SPOT-Seq-RNA: Predicting protein-RNA complex structure and RNA-binding function by fold recognition and binding affinity prediction

RNA-binding proteins (RBPs) play key roles in RNA metabolism and post-transcriptional regulation. Computational methods have been developed separately for prediction of RBPs and RNA-binding residues by machine-learning techniques and prediction of protein-RNA complex structures by rigid or semiflexible structure-to-structure docking. Here, we describe a template-based technique called SPOT-Seq-RNA that integrates prediction of RBPs, RNA-binding residues, and protein-RNA complex structures into a single package. This integration is achieved by combining template-based structure-prediction software, SPARKS X, with binding affinity prediction software, DRNA. This tool yields reasonable sensitivity (46 %) and high precision (84 %) for an independent test set of 215 RBPs and 5,766 non-RBPs. SPOT-Seq-RNA is computationally efficient for genome-scale prediction of RBPs and protein-RNA complex structures. Its application to human genome study has revealed a similar sensitivity and ability to uncover hundreds of novel RBPs beyond simple homology. The online server and downloadable version of SPOT-Seq-RNA are available at http://sparks-lab.org/server/SPOT-Seq-RNA/

Exact ground states for the four-electron problem in a two-dimensional finite Hubbard square system

We present exact explicit analytical results describing the exact ground state of four electrons in a two dimensional square Hubbard cluster containing 16 sites taken with periodic boundary conditions. The presented procedure, which works for arbitrary even particle number and lattice sites, is based on explicitly given symmetry adapted base vectors constructed in r-space. The Hamiltonian acting on these states generates a closed system of 85 linear equations providing by its minimum eigenvalue the exact ground state of the system. The presented results, described with the aim to generate further creative developments, not only show how the ground state can be exactly obtained and what kind of contributions enter in its construction, but emphasize further characteristics of the spectrum. On this line i) possible explications are found regarding why weak coupling expansions often provide a good approximation for the Hubbard model at intermediate couplings, or ii) explicitly given low lying energy states of the kinetic energy, avoiding double occupancy, suggest new roots for pairing mechanism attracting decrease in the kinetic energy, as emphasized by kinetic energy driven superconductivity theories.Comment: 37 pages, 18 figure

Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients

<br>Background:Prostate cancer cell growth is dependent upon androgen receptor (AR) activation, which is regulated by specific kinases. The aim of the current study is to establish if AR phosphorylation by Cdk1 or ERK1/2 is of prognostic significance.</br> <br>Methods: Scansite 2.0 was utilised to predict which AR sites are phosphorylated by Cdk1 and ERK1/2. Immunohistochemistry for these sites was then performed on 90 hormone-naive prostate cancer specimens. The interaction between Cdk1/ERK1/2 and AR phosphorylation was investigated in vitro using LNCaP cells.</br><br>Results:Phosphorylation of AR at serine 515 (pAR(S515)) and PSA at diagnosis were independently associated with decreased time to biochemical relapse. Cdk1 and pCdk1(161), but not ERK1/2, correlated with pAR(S515). High expression of pAR(S515) in patients with a PSA at diagnosis of ≤20 ng ml(-1) was associated with shorter time to biochemical relapse (P=0.019). This translated into a reduction in disease-specific survival (10-year survival, 38.1% vs 100%, P<0.001). In vitro studies demonstrated that treatment with Roscovitine (a Cdk inhibitor) caused a reduction in pCdk1(161) expression, pAR(S515)expression and cellular proliferation.</br> <br>Conclusion: In prostate cancer patients with PSA at diagnosis of ≤20 ng ml(-1), phosphorylation of AR at serine 515 by Cdk1 may be an independent prognostic marker.</br&gt

Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO(2) in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths

A novel series of compositionally biased substitution matrices for comparing Plasmodium proteins

