bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interspecific allometric scaling in eDNA production in fishes reflects physiological and surface area allometry
Authors: Yates M.C , Wilcox T. W. , Stoeckle M.Y. , Heath D.D. 
Published: May 2022

AbstractRelating environmental DNA (eDNA) signal strength to organism abundance requires a fundamental understanding of eDNA production. A number of studies have demonstrated that eDNA production may scale allometrically – that is, larger organisms tend to exhibit lower mass-specific eDNA production rates, likely due to allometric scaling in key processes related to eDNA production (e.g. surface area, excretion/egestion). While most previous studies have examined intra-specific allometry, physiological rates and organism surface area also scale allometrically across species. We therefore hypothesize that eDNA production will similarly exhibit inter-specific allometric scaling. To evaluate this hypothesis, we reanalyzed previously published eDNA data from Stoeckle et al. (2021) which compared metabarcoding read count to organism count and biomass data obtained from trawl surveys. Using a Bayesian model we empirically estimated the value of the allometric scaling coefficient (‘b’) for bony fishes to be 0.67 (credible interval = 0.58 – 0.77), although our model failed to converge for chondrichthyan species. We found that integrating allometry significantly improved correlations between organism abundance and metabarcoding read count relative to traditional metrics of abundance (density and biomass) for bony fishes. Although substantial unexplained variation remains in the relationship between read count and organism abundance, our study provides evidence that eDNA production tends to scale allometrically across species. Future studies investigating the relationship between eDNA signal strength and metrics of fish abundance could potentially be improved by accounting for allometry – a scaling coefficient value of ∼2/3 appears to be both theoretically and empirically justified.
Circulating U13 small nucleolar RNA as a candidate biomarker for Huntington’s disease
Authors: Romano Silvia , Romano Carmela , Peconi Martina , Fiore Alessia , Bellucci Gianmarco , Morena Emanuele , Troili Fernanda , Cipollini Virginia , Annibali Viviana , Giglio Simona , Mechelli Rosella , Ferraldeschi Michela , Veneziano Liana , Mantuano Elide , Sani Gabriele , Vecchione Andrea , Umeton Renato , Giubilei Franco , Salvetti Marco , Corbo Rosa Maria , Scarabino Daniela , Ristori Giovanni 
Published: May 2022

AbstractBackground and ObjectivesFluid biomarkers are a recent field of interest in Huntington disease (HD). We focused on small circulating RNAs from plasma of subjects with prodromal (pre-HD) and overt disease by a two-stage approach: an unbiased investigation by an array method and a validation study to quantify a significant small nucleolar RNA.MethodsThrough Affymetrix Gene-Chip-miRNA-Array we performed an exploratory study on 9 HD patients, 8 healthy subjects (HS) and 5 psychiatric patients (PP; who share drugs with HD patients, to control for iatrogenic effects). Through real time PCR we validated the results in an independent population of 24 HD patients, 15 pre-HD, 24 PP, 28 Alzheimer’s disease (AD) patients (added to control the disease-specificity of our finding) and 23 HS. A bioinformatic analysis was also performed to interpret our finding.ResultsThe microarray results showed a significant signal for U13 small nucleolar RNA (SNORD13) that was increased in plasma of HD patients compared to controls (fold change, 1.54, p =0.003 HD vs. HS, and fold change 1.44 p = 0.0026 HD vs. PP). In the validation population the significant increase in HD patients was evident compared to both pre-HD and the three control groups (p<0.00001). The plasma levels of SNORD13 correlated with the status of mutant huntingtin carrier and the disease duration (respectively R=0.69; p<0.000001; R=0.49; p=0.015). Through receiver operating characteristic (ROC) curve analysis, we showed high accuracy of plasmatic SNORD13 in discriminating HD patients from pre-HD and control groups (AUC=0.963), outperforming values reported in another study for intrathecal or plasmatic mutant huntingtin and neurofilament light chain as biomarkers of overt HD. The bioinformatic analysis on SNORD13 interactome and pathway analysis showed enrichments for factors involved in nuclear functions beyond the ribosome biogenesis.DiscussionWe report the unprecedented finding of a potential role of small nucleolar RNAs in HD. Circulating SNORD13 seems a good biomarker for clinical purposes. It seems to be specific for HD and to peripherally report a plausible ‘tipping point’ in the pathogenic cascade at neuronal level, possibly paving the way for new therapeutic targets.
Ventral Hippocampal Infusions of C20:0 Ceramide Stimulate Microglia and Induce Anhedonia-like Behavior in Female and Male Rats
Authors: Sambolín Lubriel , Feliciano Adariana , Tirado Lizmarie , Suárez Cristina , Pacheco Dariangelly , Fonseca Wilfred , Hernández Anixa , Colón Maria , Porter James 
Published: May 2022

