bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Genomics Validation of PPAR gamma Signalling in PASMCs: Therapeutic Implications for Pulmonary Arterial Hypertension
Authors: Su Renzhi , Pritazahra Armalya , Saverimuttu Shirin C.C. , Clapp Lucie H , Lovering Ruth C , Patel Jigisha A
Published: December 2024

Gene Ontology (GO) is a tool which provides gene functional annotations, an essential resource for knowledge discovery and the analysis of biological datasets. Although considerable research has quantified the functional similarity between gene products and physiological processes, there is a need to identify which of these may contribute to pathophysiological states in humans. Previous studies have identified the role of PPARG in multiple signalling pathways, particularly those of TGFB1 and BMP2, in pulmonary artery smooth muscle cells and their relation to pulmonary arterial hypertension (PAH). To enhance the description of PPARG in the GO resource we systematically curated the proteins it interacts with and its physiological role in PASMCs. In addition, we curated the microRNAs that play a role in PAH through their regulation of PPARG expression and their downstream impact on cellular processes. This project curated experimental evidence describing 101 human miRNAs that regulate the expression of 17 PPARG signalling pathway-relevant proteins. Of these, 91 of our curated miRNAs were previously unannotated in terms of directly regulating the expression of these priority proteins. By submitting these annotations to the GO Consortium database, we have significantly expanded the breadth and depth of the GO description of PPARG-associated signalling pathways.
ANKRD5: a key component of the axoneme required for sperm motility and male fertility
Authors: Yu Shuntai , Yin Guoliang , Jin Peng , Zhang Weilin , Tian Yingchao , Xu Xiaotong , Shao Tianyu , Li Yushan , Sun Fei , Zhu Yun , Wang Fengchao
Published: December 2024

Sperm motility is crucial for male reproduction and relies on the structural integrity of the sperm axoneme, which has a “9+2” microtubule configuration. This structure includes nine outer microtubule doublets that house various macromolecular complexes. The nexin-dynein regulatory complex (N-DRC) forms a crossbridge between the outer microtubule doublets, stabilizing them and facilitates sperm tail bending. Our investigation of ANKRD5, which is highly expressed in the sperm axoneme, reveals its interaction with TCTE1 and DRC4/GAS8, both key components of the N-DRC. The components of the N-DRC are often vital for sperm motility. ANKRD5-/-mice exhibited reduced sperm motility and male infertility; however transmission electron microscopy and cryoelectron tomography showed no significant alterations in microtubule doublets. Moreover, ANKRD5 deficiency did not affect ATP levels, and its interactions with TCTE1 and DRC4/GAS8 were found to be independent of calcium regulation. These findings establish that ANKRD5 is critical for maintaining axoneme stability, which is important for sperm motility.

Significance Statement

Male infertility affects 8%-12% of men globally, with defects in sperm motility accounting for 40%-50% of these cases. The axoneme, serving as the sperm’s motor apparatus, features a 9+2 microtubule arrangement, with the nexin-dynein regulatory complex (N-DRC) providing essential structural support between outer microtubule doublets. Understanding the synergistic relationship between the N-DRC’s structure and its protein composition is crucial for advancing male reproductive biology. In this study, we identify the protein ANKRD5 as a component of the axoneme that can interact with N-DRC components, which is crucial for sperm motility. This discovery enhances our understanding of sperm motility mechanisms and suggests potential targets for male contraceptive development.
Fusions of catalytically inactive RusA to FokI nuclease coupled with PNA enable programable site-specific double-stranded DNA breaks
Authors: Saleh Ahmed , Sivakrishna Rao Gundra , Wang Qiaochu , Mahfouz Magdy
Published: December 2024

Programmable site-specific nucleases have revolutionized the genome editing. However, these systems still face challenges such as guide dependency, delivery issues, and off-target effects. Harnessing the natural functions of structure-guided nucleases offer promising alternatives for generating site-specific double-strand DNA breaks. Yet, structure-guided nucleases require precise reaction conditions and validation forin-vivoapplicability. To address these limitations, we developed thePNA-CoupledFokI-(d)RusA(PC-FIRA) system. PC-FIRA combines the sequence-specific binding ability of peptide nucleic acids (PNAs) with the catalytic efficiency of FokI nuclease fused to a structurally-guided inactive RusA resolvase (FokI-(d)RusA). This system allows for precise double-strand DNA breaks without the constraints of existing site-specific nuclease and structure-guided nucleases. Throughin vitrooptimizations, we achieved high target specificity and cleavage efficiency. This included adjusting incubation temperature, buffer composition, ion concentration, and cleavage timing. Diverse DNA structures, such as Holliday Junctions, linear, and circular DNA, were tested demonstrating the potential activity on different target forms. Further investigation has revealed the PC-FIRA system capacity for facilitating the precise deletion of large DNA fragments. This can be useful in cloning, large-fragment DNA assembly, and genome engineering, with promising applications in biotechnology, medicine, agriculture, and synthetic biology.
Purifying circular RNA by ultrafiltration
Authors: Guillen-Cuevas Karen , Lu Xiaoming , Birtwistle Marc R. , Husson Scott M.
Published: December 2024

