bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequency and duration of sensory flicker controls astrocyte and neuron specific transcriptional profiles in 5xFAD mice
Authors: Bitarafan Sara , Pybus Alyssa F. , Rivera Moctezuma Felix G. , Adibi Mohammad , Franklin Tina C. , Singer Annabelle C. , Wood Levi B. 
Published: May 2024

AbstractBackgroundCurrent clinical trials are investigating gamma frequency sensory stimulation as a potential therapeutic strategy for Alzheimer’s disease, yet we lack a comprehensive picture of the effects of this stimulation on multiple aspects of brain function. While most prior research has focused on gamma frequency sensory stimulation, we previously showed that exposing mice to visual flickering stimulation increased MAPK and NFκB signaling in the visual cortex in a manner dependent on duration and frequency of sensory stimulation exposure. Because these pathways control multiple neuronal and glial functions and are differentially activated based on the duration and frequency of flicker stimulation, we aimed to define the transcriptional effects of different frequencies and durations of flicker stimulation on multiple brain functions.MethodsWe exposed 5xFAD mice to different frequencies of audio/visual flicker stimulation (constant light, 10Hz, 20Hz, 40Hz) for durations of 0.5hr, 1hr, or 4hr, then used bulk RNAseq to profile transcriptional changes within the visual cortex and hippocampus tissues. Using weighted gene co-expression network analysis, we identified modules of co-expressed genes controlled by frequency and/or duration of stimulation.ResultsWithin the visual cortex, we found that all stimulation frequencies caused fast activation of a module of immune genes within 1hr and slower suppression of synaptic genes after 4hrs of stimulation. Interestingly, all frequencies of stimulation led to slow suppression of astrocyte specific gene sets, while activation of neuronal gene sets was frequency and duration specific. In contrast, in the hippocampus, immune and synaptic modules were suppressed based on the frequency of stimulation. Specifically,10Hz activated a module of genes associated with mitochondrial function, metabolism, and synaptic translation while 10Hz rapidly suppressed a module of genes linked to neurotransmitter activity.ConclusionCollectively, our data indicate that the frequency and duration of flicker stimulation controls immune, neuronal, and metabolic genes in multiple regions of the brain affected by Alzheimer’s disease. Flicker stimulation may thus represent a potential therapeutic strategy that can be tuned based on the brain region and the specific cellular process to be modulated.
Human Breast Milk EVs Mitigate Endothelial Dysfunction: Preliminary Study
Authors: Cho Young-Eun , Chen Shaoshuai , Crouch Keith , Shutt Damon , Kaufman Justin , Singh Brajesh 
Published: May 2024

AbstractBackgroundEndothelial cell (EC) dysfunction is an early indicator of failing vascular integrity, leading to various cardiovascular diseases. Toll-like receptor 4 (TLR4) activation is a key mechanism. Milk-derived extracellular vesicles (EVs) are known for their anti-inflammatory properties, particularly in suppressing TLR4 activation in damaged intestinal epithelial cells. This study explores the therapeutic potential of human breast milk EVs (bEVs) in EC dysfunction related to cardiovascular diseases.MethodsHuman breast milk EVs (bEVs) were isolated from healthy nursing mothers using ultracentrifugation. bEVs were applied to LPS-treated HUVECs, and the expression of inflammatory markers was measured using qPCR and western blotting. Angiogenesis was assessed via a wound assay. Additionally, bEVs were orally administered weekly for six weeks to high-fat diet-induced obese mice and lean mice. Metabolic phenotype characteristics and EC-dependent vasorelaxation were evaluated.ResultsbEV pre-treatment inhibited LPS-induced expression of inflammatory genes, including IL-6, IL-1b and VCAM-1. It also suppressed phospho-NFkB and TLR4 protein expression. bEVs enhanced EC migration, significantly increasing wound closure. Oral administration of bEVs restored impaired EC-dependent vasorelaxation in the mesenteric artery of obese mice, though metabolic parameters remained unchanged.ConclusionOur findings demonstrate the beneficial effects of bEVs on EC dysfunction, highlighting their potential as novel therapeutics for cardiovascular diseases. Future studies will focus on identifying specific bEV cargos and further evaluating their therapeutic effects on EC dysfunction.
The transcriptional landscape of metastatic hormone-naïve prostate cancer
Authors: Martin-Martin Natalia , Garcia-Longarte Saioa , Corres-Mendizabal Jon , Lazcano Uxue , Astobiza Ianire , Bozal-Basterra Laura , Herranz Nicolas , van Splunder Hielke , Carlevaris Onintza , Pujana-Vaquerizo Mikel , Blasco María Teresa , Aransay Ana M. , Rosino Antonio , Tudela Julian , Jimenez Daniel , Martinez Alberto , Salca Andrei , Santos-Martín Aida , Rey Sofía , Ugalde-Olano Aitziber , Gonzalo David , Graupera Mariona , Gomis Roger R. , Mateo Joaquin , Unda Miguel , Gonzalez-Billalabeitia Enrique , Loizaga-Iriarte Ana , Mendizabal Isabel , Carracedo Arkaitz 
Published: May 2024

