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PubMed2000

Iron hydrogenases and the evolution of anaerobic eukaryotes.

Hydrogenases, oxygen-sensitive enzymes that can make hydrogen gas, are key to the function of hydrogen-producing organelles (hydrogenosomes), which occur in anaerobic protozoa scattered throughout the eukaryotic tree. Hydrogenases also play a central role in the hydrogen and syntrophic hypotheses for eukaryogenesis. Here, we show that sequences related to iron-only hydrogenases ([Fe] hydrogenases) are more widely distributed among eukaryotes than reports of hydrogen production have suggested. Genes encoding small proteins which contain conserved structural features unique to [Fe] hydrogenases were identified on all well-surveyed aerobic eukaryote genomes. Longer sequences encoding [Fe] hydrogenases also occur in the anaerobic eukaryotes Entamoeba histolytica and Spironucleus barkhanus, both of which lack hydrogenosomes. We also identified a new [Fe] hydrogenase sequence from Trichomonas vaginalis, bringing the total of [Fe] hydrogenases reported for this organism to three, all of which may function within its hydrogenosomes. Phylogenetic analysis and hypothesis testing using likelihood ratio tests and parametric bootstrapping suggest that the [Fe] hydrogenases in anaerobic eukaryotes are not monophyletic. Iron-only hydrogenases from Entamoeba, Spironucleus, and Trichomonas are plausibly monophyletic, consistent with the hypothesis that a gene for [Fe] hydrogenase was already present on the genome of the common, perhaps also anaerobic, ancestor of these phylogenetically distinct eukaryotes. Trees where the [Fe] hydrogenase from the hydrogenosomal ciliate Nyctotherus was constrained to be monophyletic with the other eukaryote sequences were rejected using a likelihood ratio test of monophyly. In most analyses, the Nyctotherus sequence formed a sister group with a [Fe] hydrogenase on the genome of the eubacterium Desulfovibrio vulgaris. Thus, it is possible that Nyctotherus obtained its hydrogenosomal [Fe] hydrogenase from a different source from Trichomonas for its hydrogenosomes. We find no support for the hypothesis that components of the Nyctotherus [Fe] hydrogenase fusion protein derive from the mitochondrial respiratory chain.

Amino Acid Sequence↗
PubMed2001

Enuresis, firesetting, and cruelty to animals: does the ego triad show predictive validity?

The hypothesis tested in this study was that the presence of enuresis and cruelty to animals in juvenile firesetters would be significantly related to recidivistic firesetting. This hypothesis was related to Yarnell's belief in an ego triad among juvenile firesetters, which linked the occurrence of enuresis, cruelty to animals and others, and firesetting. No relationship was found between groups for firesetting recidivism and enuresis. However, juveniles who were identified as being cruel to animals were more likely than those who were not cruel to animals to engage in recidivistic firesetting behaviors.

Adolescent↗
PubMed1989

Epidemiologic evidence for the development of serovar-specific immunity after gonococcal infection.

We tested the hypothesis that strain-specific immunity occurs after gonococcal infection in a longitudinal study of 227 prostitutes resident in one small community who experienced frequent gonococcal infections. Women were examined and cultured for Neisseria gonorrhoeae at 2-wk intervals. Gonococcal isolates were typed according to protein 1 serovar, auxotype, and beta-lactamase plasmid type, and classified as to serovar and strain. The hypothesis was tested by comparing the predictions of the hypothesis with the observations of the study. Over the 14-mo period of the study, major changes in the prevalence of specific serovars were observed in the gonococcal population infecting these women. Women with HIV infection experienced a higher rate of gonococcal infection (0.56 +/- 0.03 vs. 0.46 +/- 0.04, P less than 0.05, t test) compared with HIV-negative women and were more likely to experience multiple infections with the same strain. The duration of prostitution was inversely related to the frequency of gonococcal infection. Women experiencing an infection with a specific gonococcal serovar were at a 2- to 10-fold reduced risk of reinfection with the same serovar, except for the 1B-1 serovar. The results of the study were consistent with all four predictions of the hypothesis. Infection with a specific gonococcal serovar results in specific but incomplete protection against subsequent infection with the homologous serovar. The mechanism of this protection remains to be determined.

Adult↗
PubMed2006

Testing for spatial clustering of amino acid replacements within protein tertiary structure.

