A dense genome-wide meta-analysis provides new QTLs, reveals breeding history trends and identifies new candidate genes for yield, plant height, grain weight, and heading time of spring barley. This study contributes new knowledge on quantitative trait loci (QTLs) and candidate genes for adaptive traits and yield in two-rowed spring barley. A meta-analysis of a network of field trials, varying in latitude and sowing date, with 151 cultivars across several European countries, increased QTL detection power compared to single-trial analyses. The traits analysed were heading date (HD), plant height (PH), thousand-grain weight (TGW), and grain yield (GY). Breaking down the analysis by the main genotype-by-environment trends revealed QTLs and candidate genes specific to conditions like sowing date and latitude. A historical look on the evolution of QTL frequencies revealed that early selection focused on PH and TGW, likely due to their high heritability. GY selection occurred later, facilitated by reduced variance in other traits. The study observed that favourable alleles for plant height were often fixed before those for grain yield and TGW. Some regions showed linkage in repulsion, suggesting targets for future breeding. Several candidate genes were identified, including known genes and new candidates based on orthology with rice. Remarkably, the deficiens allele of gene Vrs1 appears associated with higher GY. These findings provide valuable insights for barley breeders aiming to improve yield and other agronomic traits.

Cannabinoids are compounds with increasing scientific interest, particularly due to their interaction with the endocannabinoid system via CBR1 and CBR2 receptors. They can interfere with appetite, pain, and sleep or develop mood changes in the individual. Cannabidiol (CBD) is a well-known cannabinoid with potential benefits, including reducing epilepsy seizures, alleviating anxiety and obsessive-compulsive disorder (OCD) symptoms, aiding in Tourette Syndrome (a neurodevelopmental disorder), depression, sleep disorders, and promising in the treatment of cancer, pain relief, and heart health. Although generally safe, CBD can have side effects, including drug metabolism interference, fertility, and liver function. In addition, it can be administered by oral, sublingual, transdermal, or inhalation via each one with different bioavailability. The application of nanotechnology, specifically through colloidal carrier systems, holds promising potential for maximizing CBD's efficacy and pharmacological profile. There are reported CBD extraction methods using ethanol, carbon dioxide, deionised water, and non-polar oils like olive or coconut oil. Green extraction methods have gained popularity due to their higher yields, shorter extraction time, and reduced costs. A specific dose with the desired effects is challenging due to individual factors, with most studies suggesting a range between less than 1 and 50 mg/kg/d. This review aims to explore the principles of CBD-based products development, focusing on extraction methods and purification processes of this cannabinoid for tinctures, topicals, and other pharmaceutical forms, as well as further research to attain the objectives.

Integrating genomic prediction (GP) and biophysical crop models has the potential to support plant breeding in defining adapting strategies to climate change. However, whether this integrated approach can actually broaden the prediction domain to unexplored environments is still unclear. We showed how crop models can extend GP to new environments and capture genotype-specific response to future climate conditions. Days to heading (HD) in spring barley was used as a case study, given the primary role of phenology for crop adaptation. Phenotypic and genomic (50 K Illumina SNP array) data for 151 two-row genotypes were used, with HD determined on 17 site x season combinations spread from the Mediterranean basin to Northern Europe. A dedicated modelling solution was developed by integrating approaches from the WARM and WOFOST crop models, with optimization algorithms used to derive accession-specific values of most relevant model parameters. GP was carried out on the model parameters with the R package rr-BLUP, and the resulting markers-derived parameters were used to simulate heading date with the crop model explicitly reproducing G x E x M interactions. Prediction accuracy for unknown genotypes was evaluated through ten-fold cross validation, whereas the capability of crop models to extend GP to unexplored environments was evaluated with a leave-one site-out cross validation. Results were encouraging, with average R2, RMSE and Nash-Sutcliffe efficiency for unknown genotypes in unexplored environments equal to 0.97, 9.27, and 0.94, respectively. Accession-specific HD under future climates (20 seasons centred on 2060 generated for the IPSL-CM6A-LR realization of SSP3-7.0) highlighted large G x E x M interactions, confirming the potential of integrating crop modelling and GP to supporting breeding programs targeting adaptation to climate change.

