bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pervasive polygenicity of complex traits inflates false positive rates in transcriptome-wide association studies
Authors: Liang Yanyu , Nyasimi Festus , Im Hae Kyung 
Published: October 2023

AbstractTranscription-wide association studies (TWAS) and related methods (xWAS) have been widely adopted in genetic studies to understand molecular traits as mediators between genetic variation and disease. However, the effect of polygenicity on the validity of these mediator–trait association tests has largely been overlooked. Given the widespread polygenicity of complex traits, it is necessary to assess the validity and accuracy of these mediator–trait association tests. We found that for highly polygenic target traits, the standard test based on linear regression is inflated, leading to greatly increased false positives rates, especially in large sample sizes. Here, we show the extent of the inflation as a function of the underlying GWAS sample size and polygenic heritability of the target trait. To address this inflation, we propose an effective variance control method, similar to genomic control, but which allows for a different correction factor for each gene. Using simulated and real data, as well as theoretical derivations, we show that our method yields calibrated false positive rates, outperforming existing approaches. We further demonstrate that methods analogous to TWAS that associate genetic predictors of mediating traits with target traits suffer from similar inflation issues. We advise developers of genetic predictors for molecular traits (including polygenic risk scores, PRS) to compute and provide the necessary inflation parameters to ensure proper false positive control. Finally, we have updated our PrediXcan software package and resources to facilitate this correction for end users.
Duox activation inDrosophilaMalpighian tubules stimulates intestinal epithelial renewal through a countercurrent flow
Authors: Liu Zhonggeng , Zhang Hongyu , Lemaitre Bruno , Li Xiaoxue 
Published: October 2023

SummaryThe gut must perform a dual role of protecting the host against toxins and pathogens while harboring mutualistic microbiota. Previous studies suggested that the NADPH oxidase Duox contributes to intestinal homeostasis inDrosophilaby producing reactive oxygen species (ROS) in the gut that stimulate epithelial renewal. We find instead that ROS generated by Duox in the Malpighian tubules leads to the production of Upd3, which enters the gut and stimulates stem cell proliferation. We describe for the first time inDrosophilathe existence of a countercurrent flow system, which pushes tubule-derived Upd3 to the anterior part of the gut and stimulates epithelial renewal at a distance. Thus, our paper clarifies the role of Duox in gut homeostasis and describes the existence of retrograde fluid flow in the gut, collectively revealing a fascinating example of inter-organ communication.
Establishment of the Meyer-Overton correlation in an artificial membrane without protein
Authors: Matsumoto Atsushi , Uesono Yukifumi 
Published: October 2023

AbstractBackgroundThe potency of anesthetics with various structures increases exponentially with lipophilicity, which is the Meyer-Overton (MO) correlation discovered over 120 years ago. The MO correlation was also observed with various biological effects and various chemicals, including alcohols; thus, the correlation represents a fundamental relationship between chemicals and organisms. The MO correlation was explained by the lipid and protein theories, although the debate has not been resolved and the principle remains unknown.MethodsThe gentle hydration method was used to form giant unilamellar vesicles (GUVs) consisting of high- and low-melting phospholipids and cholesterol in the presence ofn-alcohols (C2-C12). Confocal fluorescence microscopy was used to determine the percentage of GUVs with domains in relation to the concentrations ofn-alcohols.Resultsn-Alcohols inhibited the domain formation of GUVs, and the half inhibitory concentration (IC50) in the aqueous phase decreased exponentially with increasing chain length (lipophilicity). In contrast, the membrane concentrations of alcohols for the inhibition, which is a product of the membrane-water partition coefficient and the IC50values, remained constant irrespective of the chain length.ConclusionsThe MO correlation is established in artificial lipid membrane, which supports the lipid theory. When alcohols reach the same critical concentration in the membrane, similar biological effects appear irrespective of the chain length, which is the principle underlying the MO correlation.Summary Statementn-Alcohols inhibit the domain formation of giant unilamellar vesicles according to the Meyer-Overton correlation.
Sequestrase chaperones protect against oxidative stress-induced protein aggregation and [PSI+] prion formation
Authors: Carter Zorana , Creamer Declan , Kouvidi Katerina , Grant Chris M. 
Published: October 2023

