text:
Academic Appointments
Professor, Statistics
Professor, Health Research & Policy
Professor (By courtesy), Biology
Member, Bio-X
Member, Child Health Research Institute
Member, Stanford Cancer Institute
Current interest centers on the application of statistics to problems arsing from biology. We are particularly interested in questions concerning gene regulation and signal transduction.
Molecular insights into somatic cell reprogramming to induced pluripotent stem cells (iPS) would aid regenerative medicine, but are difficult to elucidate in iPS because of their heterogeneity, as relatively few cells undergo reprogramming (0.1-1%; refs , ). To identify early acting regulators, we capitalized on non-dividing heterokaryons (mouse embryonic stem cells fused to human fibroblasts), in which reprogramming towards pluripotency is efficient and rapid, enabling the identification of transient regulators required at the onset. We used bi-species transcriptome-wide RNA-seq to quantify transcriptional changes in the human somatic nucleus during reprogramming towards pluripotency in heterokaryons. During heterokaryon reprogramming, the cytokine interleukin 6 (IL6), which is not detectable at significant levels in embryonic stem cells, was induced 50-fold. A 4-day culture with IL6 at the onset of iPS reprogramming replaced stably transduced oncogenic c-Myc such that transduction of only Oct4, Klf4 and Sox2 was required. IL6 also activated another Jak/Stat target, the serine/threonine kinase gene Pim1, which accounted for the IL6-mediated twofold increase in iPS frequency. In contrast, LIF, another induced GP130 ligand, failed to increase iPS frequency or activate c-Myc or Pim1, thereby revealing a differential role for the two Jak/Stat inducers in iPS generation. These findings demonstrate the power of heterokaryon bi-species global RNA-seq to identify early acting regulators of reprogramming, for example, extrinsic replacements for stably transduced transcription factors such as the potent oncogene c-Myc.
View details for DOI 10.1038/ncb2835
View details for PubMedID 23995732
To test whether the probability of having a live birth (LB) with the first IVF cycle (C1) can be predicted and personalized for patients in diverse environments.Retrospective validation of multicenter prediction model.Three university-affiliated outpatient IVF clinics located in different countries.Using primary models aggregated from >13,000 C1s, we applied the boosted tree method to train a preIVF-diversity model (PreIVF-D) with 1,061 C1s from 2008 to 2009, and validated predicted LB probabilities with an independent dataset comprising 1,058 C1s from 2008 to 2009.None.Predictive power, reclassification, receiver operator characteristic analysis, calibration, dynamic range.Overall, with PreIVF-D, 86% of cases had significantly different LB probabilities compared with age control, and more than one-half had higher LB probabilities. Specifically, 42% of patients could have been identified by PreIVF-D to have a personalized predicted success rate >45%, whereas an age-control model could not differentiate them from others. Furthermore, PreIVF-D showed improved predictive power, with 36% improved log-likelihood (or 9.0-fold by log-scale; >1,000-fold linear scale), and prediction errors for subgroups ranged from 0.9% to 3.7%.Validated prediction of personalized LB probabilities from diverse multiple sources identify excellent prognoses in more than one-half of patients.
View details for DOI 10.1016/j.fertnstert.2013.02.016
View details for Web of Science ID 000320505900028
View details for PubMedID 23522806
View details for DOI 10.1371/journal.pcbi.1002935
View details for Web of Science ID 000316864200010
The Xenopus embryo has provided key insights into fate specification, the cell cycle, and other fundamental developmental and cellular processes, yet a comprehensive understanding of its transcriptome is lacking. Here, we used paired end RNA sequencing (RNA-seq) to explore the transcriptome of Xenopus tropicalis in 23 distinct developmental stages. We determined expression levels of all genes annotated in RefSeq and Ensembl and showed for the first time on a genome-wide scale that, despite a general state of transcriptional silence in the earliest stages of development, approximately 150 genes are transcribed prior to the midblastula transition. In addition, our splicing analysis uncovered more than 10,000 novel splice junctions at each stage and revealed that many known genes have additional unannotated isoforms. Furthermore, we used Cufflinks to reconstruct transcripts from our RNA-seq data and found that ∼13.5% of the final contigs are derived from novel transcribed regions, both within introns and in intergenic regions. We then developed a filtering pipeline to separate protein-coding transcripts from noncoding RNAs and identified a confident set of 6686 noncoding transcripts in 3859 genomic loci. Since the current reference genome, XenTro3, consists of hundreds of scaffolds instead of full chromosomes, we also performed de novo reconstruction of the transcriptome using Trinity and uncovered hundreds of transcripts that are missing from the genome. Collectively, our data will not only aid in completing the assembly of the Xenopus tropicalis genome but will also serve as a valuable resource for gene discovery and for unraveling the fundamental mechanisms of vertebrate embryogenesis.
View details for DOI 10.1101/gr.141424.112
View details for Web of Science ID 000312963400019
View details for PubMedID 22960373
Current generation DNA sequencing instruments are moving closer to seamlessly sequencing genomes of entire populations as a routine part of scientific investigation. However, while significant inroads have been made identifying small nucleotide variation and structural variations in DNA that impact phenotypes of interest, progress has not been as dramatic regarding epigenetic changes and base-level damage to DNA, largely due to technological limitations in assaying all known and unknown types of modifications at genome scale. Recently, single-molecule real time (SMRT) sequencing has been reported to identify kinetic variation (KV) events that have been demonstrated to reflect epigenetic changes of every known type, providing a path forward for detecting base modifications as a routine part of sequencing. However, to date no statistical framework has been proposed to enhance the power to detect these events while also controlling for false-positive events. By modeling enzyme kinetics in the neighborhood of an arbitrary location in a genomic region of interest as a conditional random field, we provide a statistical framework for incorporating kinetic information at a test position of interest as well as at neighboring sites that help enhance the power to detect KV events. The performance of this and related models is explored, with the best-performing model applied to plasmid DNA isolated from Escherichia coli and mitochondrial DNA isolated from human brain tissue. We highlight widespread kinetic variation events, some of which strongly associate with known modification events, while others represent putative chemically modified sites of unknown types.
View details for DOI 10.1101/gr.136739.111
View details for Web of Science ID 000312963400012
View details for PubMedID 23093720
Landmark events occur in a coordinated manner during pre-implantation development of the mammalian embryo, yet the regulatory network that orchestrates these events remains largely unknown. Here, we present the first systematic investigation of the network in pre-implantation mouse embryos using morpholino-mediated gene knockdowns of key embryonic stem cell (ESC) factors followed by detailed transcriptome analysis of pooled embryos, single embryos, and individual blastomeres. We delineated the regulons of Oct4, Sall4, and Nanog and identified a set of metabolism- and transport-related genes that were controlled by these transcription factors in embryos but not in ESCs. Strikingly, the knockdown embryos arrested at a range of developmental stages. We provided evidence that the DNA methyltransferase Dnmt3b has a role in determining the extent to which a knockdown embryo can develop. We further showed that the feed-forward loop comprising Dnmt3b, the pluripotency factors, and the miR-290-295 cluster exemplifies a network motif that buffers embryos against gene expression noise. Our findings indicate that Oct4, Sall4, and Nanog form a robust and integrated network to govern mammalian pre-implantation development.
View details for DOI 10.1038/msb.2012.65
View details for Web of Science ID 000314415800002
View details for PubMedID 23295861
In the vertebrate neural tube, regional Sonic hedgehog (Shh) signaling invokes a time- and concentration-dependent induction of six different cell populations mediated through Gli transcriptional regulators. Elsewhere in the embryo, Shh/Gli responses invoke different tissue-appropriate regulatory programs. A genome-scale analysis of DNA binding by Gli1 and Sox2, a pan-neural determinant, identified a set of shared regulatory regions associated with key factors central to cell fate determination and neural tube patterning. Functional analysis in transgenic mice validates core enhancers for each of these factors and demonstrates the dual requirement for Gli1 and Sox2 inputs for neural enhancer activity. Furthermore, through an unbiased determination of Gli-binding site preferences and analysis of binding site variants in the developing mammalian CNS, we demonstrate that differential Gli-binding affinity underlies threshold-level activator responses to Shh input. In summary, our results highlight Sox2 input as a context-specific determinant of the neural-specific Shh response and differential Gli-binding site affinity as an important cis-regulatory property critical for interpreting Shh morphogen action in the mammalian neural tube.
View details for DOI 10.1101/gad.207142.112
View details for Web of Science ID 000312775700012
View details for PubMedID 23249739
Retroviral overexpression of reprogramming factors (Oct4, Sox2, Klf4, c-Myc) generates induced pluripotent stem cells (iPSCs). However, the integration of foreign DNA could induce genomic dysregulation. Cell-permeant proteins (CPPs) could overcome this limitation. To date, this approach has proved exceedingly inefficient. We discovered a striking difference in the pattern of gene expression induced by viral versus CPP-based delivery of the reprogramming factors, suggesting that a signaling pathway required for efficient nuclear reprogramming was activated by the retroviral, but not CPP approach. In gain- and loss-of-function studies, we find that the toll-like receptor 3 (TLR3) pathway enables efficient induction of pluripotency by viral or mmRNA approaches. Stimulation of TLR3 causes rapid and global changes in the expression of epigenetic modifiers to enhance chromatin remodeling and nuclear reprogramming. Activation of inflammatory pathways are required for efficient nuclear reprogramming in the induction of pluripotency.
View details for DOI 10.1016/j.cell.2012.09.034
View details for Web of Science ID 000310529300012
View details for PubMedID 23101625
The recent development of third generation sequencing (TGS) generates much longer reads than second generation sequencing (SGS) and thus provides a chance to solve problems that are difficult to study through SGS alone. However, higher raw read error rates are an intrinsic drawback in most TGS technologies. Here we present a computational method, LSC, to perform error correction of TGS long reads (LR) by SGS short reads (SR). Aiming to reduce the error rate in homopolymer runs in the main TGS platform, the PacBio® RS, LSC applies a homopolymer compression (HC) transformation strategy to increase the sensitivity of SR-LR alignment without scarifying alignment accuracy. We applied LSC to 100,000 PacBio long reads from human brain cerebellum RNA-seq data and 64 million single-end 75 bp reads from human brain RNA-seq data. The results show LSC can correct PacBio long reads to reduce the error rate by more than 3 folds. The improved accuracy greatly benefits many downstream analyses, such as directional gene isoform detection in RNA-seq study. Compared with another hybrid correction tool, LSC can achieve over double the sensitivity and similar specificity.