### Competing Interest Statement The authors have declared no competing interest. Agencia Estatal de Investigación, https://ror.org/003x0zc53, AGL2016-80967-R, PID2019 111621RB I00, PID2022 142116OB I00 Gobierno de Aragón, https://ror.org/0425pg203, Pre-doctoral grant to Francesc Montardit-Tarda, call 2019-2023

Abstract Background: The integration of next-generation sequencing (NGS) into routine clinical practice is often hindered by financial and logistical challenges, resulting in diagnostic and therapeutic disparities among patients. Addressing these issues, the SOLTI-1903 HOPE study (NCT04497285) seeks to evaluate the feasibility of implementing a molecular screening program that actively involves patients with advanced breast cancer (ABC) in the management of their disease. By empowering patients, this study aims to gain a comprehensive understanding of the genomic landscape of ABC and to facilitate patient access to matched targeted therapies in Spain Methods: In the SOLTI-1903 HOPE study, a patient-centric approach was adopted, allowing patients living anywhere in Spain, and diagnosed with ABC, to actively lead their inclusion, participation, and follow-up using a digital tool (DT). Patients signed an informant consent, and then provided clinical information and underwent a liquid biopsy (LBx) using the Guardant360 panel at a local laboratory. LBx samples could be obtained at the moment of progressive disease (PD), when a new line of treatment was started < 8 weeks before extraction (PT), or during treatment with stable disease o partial response lasting more than 8 weeks (SD/PR). Clinical and molecular findings were evaluated by a Molecular Advisory Board (MAB), which generated a comprehensive report explaining the observed alterations and listing potentially beneficial matched targeted treatments. The primary endpoint of this subanalysis was to compare the genomic outcomes between LBx samples obtained at SD and those obtained at PD or PT. In the study, tissue samples were also collected and analysed by Foundation but this analysis will be reported in other communications. Results: From October 2020 to May 2023, a total of 273 blood samples were obtained from 253 patients diagnosed with ABC, with the majority being HR+/HER2- (81%), followed by HER2-positive (13%) and triple-negative (6%). Mean turnaround time was 10.9 days from blood collection to final result. Despite nearly 40% of patients being SD or PR, in 79.9% of the LBx (n=218), one or more genomic alterations were detected, and among these, 74.0% (n=202) were classified as pathogenic. Among the 74 genes analyzed by the Guardant360 panel, 8 genes were classified as tiers I-III according to the ESCAT levels of clinical relevance. In 150 LBx samples (54.9%), one or more pathogenic alterations were associated with ESCAT levels I-III, while only the remaining 52 LBx samples (19.1%) with pathogenic alterations were not associated with any ESCAT levels I-III. Among the analyzed LBx samples, a total of 928 distinct gene alterations were identified. Of these, 650 alterations (70.1%) were classified as pathogenic, while 278 (29.9%) were categorized as variants of unknown significance or lacked a reported impact. Notably, 25% (n=323) of the pathogenic gene alterations were further classified as ESCAT I-III. Out of the 273 LBx samples, 140 were obtained at PD, 30 at PT, and 103 at SD/PR. Circulating tumor DNA (ctDNA) was detected in 91.4% of PD samples, 86.7% of PT samples, and 62.1% of SD/PR samples (p< 0.001). Alterations classified as ESCAT levels I-III were observed in 70% of PD samples, 60% of PT samples, and 33% of SD/PR samples (p< 0.001). In 20 patients, LBx was repeated, with 16 of them having the first LBx obtained during SD/PR and the second LBx collected during PD or PT. The detection rate of ctDNA increased significantly from 18.7% (n=3) to 87.5% (n=14) (p< 0.001). The number of LBx samples with ESCAT levels I-III alterations also showed a significant increase from 12.5% (n=2) to 68.7% (n=11) (p=0.0032). Conclusions: Our findings highlight the importance of obtaining LBx samples during disease progression -compared to SD/PR- to gain greater genomic informativeness and better guide personalized treatment approaches for patients with advanced breast cancer. Citation Format: Tomás Pascual, Elia Seguí, Ruben Olivera-Salguero, Juan Miguel Cejalvo, Mafalda Oliveira, Pablo Tolosa, Maria Vidal, Marcos Malumbres, Joaquín Gavilá, Cristina Saura, Sonia Pernas, Rafael López, Mireia Margelí, Judith Balmaña, Montserrat Muñoz, Isabel Blancas, Valentina Boni, Eva Ciruelos, Elena Galve, Antonia Perelló, Rodrigo Sánchez-Bayona, Susana De La Cruz, Miguel De La Hoya, Aura Blanch-Torras, Rosana Sposito, Jordi Canes, Helena Masanas, Rosa Olmos, Margarita Forns, Maria José Prieto, Ana Casas, Aleix Prat. Enhancing Informative Outcomes with Liquid Biopsy in a Real-World Population of Patients with Advanced Breast Cancer: Analysis of the SOLTI-1903 HOPE Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-02.

