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R Farber

Publications and source records attributed to R Farber.

18 recordsLinked to original sources
PubMed2001

Exploring protein sequence space using knowledge-based potentials.

Knowledge-based potentials can be used to decide whether an amino acid sequence is likely to fold into a prescribed native protein structure. We use this idea to survey the sequence-structure relations in protein space. In particular, we test the following two propositions which were found to be important for efficient evolution: the sequences folding into a particular native fold form extensive neutral networks that percolate through sequence space. The neutral networks of any two native folds approach each other to within a few point mutations. Computer simulations using two very different potential functions, M. Sippl's PROSA pair potential and a neural network based potential, are used to verify these claims.

Amino Acid Sequence↗
PubMed2001

The geometry of shape space: application to influenza.

Shape space was proposed over 20 years ago as a conceptual formalism in which to represent antibody/antigen binding. It has since played a key role in computational immunology. Antigens and antibodies are considered to be points in an abstract "shape space", where coordinates of points in this space represent generalized physico-chemical properties associated with various (unspecified) physical properties related to binding, such as geometric shape, hydrophobicity, charge, etc. Distances in shape space between points representing antibodies and (the shape complement) of antigens are assumed to be related to their affinity, with small distances corresponding to high affinity. In this paper, we provide algorithms, related to metric and ordinal multidimensional scaling algorithms first developed in the mathematical psychology literature, which construct explicit, quantitative coordinates for points in shape space given experimental data such as hemagglutination inhibition assays, or other general affinity assays. Previously, such coordinates had been conceptual constructs and totally implicit. The dimension of shape space deduced from hemagglutination inhibition assays for influenza is low, approximately five dimensional. The deduction of the explicit geometry of shape space given experimental affinity data provides new ways to quantify the similarity of antibodies to antibodies, antigens to antigens, and the affinity of antigens to antibodies. This has potential utility in, e.g. strain selection decisions for annual influenza vaccines, among other applications. The analysis techniques presented here are not restricted to the analysis of antibody-antigen interactions and are generally applicable to affinity data resulting from binding assays.

Algorithms↗
PubMed2001

Potential particulate impacts at the Grand Canyon from northwestern Mexico.

Project MOHAVE was a major air quality and visibility research program conducted from 1990 to 1999 to investigate the causes of visibility impairment in the Grand Canyon National Park region. At Meadview, a remote monitoring site just west of the Grand Canyon National Park, on September 1 and 2, 1992, the concentrations of sulfate (3.1 and 4.3 microg sulfate/m3) were the highest seen in 6 years of monitoring at this site. During this period, the concentrations of SO2 at Meadview were also abnormally high and approximately three times the sulfate concentrations, on a nmol/m3 basis. High concentrations of sulfate and SO2 extended south into southern Arizona and northwestern Mexico. Based on ambient atmospheric conditions, emissions from the Mohave Power Project (MPP) 110 km upwind of Meadview could not have been responsible for the majority of the regionally observed sulfur oxides. The geographical distribution of SO2 and sulfate, and available source information suggest that northwestern Mexico was a significant source of the unusually high observed sulfur oxides. A CMB model developed during Project MOHAVE was used to apportion sulfur oxides at Meadview and other sampling sites throughout the study region for August 31-September 2, 1992. The results indicate that the contribution of MPP to sulfate at Meadview was typical. However, the transport of SOx from northwestern Mexico was elevated throughout much of the region during this time period. This led to the large increase in sulfate concentrations at Meadview on September 1 and 2. These results indicate that emissions from Mexico can be a significant source of particulate material in the Grand Canyon.

Air Movements↗
PubMed2000

Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3.

The release of mitochondrial cytochrome c by genotoxic stress induces the formation of a cytosolic complex with Apaf-1 (mammalian CED4 homolog) and thereby the activation of procaspase-3 (cas-3) and procaspase-9 (cas-9). Here we demonstrate that heat-shock protein 27 (Hsp27) inhibits cytochrome c (cyt c)-dependent activation of cas-3. Hsp27 had no effect on cyt c release, Apaf-1 and cas-9 activation. By contrast, our results show that Hsp27 associates with cas-3, but not Apaf-1 or cas-9, and inhibits activation of cas-3 by cas-9-mediated proteolysis. Furthermore, the present results demonstrate that immunodepletion of Hsp27 depletes cas-3. Importantly, treatment of cells with DNA damaging agents dissociates the Hsp27/cas-3 complex and relieves inhibition of cas-3 activation. These findings define a novel function for Hsp27 and provide the first evidence that a heat shock protein represses cas-3 activation.