<p>Abstract</p> <p>Background</p> <p>The most common substitution matrices currently used (BLOSUM and PAM) are based on protein sequences with average amino acid distributions, thus they do not represent a fully accurate substitution model for proteins characterized by a biased amino acid composition. This problem has been addressed recently by adjusting existing matrices, however, to date, no empirical approach has been taken to build matrices which offer a substitution model for comparing proteins sharing an amino acid compositional bias. Here, we present a novel procedure to construct series of symmetrical substitution matrices to align proteins from similarly biased <it>Plasmodium </it>proteomes.</p> <p>Results</p> <p>We generated substitution matrices by selecting from the BLOCKS database those multiple alignments with a compositional bias similar to that of <it>P. falciparum </it>and <it>P. yoelii </it>proteins. A novel 'fuzzy' clustering method was adopted to group sequences within these alignments, showing that this method retains more complete information on the amino acid substitutions when compared to hierarchical clustering. We assessed the performance against the BLOSUM62 series and showed that the usage of our matrices results in an improvement in the performance of BLAST database searches, greatly reducing the number of false positive hits. We then demonstrated applications of the use of novel matrices to improve the annotation of homologs between the two <it>Plasmodium </it>species and to classify members of the <it>P. falciparum </it>RIFIN/STEVOR family.</p> <p>Conclusion</p> <p>We confirmed that in the case of compositionally biased proteins, standard BLOSUM matrices are not suited for optimal alignments, and specific substitution matrices are required. In addition, we showed that the usage of these matrices leads to a reduction of false positive hits, facilitating the automatic annotation process.</p

In-reach specialist nursing teams for residential care homes : uptake of services, impact on care provision and cost-effectiveness

Background: A joint NHS-Local Authority initiative in England designed to provide a dedicated nursing and physiotherapy in-reach team (IRT) to four residential care homes has been evaluated.The IRT supported 131 residents and maintained 15 'virtual' beds for specialist nursing in these care homes. Methods: Data captured prospectively (July 2005 to June 2007) included: numbers of referrals; reason for referral; outcome (e.g. admission to IRT bed, short-term IRT support); length of stay in IRT; prevented hospital admissions; early hospital discharges; avoided nursing home transfers; and detection of unrecognised illnesses. An economic analysis was undertaken. Results: 733 referrals were made during the 2 years (range 0.5 to 13.0 per resident per annum)resulting in a total of 6,528 visits. Two thirds of referrals aimed at maintaining the resident's independence in the care home. According to expert panel assessment, 197 hospital admissions were averted over the period; 20 early discharges facilitated; and 28 resident transfers to a nursing home prevented. Detection of previously unrecognised illnesses accounted for a high number of visits. Investment in IRT equalled £44.38 per resident per week. Savings through reduced hospital admissions, early discharges, delayed transfers to nursing homes, and identification of previously unrecognised illnesses are conservatively estimated to produce a final reduction in care cost of £6.33 per resident per week. A sensitivity analysis indicates this figure might range from a weekly overall saving of £36.90 per resident to a 'worst case' estimate of £2.70 extra expenditure per resident per week. Evaluation early in implementation may underestimate some cost-saving activities and greater savings may emerge over a longer time period. Similarly, IRT costs may reduce over time due to the potential for refinement of team without major loss in effectiveness. Conclusion: Introduction of a specialist nursing in-reach team for residential homes is at least cost neutral and, in all probability, cost saving. Further benefits include development of new skills in the care home workforce and enhanced quality of care. Residents are enabled to stay in familiar surroundings rather than unnecessarily spending time in hospital or being transferred to a higher dependency nursing home setting

Younger adult type 2 diabetic patients have poorer glycaemic control: A cross-sectional study in a primary care setting in Singapore

10.1186/1472-6823-13-18BMC Endocrine Disorders13-BEDM

Association between novel TARDBP mutations and Chinese patients with amyotrophic lateral sclerosis