ABSTRACTIncreased long-chain C20:0 ceramides have been found in the serum of patients with depression. Moreover, ceramides are linked with increased microglia reactivity and inflammatory cytokine production, which are associated with depression. Since ceramides can readily cross the blood brain barrier, peripheral C20:0 ceramides could enter the brain, activate microglia, and induce depressive-like behavior. In this study, we determined whether localized infusion of C20:0 ceramides into the ventral hippocampus (VH) of rats is sufficient to activate microglia and induce depressive-like behaviors. Adult male and female rats received infusions of C20:0 ceramides or vehicle solution every other day for 2 weeks. After the third infusion, C20:0-infused animals showed reduced sucrose preference suggesting anhedonia-like behavior. However, 4-6 days after the last infusion, animals infused with C20:0 ceramides did not show anhedonia-like or despair-like behavior suggesting the behavioral effect was reversible. After the final behavioral test, C20:0-infused animals had more Iba-1+ microglia in the VH. Despite the increased number of VH microglia, the expression of inflammatory genes was not increased. In conclusion, our data suggest that localized increases in C20:0 ceramides in the VH are sufficient to induce microglia activation and reversible anhedonia-like behavior.
Cocaine regulation of Nr4a1 chromatin bivalency and mRNA in male and female mice
Authors: Fischer Delaney K. , Krick Keegan S. , Han Chloe , Woolf Morgan , Heller Elizabeth A. 
Published: May 2022

ABSTRACTBACKGROUNDCocaine epigenetically regulates gene expression via changes in histone post-translational modifications (HPTMs). We previously found that the immediate early gene Nr4a1 is epigenetically activated by cocaine in mouse brain reward regions. HPTMs act combinatorically, yet few studies examine multiple HPTMs at a single gene. Bivalent gene promoters are simultaneously enriched in both activating (H3K4me3 (K4)) and repressive (H3K27me3 (K27)) HPTMs. As such, bivalent genes are lowly expressed but poised for activity-dependent gene regulation. In the current study, we defined regulation of K4&K27 bivalency at Nr4a1 following cocaine treatment in male and female mice. The inclusion of female mice can shed light on the epidemiological relevance of sex to cocaine use disorder.METHODSMale and female mice were injected with saline or cocaine (i.p. 20mg/kg). We applied sequential chromatin immunoprecipitation and qPCR to define Nr4a1 bivalency and expression in striatum (STR), prefrontal cortex (PFC), and hippocampus (HPC). Pearson’s correlation matrices quantified relationships within each brain region across treatment conditions for each sex.RESULTSWe defined K4&K27 bivalency at the Nr4a1 promoter in all three brain regions, in both sexes. In female STR, cocaine increased Nr4a1 mRNA, coupled to maintenance of Nr4a1 K4&K27 bivalency. In male STR, cocaine enriched repressive H3K27me3 and K4&K27 bivalency at Nr4a1 and failed to increase Nr4a1 mRNA. Furthermore, cocaine epigenetically regulated a putative NR4A1 target, Cartpt, in male PFC.CONCLUSIONThis study defined the epigenetic regulation of Nr4a1 in reward brain regions in male and female mice. Cocaine treatment in female mice increased Nr4a1 mRNA in STR, but there was no change in Nr4a1 H3K27me3 or K4&K27 promoter bivalency. Following cocaine treatment in male mice, Nr4a1 mRNA did not change in STR, HPC, or PFC, and Nr4a1 H3K27me3 and K4&K27 promoter bivalency increased in the STR.
Comprehensive phylogenetic analysis of the ribonucleotide reductase family reveals an ancestral clade and the role of insertions and extensions in diversification
Authors: Burnim Audrey A. , Spence Matthew A. , Xu Da , Jackson Colin , Ando Nozomi 
Published: May 2022

