bluuebunny/crossref_metadata_2025 huggingface dataset:
Attention and Retention Effects of Culturally Targeted Billboard Messages: An Eye-Tracking Study Using Immersive Virtual Reality
Authors: Jeon Moonsun , Lim Sue , Lapinski Maria K. , Spates Stephen A. , Bente Gary , Schmälzle Ralf
Published: September 2024

Targeting, the creation of a match between message content and receiver characteristics, is a key strategy in communication message design. Cultural targeting, or adapting message characteristics to be congruent with a group’s cultural knowledge, appearance, or beliefs of recipients, is used in practice and is a potentially effective strategy to boost the relevance of a message, affecting attention to messages and enhancing effects. However, many open questions remain regarding the mechanisms and consequences of targeting. This is partly due to methodological challenges in experimentally manipulating messages that match cultural recipient characteristics while simultaneously measuring effects and balancing experimental control and realism. Here, we used a novel VR-based paradigm in which participants drove along a virtual highway flanked by billboards with varying message designs. Specifically, we manipulated the message design to either match or mismatch peoples’ cultures of origin. We used unobtrusive eye tracking to assess participants’ attention (i.e., for how long and how often they look at matched vs. unmatched billboards). Results show a tendency of the participants to inspect culturally matched billboards more often and for longer. We further found that matched billboards produce better recall, indicating more efficient encoding and storage of the messages. Our results underscore the effectiveness of cultural targeting and demonstrate how researchers can rigorously manipulate relevant message factors using virtual environments. We discuss the implications of these findings regarding theories of cultural targeting and methodological perspectives for the objective measurement of exposure factors through eye tracking.
Longitudinal trajectories of aperiodic EEG activity in early to middle childhood
Authors: Sacks Dashiell D. , Valdes Viviane , Wilkinson Carol L. , Levin April R. , Nelson Charles A. , Enlow Michelle Bosquet
Published: September 2024

Background

Emerging evidence suggests that aperiodic EEG activity may follow a nonlinear growth trajectory in childhood. However, existing studies are limited by small assessment windows and cross-sectional samples that are unable to fully capture these patterns. The current study aimed to characterize the developmental trajectories of aperiodic activity longitudinally from infancy to middle childhood. We examined potential trajectory differences by sex and brain region. We further investigated whether aperiodic activity is associated with maternal anxiety symptoms, and whether these associations vary because of differential development trajectories.

Methods

A community sample of children and their parents (N=391) enrolled in a longitudinal study of emotion processing were assessed at infancy, and at ages 3 years, 5 years, and 7 years. Analyses included individual growth curve and mixed effect models. Developmental trajectories of the aperiodic slope and offset were investigated across whole brain, frontal, central, temporal, and posterior regions. Associations of whole brain slope and offset with maternal anxiety symptoms were also examined.

Results

Developmental trajectories for both slope and offset were generally characterized by a relative increase in early childhood and a subsequent decrease or stabilization by age 7, with variation by brain region. Females showed relatively steeper slopes at some ages, and males showed relatively greater offset at certain ages. Maternal anxiety was negatively associated with slope at 3 years and positively associated with slope at 7 years.

Conclusions

The longitudinal developmental trajectory of aperiodic slope in early childhood is nonlinear and shows variation by sex and brain region. The magnitude and direction of associations with maternal anxiety varied by age, corresponding with changes in trajectories. Developmental stage should be considered when interpreting findings related to aperiodic activity in childhood.
Primary cilia promote EMT-induced triple-negative breast tumor heterogeneity and resistance to therapy
Authors: Tessier Camille , Derrien Jennifer , Dupuy Aurore , Pele Thomas , Moquet Martin , Roul Julie , Douillard Elise , El Harrif Camille , Pinson Xavier , Le Gallo Matthieu , Godey Florence , Tas Patrick , Viel Roselyne , Prigent Claude , Letouze Eric , Suzanne Peggy , Dallemagne Patrick , Campone Mario , Weinberg Robert , Lees Jacqueline , Juin Philippe , Guen Vincent
Published: September 2024

Tumor heterogeneity and plasticity, driven by Epithelial-Mesenchymal Transition (EMT), enable cancer therapeutic resistance. We previously showed that EMT promotes primary cilia formation, which enables stemness and tumorigenesis in triple-negative breast cancer (TNBC). Here, we establish a role for primary cilia in human TNBC chemotherapeutic resistance. We developed patient-derived organoids, and showed that these recapitulated the cellular heterogeneity of TNBC biopsies. Notably, one of the identified cell states bore a quasi-mesenchymal phenotype, primary cilia, and stemness signatures. We treated our TNBC organoids with chemotherapeutics and observed partial killing. The surviving cells with organoid-reconstituting capacity showed selective enrichment for the quasi-mesenchymal ciliated cell subpopulation. Genomic analyses argue that this enrichment reflects a combination of pre-existing cells and ones that arose through drug-induced cellular plasticity. We developed a family of small-molecule inhibitors of ciliogenesis and show that these, or genetic ablation of primary cilia, suppress chemoresistance. We conclude that primary cilia help TNBC to evade chemotherapy.
Ethograms reveal a fear conditioned visual cue to organize diverse behaviors
Authors: Williams David C. , Chu Amanda , Gordon Nicholas T. , DuBois Aleah M. , Qian Suhui , Valvo Genevieve , Shen Selena , Boyce Jacob B. , Fitzpatrick Anaise C. , Moaddab Mahsa , Russell Emma L. , Counsman Liliuokalani , McDannald Michael A.
Published: September 2024

