bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficient numerosity estimation under limited time
Authors: Heng Joseph A. , Woodford Michael , Polania Rafael 
Published: July 2023

AbstractThe ability to rapidly estimate non-symbolic numerical quantities is a well-conserved sense across species with clear evolutionary advantages. Despite its importance, the rapid representation and estimation of numerosity is surprisingly imprecise and biased. However, a formal explanation for this seemingly irrational behavior remains unclear. We develop a unified normative theory of numerosity estimation that parsimoniously incorporates in a single framework information processing constraints alongside Brownian diffusion noise to capture the effects of time exposure of sensory estimations, logarithmic encoding of numerosity representations, and optimal inference via Bayesian decoding. We show that for a given allowable biological capacity constraint our model naturally endogenizes time perception during noisy efficient encoding to predict the complete posterior distribution of numerosity estimates. This model accurately predicts many features of human numerosity estimation as a function of temporal exposure, indicating that humans can rapidly and efficiently sample numerosity information over time. Additionally, we demonstrate how our model fundamentally differs from a thermodynamically-inspired formalization of bounded rationality, where information processing is modeled as acting to shift away from default states. The mechanism we propose is the likely origin of a variety of numerical cognition patterns observed in humans and other animals.Author summaryHumans have the ability to estimate the number of elements in a set without counting. We share this ability with other species, suggesting that it is evolutionarily relevant. However, despite its relevance, this sense is variable and biased. What is the origin of these imprecisions? We take the view that they are the result of an optimal use of limited neural resources. Because of these limitations, stimuli are encoded with noise. The observer then optimally decodes these noisy representations, taking into account its knowledge of the distribution of stimuli. We build on this view and incorporate stimulus presentation time (or contrast) directly into the encoding process using Brownian motion. This model can parsimoniously predict key characteristics of our perception and outperforms quantitatively and qualitatively a popular modeling approach that considers resource limitations at the stage of the response rather than the encoding.
“In silicocharacterization of Protein L-Iso-Aspartate-O-Methyltransferases (PIMT) ofShigella flexneri”
Authors: Gupta Akanksha , Mardi Pragati , Saumya  , Mishra Prasanta Kumar K. 
Published: July 2023

AbstractThere are only a few protein repair enzymes known. One of them, Protein Iso-Aspartate Methyltransferases (PIMT), also known as Protein Carboxyl Methyltransferases (PCMT), is responsible for converting Iso-Aspartate (abnormal amino acid residues) to Aspartate (normal amino acid residues). PCMT is an enzyme found in a wide range of living organisms. In the present study, the amino acid sequence of PIMT ofShigella flexneriwas retrieved and the 3D structure is predicted. Further, it is characterized byin silicoapproaches and its interaction with one of the target proteinsi. e. rpoS is studied.
Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution
Authors: Yadav Manish K. , Sarma Parishmita , Ganguly Manisankar , Mishra Sudha , Maharana Jagannath , Zaidi Nashrah , Dalal Annu , Singh Vinay , Saha Sayantan , Mahajan Gargi , Sharma Saloni , Chami Mohamed , Banerjee Ramanuj , Shukla Arun K. 
Published: July 2023

AbstractThe Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical G protein-coupled receptor that plays a central role in the inhibition of lipolytic and atherogenic activities in our body. Interestingly, GPR109A activation also results in vasodilation that is linked to the side-effect of flushing associated with dyslipidemia drugs such as niacin. This receptor continues to be a key target for developing novel pharmacophores and lead compounds as potential therapeutics in dyslipidemia with minimized flushing response, however, the lack of structural insights into agonist-binding and receptor activation has limited the efforts. Here, we present five different cryo-EM structures of the GPR109A-G-protein complexes with the receptor bound to dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures allow us to visualize the binding mechanism of agonists with a conserved molecular interaction network, and elucidate the previously lacking molecular basis of receptor activation and transducer-coupling. Importantly, cellular pharmacology experiments, guided by the structural framework determined here, elucidate pathway-selective biased signaling elicited by the non-flushing agonists. Finally, taking lead from the structural insights, we successfully engineered receptor mutants via single amino acid substitutions that either fail to elicit agonist-induced transducer-coupling or exhibits G-protein signaling bias. Taken together, our study provides previously lacking structural framework to understand the agonist-binding and activation of GPR109A, and opens up the possibilities of structure-guided novel drug discovery targeting this therapeutically important receptor.
Comparisons of two receptor pathways in a single cell-type reveal features of signalling specificity
Authors: Ma Yan , Flückiger Isabelle , Nicolet Jade , Pang Jia , Dickinson Joe , De Bellis Damien , Emonet Aurélia , Fujita Satoshi , Geldner Niko 
Published: July 2023

