Toward an Interactive, Patient-Specific, VR-Based Obstetrics Simulator

This paper presents a nascent collaborative effort to achieve a Virtual Reality (VR)-based, real-time, haptics-driven patient-specific obstetrics simulator. The high-level architecture and preliminary results are presented here; the latter are based on offline birthing simulation developed by team in conjunction with open-source visualization tools. The cornerstones of this simulator will be high-fidelity generic offline birthing simulation, an anatomy-to-image nonrigid registration pipeline exploiting fetal MRI, the open-source interactive medical simulation toolkit IMSTK augmented by high-throughput deep learning-based soft tissue deformation, open-source musculoskeletal dynamics simulation platform SimTk for representing fetal motion. The initial emphasis will be on shoulder dystocia. The two main advantages of VR simulation over the current state of the art, birthing mannequins, are first that VR simulation enables training on several maneuvers by the obstetrics resident while the mannequin typically supports one maneuver, and second, a VR system flexibly supports patient-specific simulation, which is basically infeasible with a mannequin

Independence in CLP Languages

Studying independence of goals has proven very useful in the context of logic programming. In particular, it has provided a formal basis for powerful automatic parallelization tools, since independence ensures that two goals may be evaluated in parallel while preserving correctness and eciency. We extend the concept of independence to constraint logic programs (CLP) and prove that it also ensures the correctness and eciency of the parallel evaluation of independent goals. Independence for CLP languages is more complex than for logic programming as search space preservation is necessary but no longer sucient for ensuring correctness and eciency. Two additional issues arise. The rst is that the cost of constraint solving may depend upon the order constraints are encountered. The second is the need to handle dynamic scheduling. We clarify these issues by proposing various types of search independence and constraint solver independence, and show how they can be combined to allow dierent optimizations, from parallelism to intelligent backtracking. Sucient conditions for independence which can be evaluated \a priori" at run-time are also proposed. Our study also yields new insights into independence in logic programming languages. In particular, we show that search space preservation is not only a sucient but also a necessary condition for ensuring correctness and eciency of parallel execution

A new antibiotic with potent activity targets MscL

The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.Irene Iscla, Robin Wray, Paul Blount, Jonah Larkins-Ford, Annie L Conery, Frederick M Ausubel, Soumya Ramu, Angela Kavanagh, Johnny X Huang, Mark A Blaskovich, Matthew A Cooper, Andres Obregon-Henao, Ian Orme, Edwin S Tjandra, Uwe H Stroeher, Melissa H Brown, Cindy Macardle, Nick van Holst, Chee Ling Tong, Ashley D Slattery, Christopher T Gibson, Colin L Raston and Ramiz A Boulo

Genomic analysis of the function of the transcription factor gata3 during development of the Mammalian inner ear

We have studied the function of the zinc finger transcription factor gata3 in auditory system development by analysing temporal profiles of gene expression during differentiation of conditionally immortal cell lines derived to model specific auditory cell types and developmental stages. We tested and applied a novel probabilistic method called the gamma Model for Oligonucleotide Signals to analyse hybridization signals from Affymetrix oligonucleotide arrays. Expression levels estimated by this method correlated closely (p<0.0001) across a 10-fold range with those measured by quantitative RT-PCR for a sample of 61 different genes. In an unbiased list of 26 genes whose temporal profiles clustered most closely with that of gata3 in all cell lines, 10 were linked to Insulin-like Growth Factor signalling, including the serine/threonine kinase Akt/PKB. Knock-down of gata3 in vitro was associated with a decrease in expression of genes linked to IGF-signalling, including IGF1, IGF2 and several IGF-binding proteins. It also led to a small decrease in protein levels of the serine-threonine kinase Akt2/PKB beta, a dramatic increase in Akt1/PKB alpha protein and relocation of Akt1/PKB alpha from the nucleus to the cytoplasm. The cyclin-dependent kinase inhibitor p27(kip1), a known target of PKB/Akt, simultaneously decreased. In heterozygous gata3 null mice the expression of gata3 correlated with high levels of activated Akt/PKB. This functional relationship could explain the diverse function of gata3 during development, the hearing loss associated with gata3 heterozygous null mice and the broader symptoms of human patients with Hearing-Deafness-Renal anomaly syndrome

