bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of FTDP-17 mutants on circular Tau RNAs
Authors: Margvelani Giorgi , Welden Justin R. , Maquera Andrea Arizaca , Van Eyk Jennifer E. , Murray Christopher , Miranda Sardon Sandra C. , Stamm Stefan 
Published: September 2023

AbstractAt least 53 mutations in the microtubule associated protein tau gene (MAPT) have been identified that cause frontotemporal dementia. 47 of these mutations are localized between exons 7 and 13. They could thus affect the formation of circular RNAs (circRNAs) from the MAPT gene that occur through backsplicing from exon 12 to either exon 10 or exon 7. We analyzed representative mutants and found that five FTDP-17 mutations increase the formation of 12➔7 circRNA and three different mutations increase the amount of 12➔10 circRNA. CircRNAs are translated after undergoing adenosine to inosine RNA editing, catalyzed by ADAR enzymes. We found that the interferon induced ADAR1-p150 isoform has the strongest effect on circTau RNA translation. ADAR1-p150 activity had a stronger effect on circTau RNA expression and strongly decreased 12➔7 circRNA, but unexpectedly increased 12➔10 circRNA. In both cases, ADAR-activity strongly promoted translation of circTau RNAs. Unexpectedly, we found that the 12➔7 circTau protein interacts with eukaryotic initiation factor 4B (eIF4B), which is reduced by four FTDP-17 mutations located in the second microtubule domain. These are the first studies of the effect of human mutations on circular RNA formation and translation. They show that point mutations influence circRNA expression levels, likely through changes in the secondary pre-mRNA structures. The effect of the mutations is surpassed by editing of the circular RNAs, leading to their translation. Thus, circular RNAs and their editing status should be considered when analyzing FTDP-17 mutations.Highlights47/53 known FTDP-17 mutations are located in regions that could influence generation of circular RNAs from the MAPT geneCircular Tau RNAs are translated after adenosine to inosine RNA editing, most effectively caused by ADAR1-p150FTDP-17 mutations influence both circTau RNA and circTau protein expression levelsCircTau protein expression levels do not correlate with circTau RNA expression levelsCircTau proteins bind to eukaryotic initiation factor 4B, which is antagonized by FTDP-17 mutations in exon 10Graphic Abstract
Negative allosteric modulation of the µ-opioid receptor
Authors: O’Brien Evan S. , Rangari Vipin Ashok , Daibani Amal El , Eans Shainnel O. , White Betsy , Wang Haoqing , Shiimura Yuki , Kumar Kaavya Krishna , Appourchaux Kevin , Huang Weijiao , Zhang Chensong , Mathiesen Jesper M. , Che Tao , McLaughlin Jay P. , Majumdar Susruta , Kobilka Brian K. 
Published: September 2023

AbstractThe µ-opioid receptor (µOR) is a well-established target for analgesia, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression, which have led to the present opioid overdose epidemic. µOR negative allosteric modulators (NAMs) may serve as powerful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. We screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist bound receptor to “steer” selections toward functional negative allosteric modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR; the molecule potently blocks the activity of orthosteric agonists and enhances the affinity of the key opioid overdose reversal molecule, naloxone. It accomplishes this by binding to a site on the extracellular vestibule proximal to naloxone, stabilizing a unique inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM perturbs orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxonein vivoto inhibit morphine-induced antinociception, respiratory depression and conditioned place preference while minimizing withdrawal behaviors. Our results provide detailed structural insights into the mechanism of a negative allosteric modulator for the µOR and demonstrate how it can be exploitedin vivo.
Mass spectrometry and split luciferase complementation assays reveal the MecA protein interactome ofStreptococcus mutans
Authors: Qin Hua , Anderson David , Zou Zhengzhong , Higashi Dustin , Borland Christina , Kreth Jens , Merritt Justin 
Published: September 2023

