Viscoelastic high-molecular-weight hyaluronic acid hydrogels support rapid glioblastoma cell invasion with leader-follower dynamics.

Hyaluronic acid (HA), the primary component of brain extracellular matrix, is increasingly used to model neuropathological processes, including glioblastoma (GBM) tumor invasion. While elastic hydrogels based on crosslinked low-molecular-weight (LMW) HA are widely exploited for this purpose and have proven valuable for discovery and screening, brain tissue is both viscoelastic and rich in high-MW (HMW) HA, and it remains unclear how these differences influence invasion. To address this question, hydrogels comprised of either HMW (1.5 MDa) or LMW (60 kDa) HA are introduced, characterized, and applied in GBM invasion studies. Unlike LMW HA hydrogels, HMW HA hydrogels relax stresses quickly, to a similar extent as brain tissue, and to a greater extent than many conventional HA-based scaffolds. GBM cells implanted within HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader-follower dynamics. Leader cells adopt dendritic morphologies, similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. This study offers new insight into how HA viscoelastic properties drive invasion and argues for the use of highly stress-relaxing materials to model GBM.

Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): five-year outcomes of a randomised trial.

Background: Concerns remain over the long-term safety of vascular endothelial growth factor (VEGF) inhibitors to treat retinopathy of prematurity (ROP). RAINBOW is an open label randomised trial comparing intravitreal ranibizumab (in 0.2 mg and 0.1 mg doses) with laser therapy in very low birthweight infants (<1500 g) with ROP. Methods: Of 201 infants completing RAINBOW, 180 were enrolled in the RAINBOW Extension Study. At 5 years, children underwent ophthalmic, development and health assessments. The primary outcome was visual acuity in the better-seeing eye. The study is registered with ClinicalTrial.gov, NCT02640664. Findings: Between 16-6-2016 and 21-4-2022, 156 children (87%) were evaluated at 5 years. Of 32 children with no acuity test result, 25 had a preferential looking test, for 4 children investigators reported low vision for each eye, and in 3 further children no vision measurement was obtained. 124 children completed the acuity assessment, the least square mean (95% CI) letter score in the better seeing eye was similar in the three trial arms-66.8 (62.9-70.7) following ranibizumab 0.2 mg, 64.6 (60.6-68.5) following ranibizumab 0.1 mg and 62.1 (57.8-66.4) following laser therapy; differences in means: ranibizumab 0.2 mg v laser: 4.7 (95% CI: -1.1, 10.5); 0.1 mg v laser: 2.5 (-3.4, 8.3); 0.2 mg v 0.1 mg: 2.2 (-3.3, 7.8). High myopia (worse than -5 dioptres) in at least one eye occurred in 4/52 (8%) children following ranibizumab 0.2 mg, 8/55 (15%) following ranibizumab 0.1 mg and 11/45 (24%) following laser therapy (0.2 mg versus laser: odds ratio: 3.99 (1.16-13.72)). Ocular and systemic secondary outcomes and adverse events were distributed similarly in each trial arm. Interpretation: 5-year outcomes confirm the findings of the original RAINBOW trial and a planned interim analysis at 2 years, including a reduced frequency of high myopia following ranibizumab treatment. No effects of treatment on non-ocular outcomes were detected. Funding: Novartis Pharma AG.

SOCS3 regulates pathological retinal angiogenesis through modulating SPP1 expression in microglia and macrophages.

Pathological ocular angiogenesis has long been associated with myeloid cell activation. However, the precise cellular and molecular mechanisms governing the intricate crosstalk between the immune system and vascular changes during ocular neovascularization formation remain elusive. In this study, we demonstrated that the absence of the suppressor of cytokine signaling 3 (SOCS3) in myeloid cells led to a substantial accumulation of microglia and macrophage subsets during the neovascularization process. Our single-cell RNA sequencing data analysis revealed a remarkable increase in the expression of the secreted phosphoprotein 1 (Spp1) gene within these microglia and macrophages, identifying subsets of Spp1-expressing microglia and macrophages during neovascularization formation in angiogenesis mouse models. Notably, the number of Spp1-expressing microglia and macrophages exhibited further elevation during neovascularization in mice lacking myeloid SOCS3. Moreover, our investigation unveiled the Spp1 gene as a direct transcriptional target gene of signal transducer and activator of transcription 3. Importantly, pharmaceutical activation of SOCS3 or blocking of SPP1 resulted in a significant reduction in pathological neovascularization. In conclusion, our study highlights the pivotal role of the SOCS3/STAT3/SPP1 axis in the regulation of pathological retinal angiogenesis.