Developing messenger RNA (mRNA) vaccines for COVID-19 renewed and intensified the interest in using mRNA for disease prevention and treatment. Despite their efficacy, linear mRNA molecules are short-lived in the human body, primarily due to enzymatic degradation at the free ends. In contrast, circular RNA (circRNA) exhibits enhanced stability and resistance to exonuclease degradation. However, this stability depends highly on purity. Unfortunately, thein vitrotranscription/self-splicing reaction products contain a mixture of circular and linear RNAs. Yet, practical methods for purifying circRNA from solutions containing linear RNA contaminants are lacking. In this study, we explored the feasibility of using ultrafiltration to purify protein-encoding circRNA produced by the self-splicing of a precursor RNA (preRNA) duringin vitrotranscription (IVT). We measured the sieving coefficients, a separation metric, of circRNA, linear precursor RNA, and nicked RNA conformers using polyethersulfone membranes with molecular weight cutoffs from 30 to 300 kDa, analyzing performance as a function of permeate flux. We also estimated the RNA critical fluxes and determined suitable operating conditions for purification. We achieved a purity of 86% with a yield above 50%. By comparison, the purity achieved by size-exclusion high-performance liquid chromatography (SE-HPLC), the leading alterative separation technology, was 41% with a yield of 45%. These findings highlight ultrafiltration as a superior method for purifying circRNA at the research scale. Its scalability suggests that it could play a critical role in enabling the large-scale manufacturing of circRNA-based therapeutics.
A Reference Tissue Implementation of Simultaneous Multifactor Bayesian Analysis (SiMBA) of PET Time Activity Curve Data
Authors: Matheson Granville J. , Lundberg Johan , Gärde Martin , Veldman Emma R. , Tateno Amane , Okubo Yoshiro , Tiger Mikael , Ogden R. Todd
Published: December 2024

PET analysis is conventionally performed as a two-stage process of quantification followed by analysis. We recently introduced SiMBA (Simultaneous Multifactor Bayesian Analysis), a hierarchical model that performs quantification and analysis for all brain regions of all individuals at once, and in so doing improves both the accuracy of parameter estimation as well as inferential efficiency. However until now, SiMBA has only been implemented for the two-tissue compartment model. We have now extended this general approach to also allow a non-invasive reference tissue implementation that includes both the full reference tissue model and the simplified reference tissue model. In simulated data, SiMBA improves quantitative parameter estimation accuracy, reducing error by, on average, 57% for binding potential (BPND). In considerations of statistical power, our simulation studies indicate that the efficiency of SiMBA modeling approximately corresponds to improvements that would require doubling the sample size if using conventional methods, with no increase in the false positive rate. We applied the model to PET data measured with [11C]AZ10419369, which binds selectively to the serotonin 1B receptor, in datasets collected at three different PET centres (n=139, n=44 and n=39). We show that SiMBA yields replicable inferences by comparing associations between PET parameters and age in the different datasets. Moreover, we show that time activity curve data from different centres can be combined in a single SiMBA model using covariates to control between-centre parameter differences, in order to harmonise data between centres. In summary, we present a novel approach for noninvasive quantification and analysis of PET time activity curve data which improves quantification and inferences, enables effective between-centre data harmonisation, and also yields replicable outcomes. This method has the potential to significantly expand the range of research questions which can be meaningfully tested using conventional sample sizes with PET imaging.
Two distinct structural variants involvingEDN3cause hyperpigmentation in chicken
Authors: Ma Cheng , Huang Xun-He , Wang Feng-Juan , Zhang Shu-Run , Shi Xian , Weng Zhuo-Xian , Du Bingwang , Zhang Ya-Ping , Andersson Leif , Peng Min-Sheng
Published: December 2024

Phenotypic diversity and its genetic basis are central questions in biology, with domesticated animals offering valuable insights due to their rapid evolution the last 10,000 years. In chickens, fibromelanosis (FM) is a striking pigmentation phenotype characterized by hyperpigmentation. A previous study identified a complex structural variant causing upregulated expression of theEndothelin 3(EDN3) gene. However, the detailed structural arrangement and functional consequences of the variant remained unclear. In this study, we conducted a comprehensive genomic survey of 692 FM chickens representing 55 breeds and uncovered two distinct structural variants causing the FM phenotype:FM*A,the previously reported complex rearrangement involving theEDN3locus1, andFM*B, a tandem duplication of a 16 kb region upstream ofEDN3. We demonstrate that both structural variants (SVs) significantly upregulateEDN3expression, withFM*Bassociated with even higher expression thanFM*A. A luciferase reporter assays showed that the 16 kb region inFM*Bcontains powerful enhancers and the copy number expansion of this element is a likely explanation forEDN3upregulation and hyperpigmentation. Furthermore, our analysis of linkage disequilibrium patterns allowed us to resolve the complex arrangement of duplications and inversion on theFM*Ahaplotype.
Spermidine alleviates depression via control of the stress response
Authors: Mackert Sarah , Niemeyer Christine , Mecdad Yara , Ebert Tim , Bajaj Thomas , Durand Sylvère , Hofer Sebastian J. , Zellner Andreas , Besteher Bianca , Engelmann Jan , Gisabella Barbara , Kempf Valerie , Heckmann Lily A. , Laakmann Marcel , Newman Emily L. , Sokn Clara , Heinz Daniel E. , Junglas Ellen , Uribe-Marino Andrés , Magnes Christoph , Klengel Claudia , Müller Anna , Opriessnig Lydia , Meinitzer Andreas , Lennarz Martina , Martin Katja M. Wirtz , Albatarni Rawan , Brockherde Marieke , Lieb Klaus , Rohner Henrik , Stoffel-Wagner Birgit , Philipsen Alexandra , Kuster Bernhard , Kölle Markus , Ressler Kerry J. , Opel Nils , Schmidt Mathias V. , Pantazopoulos Harry , Müller Marianne B. , Kroemer Guido , Eisenberg Tobias , Hartmann Jakob , Madeo Frank , Gassen Nils C.
Published: December 2024

