bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opioid use disorder and brain health: observational and genetic associations
Authors: Javidnia Sara , Roe James M. , Karhunen Ville , Gill Dipender , Bell Steven , Deak Joseph , Levey Daniel , Cronje Toinet , Burgess Stephen , Gelernter Joel , Ebmeier Klaus P. , Topiwala Anya 
Published: December 2024

AbstractBackgroundThe long-term impact of opioid use disorder (OUD) on brain health has been little explored although of potentially high public health importance.ObjectivesTo investigate the potential causal impact of OUD on later life brain health outcomes, including dementia, stroke and brain structure.MethodsObservational and Mendelian randomization (MR) analyses were conducted. Participants included in observational analyses were enrolled in the US Million Veteran Program (MVP). Cox proportional hazards were used to examine the association between electronic health record (EHR)-derived diagnoses of OUD and incident dementia in European and African ancestry populations. Two-sample MR was applied to explore the association between genetic predisposition to OUD and dementia, as well as key endophenotypes including brain structure. Several analyses were used for insight into aetiological pathways, including cis-MR to assess the impact of genetically-proxied opioid receptor perturbation, Bayesian colocalization, and polygenic risk score analyses of longitudinal brain changes in non-opioid users from the Lifebrain project (n=229).ResultsAmongst 222,518 MVP participants, 8397 developed dementia during follow up. Participants with OUD (n=9,399) were younger and more likely to be male. In observational analyses, OUD was associated with a higher risk of incident all-cause dementia (hazard ratio [HR]=1.56, 95% confidence interval [CI] [1.39,1.76];p=2.23×10-13), Alzheimer’s [HR=1.40[1.04,1.87]; p=0.02) and vascular dementia (HR=1.49[1.19,1.86];p=0.0004). In the genetic analysis, genetically-proxied OUD also associated with higher dementia risk. A doubling in genetically-proxied OUD prevalence was associated with a 77% increase in odds of dementia (IVW OR=1.77[1.43,2.19];p=1.69×10⁻⁷). Variation in μ-opioid receptor genes were strongly associated with dementia risk. No significant associations were observed with brain structure in non-opioid users, nor in lower powered non-European ancestry groups.ConclusionsThese findings suggest a potential causal impact of opioid use disorder on dementia. Genetic analyses supported an aetiological role of μ-opioid receptor pathways. Further pharmacovigilance and investigation into the long-term effects of opioids on brain health are warranted.
Detecting Clinically Relevant Topological Structures in Multiplexed Spatial Proteomics Imaging Using TopKAT
Authors: Samorodnitsky Sarah , Campbell Katie , Little Amarise , Ling Wodan , Zhao Ni , Chen Yen-Chi , Wu Michael C. 
Published: December 2024

AbstractNovel multiplexed spatial proteomics imaging platforms expose the spatial architecture of cells in the tumor microenvironment (TME). The diverse cell population in the TME, including its spatial context, has been shown to have important clinical implications, correlating with disease prognosis and treatment response. The accelerating implementation of spatial proteomic technologies motivates new statistical models to test if cell-level images associate with patient-level endpoints. Few existing methods can robustly characterize the geometry of the spatial arrangement of cells and also yield both a valid and powerful test for association with patient-level outcomes. We propose a topology-based approach that combines persistent homology with kernel testing to determine if topological structures created by cells predict continuous, binary, or survival clinical endpoints. We term our method TopKAT (Topological Kernel Association Test) and show that it can be more powerful than statistical tests grounded in the spatial point process model, particularly when cells arise along the boundary of a ring. We demonstrate the properties of TopKAT through simulation studies and apply it to two studies of triple negative breast cancer where we show that TopKAT recovers clinically relevant topological structures in the spatial distribution of immune and tumor cells.
The impact of introducing meningococcal C/ACWY booster vaccination among adolescents in Germany: a dynamic transmission modelling study
Authors: Günther Felix , Reinacher Ulrich , Chisholm Sarah , Griskaitis Matas , Höhle Michael , Scholz Stefan , Schönfeld Viktoria , Wichmann Ole , Harder Thomas , Sandmann Frank G. 
Published: December 2024