Effect of a QTL on wheat chromosome 5B associated with enhanced root dry mass on transpiration and nitrogen uptake under contrasting drought scenarios in wheat.

BACKGROUND: A sufficient nitrogen supply is crucial for high-quality wheat yields. However, the use of nitrogen fertilization can also negatively influence ecosystems due to leaching or volatile atmospheric emissions. Drought events, increasingly prevalent in many crop production areas, significantly impact nitrogen uptake. Breeding more efficient wheat varieties is necessary to achieve acceptable yields with limited nitrogen and water. Crop root systems play a crucial role as the primary organ for absorbing water and nutrients. To investigate the impact of an enhanced root system on nitrogen and water use efficiency in wheat under various irrigation conditions, this study conducted two experiments using precision phenotyping platforms for controlled drought stress treatment. Experiment 1 involved four contrasting winter wheat genotypes. It included the Chinese variety Ning0604, carrying a quantitative trait locus (QTL) on chromosome 5B associated with a higher root dry biomass, and three elite German varieties, Elixer, Genius, and Leandrus. Experiment 2 compared near-isogenic lines (NIL) of the three elite varieties, each containing introgressions of the QTL on chromosome 5B linked to root dry mass. In both experiments, nitrogen partitioning was tracked via isotope discrimination after fertilization with 5 Atom % 15N-labeled KNO3-. RESULTS: In experiment 1 the quantification by 15N isotope discrimination revealed significantly (p < 0.05) higher nitrogen derived from fertilizer in the root organ for Ning0604 than those of the three German varieties. In experiment 2, two out of three NILs showed a significantly (p < 0.05) higher uptake of N derived from fertilizer than their respective recipient line under well-watered conditions. Furthermore, significantly lower transpiration rates (p < 0.1) were observed in one NIL compared to its respective recipient. CONCLUSIONS: The combination of the DroughtSpotter facility coupled with 15N tracer-based tracking of N uptake and remobilization extends the insight into the impact of genetically altered root biomass on wheat NUE and WUE under different water availability scenarios. The study shows the potential for how a modified genetic constitution of the locus on wheat chromosome 5B can reduce transpiration and enhance N uptake. The dependence of the observations on the recipient and water availability suggests a need for further research to investigate the interaction with genetic background traits.

Clinical Landscape of Central Serous Chorioretinopathy in Germany - Retina.net CSC Registry Report No 1.

BACKGROUND: The German Registry of Central serous chorioretinopathy (CSC) collects data on CSC patients in a nationwide multicenter approach to analyze epidemiology, risk factors, clinical presentations as well as diagnosis and treatment patterns. MATERIAL AND METHODS: In this multicenter cohort study, patients with CSC were enrolled in nine tertiary referral centers in Germany between January 2022 and June 2023. After consenting to the study, demographic data, risk factors, reported symptoms, best corrected visual acuity (BCVA), funduscopic findings, disease severity, and diagnostic and treatment decisions were recorded and analyzed. RESULTS: A total of 539 eyes of 411 CSC patients were enrolled in this study including 308 male (75%) and 103 female (25%). Patients were predominantly of Caucasian origin and had a mean age of 55.5 years (IQR 41.0 - 70.0). 28% of eyes were classified as acute (<4 months duration) CSC, 28% as chronic (>4 months duration) CSC, 21% as inactive CSC, 11% as chronic atrophic CSC, and 12% as CSC with secondary CNV. 128 patients (31%) demonstrated bilateral CSC. The most common risk factors reported were psychological stress (52%), smoking (38%), arterial hypertension (38%), and a history of or current use of steroids (30%). Most frequently encountered symptoms included decreased visual acuity (76%), metamorphopsia (49%), relative scotoma (47%), blurred vision (19%), and dyschromatopsia (9%). Mean logMAR BCVA on initial examination was 0.2 (≈20/30, IQR 0.2 - 0.4), but showed significant variation with a tendency of lower BCVA in chronic cases. At the baseline visit, 74% of the overall cohort received no treatment, while 19% underwent local treatment and only 2% systemic treatment. Of the local therapies, anti-VEGF injections were the most frequently performed procedure (33%, mainly for secondary CNV), followed by micropulse laser (28%), focal non-pulsed laser (23%), photodynamic therapy (14%), and nonsteroidal anti-inflammatory eye drops (2%). Among intravitreal anti-VEGF agents, aflibercept was used most frequently, followed by bevacizumab and ranibizumab. DISCUSSION: This registry represents one of the largest cohorts of European patients with CSC to date. Patient age and the proportion of women was higher than expected and bilateral active disease was lower than anticipated, highlighting that neither age nor gender should be overemphasized when diagnosing CSC. Therapeutic interventions are heterogeneous and include photodynamic therapy, micropulse laser and anti-VEGF injections in case of secondary CNV.

