Active Transcriptional Repression by the Rb–E2F Complex Mediates G1 Arrest Triggered by p16INK4a, TGFβ, and Contact Inhibition

AbstractRb inhibits progression from G1 to S phase of the cell cycle. It associates with a number of cellular proteins; however, the nature of these interactions and their relative significance in cell cycle regulation are still unclear. We present evidence that Rb must normally interact with the E2F family of transcription factors to arrest cells in G1, and that this arrest results from active transcriptional repression by the Rb–E2F complex, not from inactivation of E2F. Thus, a major role of E2F in cell cycle regulation is assembly of this repressor complex. We demonstrate that active repression by Rb–E2F mediates the G1 arrest triggered by TGFβ, p16INK4a, and contact inhibition

Mitotic polarization of transcription factors during asymmetric division establishes fate of forming cancer cells

A model of K-Ras-initiated lung cancer was used to follow the transition of precancerous adenoma to adenocarcinoma. In hypoxic, Tgf-β1-rich interiors of adenomas, we show that adenoma cells divide asymmetrically to produce cancer-generating cells highlighted by epithelial mesenchymal transition and a CD44/Zeb1 loop. In these cells, Zeb1 represses the Smad inhibitor Zeb2/Sip1, causing Pten loss and launching Tgf-β1 signaling that drives nuclear translocation of Yap1. Surprisingly, the nuclear polarization of transcription factors during mitosis establishes parent and daughter fates prior to cytokinesis in sequential asymmetric divisions that generate cancer cells from precancerous lesions. Mutation or knockdown of Zeb1 in the lung blocked the production of CD44hi, Zeb1hi cancer-generating cells from adenoma cells. A CD44/Zeb1 loop then initiates two-step transition of precancerous cells to cancer cells via a stable intermediate population of cancer-generating cells. We show these initial cancer-generating cells are independent of cancer stem cells generated in tumors by p53-regulated reprogramming of existing cancer cells

Modern risk management through the lens of the ethical organizational culture

Most recent efforts to create guidance for modern risk management practices emphasize the importance of connecting risk management policy and practice with an organization’s culture and values. However, identifying or establishing that connection is not widely discussed or understood. What does it mean to state that risk management is an expression of an organization’s values? This article discusses the basis for identifying the connection between organizational values through the lens of the Ethical Organizational Culture and attempts to draw out linkages with current risk management thinking on the subject. The stablishment of a basis of identifying organizational values and their link to risk management policy and practice is illustrated through a case analysis of the Veritas Institute’s Self-Assessment and Improvement methodology

The Variable Stars and Blue Horizontal Branch of the Metal-Rich Globular Cluster NGC 6441

We present time-series VI photometry of the metal-rich ([Fe/H] = -0.53) globular cluster NGC 6441. Our color-magnitude diagram shows that the extended blue horizontal branch seen in Hubble Space Telescope data exists in the outermost reaches of the cluster. The red clump slopes nearly parallel to the reddening vector. A component of this slope is due to differential reddening, but part is intrinsic. The blue horizontal branch stars are more centrally concentrated than the red clump stars. We have discovered about 50 new variable stars near NGC 6441, among them eight or more RR Lyrae stars which are very probably cluster members. Comprehensive period searches over the range 0.2-1.0 days yielded unusually long periods (0.5-0.9 days) for the fundamental pulsators compared with field RR Lyrae of the same metallicity. Three similar long-period RR Lyrae are known in other metal-rich globulars. With over ten examples in hand, it seems that a distinct sub-class of RR Lyrae is emerging. The observed properties of the horizontal branch stars are in reasonable agreement with recent models which invoke deep mixing to enhance the atmospheric helium abundance, while they conflict with models which assume high initial helium abundance. The light curves of the c-type RR Lyrae seem to have unusually long rise times and sharp minima. Reproducing these light curves in stellar pulsation models may provide another means of constraining the physical variables responsible for the anomalous blue horizontal branch extension and sloped red clump observed in NGC 6441.Comment: 30 pages plus 6 EPS and 6 JPEG figures; uses AAS TeX. Accepted by the Astronomical Journal. Minor changes include computing He abundance, modifications to Figs 1 and 8, and expansion on idea that blue HB stars may be produced in binarie

