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Conventional chemotherapy: millions of cures, unresolved therapeutic index
No full textInternational audienceIn recent decades, millions of patients with cancer have been cured by chemotherapy alone. By ‘cure’, we mean that patients with cancers that would be fatal if left untreated receive a time-limited course of chemotherapy and their cancer disappears, never to return. In an era when hundreds of thousands of cancer genomes have been sequenced, a remarkable fact persists: in most patients who have been cured, we still do not fully understand the mechanisms underlying the therapeutic index by which the tumour cells are killed, but normal cells are somehow spared. In contrast, in more recent years, patients with cancer have benefited from targeted therapies that usually do not cure but whose mechanisms of therapeutic index are, at least superficially, understood. In this Perspective, we will explore the various and sometimes contradictory models that have attempted to explain why chemotherapy can cure some patients with cancer, and what gaps in our understanding of the therapeutic index of chemotherapy remain to be filled. We will summarize principles which have benefited curative conventional chemotherapy regimens in the past, principles which might be deployed in constructing combinations that include modern targeted therapies
Feeding the Black-Holes : From cooling filaments to H2 accretion disks
No full textInternational audienceBrightest Cluster Galaxies (BCGs) are unique direct evidence of AGN-feedback caught in the act. The large cavities inflated by the AGN-radio lobes have pushed the hot intra-cluster medium and made gigantic bubbles raising buoyantly in the ICM. BCGs lying at the center of cool core clusters (short cooling time) are also surrounded by a huge network of kpc-scale filaments, visible in the optical and detected in warm H2 and cold CO. Those cold filaments are likely formed via thermal instabilities in the low-entropy cluster core. There is strong evidence that AGN-jets themselves play an important role in the local compression and cooling of this gas. BCGs are thus the best objects to study this key piece of the feedback. Once cooled the gas can settle down in the galaxy and feed the central Black Hole, powering the feedback engine. To understand the detailed circulation of the cold gas is of prime importance. The spatial resolution and sensitivity of JWST with MRS and MIRI can (i) map the H2 lines tracing the bulk of the mass in the filaments and seek warm dust at large scales; it can also help (ii) determine the main excitation processes in the filaments (and confirm the important role of shocks) via mid-IR line diagnostics and (iii) map the expected central molecular disks, a yet unobserved element of the feedback cycle
A biconical ionised gas outflow and evidence of positive feedback in NGC 7172 uncovered by MIRI/JWST
No full textInternational audienceWe present observations of the type-2 Seyfert NGC 7172 obtained with the medium-resolution spectrometer (MRS) of the Mid-Infrared Instrument (MIRI) on board the James Webb Space Telescope (JWST). This galaxy hosts one of the lowest ionised gas mass outflow rates (Ṁout ∼ 0.005 M⊙ yr‑1) in a sample of six active galactic nuclei (AGN) with similar bolometric luminosities (log Lbol ∼ 44 erg s‑1) within the Galactic Activity, Torus, and Outflow Survey (GATOS). We aim to understand the properties of the ionised gas outflow and its impact on the host galaxy. We mainly used the ionised gas emission lines from the neon transitions, which cover a broad range of ionisation potentials (IPs) from ∼20 eV to ∼130 eV. We applied parametric and non-parametric methods to characterise the line emission and kinematics. The low excitation lines (IP < 25 eV, e.g. [Ne II]) trace the rotating disc emission. The high excitation lines (IP > 90 eV, e.g. [Ne V]), which are likely photoionised exclusively by the AGN, are expanding in the direction nearly perpendicular to the disc of the galaxy, with maximum projected velocities in the range of ∼350–500 km s‑1. In particular, [Ne V] and [Ne VI] lines reveal a biconical ionised gas outflow emerging north-south from the nuclear region, extending at least ∼2.5″ N and 3.8″ S (projected distance of ∼450 and 680 pc, respectively). Most of the emission arising in the northern part of the cone was not previously detected due to obscuration. Given the almost face-on orientation of the outflow and the almost edge-on orientation of the galaxy, NGC 7172 may be a case of weak coupling. Nevertheless, we found evidence of positive feedback in two distinct outflowing clumps at projected distances of 3.1″ and 4.3″ (i.e. ∼560 and 780 pc) south-west of the AGN. We estimated a star formation rate in these regions using the [Ne II] and [Ne III] luminosities of 0.08 M⊙ yr‑1, which is ∼10% of that found in the circumnuclear ring. The star formation activity might have been triggered by the interaction between the ionised gas outflow and the interstellar medium of the galaxy