View details for DOI 10.1371/journal.pone.0046679
View details for Web of Science ID 000309580800039
View details for PubMedID 23056399
Next-generation sequence analysis has become an important task both in laboratory and clinical settings. A key stage in the majority sequence analysis workflows, such as resequencing, is the alignment of genomic reads to a reference genome. The accurate alignment of reads with large indels is a computationally challenging task for researchers.We introduce SeqAlto as a new algorithm for read alignment. For reads longer than or equal to 100 bp, SeqAlto is up to 10 × faster than existing algorithms, while retaining high accuracy and the ability to align reads with large (up to 50 bp) indels. This improvement in efficiency is particularly important in the analysis of future sequencing data where the number of reads approaches many billions. Furthermore, SeqAlto uses less than 8 GB of memory to align against the human genome. SeqAlto is benchmarked against several existing tools with both real and simulated data.Linux and Mac OS X binaries free for academic use are available at http://firstname.lastname@example.com.
View details for DOI 10.1093/bioinformatics/bts450
View details for Web of Science ID 000308532300059
View details for PubMedID 22811546
A balance between Six2-dependent self-renewal and canonical Wnt signaling-directed commitment regulates mammalian nephrogenesis. Intersectional studies using chromatin immunoprecipitation and transcriptional profiling identified direct target genes shared by each pathway within nephron progenitors. Wnt4 and Fgf8 are essential for progenitor commitment; cis-regulatory modules flanking each gene are cobound by Six2 and β-catenin and are dependent on conserved Lef/Tcf binding sites for activity. In vitro and in vivo analyses suggest that Six2 and Lef/Tcf factors form a regulatory complex that promotes progenitor maintenance while entry of β-catenin into this complex promotes nephrogenesis. Alternative transcriptional responses associated with Six2 and β-catenin cobinding events occur through non-Lef/Tcf DNA binding mechanisms, highlighting the regulatory complexity downstream of Wnt signaling in the developing mammalian kidney.
View details for DOI 10.1016/j.devcel.2012.07.008
View details for Web of Science ID 000308776400019
View details for PubMedID 22902740
To report and evaluate the performance and utility of an approach to predicting IVF-double embryo transfer (DET) multiple birth risks that is evidence-based, clinic-specific, and considers each patient's clinical profile.Retrospective prediction modeling.An outpatient university-affiliated IVF clinic.We used boosted tree methods to analyze 2,413 independent IVF-DET treatment cycles that resulted in live births. The IVF cycles were retrieved from a database that comprised more than 33,000 IVF cycles.None.The performance of this prediction model, MBP-BIVF, was validated by an independent data set, to evaluate predictive power, discrimination, dynamic range, and reclassification.Multiple birth probabilities ranging from 11.8% to 54.8% were predicted by the model and were significantly different from control predictions in more than half of the patients. The prediction model showed an improvement of 146% in predictive power and 16.0% in discrimination over control. The population standard error was 1.8%.We showed that IVF patients have inherently different risks of multiple birth, even when DET is specified, and this risk can be predicted before ET. The use of clinic-specific prediction models provides an evidence-based and personalized method to counsel patients.
View details for DOI 10.1016/j.fertnstert.2012.04.011
View details for Web of Science ID 000305950200020
View details for PubMedID 22673597
Linkage and association analysis based on haplotype transmission disequilibrium can be more informative than single marker analysis. Several works have been proposed in recent years to extend the transmission disequilibrium test (TDT) to haplotypes. Among them, a powerful approach called the evolutionary tree TDT (ET-TDT) incorporates information about the evolutionary relationship among haplotypes using the cladogram of the locus.In this work we extend this approach by taking into consideration the sparsity of causal mutations in the evolutionary history. We first introduce the notion of a Bradley-Terry (BT) graph representation of a haplotype locus. The most important property of the BT graph is that sparsity of the edge set of the graph corresponds to small number of causal mutations in the evolution of the haplotypes. We then propose a method to test the null hypothesis of no linkage and association against sparse alternatives under which a small number of edges on the BT graph have non-nil effects.We compare the performance of our approach to that of the ET-TDT through a power study, and show that incorporating sparsity of causal mutations can significantly improve the power of a haplotype-based TDT.
View details for DOI 10.1159/000335937
View details for Web of Science ID 000302111100008
View details for PubMedID 22398955
View details for DOI 10.1198/jasa.2011.tm10003
View details for Web of Science ID 000299662900026
View details for Web of Science ID 000290459900002
We show that high quality microarray gene expression profiles can be obtained following FACS sorting of cells using combinations of transcription factors. We use this transcription factor FACS (tfFACS) methodology to perform a genomic analysis of hESC-derived endodermal lineages marked by combinations of SOX17, GATA4, and CXCR4, and find that triple positive cells have a much stronger definitive endoderm signature than other combinations of these markers. Additionally, SOX17(+) GATA4(+) cells can be obtained at a much earlier stage of differentiation, prior to expression of CXCR4(+) cells, providing an important new tool to isolate this earlier definitive endoderm subtype. Overall, tfFACS represents an advancement in FACS technology which broadly crosses multiple disciplines, most notably in regenerative medicine to redefine cellular populations.
View details for DOI 10.1371/journal.pone.0017536
View details for Web of Science ID 000288170900026
View details for PubMedID 21408072
A 6.9 million-feature oligonucleotide array of the human transcriptome [Glue Grant human transcriptome (GG-H array)] has been developed for high-throughput and cost-effective analyses in clinical studies. This array allows comprehensive examination of gene expression and genome-wide identification of alternative splicing as well as detection of coding SNPs and noncoding transcripts. The performance of the array was examined and compared with mRNA sequencing (RNA-Seq) results over multiple independent replicates of liver and muscle samples. Compared with RNA-Seq of 46 million uniquely mappable reads per replicate, the GG-H array is highly reproducible in estimating gene and exon abundance. Although both platforms detect similar expression changes at the gene level, the GG-H array is more sensitive at the exon level. Deeper sequencing is required to adequately cover low-abundance transcripts. The array has been implemented in a multicenter clinical program and has generated high-quality, reproducible data. Considering the clinical trial requirements of cost, sample availability, and throughput, the GG-H array has a wide range of applications. An emerging approach for large-scale clinical genomic studies is to first use RNA-Seq to the sufficient depth for the discovery of transcriptome elements relevant to the disease process followed by high-throughput and reliable screening of these elements on thousands of patient samples using custom-designed arrays.
View details for DOI 10.1073/pnas.1019753108
View details for Web of Science ID 000287844400051
View details for PubMedID 21317363
View details for DOI 10.1214/10-STS343
View details for Web of Science ID 000292424900013
The two haploid genome sequences that a person inherits from the two parents represent the most fundamentally useful type of genetic information for the study of heritable diseases and the development of personalized medicine. Because of the difficulty in obtaining long-range phase information, current sequencing methods are unable to provide this information. Here, we introduce and show feasibility of a scalable approach capable of generating genomic sequences completely phased across the entire chromosome.
View details for DOI 10.1073/pnas.1016725108
View details for Web of Science ID 000285915000007
View details for PubMedID 21169219
Chromatin immunoprecipitation coupled with ultra-high-throug put parallel DNA sequencing (ChIP-seq) is an effective technology for the investigation of genome-wide protein-DNA interactions. Examples of applications include the studies of RNA polymerases transcription, transcriptional regulation, and histone modifications. The technology provides accurate and high-resolution mapping of the protein-DNA binding loci that are important in the understanding of many processes in development and diseases. Since the introduction of ChIP-seq experiments in 2007, many statistical and computational methods have been developed to support the analysis of the massive datasets from these experiments. However, because of the complex, multistaged analysis workflow, it is still difficult for an experimental investigator to conduct the analysis of his or her own ChIP-seq data. In this chapter, we review the basic design of ChIP-seq experiments and provide an in-depth tutorial on how to prepare, to preprocess, and to analyze ChIP-seq datasets. The tutorial is based on a revised version of our software package CisGenome, which was designed to encompass most standard tasks in ChIP-seq data analysis. Relevant statistical and computational issues will be highlighted, discussed, and illustrated by means of real data examples.
View details for DOI 10.1016/B978-0-12-385075-1.00003-2
View details for Web of Science ID 000291321200003
View details for PubMedID 21601082
Brassinosteroids (BRs) regulate a wide range of developmental and physiological processes in plants through a receptor-kinase signaling pathway that controls the BZR transcription factors. Here, we use transcript profiling and chromatin-immunoprecipitation microarray (ChIP-chip) experiments to identify 953 BR-regulated BZR1 target (BRBT) genes. Functional studies of selected BRBTs further demonstrate roles in BR promotion of cell elongation. The BRBT genes reveal numerous molecular links between the BR-signaling pathway and downstream components involved in developmental and physiological processes. Furthermore, the results reveal extensive crosstalk between BR and other hormonal and light-signaling pathways at multiple levels. For example, BZR1 not only controls the expression of many signaling components of other hormonal and light pathways but also coregulates common target genes with light-signaling transcription factors. Our results provide a genomic map of steroid hormone actions in plants that reveals a regulatory network that integrates hormonal and light-signaling pathways for plant growth regulation.
