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1.
Toxicol Sci ; 195(2): 155-168, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37486259

RESUMO

The molecular mechanisms connecting environmental exposures to adverse endpoints are often unknown, reflecting knowledge gaps. At the Comparative Toxicogenomics Database (CTD), we developed a bioinformatics approach that integrates manually curated, literature-based interactions from CTD to generate a "CGPD-tetramer": a 4-unit block of information organized as a step-wise molecular mechanism linking an initiating Chemical, an interacting Gene, a Phenotype, and a Disease outcome. Here, we describe a novel, user-friendly tool called CTD Tetramers that generates these evidence-based CGPD-tetramers for any curated chemical, gene, phenotype, or disease of interest. Tetramers offer potential solutions for the unknown underlying mechanisms and intermediary phenotypes connecting a chemical exposure to a disease. Additionally, multiple tetramers can be assembled to construct detailed modes-of-action for chemical-induced disease pathways. As well, tetramers can help inform environmental influences on adverse outcome pathways (AOPs). We demonstrate the tool's utility with relevant use cases for a variety of environmental chemicals (eg, perfluoroalkyl substances, bisphenol A), phenotypes (eg, apoptosis, spermatogenesis, inflammatory response), and diseases (eg, asthma, obesity, male infertility). Finally, we map AOP adverse outcome terms to corresponding CTD terms, allowing users to query for tetramers that can help augment AOP pathways with additional stressors, genes, and phenotypes, as well as formulate potential AOP disease networks (eg, liver cirrhosis and prostate cancer). This novel tool, as part of the complete suite of tools offered at CTD, provides users with computational datasets and their supporting evidence to potentially fill exposure knowledge gaps and develop testable hypotheses about environmental health.


Assuntos
Saúde Ambiental , Toxicogenética , Masculino , Humanos , Bases de Dados Factuais , Fenótipo , Exposição Ambiental
2.
Forensic Sci Int Genet ; 35: 113-122, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29727813

RESUMO

STRmix™ uses several laboratory specific parameters to calibrate the stochastic model for peak heights. These are modelled on empirical observations specific to the instruments and protocol used in the analysis. The extent to which these parameters can be borrowed from laboratories with similar technology and protocols without affecting the accuracy of the system is investigated using a sensitivity analysis. Parameters are first calibrated to a publicly available dataset, after which a large number of likelihood ratios are computed for true contributors and non-contributors using both the calibrated parameters and several borrowed parameters. Differences in the LR caused by using different sets of parameter values are found to be negligible.


Assuntos
Repetições de Microssatélites , Modelos Estatísticos , Probabilidade , Software , Alelos , Impressões Digitais de DNA , Genética Forense , Técnicas de Genotipagem , Humanos
3.
Forensic Sci Int Genet ; 34: 11-24, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29367014

RESUMO

We report a large compilation of the internal validations of the probabilistic genotyping software STRmix™. Thirty one laboratories contributed data resulting in 2825 mixtures comprising three to six donors and a wide range of multiplex, equipment, mixture proportions and templates. Previously reported trends in the LR were confirmed including less discriminatory LRs occurring both for donors and non-donors at low template (for the donor in question) and at high contributor number. We were unable to isolate an effect of allelic sharing. Any apparent effect appears to be largely confounded with increased contributor number.


Assuntos
DNA/genética , Genótipo , Repetições de Microssatélites , Probabilidade , Software , Alelos , Impressões Digitais de DNA , Humanos , Laboratórios , Funções Verossimilhança
4.
J Neurosci ; 35(20): 7878-91, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25995473

