Superfamily Assignments for the Yeast Proteome through Integration of Structure Prediction with the Gene Ontology

Saccharomyces cerevisiae is one of the best-studied model organisms, yet the three-dimensional structure and molecular function of many yeast proteins remain unknown. Yeast proteins were parsed into 14,934 domains, and those lacking sequence similarity to proteins of known structure were folded using the Rosetta de novo structure prediction method on the World Community Grid. This structural data was integrated with process, component, and function annotations from the Saccharomyces Genome Database to assign yeast protein domains to SCOP superfamilies using a simple Bayesian approach. We have predicted the structure of 3,338 putative domains and assigned SCOP superfamily annotations to 581 of them. We have also assigned structural annotations to 7,094 predicted domains based on fold recognition and homology modeling methods. The domain predictions and structural information are available in an online database at http://rd.plos.org/10.1371_journal.pbio.0050076_01

Possible ways to enhance renin-angiotensin prescribing efficiency : Republic of Serbia as a case history?

Multiple reforms have been instigated across Europe to enhance prescribing efficiency. Supply-side reforms in the Republic of Serbia include measures to lower the price of generics and originators, with demand-side measures including patient copayments and prescribing restrictions. Specific measures for renin-angiotensin inhibitor drugs include a 50% copayment for angiotensin receptor blockers (ARBs) versus approximately 50 cents per prescription for established angiotensin-converting enzyme inhibitors (ACEIs), as there is no perceived difference in effectiveness between the two classes. To assess the influence of these measures on ARB utilization, as well as reimbursed prices of ACEIs and ARBs over time. Observational retrospective case study of all ambulatory care patients in the Republic of Serbia's Health Insurance Fund database who were dispensed at least one ACEI or ARB alone or in combination (fixed dose combination [FDC]) between 2005 and 2011. Utilization measured in defined daily doses (DDDs) and only reimbursed expenditure (overall and expenditure/DDD) as Health Insurance perspective. There was a 1.8-fold increase in renin-angiotensin inhibitor drug utilization, rising to 207.4 DDDs/1000 inhabitants per day in 2011. This is driven principally by a 19.6-fold increase in ACEI FDCs. There was only limited utilization of ARBs at just 2% of total renin-angiotensin inhibitor drugs in 2011. Reimbursed expenditure increased 2.54-fold due to an appreciable increase in ACEI FDC utilization at approximately twice the cost of ACEIs in recent years. Alongside this, we noted considerable differences in expenditure/DDD for different ACEIs. High patient copayments for ARBs appreciably limited their utilization in Serbia, which mirrors the findings from other studies. Potential future measures to enhance prescribing efficiency include reference pricing for ACEIs based on the lowest price of an established ACEI. In addition, reference pricing for FDCs should be based on the reference price of the individual components combined. This builds on recent reforms restricting the reimbursement of FDCs until 3 months after individual components have been prescribed separately

CD40 expression in uterine tissues: A key regulator of cytokine expression by fibroblasts

CD40 is a cell surface receptor initially discovered on cells of the hemopoietic lineage. Its primary role on immune cells is to enhance their activation and hence their production of cytokines and immunomodulatory molecules. Recently, CD40 has also been detected on human fibroblasts. An emerging view of the fibroblast is that it is far more than a structural cell, being capable of intimate interaction with cells of the immune system. In fibroblasts from several tissues, the engagement of CD40 with its ligand (CD40L) resulted in the secretion of proinflammatory molecules such as interleukin-6 (IL-6) and IL-8. Currently, there are few data about the presence of the CD40-CD40L system in female reproductive tissues. This study investigates the expression of CD40 by human endometrium, myometrium, and cenix both in situ and in tissue explant-derived fibroblasts. CD40 was detected mainly in the perivascular region of endometrium, myometrium, and cervix. Light staining for CD40 was observed in stromal elements. Additionally, the basal epithelium of cenix expressed CD40. Fibroblastic cells derived from all three sources express low levels of CD40, and this is up-regulated with interferon-gamma treatment (500 U/mL; 72 h). When activated with interferon-gamma and CD40L, the fibroblasts secreted increased amounts of IL-6, IL-8, and MCP-1. These data suggest that the CD40-CD40L system may provide a link between the resident structural cells of these reproductive tissues and the infiltrating immune cells or activated platelets that may express CD40L. The possible interaction of CD40 with CD40L may be particularly important during events such as menstruation and cervical ripening, where up-regulation of the proinflammatory molecules IL-6 and IL-8 is viewed as critical for these processes. In addition, dysregulation of this system may be a contributory factor to problems such as menstrual dysfunction and preterm labor

De novo prediction of three-dimensional structures for major protein families

As the number of gene sequences in databases, public and private, increase dramatically, so do the number of genes of unknown function. Of the protein sequences currently available approximatel

Interface management of pharmacotherapy : joint hospital and primary care drug recommendations

Purpose: In September 2012 an interactive course on the "Interface Management of Pharmacotherapy" was organized by the Stockholm Drug and Therapeutics Committee in cooperation with Department of Clinical Pharmacology at Karolinska Institutet and at Karolinska University Hospital in Stockholm, Sweden, in collaboration with the WHO. The basis for the course was the "Stockholm model" for the rational use of medicines but also contained presentations about successful models in interface management of pharmacotherapy in other European countries. Methods: The "Stockholm model " consists of 8 components: 1) Independent Drug and Therapeutics Committee with key role for respected drug experts with policy for "interest of conflicts", 2) The "Wise List", recommendations of medicines jointly for primary and hospital care, 3) Communication strategy with continuous medical education, 4) Systematic introduction of new expensive medicines, 5) E-pharmacological support at "point of care", 6) Methods and tools for follow-up of medicines use, 7) Medicines policy strategy and 8) Operative resources. Results: The course highlighted the importance of efficient and targeted communication of drug recommendations building on trust among prescribers and patients for the guidelines to achieve high adherence. Trust is achieved by independent Drug and Therapeutics Committees with a key role for respected experts and a strict policy for "conflicts of interest". Representations of GPs are also crucial for successful implementation, being the link between evidence based medicine and practice. Conclusion: The successful models in Scotland and in Stockholm as well as the ongoing work in Catalonia were considered as examples of multifaceted approaches to improve the quality of medicine use across primary and hospital care

The genetic prehistory of the New World Arctic

The New World Arctic, the last region of the Americas to be populated by humans, has a relatively well-researched archaeology, but an understanding of its genetic history is lacking. We present genome-wide sequence data from ancient and present-day humans from Greenland, Arctic Canada, Alaska, Aleutian Islands, and Siberia. We show that Paleo-Eskimos (~3000 BCE to 1300 CE) represent a migration pulse into the Americas independent of both Native American and Inuit expansions. Furthermore, the genetic continuity characterizing the Paleo-Eskimo period was interrupted by the arrival of a new population, representing the ancestors of present-day Inuit, with evidence of past gene flow between these lineages. Despite periodic abandonment of major Arctic regions, a single Paleo-Eskimo metapopulation likely survived in near-isolation for more than 4000 years, only to vanish around 700 years ago