Depression is a stress-associated disorder, and it represents a major global health issue. Its pathophysiology is complex and remains insufficiently understood, with current medications often showing limited efficacy and undesirable side effects. Here, we identify imbalanced polyamine levels and dysregulated autophagy as key components of the acute stress response in humans, and as hallmarks of chronic stress and depressive disorders. Moreover, conventional antidepressant pharmacotherapy increases endogenous plasma concentrations of the polyamine spermidine exclusively in patients who respond to the treatment, suggesting a link between spermidine and successful outcomes. In a clinical trial, involving drug-naive depressed individuals, three weeks of spermidine supplementation increased autophagy and alleviated symptoms of depression. Behavioral and mechanistic findings of spermidine supplementation were validated in various mouse stress and depression models. In summary, spermidine supplementation mitigates polyamine dysregulation and stimulates autophagy under pathological stress conditions, offering a novel and well-tolerated treatment approach for stress-related depressive disorders.
Frizzled1 and Frizzled2 are not redundant for competitive survival under low-Wingless levels in the developingDrosophilawing epithelium
Authors: Hingole Swapnil , Verma Kritika , Chaudhary Varun
Published: December 2024

In theDrosophilawing epithelium, canonical Wnt signaling is activated by the gradient of secreted Wingless protein (Wnt1 homolog), which interacts redundantly with the Frizzled1 and Frizzled2 receptors. While sharing overlapping functions, these receptors also have distinct non-canonical roles and exhibit differential expression patterns along the Wingless gradient. Moreover, Frizzled2, unlike Frizzled1, is thought to be essential for sustaining low-level Wingless signaling and promoting cell survival in the absence of the ligand. This raises the possibility of the two receptors acting differently along the Wingless gradient. In this study, we investigated the role of these receptors in cell survival across varying Wingless levels. We find that the loss of Frizzled2 in cells at a distance from the Wingless-producing cells—where Wingless levels are low— leads to competitive elimination of cells. In contrast, Frizzled1 is dispensable for cell survival, regardless of distance from the Wingless source. Our findings show that Frizzled2 is essential for competitive cell survival under low-Wingless conditions and the two receptors are not equally redundant across the Wingless concentration gradient, providing insight into a mechanism for spatial and temporal precision in developmental signaling.
From womb to crib: How fetal activity patternsin uteroreveal postnatal sleep behavior
Authors: Markovic Andjela , Mühlematter Christophe , Blume Christine , Zimmermann Petra , Kurth Salome
Published: December 2024

Importance

The human circadian system, a critical biological mechanism governing the sleep-wake cycle, begins to oscillate before birth. Distinct fetal behavioral states have been described using short-duration ultrasound recordings, but the alignment of fetal activity with day and night cycles (i.e., diurnal rhythms) remains poorly understood due to the lack of long-term monitoring. Accordingly, a substantial knowledge gap exists concerning the evolution of fetal diurnal rhythms into infant sleep-wake cycles.

Objective

To investigate the development of fetal diurnal rhythms and their evolution into postnatal infant sleep, as well as the role of maternal factors and melatonin in shaping early circadian entrainment.

Methods

In this cohort study, conducted in 2022 and 2023, we collected over 20 000 hours of wearable acceleration and temperature data from 32 fetuses and their mothers during continuous 5-day monitoring in the third trimester of pregnancy. The cohort was subsequently followed longitudinally from the prenatal period through 6 months postpartum, with infant sleep outcomes assessed at three key time points (first postnatal weeks, 3 months, and 6 months) using sleep diaries and questionnaires. The first postnatal assessment additionally included breast milk and infant stool sample collection.

Results

Multi-level modelling revealed early diurnal rhythms in fetuses that align with maternal activity and circadian rhythms. Random Forest analyses identified fetal day/night sleep duration ratio – a simplified proxy for fetal circadian entrainment – as the strongest predictor of postnatal infant sleep, with fetuses preferring nighttime sleep maintaining this preference postnatally. Maternal sleep regularity (i.e., consistent sleep patterns characterized by low day-to-day variability in sleep timing) during pregnancy also predicted infant sleep, associating with a stronger preference for nighttime sleep in infants.