Recognizing and responding to threat cues is essential to survival. In rats, freezing is the most common behavior measured. Previously we demonstrated a threat cue can organize diverse behaviors (Chu et al., 2024). However, the experimental design of Chu et al. (2024) was complex and the findings descriptive. Here, we gave female and male Long Evans rats simple paired or unpaired presentations of a light and foot shock (8 total) in a conditioned suppression setting, using a range of shock intensities (0.15, 0.25, 0.35 or 0.5 mA). We found that conditioned suppression was only observed at higher foot shock intensities (0.35 mA and 0.5 mA). We constructed comprehensive, temporal ethograms by scoring 22,272 frames of behavior for 12 mutually exclusive behavior categories in 200 ms intervals around cue presentation. A 0.5 mA and 0.35 mA shock-paired visual cue suppressed reward seeking, rearing and scaling, as well as light-directed rearing and light-directed scaling. The shock-paired visual paired cue further elicited locomotion and freezing. Linear discriminant analyses showed that ethogram data could accurately classify rats into paired and unpaired groups. Considering the complete ethogram data produced superior classification than considering subsets of behaviors. The results demonstrate diverse threat-elicited behaviors – in a simple Pavlovian fear conditioning design – containing sufficient information to distinguish the fear learning status of individual rats.
Contrasting patterns of specificity and transfer in human odor discrimination learning
Authors: Chang Xiaoyue , Tan Huibang , Niu Jiehui , Yuan Kaiqi , Chen Rui , Zhou Wen
Published: September 2024

Practice enhances olfactory performance. However, laboratory studies to date suggest that olfactory learning is largely restricted to the trained odors, posing a significant challenge for training-based rehabilitation therapies for olfactory loss. In this study, we introduce various types of odors to olfactory discrimination training, conducted unilaterally. We demonstrate contrasting patterns of specificity and transfer of learning, independent of adaptation and task difficulty. Individuals trained with odor mixtures of different ratios show long-term perceptual gains that completely transfer to the untrained nostril and effectively generalize to untrained mixtures dissimilar in structure and odor quality from the trained ones. Conversely, those trained with odor enantiomers show no transfer of learning across nostrils or to unrelated enantiomers, replicating our earlier findings (Feng & Zhou, 2019). Our observations indicate that concentration ratio and chirality represent distinct olfactory attributes. Furthermore, discrimination learning occurs at different stages of olfactory processing, depending on which attribute is task-relevant. These findings open up new avenues to enhance the effectiveness of olfactory training.
The cardiac, respiratory and gastric rhythms independently modulate corticospinal excitability
Authors: Engelen Tahnée , Schuhmann Teresa , Sack Alexander T. , Tallon-Baudry Catherine
Published: September 2024

Interoception refers to the sensing of the internal state of the body and encompasses various bodily axes. Yet many interoceptive signals display unique qualities. The heart, lungs, and stomach each have their distinct frequencies, afferent pathways, and respective functions. At the same time each of these organs has been demonstrated to interact with neural activity and behaviour. To what extent then should different organs be treated as separate modalities in interoception? We here aim to answer this question by assessing in human participants whether the phase of these visceral rhythms is coupled to the corticospinal excitability of the motor system, and whether this coupling happens in an organ-specific or organ-general manner. We combined continuous physiological recordings with single pulse Transcranial Magnetic Stimulation (TMS) to probe phase-amplitude coupling between the phase of the cardiac, respiratory, and gastric rhythm and the amplitude of Motor Evoked Potentials (MEP). All three visceral rhythms contributed to MEP amplitude with similar effect sizes at the group level. However, we found no relation between coupling strengths with corticospinal excitability between the three organs. Thus, participants displaying high coupling with one organ did not necessarily display high coupling to the other organs, suggestive of unique interoceptive profiles. There was also no link between self-reported awareness of the organ and the actual coupling, suggesting these are distinct dimensions of interoception. Together these results show that each coupling is mediated by at least partially independent mechanisms.
Adult oligodendrogenesis gates arcuate neuronal glucose sensing through remodelling of the blood-hypothalamus barrier via ADAMTS4
Authors: Buller Sophie , Staricoff Emily O. , Riches Christine , Tsang Anthony , Josipovic Masa , Ikemura Kentaro , Opoku Gabriel , Sato Ikumi , Hirohata Satoshi , Stenzel Saskia , Nayar Stuart G. , Vega Marta Ramos , Hecksher-Sørensen Jacob , Timmler Sebastian , Dowsett Georgina K.C. , Lam Brian Y.H. , Yeo Giles S.H. , Alonge Kimberly M. , Li Huiliang , Richardson William D. , Evans Mark L. , Blouet Clemence
Published: September 2024