Widely used models of protein evolution ignore protein structure. Therefore, these models do not predict spatial clustering of amino acid replacements with respect to tertiary structure. One formal and biologically implausible possibility is that there is no tendency for amino acid replacements to be spatially clustered during evolution. An alternative to this is that amino acid replacements are spatially clustered and this spatial clustering can be fully explained by a tendency for similar rates of amino acid replacement at sites that are nearby in protein tertiary structure. A third possibility is that the amount of clustering exceeds that which can be explained solely on the basis of independently evolving protein sites with spatially clustered replacement rates. We introduce two simple and not very parametric hypothesis tests that help distinguish these three possibilities. We then apply these tests to 273 homologous protein families. The null hypothesis of no spatial clustering is rejected for 102 of 273 families. The explanation of spatially clustered rates but independent change among sites is rejected for 43 families. These findings need to be reconciled with the common practice of basing evolutionary inferences on models that assume independent change among sites.

Amino Acid Substitution↗
PubMed2000

Growth of skeletal components in the young squirrel monkey (Saimiri sciureus boliviensis): a longitudinal experiment.

A functional skeletal criterion, as an extension of the van der Klaauw's cranial theory, was adopted in the present study. The null hypothesis tested was: "The major skeletal components of the platyrrhine body grow linearly, regardless of their functional dependence to different demands." The acceptance of the hypothesis will imply that all Saimiri skeletal growth may be satisfactorily explained by independent variables in a single equation. The rejection will suggest that such skeletal growth patterns have to be explained by variables in several different equations, and perhaps these equations may vary with the effect of sex and undernutrition. Control and undernourished squirrel monkeys were radiographed monthly for 2 years; they were also measured; and their volumetric and morphometric neurocranial, facial, and pelvic indices were calculated. The curves that best described each of the 24-point sequences were obtained. Three main growth patterns were observed: 1) Simple linear (femur length for all groups, and pelvic index for control and undernourished females), for which the simple regression equation explained more than 95% of the variation; 2) Complex linear (pelvic index for control and undernourished males, and neurocranial and facial indices for all of the groups), for which more than 95% of the variation was explained by one of the four four-function type equations; and 3) Noncorrelated with age (neurofacial index for undernourished males, and pelviofemoral index for control females and undernourished males and females), which showed nonsignificant correlations with respect to age. The food intake and the oscillations of the environmental temperature might help to explain the undulating growth trajectory observed in the complex linear components.

Animals↗
PubMed2005

Assessing contaminant sensitivity of endangered and threatened aquatic species: part II. Chronic toxicity of copper and pentachlorophenol to two endangered species and two surrogate species.

Early life-stage toxicity tests with copper and pentachlorophenol (PCP) were conducted with two species listed under the United States Endangered Species Act (the endangered fountain darter, Etheostoma fonticola, and the threatened spotfin chub, Cyprinella monacha) and two commonly tested species (fathead minnow, Pimephales promelas, and rainbow trout, Oncorhynchus mykiss). Results were compared using lowest-observed effect concentrations (LOECs) based on statistical hypothesis tests and by point estimates derived by linear interpolation and logistic regression. Sublethal end points, growth (mean individual dry weight) and biomass (total dry weight per replicate) were usually more sensitive than survival. The biomass end point was equally sensitive as growth and had less among-test variation. Effect concentrations based on linear interpolation were less variable than LOECs, which corresponded to effects ranging from 9% to 76% relative to controls and were consistent with thresholds based on logistic regression. Fountain darter was the most sensitive species for both chemicals tested, with effect concentrations for biomass at < or = 11 microg/L (LOEC and 25% inhibition concentration [IC25]) for copper and at 21 microg/L (IC25) for PCP, but spotfin chub was no more sensitive than the commonly tested species. Effect concentrations for fountain darter were lower than current chronic water quality criteria for both copper and PCP. Protectiveness of chronic water-quality criteria for threatened and endangered species could be improved by the use of safety factors or by conducting additional chronic toxicity tests with species and chemicals of concern.

Animals↗
PubMed1983

Analysis of interactions between treatments applied concurrently onto biological systems.

A program, written in BASIC, has been developed to analyse results of experiments studying individual and combined effect of two treatments (physical or chemical) on a biological system. Analysis is done in regard to: (1) level of significance selected for statistical test; (2) number of data available; (3) expected combined effect of treatments resulting from addition which is computed using an original formula; (4) experimental hypothesis tested. Using this program we have determined that there is a highly significant synergism between ampicillin (antibiotic) and amprolium (antiparasitic drug) to reduce the growth of some enteric bacterial strains which have a plasmidic resistance to ampicillin. Other applications are suggested.