View details for DOI 10.1016/j.devcel.2010.10.010
View details for Web of Science ID 000284516300016
View details for PubMedID 21074725
View details for DOI 10.1214/10-STS341
View details for Web of Science ID 000288497200006
Nearly 75% of in vitro fertilization (IVF) treatments do not result in live births and patients are largely guided by a generalized age-based prognostic stratification. We sought to provide personalized and validated prognosis by using available clinical and embryo data from prior, failed treatments to predict live birth probabilities in the subsequent treatment. We generated a boosted tree model, IVFBT, by training it with IVF outcomes data from 1,676 first cycles (C1s) from 2003-2006, followed by external validation with 634 cycles from 2007-2008, respectively. We tested whether this model could predict the probability of having a live birth in the subsequent treatment (C2). By using nondeterministic methods to identify prognostic factors and their relative nonredundant contribution, we generated a prediction model, IVF(BT), that was superior to the age-based control by providing over 1,000-fold improvement to fit new data (p<0.05), and increased discrimination by receiver-operative characteristic analysis (area-under-the-curve, 0.80 vs. 0.68 for C1, 0.68 vs. 0.58 for C2). IVFBT provided predictions that were more accurate for approximately 83% of C1 and approximately 60% of C2 cycles that were out of the range predicted by age. Over half of those patients were reclassified to have higher live birth probabilities. We showed that data from a prior cycle could be used effectively to provide personalized and validated live birth probabilities in a subsequent cycle. Our approach may be replicated and further validated in other IVF clinics.
View details for DOI 10.1073/pnas.1002296107
View details for Web of Science ID 000280605900006
View details for PubMedID 20643955
Alternative splicing is a prevalent post-transcriptional process, which is not only important to normal cellular function but is also involved in human diseases. The newly developed second generation sequencing technique provides high-throughput data (RNA-seq data) to study alternative splicing events in different types of cells. Here, we present a computational method, SpliceMap, to detect splice junctions from RNA-seq data. This method does not depend on any existing annotation of gene structures and is capable of finding novel splice junctions with high sensitivity and specificity. It can handle long reads (50-100 nt) and can exploit paired-read information to improve mapping accuracy. Several parameters are included in the output to indicate the reliability of the predicted junction and help filter out false predictions. We applied SpliceMap to analyze 23 million paired 50-nt reads from human brain tissue. The results show at this depth of sequencing, RNA-seq can support reliable detection of splice junctions except for those that are present at very low level. Compared to current methods, SpliceMap can achieve 12% higher sensitivity without sacrificing specificity.
View details for DOI 10.1093/nar/gkq211
View details for Web of Science ID 000280922400010
View details for PubMedID 20371516
We present an open source, platform independent tool, called CisGenome Browser, which can work together with any other data analysis program to serve as a flexible component for genomic data visualization. It can also work by itself as a standalone genome browser. By working as a light-weight web server, CisGenome Browser is a convenient tool for data sharing between labs. It has features that are specifically designed for ultra high-throughput sequencing data visualization.http://biogibbs.stanford.edu/ approximately jiangh/browser/
View details for DOI 10.1093/bioinformatics/btq286
View details for Web of Science ID 000279474400017
View details for PubMedID 20513664
Due to the complex nature of common diseases, their etiology is likely to involve "uncommon but strong" (UBS) interactive effects--i.e. allelic combinations that are each present in only a small fraction of the patients but associated with high disease risk. However, the identification of such effects using standard methods for testing association can be difficult. In this work, we introduce a method for testing interactions that is particularly powerful in detecting UBS effects. The method consists of two modules--one is a pattern counting algorithm designed for efficiently evaluating the risk significance of each marker combination, and the other is a sequential permutation scheme for multiple testing correction. We demonstrate the work of our method using a candidate gene data set for cardiovascular and coronary diseases with an injected UBS three-locus interaction. In addition, we investigate the power and false rejection properties of our method using data sets simulated from a joint dominance three-locus model that gives rise to UBS interactive effects. The results show that our method can be much more powerful than standard approaches such as trend test and multifactor dimensionality reduction for detecting UBS interactions.
View details for DOI 10.1002/gepi.20496
View details for Web of Science ID 000280349600007
View details for PubMedID 20583286
Time-course microarray experiments are capable of capturing dynamic gene expression profiles. It is important to study how these dynamic profiles depend on the multiple factors that characterize the experimental condition under which the time course is observed. Analytic methods are needed to simultaneously handle the time course and factorial structure in the data. We developed a method to evaluate factor effects by pooling information across the time course while accounting for multiple testing and nonnormality of the microarray data. The method effectively extracts gene-specific response features and models their dependency on the experimental factors. Both longitudinal and cross-sectional time-course data can be handled by our approach. The method was used to analyze the impact of age on the temporal gene response to burn injury in a large-scale clinical study. Our analysis reveals that 21% of the genes responsive to burn are age-specific, among which expressions of mitochondria and immunoglobulin genes are differentially perturbed in pediatric and adult patients by burn injury. These new findings in the body's response to burn injury between children and adults support further investigations of therapeutic options targeting specific age groups. The methodology proposed here has been implemented in R package "TANOVA" and submitted to the Comprehensive R Archive Network at http://www.r-project.org/. It is also available for download at http://gluegrant1.stanford.edu/TANOVA/.
View details for DOI 10.1073/pnas.1002757107
View details for PubMedID 20479259
View details for DOI 10.1214/09-AOS755
View details for Web of Science ID 000277471000006
Many genes initially identified for their roles in cell fate determination or signaling during development can have a significant impact on tumorigenesis. In the developing cerebellum, Sonic hedgehog (Shh) stimulates the proliferation of granule neuron precursor cells (GNPs) by activating the Gli transcription factors. Inappropriate activation of Shh target genes results in unrestrained cell division and eventually medulloblastoma, the most common pediatric brain malignancy. We find dramatic differences in the gene networks that are directly driven by the Gli1 transcription factor in GNPs and medulloblastoma. Gli1 binding location analysis revealed hundreds of genomic loci bound by Gli1 in normal and cancer cells. Only one third of the genes bound by Gli1 in GNPs were also bound in tumor cells. Correlation with gene expression levels indicated that 116 genes were preferentially transcribed in tumors, whereas 132 genes were target genes in both GNPs and medulloblastoma. Quantitative PCR and in situ hybridization for some putative target genes support their direct regulation by Gli. The results indicate that transformation of normal GNPs into deadly tumor cells is accompanied by a distinct set of Gli-regulated genes and may provide candidates for targeted therapies.
View details for DOI 10.1073/pnas.1004602107
View details for Web of Science ID 000278054700048
View details for PubMedID 20460306
Complex interactions between genes or proteins contribute substantially to phenotypic evolution. We present a probabilistic model and a maximum likelihood approach for cross-species clustering analysis and for identification of conserved as well as species-specific co-expression modules. This model enables a "soft" cross-species clustering (SCSC) approach by encouraging but not enforcing orthologous genes to be grouped into the same cluster. SCSC is therefore robust to obscure orthologous relationships and can reflect different functional roles of orthologous genes in different species. We generated a time-course gene expression dataset for differentiating mouse embryonic stem (ES) cells, and compiled a dataset of published gene expression data on differentiating human ES cells. Applying SCSC to analyze these datasets, we identified conserved and species-specific gene regulatory modules. Together with protein-DNA binding data, an SCSC cluster specifically induced in murine ES cells indicated that the KLF2/4/5 transcription factors, although critical to maintaining the pluripotent phenotype in mouse ES cells, were decoupled from the OCT4/SOX2/NANOG regulatory module in human ES cells. Two of the target genes of murine KLF2/4/5, LIN28 and NODAL, were rewired to be targets of OCT4/SOX2/NANOG in human ES cells. Moreover, by mapping SCSC clusters onto KEGG signaling pathways, we identified the signal transduction components that were induced in pluripotent ES cells in either a conserved or a species-specific manner. These results suggest that the pluripotent cell identity can be established and maintained through more than one gene regulatory network.
View details for DOI 10.1371/journal.pcbi.1000707
View details for Web of Science ID 000278125200015
View details for PubMedID 20300647
After mapping, RNA-Seq data can be summarized by a sequence of read counts commonly modeled as Poisson variables with constant rates along each transcript, which actually fit data poorly. We suggest using variable rates for different positions, and propose two models to predict these rates based on local sequences. These models explain more than 50% of the variations and can lead to improved estimates of gene and isoform expressions for both Illumina and Applied Biosystems data.
View details for DOI 10.1186/gb-2010-11-5-r50
View details for Web of Science ID 000279631000015
View details for PubMedID 20459815
Next-generation sequencing has greatly increased the scope and the resolution of transcriptional regulation study. RNA sequencing (RNA-Seq) and ChIP-Seq experiments are now generating comprehensive data on transcript abundance and on regulator-DNA interactions. We propose an approach for an integrated analysis of these data based on feature extraction of ChIP-Seq signals, principal component analysis, and regression-based component selection. Compared with traditional methods, our approach not only offers higher power in predicting gene expression from ChIP-Seq data but also provides a way to capture cooperation among regulators. In mouse embryonic stem cells (ESCs), we find that a remarkably high proportion of variation in gene expression (65%) can be explained by the binding signals of 12 transcription factors (TFs). Two groups of TFs are identified. Whereas the first group (E2f1, Myc, Mycn, and Zfx) act as activators in general, the second group (Oct4, Nanog, Sox2, Smad1, Stat3, Tcfcp2l1, and Esrrb) may serve as either activator or repressor depending on the target. The two groups of TFs cooperate tightly to activate genes that are differentially up-regulated in ESCs. In the absence of binding by the first group, the binding of the second group is associated with genes that are repressed in ESCs and derepressed upon early differentiation.
View details for DOI 10.1073/pnas.0904863106
View details for Web of Science ID 000272994200013
View details for PubMedID 19995984
Splice junction microarrays and RNA-seq are two popular ways of quantifying splice variants within a cell. Unfortunately, isoform expressions cannot always be determined from the expressions of individual exons and splice junctions. While this issue has been noted before, the extent of the problem on various platforms has not yet been explored, nor have potential remedies been presented.We propose criteria that will guarantee identifiability of an isoform deconvolution model on exon and splice junction arrays and in RNA-Seq. We show that up to 97% of 2256 alternatively spliced human genes selected from the RefSeq database lead to identifiable gene models in RNA-seq, with similar results in mouse. However, in the Human Exon array only 26% of these genes lead to identifiable models, and even in the most comprehensive splice junction array only 69% lead to identifiable models.Supplementary data are available at Bioinformatics online.
