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D Fischer

Publications and source records attributed to D Fischer.

At least 91 records · Page 5Linked to original sources
PubMed2000

MaxSub: an automated measure for the assessment of protein structure prediction quality.

MOTIVATION: Evaluating the accuracy of predicted models is critical for assessing structure prediction methods. Because this problem is not trivial, a large number of different assessment measures have been proposed by various authors, and it has already become an active subfield of research (Moult et al. (1997,1999) and CAFASP (Fischer et al. 1999) prediction experiments have demonstrated that it has been difficult to choose one single, 'best' method to be used in the evaluation. Consequently, the CASP3 evaluation was carried out using an extensive set of especially developed numerical measures, coupled with human-expert intervention. As part of our efforts towards a higher level of automation in the structure prediction field, here we investigate the suitability of a fully automated, simple, objective, quantitative and reproducible method that can be used in the automatic assessment of models in the upcoming CAFASP2 experiment. Such a method should (a) produce one single number that measures the quality of a predicted model and (b) perform similarly to human-expert evaluations. RESULTS: MaxSub is a new and independently developed method that further builds and extends some of the evaluation methods introduced at CASP3. MaxSub aims at identifying the largest subset of C(alpha) atoms of a model that superimpose 'well' over the experimental structure, and produces a single normalized score that represents the quality of the model. Because there exists no evaluation method for assessment measures of predicted models, it is not easy to evaluate how good our new measure is. Even though an exact comparison of MaxSub and the CASP3 assessment is not straightforward, here we use a test-bed extracted from the CASP3 fold-recognition models. A rough qualitative comparison of the performance of MaxSub vis-a-vis the human-expert assessment carried out at CASP3 shows that there is a good agreement for the more accurate models and for the better predicting groups. As expected, some differences were observed among the medium to poor models and groups. Overall, the top six predicting groups ranked using the fully automated MaxSub are also the top six groups ranked at CASP3. We conclude that MaxSub is a suitable method for the automatic evaluation of models.

Algorithms↗
PubMed2000

The 2000 Olympic Games of protein structure prediction; fully automated programs are being evaluated vis-à-vis human teams in the protein structure prediction experiment CAFASP2.

In this commentary, we describe two new protein structure prediction experiments being run in parallel with the CASP experiment, which together may be regarded as the 2000 Olympic Games of structure prediction. The first new experiment is CAFASP, the Critical Assessment of Fully Automated Structure Prediction. In CAFASP, the participants are fully automated programs or Internet servers, and here the automated results of the programs are evaluated, without any human intervention. The second new experiment, named LiveBench, follows the CAFASP ideology in that it is aimed towards the evaluation of automatic servers only, while it runs on a large set of prediction targets and in a continuous fashion. Researchers will be watching the 2000 protein structure prediction Olympic Games, to be held in December, in order to learn about the advances in the classical 'human-plus-machine' CASP category, the fully automated CAFASP category, and the comparison between the two.

Amino Acid Sequence↗
PubMed2000

Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate.

Glucocorticoid receptor (GR) activation induces apoptosis of granule cells in the hippocampus. In contrast, neuroprotection is seen after mineralocorticoid receptor (MR) activation. To date there is no in vivo evidence for direct interactions between corticosteroids and any of the key regulatory molecules of programmed cell death. In this report, we show that the opposing actions of MR and GR on neuronal survival result from their ability to differentially influence the expression of members of the bcl-2 gene family; specifically, in the rat hippocampus, activation of GR induces cell death by increasing the ratio of the proapoptotic molecule Bax relative to the antiapoptotic molecules Bcl-2 or Bcl-x(L); the opposite effect is observed after stimulation of MR. The same results were obtained in both young and aged animals; however, older subjects (which were more susceptible to GR-mediated apoptosis) tended to express the antiapoptotic genes more robustly. Using a loss-of-function mouse model, we corroborated the observations made in the rat, demonstrating Bax to be essential in the GR-mediated cell death-signaling cascade. In addition, we show that GR activation increases and MR activation decreases levels of the tumor suppressor protein p53 (a direct transcriptional regulator of bax and bcl-2 genes), thus providing new information on the early genetic events linking corticosteroid receptors with apoptosis in the nervous system.

Aging↗
PubMed2000

Left hydronephrosis caused by Crohn disease successfully treated conservatively.

