186 research outputs found
The promoters of human cell cycle genes integrate signals from two tumor suppressive pathways during cellular transformation
Deciphering regulatory events that drive malignant transformation represents
a major challenge for systems biology. Here we analyzed genome-wide
transcription profiling of an in-vitro transformation process. We focused on a
cluster of genes whose expression levels increased as a function of p53 and
p16INK4A tumor suppressors inactivation. This cluster predominantly consists of
cell cycle genes and constitutes a signature of a diversity of cancers. By
linking expression profiles of the genes in the cluster with the dynamic
behavior of p53 and p16INK4A, we identified a promoter architecture that
integrates signals from the two tumor suppressive channels and that maps their
activity onto distinct levels of expression of the cell cycle genes, which in
turn, correspond to different cellular proliferation rates. Taking components
of the mitotic spindle as an example, we experimentally verified our
predictions that p53-mediated transcriptional repression of several of these
novel targets is dependent on the activities of p21, NFY and E2F. Our study
demonstrates how a well-controlled transformation process allows linking
between gene expression, promoter architecture and activity of upstream
signaling molecules.Comment: To appear in Molecular Systems Biolog
Airports at Risk: The Impact of Information Sources on Security Decisions
Security decisions in high risk organizations such as airports involve obtaining ongoing and frequent information about potential threats. Utilizing questionnaire survey data from a sample of airport
employees in European Airports across the continent, we analyzed
how both formal and informal sources of security information affect employee's decisions to comply with the security rules and
directives. This led us to trace information network flows to assess its impact on the degree employees making security decisions comply or deviate with the prescribed security rules. The results of the multivariate analysis showed that security information obtained through formal and informal networks differentially determine if employee will comply or not with the rules. Information sources emanating from the informal network tends to encourage employees to be more flexible in their security decisions
while formal sources lead to be more rigid with complying with rules and protocols. These results suggest that alongside the formal administrative structure of airports, there exists a diverse and pervasiveness set of informal communications networks that are a potent factor in determining airport security levels
Delineation of Cohen Syndrome Following a Large-Scale Genotype-Phenotype Screen
Cohen syndrome is an autosomal recessive condition associated with developmental delay, facial dysmorphism, pigmentary retinopathy, and neutropenia. The pleiotropic phenotype, combined with insufficient clinical data, often leads to an erroneous diagnosis and has led to confusion in the literature. Here, we report the results of a comprehensive genotype-phenotype study on the largest cohort of patients with Cohen syndrome assembled to date. We found 22 different COH1 mutations, of which 19 are novel, in probands identified by our diagnostic criteria. In addition, we identified another three novel mutations in patients with incomplete clinical data. By contrast, no COH1 mutations were found in patients with a provisional diagnosis of Cohen syndrome who did not fulfill the diagnostic criteria (“Cohen-like” syndrome). This study provides a molecular confirmation of the clinical phenotype associated with Cohen syndrome and provides a basis for laboratory screening that will be valuable in its diagnosis
Wide-Scale Analysis of Human Functional Transcription Factor Binding Reveals a Strong Bias towards the Transcription Start Site
We introduce a novel method to screen the promoters of a set of genes with
shared biological function, against a precompiled library of motifs, and find
those motifs which are statistically over-represented in the gene set. The gene
sets were obtained from the functional Gene Ontology (GO) classification; for
each set and motif we optimized the sequence similarity score threshold,
independently for every location window (measured with respect to the TSS),
taking into account the location dependent nucleotide heterogeneity along the
promoters of the target genes. We performed a high throughput analysis,
searching the promoters (from 200bp downstream to 1000bp upstream the TSS), of
more than 8000 human and 23,000 mouse genes, for 134 functional Gene Ontology
classes and for 412 known DNA motifs. When combined with binding site and
location conservation between human and mouse, the method identifies with high
probability functional binding sites that regulate groups of biologically
related genes. We found many location-sensitive functional binding events and
showed that they clustered close to the TSS. Our method and findings were put
to several experimental tests. By allowing a "flexible" threshold and combining
our functional class and location specific search method with conservation
between human and mouse, we are able to identify reliably functional TF binding
sites. This is an essential step towards constructing regulatory networks and
elucidating the design principles that govern transcriptional regulation of
expression. The promoter region proximal to the TSS appears to be of central
importance for regulation of transcription in human and mouse, just as it is in
bacteria and yeast.Comment: 31 pages, including Supplementary Information and figure
Morbidity and Mortality After Benign Prostatic Hyperplasia Surgery: Data from the American College of Surgeons National Surgical Quality Improvement Program
