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The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2(AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1(AZ20). The clinical candidate 2has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2is currently being tested in multiple phase I/II trials as an anticancer agent.

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In both published papers and in guidelines of regulatory agencies and voluntary standards, examples can be found where the assumption is made that what will capture attention is that which is salient or conspicuous, and that these qualities are both necessary and sufficient to capture attention. A review of the published, peer-reviewed literature on attention capture, however, invites the conclusion that there are very few features of an object that will draw attention to themselves without or against the observer’s intentions. The ability of warnings to draw attention to themselves involuntarily is discussed within the context of the extant attention capture literature.

Wider exploration of ethanol coproduct uses is necessary as the ethanol industry continues to face challenges. Currently, process streams such as thin stillage and condensed distillers solubles (CDS) are processed into distillers dried grains with solubles and used as animal feeds, but other higher value opportunities may exist. The objective of this study was to identify chemical components and quantify physical properties of CDS and thin stillage. Protein, organic acid, and sugar profiles were determined. Zein protein was identified, and glycerol was determined to have a concentration of 18.8 g/L in thin stillage and 63.2 g/L in CDS. Physical properties including density, thermal conductivity, thermal diffusivity, and rheological behaviors were also examined. Thermal conductivity of thin stillage and CDS was approximately 0.54 and 0.45 W/m°C, respectively. Quantification of the physical properties and identification of the chemical constituents pave the way for exploration of new value-added uses for thin stillage and CDS.

This article reviews sociological approaches to the production, evaluation, and diffusion of knowledge in the arena of scholarly production – the sciences, social sciences, and humanities. At first glance, sociological approaches to scholarly knowledge production seem to congeal around the hard sciences, on the one hand, and philosophy, on the other. I eschew this polarization and construct an analytic frame of reference for analyzing the sociological dimensions of scholarly production more generally. This article maps successive phases of sociological approaches to scholarly production, by overlaying and distinguishing among theories in the sociology of knowledge, sociology of science, and sociology of intellectuals. I analyze classical theorists’ emphases on class analysis and the social function of intellectuals; mid‐century adaptations of functionalism, social structure theory, and institutional theory to analyze intellectual and academic life; critical and reflexive theories, including feminist critiques of science and knowledge; recent emphases on how social movement politics and social networks influence intellectual change; theories of the university as a professional arena and a field of culture production; and studies of knowledge‐making practices in group research situations. In addition to arguing for more theoretical and methodological precision in analyses of scholarly and scientific knowledge‐making, I conclude with cautionary tales and future prospects for sociological studies of modern academic life.

Consumer products available today in the United States often have safety information on and accompanying them. This practice is far more common now than earlier in the 20thcentury. In this paper, the evolution of the use of warnings with consumer products is examined as they appeared in voluntary standards provided by one national standard making body, the American Society for Testing and Materials (ASTM). ASTM had been developing consensus voluntary standards since 1898, but it was not until the 1970s that it first focused on consumer products. Over the next three decades there were increases in the number and type of consumer products included. Further, for any given product, the amount of safety information frequently increased with subsequent revisions of a standard. These trends in warnings generally parallel the patterns observed with federally mandated warnings for consumer products.

Objects that are readily detectable and visible are not always noticed. Demonstrating the difficulty of detecting objects in a scene to people who are already expecting to see them and are aware of the objects' presence poses a challenge. In the following study, two conspicuous objects were placed in the back seat of a sport utility vehicle (SUV). The study parameters were selected in an attempt to replicate a situation involved in a criminal investigation, to test the hypothesis that drivers routinely check the back seat of the car before driving away, and to determine the likelihood of drivers noticing what would seem to be a salient set of objects in the rear seat. Two child-sized mannequins were placed in a prone position on the back seat of a large SUV. Naïve subjects were asked to get in and drive the SUV 1.6 miles around a closed track at night. Twenty-seven out of 30 participants failed to notice the mannequins in the vehicle. Visual performance limitations, environmental expectations and “inattentional blindness” effects can account for the results and are discussed in this paper.

Consumer products currently sold in the United States often come with extensive safety information, but the presentation of large amounts of such material was not always the case. We reviewed federally mandated hazard labeling as it evolved during the 20thcentury by documenting changes in labeling requirements for home-use products prescribed by federal statutes. Our review indicated that during the course of the 20thcentury, there was a dramatic change in the presence, prevalence and specificity of hazard warning requirements. In the early years, Congress concentrated on truth in labeling of contents and quality. This labeling identified hazardous agents in some products. However, as the century progressed, Congress gradually added requirements that could include descriptions of the mechanisms, consequences, and means for avoidance of such hazards. Moreover, the 1960's and especially the 1970's brought a dramatic expansion in the number and types of products required to bear hazard labels.