Brain glucose sensing is critical for survival during hypoglycaemia and tunes the level of defended blood glucose, which goes up in diabetes. Neuronal glucose sensing neurons and mechanisms have been identified, but how these neurons access blood concentrations of glucose to adjust their output and maintain glucose homeostasis is unclear. Here, we demonstrate that adult oligodendrogenesis in the median eminence (ME) is modulated by changes in circulating glucose levels and rapidly upregulated by hypoglycaemia. We show that genetic blockade of new OL production in adult mice impairs the regulation of glucose homeostasis, the integrity of the ME blood-hypothalamus barrier, and neuronal glucose sensing in the arcuate nucleus of the hypothalamus (ARH). Unexpectedly, functional integrity of adult-formed myelin is not required for the maintenance of glucose homeostasis. Instead, newly formed OLs exert their glucoregulatory actions via the synthesis of A disintegrin and metallopeptidase with thrombospondin motifs 4 (ADAMTS4), a metallopeptidase expressed exclusively by OLs and dependent on adult OL genesis to maintain its expression in the ME. Both lack ofAdamts4and ADAMTS4 gain-of-function are associated with impaired glucose homeostasis and remodelling of the blood-hypothalamus barrier, indicating that optimal ADAMTS4 expression is required for the integrity of vascular permeability and normal glycaemic control. Finally, we show that ME ADAMTS4 expression is regulated by changes in peripheral glycaemia and is dysregulated in diabetes, providing a mechanism by which ME OLs contribute to the regulation of glucose homeostasis.
Quantitative cytoarchitectural phenotyping of deparaffinized human brain tissues
Authors: Meo Danila Di , Sorelli Michele , Ramazzotti Josephine , Cheli Franco , Bradley Samuel , Perego Laura , Lorenzon Beatrice , Mazzamuto Giacomo , Emmi Aron , Porzionato Andrea , Caro Raffaele De , Garbelli Rita , Biancheri Dalila , Pelorosso Cristiana , Conti Valerio , Guerrini Renzo , Pavone Francesco S. , Costantini Irene
Published: September 2024

Advanced 3D imaging techniques and image segmentation and classification methods can profoundly transform biomedical research by offering deep insights into the cytoarchitecture of the human brain in relation to pathological conditions. Here, we propose a comprehensive pipeline for performing 3D imaging and automated quantitative cellular phenotyping on Formalin-Fixed Paraffin-Embedded (FFPE) human brain specimens, a valuable yet underutilized resource. We exploited the versatility of our method by applying it to different human specimens from both adult and pediatric, normal and abnormal brain regions. Quantitative data on neuronal volume, ellipticity, local density, and spatial clustering level were obtained from a machine learning-based analysis of the 3D cytoarchitectural organization of cells identified by different molecular markers in two subjects with malformations of cortical development (MCD). This approach will grant access to a wide range of physiological and pathological paraffin-embedded clinical specimens, allowing for volumetric imaging and quantitative analysis of human brain samples at cellular resolution. Possible genotype-phenotype correlations can be unveiled, providing new insights into the pathogenesis of various brain diseases and enlarging treatment opportunities.
In the brain of the beholder: bi-stable motion reveals mesoscopic-scale feedback modulation in V1
Authors: Pizzuti Alessandra , Gulban Omer Faruk , Huber Laurentius (Renzo) , Peters Judith , Goebel Rainer
Published: September 2024

Understanding the neural processes underlying conscious perception remains a central goal in neuroscience. Visual illusions, whether static or dynamic, provide an effective ecological paradigm for studying conscious perception, as they induce subjective experiences from constant visual inputs. While previous neuroimaging studies have dissociated perceptual interpretation of visual motion from sensory input within the motion-sensitive area (hMT+) in humans, less is known about the role of V1 and its relationship to hMT+ during a bistable perception. To address this, we conducted a layer-fMRI study at 7 T with human participants exposed to a bistable motion quartet stimulus. Despite a constant sensory input, the bistable motion quartet elicits switching horizontal and vertical apparent motion percepts likely due to lateral and feedback connections across low and high-level brain regions (feedback processing). As control, we used an unambiguous version of the motion quartet, hereafter referred to as physical motion stimulus, where horizontal and vertical motion is physically presented as visual stimulus in an alternated fashion (feedforward processing). With the advantage of a sub-millimeter resolution gained at ultra-high field (7 Tesla), we aimed to unveil the differential laminar modulation of V1 (low visual area) and hMT+ (high-visual area) during the physical and bistable condition. Our results indicate that: 1) hMT+ functional activity correlates with conscious perception during both physical and ambiguous stimuli with similar strength. There is no evidence of differential laminar profiles in hMT+ between the two experimental conditions. 2) Between inducer squares, V1 shows a significantly reduced functional response to the ambiguous stimulus compared to the physical stimulus, as it primarily reflects feedback signals with diminished feedforward input. Distinct V1 laminar profiles differentiate the two experimental conditions. 3) The temporal dynamics of V1 and hMT+ become more similar during the ambiguous condition. 4) V1 exhibits reduced specificity to horizontal and vertical motion perception during the ambiguous condition at the retinotopic locations corresponding to the perceived motion. Our findings demonstrate that during the ambiguous condition, there is a stronger temporal coupling between hMT+ and V1 due to feedback signals from hMT+ to V1. Such feedback to V1 might be contributing to the stabilization of the vivid perception of directed motion at the face of constant ambiguous stimulation.
MITF Targets in Gastrointestinal Stromal Tumors: Implications in Autophagy and Extracellular Vesicle Secretion
Authors: Proaño-Pérez Elizabeth , Serrano-Candelas Eva , Guerrero Mario , Gómez-Peregrina David , Llorens Carlos , Soriano Beatriz , Gámez-Valero Ana , Herrero-Lorenzo Marina , Martí Eulalia , Serrano César , Martin Margarita
Published: September 2024