Conclusions and relevance

These findings highlight the potential influence of intrauterine and maternal factors on the evolution of circadian entrainment. Our study contributes to a broader understanding of the earliest emergence of circadian rhythms, supporting future research on their long-term health impacts. Maternal sleep regularity stands out as the earliest modifiable target for interventions, offering an actionable pathway to promote infant circadian entrainment, with potential long-term benefits for family dynamics and well-being.
Exploring the Aβ Plaque Microenvironment in Alzheimer’s Disease Mice by Multimodal Lipid-Protein-Histology Imaging on a Benchtop Mass Spectrometer
Authors: Müller Elisabeth , Enzlein Thomas , Niemeyer Dagmar , von Ammon Livia , Stumpo Katherine , Biber Knut , Klein Corinna , Hopf Carsten
Published: December 2024

Amyloid-β (Aβ) plaque deposits in the brain are a hallmark of Alzheimer’s disease (AD) neuropathology. Plaques consist of complex mixtures of peptides like Aβ1-42, characteristic lipids such as gangliosides, and they are targeted by reactive microglia and astrocytes. In pharmaceutical research and development it is therefore a formidable challenge to contextualize different biomolecular classes and cell types of the Aβ plaque microenvironment in a coherent experimental workflow on a single tissue section and on a benchtop imaging reader. Here, we developed such a workflow that combines lipid MALDI mass spectrometry imaging using a vacuum-stable matrix with histopathology stains and with MALDI HiPLEX-immunohistochemistry of plaques and multiple protein markers on a bench-top imaging mass spectrometer. The three data layers consisting of lipid, protein markers, and histology can be co-registered and evaluated together. Multimodal data analysis suggests extensive co-localization of Aβ plaques with the peptide precursor protein, with a defined subset of lipids and with reactive glia cells on a single brain section of APP/PS1 AD model mice. Plaque-associated lipids like ganglioside GM2 and phosphatidylinositol PI38:4 isoforms were readily identified using the tandem MS-capabilities of the mass spectrometer. Taken together, our data suggests that complex pathology involving multiple lipids, proteins and cell types can be interrogated by this spatial multiomics workflow on an easy-to-use benchtop mass spectrometer.
Modulation of sensory input to the spinal cord by peripheral afferent fibres. Searching for relays
Authors: Sławińska Urszula , Hammar Ingela , Jankowska Elzbieta
Published: December 2024

A long-lasting GABA-dependent increase in the excitability of afferent fibres, and thus modulation of the sensory input to the spinal cord, may be evoked by epidural polarization. However, the direct effects of fibre polarization are short-lasting and the sustained increase in their excitability appears to be secondary to the release of GABA from nearby astrocytes. We have now investigated whether the modulation of spinal sensory input by stimulation of a peripheral nerve, previously attributed to synaptically evoked intraspinal field potentials, is evoked in a similar way. However, as neither its dependence on GABA nor its relays have been investigated, we addressed the question of whether the increase in the excitability of epidurally stimulated afferent fibres following a peripheral nerve stimulation does or does not depend on GABA and whether it might be mediated by astrocytes. The effects of conditioning stimulation of the tibial nerve were evaluated from changes in the excitability of both group I and group II muscle afferents, estimated from action potentials recorded in peripheral nerves and in field potentials recorded in the dorsal horn respectively in acute experiments on deeply anaesthetized rats. The excitability of the afferents was increased by stimulation of group II and/or cutaneous but not group I muscle afferents. The effects were significantly weakened by blocking GABA channels by gabazine, and by astrocyte toxin L-alpha-aminoadipic acid (L-AAA), indicating that the excitability of both group I and group II afferent fibres may be modulated by GABAergic astrocytes, the new role played by astrocytes.
Not enough pleasure? Influence of hallucination proneness on sensory feedback processing of positive self-voice
Authors: Duggirala Suvarnalata Xanthate , Schwartze Michael , Goller Lisa K. , Linden David E. J. , Pinheiro Ana P. , Kotz Sonja A.
Published: December 2024

Ample research explored changes in sensory feedback processing of the self-voice as well as the control of attention allocation in voice hearers, including both non-clinical voice hearers and voice hearers with a psychotic disorder. While the attentional bias toward negative emotional information in voice hearers with a psychotic disorder due to heightened sensitivity towards threat/danger is well established, it remains unclear how positive emotion captures or controls attention. Manipulating the certainty of sensory feedback to the self-voice, transitioning from fully neutral to entirely positive (100% neutral, 60-40% neutral-pleasure, 50-50% neutral-pleasure, 40-60% neutral-pleasure, 100% pleasure), provides an opportunity to investigate attentional control and sensory feedback processing in positive self-voice as a function of hallucination proneness (HP). Participants with different HP scores self-generated and passively listened to their own voices during EEG recordings. N100 or P200 responses to self-generated and externally-generated self-voices did not differ. Further, HP did not modulate N100/P200 responses. These null findings might result from the minimal perceptual discriminability among the five types of voices varying in pleasure content. This might have led to less variation in certainty regarding the sensory feedback to self-voice, and consequently a lack of differential engagement of attentional resources. The lack of a global N100 suppression effect prompts inquiry into the association of sense of ownership/agency and pleasure.
GRU-SCANET: Unleashing the Power of GRU-based Sinusoidal CApture Network for Precision-driven Named Entity Recognition
Authors: Happi Happi Bill Gates , Pelap Geraud Fokou , Symeonidou Danai , Larmande Pierre
Published: December 2024

Motivation

Pre-trained Language Models (PLMs) have achieved remarkable performance across various natural language processing tasks. However, they encounter challenges in biomedical Named Entity Recognition (NER), such as high computational costs and the need for complex fine-tuning. These limitations hinder the efficient recognition of biological entities, especially within specialized corpora. To address these issues, we introduce GRU-SCANET (Gated Recurrent Unit-based Sinusoidal Capture Network), a novel architecture that directly models the relationship between input tokens and entity classes. Our approach offers a computationally efficient alternative for extracting biological entities by capturing contextual dependencies within biomedical texts.

