bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age-associated transcriptomic and epigenetic alterations in mouse hippocampus
Authors: Bilgic Merve , Gotoh Yukiko , Kishi Yusuke 
Published: September 2024

ABSTRACTAging represents a major risk for human neurodegenerative disorders, such as dementia and Alzheimer’s disease, and is associated with a functional decline in neurons and impaired synaptic plasticity, leading to a gradual decline in memory. Previous research has identified molecular and functional changes associated with aging through transcriptomic studies and neuronal excitability measurements, while the role of chromatin-level regulation in vulnerability to aging-related diseases is not well understood. Moreover, the causal relationship between molecular alterations and aging-associated decline in functions of different cell types remains poorly understood. Here, we systematically characterized gene regulatory networks in a cell type–specific manner in the aging mouse hippocampus, a central brain region involved in learning and memory formation, by simultaneously profiling gene expression and chromatin accessibility at a single nuclei level. The analysis of multiome (RNA and ATAC) sequencing recapitulated the diversity of glial and neuronal cell types in the hippocampus, and allowed revealing transcriptomic and chromatin accessibility level changes in different cell types, among which oligodendrocytes and dentate gyrus (DG) neurons exhibited the most drastic changes. We found that aging-dependent chromatin-level changes were more pronounced than transcriptomic changes for genes related to synaptic plasticity among neurons. Our data suggest that BACH2, a candidate transcription factor in the aging- mediated functional decline of DG neurons, potentially regulates genes associated with synaptic plasticity, cell death, and inflammation during aging.
Left Atrial Strain as a Predictor of Cardiac Dysfunction in a Murine Model of Pressure Overload
Authors: Salvas John P. , Moore-Morris Thomas , Goergen Craig J. , Sicard Pierre 
Published: September 2024

AbstractAimLeft atrial (LA) strain is emerging as a valuable metric for evaluating cardiac function, particularly under pathological conditions such as pressure overload. This preclinical study investigates the predictive utility of LA strain on cardiac function in a murine model subjected to pressure overload, mimicking pathologies such as hypertension and aortic stenosis.MethodsHigh resolution ultrasound was performed in a cohort of mice (n=16) to evaluate left atrial and left ventricular function at baseline and 2- and 4-weeks after transverse aortic constriction (TAC). Acute adaptations in cardiac function were assessed in a subgroup of mice (n=10) with 3-days post TAC imaging.ResultsWe report an increase in LA max volume from 11.0 ± 4.3µL at baseline to 26.7 ± 16.7µL at 4 weeks (p=0.002) and a decrease in LA strain from 19.6 ± 4.8% at baseline to 10.1 ± 6.3% at 4 weeks (p=0.006). In the acute phase, LA strain dysfunction was present at 3-days (p<0.001) prior to alterations in LA volume (p=0.856) or left ventricular (LV) ejection fraction (p=0.120). LA strain correlated with key indicators of cardiac performance including left ventricular (LV) ejection fraction (r=0.563,p<0.001), longitudinal strain (r=-0.643,p<0.001) and strain rate (r=0.387,p=0.007). Furthermore, markers of atrial structure and function including LA max volume (AUC=0.858,p<0.001), ejection fraction (AUC=0.901p<0.001), and strain (AUC=0.878,p<0.001) all predicted LV dysfunction.ConclusionLA strain and function assessments provide a reliable, non-invasive method for early detection and prediction of cardiac dysfunction in a model of pressure overload.
A non-catalytic function for Rad18 in sustaining glioblastoma proliferation
Authors: Kermi Chames , Benbahouche Nour , Stefancikova Lenka , Siegfried Aurore , Pascussi Jean-Marc , Pannequin Julie , Moreaux Jérôme , Egger Tom , Hugnot Jean-Philippe , Delisle Marie-Bernadette , Moyal Elizabeth , Uro-Coste Emmanuelle , Maiorano Domenico 
Published: September 2024