AbstractMisfolded proteins are usually refolded to their functional conformations or degraded by quality control mechanisms. When misfolded proteins evade quality control, they can be sequestered to specific sites within cells to prevent the potential dysfunction and toxicity that arises from protein aggregation. Btn2 and Hsp42 are compartment-specific sequestrases that play key roles in the assembly of these deposition sites. Their exact intracellular functions and substrates are not well defined, particularly since no stress sensitivity has been reported in deletion mutants. We show here that Btn2 and Hsp42 are required for oxidant tolerance and act to sequestering misfolded proteins into defined PQC sites following ROS exposure. We have used the Sup35 translation termination factor as a model oxidized protein to show that protein aggregation is elevated and widespread in mutants lacking Btn2 and Hsp42. Oxidant-induced prion formation is also elevated in sequestrase mutants consistent with the idea that Btn2 and Hsp42 function to sequester oxidatively damaged Sup35, thus preventing templating to form its heritable prion form. Taken together, our data identify protein sequestration as key antioxidant defence mechanism that functions to mitigate the damaging consequences of protein oxidation-induced aggregation.
Developing oak buds produce volatile emissions in response to herbivory by freshly hatched caterpillars
Authors: Graham Jessica L. , Staudt Michael , Buatois Bruno , Caro Samuel P. 
Published: October 2023

AbstractPlant responses to damage by insectivorous herbivores is well documented in mature leaves. The resulting herbivore-induced plant volatiles (HIPVs) protect the plant by attracting carnivorous arthropods and even some insectivorous vertebrates, to parasitize or consume the plant invaders. However, very little is known about plant production of HIPVs in developing buds, particularly when herbivorous insects are too small to be considered a prey item. It is additionally unclear whether plants respond differently to generalist and specialist chewing insects that overlap in distribution. Therefore, we compared HIPV production of Downy oak (Quercus pubescensWilld.) buds infested with freshly hatched caterpillars ofTortrix viridana(specialist) andOperophtera brumata(generalist), against uninfested buds. Of the compounds identified in both years of the experiment, we found that (Z)-hex-3-enyl acetate, (E)-β-ocimene, acetophenone, linalool, (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT), methyl salicylate,α-copaene,α-humulene, (E)-caryophyllene, and (E,E)-α-farnesene were higher in infested buds compared to controls. We found no difference in HIPV production between the specialist and the generalist herbivores. Production of HIPVs was also associated with leaf damage, with higher HIPV production in more severely attacked buds. Thus, our study shows that oak trees already start responding to insect herbivory before leaves are developed, by producing compounds similar to those found in damaged mature leaves. Future work should focus on how Downy oak may benefit from initiating alarm cues at a time when carnivorous arthropods and insectivorous vertebrates are unable to use herbivorous insects as host or food.
Efficient axonal trafficking of endolysosomes depends on the balanced ratio of microtubule tyrosination and detyrosination
Authors: Konietzny Anja , Peris Leticia , Han Yuhao , Popp Yannes , Bommel Bas van , Sharma Aditi , Delagrange Philippe , Arbez Nicolas , Moutin Marie-Jo , Mikhaylova Marina 
Published: October 2023

AbstractIn neurons, the microtubule (MT) cytoskeleton forms the basis for long-distance protein transport from the cell body into and out of dendrites and axon. To maintain neuronal polarity, the axon initial segment (AIS) serves as a physical barrier, separating the axon from the somatodendritic compartment and acting as a filter for axonal cargo. Selective trafficking is further instructed by axonal enrichment of MT post-translational modifications, which affect MT dynamics and the activity of motor proteins. Here, we compared two knockout mouse lines lacking the respective enzymes for MT tyrosination and detyrosination and we found that both knockouts led to a shortening of the AIS. Neurons from both lines also showed an increased immobile fraction of endolysosomes present in the axon, whereas mobile organelles displayed shortened run distances in the retrograde direction. Overall, our results highlight the importance of maintaining the balance of tyrosinated/detyrosinated MT for proper AIS length and axonal transport processes.Summary StatementDespite opposite effects on microtubule dynamics, shifting the balance of microtubule tyrosination/detyrosination in either direction resulted in surprisingly similar defects in axonal organelle transport.
Di- and tri-methylation of histone H3K36 play distinct roles in DNA double-strand break repair
Authors: Chen Runfa , Zhao Meng-Jie , Li Yu-Min , Liu Ao-Hui , Wang Ru-Xin , Mei Yu-Chao , Chen Xuefeng , Du Hai-Ning 
Published: October 2023

