Delayed plasma kallikrein inhibition fosters post-stroke recovery by reducing thrombo-inflammation.

Activation of the kallikrein-kinin system promotes vascular leakage, inflammation, and neurodegeneration in ischemic stroke. Inhibition of plasma kallikrein (PK) - a key component of the KKS - in the acute phase of ischemic stroke has been reported to reduce thrombosis, inflammation, and damage to the blood-brain barrier. However, the role of PK during the recovery phase after cerebral ischemia is unknown. To this end, we evaluated the effect of subacute PK inhibition starting from day 3 on the recovery process after transient middle artery occlusion (tMCAO). Our study demonstrated a protective effect of PK inhibition by reducing infarct volume and improving functional outcome at day 7 after tMCAO. In addition, we observed reduced thrombus formation in cerebral microvessels, fewer infiltrated immune cells, and an improvement in blood-brain barrier integrity. This protective effect was facilitated by promoting tight junction reintegration, reducing detrimental matrix metalloproteinases, and upregulating regenerative angiogenic markers. Our findings suggest that PK inhibition in the subacute phase might be a promising approach to accelerate the post-stroke recovery process.

Normal values of the fronto-occipital relationship in fetuses between 18 and 40 weeks at two maternal fetal medicine units: Bogotá, Colombia.

OBJECTIVE: To establish nomograms for linear measurements of the frontal and occipital horns of the lateral ventricle and their relationship, in pregnant patients between 18 and 40 weeks of gestation and having attended 2 units of Maternal Fetal Medicine in Bogotá-Colombia. METHODOLOGY: A descriptive cross-sectional study with an analytical component was carried out on pregnant patients who utilized the ultrasound services at 2 Maternal-Fetal Medicine units in Bogotá, between 18 and 40 weeks of pregnancy who underwent measurement. From the anterior and posterior horns of the lateral ventricles, the fronto-occipital ratio was calculated at each gestational week, and nomograms were created for each of these variables. RESULTS: Nine hundred and seventy-eight patients were included in the study. The distance of the frontal horns ranged between 6.9 and 51.6 mm with a mean of 19.1 ± 5.8 mm; that of the occipital horns had a measurement between 8.7 and 53 mm with a mean of 28, 1 ± 8.9 mm; on the other hand, the fronto-occipital ratio (FOR) yielded a mean of 0.365 ± 0.067 (0.136-0.616) without bearing any relation to gestational age. The trend of normal values for the studied population is displayed, plotted in percentile curves and nomograms for each gestational age. CONCLUSION: The measurement of the frontal and occipital horns, and the calculation of the fronto-occipital relationship is technically possible between 18 and 40 weeks, finding that the anterior and posterior horns have a positive linear relationship with gestational age. Contrarily, the FOR does not correlate with the gestational age, it was possible to establish a table of percentiles that allows determining the normal values for these measurements during pregnancy.

Quality of Life and Treatment-Related Side Effects in Patients With HR+/HER2- Advanced Breast Cancer: Findings From a Multicountry Survey.

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.

Sense in sensitivity: difference in the meaning of photoperiod insensitivity between wheat and barley.

The description of long photoperiod sensitivity in wheat and barley is a cause of confusion for researchers working with these crops, usually accustomed to free exchange of physiological and genetic knowledge of such similar crops. Indeed, wheat and barley scientists customarily quote studies of either crop species when researching one of them. Among their numerous similarities, the main gene controlling the long photoperiod sensitivity is the same in both crops (PPD1; PPD-H1 in barley and PPD-D1 in hexaploid wheat). However, the photoperiod responses are different: (i) the main dominant allele inducing shorter time to anthesis is the insensitive allele in wheat (Ppd-D1a) but the sensitive allele in barley (Ppd-H1) (i.e. sensitivity to photoperiod produces opposite effects on time to heading in wheat and barley); (ii) the main 'insensitive' allele in wheat, Ppd-D1a, does confer insensitivity, whilst that of barley reduces the sensitivity but still responds to photoperiod. The different behaviour of PPD1 genes in wheat and barley is put in a common framework based on the similarities and differences of the molecular bases of their mutations, which include polymorphism at gene expression levels, copy number variation, and sequence of coding regions. This common perspective sheds light on a source of confusion for cereal researchers, and prompts us to recommend accounting for the photoperiod sensitivity status of the plant materials when conducting research on genetic control of phenology. Finally, we provide advice to facilitate the management of natural PPD1 diversity in breeding programmes and suggest targets for further modification through gene editing, based on mutual knowledge on the two crops.

