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Greenhouse Gas (GHG) emissions pose a global climate challenge and the mining sector is a large contributor. Diurnal and seasonal variations of area-fugitive methane advective flux, released from an open-pit mine and a tailings pond, from a facility in northern Canada, were simulated in spring 2018 and winter 2019, using the Weather Research and Forecasting (WRF) model. The methane mixing ratio boundary conditions for the WRF model were obtained from the in-situ field measurements, using Los Gatos Research Ultra-Portable Greenhouse Gas Analyzers (LGRs), placed in various locations surrounding the mine pit and a tailings pond. The simulated advective flux was influenced by local and synoptic weather conditions in spring and winter, respectively. Overall, the average total advective flux in the spring was greater than that in the winter by 36% and 75%, for the mine and pond, respectively. Diurnal variations of flux were notable in the spring, characterized by low flux during thermally stable (nighttime) and high flux during thermally unstable (daytime) conditions. The model predictions of the methane mixing ratio were in reasonable agreement with limited aircraft observations (R2=0.68). The findings shed new light in understanding the area-fugitive advective flux from complex terrains and call for more rigorous observations in support of the findings.

Recent studies have detailed a remarkable degree of genetic and linguistic diversity in Northern Island Melanesia. Here we utilize that diversity to examine two models of genetic and linguistic coevolution. The first model predicts that genetic and linguistic correspondences formed following population splits and isolation at the time of early range expansions into the region. The second is analogous to the genetic model of isolation by distance, and it predicts that genetic and linguistic correspondences formed through continuing genetic and linguistic exchange between neighboring populations. We tested the predictions of the two models by comparing observed and simulated patterns of genetic variation, genetic and linguistic trees, and matrices of genetic, linguistic, and geographic distances. The data consist of 751 autosomal microsatellites and 108 structural linguistic features collected from 33 Northern Island Melanesian populations. The results of the tests indicate that linguistic and genetic exchange have erased any evidence of a splitting and isolation process that might have occurred early in the settlement history of the region. The correlation patterns are also inconsistent with the predictions of the isolation by distance coevolutionary process in the larger Northern Island Melanesian region, but there is strong evidence for the process in the rugged interior of the largest island in the region (New Britain). There we found some of the strongest recorded correlations between genetic, linguistic, and geographic distances. We also found that, throughout the region, linguistic features have generally been less likely to diffuse across population boundaries than genes. The results from our study, based on exceptionally fine-grained data, show that local genetic and linguistic exchange are likely to obscure evidence of the early history of a region, and that language barriers do not particularly hinder genetic exchange. In contrast, global patterns may emphasize more ancient demographic events, including population splits associated with the early colonization of major world regions.

Human genetic diversity in the Pacific has not been adequately sampled, particularly in Melanesia. As a result, population relationships there have been open to debate. A genome scan of autosomal markers (687 microsatellites and 203 insertions/deletions) on 952 individuals from 41 Pacific populations now provides the basis for understanding the remarkable nature of Melanesian variation, and for a more accurate comparison of these Pacific populations with previously studied groups from other regions. It also shows how textured human population variation can be in particular circumstances. Genetic diversity within individual Pacific populations is shown to be very low, while differentiation among Melanesian groups is high. Melanesian differentiation varies not only between islands, but also by island size and topographical complexity. The greatest distinctions are among the isolated groups in large island interiors, which are also the most internally homogeneous. The pattern loosely tracks language distinctions. Papuan-speaking groups are the most differentiated, and Austronesian or Oceanic-speaking groups, which tend to live along the coastlines, are more intermixed. A small "Austronesian" genetic signature (always

