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Breast cancer is the most common malignant neoplasm in women. Despite progress to date, 700,000 women worldwide died of this disease in 2020. Apparently, the prognostic markers currently used in the clinic are not sufficient to determine the most appropriate treatment. For this reason, great efforts have been made in recent years to identify new molecular biomarkers that will allow more precise and personalized therapeutic decisions in both primary and recurrent breast cancers. These molecular biomarkers include genetic and post-transcriptional alterations, changes in protein expression, as well as metabolic, immunological or microbial changes identified by multiple omics technologies (e.g., genomics, epigenomics, transcriptomics, proteomics, glycomics, metabolomics, lipidomics, immunomics and microbiomics). This review summarizes studies based on omics analysis that have identified new biomarkers for diagnosis, patient stratification, differentiation between stages of tumor development (initiation, progression, and metastasis/recurrence), and their relevance for treatment selection. Furthermore, this review highlights the importance of clinical trials based on multiomics studies and the need to advance in this direction in order to establish personalized therapies and prolong disease-free survival of these patients in the future.

Autophagy inducers can prevent cardiovascular aging and age-associated diseases including atherosclerosis. Therefore, we hypothesized that autophagy-inducing compounds that act on atherosclerosis-relevant cells might have a protective role in the development of atherosclerosis. Here we identified 3,4-dimethoxychalcone (3,4-DC) as an inducer of autophagy in several cell lines from endothelial, myocardial and myeloid/macrophagic origin, as demonstrated by the aggregation of the autophagosome marker GFP-LC3 in the cytoplasm of cells, as well as the downregulation of its nuclear pool indicative of autophagic flux. In this respect, 3,4-DC showed a broader autophagy-inducing activity than another chalcone (4,4- dimethoxychalcone), spermidine and triethylene tetramine. Thus, we characterized the potential antiatherogenic activity of 3,4-DC in two different mouse models, namely, (i) neointima formation with smooth muscle expansion of vein segments grafted to the carotid artery and (ii) genetically predisposed ApoE−/− mice fed an atherogenic diet. In the vein graft model, local application of 3,4-DC was able to maintain the lumen of vessels and to reduce neointima lesions. In the diet-induced model, intraperitoneal injections of 3,4-DC significantly reduced the number of atherosclerotic lesions in the aorta. In conclusion, 3,4-DC stands out as an autophagy inducer with potent antiatherogenic activity.

The shallowest intracrustal layer (extending to 8 ± 2 km depth) beneath the Mars InSight Lander site exhibits low seismic wave velocity, which is likely related to a combination of high porosity and other lithological factors. The SsPp phase, an SV- to P-wave reflection on the receiver side, is naturally suited for constraining the seismic structure of this top crustal layer since its prominent signal makes it observable with a single station without the need for stacking. We have analyzed six broadband and low-frequency seismic events recorded on Mars and made the first coherent detection of the SsPp phase on the red planet. The timing and amplitude of SsPp confirm the existence of the ∼8 km interface in the crust and the large wave speed (or impedance) contrast across it. With our new constraints from the SsPp phase, we determined that the average P-wave speed in the top crustal layer is between 2.5 and 3.2 km/s, which is a more precise and robust estimate than the previous range of 2.0–3.5 km/s obtained by receiver function analysis. The low velocity of Layer 1 likely results from the presence of relatively low-density lithified sedimentary rocks and/or aqueously altered igneous rocks that also have a significant amount of porosity, possibly as much as 22%–30% by volume (assuming an aspect ratio of 0.1 for the pore space). These porosities and average P-wave speeds are compatible with our current understanding of the upper crustal stratigraphy beneath the InSight Lander site.

Deep Slow Slip and Tremors (SSTs) are a combination of transient clusters of tectonic tremors and slow slip associated with extremely elevated fluid pressures. SSTs are thought to reflect a transition from viscous to brittle plate interface rheology and likely exert a first-order control on megathrust seismicity. Nevertheless, the deformation mechanisms governing the source of SSTs remain elusive. We herein document the occurrence of vein networks precipitated and brecciated within the deep SST region under blueschist-facies conditions. These lawsonite-rich vein sets exhibit extensive evidence of brittle deformation and are spatially related to localized, finely milled (cataclastic) shear bands. Petro-geochemical data reveal that brittle deformation was accompanied by the injection of several ultramafic-, mafic- and metasedimentary-derived fluid pulses, imprinting characteristic Cr, high field strength elements, and light over heavy rare earth elements positive anomalies in the vein breccias while leaching light rare earth elements from the cataclastic blueschist host. Our results suggest that metamorphic veins represent zones of mechanical anisotropy within the rock volume prone to localized shearing, brittle deformation and episodic injection of externally derived fluids. These networks demonstrate the importance of former vein sets as structural heterogeneities in triggering fluid-controlled brittle creep events. The combined effects of high pore fluid pressures and rheological heterogeneities in the form of metamorphic veins could trigger the nucleation and propagation of SSTs at the margins of this mechanically anisotropic environment, and thus determine where slip will take place along deep subduction interfaces.