AbstractRibonucleotide reductases (RNRs) are used by all organisms and many viruses to catalyze an essential step in the de novo biosynthesis of DNA precursors. RNRs are remarkably diverse by primary sequence and cofactor requirement, while sharing a conserved fold and radical-based mechanism for nucleotide reduction. Here, we structurally aligned the diverse RNR family by the conserved catalytic barrel to reconstruct the first large-scale phylogeny consisting of 6,779 sequences that unites all extant classes of the RNR family and performed evo-velocity analysis to independently validate our evolutionary model. With a robust phylogeny in-hand, we uncovered a novel, phylogenetically distinct clade that is placed as ancestral to the classes I and II RNRs, which we have termed clade Ø. We employed small-angle X-ray scattering (SAXS), cryogenic-electron microscopy (cryo-EM), and AlphaFold2 to investigate a member of this clade from Synechococcus phage S-CBP4 and report the most minimal RNR architecture to-date. Using the catalytic barrel as a starting point for diversification, we traced the evolutionarily relatedness of insertions and extensions that confer the diversity observed in the RNR family. Based on our analyses, we propose an evolutionary model of diversification in the RNR family and delineate how our phylogeny can be used as a roadmap for targeted future study.
Placental mammal derived microRNAs alter pathways in the endometrial epithelia important for endometrial function
Authors: Hume Laura , Edge Jessica C. , Tinning Haidee , Wang Dapeng , Taylor Alysha S. , Ovchinnikov Vladimir , Geijer-Simpson Annika , Vrljicak Pavle , Brosens Jan J. , Lucas Emma S. , Simson Nigel A.B. , Shillito Jane , Forbes Karen , O’Connell Mary J. , Forde Niamh 
Published: May 2022

ABSTRACTWe tested the hypothesis that a panel of placental mammal-specific miRNAs and their targets play important to establish receptivity to implantation and their dysregulated expression may be a feature in women with early pregnancy loss. Relative expression levels of miR-340-5p, −542-3p, and −671-5p all increased following treatment of Ishikawa cells with progesterone (10 μg/ml) for 24 hrs (p < 0.05). RNA sequencing of these P4-treated cells identified co-ordinate changes to 6,367 transcripts of which 1713 were predicted targets of miR-340-5p, 670 of miR-542-3p, and 618 of miR-671-5p. Quantitative proteomic analysis of Ishikawa cells transfected with mimic or inhibitor (48 hrs: n=3 biological replicates) for each of the P4-regulated miRNAs was carried out to identify targets of these miRNAs. Excluding off target effects, mir-340-5p mimic altered 1,369 proteins while inhibition changed expression of 376 proteins (p < 0.05) of which, 72 were common to both treatments. A total of 280 proteins were identified between predicted (mirDB) and confirmed (in vitro) targets. In total, 171 proteins predicted to be targets by mirDB were altered in vitro by treatment with miR-340-5p mimic or inhibitor and were also altered by treatment of endometrial epithelial cells with P4. In vitro targets of miR-542-3p identified 1,378 proteins altered by mimic while inhibition altered 975 a core of 200 proteins were changed by both. 100 protein targets were predicted and only 46 proteins were P4 regulated. miR-671-mimic altered 1,252 proteins with inhibition changing 492 proteins of which 97 were common to both, 95 were miDB predicted targets and 46 were also P4-regulated. All miRNAs were detected in endometrial biopsies taken from patients during the luteal phase of their cycle, irrespective of prior or future pregnancy outcomes Expression of mir-340-5p showed an overall increase in patients who had previously suffered a miscarriage and had a subsequent miscarriage, as compared to those who had infertility or previous miscarriage and subsequently went on to have a life birth outcome. The regulation of these miRNAs and their protein targets regulate the function of transport and secretion, and adhesion of the endometrial epithelia required for successful implantation in humans. Dysfunction of these miRNAs (and therefore the targets they regulate) may contribute to endometrial-derived recurrent pregnancy loss in women.
The genomic basis and environmental correlates of local adaptation in the Atlantic horse mackerel (Trachurus trachurus)
Authors: Fuentes-Pardo Angela P. , Farrell Edward D. , Pettersson Mats E. , Sprehn C. Grace , Andersson Leif 
Published: May 2022

AbstractUnderstanding how populations adapt to local environments is increasingly important to prevent biodiversity loss due to climate change. Here we examined whole-genome variation of twelve Atlantic horse mackerel samples from the North Sea to North Africa, and the western Mediterranean Sea. This marine migratory benthopelagic fish is one of the most widely distributed and commercially important species in the eastern Atlantic. We found low population structure at neutral loci, but high differentiation at adaptive loci distinguishing the western Mediterranean and the North Sea populations from other Atlantic locations. Candidate genes distinctive of the Mediterranean include a green-sensitive-opsin harbouring two missense mutations that might fine-tune the spectral sensitivity to blue-green light conditions. Candidate genes characteristic of the North Sea could play a critical role in cold tolerance (energy metabolism and cell membrane structure) and increased sensitivity to odours, presumably to compensate reduced visibility in turbid waters. We also discovered a putative chromosomal inversion (9.9 Mb) that follows a climate-related latitudinal cline with a break near mid Portugal. Genome-environment association analysis indicated that seawater-dissolved oxygen concentration and temperature are likely the main environmental drivers of local adaptation. Our genomic data broadly supports the current stock divisions, but recommends revision of the western and southern stock boundaries. We developed a reduced SNP panel that genetically discriminate the North Sea and North Africa from neighbouring populations. Our study highlights the importance of life history and chromosomal inversions in adaptation with gene flow, and the complexity of evolutionary and ecological processes involved in local adaptation.
Loss of Myosin-1e biases MMTV-PyMT induced breast cancer towards a differentiated and secretory state
Authors: Plante Eric L. , Chase Sharon E. , de Jong Ebbing P. , Curtis Theresa M. , Garone Michael E. , Krendel Mira 
Published: May 2022

AbstractExpression of the unconventional myosin, Myosin-1e (Myo1e), has been shown to contribute to tumor progression in the MMTV-PyMT mouse model of mammary tumorigenesis and is associated with poor outcome in breast cancer patients. However, the specific effects of Myo1e expression on the mammary tumor cells remain unidentified. Here, we used Myo1e-KO and wild-type (WT) MMTV-PyMT mice on a pure genetic background to further investigate the molecular and cellular effects of Myo1e expression. Myo1e-WT tumors were characterized by an increased abundance of intra-epithelial macrophages and lower amounts of the extracellular matrix. Transcriptomic profiling of WT and Myo1e-KO tumors identified a pattern of differential expression of tumor suppressor and tumor-promoting genes that was consistent with the observed differences in tumor progression and morphology between the genotypes, and also revealed differential expression of genes associated with secretion and cell-cell adhesion. In agreement with the RNA-seq findings, Myo1e-expressing tumor cells exhibited increased proliferation and elevated nuclear enrichment of YAP1 transcriptional activator compared to Myo1e-KO tumor cells. To investigate tumor cell-autonomous effects of Myo1e expression, we used the epithelial cell line PY-230 derived from the MMTV-PyMT-induced mouse tumor to create Myo1e-depleted cells by Crispr-mediated genome editing. Cells deficient in Myo1e had increased expression of genes encoding milk components compared to the wild-type cells. Electric cell-substrate impedance sensing (ECIS) measurements showed that depletion of Myo1e in PY-230 cells resulted in increased resistance to electrical current indicating enhanced epithelial barrier function. Overall, we find that Myo1e expression biases tumors towards a less-differentiated, pro-tumorigenic state, and that depletion of Myo1e is associated with a pro-secretory, more differentiated state.
Fic-mediated AMPylation tempers the Unfolded Protein Response during physiological stress
Authors: Casey Amanda K. , Gray Hillery F. , Chimalapati Suneeta , Hernandez Genaro , Moehlman Andrew , Stewart Nathan , Fields Hazel A. , Gulen Burak , Servage Kelly A. , Stefanius Karoliina , Blevins Aubrie , Daoud Elena , Evers Bret , Krämer Helmut , Orth Kim 
Published: May 2022

AbstractThe proper balance of synthesis, folding, modification and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum (ER) become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage. Previously, we discovered that the bifunctional enzyme Fic can modulate the UPR response via post-translational modification of BiP by AMPylation and deAMPylation. Loss of fic in Drosophila leads to vision defects and altered UPR activation in the fly eye. To investigate the importance of Fic-mediated AMPylation in a mammalian system, we generated a conditional null allele of Fic in mice and characterized the effect of Fic loss on the exocrine pancreas. Compared to controls, Fic-/- mice exhibit elevated serum markers for pancreatic dysfunction and display enhanced UPR signaling in the exocrine pancreas in response to physiologic and pharmacological stress. In addition, both fic-/- flies and Fic-/- mice show reduced capacity to recover from damage by stress that triggers the UPR. These findings show that Fic- mediated AMPylation acts as a molecular rheostat that is required to temper the UPR response in the mammalian pancreas during physiological stress.
Mediator-RNA Polymerase II Interactions Critical for Transcriptional Activation Are Mediated by the N-terminal Half of MED14 and C-terminal Domain of RPB1
Authors: Baris Yasemin , Jabbar Javaid , Yozgat Yasemin , Cigirgan Ege , Bay Sadik , Tucer Merve Erden , Aslan Volkan , Dinccelik-Aslan Melike , Cevher Murat Alper 
Published: May 2022

