Self-supervised learning in non-small cell lung cancer discovers novel morphological clusters linked to patient outcome and molecular phenotypes

Histopathological images provide the definitive source of cancer diagnosis, containing information used by pathologists to identify and subclassify malignant disease, and to guide therapeutic choices. These images contain vast amounts of information, much of which is currently unavailable to human interpretation. Supervised deep learning approaches have been powerful for classification tasks, but they are inherently limited by the cost and quality of annotations. Therefore, we developed Histomorphological Phenotype Learning, an unsupervised methodology, which requires no annotations and operates via the self-discovery of discriminatory image features in small image tiles. Tiles are grouped into morphologically similar clusters which appear to represent recurrent modes of tumor growth emerging under natural selection. These clusters have distinct features which can be identified using orthogonal methods. Applied to lung cancer tissues, we show that they align closely with patient outcomes, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype

Geometry of Vaidya spacetimes

International audienceWe investigate the geometrical structure of Vaidya’s spacetime in the case of a white hole with decreasing mass, stabilising to a black hole in finite or infinite time or evaporating completely. Our approach relies on a detailed analysis of the ordinary differential equation describing the incoming principal null geodesics, among which are the generators of the past horizon. We devote special attention to the case of a complete evaporation in infinite time and establish the existence of an asymptotic light-like singularity of the conformal curvature, touching both the past space-like singularity and future time-like infinity. This singularity is present independently of the decay rate of the mass. We derive an explicit formula that relates directly the strength of this null singularity to the asymptotic behaviour of the mass function

Density measurement of fine aerosol fractions from wood combustion sources using ELPI distributions and image processing techniques

International audienceAerosols from combustion sources are of high concern since they present a risk for health and environment. Particle size distribution of aerosols and in particular number size distribution are easily and quickly obtained using an Electrical Low Pressure Impactor (ELPI). However, this technique is depending of aerosol density; q, which may lead to biased particle size distributions. Aerosol density from combustion sources is usually not well known and depends on several parameters. Aerosol density cannot be measured with usual methods since there is generally not enough matter collected on each stage of the ELPI. Our approach uses electronic microscopy to evaluate q at each impaction stage in order to increase the accuracy of the number size distributions resulting from the ELPI measurements. Particles were collected on glass substrates deposited on each impaction stages. Images were obtained using a scanning electron microscope and image processing tools were applied. This method was first tested with silica particles resulting from a combustion process which have a constant density found to be comprised between 2.2 and 2.4 g cm 3 for stages 2 (57 and 95 nm) and 3 (95 and 158 nm), respectively. Once validated, this method was used to determine the density of wood combustion aerosols. The results match well for fly ashes from wood combustion with densities varying from 1.1 to 3.0 g cm 3 for particles of mean equivalent diameter ranging from 69 to 157 nm, respectively

Effect of spirulina and silicon‐enriched spirulina on metabolic syndrome features, oxidative stress and mitochondrial activity in Zucker fatty rats

International audienceThe use of Spirulina platensis (Sp) as a functional food was suggested decades ago. Biological incorporation of Silicon (Si) into Sp increases its bioavailability for potential food supplement applications. This work aimed at determining the effects of Sp and Si-enriched Sp (Sp+Si) on metabolic syndrome features in Zucker fatty rats. Thirty Zucker fatty rats were divided into three groups and supplemented with placebo or Sp or Sp+Si croquettes for 12 weeks. Food consumption, glucose intolerance, hepatic steatosis, and mitochondrial and oxidative stress were determined. Zucker fatty rats exhibited several hepatic metabolic alterations as well as mitochondrial and oxidative stress perturbations. The intake of Sp increased plasma TG levels and decreased the hepatic NADPH oxidase activity and ameliorated transitorily the glucose intolerance. However, Si-spirulina does not appear to have more beneficial effects than spirulina alone. Other experiments with different species of rats/mice, different diets, or durations of diet intake should be undertaken to confirm or infirm these results. PRACTICAL APPLICATIONS: Glucose intolerance and hepatic steatosis, two major components of metabolic syndrome, are increasing and becomes a major public health issue. Use of Spirulina platensis (Sp) as a functional food was suggested as a protein-dense food source. Bioavailable silicon (Si) may be an essential nutrient for higher animals, including humans. Sp but not Sp+Si decreased liver NADPH oxidase activity and improved transitorily glucose tolerance. This is the first study where Sp and Sp+Si effect on glucose intolerance is reported in Zucker rat. Other experiments should be undertaken to confirm or infirm invalidate the beneficial effects of Sp+Si supplement in the metabolic syndrome features

Coupling of ATPase activity, microtubule binding, and mechanics in the dynein motor domain.

