bluuebunny/crossref_metadata_2025_split huggingface dataset:
A dopamine-dependent mechanism for reward-induced modification of fear memories
Authors: Kong Mi-Seon , Jo Yong S. , Sethi Ekayana , Pyeon Gyeong Hee , Zweifel Larry S. 
Published: September 2024

AbstractA positive mental state has been shown to modulate fear-related emotions associated with the recall of fear memories. These, and other observations suggest the presence of central brain mechanisms for affective states to interact. The neurotransmitter dopamine is important for both reward- and fear-related processes, but it is unclear whether dopamine contributes to such affective interactions. Here, we show that precisely timed reward-induced activation of dopamine neurons in mice potently modifies fear memories and enhances their extinction. This reward-based switch in fear states is associated with changes in dopamine release and dopamine-dependent regulation of fear encoding in the central amygdala (CeA). These data provide a central mechanism for reward-induced modification of fear states that have broad implications for treating generalized fear disorders.SummaryReward-induced dopamine release in the central amygdala switches fear states and modifies fear encoding.
The effect of glucose restriction on cancer cell contractility: A threshold response in U-87 glioma
Authors: Kong Albert , Pallaoro Alessia , Yapp Donald , Elfring Gwynn J. , Bacca Mattia 
Published: September 2024

Cells rely on contractility to proliferate, and cancerous ones exhibit an increased glucose dependence. It is therefore hypothesized that glucose restriction can mitigate cancer cell proliferation by ’stunting’ their contractility. However, glucose-restriction studies have mostly been based on experiments that have yielded conflicting results; some cells become less contractile under glucose-restriction, intuitively, while, others become surprisingly more contractile. Active mechanistic modeling may prove fruitful in resolving these conflicts. In this study, we develop a model for glucose-mediated cell contractility to capture the mechanical implications of glucose restriction. The model is calibrated on cell contraction data taken from 2D-cultured glioma cells, laying on a collagen substrate. The model predicts the existence of a critical level of glucose restriction that must be exceeded for contractility to be affected, and this is validated by our experiments. Our model provides an initial step toward a fundamental understanding of the metabolic implications of cell contractility, particularly in the context of glucose restriction: an essential step in cancer studies.significanceThis study advances our understanding of how glucose restriction affects cancer cell contractility, an essential factor in cell proliferation. Our findings reveal that cells require severe glucose deprivation before exhibiting reduced contractility, highlighting a threshold response. This indicates that the cytoskeleton, a key structural component, remains active until a significant reduction in energy supply forces the cell into a lower energy state. These insights provide critical knowledge about the metabolic hierarchy within cells, contributing to the broader study of cancer metabolism and potential therapeutic strategies aimed at disrupting cellular energy pathways.
Paired C-type lectin receptors mediate specific recognition of divergent oomycete pathogens inC. elegans
Authors: Liu Kenneth , Grover Manish , Trusch Franziska , Vagena-Pantoula Christina , Ippolito Domenica , Barkoulas Michalis 
Published: September 2024

SummaryInnate immune responses can be initiated through the detection of pathogen or damage-associated molecular patterns by host receptors that are often present on the surface of immune cells. While certain invertebrates likeCaenorhabditis eleganslack professional immune cells, they still respond to infection in a pathogen-specific manner. It has been debated for years whether homologues of the canonical pathogen recognition receptors are also functioning in the nematode. Here we show that C-type lectin receptors mediate species-specific recognition of divergent oomycetes inC. elegans.A CLEC-27/CLEC-35 pair is essential for recognition of the oomyceteMyzocytiopsis humicola, while a CLEC-26/CLEC-36 pair is required for detection ofHaptoglossa zoospora.Bothclecpairs are transcriptionally regulated through a shared promoter by the conserved PRD-like homeodomain transcription factor CEH-37/OTX2 and act in sensory neurons and the anterior intestine to trigger a protective immune response in the epidermis. This system enables redundant tissue sensing of oomycete threats through canonical CLEC receptors and host defense via cross-tissue communication.HighlightsA CLEC-27/CLEC-35 pair is required for recognition of the oomyceteMyzocytiopsis humicolaA CLEC-26/CLEC-36 pair is required for recognition of the oomyceteHaptoglossa zoosporaBoth CLEC pairs are co-regulated by the homeodomain transcription factor CEH-37/OTX2Both CLEC pairs function redundantly in sensory neurons and the intestine for host defense
Early Events in G-quadruplex Folding Captured by Time-Resolved Small-Angle X-Ray Scattering
Authors: Monsen Robert C. , Sabo T. Michael , Gray Robert , Hopkins Jesse B. , Chaires Jonathan B. 
Published: September 2024

