Raf kinases are essential for normal Ras-Raf-MEK-ERK pathway signaling, and activating mutations in components of this pathway are associated with a variety of human cancers, as well as the related ...developmental disorders Noonan, LEOPARD, and cardiofaciocutaneous syndromes. Although the Raf kinases are known to dimerize during normal and disease-associated Raf signaling, the functional significance of Raf dimerization has not been fully elucidated. Here, using mutational analysis and a peptide inhibitor, we show that dimerization is required for normal Ras-dependent Raf activation and for the biological function of disease-associated Raf mutants with moderate, low, or impaired kinase activity. However, dimerization is not needed for the function of B-Raf mutants with high catalytic activity, such as V600E-B-Raf. Importantly, we find that a dimer interface peptide can effectively block Raf dimerization and inhibit Raf signaling when dimerization is required for Raf function, thus identifying the Raf dimer interface as a therapeutic target.
► Raf dimerization is required for normal Ras-dependent Raf activation ► Function of Raf mutants with all but high catalytic activity requires dimerization ► A dimerization inhibitor peptide blocks Raf signaling and induces apoptosis
Summary Background Healthy life expectancy (HALE) summarises mortality and non-fatal outcomes in a single measure of average population health. It has been used to compare health between countries, ...or to measure changes over time. These comparisons can inform policy questions that depend on how morbidity changes as mortality decreases. We characterise current HALE and changes over the past two decades in 187 countries. Methods Using inputs from the Global Burden of Disease Study (GBD) 2010, we assessed HALE for 1990 and 2010. We calculated HALE with life table methods, incorporating estimates of average health over each age interval. Inputs from GBD 2010 included age-specific information for mortality rates and prevalence of 1160 sequelae, and disability weights associated with 220 distinct health states relating to these sequelae. We computed estimates of average overall health for each age group, adjusting for comorbidity with a Monte Carlo simulation method to capture how multiple morbidities can combine in an individual. We incorporated these estimates in the life table by the Sullivan method to produce HALE estimates for each population defined by sex, country, and year. We estimated the contributions of changes in child mortality, adult mortality, and disability to overall change in population health between 1990 and 2010. Findings In 2010, global male HALE at birth was 59·0 years (uncertainty interval 57·3–60·6) and global female HALE at birth was 63·2 years (61·4–65·0). HALE increased more slowly than did life expectancy over the past 20 years, with each 1-year increase in life expectancy at birth associated with a 10-month increase in HALE. Across countries in 2010, male HALE at birth ranged from 27·8 years (17·2–36·5) in Haiti, to 70·6 years (68·6–72·2) in Japan. Female HALE at birth ranged from 37·1 years (26·8–43·8) in Haiti, to 75·5 years (73·3–77·3) in Japan. Between 1990 and 2010, male HALE increased by 5 years or more in 48 countries compared with 43 countries for female HALE, while male HALE decreased in 22 countries and 11 for female HALE. Between countries and over time, life expectancy was strongly and positively related to number of years lost to disability. This relation was consistent between sexes, in cross-sectional and longitudinal analysis, and when assessed at birth, or at age 50 years. Changes in disability had small effects on changes in HALE compared with changes in mortality. Interpretation HALE differs substantially between countries. As life expectancy has increased, the number of healthy years lost to disability has also increased in most countries, consistent with the expansion of morbidity hypothesis, which has implications for health planning and health-care expenditure. Compared with substantial progress in reduction of mortality over the past two decades, relatively little progress has been made in reduction of the overall effect of non-fatal disease and injury on population health. HALE is an attractive indicator for monitoring health post-2015. Funding The Bill & Melinda Gates Foundation
Abstract
We present a novel interpretation of the previously puzzling different behaviours of stellar populations of the Milky Way’s bulge. We first show, by means of pure N-body simulations, that ...initially co-spatial stellar populations with different in-plane random motions separate when a bar forms. The radially cooler populations form a strong bar, and are vertically thin and peanut-shaped, while the hotter populations form a weaker bar and become a vertically thicker box. We demonstrate that it is the radial, not the vertical, velocity dispersion that dominates this evolution. Assuming that early stellar discs heat rapidly as they form, then both the in-plane and vertical random motions correlate with stellar age and chemistry, leading to different density distributions for metal-rich and metal-poor stars. We then use a high-resolution simulation, in which all stars form out of gas, to demonstrate that this is what happens. When we apply these results to the Milky Way we show that a very broad range of observed trends for ages, densities, kinematics
and chemistries, that have been presented as evidence for contradictory paths to the formation of the bulge, are in fact consistent with a bulge which formed from a continuum of disc stellar populations which were kinematically separated by the bar. For the first time, we are able to account for the bulge’s main trends via a model in which the bulge formed largely in situ. Since the model is generic, we also predict the general appearance of stellar population maps of external edge-on galaxies.
