Selection on structural allelic variation biases plasticity estimates

Wang and Althoff (2019) explored the capacity of Drosophila melanogaster to exhibit adaptive plasticity in a novel environment. In a full-sib, half-sib design, they scored the activity of the enzyme alcohol dehydrogenase (ADH) and plastic responses, measured as changes in ADH activity across ethanol concentrations in the range of 0-10% (natural variation) and 16% (the novel environment). ADH activity increased with alcohol concentration, and there was a positive association between larval viability and ADH activity in the novel environment. They also reported that families exhibiting greater plasticity had higher larval survival in the novel environment, concluding that ADH plasticity is adaptive. However, the four authors now concur that, since the study estimated plasticity from phenotypic differences across environments using full-sib families, it is not possible to disentangle the contributions of allele frequency changes at the Adh locus from regulatory control at loci known to influence ADH activity. Selective changes in allele frequencies may thus conflate estimates of plasticity; any type of "plasticity" (adaptive, neutral, or maladaptive) could be inferred depending on allele frequencies. The problem of scoring sib-groups after selection should be considered in any plasticity study that cannot use replicated genotypes. Researchers should monitor changes in allele frequencies as one mechanism to deal with this issue.info:eu-repo/semantics/publishedVersio

Small-scale CMB Temperature and Polarization Anisotropies due to Patchy Reionization

We study contributions from inhomogeneous (patchy) reionization to arcminute scale ($1000 < \ell < 10,000$) cosmic microwave background (CMB) anisotropies. We show that inhomogeneities in the ionization fraction, rather than in the mean density, dominate both the temperature and the polarization power spectra. Depending on the ionization history and the clustering bias of the ionizing sources, we find that rms temperature fluctuations range from 2 $\mu$K to 8 $\mu$K and the corresponding values for polarization are over two orders of magnitude smaller. Reionization can significantly bias cosmological parameter estimates and degrade gravitational lensing potential reconstruction from temperature maps but not from polarization maps. We demonstrate that a simple modeling of the reionization temperature power spectrum may be sufficient to remove the parameter bias. The high-$\ell$ temperature power spectrum will contain some limited information about the sources of reionization.Comment: 11 pages, 8 figures. Minor changes to match version accepted by Ap

Production of Pure Drug Nanocrystals and Nano Co-crystals by Confinement Methods

The use of drug nanocrystals in the drug formulation is increasing due to the large number of poorly water-soluble drug compounds synthetized and due to the advantages brought by the nanonization process. The downsizing processes are done using a top-down approach (milling and homogenization currently employed at the industrial level), while the crystallization process is performed by bottom-up techniques (e.g., antisolvent precipitation to the use of supercritical fluids or spray and freeze drying). In addition, the production of nanocrystals in confined environment can be achieved within microfluidics channels. This review analyzes the processes for the preparation of nanocrystals and co-crystals, divided by top-down and bottom-up approaches, together with their combinations. The combination of both strategies merges the favorable features of each process and avoids the disadvantages of single processes. Overall, the applicability of drug nanocrystals is highlighted by the widespread research on the production processes at the engineering, pharmaceutical, and nanotechnology level.Peer reviewe

Quantum entanglement and phase transition in a two-dimensional photon-photon pair model

We propose a two-dimensional model consisting of photons and photon pairs. In the model, the mixed gas of photons and photon pairs is formally equivalent to a two-dimensional system of massive bosons with non-vanishing chemical potential, which implies the existence of two possible condensate phases. Using the variational method, we discuss the quantum phase transition of the mixed gas and obtain the critical coupling line analytically. Moreover, we also find that the phase transition of the photon gas can be interpreted as second harmonic generation. We then discuss the entanglement between photons and photon pairs. Additionally, we also illustrate how the entanglement between photons and photon pairs can be associated with the phase transition of the system.Comment: 14 pages, 5 figure

Probing the peak of the star formation rate density with the extragalactic background light

