bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unraveling the Impact of W215A/E217A Mutations on Thrombin’s Dynamics and Thrombomodulin Binding through Molecular Dynamics Simulations
Authors: Wu Dizhou , Salsbury Freddie R. 
Published: December 2023

AbstractThrombin, a central serine protease in hemostasis, exhibits dual functionality in coagulation processes—favoring fibrinogen cleavage in its native form while shifting towards protein C activation when complexed with thrombomodulin (TM). Thrombin also plays roles in cancer-associated thrombosis and may be involved in metastasis and tumorigenesis. The W215A/E217A (WE) double mutant of thrombin presents a unique case, with its fibrinogen cleavage activity diminished by 19,000-fold, contrasting a modest 7-fold reduction in protein C activation in the presence of TM. The differential substrate specificity of this mutant raises fundamental questions about the underlying molecular mechanisms. In this study, we employed all-atom microsecond-scale molecular dynamics (MD) simulations, complemented by Root Mean Square Fluctuation (RMSF) analysis, clustering algorithms, PCA-based free-energy surfaces, and logistic regression modeling, to dissect the structural and allosteric changes driving thrombin’s substrate specificity. Our results unveil distinct conformational states within the catalytic triad, each optimized for specific substrate interactions. We demonstrate that the WE mutations synergize with TM456 binding, resulting in altered hydrogen bond networks and distinct free energy landscapes. A key finding of our research is the identification of ARG125 as a pivotal element in these interactions, consistently forming critical hydrogen bonds across different thrombin variants. The persistent role of ARG125 not only elucidates aspects of thrombin’s functional plasticity but also positions it as a promising target for novel therapies. This comprehensive analysis enhances our understanding of thrombin’s structural dynamics, paving the way for more effective and targeted therapeutics.
General Anesthesia Activates a Central Anxiolytic Center in the BNST
Authors: Lu Dongye , Choi Seonmi , Park Jaehong , Kim Jiwoo , Zhao Shengli , Uldry Lavergne Camille G. , Desimone Quinn , Chen Bin , Han Bao-Xia , Wang Fan , Goldstein Nitsan 
Published: December 2023

SUMMARYLow doses of general anesthetics like ketamine and dexmedetomidine have anxiolytic properties independent of their sedative effects. How these different drugs exert these anxiolytic effects is not well understood. We discovered a population of GABAergic neurons in the oval division of the bed nucleus of the stria terminalis that is activated by multiple anesthetics and the anxiolytic drug diazepam (ovBNSTGA). A majority of ovBNSTGAneurons express neurotensin receptor 1 (Ntsr1) and innervate brain regions known to regulate anxiety and stress responses. Optogenetic activation ovBNSTGAor ovBNSTNtsr1neurons significantly attenuated anxiety-like behaviors in both naïve animals and mice with inflammatory pain, while inhibition of these cells increased anxiety. Notably, activation of these neurons decreased heart rate and increased heart rate variability, suggesting that they reduce anxiety through modulation of the autonomic nervous system. Our study identifies ovBNSTGA/ovBNSTNtsr1neurons as one of the brain’s endogenous anxiolytic centers and a potential therapeutic target for treating anxiety-related disorders.HIGHLIGHTSGeneral anesthetics and anxiolytics activate a population of neurons in the ovBNSTAnesthesia-activated ovBNST neurons bidirectionally modulate anxiety-like behaviorMost anesthesia-activated ovBNST neurons express neurotensin receptor 1ovBNSTNtsr1neuron activation shifts autonomic responses to an anxiolytic state
Combinatorial microRNA activity is essential for the transition of pluripotent cells from proliferation into dormancy
Authors: Iyer Dhanur P. , Moyon Lambert , Ringeling Francisca R. , Cheng Chieh-Yu , Wittler Lars , Canzar Stefan , Marsico Annalisa , Bulut-Karslioglu Aydan 
Published: December 2023