The B-cell lymphoma 2 (Bcl-2) family of proteins is the main regulator of apoptosis. However, multiple emerging evidence has revealed that Bcl-2 family proteins are also involved in cellular senescence. On the one hand, the different expression of these proteins determines the entry into senescence. On the other hand, entry into senescence modulates the expression of these proteins, generally conferring resistance to apoptosis. With some exceptions, senescent cells are characterized by the upregulation of antiapoptotic proteins and downregulation of proapoptotic proteins. Under physiological conditions, freshly formed tetraploid cells die by apoptosis due to the tetraploidy checkpoint. However, suppression of Bcl-2 associated x protein (Bax), as well as overexpression of Bcl-2, favors the appearance and survival of tetraploid cells. Furthermore, it is noteworthy that our laboratory has shown that the joint absence of Bax and Bcl-2 antagonist/killer (Bak) favors the entry into senescence of tetraploid cells. Certain microtubule inhibitory chemotherapies, such as taxanes and vinca alkaloids, induce the generation of tetraploid cells. Moreover, the combined use of inhibitors of antiapoptotic proteins of the Bcl-2 family with microtubule inhibitors increases their efficacy. In this review, we aim to shed light on the involvement of the Bcl-2 family of proteins in the senescence program activated after tetraploidization and the possibility of using this knowledge to create a new therapeutic strategy targeting cancer cells.

We present the complete genome sequence of Bradyrhizobium sp. strain C-145, one of the most widely used nitrogen-fixing rhizobacteria for inoculating peanut crops in Argentina. The genome consists of 9.53 Mbp in a single circular chromosome and was determined using a hybrid long- and short-read assembly approach.

Primary ovarian insufficiency (POI) causes female infertility by abolishing normal ovarian function. Although its genetic etiology has been extensively investigated, most POI cases remain unexplained. Using whole-exome sequencing, we identified a homozygous variant in RAD51B –(c.92delT) in two sisters with POI. In vitro studies revealed that this variant leads to translation reinitiation at methionine 64. Here, we show that this is a pathogenic hypomorphic variant in a mouse model. Rad51bc.92delT/c.92delT mice exhibited meiotic DNA repair defects due to RAD51 and HSF2BP/BMRE1 accumulation in the chromosome axes leading to a reduction in the number of crossovers. Interestingly, the interaction of RAD51B-c.92delT with RAD51C and with its newly identified interactors RAD51 and HELQ was abrogated or diminished. Repair of mitomycin-C-induced chromosomal aberrations was impaired in RAD51B/Rad51b-c.92delT human and mouse somatic cells in vitro and in explanted mouse bone marrow cells. Accordingly, Rad51b-c.92delT variant reduced replication fork progression of patient-derived lymphoblastoid cell lines and pluripotent reprogramming efficiency of primary mouse embryonic fibroblasts. Finally, Rad51bc.92delT/c.92delT mice displayed increased incidence of pituitary gland hyperplasia. These results provide new mechanistic insights into the role of RAD51B not only in meiosis but in the maintenance of somatic genome stability.

The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum.

SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic infections to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic and immunological determinants of resistance to infection per se remain unknown. Following the discovery that autosomal recessive deficiency in the DARC chemokine receptor confers resistance to Plasmodium vivax, autosomal recessive deficiencies of chemokine receptor 5 (CCR5) and the enzyme FUT2 were shown to underlie resistance to HIV-1 and noroviruses, respectively. Along the same lines, we propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection.

info:eu-repo/semantics/nonPublished

info:eu-repo/semantics/nonPublished

Elucidating the mechanisms underlying chromatin maintenance upon genome replication is critical for the understanding of how gene expression programs and cell identity are preserved across cell divisions. Here, we describe two recently developed techniques, chromatin occupancy after replication (ChOR)-seq and sister chromatids after replication (SCAR)-seq, that profile chromatin occupancy on newly replicated DNA in mammalian cells in 5 d of bench work. Both techniques share a common strategy that includes pulse labeling of newly synthesized DNA and chromatin immunoprecipitation (ChIP), followed by purification and high-throughput sequencing. Whereas ChOR-seq quantitatively profiles the post-replicative abundance of histone modifications and chromatin-associated proteins, SCAR-seq distinguishes chromatin occupancy between nascent sister chromatids. Together, these two complementary techniques have unraveled key mechanisms controlling the inheritance of modified histones during replication and revealed locus-specific dynamics of histone modifications across the cell cycle. Here, we provide the experimental protocols and bioinformatic pipelines for these methods.