The evolutionary demography of duplicate genes

Key words: gene duplication, genome evolution, genome size Although gene duplication has generally been viewed as a necessary source of material for the origin of evolu-tionary novelties, the rates of origin, loss, and preservation of gene duplicates are not well understood. Applying steady-state demographic techniques to the age distributions of duplicate genes censused in seven completely sequenced genomes, we estimate the average rate of duplication of a eukaryotic gene to be on the order of 0.01/ gene/million years, which is of the same order of magnitude as the mutation rate per nucleotide site. However, the average half-life of duplicate genes is relatively small, on the order of 4.0 million years. Significant inter-specific variation in these rates appears to be responsible for differences in species-specific genome sizes that arise as a consequence of a quasi-equilibrium birth-death process. Most duplicated genes experience a brief period of relaxed selection early in their history and a minority exhibit the signature of directional selection, but those that survive more than a few million years eventually experience strong purifying selection. Thus, although most theoretical work on the gene-duplication process has focused on issues related to adaptive evolution, the origin of a new function appears to be a very rare fate for a duplicate gene. A more significant role of the duplication process may be the generation of microchromosomal rearrangements through reciprocal silencing of alternativ

BRCA1 Interacts with Smad3 and Regulates Smad3-Mediated TGF-β Signaling during Oxidative Stress Responses

BRCA1 is a key regulatory protein participating in cell cycle checkpoint and DNA damage repair networks. BRCA1 plays important roles in protecting numerous cellular processes in response to cell damaging signals. Transforming growth factor-beta (TGF-beta) is a potent regulator of growth, apoptosis and invasiveness of tumor cells. TFG-beta activates Smad signaling via its two cell surface receptors, the TbetaRII and ALK5/TbetaRI, leading to Smad-mediated transcriptional regulation.Here, we report an important role of BRCA1 in modulating TGF-beta signaling during oxidative stress responses. Wild-type (WT) BRCA1, but not mutated BRCA1 failed to activate TGF-beta mediated transactivation of the TGF-beta responsive reporter, p3TP-Lux. Further, WT-BRCA1, but not mutated BRCA1 increased the expression of Smad3 protein in a dose-dependent manner, while silencing of WT-BRCA1 by siRNA decreased Smad3 and Smad4 interaction induced by TGF-beta in MCF-7 breast cancer cells. BRCA1 interacted with Smad3 upon TGF-beta1 stimulation in MCF-7 cells and this interaction was mediated via the domain of 298-436aa of BRCA1 and Smad3 domain of 207-426aa. In addition, H(2)O(2) increased the colocalization and the interaction of Smad3 with WT-BRCA1. Interestingly, TGF-beta1 induced Smad3 and Smad4 interaction was increased in the presence of H(2)O(2) in cells expressing WT-BRCA1, while the TGF-beta1 induced interaction between Smad3 and Smad4 was decreased upon H(2)O(2) treatment in a dose-dependent manner in HCC1937 breast cancer cells, deficient for endogenous BRCA1. This interaction between Smad3 and Smad4 was increased in reconstituted HCC1937 cells expressing WT-BRCA1 (HCC1937/BRCA1). Further, loss of BRCA1 resulted in H(2)O(2) induced nuclear export of phosphor-Smad3 protein to the cytoplasm, resulting decreased of Smad3 and Smad4 interaction induced by TGF-beta and in significant decrease in Smad3 and Smad4 transcriptional activities.These results strongly suggest that loss or reduction of BRCA1 alters TGF-beta growth inhibiting activity via Smad3 during oxidative stress responses

TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM) on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta) signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited.</p> <p>Methods</p> <p>Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF-beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4) in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2) vs. high-grade (i.e. grade 3 and 4)), lymph node metastasis, distant metastasis, 5 year cancer related survival) using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed.</p> <p>Results</p> <p>High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and shorter survival. Stromal TGF-beta receptor 2 expression was an independent prognostic factor for cancer related survival.</p> <p>Conclusion</p> <p>Histological phenotype and clinical behaviour of colon cancer is not only influenced by mutational incidents in tumour cells but also affected by interaction of tumour tissue with inflammatory cells like macrophages and associated stroma and TGF-beta signalling is one important part of this crosstalk. Further studies are needed to elucidate the exact mechanisms.</p