Altered patterns of gene duplication and differential gene gain and loss in fungal pathogens

<p>Abstract</p> <p>Background</p> <p>Duplication, followed by fixation or random loss of novel genes, contributes to genome evolution. Particular outcomes of duplication events are possibly associated with pathogenic life histories in fungi. To date, differential gene gain and loss have not been studied at genomic scales in fungal pathogens, despite this phenomenon's known importance in virulence in bacteria and viruses.</p> <p>Results</p> <p>To determine if patterns of gene duplication differed between pathogens and non-pathogens, we identified gene families across nine euascomycete and two basidiomycete species. Gene family size distributions were fit to power laws to compare gene duplication trends in pathogens <it>versus </it>non-pathogens. Fungal phytopathogens showed globally altered patterns of gene duplication, as indicated by differences in gene family size distribution. We also identified sixteen examples of gene family expansion and five instances of gene family contraction in pathogenic lineages. Expanded gene families included those predicted to be important in melanin biosynthesis, host cell wall degradation and transport functions. Contracted families included those encoding genes involved in toxin production, genes with oxidoreductase activity, as well as subunits of the vacuolar ATPase complex. Surveys of the functional distribution of gene duplicates indicated that pathogens show enrichment for gene duplicates associated with receptor and hydrolase activities, while euascomycete pathogens appeared to have not only these differences, but also significantly more duplicates associated with regulatory and carbohydrate binding functions.</p> <p>Conclusion</p> <p>Differences in the overall levels of gene duplication in phytopathogenic species <it>versus </it>non-pathogenic relatives implicate gene inventory flux as an important virulence-associated process in fungi. We hypothesize that the observed patterns of gene duplicate enrichment, gene family expansion and contraction reflect adaptation within pathogenic life histories. These adaptations were likely shaped by ancient, as well as contemporary, intimate associations with monocot hosts.</p

Hydraulic Apparatus for Mechanical Testing of Nuts

The figure depicts an apparatus for mechanical testing of nuts. In the original application for which the apparatus was developed, the nuts are of a frangible type designed for use with pyrotechnic devices in spacecraft applications in which there are requirements for rapid, one-time separations of structures that are bolted together. The apparatus can also be used to test nonfrangible nuts engaged without pyrotechnic devices. This apparatus was developed to replace prior testing systems that were extremely heavy and immobile and characterized by long setup times (of the order of an hour for each nut to be tested). This apparatus is mobile, and the setup for each test can now be completed in about five minutes. The apparatus can load a nut under test with a static axial force of as much as 6.8 x 10(exp 5) lb (3.0 MN) and a static moment of as much as 8.5 x 10(exp 4) lb in. (9.6 x 10(exp 3) N(raised dot)m) for a predetermined amount of time. In the case of a test of a frangible nut, the pyrotechnic devices can be exploded to break the nut while the load is applied, in which case the breakage of the nut relieves the load. The apparatus can be operated remotely for safety during an explosive test. The load-generating portion of the apparatus is driven by low-pressure compressed air; the remainder of the apparatus is driven by 110-Vac electricity. From its source, the compressed air is fed to the apparatus through a regulator and a manually operated valve. The regulated compressed air is fed to a pneumatically driven hydraulic pump, which pressurizes oil in a hydraulic cylinder, thereby causing a load to be applied via a hydraulic nut (not to be confused with the nut under test). During operation, the hydraulic pressure is correlated with the applied axial load, which is verified by use of a load cell. Prior to operation, one end of a test stud (which could be an ordinary threaded rod or bolt) is installed in the hydraulic nut. The other end of the test stud passes through a bearing plate; a load cell is slid onto that end, and then the nut to be tested is threaded onto that end and tightened until the nut and load cell press gently against the bearing plate