SUMMARYDormancy is a key feature of stem cell function in adult tissues as well as embryonic cells in the context of diapause. The establishment of dormancy is an active process that involves extensive transcriptional, epigenetic, and metabolic rewiring1,2. How these processes are coordinated to successfully transition cells to the resting dormant state remains unclear. Here we show that microRNA activity, which is otherwise dispensable for pre-implantation development, is essential for the adaptation of early mouse embryos to the dormant state of diapause. In particular, the pluripotent epiblast depends on miRNA activity, the absence of which results in loss of pluripotent cells. Through integration of high-sensitivity small RNA expression profiling of individual embryos and protein expression of miRNA targets with public data of protein-protein interactions, we constructed the miRNA-mediated regulatory network of mouse early embryos specific to diapause. We find that individual miRNAs contribute to the combinatorial regulation by the network and the perturbation of the network compromises embryo survival in diapause. Without miRNAs, nuclear and cytoplasmic bodies show aberrant expression, concurrent with splicing defects. We identified the nutrient-sensitive transcription factor TFE3 as an upstream regulator of diapause-specific miRNAs, linking cytoplasmic mTOR activity to nuclear miRNA biogenesis. Our results place miRNAs as a critical regulatory layer for the molecular rewiring of early embryos to establish dormancy.
Characterization ofNEBmutations in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects
Authors: Karimi Esmat , van der Borgh Mila , Lindqvist Johan , Gohlke Jochen , Hourani Zaynab , Kolb Justin , Cossette Stacy , Lawlor Michael W. , Ottenheijm Coen , Granzier Henk 
Published: December 2023

AbstractNebulin, a critical protein of the skeletal muscle thin filament, plays important roles in physiological processes such as regulating thin filament length (TFL), cross-bridge cycling, and myofibril alignment. Mutations in the nebulin gene (NEB) cause NEB-based nemaline myopathy (NEM2), a genetically heterogeneous disorder characterized by hypotonia and muscle weakness, currently lacking therapies targeting the underlying pathological mechanisms. In this study, we examined a cohort of ten NEM2 patients, each with unique mutations, aiming to understand their impact on mRNA, protein, and functional levels. Results show that truncation mutations affectNEBmRNA stability and lead to nonsense-mediated decay of the mutated transcript. Moreover, a high incidence of cryptic splice site activation was found in patients with splicing mutations which is expected to disrupt the actin-binding sites of nebulin. Determination of protein levels revealed patients with relatively normal nebulin levels and others with markedly reduced nebulin. We observed a positive relation between the reduction in nebulin and a reduction in TFL, and a positive relation between the reduction in nebulin level and the reduction in tension (both maximal and submaximal tension). Interestingly, our study revealed a duplication mutation in nebulin that resulted in a larger nebulin protein and longer TFL. Additionally, we investigated the effect of Omecamtiv mecarbil (OM), a small-molecule activator of cardiac myosin, on force production of type I muscle fibers of NEM2 patients. OM treatment substantially increased submaximal tension across all NEM2 patients ranging from 87-318%, with the largest effects in patients with the lowest level of nebulin. In summary, this study indicates that post-transcriptional or post-translational mechanisms regulate nebulin expression. Moreover, we propose that the pathomechanism of NEM2 involves not only shortened but also elongated thin filaments, along with the disruption of actin-binding sites resulting from splicing mutations. Significantly, our findings highlight the potential of OM treatment to improve skeletal muscle function in NEM2 patients, especially those with large reductions in nebulin levels.
TipN’s involvement with centromere segregation in Caulobacter crescentus
Authors: Letzkus Morgan , Trela Corey , Mera Paola E. 
Published: December 2023

ABSTRACTBacteria’s ability to maintain chromosomal integrity throughout their life cycle is crucial for their survival. InCaulobacter crescentus, the polar factor TipN has been proposed to be involved with the partitioning system ParABS. However, cells withtipNknocked out display subtleparSsegregation defects. We hypothesized that TipN’s role withparSsegregation is obscured by other forces that are ParABS-independent. To test our hypothesis, we removed one of those forces – chromosome replication – and analyzed the role of TipN with ParA. We first demonstrate that ParA retains its ability to transport the centromeric regionparSfrom the stalked pole to the opposite pole in the absence of chromosome replication. Our data revealed that in the absence of chromosome replication, TipN becomes essential for ParA’s ability to transportparS. Furthermore, we identify a potential connection between the replication initiator DnaA and TipN. Although TipN is not essential for viability,tipNknockout cells lose viability when the regulation of DnaA levels is altered. Our data suggest that the DnaA-dependent susceptibility oftipNknockout cells is connected toparSsegregation. Collectively, this work provides insights into the complex regulation involved in the coordination of chromosome replication and segregation in bacteria.
Effects of oscillation phase on discrimination performance in a visual tilt illusion
Authors: Williams Jessica G. , Harrison William J. , Beale Henry A. , Mattingley Jason B. , Harris Anthony M. 
Published: December 2023

