bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Bile Acids with Connectivity of Executive Control and Default Mode Networks in Patients with Major Depression
Authors: Dunlop Boadie W. , Cha Jungho , Mayberg Helen S. , Choi Ki Sueng , Edward Craighead W. , MahmoudianDehkordi Siamak , Bhattacharyya Sudeepa , John Rush A. , Kaddurah-Daouk Rima 
Published: December 2024

ABSTRACTObjectiveBile acids may contribute to pathophysiologic markers of Alzheimer’s disease, including disruptions of the executive control network (ECN) and the default mode network (DMN). Cognitive dysfunction is common in major depressive disorder (MDD), but whether bile acids impact these networks in MDD patients is unknown.MethodsResting state functional magnetic resonance imaging (fMRI) scans and blood measures of four bile acids from 74 treatment-naïve adults with MDD were analyzed. Dorsolateral prefrontal cortex (DLPFC) seeds were used to examine connectivity of the ECN and posterior cingulate cortex (PCC) seeds were used for the DMN. Using a whole-brain analysis, the functional connectivity of these seeds was correlated with serum levels chenodeoxycholic acid (CDCA) and its bacterially-derived secondary bile acid, lithocholic acid (LCA).ResultsCDCA levels were strongly and inversely correlated with connectivity between DLPFC regions of the ECN (R2= .401, p<.001). LCA levels were strongly and positively correlated with connectivity of the DLPFC and left inferior temporal cortex of the ECN (R2=.263, p<.001). The LCA/CDCA ratio was strongly and positively correlated with connectivity of the DLPFC with two components of the ECN: bilateral inferior temporal cortex and the left superior and inferior parietal lobules (all R2>.24, all p<.001). For the DMN, the LCA/CDCA ratio was strongly and negatively correlated with connectivity of the PCC with multiple bilateral insula regions (all R2>0.25, all p<.001).ConclusionsThe relationship between LCA and CDCA levels and functional connectivity of the ECN and DMN suggests potential shared pathophysiologic processes between Alzheimer’s disease and MDD.
Automated Analysis of Bird Head Motion from Videos in Unconstrained Settings
Authors: Santos-Lopes Marco , Araújo Ricardo , David Romain , Correia Paulo L. 
Published: December 2024

AbstractThis study introduces a framework applicable to videos of habitual behaviors of multiple bird species to automatically assess head angular velocities and frequencies during various behaviors in natural habitats. The process involves detecting birds, identifying key points on their heads, and tracking changes in their positions over time. Bird detection and key point extraction were trained on publicly available datasets, including Animal Kingdom, NABirds, Birdsnap, CUB-200-2011, and eBird, featuring videos and images of diverse bird species in uncontrolled settings. Initial challenges arose due to the complexity of video backgrounds, leading to misidentifications and inaccurate key point estimates. These issues were addressed through validation, refinement, filtering, and smoothing steps. Head angular velocities and rotation frequencies were computed from the refined key points. The algorithm performed well at moderate speeds but was limited by the 30 Hz frame rate of most eBird videos, which constrained measurable angular velocities and frequencies and caused motion blur, affecting key point detection. Our findings suggest that the framework may provide plausible estimates of head motion but also emphasize the importance of high frame rate videos in future research, including extensive comparisons against ground truth data, to fully characterize bird head movements.
BenchXAI: Comprehensive Benchmarking of Post-hoc Explainable AI Methods on Multi-Modal Biomedical Data
Authors: Metsch Jacqueline Michelle , Hauschild Anne-Christin 
Published: December 2024

