The Strength and Nature of Bequest Motives in the United States

In this paper, we analyze the strength and nature of bequest motives in the United States using data from the 2000 Health and Retirement Study (HRS). The results of our analysis suggest that bequest motives are very strong in the United States and that they are altruistically motivated. This suggests that the altruism (or dynasty) model applies in the United States and that the selfish life cycle model does not apply. Moreover, our results also suggest that older, wealthier, married, more highly educated, Caucasian, healthy, and non-religious individuals are more likely to leave a bequest than other individuals.Bequests, Bequest Motives, Altruism, Life Cycle Model, Household Behavior

An Activating Mutation in sos-1 Identifies Its Dbl Domain as a Critical Inhibitor of the Epidermal Growth Factor Receptor Pathway during Caenorhabditis elegans Vulval Development

Proper regulation of receptor tyrosine kinase (RTK)-Ras-mitogen-activated protein kinase (MAPK) signaling pathways is critical for normal development and the prevention of cancer. SOS is a dual-function guanine nucleotide exchange factor (GEF) that catalyzes exchange on Ras and Rac. Although the physiologic role of SOS and its CDC25 domain in RTK-mediated Ras activation is well established, the in vivo function of its Dbl Rac GEF domain is less clear. We have identified a novel gain-of-function missense mutation in the Dbl domain of Caenorhabditis elegans SOS-1 that promotes epidermal growth factor receptor (EGFR) signaling in vivo. Our data indicate that a major developmental function of the Dbl domain is to inhibit EGF-dependent MAPK activation. The amount of inhibition conferred by the Dbl domain is equal to that of established trans-acting inhibitors of the EGFR pathway, including c-Cbl and RasGAP, and more than that of MAPK phosphatase. In conjunction with molecular modeling, our data suggest that the C. elegans mutation, as well as an equivalent mutation in human SOS1, activates the MAPK pathway by disrupting an autoinhibitory function of the Dbl domain on Ras activation. Our work suggests that functionally similar point mutations in humans could directly contribute to disease

Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study

BACKGROUND: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab ± chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented. METHODS: Patients ≥ 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score ≥ 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1-5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy). RESULTS: In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8-24.1) and 17.5 months (range 1.7-20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma

Modular Storage Key Management for Heterogeneous Hardware and Software

A server may be divided into one or more divisions, which each may include at least one processing device and one or more data sources. Each data source may include a media encryption key (MEK) that encrypts/decrypts the contents of the data source. The MEK may be encrypted. A processing device of a division may include a node secret seed (NSS) that the processing device may use with a key derivation function to generate an access key. The processing device can use the access key to decrypt the MEK of a data source. To secure the NSS, the processing device may encrypt the NSS, send the encrypted NSS to another processing device outside the division, and the other processing device can encrypt the already-encrypted NSS again and send the double wrapped NSS back to the first processing device. The server may have an access key emergency data recovery procedure

Complete multiwavelength evolution of galactic black hole transients during outburst decay I: conditions for "compact" jet formation

Compact, steady jets are observed in the near infrared and radio bands in the hard state of Galactic black hole transients as their luminosity decreases and the source moves towards a quiescent state. Recent radio observations indicate that the jets turn o completely in the soft state, therefore multiwavelength monitoring of black hole transients are essential to probe the formation of jets. In this work we conducted a systematic study of all black hole transients with near infrared and radio coverage during their outburst decays. We characterized the timescales of changes in X-ray spectral and temporal properties and also in near infrared and/or in radio emission. We confirmed that state transitions occur in black hole transients at a very similar fraction of their respective Eddington luminosities. We also found that the near infrared flux increase that could be due to the formation of a compact jet is delayed by a time period of days with respect to the formation of a corona. Finally, we found a threshold disk Eddington luminosity fraction for the compact jets to form. We explain these results with a model such that the increase in the near infrared flux corresponds to a transition from a patchy, small scale height corona along with an optically thin out flow to a large scale height corona that allows for collimation of a steady compact jet. We discuss the timescale of jet formation in terms of transport of magnetic fields from the outer parts of the disk, and also consider two alternative explanations for the multiwavelength emission: hot inner accretion flows and irradiation