AbstractMecA is a highly conserved adaptor protein encoded by prokaryotes from theBacillotaphylum. MecA mutants exhibit similar pleiotropic defects in a variety of organisms, although most of these phenotypes currently lack a mechanistic basis. MecA mediates ClpCP-dependent proteolysis of its substrates, but only several such substrates have been reported in the literature and there are suggestions that proteolysis-independent regulatory mechanisms may also exist. Here, we provide the first comprehensive characterization of the MecA interactome and further assess its regulatory role in Clp-dependent proteolysis. Untargeted coimmunoprecipitation assays coupled with mass spectrometry revealed that the MecA ortholog from the oral pathobiontStreptococcus mutanslikely serves as a major protein interaction network hub by potentially complexing with >100 distinct protein substrates, most of which function in highly conserved metabolic pathways. The interactome results were independently verified using a newly developed prokaryotic split luciferase complementation assay (SLCA) to detect MecA protein-protein interactionsin vivo. In addition, we further develop a new application of SLCA to supportin vivomeasurements of MecA relative protein binding affinities. SLCA results were independently verified using targeted coimmunoprecipitation assays, suggesting the general utility of this approach for prokaryotic protein-protein interaction studies. Our results indicate that MecA indeed regulates its interactome through both Clp-dependent proteolysis as well as through an as yet undefined proteolysis-independent mechanism that may affect more than half of its protein interactome. This suggests a significant aspect of MecA regulatory function still has yet to be discovered.
No evidence for a causal contribution of bioavailable testosterone to ADHD in sex-combined and sex-specific two-sample Mendelian randomization studies
Authors: Dinkelbach Lars , Peters Triinu , Grasemann Corinna , Hebebrand Johannes , Hinney Anke , Hirtz Raphael 
Published: September 2023

AbstractThe higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk were found, neither in males (inverse-variance weighted (IVW): beta=0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta=0.24, 95%-CI [0.09, 0.39). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.
Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial
Authors: Olsen Thomas , Stolt Emma , Øvrebø Bente , Elshorbagy Amany , Tore Elena C. , Lee-Ødegård Sindre , Troensegaard Hannibal , Johannessen Hanna , Doeland Beate , Vo Anna A. D. , Dahl Anja F. , Svendsen Karianne , Thoresen Magne , Refsum Helga , Rising Russell , Barvíková Kristýna , van Greevenbroek Marleen , Kožich Viktor , Retterstøl Kjetil , Vinknes Kathrine J. 
Published: September 2023

AbstractDietary sulfur amino acid restriction (SAAR) improves metabolic health in animals, but in humans, SAAR has not been investigated in translational clinical trials. In this study, we investigated the effect of dietary SAAR on body weight, body composition, resting metabolic rate, gene expression profiles in white adipose tissue (WAT), and an extensive blood biomarker profile in 59 humans with overweight and obesity in a double-blind, randomized controlled trial (ClinicalTrials.gov:NCT04701346). Participants were randomized to a plant-based diet low (∼2 g/d, SAAR) or high (∼5.6 g/d, control group) in sulfur amino acids. The diets were provided in full to the participants. After 8 weeks of intervention, SAAR led to a ∼20 % greater weight loss compared to controls (β (95 % CI) -1.14 (-2.04, -0.25) kg, p = 0.012). Despite greater weight loss, resting metabolic rate remained similar between groups. Furthermore, SAAR decreased serum leptin, and increased ketone bodies compared to controls. In WAT, 20 genes were upregulated whereas 24 genes were downregulated (FDR < 5 %) in the SAAR group compared to controls. Generally applicable gene set enrichment analyses revealed that processes associated with ribosomes were upregulated, whereas processer related to structural components were downregulated. In conclusion, our study shows that SAAR leads to weight loss and metabolic benefits. Further research SAAR is needed to investigate the therapeutic potential for metabolic conditions in humans.
Dendrite: A Structured, Accessible, and Queryable Pathology Search Database for Streamlined Experiment Planning
Authors: Lu Yunrui , Hamilton Robert , Greenberg Jack , Srinivasan Gokul , Shah Parth , Preum Sarah , Pettus Jason , Vaickus Louis , Levy Joshua 
Published: September 2023

AbstractPathology reports contain vital information, yet a significant portion of this data remains underutilized in electronic medical record systems due to the unstructured and varied nature of reporting. Although synoptic reporting has introduced reporting standards, the majority of pathology text remains free-form, necessitating additional processing to enable accessibility for research and clinical applications. This paper presents Dendrite, a web application designed to enhance pathology research by providing intelligent search capabilities and streamlining the creation of study cohorts. Leveraging expert knowledge and natural language processing algorithms, Dendrite converts free-form pathology reports into structured formats, facilitating easier querying and analysis. Using a custom Python script, Dendrite organizes pathology report data, enabling record linkages, text searches, and structured drop-down menus for information filtering and integration. A companion web application enables data exploration and export, showcasing its potential for further analysis and research. Dendrite, derived from existing laboratory information systems, outperforms existing implementations in terms of speed, responsiveness, and flexibility. With its efficient search functionality and support for clinical research and quality improvement efforts in the pathology field, Dendrite proves to be a valuable tool for pathologists. Future enhancements encompass user management integration, integration of natural language processing and machine learning to enhance structured reporting capabilities and seamless integration of Dendrite with the vast repository of genomics and imaging data.
WITHDRAWN: Prenatal exposure to wildfire-related PM2.5and respiratory infections by age 1 year: A population-based case-control analysis of critical developmental windows
Authors: Lan Qingyi , Weinberger Kate , Luke Sabrina , Lavigne Eric , Weichenthal Scott , Henderson Sarah B. 
Published: September 2023