AbstractThe increasing digitalisation of multi-modal data in medicine and novel artificial intelligence (AI) algorithms opens up a large number of opportunities for predictive models. In particular, deep learning models show great performance in the medical field. A major limitation of such powerful but complex models originates from their ’black-box’ nature. Recently, a variety of explainable AI (XAI) methods have been introduced to address this lack of transparency and trust in medical AI. However, the majority of such methods have solely been evaluated on single data modalities. Meanwhile, with the increasing number of XAI methods, integrative XAI frameworks and benchmarks are essential to compare their performance on different tasks. For that reason, we developed BenchXAI, a novel XAI benchmarking package supporting comprehensive evaluation of fifteen XAI methods, investigating their robustness, suitability, and limitations in biomedical data. We employed BenchXAI to validate these methods in three common biomedical tasks, namely clinical data, medical image and signal data, and biomolecular data. Our newly designed sample-wise normalisation approach for post-hoc XAI methods enables the statistical evaluation and visualisation of performance and robustness. We found that the XAI methods Integrated Gradients, DeepLift, DeepLiftShap, and GradientShap performed well over all three tasks, while methods like Deconvolution, Guided Backpropagation, and LRP-α1-β0 struggled for some tasks. With acts such as the EU AI Act the application of XAI in the biomedical domain becomes more and more essential. Our evaluation study represents a first step toward verifying the suitability of different XAI methods for various medical domains.
A biocatalytic platform for the production of substituted 2-quinolones and (thio)coumarins
Authors: Sokolova Nika , Osipyan Angelina , Zhang Lili , Groves Matthew R. , Schmidt Sandy , Haslinger Kristina 
Published: December 2024

Abstract2-quinolones are privileged scaffolds for drug discovery that are relatively rare in nature. Here, we characterise two promiscuous fungal polyketide synthases AthePKS and FerePKS, which we had previously found to produce quinolonesin vitro. We challenged the enzymes with several substituted anthranilic acid derivatives, revealing their ability to produce precursors of pharmaceutically relevant quinolones. We also discovered that AthePKS and FerePKS accept other 2-substituted benzoic acids, leading to the formation of coumarin and thiocoumarin scaffolds. We applied AthePKS in an artificial enzymatic cascade towards an antimicrobial 4-methoxy-1-methyl-2-quinolone and demonstrated itsin vivofeasibility by successfully expressing the pathway inEscherichia coli. Lastly, we determined the crystal structure of AthePKS, suggesting hotspots for enhancing its catalytic efficiency by enzyme engineering. Our results provide a framework for further engineering of enzymatic routes towards privileged heteroaromatic scaffolds and derivatives thereof.
Photoreceptor cell death mechanism in light damage
Authors: Bruera Manuel G. , Contin María A. 
Published: December 2024

AbstractLight is one of the most ambient agents harmful to the retina. In Wistar rats prolonged exposure to 200 lux of LED light promotes photoreceptors cells death after 6 days. The possibility to know the cell photoreceptors death mechanism increases the likelihood to find a mixture of therapy with inhibitors or antagonists with anti-inflammatory and antioxidant effects. This study tested the cell death mechanism to elucidate the possible underlying molecular mechanisms. Adult male rats were exposed to 200 lux of LED light by different periods of constant light. The study focused on apoptosis and necroptosis pathways. Our findings reveal that necroptosis is an active pathway in retinal degeneration, occurring in both photoreceptors and glial cells, while apoptosis seem to be inactive during the studied time points.
The Septin Cytoskeleton excludes the Cdc42 GAP Rga4 from growing sites to promote bipolarity in fission yeast
Authors: McDuffie Justin , Chang Goeun , Das Maitreyi 
Published: December 2024

ABSTRACTThe conserved GTPase Cdc42 regulates polarity in most eukaryotes and is spatiotemporally regulated to confine growth to discreet areas throughout the cell cycle. Cdc42 activity stops at the growing ends of fission yeast during mitosis and resumes after division when the ends remove the inactivator/GAP Rga4. In interphase, Rga4 appear punctate at the cell sides restricted from the growing ends. During mitosis, Rga4 appears homogeneous and localizes to the ends. We show that this cell-cycle-dependent Rga4 localization is septin cytoskeleton-dependent. Septins forms linear filaments along the sides during interphase. In mitosis, the septins recede from the sides and form a ring at the division site. In septin mutants, Rga4 is mobile, homogeneously distributed and localizes to the ends, regardless of cell-cycle stage. Accordingly, septin mutants show delayed Cdc42 reactivation after division and are monopolar with disrupted Cdc42 activation dynamics. Our data describe an unusual form of polarity regulation where a septin-dependent physical barrier restricts GAP localization for proper Cdc42 dynamics.SummaryCell-cycle-dependent Rga4 localization pattern is controlled by the septin cytoskeleton to promote bipolar growth. In interphase, the septin cytoskeleton at the cell sides restricts Rga4 mobility and localization away from the cell ends to promote proper Cdc42 activation dynamics.
Neuronal representation of the decisional reference point in monkeys
Authors: Nguyen Duc , Rich Erin L. , Wallis Joni D. , Louie Kenway , Glimcher Paul W. 
Published: December 2024