AbstractTime-resolved small-angle X-ray experiments (TR-SAXS) are reported here that capture and quantify a previously unknown rapid collapse of the unfolded oligonucleotide as an early step in G4 folding of hybrid 1 and hybrid 2 telomeric G-quadruplex structures. The rapid collapse, initiated by a pH jump, is characterized by an exponential decrease in the radius of gyration from 20.6 to 12.6 Å. The collapse is monophasic and is complete in less than 600 ms. Additional hand-mixing pH-jump kinetic studies show that slower kinetic steps follow the collapse. The folded and unfolded states at equilibrium were further characterized by SAXS studies and other biophysical tools, to show that G4 unfolding was complete at alkaline pH, but not in LiCl solution as is often claimed. The SAXS Ensemble Optimization Method (EOM) analysis reveals models of the unfolded state as a dynamic ensemble of flexible oligonucleotide chains with a variety of transient hairpin structures. These results suggest a G4 folding pathway in which a rapid collapse, analogous to molten globule formation seen in proteins, is followed by a confined conformational search within the collapsed particle to form the native contacts ultimately found in the stable folded form.
Structural basis of the excitatory amino acid transporter 3 substrate recognition
Authors: Qiu Biao , Boudker Olga 
Published: September 2024

AbstractExcitatory amino acid transporters (EAATs) reside on cell surfaces and uptake substrates, including L-glutamate, L-aspartate, and D-aspartate, using ion gradients. Among five EAATs, EAAT3 is the only isoform that can efficiently transport L-cysteine, a substrate for glutathione synthesis. Recent work suggests that EAAT3 also transports the oncometabolite R-2-hydroxyglutarate (R-2HG). Here, we examined the structural basis of substrate promiscuity by determining the cryo-EM structures of EAAT3 bound to different substrates. We found that L-cysteine binds to EAAT3 in thiolate form, and EAAT3 recognizes different substrates by fine-tuning local conformations of the coordinating residues. However, using purified human EAAT3, we could not observe R-2HG binding or transport. Imaging of EAAT3 bound to L-cysteine revealed several conformational states, including an outward-facing state with a semi-open gate and a disrupted sodium-binding site. These structures illustrate that the full gate closure, coupled with the binding of the last sodium ion, occurs after substrate binding. Furthermore, we observed that different substrates affect how the transporter distributes between a fully outward-facing conformation and intermediate occluded states on a path to the inward-facing conformation, suggesting that translocation rates are substrate-dependent.
Grb2 Phosphorylation Antagonizes EGFR-driven Ras Activation by Interfering with Condensate Assembly
Authors: Phan Henry T. , Lin Chun-Wei , Stinger Brittany L. , DeGrandchamp Joseph B. , Nugent Lew L.J. , Huang Serena J. , Groves Jay T. 
Published: September 2024

AbstractUpon ligand binding, the kinase domain of EGFR phosphorylates multiple tyrosine residues on the receptor cytoplasmic tail through a trans-autophosphorylation process. Phosphotyrosine sites on activated receptors recruit Grb2, which further recruits SOS to initiate downstream signaling by activating Ras. Multivalent binding between SOS and Grb2, as well as direct Grb2:Grb2 interactions, contribute to formation of a protein condensate of activated EGFR. The condensed state of EGFR facilitates autoinhibition release in SOS and exerts regulatory control over signal propagation from activated EGFR to Ras. While kinase activity of EGFR is an essential driver of this signaling process, phosphorylation at residue Y160 on Grb2 blocks Grb2:Grb2 binding and can interfere with EGFR condensation. Here, using a reconstituted system, we examine how titrating kinase activity in the EGFR system can both promote and inhibit signal output to Ras. The results reveal how effects of tyrosine kinase inhibition can, under some circumstances, promote Ras activation by inhibiting negative feedback through Grb2 phosphorylation and disruption of a Grb2 SH2/SH3 dimer interface.Statement of SignificanceActivated EGFR forms a biomolecular condensate, via linkage of multiple EGFR through Grb2 and SOS, and the condensation state of EGFR influences signal propagation to Ras. While tyrosine phosphorylation is a critical step in EGFR activation, phosphorylation of Grb2 can have an inhibitory effect on EGFR condensation and subsequent Ras activation. Under some conditions, kinase inhibition can promote signaling from EGFR to Ras.
Molecular Evolution of Gustatory Receptors in theAnopheles gambiaeComplex
Authors: Popkin-Hall Zachary R. , Slotman Michel A. 
Published: September 2024

