bluuebunny/crossref_metadata_2025_split huggingface dataset:
De novodesign of proteins that bind naphthalenediimides, powerful photooxidants with tunable photophysical properties
Authors: Mann Samuel I. , Lin Zhi , Tan Sophia K. , Zhu Jiaqi , Widel Zachary X. W. , Bakanas Ian , Mansergh Jarrett P. , Liu Rui , Kelly Mark J. S. , Wu Yibing , Wells James A. , Therien Michael J. , DeGrado William F. 
Published: October 2024

ABSTRACTDe novoprotein design provides a framework to test our understanding of protein function and to build proteins with cofactors and functions not found in nature. Here, we report the design of proteins designed to bind powerful photooxidants and the evaluation of the use of these proteins to generate diffusible small molecule reactive species for applications in proximity labeling. Because excited state dynamics are influenced by the dynamics and hydration of a photo-oxidant’s environment, it was important to not only design a binding site, but also to evaluate its dynamic properties. Thus, we used computational design in conjunction with molecular dynamics (MD) simulations to design a protein, designated NBP (NDIBindingProtein) that held a naphthalenediimide (NDI), a powerful photooxidant, in a programable molecular environment. Solution NMR confirmed the structure of the complex. We evaluated two NDI cofactors in thisde novoprotein, using ultra-fast pump-probe spectroscopy to evaluate light-triggered intra- and intermolecular electron transfer function. Moreover, we demonstrated the utility of this platform to activate multiple molecular probes for protein proximity labeling.
Loss of SARM1 protects against retinal ganglion cell degeneration in Autosomal Dominant Optic Atrophy
Authors: Ding Chen , Ndiaye Papa S. , Campbell Sydney R. , Fry Michelle Y. , Gong Jincheng , Wienbar Sophia R. , Gibbs Whitney , Morquette Philippe , Chao Luke H. , Do Michael Tri H. , Schwarz Thomas L. 
Published: October 2024

SummaryAutosomal Dominant Optic Atrophy (ADOA), the most prevalent inherited optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in theOPA1gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. Here, we present a novel mouse model carrying the pathogenicOpa1R290Q/+allele that recapitulates key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identify SARM1, a neurodegeneration switch, as a key driver of RGC degeneration in these mice.Sarm1knockout nearly completely suppresses all the degeneration phenotypes. Additionally, we show that SARM1 is located within the mitochondrial intermembrane space (IMS). These findings indicate that SARM1 is activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.
Creased ciliary flocks shape unfolding dynamics via information bottlenecks in an aneural animal
Authors: Brannon Charlotte M. , Prakash Manu 
Published: October 2024

AbstractMulticellular organisms utilize thin sheet folding to achieve functional three-dimensional forms. During embryonic development, stereotypical epithelial folds emerge from active cellular and molecular processes including cell shape change and differential cell growth. Active thin sheet folding promises to be a powerful design technique in the fields of active solids, soft robotics, and synthetic biology. However, the general principles of active thin sheet folding remain poorly understood. Here we discover a non-canonical cilia-driven thin sheet folding behavior exhibited by basal animalTrichoplax adhaerens. Through volumetric imaging, we found that, despite having no nervous system,T. adhaerenshas the remarkable ability to resolve complex body folding states in a non-stereotypical fashion using a carpet of collectively flocking cilia. Cilia-resolved imaging revealed that folds create crease defects in the animal’s ciliary carpet, which act as information bottlenecks to break collective behavior of cilia. In turn, these bottlenecks enable the disjointed locomotion required for fold removal. These findings point to a two-way coupling mechanism, wherein ciliary activity shapes the animal’s folding state and vice versa. Our work demonstrates the broad configuration space of non-stereotypical active folding and highlights the power of distributed activity to drive folding and unfolding of a thin multicellular sheet. We anticipate our study to be a starting point for the establishment of a new class of distributed active origami wherein fold lines themselves are dynamic and motile, with implications in engineering of self-folding materials. Additionally, our work reveals a new facet of the Placozoan behavioral repertoire, which extends our understanding of mechanical intelligence in the absence of a nervous system.
Single-cell RNA-seq Reveals Early Transcriptional Programs of the Maternal to Zygote Transition in Mice and Rats
Authors: Su Yangqi , Kouranova Evguenia , Shea Jonathan , Cui Xiaoxia , Su Zhengchang 
Published: October 2024

