Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Specificity of RSG-1.2 Peptide Binding to RRE-IIB RNA Element of HIV-1 over Rev Peptide Is Mainly Enthalpic in Origin

Rev is an essential HIV-1 regulatory protein which binds to the Rev responsive element (RRE) present within the env gene of HIV-1 RNA genome. This binding facilitates the transport of the RNA to the cytoplasm, which in turn triggers the switch between viral latency and active viral replication. Essential components of this complex have been localized to a minimal arginine rich Rev peptide and stem IIB region of RRE. A synthetic peptide known as RSG-1.2 binds with high binding affinity and specificity to the RRE-IIB than the Rev peptide, however the thermodynamic basis of this specificity has not yet been addressed. The present study aims to probe the thermodynamic origin of this specificity of RSG-1.2 over Rev Peptide for RRE-IIB. The temperature dependent melting studies show that RSG-1.2 binding stabilizes the RRE structure significantly (DT m = 4.3uC), in contrast to Rev binding. Interestingly the thermodynamic signatures of the binding have also been found to be different for both the peptides. At pH 7.5, RSG-1.2 binds RRE-IIB with a Ka = 16.260.6610 7 M 21 where enthalpic change DH = 213.960.1 kcal/mol is the main driving force with limited unfavorable contribution from entropic change TDS = 22.860.1 kcal/mol. A large part of DH may be due to specific stacking between U72 and Arg15. In contrast binding of Rev (K a = 3.160.4610 7 M 21) is driven mainly by entropy (DH = 0 kcal/mol and TDS = 10.260.2 kcal/mol) which arises fro

Oligosaccharides from feces of preterm infants fed on breast milk

Nine neutral and five acidic oligosaccharides were isolated from feces of a preterm (30th postmenstrual week) blood group A nonsecretor infant fed on pooled breast milk. Structural analyses were carried out using sugar and methylation analyses, fast atom bombardment mass spectrometry, and 1H NMR. The acidic oligosaccharides are well-known components of human milk. The neutral oligosaccharides are characteristic of nonsecretor milk. Surprisingly, no secretor gene-dependent oligosaccharides were present in the feces. Another preterm (27th postmenstrual week) blood group A, secretor infant fed on pooled breast milk showed the same fecal oligosaccharide pattern as above during the first week after birth, despite being a secretor individual. Also notable was the absence of blood group A-active oligosaccharides in this sample. Another sample of feces collected 8 weeks later from the latter infant contained the expected blood group A-active oligosaccharides. Furthermore, free sialic acid was present at the cost of the sialyl oligosaccharides seen earlier. Thus, infants born prematurely do not show the same degree of development of oligosaccharide metabolism as their more mature counterparts

Oligosaccharides from faeces of a blood-group B, breast-fed infant

Eight oligosaccharides have been isolated from faeces of a blood group B, secretor, breast-fed infant and characterized by sugar and methylation analysis, f.a.b. mass spectrometry and 1H-n.m.r. spectroscopy. One of these oligosaccharides has not previously been reported and is a tri-L-fucosyl derivative of lacto-N-hexaose. The other compounds were identical to oligosaccharides found in human milk. Several of the reported compounds require the secretor dependent 2'-fucosyltransferase for their biosynthesis. Since the mother of this child was an O(H) non-secretor, an intestinal biosynthesis of at least some of these compounds is strongly indicated. No blood group B active oligosaccharides were detected which is in sharp contrast to the oligosaccharide excretion in faeces from a blood group A infant [Sabharwal et al., Mol. Immunol., 21 (1984) 1105-1112] in which all the major oligosaccharides isolated were blood group A active

Clustered metallothionein genes are co-regulated in rice and ectopic expression of <it>OsMT1e-P</it> confers multiple abiotic stress tolerance in tobacco via ROS scavenging