RESUMO

During nervous system development, critical periods are usually defined as early periods during which manipulations dramatically change neuronal structure or function, whereas the same manipulations in mature animals have little or no effect on the same property. Neurons in the ventral cochlear nucleus (CN) are dependent on excitatory afferent input for survival during a critical period of development. Cochlear removal in young mammals and birds results in rapid death of target neurons in the CN. Cochlear removal in older animals results in little or no neuron death. However, the extent to which hair-cell-specific afferent activity prevents neuronal death in the neonatal brain is unknown. We further explore this phenomenon using a new mouse model that allows temporal control of cochlear hair cell deletion. Hair cells express the human diphtheria toxin (DT) receptor behind the Pou4f3 promoter. Injections of DT resulted in nearly complete loss of organ of Corti hair cells within 1 week of injection regardless of the age of injection. Injection of DT did not influence surrounding supporting cells directly in the sensory epithelium or spiral ganglion neurons (SGNs). Loss of hair cells in neonates resulted in rapid and profound neuronal loss in the ventral CN, but not when hair cells were eliminated at a more mature age. In addition, normal survival of SGNs was dependent on hair cell integrity early in development and less so in mature animals. This defines a previously undocumented critical period for SGN survival.


Assuntos
Núcleo Coclear/crescimento & desenvolvimento , Células Ciliadas Auditivas/citologia , Gânglio Espiral da Cóclea/crescimento & desenvolvimento , Animais , Morte Celular , Núcleo Coclear/citologia , Núcleo Coclear/fisiologia , Toxina Diftérica/farmacologia , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Audição , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Gânglio Espiral da Cóclea/citologia , Gânglio Espiral da Cóclea/fisiologia
5.
J Huntingtons Dis ; 1(2): 221-41, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23833693

RESUMO

Mouse strain background can influence vulnerability to excitotoxic neuronal cell death and potentially modulate phenotypes in transgenic mouse models of human disease. Evidence supports a contribution of excitotoxicity to the selective death of medium spiny neurons in Huntington's disease (HD). Here, we assess whether strain differences in excitotoxic vulnerability influence striatal cell death in a knock-in mouse model of HD. Previous studies that evaluated resistance to excitotoxic lesions in several mouse models of HD had variable outcomes. In the present study, we directly compare one model on two different background strains to test the contribution of strain to excitotoxicity-mediated neurodegeneration. Mice of the FVB/N strain, which are highly vulnerable to excitotoxicity, become extremely resistant to quinolinic acid-induced striatal neurodegeneration with age, when carrying a huntingtin (Htt) allele expressing a HD transgene (CAG140). The resistance is much greater than the age-dependent resistance that has been previously reported in YAC128 mice. By 12 months of age, both heterozygous and homozygous FVB.CAG140 mice displayed virtually complete resistance to quinolinic acid-induced striatal neurodegeneration. A similar resistance develops in CAG140 mice on a C57BL/6N background although the effect size is smaller because C57BL/6N mice are already resistant due to genetic background. In a direct comparison with the YAC128 mice, FVB.CAG140 mice have greater resistance. FVB.CAG140 mice are also resistant to neurodegeneration following kainic acid-induced status epilepticus suggesting the existence of a common cellular mechanism that provides protection against multiple types of excitotoxic insult. These findings establish FVB.CAG140 mice as a useful model to investigate the cellular and molecular mechanisms that confer neuroprotection against excitotoxicity.


Assuntos
Envelhecimento/patologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Doença de Huntington/patologia , Ácido Quinolínico , Animais , Relação Dose-Resposta a Droga , Proteína Huntingtina , Doença de Huntington/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Especificidade da Espécie
6.
J Comp Neurol ; 519(14): 2852-69, 2011 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-21618218

RESUMO

Over the past century, the question of whether the cells of origin of the corticospinal tract (CST) die following spinal cord injury (SCI) has been debated. A recent study reported an approximately 20% loss of retrogradely labeled cortical motoneurons following damage to their axons resulting from SCI at T9 (Hains et al. [2003] J. Comp. Neurol. 462:328-341). In follow-up studies, however, we failed to find any evidence of loss of CST axons in the medullary pyramid, which must occur if CST neurons die. Here, we seek to resolve the discrepancy by re-evaluating possible loss of CST neurons using the same techniques as Hains et al. (quantitative analysis of retrograde labeling and staining for cell death markers including TUNEL and Hoechst labeling of the nuclei). Following either dorsal funiculus lesions at thoracic level 9 (T9) or lateral hemisection at cervical level 5 (C5), our results reveal no evidence for a loss of retrogradely labeled neurons and no evidence for TUNEL staining of axotomized cortical motoneurons. These results indicate that CST cell bodies do not undergo retrograde cell death following SCI, and therefore targeting such cell death is not a valid therapeutic target.


