Friday, August 31, 2012

Evolutionary diagnosis method for variants in personal exomes

http://www.nature.com/nmeth/journal/v9/n9/full/nmeth.2147.html?WT.ec_id=NMETH-201209

Each human exome contains thousands of nonsynonymous single-nucleotide variants (nSNVs) that have unknown biological effects. The potential impact of nSNVs on biological function is now routinely assessed using computational methods for application in biomedical research and clinical genome profiling reports. Of the variants receiving a non-neutral (function-damaging) prediction, those at evolutionarily conserved sites are frequently of heightened interest for scientists and clinicians because such sites are among the most critical for proper protein function. Indeed, a majority of amino acid mutations that have been investigated experimentally are located at ultraconserved sites1, which show no amino acid residue difference among diverse species spanning over 500 million years of evolution (Supplementary Fig. 1). Functionally damaging mutants at these sites are likely to have significant consequences for health and disease.
For these ultraconserved sites, we estimated the false positive rate (FPR) of two state-of-the-art computational tools, Condel2 and PolyPhen-2 (ref. 3), by using the standard collection of neutral variants (HumVar3) that was used to train and test these two tools (Table 1).Our analysis revealed a high FPR for Condel (89%) and PolyPhen-2 (75%). For 73% of the neutral nSNVs in HumVar, both produced a function-damaging prediction. Additionally, the overall accuracy of these tools at ultraconserved positions was low (55% and 60%, respectively). Therefore, predictions produced by current computational tools may mislead downstream experimental and clinical investigations aimed at studying functionally important sites.
 A web server for evaluating novel variants with EvoD is available at http://barn.asu.edu/EvoD/.

Thursday, August 30, 2012

Update your Java now to avoid being exploited

http://www.isjavaexploitable.com/

http://krebsonsecurity.com/how-to-unplug-java-from-the-browser/

Uninstall your old Java and install the Java 1.7.0_07 update 

confabulation

confabulation

 is a memory disturbance that is characterized by verbal statements or actions that inaccurately describe history, background, and present situations.[1] Confabulation is considered “honest lying,” but is distinct from lying because there is typically no intent to deceive and the individual is unaware that their information is false.

http://en.wikipedia.org/wiki/Confabulation

Science books

http://www.nature.com/nature/journal/v488/n7413/full/488587a.html?WT.ec_id=NATURE-20120830

Higgs: The Invention and Discovery of the 'God Particle'

Jim Baggott Oxford University Press 304 pp. £14.99 (2012)

1912: The Year the World Discovered Antarctica

Chris Turney Bodley Head 368 pp. £20 (2012)

The Stardust Revolution: The New Story of Our Origin in the Stars

Jacob Berkowitz Prometheus 312 pp. £23.95 (2012)

On a Farther Shore: The Life and Legacy of Rachel Carson

William Souder Crown 544 pp. £19.99 (2012)

Marie Curie and Her Daughters: The Private Lives of Science's First Family

Shelley Emling Palgrave Macmillan 256 pp. £16.99 (2012)
 http://en.wikipedia.org/wiki/Marie_Curie
Her achievements included a theory of radioactivity (a term that she coined), techniques for isolating radioactive isotopes, and the discovery of two elements, polonium and radium. Under her direction, the world's first studies were conducted into the treatment of neoplasms, using radioactive isotopes. She founded the Curie Institutes in Paris and in Warsaw, which remain major centres of medical research today.

Monday, August 27, 2012

Subgroup-specific structural variation across 1,000 medulloblastoma genomes

http://www.nature.com/nature/journal/v488/n7409/full/nature11327.html

Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Subject terms: Cancer Genetics Genomics Cell biology

Thursday, August 23, 2012

Fathers bequeath more mutations as they age

http://www.nature.com/news/fathers-bequeath-more-mutations-as-they-age-1.11247

That year has finally arrived: whole-genome sequencing of dozens of Icelandic families has at last provided the evidence that eluded Haldane. More­over, a study published in Nature finds that the age at which a father sires children determines how many mutations those offspring inherit2. By starting families in their thirties, forties and beyond, men could be increasing the chances that their children will develop autism, schizophrenia and other diseases often linked to new mutations. “The older we are as fathers, the more likely we will pass on our mutations,” says lead author Kári Stefánsson, chief executive of deCODE Genetics in Reykjavik. “The more mutations we pass on, the more likely that one of them is going to be deleterious.”

