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Stable low-level expression of p21(WAF1/CIP1 )in A549 human bronchogenic carcinoma cell line-derived clones down-regulates E2F1 mRNA and restores cell proliferation control

BACKGROUND: Deregulated cell cycle progression and loss of proliferation control are key properties of malignant cells. In previous studies, an interactive transcript abundance index (ITAI) comprising three cell cycle control genes, [MYC × E2F1]/p21 accurately distinguished normal from malignant bronchial epithelial cells (BEC), using a cut-off threshold of 7,000. This cut-off is represented by a line with a slope of 7,000 on a bivariate plot of p21 versus [MYC × E2F1], with malignant BEC above the line and normal BEC below the line. This study was an effort to better quantify, at the transcript abundance level, the difference between normal and malignant BEC. The hypothesis was tested that experimental elevation of p21 in a malignant BEC line would decrease the value of the [MYC × E2F1]/p21 ITAI to a level below this line, resulting in loss of immortality and limited cell population doubling capacity. In order to test the hypothesis, a p21 expression vector was transfected into the A549 human bronchogenic carcinoma cell line, which has low constitutive p21 TA expression relative to normal BEC. RESULTS: Following transfection of p21, four A549/p21 clones with stable two-fold up-regulated p21 expression were isolated and expanded. For each clone, the increase in p21 transcript abundance (TA) was associated with increased total p21 protein level, more than 5-fold reduction in E2F1 TA, and 10-fold reduction in the [MYC × E2F1]/p21 ITAI to a value below the cut-off threshold. These changes in regulation of cell cycle control genes were associated with restoration of cell proliferation control. Specifically, each transfectant was capable of only 15 population doublings compared with unlimited population doublings for parental A549. This change was associated with an approximate 2-fold increase in population doubling time to 38.4 hours (from 22.3 hrs), resumption of contact-inhibition, and reduced dividing cell fraction as measured by flow cytometric DNA analysis. CONCLUSION: These results, likely due to increased p21-mediated down-regulation of E2F1 TA at the G1/S phase transition, are consistent with our hypothesis. Specifically, they provide experimental confirmation that a line with slope of 7,000 on the p21 versus [MYC × E2F1] bivariate plot quantifies the difference between normal and malignant BEC at the level of transcript abundance

Detection of Silver in Metal-Poor Stars

The resonance lines of neutral silver appearing at 3280, 3382 Å in the near-ultraviolet spectral region have been identified on Keck I HIRES spectra of four halo stars with metallicities -1.3 ≥ [Fe/H] ≥ -2.2. This represents the first detection in metal-poor stars of an element in the atomic number range 41 ≤ Z ≤ 55. The mean relative silver abundance is [Ag/Fe] +0.2, with little star-to-star variation. Silver abundance upper limits in three other metal-poor stars are consistent with this mean value. The modest overabundance of silver is similar to the overabundances in this metallicity range exhibited by other neutron-capture elements whose primary nucleosynthesis origin is the r-process (such as europium and dysprosium)

Serologic Evidence of Widespread Everglades Virus Activity in Dogs, Florida

Everglades virus (EVEV), an alphavirus in the Venezuelan equine encephalitis complex, circulates among rodents and vector mosquitoes in Florida and occasionally infects humans. It causes febrile disease, sometimes accompanied by neurologic manifestations. Although previous surveys showed high seroprevalence in humans, EVEV infections may be underdiagnosed because the disease is not severe enough to warrant a clinic visit or the undifferentiated presentations complicate diagnosis. Documented EVEV activity, as recent as 1993, was limited to south Florida. Using dogs as sentinels, a serosurvey was conducted to evaluate whether EVEV circulated recently in Florida and whether EVEV's spatial distribution parallels that of the mosquito vector, Culex cedecei. Four percent of dog sera contained neutralizing EVEV antibodies, and many seropositive animals lived farther north than both recorded EVEV activity and the principal vector. These results indicate that EVEV is widespread in Florida and may be an important, unrecognized cause of human illness

