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Aging is characterized by the accumulation of proteins that display amyloid-like behavior. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that amyloid-like proteins are produced in a variety of human cell types, including stem cells, brain organoids and fully differentiated neurons by mistakes that occur in messenger RNA molecules. Some of these mistakes generate mutant proteins already known to cause disease, while others generate proteins that have not been observed before. Moreover, we show that these mistakes increase when cells are exposed to DNA damage, a major hallmark of human aging. When taken together, these experiments suggest a mechanistic link between the normal aging process and age-related diseases.

Abstract Aging is characterized by the accumulation of proteins that display amyloid-like behavior. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that amyloid-like proteins are produced in a variety of human cell types, including stem cells, brain organoids and fully differentiated neurons by mistakes that occur in messenger RNA molecules. Some of these mistakes generate mutant proteins already known to cause disease, while others generate proteins that have not been observed before. Moreover, we show that these mistakes increase when cells are exposed to DNA damage, a major hallmark of human aging. When taken together, these experiments suggest a mechanistic link between the normal aging process and age-related diseases.

The continuum councils established within the framework of the ACORDA project serve as departmental forums dedicated to discussions and local initiatives. The project was initially conceptualized with the goal of uniting the various stakeholders in the guidance process. It’s aim was to foster collaboration and provide support, ultimately facilitating a more successful transition for students into higher education. This article delves into the role of continuum councils, drawing insights from data gathered during two council sessions within the same department. The findings underscore that these councils serve as a valuable platform for cultivating collective engagement among diverse participants, facilitating the exchange of experiential knowledge, and fostering a shared understanding of guidance principles.

Oncogenic fusions formed through chromosomal rearrangements are hallmarks of childhood cancer that define cancer subtype, predict outcome, persist through treatment, and can be ideal therapeutic targets. However, mechanistic understanding of the etiology of oncogenic fusions remains elusive. Here we report a comprehensive detection of 272 oncogenic fusion gene pairs by using tumor transcriptome sequencing data from 5190 childhood cancer patients. We identify diverse factors, including translation frame, protein domain, splicing, and gene length, that shape the formation of oncogenic fusions. Our mathematical modeling reveals a strong link between differential selection pressure and clinical outcome in CBFB-MYH11. We discover 4 oncogenic fusions, including RUNX1-RUNX1T1, TCF3-PBX1, CBFA2T3-GLIS2, and KMT2A-AFDN, with promoter-hijacking-like features that may offer alternative strategies for therapeutic targeting. We uncover extensive alternative splicing in oncogenic fusions including KMT2A-MLLT3, KMT2A-MLLT10, C11orf95-RELA, NUP98-NSD1, KMT2A-AFDN and ETV6-RUNX1. We discover neo splice sites in 18 oncogenic fusion gene pairs and demonstrate that such splice sites confer therapeutic vulnerability for etiology-based genome editing. Our study reveals general principles on the etiology of oncogenic fusions in childhood cancer and suggests profound clinical implications including etiology-based risk stratification and genome-editing-based therapeutics.

Human activity impacts the evolutionary trajectories of many species worldwide. Global trade of agricultural goods contributes to the dispersal of pathogens reshaping their genetic makeup and providing opportunities for virulence gains. Understanding how pathogens surmount control strategies and cope with new climates is crucial to predicting the future impact of crop pathogens. Here, we address this by assembling a global thousand-genome panel of Zymoseptoria tritici, a major fungal pathogen of wheat reported in all production areas worldwide. We identify the global invasion routes and ongoing genetic exchange of the pathogen among wheat-growing regions. We find that the global expansion was accompanied by increased activity of transposable elements and weakened genomic defenses. Finally, we find significant standing variation for adaptation to new climates encountered during the global spread. Our work shows how large population genomic panels enable deep insights into the evolutionary trajectory of a major crop pathogen.