This study contributes new knowledge on quantitative trait loci (QTLs) and candidate genes for adaptive traits and yield in two-rowed spring barley. A meta-analysis of a network of field trials, varying in latitude and sowing date, with 151 cultivars across several European countries, increased QTL detection power compared to single-trial analyses. The traits analysed were heading date (HD), plant height (PH), thousand-grain weight (TGW), and grain yield (GY). Breaking down the analysis by the main genotype-by-environment trends revealed QTLs and candidate genes specific to conditions like sowing date and latitude. A historical look on the evolution of QTL frequencies revealed that early selection focused on PH and TGW, likely due to their high heritability. GY selection occurred later, facilitated by reduced variance in other traits. The study observed that favourable alleles for plant height were often fixed before those for grain yield and TGW. Some regions showed linkage in repulsion, suggesting targets for future breeding. Several candidate genes were identified, including known genes and new candidates based on orthology with rice. Remarkably, the deficiens allele of gene Vrs1 , appears associated to higher GY. These findings provide valuable insights for barley breeders aiming to improve yield, and other agronomic traits. Highlight A dense genome-wide meta-analysis provides new QTLs, reveals breeding history trends and identifies new candidate genes for yield, plant height, grain weight and heading time of spring barley. ### Competing Interest Statement The authors have declared no competing interest.

Nowadays, resveratrol, a polyphenolic phytoalexin is increasingly included in the formulas of cosmetic products and dermatology as an active ingredient, as a consequence of the well-known health beneficial properties, namely antioxidant, anti-inflammatory, anti-viral and anti-bacterial effects. This important compound can be biosynthesized naturally by plants or by industrial synthetic processes. Apart from its anti-inflammatory and antioxidant effects, a broad spectrum of effects has been attributed to the use of this compound such as anti-aging, skin-whitening, anti-angiogenic, collagen I and III stimulation (in fibroblasts) and estrogen-like effects, as well as the ability to protect cells against hydrogen peroxide-induced oxidative stress and UV-irradiation-mediated cell death. In cosmetology and dermatology has been popular because of its ability to penetrate the skin barrier and its anti-aging activity. In fact, resveratrol as an important impact on the regulation of inflammation and, as consequence, repair-related processes in skin. Furthermore, when administered either topically or orally has been proven to be safe and also to overcome the skin barrier. This review will focus in its potential application on melasma treatment and in photo-aging. Resveratrol chemistry, pharmacology, mechanism of action and evidence of its efficacy as photo skin aging protector and its potential use in melasma is discussed.

