bluuebunny/crossref_metadata_2025_split huggingface dataset:
Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR
Authors: Burger Wessel A. C. , Pham Vi , Vuckovic Ziva , Powers Alexander S. , Mobbs Jesse I. , Laloudakis Yianni , Glukhova Alisa , Wootten Denise , Tobin Andrew B. , Sexton Patrick M. , Paul Steven M. , Felder Christian C. , Danev Radostin , Dror Ron O. , Christopoulos Arthur , Valant Celine , Thal David M. 
Published: September 2023

AbstractThe M4 muscarinic acetylcholine receptor (M4 mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, cognition, and addiction. The mAChR agonist, xanomeline, has provided significant improvement in the Positive and Negative Symptom Scale (PANSS) scores in a Phase II clinical trial for the treatment of patients suffering from schizophrenia. Here we report the active state cryo-EM structure of xanomeline bound to the human M4 mAChR in complex with the heterotrimeric Gi1 transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M4 mAChR, with one molecule bound in the orthosteric (acetylcholine-binding) site and a second molecule in an extracellular vestibular allosteric site. Molecular dynamic simulations supports the structural findings, and pharmacological validation confirmed that xanomeline acts as a dual orthosteric and allosteric ligand at the human M4 mAChR. These findings provide a basis for further understanding xanomeline’s complex pharmacology and highlight the myriad of ways through which clinically relevant ligands can bind to and regulate GPCRs.
Evolutionary selection of proteins with two folds
Authors: Schafer Joseph W. , Porter Lauren L. 
Published: September 2023

AbstractAlthough most globular proteins fold into a single stable structure, an increasing number have been shown to remodel their secondary and tertiary structures in response to cellular stimuli. State-of-the-art algorithms predict that these fold-switching proteins adopt only one stable structure, missing their functionally critical alternative folds. Why these algorithms predict a single fold is unclear, but all of them infer protein structure from coevolved amino acid pairs. Here, we hypothesize that coevolutionary signatures are being missed. Suspecting that single-fold variants could be masking these signatures, we developed an approach, called Alternative Contact Enhancement (ACE), to search both highly diverse protein superfamilies–composed of single-fold and fold-switching variants–and protein subfamilies with more fold-switching variants. ACE successfully revealed coevolution of amino acid pairs uniquely corresponding to both conformations of 56/56 fold-switching proteins from distinct families. Then, we used ACE-derived contacts to (1) predict two experimentally consistent conformations of a candidate protein with unsolved structure and (2) develop a blind prediction pipeline for fold-switching proteins. The discovery of widespread dual-fold coevolution indicates that fold-switching sequences have been preserved by natural selection, implying that their functionalities provide evolutionary advantage and paving the way for predictions of diverse protein structures from single sequences.
A systematic discrepancy between the short circuit current and the integrated quantum efficiency in perovskite solar cells
Authors: Saliba Michael , Unger Eva , Etgar Lioz , Luo Jingshan , Jacobsson T. Jesper 
Published: September 2023

AbstractHalide perovskites solar cells are now approaching commercialisation. In this transition from academic research towards industrialisation, standardized testing protocols and reliable dissemination of performance metrics are crucial. In this study, we analyze data from over 16,000 publications in the Perovskite Database to investigate the assumed equality between the integrated external quantum efficiency and the short circuit current from JV measurements. We find a systematic discrepancy with the JV-values being on average 4% larger. This discrepancy persists across time, perovskite composition, and device architecture, indicating the need to explore new perovskite physics and update reporting protocols and assumptions in the field.
Bacteroides Fragilis in the gut microbiomes of Alzheimer’s disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice
Authors: Xia Yiyuan , Xiao Yifan , Wang Zhi-Hao , Liu Xia , Alam Ashfaqul M. , Haran John P. , McCormick Beth A. , Shu Xiji , Wang Xiaochuan , Ye Keqiang 
Published: September 2023

