bluuebunny/crossref_metadata_2025_split huggingface dataset:
RRIkinDP: Direct Paths RNA-RNA Interaction Kinetics Model
Authors: Waldl Maria , Beckmann Irene K. , Will Sebastian , Hofacker Ivo L. 
Published: July 2023

AbstractInteractions between RNAs are an essential mechanism in gene regulation. State-of-the-art tools predict RNA-RNA interactions based on thermodynamic stability but largely neglect kinetic effects. To overcome this limitation, we propose novel models of RNA-RNA interaction dynamics. On this basis we can improve our understanding of general principles that govern RNA-RNA interaction formation and improve target prediction tools.While the dynamics of secondary structure formation of single RNAs have been successfully modeled using transition systems between conformations [2, 10], analogous approaches for RNA-RNA interaction quickly lead to infeasibly large systems. Therefore, we propose reducing the interaction system to the direct trajectories (shortest paths) from possible first contacts to full hybridization. This key idea enables studying general principles and relevant features of the interaction formation as well as model details; e.g. the relative speed of intra- and intermolecular folding.Due to the design of our RNA kinetics model, features like energy barriers can be computed efficiently. In the future, this could enable refining genome-wide target predictions through kinetic criteria. Beyond these immediate practical improvements, it could shed light on general principles like the long-debated influence of the accessibility of the initial contact site.RRIkinDP is is available on GitHub athttps://github.com/mwaldl/RRIkinDP.
A Compact and Effective Photon-Resolved Image Scanning Microscope
Authors: Tortarolo Giorgio , Zunino Alessandro , Piazza Simonluca , Donato Mattia , Zappone Sabrina , Pierzyńska-Mach Agnieszka , Castello Marco , Vicidomini Giuseppe 
Published: July 2023

AbstractFluorescence confocal laser-scanning microscopy (LSM) is one of the most popular tools for life science research. This popularity is expected to grow thanks to single-photon array detectors tailored for LSM. These detectors offer unique single-photon spatiotemporal information, opening new perspectives for gentle and quantitative super-resolution imaging. However, a flawless recording of this information poses significant challenges for the microscope data-acquisition system. Here, we present a data-acquisition module based on the digital frequency domain principle, able to record photons’ essential spatial and temporal features. We use this module to extend the capabilities of established imaging techniques based on single-photon avalanche diode (SPAD) array detectors, such as fluorescence lifetime image scanning microscopy. Furthermore, we use the module to introduce a robust multi-species approach encoding the fluorophore’s excitation spectra in the time domain. Lastly, we combine time-resolved stimulated emission depletion microscopy with image scanning microscopy, boosting spatial resolution. Our results demonstrate how a conventional fluorescence laser scanning microscope can transform into a simple, information-rich, super-resolved imaging system with the simple addition of a SPAD array detector with a tailored data acquisition system. We expected a blooming of advanced single-photon imaging techniques which effectively harness all the sample information encoded in each photon.
The previously uncharacterized RnpM (YlxR) protein modulates the activity of ribonuclease P inBacillus subtilis
Authors: Wicke Dennis , Neumann Piotr , Gößringer Markus , Chernev Aleksandar , Poehlein Anja , Daniel Rolf , Urlaub Henning , Hartmann Roland K. , Ficner Ralf , Stülke Jörg 
Published: July 2023

ABSTRACTEven thoughBacillus subtilisis one of the most studied organisms, no function has been identified for about 20% of its proteins. Among these unknown proteins are several RNA- and ribosome-binding proteins suggesting that they exert functions in cellular information processing. In this work, we have investigated the RNA-binding protein YlxR. This protein is widely conserved in bacteria and strongly constitutively expressed inB. subtilissuggesting an important function. We have identified the RNA subunit of the essential RNase P as the binding partner of YlxR. The main activity of RNase P is the processing of 5’ ends of pre-tRNAs.In vitroprocessing assays demonstrated that the presence of YlxR results in reduced RNase P activity. Chemical cross-linking studies followed byin silicodocking analysis and experiments with site-directed mutant proteins suggest that YlxR binds to the region of the RNase P RNA that is important for binding and cleavage of the pre-tRNA substrate. We conclude that the YlxR protein is a novel interaction partner of the RNA subunit of RNase P that serves to finetune RNase P activity to ensure appropriate amounts of mature tRNAs for translation. We rename the YlxR protein RnpM for RNase P modulator.
High-quality co-expression networks for accurate gene function predictions in the fungal cell factoryAspergillus nigerand beyond
Authors: Schäpe Paul , Starke Stephan , Schuetze Tabea , Basenko Evelina , Jung Sascha , Cairns Timothy , Meyer Vera 
Published: July 2023