As one part of a three-part package to reduce the likelihood of children becoming inadvertently trapped in automobile trunks, an internal trunk release mechanism was developed that would be obvious to young children as a way to open a locked trunk from the inside. Eighty-one children between the ages of three and seven voluntarily entered several disguised automobile trunks that had been separated from the rest of the vehicles and instrumented with audio and video monitoring equipment. The children attempted to find a way out of the trunk with no instructions about how to accomplish the task. Nine different mechanisms ranging from pull cords to light switches and door handles were examined. The most successful mechanism was found to be a yellow, lever-type door handle. This paper describes the development procedure and the responses of the children to the different mechanisms.

The population densities of sediment-inhabiting flagellates sampled from a shallow eutrophic lake in April 1986 were investigated at intervals of 1 or 1.5 h over a twenty hour period in the laboratory under natural irradiance and in controlled conditions. In natural irradiance the flagellates exhibited a vertical migration rhythm up onto the sediment surface after dawn and down into the sediment during the afternoon. Details of the timing of the migration movements and period of time flagellates were present on the sediment surface differed between species and five flagellate groups: trachelomonads, green euglenoids, Chamydomonads, chrysophytes and cryptomonads. During daylight, twenty-seven species maintained population maxima at the surface of the sediment on eight occasions. The species composition of these maxima differed and eight species were found to have two maxima on the surface of the sediment at different times of day. Numbers of three species of chrysophycean flagellates and Rhodomonas minuta increased again on the sediment surface after dark. Under continuous irradiance at 10°C, the migration cycle of all five groups of flagellates was affected. Some evidence for an endogenous nature of this rhythm was found for green euglenoids and Chamydomonads. Numbers of chrysophytes, particularly Synura spp. increased in constant light in the surface layers of sediment.

Although the most serious accident mode associated with extension ladder use has always been “falling off the ladder” there has been increasing attention, recently, on “contact with electric current” or electrocution accidents primarily with aluminum ladders. The U.S. Consumer Product Safety Commission (CPSC) has made several recommendations to address this problem from a technical approach. They have proposed insulating and/or isolating the ladder electrically or replacing it with a fiberglass ladder. Long extension ladders are heavy, and proposed recommendations by the CPSC to make aluminum extension ladders nonconductive include replacing them with fiberglass extension ladders, which will definitely result in a heavier ladder. A heavier ladder has implications for the characteristics of the user population and for types of injury patterns.Occupational accident data show that ladder associated accidents directly related to ladder weight, such as overexertion, are more likely. If ladder weight were increased for example, by using exclusively nonconductive fiberglass ladders, overexertion would be a greater concern. A statics model was developed that uses a variety of variables relevant to the ladder erection process to determine the amount of force required of users to erect various types of extension ladders. Anthropometric data on the male and the female adult population were compared to the ladder user requirements. The percentages of males and of females capable of erecting 12.2-meter (40-foot) extension ladders were determined. Only three percent of female adults have the strength and reach height to erect 12.2-meter (40-foot) fiberglass extension ladders. Mandated use of 12.2-meter (40-foot) fiberglass extension ladders would greatly restrict the numbers of females who could perform jobs requiring the use of such ladders.

This paper presents the results of analyses of injury and fatality accidents associated with the occupational use of metal extension ladders. Data contained in seven different data bases differing in geographic representation and level of severity of injury were analyzed to identify the type of accidents that occur and their frequency. In addition, the risks of fatality and of electrocution fatality associated with occupational use of extension ladders were estimated and compared with the fatal risk for various occupations. The overall fatal risk for extension ladder use by workers is less than the overall fatality risk for the construction industry.

Child-resistant containers and other child-resistant mechanisms have been a child-safety strategy for years. Research is reviewed concerning the difficulty of designing a child-resistant mechanism that is also acceptable to adult users.

The term warning is applied to a variety of stimuli. From a safety standpoint, the most appropriate definition of warning ties it to any information that has the potential to change behavior and prevent accidents. The results of an extensive literature review suggest that warnings are unlikely to be effective unless a series of conditions are met. The failure of many intended warnings, including most on-product warning labels, to reduce accidents reflects the difficulty of overcoming the problems inherent in their use.