AbstractGut dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors’ fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPβ transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPβ transgenic mice.
Doubling of surface oceanic meridional heat transport by non-symmetry of mesoscale eddies
Authors: Wang Hailin , Qiu Bo , Liu Hanrui , Zhang Zhengguang 
Published: September 2023

AbstractOceanic transport of heat by ubiquitous mesoscale eddies plays a critical role in regulating climate variability and redistributing excess heat absorbed by ocean under global warming. Eddies have long been simplified as axisymmetric vortices and their influence on heat transport remains unclear. Here, we combine satellite and drifter data and show that oceanic mesoscale eddies are asymmetric and directionally-dependent, and are controlled by their self-sustaining nature and their dynamical environment. Both the direction and amplitude of eddy-induced heat fluxes are significantly influenced by eddy’s asymmetry and directional dependence. When the eddy velocity field is decomposed into asymmetric and symmetric components, the eddy kinetic energy exhibits a nearly equal partition between these two components. The total eddy-induced meridional heat flux similarly doubles the heat flux induced by the symmetric components, highlighting the crucial contribution of eddy asymmetry on the magnitude of eddy-induced oceanic heat transport.
Stacking transfer of wafer-scale graphene-based van der Waals superlattices
Authors: Yuan Guowen , Liu Weilin , Huang Xianlei , Wan Zihao , Wang Chao , Yao Bing , Sun Wenjie , Zheng Hang , Yang Kehan , Zhou Zhenjia , Nie Yuefeng , Xu Jie , Gao Libo 
Published: September 2023

AbstractHigh-quality graphene-based van der Waals superlattices are crucial for investigating physical properties and developing functional devices. However, achieving homogeneous wafer-scale graphene-based superlattices with controlled twist angles is challenging. Here, we present a flat-to-flat transfer method for fabricating wafer-scale graphene and graphene-based superlattices. The aqueous solution between graphene and substrate is removed by a two-step spinning-assisted dehydration procedure with the optimal wetting angle. Proton-assisted treatment is further used to clean graphene surfaces and interfaces, which also decouples graphene and neutralizes the doping levels. Twist angles between different layers are accurately controlled by adjusting the macroscopic stacking angle through their wafer flats. Transferred films exhibit minimal defects, homogeneous morphology, and uniform electrical properties over wafer scale. Even at room temperature, robust quantum Hall effects are observed in graphene films with centimetre-scale linewidth. Our stacking transfer method can facilitate the fabrication of graphene-based van der Waals superlattices and accelerate functional device applications.
A catalytically active oscillator made from small organic molecules
Authors: ter Harmsel Matthijs , Maguire Oliver R. , Runikhina Sofiya A. , Wong Albert S. Y. , Huck Wilhelm T. S. , Harutyunyan Syuzanna R. 
Published: September 2023

AbstractOscillatory systems regulate many biological processes, including key cellular functions such as metabolism and cell division, as well as larger-scale processes such as circadian rhythm and heartbeat1–4. Abiotic chemical oscillations, discovered originally in inorganic systems5,6, inspired the development of various synthetic oscillators for application as autonomous time-keeping systems in analytical chemistry, materials chemistry and the biomedical field7–17. Expanding their role beyond that of a pacemaker by having synthetic chemical oscillators periodically drive a secondary function would turn them into significantly more powerful tools. However, this is not trivial because the participation of components of the oscillator in the secondary function might jeopardize its time-keeping ability. We now report a small molecule oscillator that can catalyse an independent chemical reaction in situ without impairing its oscillating properties. In a flow system, the concentration of the catalytically active product of the oscillator shows sustained oscillations and the catalysed reaction is accelerated only during concentration peaks. Augmentation of synthetic oscillators with periodic catalytic action allows the construction of complex systems that, in the future, may benefit applications in automated synthesis, systems and polymerization chemistry and periodic drug delivery.
Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis
Authors: Gelot Camille , Kovacs Marton Tibor , Miron Simona , Mylne Emilie , Haan Alexis , Boeffard-Dosierre Liza , Ghouil Rania , Popova Tatiana , Dingli Florent , Loew Damarys , Guirouilh-Barbat Josée , Del Nery Elaine , Zinn-Justin Sophie , Ceccaldi Raphael 
Published: September 2023