Design and implementation of a generalized laboratory data model

<p>Abstract</p> <p>Background</p> <p>Investigators in the biological sciences continue to exploit laboratory automation methods and have dramatically increased the rates at which they can generate data. In many environments, the methods themselves also evolve in a rapid and fluid manner. These observations point to the importance of robust information management systems in the modern laboratory. Designing and implementing such systems is non-trivial and it appears that in many cases a database project ultimately proves unserviceable.</p> <p>Results</p> <p>We describe a general modeling framework for laboratory data and its implementation as an information management system. The model utilizes several abstraction techniques, focusing especially on the concepts of inheritance and meta-data. Traditional approaches commingle event-oriented data with regular entity data in <it>ad hoc </it>ways. Instead, we define distinct regular entity and event schemas, but fully integrate these via a standardized interface. The design allows straightforward definition of a "processing pipeline" as a sequence of events, obviating the need for separate workflow management systems. A layer above the event-oriented schema integrates events into a workflow by defining "processing directives", which act as automated project managers of items in the system. Directives can be added or modified in an almost trivial fashion, i.e., without the need for schema modification or re-certification of applications. Association between regular entities and events is managed via simple "many-to-many" relationships. We describe the programming interface, as well as techniques for handling input/output, process control, and state transitions.</p> <p>Conclusion</p> <p>The implementation described here has served as the Washington University Genome Sequencing Center's primary information system for several years. It handles all transactions underlying a throughput rate of about 9 million sequencing reactions of various kinds per month and has handily weathered a number of major pipeline reconfigurations. The basic data model can be readily adapted to other high-volume processing environments.</p

Cyclooxygenase-2 overexpression abrogates the antiproliferative effects of TGF-β

The influence of cyclooxygenase-2 (COX-2) overexpression on the development of tumours has been well documented. The underlying mechanism however has still not been completely elucidated. An escape of proliferating cells from the regulatory influence of TGF-β for example in the intestine has been discussed as well as a preponderance or prolongation of growth factor stimulation. The experiments presented here demonstrated that COX-2 transfection of a TGF-β-sensitive cell line abrogates the growth inhibitory effects of TGF-β. However, analysis of the TGF-β/Smad-signalling pathway clearly revealed that COX-2 overexpression did not interfere with that. Neither TGF-receptor expression nor Smad phosphorylation and signal transfer into the nucleus were influenced by COX-2 overexpression. In addition, a TGF-β reporter assay revealed no difference between controls and COX-2-transfected cells. Thus, the proliferation inhibiting effects must have been well compensated by growth-inducing stimuli. Indications for this came from experiments showing an induction of TGF-α expression and secretion with a higher and prolonged stimulation of the ERK 1/2 (p42/44) pathway in COX-2 transfectants. This effect could have been triggered by direct prostaglandin receptor stimulation or changes in intracellular lipid mediators. An increase in PPAR signalling as proven by a reporter assay is indication for the latter. Therefore, inhibiting both COX-2 as well as the PPAR and TGF/EGF pathway could be effective in the inhibition of adenoma or even carcinoma development in the intestine

Mitochondrial Pseudogenes in the Nuclear Genomes of Drosophila

Mitochondrial pseudogenes in nuclear chromosomes (numts) have been detected in the genomes of a diverse range of eukaryotic species. However, the numt content of different genomes and their properties is not uniform, and study of these differences provides insight into the mechanisms and dynamics of genome evolution in different organisms. In the genus Drosophila, numts have previously only been identified on a genome-wide scale in the melanogaster subgroup. The present study extends the identification to 11 species of the Drosophila genus. We identify a total of 302 numts and show that the numt complement is highly variable in Drosophilids, ranging from just 4 in D. melanogaster to 67 in D. willistoni, broadly correlating with genome size. Many numts have undergone large-scale rearrangements in the nucleus, including interruptions, inversions, deletions and duplications of sequence of variable size. Estimating the age of the numts in the nucleus by phylogenetic tree reconstruction reveals the vast majority of numts to be recent gains, 90% having arisen on terminal branches of the species tree. By identifying paralogs and counting duplications among the extant numts we estimate that 23% of extant numts arose through post-insertion duplications. We estimate genus average rates of insertion of 0.75 per million years, and a duplication rate of 0.010 duplications per numt per million years