RESUMEN
Mixed models have been used extensively in quantitative genetics to study continuous and discrete traits. A standard quantitative genetic model proposes that the effects of levels of some random factor (e.g., sire) are correlated accordingly with their relationships. For this reason, routines for mixed models available in standard packages cannot be used for genetic analysis. The pedigreemm package of R was developed as an extension of the lme4 package, and allows mixed models with correlated random effects to be fitted for Gaussian, binary, and count responses. Following the method of Harville and Callanan (1989), a correlation between levels of the grouping factor (e.g., sire) is induced by post-multiplying the incidence matrix of the levels of this random factor by the Cholesky factor of the corresponding (co)variance matrix (e.g., the numerator relationship matrix between sires). Estimation methods available in pedigreemm include approximations to maximum likelihood and REML. This note describes the classes of models that can be fitted using pedigreemm and presents examples that illustrate its use.
Asunto(s)
Crianza de Animales Domésticos/métodos , Animales Domésticos/genética , Cruzamiento/métodos , Modelos Genéticos , Animales , Bovinos , Femenino , Hibridación Genética/genética , Endogamia , Lactancia/genética , Masculino , Fenotipo , Distribución de PoissonRESUMEN
Typically, clinical mastitis is coded as the presence or absence of disease in a given lactation, and records are analyzed with either linear models or binary threshold models. Because the presence of mastitis may include cows with multiple episodes, there is a loss of information when counts are treated as binary responses. Poisson models are appropriated for random variables measured as the number of events, and although these models are used extensively in studying the epidemiology of mastitis, they have rarely been used for studying the genetic aspects of mastitis. Ordinal threshold models are pertinent for ordered categorical responses; although one can hypothesize that the number of clinical mastitis episodes per animal reflects a continuous underlying increase in mastitis susceptibility, these models have rarely been used in genetic analysis of mastitis. The objective of this study was to compare probit, Poisson, and ordinal threshold models for the genetic evaluation of US Holstein sires for clinical mastitis. Mastitis was measured as a binary trait or as the number of mastitis cases. Data from 44,908 first-parity cows recorded in on-farm herd management software were gathered, edited, and processed for the present study. The cows were daughters of 1,861 sires, distributed over 94 herds. Predictive ability was assessed via a 5-fold cross-validation using 2 loss functions: mean squared error of prediction (MSEP) as the end point and a cost difference function. The heritability estimates were 0.061 for mastitis measured as a binary trait in the probit model and 0.085 and 0.132 for the number of mastitis cases in the ordinal threshold and Poisson models, respectively; because of scale differences, only the probit and ordinal threshold models are directly comparable. Among healthy animals, MSEP was smallest for the probit model, and the cost function was smallest for the ordinal threshold model. Among diseased animals, MSEP and the cost function were smallest for the Poisson model, followed by the ordinal threshold model. In general, the models for count variables more accurately identified diseased animals and more accurately predicted mastitis costs. Healthy animals were more accurately identified by the probit model.
Asunto(s)
Predisposición Genética a la Enfermedad , Mastitis Bovina/genética , Modelos Estadísticos , Animales , Cruzamiento , Bovinos , Femenino , Masculino , Distribución de Poisson , Programas InformáticosRESUMEN
To understand the role of the [4Fe-4S](2+) cluster in controlling the activity of the Escherichia coli transcription factor FNR (fumarate nitrate reduction) during changes in O(2) availability, we have characterized a mutant FNR protein containing a substitution of Leu-28 with His (FNR-L28H) which, unlike its wild type (WT) counterpart, is functional under aerobic growth conditions. The His-28 substitution appears to stabilize the [4Fe-4S](2+) cluster of FNR-L28H in the presence of O(2) because air-exposed FNR-L28H did not undergo the rapid [4Fe-4S](2+) to [2Fe-2S](2+) cluster conversion or concomitant loss in site-specific DNA binding and dimerization, which are characteristic of WT-FNR under these conditions. This increased cluster stability was not a result of His-28 replacing the WT-FNR cluster ligands because substitution of any of these four Cys residues (cysteine 20, 23, 29, or 122) with Ser resulted in [4Fe-4S](2+) cluster-deficient preparations of FNR-L28H. The Mössbauer spectra of FNR-L28H indicated that the coordination environment of the [4Fe-4S](2+) cluster did not differ from that of WT-FNR. Whole cell Mössbauer spectroscopy showed that aerobically grown cells overexpressing FNR-L28H had levels of the FNR species containing the [4Fe-4S](2+) cluster similar to those of cells grown under anaerobic conditions. Thus, the increase in cluster stability is sufficient to allow accumulation of the [4Fe-4S](2+) cluster form of FNR-L28H under aerobic conditions and provides a reasonable explanation for why this mutant protein is functional under aerobic growth conditions. From these results, we present a model to explain how WT-FNR is normally inactivated under aerobic growth conditions.
