Probabilistic approaches for modeling text structure and their application to text-to-text generation

Since the early days of generation research, it has been acknowledged that modeling the global structure of a document is crucial for producing coherent, readable output. However, traditional knowledge-intensive approaches have been of limited utility in addressing this problem since they cannot be effectively scaled to operate in domain-independent, large-scale applications. Due to this difficulty, existing text-to-text generation systems rarely rely on such structural information when producing an output text. Consequently, texts generated by these methods do not match the quality of those written by humans – they are often fraught with severe coherence violations and disfluencies. In this chapter, I will present probabilistic models of document structure that can be effectively learned from raw document collections. This feature distinguishes these new models from traditional knowledge intensive approaches used in symbolic concept-to-text generation. Our results demonstrate that these probabilistic models can be directly applied to content organization, and suggest that these models can prove useful in an even broader range of text-to-text applications than we have considered here.National Science Foundation (U.S.) (CAREER grant IIS- 0448168)Microsoft Research. New Faculty Fellowshi

Exploiting the Bipartite Structure of Entity Grids for Document Coherence and Retrieval

International audienceDocument coherence describes how much sense text makes in terms of its logical organisation and discourse flow. Even though coherence is a relatively difficult notion to quantify precisely, it can be approximated automatically. This type of coherence modelling is not only interesting in itself, but also useful for a number of other text processing tasks, including Information Retrieval (IR), where adjusting the ranking of documents according to both their relevance and their coherence has been shown to increase retrieval effectiveness.The state of the art in unsupervised coherence modelling represents documents as bipartite graphs of sentences and discourse entities, and then projects these bipartite graphs into one–mode undirected graphs. However, one–mode projections may incur significant loss of the information present in the original bipartite structure. To address this we present three novel graph metrics that compute document coherence on the original bipartite graph of sentences and entities. Evaluation on standard settings shows that: (i) one of our coherence metrics beats the state of the art in terms of coherence accuracy; and (ii) all three of our coherence metrics improve retrieval effectiveness because, as closer analysis reveals, they capture aspects of document quality that go undetected by both keyword-based standard ranking and by spam filtering. This work contributes document coherence metrics that are theoretically principled, parameter-free, and useful to IR

Prevalence of pathological internet use among adolescents in Europe: demographic and social factors.

AIMS: To investigate the prevalence of pathological internet use (PIU) and maladaptive internet use (MIU) among adolescents in 11 European countries in relation to demographic, social factors and internet accessibility. DESIGN: Cross-sectional survey. SETTING: The 7th Framework European Union (EU) funded project, Saving and Empowering Young Lives in Europe (SEYLE), is a randomized controlled trial (RCT) evaluating interventions for risk behaviours among adolescents in Austria, Estonia, France, Germany, Hungary, Ireland, Israel, Italy, Romania, Slovenia and Spain, with Sweden serving as the coordinating centre. PARTICIPANTS: A total of 11 956 adolescents (female/male: 6731/5225; mean age: 14.9 ± 0.89) recruited from randomly selected schools within the 11 study sites. MEASUREMENTS: Internet users were classified by gender into three categories: adaptive, maladaptive and pathological, based on their score in the Young Diagnostic Questionnaire for Internet Addiction (YDQ). FINDINGS: The overall prevalence of PIU was 4.4%; it was higher among males than females (5.2% versus 3.8%) and differed between countries (χ(2)  = 309.98; d.f. = 20; P < 0.001). PIU correlated significantly with mean hours online and male gender. The highest-ranked online activities were watching videos, frequenting chatrooms and social networking; significantly higher rates of playing single-user games were found in males and social networking in females. Living in metropolitan areas was associated with PIU. Students not living with a biological parent, low parental involvement and parental unemployment showed the highest relative risks of both MIU and PIU. CONCLUSIONS: Across a range of countries in Europe, using the Young Diagnostic Questionnaire for Internet Addiction yields a prevalence of 'pathological internet use' of 4.4% among adolescents, but varies by country and gender; adolescents lacking emotional and psychological support are at highest risk

Isolation of a small molecule inhibitor of DNA base excision repair

The base excision repair (BER) pathway is essential for the removal of DNA bases damaged by alkylation or oxidation. A key step in BER is the processing of an apurinic/apyrimidinic (AP) site intermediate by an AP endonuclease. The major AP endonuclease in human cells (APE1, also termed HAP1 and Ref-1) accounts for >95% of the total AP endonuclease activity, and is essential for the protection of cells against the toxic effects of several classes of DNA damaging agents. Moreover, APE1 overexpression has been linked to radio- and chemo-resistance in human tumors. Using a newly developed high-throughput screen, several chemical inhibitors of APE1 have been isolated. Amongst these, CRT0044876 was identified as a potent and selective APE1 inhibitor. CRT0044876 inhibits the AP endonuclease, 3′-phosphodiesterase and 3′-phosphatase activities of APE1 at low micromolar concentrations, and is a specific inhibitor of the exonuclease III family of enzymes to which APE1 belongs. At non-cytotoxic concentrations, CRT0044876 potentiates the cytotoxicity of several DNA base-targeting compounds. This enhancement of cytotoxicity is associated with an accumulation of unrepaired AP sites. In silico modeling studies suggest that CRT0044876 binds to the active site of APE1. These studies provide both a novel reagent for probing APE1 function in human cells, and a rational basis for the development of APE1-targeting drugs for antitumor therapy