Previous studies have identified Microphthalmia-associated Transcription Factor (MITF) involvement in regulating Gastrointestinal Stromal Tumors (GIST) growth and cell cycle progression. This study uses Chromatin Immunoprecipitation combined with high-throughput sequencing (ChIP-seq) and RNA sequencing to explore MITF-modulated genes in GIST. Our findings reveal that MITF regulates genes involved in lysosome biogenesis, vesicle generation, autophagy, and mTOR signaling pathways. Comparative transcriptome analysis following MITF silencing in GIST cells shows differential enrichment in mTOR signaling, impacting tumor growth and autophagy. In the context of cancer, the interplay between autophagy and extracellular vesicle release can influence tumor progression and metastasis. We examined MITF’s role in autophagy and extracellular vesicle (EV) production in GIST, finding that MITF overexpression increases autophagy, as shown by elevated LC3II levels while silencing MITF disrupts autophagosome and autolysosome formation. Despite no significant changes in EV size or number, MITF silencing notably reduces KIT expression in EV content. KIT secretion in EVs has been linked to GIST metastasis, suggesting that MITF is a crucial target for managing tumor growth and metastasis in GIST.
High fidelity genetic markers for sexingCannabis sativaseedlings
Authors: Prentout Djivan , El Aoudati Salma , Mathis Fabienne , Marais Gabriel AB , Henri Hélène
Published: September 2024

The uses ofCannabis sativa, a dioecious species with an XY sex chromosome system, are varying from fiber and oil to cannabinoids, among others. In most cases, males are undesirable and the sexual dimorphism at immature plants is too subtle for reliable phenotypic sexing, making genetic approaches promising. In this technical note, we present a multiplex PCR-mix, that includes two markers of Y-specific coding regions and one autosomal control marker. This PCR-mix, tested across 12 hemp-type cultivars, encompassing approximately 200 individuals, achieved a 99.5% success rate in identifying the sex ofC. sativaseedlings.
Pushing the limits of single molecule transcript sequencing to uncover the largest disease-associated transcript isoforms in the human neural retina
Authors: Stemerdink Merel , Riepe Tabea , Zomer Nick , Salz Renee , Kwint Michael , Timmermans Raoul , Ferrari Barbara , Ferrari Stefano , Dueñas Rey Alfredo , Delanote Emma , de Bruijn Suzanne E. , Kremer Hannie , Roosing Susanne , Coppieters Frauke , Hoischen Alexander , Cremers Frans P. M. , ’t Hoen Peter A.C. , van Wijk Erwin , de Vrieze Erik
Published: September 2024

Sequencing technologies have long limited the comprehensive investigation of large transcripts associated with inherited retinal diseases (IRDs) like Usher syndrome, which involves 11 associated genes with transcripts up to 19.6 kb. To address this, we used PacBio long-read mRNA isoform sequencing (Iso-Seq) following standard library preparation and an optimized workflow to enrich for long transcripts in the human neural retina. While our workflow achieved sequencing of transcripts up to 15 kb, this was insufficient for Usher syndrome-associated genesUSH2AandADGRV1, with transcripts of 18.9 kb and 19.6 kb, respectively. To overcome this, we employed the Samplix Xdrop System for indirect target enrichment of cDNA, a technique typically used for genomic DNA capture. This method facilitated the successful capture and sequencing ofADGRV1transcripts as well as the full-length 18.9 kbUSH2Atranscripts. By combining algorithmic analysis with detailed manual curation of sequenced reads, we identified novel isoforms and alternative splicing events across the 11 Usher syndrome-associated genes, with implications for diagnostics and therapy development. Our findings demonstrate the Xdrop system’s adaptability for cDNA capture and the advantages of integrating computational and manual transcript analyses. The full neural retina sequencing dataset is available via EGA under identifier EGAD50000000720.
Validity of a New Stress Induction Protocol using Speech Improvisation (IMPRO)
Authors: Saskovets Marina , Lohachov Mykhailo , Liang Zilu , Piumarta Ian
Published: September 2024