On the Clinical Pharmacology of Reactive Oxygen Species.

Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data-enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine. SIGNIFICANCE STATEMENT: Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmacological targeting focused on selective modulation of ROS enzymatic sources, 2) mechanism-based redefinition of diseases, and 3) network pharmacology within the ROS field, altogether toward the new era of ROS pharmacology in precision medicine.

Revealing the Beauty Potential of Grape Stems: Harnessing Phenolic Compounds for Cosmetics.

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.

Microbial Hyaluronic Acid Production: A Review.

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.

Thromboinflammation in Brain Ischemia: Recent Updates and Future Perspectives.

Despite decades of promising preclinical validation and clinical translation, ischemic stroke still remains as one of the leading causes of death and disability worldwide. Within its complex pathophysiological signatures, thrombosis and inflammation, that is, thromboinflammation, are highly interconnected processes leading to cerebral vessel occlusion, inflammatory responses, and severe neuronal damage following the ischemic event. Hence, we here review the most recent updates on thromboinflammatory-dependent mediators relevant after stroke focusing on recent discoveries on platelet modulation, a potential regulation of the innate and adaptive immune system in thromboinflammation, utterly providing a thorough up-to-date overview of all therapeutic approaches currently undergoing clinical trial.

From single drug targets to synergistic network pharmacology in ischemic stroke.

Drug discovery faces an efficacy crisis to which ineffective mainly single-target and symptom-based rather than mechanistic approaches have contributed. We here explore a mechanism-based disease definition for network pharmacology. Beginning with a primary causal target, we extend this to a second using guilt-by-association analysis. We then validate our prediction and explore synergy using both cellular in vitro and mouse in vivo models. As a disease model we chose ischemic stroke, one of the highest unmet medical need indications in medicine, and reactive oxygen species forming NADPH oxidase type 4 (Nox4) as a primary causal therapeutic target. For network analysis, we use classical protein-protein interactions but also metabolite-dependent interactions. Based on this protein-metabolite network, we conduct a gene ontology-based semantic similarity ranking to find suitable synergistic cotargets for network pharmacology. We identify the nitric oxide synthase (Nos1 to 3) gene family as the closest target to Nox4 Indeed, when combining a NOS and a NOX inhibitor at subthreshold concentrations, we observe pharmacological synergy as evidenced by reduced cell death, reduced infarct size, stabilized blood-brain barrier, reduced reoxygenation-induced leakage, and preserved neuromotor function, all in a supraadditive manner. Thus, protein-metabolite network analysis, for example guilt by association, can predict and pair synergistic mechanistic disease targets for systems medicine-driven network pharmacology. Such approaches may in the future reduce the risk of failure in single-target and symptom-based drug discovery and therapy.

Perceived stress in different countries at the beginning of the coronavirus pandemic.

OBJECTIVE: The coronavirus has spread around the world, causing an ongoing pandemic. After the lockdown and quarantine protocols, an evaluation of the population's current emotional state was made through a web-based survey available in both English and Spanish. The objective was to observe how respondents perceived stress and worry as a result of COVID-19. METHODS: The survey gathered data across three sections: socio-demographic data, the Perceived Stress Scale (PSS-10) by Cohen, and additional queries on current worries and behaviors due to this pandemic. RESULTS: The survey received 1523 respondents from 48 countries. The mean of the PSS-10 score was 17.4 (SD 6.5). Significantly higher scores were observed among women, young adults, students, and those who expressed concern about getting infected and considered themselves high-risk. No significant differences were observed between health professionals and other professions. CONCLUSIONS: We describe an increase in stress levels due to the COVID-19 and point out groups at high risk. These findings could help to address the mental health care that is needed.

Neural oscillations track natural but not artificial fast speech: Novel insights from speech-brain coupling using MEG.

Neural oscillations contribute to speech parsing via cortical tracking of hierarchical linguistic structures, including syllable rate. While the properties of neural entrainment have been largely probed with speech stimuli at either normal or artificially accelerated rates, the important case of natural fast speech has been largely overlooked. Using magnetoencephalography, we found that listening to naturally-produced speech was associated with cortico-acoustic coupling, both at normal (∼6 syllables/s) and fast (∼9 syllables/s) rates, with a corresponding shift in peak entrainment frequency. Interestingly, time-compressed sentences did not yield such coupling, despite being generated at the same rate as the natural fast sentences. Additionally, neural activity in right motor cortex exhibited stronger tuning to natural fast rather than to artificially accelerated speech, and showed evidence for stronger phase-coupling with left temporo-parietal and motor areas. These findings are highly relevant for our understanding of the role played by auditory and motor cortex oscillations in the perception of naturally produced speech.

