Anthracycline-induced cardiovascular toxicity: validation of the Heart Failure Association and International Cardio-Oncology Society risk score.

BACKGROUND AND AIMS: Baseline cardiovascular toxicity risk stratification is critical in cardio-oncology. The Heart Failure Association (HFA) and International Cardio-Oncology Society (ICOS) score aims to assess this risk but lacks real-life validation. This study validates the HFA-ICOS score for anthracycline-induced cardiovascular toxicity. METHODS: Anthracycline-treated patients in the CARDIOTOX registry (NCT02039622) were stratified by the HFA-ICOS score. The primary endpoint was symptomatic or moderate to severe asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), with all-cause mortality and cardiovascular mortality as secondary endpoints. RESULTS: The analysis included 1066 patients (mean age 54 ± 14 years; 81.9% women; 24.5% ≥65 years). According to the HFA-ICOS criteria, 571 patients (53.6%) were classified as low risk, 333 (31.2%) as moderate risk, 152 (14.3%) as high risk, and 10 (0.9%) as very high risk. Median follow-up was 54.8 months (interquartile range 24.6-81.8). A total of 197 patients (18.4%) died, and 718 (67.3%) developed CTRCD (symptomatic: n = 45; moderate to severe asymptomatic: n = 24; and mild asymptomatic: n = 649). Incidence rates of symptomatic or moderate to severe symptomatic CTRCD and all-cause mortality significantly increased with HFA-ICOS score [hazard ratio 28.74, 95% confidence interval (CI) 9.33-88.5; P < .001, and hazard ratio 7.43, 95% CI 3.21-17.2; P < .001) for very high-risk patients. The predictive model demonstrated good calibration (Brier score 0.04, 95% CI 0.03-0.05) and discrimination (area under the curve 0.78, 95% CI 0.70-0.82; Uno's C-statistic 0.78, 95% CI 0.71-0.84) for predicting symptomatic or severe/moderate asymptomatic CTRCD at 12 months. CONCLUSIONS: The HFA-ICOS score effectively categorizes patients by cardiovascular toxicity risk and demonstrates strong predictive ability for high-risk anthracycline-related cardiovascular toxicity and all-cause mortality.

Bread wheat satellitome: a complex scenario in a huge genome.

In bread wheat (Triticum aestivum L.), chromosome associations during meiosis are extremely regulated and initiate at the telomeres and subtelomeres, which are enriched in satellite DNA (satDNA). We present the study and characterization of the bread wheat satellitome to shed light on the molecular organization of wheat subtelomeres. Our results revealed that the 2.53% of bread wheat genome is composed by satDNA and subtelomeres are particularly enriched in such DNA sequences. Thirty-four satellite DNA (21 for the first time in this work) have been identified, analyzed and cytogenetically validated. Many of the satDNAs were specifically found at particular subtelomeric chromosome regions revealing the asymmetry in subtelomere organisation among the wheat subgenomes, which might play a role in proper homologous recognition and pairing during meiosis. An integrated physical map of the wheat satellitome was also constructed. To the best of our knowledge, our results show that the combination of both cytogenetics and genome research allowed the first comprehensive analysis of the wheat satellitome, shedding light on the complex wheat genome organization, especially on the polymorphic nature of subtelomeres and their putative implication in chromosome recognition and pairing during meiosis.

Highly divergent satellitomes of two barley species of agronomic importance, Hordeum chilense and H. vulgare.

In this paper, we have performed an in-depth study of the complete set of the satellite DNA (satDNA) families (i.e. the satellitomes) in the genome of two barley species of agronomic value in a breeding framework, H. chilense (H1 and H7 accessions) and H. vulgare (H106 accession), which can be useful tools for studying chromosome associations during meiosis. The study has led to the analysis of a total of 18 satDNA families in H. vulgare, 25 satDNA families in H. chilense (accession H1) and 27 satDNA families in H. chilense (accession H7) that constitute 46 different satDNA families forming 36 homology groups. Our study highlights different important contributions of evolutionary and applied interests. Thus, both barley species show very divergent satDNA profiles, which could be partly explained by the differential effects of domestication versus wildlife. Divergence derives from the differential amplification of different common ancestral satellites and the emergence of new satellites in H. chilense, usually from pre-existing ones but also random sequences. There are also differences between the two H. chilense accessions, which support genetically distinct groups. The fluorescence in situ hybridization (FISH) patterns of some satDNAs yield distinctive genetic markers for the identification of specific H. chilense or H. vulgare chromosomes. Some of the satellites have peculiar structures or are related to transposable elements which provide information about their origin and expansion. Among these, we discuss the existence of different (peri)centromeric satellites that supply this region with some plasticity important for centromere evolution. These peri(centromeric) satDNAs and the set of subtelomeric satDNAs (a total of 38 different families) are analyzed in the framework of breeding as the high diversity found in the subtelomeric regions might support their putative implication in chromosome recognition and pairing during meiosis, a key point in the production of addition/substitution lines and hybrids.