This paper proposes a novel stress induction protocol utilizing speech improvisation — Interactive Multitask Performance Response Observation (IMPRO) — in front of an audience. This approach aims to induce stress through a combination of public speaking, cognitive effort, and challenge to maintain a spontaneous narrative. We investigate the validity of this novel approach by examining physiological responses of 35 healthy participants aged 18 to 38. Saliva cortisol was measured as the ground truth for mental stress assessment. In addition, electrodermal activity (EDA) was used as a non-invasive measure of sympathetic activation, offering real-time data with high resolution. Functional near-infrared spectroscopy (fNIRS) measurement was performed to assess the cortical hemodynamic responses induced by the IMPRO protocol. We focused on hemodynamics in the prefrontal cortex (PFC), a region associated with stress processing. We found that cortisol levels and EDA significantly increased in response to the stress task compared to the baseline. We also observed a significant change in PFC hemodynamic levels in a set of channels compared to the baseline, with a higher overall increase in the right frontopolar area compared to the left. In conclusion, our findings validated IMPRO as an effective and easy to perform method for mental stress induction.
SCAMPI: A scalable statistical framework for genome-wide interaction testing harnessing cross-trait correlations
Authors: Bian Shijia , Bass Andrew J. , Liu Yue , Wingo Aliza P. , Wingo Thomas , Cutler David J. , Epstein Michael P.
Published: September 2024

Family-based heritability estimates of complex traits are often considerably larger than their single-nucleotide polymorphism (SNP) heritability estimates. This discrepancy may be due to non-additive effects of genetic variation, including variation that interacts with other genes or environmental factors to influence the trait. Variance-based procedures provide a computationally efficient strategy to screen for SNPs with potential interaction effects without requiring the specification of the interacting variable. While valuable, such variance-based tests consider only a single trait and ignore likely pleiotropy among related traits that, if present, could improve power to detect such interaction effects. To fill this gap, we propose SCAMPI (Scalable Cauchy Aggregate test using Multiple Phenotypes to test Interactions), which screens for variants with interaction effects across multiple traits. SCAMPI is motivated by the observation that SNPs with pleiotropic interaction effects induce genotypic differences in the patterns of correlation among traits. By studying such patterns across genotype categories among multiple traits, we show that SCAMPI has improved performance over traditional univariate variance-based methods. Like those traditional variance-based tests, SCAMPI permits the screening of interaction effects without requiring the specification of the interaction variable and is further computationally scalable to biobank data. We employed SCAMPI to screen for interacting SNPs associated with four lipid-related traits in the UK Biobank and identified multiple gene regions missed by existing univariate variance-based tests. SCAMPI is implemented in software for public use.
Subcellular Level Spatial Transcriptomics with PHOTON
Authors: Rajachandran Shreya , Xu Qianlan , Cao Qiqi , Zhang Xin , Chen Fei , Mangiameli Sarah M. , Chen Haiqi
Published: September 2024

The subcellular localization of RNA is closely linked to its function. Many RNA species are partitioned into organelles and other subcellular compartments for storage, processing, translation, or degradation. Thus, capturing the subcellular spatial distribution of RNA would directly contribute to the understanding of RNA functions and regulation. Here, we present PHOTON (Photoselection of Transcriptome over Nanoscale), a method which combines high resolution imaging with high throughput sequencing to achieve spatial transcriptome profiling at subcellular resolution. We demonstrate PHOTON as a versatile tool to accurately capture the transcriptome of target cell typesin situat the tissue level such as granulosa cells in the ovary, as well as RNA content within subcellular compartments such as the nucleolus and the stress granule. Using PHOTON, we also reveal the functional role of m6A modification on mRNA partitioning into stress granules. These results collectively demonstrate that PHOTON is a flexible and generalizable platform for understanding subcellular molecular dynamics through the transcriptomic lens.
On the design and stability of cancer adaptive therapy cycles: deterministic and stochastic models
Authors: Vilela Yuri G. , Fassoni Artur C. , Neves Armando G. M.
Published: September 2024

Adaptive therapy is a promising paradigm for treating cancers, that exploits competitive interactions between drug-sensitive and drug-resistant cells, thereby avoiding or delaying treatment failure due to evolution of drug resistance within the tumor. Previous studies have shown the mathematical possibility of building cyclic schemes of drug administration which restore tumor composition to its exact initial value in deterministic models. However, algorithms for cycle design, the conditions on which such algorithms are certain to work, as well as conditions for cycle stability remain elusive. Here, we state biologically motivated hypotheses that guarantee existence of such cycles in two deterministic classes of mathematical models already considered in the literature: Lotka-Volterra and adjusted replicator dynamics. We stress that not only existence of cyclic schemes, but also stability of such cycles is a relevant feature for applications in real clinical scenarios. We also analyze stochastic versions of the above deterministic models, a necessary step if we want to take into account that real tumors are composed by a finite population of cells subject to randomness, a relevant feature in the context of low tumor burden. We argue that the stability of the deterministic cycles is also relevant for the stochastic version of the models. In fact, Dua, Ma and Newton [Cancers (2021)] and Park and Newton [Phys. Rev. E (2023)] observed breakdown of deterministic cycles in a stochastic model (Moran process) for a tumor. Our findings indicate that the breakdown phenomenon is not due to stochasticity itself, but to the deterministic instability inherent in the cycles of the referenced papers. We then illustrate how stable deterministic cycles avoid for very large times the breakdown of cyclic treatments in stochastic tumor models.
Randomly oriented microgrooved hydrogel guides cellular motility, modulates speed, and governs directionality of cellular spread
Authors: Ghosh Biswajoy , Agarwal Krishna
Published: September 2024