Withdrawal StatementThe authors have withdrawn this manuscript because they identified major flaws in their methods, and after re-analysis, their previous conclusion could not be supported. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Orientation tests and long-term movement phenology establish the red admiralVanessa atalantaas an applicable model for navigation research in migratory butterflies
Authors: Pakhomov Alexander , Jansons Roberts , Shapoval Nazar , Cellarius Fyodor , Shapoval Anatoly , Lindecke Oliver 
Published: September 2023

AbstractAnimal migrations are disappearing globally, while insect populations are on alarming declines. Both ecosystem degradations, influenced by unpredictable impacts of climate change, are also exacerbated by human activities such as intensified land use and various forms of environmental pollution. Butterfly migrations may serve as sensitive indicator phenomena of these broader environmental changes. While the transcontinental journeys of one of the most famous Lepidopteran species, the North American monarch butterfly,Danaus plexippus, are documented in depth, they are a geographically restricted phenomenon. Comprehensive studies from other areas and on other migratory butterflies like the European red admiral,Vanessa atalanta, are notably sparse. In addition, the details of their navigational capacities and how they might be affected by the aforementioned changes remain largely enigmatic. Against this backdrop, we seek to establish the red admiral as a model for insect movement phenology and navigation behaviour which both might be impacted by environmental changes. Employing a combination of orientation tests, utilizing flight-simulators and free-flight trials during late summer, together with a 23-year study on movement phenology at a coastal migration flyway, the Baltic Sea coast, we offer broad insights into red admiral migration. In our experiments, butterflies exhibited a southwestern orientation on the Courish Spit and chose a south-southeastern trajectory in free-flight trials after translocation at the Latvian Baltic Sea coast. Directional records from decades-long trapping data, based on more than 16,000 individuals, match these findings. Nevertheless, we also found reverse movements to occur under some circumstances. At the same time, the observed estimated median dates of red admiral passages did change by one day only between decades, however, generally more butterflies were recorded in recent years. Our data thus suggest a certain degree of adaptability in the butterflies’ movement behaviour, indicating an innate migration schedule, possibly supported by a flexible navigational capacity. As the world is facing biodiversity loss at a high rate, long-term monitorings of indicator species become important. By establishing the red admirals as a model for butterfly migration, we expect insights into broader movement patterns and navigational strategies in Lepidoptera negotiating human-dominated environments, filling a crucial gap in our current understanding of these interdependent aspects of insect biology.
Progesterone induces meiosis through two obligate co-receptors with PLA2 activity
Authors: Nader Nancy , Assaf Lama , Zarif Lubna , Halama Anna , Yadav Sharan , Dib Maya , Attarwala Nabeel , Chen Qiuying , Suhre Karsten , Gross Steven S. , Machaca Khaled 
Published: September 2023

AbstractThe steroid hormone progesterone (P4) regulates multiple aspects of reproductive and metabolic physiology. Classical P4 signaling operates through nuclear receptors that regulate transcription. In addition, P4 signals through membrane P4 receptors (mPRs) in a rapid nongenomic modality. Despite the established physiological importance of P4 nongenomic signaling, the details of its signal transduction cascade remain elusive. Here, usingXenopusoocyte maturation as a well- established physiological readout of nongenomic P4 signaling, we identify the lipid hydrolase ABHD2 (α/β hydrolase domain-containing protein 2) as an essential mPRβ co-receptor to trigger meiosis. We show using functional assays coupled to unbiased and targeted cell-based lipidomics that ABHD2 possesses a phospholipase A2 (PLA2) activity that requires mPRβ. This PLA2 activity bifurcates P4 signaling by inducing clathrin-dependent endocytosis of mPRβ, resulting in the production of lipid messengers that are G-protein coupled receptors agonists. Therefore, P4 drives meiosis by inducing an ABHD2 PLA2 activity that requires both mPRβ and ABHD2 as obligate co-receptors.Significance StatementNongenomic progesterone signaling is important for many physiological functions yet the details of its signaling remain elusive. Here we define the early signaling steps downstream of membrane progesterone receptor β (mPRβ) duringXenopusoocyte meiosis. We show that progesterone requires two cell membrane receptors to work in unison to signal. The co-receptor complex possesses lipase activity that produces lipid messenger and induces receptor endocytosis to trigger meiosis progression. Our findings have broad physiological implications because nongenomic progesterone signaling operates in many tissues and regulates reproduction and metabolism.
Accelerated physiology and increased energy expenditure in animals and humans with mitochondrial defects: A meta-analysis
Authors: Sercel Alexander J. , Sturm Gabriel , Shaulson Evan D. , Gallagher Dympna , St-Onge Marie-Pierre , Kempes Christopher P. , Pontzer Herman , Hirano Michio , Picard Martin 
Published: September 2023