A massive multiphase plume of gas in Abell 2390's brightest cluster galaxy
No full textInternational audienceWe present new ALMA CO(2-1) observations tracing of molecular gas in Abell 2390's brightest cluster galaxy, where half the gas is located in a one-sided plume extending 15 kpc out from the galaxy centre. This molecular gas has a smooth and positive velocity gradient, and is receding 250 km s-1 faster at its farthest point than at the galaxy centre. To constrain the plume's origin, we analyse our new observations alongside existing X-ray, optical, and radio data. We consider the possibility that the plume is a jet-driven outflow with lifting aided by jet-inflated X-ray bubbles, is a trail of gas stripped from the main galaxy by ram pressure, or is formed of more recently cooled and infalling gas. The galaxy's star formation and gas cooling rate suggest the lifespan of its molecular gas may be low compared with the plume's age - which would favour a recently cooled plume. Molecular gas in close proximity to the active galactic nucleus is also indicated by 250 km s-1 wide CO(2-1) absorption against the radio core, as well as previously detected CO(1-0) and H I absorption. This absorption is optically thick and has a line-of-sight velocity towards the galaxy centre of 200 km s-1. We discuss simple models to explain its origin
Governing Access to Nationality Through Paperwork: The Discretionary Uses of Documentation for Naturalisation in Belgium, France and the United Kingdom
No full textInternational audienceSocial Policy & Administration published by John Wiley & Sons Ltd.In this paper, we examine the discretionary uses of documentation in the implementation of naturalisation through a comparative perspective focusing on Belgium, France and the United Kingdom. We investigate the organisational and professional factors that are likely to impact variation in the uses of discretion based on documentation. Belgium, France and the United Kingdom represent three interesting case studies involving different actors with different mandates. In Belgium, municipal agents are responsible for a mandatory check of applicants documents before transferring the naturalisation application to public prosecutors. While only the latter have the mandate to check that the legal requirements are met, most municipal agents are involved in the examination of the requirements. In France, before the digitisation of nationality acquisition in 2023, the initial acceptance of an application involved prefectural agents who had the power to refuse application registration if the documentation was deemed insufficient or u2018non-compliantu2019. In the United Kingdom, u2018Nationality Checking Servicesu2019 (NCS) were available until 2019 in local register offices for an optional check of the application before the transfer to the Home Office, which remains the decision-making body on nationality applications. As United Kingdom law regulates strictly immigration advice, NCSs were often unwilling to express themselves on the chances of an application. Drawing on ethnographic fieldwork consisting of interviews with implementation agents in the three countries and observations of their interactions with applicants, this paper contributes to shedding light on what drives variations in the governance of access to nationality through paperwork
Phase transitions of FeO under laser shock compression
No full textWe present in-situ x-ray diffraction and velocity measurements of FeO under laser shock compression at pressures between 38-116 GPa. None of the phases reported by static compression studies were observed. Instead, we observed an isostructural phase transition from -FeO to a new -FeO phase at a pressure of 50-62 GPa. The -FeO phase differs from -FeO by an 11% volume drop and a different unit cell compressibility. We further observed a two-wave structure in the velocity profile, which can be related to an intermediate regime where both and phases coexist. Density functional theory calculations with a Hubbard parameter indicate that the observed unit cell volume drop can be associated with a spin transition following a magnetic collapse