Cell migration is a fundamental biological process, yet the mechanisms underlying how cells sense and navigate complex environments remain poorly understood. In this study, we developed a system of randomly oriented microgrooves, designed at cellular length scales, to explore motility intelligence in response to varied topographies. These microgrooves allowed cells to freely choose their migratory paths, revealing key insights into how cells sense and adapt to topological cues. Using fibroblast cells migrating over these grooved substrates, we examined cellular processes such as actin cytoskeleton remodeling, cell adhesion dynamics, and the impact of groove alignment on migration speed and directionality. Our results demonstrate that cells align their cytoskeletal structures to groove geometries, forming actin-rich anchors that enhance migration in groove-aligned environments. Cells migrating in grooves aligned with their intrinsic polarity exhibited faster, more directed migration compared to those in misaligned or control conditions. This work advances our understanding of cell-topology interaction and provides new perspectives for tissue engineering applications in cancer therapy and wound healing.
Distinct Stromal Cell Populations Define the B-cell Acute Lymphoblastic Leukemia Microenvironment
Authors: Blanco Mauricio N. Ferrao , Kazybay Bexultan , Belderbos Mirjam , Heidenreich Olaf , Vormoor Hermann Josef
Published: September 2024

The bone marrow microenvironment is critical for B-cell acute lymphoblastic leukemia (B-ALL) but its cellular heterogeneity remains poorly defined. Here, we employed single-cell RNA sequencing to comprehensively characterize the stromal and hematopoietic niches in pediatric B-ALL. Our analysis revealed two distinct mesenchymal stromal cell (MSC) populations as primary leukemia-supportive niches: early mesenchymal progenitors and adipogenic progenitors. Single-cell transcriptomic analysis infers that ALL blasts use distinct cell-cell interactions to communicate with the different stromal populations. Purified adipogenic progenitors from the bone of children with ALL support survival of the leukemic blastsex vivoand their signature is enriched in relapse samples. Our data establish adipogenic progenitors as a distinct and novel component of the ALL niche.
In silicostudy of selected alkaloids as dual inhibitors of β and γ-Secretases for Alzheimer’s disease
Authors: Onifade Isreal Ayobami , Umar Haruna Isiyaku , Aborode Abdullahi Tunde , Awaji Aeshah A. , Jegede Ifeoluwapo Deborah , Adeleye Bunmi Helen , Fatoba Dorcas Oladayo
Published: September 2024

Alzheimer’s disease (AD) has become ubiquitous as the number of elderly individuals increases and has been conceived as a socioeconomic problem lately. To date, no success is recorded for disease-modifying therapies for AD but only drugs for symptomatic relief exist. Research has been centered on the role of β-amyloid on the pathogenesis of AD, which has led to the development of drugs that target Aβ (β and γ-Secretase inhibitors) to reduce the amount of Aβ formed. However, the existing β and γ-Secretase inhibitors were associated with harmful side effects, low efficacy, and inability to cross the blood-brain barrier. Thus, in this current study, 54 alkaloids from the PhytoHub server (phytohub.eu), and two approved drugs were docked against β-Secretases. Additionally, galantamine and 5 alkaloids with the utmost binding potential with β-secretase were subjected to pharmacokinetics evaluation and docked against γ-secretase. . From our result, 5 compounds displayed for both docking periods, with demissidine, solasodine, tomatidine, and solanidine having better BE than the control drugs. Based on the Pharmacokinetics evaluation, 4 compounds possessed good pharmacokinetic evaluation and biological activities than galantamine. This study suggests that demissidine, solasodine, tomatidine, and solanidine are promising dual inhibitors against β and γ-Secretase proteinsin silico. However, there is an urgent need to carry out in vitro and in vivo experiments on these new leads to validate the findings of this study.
Islet amyloid disrupts MHC Class II antigen presentation and protects NOD mice from autoimmune diabetes
Authors: Denroche Heather C , Ng Tori , Velghe Jane , Suen Imelda , Stanley Liam , Nackiewicz Dominika , Komba Mitsu , Chen Sam , Soukhatcheva Galina , Dai Lei , Verchere C. Bruce
Published: September 2024

Islet amyloid contributes to beta cell failure in type 2 diabetes through several mechanisms, one being the potent induction of local islet inflammation through activating inflammatory pathways in islet macrophages. We performed an unbiased phenotypic investigation of islet macrophages in the early stage of islet amyloid formation using single cell RNA sequencing of resident islet macrophages in mice with and without the amyloidogenic form of human islet amyloid polypeptide (hIAPP). This revealed that MHC Class II antigen presentation genes were strongly down-regulated in islet macrophages during islet amyloid formation. As islet amyloid has recently been reported in pancreases of people with type 1 diabetes, we sought to investigate the impact of islet amyloid in the NOD mouse model of type 1 diabetes. Both overexpression and physiological expression of hIAPP delayed diabetes in NOD mice relative to littermate controls, corresponding with decreased markers of antigen presentation and activation, as well as decreased immune cell infiltration in islets. Adoptive transfer studies showed that systemic autoimmune function remained intact and beta cells from hIAPP transgenic mice did not evade immune recognition by diabetogenic T cells, collectively indicating the protection from diabetes was mediated by localized disruption of antigen presentation in the pancreas. Consistent with this, incubation of dendritic cells with IAPP aggregates decreased MHC Class II surface expression and diminished antigen-specific T cell activation in vitro, through a phagocytosis-dependent mechanism.

