The β3 adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent β3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β3 adrenergic activity is given.

The existence of mutually correlated thin and rotating planes of satellite galaxies around both the Milky Way (MW) and Andromeda (M31) calls for an explanation. Previous work in Milgromian dynamics (MOND) indicated that a past MW–M31 encounter might have led to the formation of these satellite planes. We perform the first-ever hydrodynamical MOND simulation of the Local Group using phantom of ramses. We show that an MW–M31 encounter at z ≈ 1, with a perigalactic distance of about 80 kpc, can yield two disc galaxies at z = 0 oriented similarly to the observed galactic discs and separated similarly to the observed M31 distance. Importantly, the tidal debris are distributed in phase space similarly to the observed MW and M31 satellite planes, with the correct preferred orbital pole for both. The MW–M31 orbital geometry is consistent with the presently observed M31 proper motion despite this not being considered as a constraint when exploring the parameter space. The mass of the tidal debris around the MW and M31 at z = 0 compare well with the mass observed in their satellite systems. The remnant discs of the two galaxies have realistic radial scale lengths and velocity dispersions, and the simulation naturally produces a much hotter stellar disc in M31 than in the MW. However, reconciling this scenario with the ages of stellar populations in satellite galaxies would require that a higher fraction of stars previously formed in the outskirts of the progenitors ended up within the tidal debris, or that the MW–M31 interaction occurred at z > 1.

An improved high-resolution and deep $A_{K_{s}}$ foreground dust extinction map is presented for the Galactic disc area within 295° ≲ l ≲ 350°, −1.0° ≲ b ≲ +1.0°. At some longitudes the map reaches up to |b| ∼ 2.25°, for a total of ∼148 deg2. The map was constructed via the Rayleigh–Jeans colour excess (RJCE) technique based on deep near-infrared (NIR) and mid-infrared (MIR) photometry. The new extinction map features a maximum bin size of 1 arcmin, and relies on NIR observations from the Two Micron All-Sky Survey (2MASS) and new data from ESO’s Vista Variables in the Vía Láctea (VVV) survey, in concert with MIR observations from the Galactic Legacy Infrared Mid-Plane Survey Extraordinaire. The VVV photometry penetrates ∼4 mag fainter than 2MASS, and provides enhanced sampling of the underlying stellar populations in this heavily obscured region. Consequently, the new results supersede existing RJCE maps tied solely to brighter photometry, revealing a systematic underestimation of extinction in prior work that was based on shallower data. The new high-resolution and large-scale extinction map presented here is readily available to the community through a web query interface.

Hot subdwarf B (sdB) stars are evolved, subluminous, helium-burning stars that most likely form when red giant stars loose their hydrogen envelope via interactions with close companions. They play an important role in our understanding of binary evolution, stellar atmospheres, and interiors. Only a small fraction of the sdB population is known to exhibit pulsations. Pulsating sdBs have typically been discovered serendipitously in various photometric surveys because specific selection criteria for the sample are lacking. Consequently, while individual properties of these stars are well known, a comprehensive understanding of the entire population remains elusive, and many related questions remain unanswered. The Gaia mission has presented an exceptional chance to create an unbiased sample by employing precise criteria and ensuring a high degree of completeness. The progression of high-precision and high-duty cycle photometric monitoring facilitated by space missions such as Kepler/K2 and the Transiting Exoplanet Survey Satellite (TESS) has yielded an unparalleled wealth of data for pulsating sdBs. We created a dataset of confirmed pulsating sdB stars by combining information from various ground- and space-based photometric surveys. With this dataset, we present a thorough approach to search for pulsating sdB stars based on the current Gaia DR3 sample. Based on TESS photometry, we discovered 61 new pulsating sdB stars and 20 variable sdBs whose source of variability remains to be determined through future spectroscopic follow-up observations.