SummaryNeural oscillations reflect fluctuations in the relative excitation/inhibition of neural systems1–5and are theorised to play a critical role in several canonical neural computations6–9and cognitive processes10–14. These theories have been supported by findings that detection of visual stimuli fluctuates with the phase of oscillations at the time of stimulus onset15–23. However, null results have emerged in studies seeking to demonstrate these effects in visual discrimination tasks24–27, raising questions about the generalisability of these phenomena to wider neural processes. Recently, we suggested that methodological limitations may mask effects of oscillation phase in higher-level sensory processing28. Thus, to test the generality of phasic influences requires a task that requires stimulus discrimination but depends on early sensory processing. Here, we examined the influence of oscillation phase in the visual tilt illusion, in which an oriented centre grating is perceived titled away from the orientation of a surround grating29. This illusion is produced by lateral inhibitory interactions in early visual processing30–32. We presented centre gratings at participants’ titrated subjective vertical angle and had participants report whether the grating appeared tilted leftward or rightward of vertical on each trial while measuring their brain activity with EEG. We observed a robust fluctuation in orientation perception across different phases of posterior alpha and theta oscillations, consistent with fluctuating illusion magnitude across the oscillatory cycle. These results confirm that oscillation phase affects complex processing involved in stimulus discrimination, consistent with their purported role in canonical computations that underpin cognition.
Flagellar beat state switching in microswimmers to select between positive and negative phototaxis
Authors: Tsang Alan C. H. , Riedel-Kruse Ingmar H. 
Published: December 2023

Microorganisms have evolved various sensor-actuator circuits to respond to environmental stimuli. However, how a given circuit can select efficiently between positive vs. negative taxis under desired vs. undesired stimuli is poorly understood. Here, we investigate how the cellular mechanism by which the chiral microswimmerEuglena graciliscan select between positive vs. negative phototaxis under low vs. high light intensity conditions, respectively. We propose three general selection mechanisms for microswimmer phototaxis. A generic biophysical model demonstrates the effectiveness of all mechanisms, but which varies for each depending on specific conditions. Experiments reveal that only a ‘photoresponse in-version’ mechanism is compatible withE. gracilisphototaxis. Specifically, a light-intensity dependent transition on the sub-second time scale between two flagellar beat states responsible for forward swimming vs. sideway turning ultimately generates positive phototaxis at low light intensity via a run-and-tumble strategy and negative phototaxis at high light intensity via a helical klinotaxis strategy. More generally, a picture emerges where a variety ofE. gracilisbehaviors over a wide range of light intensities as reported in the literature can be explained by the coordinated switching between just these two flagellar beating states over time. These results provide design principles for simple two-state switching mechanisms in natural and synthetic microswimmers to operate under both noisy and saturated stimulus conditions.LAY ABSTRACTOur experimental and theoretical results explain how the single cellEuglena gracilisachieves both positive and negative phototaxis. Our insights are then able to synthesise a larger number of previously described observations onE. gracilisphotoresponses and photobehaviors due to a concise two-state model of flagellar beating. These insight will likely inform the behaviors of other natural microswimmers as well as the design of synthetic ones.
Daily dynamics of resting-state EEG theta and gamma fluctuations are associated with cognitive performance in healthy aging
Authors: Bennis Kenza , Eustache Francis , Collette Fabienne , Vandewalle Gilles , Hinault Thomas 
Published: December 2023

AbstractHealthy age-related cognitive changes are highly heterogeneous across individuals. This variability is increasingly explained through the lens of spontaneous fluctuations of brain activity, now considered as powerful index of age-related changes. However, brain activity is a biological process modulated by circadian rhythms, and how these fluctuations evolve throughout the day is under investigated. Assessing the daily dynamics of brain fluctuations involves the use of techniques measuring the temporal dynamics of synchronized communications between brain regions, such as electroencephalography. We found that theta and gamma daily fluctuations in the salience-control executive inter-network (SN-CEN) are associated with distinct mechanisms underlying cognitive heterogeneity in aging. Higher levels of SN-CEN theta daily fluctuations appear to be deleterious for memory performance and were associated with higher tau/neuroinflammation rates. In contrast, higher levels of gamma daily fluctuations are positively associated with executive performance, and were associated with lower rate of β-amyloid deposition. Thus, accounting for daily EEG fluctuations of brain activity contributes to better understand subtle brain changes underlying individuals’ cognitive performance in healthy aging.
Exploring serial crystallography for drug discovery
Authors: Dunge A. , Phan C. , Uwangue O , Bjelcic M. , Gunnarsson J. , Wehlander G. , Käck H. , Brändén G. 
Published: December 2023