CRISPR/Cas9 editing of two adenine phosphoribosyl transferase coding genes reveals the functional specialization of adenine salvage proteins in common bean.

Adenine metabolism is important for common bean (Phaseolus vulgaris L) productivity since this legume uses ureides derived from the oxidation of purine nucleotides, as their primary nitrogen storage molecules. Purine nucleotides are produced from de novo synthesis or through salvage pathways. Adenine phosphoribosyl transferase (APRT) is the enzyme dedicated to adenine nucleobase salvage for nucleotide synthesis, but it also acts on the inactivation of cytokinin bases. In common bean, the APRT enzyme is encoded by four genes. Gene expression analysis, biochemical properties and subcellular location suggest functional differences among the common bean APRT isoforms. CRISPR/Cas9 targeted downregulation of two of the four PvAPRTs followed by metabolomics and physiological analyses of targeted hairy roots reveals that, although the two proteins have redundant functions, PvAPRT1 mostly participates in the salvage of adenine, whereas PvAPRT5 is the predominant form in the regulation of cytokinin homeostasis and stress responses with a high impact in root and nodule growth.

The highly dynamic satellitomes of cultivated wheat species.

BACKGROUND AND AIMS: Durum wheat, Triticum turgidum, and bread wheat, Triticum aestivum, are two allopolyploid species of very recent origin that have been subjected to intense selection programs during the thousands of years they have been cultivated. In this paper, we study the durum wheat satellitome and establish a comparative analysis with the previously published bread wheat satellitome. METHODS: We revealed the durum wheat satellitome using the satMiner protocol which is based on consecutive rounds of clustering of Illumina reads by RepeatExplorer2, and estimated abundance and variation for each identified satDNA with RepeatMasker v4.0.5. We have also performed a deep satDNA families characterization including chromosomal location by Fluorescence In Situ Hybridization (FISH) in durum wheat and its comparison with FISH patterns in bread wheat. Basic Local Alignment Search Tool (BLAST®) was used for trailing each satDNA in the assembly of durum wheat genome through NCBI's Genome Data Viewer (GDW) and the genome assemblies of both species were compared. Sequence divergence and consensus turnover rate (CTR) between homologous satDNA families of durum and bread wheat were estimated using MEGA11. KEY RESULTS: This study reveals that in an exceedingly short period, significant qualitative and quantitative changes have occurred in the set of satellite DNAs (satDNAs) of both species, with expansions/contractions of the number of repeats and the loci per satellite, different in each species, and a high rate of sequence change for most of these satellites, in addition to the emergence/loss of satDNAs not shared between the two species analysed. These evolutionary changes in satDNA are common between species but what is truly remarkable and novel about this study is that these processes have taken place in less than the last ~8000 years separating the two species, indicating an accelerated evolution of their satDNAs. CONCLUSIONS: These results, together with the relationship of many of these satellites with transposable elements and the polymorphisms they generate at the level of centromeres and subtelomeric regions of their chromosomes, are analysed and discussed in the context of the evolutionary origin of these species and the selection pressure exerted by man throughout the history of their cultivation.

The nonpathogenic strain of Fusarium oxysporum FO12 induces Fe deficiency responses in cucumber (Cucumis sativus L.) plants.

