CXCR1 is one of two high-affinity receptors for the CXC chemokine interleukin-8 (IL-8), a major mediator of immune and inflammatory responses implicated in many disorders, including tumour growth. ...IL-8, released in response to inflammatory stimuli, binds to the extracellular side of CXCR1. The ligand-activated intracellular signalling pathways result in neutrophil migration to the site of inflammation. CXCR1 is a class A, rhodopsin-like G-protein-coupled receptor (GPCR), the largest class of integral membrane proteins responsible for cellular signal transduction and targeted as drug receptors. Despite its importance, the molecular mechanism of CXCR1 signal transduction is poorly understood owing to the limited structural information available. Recent structural determination of GPCRs has advanced by modifying the receptors with stabilizing mutations, insertion of the protein T4 lysozyme and truncations of their amino acid sequences, as well as addition of stabilizing antibodies and small molecules that facilitate crystallization in cubic phase monoolein mixtures. The intracellular loops of GPCRs are crucial for G-protein interactions, and activation of CXCR1 involves both amino-terminal residues and extracellular loops. Our previous nuclear magnetic resonance studies indicate that IL-8 binding to the N-terminal residues is mediated by the membrane, underscoring the importance of the phospholipid bilayer for physiological activity. Here we report the three-dimensional structure of human CXCR1 determined by NMR spectroscopy. The receptor is in liquid crystalline phospholipid bilayers, without modification of its amino acid sequence and under physiological conditions. Features important for intracellular G-protein activation and signal transduction are revealed. The structure of human CXCR1 in a lipid bilayer should help to facilitate the discovery of new compounds that interact with GPCRs and combat diseases such as breast cancer.
In the last decades, due to climate changes, soil deterioration, and Land Use/Land Cover Changes (LULCCs), land degradation risk has become one of the most important ecological issues at the global ...level. Land degradation involves two interlocking systems: the natural ecosystem and the socio-economic system. The complexity of land degradation processes should be addressed using a multidisciplinary approach. Therefore, the aim of this work is to assess diachronically land degradation dynamics under changing land covers. This paper analyzes LULCCs and the parallel increase in the level of land sensitivity to degradation along the coastal belt of Sardinia (Italy), a typical Mediterranean region where human pressure affects the landscape characteristics through fires, intensive agricultural practices, land abandonment, urban sprawl, and tourism concentration. Results reveal that two factors mainly affect the level of land sensitivity to degradation in the study area: (i) land abandonment and (ii) unsustainable use of rural and peri-urban areas. Taken together, these factors represent the primary cause of the LULCCs observed in coastal Sardinia. By linking the structural features of the Mediterranean landscape with its functional land degradation dynamics over time, these results contribute to orienting policies for sustainable land management in Mediterranean coastal areas.
The effects of circadian misalignment and work shift on oxidative stress profile of shift workers have not been explored in the literature. The present study aimed to evaluate the role of shift work ...(day and night) and social jetlag - a measure of circadian misalignment - with oxidative stress markers. A cross-sectional study was performed with 79 men (21-65 years old, 27.56 ± 4.0 kg/m
) who worked the night shift (n = 37) or daytime (n = 42). The analyzed variables included anthropometric measures and determination of systemic levels of markers of oxidative damage and antioxidant defense. Social jetlag was calculated by the absolute difference between the mean sleep point on working and rest days. The night group presented higher systemic values of thiobarbituric acid reactive substances and hydrogen peroxide, and lower levels of nitrite, total antioxidant capacity, and catalase and superoxide dismutase activities in relation to the day group. However, social jetlag was not associated with oxidative stress-related biomarkers analyzed in the night group. These results suggest that the night worker has higher levels of oxidative stress damage and lower levels of antioxidant defenses, while social jetlag was not a possible responsible factor for this condition.