Wednesday, August 22, 2012

The time is right to confront misconduct

http://www.nature.com/news/the-time-is-right-to-confront-misconduct-1.11085?WT.ec_id=NEWS-20120807

Considerable hard data have emerged on the scale of misconduct. A metastudy (D. Fanelli PLoS ONE 4, e5738; 2009) and a detailed screening of all images in papers accepted by The Journal of Cell Biology (M. Rossner The Scientist 20 (3), 24; 2006) each suggest that roughly 1% of published papers are fraudulent. That would be about 20,000 papers worldwide each year.

Why great Olympic feats raise suspicions

http://www.nature.com/news/why-great-olympic-feats-raise-suspicions-1.11109?WT.ec_id=NEWS-20120807

Was Ye’s performance anomalous?

Yes. Her time in the 400 IM was more than 7 seconds faster than her time in the same event at a major meet in July 2011. But what really raised eyebrows was her showing in the last 50 metres, which she swam faster than US swimmer Ryan Lochte did when he won gold in the men’s 400 IM on Saturday, with the second-fastest time ever for that event.

Tissue engineering: The brainmaker

With his knack for knowing what stem cells want, Yoshiki Sasai has grown an eye and parts of a brain in a dish.

'He' is Yoshiki Sasai, a stem-cell biologist at the RIKEN Center for Developmental Biology in Kobe, Japan. Sasai has impressed many researchers with his green-fingered talent for coaxing neural stem cells to grow into elaborate structures. As well as the optic cup1, he has cultivated the delicate tissue layers of the cerebral cortex2 and a rudimentary, hormone-making pituitary gland3. He is now well on the way to growing a cerebellum4 — the brain structure that coordinates movement and balance. “These papers make for the most addictive series of stem-cell papers in recent years,” says Luc Leyns, a stem-cell scientist at the Free University of Brussels.

And is tissue formation driven by a genetic program intrinsic to cells, or shaped by external cues from neighbouring tissues? By combining intuition with patient trial and error, Sasai has found that it takes a delicate balance of both: he concocts controlled environments that feed cells physical and chemical signals, but also gives them free rein to 'do their thing' and organize themselves into issues. He sometimes refers to himself as a Japanese matchmaker who knows that, having been brought together, two strangers need to be left alone. “They know what to do,” he says. “They interact in a delicate manner, and if the external cues are too strong, it will override the internal ones.”
  
http://www.nature.com/news/tissue-engineering-the-brainmaker-1.11232

Evaluating the consistency of gene sets used in the analysis of bacterial gene expression data

MicrobesOnline (MO) uses the  method of Price et al. [21] to create MO Predicted Operons

The SEED organizes functional roles for genes into  Subsystems (SS) that represent components of cellular processes and cellular structures;

http://www.biomedcentral.com/content/pdf/1471-2105-13-193.pdf

http://www.theseed.org/wiki/Home_of_the_SEED
http://microbesonline.org/cgi-bin/fetchLocus.cgi?locus=37563&disp=0

Transforming clinical microbiology with bacterial genome sequencing

Summary


http://www.nature.com/nrg/journal/v13/n9/abs/nrg3226.html

Next-gen sequencing
http://www.nature.com/nrg/series/nextgeneration/index.html?WT.ec_id=NRG-201209 

The nerve of ovulation-inducing factor in semen

Marcelo H. Rattoa, Yvonne A. Leducb, Ximena P. Valderramac, Karin E. van Straatend, Louis T. J. Delbaereb,1, Roger A. Piersone, and Gregg P. Adamsf,2

http://www.pnas.org/content/early/2012/08/15/1206273109.abstract
http://www.vancouversun.com/health/sexual-health/Hormone+semen+behind+oops+babies+researchers/7124802/story.html

A component in seminal fluid elicits an ovulatory response and has
been discovered in every species examined thus far. The existence of
an ovulation-inducing factor (OIF) in seminal plasma has broad impli-
cations and evokes questions about identity, tissue sources, mecha-
nism of action, role among species, and clinical relevance in infertility.
Most of these questions remain unanswered. The goal of this study
was to determine the identity of OIF in support of the hypothesis that
it is a single distinct and widely conserved entity. Seminal plasma
from llamas and bulls was used as representative of induced and
spontaneous ovulators, respectively. A fraction isolated from llama
seminal plasma by column chromatography was identified as OIF by
eliciting luteinizing hormone (LH) release and ovulation in llamas.
MALDI-TOF revealed a molecular mass of 13,221 Da, and 12–23 aa
sequences of OIF had homology with human, porcine, bovine, and
murine sequences of β nerve growth factor (β-NGF). X-ray diffraction
data were used to solve the full sequence and structure of OIF as
β-NGF. Neurite development and up-regulation of trkA in phaeochro-
mocytoma (PC12) cells in vitro confirmed NGF-like properties of OIF.
Western blot analysis of llama and bull seminal plasma confirmed
immunorecognition of OIF using polyclonal mouse anti-NGF, and ad-
ministration of β-NGF from mouse submandibular glands induced
ovulation in llamas. We conclude that OIF in seminal plasma is
β-NGF and that it is highly conserved. An endocrine route of action
of NGF elucidates a previously unknown pathway for the direct in-
fluence of the male on the hypothalamo–pituitary–gonadal axis of
the inseminated female.