AbstractMetastatic hormone-naïve prostate cancer (mHNPC) is an infrequent form of this tumour type that is characterized by metastasis at the time of diagnosis and accounts for 50% of prostate cancer-related deaths. Despite the extensive characterization of localized and metastatic castration resistant prostate cancer (mCRPC), the molecular characteristics of mHNPC remain largely unexplored. Here we provide the first extensive transcriptomics characterization of mHNPC. We generated discovery and validation bulk and single-cell RNA-Seq datasets and performed integrative computational analysis in combination with experimental studies. Our results provide unprecedented evidence of the distinctive transcriptional profile of mHNPC and identify stroma remodelling as a predominant feature of these tumours. Importantly, we discover a central role for the transcription factor SOX11 in triggering a heterotypic communication that is associated to the acquisition of metastatic properties. Our study will constitute an invaluable resource for a profound understanding of mHNPC that can influence patient management.
3D-bioprinted patient-specific organotypic bone model mimicking mineralization dysregulation inFKBP10-related osteogenesis imperfecta
Authors: Griesbach Julia , de Leeuw Anke , Minacci Tanja , Kodiyan Ben , Ndarugendamwo Timothée , Lim Pei Jin , Rohrbach Marianne , Rubert Marina , Rüger Matthias , Giunta Cecilia , Schulte Friederike A. , Müller Ralph 
Published: May 2024

AbstractOsteogenesis imperfecta (OI) is a heterogeneous group of rare genetic diseases characterized by increased bone fragility and deformities. The pathomechanisms of OI are poorly understood, hindering the development of disease-specific therapy. Addressing the limited understanding of OI and the lack of targeted treatments remains a challenge, given its varied symptoms and large clinical spectrum. Animal models have greatly advanced the understanding of the disease; however, the heterogeneity and subtype-specific symptoms are difficult to translate to humans.In vitromodels offer a promising tool for translational medicine, as they have the potential to yield patient-specific insights in a controlled environment using patient derived-cells. We used mechanically loaded 3D-bioprinted patient-specific organotypic bone models and time-lapsed micro-computed tomography to demonstrate dysregulation of mineralization inFKBP10-related OI compared to healthy controls. In contrast to healthy controls, tissue mineral density and stiffness were decoupled, such that hypermineralization observed in OI samples did not lead to increased stiffness. Additionally, we were able to replicate experimental stiffness using sample specific micro-finite element analysis. This allowed us to show mineral formation in regions of high local strain, suggesting mechanoregulation inFKBP10-related OI organotypic bone models is comparable to healthy controls. Regional analysis of mineralization showed increased heterogeneous mineralization, microarchitectural inhomogeneities and scaffold microporosity of OI samples compared to healthy controls. Our results suggest that the observed dysregulation of mineralization is the main driver for the altered mineral-mechanics properties observed inFKBP10-related organotypic bone models.One Sentence SummaryOrganotypic bone models demonstrate dysregulated mineralization in osteogenesis imperfecta samples compared to healthy controls.
Intercellular adhesion molecule-1 reprograms microglia to improve cognitive functions by inhibiting ERK/STAT3 signalling pathway in a model of Alzheimer’s disease
Authors: Goswami Soumita , Biswas Subhas Chandra 
Published: May 2024