Anti-Bacterial Agents↗
PubMed2006

Contribution of intramuscular oxidative metabolism to total ATP production during forearm isometric exercise at varying intensities.

It is not fully clear whether intramuscular oxidative metabolism contributes to total adenosine triphosphate (ATP) production during forearm isometric exercise at varying intensities. We tested hypothesis that oxidative metabolism with intramuscular O2 contributes to lessen the dependence on anaerobic metabolism, in particular phosphocreatine (PCr) breakdown. Seven male subjects were tested for changes in muscle oxygenation (MO2) and high-energy phosphates in forearm flexor muscles at rest and during exercise under arterial occlusion by 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and near infrared spectroscopy (NIRS). Isometric wrist flexion exercise was performed for 1 min or until exhaustion at intensities corresponding to 30%, 50% and 70% of maximal voluntary contraction (MVC) under intramuscular O2 (Intramuscular O2-Ex) and anaerobic (Anaero-Ex) conditions. Oxidative ATP production in Intramuscular O2-Ex was calculated as 0.05 +/- 0.01 mM/s for 30%MVC, 0.08 +/- 0.01 mM/s for 50%MVC and 0.11 +/- 0.01 mM/s for 70%MVC. At a lower intensity (30%MVC), PCr breakdown rate (0.17 +/- 0.02 mM/s) of Anaero-Ex was significantly higher than the rate (0.13 +/- 0.01 mM/s) of Intramuscular O2-Ex (p < 0.05). There was no significant difference in ATP production rates through PCr breakdown and glycolysis between Intramuscular O2-Ex and Anaero-Ex at the higher intensities (50% and 70%MVC). In conclusion, intramuscular oxidative metabolism plays a significant role in reducing the dependence on PCr breakdown during isometric exercise at a lower intensity (30%MVC).

Adenosine Triphosphate↗
PubMed1988

Three tests of the hypothesis that glutamate is the sensory hair cell transmitter in the frog semicircular canal.

Three series of experiments were devised to test the hypothesis that glutamate is the transmitter released by sensory hair cells of the frog semicircular canal. These three tests were: 1 - The Tolerance experiment (i.e. making the preparation tolerant to injected Glu yet still capable of responding to endogenous transmitter). 2 - The Glu Decarboxylase experiment (i.e. bathing the preparation in sufficient enzyme to prevent the effects of exogenous Glu by degrading it without affecting the response to endogenous transmitter) and; 3 - The Diltiazem experiment (i.e. using the calcium channel antagonist, diltiazem, to prevent the effect of exogenous Glu and yet not to interfere with endogenous transmitter release and action). The Tolerance and Diltiazem experiments produced results indicative of a clear dissociation between exogenous Glu and natural transmitter. The Glu decarboxylase experiment results were not so clear, producing both evidence for and against the hypothesis.

Animals↗
PubMedDate not supplied

Neural systems behind word and concept retrieval.

Using both the lesion method and functional imaging (positron emission tomography) in large cohorts of subjects investigated with the same experimental tasks, we tested the following hypotheses: (A) that the retrieval of words which denote concrete entities belonging to distinct conceptual categories depends upon partially segregated regions in higher-order cortices of the left temporal lobe; and (B) that the retrieval of conceptual knowledge pertaining to the same concrete entities also depends on partially segregated regions; however, those regions will be different from those postulated in hypothesis A, and located predominantly in the right hemisphere (the second hypothesis tested only with the lesion method). The analyses provide support for hypothesis A in that several regions outside the classical Broca and Wernicke language areas are involved in name retrieval of concrete entities, and that there is a partial segregation in the temporal lobe with respect to the conceptual category to which the entities belong, and partial support for hypothesis B in that retrieval of conceptual knowledge is partially segregated from name retrieval in the lesion study. Those regions identified here are seen as parts of flexible, multi-component systems serving concept and word retrieval for concrete entities belonging to different conceptual categories. By comparing different approaches the article also addresses a number of method issues that have surfaced in recent studies in this field.

Adult↗
PubMed2002

Thresholding of statistical maps in functional neuroimaging using the false discovery rate.

