Monte Carlo Procedure for Protein Design

A new method for sequence optimization in protein models is presented. The approach, which has inherited its basic philosophy from recent work by Deutsch and Kurosky [Phys. Rev. Lett. 76, 323 (1996)] by maximizing conditional probabilities rather than minimizing energy functions, is based upon a novel and very efficient multisequence Monte Carlo scheme. By construction, the method ensures that the designed sequences represent good folders thermodynamically. A bootstrap procedure for the sequence space search is devised making very large chains feasible. The algorithm is successfully explored on the two-dimensional HP model with chain lengths N=16, 18 and 32.Comment: 7 pages LaTeX, 4 Postscript figures; minor change

An intuitionistic approach to scoring DNA sequences against transcription factor binding site motifs

Background: Transcription factors (TFs) control transcription by binding to specific regions of DNA called transcription factor binding sites (TFBSs). The identification of TFBSs is a crucial problem in computational biology and includes the subtask of predicting the location of known TFBS motifs in a given DNA sequence. It has previously been shown that, when scoring matches to known TFBS motifs, interdependencies between positions within a motif should be taken into account. However, this remains a challenging task owing to the fact that sequences similar to those of known TFBSs can occur by chance with a relatively high frequency. Here we present a new method for matching sequences to TFBS motifs based on intuitionistic fuzzy sets (IFS) theory, an approach that has been shown to be particularly appropriate for tackling problems that embody a high degree of uncertainty. Results: We propose SCintuit, a new scoring method for measuring sequence-motif affinity based on IFS theory. Unlike existing methods that consider dependencies between positions, SCintuit is designed to prevent overestimation of less conserved positions of TFBSs. For a given pair of bases, SCintuit is computed not only as a function of their combined probability of occurrence, but also taking into account the individual importance of each single base at its corresponding position. We used SCintuit to identify known TFBSs in DNA sequences. Our method provides excellent results when dealing with both synthetic and real data, outperforming the sensitivity and the specificity of two existing methods in all the experiments we performed. Conclusions: The results show that SCintuit improves the prediction quality for TFs of the existing approaches without compromising sensitivity. In addition, we show how SCintuit can be successfully applied to real research problems. In this study the reliability of the IFS theory for motif discovery tasks is proven

Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome.

yesEpigenetic information is available from contemporary organisms, but is difficult to track back in evolutionary time. Here, we show that genome-wide epigenetic information can be gathered directly from next-generation sequence reads of DNA isolated from ancient remains. Using the genome sequence data generated from hair shafts of a 4000-yr-old Paleo- Eskimo belonging to the Saqqaq culture, we generate the first ancient nucleosome map coupled with a genome-wide survey of cytosine methylation levels. The validity of both nucleosome map and methylation levels were confirmed by the recovery of the expected signals at promoter regions, exon/intron boundaries, and CTCF sites. The top-scoring nucleosome calls revealed distinct DNA positioning biases, attesting to nucleotide-level accuracy. The ancient methylation levels exhibited high conservation over time, clustering closely with modern hair tissues. Using ancient methylation information, we estimated the age at death of the Saqqaq individual and illustrate how epigenetic information can be used to infer ancient gene expression. Similar epigenetic signatures were found in other fossil material, such as 110,000- to 130,000-yr-old bones, supporting the contention that ancient epigenomic information can be reconstructed from a deep past. Our findings lay the foundation for extracting epigenomic information from ancient samples, allowing shifts in epialleles to be tracked through evolutionary time, as well as providing an original window into modern epigenomics

Features of mammalian microRNA promoters emerge from polymerase II chromatin immunoprecipitation data