The Histone Acetyltransferase MOF Is a Key Regulator of the Embryonic Stem Cell Core Transcriptional Network

Xiangzhi Li,1,2,6 Li Li,4,6 Ruchi Pandey,2 Jung S. Byun,5 Kevin Gardner,5 Zhaohui Qin,4 and Yali Dou2,3,*

www.ncbi.nlm.nih.gov/pubmed/22862943

Pluripotent embryonic stem cells (ESCs) maintain
self-renewal and the potential for rapid response to
differentiation cues. Both ESC features are subject
to epigenetic regulation. Here we show that the
histone acetyltransferase Mof plays an essential
role in the maintenance of ESC self-renewal and plu-
ripotency. ESCs with Mof deletion lose characteristic
morphology, alkaline phosphatase (AP) staining, and
differentiation potential. They also have aberrant
expression of the core transcription factors Nanog,
Oct4, and Sox2. Importantly, the phenotypes of Mof
null ESCs can be partially suppressed by Nanog
overexpression, supporting the idea that Mof func-
tions as an upstream regulator of Nanog in ESCs.
Genome-wide ChIP-sequencing and transcriptome
analyses further demonstrate that Mof is an integral
component of the ESC core transcriptional network
and that Mof primes genes for diverse develop-
mental programs. Mof is also required for Wdr5
recruitment and H3K4 methylation at key regulatory
loci, highlighting the complexity and interconnectiv-
ity of various chromatin regulators in ESCs.

Tuesday, August 21, 2012

False discovery rate (FDR) vs Family wise error rate

The goal of multiple comparisons corrections is to reduce the number of false positives. 
 
False discovery rate (FDR)
- controlling for the proportion of discoveries (significant results) that are false positives
- At FDR of 10%, you're willing to accept 10% of the significant results to be false positives
- use Benjamini-Hochberg

Family wise error rate (FWER)
- more stringent
- At 0.05 family wise error rate, for 100 statistical tests, you will need P < 0.0005 (=0.05/100)
- use Bonferonni


http://udel.edu/~mcdonald/statmultcomp.html

Monday, August 20, 2012

Future of Data: Encoded in DNA

http://online.wsj.com/article/SB10000872396390444233104577593291643488120.html#articleTabs%3Darticle

Next-Generation Digital Information Storage in DNA


http://www.sciencemag.org/content/early/2012/08/15/science.1226355

Digital information is accumulating at an astounding rate, straining our ability to store and archive it. DNA is among the most dense and stable information media known. The development of new technologies in both DNA synthesis and sequencing make DNA an increasingly feasible digital storage medium. Here, we develop a strategy to encode arbitrary digital information in DNA, write a 5.27-megabit book using DNA microchips, and read the book using next-generation DNA sequencing.


Friday, August 17, 2012

Blood vessel directs cells

http://www.nature.com/nature/journal/v486/n7404/full/486442b.html

The first blood vessel formed in the embryo — the dorsal aorta — coordinates the formation of the sympathetic nervous system and the medulla of the adrenal gland, both of which marshal the body's fight-or-flight response.
The nervous system and the adrenal medulla are derived from progenitor neural-crest cells — some of which migrate towards the dorsal aorta during early development. Yoshiko Takahashi of Kyoto University in Japan and her colleagues studied developing chick and mouse embryos and found that the dorsal aorta secretes bone morphogenetic proteins. These stimulate the production of signalling molecules that, in turn, attract some of the neural-crest cells. Bone morphogenetic proteins are then involved in the formation of the separate lineages that give rise to the adrenal gland and the sympathetic nervous system.
 Science 336, 15781581 (2012)

A global map of human gene expression.


The experiment contains systematically annotated and consistently normalized human gene expression data matrix of 5372 samples integrated from 206 public experiments of a HG-U133A array platform. The dataset is a subset of a larger pool of 9004 samples gathered from ArrayExpress and GEO websites and checked for quality assessment and suitability for data co-analysis as described by Bolstad et al 2005. The sample annotations have been subject to semiautomatic curation and manual generalization of 369 biological groups which have been additionally organized into blood/non-blood, 14 and 15 meta-classes.
Lukk et al. (2010), Nature Biotech.