AbstractHistone H3 Lys36 (H3K36) methylation and its associated modifiers are crucial for DNA double-strand break (DSB) repair, but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways is unclear. Here, we unveil the distinct roles of H3K36 dimethylation (H3K36me2) and H3K36 trimethylation (H3K36me3) in DSB repair via non-homologous end joining (NHEJ) or homologous recombination (HR). Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency. yKu70 and Rfa1 bind H3K36me2- or H3K36me3-modified peptides and chromatin, respectively. Disrupting these interactions impairs yKu70 and Rfa1 recruitment to damaged H3K36me2- or H3K36me3-rich loci, increasing DNA damage sensitivity and decreasing repair efficiency. Conversely, H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit yKu70 or Rfa1 under DSB stress. Importantly, human KU70 and RPA1, the homologs of yKu70 and Rfa1, exclusively associate with H3K36me2 and H3K36me3 in a conserved manner. These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways, highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.
Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia
Authors: Sciarretta Francesca , Zaccaria Fabio , Ninni Andrea , Ceci Veronica , Turchi Riccardo , Apolloni Savina , Milani Martina , Valle Ilaria Della , Tiberi Marta , Chiurchiù Valerio , D’Ambrosi Nadia , Pedretti Silvia , Mitro Nico , Aquilano Katia , Lettieri-Barbato Daniele 
Published: October 2023

ABSTRACTImmunometabolism investigates the complex interplay between the immune system and cellular metabolism. This study highlights the effects of mitochondrial frataxin (FXN) depletion, which causes Friedreich’s ataxia (FRDA), a neurodegenerative condition characterized by coordination and muscle control deficiencies. Using single-cell RNA sequencing, we identified specific cell groups in the cerebellum of a FRDA mouse model, emphasizing a notable inflammatory microglial response. These FXN-deficient microglia cells exhibited enhanced inflammatory reactions. Furthermore, our metabolomic analyses revealed increased glycolysis and itaconate production in these cells, possibly driving the inflammation. Remarkably, butyrate treatment counteracted these immunometabolic changes, triggered an antioxidant response via the itaconate-Nrf2-GSH pathways, and dampened inflammation. The study also pinpointed Hcar2 (GPR109A) as a potential agent for butyrate anti-inflammatory impact on microglia. Tests on FRDA mice highlighted the neuroprotective attributes of butyrate intake, bolstering neuromotor performance. In essence, our findings shed light on how cerebellar microglia activation contributes to FRDA and highlight butyrate potential to alleviate neuroinflammation, rectify metabolic imbalances, and boost neuromotor capabilities in FRDA and similar conditions.
A precise balance of TETRASPANIN1/TORNADO2 activity is required for vascular proliferation and ground tissue patterning in Arabidopsis
Authors: Konstantinova Nataliia , Mor Eliana , Verhelst Eline , Nolf Jonah , Vereecken Kenzo , Wang Feng , Van Damme Daniel , De Rybel Bert , Glanc Matouš 
Published: October 2023

AbstractThe molecular mechanisms guiding oriented cell divisions in the root vascular tissues ofArabidopsis thalianaare still poorly characterized. By overlapping bulk and single-cell transcriptomic datasets, we unveiledTETRASPANIN1 (TET1)as a putative regulator in this process.TET1is expressed in root vascular cells and loss-of-function mutants contain fewer vascular cells files. We further generated and characterized a CRISPR deletion mutant and show, unlike previously described mutants, that the full knock out is additionally missing endodermal cells in a stochastic way. Finally, we show that HA-tagged versions of TET1 are functional in contrast to fluorescent TET1 translational fusions. Immunostaining using HA-TET1 lines complementing the mutant phenotype revealed a dual plasma membrane and intracellular localization in the root vasculature and a polar membrane localization in young cortex, endodermal and initial cells. Taken together, we show that TET1 is involved in both vascular proliferation and ground tissue patterning. Our initial results pave the way for future work into deciphering its precise mode of action.Summary statementThis study reveals a novel role of tetraspanin TET1/TRN2 in root vascular development and ground tissue patterning in the model plantArabidopsis thaliana.
Electrosensory and metabolic responses of weakly electric fish to changing water conductivity
Authors: Wiser Shannon D. , Markham Michael R. 
Published: October 2023