We report the case of a 35-year-old man who presented with fever, diarrhea, and a left abdominal mass. Diagnostic studies confirmed Crohn disease and revealed an abdominal mass obstructing the left ureter with hydroureter and hydronephrosis. The patient was successfully treated conservatively, with corticosteroids and mesalamine, A review of the literature indicates a predominance of right ureteral involvement in Crohn disease, associated with a high incidence of ileocecal disease. Most of these patients were treated surgically, with resection of ileocecal lesion and/or ureterolysis. Ureteral obstruction as a complication of Crohn disease is discussed, with emphasis on conservative treatment.

Adult↗
PubMed2000

Significance of saliva for the denture-wearing population.

UNLABELLED: This paper summarises a series of studies already published in German and presents new data related to the aetiology of the 'dry mouth' and its associated problems. AIMS: To study factors affecting mucous and serous salivary gland secretion, the aetiology of the 'dry mouth' and its associated problems, causative factors for hyposalivation and it's treatment. SETTING: Two university dental hospitals. SUBJECTS: 587 denture wearers and 521 control subjects, and autopsy material. INTERVENTIONS: Exercise, chewing, water, oestrogen, pilocarpine, and anetholtrithion therapy, biopsy of the minor glands. MAIN OUTCOME MEASURES: Palatal secretion (PAL, microL/cm2/min) and parotid salivary flow (PAR), subjective complaints and clinical findings. RESULTS: Resting flow rates for PAL between 0 and 65 microliters/cm2/min were seen in every age group. The flow rates of PAR (0 to 3.7 ml/10 min) were not correlated with PAL. Most patients with a resting flow rate of PAL < or = 6.0 microliters/cm2 suffer from a 'dry mouth' and Burning Mouth Syndrome (BMS) or oral dysaesthesia (OD) with or without chronic lesions of the oral mucosa. Etiological factors for the incidence of reduced PAL and associated problems include xerostomic drugs, oestrogen deficiency, radiotherapy, thyroid dysfunction, smoking or continuous wearing of complete upper dentures. PAL also correlated with the retention of upper complete dentures. PAL was correlated with the water content of epithelial tissues. PAL and PAR were both increased by drinking ample fluid, improving their circulation by physical exercises, chewing intensively, or taking oestrogens, pilocarpine, anetholtrithion. CONCLUSIONS: Variation in palatal salivary secretion occurs and is clinically important.

Adult↗
PubMed2000

Photoreceptor degeneration in the RCS rat attenuates dendritic transport and axonal regeneration of ganglion cells.

PURPOSE: Photoreceptor loss in the Royal College of Surgeons (RCS) rat deprives the retinal ganglion cells (RGCs) of sensory input, which could interfere with RGC physiology. Whether axonal and dendritic transport is altered, and whether RGCs retain their capacity to regenerate their axons, both in vivo and in culture, was ascertained. METHODS: The study was conducted at postnatal days (P) 30 (while most photoreceptors are still intact), P90 (photoreceptors being almost completely absent), and P180 (approximately 3 months after photoreceptor disappearance). RGCs were studied with retrograde transport of the fluorescent dye 4Di-10ASP. Dendritic transport was also studied with 4Di-10ASP that is transported from the cell bodies into the RGC dendrites. Regeneration of RGC axons in vivo was monitored in the grafting paradigm of replacing the cut optic nerve (ON) with a sciatic nerve (SN) piece. Cell counts were performed in retinal wholemounts. Axonal regrowth in vitro was assessed in organotypic cultures of retinal stripes. RESULTS: Photoreceptor dystrophy did not adversely affect retrograde axonal transport but attenuated dendritic transport compared with the wild-type control rats. Axons of RGCs were able to regenerate if provided with a SN graft, and regeneration was observed to be similar between RCS and wild-type rats at P30 but differed significantly at P90 and P180. In addition to an age-dependent decline in the regenerative ability, seen also in control animals, the number of RCS RGCs able to regenerate declined drastically beginning at 3 months. It is plausible that the intraretinal reorganization, as a consequence of photoreceptor disappearance, interferes with the regenerative ability of the RGCs. CONCLUSIONS: The findings suggest for the first time that diminution of photoreceptor sensory input does not induce detectable death of RGCs until P180, but that it attenuates certain ganglion cell functions like intraretinal dendritic transport and propensity for axonal regeneration.