AbstractBackgroundIn Germany, primary vaccination against invasive meningococcal disease (IMD) serogroup C aims to reduce the highest burden of IMD in infants aged 12-23 month. Due to another IMD-peak in adolescents, we modelled the potential impact of introducing adolescent boosters with conjugate meningococcal C or ACWY (MenC/MenACWY) vaccines.MethodsWe built an age- and serogroup-structured dynamic-transmission model for Germany, which we calibrated to national surveillance data in 2005-2019. We simulated five vaccination scenarios of either continuing with the current MenC primary vaccination (scenario 1), or additionally introducing MenC or MenACWY boosters at age 13 years (scenarios 2-3) or 16 years (scenarios 4-5). We performed comprehensive sensitivity analyses, including on the protection against carriage and serotype replacement.ResultsThe calibrated model projected for scenario 1 an annual mean of 243 (95%-uncertainty interval: 220-258) expected IMD cases over a 10-year period. Introducing the MenC booster prevented an estimated 5 (3.9-6.7) and the MenACWY booster 8 (6.7-9.1) IMD cases per year on average (scenario 2 and 3). The number-needed-to-vaccinate (NNVs) to prevent one IMD case were 140,000 (100,000-180,000) and 91,000 (76,000-100,000), respectively. To prevent one sequela or death, NNVs were higher (i.e., less efficient). Results were broadly similar for scenarios 4-5. Simulations suggested relevant serotype replacement starting eight-to-ten years after introducing the MenACWY booster.ConclusionsIntroducing adolescent MenC or MenACWY boosters marginally reduces the expected IMD burden in Germany. Effectiveness and efficiency of evaluated strategies depend on future incidence. The magnitude of future serotype replacement for the MenACWY vaccine is highly uncertain.
Tumor-associated macrophages enhance tumor innervation and spinal cord repair
Authors: Dolci Sissi , Mannino Loris , Campanelli Alessandra , Rossi Eros , Bottani Emanuela , Ciarpella Francesca , Karkossa Isabel , Setten Elisa , Savino Benedetta , Pruonto Giulia , Piazza Nicola , Gianoli Stefano , Amenta Alessia , Busetto Giuseppe , Pezzotta Alex , Di Chio Marzia , Castagna Alessandra , Martinelli Nicolò , Barone Ilaria , Boschi Federico , Doherty Adam , Scupoli Maria Teresa , Cavallini Chiara , Malpeli Giorgio , Malik Zulkifal , Sagripanti Ludovica , Silani Vincenzo , Cristofori Patrizia , Scanziani Eugenio , Sandri Marco , Pistocchi Anna , Bossolasco Patrizia , Endrizzi Marco , Schubert Kristin , Fumagalli Guido Francesco , Locati Massimo , Bifari Francesco , Decimo Ilaria 
Published: December 2024

AbstractTumor-associated macrophages (TAM) enhance cancer progression by promoting angiogenesis, extracellular matrix (ECM) remodeling, and immune suppression. Nerve infiltration is a hallmark of various cancers and is known to directly contribute to tumor growth. However, the role of TAM in promoting intratumoral nerve growth remains poorly understood. In this study, we demonstrate that TAM expressed a distinct “neural growth” gene signature. TAM actively enhance neural growth within tumors and directly promote neurites outgrowth. We identify secreted phosphoprotein 1 (Spp1) as a key mediator of TAM-driven neural growth activity, which triggers neuronal mTORC2 signaling.Leveraging this new neural growth function, which added to the TAM wound healing properties, we explored TAM potential to repair central nervous system. Adoptive transfer ofin vitro-generated TAM in a severe complete-compressive-contusive spinal cord injury (scSCI) model, not only repaired the damaged neural parenchyma by improving tissue oxygenation, ECM remodeling, and dampening chronic inflammation, but also resulted in neural regrowth and partial functional motor recovery. Proteomic analysis and subsequent functional validation confirmed that TAM-induced spinal cord regeneration is mediated through the activation of neural mTORC2 signaling pathways.Collectively, our data unveil a previously unrecognized role of TAM in tumor innervation, neural growth, and neural tissue repair.
Non-invasive diagnosis of early chronic colitis cancerization via amplified sensing of miRNA-21 in NIR-IIb window
Authors: Zhai Fuheng , Yun Baofeng , Ming Jiang , Li Benhao , Yu Tianyu , Liu Xiao , Wang Xusheng , Chen Zi-Han , Song Changfeng , Zhao Mengyao , Li Jiyu , Liang Aibin , Zhang Fan 
Published: December 2024