AbstractCo-expression networks have recently emerged as a useful approach for updating and improving gene annotation at a near-genome level. This is based on the hypothesis that function can be inferred by delineating transcriptional networks in which a gene of interest is embedded. In this study, we generated a co-expression network for the filamentous cell factoryAspergillus nigerfrom 128 RNA-seq experiments. We confirm that over 70% of the >14,000A. nigergenes are represented in this network and show that gene functions can be accurately predicted as evidenced by analysis of various control sub-networks. Our analyses further indicate that this RNA-seq co-expression network has a higher predictive power compared to the microarray co-expression network that we published in 2019. To demonstrate the potential of the new co-expression network to unveil complex and non-intuitive predictions for gene regulation phenomena, we provide here new insights into the temporal, spatial and metabolic expression profile that connects a secreted antifungal peptide with mycelial growth, asexual development, secondary metabolism and pectin degradation inA. niger. To empower biologists to generate or apply co-expression networks in the fungal kingdom and beyond, we also demonstrate that (i) high quality networks can be generated from only 32 transcriptional experiments; (ii) such low numbers of experiments can be safely compensated for by using higher thresholds for defining co-expression pairs; and (iii) a ‘safety in numbers’ rule applies, whereby experimental conditions have limited impacts on network content provided a certain number of experiments are included.
RecurrentFBXW7mutations bypass Wnt/β-catenin addiction in cancer
Authors: Zhong Zheng , Virshup David M. 
Published: July 2023

AbstractPathologic Wnt/β-catenin signaling drives various cancers, leading to multiple approaches to drug this pathway. Appropriate patient selection can maximize success of these interventions. Wnt ligand addiction is a druggable vulnerability inRNF43-mutant/RSPO-fusion cancers. However, pharmacologically targeting the biogenesis of Wnt ligands, e.g., with PORCN inhibitors, has shown mixed therapeutic responses, possibly due to tumor heterogeneity. Here we show that the tumor suppressorFBXW7is frequently mutated inRNF43-mutant/RSPO-fusion tumors, andFBXW7mutations cause intrinsic resistance to anti-Wnt therapies. Mechanistically, inactivation of FBXW7 stabilizes multiple oncoproteins including Cyclin E and MYC, and antagonizes the cytostatic effect of Wnt inhibitors. Moreover, althoughFBXW7mutations do not mitigate β-catenin degradation upon Wnt inhibition,FBXW7-mutantRNF43-mutant/RSPO-fusion cancers instead lose dependence on β-catenin signaling, accompanied by dedifferentiation and loss of lineage specificity. TheseFBXW7-mutant Wnt/β-catenin-independent tumors are susceptible to multi-CDK inhibition by dinaciclib. An in depth understanding of primary resistance to anti-Wnt/β-catenin therapies allows for more appropriate patient selection and use of alternative mechanism-based therapies.
Chromatin activity of IκBα mediates the exit from naïve pluripotency
Authors: Palma Luis G. , Álvarez-Villanueva Daniel , Maqueda María , Barrero Mercedes , Iglesias Arnau , Bertran Joan , Álvarez-Errico Damiana , García-Prieto Carlos A. , Ballaré Cecilia , Rodriguez-Cortez Virginia , Bueno Clara , Vidal August , Villanueva Alberto , Menéndez Pablo , Stik Gregoire , Di Croce Luciano , Payer Bernhard , Esteller Manel , Espinosa Lluís , Bigas Anna 
Published: July 2023