AbstractDNA double-strand breaks (DSBs) are deleterious lesions that challenge genome integrity. To mitigate this threat, human cells rely on the activity of multiple DNA repair machineries that are tightly regulated throughout the cell cycle1. In interphase, DSBs are mainly repaired by non-homologous end joining and homologous recombination2. However, these pathways are completely inhibited in mitosis3–5, leaving the fate of mitotic DSBs unknown. Here we show that DNA polymerase theta6 (Polθ) repairs mitotic DSBs and thereby maintains genome integrity. In contrast to other DSB repair factors, Polθ function is activated in mitosis upon phosphorylation by Polo-like kinase 1 (PLK1). Phosphorylated Polθ is recruited by a direct interaction with the BRCA1 C-terminal domains of TOPBP1 to mitotic DSBs, where it mediates joining of broken DNA ends. Loss of Polθ leads to defective repair of mitotic DSBs, resulting in a loss of genome integrity. This is further exacerbated in cells that are deficient in homologous recombination, where loss of mitotic DSB repair by Polθ results in cell death. Our results identify mitotic DSB repair as the underlying cause of synthetic lethality between Polθ and homologous recombination. Together, our findings reveal the critical importance of mitotic DSB repair in the maintenance of genome integrity.
Isolation of Spirosoma foliorum sp. nov. from the fallen leaf of Acer palmatum by a novel cultivation technique
Authors: Han Ho Le , Nurcahyanto Dian Alfian , Muhammad Neak , Lee Yong-Jae , Nguyen Tra T. H. , Kim Song-Gun , Chan Sook Sin , Khoo Kuan Shiong , Chew Kit Wayne , Show Pau Loke , Tran Thi Ngoc Thu , Nguyen Thi Dong Phuong , Chiu Chen Yaw 
Published: September 2023

AbstractIn the effort of isolating novel microbial species, the strain PL0132T was isolated from a fallen leaf under fresh water at a stream, which glided when grown on a tap water medium (without nutrients). The strain was determined to be Gram-negative, strictly aerobic, and rod-shaped, which grew optimally at 25 °C, pH 6–7, and the strain tolerates 1% (w/v) NaCl concentration. The complete genome of strain PL0132T comprises one contig with a sequencing depth of 76×, consisting of 8,853,064 base pairs and the genomic DNA G + C content was 46.7% (genome). 16S rRNA gene sequence analysis revealed that strain PL0132T represents a member of the phylum Bacteroidetes and is affiliated with the genus Spirosoma. Based on genomic, phenotypic, and chemotaxonomic characteristics, the strain PL0132T represents a novel species of the genus Spirosoma, for which the name Spirosoma foliorum sp. nov. is proposed (= KCTC 72228 T = InaCC B1447T).
Gut commensal Kineothrix alysoides mitigates liver dysfunction by restoring lipid metabolism and gut microbial balance
Authors: Choi Kyoung Jin , Yoon Mi Young , Kim Ji-Eun , Yoon Sang Sun 
Published: September 2023

AbstractMetabolic dysfunction-associated steatotic liver disease (MASLD), previously known as Non-Alcoholic Fatty Liver Disease, is a widespread liver condition characterized by excessive fat buildup in hepatocytes without significant alcohol consumption. Manipulation of the gut microbiome has been considered to prevent and improve the occurrence and progression of MASLD, particularly through the gut-liver axis. This study aimed to investigate the correlation between the gut microbiome and liver function and determine whether the gut microbiome can ameliorate MASLD. We comparatively analyzed the gut microbiome composition between mice fed normal chow and those fed a high-fat diet and observed that the abundance of Kineothrix alysoides decreased in the high-fat group. Further analysis showed that treatment with K. alysoides in the high-fat diet group led to decreased weight loss, and MASLD attenuation. Importantly, K. alysoides treatment attenuated MASLD in mice fed a high-fat, high-fructose diet (HFHF), which can cause advanced liver damage. Furthermore, administration of K. alysoides altered the gut microbial composition in the HFHF diet group and improved MASLD. Overall, these findings demonstrate the potential of K. alysoides in restoring gut health and facilitating lipid metabolism to prevent and treat MASLD.
Novel cationic cryptides in Penaeus vannamei demonstrate antimicrobial and anti-cancer activities
Authors: Abd El-Aal Amr Adel Ahmed , Jayakumar Fairen Angelin , Lahiri Chandrajit , Tan Kuan Onn , Reginald Kavita 
Published: September 2023

