Development, manufacturing and testing of small launcher structures from Portugal

During the last decades the industry has seen the number of Earth orbiting satellites rise, mostly due to the need to monitor Earth as well as to establish global communication networks. Nano, micro, and small satellites have been a prime tool for answering these needs, with large and mega constellations planned, leading to a potential launch gap. An effective and commercially appealing solution is the development of small launchers, as these can complement the current available launch opportunity offer, serving a large pool of different types of clients, with a flexible and custom service that large conventional launchers cannot adequately assure. Rocket Factory Augsburg has partnered with CEiiA for the development of several structures for the RFA One rocket. The objective has been the design of solutions that are low-cost, light, and custom-made, applying design and manufacturing concepts as well as technologies from other industries, like the aeronautical and automotive, to the aerospace one. This allows for the implementation of a New Space approach to the launcher segment, while also building a supply chain and a set of solutions that enables the industrialisation of such structures for this and future small launchers. The two main systems under development have been a versatile Kick-Stage, for payload carrying and orbit insertion, and a sturdy Payload Fairing. Even though the use of components off-the-shelf have been widely accepted in the space industry for satellites, these two systems pose different challenges as they must be: highly reliable during the most extreme conditions imposed by the launch, so that they can be considered safe to launch all types of payloads. This paper thus dives deep on the solutions developed in the last few years, presenting also lessons learned during the manufacturing and testing of these structures.Comment: 10 pages, 13 figures, Manuscript presented at the 73rd International Astronautical Congress, IAC 2022, Paris, France, 18 - 22 September 202

Massive migration from the steppe is a source for Indo-European languages in Europe

We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost four hundred thousand polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of western and far eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ~8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary, and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ~24,000 year old Siberian6 . By ~6,000-5,000 years ago, a resurgence of hunter-gatherer ancestry had occurred throughout much of Europe, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ~4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ~3/4 of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ~3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for the theory of a steppe origin of at least some of the Indo-European languages of Europe

Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas

KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.This work was supported by grants from the European Research Council (ERC-GA 695566, THERACAN); the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación (MCIN/AEI/10.13039/501100011033) (grant RTC2017-6576-1), cofunded by ERDF “A way of making Europe”; the Autonomous Community of Madrid (B2017/BMD-3884 iLung-CM), cofunded by FSE and ERDF “A way of making Europe”; the CRIS Cancer Foundation, the Scientific Foundation of the Spanish Association Against Cancer (GC166173694BARB); an ERA PerMed grant, funded by the Instituto de Salud Carlos III (AC20/00114), the Scientific Foundation of the Spanish Association Against Cancer (PERME20707BARB) and the European Union’s Horizon 2020 program (779282) to MB; and the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación (grant RTI2018-094664-B-I00), cofunded by ERDF “A way of making Europe” to MM and MB. Additional funding included grants from the Spanish National Research and Development Plan, Instituto de Salud Carlos III, ERDF “A way of making Europe” (PI20/01837 and DTS19/00111); the Scientific Foundation of the Spanish Association Against Cancer (LABAE20049RODR) to SRP; the Instituto de Salud Carlos III (PI19/00514), cofunded by ERDF “A way of making Europe” to CG; the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación (grant PID2020-116705RB-I00); and the Scientific Foundation of the Spanish Association Against Cancer (LABAE211678DROS) to MD. MB is a recipient of an endowed chair from the AXA Research Fund. M Salmón was supported by a predoctoral contract “Severo Ochoa” (BES-2016-079096) from the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación. OB is a recipient of a fellowship from the Formación de Personal Investigador (FPI) program of the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación. FFG was supported by a Formación de Profesorado Universitario (FPU) fellowship from the Ministerio de Universidades

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

Comparison of Chemical Composition, Physicochemical Parameters, and Antioxidant and Antibacterial Activity of the Essential Oil of Cultivated and Wild Mexican Oregano Poliomintha longiflora Gray