Melanesian populations are known for their diversity, but it has been hard to grasp the pattern of the variation or its underlying dynamic. Using 1,223 mitochondrial DNA (mtDNA) sequences from hypervariable regions 1 and 2 (HVR1 and HVR2) from 32 populations, we found the among-group variation is structured by island, island size, and also by language affiliation. The more isolated inland Papuan-speaking groups on the largest islands have the greatest distinctions, while shore dwelling populations are considerably less diverse (at the same time, within-group haplotype diversity is less in the most isolated groups). Persistent differences between shore and inland groups in effective population sizes and marital migration rates probably cause these differences. We also add 16 whole sequences to the Melanesian mtDNA phylogenies. We identify the likely origins of a number of the haplogroups and ancient branches in specific islands, point to some ancient mtDNA connections between Near Oceania and Australia, and show additional Holocene connections between Island Southeast Asia/Taiwan and Island Melanesia with branches of haplogroup E. Coalescence estimates based on synonymous transitions in the coding region suggest an initial settlement and expansion in the region at approximately 30-50,000 years before present (YBP), and a second important expansion from Island Southeast Asia/Taiwan during the interval approximately 3,500-8,000 YBP. However, there are some important variance components in molecular dating that have been overlooked, and the specific nature of ancestral (maternal) Austronesian influence in this region remains unresolved.

The aim of this paper is to present a comprehensive description of the ideophones of Teko, a Tupi language spoken in French Guiana. This word class, previously only briefly described, is defined in this paper through a systematic comparison to nouns and verbs, at various levels: phonology, word structure, prosody, semantic, morphology, syntax and discourse use. When relevant, it offers quantitative analyses with statistical tests to support the comparison. The analysis is based on a lexical database of 177 ideophones, 420 occurrences in texts and a subset of 101 tokens with audio-recording. It particularly investigates in detail various aspects of prosody, including syllabic structure, pitch, intensity and duration, and pauses. Contrary to the common view on ideophones that postulates a rather marginal status of the latter, this paper shows that ideophones are in fact rather well integrated in the linguistic system of Teko. They yet show regularities that require to consider them a distinct word category. This paper aims at contributing to the growing literature on the cross-linguistic definition and description of ideophones.

A set of alkyl-/1H-1,2,3-triazole-based dimers was strategically designed and synthesized to evaluate their in vitro anti-mycobacterial activities against Mycobacterium tuberculosis and the non-tuberculous Mycobacterium abscessus strains. Systematic variations in the nature (alkyl/1H-1,2,3-triazole) and positioning of the linker were implemented based on the docking scores observed in the binding sites identified in the crystal structures of InhA from M. tuberculosis and M. abscessus. However, the in vitro evaluation results revealed that the synthesized compounds did not exhibit inhibitory effects on the growth of mycobacteria, even at the highest tested concentrations. The elevated lipophilicity values determined through ADMET studies for these synthesized dimers might be a contributing factor to their poor activity profiles.

Objectives Migrants from high HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV) endemicity regions have a great burden of these infections and related diseases in the host countries. This study aimed to assess the predictive capacity of the Test Rapide d'Orientation Diagnostique (TROD) Screen questionnaire for HIV, HBV and HCV infections among migrants arriving in France.Design An observational and multicentre study was conducted among migrants. A self-questionnaire on demographic characteristics, personal medical history and sexual behaviours was completed.Setting The study was conducted in the centres of the French Office for Immigration and Integration (OFII).Participants Convenience sampling was used to select and recruit adult migrants between January 2017 and March 2020.Outcome measures Participants were tested for HIV, HBV and HCV with rapid tests. For each infection, the test performance was assessed using receiver operating characteristics curves, using area under the curve (AUC) as a measure of accuracy.Results Among 21 133 regular migrants seen in OFII centres, 15 343 were included in the study. The participants’ mean age was 35.6 years (SD±11.1). The prevalence (95% CI) of HBV, HCV and HIV was 2.0% (1.8% to 2.2%), 0.3% (0.2% to 0.4%) and 0.3% (0.2% to 0.4%), respectively. Based on the sensitivity–specificity curve analysis, the cut-off points (95% CI) chosen for the risk score were: 2.5 (2.5 to 7.5) for HBV infection in men; 6.5 (0.5 to 6.5) for HBV infection in women; 9.5 (9.5 to 12.5) for HCV infection; and 10.5 (10.0 to 18.5) for HIV infection. Test performance was highest for HIV (AUC=82.15% (95% CI 74.54% to 87.99%)), followed by that for HBV in men (AUC=79.22%, (95% CI 76.18% to 82.26%)), for HBV in women (AUC=78.83 (95% CI 74.54% to 82.10%)) and that for HCV (AUC=75.95% (95% CI 68.58% to 83.32%)).Conclusion The TROD screen questionnaire showed good overall performance for predicting HIV, HBV and HCV infections among migrants in OFII centres. It could be used to optimise screening for these infections and to propose rapid screening tests to those who are at high risk.Trial registration number NCT02959684.

