Gravitationally bound three-body systems have been studied for hundreds of years and are common in our Galaxy. They show complex orbital interactions, which can constrain the compositions, masses and ...interior structures of the bodies and test theories of gravity, if sufficiently precise measurements are available. A triple system containing a radio pulsar could provide such measurements, but the only previously known such system, PSR B1620-26 (refs 7, 8; with a millisecond pulsar, a white dwarf, and a planetary-mass object in an orbit of several decades), shows only weak interactions. Here we report precision timing and multiwavelength observations of PSR J0337+1715, a millisecond pulsar in a hierarchical triple system with two other stars. Strong gravitational interactions are apparent and provide the masses of the pulsar MSymbol: see text(1.4378(13), where MSymbol: see textis the solar mass and the parentheses contain the uncertainty in the final decimal places) and the two white dwarf companions (0.19751(15)MSymbol: see text and 0.4101(3))MSymbol: see text, as well as the inclinations of the orbits (both about 39.2°). The unexpectedly coplanar and nearly circular orbits indicate a complex and exotic evolutionary past that differs from those of known stellar systems. The gravitational field of the outer white dwarf strongly accelerates the inner binary containing the neutron star, and the system will thus provide an ideal laboratory in which to test the strong equivalence principle of general relativity.
Vav proteins are guanine nucleotide exchange factors (GEFs) for Rho family GTPases. They control processes including T cell activation, phagocytosis, and migration of normal and transformed cells. We ...report the structure and biophysical and cellular analyses of the five-domain autoinhibitory element of Vav1. The catalytic Dbl homology (DH) domain of Vav1 is controlled by two energetically coupled processes. The DH active site is directly, but weakly, inhibited by a helix from the adjacent Acidic domain. This core interaction is strengthened 10-fold by contacts of the calponin homology (CH) domain with the Acidic, pleckstrin homology, and DH domains. This construction enables efficient, stepwise relief of autoinhibition: initial phosphorylation events disrupt the modulatory CH contacts, facilitating phosphorylation of the inhibitory helix and consequent GEF activation. Our findings illustrate how the opposing requirements of strong suppression of activity and rapid kinetics of activation can be achieved in multidomain systems.
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► The structure is determined of the five-domain autoinhibitory element of Vav1 ► The Vav1 Dbl homology domain is inhibited by cooperative interdomain interactions ► Inhibition is relieved in stepwise fashion by phosphorylation ► The energetics of multidomain systems enable strong inhibition and rapid activation
ABSTRACT
Most stars form in highly clustered environments within molecular clouds, but eventually disperse into the distributed stellar field population. Exactly how the stellar distribution evolves ...from the embedded stage into gas-free associations and (bound) clusters is poorly understood. We investigate the long-term evolution of stars formed in the starforge simulation suite – a set of radiation-magnetohydrodynamic simulations of star-forming turbulent clouds that include all key stellar feedback processes inherent to star formation. We use nbody6++gpu to follow the evolution of the young stellar systems after gas removal. We use HDBSCAN to define stellar groups and analyse the stellar kinematics to identify the true bound star clusters. The conditions modeled by the simulations, i.e. global cloud surface densities below 0.15 g cm−2, star formation efficiencies below 15 per cent, and gas expulsion time-scales shorter than a free fall time, primarily produce expanding stellar associations and small clusters. The largest star clusters, which have ∼1000 bound members, form in the densest and lowest velocity dispersion clouds, representing ∼32 and 39 per cent of the stars in the simulations, respectively. The cloud’s early dynamical state plays a significant role in setting the classical star formation efficiency versus bound fraction relation. All stellar groups follow a narrow mass-velocity dispersion power-law relation at 10 Myr with a power-law index of 0.21. This correlation result in a distinct mass–size relationship for bound clusters. We also provide valuable constraints on the gas dispersal time-scale during the star formation process and analyse the implications for the formation of bound systems.
Prostate cancer cells are characterized by a remarkably low proliferative rate and the production of high levels of prostate-specific proteases. Protein-based toxins are attractive candidates for ...prostate cancer therapy because they kill cells via proliferation-independent mechanisms. However, the non-specific cytotoxicity of these potent cytotoxins must be redirected to avoid toxicity to normal tissues. Prostate-Specific Membrane Antigen (PSMA) is membrane-bound carboxypeptidase that is highly expressed by prostate cancer cells. Potent dipeptide PSMA inhibitors have been developed that can selectively deliver and concentrate imaging agents within prostate cancer cells based on continuous PSMA internalization and endosomal cycling. On this basis, we conjugated a PSMA inhibitor to the apoptosis-inducing human protease Granzyme B and the potent Pseudomonas exotoxin protein toxin fragment, PE35. We assessed selective PSMA binding and entrance into tumor cell to induce cell death. We demonstrated these agents selectively bound to PSMA and became internalized. PSMA-targeted PE35 toxin was selectively toxic to PSMA producing cells in vitro. Intratumoral and intravenous administration of this toxin produced marked tumor killing of PSMA-producing xenografts with minimal host toxicity. These studies demonstrate that urea-based PSMA inhibitors represent a simpler, less expensive alternative to antibodies as a means to deliver cytotoxic proteins to prostate cancer cells.
ABSTRACT
Most observed stars are part of a multiple star system, but the formation of such systems and the role of environment and various physical processes is still poorly understood. We present a ...suite of radiation-magnetohydrodynamic simulations of star-forming molecular clouds from the STARFORGE project that include stellar feedback with varied initial surface density, magnetic fields, level of turbulence, metallicity, interstellar radiation field, simulation geometry and turbulent driving. In our fiducial cloud, the raw simulation data reproduces the observed multiplicity fractions for Solar-type and higher mass stars, similar to previous works. However, after correcting for observational incompleteness the simulation underpredicts these values. The discrepancy is likely due to the lack of disc fragmentation, as the simulation only resolves multiples that form either through capture or core fragmentation. The raw mass distribution of companions is consistent with randomly drawing from the initial mass function for the companions of $\gt 1\, \mathrm{M}_{\rm \odot }$ stars. However, accounting for observational incompleteness produces a flatter distribution similar to observations. We show that stellar multiplicity changes as the cloud evolves and anticorrelates with stellar density. This relationship also explains most multiplicity variations between runs, i.e. variations in the initial conditions that increase stellar density (increased surface density, reduced turbulence) also act to decrease multiplicity. While other parameters, such as metallicity, interstellar radiation, and geometry significantly affect the star formation history or the IMF, varying them produces no clear trend in stellar multiplicity properties.
Context. Catalogue cross-correlation is essential to building large sets of multi-wavelength data, whether it be to study the properties of populations of astrophysical objects or to build reference ...catalogues (or timeseries) from survey observations. Nevertheless, resorting to automated processes with limited sets of information available on large numbers of sources detected at different epochs with various filters and instruments inevitably leads to spurious associations. We need both statistical criteria to select detections to be merged as unique sources, and statistical indicators helping in achieving compromises between completeness and reliability of selected associations. Aims. We lay the foundations of a statistical framework for multi-catalogue cross-correlation and cross-identification based on explicit simplified catalogue models. A proper identification process should rely on both astrometric and photometric data. Under some conditions, the astrometric part and the photometric part can be processed separately and merged a posteriori to provide a single global probability of identification. The present paper addresses almost exclusively the astrometrical part and specifies the proper probabilities to be merged with photometric likelihoods. Methods. To select matching candidates in n catalogues, we used the Chi (or, indifferently, the Chi-square) test with 2(n−1) degrees of freedom. We thus call this cross-match a χ-match. In order to use Bayes’ formula, we considered exhaustive sets of hypotheses based on combinatorial analysis. The volume of the χ-test domain of acceptance – a 2(n−1)-dimensional acceptance ellipsoid – is used to estimate the expected numbers of spurious associations. We derived priors for those numbers using a frequentist approach relying on simple geometrical considerations. Likelihoods are based on standard Rayleigh, χ and Poisson distributions that we normalized over the χ-test acceptance domain. We validated our theoretical results by generating and cross-matching synthetic catalogues. Results. The results we obtain do not depend on the order used to cross-correlate the catalogues. We applied the formalism described in the present paper to build the multi-wavelength catalogues used for the science cases of the Astronomical Resource Cross-matching for High Energy Studies (ARCHES) project. Our cross-matching engine is publicly available through a multi-purpose web interface. In a longer term, we plan to integrate this tool into the CDS XMatch Service.
ABSTRACT
Simulations of isolated giant molecular clouds (GMCs) are an important tool for studying the dynamics of star formation, but their turbulent initial conditions (ICs) are uncertain. Most ...simulations have either initialized a velocity field with a prescribed power spectrum on a smooth density field (failing to model the full structure of turbulence) or ‘stirred’ turbulence with periodic boundary conditions (which may not model real GMC boundary conditions). We develop and test a new GMC simulation setup (called turbsphere) that combines advantages of both approaches: we continuously stir an isolated cloud to model the energy cascade from larger scales, and use a static potential to confine the gas. The resulting cloud and surrounding envelope achieve a quasi-equilibrium state with the desired hallmarks of supersonic ISM turbulence (e.g. density PDF and a ∼k−2 velocity power spectrum), whose bulk properties can be tuned as desired. We use the final stirred state as initial conditions for star formation simulations with self-gravity, both with and without continued driving and protostellar jet feedback, respectively. We then disentangle the respective effects of the turbulent cascade, simulation geometry, external driving, and gravity/MHD boundary conditions on the resulting star formation. Without external driving, the new setup obtains results similar to previous simple spherical cloud setups, but external driving can suppress star formation considerably in the new setup. Periodic box simulations with the same dimensions and turbulence parameters form stars significantly slower, highlighting the importance of boundary conditions and the presence or absence of a global collapse mode in the results of star formation calculations.
In cattle, the X chromosome accounts for approximately 3 and 6% of the genome in bulls and cows, respectively. In spite of the large size of this chromosome, very few studies report analysis of the X ...chromosome in genome-wide association studies and genomic selection. This lack of genetic interrogation is likely due to the complexities of undertaking these studies given the hemizygous state of some, but not all, of the X chromosome in males. The first step in facilitating analysis of this gene-rich chromosome is to accurately identify coordinates for the pseudoautosomal boundary (PAB) to split the chromosome into a region that may be treated as autosomal sequence (pseudoautosomal region) and a region that requires more complex statistical models. With the recent release of ARS-UCD1.2, a more complete and accurate assembly of the cattle genome than was previously available, it is timely to fine map the PAB for the first time. Here we report the use of SNP chip genotypes, short-read sequences, and long-read sequences to fine map the PAB (X chromosome:133,300,518) and simultaneously determine the neighboring regions of reduced homology and true pseudoautosomal region. These results greatly facilitate the inclusion of the X chromosome in genome-wide association studies, genomic selection, and other genetic analysis undertaken on this reference genome.
Left ventricular (LV) circumferential strain (Ecc) is a sensitive index of regional myocardial function. Currently, no studies have assessed its prognostic value in general population. We sought to ...investigate whether Ecc has a prognostic value for predicting incident heart failure (HF) and other major cardiovascular events in asymptomatic individuals without a history of previous cardiovascular diseases.
We, prospectively, assessed incident HF and atherosclerotic events during a 5.5 ± 1.3-year period in 1768 asymptomatic individuals aged 45-84 (mean age 65 years; 47% female) who underwent tagged magnetic resonance imaging for strain determination. During the follow-up period, 39 (2.2%) participants experienced incident HF and 108 (6.1%) participants had atherosclerotic cardiovascular events. Average of peak Ecc of 12-LV segments (Ecc-global) and mid-slice (Ecc-mid) was -17.0 ± 2.4 and -17.5 ± 2.7%, respectively. Participants with average absolute Ecc-mid lower than -16.9% had a higher cumulative hazard of incident HF (log-rank test, P = 0.001). In cox regression analysis, Ecc-mid predicted incident HF independent of age, diabetes status, hypertension, interim myocardial infarction, LV mass index, and LV ejection fraction (hazard ratio 1.15 per 1%, 95% CI: 1.01-1.31, P = 0.03). This relationship remained significant after adjustment for LV-end-systolic wall stress into covariates. In addition, by adding Ecc-mid to risk factors, LV ejection fraction, and the LV mass index, both the global χ(2) value (76.6 vs. 82.4, P = 0.04) and category-less net-reclassification index (P = 0.01, SE = 0.18, z = 2.53) were augmented for predicting HF. Circumferential strain was also significantly related to the composite atherosclerotic cardiovascular events, but its relationship was attenuated after introducing the LV mass index.
Circumferential shortening provides robust, independent, and incremental predictive value for incident HF in asymptomatic subjects without any history of previous clinical cardiovascular disease.
http://www.clinicaltrials.gov. Unique identifier: NCT00005487.
Protein motions are important to activity, but quantitative relationships between internal dynamics and function are not well understood. The Dbl homology (DH) domain of the proto-oncoprotein and ...guanine nucleotide exchange factor Vav1 is autoinhibited through interactions between its catalytic surface and a helix from an N-terminal acidic region. Phosphorylation of the helix relieves autoinhibition. Here we show by NMR spectroscopy that the autoinhibited DH domain exists in equilibrium between a ground state, where the active site is blocked by the inhibitory helix, and an excited state, where the helix is dissociated. Across a series of mutants that differentially sample these states, catalytic activity of the autoinhibited protein and its rate of phosphorylation are linearly dependent on the population of the excited state. Thus, internal dynamics are required for and control both basal activity and the rate of full activation of the autoinhibited DH domain.
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