ABSTRACTMediator is a large and evolutionarily conserved coactivator complex essential for RNA polymerase II (Pol II)-mediated gene regulation at multiple steps of the transcription process, including preinitiation complex (PIC) assembly and function. Here, we used the MultiBac baculovirus expression system to generate recombinant human core Mediator subcomplexes and subsequent biochemical approaches to dissect the mechanism by which Mediator facilitates direct recruitment of Pol II to core promoters. Our results highlight a pivotal role in this process for the N-terminal half (NTD) of the MED14 subunit. We show that a reconstituted 15-subunit human core Mediator complex that contains only the MED14-NTD is fully functional in facilitating both basal and activated (p53) transcription. This complex directly interacts with the C-terminal domain (CTD) of the RPB1 subunit of Pol II (RPB1 CTD) and is required for recruiting Pol II to core promoters. Moreover, recombinant RPB1 can completely reverse the human core Mediator-Pol II interaction. Notably, the human MED14-NTD region has secondary structure conservation with Schizosaccharomyces pombe. In addition, reanalysis of published cryo-EM structures of yeast Mediator-Pol II complexes strongly supports our conclusion. Thus, our analyses provide critical new insights into how Mediator binds to Pol II and recruits it to the promoters to facilitate transcription.
Neurite outgrowth deficits caused by rare PLXNB1 mutation in pediatric bipolar disorder
Authors: Yang Guang , Parker Ethan , Gorsi Bushra , Liebowitz Mark , Maguire Colin , King Jace B. , Coon Hilary , Lopez-Larson Melissa , Anderson Jeffrey , Yandell Mark , Shcheglovitov Alex 
Published: May 2022

AbstractPediatric Bipolar Disorder (PBD) is a severe mood dysregulation condition that affects 0.5–1% of children and teens in the United States. It is associated with recurrent episodes of psychosis and depression and an increased risk of suicidality. However, the genetics and neuropathology of PBD are largely unknown. Here, we used a combinatorial family-based approach to characterize the cellular, molecular, genetic, and network-level deficits associated with PBD. We recruited a PBD patient and three unaffected family members from a family with a history of psychiatric illnesses. Using resting-state functional magnetic resonance imaging (rs-fMRI), we detected altered resting-state functional connectivity in the patient as compared to the unaffected sibling. Using transcriptomic profiling of patient and control induced pluripotent stem cell (iPSC) derived telencephalic organoids, we found aberrant signaling in the molecular pathways related to neurite outgrowth. We corroborated the presence of neurite outgrowth deficits in patient iPSC-derived cortical neurons and identified a rare homozygous loss-of-functionPLXNB1variant (c.1360C>C; p.Ser454Arg) in the patient. Expression of wild-typePLXNB1, but not the variant, rescued neurite outgrowth deficit in patient neurons, and expression of the variant caused neurite outgrowth deficit in cortical neurons fromPlxnB1knock-out mice. These results indicate that dysregulated PLXNB1 signaling may contribute to an increased risk of PBD and other mood dysregulation-related disorders by disrupting neurite outgrowth and functional brain connectivity. Overall, the study established and validated a novel family-based combinatorial approach for studying cellular and molecular deficits in psychiatric disorders.
10.4 Million Children Affected by COVID-19-associated Orphanhood and Caregiver Death: An Imperative for Action
Authors: Hillis Susan , Ntwali N’konzi Joel-Pascal , Msemburi William , Cluver Lucie , Villaveces Andrés , Flaxman Seth , Unwin H. Juliette T. 
Published: May 2022

AbstractThe new WHO estimates for COVID-19 excess deaths allow us to generate supdated and more accurate models of COVID-19 associated orphanhood and caregiver loss. Using methodology established in prior studies, we combine age-specific fertility and excess death estimates from January 2020 to May 2022. We find 10.4 million children have lost a parent or caregiver due to COVID-associated excess deaths, and 7.5 million children have experienced COVID-associated orphanhood. Without supportive intervention, caregiver loss can bring severe risks of poverty, school dropout, sexual exploitation, and mental health distress. It is essential that evidence-based care for these children is integrated into all national response plans as a caring action to protect children from immediate and long-term harms of COVID-19.