AbstractThe maternal to zygote transition in mammals has been an area of intensive research over the past few decades, with an ever-changing landscape of understanding that has accompanied the rapid development of cell-profiling technology. Utilizing a full-length single cell RNA-seq protocol, we profiled mature oocytes and zygotes of mice and rats to uncover elusive transcriptomic dynamics during the maternal to zygote transition. We confirm the existence of early gene expression in the mouse zygote while revealing a similar chain of events occurring in the rat zygote. We observe an increase in nascent transcription in both species. Moreover, we find subtle but pervasive signals of differential splicing of genes related to key early zygotic activities occurring in both species. Meanwhile, we find distinct profiles of alternative polyadenylation between zygotes and oocytes in both species, particularly, in genes related to major processes within the zygotes. Finally, although a more dynamic transcriptomic landscape exists in the mouse zygote, the rat zygote also displays similar transcriptomic features, suggesting that minor zygotic activation in rat occurs earlier than originally thought.
N-Acetyl-2-Aminofluorene (AAF):In vivotemporal expression patterns of growth cycle-dependent macromolecular binding constants KD[APPARENT]and BMAX[APPARENT]are revealed by primary cultures of premalignant hepatocytes derived from a multi-cyclic hepatocarcinogenic feeding regimen
Authors: Koch K.S. , Moran T. , Sell S. , Leffert H.L. 
Published: October 2024

ABSTRACTBiochemical investigations of the hepatoprocarcinogen N-acetyl-2-aminofluorene (AAF) have shown that normal adult rat hepatocytes in primary culture express two sets of pharmacokinetic constants – designated Systems I and II, and Sites I and II – associated respectively with themetabolism(System I [high-affinity Km[APPARENT]and low-velocity VMAX[APPARENT]] and System II [low-affinity Km APPARENT]and high-velocity VMAX[APPARENT]]), and the macromolecular binding(Site I [high-affinityKD[APPARENT]and low capacityBMAX[APPARENT]] and Site II ([low-affinityKD[APPARENT]and high-capacityBMAX[APPARENT]]) of AAF. Additional findings – that genomically saturating levels of AAF-DNA adducts form far below reported extracellular AAF concentrations required to block replicative and repair DNA synthesis; and, that biphasic Site I and Site II BMAX[APPARENT]and KD[APPARENT]expression curves varied inversely with respect to time and magnitude during hepatocyte growth – led us to wonder how macromolecular binding constants are expressed during chemical hepatocarcinogenesis. These questions were addressed by Scatchard analysis measurements through five consecutive AAF feeding cycles. Notably, cultured premalignant hepatocytes displayed reduced and elevated BMAX[APPARENT]and KD[APPARENT]levels, respectively, akin to the Site I and Site II expression curves observed during hepatocyte growth transitionsin vitro. In contrast, prominent hepatocellular functions such as N-OH-AAF production, DNA replication, cell aggregation and resistance to AAF toxicity displayed different temporal trajectories.Impact StatementStriking similarities are observed between both Site I and Site II BMAXand KDexpression curves duringin vitroandin vivopremalignant growth transitions. These new findings fit earlier ones that hepatocytes growing during carcinogen exposure manifest fewer intranuclear AAF-DNA adducts. How this phenomenon leads to malignancy remains unclear.
The c-di-GMP effector FleQ controls alginate production by repressing transcription of thealgDgene inAzotobacter vinelandii
Authors: Barrios-Rafael Víctor V. , Ahumada-Manuel Carlos L. , Orgaz-Hidalgo Scherezada , Nava-Galeana Jessica , Guzmán Josefina , Moreno Soledad , Bustamente Victor , Núñez Cinthia 
Published: October 2024