MAIN CONCLUSION: FO12 strain enhances Fe deficiency responses in cucumber plants, probably through the production of ethylene and NO in the subapical regions of the roots. Rhizosphere microorganisms can elicit induced systemic resistance (ISR) in plants. This type of resistance involves complex mechanisms that confer protection to the plant against pathogen attack. Additionally, it has been reported by several studies that ISR and Fe deficiency responses are modulated by common pathways, involving some phytohormones and signaling molecules, like ethylene and nitric oxide (NO). The aim of this study was to determine whether the nonpathogenic strain of Fusarium oxysporum FO12 can induce Fe deficiency responses in cucumber (Cucumis sativus L.) plants. Our results demonstrate that the root inoculation of cucumber plants with the FO12 strain promotes plant growth after several days of cultivation, as well as rhizosphere acidification and enhancement of ferric reductase activity. Moreover, Fe-related genes, such as FRO1, IRT1 and HA1, are upregulated at certain times after FO12 inoculation either upon Fe-deficiency or Fe-sufficient conditions. Furthermore, it has been found that this fungus colonizes root cortical tissues, promoting the upregulation of ethylene synthesis genes and NO production in the root subapical regions. To better understand the effects of the FO12 strain on field conditions, cucumber plants were inoculated and cultivated in a calcareous soil under greenhouse conditions. The results obtained show a modification of some physiological parameters in the inoculated plants, such as flowering and reduction of tissue necrosis. Overall, the results suggest that the FO12 strain could have a great potential as a Fe biofertilizer and biostimulant.

Extended π-Conjugation and Structural Planarity Effects of Symmetrical D-π-A-π-D Naphthalene and Perylene Diimide Semiconductors on n-type Electrical Properties.

A series of donor-π-acceptor-π-donor (D-π-A-π-D) compounds based on naphthalendiimide (NDI) and perylenediimide (PDI) central cores combined with triphenylamine and phenylcarbazole donor groups have been synthesized, characterized and tested in top-contact/bottom gate organic field-effect transistors (OFETs). The results showed high electron mobilities, up to 0.3 cm2 V-1 s-1 , in the case of NDI derivatives and moderate values of around 10-3  cm2 V-1 s-1 for PDI-based semiconductors. Quantum chemical calculations were performed in order to support the experimental data. The results suggest that adequate molecular characteristics and larger crystalline domains in NDI vs. PDI semiconducting films may be the reasons behind the enhanced electrical properties of NDI derivatives. Furthermore, when the lateral donor substituents are triphenylamine groups, the mobilities were slightly higher in comparison to phenylcarbazole donor groups due to an improved electron-donating character. Other characterization techniques, such as AFM, X-ray diffraction or spectroelectrochemistry, among others, have been performed to analyze supramolecular order, charge carriers' nature and stability, parameters closely related to charge transport characteristics.

International regulatory uses of acute systemic toxicity data and integration of new approach methodologies.

Chemical regulatory authorities around the world require systemic toxicity data from acute exposures via the oral, dermal, and inhalation routes for human health risk assessment. To identify opportunities for regulatory uses of non-animal replacements for these tests, we reviewed acute systemic toxicity testing requirements for jurisdictions that participate in the International Cooperation on Alternative Test Methods (ICATM): Brazil, Canada, China, the European Union, Japan, South Korea, Taiwan, and the USA. The chemical sectors included in our review of each jurisdiction were cosmetics, consumer products, industrial chemicals, pharmaceuticals, medical devices, and pesticides. We found acute systemic toxicity data were most often required for hazard assessment, classification, and labeling, and to a lesser extent quantitative risk assessment. Where animal methods were required, animal reduction methods were typically recommended. For many jurisdictions and chemical sectors, non-animal alternatives are not accepted, but several jurisdictions provide guidance to support the use of test waivers to reduce animal use for specific applications. An understanding of international regulatory requirements for acute systemic toxicity testing will inform ICATM's strategy for the development, acceptance, and implementation of non-animal alternatives to assess the health hazards and risks associated with acute toxicity.

Donor-Acceptor-Donor 1H-Benzo[d]imidazole Derivatives as Optical Waveguides.