Capturing Cytoskeleton-Based Agitation of The Mouse Oocyte Nucleus Across Spatial Scales
No full textInternational audienceA major challenge in understanding the causes of female infertility is to elucidate mechanisms governing the development of female germ cells, named oocytes. Their development is marked by cell growth and subsequent divisions, two critical phases that prepare the oocyte for fusion with sperm to initiate embryogenesis. During growth, oocytes reorganize their cytoplasm to position the nucleus at the cell center, an event predictive of successful oocyte development in mice and humans and, thus, their embryogenic potential. In mouse oocytes, this cytoplasmic reorganization was shown to be driven by the cytoskeleton, the activity of which generates mechanical forces that agitate, reposition, and penetrate the nucleus. Consequently, this cytoplasmic-to-nucleoplasmic force transmission tunes the dynamics of nuclear RNA-processing organelles known as biomolecular condensates. This protocol provides an experimental framework to document, with high temporal resolution, the impact of the cytoskeleton on the nucleus across spatial scales in mouse oocytes. It details the imaging and image analysis steps and tools necessary to evaluate i) cytoskeletal activity in the oocyte cytoplasm, ii) cytoskeleton-based agitation of the oocyte nucleus, and iii) its effects on biomolecular condensate dynamics in the oocyte nucleoplasm. Beyond oocyte biology, the methods elaborated here can be adapted for use in somatic cells to similarly address cytoskeleton-based tuning of nuclear dynamics across scales
Functional contribution of astrocytic Kir4.1 channels to spasticity after spinal cord injury
No full textInternational audienceSpasticity, a prevalent motor issue characterized by network hyperexcitability, causes pain and discomfort, with existing treatments offering limited relief. While past research has focused on neuronal factors, the role of astrocytes in spasticity has been overlooked. This study explores the potential of restoring astrocytic potassium (K + ) uptake to reduce spasticity following SCI. Astrocytes buffer extracellular K + via Kir4.1 channels, preventing neuronal hyperexcitability. Following spinal cord injury (SCI), Kir4.1 levels decrease at the injury site, though the consequences and mechanisms of this reduction within the motor output area have not been investigated. Utilizing advanced techniques, we demonstrate that lumbar astrocytes in a juvenile thoracic SCI mouse model switch to reactive phenotype, displaying morpho-functional and pro-inflammatory changes. These astrocytes also experience NBCe1-mediated intracellular acidosis, leading to Kir4.1 dysfunction and impaired K + uptake. Enhancing Kir4.1 function reduces spasticity in SCI mice, revealing new therapeutic targets for neurological diseases associated with neuronal hyperexcitability. Highlights Lumbar astrocytes adopt a reactive phenotype following a thoracic SCI NBCe1-mediated acidosis in astrocytes disrupts Kir4.1 function post-SCI. Impaired K+ uptake leads to motoneuron hyperexcitability post-SCI. Enhanced astroglial Kir4.1 function reduces spastic-like symptoms in SCI mice
Inferring the location and orientation of cell divisions on time-lapse image sequences
No full textWe propose a two-stage method to characterize cell divisions. In a first stage, the division detection problem is recast into a semantic segmentation task on image sequences. In a second stage, a local regression on individual divisions yields the orientation and distance between daughter cells. We apply our formalism to confocal image sequences of neural tube formation in chicken embryos, where divisions occur within a well-defined plane. We show that our two-stage method can be implemented using simple networks, e.g. a U-Net for the segmentation and a 4-layer CNN for the regression. Optimization of the networks was achieved through a systematic exploration of hyperparameters. In particular, we show that considering several frames as inputs significantly improves the segmentation performance. We reach a performance of 96% in the F1 measure for the detection and errors for the angle, which are within the bounds of the uncertainty of the ground-truth annotation dataset