mTOR Signalling in Health and Disease 443 Signalling by amino acid nutrients

Abstract It is clear that mTORC1 (mammalian target of rapamycin complex 1) is regulated by the presence of ambient amino acid nutrients. However, the mechanism by which amino acids regulate mTORC1 is still open to question, despite extensive efforts. Our recent work has revealed that PR61ε, a B56 family regulatory subunit of PP2A (protein phosphatase 2A), associates with and regulates the activity of MAP4K3 (mitogenactivated protein kinase kinase kinase kinase 3), a protein kinase regulated by amino acid sufficiency that acts upstream of mTORC1. In searching for a physiological process regulated by amino acids, we have demonstrated recently that arginine plays a role in the activation of LPS (lipopolysaccharide)-induced MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK signalling in macrophages. PP2A similarly associates with the upstream regulator of MEK in this signalling pathway, TPL-2 (tumour progression locus-2), in response to arginine availability. Thus PP2A is a negative regulator of both MAP4K3 and TPL-2 in both mTORC1 and MEK/ERK signalling pathways

Capillary-Gravity Waves on Depth-Dependent Currents: Consequences for the Wave Resistance

We study theoretically the capillary-gravity waves created at the water-air interface by a small two-dimensional perturbation when a depth-dependent current is initially present in the fluid. Assuming linear wave theory, we derive a general expression of the wave resistance experienced by the perturbation as a function of the current profile in the case of an inviscid fluid. We then analyze and discuss in details the behavior of the wave resistance in the particular case of a linear current, a valid approximation for some wind generated currents.Comment: Submitted to EP

Author Correction: 150,000-year palaeoclimate record from northern Ethiopia supports early, multiple dispersals of modern humans from Africa

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

Revealing the High-Redshift Star Formation Rate with Gamma-Ray Bursts

While the high-z frontier of star formation rate (SFR) studies has advanced rapidly, direct measurements beyond z ~ 4 remain difficult, as shown by significant disagreements among different results. Gamma-ray bursts, owing to their brightness and association with massive stars, offer hope of clarifying this situation, provided that the GRB rate can be properly related to the SFR. The Swift GRB data reveal an increasing evolution in the GRB rate relative to the SFR at intermediate z; taking this into account, we use the highest-z GRB data to make a new determination of the SFR at z = 4-7. Our results exceed the lowest direct SFR measurements, and imply that no steep drop exists in the SFR up to at least z ~ 6.5. We discuss the implications of our result for cosmic reionization, the efficiency of the universe in producing stellar-mass black holes, and ``GRB feedback'' in star-forming hosts.Comment: 4 pages, 2 figures; ApJ Letters, in pres

Targeted next generation sequencing as a tool for precision medicine

Background: Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1∗28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response. Methods: A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms. Results: Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1∗28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy. Conclusions: PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine

Wild to domestic and back again: the dynamics of fallow deer management in medieval England (c.11th-16th century AD)

This paper presents the results of the first comprehensive scientific study of the fallow deer, a non-native species whose medieval-period introduction to Britain transformed the cultural landscape. It brings together data from traditional zooarchaeological analyses with those derived from new ageing techniques as well as the results of a programme of radiocarbon dating, multi-element isotope studies and genetic analyses. These new data are here integrated with historical and landscape evidence to examine changing patterns of fallow deer translocation and management in medieval England between the 11th and 16th century AD

Radiation-Hydrodynamic Simulations of the Formation of Orion-Like Star Clusters I. Implications for the Origin of the Initial Mass Function