ABSTRACTMycobacterium abscessus, an emerging pathogen responsible for severe pulmonary infections in cystic fibrosis patients, displays either a smooth (S) or a rough (R) morphotype. Infections with M. abscessus R are associated with increased pathogenicity in animal models and humans. While the S-to-R transition correlating with reduced glycopeptidolipid (GPL) production is well-documented, the recent screening of a transposon library revealed additional gene candidates located outside of the GPL locus involved in this transition. These genes include MAB_1470c, encoding the putative lipoprotein peptidase LpqM. However, experimental confirmation of the implication of this gene in the morphotype switch is lacking. Herein, we re-examined the role of MAB_1470c, and its homolog MAB_1466c, in colonial morphotype changes by generating unmarked deletion mutants in M. abscessus S. Our results indicate that the morphotype of these mutants stayed smooth in different media. Unexpectedly, the intracellular growth of ΔMAB_1470c and ΔMAB_1466c in THP-1 macrophages was significantly reduced as compared to the parental S strain, and these defects were rescued upon complementation with their corresponding genes. Strikingly, the intracellular survival defect was further exacerbated in a mutant lacking both MAB_1470c and MAB_1466c genes. This implies that, despite their primary sequence relatedness, the two proteins are not functionally redundant. Collectively, this suggests that these two LpqM-related lipoproteins are unlikely to be involved in the S-to-R transition but are key players for intramacrophage survival of M. abscessus.IMPORTANCEMycobacterium abscessus causes persistent infections in patients with underlying pulmonary diseases, resulting in progressive lung function deterioration. The rough (R) morphotype is well-established as associated with chronic and more aggressive infections in patients. In this study, we individually and simultaneously deleted the MAB_1470c and MAB_1466c genes in M. abscessus S, without observing changes in colony morphotypes. However, these mutants exhibited a severe impairment in their ability to survive within human macrophages, highlighting the critical role of these two lipoproteins in M. abscessus virulence.

Background: Recent studies increasingly show the implication of medicinal plants in cancer management. Acmella caulirhiza, a plant belonging to the Asteraceae is traditionally used as an analgesic and anti-inflammatory agent to fight against diseases like cancer. Purpose: This study aimed to evaluate the antitumoral properties of the aqueous extract of leaves and flowers of A. caulirhiza (AE-Ac). Methods: After phytochemical characterization, the cytotoxic activity of AE-Ac on MCF-7 breast cancer lines was carried out using the MTT method. For in vivo study, 36 female Wistar rats (6 weeks old) were randomly divided into 6 groups (n = 6 each) as follows: normal control receiving distilled water (NC), positive control receiving distilled water (DMBA), 3 test groups (receiving either 75, 150 or 300 mg/kg.Bw of AE-Ac (AE-Ac 75, AE-Ac 150 and AE-Ac 300 respectively)) and a reference group (Tam) receiving Tamoxifen at 3.3 mg/kg.Bw. They were fed with a high-fat diet daily. After 2 weeks all groups except the NC group were treated with a single dose of DMBA (7,12-Dimethylbenz (a) anthracene) (50 mg/kg. Bw) by intraperitoneal injection. Daily treatments were administered by intragastric intubation for 12 weeks. At the end, animals were sacrificed after 12 h of fasting and blood was collected for biochemical analysis. The mammary glands were isolated for histological analysis. Results: AE-Ac contains bioactive compounds amongst which stigmasterol, phytol, ellagic acid, phenol, sterols, alkaloids, flavonoids. AE-Ac was more active at 72 h (IC50 = 114.86 µg/mL) on MCF-7 cells. The cancer-treated groups exhibited the lowest percentage of weight gain variation, particularly the group receiving the reference molecule (Tamoxifen) (68.12 %) followed by the AE-Ac 150 group (92.45 %). AE-Ac at 150 and 300 mg/kg-Bw significantly reduced tumor volume and CA 15-3 levels (p = 0.004). Histological analysis of the mammary gland revealed more extensive ascini destruction in the AE-Ac 75 group followed by the DMBA group. Treatment with the 150 mg/kg.Bw ameliorated antioxidant enzyme (SOD and Catalase (p < 0.001)) activities, pro-oxidant levels (NO● and HO●), as well as inflammatory parameters (TNF-α and EGF; RBC, Hb, PLT) (p < 0.05). Conclusion: These results suggest that AE-Ac can be a good candidate as a complementary agent in breast cancer management.