Actins↗
PubMed1999

Inflammatory reactions associated with a calcium sulfate bone substitute.

OBJECTIVES: Loss of bone substance is a major source of disability that often requires grafting. Recently developed synthetic bone grafts have generated a lot of enthusiasm due to the lack of immunological reactions and infectious disease transmission risk. The current work describes some peculiar complications related to the use of calcium sulfate granules. METHODS: 15 implantations of calcium sulfate pellets Osteoset (Wright Medical Technology) were performed following resection of bone tumors at our service during 1999. Clinical or computerized tomography scans were available in all patients. RESULTS: 3 cases were encountered in which a severe inflammatory reaction developed. In one case serous drainage and an allergic reaction obligated graft removal. In another case, inflammation resolved two months following implantation. In the last case, wound breakdown occurred. CONCLUSIONS: A sterile inflammatory response has previously hindered the use of absorbable poly-lactic and poly-glycolic acid rods. Apparently due to rapid graft resorption, the resulting calcium-rich fluid incites inflammation. The single case of an allergic reaction is interesting. An allergy to plaster of Paris is rare and related to minor additives. These were not present in the bone substitute used. Inflammatory complications should be considered when assessing the risk-benefit ratio of using different types of bone replacement materials, and comparing allogeneic grafts to synthetic ones.

Adult↗
PubMed1995

Neural net representations of empirical protein potentials.

Recently, there has been considerable interest in deriving and applying knowledge-based, empirical potential functions for proteins. These empirical potentials have been derived from the statistics of interacting, spatially neighboring residues, as may be obtained from databases of known protein crystal structures. In this paper we employ neural networks to redefine empirical potential functions from the point of view of discrimination functions. This approach generalizes previous work, in which simple frequency counting statistics are used on a database of known protein structures. This generalization allows us to avoid restriction to strictly pairwise interactions. Instead of frequency counting to fix adjustable parameters, one now optimizes an objective function involving a neural network parameterized probability distribution. We show how our method reduces to previous work in special situations, but also allows extensions to include orders of interaction beyond pairwise interaction. Given the close packing of proteins, steric interactions etc., the inclusion of higher order interactions is critical for developing an accurate potential. A key feature in the approach we advocate is the development of a representation to describe the spatial location of interacting residues that exist in a sphere of small fixed radius around each residue. This is a "shape representation" problem that has a natural solution for the interaction neighborhoods of protein residues. We demonstrate in a series of numerical experiments that the neural network approach improves discrimination over that obtained by previous methodologies limited to pair-wise interactions.

Amino Acid Sequence↗
PubMed1994

Experimental ureteral obstruction in the fetal opossum: histologic assessment.

In the North American opossum, Didelphis virginiana unilateral complete ureteral obstruction (ECO) and partial unilateral (EPO) ureteral obstruction were created during the early metanephric stage of kidney development in pups attached to the teat (approximately 4.5 cm. long, 20 days old). At 70 days of pouch life (full-term equivalent in the human) some completely obstructed ureters were unobstructed with reanastomosis in the bladder (RECO). Other pups underwent unilateral complete ureteral ligation at this full-term equivalent (70 days of pouch life) and constituted the late obstruction (LCO) group. Unoperated animals constituted the control (C) group. All animals were harvested when full grown (.7 to 2.2 kg.), and paraffin sections of the kidneys were stained with hematoxylin and eosin and Masson's Trichrome. In each a semiquantitative assessment of 24 histologic features was made and a digital score assigned. All experimental groups except EPO demonstrated significant epithelial and mesenchymal alterations. The changes can be broadly categorized as those secondary to obstruction of urine flow (dilation and cystic changes), those affecting epithelial differentiation in both cortex and medulla and those affecting mesenchymal differentiation. The EPO group demonstrated significantly fewer glomerular generations than did control kidneys. For all other characteristics studied, the EPO group did not differ from control. The ECO group demonstrated significant changes when compared with control for most parameters studied. Medullary dysplasia was more prominent in kidneys obstructed early. Reanastomosis (RECO) at a full-term equivalent did ameliorate the changes of medullary dysplasia and cortical atrophy. More collecting duct hyperplasia, cortical and medullary aplasia were present in the LCO group compared with the ECO. The LCO group also had less primitive duct formation and less medullary dysplasia than the ECO group. Renal blastema, previously unreported in experimental obstruction, was present in 41% of experimental kidneys.