AbstractMitochondria are key energy transforming organelles in mammalian cells. However, how defects in oxidative phosphorylation (OxPhos) and other mitochondrial functions influence whole-body energy expenditure (EE) has not been rigorously studied. Cellular and organismal responses to OxPhos defects likely involve a combination of functionaldownregulationto conserve energy and compensatoryupregulationof stress responses. If the energy cost of compensatory responses exceeds the potential energy savings of functional downregulation, as recent work suggests, the result would be an increase in total EE. To address the hypothesis that OxPhos defects increase the energetic cost of living, we performed a meta-analysis of available studies reporting EE in animal models with mitochondrial gene defects. Of all reported experimental conditions (n = 91, from 29 studies), 51% reported a >10% elevation in EE relative to control animals, compared to 11% reporting <10% reduction in EE (p<0.0001, Chi-square). Of the experimental conditions where locomotor activity was also quantified, 39% showed that OxPhos-deficient animals had elevated EE despite reduced locomotor activity, which would be expected to decrease EE. To extend this finding in humans, we re-analyzed a high-quality clinical and multi-omics dataset (Sharma et al. 2021) of mitochondrial disease patients with the m.3243A>G mutation. This analysis similarly indicates an upregulation of energetically costly physiological, immune, and metabolic parameters in people with OxPhos deficiency. These results suggest that animals and humans with mitochondrial defects must expend more energy to sustain life, a state clinically calledhypermetabolism. High-quality human energetics studies are needed to understand the magnitude, mechanisms, and modifiability of hypermetabolism in mitochondrial disorders.
Parallel G-quadruplex folds via multiple paths involving G-tract stacking and structuring from coil ensemble
Authors: Pokorná Pavlína , Mlýnský Vojtěch , Bussi Giovanni , Šponer Jiří , Stadlbauer Petr 
Published: September 2023

ABSTRACTG-quadruplexes (G4s) are non-canonical nucleic acid structures that fold through complex processes. Characterization of G4 folding landscape contributes to comprehending G4 roles in gene regulation but is challenging for experiments and computations. Here we investigate the folding of a three-quartet parallel DNA G4 with (GGGA)3GGG sequence using all-atom explicit-solvent enhanced-sampling molecular dynamics (MD) simulations. We suggest an early formation of guanine stacks in the G-tracts, which behave as semi-rigid blocks in the folding process. The parallel G4 folding is initiated by the formation of a collapsed compact coil-like ensemble. Structuring of the G4 from the coil then proceeds via various cross-like, hairpin, slip-stranded, and two-quartet ensembles and can bypass the G-triplex structure. While parallel G-hairpins are extremely unstable when isolated, they are more stable inside the coil structure. Folding of parallel G4 does not appear to involve any salient intermediates and, instead, it is an extremely multiple-pathway process. On the methodology side, we show that the AMBER DNA force field predicts the folded G4 to be less stable than the unfolded ensemble, uncovering substantial force-field issues. Overall, we provide unique atomistic insights into the folding landscape of parallel-stranded G4 but also reveal limitations of the state-of-the-art MD techniques.
Faa1 membrane binding drives positive feedback in autophagosome biogenesis via fatty acid activation
Authors: Baumann Verena , Achleitner Sonja , Tulli Susanna , Schuschnig Martina , Klune Lara , Martens Sascha 
Published: September 2023

AbstractAutophagy serves as a stress response pathway by mediating the degradation of cellular material within lysosomes. In autophagy this material is encapsulated in double membrane vesicles termed autophagosomes, which form from precursors referred to as phagophores. Phagophores grow by lipid influx from the endoplasmic reticulum into Atg9-positive compartments and local lipid synthesis provides lipids for their expansion. How phagophore nucleation and expansion are coordinated with lipid synthesis is unclear. Here, we show that Faa1, an enzyme activating fatty acids, is directly recruited to Atg9 vesicles. We further show that Faa1 binds to negatively charged membranes. We define the membrane binding surface in Faa1 and show that membrane binding is required for its enzymatic activity. In cells, membrane binding by Faa1 is required for its recruitment to phagophores and promotes autophagosome biogenesis. Our results suggest a positive feedback loop coupling phagophore nucleation and expansion to lipid synthesis.SummaryBaumann, Achleitner, Tulli et al. dissect Faa1 function and recruitment during autophagy. They discover that Faa1 directly binds membranes via a positively charged surface. This is a prerequisite for Faa1’s enzymatic activity sustaining autophagosome biogenesis.