BackgroundBlocking the CD47 “don’t eat me”-signal on tumor cells with monoclonal antibodies or fusion proteins has shown limited clinical activity in hematologic malignancies and solid tumors thus far. Main side effects are associated with non-tumor targeted binding to CD47 particularly on blood cells.MethodsWe present here the generation and preclinical development of NILK-2401, a CEACAM5×CD47 bispecific antibody (BsAb) composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format).ResultsNILK-2401 is a fully human BsAb binding the CEACAM5 N-terminal domain on tumor cells by its lambda light chain arm with an affinity of ≈4 nM and CD47 with its kappa chain arm with an intendedly low affinity of ≈500 nM to enabling tumor-specific blockade of the CD47-SIRPα interaction. For increased activity, NILK-2401 features a functional IgG1 Fc-part. NILK-2401 eliminates CEACAM5-positive tumor cell lines (3/3 colorectal, 2/2 gastric, 2/2 lung) with EC50 for antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity ranging from 0.38 to 25.84 nM and 0.04 to 0.25 nM, respectively. NILK-2401 binds neither CD47-positive/CEACAM5-negative cell lines nor primary epithelial cells. No erythrophagocytosis or platelet activation is observed. Quantification of the pre-existing NILK-2401-reactive T-cell repertoire in the blood of 14 healthy donors with diverse HLA molecules shows a low immunogenic potential. In vivo, NILK-2401 significantly delayed tumor growth in a NOD-SCID colon cancer model and a syngeneic mouse model using human CD47/human SIRPα transgenic mice and prolonged survival. In cynomolgus monkeys, single doses of 0.5 and 20 mg/kg were well tolerated; PK linked to anti-CD47 and Fc-binding seemed to be more than dose-proportional for Cmax and AUC0-inf. Data were validated in human FcRn TG32 mice. Combination of a CEACAM5-targeting T-cell engager (NILK-2301) with NILK-2401 can either boost NILK-2301 activity (Emax) up to 2.5-fold or allows reaching equal NILK-2301 activity at >600-fold (LS174T) to >3,000-fold (MKN-45) lower doses.ConclusionNILK-2401 combines promising preclinical activity with limited potential side effects due to the tumor-targeted blockade of CD47 and low immunogenicity and is planned to enter clinical testing.

Abstract The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease.

Abstract Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherapy. The phase I part included 6 patients with untreated locally-advanced or mTNBC to determine the safety and recommended phase II dose of the anti-CD73 antibody oleclumab in combination with the anti-PD-L1 durvalumab and 12 cycles of weekly carboplatin and paclitaxel. In the phase II part, 127 women were randomized 1:1 to receive chemo-immunotherapy, with (arm A) or without (arm B) oleclumab. The primary endpoint was the clinical benefit rate at week 24, defined as stable disease, partial or complete response per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, survival outcomes (progression-free survival and overall survival), and safety. The trial did not meet its primary endpoint, as the 24-week clinical benefit rate was not significantly improved by adding oleclumab (43% vs. 44%, p = 0.61). Exploratory median progression-free survival was 5.9 months in arm A as compared to 7.0 months in arm B (p = 0.90). The safety profile was manageable in both arms.

Abstract Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies.

