Plant-Symbiotic Fungi as Chemical Engineers: Multi-Genome Analysis of the Clavicipitaceae Reveals Dynamics of Alkaloid Loci

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some—including the infamous ergot alkaloids—have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses

Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the Clavicipitaceae reveals dynamics of alkaloid Loci

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some—including the infamous ergot alkaloids—have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses

HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

A New Yardstick and Tool for Personalized Vocabulary Building

The goal of this research is to increase the value of each individual student&apos;s vocabulary by finding words that the student doesn’t know, needs to, and is ready to learn. To help identify such words, a better model of how well any given word is expected to be known was created. This is accomplished by using a semantic language model, LSA, to track how every word changes with the addition of more and more text from an appropriate corpus. We define the “maturity” of a word as the degree to which it has become similar to that after training on the entire corpus. An individual student’s average vocabulary level can then be placed on the word-maturity scale by an adaptive test. Finally, the words that the student did or did not know on the test can be used to predict what other words the same student knows by using multiple maturity models trained on random samples of typical educational readings. This detailed information can be used to generate highly customized vocabulary teaching and testing exercises, such as Cloze tests

Inflammatory Bowel Disease: A Canadian Burden of Illness Review

BACKGROUND: Inflammatory bowel diseases (IBD) – Crohn’s disease (CD) and ulcerative colitis (UC) – significantly impact quality of life and account for substantial costs to the health care system and society

Robust Resource Allocation in a Massive Multiplayer Online Gaming Environment

The environment considered in this research is a massive multiplayer online gaming (MMOG) environment. Each user controls an avatar (an image that represents and is manipulated by a user) in a virtual world and interacts with other users. An important aspect of MMOG is maintaining a fair environment among users (i.e., not give an unfair advantage to users with faster connections or more powerful computers). The experience (either positive or negative) the user has with the MMOG environment is dependent on how quickly the game world responds to the user’s actions. This study focuses on scaling the system based on demand, while maintaining an environment that guarantees fairness. Consider an environment where there is a main server (MS) that controls the state of the virtual world. If the performance falls below acceptable standards, the MS can off-load calculations to secondary servers (SSs). An SS is a user’s computer that is converted into a server. Four heuristics are proposed for determining the number of SSs, which users are converted to SSs, and how users are assigned to the SSs and the MS. The goal of the heuristics is to provide a “fair ” environment for all the users, and to be “robust ” against the uncertainty of the number of new players that may join a given system configuration. The heuristics are evaluated and compared by simulation

This article has been accepted for publication in a future issue of this journal, but has not been fully edited. Content may change prior to final publication. IEEE TRANSACTIONS ON COMPUTERS Resource Allocation in a Client/Server System for Massive Multi-

The creation of a Massive Multi-Player On-line Game (MMOG) has significant costs, such as maintenance of server rooms, server administration, and customer service. The capacity of servers in a client/server MMOG is hard to scale and cannot adjust quickly to peaks in demand while maintaining the required response time. To handle these peaks in demand, we propose to employ users ’ computers as secondary servers. The introduction of users ’ computers as secondary servers allows the performance of the MMOG to support an increase in users. Here, we consider two cases. First, for the minimization of the response times from the server, we develop and implement five static heuristics to implement a secondary server scheme that reduces the time taken to compute the state of the MMOG. Second, for our study on fairness, the goal of the heuristics is to provide a “fair ” environment for all the users (in terms of similar response times), and to be “robust ” against the uncertainty of the number of new players that may join a given system configuration. The number of heterogeneous secondary servers, conversion of a player to a secondary server, and assignment of players to secondary servers are determined by the heuristics implemented in this study. I