Mexican oregano Poliomintha longiflora Gray located in the municipality of Higueras, Nuevo Leon, Mexico was collected during the autumn (September, OCO), winter (January, OCI) and summer (June, OCV) seasons, under cultivation conditions. It was also collected in wild conditions during the autumn (OSO). Essential oil (EO) was extracted from leaves and the color, refractive index and density were reported. The EO yield, antioxidant activity by ORAC assay, thymol and carvacrol concentration and antibacterial activity were statistically compared (p-value = 0.05). Among the various harvests, the highest EO yield, antioxidant activity, thymol and carvacrol content and antibacterial activity against Salmonella Typhi were observed in leaves harvested in autumn. In order to compare wild oregano with cultivated oregano, analyses were performed in the season with the highest essential oil yield and antioxidant activity, recorded in autumn. The main difference found was the ratio of thymol:carvacrol in wild oregano oil, which was 1:8.6, while in cultivated oregano, it was approximately 1:2, which was maintained in all three seasons. The EO on wild conditions showed the best antibacterial activity in Salmonella Typhi. On the other hand, wild and cultivated oregano showed similar antioxidant activity. One advantage of the use of cultivated oregano is that its supply is guaranteed, in contrast to that of wild oregano

Community-Based Approaches to Reducing Health Inequities and Fostering Environmental Justice through Global Youth-Engaged Citizen Science

Growing socioeconomic and structural disparities within and between nations have created unprecedented health inequities that have been felt most keenly among the world’s youth. While policy approaches can help to mitigate such inequities, they are often challenging to enact in under-resourced and marginalized communities. Community-engaged participatory action research provides an alternative or complementary means for addressing the physical and social environmental contexts that can impact health inequities. The purpose of this article is to describe the application of a particular form of technology-enabled participatory action research, called the Our Voice citizen science research model, with youth. An overview of 20 Our Voice studies occurring across five continents indicates that youth and young adults from varied backgrounds and with interests in diverse issues affecting their communities can participate successfully in multiple contributory research processes, including those representing the full scientific endeavor. These activities can, in turn, lead to changes in physical and social environments of relevance to health, wellbeing, and, at times, climate stabilization. The article ends with future directions for the advancement of this type of community-engaged citizen science among young people across the socioeconomic spectrum

Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4

We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10-34, OR = 1.43[1.26-1.60]) and rs1234317-T (P = 1.16×10-28, OR = 1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait. © 2013 Manku et al

Factorial validity of the Toronto Alexithymia Scale (TAS-20) in clinical samples: A critical examination of the literature and a psychometric study in anorexia nervosa

There is extensive use of the 20-item Toronto Alexithymia Scale (TAS-20) in research and clinical practice in anorexia nervosa (AN), though it is not empirically established in this population. This study aims to examine the factorial validity of the TAS-20 in a Portuguese AN sample (N = 125), testing four different models (ranging from 1 to 4 factors) that were identified in critical examination of existing factor analytic studies. Results of confirmatory factor analysis (CFA) suggested that the three-factor solution, measuring difficulty identifying (DIF) and describing feelings (DDF), and externally oriented thinking (EOT), was the best fitting model. The quality of measurement improves if two EOT items (16 and 18) are eliminated. Internal consistency of EOT was low and decreased with age. The results provide support for the factorial validity of the TAS-20 in AN. Nevertheless, the measurement of EOT requires some caution and may be problematic in AN adolescents.Center for Psychology at the University of Porto, Portuguese Science Foundation (FCT UID/PSI/00050/2013) and EU FEDER through COMPETE 2020 program (POCI-01-0145-FEDER-007294info:eu-repo/semantics/acceptedVersio

Genome of Herbaspirillum seropedicae Strain SmR1, a Specialized Diazotrophic Endophyte of Tropical Grasses

The molecular mechanisms of plant recognition, colonization, and nutrient exchange between diazotrophic endophytes and plants are scarcely known. Herbaspirillum seropedicae is an endophytic bacterium capable of colonizing intercellular spaces of grasses such as rice and sugar cane. The genome of H. seropedicae strain SmR1 was sequenced and annotated by The Paraná State Genome Programme—GENOPAR. The genome is composed of a circular chromosome of 5,513,887 bp and contains a total of 4,804 genes. The genome sequence revealed that H. seropedicae is a highly versatile microorganism with capacity to metabolize a wide range of carbon and nitrogen sources and with possession of four distinct terminal oxidases. The genome contains a multitude of protein secretion systems, including type I, type II, type III, type V, and type VI secretion systems, and type IV pili, suggesting a high potential to interact with host plants. H. seropedicae is able to synthesize indole acetic acid as reflected by the four IAA biosynthetic pathways present. A gene coding for ACC deaminase, which may be involved in modulating the associated plant ethylene-signaling pathway, is also present. Genes for hemagglutinins/hemolysins/adhesins were found and may play a role in plant cell surface adhesion. These features may endow H. seropedicae with the ability to establish an endophytic life-style in a large number of plant species