Istvan Albert

Structural vulnerability of the North American power grid.

The magnitude of the August 2003 blackout affecting the United States has put the challenges of energy transmission and distribution into limelight. Despite all the interest and concerted effort, the complexity and interconnectivity of the electric infrastructure precluded us for a long time from understanding why certain events happened. In this paper we study the power grid from a network perspective and determine its ability to transfer power between generators and consumers when certain nodes are disrupted. We find that the power grid is robust to most perturbations, yet disturbances affecting key transmission substations greatly reduce its ability to function. We emphasize that the global properties of the underlying network must be understood as they greatly affect local behavior.

Nucleosome organization in the Drosophila genome

Comparative genomics of nucleosome positions provides a powerful means for understanding how the organization of chromatin and the transcription machinery co-evolve. Here we produce a high-resolution reference map of H2A.Z and bulk nucleosome locations across the genome of the fly Drosophila melanogaster and compare it to that from the yeast Saccharomyces cerevisiae. Like Saccharomyces, Drosophila nucleosomes are organized around active transcription start sites in a canonical -1, nucleosome-free region, +1 arrangement. However, Drosophila does not incorporate H2A.Z into the -1 nucleosome and does not bury its transcriptional start site in the +1 nucleosome. At thousands of genes, RNA polymerase II engages the +1 nucleosome and pauses. How the transcription initiation machinery contends with the +1 nucleosome seems to be fundamentally different across major eukaryotic lines.

Translational and rotational settings of H2A.Z nucleosomes across the Saccharomyces cerevisiae genome

The nucleosome is the fundamental building block of eukaryotic chromosomes. Access to genetic information encoded in chromosomes is dependent on the position of nucleosomes along the DNA. Alternative locations just a few nucleotides apart can have profound effects on gene expression. Yet the nucleosomal context in which chromosomal and gene regulatory elements reside remains ill-defined on a genomic scale. Here we sequence the DNA of 322,000 individual Saccharomyces cerevisiae nucleosomes, containing the histone variant H2A.Z, to provide a comprehensive map of H2A.Z nucleosomes in functionally important regions. With a median 4-base-pair resolution, we identify new and established signatures of nucleosome positioning. A single predominant rotational setting and multiple translational settings are evident. Chromosomal elements, ranging from telomeres to centromeres and transcriptional units, are found to possess characteristic nucleosomal architecture that may be important for their function. Promoter regulatory elements, including transcription factor binding sites and transcriptional start sites, show topological relationships with nucleosomes, such that transcription factor binding sites tend to be rotationally exposed on the nucleosome surface near its border. Transcriptional start sites tended to reside about one helical turn inside the nucleosome border. These findings reveal an intimate relationship between chromatin architecture and the underlying DNA sequence it regulates.

MovieLens unplugged: experiences with an occasionally connected recommender system

Recommender systems have changed the way people shop online. Recommender systems on wireless mobile devices may have the same impact on the way people shop in stores. We present our experience with implementing a recommender system on a PDA that is occasionally connected to the network. This interface helps users of the MovieLens movie recommendation service select movies to rent, buy, or see while away from their computer. The results of a nine month field study show that although there are several challenges to overcome, mobile recommender systems have the potential to provide value to their users today

Getting to know you: learning new user preferences in recommender systems

Recommender systems have become valuable resources for users seeking intelligent ways to search through the enormous volume of information available to them. One crucial unsolved problem for recommender systems is how best to learn about a new user. In this paper we study six techniques that collaborative filtering recommender systems can use to learn about new users. These techniques select a sequence of items for the collaborative filtering system to present to each new user for rating. The techniques include the use of information theory to select the items that will give the most value to the recommender system, aggregate statistics to select the items the user is most likely to have an opinion about, balanced techniques that seek to maximize the expected number of bits learned per presented item, and personalized techniques that predict which items a user will have an opinion about. We study the techniques thru offline experiments with a large pre-existing user data set, and thru a live experiment with over 300 users. We show that the choice of learning technique significantly affects the user experience, in both the user effort and the accuracy of the resulting predictions.

Phase III Study of Carboplatin and Paclitaxel Alone or With Sorafenib in Advanced Non–Small-Cell Lung Cancer

PURPOSE This phase III, multicenter, randomized, placebo-controlled trial assessed the efficacy and safety of sorafenib, an oral multikinase inhibitor, in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with unresectable stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Nine hundred twenty-six patients were randomly assigned to receive up to six 21-day cycles of carboplatin area under the curve 6 and paclitaxel 200 mg/m(2) (CP) on day 1, followed by either sorafenib 400 mg twice a day (n = 464, arm A) or placebo (n = 462, arm B) on days 2 to 19. The maintenance phase after CP consisted of sorafenib 400 mg or placebo twice a day. The primary end point was overall survival (OS); secondary end points included progression-free survival and tumor response. RESULTS Overall demographics were balanced between arms; 223 patients (24%) had squamous cell histology. On the basis of a planned interim analysis, median OS was 10.7 months in arm A and 10.6 months in arm B (hazard ratio [HR] = 1.15; 95% CI, 0.94 to 1.41; P = .915). The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point. A prespecified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B (HR = 1.85; 95% CI, 1.22 to 2.81). Main grade 3 or 4 sorafenib-related toxicities included rash (8.4%), hand-foot skin reaction (7.8%), and diarrhea (3.5%). CONCLUSION No clinical benefit was observed from adding sorafenib to CP chemotherapy as first-line treatment for NSCLC.

Nucleosome positions predicted through comparative genomics.

DNA sequence has long been recognized as an important contributor to nucleosome positioning, which has the potential to regulate access to genes. The extent to which the nucleosomal architecture at promoters is delineated by the underlying sequence is now being worked out. Here we use comparative genomics to report a genome-wide map of nucleosome positioning sequences (NPSs) located in the vicinity of all Saccharomyces cerevisiae genes. We find that the underlying DNA sequence provides a very good predictor of nucleosome locations that have been experimentally mapped to a small fraction of the genome. Notably, distinct classes of genes possess characteristic arrangements of NPSs that may be important for their regulation. In particular, genes that have a relatively compact NPS arrangement over the promoter region tend to have a TATA box buried in an NPS and tend to be highly regulated by chromatin modifying and remodeling factors.

On the recommending of citations for research papers

Collaborative filtering has proven to be valuable for recommending items in many different domains. In this paper, we explore the use of collaborative filtering to recommend research papers, using the citation web between papers to create the ratings matrix. Specifically, we tested the ability of collaborative filtering to recommend citations that would be suitable additional references for a target research paper. We investigated six algorithms for selecting citations, evaluating them through offline experiments against a database of over 186,000 research papers contained in ResearchIndex. We also performed an online experiment with over 120 users to gauge user opinion of the effectiveness of the algorithms and of the utility of such recommendations for common research tasks. We found large differences in the accuracy of the algorithms in the offline experiment, especially when balanced for coverage. In the online experiment, users felt they received quality recommendations, and were enthusiastic about the idea of receiving recommendations in this domain.

Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity

The antioxidant tempol reduces obesity in mice. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-β-muricholic acid (T-β-MCA). T-β-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, which is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signalling in the intestine. High-fat diet-fed intestine-specific Fxr-null (Fxr(ΔIE)) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in Fxr(ΔIE) mice, suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signalling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs.

Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet-induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota-associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment.