An initial event in insect innate immune response: structural and biological studies of interactions between β-1,3-glucan and the N-terminal domain of β-1,3-glucan recognition protein

In response to invading microorganisms, insect β-1,3-glucan recognition protein (βGRP), a soluble receptor in the hemolymph, binds to the surfaces of bacteria and fungi and activates serine protease cascades that promote destruction of pathogens by means of melanization or expression of antimicrobial peptides. Here we report on the NMR solution structure of the N-terminal domain of βGRP (N-βGRP) from Indian meal moth (Plodia interpunctella), which is sufficient to activate the prophenoloxidase (proPO) pathway resulting in melanin formation. NMR and isothermal calorimetric titrations of N-βGRP with laminarihexaose, a glucose hexamer containing β-1,3 links, suggest a weak binding of the ligand. However, addition of laminarin, a glucose polysaccharide (~ 6 kDa) containing β-1,3 and β-1,6 links that activates the proPO pathway, to N-βGRP results in the loss of NMR cross-peaks from the backbone 15N-1H groups of the protein, suggesting the formation of a large complex. Analytical ultra centrifugation (AUC) studies of formation of N-βGRP:laminarin complex show that ligand-binding induces sel-fassociation of the protein:carbohydrate complex into a macro structure, likely containing six protein and three laminarin molecules (~ 102 kDa). The macro complex is quite stable, as it does not undergo dissociation upon dilution to sub-micromolar concentrations. The structural model thus derived from the present studies for N-βGRP:laminarin complex in solution differs from the one in which a single N-βGRP molecule has been proposed to bind to a triple helical form of laminarin on the basis of an X-ray crystallographic structure of N-βGRP:laminarihexaose complex [Kanagawa, M., Satoh, T., Ikeda, A., Adachi, Y., Ohno, N., and Yamaguchi, Y. (2011) J. Biol. Chem. 286, 29158-29165]. AUC studies and phenoloxidase activation measurements carried out with the designed mutants of N-βGRP indicate that electrostatic interactions involving Asp45, Arg54, and Asp68 between the ligand-bound protein molecules contribute in part to the stability of N-βGRP:laminarin macro complex and that a decreased stability is accompanied by a reduced activation of the proPO pathway. Increased β-1,6 branching in laminarin also results in destabilization of the macro complex. These novel findings suggest that ligand-induced self-association of βGRP:β-1,3-glucan complex may form a platform on a microbial surface for recruitment of downstream proteases, as a means of amplification of the initial signal of pathogen recognition for the activation of the proPO pathway

Helping the Working Poor: Employer- vs. Employee-Based Subsidies

In the United States and Europe there has been renewed interest in subsidizing firms that employ disadvantaged workers as a means of addressing poverty and other social problems. In contrast, the prevailing practice is largely to provide social welfare benefits directly to individuals. Which approach is better? We re-examine the relative merits of employee- versus employer-based labor market subsidies and conclude there are good reasons to continue to rely on the direct, employee-based approach. In practice, low-wage workers are seldom either low-skill or low-income workers. Furthermore, workers who might quality for a firm-based subsidy are reluctant to so identify themselves for fear of being stigmatized or labeled as needy. Thus, employer-based subsidy programs have lower participation rates and correspondingly higher per capita expenditures than employee-based subsidy programs

Contextual-value approach to the generalized measurement of observables

We present a detailed motivation for and definition of the contextual values of an observable, which were introduced by Dressel et al. [Phys. Rev. Lett. 104 240401 (2010)]. The theory of contextual values extends the well-established theory of generalized state measurements by bridging the gap between partial state collapse and the observables that represent physically relevant information about the system. To emphasize the general utility of the concept, we first construct the full theory of contextual values within an operational formulation of classical probability theory, paying special attention to observable construction, detector coupling, generalized measurement, and measurement disturbance. We then extend the results to quantum probability theory built as a superstructure on the classical theory, pointing out both the classical correspondences to and the full quantum generalizations of both L\"uder's rule and the Aharonov-Bergmann-Lebowitz rule in the process. We find in both cases that the contextual values of a system observable form a generalized spectrum that is associated with the independent outcomes of a partially correlated and generally ambiguous detector; the eigenvalues are a special case when the detector is perfectly correlated and unambiguous. To illustrate the approach, we apply the technique to both a classical example of marble color detection and a quantum example of polarization detection. For the quantum example we detail two devices: Fresnel reflection from a glass coverslip, and continuous beam displacement from a calcite crystal. We also analyze the three-box paradox to demonstrate that no negative probabilities are necessary in its analysis. Finally, we provide a derivation of the quantum weak value as a limit point of a pre- and postselected conditioned average and provide sufficient conditions for the derivation to hold.Comment: 36 pages, 5 figures, published versio

A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection

The HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-based trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting. Despite extensive analysis, the role of these functions in viral infection and pathogenesis is unclear. An SIV molecular clone (SIVmac239) in which this signal is inactivated by deletion of Gly-720 and Tyr-721 (SIVmac239ΔGY), replicates acutely to high levels in pigtail macaques (PTM) but is rapidly controlled. However, we previously reported that rhesus macaques and PTM can progress to AIDS following SIVmac239ΔGY infection in association with novel amino acid changes in the Env cytoplasmic domain. These included an R722G flanking the ΔGY deletion and a nine nucleotide deletion encoding amino acids 734–736 (ΔQTH) that overlaps the rev and tat open reading frames. We show that molecular clones containing these mutations reconstitute signals for both endocytosis and polarized sorting. In one PTM, a novel genotype was selected that generated a new signal for polarized sorting but not endocytosis. This genotype, together with the ΔGY mutation, was conserved in association with high viral loads for several months when introduced into naïve PTMs. For the first time, our findings reveal strong selection pressure for Env endocytosis and particularly for polarized sorting during pathogenic SIV infection in vivo

Cosmology from Cross-Correlation of ACT-DR4 CMB Lensing and DES-Y3 Cosmic Shear

Cross-correlation between weak lensing of the Cosmic Microwave Background (CMB) and weak lensing of galaxies offers a way to place robust constraints on cosmological and astrophysical parameters with reduced sensitivity to certain systematic effects affecting individual surveys. We measure the angular cross-power spectrum between the Atacama Cosmology Telescope (ACT) DR4 CMB lensing and the galaxy weak lensing measured by the Dark Energy Survey (DES) Y3 data. Our baseline analysis uses the CMB convergence map derived from ACT-DR4 and $\textit{Planck}$ data, where most of the contamination due to the thermal Sunyaev Zel'dovich effect is removed, thus avoiding important systematics in the cross-correlation. In our modelling, we consider the nuisance parameters of the photometric uncertainty, multiplicative shear bias and intrinsic alignment of galaxies. The resulting cross-power spectrum has a signal-to-noise ratio $= 7.1$ and passes a set of null tests. We use it to infer the amplitude of the fluctuations in the matter distribution ($S_8 \equiv \sigma_8 (\Omega_{\rm m}/0.3)^{0.5} = 0.782\pm 0.059$) with informative but well-motivated priors on the nuisance parameters. We also investigate the validity of these priors by significantly relaxing them and checking the consistency of the resulting posteriors, finding them consistent, albeit only with relatively weak constraints. This cross-correlation measurement will improve significantly with the new ACT-DR6 lensing map and form a key component of the joint 6x2pt analysis between DES and ACT.Comment: 26 pages, 30 figures (including appendices). Data associated with this article is available at https://github.com/itrharrison/actdr4kappa-x-desy3gamma-dat

The impact of trained patient educators on musculoskeletal clinical skills attainment in pre-clerkship medical students

<p>Abstract</p> <p>Background</p> <p>Despite the high burden of musculoskeletal (MSK) diseases, few generalists are comfortable teaching MSK physical examination (PE) skills. Patient Partners^®in Arthritis (PP^®IA) is a standardized patient educator program that could potentially supplement current MSK PE teaching. This study aims to determine if differences exist in MSK PE skills between non-MSK specialist physician and PP^®IA taught students.</p> <p>Methods</p> <p>Pre-clerkship medical students attended 2-hour small group MSK PE teaching by either non-MSK specialist physician tutors or by PP^®IA. All students underwent an MSK OSCE and completed retrospective pre-post questionnaires regarding comfort with MSK PE and interest in MSK.</p> <p>Results</p> <p>83 students completed the OSCE (42 PP^®IA, 41 physician taught) and 82 completed the questionnaire (42 PP^®IA, 40 physician taught). There were no significant differences between groups in OSCE scores. For all questionnaire items, post-session ratings were significantly higher than pre-session ratings for both groups. In exploratory analysis PP^®IA students showed significantly greater improvement in 12 of 22 questions including three of five patient-centred learning questions.</p> <p>Conclusions</p> <p>PP^®IA MSK PE teaching is as good as non-MSK specialist physician tutor teaching when measured by a five station OSCE and provide an excellent complementary resource to address current deficits in MSK PE teaching.</p

Detection of the significant impact of source clustering on higher-order statistics with DES Year 3 weak gravitational lensing data

We demonstrate and measure the impact of source galaxy clustering on higher-order summary statistics of weak gravitational lensing data. By comparing simulated data with galaxies that either trace or do not trace the underlying density field, we show this effect can exceed measurement uncertainties for common higher-order statistics for certain analysis choices. Source clustering effects are larger at small scales and for statistics applied to combinations of low and high redshift samples, and diminish at high redshift. We evaluate the impact on different weak lensing observables, finding that third moments and wavelet phase harmonics are more affected than peak count statistics. Using Dark Energy Survey Year 3 data we construct null tests for the source-clustering-free case, finding a $p$-value of $p=4\times10^{-3}$ (2.6 $\sigma$) using third-order map moments and $p=3\times10^{-11}$ (6.5 $\sigma$) using wavelet phase harmonics. The impact of source clustering on cosmological inference can be either be included in the model or minimized through \textit{ad-hoc} procedures (e.g. scale cuts). We verify that the procedures adopted in existing DES Y3 cosmological analyses (using map moments and peaks) were sufficient to render this effect negligible. Failing to account for source clustering can significantly impact cosmological inference from higher-order gravitational lensing statistics, e.g. higher-order N-point functions, wavelet-moment observables (including phase harmonics and scattering transforms), and deep learning or field level summary statistics of weak lensing maps. We provide recipes both to minimise the impact of source clustering and to incorporate source clustering effects into forward-modelled mock data.Comment: 5 pages, 2 figures, submitted to MNRAS Letter

Beyond the 3rd moment: A practical study of using lensing convergence CDFs for cosmology with DES Y3

Widefield surveys of the sky probe many clustered scalar fields -- such as galaxy counts, lensing potential, gas pressure, etc. -- that are sensitive to different cosmological and astrophysical processes. Our ability to constrain such processes from these fields depends crucially on the statistics chosen to summarize the field. In this work, we explore the cumulative distribution function (CDF) at multiple scales as a summary of the galaxy lensing convergence field. Using a suite of N-body lightcone simulations, we show the CDFs' constraining power is modestly better than that of the 2nd and 3rd moments of the field, as they approximately capture the information from all moments of the field in a concise data vector. We then study the practical aspects of applying the CDFs to observational data, using the first three years of the Dark Energy Survey (DES Y3) data as an example, and compute the impact of different systematics on the CDFs. The contributions from the point spread function are 2-3 orders of magnitude below the cosmological signal, while those from reduced shear approximation contribute $\lesssim 1\%$ to the signal. Source clustering effects and baryon imprints contribute $1-10\%$. Enforcing scale cuts to limit systematics-driven biases in parameter constraints degrades these constraints a noticeable amount, and this degradation is similar for the CDFs and the moments. We also detect correlations between the observed convergence field and the shape noise field at $13\sigma$. We find that the non-Gaussian correlations in the noise field must be modeled accurately to use the CDFs, or other statistics sensitive to all moments, as a rigorous cosmology tool.Comment: 21 pages, 12 figure

Detection of the significant impact of source clustering on higher-order statistics with DES Year 3 weak gravitational lensing data

We measure the impact of source galaxy clustering on higher-order summary statistics of weak gravitational lensing data. By comparing simulated data with galaxies that either trace or do not trace the underlying density field, we show this effect can exceed measurement uncertainties for common higher-order statistics for certain analysis choices. We evaluate the impact on different weak lensing observables, finding that third moments and wavelet phase harmonics are more affected than peak count statistics. Using Dark Energy Survey Year 3 data we construct null tests for the source-clustering-free case, finding a p-value of p = 4 × 10−3 (2.6σ) using third-order map moments and p = 3 × 10−11 (6.5σ) using wavelet phase harmonics. The impact of source clustering on cosmological inference can be either be included in the model or minimized through ad-hoc procedures (e.g. scale cuts). We verify that the procedures adopted in existing DES Y3 cosmological analyses were sufficient to render this effect negligible. Failing to account for source clustering can significantly impact cosmological inference from higher-order gravitational lensing statistics, e.g. higher-order N-point functions, wavelet-moment observables, and deep learning or field level summary statistics of weak lensing maps