FATP5 is indispensable for the growth of intrahepatic cholangiocarcinoma.

Altered lipid metabolism is a common hallmark of various cancers, including Intrahepatic Cholangiocarcinoma (ICC), a highly lethal carcinoma that lacks effective treatment options. To elucidate the lipid metabolism changes in ICC, we coupled the expression of the firefly luciferase gene (FFL) to AKT1 (AKT-FFL) via an IRES linker, and then hydrodynamically injected mice with AKT-FFL and Notch1 intracellular cytoplasmic domain (NICD) to establish a luciferase-positive ICC model. This model not only enabled us to monitor and quantify tumor growth by injecting the mice with luciferin, but also allowed us to assess the fatty acid uptake rate by injecting the mice with free fatty acid luciferin (FFA-Luc). The ICC model exhibited robust uptake of exogenous fatty acids compared with the HCC model induced by AKT-FFL/ neuroblastoma Ras (Ras). Lipidomics analysis showed a dramatically higher level of fatty acid in ICC, further supporting the increased fatty acids uptake. Mechanistic studies identified FATP5 as the predominant mediator of fatty acid uptake required for ICC growth using Fatp5 knockout mice and AAV-based shRNA silencing of Fatp5. Our study discovered a novel therapeutic target for the treatment of ICC and shed light on the contributions of lipid metabolism to ICC development. Implications: This study provides the first in vivo evidence that FATP5 is a potential therapeutic target for treating ICC.

Systemic exposure to aflibercept after intravitreal injection in premature neonates with retinopathy of prematurity: results from the FIREFLEYE randomized phase 3 study.

BACKGROUND: There are no data on pharmacokinetics, pharmacodynamics, and immunogenicity of intravitreal aflibercept in preterm infants with retinopathy of prematurity (ROP). FIREFLEYE compared aflibercept 0.4 mg/eye and laser photocoagulation in infants with acute-phase ROP requiring treatment. METHODS: Infants (gestational age ≤32 weeks or birthweight ≤1500 g) with treatment-requiring ROP in ≥1 eye were randomized 2:1 to receive aflibercept 0.4 mg or laser photocoagulation at baseline in this 24-week, randomized, open-label, noninferiority, phase 3 study. Endpoints include concentrations of free and adjusted bound aflibercept in plasma, pharmacokinetic/pharmacodynamic exploration of systemic anti-vascular endothelial growth factor effects, and immunogenicity. RESULTS: Of 113 treated infants, 75 received aflibercept 0.4 mg per eye at baseline (mean chronological age: 10.4 weeks), mostly bilaterally (71 infants), and with 1 injection/eye (120/146 eyes). Concentrations of free aflibercept were highly variable, with maximum concentration at day 1, declining thereafter. Plasma concentrations of adjusted bound (pharmacologically inactive) aflibercept increased from day 1 to week 4, decreasing up to week 24. Six infants experienced treatment-emergent serious adverse events within 30 days of treatment; aflibercept concentrations were within the range observed in other infants. There was no pattern between free and adjusted bound aflibercept concentrations and blood pressure changes up to week 4. A low-titer (1:30), non-neutralizing, treatment-emergent anti-drug antibody response was reported in 1 infant, though was not clinically relevant. CONCLUSIONS: 24-week data suggest intravitreal aflibercept for treatment of acute-phase ROP is not associated with clinically relevant effects on blood pressure, further systemic adverse events, or immunogenicity. GOV IDENTIFIER: NCT04004208.

Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.

Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.

Temporal and species-specific resistance of sugar beet to green peach aphid and black bean aphid: mechanisms and implications for breeding.

BACKGROUND: Sugar beet (Beta vulgaris ssp. vulgaris), a key crop for sugar production, faces significant yield losses caused by the black bean aphid Aphis fabae (Scop.) and the green peach aphid Myzus persicae (Sulzer), which also transmits viruses. The restriction on neonicotinoid usage in Europe has intensified this problem, emphasizing the urgent need for breeding resistant crop varieties. This study evaluated 26 sugar beet germplasms for resistance against both aphid species by using performance and feeding behavior assays. Additionally, whole plant bioassays and semi-field experiments were carried out with Myzus persicae. RESULTS: Our findings demonstrate the presence of temporal resistance against both aphid species in the primary sugar beet gene pool. Beet yellows virus (BYV) carrying aphids showed enhanced performance. Different levels of plant defense mechanisms were involved including resistance against Myzus persicae before reaching the phloem, particularly in sugar beet line G3. In contrast, resistance against Aphis fabae turned out to be predominately phloem-located. Furthermore, a high incidence of black inclusion bodies inside the stomach of Myzus persicae was observed for approximately 85% of the plant genotypes tested, indicating a general and strong incompatibility between sugar beet and Myzus persicae in an initial phase of interaction. CONCLUSION: Sugar beet resistance against aphids involved different mechanisms and is species-specific. The identification of these mechanisms and interactions represents a crucial milestone in advancing the breeding of sugar beet varieties with improved resistance. © 2023 Julius Kühn-Institut and The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Treated Cases of Retinopathy of Prematurity in Germany: 10-Year Data from the Retina.net Retinopathy of Prematurity Registry.

PURPOSE: To analyze changes in demographic parameters and retreatment patterns over a 10-year period in a clinical routine setting of infants with retinopathy of prematurity (ROP) requiring treatment documented in the German Retina.net ROP registry. DESIGN: Multicenter, noninterventional, observational registry study recruiting patients treated for ROP. SUBJECTS: A total of 692 eyes of 353 infants treated for ROP were documented in the Retina.net ROP registry over a 10-year period between 2011 and 2020. These cases cover about 15% of all infants treated for ROP in Germany. METHODS: The Retina.net ROP registry was established in 2012 to jointly collect information on infants treated for ROP. The database collects information on demographic parameters (gestational age [GA], birth weight, neonatal comorbidities) as well as treatment parameters (type of treatment, weight and age at treatment, and stage of ROP). A total of 19 centers contributed to the analysis. This is the 10-year analysis of data from 2011 to 2020, in which we focus on changes over time regarding the respective parameters. MAIN OUTCOME MEASURES: Changes over time in demographic parameters and treatment patterns for ROP in Germany. RESULTS: The overall incidence of treatment requiring ROP was 3.5% of all infants screened for ROP at participating centers. Gestational age, weight at birth, and weight at treatment remained stable over the 10-year period, whereas postmenstrual and postnatal age at treatment increased moderately but statistically significantly over the years. The most prevalent ROP severity stage at treatment was stage 3+ in zone II (76.6% of all treated eyes). Treatment patterns changed considerably from predominantly laser treatments in 2011 (75% of all treated eyes) to predominantly ranibizumab treatments in 2020 (60.9% of all treated eyes). The overall retreatment rate was 15.6%. Retreatment rates differed between initial treatment modalities (14.1% after laser coagulation, 12% after bevacizumab and 24.5% after ranibizumab). Treatment-associated systemic or ophthalmic complications were rare. CONCLUSIONS: This data analysis represents one of the largest documented cohorts of infants treated for ROP. The data on demographic parameters and treatment patterns provide useful information for further improvement of ROP management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Past, Present, and Future of Wheat Dwarf Virus Management-A Review.