Animals↗
PubMed1993

Role of transcranial Doppler in neuroradiological treatment of intracranial vasospasm.

BACKGROUND AND PURPOSE: The expanded role of interventional neuroradiological treatment for post-subarachnoid hemorrhage vasospasm has highlighted the diagnostic utility of transcranial Doppler studies in this condition. The role of transcranial Doppler in follow-up and determining the need for repeat intervention has not been previously emphasized. SUMMARY OF REPORT: Intracranial angioplasty for clinically evident vasospasm after subarachnoid hemorrhage was performed in four patients. In two patients, transcranial Doppler flow velocities remained elevated despite initial anatomic correction of the vasospasm. Reangiography revealed new areas of involvement by vasospasm. Reangioplasty or papaverine infusion treatment of the new lesions resulted in decreased flow velocities and clinical improvement in all patients. CONCLUSIONS: Transcranial Doppler has a more significant role than has been previously emphasized in the management of patients undergoing interventional neuroradiological treatment for intracranial vasospasm. Specifically, the persistence of elevated transcranial Doppler flow velocities after intracranial angioplasty suggests the need for repeat angiographic evaluation and possibly further therapy.

Aged↗
PubMed1992

Determination of eukaryotic protein coding regions using neural networks and information theory.

Our previous work applied neural network techniques to the problem of discriminating open reading frame (ORF) sequences taken from introns versus exons. The method counted the codon frequencies in an ORF of a specified length, and then used this codon frequency representation of DNA fragments to train a neural net (essentially a Perceptron with a sigmoidal, or "soft step function", output) to perform this discrimination. After training, the network was then applied to a disjoint "predict" set of data to assess accuracy. The resulting accuracy in our previous work was 98.4%, exceeding accuracies reported in the literature at that time for other algorithms. Here, we report even higher accuracies stemming from calculations of mutual information (a correlation measure) of spatially separated codons in exons, and in introns. Significant mutual information exists in exons, but not in introns, between adjacent codons. This suggests that dicodon frequencies of adjacent codons are important for intron/exon discrimination. We report that accuracies obtained using a neural net trained on the frequency of dicodons is significantly higher at smaller fragment lengths than even our original results using codon frequencies, which were already higher than simple statistical methods that also used codon frequencies. We also report accuracies obtained from including codon and dicodon statistics in all six reading frames, i.e. the three frames on the original and complement strand. Inclusion of six-frame statistics increases the accuracy still further. We also compare these neural net results to a Bayesian statistical prediction method that assumes independent codon frequencies in each position. The performance of the Bayesian scheme is poorer than any of the neural based schemes, however many methods reported in the literature either explicitly, or implicitly, use this method. Specifically, Bayesian prediction schemes based on codon frequencies achieve 90.9% accuracy on 90 codon ORFs, while our best neural net scheme reaches 99.4% accuracy on 60 codon ORFs. "Accuracy" is defined as the average of the exon and intron sensitivities. Achievement of sufficiently high accuracies on short fragment lengths can be useful in providing a computational means of finding coding regions in unannotated DNA sequences such as those arising from the mega-base sequencing efforts of the Human Genome Project. We caution that the high accuracies reported here do not represent a complete solution to the problem of identifying exons in "raw" base sequences. The accuracies are considerably lower from exons of small length, although still higher than accuracies reported in the literature for other methods. Short exon lengths are not uncommon.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗
PubMed1991

Correlation of phenotypic and genetic heterogeneity in cystic fibrosis: variability in sweat electrolyte levels contributes to heterogeneity and is increased with the XV-2c/KM19 B haplotype.