Trajectories of alcohol consumption during life and the risk of developing breast cancer.

BACKGROUND: Whether there are lifetime points of greater sensitivity to the deleterious effects of alcohol intake on the breasts remains inconclusive. OBJECTIVE: To compare the influence of distinctive trajectories of alcohol consumption throughout a woman's life on development of breast cancer (BC). METHODS: 1278 confirmed invasive BC cases and matched (by age and residence) controls from the Epi-GEICAM study (Spain) were used. The novel group-based trajectory modelling was used to identify different alcohol consumption trajectories throughout women's lifetime. RESULTS: Four alcohol trajectories were identified. The first comprised women (45%) with low alcohol consumption (<5 g/day) throughout their life. The second included those (33%) who gradually moved from a low alcohol consumption in adolescence to a moderate in adulthood (5 to <15 g/day), never having a high consumption; and oppositely, women in the third trajectory (16%) moved from moderate consumption in adolescence, to a lower consumption in adulthood. Women in the fourth (6%) moved from a moderate alcohol consumption in adolescence to the highest consumption in adulthood (≥15 g/day), never having a low alcohol consumption. Comparing with the first trajectory, the fourth doubled BC risk (OR 2.19; 95% CI 1.27, 3.77), followed by the third (OR 1.44; 0.96, 2.16) and ultimately by the second trajectory (OR 1.17; 0.86, 1.58). The magnitude of BC risk was greater in postmenopausal women, especially in those with underweight or normal weight. When alcohol consumption was independently examined at each life stage, ≥15 g/day of alcohol consumption in adolescence was strongly associated with BC risk followed by consumption in adulthood. CONCLUSIONS: The greater the alcohol consumption accumulated throughout life, the greater the risk of BC, especially in postmenopausal women. Alcohol consumption during adolescence may particularly influence BC risk.

Inhibiting SUMO1-mediated SUMOylation induces autophagy-mediated cancer cell death and reduces tumour cell invasion via RAC1.

Post-translational modifications directly control protein activity and, thus, they represent an important means to regulate the responses of cells to different stimuli. Protein SUMOylation has recently been recognised as one such modification, and it has been associated with various diseases, including different types of cancer. However, the precise way that changes in SUMOylation influence the tumorigenic properties of cells remains to be fully clarified. Here, we show that blocking the SUMO pathway by depleting SUMO1 and UBC9, or by exposure to ginkgolic acid C15:1 or 2-D08 (two different SUMOylation inhibitors), induces cell death, also inhibiting the invasiveness of tumour cells. Indeed, diminishing the formation of SUMO1 complexes induces autophagy-mediated cancer cell death through increasing the expression of Tribbles pseudokinase 3 (TRIB3). Moreover, we found that blocking the SUMO pathway inhibits tumour cell invasion by decreasing RAC1 SUMOylation. These findings shed new light on the mechanisms by which SUMO1 modifications regulate the survival, and the migratory and invasive capacity of tumour cells, potentially establishing the bases to develop novel anti-cancer treatments based on the inhibition of SUMOylation.

Major flowering time genes of barley: allelic diversity, effects, and comparison with wheat.

KEY MESSAGE: This review summarizes the allelic series, effects, interactions between genes and with the environment, for the major flowering time genes that drive phenological adaptation of barley. The optimization of phenology is a major goal of plant breeding addressing the production of high-yielding varieties adapted to changing climatic conditions. Flowering time in cereals is regulated by genetic networks that respond predominately to day length and temperature. Allelic diversity at these genes is at the basis of barley wide adaptation. Detailed knowledge of their effects, and genetic and environmental interactions will facilitate plant breeders manipulating flowering time in cereal germplasm enhancement, by exploiting appropriate gene combinations. This review describes a catalogue of alleles found in QTL studies by barley geneticists, corresponding to the genetic diversity at major flowering time genes, the main drivers of barley phenological adaptation: VRN-H1 (HvBM5A), VRN-H2 (HvZCCTa-c), VRN-H3 (HvFT1), PPD-H1 (HvPRR37), PPD-H2 (HvFT3), and eam6/eps2 (HvCEN). For each gene, allelic series, size and direction of QTL effects, interactions between genes and with the environment are presented. Pleiotropic effects on agronomically important traits such as grain yield are also discussed. The review includes brief comments on additional genes with large effects on phenology that became relevant in modern barley breeding. The parallelisms between flowering time allelic variation between the two most cultivated Triticeae species (barley and wheat) are also outlined. This work is mostly based on previously published data, although we added some new data and hypothesis supported by a number of studies. This review shows the wide variety of allelic effects that provide enormous plasticity in barley flowering behavior, which opens new avenues to breeders for fine-tuning phenology of the barley crop.