AbstractThe Rad18 E3 ubiquitin ligase, a non-essential gene, is a key regulator of DNA damage tolerance that also functions in repair of DNA double strand breaks. Rad18 is overexpressed in the aggressive brain cancer glioblastoma (GBM) and its downregulation sensitizes glioblastoma cells to DNA damaging agents. Here we show that Rad18 has an essential role in GBM cells proliferation in the absence of external damage, surprisingly independent of its catalytic activity. Rad18 downregulation leads to cell cycle arrest in the G1 phase in the absence of apparent DNA damage. We also show that Rad18 sustains GBM stem cells self-renewal and survival, as well as the growth of tumor orthotropic xenografts in mice. We also show that increased Rad18 expression enhances the growth of non-transformed cells and induces features of oncogenic transformation. Mechanistically, we show that Rad18 downregulation negatively regulates the Hippo pathway by interfering with the nuclear retention of the YAP1 transcription factor. Altogether, these data show that Rad18 has an essential, non-catalytic function, in GBM proliferation, and propose Rad18 as a key target to sensitize GBM to therapy.
Unveiling the potential of neuron-targeted dendriplexes for siRNA delivery using a PNS-CNS-on-Chip
Authors: Spencer Ana P. , Xavier Miguel , Guimarães Sofia C. , Vilaça Adriana , Ionescu Ariel , Santos Rafael , Lázaro María , Perlson Eran , Leiro Victoria , Maoz Ben M. , Pêgo Ana P. 
Published: September 2024

AbstractNeurological disorders, a leading global cause of death, encompass conditions affecting the peripheral and central nervous systems (PNS and CNS, respectively). Limited axon regeneration is a significant challenge in these disorders, and it is linked to proteins like PTEN. RNA-based therapeutics, particularly siRNAs, hold potential for silencing these inhibitory pathways, but their clinical application is hindered by poor stability and cellular uptake. Our study addressed this challenge with the development of novel, fully biodegradable dendritic nanoparticles designed specifically for neuron targeting. These nanoparticles were functionalized with the neurotropic binding domain of tetanus toxin, enhancing selective neuronal targeting and cellular internalization. We demonstrated that these dendriplexes not only maintain biocompatibility and efficient siRNA delivery in neuronal cultures but also significantly enhance axonal growth, as shown in microfluidic models. In a groundbreaking PNS-CNS-on-Chip, dendriplexes exhibited effective migration from PNS to CNS neurons, highlighting their potential for targeted therapeutic delivery. This study pioneers the application of microfluidics to demonstrate the CNS targeting of dendriplexes, paving the way for innovative treatments in the field of nanomedicine.
Harmonization of Structural Brain Connectivity through Distribution Matching
Authors: Zhou Zhen , Fischl Bruce , Aganj Iman 
Published: September 2024

AbstractThe increasing prevalence of multi-site diffusion-weighted magnetic resonance imaging (dMRI) studies potentially offers enhanced statistical power for investigating brain structure. However, these studies face challenges due to variations in scanner hardware and acquisition protocols. While several methods exist for dMRI data harmonization, few specifically address structural brain connectivity. We introduce a new distribution-matching approach to harmonizing structural brain connectivity across different sites and scanners. We evaluate our method using structural brain connectivity data from two distinct datasets of OASIS-3 and ADNI-2, comparing its performance to the widely used ComBat method. Our approach is meant to align the statistical properties of connectivity data from these two datasets. We examine the impact of harmonization on the correlation of brain connectivity with the Mini-Mental State Examination score and age. Our results demonstrate that our distribution-matching technique more effectively harmonizes structural brain connectivity, often producing stronger and more significant correlations compared to ComBat. Qualitative assessments illustrate the desired distributional alignment of ADNI-2 with OASIS-3, while quantitative evaluations confirm robust performance. This work contributes to the growing field of dMRI harmonization, potentially improving the reliability and comparability of structural connectivity studies that combine data from different sources in neuroscientific and clinical research.
Imputed DNA methylation outperforms measured loci associations with smoking and chronological age
Authors: Richmond Anne , Mur Jure , Harris Sarah E , Corley Janie , Elliott Hannah R , Foley Christopher N , Hannon Eilis , Kuncheva Zhana , Min Josine L , Moqri Mahdi , Ndiaye Magatte , Sun Benjamin B , Vallejos Catalina A , Ying Kejun , Gladyshev Vadim N , Cox Simon R , McCartney Daniel L , Marioni Riccardo E 
Published: September 2024

AbstractMulti-locus signatures of blood-based DNA methylation are well-established biomarkers for lifestyle and health outcomes. Here, we focus on two CpGs that are strongly associated with age and smoking behaviour. Imputing these loci via epigenome-wide CpGs results in stronger associations with outcomes in external datasets compared to directly measured CpGs. If extended epigenome-wide, CpG imputation could augment historic arrays and recently-released, inexpensive but lower-content arrays, thereby yielding better-powered association studies.
Synthetic metabolic pathways for ethylene glycol assimilation outperform natural counterparts
Authors: Feigis Michelle , Mahadevan Radhakrishnan 
Published: September 2024

AbstractBiomanufacturing can play a pivotal role in the transition away from fossil fuel dependence for the production of chemicals and fuels. There is growing interest in alternative bioproduction feedstocks to conventional sugars that do not compete for land use with food production. Ethylene glycol, a C2 compound that can be recovered from plastic waste or derived from CO2with increasing efficiency, is gaining attention as a carbon source for microbial processes. Here we review the natural and synthetic metabolic pathways currently available for ethylene glycol assimilation. The pathways are compared in terms of their maximum theoretical yields for biomass and value-added products, thermodynamic favourability, minimum enzyme costs, and orthogonality to central carbon metabolism. We find that synthetic pathways outperform their natural counterparts in terms of higher thermodynamic driving forces, reduced enzyme costs, and higher theoretical yields for the majority of bioproducts analyzed as well as for biomass. However, natural assimilation pathways are equally or even more orthogonal to growth-associated reactions than synthetic pathways. Given these tradeoffs, the optimal EG assimilation pathway may depend on product and process choice.
Enhanced CRISPR/Cas-Based Immunoassay through Magnetic Proximity Extension and Detection
Authors: Shao Fangchi , Hu Jiumei , Zhang Pengfei , Akarapipad Patarajarin , Park Joon Soo , Lei Hanran , Hsieh Kuangwen , Wang Tza-Huei 
Published: September 2024

AbstractClustered regularly interspaced short palindromic repeats (CRISPR)/Cas-associated systems have recently emerged as a focal point for developing next-generation molecular diagnosis, particularly for nucleic acid detection. However, the detection of proteins is equally critical across diverse applications in biology, medicine, and the food industry, especially for diagnosing and prognosing diseases like cancer, Alzheimer’s and cardiovascular conditions. Despite recent efforts to adapt CRISPR/Cas systems for protein detection with immunoassays, these methods typically achieved sensitivity only in the femtomolar to picomolar range, underscoring the need for enhanced detection capabilities. To address this, we developed CRISPR-AMPED, an innovative CRISPR/Cas-based immunoassay enhanced by magnetic proximity extension and detection. This approach combines proximity extension assay (PEA) with magnetic beads that converts protein into DNA barcodes for quantification with effective washing steps to minimize non-specific binding and hybridization, therefore reducing background noise and increasing detection sensitivity. The resulting DNA barcodes are then detected through isothermal nucleic acid amplification testing (NAAT) using recombinase polymerase amplification (RPA) coupled with the CRISPR/Cas12a system, replacing the traditional PCR. This integration eliminates the need for thermocycling and bulky equipment, reduces amplification time, and provides simultaneous target and signal amplification, thereby significantly boosting detection sensitivity. CRISPR-AMPED achieves attomolar level sensitivity, surpassing ELISA by over three orders of magnitude and outperforming existing CRISPR/Cas-based detection systems. Additionally, our smartphone-based detection device demonstrates potential for point-of-care applications, and the digital format extends dynamic range and enhances quantitation precision. We believe CRISPR-AMPED represents a significant advancement in the field of protein detection.
Residence Times and Legacy of Biogenic Carbon in Ocean Reservoirs
Authors: Visser André W. 
Published: September 2024

Quantifying the sequestration potential of biologically driven carbon fluxes in the ocean depends critically on residence times – how long carbon remains stored in reservoirs before being re-exposed to the atmosphere. Simple mass balance provides estimates for many of the major ocean biogenic carbon reservoirs. For vegetated coastal ecosystems (mangroves, sea grass meadows, salt marshes) that globally store 20 to 40 PgC, this is 200 to 500 years, while for the biological carbon pump, a reservoir of about 2000 PgC, it is between 200 to 800 years. Over these time scales respective reservoirs reach equilibrium if left undisturbed. Importantly, near equilibrium of ocean reservoirs during the Holocene can be inferred from the near steady atmospheric concentrations during this period. The degradation of habitats and the over-exploitation of living marine resources particularly in the last 75 years have tipped these natural processes out of balance, to the extent where many are now net emitters of legacy carbon back to the atmosphere. The analysis exposes a conflict between how sequestration is reported in oceanographic literature and how it is understood with regards durable carbon capture and storage. Nature-based solutions can be sought to address parts of the climate crisis, by improving ecosystem health and biodiversity, but are unlikely to provide solutions to carbon management on a scale commensurate with anthropogenic emissions. The best we can do is to limit net emissions by restoring what we can, and to ensure that future practices do not further tip ocean carbon reservoirs out of balance.Significance StatementMarine animals and plants maintain large pools of carbon in the ocean and coastal areas that have been laid down by generations past. This legacy carbon is continuously being recycled on time scales of 100s of years. Left undisturbed, as they were for most of the last 10000 years, these carbon pools tend to equilibrium; flux in equals flux out. Human activities such as over fishing and coastal construction, particularly in the past 75 years, have tipped these natural cycles out of balance to the extent where many pools are now net emitters of carbon. Conservation and restoration of marine habitats can bring these cycles back into balance but cannot be counted as offsetting fossil fuel emissions.
Nested inference of pairwise interactions from strain frequency data across settings and context-dependent mutual invasibilities
Authors: Le Thi Minh Thao , Madec Sten , Gjini Erida 
Published: September 2024

AbstractHow does coexistence of multiple species or pathogen strains arise in a system? What do coexistence patterns in time and space reveal about the epidemiology, ecology and evolution of such systems? Species abundance patterns often defy fully mechanistic explanations, especially when compositional variation and relative taxa abundances differ across settings. To link such variation to deterministic biological processes in acause-and-effectfashion requires modeling frameworks that are general in spirit, simple enough to understand and implement, and easily-applicable to multi-site data and their environmental gradients. Here, we propose a method to study variation in serotype frequencies ofStreptococcus pneumoniaebacteria across different geographic endemic settings. We use the framework of replicator dynamics, derived for a multi-strainSISmodel with co-colonization, to extract from 5 countries data fundamental parameters of inter-strain interactions, based on pairwise invasion fitnesses and their context-dependence. We integrate serotype frequency distributions and serotype identities (SAD + identities) collected from cross-sectional epidemiological surveys in Denmark, Nepal, Iran, Brazil and Mozambique. The snapshot observations are modelled under the same nested framework, by which we present a rationale for mechanistically linking and fitting multi-strain distributions across sites. Besides yielding an effective numerical estimation for more than 70% of the 92 × 92 (αij) in the pneumococcus serotype interaction matrix, this study offers a new proof-of-concept in the inference of random multi-species interactions. We show that in pneumococcus the vast majority of standardized interaction coefficients in co-colonization are concentrated near zero, with a few serotype pairs displaying extreme deviations from the mean. This statistical pattern confirms that the co-colonization coefficients in pneumococcus display a random probability distribution governed by a limited set of parameters, which are slightly modulated in each epidemiological context to shape coexistence. We also discuss key assumptions that must be carefully balanced in the estimation procedure. Our study paves the way for a deeper qualitative and quantitative understanding of the high-dimensional interaction landscape in multi-strain co-colonization systems.
Glia multitask to compensate for neighboring glial cell dysfunction
Authors: Beachum Allison N. , Salazar Gabriela , Nachbar Amelia , Krause Kevin , Klose Hannah , Meyer Kate , Maserejian Ariana , Ross Grace , Boyd Hannah , Weigel Thaddeus , Ambaye Lydia , Miller Hayes , Coutinho-Budd Jaeda 
Published: September 2024

SummaryAs glia mature, they undergo glial tiling to abut one another without invading each other’s boundaries. Upon the loss of the secreted neurotrophin Spätzle3 (Spz3),Drosophilacortex glia transform morphologically and lose their intricate interactions with neurons and surrounding glial subtypes. Here, we reveal that all neighboring glial cell types (astrocytes, ensheathing glia, and subperineurial glia) react by extending processes into the previous cortex glial territory to compensate for lost cortex glial function and reduce the buildup of neuronal debris. However, the loss of Spz3 alone is not sufficient for glia to cross their natural borders, as blocking CNS growth via nutrient-restriction blocks the aberrant infiltration induced by the loss of Spz3. Surprisingly, even when these neighboring glia divert their cellular resources beyond their typical borders to take on new compensatory roles, they are able to multitask to continue to preserve their own normal functions to maintain CNS homeostasis.Graphical Abstract
BayesQuantify: an R package utilized to refine the ACMG/AMP criteria according to the Bayesian framework
Authors: Liu Sihan , Feng Xiaoshu , Bu Fengxiao 
Published: September 2024

AbstractImproving the precision and accuracy of variant classification in clinical genetic testing involves further specification and stratification of the ACMG/AMP criteria. The Bayesian framework proposed by ClinGen has provided a mathematical foundation for evidence refinement, successfully quantifying, and extending the evidence strengths of PS1, PS4, PM5, and PP3/BP4. However, existing software and tools designed for quantifying the evidence strength and establishing corresponding thresholds to refine the ACMG/AMP criteria are lacking. To address this gap, we have developedBayesQuantify, an R package that aims to provide users with a unified resource for quantifying the strength of evidence for ACMG/AMP criteria using a naive Bayes classifier. By analyzing publicly available data, we demonstrateBayesQuantify’s capability to offer objective and consistent refinement of the ACMG/AMP evidence. BayesQuantify is available from GitHub athttps://github.com/liusihan/BayesQuantify.
Adipocyte progenitors are primary contributors to the disrupted epithelial niche that is sustained following abrupt mammary gland involution
Authors: Nuthalapati Prashant , Maiti Dibyo , Kwende Sharon A. , Maity Subhajit , Ning Dun , Joshi Purna A. 
Published: September 2024

SummaryA short duration of breastfeeding is a risk factor for the development of high-mortality, postpartum, triple-negative breast cancer. The intrinsic properties of cancer-initiating epithelial cells that persist following breastfeeding cessation and mammary gland remodeling are poorly understood. Previously, we showed that Platelet-Derived Growth Factor Receptor alpha (PDGFRα)-expressing stromal mammary adipocyte progenitors (MAPs) differentiate into epithelial luminal progenitors in the adult gland. In the current study, we demonstrate that MAP-derived luminal progenitors retain a mesenchymal transcriptomic signature. In an abrupt involution model that mimics a short breastfeeding duration, MAP-derived luminal progenitors persist and dominate luminal epithelia, undergoing transcriptomic alterations that signify a distinct ferrometabolic state linked to cancer. Concurrently, MAPs adopt an alternative interferon-mediated profibrotic and invasive stromal fate. Our work uncovers MAPs to be the primary cellular origin of a pathological stromal and epithelial microenvironment following abrupt involution, presenting a potential therapeutic target in postpartum breast cancer.
Mitochondrial complex I deficiency occurs in skeletal muscle of a subgroup of individuals with Parkinson’s disease
Authors: Kverneng Simon Ulvenes , Stige Kjersti Eline , Berven Haakon , Mostafavi Sepideh , Lundervold Katarina , Brischigliaro Michele , Brakedal Brage , Skeie Geir Olve , Flønes Irene Hana , Toker Lilah , Fernandez-Vizarra Erika , Skogseth Ragnhild Eide , Haugarvoll Kristoffer , Torres Cleuren Yamila N , Dölle Christian , Nido Gonzalo S , Tzoulis Charalampos 
Published: September 2024

AbstractWidespread neuronal complex I (CI) deficiency was recently reported to be a characteristic in a subgroup of individuals with idiopathic Parkinson’s disease (PD). Here, we sought to determine whether a CI deficient subgroup could be discerned using clinically accessible muscle biopsy. Vastus lateralis needle biopsies were collected from 83 individuals with PD and 29 neurologically healthy controls and analyzed by immunohistochemistry for complexes I and IV, cytochrome c oxidase/succinate dehydrogenase (COX/SDH) histochemistry, and spectrophotometric activity assays of complexes I-IV. Mitochondrial DNA (mtDNA) copy number, deletions, and point variation were analyzed in single muscle fibers and bulk biopsy samples. PD muscle exhibited reduced CI activity at the group level, with 9% of cases falling below two standard deviations of the control group. This deficiency was not associated with mtDNA abnormalities. Our findings support the existence of a PD subpopulation characterized by CI pathology and suggest that stratification by extra-neural mitochondrial dysfunction may be informative for selecting individuals for clinical trials.