AbstractBackgroundMosquitoes in theAnopheles(An.)gambiaespecies complex are major vectors ofPlasmodium falciparummalaria. One reason for this is the high anthropophily of the constituent speciesAn. coluzzii,An. gambiaesensu stricto, andAn. arabiensis. In contrast, their sister speciesAn. quadriannulatusis highly zoophilic.Anophelesmosquitoes largely rely on chemical cues for host-seeking, which are primarily detected by four chemosensory gene families: olfactory receptors (Ors), ionotropic receptors (Irs), gustatory receptors (Grs), and odorant binding proteins (Obps). Genes from these families that have been implicated in host adaptation show evidence of positive selection in other insect species, including other mosquitoes. As such, we analyzed the molecular evolutionary patterns of the gustatory receptors within theAnopheles gambiaecomplex, with a particular interest in identifyingGrsthat show evidence of positive selection in highly anthropophilic species.ResultsWe identified sixteenGrsthat show evidence of potential positive selection using the McDonald-Kreitman test, including four putative sugar receptors and twoGrswith unknown ligands that are relatively highly expressed in chemosensory organs of eitherAn. coluzziiorAn. quadriannulatus. In addition, we identified twelveGrsthat show evidence of potential purifying selection using the McDonald-Kreitman test, and twelveGrsthat may have experienced a selective sweep using the DH test, including three putative sugar receptors and the carbon dioxide receptorGr24. We also identified both positive and purifying selection in the coastal speciesAn. melas(West Africa) andAn. merus(East Africa).ConclusionsOur results, together with transcriptomic data, identify fourGrsas possible candidates for involvement in the evolution of vertebrate host preference in theAn. gambiaecomplex, as may have occurred in theAn. farauticomplex. They also point to sugar receptors as playing a role in recent adaptation of some of these species. As the vast majority ofGrshave unknown functions and much is still unknown about the role ofGrsin these species, a more complete interpretation of our data necessitates further characterization of these genes.
Frame-shift mutation ofInCOmight cause early flowering of Japanese morning glory and might have contributed to northward expansion
Authors: Katsuyama Hiroaki , Ito Takuro , Ezura Kyousuke , Haque Emdadul , Hoshino Atsushi , Nitasaka Eiji , Ono Michiyuki , Sato Shusei , Isobe Sachiko , Fukuoka Hiroyuki , Watanabe Nobuyoshi , Kuboyama Tsutomu 
Published: September 2024

AbstractJapanese morning glory (Ipomoea nil), a short day plant, has been used for studying flowering times. Here, quantitative trait loci (QTL) analysis for days from sowing to flowering (DTF) of F2betweenI. nilvar. Tokyo Kokei Standard (TKS) andI. hederacealine var. Q65, an early flowering variety, revealed four QTLs:QTL Ipomoea Flowering 1–4(qIF1–4). The position ofqIF3, which had the most significant effect among the four QTLs, corresponds with that ofI. nil(orI. hederacea)CONSTANS(InCO/IhCO) in the linkage map. There is a single-base In/Del in the coding sequence ofInCO/IhCO. The single-base deletion (SBD) causes a frame-shift mutation and loss of function in TKS allele (inco-1).I. nilaccessions bearinginco-1tend to flower early, similarly to rice varieties bearing the loss of function allele ofCOortholog,hd1. Consequently,inco-1was inferred to reduce DTF. This inferred effect ofinco-1corresponds with the effect of the TKS allele ofqIF3. Becauseinco-1is found exclusively in Asian accessions, the SBD ininco-1might have played an important role in the expansion of Japanese morning glories, originally native to the tropical regions of the Americas, into temperate Asia.
Insights into the low-temperature adaptation of an enzyme as studied through ancestral sequence reconstruction
Authors: Cui Shuang , Furukawa Ryutaro , Akanuma Satoshi 
Published: September 2024

