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Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

BackgroundWhite matter hyperintensities (WMH), a biomarker of small vessel disease, are often found in Alzheimer’s disease (AD) and their advanced detection and quantification can be beneficial for research and clinical applications. To investigate WMH in large-scale multicenter studies on cognitive impairment and AD, appropriate automated WMH segmentation algorithms are required. This study aimed to compare the performance of segmentation tools and provide information on their application in multicenter research.MethodsWe used a pseudo-randomly selected dataset (n = 50) from the DZNE-multicenter observational Longitudinal Cognitive Impairment and Dementia Study (DELCODE) that included 3D fluid-attenuated inversion recovery (FLAIR) images from participants across the cognitive continuum. Performances of top-rated algorithms for automated WMH segmentation [Brain Intensity Abnormality Classification Algorithm (BIANCA), lesion segmentation toolbox (LST), lesion growth algorithm (LGA), LST lesion prediction algorithm (LPA), pgs, and sysu_media] were compared to manual reference segmentation (RS).ResultsAcross tools, segmentation performance was moderate for global WMH volume and number of detected lesions. After retraining on a DELCODE subset, the deep learning algorithm sysu_media showed the highest performances with an average Dice’s coefficient of 0.702 (±0.109 SD) for volume and a mean F1-score of 0.642 (±0.109 SD) for the number of lesions. The intra-class correlation was excellent for all algorithms (>0.9) but BIANCA (0.835). Performance improved with high WMH burden and varied across brain regions.ConclusionTo conclude, the deep learning algorithm, when retrained, performed well in the multicenter context. Nevertheless, the performance was close to traditional methods. We provide methodological recommendations for future studies using automated WMH segmentation to quantify and assess WMH along the continuum of cognitive impairment and AD dementia.

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Objective: Recognition memory is widely accepted as a dual process-based model, namely familiarity and recollection. However, the location of their specific neurobiological substrates remains unclear. Similar to hippocampal damage, fornix damage has been associated with recollection memory but not familiarity memory deficits. To understand the neural basis of recognition memory, determining the importance of the fornix and its hippocampal connections is essential. Methods: Recognition memory was examined in a 45-year-old male who underwent a complete bilateral fornix section following the removal of a third ventricle colloid cyst. The application of familiarity and recollection for recognition memory decisions was investigated via an immediate and delayed associative recognition test and an immediate and delayed forced-choice task in the patient and a control group (N = 15) over a two-year follow-up period. Complete demographic, neuropsychological, neuropsychiatric, and neuroradiological characterizations of this patient were performed. Results: Persistent immediate and delayed verbal recollection memory deficits were observed in the patient. Moreover, delayed familiarity-based recognition memory declined gradually over the follow-up period, immediate familiarity-based recognition memory was unaffected, and reduced non-verbal memory improved. Conclusion: The present findings support models that the extended hippocampal system, including the fornices, does not appear to play a role in familiarity memory but is particularly important for recollection memory. Moreover, our study suggests that bilateral fornix transection may be associated with relatively functional recovery of non-verbal memory. [ABSTRACT FROM AUTHOR]

Immunopeptidomics is the area of knowledge focused on the study of peptides assembled in the major histocompatibility complex (MHC), or human leukocyte antigen (HLA) in humans, which could activate the immune response via specific and selective T cell recognition. Advances in high-sensitivity mass spectrometry have enabled the detailed identification and quantification of the immunopeptidome, significantly impacting fields like oncology, infections, and autoimmune diseases. Current immunopeptidomics approaches primarily focus on workflows to identify immunopeptides from HLA molecules, requiring the isolation of the HLA from relevant cells or tissues. Common critical steps in these workflows, such as cell lysis, HLA immunoenrichment, and peptide isolation, significantly influence outcomes. A systematic evaluation of these steps led to the creation of an 'Immunopeptidome Score' to enhance the reproducibility and robustness of these workflows. This score, derived from LC-MS/MS datasets (ProteomeXchange identifier PXD038165), in combination with available information from public databases, aids in optimizing the immunopeptidome characterization process. The 'Immunopeptidome Score' has been applied in a systematic analysis of protein extraction, HLA immunoprecipitation, and peptide recovery yields across several tumor cell lines enabling the selection of peptides with optimal features and, therefore, the identification of potential biomarker and therapeutic targets. [ABSTRACT FROM AUTHOR]

Green hydrogen is poised to play a crucial role in the energy-transition process in developed countries over the coming years, particularly in those countries aiming to achieve net-zero emissions. Consequently, the for green hydrogen is expected to rise significantly. This article explores the fundamental methods of producing hydrogen, focusing on the oxidation reaction within a thermochemical solar cycle for the dissociation of steam. Solar thermochemical cycles have been extensively researched, yet they remain in the development stage as research groups strive to identify optimal materials and conditions to enhance process efficiency, especially at high temperatures. The article analyses theoretical foundations drawn from exhaustive scientific studies related to the oxidation of iron in steam, the relationship with the activation energy of the corrosive process, thermodynamic aspects, and the kinetic model of a heterogeneous reaction. Additionally, it presents various mechanisms of high-temperature oxidation, pH effects, reactors, and materials (including fluidized beds). This scientific review suggests that hydrogen production via a thermochemical cycle is more efficient than production via electrochemical processes (such as electrolysis), provided the limitations of the cycle's reduction stage can be overcome. [ABSTRACT FROM AUTHOR]