In recent decades, geodynamic modelers have aimed to comprehend key factors governing continental rifting, such as the extension rate, lithospheric thickness, Moho mechanical coupling, and mantle convection’s thermal influence. While prior models offered insights into rifting processes, they lacked the calibration to specific Earth regions. Introducing heterogeneities into the model does in some cases help to calibrate the simulation results to a geological data from a specific region. Acknowledging structural inheritance as a form of kinematic forcing in the models, and recognizing the challenge of anticipating and identifying all inherited geological structures present before rifting, a new modeling approach was devised. This method integrates a new kinematic module into the pTatin2D code, allowing for calibrating numerical simulations with regional geological and geophysical dataset over time while solving for mechanical balance using Stokes flow to ensure that crustal deformation remains consistent with mantle dynamics. By calibrating against a 2D cross-section extracted from the final state of a 3D model, we show that the approach predicts thermal history and deformation paths beyond calibration points. In particular, the thermo-mechanical feedback can help mitigate some uncertainties in the deformation path. Applied to Iberia–Newfoundland margins, the method demonstrates effectiveness in real-case scenarios, aligning with previous reconstructions by incorporating faults and lower crustal flow.

In this paper, we propose a global modelling for vector field approximation from a given finite set of vectors (corresponding to the wind velocity field or marine currents). In the modelling, we propose using the minimization on a Hilbert space of an energy functional that includes a fidelity criterion to the data and a smoothing term. We discretize the continuous problem using a finite elements method. We then propose taking into account the topographic effects on the wind velocity field, and visualization using a free library is also proposed, which constitutes an added value compared to other vector field approximation models.

Abstract The human sulfatase HSulf-2 is one of only two known endosulfatases that play a decisive role in modulating the binding properties of heparan sulfate proteoglycans on the cell surface and in the extracellular matrix. Recently, HSulf-2 was shown to exhibit an unusual post-translational modification consisting of a sulfated glycosaminoglycan chain. This study describes the structural characterization of this glycosaminoglycan (GAG) and provides new data on its impact on the catalytic properties of HSulf-2. The unrevealed nature of this GAG chain is identified as a chondroitin/dermatan sulfate (CS/DS) mixed chain, as shown by mass spectrometry combined with NMR analysis. It consists primarily of 6-O and 4-O monosulfated disaccharide units, with a slight predominance of the 4-O-sulfation. Using atomic force microscopy, we show that this unique post-translational modification dramatically impacts the enzyme hydrodynamic volume. We identified human hyaluronidase-4 as a secreted hydrolase that can digest HSulf-2 GAG chain. We also showed that HSulf-2 is able to efficiently 6-O-desulfate antithrombin III binding pentasaccharide motif, and that this activity was enhanced upon removal of the GAG chain. Finally, we identified five N-glycosylation sites on the protein and showed that, although required, reduced N-glycosylation profiles were sufficient to sustain HSulf-2 integrity.

AIM: To assess the concordance between diagnosing orbital lesions by clinical examination, orbital imaging, and histological evaluation, in order to help guide future research and clinical practice. METHODS: A retrospective analysis was undertaken at a large regional tertiary referral centre of all surgical orbital biopsies performed over a 5-year period, from 1st January 2015 until 31st December 2019. Accuracy and concordance between clinical, radiological and histological diagnoses are reported as percentage sensitivity and positive predictive value. RESULTS: A total of 128 operations involving 111 patients were identified. Overall, sensitivities of 47.7% for clinical and 37.3% for radiological diagnoses were found when compared to the histological gold standard. Vascular lesions that have characteristic clinical and radiological features had the highest sensitivity at 71.4% and 57.1%, respectively. Inflammatory conditions showed the lowest sensitivity in both clinical (30.3%) and radiological (18.2%) diagnoses. The PPV for inflammatory conditions were 47.6% for clinical and 30.0% for radiological diagnoses. CONCLUSION: Accurate diagnoses are difficult to reach by relying on clinical examination and imaging alone. Surgical orbital biopsy with histological diagnosis should remain the gold standard approach for definitively identifying orbital lesions. Although larger scale prospective studies would help further refine concordance and guide future research avenues.

