Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker.

Profenofos is a direct acting phosphorothioate organophosphorus (OP) pesticide capable of inhibiting β-esterases such as acetylcholinesterase, butyrylcholinesterase, and carboxylesterase. Profenofos is known to be detoxified to the biologically inactive metabolite, 4-bromo-2-chlorophenol (BCP); however, limited data are available regarding the use of urinary BCP as an exposure biomarker in humans. A pilot study conducted in Egyptian agriculture workers, demonstrated that urinary BCP levels prior to application (3.3-30.0 μg/g creatinine) were elevated to 34.5-3,566 μg/g creatinine during the time workers were applying profenofos to cotton fields. Subsequently, the in vitro enzymatic formation of BCP was examined using pooled human liver microsomes and recombinant human cytochrome P-450s (CYPs) incubated with profenofos. Of the nine human CYPs studied, only CYPs 3A4, 2B6, and 2C19 were able to metabolize profenofos to BCP. Kinetic studies indicated that CYP 2C19 has the lowest Km, 0.516 μM followed by 2B6 (Km=1.02 μM) and 3A4 (Km=18.9μM). The Vmax for BCP formation was 47.9, 25.1, and 19.2 nmol/min/nmol CYP for CYP2B6, 2C19, and 3A4, respectively. Intrinsic clearance (Vmax/Km) values of 48.8, 46.9, and 1.02 ml/min/nmol CYP 2C19, 2B6, and 3A4, respectively, indicate that CYP2C19 and CYP2B6 are primarily responsible for the detoxification of profenofos. These findings support the use of urinary BCP as a biomarker of exposure to profenofos in humans and suggest polymorphisms in CYP 2C19 and CYP 2B6 as potential biomarkers of susceptibility

Tbx1 Regulates the BMP-Smad1 Pathway in a Transcription Independent Manner

Tbx1 is a T-box transcription factor implicated in DiGeorge syndrome. The molecular function of Tbx1 is unclear although it can transactivate reporters with T-box binding elements. We discovered that Tbx1 binds Smad1 and suppresses the Bmp4/Smad1 signaling. Tbx1 interferes with Smad1 to Smad4 binding, and a mutation of Tbx1 that abolishes transactivation, does not affect Smad1 binding nor does affect the ability to suppress Smad1 activity. In addition, a disease-associated mutation of TBX1 that does not prevent transactivation, prevents the TBX1-SMAD1 interaction. Expression of Tbx1 in transgenic mice generates phenotypes similar to those associated with loss of a Bmp receptor. One phenotype could be rescued by transgenic Smad1 expression. Our data indicate that Tbx1 interferes with Bmp/Smad1 signaling and provide strong evidence that a T-box transcription factor has functions unrelated to transactivation

Carboxypeptidase A6 in Zebrafish Development and Implications for VIth Cranial Nerve Pathfinding

Carboxypeptidase A6 (CPA6) is an extracellular protease that cleaves carboxy-terminal hydrophobic amino acids and has been implicated in the defective innervation of the lateral rectus muscle by the VIth cranial nerve in Duane syndrome. In order to investigate the role of CPA6 in development, in particular its potential role in axon guidance, the zebrafish ortholog was identified and cloned. Zebrafish CPA6 was secreted and interacted with the extracellular matrix where it had a neutral pH optimum and specificity for C-terminal hydrophobic amino acids. Transient mRNA expression was found in newly formed somites, pectoral fin buds, the stomodeum and a conspicuous condensation posterior to the eye. Markers showed this tissue was not myogenic in nature. Rather, the CPA6 localization overlapped with a chondrogenic site which subsequently forms the walls of a myodome surrounding the lateral rectus muscle. No other zebrafish CPA gene exhibited a similar expression profile. Morpholino-mediated knockdown of CPA6 combined with retrograde labeling and horizontal eye movement analyses demonstrated that deficiency of CPA6 alone did not affect either VIth nerve development or function in the zebrafish. We suggest that mutations in other genes and/or enhancer elements, together with defective CPA6 expression, may be required for altered VIth nerve pathfinding. If mutations in CPA6 contribute to Duane syndrome, our results also suggest that Duane syndrome can be a chondrogenic rather than a myogenic or neurogenic developmental disorder

Deterministic Sampling and Range Counting in Geometric Data Streams

We present memory-efficient deterministic algorithms for constructing epsilon-nets and epsilon-approximations of streams of geometric data. Unlike probabilistic approaches, these deterministic samples provide guaranteed bounds on their approximation factors. We show how our deterministic samples can be used to answer approximate online iceberg geometric queries on data streams. We use these techniques to approximate several robust statistics of geometric data streams, including Tukey depth, simplicial depth, regression depth, the Thiel-Sen estimator, and the least median of squares. Our algorithms use only a polylogarithmic amount of memory, provided the desired approximation factors are inverse-polylogarithmic. We also include a lower bound for non-iceberg geometric queries.Comment: 12 pages, 1 figur