<p>Abstract</p> <p>Background</p> <p><it>TARDBP </it>mutations have been reported in patients with amyotrophic lateral sclerosis (ALS) in different populations except Chinese. The present aim is to investigate the association between <it>TARDBP </it>mutations and Chinese patients with ALS.</p> <p>Methods</p> <p>71 SALS patients and 5 FALS families with non-<it>SOD1 </it>mutations were screened for <it>TARDBP </it>mutations via direct sequencing.</p> <p>Results</p> <p>A novel heterozygous variation, Ser292Asn (875G>A), was identified in the proband and 4 asymptomatic relatives including the children of the dead patient from a FALS family. Thus the dead patient, the proband's brother, was speculated to carry Ser292Asn though his sample was unavailable to the detection. This variation was not found in 200 unrelated control subjects. A homology search of the TDP-43 protein in different species demonstrated that it was highly conserved. Also, it was predicted to be deleterious to protein function with SIFT-calculated probabilities of 0.00. Therefore, Ser292Asn is predicted to be a pathogenic mutation. In addition, we have found two silent mutations (Gly40Gly and Ala366Ala) and one novel polymorphism (239-18t>c).</p> <p>Conclusions</p> <p>The present data have extended the spectrum of <it>TARDBP </it>mutations and polymorphisms, and supported the pathological role of TDP-43 in Chinese ALS patients.</p

Cataloguing functionally relevant polymorphisms in gene DNA ligase I: a computational approach

A computational approach for identifying functionally relevant SNPs in gene LIG1 has been proposed. LIG1 is a crucial gene which is involved in excision repair pathways and mutations in this gene may lead to increase sensitivity towards DNA damaging agents. A total of 792 SNPs were reported to be associated with gene LIG1 in dbSNP. Different web server namely SIFT, PolyPhen, CUPSAT, FASTSNP, MAPPER and dbSMR were used to identify potentially functional SNPs in gene LIG1. SIFT, PolyPhen and CUPSAT servers predicted eleven nsSNPs to be intolerant, thirteen nsSNP to be damaging and two nsSNPs have the potential to destabilize protein structure. The nsSNP rs11666150 was predicted to be damaging by all three servers and its mutant structure showed significant increase in overall energy. FASTSNP predicted twenty SNPs to be present in splicing modifier binding sites while rSNP module from MAPPER server predicted nine SNPs to influence the binding of transcription factors. The results from the study may provide vital clues in establishing affect of polymorphism on phenotype and in elucidating drug response

Urinary Transforming Growth Factor-beta 1 as a marker of response to immunosuppressive treatment, in patients with crescentic nephritis

BACKGROUND: Crescentic nephritis is characterized by formation of cellular crescents that soon become fibrotic and result in irreversible damage, unless an effective immunosuppressive therapy is rapidly commenced. TGF-β(1 )is involved in the development of crescents through various pathways. The aim of this study was to identify whether the determination of urinary TGF-β(1 )levels in patients with crescentic nephritis could be used as a marker of response to treatment. METHODS: Fifteen patients with crescentic nephritis were included in the study. The renal expression of TGF-β(1 )was estimated in biopsy sections by immunohistochemistry and urinary TGF-β(1 )levels were determined by quantitative sandwich enzyme immunoassay (EIA). TGF-β(1 )levels were determined at the time of renal biopsy, before the initiation of immunosuppressive treatment (corticosteroids, cyclophosphamide and plasma exchange). Twelve patients with other types of proliferative glomerulonephritis and ten healthy subjects were used as controls. RESULTS: Improvement of renal function with immunosuppressive therapy was observed in 6 and stabilization in 4 patients (serum creatinine from 3.2 ± 1.5 to 1.4 ± 0.1 mg/dl and from 4.4 ± 1.2 to 4.1 ± 0.6 mg/dl, respectively). In 5 patients, with severe impairment of renal function who started on dialysis, no improvement was noted. The main histological feature differentiating these 5 patients from others with improved or stabilized renal function was the percentage patients with poor response to treatment were the percentage of glomeruli with crescents and the presence of ruptured Bowman's capsule and glomerular necrosis. Urinary TGF-β(1 )levels were significantly higher in patients who showed no improvement of renal function with immunosuppressive therapy (930 ± 126 ng/24 h vs. 376 ± 84 ng/24 h, p < 0.01). TGF-β(1 )was identified in crescents and tubular epithelial cells, whereas a significant correlation of TGF-β(1 )immunostaining with the presence of fibrocellular cresents was observed (r = 0.531, p < 0,05). CONCLUSION: Increased TGF-β(1 )renal expression and urinary excretion that is related to the response to immunosuppressive therapy was observed in patients with crescentic nephritis. Evaluation of urinary TGF-β(1 )levels may be proved a useful marker of clinical outcome in patients with crescentic nephritis