Fast Radio Burst Discovered in the Arecibo Pulsar ALFA Survey

Recent work has exploited pulsar survey data to identify temporally isolated, millisecond-duration radio bursts with large dispersion measures (DMs). These bursts have been interpreted as arising from a population of extragalactic sources, in which case they would provide unprecedented opportunities for probing the intergalactic medium; they may also be linked to new source classes. Until now, however, all so-called fast radio bursts (FRBs) have been detected with the Parkes radio telescope and its 13-beam receiver, casting some concern about the astrophysical nature of these signals. Here we present FRB 121102, the first FRB discovery from a geographic location other than Parkes. FRB 121102 was found in the Galactic anti-center region in the 1.4 GHz Pulsar Arecibo L-band Feed Array (ALFA) survey with the Arecibo Observatory with a DM = 557.4 ± 2.0 pc cm–3, pulse width of 3.0 ± 0.5 ms, and no evidence of interstellar scattering. The observed delay of the signal arrival time with frequency agrees precisely with the expectation of dispersion through an ionized medium. Despite its low Galactic latitude (b = –02), the burst has three times the maximum Galactic DM expected along this particular line of sight, suggesting an extragalactic origin. A peculiar aspect of the signal is an inverted spectrum; we interpret this as a consequence of being detected in a sidelobe of the ALFA receiver. FRB 121102\u27s brightness, duration, and the inferred event rate are all consistent with the properties of the previously detected Parkes bursts

Diversity of animal communities on southwestern rangelands: Species patterns, habitat relationships, and land management

The rangelands of the southwestern United States comprise a mosaic of biome types, including deserts, grasslands, chaparral, woodlands, forests, subalpine meadows, and alpine tundra. Taken together, these ecosystems support exceptionally high numbers of vertebrate and invertebrate animal species. Biogeographic patterns of mammal, bird, and reptile species across North America show trends of increasing species numbers for these vertebrate groups, and some invertebrate groups, occur in Texas, New Mexico, Arizona, and California, especially in the border region with Mexico. Underlying causes of the region\u27s high biodiversity are related to (1) the elevational variability inherent in the basin-and-range topography, with its concomitant range of climate conditions, (2) the diverse biogeographic history of the region, particularly with respect to the merging of major faunal groups during glacier retreats, and (3) the architectural variations in vegetation structure across the region\u27s component ecosystems. Climate dynamics and disturbance also play major roles in maintaining a habitat mosaic, promoting greater regional faunal diversity. Disturbances affect animal diversity at many scales, from individuals\u27 home ranges to continental species\u27 distributions. Human activities have generated new suites of disturbances (livestock grazing, timber harvesting, mining, agriculture, prescribed fires, construction of roads and buildings), many of which contribute to the habitat patchiness of the landscape. Studies have shown that these disturbances prove beneficial to some species and detrimental to others. Hence, local increases in biodiversity can be orchestrated by creating or maintaining habitat diversity and disturbance regimes. Such management strategies can be scaled up to regional landscapes, in which areas of intensive human land use and disturbance are interspersed with regions of little or no human interference. Historically, this has been accomplished at local or state levels on an ad hoc bases (i.e., crisis management), with little evidence of long-term, large-scale, regional planning or coordination. If faunal biodiversity is to be preserved and enhanced on southwestern rangelands, human activities must be managed in a fashion that integrates faunal biology, resource requirements, and movement patterns with landscape scale attributes. Therefore, the task of the modern land manager will be to balance carefully the various scales and intensities of human activities, for the purpose of promoting sustainable use of natural resources and assuring the maintenance or enhancement of biodiversity. Future regional planning for biodiversity attributes will clearly require extensive communication and close cooperation among concerned citizens, private landowners, scientists, and government land managers