SummaryTo respond appropriately to diverse stimuli, cells harbour numerous receptor pathways yet share downstream signalling components. Mitogen-Activated Protein Kinase (MPK) cascades, present in all eukaryotes, act as central hubs shared amongst diverse signalling pathways. How signalling specificity is maintained within a single plant cell-type is not well understood. We engineered a genetic background for direct comparisons of a developmental and an immunity pathway in the Arabidopsis root endodermis. We show the two pathways maintain distinct outputs despite similar MPK phosphorylation patterns. Systematic activation of all individual MPK Kinases (MKKs) in the endodermis revealed that different MKK groups can drive distinct outputs. We propose that specificity is achieved through a balance of combinatorial activation and cross-pathway inhibition within the MPK cascade. Our findings demonstrate the ability of MPK cascades to generate diverse outputs in one plant cell-type, providing new insights into the mechanisms contributing to signalling specificity.
Oscillatory waveform shape and temporal spike correlations differ across bat frontal and auditory cortex
Authors: García-Rosales Francisco , Schaworonkow Natalie , Hechavarria Julio C. 
Published: July 2023

AbstractNeural oscillations are associated with diverse computations in the mammalian brain. The waveform shape of oscillatory activity measured in cortex relates to local physiology, and can be informative about aberrant or dynamically changing states. However, how waveform shape differs across distant yet functionally and anatomically related cortical regions is largely unknown. In this study, we capitalize on simultaneous recordings of local field potentials (LFPs) in the auditory and frontal cortices of awake, maleCarollia perspicillatabats to examine, on a cycle-by-cycle basis, waveform shape differences across cortical regions. We find that waveform shape differs markedly in the fronto-auditory circuit even for temporally correlated rhythmic activity in comparable frequency ranges (i.e. in the delta and gamma bands) during spontaneous activity. In addition, we report consistent differences between areas in the variability of waveform shape across individual cycles. A conceptual model predicts higher spike-spike and spike-LFP correlations in regions with more asymmetric shape, a phenomenon that was observed in the data: spike-spike and spike-LFP correlations were higher in frontal cortex. The model suggests a relationship between waveform shape differences and differences in spike correlations across cortical areas. Altogether, these results indicate that oscillatory activity in frontal and auditory cortex possess distinct dynamics related to the anatomical and functional diversity of the fronto-auditory circuit.Significance statementThe brain activity of many animals displays intricate oscillations, which are usually characterized in terms of their frequency and amplitude. Here, we study oscillations from the bat frontal and auditory cortices on a cycle-by-cycle basis, additionally focusing on their characteristic waveform shape. The study reveals clear differences across regions in waveform shape and oscillatory regularity, even when the frequency of the oscillations is similar. A conceptual model predicts that more asymmetric waveforms result from stronger correlations between neural spikes and electrical field activity. Such predictions were supported by the data. The findings shed light onto the unique properties of different cortical areas, providing key insights into the distinctive physiology and functional diversity within the fronto-auditory circuit.
The substrate quality of CK2 target sites has a determinant role on their function and evolution
Authors: Bradley David , Garand Chantal , Belda Hugo , Gagnon-Arsenault Isabelle , Treeck Moritz , Elowe Sabine , Landry Christian R 
Published: July 2023

AbstractMost biological processes are regulated by peptide-recognition modules (PRMs) that bind to short linear motifs (SLiMs). Such interactions are rapidly reversible and often occur at low affinity. The protein kinase domain represents one such binding module, and known substrates may have full or only partial matches to the kinase recognition motif, a property known as ‘substrate quality’. However, it is not yet clear whether differences in substrate quality represent neutral variation along the phosphosite sequence or if these differences have functional consequences that are subject to selection. We explore this question in detail for the acidophilic kinase CK2. CK2 is well-characterised, clinically important, and a fundamental enzyme for many aspects of cell biology. We show that optimal CK2 sites are phosphorylated at maximal stoichiometries and found in many conditions whereas minimal substrates are phosphorylated at lower stoichiometries, are more dynamic during the cell cycle, and have regulatory functions. Optimal CK2 sites also tend to be older and more conserved than minimal sites, and evolutionary simulations indicate that the substrate quality of CK2 phosphosites is often tuned by selection. For intermediate target sites, increases or decreases to substrate quality may be deleterious, which we demonstrate experimentally for a CK2 substrate at the kinetochore. The results together suggest that minimal and optimal phosphosites are strongly differentiated in terms of their functional and evolutionary properties.
β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain
Authors: Madhavan SS , Roa Diaz S , Peralta S , Nomura M , King CD , Lin A , Bhaumik D , Shah S , Blade T , Gray W , Chamoli M , Eap B , Panda O , Diaz D , Garcia TY , Stubbs BJ , Lithgow GJ , Schilling B , Verdin E , Chaudhuri AR , Newman JC 
Published: July 2023