Wheat dwarf disease (WDD) is an important disease of monocotyledonous species, including economically important cereals. The causative pathogen, wheat dwarf virus (WDV), is persistently transmitted mainly by the leafhopper Psammotettix alienus and can lead to high yield losses. Due to climate change, the periods of vector activity increased, and the vectors have spread to new habitats, leading to an increased importance of WDV in large parts of Europe. In the light of integrated pest management, cultivation practices and the use of resistant/tolerant host plants are currently the only effective methods to control WDV. However, knowledge of the pathosystem and epidemiology of WDD is limited, and the few known sources of genetic tolerance indicate that further research is needed. Considering the economic importance of WDD and its likely increasing relevance in the coming decades, this study provides a comprehensive compilation of knowledge on the most important aspects with information on the causal virus, its vector, symptoms, host range, and control strategies. In addition, the current status of genetic and breeding efforts to control and manage this disease in wheat will be discussed, as this is crucial to effectively manage the disease under changing environmental conditions and minimize impending yield losses.

Erythrocyte transfusions are associated with retinopathy of prematurity in extremely low gestational age newborns.

AIM: Retinopathy of prematurity (ROP) is a major morbidity in preterm infants causing visual impairment including blindness. Prevention and timely treatment are critical. We investigated the potential role of red blood cell (RBC) transfusions as risk factor for ROP development. METHODS: Retrospective cohort study of data from 68 tertiary level neonatal intensive care units in Germany. Preterm infants born at 22 + 0 to 28 + 6 weeks of gestation between January 2009 and December 2021 were enrolled. RESULTS: We included n = 12 565 infants. Prevalence of any ROP was 49.2% with most infants being diagnosed with stage 1 (21.5%) and 2 disease (17.2%). ROP stage 3 was present in 10.2%, stage 4 in 0.3%, and ROP requiring treatment in 6.6%. Infants with ROP had significantly more frequently a history of RBC transfusions. Adjusting for confounders, RBC transfusions were associated with increased odds of ROP (OR 1.4, p < 0.001), ROP progression (OR 2.1, p < 0.01) and ROP requiring treatment (OR 3.6, p < 0.001). Restrictive transfusion approaches correlated with decreased (OR 0.7, p < 0.001), liberal regimes with increased odds (OR 1.2, p = 0.001). CONCLUSION: The present study confirmed an association of RBC transfusions and ROP. Our findings emphasise the need for anaemia prevention and critical re-evaluation of transfusion practices in preterm infants.

Development of a joint set of database parameters for the EU-ROP and Fight Childhood Blindness! ROP Registries.

BACKGROUND/AIMS: The incidence of retinopathy of prematurity (ROP) is increasing and treatment options are expanding, often without accompanying safety data. We aimed to define a minimal, patient-centred data set that is feasible to collect in clinical practice and can be used collaboratively to track and compare outcomes of ROP treatment with a view to improving patient outcomes. METHODS: A multinational group of clinicians and a patient representative with expertise in ROP and registry development collaborated to develop a data set that focused on real-world parameters and outcomes that were patient centred, minimal and feasible to collect in routine clinical practice. RESULTS: For babies receiving ROP treatment, we recommend patient demographics, systemic comorbidities, ROP status, treatment details, ophthalmic and systemic complications of treatment, ophthalmic and neurodevelopmental outcomes at initial treatment, any episodes of retreatment and follow-up examinations in the short and long-term to be collected for use in ROP studies, registries and routine clinical practice. CONCLUSIONS: We recommend these parameters to be used in registries and future studies of ROP treatment, to reduce the variation seen in previous reports and allow meaningful assessments and comparisons. They form the basis of the EU-ROP and the Fight Childhood Blindness! ROP Registries.

Circulating MicroRNAs as Biomarker for Vessel-Associated Retinal Diseases.

INTRODUCTION: Vessel-associated retinal diseases are a major cause of blindness and severe visual impairment. The identification of appropriate biomarkers is of great importance to better anticipate disease progression and establish more targeted treatment options. MicroRNAs (miRNAs) are short, single-stranded, noncoding ribonucleic acids that are involved in the posttranscriptional regulation of gene expression through hybridization with messenger RNA. The expression of certain miRNAs can be different in patients with pathological processes and can be used for the detection and differentiation of various diseases. In this study, we investigate to what extent previously in vitro identified miRNAs are present as cell-free circulating miRNAs in the serum and vitreous of human patients with and without vessel-associated retinal diseases. METHODS: Relative quantification by quantitative real-time polymerase chain reaction was used to analyze miRNA expression in patients with vessel-associated retinal diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinal vein occlusion compared with control patients. RESULTS: In serum samples, miR-29a-3p and miR-192-5p showed increased expression in patients with neovascular AMD relative to control patients. Similarly, miR-335-5p, miR-192-5p, and miR-194-5p showed increased expression in serum from patients with proliferative DR. In vitreous samples, miR-100-5p was decreased in patients with proliferative DR. Differentially expressed miRNAs showed good diagnostic accuracy in receiver operating characteristic (ROC) and area under the ROC curve analysis. CONCLUSION: The miRNAs investigated in this study may have the potential to serve as biomarkers for vessel-associated retinal diseases. Combining multiple miRNAs may enhance the predictive power of the analysis.