In mammals, temperature-sensitive TRP channels make membrane conductance of cells extremely temperature dependent, allowing the detection of temperature ranging from noxious cold to noxious heat. We progressively deleted the distal carboxyl terminus domain (CTD) of the cold-activated melastatin receptor channel, TRPM8. We found that the enthalpy change associated with channel gating is proportional to the length of the CTD. Deletion of the last 36 amino acids of the CTD transforms TRPM8 into a reduced temperature-sensitivity channel (Q10 ∼4). Exposing the intracellular domain to a denaturing agent increases the energy required to open the channel indicating that cold drives channel gating by stabilizing the folded state of the CTD. Experiments in the presence of an osmoticant agent suggest that channel gating involves a change in solute-inaccessible volume in the CTD of ∼1,900 Å3. This volume matches the void space inside the coiled coil according to the cryogenic electron microscopy structure of TRPM8. The results indicate that a folding–unfolding reaction of a specialized temperature-sensitive structure is coupled to TRPM8 gating.

We introduce a framization of the Hecke algebra of type B . For this framization, we construct a faithful tensorial representation and two linear bases. We also construct a Markov trace on such an algebra, and from this trace we derive isotopy invariants for framed and classical knots and links in the solid torus.

The merger of two or more galaxies can enhance the inflow of material from galactic scales into the close environments of active galactic nuclei (AGNs), obscuring and feeding the supermassive black hole (SMBH). Both recent simulations and observations of AGN in mergers have confirmed that mergers are related to strong nuclear obscuration. However, it is still unclear how AGN obscuration evolves in the last phases of the merger process. We study a sample of 60 luminous and ultra-luminous IR galaxies (U/LIRGs) from the GOALS sample observed by NuSTAR. We find that the fraction of AGNs that are Compton thick (CT; NH ≥ 1024 cm−2) peaks at 74+14−19 per cent at a late merger stage, prior to coalescence, when the nuclei have projected separations (dsep) of 0.4–6 kpc. A similar peak is also observed in the median NH [(1.6 ± 0.5) × 1024 cm−2]. The vast majority (85+7−9 per cent) of the AGNs in the final merger stages (dsep 10 kpc) are heavily obscured (NH ≥ 1023 cm−2), and the median NH of the accreting SMBHs in our sample is systematically higher than that of local hard X-ray-selected AGN, regardless of the merger stage. This implies that these objects have very obscured nuclear environments, with the NH ≥ 1023 cm−2 gas almost completely covering the AGN in late mergers. CT AGNs tend to have systematically higher absorption-corrected X-ray luminosities than less obscured sources. This could either be due to an evolutionary effect, with more obscured sources accreting more rapidly because they have more gas available in their surroundings, or to a selection bias. The latter scenario would imply that we are still missing a large fraction of heavily obscured, lower luminosity (L2−10 1043 erg s−1) AGNs in U/LIRGs.

Motivated by two seminal models proposed to explain the Universe acceleration, this paper is devoted to study a hybrid model which is constructed through a generalized Chaplygin gas with the addition of a bulk viscosity. We call the model a viscous generalized Chaplygin gas (VGCG) and its free parameters are constrained through several cosmological data like the Observational Hubble Parameter, Type Ia Supernovae, Baryon Acoustic Oscillations, Strong Lensing Systems, HII Galaxies and using Joint Bayesian analysis. In addition, we implement a Om-diagnostic to analyze the VGCC dynamics and its difference with the standard cosmological model. The hybrid model shows important differences when compared with the standard cosmological model. Finally, based on our Joint analysis we find that the VGCG could be an interesting candidate to alleviate the well-known Hubble constant tension.

We enlarge the classes of inflaton and quintessence fields by generalizing the pseudo-Nambu–Goldstone boson potential by means of elliptic Jacobian functions, which are characterized by a parameter [Formula: see text]. We use such a generalization to implement an inflationary era and a late acceleration of the universe. As an inflationary model, the Jacobian generalization leads us to a number of e-foldings and a primordial spectrum of perturbations compatible with the Planck Collaboration 2015. As a quintessence model, a study of the evolution of its equation-of-state (EoS) and its [Formula: see text]–[Formula: see text] plane helps us to classify it as a thawing model. This allows us to consider analytical approximations for the EoS recently discovered for thawing quintessence. By using JLA supernovae Ia and Hubble parameter [Formula: see text] data sets, we perform an observational analysis of the viability of the model as quintessence.