► Function and regulation of 14-3-3 binding interactions in RTK/Ras signaling. ► New regulators of 14-3-3 binding interactions in the Hippo pathway. ► 14-3-3 and cell migration: role in regulating ...the actin cytoskeleton. ► 14-3-3 and EMT: implications for cancer progression. ► 14-3-3 proteins: clinical significance in human cancer.
The 14-3-3 proteins were the first phosphoserine/phosphothreonine-binding proteins to be discovered, a finding that provided the foundation for their prominent role in cell signaling. 14-3-3 family members interact with a wide spectrum of proteins including transcription factors, biosynthetic enzymes, cytoskeletal proteins, signaling molecules, apoptosis factors, and tumor suppressors. The interaction with 14-3-3 can have a profound effect on a target protein, altering its localization, stability, conformation, phosphorylation state, activity, and/or molecular interactions. Thus, by modulating the function of a diverse array of binding partners, 14-3-3 proteins have become key regulatory components in many vital cellular processes – processes that are crucial for normal growth and development and that often become dysregulated in human cancer. This review will examine the recent advances that further elucidate the role of 14-3-3 proteins in normal growth and cancer signaling with a particular emphasis on the signaling pathways that impact cell proliferation, cell migration, and epithelial-to-mesenchymal transition.
We use data from the Radial Velocity Experiment (RAVE) and the Tycho-Gaia astrometric solution (TGAS) catalogue to compute the velocity fields yielded by the radial (V-R), azimuthal (V-phi), and ...vertical (V-z) components of associated Galactocentric velocity. We search in particular for variation in all three velocity components with distance above and below the disc midplane, as well as how each component of V-z (line-of-sight and tangential velocity projections) modifies the obtained vertical structure. To study the dependence of velocity on proper motion and distance, we use two main samples: a RAVE sample including proper motions from the Tycho-2, PPMXL, and UCAC4 catalogues, and a RAVE-TGAS sample with inferred distances and proper motions from the TGAS and UCAC5 catalogues. In both samples, we identify asymmetries in V-R and V-z. Below the plane, we find the largest radial gradient to be partial derivative V-R/partial derivative R = -7.01 +/- 0.61 km s(-1) kpc(-1), in agreement with recent studies. Above the plane, we find a similar gradient with partial derivative V-R/partial derivative R = -9.42 +/- 1.77 km s(-1) kpc(-1). By comparing our results with previous studies, we find that the structure in V-z is strongly dependent on the adopted proper motions. Using the Galaxia Milky Way model, we demonstrate that distance uncertainties can create artificial wave-like patterns. In contrast to previous suggestions of a breathing mode seen in RAVE data, our results support a combination of bending and breathing modes, likely generated by a combination of external or internal and external mechanisms.
We present the metallicity results from the ARGOS spectroscopic survey of the Galactic bulge. Our aim is to understand the formation of the Galactic bulge: did it form via mergers, as expected from Λ ...cold dark matter theory, or from disc instabilities, as suggested by its boxy/peanut shape, or both? Our stars are mostly red clump giants, which have a well-defined absolute magnitude from which distances can be determined. We have obtained spectra for 28 000 stars at a spectral resolution of R = 11 000. From these spectra, we have determined stellar parameters and distances to an accuracy of <1.5 kpc. The stars in the inner Galaxy span a large range in Fe/H, −2.8 ≤ Fe/H ≤ +0.6. From the spatial distribution of the red clump stars as a function of Fe/H, we propose that the stars with Fe/H > −0.5 are part of the boxy/peanut bar/bulge. We associate the lower metallicity stars (Fe/H < −0.5) with the thick disc, which may be puffed up in the inner region, and with the inner regions of the metal-weak thick disc and inner halo. For the bulge stars with Fe/H > −0.5, we find two discrete populations: (i) stars with Fe/H −0.25 which provide a roughly constant fraction of the stars in the latitude interval b = −5° to −10°, and (ii) a kinematically colder, more metal-rich population with mean Fe/H +0.15 which is more prominent closer to the plane. The changing ratio of these components with latitude appears as a vertical abundance gradient of the bulge. We attribute both of these bulge components to instability-driven bar/bulge formation from the thin disc. We associate the thicker component with the stars of the early less metal-rich thin disc, and associate the more metal-rich population concentrated to the plane with the colder more metal-rich stars of the early thin disc, similar to the colder and younger more metal-rich stars seen in the thin disc in the solar neighbourhood today. We do not exclude a weak underlying classical merger-generated bulge component, but see no obvious kinematic association of any of our bulge stars with such a classical bulge component. The clear spatial and kinematic separation of the two bulge populations (i) and (ii) makes it unlikely that any significant merger event could have affected the inner regions of the Galaxy since the time when the bulge-forming instabilities occurred.
