Context.Thanks to remarkable progress, radial velocity surveys are now able to detect terrestrial planets at habitable distance from low-mass stars. Recently, two planets with minimum masses below 10 ...$M_{\oplus}$ have been reported in a triple system around the M-type star Gliese 581. These planets are found at orbital distances comparable to the location of the boundaries of the habitable zone of their star. Aims.In this study, we assess the habitability of planets Gl 581c and Gl 581d (assuming that their actual masses are close to their minimum masses) by estimating the locations of the habitable-zone boundaries of the star and discussing the uncertainties affecting their determination. An additional purpose of this paper is to provide simplified formulae for estimating the edges of the habitable zone. These may be used to evaluate the astrobiological potential of terrestrial exoplanets that will hopefully be discovered in the near future. Methods.Using results from radiative-convective atmospheric models and constraints from the evolution of Venus and Mars, we derive theoretical and empirical habitable distances for stars of F, G, K, and M spectral types. Results.Planets Gl 581c and Gl 581d are near to, but outside, what can be considered as the conservative habitable zone. Planet “c” receives 30% more energy from its star than Venus from the Sun, with an increased radiative forcing caused by the spectral energy distribution of Gl 581. This planet is thus unlikely to host liquid water, although its habitability cannot be positively ruled out by theoretical models due to uncertainties affecting cloud properties and cloud cover. Highly reflective clouds covering at least 75% of the day side of the planet could indeed prevent the water reservoir from being entirely vaporized. Irradiation conditions of planet “d” are comparable to those of early Mars, which is known to have hosted surface liquid water. Thanks to the greenhouse effect of CO2-ice clouds, also invoked to explain the early Martian climate, planet “d” might be a better candidate for the first exoplanet known to be potentially habitable. A mixture of several greenhouse gases could also maintain habitable conditions on this planet, although the geochemical processes that could stabilize such a super-greenhouse atmosphere are still unknown.
In this paper, we explicitly point out the reasons why Special Relativity must be considered as the source of electron deep orbits, and dominates their behavior. We show that the cause is the ...quadratic form of the relativistic expression of energy, and this clearly appears when we explicitly develop the relativistic Schrödinger equation and compare it with the non-relativistic one.
Conducted in the northeast Atlantic Ocean (15°20′–21°20′W, 38°N–45°N), the Programme Océan Multidisciplinaire Méso Echelle (POMME) is a research project aimed at a better understanding of the ...biological production and the carbon budget of the region in relation to the formation mechanisms of the 11°–12°C mode water of the northeast Atlantic. With the help of two research vessels, several tens of floats and drifters, and nine moorings, the field experiment was carried out between autumn 2000 and autumn 2001, with a more intensive phase in the winter and early spring of 2001. The field experiment resolved small (several kilometers) to regional (several hundred kilometers) scales and daily to seasonal variability. A first analysis of the rich data set focused on the large‐scale and the mesoscale variability. It shows that the distribution of water mass characteristics and biological activity is strongly influenced by the mesoscales in this supposedly quiet transition zone between the subtropical and subpolar gyres. The seasonal variability, however, presents an imprint of the large‐scale structures with a clear north‐south gradient in properties and budgets. This region is found on an annual average to be a sink of atmospheric CO2. Smaller scales, associated with fronts and filaments, were clearly observed in many fields (temperature, but also chlorophyll, oxygen, biogenic particles, etc.), with modeling studies suggesting that they play a significant role in subduction, ventilation, and transport of biogeochemical tracers in the POMME region.
Chemotherapy still constitutes the standard of care for the treatment of most neoplastic diseases. Certain chemotherapeutics from the oncological armamentarium are able to trigger pre‐mortem stress ...signals that lead to immunogenic cell death (ICD), thus inducing an antitumor immune response and mediating long‐term tumor growth reduction. Here, we used an established model, built on artificial intelligence to identify, among a library of 50,000 compounds, anticancer agents that, based on their molecular descriptors, were predicted to induce ICD. This algorithm led us to the identification of dactinomycin (DACT, best known as actinomycin D), a highly potent cytotoxicant and ICD inducer that mediates immune‐dependent anticancer effects in vivo. Since DACT is commonly used as an inhibitor of DNA to RNA transcription, we investigated whether other experimentally established or algorithm‐selected, clinically employed ICD inducers would share this characteristic. As a common leitmotif, a panel of pharmacological ICD stimulators inhibited transcription and secondarily translation. These results establish the inhibition of RNA synthesis as an initial event for ICD induction.
Synopsis
Anticancer drugs that trigger immunogenic cell death (ICD) are particularly efficient because they mobilize the host immune system against malignant cells expressing tumor‐associated antigens. Dactinomycin is identified as an ICD inducer and showed to stimulate anticancer immune responses in vivo.
An algorithm designed to discover cancer cell‐killing drugs with immunostimulatory properties led to the identification of dactinomycin (DACT, also known as actinomycin D), as an ICD inducer.
DACT induces all hallmarks ICD including phosphorylation of eukaryotic initiation factor 2a (eIF2a) in the context of a partial endoplasmic reticulum stress response, as well as cell surface exposure of calreticulin.
DACT stimulated anticancer immune responses in vivo with an improvement of the ratio of cytotoxic T lymphocytes over regulatory T cells in tumor‐infiltrating lymphocytes, while sensitizing tumors to subsequent immunotherapy with a PD‐1‐blocking antibody.
DACT is a known transcriptional inhibitor, and a range of distinct ICD inducers were found to potently inhibit transcription and translation, as documented for anthracyclines, crizotinib, lurbinectedin and oxaliplatin.
Artificial intelligence applied to a library of 50,000 drugs corroborated that transcription and translation inhibitors have a higher probability to induce ICD than other classes of antineoplastics.
Anticancer drugs that trigger immunogenic cell death (ICD) are particularly efficient because they mobilize the host immune system against malignant cells expressing tumor‐associated antigens. Dactinomycin is identified as an ICD inducer and showed to stimulate anticancer immune responses in vivo.
Within the Central waters of the North Atlantic Ocean there is a significant east–west difference in salinity, similar to that caused by Mediterranean Water at deeper levels. In this paper we ...hypothesize that the salinity of the Central Water
is influenced by the saline Mediterranean Outflow Water, despite physical separation of the two water masses by a salinity minimum over most of the ocean basin. It is suggested that there occurs a cross-isopycnal flux of salinity from the Mediterranean Outflow Water towards the low-density Central Water (detrainment) in the eastern Gulf of Cadiz, not far from the Strait of Gibraltar, where the two water masses are in physical contact. Laboratory experiments, inverse modeling and direct current observations are applied to support the hypothesis.
Chronic inflammation drives proliferative responses, hence increasing cellular multiplication with the consequent risk of malignant transformation. Autoimmune responses against self-antigens drive ...chronic inflammation but may also enhance cancer immunosurveillance with the consequent reduction of tumor incidence and progression. These notions, which have been well established at the preclinical level, may explain the generally positive associations between immune-inflammatory diseases but also some negative associations, for example between breast cancer and rheumatoid arthritis or systemic lupus erythematosus, which have recently been confirmed in a study enrolling close to half a million participants from the UK Biobank.
Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which ...cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.
For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 ...(FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of
, calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of
. These findings have potential implications for the clinical management of FPR1-deficient patients. SIGNIFICANCE: The loss-of-function variant rs867228 in
, harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking
, suggesting a personalized strategy for compensating for the FPR1 defect.
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