Asunto(s)
Proteínas Bacterianas/genética , Proteínas de Escherichia coli , Escherichia coli/metabolismo , Proteínas Hierro-Azufre/genética , Oxígeno/farmacología , Aerobiosis , Anaerobiosis , Proteínas Bacterianas/química , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Dimerización , Proteínas Hierro-Azufre/química , Mutación , Espectrofotometría , Espectroscopía de Mossbauer , Sulfuros/análisis , Factores de Transcripción/química , Factores de Transcripción/genéticaRESUMEN
The global regulator FNR (for fumarate nitrate reduction) controls the transcription of >100 genes whose products facilitate adaptation of Escherichia coli to growth under O2-limiting conditions. Previous Mössbauer studies have shown that anaerobically purified FNR contains a [4Fe-4S]2+ cluster that, on exposure to oxygen, is converted into a [2Fe-2S]2+ cluster, a process that decreases DNA binding by FNR. Using 57Fe Mössbauer spectroscopy of E. coli cells containing overexpressed FNR, we show here that the same cluster conversion also occurs in vivo on exposure to O2. Furthermore, the data show that a significant amount of the [4Fe-4S]2+ cluster is regenerated when the cells are shifted back to an anaerobic environment. The present study also demonstrates that 57Fe Mössbauer spectroscopy can be employed to study the in vivo behavior of (overexpressed) proteins. The use of this technique to study other iron-containing cell components is discussed.
Asunto(s)
Proteínas Bacterianas/metabolismo , Proteínas de Escherichia coli , Escherichia coli/metabolismo , Proteínas Hierro-Azufre/metabolismo , Factores de Transcripción/metabolismo , Proteínas Bacterianas/química , Escherichia coli/química , Proteínas Hierro-Azufre/química , Espectroscopía de Mossbauer , Transcripción Genética , Activación TranscripcionalRESUMEN
BACKGROUND: The histologic diagnosis of atypical ductal hyperplasia (ADH) has been reported as having a high rate of malignancy, either ductal carcinoma in situ (DCIS) or invasive ductal carcinoma (IDC). We reviewed our surgical group's experience with stereotactic core-needle biopsies (SCNB), specifically looking at the follow-up of ADH. METHODS: From November 1994 through July 1997 our group performed 539 SCNB. Twenty-one patients (4%) were diagnosed as ADH. Eighteen patients had subsequent wire-localized excisional biopsies. Three patients were followed up mammographically. One patient refused follow-up. RESULTS: Of the 18 patients who underwent excisional biopsies, 2 patients were found to have DCIS and 1 patient had lobular carcinoma in-situ. There were no cases of IDC. CONCLUSION: Our results show a much lower incidence of malignancy in cases of ADH found on SCNB than has been previously reported. While the standard of care is still to follow up ADH found on SCNB with excisional biopsy, more data may justify following up certain subsets of patients.
Asunto(s)
Biopsia con Aguja/métodos , Mama/patología , Biopsia con Aguja/instrumentación , Biopsia con Aguja/estadística & datos numéricos , Enfermedades de la Mama/patología , Neoplasias de la Mama/patología , Calcinosis/patología , Carcinoma Ductal de Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Hiperplasia/patología , Sensibilidad y Especificidad , Técnicas Estereotáxicas/instrumentación , Técnicas Estereotáxicas/estadística & datos numéricosRESUMEN
In order to gain insight into the mechanism by which the Escherichia coli transcription factor FNR* is activated in response to anaerobiosis, we have analyzed FNR mutant proteins which, unlike the wild-type protein, stimulate gene expression in the presence of oxygen in vivo. Cell extracts containing seven different FNR* mutant proteins were tested in vitro for the ability to bind to the FNR consensus DNA site in a gel retardation assay under aerobic conditions. At the concentration of protein tested, only extracts which contained FNR* mutant proteins with amino acid substitutions at position 154 showed significant DNA binding. The three position-154 FNR* mutant proteins could be further distinguished from the other mutant proteins by analysis of the in vivo phenotypes of FNR* proteins containing amino acid substitutions at either of two essential cysteine residues. In the presence of oxygen, FNR* mutant proteins with amino acid substitutions at position 154 were the least affected when either Cys-23 or Cys-122 was substituted for Ser. On the basis of these in vivo and in vitro analyses, FNR* mutant proteins appear to segregate into at least two classes. Thus, it appears that each class of FNR* substitutions alters the normal pathway of FNR activation in response to oxygen deprivation by a different mechanism.