ABSTRACTThe reward reference point serves as a hidden benchmark for evaluating options in decision-making. Despite extensive behavioral evidence for reference-dependence, no neural representation of the reference point has been discovered. We analyzed single neuron activity from macaque monkeys performing a decision-making task designed to orthogonalize objective reward values from the reference point. Regression analyses of neuronal activity across six frontal brain regions identified a robust neural representation of the reference point in the ventral bank of anterior cingulate cortex (vbACC). Activity in the dorsal bank of anterior cingulate cortex and the dorsolateral prefrontal cortex, in contrast, encoded the reference-dependent subjective values of the rewards offered or obtained on each trial. The temporal dynamics of these signals and connections between these regions suggest a dedicated neural circuit implementing reference-dependent reward encoding, with the vbACC serving as the reference point signal source modulating activity in other frontal value-encoding areas.
Exploring the specific predictive ability of multiple domains of spatial ability on STEM educational outcomes
Authors: Zhou Quan , Wang Ziye , Rimfeld Kaili , Allegrini Andrea G. , Plomin Robert , Malanchini Margherita 
Published: December 2024

AbstractResearch has implicated spatial ability as a robust predictor of aptitude, interest, and choice in STEM education and career pursuits. We address three under-explored questions regarding the role of spatial ability in STEM. First, can spatial ability consistently predict STEM success beyond other cognitive skills? Second, what aspects of spatial ability, if any, can predict success in STEM more accurately? Third, to what extent can genetic and environmental factors account for these predictions?We addressed these questions by leveraging data from the Twins Early Development Study (N = 3,936; age range = 16-22) and using 16 tests that assessed three domains of spatial ability: navigation, object manipulation, and visualization. Results show that all three domains are highly predictive of STEM educational outcomes, especially STEM degree choice. These associations persisted after accounting for verbal and general cognitive abilities (g), albeit attenuated. Associations were strongest for tests of object manipulation (e.g., 2D and 3D drawing, pattern assembly and mental rotation). Genetic factors accounted for most of the observed associations between spatial ability and STEM outcomes (62% - 86%) —genetic variance was mostly shared withg(∼ 40%) and, to a lesser extent, verbal ability (∼ 25%).Our findings highlight the potential utility of spatial ability as a specific predictor of success in STEM education and career choice beyond other cognitive abilities. Screening for and training spatial skills is likely useful for identifying potential, fostering talent, and improving outcomes in STEM.Significance StatementLeveraging a comprehensive battery of 16 spatial ability tests across multiple domains, we show that spatial ability has specific utility for predicting success in STEM education. Spatial skills predict success in STEM above and beyond other cognitive abilities, particularly when it comes to STEM engagement and pursuing further STEM education. Thus, spatial skills may be a fruitful target for policymakers, stakeholders, and industries looking to develop interventions, identify and foster talent, and reduce outcome disparities.
Sex-dimorphic gene regulation in murine macrophages across niches
Authors: McGill Cassandra J. , White Olivia S. , Lu Ryan J. , Sampathkumar Nirmal K. , Benayoun Bérénice A. 
Published: December 2024

AbstractMacrophages are a key cell type of the innate immune system and are involved at all steps of inflammation: (i) they present antigens to initiate inflammation, (ii) they clear up foreign bodies through phagocytosis, and (iii) they resolve inflammation by removing or deactivating mediator cells. Many subtypes of macrophages have been identified, classified by their niche and/or embryonic origin. In order to better develop therapies for conditions with macrophage dysfunction, it is crucial to decipher potential sex-differences in key physiological mediators of inflammation so that treatment efficacy can be ensured regardless of biological sex. Here, we conduct a meta-analysis approach of transcriptomics datasets for malevs. female mouse macrophages across 8 niches to characterize conserved sex-dimorphic pathways in macrophages across origins and niches. For this purpose, we leveraged new and publicly available RNA-sequencing datasets from murine macrophages, preprocessed these datasets and filtered them based on objective QC criteria, and performed differential gene expression analysis using sex as the covariate of interest. Differentially expressed (DE) genes were compared across datasets and macrophage subsets, and functional enrichment analysis was performed to identify sex-specific functional differences. Consistent with their presence on the sex chromosomes, three genes were found to be differentially expressed across all datasets (i.e.Xist,Eif2s3y, andDdx3y). More broadly, we found that female-biased pathways across macrophage niches are more consistent than male-biased pathways, specifically relating to components of the extracellular matrix. Our findings increase our understanding of transcriptional similarities across macrophage niches and underscore the importance of including sex as a biological variable in immune-related studies.HighlightsAcross 17 independently transcriptomic macrophage datasets, three genes are always differentially expressed between males and females:Ddx3y,Eif2s3y, andXist.Jaccard analysis reveals female macrophages have more stereotypical transcriptional profile than male macrophages across niches.Functional enrichment analyses show that female-biased pathways across macrophage subtypes are enriched for extracellular matrix-related genes.
Protein CREATE enables closed-loop design ofde novosynthetic protein binders
Authors: Lourenço Alec , Subramanian Arjuna , Spencer Ryan , Anaya Michael , Miao Jiapei , Fu William , Chow Eric , Thomson Matt 
Published: December 2024

AbstractProteins have proven to be useful agents in a variety of fields, from serving as potent therapeutics to enabling complex catalysis for chemical manufacture. However, they remain difficult to design and are instead typically selected for using extensive screens or directed evolution. Recent developments in protein large language models have enabled fast generation of diverse protein sequences in unexplored regions of protein space predicted to fold into varied structures, bind relevant targets, and catalyze novel reactions. Nevertheless, we lack methods to characterize these proteins experimentally at scale and update generative models based on those results. We describe Protein CREATE (Computational Redesign via an Experiment-Augmented Training Engine), an integrated computational and experimental pipeline that incorporates an experimental workflow leveraging next generation sequencing and phage display with single-molecule readouts to collect vast amounts of quantitative binding data for updating protein large language models. We use Protein CREATE to generate and assay thousands of designed binders to IL-7 receptorαand insulin receptor with parallel positive and negative selections to identify on-target binders. We discover not only individual novel binders but also features of ligand-receptor binding, including preservation of the IL7Rα- ligand hydrophobic interface specifically and existence of multiple approaches to contact the insulin receptor. We also demonstrate the importance of structural features, such as the lack of unpaired cysteine residues, toward design fidelity and find computational pre-screening metrics, such as interchain predicted TM scoring (iPTM), while useful, are imperfect predictors as they neither guarantee experimental binding nor rule it out. We use the data collected from Protein CREATE to score designs from the initial generative models. Globally, Protein CREATE will power future closed-loop design-build-test cycles to enable fine-grained design of protein binders.
Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin (ttn.2) Variants
Authors: Santiago Celine F. , Huttner Inken G , Brien Ailbhe O , Bennett Pauline M. , Cvetkovska Jasmina , Chand Renee , Holt Mark , Trivedi Gunjan , Wang Louis W. , Smith Kelly A. , Gautel Mathias , Fatkin Diane , Hinits Yaniv 
Published: December 2024