The heat and capsaicin receptor TRPV1 channel is widely expressed in nerve terminals of dorsal root ganglia (DRGs) and trigeminal ganglia innervating the body and face, respectively, as well as in other tissues and organs including central nervous system. The TRPV1 channel is a versatile receptor that detects harmful heat, pain, and various internal and external ligands. Hence, it operates as a polymodal sensory channel. Many pathological conditions including neuroinflammation, cancer, psychiatric disorders, and pathological pain, are linked to the abnormal functioning of the TRPV1 in peripheral tissues. Intense biomedical research is underway to discover compounds that can modulate the channel and provide pain relief. The molecular mechanisms underlying temperature sensing remain largely unknown, although they are closely linked to pain transduction. Prolonged exposure to capsaicin generates analgesia, hence numerous capsaicin analogs have been developed to discover efficient analgesics for pain relief. The emergence of in silico tools offered significant techniques for molecular modeling and machine learning algorithms to indentify druggable sites in the channel and for repositioning of current drugs aimed at TRPV1. Here we recapitulate the physiological and pathophysiological functions of the TRPV1 channel, including structural models obtained through cryo-EM, pharmacological compounds tested on TRPV1, and the in silico tools for drug discovery and repositioning.

We present Atacama Large Millimeter/Submillimeter Array (ALMA) continuum observations of a sample of nine star-forming galaxies at redshifts 1.47 and 2.23 selected from the High-z Emission Line Survey (HiZELS). Four galaxies in our sample are detected at high significance by ALMA at a resolution of 0${_{.}^{\prime\prime}}$25 at rest-frame 355 μm. Together with the previously observed H α emission, from adaptive optics-assisted integral-field-unit spectroscopy (∼0${_{.}^{\prime\prime}}$15 resolution), and F606W and F140W imaging from the Hubble Space Telescope (∼0${_{.}^{\prime\prime}}$2 resolution), we study the star formation activity, stellar and dust mass in these high-redshift galaxies at ∼kpc-scale resolution. We find that ALMA detection rates are higher for more massive galaxies (M* > 1010.5 M⊙) and higher [N ii]/H α ratios (>0.25, a proxy for gas-phase metallicity). The dust extends out to a radius of 8 kpc, with a smooth structure, even for those galaxies presenting clumpy H α morphologies. The half-light radii (Rdust) derived for the detected galaxies are of the order ∼4.5 kpc, more than twice the size of submillimetre-selected galaxies at a similar redshift. Our global star formation rate estimates – from far-infrared and extinction-corrected H α luminosities – are in good agreement. However, the different morphologies of the different phases of the interstellar medium suggest complex extinction properties of the high-redshift normal galaxies.

Obscuration and confusion conspire to limit our knowledge of the inner Milky Way. Even at moderate distances, the identification of stellar systems becomes compounded by the extremely high density of background sources. Here, we provide a very revealing example of these complications by unveiling a large, massive, young cluster in the Sagittarius arm that has escaped detection until now despite containing more than 30 stars brighter than G = 13. By combining Gaia DR2 astrometry, Gaia and 2MASS photometry, and optical spectroscopy, we find that the new cluster, which we name Valparaiso 1, located at ∼ 2.3 kpc, is about 75 Ma old and includes a large complement of evolved stars, among which we highlight the 4 d classical Cepheid CM Sct and an M-type giant that probably represents the first detection of an asymptotic giant branch star in a Galactic young open cluster. Although strong differential reddening renders accurate parameter determination unfeasible with the current data set, direct comparison to clusters of similar age suggests that Valparaiso 1 was born as one of the most massive clusters in the solar neighbourhood, with an initial mass close to 104 M.

Context. Currently, one of the standard procedures used to determine stellar and wind parameters of massive stars involves to comparing the observed spectral lines with a grid of synthetic lines. These synthetic lines are calculated using non-local thermodynamic equilibrium radiative transfer codes. In this standard procedure, after estimating the stellar-projected rotational speed (v sin i), all synthetic models need to be convolved using this value in order to perform the comparison with the observed line and estimate the stellar parameters. Aims. In this work, we propose a methodology to deconvolve the observed line profile to one from a non-rotating star. Thus, to perform a comparison, we will not need to convolve all the synthetic profiles, saving significant time and resources. Methods. The proposed deconvolution method is based on transforming this inverse problem into an optimization of a direct problem. We propose using a Gaussian sum approximation (GSA) to obtain the line profile without the broadening effect due to stellar rotation. After selecting the most adequate model to derive the fundamental GSA parameters, we convolved it with the known v sin i in order to obtain the profile considering the v sin i. Finally, we compared this approximated line profile directly with the observed spectrum. Results. The performance of the proposed method is analyzed using synthetic and observed lines. The results show that the proposed deconvolution method yields accurate non-rotating profiles. Conclusions. The proposed approach utilizing GSA is an accurate method to deconvolve spectral lines.