ABSTRACT Consistent gene annotation in crops is becoming harder as genomes for new cultivars are frequently published. Gene sets from recently sequenced accessions have different gene identifiers to those on the reference accession, and might be of higher quality due to technical advances. For these reasons there is a need to define pangenes, which represent all known syntenic orthologues for a gene model and can be linked back to the original annotation sources. A pangene set effectively summarizes our current understanding of the coding potential of a crop and can be used to inform gene model annotation in new cultivars. Here we present an approach (get_pangenes) to identify and analyze pangenes that is not biased towards the reference annotation. The method involves computing Whole Genome Alignments (WGA), which are used to estimate gene model overlaps. After a benchmark on Arabidopsis , rice, wheat and barley datasets, we find that minimap2 performs better than the GSAlign WGA algorithm. Our results show that pangenes recapitulate known phylogeny-based orthologies while adding extra core gene models in rice. More importantly, get_pangenes can also produce clusters of genome segments (gDNA) that overlap with gene models annotated in other cultivars. By lifting-over CDS sequences, gDNA clusters can help refine gene models across individuals and confirm or reject observed gene Presence-Absence Variation. A collection of flowering-related genes from the barley pangenome are discussed in detail. Documentation and source code are available at https://github.com/Ensembl/plant-scripts .

Crop pangenomes made from individual cultivar assemblies promise easy access to conserved genes, but genome content variability and inconsistent identifiers hamper their exploration. To address this, we define pangenes, which summarize a species coding potential and link back to original annotations. The protocol get_pangenes performs whole genome alignments (WGA) to call syntenic gene models based on coordinate overlaps. A benchmark with small and large plant genomes shows that pangenes recapitulate phylogeny-based orthologies and produce complete soft-core gene sets. Moreover, WGAs support lift-over and help confirm gene presence-absence variation. Source code and documentation: https://github.com/Ensembl/plant-scripts .

Light quality influence on barley development is poorly understood. We exposed three barley genotypes with either sensitive or insensitive response to two light sources producing different light spectra, fluorescent bulbs, and metal halide lamps, keeping constant light intensity, duration, and temperature. Through RNA-seq, we identified the main genes and pathways involved in the genotypic responses. A first analysis identified genotypic differences in gene expression of development-related genes, including photoreceptors and flowering time genes. Genes from the vernalization pathway of light quality-sensitive genotypes were affected by fluorescent light. In particular, vernalization-related repressors reacted differently: HvVRN2 did not experience relevant changes, whereas HvOS2 expression increased under fluorescent light. To identify the genes primarily related to light quality responses, and avoid the confounding effect of plant developmental stage, genes influenced by development were masked in a second analysis. Quantitative expression levels of PPD-H1, which influenced HvVRN1 and HvFT1, explained genotypic differences in development. Upstream mechanisms (light signaling and circadian clock) were also altered, but no specific genes linking photoreceptors and the photoperiod pathway were identified. The variety of light-quality sensitivities reveals the presence of possible mechanisms of adaptation of winter and facultative barley to latitudinal variation in light quality, which deserves further research.

Microbial production of hyaluronic acid (HA) is an area of research that has been gaining attention in recent years due to the increasing demand for this biopolymer for several industrial applications. Hyaluronic acid is a linear, non-sulfated glycosaminoglycan that is widely distributed in nature and is mainly composed of repeating units of N-acetylglucosamine and glucuronic acid. It has a wide and unique range of properties such as viscoelasticity, lubrication, and hydration, which makes it an attractive material for several industrial applications such as cosmetics, pharmaceuticals, and medical devices. This review presents and discusses the available fermentation strategies to produce hyaluronic acid.