The extragalactic background light (EBL), i.e., the diffuse meta-galactic photon field in the ultraviolet to infrared, is dominated by the emission from stars in galaxies. It is, therefore, intimately connected with the integrated star formation rate density (SFRD). In this paper, the SFRD is constrained using recent limits on the EBL density derived from observations of distant sources of high and very-high energy gamma-rays. The stellar EBL contribution is modeled utilizing simple stellar population spectra including dust attenuation and emission. For modeling the SFRD up to z=4 a broken power law function in z+1 is assumed. A wide range of values for the different model parameters (SFRD(z), metallicity, dust absorption) is investigated and their impact on the resulting EBL is studied. The calculated EBL densities are compared with the specific EBL density limits and constraints on the SFRD are derived. For the fiducial model, adopting a Chabrier initial mass function (IMF) and a second power law index for the SFRD of beta=0.3, the SFRD is constrained to <~ 0.1 M_solar yr^-1 Mpc^-3 and < 0.2 M_solar yr^-1 Mpc^-3 for a redshift of z~1 and z~2, respectively. The limits for a redshift of z~1 are in tension with SFRD measurements derived from instantaneous star formation tracers. While the tension for the conservative fiducial model in this study is not yet overly strong, the tension increases when applying plausible changes to the model parameters, e.g., using a Salpeter instead of a Chabrier IMF or a adopting a sub-solar metallicity.Comment: 10 pages, 12 figure, accepted for publication in MNRAS, v3: clarifications following referee's comments, conclusions unchange

Discovery of spirooxadiazoline oxindoles with dual-stage antimalarial activity

© 2022 Published by Elsevier Masson SAS.Malaria remains a prevalent infectious disease in developing countries. The first-line therapeutic options are based on combinations of fast-acting artemisinin derivatives and longer-acting synthetic drugs. However, the emergence of resistance to these first-line treatments represents a serious risk, and the discovery of new effective drugs is urgently required. For this reason, new antimalarial chemotypes with new mechanisms of action, and ideally with activity against multiple parasite stages, are needed. We report a new scaffold with dual-stage (blood and liver) antiplasmodial activity. Twenty-six spirooxadiazoline oxindoles were synthesized and screened against the erythrocytic stage of the human malaria parasite P. falciparum. The most active compounds were also tested against the liver-stage of the murine parasite P. berghei. Seven compounds emerged as dual-stage antimalarials, with IC50 values in the low micromolar range. Due to structural similarity with cipargamin, which is thought to inhibit blood-stage P. falciparum growth via inhibition of the Na + efflux pump PfATP4, we tested one of the most active compounds for anti-PfATP4 activity. Our results suggest that this target is not the primary target of spirooxadiazoline oxindoles and further studies are ongoing to identify the main mechanism of action of this scaffold.This work was supported by FCT (Fundação para a Ciência e a Tecnologia, I.P.) through iMed.ULisboa (UID/DTP/04138/2019), project PTDC/QUI-QOR/29664/2017, and PhD fellowship SFRH/BD/137544/2018 (E. Lopes). The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project Nº 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). Financial support from FCT and Portugal 2020 to the Portuguese Mass Spectrometry Network (Rede Nacional de Espectrometria de Massa – RNEM; LISBOA-01-0145-FEDER-402-022125) is also acknowledged.info:eu-repo/semantics/publishedVersio

Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates cell-intrinsic protective antioxidant responses, while the peptide hormone hepcidin maintains systemic iron homoeostasis, but is pathophysiologically decreased in haemochromatosis and β-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives bone morphogenetic protein 6 (Bmp6) expression in liver sinusoidal endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6–hepcidin response to oral and parenteral iron is impaired, and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6–hepcidin axis, improving iron homoeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in β-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to the control of systemic iron homoeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders

Surface Adsorption-Mediated Ultrahigh Efficient Peptide Encapsulation with a Precise Ratiometric Control for Type 1 and 2 Diabetic Therapy