We have reinvestigated a classification of clinical heterogeneity among cystic fibrosis (CF) patients that we previously reported and investigated the possible relationship of the identified CF subgroups to haplotypes around the CF gene and to HLA-DR haplotypes. Age-corrected values for sweat electrolytes, rate of progression of lung disease as assessed by Brasfield chest x-ray scores, and severity of pancreatic insufficiency as assessed by daily supplemented enzyme dosage were obtained for 55, 59, and 59 patients, respectively. XV-2c and KM19 RFLPs were determined by hybridization to TaqI and PstI digests of human genomic DNA, respectively, and analysis of mutations by PCR amplification followed by allele-specific oligo-deoxynucleotide hybridization was performed for 29 patients. HLA-DR restriction fragment length polymorphisms (RFLPs) were determined by hybridization of cDNA beta 1 and genomic DQ alpha probes to TaqI digests of human genomic DNA. The results show that the previous subdivision on the basis of age-corrected levels of sweat electrolytes, as well as measures of severity of lung disease and pancreatic disease, is valid. In addition, the C and D haplotypes are associated with lower age-corrected sweat sodium level. No significant relationship between CF haplotypes and the other two disease variables or between HLA-DR haplotypes and any of the clinical variables was found.

Child↗
PubMed1990

Experimental ureteral obstruction in the fetal opossum. I. Renal functional assessment.

The North American opossum Didelphis virginiana was used as a model for fetal urinary obstruction. In this animal the fetus develops on a teat in a pouch and, therefore, it is accessible to surgical intervention. Unilateral ureteral obstruction was created at a mid trimester developmental equivalent in 8 pups, late ureteral obstruction was created in a similar fashion in 6 pups at a full-term equivalent and unobstruction of 9 pups was accomplished with a ureteroneocystostomy at a full-term equivalent. After early intervention 6 pups were found to have only partial ureteral obstruction as measured by mild dilatation and probe patency of the ureter. The control group consisted of 11 unoperated animals. The animals were maintained until adulthood when they were harvested after obtaining creatinine clearances from both kidneys. All dilated urinary systems were cultured for bacteria and they were sterile.

Animals↗
PubMed1990

Frequency of the delta Phe508 mutation and correlation with XV.2c/KM-19 haplotypes in an American population of cystic fibrosis patients: results of a collaborative study.

The cystic fibrosis (CF) gene has been recently cloned, and a deletion of 3 basepairs (bp) of DNA was found on most of the CF chromosomes. This deletion leads to the synthesis of a protein that lacks a phenylalanine residue at position 508. Using two polymerase chain reaction protocols to study the frequency of this mutation in a series of 192 CF patients, we found the mutation on 72% of affected chromosomes. We then used this value to calculate the predictive value of a negative test result in a population-based screening program for CF carrier status. Haplotype analysis with the polymorphic markers XV.2c and KM-19 on 239 CF chromosomes revealed that 90.7% of CF chromosomes with the deletion had a single haplotype. This haplotype was also associated with 60.4% of CF chromosomes with unknown mutations. These values can be used to calculate the probability of whether an individual from the general population is a carrier of any CF mutation.

Base Sequence↗
PubMed1985

Prediction of carotid disease by ultrasound and digital subtraction angiography.

Ultrasound (US) technology (B-mode real-time imaging and Doppler signal analysis) and digital subtraction angiography (DSAV) were prospectively compared in 90 consecutive patients. Twenty-four endarterectomy specimens became available. The DSAV was uninterpretable in 9.4% of vessels and US, in 8.3%. Estimation of degree of stenosis by both modalities agreed well with endarterectomy specimens. Neither predicted the presence or absence of ulceration accurately. Not considering occlusions (where DSAV is probably more accurate), no clear superiority as a screening test compared against a common standard was demonstrated for either. In all 148 vessels with adequate studies by both, the technologies agreed in categorizing stenosis (less than or equal to 50% v greater than 50% diameter stenosis) in 89%. Correlation was poor for occlusions and ulceration. If DSAV were definitive, US would be an effective screen for surgically relevant stenosis with a negative predictive value of 95%.

Aged↗
PubMed1984

B-mode real-time ultrasonic carotid imaging: impact on decision-making and prediction of surgical findings.

