Translational Approach Research Articles

PLB2Tau mice are impaired in novel and temporal object recognition and show corresponding traits in brain MRI

Recent clinical trials targeting tau protein aggregation have heightened interest in tau-based therapies for dementia. Success of such treatments depends crucially on translation from non-clinical animal models. Here, we present the age profile of the PLB2Tau knock-in model of fronto-temporal dementia in terms of cognition, and by utilising a directly translatable magnetic resonance imaging approach. Separate cohorts of mice aged 3, 6 and 12 months were tested in an object recognition protocol interrogating visual, spatial, and temporal discrimination in consecutive tests. Upon completion of their behavioural testing, animals were recorded in a 7T MRI for brain structural integrity and diffusion tensor imaging (DTI) analysis.We report that PLB2Tau mice presented with an age-dependent deficit in novel object discrimination relative to wild-type controls at 6 and 12 months. Spatial and temporal discrimination, though not significantly different from controls, appeared extremely challenging for PLB2Tau subjects, especially at 12 months, since they explored objects less than controls and were devoid of memory. Controls readily recalled all relevant object-related information. At the same time, the T2 weighted voxel-based image analysis revealed a progressive shrinkage of total brain volumes in 6- and 12-month-old PLB2Tau mice as well as relative striatal, but not hippocampal volumes. A regional DTI analysis yielded only reduced mean diffusivity of the fimbria, but not CA1 or dentate gyrus, amygdala, cingulate cortex, or corpus callosum.These data confirm the PLB2Tau mouse as a translationally useful model for dementia research and suggest the importance of the hippocampal input as a determinant for novel object discrimination.

Evaluation of a strategic academic-government partnership to advance COVID-19 clinical practice guidelines access and uptake in South Africa

IntroductionAcademic–government partnerships are important to advance timely, responsive and relevant evidence for decision-making (policy, guideline, law and regulation) deliberations. Deliberate and strategic integrated knowledge translation (KT) approaches within such partnerships...

Emergency findings detected by [18F]-FDG PET/contrast-enhanced CT: A translational approach

AbstractObjective2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) can be developed in association with contrast-enhanced CT (ceCT), specifically in oncologic patients. This study aimed to evaluate emergency cases incidentally detected in our clinical practice with [18F]-FDG PET/ceCT.MethodWe retrospectively evaluated 3661 [18F]-FDG PET/ceCT, developed between 2017 and 2023, collecting emergency cases needing prompt treatment.ResultsIn 34/3661 patients (0.9%) an emergency case was recorded, in particular through contrast-enhanced CT, linked to a vascular (65%) or extravascular (35%) disease. The more frequent findings were pulmonary thromboembolism (0.5%). [18F]-FDG PET/CT was positive in 13/34 cases.ConclusionsA significant minority of patients undergoing PET/ceCT present vascular or extravascular emergency diseases. The [18F]-FDG uptake improves confidence in diagnosing inflammatory findings. Properly trained diagnostic physicians approaching PET/ceCT can change the prognosis of a small but significant number of cancer patients through a life-saving approach. Future studies are needed to ensure the possibility of emergency findings with non-[18F]-FDG tracers.

Understanding ubiquitination in neurodevelopment by integrating insights across space and time.

Ubiquitination regulates a myriad of eukaryotic signaling cascades by modifying substrate proteins, thereby determining their functions and fates. In this perspective, we discuss current challenges in investigating the ubiquitin system in the developing brain. We foster the concept that ubiquitination pathways are spatiotemporally regulated and tightly intertwined with molecular and cellular transitions during neurogenesis and neural circuit assembly. Focusing on the neurologically highly relevant class of homologous to E6AP C-terminus (HECT) ubiquitin ligases, we propose cross-disciplinary translational approaches bridging state-of-the-art cell biology, proteomics, biochemistry, structural biology and neuroscience to dissect ubiquitination in neurodevelopment and its specific perturbations in brain diseases. We highlight that a comprehensive understanding of ubiquitin signaling in the brain may reveal new horizons in basic neuroscience and clinical applications.