Finding objective and effective thresholds for voxelwise statistics derived from neuroimaging data has been a long-standing problem. With at least one test performed for every voxel in an image, some correction of the thresholds is needed to control the error rates, but standard procedures for multiple hypothesis testing (e.g., Bonferroni) tend to not be sensitive enough to be useful in this context. This paper introduces to the neuroscience literature statistical procedures for controlling the false discovery rate (FDR). Recent theoretical work in statistics suggests that FDR-controlling procedures will be effective for the analysis of neuroimaging data. These procedures operate simultaneously on all voxelwise test statistics to determine which tests should be considered statistically significant. The innovation of the procedures is that they control the expected proportion of the rejected hypotheses that are falsely rejected. We demonstrate this approach using both simulations and functional magnetic resonance imaging data from two simple experiments.

Adult↗
PubMed1994

Neuropsychological changes in children with cancer: the treatment of missing data in longitudinal studies.

Researchers conducting longitudinal studies with children or adults are inevitably confronted with problems of attrition and missing data. Missing data in longitudinal studies is frequently handled by excluding from analyses those cases for whom data are incomplete. This approach to missing data is not optimal. On the one hand, if data are missing at random, then dropping incomplete cases ignores information collected on those cases that could be used to improve estimates of population parameters (e.g., means, variances, covariances, and growth rates) and improve the power of significance tests of statistical hypotheses. On the other hand, if data are not missing at random, then dropping incomplete cases leads to biased parameter estimates and hypothesis tests that may be internally and externally invalid. This study uses three years of follow-up data from a longitudinal investigation of neuropsychological outcomes of cancer in children to demonstrate the problems presented by missing data in repeated measures designs and some solutions. In evaluating potential biasing effects of attrition, the study extends previous research on neuropsychological outcomes in pediatric cancer by inclusion of patients whose disease had relapsed, and by comparison of surviving and nonsurviving patients. Although the data presented have specific relevance to the study of neuropsychological outcome in pediatric cancer, the problems of missing data and the solutions presented are relevant to a wide variety of diseases and conditions of interest to researchers in child and adult neuropsychology.

Adolescent↗
PubMed1983

Prognostic value of submaximal exercise radionuclide ventriculography after myocardial infarction.

Submaximal exercise testing with radionuclide ventriculography (RVG) was performed in 117 patients before hospital discharge 17 +/- 7 days (+/- standard deviation) after an acute myocardial infarction (MI). The hypothesis tested in these studies was that submaximal exercise testing coupled to RVG allows the identification of patients at risk for future ischemic events in the subsequent 6 months, irrespective of MI location and type. The sites of MI were characterized as anterior transmural in 33, inferior transmural in 39, limited nontransmural in 18, extensive nontransmural in 24 and indeterminant in 3. During 6 months of follow-up, 9 patients died, 14 had recurrent MI, 18 had refractory angina pectoris, 16 had limiting angina and 17 had congestive heart failure. Discriminant function analysis ranked exercise changes in left ventricular (LV) ejection fraction and end-systolic volume the most important of all clinical, exercise and scintigraphic variables for predicting future cardiac events. The predictive accuracy of changes in LV ejection fraction and end-systolic volume were 93 and 91%, respectively, for the entire group, and were significantly more sensitive than any degree of ST-segment depression or elevation (p less than 0.001). These findings were generally independent of MI location and type. Thus, submaximal exercise RVG after MI is an accurate means of identifying patients at risk for major cardiac events in the 6 months after hospital discharge.

Angina Pectoris↗
PubMed2003

Biotic element analysis in biogeography.

Biotic element analysis is an alternative to the areas-of-endemism approach for recognizing the presence or absence of vicariance events in a given region. If an ancestral biota was fragmented by vicariance events, biotic elements or clusters of distribution areas should emerge. We propose a statistical test for clustering of distribution areas based on a Monte Carlo simulation with a null model that considers the spatial autocorrelation in the data. The hypothesis tested is that the observed degree of clustering of ranges can be explained by the range size distribution, the varying number of taxa per cell, and the spatial autocorrelation of the occurrences of a taxon alone. A method for the delimitation of biotic elements which uses model-based Gaussian clustering is introduced. We demonstrate our methods and show the importance of grid size by means of a case study, an analysis of the distribution patterns of southern African species of the weevil genus Scobius. The example highlights the difficulties in delimiting areas of endemism if dispersal has occurred and illustrates the advantages of the biotic element approach.

Animals↗
PubMed2004

Echinacea purpurea for prevention of experimental rhinovirus colds.