An Instrument to Enable Identification of Anthropogenic CO2 Emissions Using Concurrent CO Measurements

We have developed an instrument concept that will enable the measurement of CO from the top of the atmosphere to the Earth's surface with very high sensitivity and at the high spatial and temporal resolutions required by the NRC Decadal Survey mission Active Sensing of Carbon Dioxide (CO2) over Nights, Days and Seasons (ASCENDS). We are developing an innovative CO sensor that will enable the ASCENDS mission to differentiate between anthropogenic and natural sources and sinks of global carbon. The NRC Decadal Survey places particular emphasis on retrieving CO information for the planetary boundary layer. Measurement made using both the 2.3 micron and 4.7 micron channels are needed to achieve the sensitivity required in the lower atmosphere where the degree of CO - CO2 correlation is indicative of anthropogenic sources of CO2. Measurements made using only the 4.7 micron channel cannot provide sufficient sensitivity to CO in the very lowest layers of the atmosphere. The fundamental method we use is Gas Filter Correlation Radiometry (GFCR), a highly successful technique used in other airborne and space-based missions for detecting trace species in the Earth's atmosphere. Our version of GFCR overcomes many of the limitations encountered by prior and existing instruments, allowing us to measure weak signals from small targets very quickly and with extremely high specificity by employing a new dual beam radiometer concept using a focal plane array. Our design will provide a means to make the desired CO measurements for the ASCENDS mission. A simple change in gas filter cell contents would allow the same hardware to measure CH4 with high precision under the nominal ASCENDS mission spatial and temporal constraints. All critical components in the sensor design are mature, many subsystems tested, and the system has been extensively modeled, bringing it to a present Technology Readiness Level (TRL) of 3 (though some individual components are at TRLs 6-9). We are presently developing critical components for the new spectrometer and advancing our understanding of the measurement requirements for both CO and CH4. This new GFCR technique/sensor will enable measurements of trace gases with high sensitivity while maintaining the inherent robustness and simplicity of the more traditional radiometer hardware. Initial estimates of cost/risk of a spacebased 2-channel GFCR indicate that our design is extremely cost effective and will fit within existing ASCENDS mission budget constraints as determined by the NRC Decadal Survey and a NASA-sponsored mission study

ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines

BACKGROUND: Although 40–50% of non-small cell lung cancer (NSCLC) tumors respond to cisplatin chemotherapy, there currently is no way to prospectively identify potential responders. The purpose of this study was to determine whether transcript abundance (TA) levels of twelve selected DNA repair or multi-drug resistance genes (LIG1, ERCC2, ERCC3, DDIT3, ABCC1, ABCC4, ABCC5, ABCC10, GTF2H2, XPA, XPC and XRCC1) were associated with cisplatin chemoresistance and could therefore contribute to the development of a predictive marker. Standardized RT (StaRT)-PCR, was employed to assess these genes in a set of NSCLC cell lines with a previously published range of sensitivity to cisplatin. Data were obtained in the form of target gene molecules relative to 10(6 )β-actin (ACTB) molecules. To cancel the effect of ACTB variation among the different cell lines individual gene expression values were incorporated into ratios of one gene to another. Each two-gene ratio was compared as a single variable to chemoresistance for each of eight NSCLC cell lines using multiple regression. In an effort to validate these results, six additional lines then were evaluated. RESULTS: Following validation, single variable models best correlated with chemoresistance (p < 0.001), were ERCC2/XPC, ABCC5/GTF2H2, ERCC2/GTF2H2, XPA/XPC and XRCC1/XPC. All single variable models were examined hierarchically to achieve two variable models. The two variable model with the highest correlation was (ABCC5/GTF2H2, ERCC2/GTF2H2) with an R(2 )value of 0.96 (p < 0.001). CONCLUSION: These results provide markers suitable for assessment of small fine needle aspirate biopsies in an effort to prospectively identify cisplatin resistant tumors