The roles of B-mode real-time ultrasonic imaging (USI) and carotid angiography (CAG) in deciding on endarterectomy were analyzed. When greater than 50% stenosis and/or complicated ulceration were predicted by both techniques, endarterectomy was undertaken in 21/25; by only CAG in 5/8; and by only USI in 10/21. In vessels with adequate surgical data, stenosis was accurately predicted by CAG in 27/32, USI in 20/32, and ulceration by both CAG and USI in 21/29. USI results were sometimes used to justify endarterectomy despite unimpressive CAG. CAG is a better predictor of stenosis, whereas both are limited in predicting ulceration.

Arterial Occlusive Diseases↗
PubMed1984

Glycosylated hemoglobin (HbA1) and hemoglobinopathies in pregnancy.

Glycosylated hemoglobin (HbA1) is considered to be representative of prior blood-glucose levels and is being used in pregnant and nonpregnant diabetic patients as a possible index of both long and short-term glucose-control. Factors other than blood-glucose concentration have been reported to affect its value. Variant hemoglobin is one of them. HbA1 and blood-glucose levels were measured in pregnant patients at high risk for diabetes for screening for abnormal carbohydrate metabolism. HbA1 was measured by cation exchange column chromatography and glucose was measured by hexokinase reaction. The mean HbA1 in patients with normal blood sugars was 6.17 +/- 0.6 percent. A value of HbA1 of less than 5 percent as measured by cation exchange column chromatography was highly predictive (P less than 0.001) of hemoglobinopathies (S or C). The mean HbA1 of randomly selected matched patients with "normal" Hb was 5.94 +/- 0.72 percent. In patients with thalassemia, HbA1 values as measured by cation exchange column chromatography were elevated despite normal carbohydrate tolerance. While interpreting the results of HbA1 in the management of pregnant diabetics, the above fact should be kept in mind.

Blood Glucose↗
PubMed1984

Use of glycosylated hemoglobin as a screen for macrosomia in gestational diabetes.

Glycosylated hemoglobin and blood sugar levels in the fasting state and two hours after oral 100 g glucose load were measured in 180 patients. Glycosylated hemoglobin was measured by cation exchange column chromatography, and blood sugar was measured by hexokinase reaction. Patients with an elevated postprandial and/or fasting blood sugar level (positive screen) subsequently underwent three-hour glucose tolerance test. The mean value of glycosylated hemoglobin in patients with a negative screen and normal hemoglobin was 6.17 +/- 0.61%; and the value for glycosylated hemoglobin in patients with class A diabetes and normal hemoglobin electrophoresis was 6.85 +/- 0.73% (P less than .001). A glycosylated hemoglobin value greater than 6.78 (mean + 1 SD) was considered elevated. Glycosylated hemoglobin values were elevated in 21 of 33 patients with gestational diabetes and in 27 of 147 patients with normal blood sugar levels. The sensitivity and specificity of glycosylated hemoglobin for the diagnosis of gestational diabetes were 63.6 and 81.6%, respectively. Fifty percent of patients with an initially elevated glycosylated hemoglobin value delivered macrosomic infants, whereas no patient with a normal glycosylated hemoglobin value had a macrosomic infant. An elevated glycosylated hemoglobin value may alert the obstetrician of a potentially elevated mean blood sugar level and may warrant aggressive management of gestational diabetes.

Birth Weight↗
PubMed1983

B-mode, real-time carotid ultrasonic imaging. Correlation with angiography.

B-mode, real-time ultrasonic imaging was prospectively evaluated as a screening test for atherosclerotic occlusive vascular disease in the carotid bifurcation region, as defined by carotid angiography in 100 carotid systems in 50 patients. Preliminary reliability studies for each technique assessed agreement between examiners. Sensitivities of ultrasonography for stenosis greater than 50% of luminal diameter, complicated plaque ulceration, complete occlusion, and "surgical disease" by any of these parameters were 79%, 26%, 25%, and 73%, respectively. Thirty-seven percent of the 100 carotid systems were found to contain surgically relevant disease by angiography, compared with 19% and 56%, respectively, of the carotid systems with negative and positive ultrasonographic results. Judicious use of ultrasonography as a screen for angiography requires awareness of these limitations.

Aged↗