Results

GRU-SCANET combines positional encoding, bidirectional GRUs (BiGRUs), an attention-based encoder, and a conditional random field (CRF) decoder to achieve high precision in entity labeling. This design effectively mitigates the challenges posed by unbalanced data across multiple corpora. Our model consistently outperforms leading benchmarks, achieving better performance than BioBERT (8/8 evaluations), PubMedBERT (5/5 evaluations), and the previous state-of-the-art (SOTA) models (8/8 evaluations), including Bern2 (5/5 evaluations). These results highlight the strength of our approach in capturing token-entity relationships more effectively than existing methods, advancing the state of biomedical NER.
Benzene metabolites increase vascular permeability by activating heat shock proteins and Rho GTPases
Authors: Zelko Igor N. , Hussain Ahtesham , Malovichko Marina V. , Wickramasinghe Nalinie , Srivastava Sanjay
Published: December 2024

Benzene is a ubiquitous environmental and occupational pollutant abundant in household products, petrochemicals, and cigarette smoke. It is also a well-known carcinogen and hematopoietic toxin. Population-based studies indicate an increased risk of heart failure in subjects exposed to inhaled benzene, which coincides with the infiltration of immune cells into the myocardium. However, the mechanisms of benzene-induced cardiovascular disease remain unknown. Our data suggests that benzene metabolites trans,trans-muconaldehyde (MA), and hydroquinone (HQ) propagate endothelial activation and apoptosis analyzed by endothelial-specific microparticles in C57BL/6J mice plasma. Subcutaneous injections of MA and HQ increased vascular permeability by 1.54 fold and 1.27 fold correspondingly. In addition, the exposure of primary cardiac microvascular endothelial cells to MA increased vascular permeability detected by transendothelial monolayer resistance and by fluorescently labeled dextrans diffusion. The bulk RNA sequencing of endothelial cells exposed to MA for 2, 6, and 24 hours showed MA-dependent upregulation of heat shock-related pathways at 2 and 6 hours, dysregulation of GTPases at 6 hours, and altered cytoskeleton organization at 24 hours of exposure. We found that the HSP70 protein induced by MA in endothelial cells is colocalized with F-actin foci. HSP70 inhibitor 17AAG and HSP90 inhibitor JG98 attenuated MA-induced endothelial permeability, while HSP activator TRC enhanced endothelial leakage. Moreover, MA induced Rac1 GTPase activity, while Rho GTPase inhibitor Y-27632 attenuated MA-induced endothelial permeability. We showed that benzene metabolites compromised the endothelial barrier by altering HSP- and GTPase-related signaling pathways.
Adult honey bee queens consume pollen and nectar
Authors: St. Clair Ashley L. , Dwyer Bridget , Shapiro Madeleine , Dolezal Adam G.
Published: December 2024

Despite the queen’s crucial reproductive role in honey bee colonies, queen diet and feeding behavior remain remarkably enigmatic, with most studies assuming they are solely fed nutritious glandular secretions (i.e., royal jelly) by workers. This colors our understanding of basic honey bee biology and how governmental agencies assess pesticide risk. We hypothesized that adult queens also consume honey and pollen. Through experiments with queenright laboratory microcolonies fed with marked diets, we demonstrate that queens are fed pollen and nectar by workers and can also feed directly. We then measured pollen content in mature, unmanipulated queens sacrificed from 43 conventional field colonies from two distinct geographical regions. Similar to workers, we found pollen in almost all queens guts, though at expectedly lower quantities than in young workers. These findings suggest queens have a more complex, dynamic diet than previously thought, raising new questions about how dietary habits and feeding behaviors influence pesticide risk and other aspects of queen biology.
High-Intensity Interval Training Outperforms Moderate Exercise to Improve Aerobic Capacity in Patients with Recent-Onset Idiopathic Inflammatory Myopathies: A Multicenter Randomized Controlled Trial
Authors: Andreasson Kristofer M. , Leijding Cecilia , Dastmalchi Maryam , Notarnicola Antonella , Gastaldello Stefano , Yamada Takashi , Sandlund Heléne , Leonard Dag , Westerblad Håkan , Lundberg Ingrid E. , Andersson Daniel C. , Alexanderson Helene
Published: December 2024

Objective

To investigate efficacy, safety, and tolerance of high-intensity interval training (HIIT) versus standard low-moderate intensity home-based exercise (CON) to improve aerobic capacity, muscle endurance, and mitochondrial function in patients with recent onset, idiopathic inflammatory myopathies (IIM).

Methods

Twenty-three patients with recent onset IIM were randomized into two groups: HIIT and CON. HIIT underwent 12 weeks of supervised high-intensity training, while CON followed a low-moderate intensity home-based exercise program. Outcomes included maximal exercise test (VO2peak, peak power, time-to-exhaustion (TTE)), mitochondrial protein expression in muscle biopsy serum levels of muscle enzymes (CK, LD, AST, ALT), muscle strength (MMT8) and disease activity (subset of MDAAT), before and after intervention.