The SOLTI-1903 HOPE study aims to assess the feasibility of a molecular screening program promoting active participation of patients with Advanced Breast Cancer (ABC) in the management of their disease to better characterize the genomic landscape of ABC and to facilitate pt access to matched-targeted therapies in Spain. HOPE (NCT04497285) is a patient-centric study where pts diagnosed with ABC lead their inclusion, participation, and follow-up through a digital tool (DT). They report clinical information and provide archival tumor samples to be analyzed by FoundationOne CDx. At progression disease, patients undergo a liquid biopsy with the Guardant360 panel. Clinical and genomic information is discussed by a Molecular Advisory Board (MAB) that issues a report explaining the alterations and enumerating potentially useful targeted treatments. Then, participants record disease evolution in the DT for 2y. The primary objective is to assess the real-world clinical practice of integrating molecular profiling into the Standard of Care management of pts with ABC. Between Oct 2020 and Feb 2022, 604 patients were included in the study, and the median age was 51 ys (range 27-82y). The most common reported IHC subtype was ER+/HER2- (74%), followed by HER2+ (14%) and triple negative (12%). 512 tumor samples were received from 423 patients, and DNA-seq results with positive results were obtained in 298 (58%) cases. Common alterations were PIK3CA mut (34%), CCND1 amp (27%), and TP53 mut (26%). Blood extractions were obtained from 378 patients, and ctDNA detection was observed in 303 (80%) cases. Frequently mutated genes were PIK3CA (38%), TP53 (38%), and ESR1 (29%). As of April 2023, the MAB reviewed 306 cases, observing at least one ESCAT I-III alteration in 75% of cases. Of these, only 15% were already known before HOPE. After a mean follow-up of 1.3ys, 20% of ABC cases discussed received a targeted treatment. Patient-centric molecular screening programs implemented on a nationwide level are viable, have the potential to impact treatment decisions in a subgroup of patients and seems more efficient to bring patients to receive treatments targeted to the identified alterations.

Abstract Background Quality of life (QOL) is a critical factor in decision-making for advanced breast cancer (ABC). There is a need to improve how QOL and treatment-related side effects (SEs) that impact it are clinically assessed. We examined healthcare professionals’ (HCPs’) and patients’ perspectives on the importance of QOL discussions and the impact of SEs on QOL in clinical settings. Patients and Methods A cross-sectional online survey was conducted (7/2020-5/2021) among oncologists, nurses, and patients with HR+/HER2− ABC in 7 countries. Results The survey was completed by 502 HCPs and 467 patients. Overall, 88% of oncologists and 49% of patients recalled QOL discussions at follow-up. In the first- through fourth-line (1L, 2L, 3L, and 4L) settings, respectively, 48%, 57%, 79%, and 85% of oncologists reported QOL was very important; 73% and 45% of patients receiving 1L and 2L treatment and 40% receiving 3L+ treatment indicated QOL was important. Patients reported that insomnia, anxiety, back pain, fatigue, diarrhea, hot flashes, low sexual interest, and loss of appetite had a moderate/severe impact on QOL. Of patients experiencing certain SEs, ≥64% did not discuss them with HCPs until there was a moderate/severe impact on QOL. In patients receiving a CDK4/6 inhibitor, SEs, including insomnia, diarrhea, back pain, and fatigue, had a moderate/severe impact on QOL. Conclusions This survey discovered disconnects between HCPs and patients with ABC on the importance of QOL discussions and the impact of SEs on QOL. These data support the use of ABC-specific QOL questionnaires that closely monitor SEs impacting QOL.

Grape stems have emerged as a promising natural ingredient in the cosmetics industry due to their abundance of phenolic compounds, known for their antioxidant and anti-inflammatory properties. These compounds have shown great potential in promoting skin health, fighting signs of aging, and shielding against environmental stressors. With high concentrations of resveratrol, flavonoids, and tannins, grape stems have garnered attention from cosmetic scientists. Research has indicated that phenolic compounds extracted from grape stems possess potent antioxidant abilities, effectively combating free radicals that accelerate aging. Moreover, these compounds have demonstrated the capacity to shield the skin from UV damage, boost collagen production, and enhance skin elasticity. Cosmetic formulations incorporating grape stem extracts have displayed promising results in addressing various skin concerns, including reducing wrinkles, fine lines, and age spots, leading to a more youthful appearance. Additionally, grape stem extracts have exhibited anti-inflammatory properties, soothing irritated skin and diminishing redness. Exploring the potential of grape stem phenolic compounds for cosmetics paves the way for sustainable and natural beauty products. By harnessing the beauty benefits of grape stems, the cosmetics industry can provide effective and eco-friendly solutions for consumers seeking natural alternatives. Ongoing research holds the promise of innovative grape stem-based formulations that could revolutionize the cosmetics market, fully unlocking the potential of these extraordinary botanical treasures.