Background: The nutritional transition observed worldwilde is linked to cardiovascular diseases. This study assessed the level of nutritional transition and its implications in the occurrence of cardiometabolic risk factors among populations living in the Far North Region of Cameroon. Methods: A cross-sectional, descriptive, and analytical study was conducted during November 2020 recruiting 350 Cameroonians of both genders aged 18 years and above in urban (Maroua), semi-urban (Kaélé) and rural (Midjivin) areas. Demographic, socioeconomic status and food habits were assessed through an interview. Anthropometric (weight, height, body mass index: BMI) and blood pressure were measured. A fasting blood sample was collected for lipid profile. Results: Mean age was higher in Kaele (44.99±16.55 years) and Midjivin (47.23±18.21 years). Urban residents of Maroua (23.38±4.80 kg/m2) and Kaele (23.13±5.01 kg/m2) had the highest BMI. Rural dwellers exhibited elevated cholesterol (220.30±70.40 mg/dL) and triglycerides (120.52±62.64 mg/dL). Diastolic blood pressure and heart rate increased significantly with urbanization. Low fruit and vegetable consumption, high alcohol intake, and low physical activity were observed in all three areas. An increased frequency of abdominal obesity, high blood pressure, hypercholesterolemia and hypertriglyceridemia were noticed in all participants. Midjivin inhabitants showed behavioral changes closer to those in Maroua, while those of Kaele had a slower rate of nutritional transition. Conclusion: People living in rural, semi-urban, and urban areas have stated the nutrition transition process in this part of the country. Thus nutritional education needs to be reinforced for a better prevention of nutritional-related morbitidies and mortalities drived by urbanization.

The increasing prevalence of cancers and the multiple side effects of cancer treatments have led researchers to constantly search for plants containing bioactive compounds with cell death properties. This work aimed at evaluating the antiproliferative effect of an Acmella caulirhiza extract. After evaluation of the in vitro antioxidant potential of the three extracts of Acmella caulirhiza (aqueous (AE-Ac), hydroethanolic (HEE-Ac), and ethanolic (EE-Ac)) through the scavenging of DPPH● and NO● radicals, the extract with the best antioxidant activity was selected for bioactive compound assessment and antiproliferative tests. Subsequently, the cytotoxic activity was evaluated on the viability of breast (MCF-7), brain (CT2A, SB-28, and GL-261), colon (MC-38), and skin (YUMM 1.7 and B16-F1) cancer lines using the MTT method. Then, the line where the extract was the most active was selected to evaluate the expression of certain genes involved in cancerogenesis by RT-PCR and the expression of cleaved caspase-3 involved in cell death mechanism by western blot. The AE-Ac showed the best scavenging activity with IC50s of 0.52 and 0.02 for DPPH● and NO●, respectively. This AE-Ac was found to contain alkaloids, flavonoids, and tannins and was more active on YUMM 1.7 cells (IC50 = 149.42 and 31.99 μg/mL for 24 and 48 h, respectively). Results also showed that AE-Ac downregulated the expression of inflammation (IL-1b p=0.017 and IL-6 p=0.028), growth factors (PDGF p=0.039, IGF p=0.034, E2F1p=0.038, and E2F2p=0.016), and antiapoptotic protein genes (Bcl-2 p=0.028 and Bcl-6 p=0.039). The cleaved caspase-3 was positively modulated by the AE-Ac inducing thus cell death by apoptosis. AE-Ac showed inhibitory effects on the expression of genes involved in cancer progression making it a potential health intervention agent that can be exploited in cancer therapy protocols.

Abstract Background Research on moderate acute malnutrition (MAM) is limited, despite its high prevalence. This study examined outcomes of bi-weekly locally available foods provided via a food voucher program (FVP) on nutritional recovery [mid-upper arm circumference (MUAC) ≥ 125 mm] from MAM (defined as MUAC between 115 and 124 mm) and identified the factors associated with recovery rate in Kaélé health district, Far North Region of Cameroon. Methods This was a prospective study with 474 MAM children aged 6–59 months. Food voucher distribution and MUAC screening were conducted at 6 bi-weekly visits or until the child was recovered. Time to recovery was evaluated with multivariate Cox proportional regression hazard models with associations quantified using adjusted hazard ratio (aHR). The trend for MUAC, including its determinants, was examined with multivariate linear mixed effect models. Results The recovery rate was 78.3% by 6 weeks after the first food basket; 3.4% remained MAM, and 5.9% were transferred for treatment for severe acute malnutrition (SAM defined as MUAC 75%). Child’s WHZ, gender and age were significant factors associated with MUAC increase and recovery from MAM in the FVP. These findings indicate the FVP approach shows promise as an effective alternative treatment for MAM with consideration of associated factors and merits further evaluation.