A new series of donor-acceptor-donor (D-A-D) structures derived from arylethynyl 1H-benzo[d]imidazole was synthesized and processed into single crystals with the goal of testing such crystals' ability to act as optical waveguides. Some crystals displayed luminescence in the 550-600 nm range and optical waveguiding behavior with optical loss coefficients around 10-2 dB/µm, which indicated a notable light transport. The crystalline structure, confirmed by X-ray diffraction, contains internal channels that are important for light propagation, as we previously reported. The combination of a 1D assembly, a single crystal structure, and notable light emission properties with low losses from self-absorption made 1H-benzo[d]imidazole derivatives appealing compounds for optical waveguide applications.

Narrative Performance and Sociopragmatic Abilities in Preschool Children are Linked to Multimodal Imitation Skills.

Over recent decades much research has analyzed the relevance of 9- to 20- month-old infants' early imitation skills (object- and language-based imitation) for language development. Yet there have been few systematic comparisons of the joint relevance of these imitative behaviors later on in development. This correlational study investigated whether multimodal imitation (gestural, prosodic, and lexical components) and object-based imitation are related to narratives and sociopragmatics in preschoolers. Thirty-one typically developing 3- to 4-year-old children performed four tasks to assess multimodal imitation, object-based imitation, narrative abilities, and sociopragmatic abilities. Results revealed that both narrative and sociopragmatic skills were significantly related to multimodal imitation, but not to object-based imitation, indicating that preschoolers' ability to imitate socially relevant multimodal cues is strongly related to language and sociocommunicative skills. Therefore, this evidence supports a broader conceptualization of imitation behaviors in the field of language development that systematically integrates prosodic, gestural, and verbal linguistic patterns.

Use of New Approach Methodologies (NAMs) in regulatory decisions for chemical safety: Report from an EPAA Deep Dive Workshop.

New Approach Methodologies (NAMs) are considered to include any in vitro, in silico or chemistry-based method, as well as the strategies to implement them, that may provide information that could inform chemical safety assessment. Current chemical legislation in the European Union is limited in its acceptance of the widespread use of NAMs. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a 'Deep Dive Workshop' to explore the use of NAMs in chemical safety assessment, the aim of which was to support regulatory decisions, whilst intending to protect human health. The workshop recognised that NAMs are currently used in many industrial sectors, with some considered as fit for regulatory purpose. Moreover, the workshop identified key discussion points that can be addressed to increase the use and regulatory acceptance of NAMs. These are based on the changes needed in frameworks for regulatory requirements and the essential needs in education, training and greater stakeholder engagement as well the gaps in the scientific basis of NAMs.

Microwave Irradiation as a Powerful Tool for the Preparation of n-Type Benzotriazole Semiconductors with Applications in Organic Field-Effect Transistors.

In this work, as an equivocal proof of the potential of microwave irradiation in organic synthesis, a complex pyrazine-decorated benzotriazole derivative that is challenging to prepare under conventional conditions has been obtained upon microwave irradiation, thus efficiently improving the process and yields, dramatically decreasing the reaction times and resulting in an environmentally friendly synthetic procedure. In addition, this useful derivative could be applied in organic electronics, specifically in organic field-effect transistors (OFETs), exhibiting the highest electron mobilities reported to date for benzotriazole discrete molecules, of around 10-2 cm2V-1s-1.

Mechanical Processing of Naturally Bent Organic Crystalline Microoptical Waveguides and Junctions.

Precise mechanical processing of optical microcrystals involves complex microscale operations viz. moving, bending, lifting, and cutting of crystals. Some of these mechanical operations can be implemented by applying mechanical force at specific points of the crystal to fabricate advanced crystalline optical junctions. Mechanically compliant flexible optical crystals are ideal candidates for the designing of such microoptical junctions. A vapor-phase growth of naturally bent optical waveguiding crystals of 1,4-bis(2-cyanophenylethynyl)benzene (1) on a surface forming different optical junctions is presented. In the solid-state, molecule 1 interacts with its neighbors via CH⋅⋅⋅N hydrogen bonding and π-π stacking. The microcrystals deposited at a glass surface exhibit moderate flexibility due to substantial surface adherence energy. The obtained network crystals also display mechanical compliance when cut precisely with sharp atomic force microscope cantilever tip, making them ideal candidates for building innovative T- and Δ-shaped optical junctions with multiple outputs. The presented micromechanical processing technique can also be effectively used as a tool to fabricate single-crystal integrated photonic devices and circuits on suitable substrates.