SUMMARYLoss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility in the aging brain. βHB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions. We demonstrate βHB-induced protein insolubility acrossin vitro,ex vivo, andin vivomouse systems. This activity is shared by select structurally similar metabolites, is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brainin vivoafter delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We have generated a comprehensive atlas of the βHB-induced protein insolublomeex vivoandin vivousing mass spectrometry proteomics, and have identified common protein domains within βHB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain, likely via βHB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.
Baited reconstruction with 2D template matching for high-resolution structure determinationin vitroandin vivowithout template bias
Authors: Lucas Bronwyn A. , Himes Benjamin A. , Grigorieff Nikolaus 
Published: July 2023

AbstractCryogenic electron microscopy (cryo-EM) has revolutionized structural biology, rapidly increasing the number of available molecular structures. Because of this, as well as advances in structure prediction, the focus of structural biology has begun to shift to studying macromolecular structures in their native cellular environment. A dominant feature of cryo-EM images is shot noise, making the identification of small particles of interest difficult. This is further compounded by structural noise if these particles are imaged against a background of other molecules, such as inside a cell. 2D template matching (2DTM) can be used to localize complexes with high precision, even in the presence of cellular background. Once localized, these particles may be averaged together in 3D reconstructions; however, regions included in the template may suffer from template bias, leading to inflated resolution estimates and making the interpretation of high-resolution features unreliable. We evaluate conditions that minimize template bias and show that molecular featuresnotpresent in the template can be reconstructed at high resolution from targets found by 2DTM, extending prior work at low-resolution.Moreover, we present a quantitative metric for template bias to aid the interpretation of 3D reconstructions calculated with particles localized using high-resolution templates and fine angular sampling.
Spatial confinement ofTrypanosoma bruceiin microfluidic traps provides a new tool to study free swimming parasites
Authors: De Niz Mariana , Frachon Emmanuel , Gobaa Samy , Bastin Philippe 
Published: July 2023

AbstractTrypanosoma bruceiis the causative agent of African trypanosomiasis and is transmitted by the tsetse fly (Glossina spp.). All stages of this extracellular parasite possess a single flagellum that is attached to the cell body and confers a high degree of motility. While several stages are amenable to culturein vitro,longitudinal high-resolution imaging of free-swimming parasites has been challenging, mostly due to the rapid flagellar beating that permanently twists the cell body. Here, using microfabrication, we generated various microfluidic devices with traps of different geometrical properties. Investigation of trap topology allowed us to define the one most suitable for singleT. bruceiconfinement within the field of view of an inverted microscope while allowing the parasite to remain motile. Chips populated with V-shaped traps allowed us to investigate various phenomena in cultured procyclic stage wild-type parasites, and to compare them with parasites whose motility was altered upon knockdown of a paraflagellar rod component. Among the properties that we investigated were trap invasion, exploratory behaviour, and the visualization of organelles labelled with fluorescent dyes. We envisage that this “Tryp-Chip” will be a useful tool for the scientific community, as it could allow high-throughput, high-temporal and high-spatial resolution imaging of free-swimmingT. bruceiparasites.
Structure and engineering of miniatureAcidibacillus sulfuroxidansCas12f1
Authors: Wu Zhaowei , Liu Dongliang , Pan Deng , Yu Haopeng , Shi Jin , Ma Jiacheng , Fu Wenhan , Wang Zhipeng , Zheng Zijie , Qu Yannan , Li Fan , Chen Weizhong , Huang Xingxu , Shen Huaizong , Ji Quanjiang 
Published: July 2023

AbstractThe miniature CRISPR-Cas12f nucleases allow for efficient delivery via cargo-size-limited adeno-associated virus delivery vehicles, thereby showing promising potential for in vivo therapeutic applications.Acidibacillus sulfuroxidansCas12f1 (AsCas12f1, 422 amino acids) is the most compact Cas12f nuclease identified to date, showing a moderate level of genome-editing activity in human cells compared to Cas9 and Cas12a. Understanding the mechanisms of why such a compact nuclease is active for genome editing would facilitate its rational engineering. Here, we report the cryo-EM structure of the AsCas12f1-sgRNA-dsDNA ternary complex, and reveal that AsCas12f1 functions as an asymmetric dimer for single-guide RNA (sgRNA) binding and DNA targeting. The detailed mechanisms for dimer formation, PAM recognition, and sgRNA accommodation are elucidated. Leading by the structural knowledge, we extensively engineer the AsCas12f1 nuclease and its corresponding sgRNA, resulting in an evolved AsCas12f1-sgRNA combination with drastically enhanced genome editing activity in human cells. These results provide further understanding of compact CRISPR systems and expand the mini CRISPR toolbox for therapeutic applications.
Attentional modulation of the cortical contribution to the frequency-following response evoked by continuous speech
Authors: Schüller Alina , Schilling Achim , Krauss Patrick , Rampp Stefan , Reichenbach Tobias 
Published: July 2023