Reflux related hospital admissions after fundoplication in children with neurological impairment: retrospective cohort study

Objective To examine the impact of fundoplication on reflux related hospital admissions for children with neurological impairment

Anastomotic complications after tracheal resection: Prognostic factors and management

ObjectiveWe sought to identify risk factors for anastomotic complications after tracheal resection and to describe the management of these patients.MethodsThis was a single-institution, retrospective review of 901 patients who underwent tracheal resection.ResultsThe indications for tracheal resection were postintubation tracheal stenosis in 589 patients, tumor in 208, idiopathic laryngotracheal stenosis in 83, and tracheoesophageal fistula in 21. Anastomotic complications occurred in 81 patients (9%). Eleven patients (1%) died after operation, 6 of anastomotic complications and 5 of other causes (odds ratio 13.0, P = .0001 for risk of death after anastomotic complication). At the end of treatment, 853 patients (95%) had a good result, whereas 37 patients (4%) had an airway maintained by tracheostomy or T-tube. The treatments of patients with an anastomotic complication were as follows: multiple dilations (n = 2), temporary tracheostomy (n = 7), temporary T-tube (n = 16), permanent tracheostomy (n = 14), permanent T-tube (n = 20), and reoperation (n = 16). Stepwise multivariable analysis revealed the following predictors of anastomotic complications: reoperation (odds ratio 3.03, 95% confidence interval 1.69-5.43, P = .002), diabetes (odds ratio 3.32, 95% confidence interval 1.76-6.26, P = .002), lengthy (≥4 cm) resections (odds ratio 2.01, 95% confidence interval 1.21-3.35, P = .007), laryngotracheal resection (odds ratio 1.80, 95% confidence interval 1.07-3.01, P = .03), age 17 years or younger (odds ratio 2.26, 95% confidence interval 1.09-4.68, P = .03), and need for tracheostomy before operation (odds ratio 1.79, 95% confidence interval 1.03-3.14, P = .04).ConclusionsTracheal resection is usually successful and has a low mortality. Anastomotic complications are uncommon, and important risk factors are reoperation, diabetes, lengthy resections, laryngotracheal resections, young age (pediatric patients), and the need for tracheostomy before operation

Omentum is highly effective in the management of complex cardiothoracic surgical problems

AbstractObjectives: Vascularized, pedicled tissue flaps are often used for cardiothoracic surgical problems complicated by factors that adversely affect healing, such as previous irradiation, established infection, or steroid use. We reviewed our experience with use of the omentum in these situations to provide a yardstick against which results with other vascularized flaps (specifically muscle flaps) could be compared. Methods: A retrospective review was undertaken of 85 consecutive patients in whom omentum was used in the chest. In 47 patients (group I), use of omentum was prophylactic to aid in the healing of closures or anastomoses considered to be at high risk for failure. In 32 patients (group II), omentum was used in the treatment of problems complicated by established infection. In 6 patients (group III), omentum was used for coverage of prosthetic chest wall replacements after extensive chest wall resection. Results: Overall, omental transposition was successful in its prophylactic or therapeutic purpose in 88% of these difficult cases (75/85). Success with omentum was achieved for 89% of patients (42/47) in group I, 91% of patients (29/32) in group II, and 67% of patients (4/6) in group III. Three patients (3.5%) had complications of omental mobilization. Four patients (4.7%) died after the operation as a result of failure of the omentum to manage the problem for which it was used. Conclusions: Results with omental transposition compare favorably with published series of similarly challenging cases managed with muscle transposition. Complications of omental mobilization are rare. We believe that its unique properties render the omentum an excellent choice of vascularized pedicle in the management of the most complex cardiothoracic surgical problems.J Thorac Cardiovasc Surg 2003;125:526-3