Asunto(s)
Proteínas Bacterianas/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Escherichia coli , Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Proteínas Hierro-Azufre , Oxígeno/farmacología , Aerobiosis , Secuencia de Aminoácidos , Anaerobiosis , Proteínas Bacterianas/genética , Cisteína/genética , Proteínas de Unión al ADN/genética , Escherichia coli/efectos de los fármacos , Operón Lac/genética , Modelos Genéticos , Datos de Secuencia Molecular , Mutación , Regiones Promotoras Genéticas/genética , Unión Proteica , Serina/genética , Relación Estructura-ActividadRESUMEN
BACKGROUND: Treatment of esophageal cancer has been primarily palliative. Recent studies have shown that preoperative combination chemo- and radiation therapy increases the effectiveness of surgical excision. PATIENTS AND METHODS: Beginning in 1990, 29 patients in the Spokane area were treated with preoperative chemo- and radiation therapy. They were 23 men and 6 women whose mean age was 66 years. Twenty-five had adenocarcinoma, of whom 3 had Barrett's esophagitis. Four had squamous cell carcinoma. The chemotherapy included fluorouracil, cisplatin, and vinblastine. Radiation was given concomitantly, BID for 21 days. Surgical excision was performed about 3 weeks after the last radiation session, pending recovery from cytopenia. RESULTS: There was 1 operative death, for an operative mortality of 3.4%. Twenty-three patients (79%) were found to have no residual cancer at the time of resection. Of this group, 8 died of metastatic cancer at a mean of 15 months postoperatively (range 1 to 28), and 15 were alive at a mean of 28 months (range 12 to 46). Six patients (21%) had residual cancer in the resected specimen, either at the primary site or--more often--in adjacent lymph nodes. Five have died at 6, 8, 9, 24, and 28 months postoperatively; 1 remains alive at 14 months. The mean survival among these 6 patients is 15 months. CONCLUSIONS: Combined chemo- and radiation therapy prior to esophagectomy appeared to improve outcome in this small series of patients with esophageal cancer. Local control was excellent, but distant metastasis continues to be a significant problem.
Asunto(s)
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Esofagectomía , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adulto , Anciano , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/secundario , Terapia Combinada , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Lomustina/administración & dosificación , Metástasis Linfática , Masculino , Persona de Mediana Edad , Neoplasia Residual/epidemiología , Complicaciones Posoperatorias/epidemiología , Cuidados Preoperatorios , Dosis de Radiación , Tasa de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
The transcription factor FNR globally regulates gene expression in response to oxygen deprivation in Escherichia coli. To understand how oxygen deprivation activates FNR, a constitutively active FNR* mutant protein, DA154, was studied to determine how this mutant bypassed the normal regulation pathway. When purified from aerobically grown cells, the DA154 protein had a larger apparent native molecular mass and an increased affinity for a consensus FNR target site as compared with wild-type FNR prepared under identical conditions. These results suggested that FNR* DA154 may bypass the normal regulation pathway by converting FNR from an inactive monomer to an active dimer under aerobic conditions. To determine whether wild-type FNR is active as a dimer under anaerobic conditions, FNR mutants were isolated that inhibit the activity of wild-type FNR by forming mixed dimers (i.e., dominant-negative mutants). These dominant-negative FNR mutants were shown to have substitutions in the putative DNA-binding domain and to be defective in binding to a consensus FNR DNA target site in vitro. One representative dominant-negative mutant, EK209, was also shown to be unable to form mixed oligomers in vivo under aerobic conditions, suggesting that FNR may be monomeric in the inactive state. Taken together, these data have led us to propose that under anaerobic conditions FNR is a dimer that is active for DNA binding, and under aerobic conditions, FNR is inactivated by conversion to a monomer.