Telemedicine retinopathy of prematurity severity score (TeleROP-SS) versus modified activity score (mROP-ActS) retrospective comparison in SUNDROP cohort.

Identifying and planning treatment for retinopathy of prematurity (ROP) using telemedicine is becoming increasingly ubiquitous, necessitating a grading system to help caretakers of at-risk infants gauge disease severity. The modified ROP Activity Scale (mROP-ActS) factors zone, stage, and plus disease into its scoring system, addressing the need for assessing ROP's totality of binocular burden via indirect ophthalmoscopy. However, there is an unmet need for an alternative score which could facilitate ROP identification and gauge disease improvement or deterioration specifically on photographic telemedicine exams. Here, we propose such a system (Telemedicine ROP Severity Score [TeleROP-SS]), which we have compared against the mROP-ActS. In our statistical analysis of 1568 exams, we saw that TeleROP-SS was able to return a score in all instances based on the gradings available from the retrospective SUNDROP cohort, while mROP-ActS obtained a score of 80.8% in right eyes and 81.1% in left eyes. For treatment-warranted ROP (TW-ROP), TeleROP-SS obtained a score of 100% and 95% in the right and left eyes respectively, while mROP-ActS obtained a score of 70% and 63% respectively. The TeleROP-SS score can identify disease improvement or deterioration on telemedicine exams, distinguish timepoints at which treatments can be given, and it has the adaptability to be modified as needed.

Stage-specific genotype-by-environment interactions determine yield components in wheat.

In cereal crops, environmental fluctuations affect different physiological processes during various developmental phases associated with the formation of yield components. Because these effects are coupled with cultivar-specific phenology, studies investigating environmental responses in different cultivars can give contradictory results regarding key phases impacting yield performance. To dissect how genotype-by-environment interactions affect grain yield in winter wheat, we estimated the sensitivities of yield components to variation in global radiation, temperature and precipitation in 220 cultivars across 81 time-windows ranging from double ridge to seed desiccation. Environmental sensitivity responses were prominent in the short-term physiological subphases of spike and kernel development, causing phenologically dependent, stage-specific genotype-by-environment interactions. Here we reconcile contradicting findings from previous studies and show previously undetected effects; for example, the positive impact of global radiation on kernel weight during canopy senescence. This deep insight into the three-way interactions between phenology, yield formation and environmental fluctuations provides comprehensive new information for breeding and modelling cereal crops.

Identification of Markers Associated with Wheat Dwarf Virus (WDV) Tolerance/Resistance in Barley (Hordeum vulgare ssp. vulgare) Using Genome-Wide Association Studies.

Wheat dwarf virus (WDV) causes an important vector transmitted virus disease, which leads to significant yield losses in barley production. Due to the fact that, at the moment, no plant protection products are approved to combat the vector Psammotettix alienus, and this disease cannot be controlled by chemical means, the use of WDV-resistant or -tolerant genotypes is the most efficient method to control and reduce the negative effects of WDV on barley growth and production. In this study, a set of 480 barley genotypes were screened to identify genotypic differences in response to WDV, and five traits were assessed under infected and noninfected conditions. In total, 32 genotypes showed resistance or tolerance to WDV. Subsequently, phenotypic data of 191 out of 480 genotypes combined with 34,408 single-nucleotide polymorphisms (SNPs) were used for a genome-wide association study to identify quantitative trait loci (QTLs) and markers linked to resistance/tolerance to WDV. Genomic regions significantly associated with WDV resistance/tolerance in barley were identified on chromosomes 3H, 4H, 5H, and 7H for traits such as relative virus titer, relative performance of total grain weight, plant height, number of ears per plant, and thousand grain weight.