Results

HIIT resulted in a 16 % increase in VO2peak L/min, significantly higher than the 1.8 % change in CON (95 % CI 0.1;0.47). Peak power and TTE also improved significantly more in HIIT, 18 % and 23 %, respectively, compared to CON, 8 % and 12 %, (95 % CI 3.9;30.8 and 00:06;03:18, respectively). Muscle biopsies (HIIT n=7, CON n=6) showed increases (p<0.05) in central mitochondrial protein expression in HIIT but not in CON, suggesting enhanced mitochondrial function. Both groups maintained stable serum muscle enzymes indicating no increase in disease activity from the intervention. Muscle disease activity remained low and unchanged in both groups (95 % CI −1.2;1.0), physician global activity and MMT8significantly improved within CON (95 % CI −1.7;-0.26 and 0.1;3.9, respectively) but not in the HIIT group. Compliance with HIIT was high, and no adverse events were reported.

Conclusion

HIIT is a highly effective and safe exercise intervention to improve aerobic fitness, muscle endurance, and mitochondrial function in patients with recent onset IIM. This approach should be considered as an adjuvant treatment in managing IIM, potentially enhancing the health for these patients.

The study was registered atClinicalTrials.gov:NCT03324152

Significance and Innovations

High-intensity interval training (HIIT) is more effective to improve aerobic capacity (peak oxygen uptake; VO2peak), increasing 16 % compared to 1.8 % change in the moderate exercise control group in patients with recent onset IIM.

HIIT produced larger exercise adaptations with increased expression of aerobic metabolism (mitochondrial) proteins in muscle tissue compared to moderate exercise.

HIIT is a safe and well tolerated exercise intervention for patients with recent onset IIM.
Patient-specific hemodynamic markers co-localise with regions of neointimal hyperplasia in an arteriovenous graft
Authors: Ninno Federica , Stokes Catriona , Aboian Edouard , Dardik Alan , Strosberg David , Balabani Stavroula , Díaz-Zuccarini Vanessa
Published: December 2024

Purpose

Most computational fluid dynamics (CFD) studies on arteriovenous grafts (AVGs) adopt idealised geometries and simplified boundary conditions (BCs), potentially resulting in misleading conclusions when attempting to predict neointimal hyperplasia (NIH) development. Moreover, they often analyse a limited range of hemodynamic indices, lack validation, and fail to link the graft-altered hemodynamics with follow-up data. This study develops a novel patient-specific CFD workflow for AVGs using pathophysiological BCs. It validates the CFD results with patient medical data and assesses the co-localisation between CFD results and NIH regions at follow-up.

Methods

Contrast-enhanced computed tomography angiography images were used to segment the patient’s AVG geometry. A uniform Doppler ultrasound (DUS)-derived velocity profile was imposed at the inlet, and three-element Windkessel models were applied at the arterial outlets of the domain. Transient, rigid-wall simulations were performed using the k-ω SST turbulence model. The CFD-derived flow waveform was compared with the patient’s DUS image to ensure validation. Turbulent kinetic energy (TKE), helicity and near-wall hemodynamic descriptors were calculated and linked with regions presenting NIH from a 4-month follow-up fistulogram.

Results

In the analysed patient, areas presenting high TKE and balanced helical flow structures at baseline exhibit NIH growth at follow-up. Transverse wall shear stress index is a stronger predictor of NIH than other commonly analysed near-wall hemodynamic indices, since luminal areas subjected to high values greatly co-localise with observed areas of remodelling.

Conclusion

This patient-specific computational workflow for AVGs could be applied to a larger cohort to unravel the link between altered hemodynamics and NIH progression in vascular access.
Genetic Analysis of Psychosis Biotypes: Shared Ancestry-Adjusted Polygenic Risk and Unique Genomic Associations
Authors: Xia Cuihua , Alliey-Rodriguez Ney , Tamminga Carol A. , Keshavan Matcheri S. , Pearlson Godfrey D. , Keedy Sarah K. , Clementz Brett , McDowell Jennifer E. , Parker David , Lencer Rebekka , Kristian Hill S. , Bishop Jeffrey R. , Ivleva Elena I. , Wen Cindy , Dai Rujia , Chen Chao , Liu Chunyu , Gershon Elliot S.
Published: December 2024

The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder and bipolar disorder with psychosis. Two recently developedpost hocancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes and isoforms showed significant genomic associations with specific Biotypes in Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in adult brain and fetal brain. TWAS inflation was addressed by inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genesTMEM140,ARTN,C1orf115,CYREN, and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately.
Sleep problems and sleep quality in the general adult population living in South Tyrol (Italy), a cross-sectional survey study
Authors: Ausserhofer Dietmar , Piccoliori Giuliano , Engl Adolf , Marino Pasqualina , Barbieri Verena , Lombardo Stefano , Gärtner Timon , Wiedermann Christian J.
Published: December 2024