The movement of a molecular motor protein along a cytoskeletal track requires communication between enzymatic, polymer-binding, and mechanical elements. Such communication is particularly complex and not well understood in the dynein motor, an ATPase that is comprised of a ring of six AAA domains, a large mechanical element (linker) spanning over the ring, and a microtubule-binding domain (MTBD) that is separated from the AAA ring by a ~ 135 Å coiled-coil stalk. We identified mutations in the stalk that disrupt directional motion, have microtubule-independent hyperactive ATPase activity, and nucleotide-independent low affinity for microtubules. Cryo-electron microscopy structures of a mutant that uncouples ATPase activity from directional movement reveal that nucleotide-dependent conformational changes occur normally in one-half of the AAA ring, but are disrupted in the other half. The large-scale linker conformational change observed in the wild-type protein is also inhibited, revealing that this conformational change is not required for ATP hydrolysis. These results demonstrate an essential role of the stalk in regulating motor activity and coupling conformational changes across the two halves of the AAA ring

CO-73 Pseudohypoparathyroïdie : distorsion du ratio de transmission maternelle des mutations perte de fonction de GNAS

National audienceIntroduction : La pseudohypoparathyroïdie de type Ia (PHPIa) et la pseudo-pseudohypoparathyroïdie (PPHP) sont deux pathologies rares, à transmission autosomique dominante, dues à une mutation perte de fonction du gène GNAS. La PPHP est causée par des mutations de l’allèle paternel, alors que la PHPIa, avec résistances hormonales, est liée à des mutations de l’allèle maternel.Objectif : Etude de la transmission des mutations de GNASPatients et méthodes : Etude rétrospective au sein d’une cohorte de 204 familles avec 360 patients présentant une PHPIa ou une PPHP, ou génotypés dans le cadre d’un diagnostic prénatal (DPN). La transmission de l’allèle muté a été comparée (test du khi-deux) à celle attendue selon l’hérédité mendélienne qui est de 50%. Afin de réduire le biais de constatation lié aux familles avec un grand nombre de patients, nous avons exclu de l’analyse les cas index des fratries étudiées.Résultats : L’analyse de transmission a été réalisée dans 114 familles nucléaires, comprenant un patient et ses descendants. La proportion de transmission maternelle de l’allèle muté est de 59% (95 porteurs sur 161 descendants), soit p=0.022. Le DPN confirmait cette distorsion, avec 7 fœtus positifs sur 11. La transmission de l’allèle paternel muté est conforme à la transmission mendélienne.Discussion : La distorsion du ratio de transmission maternelle a été décrite dans d’autres pathologies autosomiques dominantes. Elle suggère un avantage sélectif des mutations maternelles de GNAS lors de la méiose chez la femme ou du développement embryonnaire, avec des conséquences sur le conseil génétique

Coupling of ATPase activity, microtubule binding, and mechanics in the dynein motor domain.

The movement of a molecular motor protein along a cytoskeletal track requires communication between enzymatic, polymer-binding, and mechanical elements. Such communication is particularly complex and not well understood in the dynein motor, an ATPase that is comprised of a ring of six AAA domains, a large mechanical element (linker) spanning over the ring, and a microtubule-binding domain (MTBD) that is separated from the AAA ring by a ~ 135 Å coiled-coil stalk. We identified mutations in the stalk that disrupt directional motion, have microtubule-independent hyperactive ATPase activity, and nucleotide-independent low affinity for microtubules. Cryo-electron microscopy structures of a mutant that uncouples ATPase activity from directional movement reveal that nucleotide-dependent conformational changes occur normally in one-half of the AAA ring, but are disrupted in the other half. The large-scale linker conformational change observed in the wild-type protein is also inhibited, revealing that this conformational change is not required for ATP hydrolysis. These results demonstrate an essential role of the stalk in regulating motor activity and coupling conformational changes across the two halves of the AAA ring