AbstractCryptides are a subfamily of bioactive peptides that exist in all living organisms. They are latently encrypted in their parent sequences and exhibit a wide range of biological activities when decrypted via in vivo or in vitro proteases. Cationic cryptides tend to be drawn to the negatively charged membranes of microbial and cancer cells, causing cell death through various mechanisms. This makes them promising candidates for alternative antimicrobial and anti-cancer therapies, as their mechanism of action is independent of gene mutations. In the current study, we employed an in silico approach to identify novel cationic cryptides with potential antimicrobial and anti-cancer activities in atypical and systematic strategy by reanalysis of a publicly available RNA-seq dataset of Pacific white shrimp (Penaus vannamei) in response to bacterial infection. Out of 12 cryptides identified, five were selected based on their net charges and potential for cell penetration. Following chemical synthesis, the cryptides were assayed in vitro to test for their biological activities. All five cryptides demonstrated a wide range of selective activity against the tested microbial and cancer cells, their anti-biofilm activities against mature biofilms, and their ability to interact with Gram-positive and negative bacterial membranes. Our research provides a framework for a comprehensive analysis of transcriptomes in various organisms to uncover novel bioactive cationic cryptides. This represents a significant step forward in combating the crisis of multi-drug-resistant microbial and cancer cells, as these cryptides neither induce mutations nor are influenced by mutations in the cells they target.
Structural and functional analysis of aquaporin-2 mutants involved in nephrogenic diabetes insipidus
Authors: Hagströmer Carl Johan , Hyld Steffen Jonas , Kreida Stefan , Al-Jubair Tamim , Frick Anna , Gourdon Pontus , Törnroth-Horsefield Susanna 
Published: September 2023

AbstractAquaporins are water channels found in the cell membrane, where they allow the passage of water molecules in and out of the cells. In the kidney collecting duct, arginine vasopressin-dependent trafficking of aquaporin-2 (AQP2) fine-tunes reabsorption of water from pre-urine, allowing precise regulation of the final urine volume. Point mutations in the gene for AQP2 may disturb this process and lead to nephrogenic diabetes insipidus (NDI), whereby patients void large volumes of highly hypo-osmotic urine. In recessive NDI, mutants of AQP2 are retained in the endoplasmic reticulum due to misfolding. Here we describe the structural and functional characterization of three AQP2 mutations associated with recessive NDI: T125M and T126M, situated close to a glycosylation site and A147T in the transmembrane region. Using a proteoliposome assay, we show that all three mutants permit the transport of water. The crystal structures of T125M and T126M together with biophysical characterization of all three mutants support that they retain the native structure, but that there is a significant destabilization of A147T. Our work provides unique molecular insights into the mechanisms behind recessive NDI as well as deepens our understanding of how misfolded proteins are recognized by the ER quality control system.
Investigating social comparison behaviour in an immersive virtual reality classroom based on eye-movement data
Authors: Hasenbein Lisa , Stark Philipp , Trautwein Ulrich , Gao Hong , Kasneci Enkelejda , Göllner Richard 
Published: September 2023