Retinal Image Augmentation using Composed GANs

Medical image analysis faces a significant challenge in the scarcity of annotated data, which is crucial for developing generalizable Deep Learning (DL) models that require extensive training data. Consequently, the field of medical image generation has garnered substantial interest and potential for further exploration. Besides widely employed data augmentation techniques, such as rotation, reflection, and scaling, Generative Adversarial Networks (GANs) have demonstrated the ability to effectively leverage additional information from datasets by generating synthetic samples from real images. In the context of retinal image synthesis, an image-to-image translation approach is frequently adopted to generate retinal images from available vessel maps, which can be scarce and resource-intensive to obtain. Deviating from prior work reliant on pre-existing vessel maps, this study proposes a learning-based model that is independent of vessel maps, utilizing Progressive Growing GAN (PGGAN) to generate vascular networks from random noise. The visual and quantitative evaluations conducted suggest that the majority of the images generated by the proposed model are substantially distinct from the training set while maintaining a high proportion of true image quality, underscoring the model's potential as a powerful tool for data augmentation.

Diagnosing recipient- vs. donor-derived posttransplant myelodysplastic neoplasm via targeted single-cell mutational profiling.

Distinguishing donor- vs. recipient-derived myelodysplastic neoplasm (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is challenging and has direct therapeutical implications. Here, we took a translational approach that we used in addition to conventional diagnostic techniques to resolve the origin of MDS in a 38-year-old patient with acquired aplastic anemia and evolving MDS after first allo-HSCT. Specifically, we used single-cell transcriptional profiling to differentiate between donor- and recipient-derived bone marrow cells and established a strategy that additionally allows identification of cells carrying the MDS-associated U2AF1S34Y variant. The patient exhibited mixed donor chimerism combined with severely reduced erythropoiesis and dysplastic morphology within the granulocytic and megakaryocytic lineage along with the MDS-associated U2AF1S34Y mutation in the bone marrow. Single-cell transcriptional profiling together with targeted enrichment of the U2AF1S34Y-specific locus further revealed that, while the immune compartment was mainly populated by donor-derived cells, myelopoiesis was predominantly driven by the recipient. Additionally, concordant with recipient-derived MDS, we found that U2AF1S34Y-mutated cells were exclusively recipient derived with X but not Y chromosome-specific gene expression. Our study highlights the clinical potential of integrating high-resolution single-cell techniques to resolve complex cases for personalized treatment decisions. The study was funded by intramural resources of the Charité- Universitätsmedizin Berlin and the Berlin Institute of Health.

Establishing Effective Patient Engagement Through a Terms of Reference to Foster Inclusivity and Empowerment in Research: Example From a Healthcare Transition Quality Indicators Project.

Patient engagement in research aims to foster meaningful partnerships, integrating patient experiences into the research process. This paper describes the development of a Terms of Reference (ToR) to support these meaningful partnerships. While engagement improves data collection and empowerment, ineffective engagement can lead to negative outcomes. A well-developed ToR promotes a structured, inclusive, and respectful process. Using an integrated knowledge translation (iKT) approach, we established a panel of youth, caregivers, healthcare providers, and healthcare leaders/decision-makers. Through collaborative discussions, we incorporated key elements into the ToR, including values, roles, decision-making processes, and recognition of contributions. To promote effective engagement the ToR included sections to encourage open, transparent and vulnerable dialogue, evaluation, and accommodations for disabilities. The ToR draft was reviewed and refined by panel members for clarity. Regular reviews and updates will keep the ToR a living document and adaptable to the evolving engagement process. The implementation of our ToR is designed to foster inclusivity, mutual respect, and accountability, avoiding tokenistic partnership, enriching the experience for patients and researchers alike, and ultimately enhancing research quality.

Umbrella-Review, Evaluation, Analysis and Communication Hub (U-REACH): a novel living umbrella review knowledge translation approach

Systematic reviews and meta-analyses have become crucial for evidence-based decision-making in recent decades. However, it is common for the results of multiple reviews on the same topic to be inconsistent,...

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.

Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallelwith the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver. These transcripts are differentially expressed across areas of steatosis in spatial transcriptomics, and several are dynamic during stages of steatosis. Circulating multi-protein signatures of steatosis strongly associate with fatty liver disease and multi-system metabolic outcomes. Using a humanized "liver-on-a-chip" model, we induce hepatic steatosis, confirming cell-specific expression of prioritized targets. These results underscore the utility of this approach to identify a prognostic, functional, dynamic "liquid biopsy" of human liver, relevant to biomarker discovery and mechanistic research applications.