This cross-sectional, population-based survey study aimed to (1) investigate the prevalence of sleep problems and poor sleep quality and (2) explore the associated sociodemographic and health-related factors. A stratified probabilistic sample of 4,000 adults aged ≥ 18 years living in the Autonomous Province of Bolzano (South Tyrol, Italy) was invited to complete a questionnaire. Sleep quality was assessed using the brief version of the Pittsburgh Sleep Quality Index. Descriptive and logistic regression analyses were performed to analyze the data. A total of 2,090 adults (53%) completed the survey. Poor sleep quality was reported by 17.8%, with 28.2% of participants reporting insufficient sleep duration (i.e., six hours or less), 12.7% having problems staying asleep (i.e. waking up to 3-4 times a week and unable to fall asleep again), and 8.7% having problems getting to sleep (i.e. >30 minutes). Sleep problems and poor sleep quality were associated with sociodemographic and health-related factors, including sex, age, mother tongue, overall health status, chronic disease, and sleep hygiene. Italian-speaking participants reported poorer sleep quality and greater difficulty staying asleep compared to German-speaking participants, highlighting potential sociocultural influences on sleep health. Sleep quality and other problems are prevalent among adults in South Tyrol. Further research on public health interventions that promote sleep health literacy and hygiene is needed.
Leveraging Stacked Classifiers for Multi-task Executive Function in Schizophrenia Yields Diagnostic and Prognostic Insights
Authors: Zhang Tongyi , Zhao Xin , Yeo B.T. Thomas , Huo Xiaoning , Eickhoff Simon B. , Chen Ji
Published: December 2024

Cognitive impairment is a central characteristic of schizophrenia. Executive functioning (EF) impairments are often seen in mental disorders, particularly schizophrenia, where they relate to adverse outcomes. As a heterogeneous construct, how specifically each dimension of EF to characterize the diagnostic and prognostic aspects of schizophrenia remains opaque. We used classification models with a stacking approach on systematically measured EFs to discriminate 195 patients with schizophrenia from healthy individuals. Baseline EF measurements were moreover employed to predict symptomatically remitted or non-remitted prognostic subgroups. EF feature importance was determined at the group-level and the ensuing individual importance scores were associated with four symptom dimensions. EF assessments of inhibitory control (interference and response inhibitions), followed by working memory, evidently predicted schizophrenia diagnosis (area under the curve [AUC]=0.87) and remission status (AUC=0.81). The models highlighted the importance of interference inhibition or working memory updating in accurately identifying individuals with schizophrenia or those in remission. These identified patients had high-level negative symptoms at baseline and those who remitted showed milder cognitive symptoms at follow-up, without differences in baseline EF or symptom severity compared to non-remitted patients. Our work indicates that impairments in specific EF dimensions in schizophrenia are differentially linked to individual symptom-load and prognostic outcomes. Thus, assessments and models based on EF may be a promising tool that can aid in the clinical evaluation of this disorder.
Interparental Gene Conversion in General Population: A Novel Mechanism For Loss of Heterozygosity
Authors: Toratani Jumpei , Tachibana Masahito , Sugawara Junichi , Sugawara Atsushi , Sato Takeki , Takahashi Yuri , Hiraga Hiroaki , Yokoyama Emi , Watanabe Zen , Saito Masatoshi , Yaegashi Nobuo , Tamiya Gen , Takayama Jun
Published: December 2024

Gene conversion is a process in which genetic material from a donor sequence is unidirectionally copied to an acceptor sequence during the homologous recombination repair of a DNA double-strand break. Although gene conversion has been widely studied in the context of meiosis, hereditary diseases, and cancer development, gene conversion between parental homologs in the zygotes remains controversial. Here, we developed a method to detect interparental gene conversions by focusing on Mendelian errors and identified gene conversion events in one out of every 21.8 births. Some of these events were observed in genetic regions, potentially affecting offspring phenotypes. Interparental gene conversion leads to the offspring inheriting two identical alleles from one parent, resulting in a loss of heterozygosity. Our findings suggest that naturally occurring interparental gene conversions may provide a novel mechanism for the development of certain genetic diseases.
On the Trade-Off between Fidelity, Utility and Privacy of Synthetic Patient Data
Authors: Adams Tim , Birkenbihl Colin , Otte Karen , Ng Hwei Geok , Rieling Jonas Adrian , Näher Anatol-Fiete , Sax Ulrich , Prasser Fabian , Fröhlich Holger ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2024

The advancement of medical research and healthcare is increasingly dependent on the analysis of patient-level data, but privacy concerns and legal constraints often hinder data sharing. Synthetic data mimicking real patient data offers a widely discussed potential solution. According to the literature, synthetic data may, however, not fully guarantee patient privacy and can vary greatly in terms of fidelity and utility. In this study, we aim to systematically investigate the trade-off between privacy, fidelity and utility of synthetic patient data. We assess synthetic data fidelity in terms of statistical similarity to real data, and utility via the performance of machine learning models trained on synthetic and tested on real data. Regarding data privacy we focus on membership inference via shadow model attacks as well as singling out and attribute inference risks. In this regard, we also consider differential privacy (DP) as a possible mechanism to probabilistically guarantee a certain level of data privacy, and we compare against classical anonymization techniques. We evaluate the fidelity, utility and privacy of synthetic data generated by five different models for three distinctive patient-level datasets. Our results show that our implementations of DP have a strongly detrimental effect on the fidelity of synthetic data, specifically its correlation structure, and therefore emphasize the need to improve techniques that effectively balance privacy, fidelity and utility in synthetic patient data generation.
Metformin, monoacylglycerol lipase expression, cognition and emotion recognition in people with multiple sclerosis and comorbid type II diabetes: A case-control study
Authors: Walker Lisa A. S. , Ramani Sanghamithra , Pumphrey Jordan D. , Islam Tamanna , Berard Jason A. , Seegobin Matthew , Buckle Mai , Lymer Jennifer M. , Freedman Mark S. , Wang Jing
Published: December 2024

Background

Diabetes (DM), a common comorbidity, results in poorer cognition in people with multiple sclerosis (PwMS). Metformin may be a treatment option given cognitive benefits. Metformin represses monoacylglycerol lipase (Mgll), accompanied by improvements in cognition in animals.