Animals↗
PubMed2000

Hybrid fold recognition: combining sequence derived properties with evolutionary information.

Recent assessments of structure prediction have demonstrated that (i) although fold recognition methods can often identify remote similarities when standard sequence search methods fail, the score of the top-ranking fold is not always significant enough to allow a confident prediction; (ii) the use of structural information such as secondary structure increases recognition accuracy; (iii) modern sequence-based methods incorporating evolutionary information from neighboring sequences can often identify very remote similarities; (iv) there is no one single method that is superior to other methods when evaluated over a wide range of targets, and (v) extensive human-expert intervention is usually required for the most difficult prediction targets. Here, I describe a new, hybrid fold recognition method that incorporates structural and evolutionary information into a single fully automated method. This work is a first attempt towards the automation of some of the processes that are often applied by human predictors. The method is tested with two cases that are often applied by human predictors. The method is tested with two fold-recognition benchmarks demonstrating a superior performance. The higher sensitivity and selectivity enable the applicability of this method at genomic scales.

Algorithms↗
PubMed2000

Clinical classification and staging.

The identification of increasingly powerful prognostic factors has led to sequential modifications of the cutaneous melanoma staging system. Changes in the staging system are anticipated as more refined prognostic factors are identified. This article provides an overview of the system, including a brief history and an introduction to recent advances in staging of patients with primary melanoma (i.e., sentinel lymphadenectomy). Practical recommendations for a stage-specific workup for the patient, which are especially important given the need for quality care in an increasingly cost-conscious environment, are provided.

Humans↗
PubMed2000

Cataractogenic lens injury prevents traumatic ganglion cell death and promotes axonal regeneration both in vivo and in culture.

PURPOSE: To examine and quantify neuroprotective and neurite-promoting activity on retinal ganglion cells (RGCs) after injury of the lens. METHODS: In adult albino rats, penetrating lens injury was performed by intraocular injection. To test for injury-induced neuroprotective effects in vivo, fluorescence-prelabeled RGCs were axotomized by subsequent crush of the optic nerve (ON) with concomitant lens injury to cause cataract. The numbers of surviving RGCs were determined in retinal wholemounts and compared between the different experimental and control groups. To examine axonal regeneration in vivo, the ON was cut and replaced with an autologous piece of sciatic nerve (SN). Retinal ganglion cells with axons that had regenerated within the SN under lens injury or control conditions were retrogradely labeled with a fluorescent dye and counted on retinal wholemounts. Neurite regeneration was also studied in adult retinal explants obtained either after lens injury or without injury. The numbers of axons were determined after 1 and 2 days in culture. Putative neurotrophins (NTs) were studied within immunohistochemistry and Western blot analysis. RESULTS: Cataractogenic lens injury performed at the same time as ON crush resulted in highly significant rescue of 746 +/- 126 RGCs/mm(2) (mean +/- SD; approximately 39% of total RGCs) 14 days after injury compared with controls without injury or with injection of buffer into the vitreous body (30 +/- 18 RGCs/mm(2)). When lens injury was performed with a delay of 3 days after ON crush, 49% of RGCs survived, whereas delay of 5 days still rescued 45% of all RGCs. In the grafting paradigm virtually all surviving RGCs after lens injury appeared to have regenerated an axon within the SN graft (763 +/- 114 RGCs/mm(2) versus 79 +/- 17 RGCs/mm(2) in controls). This rate of regeneration corresponds to approximately 40% of all RGCs. In the regeneration paradigm in vitro preceding lens injury and ON crush 5 days previous resulted in a maximum of regeneration of 273 +/- 39 fibers/explant after 1 day and 574 +/- 38 fibers/explant after 2 days in vitro. In comparison, in control retinal pieces without lens injury 28 +/- 13 fibers/explant grew out at 1 day, and 97 +/- 37 fibers/explant grew out at 2 days in culture. Immunohistochemical and Western blot analysis of potential NTs in the injured lens revealed no expression of ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), NT-4, nerve growth factor (NGF), and basic fibroblast growth factor (bFGF). CONCLUSIONS: The findings indicate that the lens contains high neuroprotective and neuritogenic activity, which is not caused by NT. Compared with the data available in the literature, this neuroprotection is quantitatively among the highest ever reported within the adult rat visual system.