A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the ability of Echinacea purpurea to prevent infection with rhinovirus type 39 (RV-39). Forty-eight previously healthy adults received echinacea or placebo, 2.5 mL 3 times per day, for 7 days before and 7 days after intranasal inoculation with RV-39. Symptoms were assessed to evaluate clinical illness. Viral culture and serologic studies were performed to evaluate the presence of rhinovirus infection. A total of 92% of echinacea recipients and 95% of placebo recipients were infected. Colds developed in 58% of echinacea recipients and 82% of placebo recipients (P=.114, by Fisher's exact test). Administration of echinacea before and after exposure to rhinovirus did not decrease the rate of infection; however, because of the small sample size, statistical hypothesis testing had relatively poor power to detect statistically significant differences in the frequency and severity of illness.

Adolescent↗
PubMed1989

Analysis of multiple tumor data from a rodent carcinogenicity experiment.

Rodent tumorigenicity experiments are conducted to determine the safety of substances for human exposure. The carcinogenicity of a substance is generally determined by statistical tests that compare the effects of treatment on the rate of tumor development at several body sites. The statistical analysis of such studies often includes hypothesis testing of the dose effect at each of the sites. However, the multiplicity of the significance tests may cause an excess overall false positive rate. In consideration of this problem, recent interest has focused on developing methods to test simultaneously for the treatment effect at multiple sites. In this paper, we propose a test that is based on the count of tumor-bearing sites. The test is appropriate regardless of tumor lethality or of treatment-related differences in the underlying mortality. Simulations are given which compare the performance of the proposed test to several other tests including a Bonferroni adjustment of site-specific tests, and the test is illustrated using the data from the large ED01 experiment.

Animals↗
PubMed1991

Usefulness of empiric chest radiography and urinalysis testing in adults with acute sickle cell pain crisis.

STUDY OBJECTIVE: To determine the usefulness of obtaining routine chest radiographs and urinalyses on adults presenting to the emergency department in acute sickle cell pain crisis. The hypothesis tested is that in some adult sickle cell patients, sickle cell pain crises are precipitated or accompanied by acute infection that may be clinically occult and that routine screening for pulmonary or urinary tract infection would identify some of these precipitating illnesses. DESIGN: Prospective clinical study. SETTING: A university hospital ED. PATIENTS: All patients more than 14 years old with S-S, S-C, or S-beta-thalassemia sickle hemoglobinopathies who presented to the ED with acute nontraumatic painful complaints during a six-month period. INTERVENTIONS: All patients underwent posteroanterior and lateral chest radiography, routine urinalysis, and CBC count with reticulocyte count. A standard questionnaire for localizing symptoms of systemic, pulmonary, and urinary tract infection was completed for each patient. Urine cultures were ordered on all patients with voiding symptoms, flank pain, and/or more than 5 WBCs or RBCs per high-power field on urinalysis. Physical examination for evidence of pulmonary and urinary tract infection was carefully performed and recorded for subsequent analysis. RESULTS: Seventy-one patients with 134 ED presentations were studied over a six-month period. Eight diagnoses of acute pneumonia were made. Four of these patients complained of chest pain (50% vs 48% overall) and three had shortness of breath (38% vs 21%). None of these patients complained of fever or symptoms of upper respiratory illness. Ten diagnoses of urinary tract infection were made. Four of these patients complained of dysuria and frequency; three complained of flank pain. Eleven of the 18 infections (61.1%) did not have a typical history for or suggestive physical or laboratory findings of bacterial infection. CONCLUSION: In sickle cell disease patients with pain crisis, routine chest radiography and urinalysis may be clinically useful and cost effective in the early diagnosis of crisis-related infection.

Acute Disease↗
PubMed1999

Significance testing of clinical data using virus dynamics models with a Markov chain Monte Carlo method: application to emergence of lamivudine-resistant hepatitis B virus.

Bayesian analysis using a virus dynamics model is demonstrated to facilitate hypothesis testing of patterns in clinical time-series. Our Markov chain Monte Carlo implementation demonstrates that the viraemia time-series observed in two sets of hepatitis B patients on antiviral (lamivudine) therapy, chronic carriers and liver transplant patients, are significantly different, overcoming clinical trial design differences that question the validity of non-parametric tests. We show that lamivudine-resistant mutants grow faster in transplant patients than in chronic carriers, which probably explains the differences in emergence times and failure rates between these two sets of patients. Incorporation of dynamic models into Bayesian parameter analysis is of general applicability in medical statistics.

Antiviral Agents↗