AbstractAzotobacter vinelandii, belonging to thePsedomonadaceaefamily, produces the exopolysaccharide alginate during its vegetative growth and also during its differentiation process to form desiccation resistant cysts. The second messenger c-di-GMP regulates a vast array of cellular processes. It is produced by diguanylate cyclases (DGC) and degraded by phosphodiesterases (PDE). InA. vinelandiithe absence of the AvgReg DGC impairs alginate synthesis while the absence of the PDE MucG increased alginate production. The effect of the different c-di-GMP levels was solely attributed to its essential role in activating the alginate polymerase complex. Here in we investigated the possible role of c-di-GMP in the control ofalgDtranscription, encoding the key enzyme of the alginate biosynthetic pathway. At artificially high or reduced levels of c-di-GMPalgDtranscription was increased, or almost abrogated, respectively. Therefore, the role of the transcriptional regulator FleQ, one of the best characterized c-di-GMP effectors, was investigated. Alginate production increased in the ΔfleQrelative to the wt strain, which agreed with increasedalgDtranscription. These phenotypes were rescued in the ΔfleQ/fleQ+ complemented strain indicating a FleQ repressing effect. EMSA assay showed that FleQ was able to directly bind to the regulatory region ofalgDwhich agreed with the presence of a FleQ binding site overlapping its RpoS-dependent promoter. InA. vinelandiithe c-di-GMP is also necessary for expression of alginate C-5 epimerase genes, essential for structuring mature cysts. Out data revealed that FleQ is not an intermediary in this regulation since its absence did not impair mature cyst formation nor affected expression ofalgE1-6genes. Collectively, our results support a model in which FleQ is the intermediary in the regulation ofalgDby c-di-GMP, exerting a direct repressing effect and reveal the existence of a FleQ-independent regulatory mechanism for the control ofA. vinelandiiencystment.
In silicomodelling and characterization of Epstein–Barr virus LMP1 protein
Authors: Salam Dayang-Sharyati D.A. , Juliyan Gunasinghe Kavinda Kashi , San Hwang Siaw , Henry Ginjom Irine Runnie , Wezen Xavier Chee , Rahman Taufiq 
Published: October 2024

AbstractLatent membrane protein 1 (LMP1) plays a crucial role in Epstein-Barr virus (EBV)’s ability to establish latency and is involved in the development and progression of EBV-associated cancers. Additionally, EBV-infected cells affect the immune responses, making it challenging for immune system to eliminate. Due to the aforementioned reasons, it is important to understand the structural features of LMP1 which is essential for the development of novel cancer therapies that target its signaling pathways. To date, there is no complete LMP1 protein structure therefore in our work, we modeled the full-length LMP1 containing the short cytoplasmic N-terminus, six transmembrane domains and a long-simulated C-terminus. Our model showed good stability and protein compactness evaluated through accelerated-Molecular Dynamics where the conformational ensemble exhibited compact folds, particularly in the transmembrane domains. Our results suggest that specific domains or motifs, predominantly in the C-terminus domain of LMP1 show promise as potential drug targets. As a whole, our work provides insights on key strucutral features of LMP1 that will allow the development of novel LMP1 therapies.
Subendothelial Calcification Increases Surface Roughness and Promotes Lipid Deposition into the Arterial Wall
Authors: Kosciuszek Nina D. , Petrosian David , Voleti Navya , Dave Param , Kelly Ian , Moussouros Daniel , Davidov Josef , Mararenko Anton , Borges Kelly A. , Nasruddin Saud A. , Padalkar Mugdha V. , Plummer Maria M. , Millan Jose Luis , Carka Dorinamaria , Beatty Brian L. , Savinova Olga V. 
Published: October 2024