Influence of chemical and electronic inhomogeneities of graphene/copper on the growth of oxide thin films: the ZnO/graphene/copper case.

The interaction of graphene with metal oxides is essential for understanding and controlling new devices' fabrication based on these materials. The growth of metal oxides on graphene/substrate systems constitutes a challenging task due to the graphene surface's hydrophobic nature. In general, different pre-treatments should be performed before deposition to ensure a homogenous growth depending on the deposition technique, the metal oxide, and the surface's specific nature. Among these factors, the initial state and interaction of graphene with its substrate is the most important. Therefore, it is imperative to study the initial local state of graphene and relate it to the early stages of metal oxides' growth characteristics. Taking as initial samples graphene grown by chemical vapor deposition on polycrystalline Cu sheets and then exposed to ambient conditions, this article presents a local study of the inhomogeneities of this air-exposed graphene and how they influence on the subsequent ZnO growth. Firstly, by spatially correlating Raman and x-ray photoemission spectroscopies at the micro and nanoscales, it is shown how chemical species present in air intercalate inhomogeneously between Graphene and Cu. The reason for this is precisely the polycrystalline nature of the Cu support. Moreover, these local inhomogeneities also affect the oxidation level of the uppermost layer of Cu and, consequently, the electronic coupling between graphene and the metallic substrate. In second place, through the same characterization techniques, it is shown how the initial state of graphene/Cu sheets influences the local inhomogeneities of the ZnO deposit during the early stages of growth in terms of both, stoichiometry and morphology. Finally, as a proof of concept, it is shown how altering the initial chemical state and interaction of Graphene with Cu can be used to control the properties of the ZnO deposits.

Structure, isomerization and dimerization processes of naringenin flavonoids.

In this study, the theoretical and experimental results on the molecular structure and reactivity of the plant flavonoids naringenin chalcone and naringenin are reported. UV-vis and Raman spectra were recorded and their main bands have been assigned theoretically. Moreover, the analysis of the naringenin chalcone-naringenin cyclization-isomerization reaction and the formation of homodimers and heterodimers have been performed within a DFT framework. The presence of H-bonded water networks is mandatory to make the cyclization energetically suitable, suggesting that this equilibrium will occur in an aqueous intracellular environment rather than in the extracellular and hydrophobic plant cuticles. Additionally, the preferential formation of homodimers stabilized by π-π stacking that will interact with other dimers by H-bonding over the formation of naringenin chalcone-naringenin heterodimers is also proposed in a hydrophobic environment. These results give a plausible model to explain how flavonoids are located within the cuticle molecular arrangement.

The Predictive Value of Non-Referential Beat Gestures: Early Use in Parent-Child Interactions Predicts Narrative Abilities at 5 Years of Age.

A longitudinal study with 45 children (Hispanic, 13%; non-Hispanic, 87%) investigated whether the early production of non-referential beat and flip gestures, as opposed to referential iconic gestures, in parent-child naturalistic interactions from 14 to 58 months old predicts narrative abilities at age 5. Results revealed that only non-referential beats significantly (p < .01) predicted later narrative productions. The pragmatic functions of the children's speech that accompany these gestures were also analyzed in a representative sample of 18 parent-child dyads, revealing that beats were typically associated with biased assertions or questions. These findings show that the early use of beats predicts narrative abilities later in development, and suggest that this relation is likely due to the pragmatic-structuring function that beats reflect in early discourse.

Integration of data across toxicity endpoints for improved safety assessment of chemicals: the example of carcinogenicity assessment.

In view of the need to enhance the assessment of consumer products called for in the EU Chemicals Strategy for Sustainability, we developed a methodology for evaluating hazard by combining information across different systemic toxicity endpoints and integrating the information with new approach methodologies. This integrates mechanistic information with a view to avoiding redundant in vivo studies, minimising reliance on apical endpoint tests and ultimately devising efficient testing strategies. Here, we present the application of our methodology to carcinogenicity assessment, mapping the available information from toxicity test methods across endpoints to the key characteristics of carcinogens. Test methods are deconstructed to allow the information they provide to be organised in a systematic way, enabling the description of the toxicity mechanisms leading to the adverse outcome. This integrated approach provides a flexible and resource-efficient means of fully exploiting test methods for which test guidelines are available to fulfil regulatory requirements for systemic toxicity assessment as well as identifying where new methods can be integrated.