Genetic diversity in developmental responses to light spectral quality in barley (Hordeum vulgare L.).

BACKGROUND: Plants use light wavelength, intensity, direction and duration to predict imminent seasonal changes and to determine when to initiate physiological and developmental processes. Among them, crop responses to light are not fully understood. Here, we study how light quality affects barley development, using two broad-spectrum light sources, metal halide (M) and fluorescent (F) lamps. Eleven varieties with known allelic variants for the major flowering time genes were evaluated under controlled conditions (long days, same light intensity). Two experiments were carried out with fully-vernalized plants: 1) control treatments (M, F); 2) shifting chambers 10 days after the start of the experiment (MF, FM). RESULTS: In general, varieties developed faster under longer exposure to M conditions. The greatest differences were due to a delay promoted by F light bulbs, especially in the time to first node appearance and until the onset of stem elongation. Yield related-traits as the number of seeds were also affected by the conditions experienced. However, not each variety responded equally, and they could be classified in insensitive and sensitive to light quality. Expression levels of flowering time genes HvVRN1, HvFT1 and PPD-H1 were high in M, while HvFT3 and HvVRN2 were higher under F conditions. The expression under shift treatments revealed also a high correlation between HvVRN1 and PPD-H1 transcript levels. CONCLUSIONS: The characterization of light quality effects has highlighted the important influence of the spectrum on early developmental stages, affecting the moment of onset of stem elongation, and further consequences on the morphology of the plant and yield components. We suggest that light spectra control the vernalization and photoperiod genes probably through the regulation of upstream elements of signalling pathways. The players behind the different responses to light spectra found deserve further research, which could help to optimize breeding strategies.

Phase III study to evaluate patient's preference of subcutaneous versus intravenous trastuzumab in HER2-positive metastatic breast cancer patients: Results from the ChangHER study (GEICAM/2012-07).

OBJECTIVE: We compared patients' preferences for intravenous (IV-t) versus subcutaneous (SC-t) trastuzumab administration. METHODS: Phase III, open-label, multicentre study in HER2-positive metastatic breast cancer. Patients were receiving IV-t for at least 4 months without progression. Randomisation was 1:1 to administer 2 cycles of SC-t with vial followed by 2 cycles with single injection device (SID) or the reverse sequence (600mg SC-t every 3 weeks for 4 cycles). PRIMARY OBJECTIVE: patients' preference for IV-t versus SC-t; secondary objectives: patients' preference for vial versus SID, healthcare professional (HCP) preference and safety. RESULTS: We randomised 166 patients in 26 sites. Median number of previous lines of chemotherapy and/or endocrine therapy was 1 (1-7). Median duration of prior IV-t was 1.8 years (0.3-14). Of the159 patients completing the questionnaires, 86.2% preferred SC-t, 6.9% preferred IV-t, and 6.9% had no preference. Patients preferred SID (59.2%) over vial (26.3%). Most (87.2%) HCP preferred SC-t of whom 51.3% and 28.2% preferred SID and vial respectively. Related adverse events included G1-2 injection site reactions in 18 patients (10.8%), G1 pain in 8 (4.8%), G1-2 allergic reaction in 2 (1.2%), one G3 heart failure and 1 G2 ejection fraction decrease. CONCLUSIONS: SC-t is preferred with no safety impact.

NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage.

Ischemic injury represents the most frequent cause of death and disability, and it remains unclear why, of all body organs, the brain is most sensitive to hypoxia. In many tissues, type 4 NADPH oxidase is induced upon ischemia or hypoxia, converting oxygen to reactive oxygen species. Here, we show in mouse models of ischemia in the heart, brain, and hindlimb that only in the brain does NADPH oxidase 4 (NOX4) lead to ischemic damage. We explain this distinct cellular distribution pattern through cell-specific knockouts. Endothelial NOX4 breaks down the BBB, while neuronal NOX4 leads to neuronal autotoxicity. Vascular smooth muscle NOX4, the common denominator of ischemia within all ischemic organs, played no apparent role. The direct neuroprotective potential of pharmacological NOX4 inhibition was confirmed in an ex vivo model, free of vascular and BBB components. Our results demonstrate that the heightened sensitivity of the brain to ischemic damage is due to an organ-specific role of NOX4 in blood-brain-barrier endothelial cells and neurons. This mechanism is conserved in at least two rodents and humans, making NOX4 a prime target for a first-in-class mechanism-based, cytoprotective therapy in the unmet high medical need indication of ischemic stroke.