Associations of Insulin and Insulin-Like Growth Factors with Physical Performance in Old Age in the Boyd Orr and Caerphilly Studies

Objective Insulin and the insulin-like growth factor (IGF) system regulate growth and are involved in determining muscle mass, strength and body composition. We hypothesised that IGF-I and IGF-II are associated with improved, and insulin with worse, physical performance in old age. Methods Physical performance was measured using the get-up and go timed walk and flamingo balance test at 63–86 years. We examined prospective associations of insulin, IGF-I, IGF-II and IGFBP-3 with physical performance in the UK-based Caerphilly Prospective Study (CaPS; n = 739 men); and cross-sectional insulin, IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in the Boyd Orr cohort (n = 182 men, 223 women). Results In confounder-adjusted models, there was some evidence in CaPS that a standard deviation (SD) increase in IGF-I was associated with 1.5% faster get-up and go test times (95% CI: −0.2%, 3.2%; p = 0.08), but little association with poor balance, 19 years later. Coefficients in Boyd Orr were in the same direction as CaPS, but consistent with chance. Higher levels of insulin were weakly associated with worse physical performance (CaPS and Boyd Orr combined: get-up and go time = 1.3% slower per SD log-transformed insulin; 95% CI: 0.0%, 2.7%; p = 0.07; OR poor balance 1.13; 95% CI; 0.98, 1.29; p = 0.08), although associations were attenuated after controlling for body mass index (BMI) and co-morbidities. In Boyd Orr, a one SD increase in IGFBP-2 was associated with 2.6% slower get-up and go times (95% CI: 0.4%, 4.8% slower; p = 0.02), but this was only seen when controlling for BMI and co-morbidities. There was no consistent evidence of associations of IGF-II, or IGFBP-3 with physical performance. Conclusions There was some evidence that high IGF-I and low insulin levels in middle-age were associated with improved physical performance in old age, but estimates were imprecise. Larger cohorts are required to confirm or refute the findings

Development and evaluation of human AP endonuclease inhibitors in melanoma and glioma cell lines

AimsModulation of DNA base excision repair (BER) has the potential to enhance response to chemotherapy and improve outcomes in tumours such as melanoma and glioma. APE1, a critical protein in BER that processes potentially cytotoxic abasic sites (AP sites), is a promising new target in cancer. In the current study, we aimed to develop small molecule inhibitors of APE1 for cancer therapy.MethodsAn industry-standard high throughput virtual screening strategy was adopted. The Sybyl8.0 (Tripos, St Louis, MO, USA) molecular modelling software suite was used to build inhibitor templates. Similarity searching strategies were then applied using ROCS 2.3 (Open Eye Scientific, Santa Fe, NM, USA) to extract pharmacophorically related subsets of compounds from a chemically diverse database of 2.6 million compounds. The compounds in these subsets were subjected to docking against the active site of the APE1 model, using the genetic algorithm-based programme GOLD2.7 (CCDC, Cambridge, UK). Predicted ligand poses were ranked on the basis of several scoring functions. The top virtual hits with promising pharmaceutical properties underwent detailed in vitro analyses using fluorescence-based APE1 cleavage assays and counter screened using endonuclease IV cleavage assays, fluorescence quenching assays and radiolabelled oligonucleotide assays. Biochemical APE1 inhibitors were then subjected to detailed cytotoxicity analyses.ResultsSeveral specific APE1 inhibitors were isolated by this approach. The IC(50) for APE1 inhibition ranged between 30 nM and 50 μM. We demonstrated that APE1 inhibitors lead to accumulation of AP sites in genomic DNA and potentiated the cytotoxicity of alkylating agents in melanoma and glioma cell lines.ConclusionsOur study provides evidence that APE1 is an emerging drug target and could have therapeutic application in patients with melanoma and glioma

The mortality rates and the space-time patterns of John Snow’s cholera epidemic map