AbstractEarly diagnosis of the colitis-associated colorectal cancer (CRC) is of great significance for improving prognosis and survival rates. However, the clinical used colonoscopy and biopsy methods are invasive and lack of sensitivity at early stage of cancerization. Herein, we present an amplified sensing strategy in the second near-infrared b (NIR-IIb, 1500-1700 nm) window for non-invasive in situ visualization of early cancerization biomarker miRNA-21. A CRC nanosensor composed of Er3+doped lanthanide nanoparticles, DNAzyme, and IR820 dye is designed as a NIR-IIb ratiometric luminescence reporter, providing rapid feedback and high sensitive miRNA-21 detection with limit of detection (LOD) of 1.26 pM. This strategy enables a non-invasive detection of colitis-associated cancerization up to ∼4 weeks ahead of the clinically used biopsy analysis, providing a promising alternative for early diagnosis of chronic colitis cancerization and guidance for therapeutic management.
MultiNMRFit: A software to fit 1D and pseudo-2D NMR spectra
Authors: Millard Pierre , Le Grégam Loïc , Dubiley Svetlana , Gosselin-Monplaisir Thomas , Lippens Guy , Charlier Cyril 
Published: December 2024

SummaryNuclear Magnetic Resonance (NMR) is widely used for quantitative analysis of metabolic systems. Accurate extraction of NMR parameters – such as chemical shift, intensity, coupling constants, and linewidth – is essential for obtaining information on the structure, concentration, and isotopic composition of metabolites. We present MultiNMRFit, an open-source software designed for high-throughput analysis of one-dimensional NMR spectra, whether acquired individually or as pseudo-2D experiments. MultiNMRFit extracts signal parameters (e.g. intensity, area, chemical shift, and coupling constants) by fitting the experimental spectra using built-in or user-defined signal models that account for multiplicity, providing high flexibility along with robust and reproducible results. The software is accessible both as a Python library and via a graphical user interface, enabling intuitive use by end-users without computational expertise. We demonstrate the robustness and flexibility of MultiNMRFit on datasets collected in metabolomics and isotope labeling studies.Availability and ImplementationMultiNMRFit is implemented in Python 3 and was tested on Unix, Windows, and MacOS platforms. The source code and the documentation are freely distributed under GPL3 license athttps://github.com/NMRTeamTBI/MultiNMRFit/.Supplementary dataSupplementary data are available online.
Stereochemical Insights into Sarpagan and Akuammiline Alkaloid Biosynthesis
Authors: Alexander Mann Scott Galeung , Paz-Galeano Malina , Shahsavarani Mohammadamin , Perley Jacob Owen , Guo Jun , Oswaldo Garza-Garcia Jorge Jonathan , Qu Yang 
Published: December 2024

AbstractThe Apocynaceae family produces a remarkable diversity of monoterpenoid indole alkaloids (MIAs), many of which possess significant pharmaceutical value. Among these, sarpagan and akuammiline alkaloids represent distinct subclasses characterized by their intricate stereochemical frameworks, derived through enzymatically controlled cyclization and rearrangement of the key precursor geissoschizine. In this study, we systematically investigated the products and stereochemical outcomes of sarpagan bridge enzymes (SBEs) and rhazimal synthases (RHS), key enzymes involved in geissoschizine cyclization and MIA diversification. Using two previously characterized enzymes alongside five newly identified enzymes from six plant species, we demonstrate that RHS enzymes fromAlstonia scholaris,Vinca minor, andAmsonia tabernaemontanaexclusively produce the 16Rrhazimal stereoisomer. In contrast, SBEs fromCatharanthus roseus,Vinca minor,Tabernaemontana elegans, andRauvolfia serpentinagenerate both 16Sakuammidine aldehyde and 16Rpolyneuridine aldehyde diastereomers in varying ratios. Remarkably, downstream esterases and deformylases epimerize and alter the stereochemical configuration, yielding naturally occurring alkaloids bearing distinct C16 stereochemistry in different species. These findings are supported by both in vitro assays andin plantasilencing of the newly identifiedC. roseusCrSBE, after we redirected the MIA flux to the otherwise muted sarpagan pathway. Our results provide a comprehensive understanding of the enzymatic control over C16 stereochemistry during SBE-mediated and RHS-mediated transformations. By elucidating how diastereomeric intermediates contribute to sarpagan MIA biosynthesis, this work addresses long-standing questions surrounding the stereochemical dynamics and enzymatic diversification of MIAs in nature.
Formal and informal mental health support in young adults with recurrently depressed parents
Authors: Jones Rhys Bevan , Weavers Bryony , Lomax Tessa , Meilak Emma , Eyre Olga , Powell Victoria , Mars Becky , Rice Frances 
Published: December 2024