Introduction and Objectives: The lockdown policy introduced in 2020 to minimize the spread of the COVID-19 pandemic, significantly affected the management and care of patients affected by hepatocellular carcinoma (HCC). The aim of this follow-up study was to determine the 12 months impact of the COVID-19 pandemic on the cohort of patients affected by HCC during the lockdown, within six French academic referral centers in the metropolitan area of Paris. Materials and Methods: We performed a 12 months follow-up of the cross-sectional study cohort included in 2020 on the management of patients affected by HCC during the first six weeks of the COVID-19 pandemic (exposed), compared to the same period in 2019 (unexposed). Overall survival were compared between the groups. Predictors of mortality were analysed with Cox regression. Results: From the initial cohort, 575 patients were included (n = 263 Exposed_COVID, n = 312 Unexposed_COVID). Overall and disease free survival at 12 months were 59.9 ± 3.2% vs. 74.3 ± 2.5% (p

In Europe, with an incidence of 7.5 cases per million, Ewing sarcoma (ES) is the second most common primary malignant bone tumor in children, adolescents and young adults, after osteosarcoma. Since the 1980s, conventional treatment has been based on the use of neoadjuvant and adjuvant chemotherapeutic agents combined with surgical resection of the tumor when possible. These treatments have increased the patient survival rate to 70% for localized forms, which drops drastically to less than 30% when patients are resistant to chemotherapy or when pulmonary metastases are present at diagnosis. However, the lack of improvement in these survival rates over the last decades points to the urgent need for new therapies. Genetically, ES is characterized by a chromosomal translocation between a member of the FET family and a member of the ETS family. In 85% of cases, the chromosomal translocation found is (11; 22) (q24; q12), between the EWS RNA-binding protein and the FLI1 transcription factor, leading to the EWS-FLI1 fusion protein. This chimeric protein acts as an oncogenic factor playing a crucial role in the development of ES. This review provides a non-exhaustive overview of ES from a clinical and biological point of view, describing its main clinical, cellular and molecular aspects.

Abstract The Variscan basement of the Aiguilles-Rouges massif (Western Alps) exposes the Servoz syncline which consists of a metavolcano-sedimentary sequence composed of (i) a volcanic unit of unknown age and origin, (ii) Early Carboniferous sedimentary series affected by the Variscan orogeny and intruded by the Montées-Pélissier pluton, and (iii) a Late Carboniferous late-orogenic sedimentary sequence. We combined field investigations, Raman Spectroscopy on Carbonaceous Material geothermometry, and LA-ICPMS U-Th-Pb geochronology on zircon in order to reappraise the sedimentary sequence of the Servoz syncline. Our results allow us to identify three distinct sedimentary formations (F1, F2 and F3). The F1 formation is composed of metagreywackes, bimodal volcanic and magmatic rocks formed during basin opening at an early rifting stage (370–350 Ma) within a back-arc geodynamic setting. This extensional regime was responsible for a high thermal event recorded by a ca. 115 °C/km apparent geothermal gradient. Local anatexis of the basement rocks under the basin is dated at 351 ± 5 Ma. Basin inversion occurred between 350 and 330 Ma in response to oblique collision, with the development of large-scale dextral shear zones and syn-kinematic 340–330 Ma granite intrusions. Subsequent dextral transtension was responsible for the opening of a pull-apart basin between ca. 330 and 310 Ma with the deposition of the F2 phyllite formation that was later deformed by the ongoing dextral transcurrent Variscan tectonics at temperatures between 200 and 350 °C. Finally, the F3 terrigenous sedimentary rocks deposited at ca. 310–290 Ma in a late-orogenic extensional basin. The Alpine-related tectonic event overprinted all the temperatures below 350 °C. Although similar basins have been recognized in other External Crystalline Massifs of the Alps, the Servoz syncline is the first example that allows a major part of the polyphase tectonic evolution, since the early stages of the Devonian, to be recognized. Comparison with similar back-arc basins from the French Central massif, the Vosges massif and the Bohemian massif suggests that the External Crystalline Massifs initially belonged to the Moldanubian hinterlands of the Variscan belt.

