Unfavorable genetic correlations between growth and wood quality traits are one of the biggest challenges in advanced conifer breeding programs. To examine and deal with such correlation, increment ...cores were sampled at breast height from 5,618 trees in 524 open-pollinated families in two 21-year-old Norway spruce progeny trials in southern Sweden, and age trends of genetic variation, genetic correlation, and efficiency of selection were investigated. Wood quality traits were measured on 12-mm increment cores using SilviScan. Heritability was moderate (~0.4–0.5) for wood density and modulus of elasticity (MOE) but low (~0.2) for microfibril angle (MFA). Different age trends were observed for wood density, MFA, and MOE, and the lower heritability of MFA relative to wood density and MOE in Norway spruce contrasted with general trends of the three wood quality traits in pine. Genetic correlations among growth, wood density, MFA, and MOE increased to a considerably high value from pith to bark with unfavorable genetic correlations (−0.6 between growth and wood density, −0.74 between growth and MOE). Age–age genetic correlations reached 0.9 after ring 4 for diameter at breast height (DBH), wood density, MFA, and MOE traits. Early selections at ring 10 for diameter and at ring 6 or 7 for wood quality traits had similar effectiveness as selection conducted at reference ring 15. Selection based on diameter alone produced 19.0 % genetic gain in diameter but resulted in 4.8 % decrease in wood density, 9.4 % decrease in MOE, and 8.0 % increase in MFA. Index selection with a restriction of no change in wood density, MOE, and MFA, respectively, produced relatively lower genetic gains in diameter (16.4, 12.2, and 14.1 %, respectively), indicating such index selection could be implemented to maintain current wood density. Index selection using economic weights is, however, recommended for maximum economic efficiency.
Shade avoidance syndrome (SAS) is well-characterized in the shade intolerant model species Arabidopsis thaliana whereas much less is known about shade tolerance response (STR), yet regulation of SAS ...and STR with reference to conifers remains poorly understood. We conducted a comparative study of two conifer species with contrasting responses to shade, Scots pine (shade-intolerant) and Norway spruce (shade-tolerant), with the aim to understand mechanisms behind SAS and STR in conifers. Pine and spruce seedlings were grown under controlled light and shade conditions, and hypocotyl and seedling elongation following different light treatments were determined in both species as indicators of shade responses. Red to farred light ratio (R:FR) was shown to trigger the shade response in Norway spruce. In Scots pine, we observed an interaction between R:FR and light intensity. RNA sequencing (RNA-Seq) data revealed that SAS and STR responses included changes in expression of genes involved primarily in hormone signalling and pigment biosynthesis. From the RNA-Seq analysis, we propose that although some aspects of shade response appear to be conserved in angiosperms and gymnosperms, yet the underlying mechanisms may be different in gymnosperms that warrants further research.
The current distribution and population structure of many species were, to a large extent, shaped by cycles of isolation in glacial refugia and subsequent population expansions. Isolation in and ...postglacial expansion through heterogeneous environments led to either neutral or adaptive divergence. Norway spruce is no exception, and its current distribution is the consequence of a constant interplay between evolutionary and demographic processes. We investigated population differentiation and adaptation of Norway spruce for juvenile growth, diameter of the stem, wood density, and tracheid traits at breast height. Data from 4461 phenotyped and genotyped Norway spruce from 396 half‐sib families in two progeny tests were used to test for divergent selection in the framework of QST vs. FST. We show that the macroscopic resultant trait (stem diameter), unlike its microscopic components (tracheid dimensions) and juvenile growth, was under divergent selection that predated the Last Glacial Maximum. Altogether, the current variation in these phenotypic traits in Norway spruce is better explained by local adaptation to ancestral environments than to current ones, where populations were partly preadapted, mainly through growth‐related traits.
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in ...advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events).
Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected.
Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio HR, 0.49 95% CI, 0.35 to 0.68; log-rank
< .0001; median, 24.0
11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4
9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 95% CI, 0.49 to 1.00; log-rank
= .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 95% CI, 0.98 to 1.031;
= .69).
Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.
Garantizar la integridad de las elecciones constituye un objetivo prioritario de los Estados democráticos. Las elecciones en el mundo digitalizado evidencian un elenco interminable de amenazas cuyo ...epicentro parte de la datificación y del uso de herramientas y técnicas al servicio de la manipulación de la voluntad política. La exigencia de transparencia, y la definición de sus requisitos, para los proveedores de la publicidad política, así como la prohibición de técnicas de segmentación de este tipo de publicidad especialmente durante la campaña electoral constituyen un deber jurídico inaplazable para el legislador nacional y europeo. De ahí que en este trabajo se analice la propuesta de la Comisión del Reglamento del Parlamento Europeo y del Consejo sobre la transparencia y la segmentación política, tras la fijación de posición del Parlamento Europeo (febrero 2023), y se reflexione sobre algunas de sus implicaciones y efectos en la normativa electoral española.
Non-small-cell lung cancer (NSCLC) is terminal in most patients with locally advanced stage disease. We aimed to assess the antitumour activity and safety of neoadjuvant chemoimmunotherapy for ...resectable stage IIIA NSCLC.