AbstractSelective attention to one of several competing speakers is required for comprehending a target speaker amongst other voices and for successful communication with them. Selective attention has been found to involve the neural tracking of low-frequency speech rhythms in the auditory cortex. Effects of selective attention have also been found in subcortical neural activities, in particular regarding the high-frequency neural response at the fundamental frequency of speech, the speech-FFR. Recent investigations have, however, shown that the speech-FFR contains cortical contributions as well. It remains unclear whether these are also modulated by selective attention. Here we employed magnetoencephalography (MEG) to assess the attentional modulation of the cortical contributions to the speech-FFR. We presented participants with two competing speech signals and analyzed the cortical responses during attentional switching between the two speakers. Our findings revealed robust attentional modulation of the cortical contribution to the speech-FFR: the neural responses were higher when the speaker was attended than when they were ignored. We also found that, regardless of attention, a voice with a lower fundamental frequency elicited a larger cortical contribution to the speech-FFR than a voice with a higher fundamental frequency. Our results show that the attentional modulation of the speech-FFR does not only occur subcortically but extends to the auditory cortex as well.
Feature selection by replicate reproducibility and non-redundancy
Authors: Capraz Tümay , Huber Wolfgang 
Published: July 2023

AbstractMotivationA fundamental step in many analyses of high-dimensional data is dimension reduction. Two basic approaches are introduction of new, synthetic coordinates, and selection of extant features. Advantages of the latter include interpretability, simplicity, transferability and modularity. A common criterion for unsupervised feature selection is variance or dynamic range. However, in practice it can occur that high-variance features are noisy, that important features have low variance, or that variances are simply not comparable across features because they are measured in unrelated numeric scales or physical units. Moreover, users may want to include measures of signal-to-noise ratio and non-redundancy into feature selection.ResultsHere, we introduce the RNR algorithm, which selects features based on (i) the reproducibility of their signal across replicates and (ii) their non-redundancy, measured by linear independence. It takes as input a typically large set of features measured on a collection of objects with two or more replicates per object. It returns an ordered list of featuresi1,i2, …,ik, where featurei1is the one with the highest reproducibility across replicates,i2that with the highest reproducibility across replicates after projecting out the dimension spanned byi1, and so on. Applications to microscopy based imaging of cells and proteomics experiments highlight benefits of the approach.AvailabilityThe RNR method is implemented in the R packageFeatSeekRand is available via Bioconductor (Huberet al., 2015) under the GPL-3 open source license.Contacttuemay.capraz@embl.de
Predictive toxicology of chemical mixtures using proteome-wide thermal profiling and protein target properties
Authors: Lizano-Fallas Veronica , del Amor Ana Carrasco , Cristobal Susana 
Published: July 2023

ABSTRACTOur capability to predict the impact of exposure to chemical mixtures on environmental and human health is limited in comparison to the advances on the chemical characterization of the exposome. Current approaches, such as new approach methodologies, rely on the chemical mixture characterization and the available toxicological knowledge of individual compounds or similar mixtures. In this study, we show a new methodological approach for assessment of chemical mixtures based on a proteome-wide identification of the protein targets and revealing the relevance of new targets based on their role in the cellular crosstalk. We applied a proteome integral solubility alteration assay to identify 24 protein targets from a chemical mixture of 2,3,7,8- tetrachlorodibenzo-p-dioxin, alpha-endosulfan, and bisphenol A among the HepG2 soluble proteome, and validated the chemical mixture-target interaction orthogonally. To define the range of interactive capability of the new targets, the data from intrinsic properties of the targets were retrieved. Introducing the target properties as criteria for a multi-criteria decision-making analysis called the analytical hierarchy process, the prioritization of targets was based on their involvement in multiple pathways. This methodological approach that we present here opens a more realistic and achievable scenario to address the impact of complex and uncharacterized chemical mixtures in biological systems.SYNOPSISMethods for unbiased identification of protein targets of chemical mixtures and prediction of their impact in human and environmental health.