bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell type-specific effects of age and sex on human cortical neurons
Authors: Chien Jo-Fan , Liu Hanqing , Wang Bang-An , Luo Chongyuan , Bartlett Anna , Castanon Rosa , Johnson Nicholas D. , Nery Joseph R. , Osteen Julia , Li Junhao , Altshul Jordan , Kenworthy Mia , Valadon Cynthia , Liem Michelle , Claffey Naomi , O’Connor Caz , Seeker Luise A , Ecker Joseph R. , Behrens M. Margarita , Mukamel Eran A. 
Published: November 2023

SummaryExcitatory and inhibitory neurons establish specialized identities early in life through cell type-specific patterns of epigenetic regulation and gene expression. Although cell types are largely stable throughout the lifespan, altered transcriptional and epigenetic regulation may contribute to cognitive changes with advanced age. Using single-nucleus multiomic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex samples from young adult and aged donors, we found widespread age- and sex-related variability in specific neuronal cell types. The proportion of GABAergic inhibitory cells, including SST and VIP expressing cells, was reduced in aged donors. On the other hand, excitatory neurons had more profound age-related changes in their gene expression and DNA methylation compared with inhibitory cells. Hundreds of genes involved in synaptic activity were downregulated, while genes located in subtelomeric regions were upregulated with age and anti-correlated with telomere length. We further mapped sex differences in autosomal gene expression and escape from X-inactivation in specific neuron types. Multiomic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.
Single-Channel EEG Artifact Identification with the Spectral Slope
Authors: Fasol Melissa C. M. , Escudero Javier , Gonzalez-Sulser Alfredo 
Published: November 2023

AbstractElectroencephalogram (EEG) signals are a valuable recording technique to diagnose neurological disorders and identify noninvasive biomarkers for clinical application, however, they are vulnerable to various artifacts. It is difficult to define exact parameters which efficiently distinguish artifacts from neural activity, and thus cleaning EEG data often relies on labor-intensive visual scoring methods. While signal processing techniques to remove artifacts exist, many state-of- the-art techniques are designed for multivariate signals, which can be challenging to implement in recording setups with few electrodes. We demonstrate how the spectral slope - a method previously used to distinguish between conscious states by linear regression of the logarithmic EEG power spectra - can also be used to identify epochs contaminated by recording artifacts in rat EEG recordings and propose this as a first pass artifact detection method. We computed the mean spectral slope for both ‘clean’ and ‘noisy’ epochs and compared the distributions among individual recordings to determine whether the decision threshold should be dynamic or fixed. We found no significant difference between the mean of these distributions and determined that a spectral slope threshold of -8μV2/Hzwas effective at identifying noisy epochs across all recordings. The accuracy of our method was evaluated against visually scored recordings and obtained an average accuracy, F1 and Cohen Kappa score of 94.2%, 86.4%, and 83%, respectively, across all epochs. Our study contributes to the automation of EEG artifact detection by presenting a straightforward initial method for identifying contaminated epochs based on the spectral slope of a single EEG channel in rodent recordings.
Novel loading protocol combines highly efficient encapsulation of exogenous therapeutic toxin with preservation of extracellular vesicles properties, uptake and cargo activity
Authors: Zuppone Stefania , Zarovni Natasa , Noguchi Kosuke , Loria Francesca , Morasso Carlo , Lohmus Andres , Nakase Ikuhiko , Vago Riccardo 
Published: November 2023

AbstractExtracellular vesicles (EVs) have mostly been investigated as carriers of biological therapeutics such as proteins and RNA. Nevertheless, small-molecule drugs of natural or synthetic origin have also been loaded into EVs, resulting in an improvement of their therapeutic properties. A few methods have been employed for EV cargo loading, but poor yield and drastic modifications of vesicles remain unsolved challenges. We tested a different strategy based on temporary pH alteration through incubation of EVs with alkaline sodium carbonate, which resulted in conspicuous exogenous molecule incorporation. In-depth characterization showed that vesicle size, morphology, composition, and uptake were not affected. Our method was more efficient than gold-standard electroporation, particularly for a potential therapeutic toxin: the plant Ribosome Inactivating Protein saporin. The encapsulated saporin resulted protected from degradation, and was efficiently conveyed to receiving cancer cells and triggered cell death. EV-delivered saporin was more cytotoxic compared to the free toxin. This approach allows both the structural preservation of vesicle properties and the transfer of protected cargo in the context of drug delivery.
Leveraging whole genome sequencing to promote genetic diversity and population health in zoo-housed western lowland gorillas
Authors: Gorzynski J. E. , Danforth M. D. , Strong V. , Kutinsky I. , Murphy H. , Lowenstine L. , Priest J. R. , Ashley E. A. 
Published: November 2023

AbstractThe sustainability of zoo populations is dependent on maintaining genetic diversity and controlling heritable disease. Here, we explore the integration of whole genome sequencing data in the management of the international zoological population of western lowland gorillas, focusing on genetic diversity and heritable diseases. By comparing kinship values derived from classical pedigree mapping and whole genome sequencing, we demonstrate that genomic data provides a more sensitive measure of relatedness. Our analysis reveals a decrease in genetic diversity due to closed breeding, emphasizing the potential for genetic intervention to mitigate negative impact on population fitness. We identify contributing factors to the decreasing genetic diversity including breeding within a closed population, unknown kinship among potential mates, and disproportionate genetic contributions from individual founders. Additionally, we highlight idiopathic myocardial fibrosis (IMF), a common cardiovascular pathology observed in zoologically housed gorillas, and identify a novel genetic variant in the TNNI3K gene that appears to be associated with this condition. These findings underscore the importance of incorporating molecular data into ex-situ population management strategies, and advocate for the adoption of advanced genomic techniques to optimize the genetic health and diversity of zoologically housed western lowland gorillas.
Transcriptomic landscape ofseedstickinArabidopsis thalianafuniculus after fertilisation
Authors: Ferreira Maria João , Silva Jessy , Takeuchi Hidenori , Suzuki Takamasa , Higashiyama Tetsuya , Coimbra Sílvia 
Published: November 2023

AbstractIn Angiosperms, the continuation of plant species is intricately dependent on the funiculus multifaceted role in nutrient transport, mechanical support, and dehiscence of seeds. SEEDSTICK (STK) is a MADS-box transcription factor involved in seed size and dehiscence, and one of the few genes identified as affecting funiculus growth. Given the importance of the funiculus to a correct seed development, allied with previous phenotypic observations ofstkmutants, we performed a transcriptomic analysis ofstkfuniculi, using RNA-sequencing, to infer on the deregulated networks of genes. The generated dataset of differentially expressed genes was enriched with cell wall biogenesis, cell cycle, sugar metabolism and transport terms, all in accordance withstkphenotype. We selected eight differentially expressed genes involved with abscission, seed development or novel functions instkfuniculus, such as hormones/secondary metabolites transport, for transcriptome validation using qPCR and/or promoter reporter lines. Overall, the analysis performed in this study allowed delving into the STK-network established in Arabidopsis funiculus, fulfilling a literature gap. Simultaneously, our findings reinforced the reliability of the transcriptome, and identified processes and new candidate genes that will enable a better understanding on the role of this sporophytic structure and how seed development may be affected by it.
Synthesis of Dendritic Cell-Targeted Polymeric Nanoparticles for Selective Delivery of mRNA Vaccines to Elicit Enhanced Immune Responses
Authors: Fan Chen-Yo , Wang Szu-Wen , Chung Cinya , Chen Chia-Yen , Chang Chia-Yen , Chen Yu-Chen , Hsu Tsui-Ling , Cheng Ting-Jen R. , Wong Chi-Huey 
Published: November 2023

ABSTRACTRecent development of SARS-CoV-2 spike mRNA vaccines to control the pandemic is a breakthrough in the field of vaccine development. mRNA vaccines are generally formulated with lipid nanoparticles (LNPs) which are composed of several lipids with specific ratios; however, they generally lack selective delivery. To develop a simpler method selective delivery of mRNA, we reported here the synthesis of biodegradable copolymers decorated with guanidine and zwitterionic groups and an aryltrimannoside ligand as polymeric nanoparticles (PNPs) for encapsulation and selective delivery of an mRNA to dendritic cells (DCs). A representative DC-targeted SARS-CoV-2 spike mRNA-PNP vaccine was shown to elicit a stronger protective immune response in mice as compared to the mRNA-LNP and mRNA-PNP vaccines without the selective delivery design. It is anticipated that this technology will be generally applicable to development of DC-targeted mRNA vaccines with enhanced immune response.TOCDendritic cell-targeted mRNA-PNP vaccines
Loss of cis-PTase function in the liver promotes a highly penetrant form of fatty liver disease that rapidly transitions to hepatocellular carcinoma
Authors: Singh Abhishek K. , Chaube Balkrishna , Citrin Kathryn M , Fowler Joseph Wayne , Lee Sungwoon , Catarino Jonatas , Knight James , Lowery Sarah , Shree Sonal , Boutagy Nabil , Ruz-Maldonado Inmaculada , Harry Kathy , Shanabrough Marya , Ross Trenton Thomas , Malaker Stacy , Suárez Yajaira , Fernández-Hernando Carlos , Grabinska Kariona , Sessa William C. 
Published: November 2023

AbstractObesity-linked fatty liver is a significant risk factor for hepatocellular carcinoma (HCC)1,2; however, the molecular mechanisms underlying the transition from non-alcoholic fatty liver disease (NAFLD) to HCC remains unclear. The present study explores the role of the endoplasmic reticulum (ER)-associated protein NgBR, an essential component of the cis-prenyltransferases (cis-PTase) enzyme3, in chronic liver disease. Here we show that genetic depletion of NgBR in hepatocytes of mice (N-LKO) intensifies triacylglycerol (TAG) accumulation, inflammatory responses, ER/oxidative stress, and liver fibrosis, ultimately resulting in HCC development with 100% penetrance after four months on a high-fat diet. Comprehensive genomic and single cell transcriptomic atlas from affected livers provides a detailed molecular analysis of the transition from liver pathophysiology to HCC development. Importantly, pharmacological inhibition of diacylglycerol acyltransferase-2 (DGAT2), a key enzyme in hepatic TAG synthesis, abrogates diet-induced liver damage and HCC burden in N-LKO mice. Overall, our findings establish NgBR/cis-PTase as a critical suppressor of NAFLD-HCC conversion and suggests that DGAT2 inhibition may serve as a promising therapeutic approach to delay HCC formation in patients with advanced non-alcoholic steatohepatitis (NASH).
Human Papillomavirus 16 replication converts SAMHD1 into a homologous recombination factor and promotes its recruitment to replicating viral DNA
Authors: James Claire D. , Youssef Aya , Prabhakar Apurva T. , Otoa Raymonde , Witt Austin , Lewis Rachel L. , Bristol Molly L. , Wang Xu , Zhang Kun , Li Renfeng , Morgan Iain M. 
Published: November 2023

AbstractWe have demonstrated that SAMHD1 (sterile alpha motif and histidine-aspartic domain HD-containing protein 1) is a restriction factor for the HPV16 life cycle. Here we demonstrate that in HPV negative cervical cancer C33a cells and human foreskin keratinocytes immortalized by HPV16 (HFK+HPV16), SAMHD1 is recruited to E1-E2 replicating DNA. Homologous recombination (HR) factors are required for HPV16 replication and viral replication promotes phosphorylation of SAMHD1, which converts it from a dNTPase to an HR factor independent from E6/E7 expression. A SAMHD1 phosphor-mimic (SAMHD1 T592D) reduces E1-E2 mediated DNA replication in C33a cells and has enhanced recruitment to the replicating DNA. In HFK+HPV16 cells SAMHD1 T592D is recruited to the viral DNA and attenuates cellular growth, but does not attenuate growth in isogenic HFK cells immortalized by E6/E7 alone. SAMHD1 T592D also attenuates the development of viral replication foci following keratinocyte differentiation. The results indicated that enhanced SAMHD1 phosphorylation could be therapeutically beneficial in cells with HPV16 replicating genomes. Protein phosphatase 2A (PP2A) can dephosphorylate SAMHD1 and PP2A function can be inhibited by endothall. We demonstrate that endothall reduces E1-E2 replication and promotes SAMHD1 recruitment to E1-E2 replicating DNA, mimicking the SAMHD1 T592D phenotypes. Finally, we demonstrate that in head and neck cancer cell lines with HPV16 episomal genomes endothall attenuates their growth and promotes recruitment of SAMHD1 to the viral genome. The results suggest that targeting cellular phosphatases has therapeutic potential for the treatment of HPV infections and cancers.ImportanceHuman papillomaviruses are causative agents in around 5% of all human cancers. The development of anti-viral therapeutics depends upon an increased understanding of the viral life cycle. Here we demonstrate that HPV16 replication converts SAMHD1 into an HR factor via phosphorylation. This phosphorylation promotes recruitment of SAMHD1 to viral DNA to assist with replication. A SAMHD1 mutant that mimics phosphorylation is hyper-recruited to viral DNA and attenuates viral replication. Expression of this mutant in HPV16 immortalized cells attenuates the growth of these cells, but not cells immortalized by the viral oncogenes E6/E7 alone. Finally, we demonstrate that the phosphatase inhibitor endothall promotes hyper-recruitment of endogenous SAMHD1 to HPV16 replicating DNA and can attenuate the growth of both HPV16 immortalized human foreskin keratinocytes and HPV16 positive head and neck cancer cell lines. We propose that phosphatase inhibitors represent a novel tool for combating HPV infections and disease.
MERS-Coronavirus across Kenya: a spatial examination of social and environmental drivers
Authors: Lawrence Ted J. , Kangogo Geoffrey , Fredman Avery , Deem Sharon L. , Fèvre Eric M. , Gluecks Ilona , Brien James D. , Shacham Enbal 
Published: November 2023

AbstractClimate and agricultural land-use change have increased the likelihood of infectious disease emergence and transmissions, but these drivers are often examined separately as synergistic effects are ignored. Further, seldom are the influence of climate and agricultural land use on emerging infectious diseases examined in a spatially explicit way at regional scales.Our objective in this study was to spatially examine the climate, agriculture, and socio-demographic factors related to agro-pastoralism that can influence the prevalence of Middle East Respiratory Syndrome coronavirus (MERS-CoV) in dromedary camels across northern Kenya. Our research questions were: 1) how has MERS-CoV in dromedary camels varied across geographic regions of northern Kenya, and 2) what climate, agriculture, and socio-demographic factors of agro-pastoralism were spatially related to the geographic variation in MERS-CoV cases? To answer our questions, we analyzed the spatial distribution of historical cases of serological evidence of MERS-CoV at the county level and applied spatial statistical analysis to examine the spatial relationships of the MERS-CoV cases between 2016 and 2018 to climate, agriculture, and socio-demographic factors of agro-pastoralism.Regional differences in MERS-CoV cases were spatially correlated with both social and environmental factors and highlight the complexity in the distribution of MERS-CoV in dromedary camels across Kenya.
Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolemia: an expert consensus statement from ERKNet and ESPN
Authors: Reijman M. Doortje , Kusters D. Meeike , Groothoff Jaap W. , Arbeiter Klaus , Dann Eldad J. , de Boer Lotte M. , de Ferranti Sarah D. , Gallo Antonio , Greber-Platzer Susanne , Hartz Jacob , Hudgins Lisa C. , Ibarretxe Daiana , Kayikcioglu Meral , Klingel Reinhard , Kolovou Genovefa D. , Oh Jun , Planken R. Nils , Stefanutti Claudia , Taylan Christina , Wiegman Albert , Schmitt Claus Peter 
Published: November 2023

AbstractHomozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid- lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid- lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is well established since three decades, lowering serum LDL-C levels by more than 70% per session. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment targets and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.
Exploring priority and year effects on plant diversity, productivity and vertical root distribution: first insights from a grassland field experiment
Authors: Alonso-Crespo Inés M. , Temperton Vicky M. , Fichtner Andreas , Niemeyer Thomas , Schloter Michael , Delory Benjamin M. 
Published: November 2023

AbstractThe order of arrival of plant species during community assembly can affect how species interact with each other. These so-called priority effects can have strong implications for the structure and functioning of plant communities. However, the extent to which the strength, direction, and persistence of priority effects are modulated by weather conditions during plant establishment (‘year effects’) is not well known.Here we present the first results from a long-term field experiment (POEM: PriOrity Effects Mechanisms) initiated in 2020 in Northern Germany to test how plant functional group (PFG) order of arrival and the year of initiation of an experiment interactively affect the structure and functioning of nutrient-poor dry acidic grasslands, both above and belowground. To do this, we established the same experiment, manipulating the order of arrival of forbs, grasses and legumes on the same site, but in different years.We found that time since establishment was a stronger driver of plant community composition than PFG order of arrival and year of initiation. These three factors interactively affected plant species diversity, with the effect of PFG order of arrival on plant species richness depending on time since establishment. Year of initiation, not PFG order of arrival, was the strongest driver of aboveground community productivity. Although we did not find any effect of PFG order of arrival on root productivity, it had a strong impact on the vertical distribution of roots. Communities where grasses were sown first rooted more shallowly than communities in which forbs or legumes were sown first.Synthesis: Our results demonstrate that plant order of arrival and year effects jointly affect plant diversity and species composition, with time since establishment also playing an important role. While year effects were more important than plant order of arrival in modulating aboveground biomass production in our nutrient-poor grassland, we showed that plant order of arrival can strongly affect the vertical distribution of roots, with communities in which forbs or legumes were sown first rooting deeper than grasses-first communities. These results suggest that a deeper understanding of priority and year effects is needed to better predict restoration outcomes.
The effect of antibiotic selection on collateral effects and evolvability of uropathogenicEscherichia coli
Authors: James Beth , Reesaul Hishikha , Kashif Sidra , Behruznia Mahboobeh , Meehan Conor J. , Domingo-Sananes Maria Rosa , Hubbard Alasdair T. M. 
Published: November 2023

AbstractTrimethoprim is recommended as a first-line treatment of urinary tract infections (UTIs) in the UK. In 2018, 31.4% ofEscherichia coliisolated from UTIs in England were trimethoprim resistant, leading to overreliance on other first and second-line antibiotics. Here, we assessed whether prior selection with trimethoprim results in collateral effects to other antibiotics recommended for the treatment of UTIs. As collateral effects, we considered changes in susceptibility, mutation-selection window and population establishment probability. We selected 10 trimethoprim-resistant derivatives from three clinical isolates of uropathogenicEscherichia coli.We found that mutations conferring trimethoprim resistance did not have any collateral effects to fosfomycin. In contrast, resistance to trimethoprim resulted in decreased susceptibility (collateral resistance) to nitrofurantoin, below the clinical breakpoint, and narrowed the mutation-selection window thereby reducing the maximum concentration for selection of nitrofurantoin resistance mutations. Our analyses demonstrate that multiple collateral responses should be accounted for when predicting and optimising antibiotic use, limiting future AMR emergence.
Evidence that variation in root anatomy contributes to local adaptation in Mexican native maize
Authors: McLaughlin Chloee M. , Li Meng , Perryman Melanie , Heymans Adrien , Schneider Hannah , Lasky Jesse R. , Sawers Ruairidh J. H. 
Published: November 2023

ABSTRACTMexican native maize (Zea maysssp.mays) is adapted to a wide range of climatic and edaphic conditions. Here, we focus specifically on the potential role of root anatomical variation in this adaptation. In light of the investment required to characterize root anatomy, we present a machine learning approach using environmental descriptors to project trait variation from a relatively small training panel onto a larger panel of genotyped and georeferenced Mexican maize accessions. The resulting models defined potential biologically relevant clines across a complex environment and were used subsequently in genotype-environment association. We found evidence of systematic variation in maize root anatomy across Mexico, notably a prevalence of trait combinations favoring a reduction in axial conductance in cooler, drier highland areas. We discuss our results in the context of previously described water-banking strategies and present candidate genes that are associated with both root anatomical and environmental variation. Our strategy is a refinement of standard environmental genome wide association analysis that is applicable whenever a training set of georeferenced phenotypic data is available.