AbstractBackgroundTruncating variants (TTNtv) in theTTNgene, encoding the giant sarcomeric protein titin, cause a range of human cardiac and skeletal muscle disorders of varying penetrance and severity. The effects of variant location on clinical manifestations are incompletely understood.MethodsWe generated six zebrafish lines carrying tv in thettn.2gene at the Z-disk, I-band, A-band, and M-band titin regions. Expression of titin transcripts was evaluated using qPCR. Phenotype analysis was performed during embryonic development and in adult hearts.ResultsUsing location-specific primers, we found a significant reduction of Z-disk and I-bandttn.2transcripts in all homozygous embryos but levels of A-band and M-band transcripts were reduced only in lines with truncations distal to thecronospromoter. Homozygous embryos uniformly died by 7-10 days post fertilization with marked impairment of cardiac morphology and function. Skeletal muscle motility and sarcomere organization were more disrupted in mutants with truncations distal to thecronospromoter compared to those proximal. The most C-terminal line (e232), which lacked only the titin kinase and M-band regions, differed from other lines, with homozygous embryos showing incorporation of truncated Ttn.2/Cronos protein and normal sarcomere assembly, but selective degradation of fast skeletal muscle sarcomeres. Heterozygous embryos were phenotypically indistinguishable from wild-type. High-frequency echocardiography in adult heterozygous fish showed reduced ventricular contraction under resting conditions in A-band mutants. Heterozygous Z-disk and I-band mutants had no significant baseline impairment but were unable to augment ventricular contraction in response to acute adrenaline exposure, indicating a lack of cardiac reserve.ConclusionsOur data suggest that cardiac and skeletal muscle dysfunction associated with truncatingttn.2variants is influenced by age, variant location, and the amount of functional titin protein. The distinctive phenotype associated with distal C-terminal truncations may reflect different requirement for C-terminal titin for maintenance of fast, slow and cardiac muscle sarcomeres.
Machine learning analysis of population-wide plasma proteins identifies hormonal biomarkers of Parkinson’s Disease
Authors: Chaudhry Fayzan , Kim Tae Wan , Elemento Olivier , Betel Doron 
Published: December 2024

AbstractAs the number of Parkinson’s patients is expected to increase with the growth of the aging population there is a growing need to identify new diagnostic markers that can be used cheaply and routinely to monitor the population, stratify patients towards treatment paths and provide new therapeutic leads. Genetic predisposition and familial forms account for only around 10% of PD cases [1] leaving a large fraction of the population with minimal effective markers for identifying high risk individuals. The establishment of population-wide omics and longitudinal health monitoring studies provides an opportunity to apply machine learning approaches on these unbiased cohorts to identify novel PD markers. Here we present the application of three machine learning models to identify protein plasma biomarkers of PD using plasma proteomics measurements from 43,408 UK Biobank subjects as the training and test set and an additional 103 samples from Parkinson’s Progression Markers Initiative (PPMI) as external validation. We identified a group of highly predictive plasma protein markers including known markers such as DDC and CALB2 as well as new markers involved in the JAK-STAT, PI3K-AKT pathways and hormonal signaling. We further demonstrate that these features are well correlated with UPDRS severity scores and stratify these to protective and adversarial features that potentially contribute to the pathogenesis of PD.
Exploration of post-insertion challenges edentulous patients present to dental practitioners during removable complete denture rehabilitation in Makerere University Dental Hospital in Uganda
Authors: Nono David , Bagenda Godfrey , Okullo Isaac , Rwenyonyi Charles Mugisha 
Published: December 2024

AbstractBackgroundEdentulism in a major global burden that contributes to disability and impairment. Globally, edentulous patients frequently receive removable complete dentures (RCDs) and though crucial, effective adaptation is still difficult. RCD remains a preferred treatment modality for edentulous patients worldwide. The frequency of full edentulism varies both within and between countries. In Uganda, 1.8% of people aged 20 years and above are edentulous. Despite advances in dental technology and material science, the successful adaptation of RCDs remains a challenge for both patients and dental professionals. Our present study aimed to explore the post-insertion challenges patients presented to dental practitioners during their rehabilitation with removable complete dentures in Makerere University Dental Hospital.MethodsThis was a qualitative study using a phenomenological technique and purposive sampling to select 25 participants. After obtaining institutional review board approval and written informed consent, semi-structured in-depth and key informant interviews of dental practitioners were conducted and the data were analyzed thematically.ResultsIt was revealed that patients with RCDs commonly reported substantial post-insertion challenges like pain and discomfort, drooling, difficulty speaking, eating, oral hygiene and salivating. Patients’ confidence and self-esteem were severely influenced by their displeasure with the way their dentures looked. Furthermore, patients frequently had denture instability. In addition, patients received helpful post-insertion advice that emphasized the significance of oral health education and support from dental practitioners. This advice included instructions on denture cleaning, maintenance and adaption.ConclusionThe present study identified several post-insertion challenges faced by patients after receiving RCDs. It is important to provide integrated support for patients and practitioners to enhance effective RCD therapy.