Aims. The study of accurate methods to estimate the distribution of stellar rotational velocities is important for understanding many aspects of stellar evolution. From such observations we obtain the projected rotational speed (v sin i) in order to recover the true distribution of the rotational velocity. To that end, we need to solve a difficult inverse problem that can be posed as a Fredholm integral of the first kind. Methods. In this work we have used a novel approach based on maximum likelihood (ML) estimation to obtain an approximation of the true rotational velocity probability density function (PDF) expressed as a sum of known distribution families. In our proposal, the measurements have been treated as random variables drawn from the projected rotational velocity PDF. We analyzed the case of Maxwellian sum approximation, where we estimated the parameters that define the sum of distributions. Results. The performance of the proposed method is analyzed using Monte Carlo simulations considering two theoretical cases for the PDF of the true rotational stellar velocities: (i) an unimodal Maxwellian probability density distribution and (ii) a bimodal Maxwellian probability density distribution. The results show that the proposed method yielded more accurate estimates in comparison with the Tikhonov regularization method, especially for small sample length (N = 50). Our proposal was evaluated using real data from three sets of measurements, and our findings were validated using three statistical tests. Conclusions. The ML approach with Maxwellian sum approximation is a accurate method to deconvolve the rotational velocity PDF, even when the sample length is small (N = 50).

The relevance of autophagy in neuronal health has been extensively reported in a plethora of conditions affecting the nervous system , such as neurodegenerative diseases , cancer, diabetes, and tissue injury , where altered autophagic activity may contribute to the pathological process . Autophagy is a dynamic pathway involving the formation of a membrane surrounding and enclosing cargoes that are delivered to lysosomal compartments for degradation. Cargoes can include large protein aggregates, organelles , or even pathogens . Traditionally, autophagy assessment relies on the measurement of LC3-II protein levels or the visualization of LC3-positive puncta. However, these approaches represent a static measurement of autophagy markers, making difficult the dissection of the actual changes in the autophagy process (activation, inhibition, or no effects), due to the dynamic regulation of LC3 viral levels. To circumvent this limitation, we previously developed an adeno-associated vector (AAV) to deliver a molecular autophagy sensor to the neuronal compartment in vivo. Here, we describe the detailed design and methods to use an engineered AAV harboring the monomeric tandem mCherry-GFP-LC3 to determine autophagic fluxes in the nervous system . Key methodological details to succeed in the use of this reporter are provided.

Neuromodulation can profoundly impact the gain and polarity of postsynaptic changes in Hebbian synaptic plasticity. An emerging pattern observed in multiple central synapses is a pull–push type of control in which activation of receptors coupled to the G-protein Gs promote long-term potentiation (LTP) at the expense of long-term depression (LTD), whereas receptors coupled to Gq promote LTD at the expense of LTP. Notably, coactivation of both Gs- and Gq-coupled receptors enhances the gain of both LTP and LTD. To account for these observations, we propose a simple kinetic model in which AMPA receptors (AMPARs) are trafficked between multiple subcompartments in and around the postsynaptic spine. In the model AMPARs in the postsynaptic density compartment (PSD) are the primary contributors to synaptic conductance. During LTP induction, AMPARs are trafficked to the PSD primarily from a relatively small perisynaptic (peri-PSD) compartment. Gs-coupled receptors promote LTP by replenishing peri-PSD through increased AMPAR exocytosis from a pool of endocytic AMPAR. During LTD induction AMPARs are trafficked in the reverse direction, from the PSD to the peri-PSD compartment, and Gq-coupled receptors promote LTD by clearing the peri-PSD compartment through increased AMPAR endocytosis. We claim that the model not only captures essential features of the pull–push neuromodulation of synaptic plasticity, but it is also consistent with other actions of neuromodulators observed in slice experiments and is compatible with the current understanding of AMPAR trafficking.