Chondrosarcomas and osteosarcomas are malignant bone tumors with a poor prognosis when unresectable or metastasized. Moreover, radiotherapy and chemotherapy could be ineffective. MiRNAs represent an alternative therapeutic approach. Based on high-throughput functional screening, we identified four miRNAs with a potential antiproliferative effect on SW1353 chondrosarcoma cells. Individual functional validations were then performed in SW1353 cells, as well as in three osteosarcoma cell lines. The antiproliferative and cytotoxic effects of miRNAs were evaluated in comparison with a positive control, miR-342-5p. The cytotoxic effect of four selected miRNAs was not confirmed on SW1353 cells, but we unambiguously revealed that miR-4270 had a potent cytotoxic effect on HOS and MG-63 osteosarcoma cell lines, but not on SaOS-2 cell line. Furthermore, like miR-342-5p, miR-4270 induced apoptosis in these two cell lines. In addition, we provided the first report of Bcl-xL as a direct target of miR-4270. MiR-4270 also decreased the expression of the anti-apoptotic protein Mcl-1, and increased the expression of the pro-apoptotic protein Bak. Our findings demonstrated that miR-4270 has tumor suppressive activity in osteosarcoma cells, particularly through Bcl-xL downregulation.

Abstract Single cell technologies allow the interrogation of tumor heterogeneity, providing insights into tumor evolution and treatment resistance. To better understand whether circulating tumor cells (CTCs) could complement metastatic biopsies for tumor genomic profiling, we characterized 11 single CTCs and 10 pooled CTC samples at the mutational and copy number aberration (CNA) levels, and compared these results with matched synchronous tumor biopsies from 3 metastatic breast cancer patients with triple-negative (TNBC), HER2-positive and estrogen receptor-positive (ER+) tumors. Similar CNA profiles and the same patient-specific driver mutations were found in bulk tissue and CTCs for the HER2-positive and TNBC tumors, whereas different CNA profiles and driver mutations were identified for the ER+ tumor, which presented two distinct clones in CTCs defined by mutations in ESR1 Y537N and TP53, respectively. Furthermore, de novo mutational signatures derived from CTCs described patient-specific biological processes. These data suggest that tumor tissue and CTCs provide complementary clinically relevant information to map tumor heterogeneity and tumor evolution.

A new class of push-pull 1,1,4,4-tetracyanobutadienes (TCBDs) chromophores bearing a γ-pyranylidene as a pro-aromatic donor group have been developed, characterized and studied for their electrochemical, photophysical and second-order nonlinear optical (NLO) properties. [2 ​+ ​2] Cycloaddition-retroelectrocyclizations (CA-RE) with tetracyanoethylene (TCNE) allowed the formation of new TCBDs by taking advantage of the electron-donating ability of γ-pyranylidene functional groups. The limits of the reaction between TCNE and the corresponding alkynes have been investigated, both in terms of reactivity and solubility. Electrochemical studies of pyranylidene-TCBD 1a-1j revealed two reversible reduction waves typical of TCBDs, and two oxidation waves originating from the γ-pyranylidene moiety. More complex electrochemical signals have been recorded when studying chromophores bearing multiple TCBD and/or γ-pyranylidene units. All pyranylidene-TCBDs showed panchromatic absorption properties, extending to the NIR in some cases. Changes made around the electron-withdrawing TCBD units significantly affected the ICT performance of the push-pull chromophores. Computational studies have been performed on this series of compounds to rationalize the origin of their optical properties. TD-DFT calculations confirmed that the synthesized pyranylidene-TCBDs are potential NLOphores. The second-order NLO properties of all chromophores were determined by the Electric Field-Induced Second Harmonic generation (EFISH) technique, and all systems exhibited valuable NLO properties with large μβEFISH values for purely organic compounds, up to 5700 10−48 ​esu.