The experiment has been slightly modified by adding biological variables (cell line, disease state, organism part, developmental stage) that are not present in the original publication.(PubMed 20379172)
  • http://www.ebi.ac.uk/gxa/experiment/E-MTAB-62
    • Supplementary methods:
      • They pulled 1925 datasets from ArrayExpress + 7079 from GEO
      • After QC (see Barrett et al. 2009 and Bolstad et al. 2003) that removes duplicates, low quality (ie CEL files not consistent with the other tested), 5372 CEL files (samples) remained
      • Probesets were mapped to genes by using the biomaRt Bioconductor package, 18,609 probes mapped to 14245 genes
      • Sample annotation were annotated using the Whatizit (Rebholz-Schuhmann et al. 2007) tool developed in EBI which converted GEO free text to MGED Ontology, followed by manual curation producing 369 terms or biological group and were divided into four 15 meta-classes
      • Performed standard coexpression using Pearson correlation, average linkage as distances between groups, PCA, differential expression with limma

Thursday, August 16, 2012

Resume's and CVs

http://www.nature.com/naturejobs/science/articles/10.1038/nj7410-241a?WT.ec_id=NATUREjobs-20120816

 Ultimately, say careers advisers, applicants need to suss out potential employers' expectations for format, language and other uncertainties by reading the advert, checking with mentors, reaching out to contacts who work for the employer and asking the employer themselves. The most brilliant research accomplishments can't work in an applicant's favour if the CV or résumé goes unread, as Sharon Milgram, director of the Office of Intramural Training and Education at the US National Institutes of Health in Bethesda, Maryland, points out. “Don't blow your chances,” she says, “by not giving me what I want.”

 In all countries, it is likely that the first viewer of an industrial application will not be a scientist, so an applicant's résumé (in the United States) or CV (in the United Kingdom and EU) should be peppered liberally with words and phrases mined from the advert. A computer will almost certainly do the initial screen to weed out non-viable candidates and assign ratings; applicants shouldn't risk their submission being deleted just because it didn't contain the appropriate keywords. “Give them every reason to screen you in instead of screening you out,” says Tringali, who adds that résumés and CVs for industry should not be overly technical.

UltraStar Deluxe: Karaoke game

UltraStar Deluxe: Karaoke game


Description


Karaoke game inspired by the Singstar™ game available on the Playstation®. It allows up to six players to sing along with music using microphones in order to score points, depending on the pitch of the voice and the rhythm of singing.
UltraStar Deluxe Web Site

OpenMRS (Open Medical Record System)

http://sourceforge.net/projects/openmrs/

OpenMRS is a community-developed, open source, enterprise electronic medical record system. Our mission is to improve health care delivery in resource-constrained environments by coordinating a global community to creates and support this software.

Wednesday, August 15, 2012

Regulatory Sequences in Eukaryotic Protein-Coding Genes

http://www.ncbi.nlm.nih.gov/books/NBK21745/

Once transcription start sites in eukaryotic DNA had been identified, analysis of the DNA sequences controlling initiation of transcription could begin. In this section, we take a closer look at various elements in the transcription-control regions that regulate transcription of eukaryotic protein-coding genes.

Transcription of genes with promoters containing a TATA box or initiator element begins at a well-defined initiation site. However,transcription of many protein-coding genes has been shown to begin at any one of multiple possible sites over an extended region, often 20 – 200 base pairs in length. As a result, such genes give rise to mRNAs with multiple alternative 5′ ends. These genes, which generally are transcribed at low rates (e.g., genes encoding the enzymes of intermediary metabolism, often called “housekeeping genes”), do not contain a TATA box or an initiator. Most genes of this type contain a CG-rich stretch of 20 – 50 nucleotides within ≈100 base pairs upstream of the start-site region. As we discuss later, a transcription factor called SP1 recognizes these CG-rich sequences. The dinucleotide CG is statistically underrepresented in vertebrate DNAs, and the presence of CG-rich regions just upstream from start sites is a distinctly nonrandom distribution. Such CpG islands, as they often are called, can be identified by their susceptibility to restriction enzymes (e.g., HpaII) that have CG in their recognition sequences. The presence of a CpG island in a newly cloned DNA fragment suggests that it may contain a transcription-initiation region. 

http://www.ncbi.nlm.nih.gov/pubmed/17123746

Prevalence of the initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters.
Yang C, Bolotin E, Jiang T, Sladek FM, Martinez E.


76% of human core promoters lack TATA-like elements, have a high GC content, and are enriched in Sp1-binding sites.