View details for DOI 10.1093/bioinformatics/btp544
View details for Web of Science ID 000272080800002
View details for PubMedID 19762346
The differentiation of embryonic stem cells is initiated by a gradual loss of pluripotency-associated transcripts and induction of differentiation genes. Accordingly, the detection of differentially expressed genes at the early stages of differentiation could assist the identification of the causal genes that either promote or inhibit differentiation. The previous methods of identifying differentially expressed genes by comparing different cell types would inevitably include a large portion of genes that respond to, rather than regulate, the differentiation process. We demonstrate through the use of biological replicates and a novel statistical approach that the gene expression data obtained without prior separation of cell types are informative for detecting differentially expressed genes at the early stages of differentiation. Applying the proposed method to analyze the differentiation of murine embryonic stem cells, we identified and then experimentally verified Smarcad1 as a novel regulator of pluripotency and self-renewal. We formalized this statistical approach as a statistical test that is generally applicable to analyze other differentiation processes.
View details for DOI 10.1371/journal.pcbi.1000607
View details for Web of Science ID 000274229000025
View details for PubMedID 20019792
The PI3K-AKT-FoxO pathway is integral to lifespan regulation in lower organisms and essential for the stability of long-lived cells in mammals. Here, we report the impact of combined FoxO1, 3, and 4 deficiencies on mammalian brain physiology with a particular emphasis on the study of the neural stem/progenitor cell (NSC) pool. We show that the FoxO family plays a prominent role in NSC proliferation and renewal. FoxO-deficient mice show initial increased brain size and proliferation of neural progenitor cells during early postnatal life, followed by precocious significant decline in the NSC pool and accompanying neurogenesis in adult brains. Mechanistically, integrated transcriptomic, promoter, and functional analyses of FoxO-deficient NSC cultures identified direct gene targets with known links to the regulation of human brain size and the control of cellular proliferation, differentiation, and oxidative defense. Thus, the FoxO family coordinately regulates diverse genes and pathways to govern key aspects of NSC homeostasis in the mammalian brain.
View details for DOI 10.1016/j.stem.2009.09.013
View details for Web of Science ID 000272019500015
View details for PubMedID 19896444
The disconnectivity graph (DG) is widely used to represent energy landscapes. Although powerful numerical methods have been developed to construct DGs for continuous potential-energy surfaces, they have difficulties in applications to discrete Hamiltonians as the case of spin-glass models. When the configuration space is large, brute force enumeration of all configurations to build a DG is not practical. We propose an alternative approach to construct DGs based on recursive partition of Monte Carlo samples from microcanonical ensembles. To characterize energy landscapes, we define the local density of states (LDOS) on a DG, with which one can compute many thermodynamic properties over local energy basins for any temperature. Estimation of LDOS is developed with DG construction. We further propose the concepts of tree entropy and local escape probability, both of which are functions of local density of states, to capture the symmetry and the roughness of a Boltzmann distribution, respectively. Our approach is applied to a study of the Sherrington-Kirkpatrick spin-glass model with N varying between 20 and 100 spins. We observe that the energy landscape is extremely asymmetric and there exists a sharp increase in local escape probability preceding the transition from spin glass to paramagnetic phase.
View details for DOI 10.1103/PhysRevE.79.051117
View details for Web of Science ID 000266500700031
View details for PubMedID 19518426
In this review, we discuss the gene regulatory network underlying the patterning of the ventral neural tube during vertebrate embryogenesis. The neural tube is partitioned into domains of distinct cell fates by inductive signals along both anterior-posterior and dorsal-ventral axes. A defining feature of the dorsal-ventral patterning is the graded distribution of Sonic hedgehog (Shh), which acts as a morphogen to specify several classes of ventral neurons in a concentration-dependent fashion. These inductive signals translate into patterned expressions of transcription factors that define different neural progenitor subtypes. Progenitor boundaries are sharpened by repressive interactions between these transcription factors. The progenitor-expressed transcription factors induce another set of transcription factors that are thought to contribute to neural identities in post-mitotic neural precursors. Thus, the gene regulatory network of the ventral neural tube patterning is characterized by hierarchical expression [inductive signal-->progenitor specifying factors (mitotic)--> precursor specifying factors (post mitotic)--> differentiated neural markers] and cross-repression between progenitor-expressed regulatory factors. Although a number of transcriptional regulators have been identified at each hierarchical level, their precise regulatory relationships are not clear. Here we discuss approaches aimed at clarifying and extending our understanding of the formation and propagation of this network.
View details for DOI 10.1016/j.bbagrm.2009.01.002
View details for Web of Science ID 000265729800008
View details for PubMedID 19445894
Microarray designs have become increasingly probe-rich, enabling targeting of specific features, such as individual exons or single nucleotide polymorphisms. These arrays have the potential to achieve quantitative high-throughput estimates of transcript abundances, but currently these estimates are affected by biases due to cross-hybridization, in which probes hybridize to off-target transcripts.To study cross-hybridization, we map Affymetrix exon array probes to a set of annotated mRNA transcripts, allowing a small number of mismatches or insertion/deletions between the two sequences. Based on a systematic study of the degree to which probes with a given match type to a transcript are affected by cross-hybridization, we developed a strategy to correct for cross-hybridization biases of gene-level expression estimates. Comparison with Solexa ultra high-throughput sequencing data demonstrates that correction for cross-hybridization leads to a significant improvement of gene expression estimates.We provide mappings between human and mouse exon array probes and off-target transcripts and provide software extending the GeneBASE program for generating gene-level expression estimates including the cross-hybridization correction http://biogibbs.stanford.edu/~kkapur/GeneBase/.
View details for DOI 10.1093/bioinformatics/btn571
View details for Web of Science ID 000261456700012
View details for PubMedID 18984598
We present CisGenome, a software system for analyzing genome-wide chromatin immunoprecipitation (ChIP) data. CisGenome is designed to meet all basic needs of ChIP data analyses, including visualization, data normalization, peak detection, false discovery rate computation, gene-peak association, and sequence and motif analysis. In addition to implementing previously published ChIP-microarray (ChIP-chip) analysis methods, the software contains statistical methods designed specifically for ChlP sequencing (ChIP-seq) data obtained by coupling ChIP with massively parallel sequencing. The modular design of CisGenome enables it to support interactive analyses through a graphic user interface as well as customized batch-mode computation for advanced data mining. A built-in browser allows visualization of array images, signals, gene structure, conservation, and DNA sequence and motif information. We demonstrate the use of these tools by a comparative analysis of ChIP-chip and ChIP-seq data for the transcription factor NRSF/REST, a study of ChIP-seq analysis with or without a negative control sample, and an analysis of a new motif in Nanog- and Sox2-binding regions.
View details for DOI 10.1038/nbt.1505
View details for Web of Science ID 000260832200025
View details for PubMedID 18978777
SeqMap is a tool for mapping large amount of short sequences to the genome. It is designed for finding all the places in a reference genome where each sequence may come from. This task is essential to the analysis of data from ultra high-throughput sequencing machines. With a carefully designed index-filtering algorithm and an efficient implementation, SeqMap can map tens of millions of short sequences to a genome of several billions of nucleotides. Multiple substitutions and insertions/deletions of the nucleotide bases in the sequences can be tolerated and therefore detected. SeqMap supports FASTA input format and various output formats, and provides command line options for tuning almost every aspect of the mapping process. A typical mapping can be done in a few hours on a desktop PC. Parallel use of SeqMap on a cluster is also very straightforward.
View details for DOI 10.1093/bioinformatics/btn429
View details for Web of Science ID 000259973500020
View details for PubMedID 18697769
Sonic hedgehog (Shh) signals via Gli transcription factors to direct digit number and identity in the vertebrate limb. We characterized the Gli-dependent cis-regulatory network through a combination of whole-genome chromatin immunoprecipitation (ChIP)-on-chip and transcriptional profiling of the developing mouse limb. These analyses identified approximately 5000 high-quality Gli3-binding sites, including all known Gli-dependent enhancers. Discrete binding regions exhibit a higher-order clustering, highlighting the complexity of cis-regulatory interactions. Further, Gli3 binds inertly to previously identified neural-specific Gli enhancers, demonstrating the accessibility of their cis-regulatory elements. Intersection of DNA binding data with gene expression profiles predicted 205 putative limb target genes. A subset of putative cis-regulatory regions were analyzed in transgenic embryos, establishing Blimp1 as a direct Gli target and identifying Gli activator signaling in a direct, long-range regulation of the BMP antagonist Gremlin. In contrast, a long-range silencer cassette downstream from Hand2 likely mediates Gli3 repression in the anterior limb. These studies provide the first comprehensive characterization of the transcriptional output of a Shh-patterning process in the mammalian embryo and a framework for elaborating regulatory networks in the developing limb.
View details for DOI 10.1101/gad.1693008
View details for Web of Science ID 000259700900010
View details for PubMedID 18832070
The differentiation of human embryonic stem cells (hESCs) into functional hepatocytes provides a powerful in vitro model system for studying the molecular mechanisms governing liver development. Furthermore, a well-characterized renewable supply of hepatocytes differentiated from hESCs could be used for in vitro assays of drug metabolism and toxicology, screening of potential antiviral agents, and cell-based therapies to treat liver disease. In this study, we describe a protocol for the differentiation of hESCs toward hepatic cells with complex cellular morphologies. Putative hepatic cells were identified and isolated using a lentiviral vector, containing the alpha-fetoprotein promoter driving enhanced green fluorescent protein expression (AFP:eGFP). Whole-genome transcriptional profiling was performed on triplicate samples of AFP:eGFP+ and AFP:eGFP- cell populations using the recently released Affymetrix Exon Array ST 1.0 (Santa Clara, CA, http://www.affymetrix.com). Statistical analysis of the transcriptional profiles demonstrated that the AFP:eGFP+ population is highly enriched for genes characteristic of hepatic cells. These data provide a unique insight into the complex process of hepatocyte differentiation, point to signaling pathways that may be manipulated to more efficiently direct the differentiation of hESCs toward mature hepatocytes, and identify molecular markers that may be used for further dissection of hepatic cell differentiation from hESCs. Disclosure of potential conflicts of interest is found at the end of this article.