AbstractBackgroundA family history of mental illness, particularly parental depression, is a risk factor for mental health difficulties in young people, with this heightened risk extending into adulthood. Evidence suggests low rates of formal mental health support in children/adolescents with depressed parents, but it is unknown whether this pattern persists into adulthood and applies to informal support.AimsWe examined the prevalence of formal and informal mental health support accessed by young adults with recurrently depressed parents. We identified factors associated with access to different support, reported satisfaction with support and identified potential facilitators/barriers to access.MethodsA mixed-method study comprising 144 young adults (mean age=23 years, range=18-28 years) who completed psychiatric assessments and reported on their use of mental health support. Regression analyses explored predictors for support. A focus group examined facilitators and barriers.ResultsYoung adults accessed a range of formal (29%) and informal (56%) support. Among those with psychiatric disorder, nearly half had not accessed formal support and one-fifth had not accessed any support. Predictors of support included psychiatric disorder, severity indicators (e.g. self-harm/suicidal thoughts, impairment), and demographic factors (e.g. education, gender).Predictors varied by type of support. Most participants reported satisfaction with support. Facilitators included role models, public mental health discussions, and practitioner training. Barriers included identifying difficulties, stigma, service limitations, and family/friends’ experiences.ConclusionsYoung adults at high risk of mental disorders accessed various mental health support. However, many did not access/receive support when needed. Further work is required to improve access to tailored support.
Automated Interpretation of Fundus Fluorescein Angiography with Multi-Retinal Lesion Segmentation
Authors: Zhao Ziwei , Huang Shoujin , Zhang Weiyi , Song Fan , Lu Yan , Shang Xianwen , He Mingguang , Shi Danli 
Published: December 2024

AbstractPurposeFundus fluorescein angiography (FFA) is essential for diagnosing and managing retinal vascular diseases, while its evaluation is time-consuming and subject to inter-observer variability. We aim to develop a deep-learning-based model for accurate multi-lesion segmentation for these diseases.MethodsA dataset comprising 428 standard 55° and 53 ultra-wide-field (UWF) FFA images was labeled for various lesions, including non-perfusion areas (NPA), microaneurysms (MA), neovascularization (NV) and laser spots. A U-net-based network was trained and validated (80%) to segment FFA lesions and then tested (20%), with performance assessed via Dice score and Intersection over Union (IoU).ResultsOur model achieved Dice scores for NPA, MA, NV, and Laser on 55° FFA images at 0.65±0.24, 0.70±0.13, 0.73±0.23 and 0.70±0.17, respectively. UWF results were slightly lower for NPA (0.48±0.21, p=0.02), MA (0.58±0.19, p=0.01), NV (0.50±0.34, p=0.14), but similar for Laser (0.74±0.03, p=0.90). Notably, NV segmentation in choroidal neovascularization achieved a high Dice score of 0.90±0.09, surpassing those in DR (0.68±0.22) and RVO (0.62±0.28), p<0.01. In RVO, NPA segmentation outperformed that in DR, scoring 0.77±0.25 versus 0.59±0.22, p<0.01, while in DR, MA segmentation was superior to that in RVO, with scores of 0.70±0.18 compared to 0.53±0.20,p<0.01. Moreover, NV segmentation was significantly stronger in venous phase (0.77±0.17) and late phase (0.75±0.24) compared to arteriovenous phase (0.50±0.32), p<0.05.ConclusionThis study has established a model for precise multi-lesion segmentation in retinal vascular diseases using 55° and UWF FFA images. This multi-lesion segmentation model has the potential to expand databases, ease grader burden and standardize FFA image interpretation, thereby improving disease management. Furthermore, it enhances interpretable AI, fostering the development of sophisticated systems and promoting cross-modal image generation for medical applications.SynopsisWe developed deep-learning models for segmenting multiple retinal lesions in both normal and ultra-field FFA images; the satisfactory performances set the foundation for quantifiable clinical biomarker assessment and building interpretable generative artificial intelligence.
Neurodevelopmental deviations in schizophrenia: Evidences from multimodal connectome-based brain ages
Authors: Fan Yun-Shuang , Yang Pengfie , Zhu Yucheng , Jing Wenfeng , Xu Yong , Guo Jing , Huang Wei , Chen Huafu 
Published: December 2024