Background Snow’s work on the Broad Street map is widely known as a pioneering example of spatial epidemiology. It lacks, however, two significant attributes required in contemporary analyses of disease incidence: population at risk and the progression of the epidemic over time. Despite this has been repeatedly suggested in the literature, no systematic investigation of these two aspects was previously carried out. Using a series of historical documents, this study constructs own data to revisit Snow’s study to examine the mortality rate at each street location and the space-time pattern of the cholera outbreak. Methods This study brings together records from a series of historical documents, and prepares own data on the estimated number of residents at each house location as well as the space-time data of the victims, and these are processed in GIS to facilitate the spatial-temporal analysis. Mortality rates and the space-time pattern in the victims’ records are explored using Kernel Density Estimation and network-based Scan Statistic, a recently developed method that detects significant concentrations of records such as the date and place of victims with respect to their distance from others along the street network. The results are visualised in a map form using a GIS platform. Results Data on mortality rates and space-time distribution of the victims were collected from various sources and were successfully merged and digitised, thus allowing the production of new map outputs and new interpretation of the 1854 cholera outbreak in London, covering more cases than Snow’s original report and also adding new insights into their space-time distribution. They confirmed that areas in the immediate vicinity of the Broad Street pump indeed suffered from excessively high mortality rates, which has been suspected for the past 160 years but remained unconfirmed. No distinctive pattern was found in the space-time distribution of victims’ locations. Conclusions The high mortality rates identified around the Broad Street pump are consistent with Snow’s theory about cholera being transmitted through contaminated water. The absence of a clear space-time pattern also indicates the water-bourne, rather than the then popular belief of air bourne, nature of cholera. The GIS data constructed in this study has an academic value and would cater for further research on Snow’s map

Identification of four families of yCCR4- and Mg(2+)-dependent endonuclease-related proteins in higher eukaryotes, and characterization of orthologs of yCCR4 with a conserved leucine-rich repeat essential for hCAF1/hPOP2 binding

BACKGROUND: The yeast yCCR4 factor belongs to the CCR4-NOT transcriptional regulatory complex, in which it interacts, through its leucine-rich repeat (LRR) motif with yPOP2. Recently, yCCR4 was shown to be a component of the major cytoplasmic mRNA deadenylase complex, and to contain a fold related to the Mg(2+)-dependent endonuclease core. RESULTS: Here, we report the identification of nineteen yCCR4-related proteins in eukaryotes (including yeast, plants and animals), which all contain the yCCR4 endonuclease-like fold, with highly conserved CCR4-specific residues. Phylogenetic and genomic analyses show that they form four distinct families, one of which contains the yCCR4 orthologs. The orthologs in animals possess a leucine-rich repeat domain. We show, using two-hybrid and far-Western assays, that the human member binds to the human yPOP2 homologs, i.e. hCAF1 and hPOP2, in a LRR-dependent manner. CONCLUSIONS: We have identified the mammalian orthologs of yCCR4 and have shown that the human member binds to the human yPOP2 homologs, thus strongly suggesting conservation of the CCR4-NOT complex from yeast to human. All members of the four identified yCCR4-related protein families show stricking conservation of the endonuclease-like catalytic motifs of the yCCR4 C-terminal domain and therefore constitute a new family of potential deadenylases in mammals

Maternal but Not Paternal Association of Ambulatory Blood Pressure With Albumin Excretion in Young Offspring With Type 1 Diabetes

OBJECTIVE: Familial predisposition to hypertension has been associated with the development of diabetic nephropathy in adults, but there are limited data in adolescents. Our aim was to assess whether parental ambulatory blood pressure (ABP) was associated with ABP and albumin excretion in young offspring with type 1 diabetes. RESEARCH DESIGN AND METHODS: Twenty-four-hour ABP monitoring was performed in 509 young offspring (mean +/- SD age 15.8 +/- 2.3 years) with type 1 diabetes, 311 fathers, and 444 mothers. Systolic (SBP) and diastolic blood pressure (DBP) measurements during 24 h, daytime, and nighttime were calculated. Three early morning urinary albumin-to-creatinine ratios (ACRs), A1C, and anthropometric parameters were available for the offspring. RESULTS: All paternal ABP parameters, except for nighttime SBP, were independently related to the offspring's ABP (24-h SBP beta = 0.18, 24-h DBP beta = 0.22, daytime SBP beta = 0.25, daytime DBP beta = 0.23, and nighttime DBP beta = 0.18; all P < 0.01). Maternal 24-h DBP (beta = 0.19, P = 0.004), daytime DBP (beta = 0.09, P = 0.04), and nighttime SBP (beta = 0.24 P = 0.001) were related to the corresponding ABP parameter in the offspring. Significant associations were found between the offspring's logACR and maternal ABP. The association with 24-h DBP (beta = 0.16, P = 0.02), daytime DBP (beta = 0.16 P = 0.02), and nighttime DBP (beta = 0.15 P = 0.03) persisted even after adjustment for the offspring's ABP. Mothers of offspring with microalbuminuria had higher ABP than mothers of offspring without microalbuminuria (all P < 0.05). CONCLUSIONS: In this cohort, parental ABP significantly influenced offspring blood pressure, therefore confirming familial influences on this trait. In addition, maternal ABP, particularly DBP, was closely related to ACR in the offspring, suggesting a dominant effect of maternal genes or an effect of the intrauterine environment on microalbuminuria risk