The cyclin kinase inhibitor p21CIP1/WAF1 limits glomerular epithelial cell proliferation in experimental glomerulonephritis

The cyclin kinase inhibitor p21CIP1/WAF1 limits glomerular epithelial cell proliferation in experimental glomerulonephritis.BackgroundDuring glomerulogenesis, visceral glomerular epithelial cells (VECs) exit the cell cycle and become terminally differentiated and quiescent. In contrast to other resident glomerular cells, VECs undergo little if any proliferation in response to injury. However, the mechanisms for this remain unclear. Cell proliferation is controlled by cell-cycle regulatory proteins where the cyclin-dependent kinase inhibitor p21Cip1,WAF1 (p21) inhibits cell proliferation and is required for differentiation of many nonrenal cell types.MethodsTo test the hypothesis that p21 is required to maintain a differentiated and quiescent VEC phenotype, experimental glomerulonephritis was induced in p21 knockout (-/-) and p21 wild-type (+/+) mice with antiglomerular antibody. DNA synthesis (proliferating cell nuclear antigen, bromodeoxyuridine staining), VEC proliferation (multilayers of cells in Bowman's space), matrix accumulation (periodic acid-Schiff, silver staining), apoptosis (TUNEL), and renal function (serum urea nitrogen) were studied on days 5 and 14 (N = 6 per time point). VECs were identified by location, morphology, ezrin staining, and electron microscopy. VEC differentiation was measured by staining for Wilms’ tumor-1 gene.ResultsKidneys from unmanipulated p21-/- mice were histologically normal and did not have increased DNA synthesis, suggesting that p21 was not required for the induction of VEC terminal differentiation. Proliferating cell nuclear antigen and bromodeoxyuridine staining was increased 4.3- and 3.3-fold, respectively, in p21-/- mice with glomerulonephritis (P < 0.0001 vs. p21+/+ mice). At each time point, VEC proliferation was also increased in nephritic p21-/- mice (P < 0.0001 vs. p21+/+ mice). VEC re-entry into the cell cycle was associated with the loss of Wilms’ tumor-1 gene staining. Nephritic p21-/- mice had increased extracellular matrix protein accumulation and apoptosis and decreased renal function (serum urea nitrogen) compared with p21+/+ mice (P < 0.001).ConclusionThese results show that the cyclin kinase inhibitor p21 is not required by VECs to attain a terminally differentiated VEC phenotype. However, the loss of p21, in disease states, is associated with VEC re-entry into the cell cycle and the development of a dedifferentiated proliferative phenotype

Systems analysis of multiple regulator perturbations allows discovery of virulence factors in Salmonella

<p>Abstract</p> <p>Background</p> <p>Systemic bacterial infections are highly regulated and complex processes that are orchestrated by numerous virulence factors. Genes that are coordinately controlled by the set of regulators required for systemic infection are potentially required for pathogenicity.</p> <p>Results</p> <p>In this study we present a systems biology approach in which sample-matched multi-omic measurements of fourteen virulence-essential regulator mutants were coupled with computational network analysis to efficiently identify <it>Salmonella </it>virulence factors. Immunoblot experiments verified network-predicted virulence factors and a subset was determined to be secreted into the host cytoplasm, suggesting that they are virulence factors directly interacting with host cellular components. Two of these, SrfN and PagK2, were required for full mouse virulence and were shown to be translocated independent of either of the type III secretion systems in <it>Salmonella </it>or the type III injectisome-related flagellar mechanism.</p> <p>Conclusions</p> <p>Integrating multi-omic datasets from <it>Salmonella </it>mutants lacking virulence regulators not only identified novel virulence factors but also defined a new class of translocated effectors involved in pathogenesis. The success of this strategy at discovery of known and novel virulence factors suggests that the approach may have applicability for other bacterial pathogens.</p