Animals↗
PubMed1999

Follow-up recommendations for patients with American Joint Committee on Cancer Stages I-III malignant melanoma.

BACKGROUND: Guidelines for follow-up of melanoma patients are not established. In 1987, a follow-up protocol was instituted at the Yale Melanoma Unit to improve upon the detection of disease recurrence in patients with American Joint Committee on Cancer Stage I-III cutaneous melanoma. The follow-up protocol consists of a patient education program and a surveillance schedule based on stage of disease. METHODS: The authors retrospectively reviewed the records of 373 patients who were seen and followed according to the surveillance protocol in the Yale Melanoma Unit between January 1988 and December 1994 to determine 1) the time interval between the initial visit and recurrence; 2) the most common method of detecting recurrences; 3) whether the surveillance schedule or the patient detects more recurrences, i.e., asymptomatic recurrences versus symptomatic recurrences; 4) whether there is any survival difference between asymptomatic and symptomatic recurrences. RESULTS: The 5-year overall survival rates for Stage I, II, and III patients were 95%, 72%, and 52%, respectively. Of the 78 recurrences, 44 (56%) were detected by physician-directed surveillance examinations and 34 (44%) by patients. Most recurrences were found within the first (47%) or second (32%) year of follow-up. The estimated 6-month hazard rates for death or recurrence were 0.0044, 0.0088, and 0.0278 for Stage I, II, and III patients, respectively. The group of asymptomatic patients with recurrence had a survival advantage over the symptomatic recurrence group. In addition, patients with locoregional recurrence had better survival than those with distant recurrence. CONCLUSIONS: Although many recurrences arise rapidly and are recognized early by patients, in this study more than half were found by surveillance examinations before symptoms were manifest. Based on the hazard ratio for recurrences, the authors recommend the following surveillance schedules in addition to the patient education program for detection of recurrences: 1) Stage I, annually; 2) Stage II, every 6 months for Years 1-2 and annually thereafter; 3) Stage III, every 3 months for Year 1, every 4 months for Year 2, and every 6 months for Years 3-5; 4) at Year 6 and beyond, all patients should have surveillance annually, due to the risk of late recurrence and/or metachronous multiple primaries.

Adolescent↗
PubMed1999

Characterization of the integration site of Yersinia high-pathogenicity island in Escherichia coli.

The high-pathogenicity island (HPI) of virulent Yersiniae consists of (i) a functional core encoding for biosynthesis and uptake of the siderophore yersiniabactin and (ii) a 5- to 13-kb AT-rich region of unknown function. This Yersinia HPI has been shown to be widely distributed among different pathotypes of Escherichia coli. In this study, the insertion site of the HPI was defined in three different E. coli strains: The enteroaggregative E. coli (EAggEC) strain 17-2, the uropathogenic (UPEC) E. coli strain 536, and the probiotic E. coli DSM6601. We demonstrated that in all three E. coli isolates the HPI is associated with the asnT tRNA (5'-extremity) and truncated in the AT-rich region (3'-extremity) since the 17-bp direct repeat (DR) of the asn tRNA that flanks the HPI in Yersinia is missing in E. coli. Moreover, in comparison to the HPI-negative E. coli K-12 strain, a uniform deletion must have taken place in the E. coli chromosome adjacent to the 3'-border of the HPI.

Escherichia coli↗
PubMed1999

GCH1 mutation in a patient with adult-onset oromandibular dystonia.

The authors report a mutation in exon 5 of GCH1 in a patient with adult-onset oromandibular dystonia and no obvious family history of dystonia. The patient responded positively to treatment with L-dopa. These findings demonstrate that GCH1 mutations must be considered even in patients with dystonic symptoms not typical of dopa-responsive dystonia.

Age of Onset↗
PubMed1999

Cell type specificity of the human endoglin promoter.