AbstractFor billions of years, enzymes have evolved in response to the changing environments in which their host organisms lived. Various lines of evidence suggest the earliest primitive organisms inhabited high-temperature environments and possessed enzymes adapted to such conditions. Consequently, extant mesophilic and psychrophilic enzymes are believed to have adapted to lower temperatures during the evolutionary process. Herein, we analyzed this low-temperature adaptation using ancestral sequence reconstruction. Previously, we generated the phylogenetic tree of 3-isopropylmalate dehydrogenases (IPMDHs) and reconstructed the sequence of the last bacterial common ancestor. The corresponding ancestral enzyme displayed high thermostability and catalytic activity at elevated temperatures but moderate activity at low temperatures (Furukawaet al.,Sci. Rep.10, 15493 (2020)). Here, to identify amino acid residues that are responsible for the low-temperature adaptation, we reconstructed and characterized all eleven evolutionary intermediates that sequentially connect the last bacterial common ancestor with extant mesophilic IPMDH fromEscherichia coli. A remarkable change in catalytic properties, from those suited for high reaction temperatures to those adapted for low temperatures, occurred between two consecutive evolutionary intermediates. Using a combination of sequence comparisons between ancestral proteins and site-directed mutagenesis analyses, three key amino acid substitutions were identified that enhance low-temperature catalytic activity. Intriguingly, amino acid substitutions that had the most significant impact on activity at low temperatures displayed no discernable effect on thermostability. However, these substitutions markedly reduced the activation energy for catalysis, thereby improving low-temperature activity. Our findings exemplify how ancestral sequence reconstruction can identify residues crucial for adaptation to low temperatures.
DupLoss-2: Improved Phylogenomic Species Tree Inference under Gene Duplication and Loss
Authors: Parsons Rachel , Bansal Mukul S. 
Published: September 2024

AbstractAccurate species tree reconstruction in the presence of widespread gene duplication and loss is a challenging problem in eukaryote phylogenomics. Many phylogenomics methods have been developed over the years to address this challenge; these range from older methods based on gene tree parsimony to newer quartet-based methods. In this work, we introduce improved software for gene tree parsimony-based species tree reconstruction under gene duplication and loss. The new software, DupLoss-2, uses an improved procedure for computing gene losses and is far more accurate and much easier to use than its previous version released over a decade ago. We thoroughly evaluate DupLoss-2 and eight other existing methods, including ASTRAL-Pro, ASTRAL-Pro 2, DISCO-ASTRAL, DISCO-ASTRID, FastMulRFS, and SpeciesRax, using existing benchmarking data and find that DupLoss-2 outperforms all other methods on most of the datasets. It delivers an average of almost 30% reduction in reconstruction error compared to iGTP-Duploss, the previous version of this software, and a 10% reduction compared to the best performing existing method. DupLoss-2 is written in C++ and is freely available open-source.
Chaperone-mediated heterotypic phase separation prevents the amyloid formation of the pathological Y145Stop variant of the prion protein
Authors: Arora Lisha , Bhowmik Dipankar , Sarkar Snehasis , Sarbahi Anusha , Rai Sandeep K. , Mukhopadhyay Samrat 
Published: September 2024

AbstractBiomolecular condensates formed via phase separation of proteins and nucleic acids are crucial for the spatiotemporal regulation of a diverse array of essential cellular functions and the maintenance of cellular homeostasis. However, aberrant liquid-to-solid phase transitions of such condensates are associated with several fatal human diseases. Such dynamic membraneless compartments can contain a range of molecular chaperones that can regulate the phase behavior of proteins involved in the formation of these biological condensates. Here, we show that a heat shock protein 40 (Hsp40), Ydj1, exhibits a holdase activity by potentiating the phase separation of a disease-associated stop codon mutant of the prion protein (Y145Stop) either by recruitment into Y145Stop condensates or via Y145Stop-Ydj1 two-component heterotypic phase separation that prevents the conformational conversion of Y145Stop into amyloid fibrils. Utilizing site-directed mutagenesis, multicolor fluorescence imaging, single-droplet steady-state and picosecond time-resolved fluorescence anisotropy, fluorescence recovery after photobleaching, and fluorescence correlation spectroscopy, we delineate the complex network of interactions that govern the heterotypic phase separation of Y145Stop and Ydj1. We also show that the properties of such heterotypic condensates can further be tuned by RNA that promotes the formation of multicomponent multiphasic protein-RNA condensates. Our vibrational Raman spectroscopy results in conjunction with atomic force microscopy imaging reveal that Ydj1 effectively redirects the self-assembly of Y145Stop towards a dynamically-arrested non-amyloidogenic pathway, preventing the formation of typical amyloid fibrils. Our findings underscore the importance of chaperone-mediated heterotypic phase separation in regulating aberrant phase transitions and amyloid formation associated with a wide range of deadly neurodegenerative diseases.
The roles of lifestyle factors and genetic risk in the association between night shift work and cholelithiasis: a prospective cohort study
Authors: He Wangping , Mi Ningning , Jin Kecheng , Jin Boru , Zhong Ruyang , Liu Zhen , Lin Yanyan , Yue Ping , Xia Bin , He Qiangsheng , Smith Fang Gao , Zhen Jie , Yuan Jinqiu , Meng Wenbo 
Published: September 2024