Exploitation of the symbiotic relationship between endophytic fungi and ryegrass is a crucial technique for reducing the incidence of insect pests. This is primarily due to the production of alkaloids, such as peramine, by the fungi. This alkaloid has been reported as both a deterrent and toxic to a variety of insects. However, insects have developed various strategies to counteract plant defenses. One of the most studied methods is their ability to sequester toxic compounds from plants. In this study, we examined the feeding preferences and adaptation to peramine in Chilesia rudis, a native Chilean larva. Using a no-choice assay, we assessed larval feeding preferences and mass gain on seven experimental lines and two commercial cultivars of endophyte-infected and non-infected ryegrass. Pupal development time and adult performance were evaluated post-assay. Additionally, we measured peramine content in larval carcasses, feces, and ryegrass leaves. Jumbo was the most preferred cultivar with 32 mm2 of leaf tissues consumed. The longest pupal development time was observed in L161 and ALTO AR1, both at 28 days. Wing length in adults was greatest in the Jumbo and L163 cultivars, measuring 1.25 cm and 1.32 cm, respectively. Peramine concentrations were detected in the bodies of C. rudis. In conclusion, this larva can adapt to endophyte-infected ryegrass and develop counter-adaptation mechanisms to mitigate the effects of peramine. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the impact of endophyte-infected ryegrass and the alkaloids (such as peramine) which it produces, on the Argentine stem weevil (Listronotus bonariensis), a pest affecting pastures crucial for extensive agriculture. Seven unnamed lines (LE161-LE167), and two Lolium perenne cultivars, Jumbo and Alto AR1, were evaluated. Leaves from LE164, LE166, and ALTO AR1 led to significant weight reduction in L. bonariensis (−13.3%, −17.1%, and −18.2%, respectively). The corresponding alkaloidal extracts from these lines, grown in greenhouse trials, exhibited an antifeedant effect in laboratory assays, resulting in reduced weevil weight (−12.5%, 8.8%, and 4.9%, respectively). When incorporated into an artificial diet, peramine induced an antifeedant effect. Liquid chromatography analysis revealed the presence of peramine in LE164, LE166, and ALTO AR1 (ranging from 46.5 to 184.2 ng g−1), while it was absent in Jumbo and other lines. These findings suggest that endophyte-induced peramine production in specific ryegrass lines negatively impacts the feeding performance of L. bonariensis, presenting a potential ecological approach for pest control in pastures crucial for extensive agriculture. One of the primary supports for extensive agriculture is pasture, which can suffer severe damage from insects including the Argentine stem weevil, Listronotus bonariensis. The main control method has been the infection of ryegrass with an endophyte fungus, forming a symbiotic association that produces alkaloids. In this study, we evaluated the impact of endophyte and peramine production on the weight of L. bonariensis across seven unnamed lines (LE161-LE167), and two Lolium perenne cultivars: Jumbo and Alto AR1. L. bonariensis adults fed on leaves from LE164, LE166, and ALTO AR1 showed weight losses of 13.3%, 17.1% and 18.2%, respectively. Similarly, the corresponding alkaloidal extract from LE164, LE166, and ALTO AR1 exhibited an antifeedant effect on L. bonariensis adults in laboratory assays, as observed through weight loss or low weight gain (−12.5%, 8.8% and 4.9%, respectively). Furthermore, one alkaloid, peramine, also elicited an antifeedant effect when incorporated into an artificial diet. Liquid chromatographic analysis of the alkaloid extract revealed that peramine was present in LE164, LE166 and ALTO AR1 in amounts ranging from 46.5–184.2 ng/g. Peramine was not detected in Jumbo and the remaining experimental lines. These data suggest that L. bonariensis were susceptible to peramine produced from endophyte infection in experimental lines LE164 and LE166, as well as ALTO AR1, affecting their feeding behavior. [ABSTRACT FROM AUTHOR]

When new antitumor therapy drugs are discovered, it is essential to address new target molecules from the point of view of chemical structure and to carry out efficient and systematic evaluation. In the case of natural products and derived compounds, it is of special importance to investigate chemomodulation to further explore antitumoral pharmacological activities. In this work, the compound podophyllic aldehyde, a cyclolignan derived from the chemomodulation of the natural product podophyllotoxin, has been evaluated for its viability, influence on the cell cycle, and effects on intracellular signaling. We used functional proteomics characterization for the evaluation. Compared with the FDA-approved drug etoposide (another podophyllotoxin derivative), we found interesting results regarding the cytotoxicity of podophyllic aldehyde. In addition, we were able to observe the effect of mitotic arrest in the treated cells. The use of podophyllic aldehyde resulted in increased cytotoxicity in solid tumor cell lines, compared to etoposide, and blocked the cycle more successfully than etoposide. High-throughput analysis of the deregulated proteins revealed a selective antimitotic mechanism of action of podophyllic aldehyde in the HT-29 cell line, in contrast with other solid and hematological tumor lines. Also, the apoptotic profile of podophyllic aldehyde was deciphered. The cell death mechanism is activated independently of the cell cycle profile. The results of these targeted analyses have also shown a significant response to the signaling of kinases, key proteins involved in signaling cascades for cell proliferation or metastasis. Thanks to this comprehensive analysis of podophyllic aldehyde, remarkable cytotoxic, antimitotic, and other antitumoral features have been discovered that will repurpose this compound for further chemical transformations and antitumoral analysis. [ABSTRACT FROM AUTHOR]