Assuntos
Apoptose/fisiologia , Córtex Cerebral/citologia , Neurônios Motores/patologia , Traumatismos da Medula Espinal/patologia , Animais , Feminino , Marcação In Situ das Extremidades Cortadas , Ratos , Ratos Sprague-Dawley
7.
J Neurosci ; 30(34): 11516-28, 2010 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-20739574

RESUMO

There is continuing controversy about whether the cells of origin of the corticospinal tract (CST) undergo retrograde cell death after spinal cord injury (SCI). All previous attempts to assess this have used imaging and/or histological techniques to assess upper motoneurons in the cerebral cortex. Here, we address the question in a novel way by assessing Wallerian degeneration and axon numbers in the medullary pyramid of Sprague Dawley rats after both acute SCI, either at cervical level 5 (C5) or thoracic level 9 (T9), and chronic SCI at T9. Our findings demonstrate that only a fraction of a percentage of the total axons in the medullary pyramid exhibit any sign of degeneration at any time after SCI--no more so than in uninjured control rats. Moreover, design-based counts of myelinated axons revealed no decrease in axon number in the medullary pyramid after SCI, regardless of injury level, severity, or time after injury. Spinal cord-injured rats had fewer myelinated axons in the medullary pyramid at 1 year after injury than aged matched controls, suggesting that injury may affect ongoing myelination of axons during aging. We conclude that SCI does not cause death of the CST cell bodies in the cortex; therefore, therapeutic strategies aimed at promoting axon regeneration of the CST in the spinal cord do not require a separate intervention to prevent retrograde degeneration of upper motoneurons in the cortex.


Assuntos
Neurônios/citologia , Tratos Piramidais/citologia , Traumatismos da Medula Espinal/patologia , Animais , Sobrevivência Celular/fisiologia , Vértebras Cervicais , Masculino , Neurônios/patologia , Neurônios/fisiologia , Tratos Piramidais/patologia , Tratos Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Vértebras Torácicas , Degeneração Walleriana/patologia
8.
Exp Neurol ; 217(1): 96-107, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19416669

RESUMO

Previous studies in mice have demonstrated that forepaw gripping ability, as measured by a grip strength meter (GSM), is dependent on the contralateral sensorimotor cortex, but this dependency changes after hemisection injury at cervical level 4 (C4). Initially, the mouse fails to grip with the forepaw ipsilateral to the hemisection but gripping recovers. Additionally, a mouse's gripping by the contralateral paw becomes independent of the sensorimotor cortex, indicating a reorganization of cortical control of gripping function (Blanco, J.E., Anderson, K.D., Steward, O. 2007. Recovery of forepaw gripping ability and reorganization of cortical motor control following cervical spinal cord injuries in mice. Exp. Neurol. 203, 333-348.). Here we explore whether a similar reorganization occurs after cervical hemisection injuries in rats. We show that as in mice, unilateral lesions of the sensorimotor cortex impair rats' griping by the contralateral paw. We also confirm from previous studies that cervical hemisections impair rats' griping by the ipsilateral paw. In contrast to mice, however there is minimal recovery of gripping after complete lateral hemisections and secondary lesions of the sensorimotor cortex continue to impair rats' gripping by the contralateral paw. Thus, forelimb gripping ability as measured by the GSM is dependent on the contralateral sensorimotor cortex in rats even after a cervical hemisection.


Assuntos
Córtex Cerebral/fisiopatologia , Membro Anterior/fisiopatologia , Lateralidade Funcional/fisiologia , Força da Mão/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Análise de Variância , Animais , Benzodiazepinas , Biotina/análogos & derivados , Biotina/metabolismo , Córtex Cerebral/lesões , Vértebras Cervicais , Dextranos/metabolismo , Feminino , Dinamômetro de Força Muscular , Tratos Piramidais/patologia , Ratos , Ratos Sprague-Dawley , Estilbamidinas/metabolismo , Fatores de Tempo
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