SummaryMaintenance of pluripotency is a multifactorial process in which NF-κB is a negative regulator. Our previous work identified a chromatin role for IκBα, the master regulator of NF-κB signaling, that is critical for the proper regulation of various tissue stem cells. Here, we found that IκBα accumulates specifically in the chromatin fraction of pluripotent embryonic stem cells. IκBα depletion does not affect NF-kB-dependent transcription, but causes a profound epigenetic rewiring in pluripotent stem cells, including alterations in H3K27me3, a histone mark catalyzed by Polycomb repression complex 2. Chromatin changes induced by IκBα depletion affect a subset of pluripotency genes and are associated with altered gene transcription. At the cellular level, IκBα-deficient embryonic stem cells are arrested in a naive pluripotency state when cultured in serum/LIF conditions and fail to exit pluripotency under differentiation conditions. By constructing separation-of-function mutants, we show that the effects of IκBα in regulating stem cell pluripotency are NF-κB-independent, but mainly rely on its chromatin-related function. Taken together, our results reveal a novel mechanism by which IκBα participates in the regulation of the pluripotent state of embryonic stem cells and shed light on the interplay between inflammatory signals and the regulation of pluripotency.
Enhancing genetically engineeredEscherichia colibioreporters for the detection of buried TNT-based landmines
Authors: Amiel Eden 
Published: July 2023

ABSTRACTTNT-based buried landmines are explosive devices consisting of mainly 2,4,6-trinitrotoluene (2,4,6-TNT), but also a 2,4-dinitrotoluene (2,4-DNT) impurity. It is reported that some 2,4-DNT impurity vapors slowly leak through land mine covers and into the soil above them, making this compound a potential indicator for the presence of buried landmines. There are several approaches to identify the presence of chemicals in the environment, one of which is based on a microbial detection system. This approach was previously used to address the challenge of remotely identifying buried landmines by applying genetically engineered microbial whole cell biosensors capable of sensing trace signatures of the explosive compound 2,4,6-TNT and its degradation product, 2,4-DNT. Upon exposure to 2,4-DNT, the genetically engineered bacterial reporter strains, containing a genetic fusion between a sensing element for 2,4-DNT (yqjFgene promoter) and a fluorescence/ bioluminescence reporting element (GFP/luxCDABEgenes), generate a measurable dose-dependent signal within the whole cell biosensor system. This biological component of a comprehensive remote sensing solution was significantly improved after several rounds of random mutagenesis to theyqjFpromoter region using a prone-to-error PCR and selection of the best mutants. In the present project further significant improvements were obtained in signal intensity, response time, and in the limit of detection, following an additional round of random mutagenesis. Two new mutants, named A10 and C5, were identified. The new mutants present high induction levels both in terms of Ratio (sample/control) and delta (sample-control), making these strains more amenable to remote detection. To isolate a more sensitive mutant, the 3rd round of random mutagenesis library (about 1000 strains) was re-exposed to lower concentration of 2,4-DNT, but no better candidate was isolated. Possible alternative approaches to lower the detection threshold of the system, such as the use of permeability mutants, are now being tested.
A disinhibitory circuit mechanism explains a general principle of peak performance during mid-level arousal
Authors: Beerendonk Lola , Mejías Jorge F. , Nuiten Stijn A. , de Gee Jan Willem , Fahrenfort Johannes J. , van Gaal Simon 
Published: July 2023