Collectively our data show that despite the well-established pro-inflammatory response of macrophages to IAPP aggregates, the uptake of IAPP aggregates during early amyloid formation also disrupts MHC Class II antigen presentation and slows beta cell autoimmunity.
Protocol for the Work And Vocational advicE (WAVE) randomised controlled trial testing the addition of vocational advice to usual primary care (Clinical Trials: NCT04543097)
Authors: Wynne-Jones G , Lewis M , Sowden G , Madan I , Walker-Bone K , Chew-Graham CA , Bromley K , Jowett S , Parsons V , Mansell G , Cooke K , Lawton SA , Saunders B , Pemberton J , Cooper C , Foster NE
Published: September 2024

Objectives

To investigate the effectiveness of adding a brief vocational advice intervention to usual care in reducing the number of days absent from work over a period of 6 months in adults given a fit note by their general practice.

Design

Multicentre, pragmatic, two parallel-arm, randomised controlled trial with health economic analyses and nested qualitative study. A computer-generated stratified block randomisation (ratio 1:1) was used to allocate arms.

Setting

Participants will be recruited from general practices in the UK.

Participants

720 adults consulting in general practice, for any health condition, and receiving a fit note who have been absent from work for more than two-weeks but less than six months.

Interventions

Participants in the intervention arm will be offered usual care and vocational advice delivered by a Vocational Support Worker (VSW) remotely via phone or videoconferencing. Participants in the control arm will be offered usual care.

Main outcome measure

Number of days off work over 6 months. Follow-up data collection is via questionnaires at 6 weeks and 6 months.

Conclusions

This paper presents the rationale, design and methods of the Work And Vocational advicE (WAVE) trial. The results of this trial will provide evidence to inform primary care practice and guide the development of services to provide support for patients with work absence.

Trial registration:Clinical Trials:NCT04543097

Protocol number: Version 5.1
Assessing the Impact of COVID-19 on Multimorbidity: Insights from Structural Equation Modeling in Colombia
Authors: Porras-Ramírez A , Rico-Mendoza A , Campos-Maya A , Cardenas-Sanchez J , Penagos-Lopez D , Gomez-Puentes A , Delgado-Quiroz N , Guarin-Muñoz L , Ortiz-Elejalde J
Published: September 2024

Background

Multimorbidity, the coexistence of multiple chronic diseases, poses significant challenges for healthcare systems worldwide. This study aims to assess the situation of multimorbidity in Colombia using structural equation models and to characterize multimorbidity by sex, age group, region, and health insurance regime between 2019 and 2023.

Methods

We conducted a cross-sectional analytical study utilizing data from the Individual Health Service Provision Registry (RIPS) and other national databases, including the Unit of Payment by Capitation (UPC) Sufficiency Study Database. Structural equation models were employed to identify and analyze multimorbidity clusters among patients with two or more chronic diseases.

Results

The study revealed a multimorbidity prevalence of 61.5% in the general population. Hypertension emerged as the most prevalent chronic condition, frequently associated with diabetes and chronic kidney disease. Multimorbidity was more common in women and individuals affiliated with the contributory insurance regime. The study also identified significant variations in multimorbidity prevalence across different regions and age groups.

Conclusions

Multimorbidity is a prevalent issue in Colombia, with substantial variations by sex, age, and insurance regime. These findings underscore the need for tailored healthcare strategies to address the diverse needs of multimorbid patients. The results provide critical insights for health service planning and management, emphasizing the importance of continued research and policy development to mitigate the burden of chronic diseases and multimorbidity in Colombia.
The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity
Authors: Guha Abhishek , Si Ying , Smith Reed , Kazamel Mohamed , Jiang Nan , Smith Katherine A. , Thalacker-Mercer Anna , Singh Brijesh K. , Ho Ritchie , Andrabi Shaida A , Silva Pereira Joao D Tavares Da , Salgado Juliana S. , Agrawal Manasi , Velic Emina Horvat , King Peter H.
Published: September 2024

Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1G93Amouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1G93Aor exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.
Assessing the risk of highly pathogenic avian influenza H5 viruses spread within French broiler and layer production networks
Authors: Hautefeuille Claire , Muñoz Facundo , Dauphin Gwenaëlle , Paul Mathilde , Peyre Marisa , Goutard Flavie
Published: September 2024

Since 2015, French poultry production is threatened almost every year by a reintroduction of highly pathogenic avian influenza H5 viruses. The duck sector was the most concerned by this crisis but other sectors such as broiler, layer and turkey were also affected by outbreaks. The objective of this work was to assess the risk of highly pathogenic avian influenza H5 virus transmission from one farm to another within the French broiler and layer production network.