View details for DOI 10.1634/stemcells.2007-0964
View details for Web of Science ID 000258297500011
View details for PubMedID 18535157
Hundreds of thousands of human embryos are cultured yearly at in vitro fertilization (IVF) centers worldwide, yet the vast majority fail to develop in culture or following transfer to the uterus. However, human embryo phenotypes have not been formally defined, and current criteria for embryo transfer largely focus on characteristics of individual embryos. We hypothesized that embryo cohort-specific variables describing sibling embryos as a group may predict developmental competence as measured by IVF cycle outcomes and serve to define human embryo phenotypes.We retrieved data for all 1117 IVF cycles performed in 2005 at Stanford University Medical Center, and further analyzed clinical data from the 665 fresh IVF, non-donor cycles and their associated 4144 embryos. Thirty variables representing patient characteristics, clinical diagnoses, treatment protocol, and embryo parameters were analyzed in an unbiased manner by regression tree models, based on dichotomous pregnancy outcomes defined by positive serum beta-human chorionic gonadotropin (beta-hCG). IVF cycle outcomes were most accurately predicted at approximately 70% by four non-redundant, embryo cohort-specific variables that, remarkably, were more informative than any measures of individual, transferred embryos: Total number of embryos, number of 8-cell embryos, rate (percentage) of cleavage arrest in the cohort and day 3 follicle stimulating hormone (FSH) level. While three of these variables captured the effects of other significant variables, only the rate of cleavage arrest was independent of any known variables.Our findings support defining human embryo phenotypes by non-redundant, prognostic variables that are specific to sibling embryos in a cohort.
View details for DOI 10.1371/journal.pone.0002562
View details for Web of Science ID 000263288200029
View details for PubMedID 18596962
View details for DOI 10.1198/016214508000000193
View details for Web of Science ID 000257897500035
We have developed a strategy for estimating gene expression on Affymetrix Exon arrays. The method includes a probe-specific background correction and a probe selection strategy in which a subset of probes with highly correlated intensities across multiple samples are chosen to summarize gene expression. Our results demonstrate that the proposed background model offers improvements over the default Affymetrix background correction and that Exon arrays may provide more accurate measurements of gene expression than traditional 3' arrays.
View details for DOI 10.1186/gb-2007-8-5-r82
View details for Web of Science ID 000246983100029
View details for PubMedID 17504534
There is great current interest in developing microarray platforms for measuring mRNA abundance at both gene level and exon level. The Affymetrix Exon Array is a new high-density gene expression microarray platform, with over six million probes targeting all annotated and predicted exons in a genome. An important question for the analysis of exon array data is how to compute overall gene expression indexes. Because of the complexity of the design of exon array probes, this problem is different in nature from summarizing gene-level expression from traditional 3' expression arrays.In this manuscript, we use exon array data from 11 human tissues to study methods for computing gene-level expression. We showed that for most genes there is a subset of exon array probes having highly correlated intensities across multiple samples. We suggest that these probes could be used as reliable indicators of overall gene expression levels. We developed a probe selection algorithm to select such a subset of highly correlated probes for each gene, and computed gene expression indexes using the selected probes.Our results demonstrate that probe selection improves gene expression estimates from exon arrays. The selected probes can be used in future analyses of other exon array datasets to compute gene expression indexes.
View details for DOI 10.1371/journal.pone.0000088
View details for Web of Science ID 000207443600087
View details for PubMedID 17183719
We present a statistical methodology that largely improves the accuracy in computational predictions of transcription factor (TF) binding sites in eukaryote genomes. This method models the cross-species conservation of binding sites without relying on accurate sequence alignment. It can be coupled with any motif-finding algorithm that searches for overrepresented sequence motifs in individual species and can increase the accuracy of the coupled motif-finding algorithm. Because this method is capable of accurately detecting TF binding sites, it also enhances our ability to predict the cis-regulatory modules. We applied this method on the published chromatin immunoprecipitation (ChIP)-chip data in Saccharomyces cerevisiae and found that its sensitivity and specificity are 9% and 14% higher than those of two recent methods. We also recovered almost all of the previously verified TF binding sites and made predictions on the cis-regulatory elements that govern the tight regulation of ribosomal protein genes in 13 eukaryote species (2 plants, 4 yeasts, 2 worms, 2 insects, and 3 mammals). These results give insights to the transcriptional regulation in eukaryotic organisms.
View details for DOI 10.1073/pnas.0504201102
View details for Web of Science ID 000233463200009
View details for PubMedID 16286651
We engage the experimental and computational challenges of de novo regulatory module discovery in a complex and largely unstudied metazoan genome. Our analysis is based on the comprehensive characterization of regulatory elements of 20 muscle genes in the chordate, Ciona savignyi. Three independent types of data we generate contribute to the characterization of a muscle-specific regulatory module: (1) Positive elements (PEs), short sequences sufficient for strong muscle expression that are identified in a high-resolution in vivo analysis; (2) CisModules (CMs), candidate regulatory modules defined by clusters of overrepresented motifs predicted de novo; and (3) Conserved elements (CEs), short noncoding sequences of strong conservation between C. savignyi and C. intestinalis. We estimate the accuracy of the computational predictions by an analysis of the intersection of these data. As final biological validation of the discovered muscle regulatory module, we implement a novel algorithm to search the genome for instances of the module and identify seven novel enhancers.
View details for DOI 10.1101/gr.4062605
View details for Web of Science ID 000232436800001
View details for PubMedID 16169925
We present a method to find motifs by simultaneously using the overrepresentation property and the evolutionary conservation property of motifs. This method is applicable to divergent species where alignment is unreliable, which overcomes a major limitation of the current methods. The method has been applied to search regulatory motifs in four yeast species based on ChIP-chip data in Saccharomyces cerevisiae and obtained 20% higher accuracy than the best current methods. We also discovered cis-regulatory elements that govern the tight regulation of ribosomal protein genes in two distantly related insects by using this method. These results demonstrate that our method will be useful for the extraction of regulatory signals in multiple genomes.
View details for DOI 10.1073/pnas.0501620102
View details for Web of Science ID 000230406000010
View details for PubMedID 15983378
Collecting and managing information is a challenging task in a genome-wide profiling research project. Most databases and online computational tools require a direct human involvement. Information and computational results are presented in various multimedia formats (e.g., text, image, PDF, word files, etc.), many of which cannot be automatically processed by computers in biologically meaningful ways. In addition, the quality of computational results is far from perfect and requires nontrivial manual examination. The timely selection, integration and interpretation of heterogeneous biological information still heavily rely on the sensibility of biologists. Biologists often feel overwhelmed by the huge amount of and the great diversity of distributed heterogeneous biological information.We developed an information management application called GeneNotes. GeneNotes is the first application that allows users to collect and manage multimedia biological information about genes/ESTs. GeneNotes provides an integrated environment for users to surf the Internet, collect notes for genes/ESTs, and retrieve notes. GeneNotes is supported by a server that integrates gene annotations from many major databases (e.g., HGNC, MGI, etc.). GeneNotes uses the integrated gene annotations to (a) identify genes given various types of gene IDs (e.g., RefSeq ID, GenBank ID, etc.), and (b) provide quick views of genes. GeneNotes is free for academic usage. The program and the tutorials are available at: http://bayes.fas.harvard.edu/genenotes/.GeneNotes provides a novel human-computer interface to assist researchers to collect and manage biological information. It also provides a platform for studying how users behave when they manipulate biological information. The results of such study can lead to innovation of more intelligent human-computer interfaces that greatly shorten the cycle of biology research.
View details for DOI 10.1186/1471-2105-6-20
View details for Web of Science ID 000227451700001
View details for PubMedID 15686593
The analysis of complex patterns of gene regulation is central to understanding the biology of cells, tissues and organisms. Patterns of gene regulation pertaining to specific biological processes can be revealed by a variety of experimental strategies, particularly microarrays and other highly parallel methods, which generate large datasets linking many genes. Although methods for detecting gene expression have improved substantially in recent years, understanding the physiological implications of complex patterns in gene expression data is a major challenge. This article presents GoSurfer, an easy-to-use graphical exploration tool with built-in statistical features that allow a rapid assessment of the biological functions represented in large gene sets. GoSurfer takes one or two list(s) of gene identifiers (Affymetrix probe set ID) as input and retrieves all the Gene Ontology (GO) terms associated with the input genes. GoSurfer visualises these GO terms in a hierarchical tree format. With GoSurfer, users can perform statistical tests to search for the GO terms that are enriched in the annotations of the input genes. These GO terms can be highlighted on the GO tree. Users can manipulate the GO tree in various ways and interactively query the genes associated with any GO term. The user-generated graphics can be saved as graphics files, and all the GO information related to the input genes can be exported as text files.GoSurfer is a Windows-based program freely available for noncommercial use and can be downloaded at http://www.gosurfer.org. Datasets used to construct the trees shown in the figures in this article are available at http://www.gosurfer.org/download/GoSurfer.zip.
View details for PubMedID 15702958


text:
Apple Store
St David's 2
63-66 Grand ArcadeCardiff, CF10 2EL
029 2055 6800Driving directions and map
|Opening hours:
|Mon - Fri:
|9:30 am - 8:00 pm
|9:30 am - 7:00 pm
|11:00 am - 5:00 pm
Apple Store
St David's 2
63-66 Grand ArcadeCardiff, CF10 2EL
029 2055 6800
How to get here:Back
The Apple Store is located in St David's Shopping Centre, on the upper level near John Lewis and opposite Hollister. St David's is located in the heart of the Cardiff city centre, a two-minute walk from the Central Library. SatNav: CF10 2EQ. Parking: St David's car parks, levels P3-P7. Public Transport: National Rail to Cardiff Central & Cardiff Queen St; multiple buses stop in the vicinity.