Background: MicroRNAs (miRNAs) are short, non-coding RNA regulators of protein coding genes. miRNAs play a very important role in diverse biological processes and various diseases. Many algorithms are able to predict miRNA genes and their targets, but their transcription regulation is still under investigation. It is generally believed that intragenic miRNAs (located in introns or exons of protein coding genes) are co-transcribed with their host genes and most intergenic miRNAs transcribed from their own RNA polymerase II (Pol II) promoter. However, the length of the primary transcripts and promoter organization is currently unknown. Methodology: We performed Pol II chromatin immunoprecipitation (ChIP)-chip using a custom array surrounding regions of known miRNA genes. To identify the true core transcription start sites of the miRNA genes we developed a new tool (CPPP). We showed that miRNA genes can be transcribed from promoters located several kilobases away and that their promoters share the same general features as those of protein coding genes. Finally, we found evidence that as many as 26% of the intragenic miRNAs may be transcribed from their own unique promoters. Conclusion: miRNA promoters have similar features to those of protein coding genes, but miRNA transcript organization is more complex. © 2009 Corcoran et al

Impact of Vitamin C on Endothelial Function and Exercise Capacity in Patients with a Fontan Circulation

Objective.  To evaluate the impact of antioxidant therapy on functional health status in Fontan‐palliated patients. Design.  Prospective, randomized, double‐blind, placebo‐controlled trial. Patients.  Fifty‐three generally asymptomatic Fontan patients. Interventions.  Patients were randomized to receive either high‐dose ascorbic acid (vitamin C) or placebo for 4 weeks. Outcome Measures.  Peripheral vascular function, as measured with endothelium‐dependent digital pulse amplitude testing (EndoPAT), and exercise capacity were assessed before and after study drug treatment. Primary outcome measures included the EndoPAT index and peripheral arterial tonometry (PAT) ratio, both validated markers of vascular function. Secondary outcome measures included peak oxygen consumption and work. Results.  Twenty‐three vitamin C‐ and 21 placebo‐assigned subjects completed the protocol (83%). Median age and time from Fontan completion were 15 (interquartile range [IQR] 11.7–18.2) and 11.9 years (IQR 9.0–15.7), respectively. Right ventricular morphology was dominant in 30 (57%). Outcome measures were similar between groups at baseline. Among all subjects, vitamin C therapy was not associated with a statistical improvement in either primary or secondary outcome measures. In subjects with abnormal vascular function at baseline, compared with placebo, vitamin C therapy more frequently resulted in normalization of the EndoPAT index (45% vs. 17%) and PAT ratio (38% vs. 13%). Conclusions.  Short‐term therapy with vitamin C does not alter endothelial function or exercise capacity in an asymptomatic Fontan population overall. Vitamin C may provide benefit to a subset of Fontan patients with abnormal vascular function.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92126/1/j.1747-0803.2011.00605.x.pd

The management of acute parathyroid crisis secondary to parathyroid carcinoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hypercalcaemic hyperparathyroid crisis is a rare but life-threatening complication of primary hyperparathyroidism. Parathyroid carcinoma is a rare malignancy with an incidence of 0.5% to 4% of all reported cases of primary hyperparathyroidism.</p> <p>Case presentation</p> <p>We report the case of a 60-year-old Caucasian man with hypercalcaemic hyperparathyroid crisis associated with parathyroid carcinoma. He presented with a classic hypercalcaemic syndrome and his serum calcium and parathyroid hormone levels were at 4.65 mmol/L and 1743 ng/L, respectively. He initially presented with a two-week history of weakness and lethargy and a one-week history of vomiting, polyuria and polydipsia. An emergency left thyroid lobectomy and left lower parathyroidectomy were performed. There was a prompt decrease in his parathyroid hormone level immediately after surgery. Histology revealed that our patient had a 4-cm parathyroid carcinoma.</p> <p>Conclusion</p> <p>In patients with parathyroid carcinoma, the optimal surgical treatment is <it>en bloc </it>resection with ipsilateral thyroid lobectomy and removal of any enlarged or abnormal lymph nodes. Surgery is the only curative treatment. In our patient, prompt surgical intervention proved successful. At six months the patient is well with no evidence of disease recurrence. This case highlights the importance of considering a hyperparathyroid storm in the context of a parathyroid carcinoma. Parathyroid carcinoma is a rare entity and our knowledge is mainly derived from case reports and retrospective studies. This case report increases awareness of this serious and life-threatening complication. This report also illustrates how prompt and appropriate management provides the best outcome for the patient.</p

Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease

PMCID: PMC3710212This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Knee arthroscopy and exercise versus exercise only for chronic patellofemoral pain syndrome: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Arthroscopy is often used to treat patients with chronic patellofemoral pain syndrome (PFPS). As there is a lack of evidence, we conducted a randomized controlled trial to study the efficacy of arthroscopy in patients with chronic PFPS.</p> <p>Methods</p> <p>A total of 56 patients with chronic PFPS were randomized into two treatment groups: an <it>arthroscopy group </it>(<it>N </it>= 28), treated with knee arthroscopy and an 8-week home exercise program, and a <it>control group </it>(<it>N </it>= 28), treated with the 8-week home exercise program only. The arthroscopy included finding-specific surgical procedures according to current recommendations. The primary outcome was the Kujala score on patellofemoral pain and function at 9 months following randomization. Secondary outcomes were visual analog scales (VASs) to assess activity-related symptoms. We also estimated the direct healthcare costs.</p> <p>Results</p> <p>Both groups showed marked improvement during the follow-up. The mean improvement in the Kujala score was 12.9 (95% confidence interval (CI) 8.2–17.6) in the arthroscopy group and 11.4 (95% CI 6.9–15.8) in the control group. However, there was no difference between the groups in mean improvement in the Kujala score (group difference 1.1 (95% CI -7.4 - 5.2)) or in any of the VAS scores. Total direct healthcare costs in the arthroscopy group were estimated to exceed on average those of the control group by €901 per patient (<it>p </it>< 0.001).</p> <p>Conclusion</p> <p>In this controlled trial involving patients with chronic PFPS, the outcome when arthroscopy was used in addition to a home exercise program was no better than when the home exercise program was used alone.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN 41800323</p

SPOT: a web-based tool for using biological databases to prioritize SNPs after a genome-wide association study

SPOT (http://spot.cgsmd.isi.edu), the SNP prioritization online tool, is a web site for integrating biological databases into the prioritization of single nucleotide polymorphisms (SNPs) for further study after a genome-wide association study (GWAS). Typically, the next step after a GWAS is to genotype the top signals in an independent replication sample. Investigators will often incorporate information from biological databases so that biologically relevant SNPs, such as those in genes related to the phenotype or with potentially non-neutral effects on gene expression such as a splice sites, are given higher priority. We recently introduced the genomic information network (GIN) method for systematically implementing this kind of strategy. The SPOT web site allows users to upload a list of SNPs and GWAS P-values and returns a prioritized list of SNPs using the GIN method. Users can specify candidate genes or genomic regions with custom levels of prioritization. The results can be downloaded or viewed in the browser where users can interactively explore the details of each SNP, including graphical representations of the GIN method. For investigators interested in incorporating biological databases into a post-GWAS SNP selection strategy, the SPOT web tool is an easily implemented and flexible solution

A computational evaluation of over-representation of regulatory motifs in the promoter regions of differentially expressed genes

BACKGROUND: Observed co-expression of a group of genes is frequently attributed to co-regulation by shared transcription factors. This assumption has led to the hypothesis that promoters of co-expressed genes should share common regulatory motifs, which forms the basis for numerous computational tools that search for these motifs. While frequently explored for yeast, the validity of the underlying hypothesis has not been assessed systematically in mammals. This demonstrates the need for a systematic and quantitative evaluation to what degree co-expressed genes share over-represented motifs for mammals. RESULTS: We identified 33 experiments for human and mouse in the ArrayExpress Database where transcription factors were manipulated and which exhibited a significant number of differentially expressed genes. We checked for over-representation of transcription factor binding sites in up- or down-regulated genes using the over-representation analysis tool oPOSSUM. In 25 out of 33 experiments, this procedure identified the binding matrices of the affected transcription factors. We also carried out de novo prediction of regulatory motifs shared by differentially expressed genes. Again, the detected motifs shared significant similarity with the matrices of the affected transcription factors. CONCLUSIONS: Our results support the claim that functional regulatory motifs are over-represented in sets of differentially expressed genes and that they can be detected with computational methods