One model for the origin of typical galactic star clusters such as the Orion Nebula Cluster (ONC) is that they form via the rapid, efficient collapse of a bound gas clump within a larger, gravitationally-unbound giant molecular cloud. However, simulations in support of this scenario have thus far have not included the radiation feedback produced by the stars; radiative simulations have been limited to significantly smaller or lower density regions. Here we use the ORION adaptive mesh refinement code to conduct the first ever radiation-hydrodynamic simulations of the global collapse scenario for the formation of an ONC-like cluster. We show that radiative feedback has a dramatic effect on the evolution: once the first ~10-20% of the gas mass is incorporated into stars, their radiative feedback raises the gas temperature high enough to suppress any further fragmentation. However, gas continues to accrete onto existing stars, and, as a result, the stellar mass distribution becomes increasingly top-heavy, eventually rendering it incompatible with the observed IMF. Systematic variation in the location of the IMF peak as star formation proceeds is incompatible with the observed invariance of the IMF between star clusters, unless some unknown mechanism synchronizes the IMFs in different clusters by ensuring that star formation is always truncated when the IMF peak reaches a particular value. We therefore conclude that the global collapse scenario, at least in its simplest form, is not compatible with the observed stellar IMF. We speculate that processes that slow down star formation, and thus reduce the accretion luminosity, may be able to resolve the problem.Comment: 17 pages, 13 figures, emulateapj format, ApJ in press; simulation movies available at http://www.ucolick.org/~krumholz/publications.htm

The Ensemble Photometric Variability of ~25000 Quasars in the Sloan Digital Sky Survey

Using a sample of over 25000 spectroscopically confirmed quasars from the Sloan Digital Sky Survey, we show how quasar variability in the rest frame optical/UV regime depends upon rest frame time lag, luminosity, rest wavelength, redshift, the presence of radio and X-ray emission, and the presence of broad absorption line systems. The time dependence of variability (the structure function) is well-fit by a single power law on timescales from days to years. There is an anti-correlation of variability amplitude with rest wavelength, and quasars are systematically bluer when brighter at all redshifts. There is a strong anti-correlation of variability with quasar luminosity. There is also a significant positive correlation of variability amplitude with redshift, indicating evolution of the quasar population or the variability mechanism. We parameterize all of these relationships. Quasars with RASS X-ray detections are significantly more variable (at optical/UV wavelengths) than those without, and radio loud quasars are marginally more variable than their radio weak counterparts. We find no significant difference in the variability of quasars with and without broad absorption line troughs. Models involving multiple discrete events or gravitational microlensing are unlikely by themselves to account for the data. So-called accretion disk instability models are promising, but more quantitative predictions are needed.Comment: 41 pages, 21 figures, AASTeX, Accepted for publication in Ap

The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins

Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors

Evidence for Reionization at z ~ 6: Detection of a Gunn-Peterson Trough in a z=6.28 Quasar

We present moderate resolution Keck spectroscopy of quasars at z=5.82, 5.99 and 6.28, discovered by the Sloan Digital Sky Survey (SDSS). We find that the Ly Alpha absorption in the spectra of these quasars evolves strongly with redshift. To z~5.7, the Ly Alpha absorption evolves as expected from an extrapolation from lower redshifts. However, in the highest redshift object, SDSSp J103027.10+052455.0 (z=6.28), the average transmitted flux is 0.0038+-0.0026 times that of the continuum level over 8450 A < lambda < 8710 A (5.95<z(abs)<6.16), consistent with zero flux. Thus the flux level drops by a factor of >150, and is consistent with zero flux in the Ly Alpha forest region immediately blueward of the Ly Alpha emission line, compared with a drop by a factor of ~10 at z(abs)~5.3. A similar break is seen at Ly Beta; because of the decreased oscillator strength of this transition, this allows us to put a considerably stronger limit, tau(eff) > 20, on the optical depth to Ly Alpha absorption at z=6. This is a clear detection of a complete Gunn-Peterson trough, caused by neutral hydrogen in the intergalactic medium. Even a small neutral hydrogen fraction in the intergalactic medium would result in an undetectable flux in the Ly Alpha forest region. Therefore, the existence of the Gunn-Peterson trough by itself does not indicate that the quasar is observed prior to the reionization epoch. However, the fast evolution of the mean absorption in these high-redshift quasars suggests that the mean ionizing background along the line of sight to this quasar has declined significantly from z~5 to 6, and the universe is approaching the reionization epoch at z~6.Comment: Revised version (2001 Sep 4) accepted by the Astronomical Journal (minor changes