Molecular and cellular determinants of L-Dopa-induced dyskinesia in Parkinson’s Disease

Treatment with L-3,4-dihydroxyphenylalanine (L-Dopa) compensates for decreased striatal dopamine (DA) levels and reduces Parkinson’s disease (PD) symptoms. However, during disease progression, L-Dopa-induced dyskinesia (LID) develops virtually in all PD patients, making the control of PD symptoms difficult. Thus, understanding the mechanisms underlying LID and the control of these motor abnormalities is a major issue in the care of PD patients. From experimental and clinical studies, a complex cascade of molecular and cellular events emerges, but the primary determinants of LID are still unclear. Here, with a translational approach, including four animal models and a wide cohort of PD patients, we show that striatal DA denervation is the major causal factor for the emergence of LID, while α-synuclein aggregates do not seem to play a significant role. Our data also support the concept that maladaptive basal ganglia plasticity is the main pathophysiological mechanism underlying LID.

In Search of Atmospheres: Directions, Methods, Perspectives (an Interview with Tonino Griffero)

The article is a commented translation from English and German of an interview, conducted in February 2024 with the Italian philosopher-phenomenologist, professor of aesthetics at the University of Rome “Tor Vergata”, the current undisputed leader in the study of (affective) atmospheres Tonino Griffero. The interview touches upon a diversity of traditions in atmospheric research (including national variation in such studies), the correlation of the notions of atmosphere with the notions of mood (Stimmung) andambiance, research methods and ways of theorizing of atmospheric phenomena by German phenomenologist Hermann Schmitz (16.05.1928–05.05.2021) and aesthetics specialist Gernot Böhme (03.01.1937–20.01.2022), and, finally, the prospects of employing the relevant methods and approaches in social sciences, including anthropology.

Developing Translation and Interpretation Skills: An Analysis of Students' Linguistic Needs

This study aimed to investigate the views of final year students of Department Languages ​​and Translation at Taibah University regarding the skills required for professional success through the needs analysis approach. This study investigated the perspectives of 100 final year translation and interpretation students at Taibah University in Saudi Arabia regarding the professional competencies needed for career success. A 21-item Likert-scale needs analysis questionnaire captured students' views. The results showed that students showed high agreement on the skill importance (M=4.55). The results showed that students at high level considered the sufficiently of current translation approach (M=3.72). Students also highly agreed on the existed substantial barriers with 3.78. Finally, students reported with very high rate (4.2) about the necessity of making changing in the curriculum practices. The study recommends aligning efforts with competency priorities reported by students promises continuously optimized outcomes. Recurring assessment input as stakeholders informs responsive planning per evolving needs amidst global demands. This methodology elevates student perspectives to guide curriculum improvements towards employer-relevant skill-building.

Dopaminergic PET to SPECT domain adaptation: a cycle GAN translation approach.

Dopamine transporter imaging is routinely used in Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) diagnosis. While [11C]CFT PET is prevalent in Asia with a large APS database, Europe relies on [123I]FP-CIT SPECT with limited APS data. Our aim was to develop a deep learning-based method to convert [11C]CFT PET images to [123I]FP-CIT SPECT images, facilitating multicenter studies and overcoming data scarcity to promote Artificial Intelligence (AI) advancements. A CycleGAN was trained on [11C]CFT PET (n = 602, 72%PD) and [123I]FP-CIT SPECT (n = 1152, 85%PD) images from PD and non-parkinsonian control (NC) subjects. The model generated synthetic SPECT images from a real PET test set (n = 67, 75%PD). Synthetic images were quantitatively and visually evaluated. Fréchet Inception Distance indicated higher similarity between synthetic and real SPECT than between synthetic SPECT and real PET. A deep learning classification model trained on synthetic SPECT achieved sensitivity of 97.2% and specificity of 90.0% on real SPECT images. Striatal specific binding ratios of synthetic SPECT were not significantly different from real SPECT. The striatal left-right differences and putamen binding ratio were significantly different only in the PD cohort. Real PET and real SPECT had higher contrast-to-noise ratio compared to synthetic SPECT. Visual grading analysis scores showed no significant differences between real and synthetic SPECT, although reduced diagnostic performance on synthetic images was observed. CycleGAN generated synthetic SPECT images visually indistinguishable from real ones and retained disease-specific information, demonstrating the feasibility of translating [11C]CFT PET to [123I]FP-CIT SPECT. This cross-modality synthesis could enhance further AI classification accuracy, supporting the diagnosis of PD and APS.