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text:
Of all the rear-entry sex positions, the 'doggy' position is almost certainly the best known. But with imagination, the loving couple can find others that are even more stimulating.
It should be said first that intercourse face to face is by far the most popular form of lovemaking, for a variety of reasons.
First, most women like to be held and have a good deal of close bodily contact during lovemaking. Second, and at risk of stating the obvious, a woman's breast and lips – two major sources of erotic stimulation – are on the front of the body, where they can be seen and 'made use of' by her lover during sex. And third, many women associate rear-entry sex positions with animal behaviour and therefore find it a turn-off.
Making the change
For a couple who make love several times a week, however, making love in positions that involve the man penetrating from the rear can be a refreshing change and can add a touch of variety to their sex lives.
The G-spot
With greater interest than ever before in the G-spot, it has been suggested by researchers that rear-entry lovemaking could actually be preferable from the woman's point of view.
In rear-entry sex positions, the man's penis stimulates the front vaginal wall and is therefore highly exciting to a woman who has a sensitive G-spot.
Practical advantages
Whatever the physical and emotional advantages and disadvantages of rear-entry positions, there are many practical advantages for the couple who enjoy making love in this way.
In a rear-entry sex position, the woman can feel exceptionally vulnerable. Some women find this highly stimulating – the thought of being penetrated and taken in an 'animal-like' way greatly turns them on. However, other women find it a turn-off because they consider it an 'unromantic' position.
For all its pleasures and advantages, rear-entry lovemaking is not very romantic. For many couples, though, this is no drawback, as the woman will want to be taken with ardour on some occasions, while on others she will want tender loving and romantic intercourse.
Try the reverse Coital Alignment Technique (CAT) to rock and grind your way to orgasm.
As human beings, we have a vast range of possibilities – and this is to our advantage. It's fashionable today for women to talk about caring men in bed who spend ages with detailed and prolonged foreplay, but this should not become a boring routine, however pleasant it might be.
Many women, in therapy, say that they greatly enjoy being taken roughly. It proves to them that they are so desirable that their man cannot keep his hands off them, which is in itself sexually flattering. It also absolves them from having to put up which much foreplay which they might find contrived, boring or repetitive.
For the man who likes to see his woman's bottom and anus, rear-entry positions can be extremely stimulating. If both partners like it, the man can caress her bottom and stimulate her anus. Because in many rear-entry sex positions, the woman's thighs are at an angle to her body – especially true in the classical 'doggy' position – penetration is quite deep, and can on occasion be very deep.
For the woman who has a sensitive G-spot, rear-entry sex positions can be especially good. The man's penis can be arranged to hit the right spot or to massage it gently, whichever the woman prefers. Even if the woman is not sensitive to G-spot stimulation, she will experience very different sensations, many of which are highly arousing, if only because of the position's novelty to her.
A woman who is shy, who wants to fantasise about another man, or who wants to be sexually satisfied but would rather not be reminded too blatantly of her partner for some reason, may find rear-entry a good way round her problem. By facing away from the man, she can enjoy her partner's penis and caresses in a somewhat anonymous way.
Rear-entry positions leave the man's hands free to caress and stimulate the woman's body. In some rear-entry positions, especially the 'doggy' position, the man has more freedom to thrust and alter the amount and angle of movement his penis makes.
Rear-entry sex positions are ideal when a woman is pregnant and finds the missionary position too uncomfortable. But her partner must limit the depth of penetration in the last few weeks of pregnancy.
Rear-entry positions range from the simple 'doggy' position to some highly adventurous positions that will please more athletic lovers.
Whatever variations you choose to try, make sure it suits both of you. If one partner finds a particular position awkward, painful or tiring, this will obviously detract a great deal from his or her enjoyment.
In the 'doggy' position, the woman kneels on the bed or the floor and her partner kneels behind and enters her. She can angle her pelvis in several different ways according to how far she leans forward and how she supports herself.
Each position gives new sensations to both. The woman can, for example, keep her body horizontal by resting on her hands and knees. She can rest on her elbows, or even lie with her arms back along her body, or put them under her forehead as her breasts support her upper body.
Penetration is extremely good, especially if the woman lies with her chest on the bed. The man has a large range of possible movements and the woman can be taken very forcefully, which many enjoy. A few women find that air becomes pushed into the vagina in some of these positions. This need not necessarily be a problem, but if the penis traps air and pushes it up into the top of the vagina it can cause pain. When the woman turns over, the air comes out with an embarrassing noise, but most couples either ignore this or are able to make a joke out of it.
For hard, deep thrusting, try having sex over the edge of the bed or a cushioned table.
A modification of the 'doggy' positions is for the woman to kneel on a low stool or table – covered with something that cushions her knees. The man stands behind her, between her open legs, and enters her.
For the more athletic, another good rear-entry position is to ask the woman to bend over with her legs wide apart and rest her hands on the floor in front of her. Her bottom and vulva are now exposed and the man can, by bending his knees a little, enter her from behind.
Movement and penetration are good, at least for the man, but the woman's movements are somewhat restricted, apart from being able to wiggle her hips from side to side to enhance the pleasure. She can, as in all rear-entry positions, contract her pelvic muscles to make it more stimulating for them both.
A restful and very enjoyable rear-entry position is 'the spoons'. The woman lies facing away from the man with her knees drawn up. The man cuddles into her body from behind and curls around and enters her. They can lie still with his penis inside her or he can move around. Penetration can be deep if she angles her body down towards the foot of the bed. He can reach round and caress the front of her body and kiss her neck and back.
In the 'reverse cowgirl' position, the man lies on the bed with his knees together and the woman kneels over his hips, facing away from him. She takes her weight on her hands placed either side of his legs. She controls the amount of movement in this rear-entry, woman-on-top position. This sex position is particularly enjoyable for the bottom-centred man as he can see her bottom and anus and caress them, while his lover takes the lead.
Another sex position is suitable for the woman with strong arms. Here, the woman leans over the bed, supporting her entire weight on her arms, and the man lifts her open legs off the ground and stands between them as he enters her from behind. Although movement is fairly limited in this position, penetration can be quite deep.
The bestselling Lovers' Guide Sexual Positions DVD, available now as a series of video downloads
Or as a region 2 DVD – click here


text:
Here's a character or two
Muhammad Ali is sometimes cited as the birthplace of the Cassis Clay's great great granddaddy ! I'm not too sure if the evidence is very sound...but it is at least possible.
Much more certain is the fact that the unflappable des lynam came from this little town, before his parents (both nurses) headed off to the uk for work. I certainly never guessed that he had strong irish roots. At this point the vast majority of readers will be thinking "who is the hell is de lynam?". Well Dessie was perhaps the UK most well known sports presenter over a period of about 40 years.Football was really his game but boxing would have figured as well. He was also well known as something of a "Ladies man"...a phrase that would perhaps haunt him after a fling with Caroline Cossey (or was it Barry ?)
Famously urbane and smooth as silk, he did make the odd gaff on-screen...including the classic :
"More football later, but first let's see the goals from the Scottish Cup final."
Cliffs of Moher
A must visit if you are in this area is the Cliffs of Moher which are about 30 miles northwest of Ennis. Quite easy to get there, from downtown you can take Cusack road to N85 then R478 to the cliffs.
Cliffs of Moher
The vast void you'll see when visiting the Cliffs have no words for me to express the wonders of nature! Go to the top, see the ruin mounted on it, enjoy the breeze, the silence and the vastity of the view. You won't regret it.
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ATF revises US Munitions Import List and extends term for import permits.
On March 27, 2014, the US Bureau of Alcohol, Tobacco, Firearms, and Explosives (ATF) published revisions to the US Munitions Import List (USMIL) as an interim final rule (IFR) effective April 28, 2014. The rule reflects ATF's first substantive revisions to articles controlled under the USMIL since early 2013 when Executive Order 13637 and a related final rule decoupled controls on permanent imports of defense articles from other defense controls. Public comments on the IFR must be submitted by June 25, 2014. In addition, on April 8, 2014, a new ATF final rule took effect extending the term of permanent import permits for articles subject to the USMIL from one year to two years. These USMIL changes may significantly impact US importers of certain defense articles and make compliance more challenging, particularly in the larger context of the President's Export Control Reform Initiative (ECR) and changes to controls on the export and temporary import of defense articles.
USMIL: Fewer Articles, More Specificity -
The USMIL is the official list of defense articles and defense services controlled by ATF for permanent import into the US. Importers of such items must register in advance with ATF and obtain a permit for the items to be imported, unless the transaction qualifies for a permit exception. The USMIL divides covered articles into numbered categories, and provides notes for additional context and reference.
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Adam Grosser:
Adam Grossert和他的可持续冰箱
Adam Grosser的项目是关于建造一种不需使用电的冰箱,并利用它把重要的需要冷藏的医疗物品运往世界各地的村庄和诊所。目前通过对一些旧技术的调整,他已经有一套系统可以做到这一点。
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How to use features in Outlook 2007 to streamline mailbox functions and tasks.
Shows how to transition smoothly between the 2003 and 2007 versions of Microsoft's email and calendaring client.
Explains how to use Outlook 2007 for increased productivity, from the basics of the interface to advanced features like filters.
"There are quite a few things that make lynda.com the best online learning platform. One of the greatest is that you guys listen and respond to your audience and I can't thank you enough for doing so." —Nathan
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13.00 ct. t.w. Smoky Quartz and 1.54 ct. t.w. Multicolored Diamond Pendant Necklace in 14kt Rose Gold. 18"
Item#: 826038
This smoldering pendant necklace showcases 13.00 ct. t.w. of smoky quartz in subtle waves of white, brown and enhanced black diamonds totaling 1.54 carats. Suspends from a rope chain with a 2" extender. 14kt rose gold pendant necklace.