A continuous multi-time stochastic model is proposed for a multi-component system, that suffers damage in its components through shocks, occurring at random instants and where the magnitude of the damage produced, by each shock, is random. Central limit theorems are stated for two sequences of martingales, which allow knowing the asymptotic distribution of the cumulative damage of the system at eventually different times depending on its components. Moreover, we introduce large deviation principles for related processes. Thresholds for the components are stated, and the multivariate stopping time limits, where each component's damage attains the corresponding threshold, are studied. The main interest of the paper is focused on introducing some useful tools for statistical inference on the parameters of the system. Cumulative damage is present in many areas of study such as earthquakes, reliability, and finance, among others, and, in this work, some of the asymptotic results obtained are applied to the analysis of infectious diseases. In particular, a hypothesis test for the infection homogeneity of the pandemic COVID 19 in Chile is carried out. This test is applied to real data and some simulations are conducted.

Reprocessed X-ray emission in active galactic nuclei can provide fundamental information about the circumnuclear environments of supermassive black holes. Recent mid-infrared studies have shown evidence of an extended dusty structure perpendicular to the torus plane. In this work, we build a self-consistent X-ray model for the Circinus Galaxy including the different physical components observed at different wavelengths and needed to reproduce both the morphological and spectral properties of this object in the mid-infrared. The model consists of four components: the accretion disc, the broad-line region (BLR), a flared disc in the equatorial plane, and a hollow cone in the polar direction. Our final model reproduces well the 3–70 keV Chandra and NuSTAR spectra of Circinus, including the complex Fe Kα zone and the spectral curvature, although several additional Gaussian lines, associated with either ionized iron or broadened Fe Kα/Kβ lines, are needed. We find that the flared disc is Compton-thick ($N_{\rm H,d}= \rm 1.01^{+0.03}_{-0.24}\times 10^{25}\, cm^{-2}$) and geometrically thick ($\mathrm{ CF}=0.55^{+0.01}_{-0.05}$), and that the hollow cone has a Compton-thin column density ($N_{\rm H,c}= \rm 2.18^{+0.47}_{-0.43}\times 10^{23}\, cm^{-2}$), which is consistent with the values inferred by mid-infrared studies. Including also the BLR, the effective line-of-sight column density is $N_{\rm H}= \rm 1.47^{+0.03}_{-0.24}\times 10^{25}\, cm^{-2}$. This approach to X-ray modelling, i.e. including all the different reprocessing structures, will be very important to fully exploit data from future X-ray missions.

A rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics and reducing the therapeutic arsenal available for treatment of infectious diseases. In the present study, we developed a new class of compounds with antibacterial activity obtained by a simple, two step synthesis and screened the products for in vitro antibacterial activity against ATCC® strains using the broth microdilution method. The compounds exhibited minimum inhibitory concentrations (MIC) of 1–32 μg/mL against Gram-positive ATCC® strains. The structure–activity relationship indicated that the thiophenol ring is essential for antibacterial activity and the substituents on the thiophenol ring module, for antibacterial activity. The most promising compounds detected by screening were tested against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. We found remarkable activity against VREF for compounds 7 and 16, were the MIC50/90 were 2/4 µg/mL and 4/4 µg/mL, respectively, while for vancomycin the MIC50/90 was 256/512 µg/mL. Neither compound affected cell viability in any of the mammalian cell lines at any of the concentrations tested. These in vitro data show that compounds 7 and 16 have an interesting potential to be developed as new antibacterial drugs against infections caused by VREF.

Hyponeoidae is a copepod family that is rare around the world, with only three species described until now. Recently, a hyponeoid copepod was found in the narrowmouthed catshark, Schroederichthys bivius , from Chile, which has not been formally described. The objective of this study is to describe morphologically a new species of Hyponeoidae, from samples of the Strait of Magellan, Southern Chile. Also, a genetic analysis, based on the COI gene, was used to determine the relatedness of the new hyponeoid species to other copepods from Siphonostomatoida, which were available in the GenBank platform. The new species belongs to the genus Tautochondria and is here described as T. magellanica n. sp. This species differs from T. dolichoura mainly in the presence of long process at each side of the buccal cone, the absence of lobes on the head and short processes on the genital complex. According to the genetic sequences, T. magellanica n. sp. was not closely related to any other species. Therefore, this result confirms that Hyponeoidae is a separate family. However, the relatedness to other genera in Siphonostomatoida is still unknown.