The Huaynaputina volcano, southern Peru, was the site of the largest historical eruption (VEI 6) in the Andes in 1600 CE, which occurred during the historic transition between the Inca Empire and the Viceroyalty of Peru. This event had severe consequences in the Central Andes and a global climatic impact. Spanish chronicles reported that at least 15 villages or settlements existed around the volcano, of which seven of them were totally destroyed by the eruption. Multidisciplinary studies have allowed us to identify and analyze the characteristics of six settlements buried by the eruption. Tephra fallout and pyroclastic current deposits (PDCs) had different impacts according to the settlement distance from the crater, the location with respect to the emplacement of PDCs along valleys, the geomorphological characteristics of the site, and type of constructions. Thus, Calicanto, Cojraque, and San Juan de Dios, located beneath the main axis of tephra dispersal lobe due west and/or on valley edges, were buried under several meters of pyroclastic deposits, while the villages of Estagagache, Chimpapampa, and Moro Moro, located to the S and SE of the lobe, were partially mantled by tephra. The 1600 CE Huaynaputina eruption created an important geological and cultural heritage, which has scientific, educational, and touristic values. Geo-touristic attractions are proposed based on identification, characterization, and qualitative evaluation of four groups totaling 17 geosites: volcanic geosites, volcanic-cultural geomorphosites, and hot springs. Seven geological roads along with seven viewpoints are proposed, which allow to value the most relevant landscapes, deposits and geological structures.

The InterEvDock3 protein docking server exploits the constraints of evolution by multiple means to generate structural models of protein assemblies. The server takes as input either several sequences or 3D structures of proteins known to interact. It returns a set of 10 consensus candidate complexes, together with interface predictions to guide further experimental validation interactively. Three key novelties were implemented in InterEvDock3 to help obtain more reliable models: users can (i) generate template-based structural models of assemblies using close and remote homologs of known 3D structure, detected through an automated search protocol, (ii) select the assembly models most consistent with contact maps from external methods that implement covariation-based contact prediction with or without deep learning and (iii) exploit a novel coevolution-based scoring scheme at atomic level, which leads to significantly higher free docking success rates. The performance of the server was validated on two large free docking benchmark databases, containing respectively 230 unbound targets (Weng dataset) and 812 models of unbound targets (PPI4DOCK dataset). Its effectiveness has also been proven on a number of challenging examples. The InterEvDock3 web interface is available at http://bioserv.rpbs.univ-paris-diderot.fr/services/InterEvDock3/.

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Annexe de la monographie / Anhang der Monografie: 'Analyse sémiologique des personnages dans les récits graphiques:Tableaux 1–7

Annexe de la monographie / Anhang der Monografie: 'Analyse sémiologique des personnages dans les récits graphiques:Tableaux 1–7

info:eu-repo/semantics/nonPublished

info:eu-repo/semantics/nonPublished

This program computes the degree of polarization (DOP) and polarization attributes for continuous three component (3-C) recordings from individual seismic stations employing sliding data windows as function of time & frequency. The employed DOP strategy has been introduced in Schimmel & Gallart (2003) using analytic signal theory in the t-domain. Later, in Schimmel & Gallart (2004), the DOP strategy has been extended to the tf-domain, but using now Eigen theory to compute the polarization attributes. Signals are identified by having a more stable polarization through a frequency dependent time window than noise. Therefore, DOP and polarization attributes are used to detect, analyze and characterize signals which are more polarized than noise. Among others, the approach permits to determine the direction of incoming Rayleigh waves and the determination of polarization spectra. E.g., this code has been used in Schimmel et al. (2011) to characterize microsesimic noise. All figures of this publication are based on the polfre output. Note that most recently, the program has also been employed to analyze ambient noise on Mars (Stutzmann et al., 2021). The program needs the SAC library to read and write data with the SAC binary format. Program descriptions are obtained by executing the codes without any flag. The package further contains Readme-files with information and simple examples to show the workflow. Programs are called through shell scripts or command line and work for Linux/Unix environments. This software was first edited in 2011 and updated in 2019.