Linear-Space Approximate Distance Oracles for Planar, Bounded-Genus, and Minor-Free Graphs

A (1 + eps)-approximate distance oracle for a graph is a data structure that supports approximate point-to-point shortest-path-distance queries. The most relevant measures for a distance-oracle construction are: space, query time, and preprocessing time. There are strong distance-oracle constructions known for planar graphs (Thorup, JACM'04) and, subsequently, minor-excluded graphs (Abraham and Gavoille, PODC'06). However, these require Omega(eps^{-1} n lg n) space for n-node graphs. We argue that a very low space requirement is essential. Since modern computer architectures involve hierarchical memory (caches, primary memory, secondary memory), a high memory requirement in effect may greatly increase the actual running time. Moreover, we would like data structures that can be deployed on small mobile devices, such as handhelds, which have relatively small primary memory. In this paper, for planar graphs, bounded-genus graphs, and minor-excluded graphs we give distance-oracle constructions that require only O(n) space. The big O hides only a fixed constant, independent of \epsilon and independent of genus or size of an excluded minor. The preprocessing times for our distance oracle are also faster than those for the previously known constructions. For planar graphs, the preprocessing time is O(n lg^2 n). However, our constructions have slower query times. For planar graphs, the query time is O(eps^{-2} lg^2 n). For our linear-space results, we can in fact ensure, for any delta > 0, that the space required is only 1 + delta times the space required just to represent the graph itself

Non-Monochromatic and Conflict-Free Coloring on Tree Spaces and Planar Network Spaces

It is well known that any set of n intervals in $\mathbb{R}^1$ admits a non-monochromatic coloring with two colors and a conflict-free coloring with three colors. We investigate generalizations of this result to colorings of objects in more complex 1-dimensional spaces, namely so-called tree spaces and planar network spaces

A Novel Analytical Framework for Dissecting the Genetic Architecture of Behavioral Symptoms in Neuropsychiatric Disorders

Background: For diagnosis of neuropsychiatric disorders, a categorical classification system is often utilized as a simple way for conceptualizing an often complex clinical picture. This approach provides an unsatisfactory model of mental illness, since in practice patients do not conform to these prototypical diagnostic categories. Family studies show notable familial co-aggregation between schizophrenia and bipolar illness and between schizoaffective disorders and both bipolar disorder and schizophrenia, revealing that mental illness does not conform to such categorical models and is likely to follow a continuum encompassing a spectrum of behavioral symptoms. Results and Methodology: We introduce an analytic framework to dissect the phenotypic heterogeneity present in complex psychiatric disorders based on the conceptual paradigm of a continuum of psychosis. The approach identifies subgroups of behavioral symptoms that are likely to be phenotypically and genetically homogenous. We have evaluated this approach through analysis of simulated data with simulated behavioral traits and predisposing genetic factors. We also apply this approach to a psychiatric dataset of a genome scan for schizophrenia for which extensive behavioral information was collected for each individual patient and their families. With this approach, we identified significant evidence for linkage among depressed individuals with two distinct symptom profiles, that is individuals with sleep disturbance symptoms with linkage on chromosome 2q13 and also a mutually exclusive group of individuals with symptoms of concentration problems with linkage on chromosome 2q35. In addition we identified a subset of individuals with schizophrenia defined by language disturbances with linkage to chromosome 2p25.1 and a group of patients with a phenotype intermediate between those of schizophrenia and schizoaffective disorder with linkage to chromosome 2p21. Conclusions: The findings presented are novel and demonstrate the efficacy of this approach in detection of genes underlying such complex human disorders as schizophrenia and depression

A well-separated pairs decomposition algorithm for k-d trees implemented on multi-core architectures

Content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence. Any further distribution of this work must maintain attribution to the author(s) and the title of the work, journal citation and DOI.Variations of k-d trees represent a fundamental data structure used in Computational Geometry with numerous applications in science. For example particle track tting in the software of the LHC experiments, and in simulations of N-body systems in the study of dynamics of interacting galaxies, particle beam physics, and molecular dynamics in biochemistry. The many-body tree methods devised by Barnes and Hutt in the 1980s and the Fast Multipole Method introduced in 1987 by Greengard and Rokhlin use variants of k-d trees to reduce the computation time upper bounds to O(n log n) and even O(n) from O(n2). We present an algorithm that uses the principle of well-separated pairs decomposition to always produce compressed trees in O(n log n) work. We present and evaluate parallel implementations for the algorithm that can take advantage of multi-core architectures.The Science and Technology Facilities Council, UK

The current status of the case report: Terminal or viable?

The case report, which has a long history in medicine, has seen its fortune wax and wane with time. We discuss the challenges facing the continued survival of the case report, including the inability of journals to cope with the increased load and increased cost of publication, ethical issues, the impact factor and the rise of evidence-based medicine. We highlight the important role that the case report will continue to play in medical research and education, as a means of sharing information and detecting novelty through observations. Most importantly, the case report serves as a stepping stone for young physicians and practitioners into the world of medical writing