Twenty patients with previously untreated ovarian cancer received intensive chemotherapy after initial surgery. Treatment comprised two courses of cyclophosphamide at 7 g/m2 with mesna, re-evaluation with second-look laparotomy where appropriate, followed by five courses of cisplatin at 100 mg/m2. Three patients achieved pathologically documented complete remission (PDCR) with high-dose cyclophosphamide, and eight patients achieved partial remission. Fifteen patients went on to receive cisplatin. Nine of these patients had no assessable disease; of six patients who were assessed for response two achieved PDCR and three achieved partial remission. The overall response rate to the sequential regimen was 14/20 (70%). High-dose cyclophosphamide was associated with marked haematological toxicity, which was cumulative and fatal in two patients. The median duration of first remission was 14 months, and the median duration of survival was 20 months. It is concluded that sequential treatment with high-dose cyclophosphamide and cisplatin appears to be no more effective than conventional treatment in advanced ovarian cancer, judging by the PDCR rate and median survival achieved.

Conflict resolution models have been widely advocated but less widely tested. Parent Effectiveness Training (PET; Gordon, 1975) and Youth Effectiveness Training (YET; Hall & Zener, 1979) incorporate a simple conflict resolution technique. PET has now received considerable empirical support (Cedar, 1985; Levant, 1983). Few studies, however, have used behavioural measures rather than questionnaires. The experimental subjects in the present study were 13 parent-adolescent dyads who completed the appropriate Effectiveness Training program (PET/YET). Assessment of videorecorded interactions in a role-play conflict situation showed significantly greater improvement in conflict resolution skills from pretraining to posttraining in the experimental group compared to the matched control group, for both parents and adolescents. No significant changes were found on the Parent Attitude Survey (Hereford, 1963), the FIRO-B (Schutz, 1967), or the Self Esteem Inventory (Coopersmith, 1967). Methodological issues and possible flow-on effects from children learning conflict resolution skills in the family are discussed.

The vertical distribution and migration of phytoplankton composed of seven organisms in a small eutrophic pool is described. Vertical migration during a 24 h period is shown to be exhibited by Pandorina morum, Mallomonas tonsurata, Chroomonas pusilla (Rhodomonas) and Ochromonas sp. in the epilimnion and Cryptomonas rufescens in the surface of the hypolimnion. The degree of horizontal variation in distribution of the organisms is discussed and found to be greatest for the microflagellates. Changes in vertical distribution are shown to be significant and result from active movement of the cells rather than from either water movement or the combined variation associated with patchiness in distribution and counting errors.Differences between the behaviour patterns of the different algae are evident and may be used to explain Hutchinson's "paradox of the plankton".

Growth of chlorophycean algae occurred during summer and autumn in the phytoplankton of Abbot's Pool. both motile and non-motile species were recorded during summer stratification and turbulent conditions in autumn. The largest standing crop in terms of biomass was produced by the growth of Pandorina and concurrently nitrate levels in the epilimnion decreased to below the level of chemical detection.Although nitrate-nitrogen and inorganic phosphorus levels in the epilimnion were severely depleted from July onwards, further growth of phytoplankton including Chlorococcum and Chlamydomas occurred. It is suggested that such nutrients may have become available from the hypolimnion via the process of eddy diffusion. From consideration of the biology of Chlorococcum and Chlamydomonas it is suggested that Chlamydomonas is at a selective advantage during the summer, yet during mixed water conditions with higher levels of nutrients growth of Chlorococcum is favoured. This hypothesis is supported by consideration of the specific rates of population increase of these two algae in Abbot's Pool during summer and autumn.

Eight species of small green algae and Stigeoclonium sp. were studied over a two-year period in phytoplankton and epipelon of Llyn Peris and Llyn Padarn. Quantitative estimations of algal standing crop were made by culturing samples from water and sediment on nutrient agar plates. Different patterns of distribution and periodicity were exhibited by the algal species studied. Chorella vulgaris var. vulgaris was most widespread and present in large numbers in both algal communities at all four study sites. Chlamydomonas moewusii var. eumetabletos was also common. All micro-green algae exhibited rapid increases in standing crop, but these were irregular. Minimum numbers were recorded during winter. Some species, such as Ankistrodesmus falcatus and Chlorogonium neglectum were of limited distribution. Ordination analyses by Reciprocal Averaging confirmed differences between the growth of micro-green algae within sites and between lakes. In general, the standing crops of micro-green algae were greater in Llyn Padarn the lower lake, and changes in these algae were greater in the plankton at the inflow than the outflow site of the lower lake. In contrast, on the sediments, there was more change in the micro-green algae at the outflow site in Llyn Padarn than at the inflow site in Llyn Peris.