Product Details (for 13.00 ct. t.w. Smoky Quartz and 1.54 ct. t.w. Multicolored Diamond Pendant Necklace in 14kt Rose Gold. 18")
Necklace Drop close DROP: A dangling or stationary detail which "drops" from a bale, strand or earring backing. Length:
1 3/4 inches
Necklace Drop Width:
7/8 inch
14kt close 14KT: Karat (abbreviated kt or K) is a unit that indicates the purity of gold in the metal. 14kt is 58.33% gold. In the United States, 14K yellow gold is most favored and used in jewelry. Rose Gold close ROSE GOLD: Gold is a precious metal which is naturally quite soft. To give it a rose color and increase its strength, gold is alloyed with other metals, such as copper and silver. The purity of the metal is indicated by a unit called a "karat," with 24kt having the highest percentage of natural gold.
Polished close POLISHED: A buffed-out finish used to produce a mirror-like shine.
Rope close ROPE: Chain links that are twisted or looped together in a pattern that creates a look similar to that of a rope.
Chain Size:
1.5 mm
Lobster close LOBSTER CLASP: named after the pinching style of the hook, this clasp is often shaped like a lobster's claw. Use your finger to work the lever to open the clasp.
Double close DOUBLE: A bale that has two loops to slide a chain through.
Fits Chain:
2 mm
Chain Included:
Gemstone 1:
Quartz close QUARTZ: From the icy shimmer of rock crystal quartz to the delicate pink of rose quartz to the moody hues of smoky quartz, this gemstone offers something for everyone. Quartz, found in endless colors and varieties, is a popular choice for bracelets, necklaces, rings and earrings. (Color: Smoky, Quantity: 2, Shape & Cutting Style: Oval close OVAL: An elliptical shape that resembles an egg. Checkerboard close CHECKERBOARD: A technique that creates a contrast of dark and light when light hits the pattern of square or diamond-shaped facets. , Weight: 13.00 ct. t.w., Size: 10X7-20X13 mm)
Gemstone 2:
Diamond close Diamond: The hardest and most brilliant of all gemstones, a diamond can make the heart race with its pure and fiery spark. An ancient symbol of love, a diamond is the preferred gemstone for tokens of affection, such as rings, earrings, necklaces and bracelets. Diamond is the birthstone for April. (Quantity: 61, Shape & Cutting Style: Round Brilliant close BRILLIANT: A gemstone cut to enhance brilliance without sacrificing much carat weight. Typically has 58 facets. , Color Grade: G-H, Clarity: SI2-I1, Weight: 0.21 ct. t.w.)
Gemstone 3:
Diamond (Color: Black, Quantity: 62, Shape & Cutting Style: Round Single-Cut close SINGLE-CUT: A gemstone cutting technique that dates back to the 1300s. Still used today, the single-cut usually features 18 facets that go in one direction without crossing each other. , Weight: 0.47 ct. t.w.)
Gemstone 4:
Diamond (Color: Brown, Quantity: 146, Shape & Cutting Style: Round Single-Cut, Clarity: SI2-I1, Weight: 0.86 ct. t.w.)
All weights and measures are approximate.
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Arizona Cardinals
ESPN NFL Insider: 'There's going to be changes in Arizona'
As the Arizona Cardinals prepare for their season finale against the rival San Francisco 49ers, the future of head coach Ken Whisenhunt continues to take center stage.
Rumors are swirling that Whisenhunt could be one of a good number of head coaches fired on "Black Monday."
ESPN NFL Insider Chris Mortensen joined The Herd with Colin Cowherd on Friday and said he believes Whisenhunt isn't the only member of Cardinals' brass who could be shown the door.
"There's going to be changes in Arizona," Mortensen said. "By the way, there's going to be a lot of general manager changes."
Mortensen said Cardinals GM Rod Graves is on thin ice with the team and he could indeed be one of the general managers on the way out.
Graves and Whisenhunt have taken a lot of heat for the Cardinals' failure at obtaining and helping to cultivate a franchise quarterback. Mortensen believes that it may be in the best interest of both Whisenhunt and the Cardinals to go their separate ways.
"Because of the quarterback situation and just how they have botched it and I know [Whisenhunt] well, I have great respect for him and I believe he will be a head coach again if he's fired," Mortensen explained. "But the quarterback thing is really on both of them and you know that the owners, the Bidwill family, are very frustrated."
While the quarterback debacle may indeed seal Whisenhunt's fate, there are other factors that indicate it could be time for a change.
The 50-year-old coach came to Arizona with the hope of using his esteemed offensive background to revamp the Cardinals' system. But in the last three years of his six season tenure, the offense has failed to meet expectations.
It's quite possible Whisenhunt could do well coaching another team, as many of his supporters suggest, but it may just be too little, too late in Arizona.
Most Popular
Cardinals Audio
- Jared Veldheer, Cardinals offensive tackle - Wednesday May 27Jared Veldheer believes the Cardinals offensive line has improved greatly.
- Justin Bethel, Cardinals defensive back - Wednesday May 27Justin Bethel discusses the big important year ahead of him.
- Rodney Gunter, Cardinals defensive lineman - Tuesday May 26Rodney Gunter has been a "sleeper" player since high school.
- Tyrann Mathieu, Cardinals safety - Tuesday May 26Tyrann Mathieu says he is feeling healthy and discusses the mentality of the defense.
- Bickley Blast - Tuesday May 26Ray McDonald's violent tendencies emerge yet again.


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Research Output for Charlie Corke
Note: The 2012, 2013, 2014, 2015 publications have not been audited.
Jump to: Publications | Grants and Consultancies | HDR completions
Charlie Corke may be from another institution or only recently joined Deakin University.
2009 External
Corke, Charlie* and de Leeuw, Evelyne (2009) Strategies to accommodate future intensive care demand in Australia, in Riley, Richard (eds), Australasian anaesthesia : a collection of continuing education lectures given in Australasia, pp. 145-150, Royal Australasian College of Surgeons, Melbourne, Vic. [BN]
DRO entry for this publication
Corke, C.*, Milnes, S., Orford, N.*, Henry, M. J.*, Foss, C.* and Porter, D. (2009) The influence of medical enduring power of attorney and advance directives on decision making by Australian intensive care doctors, Critical care and resuscitation, vol. 11, no. 2, pp. 122-128, Australasian Academy of Critical Care Medicine, Bedford Park, S. Aust. [C1]
ERA journal ID: 15971 – Scopus EID: 2-s2.0-68049114507
Citation counts: Scopus - 2, Thomson - 3
DRO entry for this publication
Corke, Charlie*, de Leeuw, Evelyne, Lo, Sing Kai and George, Carol* (2009) Predicting future intensive care demand in Australia, Critical care and resuscitation, vol. 11, no. 4, pp. 257-260, Australasian Academy of Critical Care Medicine, Bedford Park, S. A. [C1]
ERA journal ID: 15971 – Scopus EID: 2-s2.0-77949432370
Citation counts: Scopus - 1, Thomson - 1
DRO entry for this publication
1999 External
Glenister, K., Corke, C.* and Watson, T. (1999) Phospholipase A2 Activity as a Marker of Bowel Ischaemia., National Scientific Conference 1999, The Australian Society for Medical Research, Australia [L3]
no DRO entry yet for this publication
Grants and Consultancies
No grants and/or consultancies found or audited – the 2014 HERDC financial return has not been completed or loaded as yet.
Higher Degree by Research Completions supervised by Charlie Corke
No completions found or audited.
- Legend:
- * Not a member of Deakin University at time of output.
DRO to publications collection last synchronised: Thursday 28th May 2015 10:04pm


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Mental illness, poverty haunted Afghan policewoman who killed American
KABUL (Reuters) – The Afghan policewoman suspected of killing a U.S. contractor at police headquarters in Kabul suffered from mental illness and was driven to suicidal despair by poverty, her children told Reuters on Wednesday.
The woman was identified by authorities as Narges Rezaeimomenabad, a 40-year-old grandmother and mother of three who moved here from Iran 10 years ago and married an Afghan man.
Spring Wish denied as suicide bomber brings down Afghan juice empire
KABUL (Reuters) – When a Taliban suicide bomber killed two people on the edge of the Afghan capital this month, there was another casualty – a global fruit juice business optimistically called "Spring Wish" which provided work for thousands of farmers across the country.
Mustafa Sadiq's empire had been expanding healthily, bringing in badly needed foreign capital, before the attack inflicted the kind of financial loss cash-strapped Afghanistan can ill afford.
Pakistan, Afghanistan trying to turn Taliban into political movement
KABUL (Reuters) – Pakistan is genuine about backing the nascent Afghan peace process and shares the Kabul government's goal of transforming the Taliban insurgency into a political movement, a senior Afghan government official told Reuters.
"They have told us that they share the vision contained in our roadmap which is basically to transform the Taliban from a military entity into a political entity to enable them to take part in the Afghan political process and peacefully seek power like any other political entity in Afghanistan, he said.
Bomber posing as peace envoy wounds Afghan spy chief
KABUL (Reuters) – A Taliban suicide bomber posing as a peace messenger wounded Afghanistan's intelligence chief in Kabul on Thursday, another sign that the government is struggling to improve security ahead of a NATO pullout in 2014.
Asadullah Khalid was wounded when the bomber struck in a meeting at a guesthouse used by the National Directorate of Security (NDS).
Taliban claim suicide attack on Afghan spy chief
KABUL (Reuters) – The Taliban said on Thursday they carried out a suicide bombing that wounded Afghanistan's intelligence chief in Kabul, another sign that the government is struggling to improve security ahead of a NATO pullout in 2014.
Asadullah Khalid was wounded when the bomber struck at a guesthouse used by the National Directorate of Security (NDS) in a heavily guarded area of the capital. The intelligence agency said he had survived a "terrorist attack".
Chinese return to Afghan mine project – minister
KABUL (Reuters) – Most of the roughly 170 Chinese workers who fled rocket attacks on the largest foreign investment project in Afghanistan have returned because of improved security, the Afghan mining minister said on Thursday.