Conceptual models of orogenic accretionary prisms assume that peak temperatures (Tmax⁡) increase towards the internal domains as crustal rocks are accreted from the lower to the upper plate. However, the recognition of pre-orogenic heating events in mountain belts questions the magnitude of thermal overprint during nappe stacking. Using Raman spectroscopy on carbonaceous material (RSCM) to calculate Tmax⁡, we have investigated the thermal record of Lower Jurassic to Eocene strata exposed along six stratigraphic sections at the front of the Digne Nappe (SW Alps), from the Devoluy Massif to the Castellane Arc. Our results highlight two groups of depth-dependent temperatures: (1) a regionally extensive and constant Tmax⁡ up to 300–330 ∘C measured in the Jurassic succession and (2) regionally variable lower temperatures (<150 ∘C) recorded either in the Upper Mesozoic or the syn-orogenic sequence. Modelling shows that the highest palaeotemperatures were achieved during the Early Cretaceous (∼ 130 Ma), associated with the Valaisan–Vocontian rifting, while the lowest Tmax⁡ reflect post-rift thermal relaxation in the Alpine foreland basin. This study provides a striking new example where mid-crustal palaeotemperatures measured in sediments accreted from the downgoing plate are inherited. An estimated peak thermal gradient of 80–90 ∘C km−1 requires a crustal thickness of 8–10 km during the Early Cretaceous, hence placing constraints for tectonic reconstruction of rift domains and geophysical interpretation of current crustal thickness in the SW Alps. These results call for the careful interpretation of palaeothermal data when they are used to identify past collisional thermal events. Where details of basin evolution are lacking, high-temperature records may be misinterpreted as syn-orogenic, which can in turn lead to an overestimation of both orogenic thickening and horizontal displacement in mountain belts.

Fungal genus Septoria causes diseases in a wide range of plants. Here, we report the first genome sequences of two strains of Septoria linicola, the causal agent of the pasmo disease of flax (Linum usitatissimum). The genome of the first strain, SE15195, was fully assembled in 16 chromosomes, while 35 unitigs were obtained for a second strain, SE14017. Structural annotations predicted 13,096 and 13,085 protein-encoding genes and transposable elements content of 19.0 and 18.1% of the genome for SE15195 and SE14017, respectively. The four smaller chromosomes 13 to 16 show genomics features of potential accessory chromosomes. The assembly of these two genomes is a new resource for studying S. linicola and improving management of pasmo. [Graphic: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Background and Aims: Development of pancreatic ductal adenocarcinoma (PDAC) is a multistep process intensively studied; however, precocious diagnosis and effective therapy still remain unsatisfactory. The role for Notch signaling in PDAC has been discussed controversially, as both cancer-promoting and cancer-antagonizing functions have been described. Thus, an improved understanding of the underlying molecular mechanisms is necessary. Here, we focused on RBPJ, the receiving transcription factor in the Notch pathway, examined its expression pattern in PDAC, and characterized its function in mouse models of pancreatic cancer development and in the regeneration process after acute pancreatitis. Methods: Conditional transgenic mouse models were used for functional analysis of RBPJ in the adult pancreas, initiation of PDAC precursor lesions, and pancreatic regeneration. Pancreata and primary acinar cells were tested for acinar-to-ductal metaplasia together with immunohistology and comprehensive transcriptional profiling by RNA sequencing. Results: We identified reduced RBPJ expression in a subset of human PDAC specimens. Ptf1α-CreERT-driven depletion of RBPJ in transgenic mice revealed that its function is dispensable for the homeostasis and maintenance of adult acinar cells. However, primary RBPJ-deficient acinar cells underwent acinar-to-ductal differentiation in ex vivo. Importantly, oncogenic KRAS expression in the context of RBPJ deficiency facilitated the development of pancreatic intraepithelial neoplasia lesions with massive fibrotic stroma formation. Interestingly, RNA-sequencing data revealed a transcriptional profile associated with the cytokine/chemokine and extracellular matrix changes. In addition, lack of RBPJ delays the course of acute pancreatitis and critically impairs it in the context of KRASG12D expression. Conclusions: Our findings imply that downregulation of RBPJ in PDAC patients derepresses Notch targets and promotes KRAS-mediated pancreatic acinar cells transformation and desmoplasia development.