Rapid On-Site Phenotyping via Field Fluorimeter Detects Differences in Photosynthetic Performance in a Hybrid-Parent Barley Germplasm Set.

Crop productivity can be expressed as the product of the amount of radiation intercepted, radiation use efficiency and harvest index. Genetic variation for components of radiation use efficiency has rarely been explored due to the lack of appropriate equipment to determine parameters at the scale needed in plant breeding. On the other hand, responses of the photosynthetic apparatus to environmental conditions have not been extensively investigated under field conditions, due to the challenges posed by the fluctuating environmental conditions. This study applies a rapid, low-cost, and reliable high-throughput phenotyping tool to explore genotypic variation for photosynthetic performance of a set of hybrid barleys and their parents under mild water-stress and unstressed field conditions. We found differences among the genotypic sets that are relevant for plant breeders and geneticists. Hybrids showed lower leaf temperature differential and higher non-photochemical quenching, resembling closer the male parents. The combination of traits detected in hybrids seems favorable, and could indicate improved photoprotection and better fitness under stress conditions. Additionally, we proved the potential of a low-cost, field-based phenotyping equipment to be used routinely in barley breeding programs for early screening for stress tolerance.

Fine-tuning of the flowering time control in winter barley: the importance of HvOS2 and HvVRN2 in non-inductive conditions.

BACKGROUND: In winter barley plants, vernalization and photoperiod cues have to be integrated to promote flowering. Plant development and expression of different flowering promoter (HvVRN1, HvCO2, PPD-H1, HvFT1, HvFT3) and repressor (HvVRN2, HvCO9 and HvOS2) genes were evaluated in two winter barley varieties under: (1) natural increasing photoperiod, without vernalization, and (2) under short day conditions in three insufficient vernalization treatments. These challenging conditions were chosen to capture non-optimal and natural responses, representative of those experienced in the Mediterranean area. RESULTS: In absence of vernalization and under increasing photoperiods, HvVRN2 expression increased with day-length, mainly between 12 and 13 h photoperiods in our latitudes. The flowering promoter gene in short days, HvFT3, was only expressed after receiving induction of cold or plant age, which was associated with low transcript levels of HvVRN2 and HvOS2. Under the sub-optimal conditions here described, great differences in development were found between the two winter barley varieties used in the study. Delayed development in 'Barberousse' was associated with increased expression levels of HvOS2. Novel variation for HvCO9 and HvOS2 is reported and might explain such differences. CONCLUSIONS: The balance between the expression of flowering promoters and repressor genes regulates the promotion towards flowering or the maintenance of the vegetative state. HvOS2, an ortholog of FLC, appears as a strong candidate to mediate in the vernalization response of barley. Natural variation found would help to exploit the plasticity in development to obtain better-adapted varieties for current and future climate conditions.

Genetic association with high-resolution climate data reveals selection footprints in the genomes of barley landraces across the Iberian Peninsula.

Landraces are local populations of crop plants adapted to a particular environment. Extant landraces are surviving genetic archives, keeping signatures of the selection processes experienced by them until settling in their current niches. This study intends to establish relationships between genetic diversity of barley (Hordeum vulgare L.) landraces collected in Spain and the climate of their collection sites. A high-resolution climatic data set (5 × 5 km spatial, 1-day temporal grid) was computed from over 2,000 temperature and 7,000 precipitation stations across peninsular Spain. This data set, spanning the period 1981-2010, was used to derive agroclimatic variables meaningful for cereal production at the collection sites of 135 barley landraces. Variables summarize temperature, precipitation, evapotranspiration, potential vernalization and frost probability at different times of the year and time scales (season and month). SNP genotyping of the landraces was carried out combining Illumina Infinium assays and genotyping-by-sequencing, yielding 9,920 biallelic markers (7,479 with position on the barley reference genome). The association of these SNPs with agroclimatic variables was analysed at two levels of genetic diversity, with and without taking into account population structure. The whole data sets and analysis pipelines are documented and available at https://eead-csic-compbio.github.io/barley-agroclimatic-association. We found differential adaptation of the germplasm groups identified to be dominated by reactions to cold temperature and late-season frost occurrence, as well as to water availability. Several significant associations pointing at specific adaptations to agroclimatic features related to temperature and water availability were observed, and candidate genes underlying some of the main regions are proposed.