebrafish which encodes a member of the id3 subfamily. High levels of transcripts accumulated in the germ ring and in the embryonic shield. Towards the end of gastrulation, Id3 was highly expressed in the anterior prechordal plate and hypoblast. At later stages, id3 expression was turned on and off in a large variety of tissues within short periods of time. These include the lateral mesoderm, the cornea, the lens, the brain, the neural crest, the retina and the fins.

Amino Acid Sequence↗
PubMedDate not supplied

Generalized fragment-substructure based property prediction method.

The need for fast and accurate predictors of pharmaceutically important properties has been increasing due to pressure from high-throughput screening, in-silico screening, and the need to more rapidly identify potential pharmacokinetic issues before drugs advance to the more expensive clinical development stages. A novel method for making predictive models based on decomposing 2D structure into component structural fragments is used to model logP, water solubility, and melting point. The fragment orientation of the method facilitates understanding of how molecules might be altered to improve the desired properties. The 2D structure-based descriptor is computed by analysis of the target molecules with a substructure searching algorithm and a set of fragments selected for chemical and pharmaceutical relevance. These are combined with partial least squares to create predictive models. The correlation coefficients achieved are 0.86 for logP (SE = 0.68), 0.73 for logS (SE = 0.89), and 0.64 (SE = 48.9 degrees) for melting point over diverse data sets of 11,447, 2427, and 5598 molecules, respectively. The models were verified via test sets of compounds not included in the training set.

Journal Article↗
PubMedDate not supplied

Grand canonical Monte Carlo simulation of ligand-protein binding.

A new application of the grand canonical thermodynamics ensemble to compute ligand-protein binding is described. The described method is sufficiently rapid that it is practical to compute ligand-protein binding free energies for a large number of poses over the entire protein surface, thus identifying multiple putative ligand binding sites. In addition, the method computes binding free energies for a large number of poses. The method is demonstrated by the simulation of two protein-ligand systems, thermolysin and T4 lysozyme, for which there is extensive thermodynamic and crystallographic data for the binding of small, rigid ligands. These low-molecular-weight ligands correspond to the molecular fragments used in computational fragment-based drug design. The simulations correctly identified the experimental binding poses and rank ordered the affinities of ligands in each of these systems.

Binding Sites↗
PubMedDate not supplied

Development and evaluation of an in silico model for hERG binding.

It has been recognized that drug-induced QT prolongation is related to blockage of the human ether-a-go-go-related gene (hERG) ion channel. Therefore, it is prudent to evaluate the hERG binding of active compounds in early stages of drug discovery. In silico approaches provide an economic and quick method to screen for potential hERG liability. A diverse set of 90 compounds with hERG IC(50) inhibition data was collected from literature references. Fragment-based QSAR descriptors and three different statistical methods, support vector regression, partial least squares, and random forests, were employed to construct QSAR models for hERG binding affinity. Important fragment descriptors relevant to hERG binding affinity were identified through an efficient feature selection method based on sparse linear support vector regression. The support vector regression predictive model built upon selected fragment descriptors outperforms the other two statistical methods in this study, resulting in an r(2) of 0.912 and 0.848 for the training and testing data sets, respectively. The support vector regression model was applied to predict hERG binding affinities of 20 in-house compounds belonging to three different series. The model predicted the relative binding affinity well for two out of three compound series. The hierarchical clustering and dendrogram results show that the compound series with the best prediction has much higher structural similarity and more neighbors of training compounds than the other two compound series, demonstrating the predictive scope of the model. The combination of a QSAR model and postprocessing analysis, such as clustering and visualization, provides a way to assess the confidence level of QSAR prediction results on the basis of similarity to the training set.

Cell Line↗