Endoglin is a component of the transforming growth factor-beta receptor complex whose expression is limited to a small number of cell types, including endothelial cells (ECs), activated monocytes, tissue macrophages and erythroid precursors. Of particular interest is its preferential expression in the vasculature of many malignant tumors, especially in view of potential therapeutic applications. We have cloned the human endoglin promoter, analyzed its structure and demonstrate that the isolated genomic fragment shows strong promoter activity in ECs (compared to other known EC-selective promoters), but not in epithelial cells and fibroblasts. These findings suggest that the endoglin promoter may prove a useful tool for the transcriptional targeting of ECs by gene therapy. We also determined the domains that are responsible for both efficient transcription and the observed preferential activity in ECs. The region around the major site of transcription initiation was found to be essential for transcription in both ECs and non-ECs. In contrast, cell type specificity does not appear to be governed by a single mechanism, but rather seems to be due to functionally distinct regulatory mechanisms acting on different upstream sequences.

3T3 Cells↗
PubMed1999

CAFASP-1: critical assessment of fully automated structure prediction methods.

The results of the first Critical Assessment of Fully Automated Structure Prediction (CAFASP-1) are presented. The objective was to evaluate the success rates of fully automatic web servers for fold recognition which are available to the community. This study was based on the targets used in the third meeting on the Critical Assessment of Techniques for Protein Structure Prediction (CASP-3). However, unlike CASP-3, the study was not a blind trial, as it was held after the structures of the targets were known. The aim was to assess the performance of methods without the user intervention that several groups used in their CASP-3 submissions. Although it is clear that "human plus machine" predictions are superior to automated ones, this CAFASP-1 experiment is extremely valuable for users of our methods; it provides an indication of the performance of the methods alone, and not of the "human plus machine" performance assessed in CASP. This information may aid users in choosing which programs they wish to use and in evaluating the reliability of the programs when applied to their specific prediction targets. In addition, evaluation of fully automated methods is particularly important to assess their applicability at genomic scales. For each target, groups submitted the top-ranking folds generated from their servers. In CAFASP-1 we concentrated on fold-recognition web servers only and evaluated only recognition of the correct fold, and not, as in CASP-3, alignment accuracy. Although some performance differences appeared within each of the four target categories used here, overall, no single server has proved markedly superior to the others. The results showed that current fully automated fold recognition servers can often identify remote similarities when pairwise sequence search methods fail. Nevertheless, in only a few cases outside the family-level targets has the score of the top-ranking fold been significant enough to allow for a confident fully automated prediction. Because the goals, rules, and procedures of CAFASP-1 were different from those used at CASP-3, the results reported here are not comparable with those reported in CASP-3. Nevertheless, it is clear that current automated fold recognition methods can not yet compete with "human-expert plus machine" predictions. Finally, CAFASP-1 has been useful in identifying the requirements for a future blind trial of automated served-based protein structure prediction.

Algorithms↗
PubMed1999

Epitope discovery using bacteriophage display: the minimum epitope of an anti-IRBP antibody.

The purpose of this study was to determine, using random peptide library (RPL) technologies, the minimal epitope requirements of the mouse monoclonal anti-interphotoreceptor-retinoid-binding protein antibody, H3B5. This previously characterized antibody is used as an example to examine whether RPL's offer a relatively easy and rapid route to obtaining detailed epitope mapping data.A pentadecamer random peptide library (RPL) displayed on the major coat protein (gene 8) of filamentous bacteriophage (F88-4-15) was used as a target for selection by the anti-IRBP monoclonal antibody, H3B5. Three rounds of library selection were performed, and 90 of the resultant RPL clones were examined for affinity to H3B5 by enzyme-linked immunosorbent assay (ELISA). DNA sequencing of ELISA positive clones provided sequence of the region encoding the random peptide. After three rounds of selection of the RPL, 76.7% of clones examined interacted with H3B5, 17.7% did not show significant binding and 6.6% bound to control antibody also. The essential elements of the peptide epitope were determined by sequence comparison of 24 clones to be the four amino-acid sequence (Aspartic or glutamic acid)-Proline-Arginine-(Leucine, Isoleucine or Valine). This motif [(D/E) PR (L/I/V)] is in agreement, but at greater resolution, than previous synthetic peptide studies where the motif AASEDPRL was identified. Other motifs were found which bound to H3B5 but did not share primary structure similarities (peptidomimetics). Selection from a RPL has rapidly defined the minimal requirements for the H3B5 epitope in fine detail. Such a process offers great potential for investigating antibody-antigen interactions and core sequences of an epitope, and enables the identification of motifs in other proteins which may be recognized by the antibody, providing information on possible cross-reactivity.

Amino Acid Sequence↗