Akt-dependent Pp2a activity is required for epidermal barrier formation during late embryonic development

Acquisition of epidermal barrier function occurs late in mouse gestation. Several days before birth a wave of barrier acquisition sweeps across murine fetal skin, converging on dorsal and ventral midlines. We investigated the molecular pathways active during epidermal barrier formation. Akt signaling increased as the barrier wave crossed epidermis and Jun was transiently dephosphorylated. Inhibitor experiments on embryonic explants showed that the dephosphorylation of Jun was dependent on both Akt and protein phosphatase 2A (Pp2a). Inhibition of Pp2a and Akt signaling also caused defects in epidermal barrier formation. These data are compatible with a model for developmental barrier acquisition mediated by Pp2a regulation of Jun dephosphorylation, downstream of Akt signaling. Support for this model was provided by siRNA-mediated knockdown of Ppp2r2a (Pr55α or B55α), a regulatory subunit of Pp2a expressed in an Akt-dependent manner in epidermis during barrier formation. Ppp2r2a reduction caused significant increase in Jun phosphorylation and interfered with the acquisition of barrier function, with barrier acquisition being restored by inhibition of Jun phosphorylation. Our data provide strong evidence that Ppp2r2a is a regulatory subunit of Pp2a that targets this phosphatase to Jun, and that Pp2a action is necessary for barrier formation. We therefore describe a novel Akt-dependent Pp2a activity that acts at least partly through Jun to affect initial barrier formation during late embryonic epidermal development

Management Jobs in the Insurance Industry: Organizational Deskilling and Rising Pay Inequality

The attention of both the research community and the popular press has begun to shift from a traditional focus on production jobs and toward management positions in part because of a perception that a fundamental change is underway in the management ranks. Unlike the temporary layoffs of production workers that were historically driven by business cycles, the changes in management job security seem to be permanent and, in large measure, driven by development inside the firm. The most important of these forces appear to be changes in the structure of management and in the organization of work processes. The authors use a unique set of data to examine the structure of management jobs among a sample of companies and observe how those jobs have changed over time. They examine changes in the skill requirements of jobs by functional area and by level in the organization, changes in the "shape" of the organization chart - the distribution of employees across management job titles - and changes in compensation for these jobs. The data were obtained from Hay Associates, and it included the internal organization of management jobs for 11 life insurance companies. The authors see a sharp expansion in the proportion of line workers, absolute declines in the number of top management positions, and only modest growth in the number of middle managers and supervisors. As a result the organization chart has changed dramatically in these companies, becoming considerably flatter. The "span of control" has increased for every level of the organization and especially for first level management. If the widening of the supervisory span of control resulted from taking decision making and responsibility from supervisors and pushing it down to line workers, it does not seem to have increased the average skill requirements of the exempt line workers. Skill requirements for the other levels rose over the period, especially for top management positions. Overall, the average level of skill in the sample fell substantially between 1986 and 1992 (even though skills rose in two of the four levels) because of a sharp shift in the distribution of employment away from management and toward line positions. The authors suggest that the best description of these patterns is that they represent upskilling of individual jobs and deskilling of organizations. Regarding compensation, none of the levels experienced increases in skill that were statically significant, but top managers received a large (28 percent) increase in pay, middle managers received a modest (10 percent) increase, and the lower two levels received virtually no increases. One conclusion is that earnings inequality is increasing substantially inside these firms in a manner that is not attributable to any increase in skill, and the dividing line for that growth in inequality is no longer exempt/nonexempt but supervisor/manager. A possible explanation for the rising inequality in compensation is that it helps offset change in the probability of promotion. The fact that the span of control is increasing and organizational chart flattening means that the probability of the average worker being promoted is declining. The decline in the probability of promotion might reduce the incentives to work hard. Increases in the compensation of top jobs increase the return to securing a promotion and may offset some of the effect produced by the decline in the probability of promotion. Another explanation is that top mangers are in "better positions to legislate their own pay increases." If true, this sample may actually underrepresent the true extent of income inequality because it consists of companies using an external consultant to help set compensation where internal consistency is an important characteristic of the pay system. These results suggest that "management" as a career will remain attractive, albeit less certain in terms of promotion prospects. Shifts to team-based approaches and the elimination of functional designations would suggest a greater need for generalists than specialists. As technology such as expert systems reduces the need for large units of "experts," the manger's skill will be in recognizing when an expert needs to be called. Leadership skills and the ability to adapt to a changing environment are two qualities that will be sought in the future. Fortunately, these skills will also be useful to team members who are not selected for promotion to mangers. Increasing income inequality may lead to distrust within the organization, though this may be offset by the technical tracks that allow highly skilled non-managers to earn equivalent levels of pay. The fact that insurance companies are relatively unique in facing no major industry-specific shocks from the outside environment suggests that these results should translate well to organizations in other industries.