This study explores the potential of Spanish germplasm for the development of hybrids adapted to southern Europe, a new region for hybrid barley (Hordeum vulgare). A set of 140 locally adapted, advanced breeding lines, developed in a Spanish public breeding program, were evaluated for their potential to widen the germplasm available for hybrid barley development. A subset of 24 lines was introduced into three-way hybrid combinations and tested in a field trial network of four locations and 2 yr. The hybrid performance of the rest of the lines was estimated based on genomic prediction models. No three-way hybrid exceeded the best check. We succeeded in identifying lines with high general combining ability, which could produce promising two-way hybrids. Some were among those tested in the field, whereas others resulted from genomic predictions, validating the strategy followed of mining locally adapted breeding lines. Rachis brittleness detected in field trials revealed a low but detrimental effect of the presence of alternative brittle mutations in the hybrid combination. The success of hybrid breeding in southern Europe requires further investigation of the underlying heterotic patterns, and appropriate management of brittle genes through prebreeding, to widen the germplasm accessible for hybrid barley breeding.

In cereals with hollow internodes, lodging resistance is influenced by morphological characteristics such as internode diameter and culm wall thickness. Despite their relevance, knowledge of the genetic control of these traits and their relationship with lodging is lacking in temperate cereals such as barley. To fill this gap, we developed an image-analysis based protocol to accurately phenotype culm diameter and culm wall thickness across 261 barley accessions. Analysis of culm trait data collected from field trials in 7 different environments revealed genetic control as supported by high heritability values, as well as genotype-by-environment interactions. The collection was structured mainly according to row-type, which had a confounding effect on culm traits as evidenced by phenotypic correlations. In addition, culm traits showed strong negative correlations with lodging but weak correlations with plant height across row-types, indicating the possibility of improving lodging resistance independent of plant height. Using 50k iSelect SNP genotyping data, we conducted multi-environment genome-wide association studies using mixed model approach across the whole panel and row-type subsets: we identified a total of 192 QTLs for the studied traits, including subpopulation-specific QTLs and several main effect loci for culm traits showing negative effects on lodging without impacting plant height. Providing first insights into the genetic architecture of culm morphology in barley and the possible role of candidate genes involved in hormone and cell wall related pathways, this work supports the potential of loci underpinning culm features to improve lodging resistance and increase barley yield stability under changing environments. One-sentence summary Genetic analysis of a diverse collection of European barleys reveals genomic regions underpinning stem morphological features associated with lodging resistance.

Health-related quality of life (HRQOL) is increasingly recognized as important when evaluating cancer treatments. The use, reporting, and analysis of patient-reported outcome measures (PROMs), however, are not standardized in clinical trials and are often poorly implemented in clinical practice. We report the results of a systematic literature review (PubMed search: January 1, 2000 to August 15, 2020) of PROM use, reporting, and analysis in phase 3 clinical trials of hormone receptor-positive (HR+) advanced breast cancer (ABC). Further inspection of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor publications was performed to examine PROMs in the HR+/human epidermal growth factor receptor 2-negative setting. A total of 88 results were identified in the initial search; 32 were included in the final analysis. Among included studies, most (66%) had been published in the last 5 years (2015 to 2020). CDK4/6 inhibitors (38%) were the most common agents reported. No clear standard for PROM use, reporting, or analysis was found. The most common PROMs were European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30; 59%) and the Functional Assessment of Cancer Therapy-Breast (FACT-B; 34%). Important differences, among studies that reported them, ranged from 5 to 10 points for the EORTC QLQ-C30 and 8 points for the FACT-B total score. This review showed that a lack of clear consistency remains for PROM use, reporting, and analysis in phase 3 clinical trials of HR+ ABC. However, HRQOL is of high interest in the literature, including for CDK4/6 inhibitors.