<p>Abstract</p> <p>Background</p> <p>Metallothioneins (MT) are low molecular weight, cysteine rich metal binding proteins, found across genera and species, but their function(s) in abiotic stress tolerance are not well documented.</p> <p>Results</p> <p>We have characterized a rice MT gene, <it>OsMT1e-P</it>, isolated from a subtractive library generated from a stressed salinity tolerant rice genotype, Pokkali. Bioinformatics analysis of the rice genome sequence revealed that this gene belongs to a multigenic family, which consists of 13 genes with 15 protein products. <it>OsMT1e-P</it> is located on chromosome XI, away from the majority of other type I genes that are clustered on chromosome XII. Various members of this MT gene cluster showed a tight co-regulation pattern under several abiotic stresses. Sequence analysis revealed the presence of conserved cysteine residues in OsMT1e-P protein. Salinity stress was found to regulate the transcript abundance of <it>OsMT1e-P</it> in a developmental and organ specific manner. Using transgenic approach, we found a positive correlation between ectopic expression of OsMT1e-P and stress tolerance. Our experiments further suggest ROS scavenging to be the possible mechanism for multiple stress tolerance conferred by OsMT1e-P.</p> <p>Conclusion</p> <p>We present an overview of MTs, describing their gene structure, genome localization and expression patterns under salinity and development in rice. We have found that ectopic expression of OsMT1e-P enhances tolerance towards multiple abiotic stresses in transgenic tobacco and the resultant plants could survive and set viable seeds under saline conditions. Taken together, the experiments presented here have indicated that ectopic expression of OsMT1e-P protects against oxidative stress primarily through efficient scavenging of reactive oxygen species.</p

Limb reconstruction in a resource-limited environment

Introduction: Limb salvage and reconstruction are often challenging and even more so in the limited resource setting. The purpose of this narrative review is to explore the strategies for addressing the unique obstacles and opportunities of limb reconstructive surgery in resource-limited environments globally. Methods: We review (1) the global burden and dimension of the problem, (2) the relevance of orthopedic forums and communication, (3) free and open-access software for deformity analysis and correction, (4) bidirectional learning opportunities, and the value of fellowships and mentoring between resource-rich and resource-limited countries, and (5) how societies like SICOT can help to tackle the problem. Finally, case examples are presented to demonstrate the choice of surgical implants, their availability in regions with limited resources, and how the universal principles of limb reconstruction can be applied, irrespective of resource availability. Results: Limb reconstruction can often be life-changing surgery with the goals of limb salvage, improved function, and ambulation. The contradiction of relatively few severe limb deformities in high-income countries (HICs) with abundant resources and the considerable burden of limb deformities in resource-limited countries is striking. Free, open access to education and software planning tools are of paramount importance to achieve this goal of limb reconstruction. Bidirectional learning, i.e., knowledge exchange between individual surgeons and societies with limited and abundant resources, can be reached via fellowships and mentoring. The presented cases highlight (1) fixator-assisted wound closure obliviating the need for plastic surgery, (2) open bone transport, and (3) hinged Ilizarov frames for correction of severe deformities. These cases underline that optimal clinical outcome can be achieved with low-cost and readily available implants when the principles of limb reconstruction are skillfully applied. Discussion: Limb lengthening and reconstruction are based on universally applicable principles. These have to be applied regardless of the planning tool or surgical implant availability to achieve the goals of limb salvage and improved quality of life

Limb reconstruction in a resource-limited environment.

IntroductionLimb salvage and reconstruction are often challenging and even more so in the limited resource setting. The purpose of this narrative review is to explore the strategies for addressing the unique obstacles and opportunities of limb reconstructive surgery in resource-limited environments globally.MethodsWe review (1) the global burden and dimension of the problem, (2) the relevance of orthopedic forums and communication, (3) free and open-access software for deformity analysis and correction, (4) bidirectional learning opportunities, and the value of fellowships and mentoring between resource-rich and resource-limited countries, and (5) how societies like SICOT can help to tackle the problem. Finally, case examples are presented to demonstrate the choice of surgical implants, their availability in regions with limited resources, and how the universal principles of limb reconstruction can be&nbsp;applied, irrespective of resource availability.ResultsLimb reconstruction can often be life-changing surgery with the goals of limb salvage, improved function, and ambulation. The contradiction of relatively few severe limb deformities in high-income countries (HICs) with abundant resources and the considerable burden of limb deformities in resource-limited countries is striking. Free, open access to education and software planning tools are of paramount importance to achieve this goal of limb reconstruction. Bidirectional learning, i.e., knowledge exchange between individual surgeons and societies with limited and abundant resources, can be reached via fellowships and mentoring. The presented cases highlight (1) fixator-assisted wound closure obliviating the need for plastic surgery, (2) open bone transport, and (3) hinged Ilizarov frames for correction of severe deformities. These cases underline that optimal clinical outcome can be achieved with low-cost and readily available implants when the principles of limb reconstruction are skillfully applied.DiscussionLimb lengthening and reconstruction are based on universally applicable principles. These have to be applied regardless of the planning tool or surgical implant availability to achieve the goals of limb salvage and improved quality of life