Mitophagy-Enhanced Nanoparticle-Engineered Mitochondria Restore Homeostasis of Mitochondrial Pool for Alleviating Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is an interstitial lung disease tightly associated with the disruption of mitochondrial pool homeostasis, a delicate balance influenced by functional and dysfunctional mitochondria within lung cells. Mitochondrial transfer is an emerging technology to increase functional mitochondria via exogenous mitochondrial delivery; however, the therapeutic effect on mitochondrial transfer is hampered during the PF process by the persistence of dysfunctional mitochondria, which is attributed to impaired mitophagy. Herein, we reported engineering mitochondria mediated by mitophagy-enhanced nanoparticle (Mito-MEN), which promoted synchronal regulation of functional and dysfunctional mitochondria for treating PF. Mitophagy-enhanced nanoparticles (MENs) were fabricated through the encapsulation of Parkin mRNA, and the electrostatic interaction favored MENs to anchor isolated healthy mitochondria for the construction of Mito-MEN. Mito-MEN increased the load of functional exogenous mitochondria by enhancing mitochondrial delivery efficiency and promoted mitophagy of dysfunctional endogenous mitochondria. In a bleomycin (BLM)-induced PF mouse model, Mito-MEN repaired mitochondrial function and efficiently relieved PF-related phenotypes. This study provides a powerful tool for synchronal adjustment of mitochondrial pool homeostasis and offers a translational approach for pan-mitochondrial disease therapies.

Calcium phosphate nanoclusters modify periodontium remodeling and minimize orthodontic relapse

Orthodontic relapse is one of the most prevalent concerns of orthodontic therapy. Relapse results in patients' teeth reverting towards their pretreatment positions, which increases the susceptibility to functional problems, dental disease, and substantially increases the financial burden for retreatment. This phenomenon is thought to be induced by rapid remodeling of the periodontal ligament (PDL) in the early stages and poor bone quality in the later stages. Current therapies including fixed or removable retainers and fiberotomies have limitations with patient compliance and invasiveness. Approaches using biocompatible biomaterials, such as calcium phosphate polymer-induced liquid precursors (PILP), are an ideal translational approach for minimizing orthodontic relapse. Here, post-orthodontic relapse is reduced after a single injection of high concentration PILP (HC-PILP) nanoclusters by altering PDL remodeling in the early stage of relapse and improving trabecular bone quality in the later stage. HC-PILP nanoclusters are achieved by using high molecular weight poly aspartic acid (PASP, 14 kDa) and poly acrylic acid (PAA, 450 kDa), which resulted in a stable solution of high calcium and phosphate concentrations without premature precipitation. In vitro results show that HC-PILP nanoclusters prevented collagen type-I mineralization, which is essential for the tooth-PDL-bone interphase. In vivo experiments show that the HC-PILP nanoclusters minimize relapse and improve the trabecular bone quality in the late stages of relapse. Interestingly, HC-PILP nanoclusters also altered the remodeling of the PDL collagen during the early stages of relapse. Further in vitro experiments showed that HC-PILP nanoclusters alter the fibrillogenesis of collagen type-I by impacting the protein secondary structure and forming aggregates. These findings propose a new approach for treating orthodontic relapse and provide additional insight into the PILP nanocluster's structure and properties on collagenous structure repair.

An assessment of translating religious and magical aspects in "Arabian nights" into English

This thesis discusses the difficulties of translating "Arabian Nights" from Arabic to English, focusing on cultural and religious elements. It analyzes translation strategies from the 19th century to the present by using Katharina Reiss' text typology framework. English translations nevertheless influenced by historical biases and misconceptions. Modern translations show more cultural sensitivity but struggle to fully convey nuances. Market expectations often lead to domestication in translation approaches. The research emphasizes the tension between making the text accessible to Western audiences while keeping its cultural authenticity. It contributes to discussions on literary translation and cultural preservation, emphasizing the need for more complex, culturally aware approaches in translating works across diverse linguistic and cultural landscapes. This study provides insights to inform future translation efforts and cross-cultural literary studies, addressing the difficult balance between reader accessibility and cultural integrity in literary translation.

Definitional Challenges in Understanding Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiomyopathy. It is often caused by mutations of genes encoding for sarcomeric or sarcomere-associated proteins. Despite its clinical importance, divergent definitions are published by major cardiology societies. Some regard HCM as a specific genetic disease, whereas others define it as a broad 'spectrum of the thick heart'. The present narrative review aimed to assess both definitions from a pathoanatomical perspective. As a conjoint interdisciplinary and translational approach is needed to further increase knowledge and improve the understanding of HCM, the PubMed database was searched using several advanced search algorithms to explore the perspectives of the (forensic) pathologist, clinician, and basic researcher regarding the difference between the definitions of HCM. This discrepancy between definitions can impact critical data, such as prevalence and mortality rate, and complicate the understanding of the disease. For example, due to the different definitions, research findings regarding molecular changes from studies applying the narrow definition cannot be simply extended to the 'spectrum' of HCM.