AbstractBackgroundPathologic schizophrenia process originate early in brain development, leading to detectable brain alterations via structural and functional magnetic resonance imaging (MRI). Recent MRI studies have sought to characterize disease effects from a brain age perspective, but developmental deviations from the typical brain age trajectory in youths with schizophrenia remain unestablished.AimThis study investigated brain development deviations in early-onset schizophrenia (EOS) patients by applying machine learning algorithms to structural and functional MRI data.MethodsMultimodal MRI data, including T1-weighted MRI (T1w-MRI), diffusion MRI, and resting-state functional MRI (rs-fMRI) data, were collected from 80 antipsychotic-naive first-episode EOS patients and 91 typically developing (TD) controls. The morphometric similarity connectome (MSC), structural connectome (SC), and functional connectome (FC) were separately constructed by using these three modalities. According to these connectivity features, eight brain age estimation models were first trained with the TD group, the best of which was then used to predict brain ages in patients. Individual brain age gaps (BAGs) were assessed as brain ages minus chronological ages.ResultsBoth the SC and MSC features performed well in brain age estimation, whereas the FC features did not. Compared with the TD controls, the EOS patients presented widened structural BAGs, with opposite trends between childhood and adolescence. These increased absolute BAG scores for EOS patients were positively correlated with the severity of their clinical symptoms.ConclusionThese findings from a multimodal brain age perspective suggest that advanced BAGs exist early in youths with schizophrenia.
Aggregation promoting sequences rather than phosphorylation are essential for Tau-mediated toxicity inDrosophila
Authors: Cooper Amber , Richardson Bradley , Ruiz Ortega Eva , Zhang Yongrui , Batchelor Ben , Vaikakkara Chithran Aarya , Liu Jie , Lian Tianshun , Ramírez Moreno Miguel , Boehme Benjamin , Abtahi Leila , Devitt George , Sivanantharajah Lovesha , Skoulakis Efthimios M. C. , Allan Douglas W. , Mudher Amritpal 
Published: December 2024

AbstractBackgroundDisease-modifying therapies for tauopathies like Alzheimer’s disease have targeted Tau hyperphosphorylation and aggregation, as both pathological manifestations are implicated in Tau-mediated toxicity. However, the relative contributions of these pathology-linked changes to Tau neurotoxicity remain unclear.MethodsLeveraging the genetic tractability ofDrosophila, we generated multiple inducible human Tau transgenes with altered phosphorylation status and/or aggregation propensity. Their individual and combined impact was testedin vivoby quantifying Tau accumulation and neurodegenerative phenotypes in the aging fly nervous system.ResultsWe report that phospho-mimicking Tau (hTau2N4RE14) induced profound neurodegeneration, supporting a neurotoxic role for phosphorylation. However, when we rendered hTau2N4RE14aggregation incompetent, by deleting the306VQIVYK311motif in the microtubule-binding region, neurotoxicity was abolished. Moreover, a peptide inhibitor targeting this motif efficaciously reduced Tau toxicity in agingDrosophila.ConclusionNeurodegeneration mediated by Tau hyperphosphorylation is gated via at least one aggregation-mediating motif on the protein. This highlights the primacy of blocking Tau aggregation in therapy, perhaps without the need to clear phosphorylated species.
Crystal structure of Fatty Acid Thioesterase A bound by 129 fragments provides diverse development opportunities
Authors: Kot Ekaterina , Ferla Matteo P. , Hollinshead Patricia H. , Tomlinson Charlie W.E. , Fearon Daren , Aschenbrenner Jasmin C. , Koekemoer Lizbé , Winokan Max , Fairhead Michael , Ni Xiaomin , England Katherine S. , Ortega Varga Laura , Montgomery Mark G. , Mulholland Nicholas P. , von Delft Frank 
Published: December 2024

AbstractTo alleviate the growing issue of herbicide resistance, diversification of the herbicide portfolio is necessary. A promising yet underutilised mode of action (MoA) are Fatty Acid Thioesterases (Fat), which terminatede novofatty acid (FA) biosynthesis by releasing fatty acids from acyl carrier protein (ACP) cofactors. These enzymes impact plant growth and sterility by determining the amount and length of FAs present. To find novel chemical matter targeting this MoA we have solved the crystal structure ofArabidopsis thalianaFatA to 1.5Å and conducted a crystallographic fragment screen which identified 141 hits. Our fragments recapitulated interactions made by current herbicides, but also targeted novel regions, namely the active site and the dimer interface. Ten fragments demonstrated on-scale potency, two of those exploiting different interactions to known herbicides. The screen also revealed large conformational changes exploited by some fragments, including stabilisation of a loop and shifts in the ACP-binding lid domain. These changes alter the accessibility of the substrate binding site by reducing the size of the apparent substrate access channel. Finally, the fragments readily lend themselves to designing compounds that both merge motifs and allow catalogue-based SAR exploration. Elaboration of one of the fragments resulted in an improvement of affinity from ∼20 μM to ∼90nM KD. Thus our data may facilitate accelerated early discovery of alternative inhibitors that are novel in both chemical scaffolds and modes of interaction.