AbstractPerceptual decision-making is highly dependent on the momentary arousal state of the brain, which fluctuates over time on a scale of hours, minutes, and even seconds. The textbook relationship between momentary arousal and task performance is captured by an inverted U-shape, as put forward in the Yerkes-Dodson law (Yerkes and Dodson, 1908). This law suggests optimal performance at moderate levels of arousal, and impaired performance at low or high arousal levels. However, despite its popularity, the evidence for this relationship in humans is mixed at best. Here, we use pupil-indexed arousal and performance data from various perceptual decision-making tasks to provide converging evidence for the inverted U-shaped relationship between spontaneous arousal fluctuations and performance across different decision types (discrimination, detection) and sensory modalities (visual, auditory). To further understand this relationship, we built a neurobiologically plausible mechanistic model and show that it is possible to reproduce our findings by incorporating two types of interneurons that are both modulated by an arousal signal. The model architecture produces two dynamical regimes under the influence of arousal: one regime in which performance increases with arousal, and another regime in which performance decreases with arousal, together forming an inverted U-shaped arousal-performance relationship. We conclude that the inverted U-shaped arousal-performance relationship is a general and robust property of sensory processing. It might be brought about by the influence of arousal on two types of interneurons that together act as a disinhibitory pathway for the neural populations that encode the available sensory evidence used for the decision.Significance statementWhen people are repeatedly performing the exact same task, their performance fluctuates over time. One of the causes of this behavioral variability is spontaneous fluctuations in arousal. According to the Yerkes-Dodson law, task performance is optimal at moderate levels of species’ arousal, with impaired performance at very low or high arousal levels. However, until now, the evidence supporting this law as a general mechanism in human decision-making is mixed, and a neural mechanism that may explain the inverted U-shaped arousal-performance relationship is lacking. We show that the Yerkes-Dodson law is a general law that holds for human observers across decision-making tasks and settings. Furthermore, we present a simple and neurobiologically plausible mechanistic model that can explain its existence.
Centrosome amplification primes for apoptosis and favors the response to chemotherapy in ovarian cancer beyond multipolar divisions
Authors: Edwards Frances , Fantozzi Giulia , Simon Anthony Y. , Morretton Jean-Philippe , Herbette Aurelie , Tijhuis Andrea E. , Wardenaar Rene , Foulane Stacy , Gemble Simon , Spierings Diana C.J. , Foijer Floris , Mariani Odette , Vincent-Salomon Anne , Roman Sergio Roman , Sastre-Garau Xavier , Goundiam Oumou , Basto Renata 
Published: July 2023

ABSTRACTCentrosome amplification is a feature of cancer cells associated with chromosome instability and invasiveness. Enhancing chromosome instability and subsequent cancer cell death via centrosome unclustering and multipolar divisions is an aimed-for therapeutic approach. Here we show that centrosome amplification favors responses to conventional chemotherapy independently of multipolar divisions and chromosome instability. We perform single-cell live imaging of chemotherapy responses in epithelial ovarian cancer cell lines and observe increased cell death when centrosome amplification is induced. By correlating cell fate with mitotic behaviors, we show that enhanced cell death occurs independently of chromosome instability. We identify that cells with centrosome amplification are primed for apoptosis. We show they are dependent on the apoptotic inhibitor BCL-XL, and that this is not a consequence of mitotic stresses associated with centrosome amplification. Given the multiple mechanisms that promote chemotherapy responses in cells with centrosome amplification, we assess such a relationship in an epithelial ovarian cancer patient cohort. We show that high centrosome numbers associate with improved chemotherapy responses and longer overall survival. Our work identifies apoptotic priming as a clinically relevant consequence of centrosome amplification, expanding our understanding of this pleiotropic cancer cell feature.
Predicting real-life creativity using resting state electroencephalography
Authors: Chhade Fatima , Tabbal Judie , Paban Véronique , Auffret Manon , Hassan Mahmoud , Vérin Marc 
Published: July 2023