Background and Purpose: With the aging population, it is becoming increasingly important to identify patients at risk for postsurgical complications who might be more suited for conservative treatment. We sought to identify predictors of morbidity after surgical treatment of benign prostatic hyperplasia (BPH) using a large national contemporary population-based cohort. Methods: Relying on the American College of Surgeons National Surgical-Quality Improvement Program (ACS-NSQIP; 2006?2011) database, we evaluated outcomes after transurethral resection of the prostate (TURP), laser vaporization of the prostate (LVP), and laser enucleation of the prostate (LEP). Outcomes included blood-transfusion rates, length of stay, complications, reintervention rates, and perioperative mortality. Multivariable logistic-regression analysis evaluated the predictors of perioperative morbidity and mortality. Results: Overall, 4794 (65.2%), 2439 (33.1%), and 126 (1.7%) patients underwent TURP, LVP, and LEP, respectively. No significant difference in overall complications (P=0.3) or perioperative mortality (P=0.5) between the three surgical groups was found. LVP was found to be associated with decreased blood transfusions (odds ratio [OR]=0.21; P=0.001), length of stay (OR=0.12; P30%) levels were the only predictors of lower overall complications and perioperative mortality. Conclusions: All three surgical modalities for BPH management were found to be safe. Advanced age and non-Caucasian race were independent predictors of adverse outcomes after BPH surgery. In patients with these attributes, conservative treatment might be a reasonable alternative. Also, preoperative hematocrit and albumin levels represent reliable predictors of adverse outcomes, suggesting that these markers should be evaluated before BPH surgery.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140378/1/end.2013.0805.pd
Prompt, early, and afterglow optical observations of five gamma-ray bursts (GRBs 100901A, 100902A, 100905A, 100906A, and 101020A)
We present results of the prompt, early, and afterglow optical observations
of five gamma-ray bursts, GRBs 100901A, 100902A, 100905A, 100906A, and 101020A,
made with the Mobile Astronomical System of TElescope-Robots in Russia
(MASTER-II net), the 1.5-m telescope of Sierra-Nevada Observatory, and the
2.56-m Nordic Optical Telescope. For two sources, GRB 100901A and GRB 100906A,
we detected optical counterparts and obtained light curves starting before
cessation of gamma-ray emission, at 113 s and 48 s after the trigger,
respectively. Observations of GRB 100906A were conducted with two polarizing
filters. Observations of the other three bursts gave the upper limits on the
optical flux; their properties are briefly discussed. More detailed analysis of
GRB 100901A and GRB 100906A supplemented by Swift data provides the following
results and indicates different origins of the prompt optical radiation in the
two bursts. The light curves patterns and spectral distributions suggest a
common production site of the prompt optical and high-energy emission in GRB
100901A. Results of spectral fits for GRB 100901A in the range from the optical
to X-rays favor power-law energy distributions with similar values of the
optical extinction in the host galaxy. GRB 100906A produced a smoothly peaking
optical light curve suggesting that the prompt optical radiation in this GRB
originated in a front shock. This is supported by a spectral analysis. We have
found that the Amati and Ghirlanda relations are satisfied for GRB 100906A. An
upper limit on the value of the optical extinction on the host of GRB 100906A
is obtained.Comment: 18 pages, 14 figures, 14 tables, 5 machine readable tables; accepted
for publication in MNRA
Cross-sectional and longitudinal construct validity of two rotator cuff disease-specific outcome measures
BACKGROUND: Disease-specific Quality Of Life (QOL) measures are devised to assess the impact of a specific disease across a spectrum of important domains of life. The purpose of this study was to examine the cross-sectional and longitudinal construct validity (sensitivity to change) of two rotator cuff disease-specific measures, the Rotator Cuff-Quality Of Life (RC-QOL) and the Western Ontario Rotator Cuff (WORC) index, in relation to one another and to other joint and limb specific measures in the same population of the patients suffering from rotator cuff pathology. METHODS: Participants enrolled were consecutive patients who received physical therapy for management of impingement syndrome or received treatment following rotator cuff repair, acromioplasty or decompression surgeries. All subjects received physical therapy treatment and completed four outcome measures at 3 single points (initial, interim, and final). Cross-sectional convergent validity was assessed at each of the 3 time-points by correlating the WORC and RC-QOL's scores to each other and to two alternative scales; a joint-specific scale, the American Shoulder and Elbow Surgeons (ASES) standardized shoulder assessment form and a limb-specific measure, the Upper Extremity Functional Index (UEFI). Non-parametric statistics (Spearman's rho and Wilcoxon-Mann-Whitney tests) examined the construct validity. The standardized response mean (SRM) was used to examine sensitivity to change. RESULTS: Forty-one participants entered the study and their scores were compared at 3 cross sectional single points. The correlation coefficients among the 4 measures varied from 0.60 to 0.91. Correlation between corresponding domains of the WORC and RC-QOL varied from 0.45 to 0.85. The known group validity was not significantly different among individual sub-scores and total scores. The final SRMs were (1.42), (1.43), (1.44), and (1.54) for the ASES, RCQOL, WORC, and UEFI respectively. CONCLUSION: The WORC and RC-QOL exhibit similar cross-sectional convergent validity in patients suffering from rotator cuff pathology. The sensitivity to change was very close among all scores, with the UEFI having the highest sensitivity. Further research is needed to examine the extent to which each physical or emotional domain contributes to prognostic or therapeutic decision-making
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