M-theory on `toric' G_2 cones and its type II reduction

We analyze a class of conical G_2 metrics admitting two commuting isometries, together with a certain one-parameter family of G_2 deformations which preserves these symmetries. Upon using recent results of Calderbank and Pedersen, we write down the explicit G_2 metric for the most general member of this family and extract the IIA reduction of M-theory on such backgrounds, as well as its type IIB dual. By studying the asymptotics of type II fields around the relevant loci, we confirm the interpretation of such backgrounds in terms of localized IIA 6-branes and delocalized IIB 5-branes. In particular, we find explicit, general expressions for the string coupling and R-R/NS-NS forms in the vicinity of these objects. Our solutions contain and generalize the field configurations relevant for certain models considered in recent work of Acharya and Witten.Comment: 45 pages, references adde

Collapsing D-branes in one-parameter models and small/large radius duality

We finalize the study of collapsing D-branes in one-parameter models by completing the analysis of the associated hypergeometric hierarchy. This brings further evidence that the phenomenon of collapsing 6-branes at the mirror of the `conifold' point in IIA compactifications on one-parameter Calabi-Yau manifolds is generic. It also completes the reduction of the study of higher periods in one-parameter models to a few families which display characteristic behaviour. One of the models we consider displays an exotic form of small-large radius duality, which is a consequence of an ``accidental'' discrete symmetry of its moduli space. We discuss the implementation of this symmetry at the level of the associated type II string compactification and its action on D-brane states. We also argue that this model admits two special Lagrangian fibrations and that the symmetry can be understood as their exchange.Comment: 34 pages, 12 figure

A Point's Point of View of Stringy Geometry

The notion of a "point" is essential to describe the topology of spacetime. Despite this, a point probably does not play a particularly distinguished role in any intrinsic formulation of string theory. We discuss one way to try to determine the notion of a point from a worldsheet point of view. The derived category description of D-branes is the key tool. The case of a flop is analyzed and Pi-stability in this context is tied in to some ideas of Bridgeland. Monodromy associated to the flop is also computed via Pi-stability and shown to be consistent with previous conjectures.Comment: 15 pages, 3 figures, ref adde

Collapsing D-Branes in Calabi-Yau Moduli Space: I

We study the quantum volume of D-branes wrapped around various cycles in Calabi-Yau manifolds, as the manifold's moduli are varied. In particular, we focus on the behaviour of these D-branes near phase transitions between distinct low energy physical descriptions of the resulting string theory. Whereas previous studies have solely considered quantum volumes in the context of two-cycles in perturbative string theory or D-branes in the specific example of the quintic hypersurface, we work more generally and find qualitatively new features. On the mathematical side, as we briefly note, our work has some interesting implications for certain issues in arithmetics.Comment: 77 pages, 15 figure

The Richit-Richards family of distributions and its use in forestry

Johnson's SB and the logit-logistic are four-parameter distribution models that may be obtained from the standard normal and logistic distributions by a four-parameter transformation. For relatively small data sets, such as diameter at breast height measurements obtained from typical sample plots, distribution models with four or less parameters have been found to be empirically adequate. However, in situations in which the distributions are complex, for example in mixed stands or when the stand has been thinned or when working with aggregated data, then distribution models with more shape parameters may prove to be necessary. By replacing the symmetric standard logistic distribution of the logit-logistic with a one-parameter “standard Richards” distribution and transforming by a five-parameter Richards function, we obtain a new six-parameter distribution model, the “Richit-Richards”. The Richit-Richards includes the “logit-Richards”, the “Richit-logistic”, and the logit-logistic as submodels. Maximum likelihood estimation is used to fit the model, and some problems in the maximum likelihood estimation of bounding parameters are discussed. An empirical case study of the Richit-Richards and its submodels is conducted on pooled diameter at breast height data from 107 sample plots of Chinese fir (Cunninghamia lanceolata (Lamb.) Hook.). It is found that the new models provide significantly better fits than the four-parameter logit-logistic for large data sets

Synaptic vesicle dynamic changes in a model of fragile X

__Background:__ Fragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs). The extent of expression level alterations of synaptic proteins affected by FMRP loss and their consequences on synaptic dynamics in FXS has not been fully investigated. __Methods:__ Here, we used an Fmr1 knockout (KO) mouse model to investigate the molecular mechanisms underlying FXS by monitoring protein expression changes using shotgun label-free liquid-chromatography mass spectrometry (LC-MSE) in brain tissue and synaptosome fractions. FXS-associated candidate proteins were validated using selected reaction monitoring (SRM) in synaptosome fractions for targeted protein quantification. Furthermore, functional alterations in synaptic release and dynamics were evaluated using live-cell imaging, and interpretation of synaptic dynamics differences was investigated using electron microscopy. __Results:__ Key findings relate to altered levels of proteins involved in GABA-signalling, especially in the cerebellum. Further exploration using microscopy studies found reduced synaptic vesicle unloading of hippocampal neurons and increased vesicle unloading in cerebellar neurons, which suggests a general decrease of synaptic transmission. __Conclusions:__ Our findings suggest that FMRP is a regulator of synaptic vesicle dynamics, which supports the role of FMRP in presynaptic functions. Taken together, these studies provide novel insights into the molecular changes associated with FXS

Global Search for New Physics with 2.0/fb at CDF

Data collected in Run II of the Fermilab Tevatron are searched for indications of new electroweak-scale physics. Rather than focusing on particular new physics scenarios, CDF data are analyzed for discrepancies with the standard model prediction. A model-independent approach (Vista) considers gross features of the data, and is sensitive to new large cross-section physics. Further sensitivity to new physics is provided by two additional algorithms: a Bump Hunter searches invariant mass distributions for "bumps" that could indicate resonant production of new particles; and the Sleuth procedure scans for data excesses at large summed transverse momentum. This combined global search for new physics in 2.0/fb of ppbar collisions at sqrt(s)=1.96 TeV reveals no indication of physics beyond the standard model.Comment: 8 pages, 7 figures. Final version which appeared in Physical Review D Rapid Communication

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification

Background Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. Methods Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. Results Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12–3.50, P-value = 4.13 × 10−15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99–2.49, P-value = 5.70 × 10−46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72–0.74). Conclusions Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

Iam hiQ—a novel pair of accuracy indices for imputed genotypes

Background Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand. Results Applying both measures to a large case–control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2). Conclusion We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data