AbstractBackgroundMicrogliosis is one of the early hallmarks of Alzheimer’s disease (AD) that plays a crucial role in AD-associated neuroinflammation. However, strategies to harness microglial activation without affecting its homeostatic function are currently lacking. Our recent finding revealed astrocyte secreted cytokine Intercellular adhesion molecule 1 (ICAM-1) improves memory and cognitive impairment in 5xFAD mice model of AD. Here, we investigated the possible mechanism of ICAM-1 that involves modification of microglial activation state and function.MethodsWe treated primary microglia cultures with amyloid-ß (Aß) in presence or absence of ICAM-1 and then assessed microglial inflammatory activation and phagocytic clearance of Aß by western blotting and confocal imaging. We further treated 5xFAD mice with ICAM-1 intraperitoneally and ICAM-1 antagonist lifitegrast intranasally to assess the beneficial effect of ICAM-1 on Aß mediated microgliosis, synaptic protein expressions and cognitive deficits.ResultsHere we report that, ICAM-1 inhibits microglial inflammatory activation by inhibiting ERK-STAT3 pathway which is indispensable for microglial inflammation. Moreover, ICAM-1 was found to potentiate microglia to engulf and eliminate Aß in primary culture and reduced Aß plaque load and associated microglial activation in 5xFAD mice hippocampus. This reduced plaque levels and associated microgliosis in turn refurbished synaptic protein expressions and improved cognition and memory in these mice. Interestingly, ICAM-1 mediated microglial modification along with cognitive improvement was partially lost when ICAM-1-LFA-1 interaction was inhibited.ConclusionTaken together these findings delineate the importance of ERK/STAT3 pathway in Aß mediated microglial inflammation and the modulatory role of ICAM-1 in microglial activation and phagocytosis in order to improve clearance of Aß and associated memory and cognitive impairments.
A recombinant CHIKV-NLuc virus identifies chondrocytes as target of Chikungunya virus in a immunocompetent mouse model
Authors: Legros Vincent , Belarbi Essia , Jeannin Patricia , Kümmerer Beate , Hardy David , Desprès Philippe , Gessain Antoine , Roques Pierre , Ceccaldi Pierre-Emmanuel , Choumet Valérie 
Published: May 2024

AbstractFirst isolated in 1953 in Tanzania, the arthritogenic Chikungunya virus (CHIKV) re-emerged globally in 2005, leading to widespread outbreaks. Unlike other arboviruses, CHIKV predominantly induces symptomatic infections (72-96%), marked by fever, myalgia, polyarthralgia, and rash. Although rarely fatal, atypical forms such as encephalopathies can occur. Notably, 75.4% of patients experience persistent arthralgias for up to three years after the acute phase. Understanding CHIKV’s pathophysiology in the joints is challenging due to the difficulties to obtain biological samples. The study employs a mouse model infected with a reporter virus expressing a Nano Luciferase to investigate the disease’s transition to chronic arthritis. The murine model reveals viral replication in metatarsi joints, particularly in chondrocytes, confirmed in primary human chondrocytes undergoing viral-induced apoptosis.Ex vivoanalysis confirmed viral replication in leg bones and articular cartilages, with histological evidence of focal erosive lesions and periarticular inflammation. The study further utilizes anin vivoimaging mouse model to monitor viral replication over time. Human chondrocytes prove susceptible to CHIKV infection, exhibiting active viral replication, bioluminescence activity, and increased viral production. CHIKV induced apoptosis, the upregulation of markers associated with cartilage remodeling and altered the cytokine production. This comprehensive study, utilizing advanced techniques and models, provides insights into CHIKV’s ability to infect articular cartilages, shedding light on the mechanisms of chronic arthritis following infection.
Microscale sampling of the coral gastric cavity reveals a gut-like microbial community
Authors: Bollati Elena , Hughes David J. , Suggett David J. , Raina Jean-Baptiste , Kühl Michael 
Published: May 2024

AbstractAnimal guts contain numerous microbes, which are critical for nutrient assimilation and pathogen defence. While corals and other Cnidaria lack a true differentiated gut, they possess gastrovascular cavities (GVCs), semi-enclosed compartments where vital processes such as digestion, reproduction and symbiotic exchanges take place. The microbiome harboured in GVCs is therefore likely key to holobiont fitness, but remains severely understudied due to challenges of working in these small compartments. Here, we developed minimally invasive methodologies to sample the GVC of coral polyps and characterise the microbial communities harboured within. We used glass capillaries, low dead volume microneedles, or nylon microswabs to sample the gastric microbiome of individual polyps from six species of corals, then applied low-input DNA extraction to characterise the microbial communities from these microliter volume samples. Microsensor measurements of GVCs revealed anoxic or hypoxic micro-niches, which persist even under prolonged illumination with saturating irradiance. These niches harboured microbial communities enriched in putatively microaerophilic or facultatively anaerobic taxa, such as Epsilonproteobacteria. Some core taxa found in the GVC ofLobophyllia hemprichiifrom the Great Barrier Reef were also detected in conspecific colonies held in aquaria, indicating that these associations are unlikely to be transient. Our findings suggest that the coral GVC is chemically and microbiologically similar to the gut of higher Metazoa. Given the importance of gut microbiomes in mediating animal health, harnessing the coral “gut microbiome” may foster novel active interventions aimed at increasing the resilience of coral reefs to the climate crisis.
Decoding the amplitude and slope of continuous signals into spikes with a spiking point neuron model
Authors: Miko Rebecca , Scheunemann Marcus , Steuber Volker , Schmuker Michael 
Published: May 2024

AbstractIn this study, we harness the signal processing potential of neurons, utilizing the Izhikevich point neuron model to efficiently decode the slope or amplitude of fluctuating continuous input signals. Using biophysically detailed compartmental neurons often requires significant computational resources. We present a novel approach to create behaviours and simulate these interactions in a lower-dimensional space, thereby reducing computational requirements. We began by conducting an extensive search of the Izhikevich parameter space, leading to the first significant outcome of our study: i) the identification of optimal parameter sets for generating slope or amplitude detectors, thereby achieving signal processing goals using neurons. Next, we compared the performance of the slope detector we discovered with a biophysically detailed two-compartmental pyramidal neuron model. Our findings revealed several key observations: ii) bursts primarily occurred on the rising edges of similar input signals, iii) our slope detector exhibited bidirectional slope detection capabilities, iv) variations in burst duration encoded the magnitude of input slopes in a graded manner. Overall, our study demonstrates the efficient and accurate simulation of dendrosomatic behaviours. Real-time applications in robotics or neuromorphic hardware can utilize our approach. While biophysically detailed compartmental neurons are compatible with such hardware, Izhikevich point neurons are more efficient. This work has the potential to facilitate the simulation of such interactions on a larger scale, encompassing a greater number of neurons and neuronal connections for the same computational power.
New insight on DNA isolation from single automated recoveredCeratocystis plataniconidia
Authors: Luchi Nicola , Pinzani Pamela , Salvianti Francesca , Mancini Irene , Santini Alberto 
Published: May 2024

AbstractSingle-cell technology is increasingly used to analyze the basis of molecular regulation and provide insights into different aspects of human diseases. Such technology is a breakthrough approach to study blood cancers by characterizing molecular information on a genome-wide scale at the single-cell level. These methods can be easily and successfully transferred to tracheomycotic plant pathogens, which cause host wilt. Ceratocystis platani is the causal agent of the Canker stain disease of plane tree (Platanus spp.), a lethal wilt disease spreading in Europe. To displace and separate different C. platani conidia types a dielectrophoretic approach was tested. The DNA of each conidium was isolated and analyzed and the target DNA was identified by a specific qPCR marker and by sequencing the amplicon. Our results showed that this technology is applicable to vascular plant pathogens. The fungal DNA was successfully extracted from single or pooled conidia and identified by both methods after whole genome amplification. The use of the single-cell technology will provide a new approach to the study of plant vascular diseases, allowing the study of single-spore molecular and physiological features not detectable in complex biological mixtures.Author summaryIn recent years, technologies for single-cell isolation have been developed in the study of human diseases, such as cancers, capable of obtaining genetic information at the single-cell level. In this study, these methods were transferred to a plant pathogen, Ceratocystis platani, which causes a lethal disease of plane tree. The single cell technique used was able to separate the different types of conidia of C. platani and analyze the DNA within each conidium. The use of single cell technology represents an important tool for the study of plant vascular diseases by allowing the study of molecular mechanisms that are difficult to detect in complex biological matrices.
T-cell receptor structures and predictive models reveal comparable alpha and beta chain structural diversity despite differing genetic complexity
Authors: Quast Nele P. , Abanades Brennan , Guloglu Bora , Karuppiah Vijaykumar , Harper Stephen , Raybould Matthew I. J. , Deane Charlotte M. 
Published: May 2024

AbstractT-cell receptor (TCR) structures are currently under-utilised in early-stage drug discovery and repertoire-scale informatics. Here, we leverage a large dataset of solved TCR structures from Immunocore to evaluate the current state-of-the-art for TCR structure prediction, and identify which regions of the TCR remain challenging to model. Through clustering analyses and the training of a TCR-specific model capable of large-scale structure prediction, we find that the alpha chain VJ-recombined loop (CDRA3) is as structurally diverse and correspondingly difficult to predict as the beta chain VDJ-recombined loop (CDRB3). This differentiates TCR variable domain loops from the genetically analogous antibody loops and supports the conjecture that both TCR alpha and beta chains are deterministic of antigen specificity. We hypothesise that the larger number of alpha chain joining genes compared to beta chain joining genes compensates for the lack of a diversity gene segment.Overall, our study demonstrates that valuable structure-function relationships can lie in alpha chains despite their simpler junctions. We also provide over 1.5M predicted TCR structures to enable repertoire structural analysis and elucidate strategies towards improving the accuracy of future TCR structure predictors.
Early development of the mineralized external skeleton of the polyplacophoran mollusk, with insight into the evolutionary history of shell plates and spicules
Authors: Yoshikawa Hiroki , Morino Yoshiaki , Wada Hiroshi 
Published: May 2024

AbstractRecent molecular phylogenetic studies have raised two questions about the evolutionary history of the calcified exoskeleton of mollusks. The first question concerns the homology of the two types of skeleton; whether spicules and shell plates share an evolutionary origin. The second question is the homology of the shell plates between chitons and other mollusks, including gastropods and bivalves. To gain insight into these questions, we examined the early development of shell plates and spicules in chitons. We identified several developmental genes that are involved in both shell plates and spicules, suggesting that spicules and shell plates share a common evolutionary origin. We also found that subpopulations of the dorsal shell field (the ridge and the plate field) have specific gene expression profiles. The differential gene expression of the ridge and plate field is not identical to the profiles of the zones of the gastropod shell field. This observation may suggest an independent evolutionary origin of the shell plates in chitons and gastropods.
Redox-driven control of Yuh1/UCHL3 impacts mitochondrial health via NEDD8/Rub1 pathway
Authors: Issa Soha , Klein Yuval , Berda Eden , Saad Shahaf , Harshuk-Shabso Dana , Sinha Abhishek , Sharaabi Yehonatan , Benhar Moran , Pick Elah 
Published: May 2024

AbstractThe ubiquitin-like protein NEDD8/Rub1 undergoes processing by the enzyme Yuh1/UCHL3 to become functional. While the processed NEDD8/Rub1 modifies Cullin-RING E3 ligases (CRLs) among all studied organisms, its role in facilitating CRL-based substrate degradation is absent inS. cerevisiae. This prompts questions about NEDD8/Rub1 functionality if it does not activate CRLs universally. Previous studies revealed that increased production of reactive oxygen species (ROS) during the glycolysis to mitochondrial respiration transition inhibits cullin NEDDylation inS. cerevisiae, yet the specific affected enzymes remain unidentified. Here, we investigate how redox changes affect Yuh1 activity, revealing a thiol-based redox switch modulating its catalytic function in response to ROS. Temporal inactivation of Yuh1 fine-tunes NEDD8/Rub1 mature and precursor species, both crucial for maintaining mitochondrial integrity and enhancing oxidative stress resilience. These findings unveil a novel role for Rub1/NEDD8 beyond CRL activation, linking redox signaling to NEDD8/Rub1 pathways.Graphical abstract