Abstract Purpose Continuity of care among different clinicians refers to consistent and coherent care management and good measures are needed. We conducted a metasummary of qualitative studies of ...patients' experience with care to identify measurable elements that recur over a variety of contexts and health conditions as the basis for a generic measure of management continuity. Methods From an initial list of 514 potential studies (1997-2007), 33 met our criteria of using qualitative methods and exploring patients' experiences of health care from various clinicians over time. They were coded independently. Consensus meetings minimized conceptual overlap between codes. Results For patients, continuity of care is experienced as security and confidence rather than seamlessness. Coordination and information transfer between professionals are assumed until proven otherwise. Care plans help clinician coordination but are rarely discerned as such by patients. Knowing what to expect and having contingency plans provides security. Information transfer includes information given to the patient, especially to support an active role in giving and receiving information, monitoring, and self-management. Having a single trusted clinician who helps navigate the system and sees the patient as a partner undergirds the experience of continuity between clinicians. Conclusion Some dimensions of continuity, such as coordination and communication among clinicians, are perceived and best assessed indirectly by patients through failures and gaps (discontinuity). Patients experience continuity directly through receiving information, having confidence and security on the care pathway, and having a relationship with a trusted clinician who anchors continuity.
Rationale
Illicit drugs may be unpredictable in terms of the time and effort required to obtain them, and this can be modeled with variable- (VR) vs. fixed-ratio (FR) schedules. In a recent ...experiment (Zamarripa et al.
2023
), the potency of cocaine to maintain choice was greatest under a VR (compared with a FR) when food was available under a FR schedule.
Objectives
The goal of the current study was to extend prior choice results with VR vs. FR schedules to a more efficient procedure with cocaine or fentanyl vs. food. Furthermore, the FR schedule of food delivery was manipulated to determine whether increased drug choice under a VR (compared with a FR) schedule depends on the size of the schedule of nondrug reinforcement.
Methods
Adult female (
n
= 2) and male (
n
= 4) monkeys chose between cocaine (0–30 µg/kg/injection) or fentanyl (0–1.0 µg/kg/injection) and food (2 pellets/delivery) under a 5-component procedure. In different conditions, food was available under a FR 25, 50, or 100 and cocaine or fentanyl were available under FR or VR 100 schedules.
Results
Cocaine’s potency to maintain choice was greatest under a VR 100 (compared with FR 100) when food was available under a FR 50 or 100, and fentanyl’s potency to maintain choice was generally greatest under a VR 100 (compared with FR 100) when food was available under a FR 25 or 100. However, outcomes between FR and VR schedules with fentanyl were less robust compared with cocaine.
Conclusion
Variability in the time and effort required to obtain illicit drugs could contribute to excessive allocation of behavior toward drug use at the expense of more predictable nondrug alternatives, supporting treatment or policies aimed at making drug access more predictable through agonist medications or a safe supply. The impact of variable requirements on drug choice may be reduced if nondrug reinforcers are relatively less costly, supporting the use of low-cost reinforcers in behavioral therapies like contingency management.
ABSTRACT
We first present a self‐consistent dynamical model in which ω Cen is formed from an ancient nucleated dwarf galaxy merging with the first generation of the Galactic thin disc in a retrograde ...manner with respect to the Galactic rotation. Our numerical simulations demonstrate that during merging between the Galaxy and the ω Cen host dwarf with MB≃−14 mag and its nucleus mass of 107 M⊙, the outer stellar envelope of the dwarf is nearly completely stripped, whereas the central nucleus can survive from the tidal stripping because of its compactness. The developed naked nucleus has a very bound retrograde orbit around the young Galactic disc, as observed for ω Cen, with apocentre and pericentre distances of ∼8 and ∼1 kpc, respectively. The Galactic tidal force can induce radial inflow of gas to the centre of the dwarf and consequently triggers moderately strong nuclear starbursts in a repetitive manner. This result implies that efficient nuclear chemical enrichment resulting from the later starbursts can be closely associated with the origin of the observed relatively young and metal‐rich stars in ω Cen. Dynamical heating by the ω Cen host can transform the young thin disc into the thick disc during merging.
We report new constraints on the local escape speed of our Galaxy. Our analysis is based on a sample of high-velocity stars from the RAVE survey and two previously published data sets. We use ...cosmological simulations of disc galaxy formation to motivate our assumptions on the shape of the velocity distribution, allowing for a significantly more precise measurement of the escape velocity compared to previous studies. We find that the escape velocity lies within the range 498 < vesc < 608 km s−1 (90 per cent confidence), with a median likelihood of 544 km s−1. The fact that v2esc is significantly greater than 2v2circ (where vcirc= 220 km s−1 is the local circular velocity) implies that there must be a significant amount of mass exterior to the solar circle, that is, this convincingly demonstrates the presence of a dark halo in the Galaxy. We use our constraints on vesc to determine the mass of the Milky Way halo for three halo profiles. For example, an adiabatically contracted NFW halo model results in a virial mass of 1.42+1.14−0.54× 1012 M⊙ and virial radius of (90 per cent confidence). For this model the circular velocity at the virial radius is 142+31−21 km s−1. Although our halo masses are model dependent, we find that they are in good agreement with each other.
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