SARS-CoV-2 is the novel coronavirus that is the causative agent of COVID-19, a sometimes-lethal respiratory infection responsible for a world-wide pandemic. The envelope (E) protein, one of four ...structural proteins encoded in the viral genome, is a 75-residue integral membrane protein whose transmembrane domain exhibits ion channel activity and whose cytoplasmic domain participates in protein-protein interactions. These activities contribute to several aspects of the viral replication-cycle, including virion assembly, budding, release, and pathogenesis. Here, we describe the structure and dynamics of full-length SARS-CoV-2 E protein in hexadecylphosphocholine micelles by NMR spectroscopy. We also characterized its interactions with four putative ion channel inhibitors. The chemical shift index and dipolar wave plots establish that E protein consists of a long transmembrane helix (residues 8-43) and a short cytoplasmic helix (residues 53-60) connected by a complex linker that exhibits some internal mobility. The conformations of the N-terminal transmembrane domain and the C-terminal cytoplasmic domain are unaffected by truncation from the intact protein. The chemical shift perturbations of E protein spectra induced by the addition of the inhibitors demonstrate that the N-terminal region (residues 6-18) is the principal binding site. The binding affinity of the inhibitors to E protein in micelles correlates with their antiviral potency in Vero E6 cells: HMA ≈ EIPA > DMA >> Amiloride, suggesting that bulky hydrophobic groups in the 5' position of the amiloride pyrazine ring play essential roles in binding to E protein and in antiviral activity. An N15A mutation increased the production of virus-like particles, induced significant chemical shift changes from residues in the inhibitor binding site, and abolished HMA binding, suggesting that Asn15 plays a key role in maintaining the protein conformation near the binding site. These studies provide the foundation for complete structure determination of E protein and for structure-based drug discovery targeting this protein.
ABSTRACT
The observation of very-high-energy γ-rays (VHE γ-rays, $E \gt 100\,$ GeV) has ledto the identification of extremely energetic processes and particle-acceleration sites both within our ...Galaxy and beyond. It is expected that VHE facilities, such as the Cherenkov Telescope Array, will explore these sources with an unprecedented level of detail. However, the transient and unpredictable nature of many important processes means that their observation requires the development of proper monitoring strategies. In this study, we estimate the properties of VHE transients that can be effectively detected by monitoring facilities. We use data collected by the Fermi-LAT instrument during its monitoring campaign to select events that are probably associated with VHE emission. We use this sample to estimate the frequency, the luminosity and the time-scales of various transients, focusing on blazar flares and gamma-ray bursts. We discuss how the balance between the field of view, sensitivity and duty cycle of an observatory affects the likelihood of detecting transients that occur at the inferred rates, and we conclude by describing the contribution that current and near-future monitoring facilities can make to the identification and study of VHE transient emission.
ABSTRACT
Gamma-ray Bursts (GRB) were discovered by satellite-based detectors as powerful sources of transient γ-ray emission. The Fermi satellite detected an increasing number of these events with ...its dedicated Gamma-ray Burst Monitor (GBM), some of which were associated with high energy photons ($E \gt 10$ GeV), by the Large Area Telescope (LAT). More recently, follow-up observations by Cherenkov telescopes detected very high energy emission ($E \gt 100$ GeV) from GRBs, opening up a new observational window with implications on the interpretation of their central engines and on the propagation of very energetic photons across the Universe. Here, we use the data published in the 2nd Fermi-LAT Gamma Ray Burst Catalogue to characterize the duration, luminosity, redshift, and light curve of the high energy GRB emission. We extrapolate these properties to the very high energy domain, comparing the results with available observations and with the potential of future instruments. We use observed and simulated GRB populations to estimate the chances of detection with wide-field ground-based γ-ray instruments. Our analysis aims to evaluate the opportunities of the Southern Wide-field-of-view Gamma-ray Observatory (SWGO), to be installed in the Southern Hemisphere, to complement CTA. We show that a low-energy observing threshold ($E_{low} \lt 200$ GeV), with good point source sensitivity ($F_{lim} \approx 10^{-11} \,\mathrm{erg\, cm^{-2}\, s^{-1}}$ in $1$ yr), are optimal requirements to work as a GRB trigger facility and to probe the burst spectral properties down to time-scales as short as $10$ s, accessing a time domain that will not be available to Imaging Atmospheric Cherenkov Telescopes instruments.
The Mercedes water Cherenkov detector Assis, P.; Bakalová, A.; Barres de Almeida, U. ...