Double Compact Objects III: Gravitational Wave Detection Rates

The unprecedented range of second-generation gravitational-wave (GW) observatories calls for refining the predictions of potential sources and detection rates. The coalescence of double compact objects (DCOs)---i.e., neutron star-neutron star (NS-NS), black hole-neutron star (BH-NS), and black hole-black hole (BH-BH) binary systems---is the most promising source of GWs for these detectors. We compute detection rates of coalescing DCOs in second-generation GW detectors using the latest models for their cosmological evolution, and implementing inspiral-merger-ringdown (IMR) gravitational waveform models in our signal-to-noise ratio calculations. We find that: (1) the inclusion of the merger/ringdown portion of the signal does not significantly affect rates for NS-NS and BH-NS systems, but it boosts rates by a factor $\sim 1.5$ for BH-BH systems; (2) in almost all of our models BH-BH systems yield by far the largest rates, followed by NS-NS and BH-NS systems, respectively, and (3) a majority of the detectable BH-BH systems were formed in the early Universe in low-metallicity environments. We make predictions for the distributions of detected binaries and discuss what the first GW detections will teach us about the astrophysics underlying binary formation and evolution.Comment: published in ApJ, 19 pages, 11 figure

Black hole - neutron star mergers: the first mass gap and kilonovae

Observations of X-ray binaries indicate a dearth of compact objects in the mass range from $\sim 2-5$ $M_{\odot}$ and the existence of this (first mass) gap has been used to advance our understanding of the engines behind core-collapse supernovae. LIGO/Virgo observations provide an independent measure of binary compact remnant masses and several candidate first mass gap objects (either NS or BH) were observed in the O3 science run. We study the formation of BH-NS mergers in the framework of isolated classical binary evolution. We use population synthesis method to evolve binary stars (Population I and II) across cosmic time. The predicted BH-NS mergers from the isolated classical binary evolution are sufficiently abundant ($\sim 0.4-10$ $Gpc^{-3} yr^{-1}$) in the local Universe ($z\approx0$) to produce the observed LIGO/Virgo candidates. We present results on the NS to BH mass ratios ($q=M_{\rm NS}/M_{\rm BH}$ ) in merging systems, showing that although systems with a mass ratio as low as $q=0.02$ can exist, only a small fraction ($\sim 0.05\%-5\%$) of LIGO/Virgo detectable BH-NS mergers have mass ratios below $q=0.05$. We find that with appropriate constraints on the (delayed) supernova engine $\sim 30-40\%$ of LIGO/Virgo BH-NS mergers may host at least one compact object in the gap. The uncertainties in the processes behind compact object formation imply that the fraction of BH-NS systems ejecting mass during the merger is $\sim 0-9\%$. In our reference we find that only $\sim 0.2\%$ of BH-NS mergers will have any mass ejection, and about the same percentage would produce kilonova bright enough to have a chance to be detected even with a large (Subaru-class) $8$m telescope. Interestingly, all these mergers will have both BH and NS in the first mass gap.Comment: 14 pages, 12 figure

Compact Binary Coalescences in the Band of Ground-based Gravitational-Wave Detectors

As the ground-based gravitational-wave telescopes LIGO, Virgo, and GEO 600 approach the era of first detections, we review the current knowledge of the coalescence rates and the mass and spin distributions of merging neutron-star and black-hole binaries. We emphasize the bi-directional connection between gravitational-wave astronomy and conventional astrophysics. Astrophysical input will make possible informed decisions about optimal detector configurations and search techniques. Meanwhile, rate upper limits, detected merger rates, and the distribution of masses and spins measured by gravitational-wave searches will constrain astrophysical parameters through comparisons with astrophysical models. Future developments necessary to the success of gravitational-wave astronomy are discussed.Comment: Replaced with version accepted by CQG

High-Sensitivity Measurement of 3He-4He Isotopic Ratios for Ultracold Neutron Experiments

