MAVE-NN: learning genotype-phenotype maps from multiplex assays of variant effect

Multiplex assays of variant effect (MAVEs) are a family of methods that includes deep mutational scanning experiments on proteins and massively parallel reporter assays on gene regulatory sequences. Despite their increasing popularity, a general strategy for inferring quantitative models of genotype-phenotype maps from MAVE data is lacking. Here we introduce MAVE-NN, a neural-network-based Python package that implements a broadly applicable information-theoretic framework for learning genotype-phenotype maps-including biophysically interpretable models-from MAVE datasets. We demonstrate MAVE-NN in multiple biological contexts, and highlight the ability of our approach to deconvolve mutational effects from otherwise confounding experimental nonlinearities and noise

The Liquidity Trap, the Real Balance Effect, and the Friedman Rule

This paper studies the behavior of the economy and the efficacy of monetary policy under zero nominal interest rates, using a model with population growth that nests, as a special case, a more conventional specification in which there is a single infinitely lived representative agent. The paper shows that with a growing population, monetary policy has distributional effects that give rise to a real balance effect, thereby eliminating the liquidity trap. These same distributional effects, however, can also work to make many agents much worse off under zero nominal interest rates than they are when the nominal interest rate is positive

The prototype colliding-wind pinwheel WR 104

Results from the most extensive study of the time-evolving dust structure around the prototype "Pinwheel" nebula WR 104 are presented. Encompassing 11 epochs in three near-infrared filter bandpasses, a homogeneous imaging data set spanning more than 6 years (or 10 orbits) is presented. Data were obtained from the highly successful Keck Aperture Masking Experiment, which can recover high fidelity images at extremely high angular resolutions, revealing the geometry of the plume with unprecedented precision. Inferred properties for the (unresolved) underlying binary and wind system are orbital period 241.5 +/- 0.5 days and angular outflow velocity of 0.28 +/- 0.02 mas/day. An optically thin cavity of angular size 13.3 +/- 1.4 mas was found to lie between the central binary and the onset of the spiral dust plume. Rotational motion of the wind system induced by the binary orbit is found to have important ramifications: entanglement of the winds results in strong shock activity far downstream from the nose of the bowshock. The far greater fraction of the winds participating in the collision may play a key role in gas compression and the nucleation of dust at large radii from the central binary and shock stagnation point. Investigation of the effects of radiative braking pointed towards significant modifications of the simple hydrostatic colliding wind geometry, extending the relevance of this phenomena to wider binary systems than previously considered. Limits placed on the maximum allowed orbital eccentricity of e < 0.06 argue strongly for a prehistory of tidal circularization in this system. Finally we discuss the implications of Earth's polar (i < 16 deg) vantage point onto a system likely to host supernova explosions at future epochs.Comment: 35 pages, 8 figures, Accepted for publication in Astrophysical Journa

Orbit and Dynamical Mass of the Late-T Dwarf Gl 758 B

Gl 758 B is a late-T dwarf orbiting a metal-rich Sun-like star at a projected separation of $\rho$ $\approx$ 1.6" (25 AU). We present four epochs of astrometry of this system with NIRC2 at Keck Observatory spanning 2010 to 2017 together with 630 radial velocities (RVs) of the host star acquired over the past two decades from McDonald Observatory, Keck Observatory, and the Automated Planet Finder at Lick Observatory. The RVs reveal that Gl 758 is accelerating with an evolving rate that varies between 2-5 m s$^{-1}$ yr$^{-1}$, consistent with the expected influence of the imaged companion Gl 758 B. A joint fit of the RVs and astrometry yields a dynamical mass of 42$^{+19}_{-7}$ M$_\mathrm{Jup}$ for the companion with a robust lower limit of 30.5 M$_\mathrm{Jup}$ at the 4-$\sigma$ level. Gl 758 B is on an eccentric orbit ($e$ = 0.26-0.67 at 95% confidence) with a semimajor axis of $a$ = $21.1_{-1.3}^{+2.7}$ AU and an orbital period of $P$ = $96_{-9}^{+21}$ yr, which takes it within $\approx$9 AU from its host star at periastron passage. Substellar evolutionary models generally underpredict the mass of Gl 758 B for nominal ages of 1-6 Gyr that have previously been adopted for the host star. This discrepancy can be reconciled if the system is older---which is consistent with activity indicators and recent isochrone fitting of the host star---or alternatively if the models are systematically overluminous by $\approx$0.1-0.2 dex. Gl 758 B is currently the lowest-mass directly imaged companion inducing a measured acceleration on its host star. In the future, bridging RVs and high-contrast imaging with the next generation of extremely large telescopes and space-based facilities will open the door to the first dynamical mass measurements of imaged exoplanets.Comment: AJ, accepte

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.

Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer