bluuebunny/crossref_metadata_2025_split huggingface dataset:
The influence of early moderate prenatal alcohol exposure and maternal diet on offspring DNA methylation: a cross-species study
Authors: Bestry Mitchell , Larcombe Alexander N. , Kresoje Nina , Chivers Emily K , Bakker Chloe , Fitzpatrick James P , Elliott Elizabeth J , Craig Jeffrey M , Muggli Evelyne , Halliday Jane , Hutchinson Delyse , Buckberry Sam , Lister Ryan , Symons Martyn , Martino David 
Published: June 2023

AbstractAlcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy in humans. Early moderate PAE was sufficient to affect site-specific DNA methylation in new-born pups without altering behavioural outcomes in adult littermates. Whole-genome bisulfite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. DNA methylation differences were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. In our murine model, a maternal diet high in folate and choline protected against some of the damaging effects of early moderate PAE on DNA methylation. Our studies demonstrate that early moderate exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions.
Using CombiCells, a platform enabling titration and combinatorial display of cell surface ligands, to study T cell antigen sensitivity by TCRs, CARs, and BiTEs
Authors: Patel Ashna , Andre Violaine , Eguiguren Sofia Bustamante , Barton Michael I. , Burton Jake , Denham Eleanor M. , Pettmann Johannes , Mørch Alexander M , Kutuzov Mikhail A. , Siller-Farfán Jesús A. , Dustin Michael L. , van der Merwe P. Anton , Dushek Omer 
Published: June 2023

AbstractUnderstanding how cellular decisions by receptor/ligand interactions at cell/cell interface has been challenging because it is difficult to independently vary the surface density of multiple ligands. Here, we exploit the SpyCatcher/SpyTag split-protein system for rapid combinatorial display of native ligands on cells (Combicells). We use this platform to assess T cell antigen sensitivity and the impact of T cell co-stimulation/co-inhibition receptors. The TCR displayed much greater sensitivity to pMHC than CARs and BiTES did to CD19. While TCR sensitivity was greatly enhanced by CD2 ligand, CAR sensitivity to CD19 was primarily but more modestly enhanced by LFA-1 ligand. Lastly, we show that the PD-1/ligand engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor/ligand interactions at cell/cell interfaces.Graphical abstractOne sentence summaryUsing CombiCells, a platform for the combinatorial display of cell surface ligands, to compare T cell antigen sensitivity mediated by TCRs, CARs, and BiTEs and its dependence on co-stimulation/co-inhibition receptor ligands
The Plasminogen-Apple-Nematode (PAN) domain suppresses JA/ET defense pathways in plants
Authors: De Kuntal , Pal Debjani , Shanks Carly M. , Yates Timothy B. , Feng Kai , Jawdy Sara S. , Hassan Md Mahmudul , Prabhakar Pradeep K. , Yang Jeong-Yeh , Chapla Digantkumar , Moremen Kelley W. , Urbanowicz Breeanna , Binder Brad M , Muchero Wellington 
Published: June 2023

AbstractSuppression of immune response is a phenomenon that enables biological processes such as gamete fertilization, cell growth, cell proliferation, endophyte recruitment, parasitism, and pathogenesis. Here, we show for the first time that the Plasminogen-Apple-Nematode (PAN) domain present in G-type lectin receptor-like kinases is essential for immunosuppression in plants. Defense pathways involving jasmonic acid and ethylene are critical for plant immunity against microbes, necrotrophic pathogens, parasites, and insects. Using twoSalix purpureaG-type lectin receptor kinases, we demonstrated that intact PAN domains suppress jasmonic acid and ethylene signaling in Arabidopsis and tobacco. Variants of the same receptors with mutated residues in this domain could trigger induction of both defense pathways. Assessment of signaling processes revealed significant differences between receptors with intact and mutated PAN domain in MAPK phosphorylation, global transcriptional reprogramming, induction of downstream signaling components, hormone biosynthesis and resistance toBotrytis cinerea. Further, we demonstrated that the domain is required for oligomerization, ubiquitination, and proteolytic degradation of these receptors. These processes were completely disrupted when conserved residues in the domain were mutated. Additionally, we have tested the hypothesis in recently characterizedArabidopsismutant which has predicted PAN domain and negatively regulates plant immunity against root nematodes.ern1.1mutant complemented with mutated PAN shows triggered immune response with elevated WRKY33 expression, hyperphosphorylation of MAPK and resistant to necrotrophic fungusBotrytis cinerea. Collectively, our results suggest that ubiquitination and proteolytic degradation mediated by the PAN domain plays a role in receptor turn-over to suppress jasmonic acid and ethylene defense signaling in plants.
Histone binding of ASF1 is required for fruiting body development, but not for genome stability in the filamentous fungusSordaria macrospora
Authors: Breuer Jan , Busche Tobias , Kalinowski Jörn , Nowrousian Minou 
Published: June 2023

AbstractThe highly conserved eukaryotic histone chaperone ASF1 is involved in the assembly and disassembly of nucleosomes during transcription, DNA replication and repair. It was the first chaperone discovered to be involved in all three of these processes. The filamentous fungusSordaria macrosporais one of only two multicellular organisms whereasf1deletions are viable, which makes it useful forin vivoanalysis of this central regulator of eukaryotic chromatin structure. Deletion ofasf1inS. macrosporaleads to sterility, a reduction of DNA methylation, and upregulation of genes that are usually weakly expressed in the wild type. Here, we focused on the functions of the highly conserved core and the divergent C-terminal tail of ASF1, studied the effects of ASF1 on histone modifications and tested its relevance for genomic stability. By Co-IP and complementation analysis we showed that substitutions of amino acid V94 or truncations of the C-terminal tail abolish histone binding and do not complement the sterile mutant phenotype. Δasf1 is sensitive to the DNA damaging agent MMS, while complementation strains, even those with non-histone-binding variants, regain wild type-like resistance. To aid in subsequent ChIP-seq and Hi-C analyses, we generated a chromosome-resolved genome assembly ofS. macrospora. ChIP-Seq analysis revealed a global increase of H3K27me3 in Δasf1, accompanied by a global decrease of H3K56ac. By using Hi-C we detected a tandem duplication of around 600 kb on chromosome 2 in the mutant. Crossing experiments indicated linkage between the viability of Δasf1 strains and the presence of the duplication.ImportanceHistone chaperones are proteins that are involved in nucleosome assembly and disassembly and can therefore influence all DNA-dependent processes including transcription, DNA replication and repair. ASF1 is a histone chaperone that is conserved throughout eukaryotes. In contrast to most other multicellular organisms, a deletion mutant ofasf1in the fungusSordaria macrosporais viable; however, the mutant is sterile. In this study, we could show that the histone binding ability of ASF1 is required for fertility inS. macrospora, whereas the function of ASF1 in maintenance of genome stability does not require histone binding. We also showed that the histone modifications H3K27me3 and H3K56ac are misregulated in the Δasf1 mutant. Furthermore, we identified a large duplication on chromosome 2 of the mutant strain that is genetically linked to the Δasf1 allele present on chromosome 6, suggesting that viability of the mutant might depend on the presence of the duplicated region.
Transcriptome of left ventricle and sinoatrial node in young and old C57 mice
Authors: Qu Jia-Hua , Tarasov Kirill V. , Tarasova Yelena S. , Chakir Khalid , Lakatta Edward G. 
Published: June 2023

AbstractAdvancing age is the most important risk factor for cardiovascular diseases (CVDs). Two types of cells within the heart pacemaker, sinoatrial node (SAN), and within the left ventricle (LV) control two crucial characteristics of heart function, heart beat rate and contraction strength. As age advances, the heart’s structure becomes remodeled, and SAN and LV cell functions deteriorate, thus increasing the risk for CVDs. However, the different molecular features of age-associated changes in SAN and LV cells have never been compared in omics scale in the context of aging. We applied deep RNA sequencing to four groups of samples, young LV, old LV, young SAN and old SAN, followed by numerous bioinformatic analyses. In addition to profiling the differences in gene expression patterns between the two heart chambers (LV vs. SAN), we also identified the chamber-specific concordant or discordant age-associated changes in: (1) genes linked to energy production related to cardiomyocyte contraction, (2) genes related to post-transcriptional processing, (3) genes involved in KEGG longevity regulating pathway, (4) prolongevity and antilongevity genes recorded and curated in the GenAge database, and (5) CVD marker genes. Our bioinformatic analysis also predicted the regulation activities and mapped the expression of upstream regulators including transcription regulators and post-transcriptional regulator miRNAs. This comprehensive analysis promotes our understanding of regulation of heart functions and will enable discovery of gene-specific therapeutic targets of CVDs in advanced age.
Metal Ions and their Effects on Antimicrobial Resistance Development in Wastewater
Authors: Sutradhar Indorica , Kalyan Prinjali , Chukwu Kelechi , Abia Akebe Luther King , Mbanga Joshua , Essack Sabiha , Hamer Davidson H. , Zaman Muhammad H. 
Published: June 2023

AbstractAntimicrobial resistance (AMR) is a global health challenge and there is increasing recognition of the role of the environment, particularly wastewater, in the development and spread of AMR. Although trace metals are common contaminants in wastewater, the quantitative effects of trace metals on AMR in wastewater settings remain understudied. We experimentally determined the interactions between common antibiotic residues and metal ions found in wastewater and investigated their effects on the development of antibiotic resistance inEscherichia coliover time. These data were then used to expand on a previously developed computational model of antibiotic resistance development in continuous flow settings to incorporate the effects of trace metals acting in combination with multiple antibiotic residues. We found that the common metal ions, copper and iron, interact with both ciprofloxacin and doxycycline at wastewater relevant concentrations. This can significantly affect resistance development due to antibiotic chelation of the metal ions causing a reduction in the antibiotics’ bioactivity. Furthermore, modeling the effect of these interactions in wastewater systems showed the potential for metal ions in wastewater to significantly increase the development of antibiotic resistantE. colipopulations. These results demonstrate the need to quantitatively understand the effects of trace metal-antibiotic interactions on AMR development in wastewater.
QRS Detection by Rules Based Multiple Channel Combinatorial Optimization
Authors: Hopenfeld Bruce 
Published: June 2023

AbstractA multiple channel QRS detector is described. Separately for each channel, the detector generates sequences of peaks and statistically scores them according to: 1) peak prominence; 2) temporal regularity; 3) peak shape similarity; and 4) number of skipped beats. In the case of unstructured rhythms, the temporal regularity score is null and does not contribute to sequence quality. If at least one winning score from any channel exceeds a quality threshold, multi-channel sequences are generated from the winning sequences’ peaks and scored according to the above measures and peak time coherence across channels. The winning multi-channel sequence is then selected. The algorithm was applied to both channels of the MIT-BIH Arrhythmia Database. Over the entire database, the sensitivity (SE) and positive predictive value (PPV) were 99.93% and 99.96% respectively. For record 203, generally considered the most difficult one in the database, the SE and PPV were 99.80% and 99.76% respectively. The present algorithm fits within the framework of a previously described algorithm that can detect sinus rhythm in high noise conditions (e.g. waist based textile electrode recordings of a jogging subject).
Unbiased single-cell morphology with self-supervised vision transformers
Authors: Doron Michael , Moutakanni Théo , Chen Zitong S. , Moshkov Nikita , Caron Mathilde , Touvron Hugo , Bojanowski Piotr , Pernice Wolfgang M. , Caicedo Juan C. 
Published: June 2023

AbstractAccurately quantifying cellular morphology at scale could substantially empower existing single-cell approaches. However, measuring cell morphology remains an active field of research, which has inspired multiple computer vision algorithms over the years. Here, we show that DINO, a vision-transformer based, self-supervised algorithm, has a remarkable ability for learning rich representations of cellular morphology without manual annotations or any other type of supervision. We evaluate DINO on a wide variety of tasks across three publicly available imaging datasets of diverse specifications and biological focus. We find that DINO encodes meaningful features of cellular morphology at multiple scales, from subcellular and single-cell resolution, to multi-cellular and aggregated experimental groups. Importantly, DINO successfully uncovers a hierarchy of biological and technical factors of variation in imaging datasets. The results show that DINO can support the study of unknown biological variation, including single-cell heterogeneity and relationships between samples, making it an excellent tool for image-based biological discovery.
Arabidopsisand Maize Terminator Strength is Determined by GC Content, Polyadenylation Motifs and Cleavage Probability
Authors: Gorjifard Sayeh , Jores Tobias , Tonnies Jackson , Mueth Nicholas A , Bubb Kerry , Wrightsman Travis , Buckler Edward S , Fields Stanley , Cuperus Josh T , Queitsch Christine 
Published: June 2023

AbstractThe 3’ end of a gene, often called a terminator, modulates mRNA stability, localization, translation, and polyadenylation. Here, we adapted Plant STARR-seq, a massively parallel reporter assay, to measure the activity of over 50,000 terminators from the plantsArabidopsis thalianaandZea mays. We characterize thousands of plant terminators, including many that outperform bacterial terminators commonly used in plants. Terminator activity is species-specific, differing in tobacco leaf and maize protoplast assays. While recapitulating known biology, our results reveal the relative contributions of polyadenylation motifs to terminator strength. We built a computational model to predict terminator strength and used it to conductin silicoevolution that generated optimized synthetic terminators. Additionally, we discover alternative polyadenylation sites across tens of thousands of terminators; however, the strongest terminators tend to have a dominant cleavage site. Our results establish features of plant terminator function and identify strong naturally occurring and synthetic terminators.
Characterization of novel fungal-algal symbiosis on LDPE plastic surfaces in the Mediterranean Sea
Authors: Itzahri Sheli , Davidov Keren , Oren Matan 
Published: June 2023

AbstractPlastic debris in the ocean serves as a stable ground for the formation of a complex ecosystem, termed plastisphere, which includes a variety of organisms from different taxonomic groups. Not much is known about the relationships between the organisms of the plastisphere communities. In this study we describe a novel symbiotic relationship between a marine fungus and several species of diatoms on plastic surfaces that were submerged in the water of a Mediterranean Sea marina in Israel. Scanning electron microscope images of the surfaces revealed a network of fungal hyphae with multiple diatom cells attached to them via the side or the tip of their body. Using DNA metabarcoding for the fungal Internal Transcribed Spacer (ITS) barcode locus, we found that the symbiotic fungus belongs to the phylum Ascomycota, and that it is more abundant on low density polyethylene (LDPE) surfaces compared to other plastic polymers and glass. We hypothesize that the observed symbiotic relationship may have mutual benefits for both parties, including surface-anchoring for the diatoms and nutritional benefits for the fungus, that reflects a recent adaptation for life on floating plastic debris.
Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons
Authors: Monko Timothy R. , Tripp Emma H. , Burr Sierra E. , Gunderson Karina N. , Lanier Lorene M. , Georgieff Michael K. , Bastian Thomas W. 
Published: June 2023

AbstractBackgroundDeveloping neurons have high thyroid hormone and iron requirements to support their metabolism and growth. Early-life iron and thyroid hormone deficiencies are prevalent, often coexist, and increase the risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid hormone levels and impairs thyroid hormone-responsive gene expression in the neonatal rat brain.ObjectiveThis study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons.MethodsIron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 days in vitro (DIV). At 11DIV and 18DIV, mRNA levels for thyroid hormone-regulated genes indexing thyroid hormone homeostasis (Hr,Crym,Dio2,Slco1c1,Slc16a2) and neurodevelopment (Nrgn,Pvalb,Klf9) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures and gene expression and ATP levels were quantified at 21DIV.ResultsAt 11DIV and 18DIV, neuronal iron deficiency decreasedNrgn, Pvalb,andCrym, and by 18DIV,Slc16a2, Slco1c1, Dio2,andHrwere increased; collectively suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal Component Analysis (PCA) reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status (Tfr1mRNA). Iron repletion from 14–21DIV restored neurodevelopmental genes, but not all thyroid hormone homeostatic genes, and ATP concentrations remained significantly altered. PCA clustering suggests that cultures replete with iron maintain a gene expression signature indicative of previous iron deficiency.ConclusionsThese novel findings suggest there is an intracellular mechanism coordinating cellular iron/thyroid hormone activities. We speculate this is a part of homeostatic response to match neuronal energy production and growth signaling for these important metabolic regulators. However, iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.
THUMPD2 catalyzesN2-methylation on the spliceosome catalytic center of U6 snRNA and regulates pre-mRNA splicing
Authors: Yang Wen-Qing , Ge Jian-Yang , Zhang Xiao-Feng , Lin Lin , Zhu Wen-Yu , Shi Yi-Gong , Xu Bei-Si , Liu Ru-Juan 
Published: June 2023

AbstractHow the relatively evolutionarily conserved spliceosome is able to manage the enormously expanded number of splicing events that occur in humans (∼200,000 vs. ∼400 reported for yeast) is not well understood. Here, we show deposition of one RNA modification-N2-methylguanosine (m2G)-on the G72 nucleoside of U6 snRNA (known to function as the catalytic center of the spliceosome) results in profoundly increased pre-mRNA splicing activity in human cells. This U6 m2G72 modification is conserved among vertebrates. Further, we demonstrate that THUMPD2 is the methyltransferase responsible for U6 m2G72 and show that it interacts with an auxiliary protein (TRMT112) to specifically recognize both sequence and structural elements of U6.THUMPD2KO blocks U6 m2G72 and down-regulates the pre-mRNA splicing activity of major spliceosome, yielding thousands of changed alternative splicing events of endogenous pre-mRNAs. Notably, the aberrantly spliced pre-mRNA population of theTHUMPD2KO cells elicits the nonsense-mediated mRNA decay (NMD) pathway and restricts cell proliferation. Our study thus demonstrates how an RNA epigenetic modification of the major spliceosome differentially regulates global pre-mRNA splicing.
The mitochondrial calcium uniporter transports Ca2+via a ligand-relay mechanism
Authors: Chan Connie , Yuan Chen-Ching , McCoy Jason G. , Ward Patrick S. , Grabarek Zenon 
Published: June 2023

AbstractThe mitochondrial calcium uniporter (mtCU) is a multicomponent Ca2+-specific channel that imparts mitochondria with the capacity to sense the cytosolic calcium signals. The metazoan mtCU comprises the pore-forming subunit MCU and the essential regulator EMRE, arranged in a tetrameric channel complex, and the Ca2+sensing peripheral proteins MICU1-3. The mechanism of mitochondrial Ca2+uptake by mtCU and its regulation is poorly understood. Our analysis of MCU structure and sequence conservation, combined with molecular dynamics simulations, mutagenesis, and functional studies, led us to conclude that the Ca2+conductance of MCU is driven by a ligand-relay mechanism, which depends on stochastic structural fluctuations in the conserved DxxE sequence. In the tetrameric structure of MCU, the four glutamate side chains of DxxE (the E-ring) chelate Ca2+directly in a high-affinity complex (site 1), which blocks the channel. The four glutamates can also switch to a hydrogen bond-mediated interaction with an incoming hydrated Ca2+transiently sequestered within the D-ring of DxxE (site 2), thus releasing the Ca2+bound at site 1. This process depends critically on the structural flexibility of DxxE imparted by the adjacent invariant Pro residue. Our results suggest that the activity of the uniporter can be regulated through the modulation of local structural dynamics.A preliminary account of this work was presented at the 67thAnnual Meeting of the Biophysical Society in San Diego, CA, February 18-22, 2023
IsEEG is better left alone?
Authors: de Cheveigné Alain 
Published: June 2023

AbstractA recent article (Delorme, A., 2023, EEG is better left alone.Scientific Reports,13, 2372.https://doi.org/10.1038/s41598-023-27528-0) proposed a metric to determine the benefit of applying pre-processing methods to EEG data. Using that metric, it concluded that most pre-processing methods donotimprove data quality. The question is revisited in this short paper, using a sample of the same data as used by that paper. It is argued that the metric is of limited applicability, and that in some situations pre-processing might be critical to make good use of the data.Note: This paper was submitted to Scientific Reports as a commentary to the paper cited and rejected without review.