Research efforts ranging from studies of solid helium to searches for a neutron electric dipole moment require isotopically purified helium with a ratio of 3He to 4He at levels below that which can be measured using traditional mass spectroscopy techniques. We demonstrate an approach to such a measurement using accelerator mass spectroscopy, reaching the 10e-14 level of sensitivity, several orders of magnitude more sensitive than other techniques. Measurements of 3He/4He in samples relevant to the measurement of the neutron lifetime indicate the need for substantial corrections. We also argue that there is a clear path forward to sensitivity increases of at least another order of magnitude.Comment: 11 pages, 10 figure

Occurrence of testicular microlithiasis in androgen insensitive hypogonadal mice

<b>Background</b>: Testicular microliths are calcifications found within the seminiferous tubules. In humans, testicular microlithiasis (TM) has an unknown etiology but may be significantly associated with testicular germ cell tumors. Factors inducing microlith development may also, therefore, act as susceptibility factors for malignant testicular conditions. Studies to identify the mechanisms of microlith development have been hampered by the lack of suitable animal models for TM.<BR/> <b>Methods</b>: This was an observational study of the testicular phenotype of different mouse models. The mouse models were: cryptorchid mice, mice lacking androgen receptors (ARs) on the Sertoli cells (SCARKO), mice with a ubiquitous loss of androgen ARs (ARKO), hypogonadal (hpg) mice which lack circulating gonadotrophins, and hpg mice crossed with SCARKO (hpg.SCARKO) and ARKO (hpg.ARKO) mice.<BR/> <b>Results</b>: Microscopic TM was seen in 94% of hpg.ARKO mice (n=16) and the mean number of microliths per testis was 81 +/- 54. Occasional small microliths were seen in 36% (n=11) of hpg testes (mean 2 +/- 0.5 per testis) and 30% (n=10) of hpg.SCARKO testes (mean 8 +/- 6 per testis). No microliths were seen in cryptorchid, ARKO or SCARKO mice. There was no significant effect of FSH or androgen on TM in hpg.ARKO mice.<BR/> <b>Conclusions</b>: We have identified a mouse model of TM and show that lack of endocrine stimulation is a cause of TM. Importantly, this model will provide a means with which to identify the mechanisms of TM development and the underlying changes in protein and gene expression

Classifying the precancers: A metadata approach

BACKGROUND: During carcinogenesis, precancers are the morphologically identifiable lesions that precede invasive cancers. In theory, the successful treatment of precancers would result in the eradication of most human cancers. Despite the importance of these lesions, there has been no effort to list and classify all of the precancers. The purpose of this study is to describe the first comprehensive taxonomy and classification of the precancers. As a novel approach to disease classification, terms and classes were annotated with metadata (data that describes the data) so that the classification could be used to link precancer terms to data elements in other biological databases. METHODS: Terms in the UMLS (Unified Medical Language System) related to precancers were extracted. Extracted terms were reviewed and additional terms added. Each precancer was assigned one of six general classes. The entire classification was assembled as an XML (eXtensible Mark-up Language) file. A Perl script converted the XML file into a browser-viewable HTML (HyperText Mark-up Language) file. RESULTS: The classification contained 4700 precancer terms, 568 distinct precancer concepts and six precancer classes: 1) Acquired microscopic precancers; 2) acquired large lesions with microscopic atypia; 3) Precursor lesions occurring with inherited hyperplastic syndromes that progress to cancer; 4) Acquired diffuse hyperplasias and diffuse metaplasias; 5) Currently unclassified entities; and 6) Superclass and modifiers. CONCLUSION: This work represents the first attempt to create a comprehensive listing of the precancers, the first attempt to classify precancers by their biological properties and the first attempt to create a pathologic classification of precancers using standard metadata (XML). The classification is placed in the public domain, and comment is invited by the authors, who are prepared to curate and modify the classification

High-sensitivity measurement of ^3He−^4He isotopic ratios for ultracold neutron experiments

Research efforts ranging from studies of solid helium to searches for a neutron electric dipole moment require isotopically purified helium with a ratio of ^3He to ^4He at levels below that which can be measured using traditional mass spectroscopy techniques. We demonstrate an approach to such a measurement using accelerator mass spectroscopy, reaching the 10^(−14) level of sensitivity, several orders of magnitude more sensitive than other techniques. Measurements of ^3He/^4He in samples relevant to the measurement of the neutron lifetime indicate the need for substantial corrections. We also argue that there is a clear path forward to sensitivity increases of at least another order of magnitude