Current EU regulatory requirements for the assessment of chemicals and cosmetic products: challenges and opportunities for introducing new approach methodologies.

The EU Directive 2010/63/EU   on the protection of animals used for scientific purposes and other EU regulations, such as REACH and the Cosmetic Products Regulation advocate for a change in the way toxicity testing is conducted. Whilst the Cosmetic Products Regulation bans animal testing altogether, REACH aims for a progressive shift from in vivo testing towards quantitative in vitro and computational approaches. Several endpoints can already be addressed using non-animal approaches including skin corrosion and irritation, serious eye damage and irritation, skin sensitisation, and mutagenicity and genotoxicity. However, for systemic effects such as acute toxicity, repeated dose toxicity and reproductive and developmental toxicity, evaluation of chemicals under REACH still heavily relies on animal tests. Here we summarise current EU regulatory requirements for the human health assessment of chemicals under REACH and the Cosmetic Products Regulation, considering the more critical endpoints and identifying the main challenges in introducing alternative methods into regulatory testing practice. This supports a recent initiative taken by the International Cooperation on Alternative Test Methods (ICATM) to summarise current regulatory requirements specific for the assessment of chemicals and cosmetic products for several human health-related endpoints, with the aim of comparing different jurisdictions and coordinating the promotion and ultimately the implementation of non-animal approaches worldwide. Recent initiatives undertaken at European level to promote the 3Rs and the use of alternative methods in current regulatory practice are also discussed.

Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry.

AIM: Cardiotoxicity (CTox) is a major side effect of cancer therapies, but uniform diagnostic criteria to guide clinical and research practices are lacking. METHODS AND RESULTS: We prospectively studied 865 patients, aged 54.7 ± 13.9; 16.3% men, scheduled for anticancer therapy related with moderate/high CTox risk. Four groups of progressive myocardial damage/dysfunction were considered according to current guidelines: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥50%; moderate, LVD with LVEF 40-49%; and severe, LVD with LVEF ≤40% or symptomatic heart failure. Cardiotoxicity was defined as new or worsening of myocardial damage/ventricular function from baseline during follow-up. Patients were followed for a median of 24 months. Cardiotoxicity was identified in 37.5% patients during follow-up [95% confidence interval (CI) 34.22-40.8%], 31.6% with mild, 2.8% moderate, and 3.1% with severe myocardial damage/dysfunction. The mortality rate in the severe CTox group was 22.9 deaths per 100 patients-year vs. 2.3 deaths per 100 patients-year in the rest of groups, hazard ratio of 10.2 (95% CI 5.5-19.2) (P < 0.001). CONCLUSIONS: The majority of patients present objective data of myocardial injury/dysfunction during or after cancer therapy. Nevertheless, severe CTox, with a strong prognostic relationship, was comparatively rare. This should be reflected in protocols for clinical and research practices.

Encouraging kids to beat: Children's beat gesture production boosts their narrative performance.

Gesture is an integral part of language development. While recent evidence shows that observing a speaker who is simultaneously producing beat gestures helps preschoolers remember and understand information and also improves the production of oral narratives, little is known about the potential value of encouraging children to produce beat gestures-as opposed to merely observing them. In this between-subjects pretest-posttest training study we examine whether encouraging children to produce beats can boost their narrative performance. A total of 47 5- to 6-year-old children were divided into two groups and exposed to a training session in which a total of six stories were presented under one of two experimental conditions: (a) the children merely observed video-recordings of a storyteller who used beat gestures and were then asked to retell the narratives; or (b) the children observed the same video-recordings and then retold the narratives but were encouraged to simultaneously use their hands in the same way the storytellers did. Pretests and posttests consisting of children's narrations of short animated cartoons were analysed for narrative structure and fluency. A comparison of scores showed that children in the group that had been encouraged to use beat gestures in the training phase performed better in both narrative structure and fluency than the group of children who were simply asked to retell the story without gesture instruction. These findings suggest that linguistically relevant body movements serve to boost language development and that embodied storytelling can be of help in narrative training.