European physical journal. C, Particles and fields,
10/2022, Letnik:
82, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The concept of a small, single-layer water Cherenkov detector, with three photomultiplier tubes (PMTs), placed at its bottom in a
120
∘
star configuration (
Mercedes
Water Cherenkov Detector) is ...presented. The PMTs are placed near the lateral walls of the stations with an adjustable inclination and may be installed inside or outside the water volume. To illustrate the technical viability of this concept and obtain a first-order estimation of its cost, an engineering design was elaborated. The sensitivity of these stations to low energy Extensive Air Shower (EAS) electrons, photons and muons is discussed, both in compact and sparse array configurations. It is shown that the analysis of the intensity and time patterns of the PMT signals, using machine learning techniques, enables the tagging of muons, achieving an excellent gamma/hadron discrimination for TeV showers. This concept minimises the station production and maintenance costs, allowing for a highly flexible and fast installation. Mercedes Water Cherenkov Detectors (WCDs) are thus well-suited for use in high-altitude large gamma-ray observatories covering an extended energy range from the low energies, closing the gap between satellite and ground-based measurements, to very high energy regions, beyond the PeV scale.
In neural systems, information is often carried by ensembles of cells rather than by individual units. Optical indicators provide a powerful means to reveal such distributed activity, particularly ...when protein-based and encodable in DNA: encodable probes can be introduced into cells, tissues, or transgenic organisms by genetic manipulation, selectively expressed in anatomically or functionally defined groups of cells, and, ideally, recorded in situ, without a requirement for exogenous cofactors. Here we describe sensors for secretion and neurotransmission that fulfil these criteria. We have developed pH-sensitive mutants of green fluorescent protein ('pHluorins') by structure-directed combinatorial mutagenesis, with the aim of exploiting the acidic pH inside secretory vesicles, to monitor vesicle exocytosis and recycling. When linked to a vesicle membrane protein, pHluorins were sorted to secretory and synaptic vesicles and reported transmission at individual synaptic boutons, as well as secretion and fusion pore 'flicker' of single secretory granules.
ABSTRACT
We consider the largest observed sample including all intermediate-frequency peaked (IBL) and high-frequency peaked (HBL) flaring blazars above 100 GeV up to redshift z = 0.6. We show that ...the best-fitting regression line of the emitted spectral indices Γem(z) is a concave parabola decreasing as z increases, thereby implying a statistical correlation between the {Γem(z)} distribution and z. This result contradicts our expectation that such a distribution should be zindependent. We argue that the above correlation does not arise from any selection bias. We show that our expectation naturally emerges provided that axion-like particles (ALPs) are put into the game. Moreover, ALPs can also explain why flat spectrum radio quasars emit up to 400 GeV, in sharp contradiction with conventional physics (CP). So, the combination of the two very different but consistent results – taken at face value – leads to a hint at an ALP with mass $m = {\cal O} (10^{-10} \, {\rm eV})$ and two-photon coupling in the range $2.94 \times 10^{- 12} \, {\rm GeV}^{- 1} \lt g_{a \gamma \gamma } \lt 0.66 \times 10^{- 10} \, {\rm GeV}^{- 1}$. As a bonus, the Universe would become considerably more transparent above energies $E \gtrsim 1 \, {\rm TeV}$ than dictated by CP. Our prediction can be checked not only by the new generation of observatories like CTA, HAWC, GAMMA-400, LHAASO, TAIGA-HiSCORE, and HERD, but also thanks to the planned laboratory experiments ALPS II (upgraded), STAX, IAXO and with other techniques now being developed by Avignone and collaborators.
Dedication: We wish to dedicate the present work to the memory of our dear friend Nanni Bignami.
Transparency of the Universe to gamma-rays De Angelis, A.; Galanti, G.; Roncadelli, M.
Monthly Notices of the Royal Astronomical Society,
07/2013, Letnik:
432, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Using the most recent observational data concerning the extragalactic background light and the radio background for a source at an arbitrary redshift in the range z
s ≤ 3, we compute the energy E
0 ...of an observed γ-ray photon in the range 10 ≤ E
0 ≤ 1013 GeV such that the resulting optical depth τγ(E
0, z
s) takes the values 1, 2, 3 and 4.6 corresponding to an observed flux dimming of e
−1 0.37, e
−2 0.14, e
−3 0.05 and e
−4.6 0.01, respectively. Below a distance D 8 kpc, we find that τγ(E
0, DH
0/c) < 1 for any value of E
0. In the limiting case of a local Universe (z
s 0), we compare our result with the one derived in 1997 by Coppi and Aharonian. The present achievement is of paramount relevance for the planned ground-based detectors like Cherenkov Telescope Array, High Altitude Water Cherenkov Experiment and Hundred Square-km Cosmic ORigin Explorer.
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