This study used the WOAH risk assessment framework. After drawing up a scenario tree of virus transmission from one farm to another, data were collected through a literature review or through experts’ elicitation. Three questionnaires were developed according to the experts’ field of expertise: avian influenza, broiler and layer sectors. The experts’ estimates were combined using a beta distribution weighted by their confidence level. A Monte Carlo iteration process was used to combine the different probabilities of the scenario tree and to assess the transmission risk.

In the broiler sector, the highest transmission probabilities were observed if the exposed farm was an indoor broiler farm and the source a broiler farm (indoor or free-range). The high transmission probability between broiler farm integrated within the same company highlighted the role of integration in this probability. In the layer sector, the highest transmission probabilities were observed if the source farm was a free-range farm and the exposed farm a production farm (indoor or free-range). The sensitivity analysis showed that the exposed farm’s biosecurity had a significant impact on the transmission probability.

Our results provide an insight on the role of each type of farms in the virus spread within the French broiler and layer production network and will be useful for the implementation of control measures such as movement restriction or vaccination.
Leveraging Pretrained Deep Protein Language Model to Predict Peptide Collision Cross Section
Authors: Nakai-Kasai Ayano , Ogata Kosuke , Ishihama Yasushi , Tanaka Toshiyuki
Published: September 2024

Collision cross section (CCS) of peptide ions provides an important separation dimension in liquid chromatography/tandem mass spectrometry-based proteomics that incorporates ion mobility spectrometry (IMS), and its accurate prediction is the basis for advanced proteomics workflows. This paper describes novel experimental data and a novel prediction model for challenging CCS prediction tasks including longer peptides that tend to have higher charge states. The proposed model is based on a pretrained deep protein language model. While the conventional prediction model requires training from scratch, the proposed model enables training with less amount of time owing to the use of the pretrained model as a feature extractor. Results of experiments with the novel experimental data show that the proposed model succeeds in drastically reducing the training time while maintaining the same or even better prediction performance compared with the conventional method. Our approach presents the possibility of prediction in a “greener” manner of various peptide properties in proteomic liquid chromatography/tandem mass spectrometry experiments.
LoVis4u: Locus Visualisation tool for comparative genomics
Authors: Egorov Artyom A. , Atkinson Gemma C.
Published: September 2024

Comparative genomic analysis often involves visualisation of alignments of genomic loci. While several software tools are available for this task, ranging from Python and R libraries to standalone graphical user interfaces, there is lack of a tool that offers fast, automated usage and the production of publication-ready vector images.

Here we present LoVis4u, a command-line tool and Python API designed for highly customizable and fast visualisation of multiple genomic loci. LoVis4u generates vector images in PDF format based on annotation data from GenBank or GFF files. It is capable of visualising entire genomes of bacteriophages as well as plasmids and user-defined regions of longer prokaryotic genomes. Additionally, LoVis4u offers optional data processing steps to identify and highlight accessory and core genes in input sequences.

Availability and Implementation

LoVis4u is implemented in Python3 and runs on Linux and MacOS. The command-line interface covers most practical use cases, while the provided Python API allows usage within a Python program, integration into external tools, and additional customisation. Source code is available at the GitHub page:github.com/art-egorov/lovis4u. Detailed documentation that includes an example-driven guide is available from the software home page:art-egorov.github.io/lovis4u.
SOX2 drives fetal reprogramming and reversible dormancy in colorectal cancer
Authors: Baulies Anna , Moncho-Amor Veronica , Drago-Garcia Diana , Kucharska Ania , Chakravarty Probir , Moreno-Valladares Manuel , Cruces-Salguero Sara , Hubl Florian , Hutton Colin , Kim Hanue , Matheu Ander , Lovell-Badge Robin , Li Vivian S. W.
Published: September 2024

Cellular plasticity plays critical roles in tissue regeneration, tumour progression and therapeutic resistance. However, the mechanism underlying this cell state transition remains elusive. Here, we show that the transcription factor SOX2 induces fetal reprogramming and reversible dormancy in colorectal cancer (CRC). SOX2 expression correlates with fetal reprogramming and poor prognosis in human primary and metastatic colorectal adenocarcinomas. In mouse CRC models, rare slow-cycling SOX2+SCA1+cells are detected in earlyApc-deleted mouse tumours that undergo slow clonal expansion over time. In contrast, the SOX2+clones were found proliferative in advancedApc-/-;KrasG12D/+;p53-/-;Tgfbr2-/-(AKPT) tumours, accompanied by dynamic cell state reprogramming from LGR5+to LGR5-SCA1+cells. Using transgenic mouse models, we demonstrate that ectopic expression of SOX2 inhibits intestinal lineage differentiation and induces fetal reprogramming. SOX2+ cells adopt dynamic cell cycle states depending on its expression level. High SOX2 expression results in hyperproliferation, whereas low SOX2 levels induce senescence-mediated dormancy. We find that loss of p53 can reverse SOX2-induced senescence, in line with the dormant cell state exit of the SOX2+ cells observed in advanced tumours. Finally, SOX2 expression is induced by 5-FU treatment in CRC. SOX2-expressing organoids exhibit increased tolerance to chemotherapy treatment, whilst deletion of SOX2 in AKPT tumour organoids sensitises drug responses. We propose that SOX2-induced plasticity and reversible dormancy promotes tumour progression and drug tolerance in CRC.