Asunto(s)
Proteínas Bacterianas/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Escherichia coli , Escherichia coli/genética , Regulación Bacteriana de la Expresión Génica , Proteínas Hierro-Azufre , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Anaerobiosis , Proteínas Bacterianas/biosíntesis , Secuencia de Bases , Cisteína/genética , Análisis Mutacional de ADN , ADN Bacteriano/metabolismo , Proteínas de Unión al ADN/biosíntesis , Genes Dominantes , Genes Reporteros , Modelos Genéticos , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Fenotipo , Conformación Proteica , Proteínas Recombinantes/biosíntesis , Análisis de Secuencia de ADN , Factores de Transcripción/biosíntesisRESUMEN
The multiphasic logistic function has recently been proposed as a model for lactation curves in dairy cattle. The applicability of several forms of this function was examined under three levels of recombinant bST administration beginning 100 d postpartum. Lactation curve models were fit to mean daily yields for each of the treatment groups and a control group. The traditional diphasic function was unable to model adequately the steep ascent and early peak in daily milk yield occurring immediately after calving in both treatment and control groups. The early portion of the lactation was more appropriately modeled using a diphasic function with a power transformation of time in the first phase, such that this phase became asymmetric. This modified diphasic function also resulted in smaller residuals and less autocorrelation than the triphasic function, which was used as a reference model, when both models were applied to the control group data. The increase in daily milk yield because of bST administration was modeled by the addition of a term consisting of a rising exponential function. Such a model may be useful for examining dosage effects in long-term bST studies in which injections begin in midlactation or later. Time series procedures reduced autocorrelation among residuals in both the control and treatment groups, and such models could be useful for removing autocorrelation in lactation curve applications that involve daily or weekly yield observations.
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Bovinos/fisiología , Hormona del Crecimiento/farmacología , Lactancia/efectos de los fármacos , Modelos Biológicos , Animales , Femenino , Lactancia/fisiología , Modelos Logísticos , Leche/metabolismoRESUMEN
We propose a general, nonlinear mixed effects model for repeated measures data and define estimators for its parameters. The proposed estimators are a natural combination of least squares estimators for nonlinear fixed effects models and maximum likelihood (or restricted maximum likelihood) estimators for linear mixed effects models. We implement Newton-Raphson estimation using previously developed computational methods for nonlinear fixed effects models and for linear mixed effects models. Two examples are presented and the connections between this work and recent work on generalized linear mixed effects models are discussed.
Asunto(s)
Biometría , Modelos Estadísticos , Algoritmos , Análisis de Varianza , Funciones de VerosimilitudRESUMEN
The growing proportion of older Americans and the projections in declining edentulousness in future cohorts of elderly necessitate elucidation of the responses of the aging human dentition to existing restorative techniques. This study investigated the results of the acid etch process as a function of age of specimen donors as well as a function of race, tooth type, and time between extraction and etch. Statistical analysis of data showed no significant effect on solubility by age, race, or length of time from extraction until etch. Molars were significantly less soluble than other teeth. The most frequently observed microscopic texture was an irregular, granular configuration termed 3g. Widely textural variation was observed in each specimen. A possible explanation for the observations is the distribution of prismless enamel. The widespread belief that older teeth are less efficaciously etched may be based on the greater frequency of composite restoration failures in the elderly, which in turn is more likely a factor of restoration size and changes in intraoral environment than of age.
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Grabado Ácido Dental , Envejecimiento , Recubrimiento Dental Adhesivo , Solubilidad del Esmalte Dental/efectos de los fármacos , Ácidos Fosfóricos/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Calcio/análisis , Esmalte Dental/análisis , Esmalte Dental/ultraestructura , Humanos , Microscopía Electrónica de Rastreo , Persona de Mediana Edad , Factores de Tiempo , DienteRESUMEN
A retrospective chart review of 507 patients who underwent cholecystectomies over an 18 month period was performed. There were 345 female patients and 162 male patients. Of the female patients, 90 (26 percent) presented with complicated disease, which was severe in 38 (11 percent). The mortality rate was 0.87 percent in the total group of female patients (3 deaths), or 7.9 percent in the 38 patients with severe disease. In the male patients, on the other hand, 96 (59 percent) presented with complicated disease, which was severe in 57 (35 percent). There were 6 deaths, for a mortality rate of 3.7 percent in the total group of male patients, or 10.5 percent in the 57 patients with severe disease. This study supports our observation that biliary tract disease is more life-threatening in men. It appears that elective cholecystectomy should be considered in the male patient who presents with asymptomatic cholelithiasis.