A surface adsorption strategy is developed to enable the engineering of microcomposites featured with ultrahigh loading capacity and precise ratiometric control of co-encapsulated peptides. In this strategy, peptide molecules (insulin, exenatide, and bivalirudin) are formulated into nanoparticles and their surface is decorated with carrier polymers. This polymer layer blocks the phase transfer of peptide nanoparticles from oil to water and, consequently, realizes ultrahigh peptide loading degree (up to 78.9%). After surface decoration, all three nanoparticles are expected to exhibit the properties of adsorbed polymer materials, which enables the co-encapsulation of insulin, exenatide, and bivalirudin with a precise ratiometric control. After solidification of this adsorbed polymer layer, the release of peptides is synchronously prolonged. With the help of encapsulation, insulin achieves 8 days of glycemic control in type 1 diabetic rats with one single injection. The co-delivery of insulin and exenatide (1:1) efficiently controls the glycemic level in type 2 diabetic rats for 8 days. Weekly administration of insulin and exenatide co-encapsulated microcomposite effectively reduces the weight gain and glycosylated hemoglobin level in type 2 diabetic rats. The surface adsorption strategy sets a new paradigm to improve the pharmacokinetic and pharmacological performance of peptides, especially for the combination of peptides.Peer reviewe

Optical vs. infrared studies of dusty galaxies and AGN: (I) Nebular emission lines

Optical nebular emission lines are commonly used to estimate the star formation rate of galaxies and the black hole accretion rate of their central active nucleus. The accuracy of the conversion from line strengths to physical properties depends upon the accuracy to which the lines can be corrected for dust attenuation. For studies of single galaxies with normal amounts of dust, most dust corrections result in the same derived properties within the errors. However, for statistical studies of populations of galaxies, or for studies of galaxies with higher dust contents such as might be found in some classes of "transition" galaxies, significant uncertainty arises from the dust attenuation correction. We compare the strength of the predominantly unobscured mid-IR [NeII]15.5um + [NeIII]12.8um emission lines to the optical H alpha emission lines in four samples of galaxies: (i) ordinary star forming galaxies, (ii) optically selected dusty galaxies, (iii) ULIRGs, (iv) Seyfert 2 galaxies. We show that a single dust attenuation curve applied to all samples can correct H alpha emission for dust attenuation to a factor better than 2. Similarly, we compare mid-IR [OIV] and optical [OIII] luminosities to find that [OIII] can be corrected to a factor better than 3. This shows that the total dust attenuation suffered by the AGN narrow line region is not significantly different to that suffered by the starforming HII regions in the galaxy. We provide explicit dust attenuation corrections, together with errors, for [OII], [OIII] and H alpha. The best-fit average attenuation curve is slightly greyer than the Milky-Way extinction law, indicating either that external galaxies have slightly different typical dust properties to the Milky Way, or that there is a significant contribution from scattering. Finally, we uncover an intriguing correlation between Silicate absorption and Balmer decrement.Comment: 19 pages, 9 figures, accepted for publication in MNRA

Piecing Together the X-ray Background: Bolometric Corrections for Active Galactic Nuclei

(Abridged) The X-ray background can be used to constrain the accretion history of Supermassive Black Holes (SMBHs) in Active Galactic Nuclei (AGN). A knowledge of the hard X-ray bolometric correction, \kappa_{2-10keV} is a vital input into these studies. Variations in the disk emission in the UV have not previously been taken into account in calculating \kappa_{2-10keV}; we show that such variations are important by constructing optical--to--X-ray SEDs for 54 AGN. In particular, we use FUSE UV and X-ray data from the literature to constrain the disk emission as well as possible. Previous work has suggested a dependence of \kappa_{2-10keV} on AGN luminosity, but we find significant spread in \kappa_{2-10keV} with no simple dependence on luminosity. Populations such as Narrow-Line Seyfert 1 nuclei (NLS1s), Radio Loud and X-ray Weak AGN may have values of \kappa_{2-10keV} differing systematically from the rest of the AGN population. Other sources of uncertainty include intrinsic extinction in the optical--UV, X-ray and UV variability and uncertainties in SMBH mass estimates. Our results suggest a more well-defined relationship between \kappa_{2-10keV} and Eddington ratio in AGN, with a transitional region at an Eddington ratio of ~0.1, below which the bolometric correction is typically 15 - 25, and above which it is typically 40 - 70. We consider the potential implied parallels with the low/hard and high/soft states in Galactic Black Hole (GBH) accretion, and present bolometric corrections for the GBH binary GX 339-4 for comparison. Our findings reinforce previous studies proposing a multi-state description of AGN accretion analogous to that for GBH binaries. Future calculations of the SMBH mass density may need to account for the possible dependence of \kappa_{2-10keV} on Eddington ratio.Comment: 19 pages, 16 figures, 3 tables. Accepted for publication in MNRA