AbstractBackgroundNight shift work has been linked to various adverse health outcomes, but its relationship with incident cholelithiasis remains unclear. This study aims to investigate the association between night shift work and the risk of cholelithiasis, assess the potential modifying effects of genetic susceptibility, and explore the mediating roles of lifestyle factors.MethodsA total of 219,810 subjects who were either in paid employment or self-employed were included in the UK Biobank. Information on current and lifetime employment were collected. Genetic risk was quantified and stratified by a polygenic risk score (PRS) incorporating 13 known cholelithiasis-associated loci. We used Cox proportional hazard models to investigate associations between night shift work and risk of cholelithiasis. Lifestyle factors measured at baseline were explored as potential mediators.ResultsDuring a median follow-up of 13.76 years, 6450 incidents of cholelithiasis were documented. Compared with day workers, the hazard ratio (HR) and 95% confidence interval (CI) of cholelithiasis was 1.09 (1.01, 1.17) for individuals with rarely/some night shifts and 1.18 (1.04, 1.35) for those with usual/permanent night shifts. Among the 62,558 participants who had reports on lifetime experience of night shift work, those with a higher frequency of night shifts and a longer length of each night shift were associated with an increased risk of cholelithiasis. Notably, individuals with usual/permanent night shifts and high genetic risk exhibited the highest risk of cholelithiasis (HR: 1.48, 95% CI: 1.21, 1.81), with day workers at low genetic risk serving as the reference. Mediation analysis indicated that a substantial portion (24.6%) of the association was mediated by BMI, followed by unhealthy alcohol intake (4.5%) and sedentary time (1.8%).ConclusionsNight shift work is associated with an increased risk of cholelithiasis, with this relationship being largely mediated by lifestyle factors. These findings suggest that reducing the frequency and duration of night shifts may help mitigate the incidence of cholelithiasis among night shift workers, particularly for those with heightened genetic susceptibility.
Neural Representations of Extrasystoles: A Predictive Coding Perspective
Authors: Reinfeld Pia , Steinfath Tim Paul , Ku Pei-Hsin , Nikulin Vadim , Neumann Jane , Villringer Arno 
Published: September 2024

AbstractThe coordinated interplay between brain and body is essential for survival, with the heart-brain axis playing a fundamental role in perceptual, cognitive and motor processes. Central to this interaction, the heart-evoked potential (HEP) represents a neural correlate of the heart activity. Further, the HEP is thought to represent a neuronal prediction for each heartbeat, raising questions about its role in arrhythmia. Yet, previous studies have primarily focused on regular heart rhythms, with only a few investigations delving into arrhythmias and, notably, none into extrasystoles, a form of benign arrhythmias that disrupt the regular heart rhythm. Extrasystoles represent a unique possibility for investigating brain responses to unexpected pronounced alterations in heart rhythm. We took advantage of the largest dataset (103 subjects with 3000 extrasystoles), including both EEG and ECG recordings, and analysed the neural response to both types of extrasystoles (supraventricular and ventricular) using multiverse approaches and control analysis in time and source space. We found that the HEP was significantly reduced for ventricular extrasystoles with underlying sources in the left insular. For the postextrasystolic beat of both types of extrasystoles, we found a significantly earlier and increased HEP originating from sources in the left frontal orbital cortex and the anterior cingulate gyri. The reduced HEP response to the ventricular extrasystole might result from inactive interoceptive cardiac pathways. In contrast, increased HEP of the postextrasystolic beat along with the anatomical neural HEP generators may reflect an interoceptive prediction error arising from a naturally occurring discrepancy between the predicted and actual heart rhythm, with a main source in the anterior cingulate gyri, a primary location for prediction error processing.