This was an open-label, multicentre, single-arm phase 2 trial done at 18 hospitals in Spain. Eligible patients were aged 18 years or older with histologically or cytologically documented treatment-naive American Joint Committee on Cancer-defined stage IIIA NSCLC that was deemed locally to be surgically resectable by a multidisciplinary clinical team, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received neoadjuvant treatment with intravenous paclitaxel (200 mg/m2) and carboplatin (area under curve 6; 6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was progression-free survival at 24 months, assessed in the modified intention-to-treat population, which included all patients who received neoadjuvant treatment, and in the per-protocol population, which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Safety was assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03081689, and is ongoing but no longer recruiting patients.
Between April 26, 2017, and Aug 25, 2018, we screened 51 patients for eligibility, of whom 46 patients were enrolled and received neoadjuvant treatment. At the time of data cutoff (Jan 31, 2020), the median duration of follow-up was 24·0 months (IQR 21·4–28·1) and 35 of 41 patients who had tumour resection were progression free. At 24 months, progression-free survival was 77·1% (95% CI 59·9–87·7). 43 (93%) of 46 patients had treatment-related adverse events during neoadjuvant treatment, and 14 (30%) had treatment-related adverse events of grade 3 or worse; however, none of the adverse events were associated with surgery delays or deaths. The most common grade 3 or worse treatment-related adverse events were increased lipase (three 7%) and febrile neutropenia (three 7%).
Our results support the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable stage IIIA NSCLC. Neoadjuvant chemoimmunotherapy could change the perception of locally advanced lung cancer as a potentially lethal disease to one that is curable.
Bristol-Myers Squibb, Instituto de Salud Carlos III, European Union's Horizon 2020 research and innovation programme.
This work analyses the influence of fine concrete fractions (<5 mm) of different natures -calcareous (HcG) and siliceous (HsT)-obtained from construction and demolition waste (C&DW) on the behaviour ...of blended cement pastes with partial replacements between 5 and 10%. The two C&DW fractions were characterised by different instrumental techniques. Subsequently, their lime-fixing capacity and the physico-mechanical properties of the blended cement pastes were analysed. Lastly, the environmental benefits of reusing these fine wastes in the manufacture of future eco-efficient cement pastes were examined. The results show that HsT and HcG exhibit weak pozzolanic activity, owing to their low reactive silica and alumina content. Despite this, the new cement pastes meet the physical and mechanical requirements of the existing regulations for common cements. It should be highlighted that the blended cement pastes initially showed a coarser pore network, but then they underwent a refinement process between 2 and 28 days, along with a gain in compressive strength, possibly due to the double pozzolanic and filler effect of the wastes. The environmental viability of the blended cements was evaluated in a Life Cycle Assessment (LCA) concluding that the overall environmental impact could be reduced in the same proportion of the replacement rate. This is in line with the Circular Economy goals and the 2030 Agenda for Sustainable Development.
Annual growth, fibre and wood properties of Norway spruce are all under strong influence from genetics, age and weather. They change dynamically, particularly at young ages. Most genetic research and ...tree improvement programs are based on data from this most dynamic phase of the life of trees, affected by differences in weather among sites and years. In the work presented, influences of age and weather were investigated and modelled at the detail of annual rings and at the sub-tree ring level of earlywood, transitionwood and latewood. The data used were analysed from increment cores sampled at age 21 years from almost 6000 Norway spruce trees of known genetic origin, grown on two sites in southern Sweden. The traits under investigation were radial growth, cell widths, cell numbers, cell wall thickness and coarseness as a measure of biomass allocation at cell level. General additive mixed models (GAMMs) were fitted to model the influences of age, local temperature and precipitation. The best models were obtained for number of tracheids formed per year, ring width, average radial tracheid width in earlywood, and ring averages for tangential tracheid width and coarseness. Considering the many sources behind the huge variation, the explained part of the variability was high. For all traits, models were developed using both total tree age and cambial age (ring number) to express age. Comparisons indicate that the number of cell divisions and ring width are under stronger control of tree age, but the other traits under stronger control of cambial age. The models provide a basis to refine data prior to genetic evaluations by compensating for estimated differences between sites and years related to age and weather rather than genetics. Other expected applications are to predict performance of genotypes in relation to site or climate and simulation of climate change scenarios.
Genome-wide association studies (GWAS) identify loci underlying the variation of complex traits. One of the main limitations of GWAS is the availability of reliable phenotypic data, particularly for ...long-lived tree species. Although an extensive amount of phenotypic data already exists in breeding programs, accounting for its high heterogeneity is a great challenge. We combine spatial and factor-analytics analyses to standardize the heterogeneous data from 120 field experiments of 483,424 progenies of Norway spruce to implement the largest reported GWAS for trees using 134 605 SNPs from exome sequencing of 5056 parental trees.
We identify 55 novel quantitative trait loci (QTLs) that are associated with phenotypic variation. The largest number of QTLs is associated with the budburst stage, followed by diameter at breast height, wood quality, and frost damage. Two QTLs with the largest effect have a pleiotropic effect for budburst stage, frost damage, and diameter and are associated with MAP3K genes. Genotype data called from exome capture, recently developed SNP array and gene expression data indirectly support this discovery.
Several important QTLs associated with growth and frost damage have been verified in several southern and northern progeny plantations, indicating that these loci can be used in QTL-assisted genomic selection. Our study also demonstrates that existing heterogeneous phenotypic data from breeding programs, collected over several decades, is an important source for GWAS and that such integration into GWAS should be a major area of inquiry in the future.
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