Llyn Padarn and Llyn Peris are linked by a small river, and although originally a single larger lake, the lakes now support contrasting algal communities. A study of the sequences of diatom remains and chrysophycean cysts present in long sediment cores has been carried out to assess the historical extent of the differences in these algae between the two lakes.Investigations have included statistical analysis to determine the precision of counting sediment samples. The most efficient sampling and counting procedure, resulting in counts of acceptable precision, involved taking a single sample of sediment from a depth horizon, preparing two replicate slides and counting the entire area of each slide. A comparison of the variation in distribution of these siliceous algae in replicate sediment samples taken from the surface sediment with the variation in distribution down the long sediment core from Llyn Padarn showed that the vertical variation greatly exceeded the horizontal variation. Thus variation in diatom numbers down the sediment core reflects changes in the alga reaching the sediments rather than horizontal patchiness of distribution in the top most layers of sediment.Studies of the sequences of diatoms and chrysophycean cysts were carried out on a 4·75 m core from Llyn Padarn and 2·1 m core from Llyn Peris representing c. 6000 years and c. 900 years of the two lakes respective history. From c. 6000 until c. 2200 years B.P., Llyn Padarn was an acid oligotrophic lake. It appears that about 2200 years B.P., Llyn Padarn became more enriched, Asterionella formosa was the most numerous diatom preserved in the sediment at this time. Reversion to oligotrophic conditions then occurred c. 2000 years B.P. The oldest material from the Peris sediment core was characterized by centric diatoms similar to those found in Padarn sediment dating from 2000 years B.P. to the surface of the Padarn core. Thus at this time, c. 900 years B.P., the algal communities in the two lakes were similar. Both lakes were oligotrophic. However, by 200 years B.P. the chemistry of the sediment core from Peris showed evidence of extensive copper and slate mining in the environment. At this time the species of siliceous algae preserved in the Peris core changed, and the current differences in algal communities in the two lakes appear to originate from this point in history.

Single sample magnetic susceptibility measurements are used to correlate synchronous levels in 16 cores of dated ( 210Pb, 137Cs) recent sediment taken from the deep and oligotrophic Llyn Peris, N. Wales, in order to provide a basis for calculating total sediment and chemical influx through time. Results show that sediment influx has steadily increased since c. 1750 A.D. to reach peak levels in the period 1966–1976 A.D., equivalent to a rise in erosion in the catchment from c. 5 t km −2yr −1to c. 42 t km −2yr −1. Comparison of down-core susceptibility fluctuations with sediment pollen and organic pigment data indicates that maximum susceptibility values relate to periods of channel erosion and minimum susceptibility values relate to periods of slate debris inwash from spoil tips in the catchment. A study of historical records reveals that pre-twentieth-century peak levels of erosion were due to the effects of extractive industries, while twentieth-century erosion has been caused by overgrazing, increased trampling pressure, and heavy construction works in the catchment.

Abstract: Cane dieback of Dawn Seedless table grapevines in the Carnarvon horticultural district of Western Australia was identified as being caused by the fungal pathogen Botryosphaeria rhodina. Symptoms of cane dieback included progressive death of shoots, canes and trunks. Shoot and cane infections were usually associated with external lesions that were bleached in appearance. Lesions often contained minute black pycnidia (0.1–0.2 mm in diameter) which were initially immersed and later became erumpent. Some shoot and cane lesions were less defined. Mature conidia were ovate (20–25 iim by 15–20 Jim), dark brown and uni-septate with longitudinal striations. Immature conidia were of similar shape and size but were hyaline, and single-celled with no striations. This is the first report of B. rhodina causing significant decline of table grapes in Western Australia.

Provides information on the nutrition needs of babies with special needs. Prime indicators of disease-related health problems during infancy; Steps that parents should make to encourage proper development of babies; Problems associated with breastfeeding babies with special needs. INSET: FEEDING TIPS.

The article presents the poem "Nostalgia," by Christine Wood. First Line: unnerved and a bit restless; Last Line: I've been thinking--nothing's been the same.