AbstractObjectiveWe have previously demonstrated that subendothelial calcification accelerates atherosclerosis in mice. This study addresses a mechanism by which subendothelial calcifications can increase low-density lipoprotein (LDL) uptake into the arterial wall.MethodsMice overexpressing tissue-nonspecific alkaline phosphatase (TNAP) in endothelial cells (eTNAP mice) were used as a model of calcification. Calcification and atherosclerosis were detected by micro-computed tomography (micro-CT) and histology. The endothelial roughness was characterized by surface metrology. A fluid-structure interaction model was used to calculate wall shear stress (WSS). The uptake of fluorescent LDL was tracedin vitroandin vivo. Human arteries were assessed for the prevalence of internal elastic lamina (IEL) calcification.ResultseTNAP mice developed more severe aortic atherosclerosis than controls on the LDL receptor mutant background (p<0.01). Subendothelial calcifications in eTNAP mice were confirmed by micro-CT. An increase in aortic surface area roughness, including the height, volume, and steepness parameters, was observed in eTNAP mice compared to controls (p<0.01). Calcifications affected near-wall hemodynamics, creating pockets of reduced WSS. Endothelial cells cultured on rough surfaces showed increased LDL uptake compared to cells cultured on smooth collagen (p<0.0001). Fluorescent LDLs were traced to subendothelial calcifications in eTNAP mice but not in controls. In humans, IEL calcification was prevalent in older adults and inversely correlated with arterial diameter (p<0.05).ConclusionSubendothelial calcification is sufficient to perturb near-wall hemodynamics, creating localized areas of reduced WSS, consistent with increased LDL uptake near calcified lesions. Subendothelial calcification may represent an alternative or concurrent mechanism for the initiation of atherosclerosis.Research perspectiveWhat is new?We tested a novel hypothesis that subendothelial microcalcification can initiate atherosclerosis.The study demonstrated that micron-sized subendothelial calcifications, induced by the overexpression of tissue-nonspecific alkaline phosphatase in the endothelium, are sufficient to perturb local hemodynamics, creating pockets of low wall shear stress, consistent with an increase in low-density lipoprotein uptake and deposition into the arterial wall in juxtaposition to calcified lesions.What are the clinical implications?We suggest that calcification of internal elastic lamina of medium-sized arteries may represent early lesions initiating atherosclerosis; however, the epidemiologic evidence for this theory is currently unavailable.
Delicate tuning of H2O2by salicylic acid, catalase 2, and AtSAP5 incites plant immunity
Authors: Chang Li , Chiu Yi-Shu , Chiang Shang-Huan , Cheng An-Po , Tzean Yuh , Yeh Hsin-Hung 
Published: October 2024

ABSTRACTSalicylic acid (SA) triggers plant immunity through redox state changes, initially oxidizing and then reducing. SA binds and inhibits the H2O2-scavenging enzyme catalase 2 (CAT2), promoting an initial oxidative state. However, a reduced state is crucial for a robust immune response. InArabidopsis, the SA-induced A20/AN1 zinc finger protein, AtSAP5, competes with SA for CAT2 binding, maintaining CAT2 activity. This reduces H2O2levels and prevents CAT2 degradation through inhibition of H2O2-induced autophagy formation, which forms a positive feedback loop to CAT2 accumulation. Consequently, cells shift to a more reduced state, activating immune responses. Our findings reveal a nuanced regulatory mechanism through which H2O2levels are controlled by SA with cross-kingdom conserved proteins AtSAP5 and CAT2, managing redox states and plant immunity.
Sequential Effects in Reaching Reveal Efficient Coding in Motor Planning
Authors: Wang Tianhe , Fang Yifan , Whitney David 
Published: October 2024

AbstractThe nervous system utilizes prior information to enhance the accuracy of perception and action. Prevailing models of motor control emphasize Bayesian models, which suggest that the system adjusts the current motor plan by integrating information from previous observations. While Bayesian integration has been extensively examined, those studies usually applied a highly stable and predictable environment. In contrast, in many real-life situations, motor goals change rapidly over time in a relatively unpredictable way, leaving it unclear whether Bayesian integration is useful in those natural environments. An alternative model that leverages prior information to improve performance is efficient coding, which suggests that the motor system maximizes the accuracy by dynamically tuning the allocation of the encoding resources based on environmental statistics. To investigate whether this adaptive mechanism operates in motor planning, we employed center-out reaching tasks with motor goals changing in a relatively unpredictable way, where Bayesian and efficient coding models predict opposite sequential effects. Consistent with the efficient coding model, we found that current movements were biased in the opposite direction of previous movements. These repulsive biases were amplified by intrinsic motor variability. Moreover, movement variability decreased when successive reaches were similar to each other. Together, these effects support the presence of efficient coding in motor planning, a novel mechanism with which the motor system maintains flexibility and high accuracy in dynamic environments.
Analyzing the Molecular Mechanism of Eucalyptol, Limonene and Pinene Enteric Capsules (QIENUO) in the Treatment of Pulmonary cystic fibrosis with Network Pharmacology and Verifying Molecular Docking
Authors: Tu Tiantaixi , Zhu Xinjie , Wang Congyin , Chen Wei , Zheng Yihu 
Published: October 2024