CSIG-17. ADHESION GPCR BAI1/ADGRB1 CAN BLOCK IGF1R-MEDIATED GROWTH SIGNALLING, INCREASE RADIOSENSITIVITY AND AUGMENT SURVIVAL IN MEDULLOBLASTOMA

Abstract Medulloblastoma (MB) is an aggressive pediatric brain tumors and increased knowledge about the disease mechanisms is needed to develop new therapeutic approaches. Brain-specific Angiogenesis Inhibitor 1 (BAI1/ADGRB1) is an adhesion GPCR receptor and tumor suppressor epigenetically silenced in MB. Our prior studies showed that BAI1 can bind the MDM2 E3 ubiquitin ligase and relocate it to the cell membrane, thereby preventing it from degrading p53 in the nucleus (Zhu et al, Cancer Cell, 2018). Whether other MDM2 targets are affected by this relocation that may be functionally important in MB development is unknown. We hypothesized that BAI1-mediated relocation of MDM2 might destabilize cell surface oncogenic receptors and found that BAI1 stimulates IGF1R poly-ubiquitination and degradation. Mechanistically, BAI1 fosters MDM2-IGF1R interaction through beta-arrestins, adaptor proteins connecting MDM2 to IGF1R. Epigenetic reactivation of BAI1 expression suppressed Stat3 and Akt signaling, and radio-sensitized MB cells, leading to significantly improved survival in orthotopic MB xenograft models in mice regardless of tumor p53 mutation status. These findings are important as they demonstrate that BAI1 has dual anti-tumor effects in MB through MDM2 membrane re-localization, stabilizing p53 and blocking IGF1R signaling. They further suggest that epigenetic targeting of BAI1 is a promising therapeutic approach for clinical translation.

Bioactive Self-Assembled Nanoregulator Enhances Hematoma Resolution and Inhibits Neuroinflammation in the Treatment of Intracerebral Hemorrhage.

Hematoma and secondary neuroinflammation continue to pose a significant challenge in the clinical treatment of intracerebral hemorrhage (ICH). This study describes a nanoregulator formed through the self-assembly of Mg2+ and signal regulatory protein α (SIRPα) DNAzyme (SDz), aimed at enhancing hematoma resolution and inhibiting neuroinflammation in the treatment of ICH. The structure of SDz collapses in response to the acidic endo/lysosomal microenvironment of microglia, releasing Mg2+ and the SIRPα DNAzyme. The Mg2+ then acts as a cofactor to activate the SIRPα DNAzyme. By blocking the CD47-SIRPα signaling pathway, microglia can rapidly and effectively phagocytose red blood cells (RBCs), thereby promoting the clearance of the hematoma. Simultaneously, Mg2+ reset the microglia to the M2 phenotype by inhibiting the MYD88/MAPK/NF-κB signaling pathway, thereby modulating the inflammatory microenvironment of ICH. This co-delivery and synergistic strategy resulted in a significant reduction in hematoma size, decreasing from 11.90 to 5.84mm3, and promoted recovery from ICH with minimal systemic side effects. This simple yet highly effective nanoplatform, which involves complex synergistic mechanisms, proves to be effective for ICH therapy and holds great promise for introducing novel perspectives into clinical and translational approaches for ICH.

Linguistic Obstacles Faced in Translating Some Unique Qur’anic Cultural Lexical Items into English: Reexploring Some Translation Approaches

This research paper aimed to identify the linguistic obstacles met in translating some unique Qur’anic cultural lexical items into English through the lens of translation approaches. The study used a qualitative descriptive method and Nord’s (1991) text analysis model in translation. The findings showed that the most used approach to translating the implication of Qur’anic cultural lexical items was that of word-for-word and verbatim translation, and this resulted in a deep meaning loss and manipulating the perfect translation. The study also found that Al-Hilali and Khan’s and Abdel-Haleem’s translation approach, contrastingly, seems to be predominantly translated text-oriented, and thus conforms to the strategy of free translation, putting pivotal descriptive details in brackets, footnotes, or as a paraphrasis. The study concluded that Pickthall was inclined to resort to a literal translation strategy, which often gives rise to obscurity and problems because it does not consider the idiomatic meaning and implicit meaning of the Qur’anic Cultural Lexical Items.