ABSTRACTNeuroscience research has shown that specific functional brain patterns can be related to creativity during multiple tasks but also at rest. Nevertheless, the electrophysiological correlates of a highly creative brain remain largely unexplored. This study aims to uncover resting-state networks related to real-life creativity using high-density electroencephalography (HD-EEG) and to test whether the strength of functional connectivity within these networks could predict individual creativity. We acquired resting-state HD-EEG data from 90 participants who completed a creativity questionnaire. We then employed connectome-based predictive modeling; a machine-learning technique that predicts behavioral measures from brain connectivity features. Using a support vector regression, our results revealed functional connectivity patterns related to high and low creativity in the gamma frequency band. In leave-one-out cross-validation, the combined model of high and low creativity networks predicted creativity scores with very good accuracy (r= 0.34, p= 0.0009). Furthermore, the model’s predictive power was established by an external validation on an independent dataset (N= 41), where we found a statistically significant relationship between the observed and predicted creativity scores (r= 0.37, p= 0.01). These findings reveal large-scale networks that could predict individual real-life creativity at rest, providing a crucial foundation for developing EEG network-based markers of creativity.
Laminar pattern of adolescent development changes in working memory neuronal activity
Authors: Zhu Junda , Hammond Benjamin M. , Zhou Xin Maizie , Constantinidis Christos 
Published: July 2023

ABSTRACTAdolescent development is characterized by an improvement in cognitive abilities, such as working memory. Neurophysiological recordings in a non-human primate model of adolescence have revealed changes in neural activity that mirror improvement in behavior, including higher firing rate during the delay intervals of working memory tasks. The laminar distribution of these changes is unknown. By some accounts, persistent activity is more pronounced in superficial layers, so we sought to determine whether changes are most pronounced there. We therefore analyzed neurophysiological recordings from neurons recorded in the young and adult stage, at different cortical depths. Superficial layers exhibited increased baseline firing rate in the adult stage. Unexpectedly, changes in persistent activity were most pronounced in the middle layers. Finally, improved discriminability of stimulus location was most evident in the deeper layers. These results reveal the laminar pattern of neural activity maturation that is associated with cognitive improvement.NEW AND NOTEWORTHYStructural brain changes are evident during adolescent development particularly in the cortical thickness of the prefrontal cortex, at a time when working memory ability increases markedly. The depth distribution of neurophysiological changes during adolescence is not known. Here we show that neurophysiological changes are not confined to superficial layers, which have most often been implicated in the maintenance of working memory. Contrary to expectations, greatest changes were evident in intermediate layers of the prefrontal cortex.
Conserved atypical cadherin, Fat2, regulates axon terminal organization in the developingDrosophilaolfactory sensory neurons
Authors: Vien Khanh M. , Duan Qichen , Yeung Chun , Volkan Pelin Cayirlioglu 
Published: July 2023

AbstractA unique and defining characteristic of the olfactory sensory circuit is its functionally organized topographic map, which requires widely dispersed olfactory sensory neurons with the same identity to converge their axons into one neuropil, a class-specific glomerulus. Understanding the process of how neuronal identity confers circuit organization is a major endeavor in the field of neurobiology due to its intricate connection to neurodegeneration and neuronal dysfunction. In the olfactory system, many aspects of circuit organization, from axon guidance to synaptic matching, are regulated by a variety of cell surface proteins (for example Robo/Slit and Toll receptors). In this paper, we’ve identified a novel atypical cadherin protein, Fat2 (also known as Kugelei), as a regulator of class-specific axon organization. Fat2 is expressed in olfactory receptor neurons (ORNs) and local interneurons (LNs) within the olfactory circuits, but little to no expression is found in projection neurons (PNs). Fat2 expression levels vary in a neuronal class-specific manner and peak during pupal development. Infat2null mutants, ORN axon terminals belonging to different ORN classes present with varying phenotypic severity with the highestfat2expressing classes being most severely affected. In the most extreme cases,fat2mutations lead to ORN degeneration. We then show evidence that suggests Fat2 intracellular domain is necessary for Fat2 function in ORN axon organization. Within the developmental context, Fat2 is required starting at early stages of olfactory circuit development specifically for precise axon retraction to further condense class-specific glomeruli. We’ve also shown that PNs’ and LNs’ expression of Fat2 likely does not contribute to ORN organization1. Lastly, we narrow down potential Fat2 intracellular domain interactors, APC family proteins (Adenomatous polyposis coli) anddop(Drop out), that likely orchestrate the cytoskeletal remodeling required for axon retraction during protoglomerular development. Altogether, we provide a foundational understanding of how Fat2 functions in olfactory circuit organization and implicate the critical role of axon retraction during glomerular maturation.