AbstractObjectiveTo explore the mechanism of Eucalyptol, Limonene and Pinene Enteric Capsules (QIENUO) in the treatment of pulmonary cystic fibrosis (CPF), analyze the common targets of QIENUO and CPF, and verify the molecular docking of core proteins and small molecules.MethodsThe main active compounds and their corresponding targets were obtained from PubChem, SwissTargetprediction, GeneCards, PharmMapper and TCMSP databases. Targets related to CPF were screened from GeneCards, OMIM, DisGeNET and TTD databases. The common “QIENUO-CPF” targets were analyzed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) through the website of Weishengxin. Protein-protein interaction (PPI) network and compound-target-pathway network were constructed by Cytoscape, and the network parameters were systematically analyzed. The interaction between core protein and monomer components was evaluated and verified by molecular docking method.Results228 active compounds target and 1354 CPF-related targets were screened out, and 92 common targets were analyzed by GO and KEGG. The results showed that the therapeutic effect of QIENUO on CPF was mainly through AMPK signaling pathway, cGMP-PKG signaling pathway and TGF-β signaling pathway. The results of molecular docking show that the binding energy of 9 of 15 pairs of ligand-receptor pairs is lower than-6 kjmol-1.ConclusionQIENUO exhibits huge potential as a therapeutic agent for the treatment of pulmonary cystic fibrosis. The specific molecular mechanism and effective active components of QIENUO treat CPF were studied and demonstrated, which provided theoretical basis for better clinical application of QIENUO.
Remote activation of place codes by gaze in a highly visual animal
Authors: Payne Hannah L. , Aronov Dmitriy 
Published: October 2024

ABSTRACTVision enables many animals to perform spatial reasoning from remote locations. By viewing distant landmarks, animals recall spatial memories and plan future trajectories. Although these spatial functions depend on hippocampal place cells, the relationship between place cells and active visual behavior is unknown. Here, we studied a highly visual animal, the chickadee, in a behavior that required alternating between remote visual search and spatial navigation. We leveraged the unique head-directed nature of avian vision to track gaze in freely moving animals. We discovered a profound link between place coding and gaze. Place cells activated not only when the chickadee was in a specific location, but also when it simply gazed at that location from a distance. Gaze coding was precisely timed by fast, ballistic head movements called “head saccades”. On each saccadic cycle, the hippocampus switched between encoding a prediction of what the bird was about to see and a reaction to what it actually saw. The temporal structure of these responses was coordinated by subclasses of interneurons that fired at different phases of the saccade. We suggest that place and gaze coding are components of a unified process by which the hippocampus represents the location that an animal is currently attending to. This process allows the hippocampus to implement both local and remote spatial functions.
Heartbeat related activity in the anterior thalamus differs between phasic and tonic REM sleep periods
Authors: Simor Péter , Lilla Róka Zita , Szalárdy Orsolya , Jordán Zsófia , Halász László , Erőss Loránd , Fabó Dániel , Bódizs Róbert 
Published: October 2024

AbstractRapid eye movement (REM) sleep is a fundamental sleep state associated with diverse functions from elemental physiological processes to higher order neurocognitive functions. A growing body of research indicates that REM sleep with eye movements (phasic REM) differs from REM periods without ocular activity (tonic) in terms of spontaneous and evoked neural responses. Studies using auditory stimulation consistently observed enhanced evoked responses in tonic versus phasic REM, indicating that the external processing is largely diminished when the eyes move during REM sleep. Whereas exteroceptive processing during sleep is widely studies, investigation on interoception (the processing of bodily signals) during sleep is scarce, and limited to scalp electroencephalographic recordings. Here we studied interoceptive processing in a group of epileptic patients (N = 11) by measuring their heartbeat-related neural activity in the anterior nucleus of the thalamus (ANT) during phasic and tonic REM sleep and resting wakefulness. Evoked potentials and beta–low gamma spectral power locked to the heartbeat were significantly different in phasic REM compared to tonic REM and wakefulness. Heartbeat-related neural signals exhibited pronounced inter-trial phase synchronization at lower (7–20 Hz) oscillatory activity in all vigilance states, but reduced gamma synchronization at later time points in phasic REM only. Tonic REM and wakefulness did not show significant differences in heartbeat-related activity in the ANT. Our findings indicate that heartbeat-related neural activity is detectable at the level of the ANT, showing distinct signatures of interoceptive processing in phasic REM compared to tonic REM and wakefulness.