Aims

To determine 1) whether metformin represses Mgll in humans, 2) if Mgll correlates with cognition/emotion recognition, and 3) if cognition differs between groups.

Methods

A convenience sample of seventeen PwMS and DM on metformin, 4 with MS and DM not on metformin, 10 with MS, and 21 healthy controls completed BICAMS and measures of premorbid ability, emotion recognition, mood and fatigue. Blood draw established Mgll levels. T-tests determined group differences in Mgll. Correlational analyses examined if Mgll correlated with cognition. ANCOVA evaluated differences in cognition/emotion recognition.

Results

Given small samples, we combined groups to determine if metformin impacted Mgll regardless of diabetes status. Significant differences in Mgll (t= -2.07,p= .05), suggested that metformin suppresses Mgll. No relationship was found between Mgll and cognition/emotion recognition. Differences were found between PwMS and DM compared to controls in verbal learning (F= 5.85,p= .02) and memory (F= 5.62,p= .02).

Conclusions

Metformin suppresses Mgll in humans suggesting metformin be evaluated as a potential MS treatment. Mgll did not correlate with cognition possibly due to sample size or methodology. Combined impact of MS and DM negatively impacts cognition, supporting literature demonstrating that vascular comorbidity increases risk of cognitive dysfunction. Findings support pursuing clinical trials evaluating metformin efficacy.
Leveraging functional annotations to map rare variants associated with Alzheimer’s disease with gruyere
Authors: Das Anjali , Lakhani Chirag , Terwagne Chloé , Lin Jui-Shan T. , Naito Tatsuhiko , Raj Towfique , Knowles David A.
Published: December 2024

The increasing availability of whole-genome sequencing (WGS) has begun to elucidate the contribution of rare variants (RVs), both coding and non-coding, to complex disease. Multiple RV association tests are available to study the relationship between genotype and phenotype, but most are restricted to per-gene models and do not fully leverage the availability of variant-level functional annotations. We propose Genome-wide Rare Variant EnRichment Evaluation (gruyere), a Bayesian probabilistic model that complements existing methods by learning global, trait-specific weights for functional annotations to improve variant prioritization. We applygruyereto WGS data from the Alzheimer’s Disease (AD) Sequencing Project, consisting of 7,966 cases and 13,412 controls, to identify AD-associated genes and annotations. Growing evidence suggests that disruption of microglial regulation is a key contributor to AD risk, yet existing methods have not had sufficient power to examine rare non-coding effects that incorporate such cell-type specific information. To address this gap, we 1) use predicted enhancer and promoter regions in microglia and other potentially relevant cell types (oligodendrocytes, astrocytes, and neurons) to define per-gene non-coding RV test sets and 2) include cell-type specific variant effect predictions (VEPs) as functional annotations.gruyereidentifies 15 significant genetic associations not detected by other RV methods and finds deep learning-based VEPs for splicing, transcription factor binding, and chromatin state are highly predictive of functional non-coding RVs. Our study establishes a novel and robust framework incorporating functional annotations, coding RVs, and cell-type associated non-coding RVs, to perform genome-wide association tests, uncovering AD-relevant genes and annotations.
Reasoning Models for Text Mining in Oncology – a Comparison Between o1 Preview and GPT-4o
Authors: Windisch Paul , Dennstädt Fabio , Schröder Christina , Zwahlen Daniel R. , Förster Robert
Published: December 2024

Purpose

Chain-of-thought prompting is a method to make a Large Language Model (LLM) generate intermediate reasoning steps when solving a complex problem to increase its performance. OpenAI’s o1 preview is an LLM that has been trained with reinforcement learning to create such a chain-of-thought internally, prior to giving a response and has been claimed to surpass various benchmarks requiring complex reasoning. The purpose of this study was to evaluate its performance for text mining in oncology.

Methods

Six hundred trials from high-impact medical journals were classified depending on whether they allowed for the inclusion of patients with localized and/or metastatic disease.

GPT–4o and o1 preview were instructed to do the same classification based on the publications’ abstracts.

Results

For predicting whether patients with localized disease were enrolled, GPT-4o and o1 preview achieved F1 scores of 0.80 (0.76 - 0.83) and 0.91 (0.89 - 0.94), respectively. For predicting whether patients with metastatic disease were enrolled, GPT-4o and o1 preview achieved F1 scores of 0.97 (0.95 - 0.98) and 0.99 (0.99 - 1.00), respectively.

Conclusion

o1 preview outperformed GPT-4o for extracting if people with localized and or metastatic disease were eligible for a trial from its abstract. o1 previews’s performance was close to human annotation but could still be improved when dealing with cancer screening and prevention trials as well as by adhering to the desired output format. While research on additional tasks is necessary, it is likely that reasoning models could become the new state of the art for text mining in oncology and various other tasks in medicine.