AbstractHigher-achieving peers have repeatedly been found to negatively impact students’ evaluations of their own academic abilities (i.e., Big-Fish-Little-Pond Effect). Building on social comparison theory, this pattern is assumed to result from students comparing themselves to their classmates; however, based on existing research designs, it remains unclear how exactly students make use of social comparison information in the classroom. To determine the extent to which students (N = 353 sixth graders) actively attend and respond to social comparison information in the form of peers’ achievement-related behaviour, we used eye-tracking data from an immersive virtual reality (IVR) classroom. IVR classrooms offer unprecedented opportunities for psychological classroom research as they allow to integrate authentic classroom scenarios with maximum experimental control. In the present study, we experimentally varied virtual classmates’ achievement-related behaviour (i.e., their hand-raising in response to the teacher’s questions) during instruction, and students’ eye and gaze data showed that they actively processed this social comparison information. Students who attended more to social comparison information (as indicated by more frequent and longer gaze durations at peer learners) had less favourable self-evaluations. We discuss implications for the future use of IVR environments to study behaviours in the classroom and beyond.
Deep learning for video-based automated pain recognition in rabbits
Authors: Feighelstein Marcelo , Ehrlich Yamit , Naftaly Li , Alpin Miriam , Nadir Shenhav , Shimshoni Ilan , Pinho Renata H. , Luna Stelio P. L. , Zamansky Anna 
Published: September 2023

AbstractDespite the wide range of uses of rabbits (Oryctolagus cuniculus) as experimental models for pain, as well as their increasing popularity as pets, pain assessment in rabbits is understudied. This study is the first to address automated detection of acute postoperative pain in rabbits. Using a dataset of video footage of n = 28 rabbits before (no pain) and after surgery (pain), we present an AI model for pain recognition using both the facial area and the body posture and reaching accuracy of above 87%. We apply a combination of 1 sec interval sampling with the Grayscale Short-Term stacking (GrayST) to incorporate temporal information for video classification at frame level and a frame selection technique to better exploit the availability of video data.
Communicating emotions, but not expressing them privately, reduces moral punishment in a Prisoner’s Dilemma game
Authors: Philippsen Ana , Mieth Laura , Buchner Axel , Bell Raoul 
Published: September 2023

AbstractThe existence of moral punishment, that is, the fact that cooperative people sacrifice resources to punish defecting partners requires an explanation. Potential explanations are that people punish defecting partners to privately express or to communicate their negative emotions in response to the experienced unfairness. If so, then providing participants with alternative ways to privately express or to communicate their emotions should reduce moral punishment. In two experiments, participants interacted with cooperating and defecting partners in a Prisoner’s Dilemma game. After each round, participants communicated their emotions to their partners (Experiments 1 and 2) or only expressed them privately (Experiment 2). Each trial concluded with a costly punishment option. Compared to a no-expression control group, moral punishment was reduced when emotions were communicated to the defecting partner but not when emotions were privately expressed. Moral punishment may thus serve to communicate emotions to defecting partners. However, moral punishment was only reduced but far from being eliminated, suggesting that the communication of emotions does not come close to replacing moral punishment. Furthermore, prompting participants to focus on their emotions had undesirable side-effects: Privately expressing emotions diminished cooperation, enhanced hypocritical punishment (i.e., punishment of defecting partners by defecting participants), and induced an unspecific bias to punish the partners irrespective of their actions.
RNA contact prediction by data efficient deep learning
Authors: Taubert Oskar , von der Lehr Fabrice , Bazarova Alina , Faber Christian , Knechtges Philipp , Weiel Marie , Debus Charlotte , Coquelin Daniel , Basermann Achim , Streit Achim , Kesselheim Stefan , Götz Markus , Schug Alexander 
Published: September 2023

AbstractOn the path to full understanding of the structure-function relationship or even design of RNA, structure prediction would offer an intriguing complement to experimental efforts. Any deep learning on RNA structure, however, is hampered by the sparsity of labeled training data. Utilizing the limited data available, we here focus on predicting spatial adjacencies ("contact maps”) as a proxy for 3D structure. Our model, BARNACLE, combines the utilization of unlabeled data through self-supervised pre-training and efficient use of the sparse labeled data through an XGBoost classifier. BARNACLE shows a considerable improvement over both the established classical baseline and a deep neural network. In order to demonstrate that our approach can be applied to tasks with similar data constraints, we show that our findings generalize to the related setting of accessible surface area prediction.