AbstractWeakly electric Gymnotiform fishes use self-generated electric organ discharges (EODs) to navigate and communicate. The electrosensory range for these processes is a function of EOD amplitude, determined by the fish’s electric organ (EO) output and the electrical conductivity of the surrounding water. Anthropogenic activity, such as deforestation, dams, and industrial/agricultural runoff, are known to increase water conductivity in neotropical habitats, likely reducing the electrosensory range of these fish. We investigated whether fish modulate EO output as means of re-expanding electrosensory range after a rapid increase in water conductivity in the pulse-typeBrachyhypopomus gauderioand the wave-typeEigenmannia virescens. Furthermore, because EOD production incurs significant metabolic costs, we assessed whether such compensation is associated with an increase in metabolic rate. Following the conductivity increaseB. gauderioincreased EOD amplitude by 20.2 ± 4.3% over six days but with no associated increase in metabolic rate, whereas the EOD amplitude ofE. virescensremained constant, accompanied by an unexpected decrease in metabolic rate. Our results suggest thatB. gauderiouses a compensation mechanism that requires no metabolic investment, such as impedance matching, or a physiological tradeoff wherein energy is diverted from other physiological processes to increase EO output. These divergent responses between species could be the result of differences in reproductive life history or evolutionary adaptations to different aquatic habitats. Continued investigation of electrosensory responses to changing water conditions will be essential for understanding the effects of anthropogenic disturbances on gymnotiforms, and potential physiological mechanisms for adapting to a rapidly changing aquatic environment.
Daylong Acoustic Recordings of Grazing and Rumination Activities in Dairy Cows
Authors: Martinez-Rau Luciano S. , Chelotti José O. , Ferrero Mariano , Utsumi Santiago A. , Planisich Alejandra M. , Vignolo Leandro D. , Giovanini Leonardo L. , Rufiner H. Leonardo , Galli Julio R. 
Published: October 2023

ABSTRACTMonitoring livestock feeding behavior may help assess animal welfare and nutritional status, and to optimize pasture management. The need for continuous and sustained monitoring requires the use of automatic techniques based on the acquisition and analysis of sensor data. This work describes an open dataset of acoustic recordings of the foraging behavior of dairy cows. The dataset includes 662 h of daily records obtained using unobtrusive and non-invasive instrumentation mounted on five lactating multiparous Holstein cows continuously monitored for six non-consecutive days in pasture and barn. Labeled recordings precisely delimiting grazing and rumination bouts are provided for a total of 400 h and for over 6,200 ingestive and rumination jaw movements. Companion information on the audio recording quality and expert-generated labels is also provided to facilitate data interpretation and analysis. This comprehensive dataset is a useful resource for studies aimed at exploring new tools and solutions for precision livestock farming.
Listeriaadhesion protein orchestrates caveolae-mediated apical junctional remodeling of epithelial barrier forL. monocytogenestranslocation
Authors: Drolia Rishi , Tenguria Shivendra , Bryant Donald B. , Thind Jessie , Amelunke Breanna , Liu Dongqi , Gallina Nicholas L.F. , Mishra Krishna K. , Samaddar Manalee , Sawale Manoj R. , Mishra Dharmendra K. , Cox Abigail , Bhunia Arun K 
Published: October 2023