Officials had been trying to convince Chinese workers to restart work at the Aynak copper deposit in Logar province, one of the most dangerous regions of the country.
Pakistan urges all Afghan insurgents to pursue peace: ambassador
KABUL (Reuters) – Pakistan hopes to persuade Afghan insurgent groups, including the lethal Haqqani network, to pursue peace but worries resistance from political factions opposed to the Taliban could undermine reconciliation efforts, Islamabad's ambassador said.
Mohammad Sadiq, speaking in an interview, also suggested U.S. efforts would be better directed at engaging insurgent groups — rather than attempting to defeat them by launching military strikes against their leaders.
No breakthrough in Afghan peace efforts before 2014: official
KABUL (Reuters) – Afghanistan's government has failed to secure direct talks with the Taliban and no significant progress is expected before 2014, when most NATO combat troops withdraw, a senior Afghan official closely involved with reconciliation efforts said on Friday.
"No breakthrough is expected before the 2014 election," the official told Reuters, speaking on condition of anonymity.
Obama must clean up Afghan politics: opposition leader
KABUL (Reuters) – Prominent Afghan opposition leader Ahmad Zia Masood has urgent advice for President Barack Obama in his second term – clean up Afghan politics before the next election or risk civil war.
Masood said a number of factors could trigger another internal conflict after most NATO combat troops leave at the end of 2014, including growing fears of another Taliban takeover.
Afghanistan rules out peace deals with Haqqanis
KABUL (Reuters) – Afghanistan welcomes the United Nations' decision to impose sanctions on the Haqqani network and would not negotiate for peace with the group blamed for several high-profile attacks in the country, the presidential spokesman said on Tuesday.
On Monday the U.N. Security Council's Taliban sanctions committee added the Haqqani network to a U.N. blacklist, the United States said.


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Marquette extends a warm welcome to course attendees through our practice of cura personalis (care for the whole person). We provide attendees with wonderful extras including healthy meals and snacks, a comfortable lecture hall and lab settings, and a beautiful campus to walk during breaks.
Please review the list of courses coming up. Click on the name of any course you may be interested and information will expand and there will be links for more information that will take you to course specifics and registration forms.
Discounted fee for Marquette Alumni, community participants welcome!
This intermediate level 3-day course is designed for rehabilitation professionals treating pelvic pain and elimination disorders who seek additional skills in the evaluation and treatment of musculoskeletal co-morbidities as well as clinical reasoning with prioritization of interventions. Participants will be provided with differential diagnosis and clinical reasoning that can be applied to their clients immediately. Internal and external pelvic floor assessment is critical for evidence based evaluation and treatment of pelvic pain and elimination disorders. This data, along with the musculoskeletal screening, can determine if the pelvic floor dysfunction is the victim or the culprit. The course is an excellent adjunct for clinicians interested in learning how to evaluate and prioritize the treatment of pelvic floor dysfunction within concurrent musculoskeletal dysfunction.
More information on the course.
An intensive four-day study of the anatomical and psycho-physiological principles essential for the development of effective treatment programs. This course meets didactic training and practicum requirements for Biofeedback Certification International Alliance (BCIA) certification in pelvic floor muscle dysfunction biofeedback. A benefit for the PT Faculty Scholarship Fund to assist graduate students in the doctor of physical therapy program. Detail information to follow.
Minimum of 14 participants to hold course.
This course is designed for licensed physical therapists with a BS or MPT degree. DPT entry-level lecture course focusing on a broad range of medical diseases and their various clinical presentations. The focus is on the use of clinical decision making skills when analyzing a patient's medical history intake and the review of systems. The course addresses screening, to include referral for conditions or diseases that are not within a physical therapist's scope of practice.More information on the course.
This course consists of an intensive four-day anatomical dissection and kinesiological review. Even-year summers focus on the lower extremity and odd-year summers focus on the upper extremity. The primary purpose of this course is to provide clinicians with a solid anatomical and kinesiologic basis for understanding normal and abnormal function of the musculoskeletal system. This information is essential for the development of effective treatment programs.
This course consists of an exciting three-day anatomical dissection of the brain and spinal cord, as well as a compelling review of recent advances in functional neuroscience. Participants will work in groups and be allotted three afternoons to perform regional dissections on embalmed human cadaveric material. The faculty consists of neuroscientists and clinicians qualified and experienced as neuroanatomical instructors. Faculty members guide 12 hours of dissection in the afternoons. These sessions are complemented by three morning lecture sessions enriched by slide, video, computer animation and microscopic presentations. Detail information to follow.
Science and technology are changing society and the way we live. In many ways, science fiction is becoming reality: what does this mean to us? Will technology eventually replace therapists? New biomedical devices make increasing amounts of data available about the status of patients (telehealth, wearable technologies, implantable devices) – do we know what to do with it? Is our role changing?
This course provides training in neuroscience applied to higher mental functions and their disorders. Participants gain an in-depth understanding of structural properties, sensorimotor systems and neurolinguistic organization of the human brain. This learning is supplemented by the guided brain dissections and neurological problem solving. Participants will also learn about the modern neuroradiological techniques, advances in neurological management of stroke and related syndromes, bioethical issues, neuropsychological concepts and neurolinguistic implications of various neurosurgical techniques. The faculty is derived from the disciplines of neurolinguistics, neuroscience, neurology, neurosurgery, law and neuroradiology.
This is an advanced three-day course designed for nurses, physical therapists, occupational therapists and other health care providers who are seeking a better understanding of the various bowel disorders that affect children, women and men; and the specific rehabilitation strategies that are useful in treating these disorders.
Minimum of 14 participants to hold course.
This 3 day course is designed for licensed health care professionals such as physical and occupational therapists, nurses, nurse practitioners, and physician assistants who are working in the area of pelvic floor dysfunction and looking to expand their knowledge with specific patient populations and treatment considerations. Clinicians will be provided with the rationale and tools to address Sexual Function and Wellness and provide strategies for treatment of Chronic Pelvic Pain. Specific content and detailed information on these topics is provided below.
Donald A Neumann, PT, Ph.D. FAPTA and Andrew Starsky, BSEE, MPT, Ph.D.
This two-day course is designed for Physical Therapists, Athletic Trainers, Occupational Therapists and PT/OT Assistants who desire a comprehensive yet practical review of the anatomy, kinesiology and treatment principles associated with the shoulder, elbow and forearm.
Information on course.
This program is recognized by the American Physical Therapy Association (APTA) as a Clinical Instructor (CI) Education and Credentialing Program and is being sponsored by Marquette University on behalf of the WI Clinical Education Consortium. The program was developed through a grant funded by APTA under the direction of principal investigator Michael J. Emery, Ed.D., PT and with co-investigators Nancy Peatman, PT, M.Ed. and Lynn Foord, MS, M.Ed., PT and with materials used by the New England Consortium of Academic Coordinators of Clinical Education, Inc. It takes 15 hours to complete the entire program for CI Education and Credentialing.
More information on course.
The Advanced Clinical Instructor Credentialing and Education Program brings two constructs together in one professional development program that advances both clinical teaching and best practice when providing student clinical education. Using a case-based and interactive approach to education, this program provides participants with the essential knowledge and skill to more effectively teach and mentor students in the context of a doctoring profession. Through the program's unique philosophy and design, best outcomes will be achieved for student learning by concurrently advancing concepts of clinical teaching and clinical practice.
More information on course.


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What kind of battery for adventuring, is Lithium up to the challenge?
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Joined: Mar 2012
Location: Russia, N56 E49.
Oddometer: 388
JoelWisman, oh how I missed your experiments!!
Just last night I studied the whole thread and remember wishing you would carry on with the envistigation, because there's so much more...
I mean, not only the aspects of your testing such as cold performance, chargers etc, but the LiFePO4 field itself is developing rapidly, with new names and products appearing.
I'd really appreciate if you could clarify a few points...
Originally Posted by
What I am seeing with the two Shorai LFX18s I have experimented with is that 14 volts and below will eventually fall out of balance, though how long it will take I don't know. 14.1 volts is marginal. 14.2 volts and above looks like it will be ok to me.
Imagine I have a bike with iron phosphate and a voltmeter.
Riding along, would probably see ~14.2-14.6 V
Imagine then some eqipment gets switched on - lights, heated gear etc...
Voltage might drop to ~13.0-13.5 on the voltmeter...
Does that mean - battery is discharging as the alternator is not able to support the consumers.
- battery is not discharging, as the alternator output is sufficient, but WILL get out of balance due to lack of current passing through it?
In other words, what minimum voltage would you suggest needs to be maintained (by regulating additional power consumption) in the system when riding as to ensure the cells are charged AND balanced?
Originally Posted by
Towpro, You hit the nail on the head. LiFePo4 needs to internally heat to provide full cranking amps, and not just when cold. Even warm LiFePo4, batteries that will start your bike fine have a large voltage drop for the first few seconds. Enough so, that even on a warm day, the the battery recommended for some bikes by some manufactures will be damaging bikes starting systems over time IMO.
Why would the starter get damaged operating at lower than optimal speed/voltage?
Or is this only applicable to certain types of starter engagement?
Originally Posted by
You don't need a special charger for LiFePO4 batteries, you just need to be sure not to charge them beyond 14.7 volts.
With a manual charger, sit with it and manually stop charging when you hit 14.7 volts.
I have a charger with one knob controlling the current (0 -10A), but obviously is i set it to, say, 1A, and connect to a poorly charged battery, it will only need a small overvoltage to maintain that amp.
As the battery gets charged, my charger ups the voltage to maintain this set current, until it reaches 15V.
Do you know if this is a what you call manual charger and if its suitable, or do I need to search for one with a set max. charging voltage of 14. what ????
Thanks for your time on this topic!!
Bli55 screwed with this post 02-21-2013 at
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The long day in Boston left many residents stuck in their homes watching TV. Some chose to congregate, and NPR's Chris Arnold went to a "lock-down party" Friday night, and spoke to happy residents after the capture of the second suspect.
Source: NPR
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