ABSTRACTThe cellular junctional architecture remodeling by LAP-Hsp60 interaction forL. monocytogenes(Lm) passage through the epithelial barrier is incompletely understood. Here, using the gerbil model, permissive to internalin (Inl) A/B-mediated pathways like in humans, we demonstrate thatLmcrosses the intestinal villi at 48 h post-infection. In contrast, the single isogenic (lap─or ΔinlA) or double (lap─ΔinlA) mutant strains show significant defects. LAP promotesLmtranslocation via endocytosis of cell-cell junctional complex in enterocytes that do not display luminal E-cadherin. In comparison, InlA-mediated transcytosis occurs in enterocytes displaying apical E-cadherin during cell extrusion and mucus expulsion from goblet cells. LAP hijacks caveolar endocytosis to traffic integral junctional proteins to the early and recycling endosomes. Pharmacological inhibition in a cell line and genetic knock-out of caveolin-1 in mice prevents LAP-induced intestinal permeability, junctional endocytosis, andLmtranslocation. Furthermore, LAP-Hsp60-dependent tight junction remodeling is also necessary for InlA access to E-cadherin forLmintestinal barrier crossing in InlA-permissive hosts.
Th2 and Th17-Associated Immunopathology Following SARS-CoV-2 Breakthrough Infection in Spike-Vaccinated ACE2-humanized Mice
Authors: Zhang Tianyi , Magazine Nicholas , McGee Michael C. , Carossino Mariano , Veggiani Gianluca , Kousoulas Konstantin G. , August Avery , Huang Weishan 
Published: October 2023

AbstractVaccines have demonstrated remarkable effectiveness in protecting against COVID-19; however, concerns regarding vaccine-associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS-CoV-2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2-biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections. To gain a deeper understanding of the potential risks and the underlying mechanisms of VAERD, we immunized ACE2-humanized mice with SARS-CoV-2 Spike protein adjuvanted with aluminum and CpG-ODN. Subsequently, we exposed them to increasing doses of SARS-CoV-2 to establish a breakthrough infection. The vaccine elicited robust neutralizing antibody responses, reduced viral titers, and enhanced host survival. However, following a breakthrough infection, vaccinated animals exhibited severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4+T cells, along with increased expression of Th2/Th17 cytokines. Intracellular flow cytometric analysis revealed a systemic Th17 inflammatory response, particularly pronounced in the lungs. Our data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1-associated immunity against COVID-19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell-mediated pulmonary immunopathology following a breakthrough infection. These findings underscore the necessity for further research to unravel the complexities of VAERD in COVID-19 and to enhance vaccine formulations for broad protection and maximum safety.Significance statementThis research investigates the safety and efficacy of a Spike protein subunit vaccine adjuvanted with Alum and CpG in an ACE2-humanized mouse model, simulating SARS-CoV-2 breakthrough infections. The study reveals that despite robust protection against severe COVID-19, vaccinated mice exhibit substantial pulmonary immunopathology, including eosinophilia and enhanced Th2 effector immunity, following breakthrough infections. Surprisingly, the study also uncovers a significant systemic Th17 inflammatory response in vaccinated mice. This research sheds light on the potential risks associated with COVID-19 vaccine breakthrough infections and the need for a comprehensive understanding of vaccine-induced immune responses, emphasizing the importance of ongoing research, surveillance, and careful vaccine development for both protection and safety in the fight against the COVID-19 pandemic.
Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection
Authors: Trevino Troy N. , Fogel Avital B. , Minshall Richard , Richner Justin M. , Lutz Sarah E. 
Published: October 2023

AbstractLeukocyte infiltration of the CNS can contribute to neuroinflammation and cognitive impairment. Brain endothelial cells regulate adhesion, activation, and diapedesis of T cells across the blood-brain barrier (BBB) in inflammatory diseases. The integral membrane protein Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on T cell CNS infiltration in respiratory viral infections is unknown. In this study, we sought to determine the role of Cav-1 at the BBB in neuroinflammation in a COVID-19 mouse model. We used mice genetically deficient in Cav-1 to test the role of this protein in T cell infiltration and cognitive impairment. We found that SARS-CoV-2 infection upregulated brain endothelial Cav-1. Moreover, SARS-CoV-2 infection increased brain endothelial cell vascular cell adhesion molecule-1 (VCAM-1) and CD3+ T cell infiltration of the hippocampus, a region important for short term learning and memory. Concordantly, we observed learning and memory deficits. Importantly, genetic deficiency in Cav-1 attenuated brain endothelial VCAM-1 expression and T cell infiltration in the hippocampus of mice with SARS-CoV-2 infection. Moreover, Cav-1 KO mice were protected from the learning and memory deficits caused by SARS-CoV-2 infection. These results indicate the importance of BBB permeability in COVID-19 neuroinflammation and suggest potential therapeutic value of targeting Cav-1 to improve disease outcomes.