AbstractStructure-based drug design is highly dependent on the availability of structures of the protein of interest in complex with lead compounds. Ideally, this information can be used to guide the chemical optimization of a compound into a pharmaceutical drug candidate. A limitation of the main structural method used today, rotational cryo-crystallography, is that it only provides structural information of the protein-complex in its frozen state. Serial crystallography is a relatively new approach that offers the possibility to study protein structures at room-temperature. Here, we explore the use of serial crystallography to determine structures of the pharmaceutical target soluble epoxide hydrolase. We introduce a new method to screen for optimal microcrystallization conditions suitable for use in serial crystallography and present a number of room-temperature ligand-bound structures of our target protein. From a comparison between the room-temperature structural data and previously published cryo-temperature structures, we describe an example of a temperature-dependent difference in ligand-binding mode and observe that flexible loops are better resolved at ambient temperature. Finally, we discuss current limitations and potential future advances of serial crystallography for use within pharmaceutical drug discovery.
Reward Expectation Reduces Representational Drift in the Hippocampus
Authors: Krishnan Seetha , Sheffield Mark E.J. 
Published: December 2023

SummarySpatial memory in the hippocampus involves dynamic neural patterns that change over days, termed representational drift. While drift may aid memory updating, excessive drift could impede retrieval. Memory retrieval is influenced by reward expectation during encoding, so we hypothesized that diminished reward expectation would exacerbate representational drift. We found that high reward expectation limited drift, with CA1 representations on one day gradually re-emerging over successive trials the following day. Conversely, the absence of reward expectation resulted in increased drift, as the gradual re-emergence of the previous day’s representation did not occur. At the single cell level, lowering reward expectation caused an immediate increase in the proportion of place-fields with low trial-to-trial reliability. These place fields were less likely to be reinstated the following day, underlying increased drift in this condition. In conclusion, heightened reward expectation improves memory encoding and retrieval by maintaining reliable place fields that are gradually reinstated across days, thereby minimizing representational drift.
Phylogeny not mimicry drives chemical variation in tropical aposematic butterflies
Authors: Blow Rachel , Ehlers Stephanie , Warren Ian , Szczerbowski Daiane , Schulz Stefan , Jiggins Chris 
Published: December 2023

AbstractChemical signals serve a vast array of functions for both intra- and interspecific communication and defence. Chemically defended, aposematic insects will advertise their noxiousness to predators with warning signals and it has been suggested that volatile compounds shared between species could send a common signal to deter avian predators, similar to colour pattern mimicry. This is exemplified in the bright, mimetic warning colours of toxic heliconiine and ithomiine butterflies. Besides defence, males in these groups also use chemicals to communicate with potential female mates and male competitors. Here, we characterise chemical profiles of male Heliconiini and Ithomiini species from a range of mimicry rings. We find that chemical distances between species are not associated with mimicry and instead show a strong phylogenetic signal. In addition, we show that the distribution of specific shared compounds does not correlate with mimicry. We propose chemical signals in these groups are primarily used for intraspecific communication and highlight the potential selective mechanisms driving chemical profile evolution, such as selection for species-specific pheromone concentrations and collective male deterrent compounds. Our findings imply that chemical profile variation among butterfly species is the product of shared ancestry. However, more research is required on the behavioural significance of compounds among butterflies and predator perception of olfactory warning signals to identify which selective pressures are exerted on specific chemical traits.
What effect do the ResearchGate writers’ altmetric scores have on scientometric indicators related to Qur’an in Scopus?
Authors: Biranvand Ali , Shojaeofard Ali , Cheraghi Zohreh 
Published: December 2023

Purpose
This study aims to investigate the impact of ResearchGate (RG) scores on the scientific indicators of Qur’anic productions in Scopus.

Design/methodology/approach
This research is fundamental in method, created in a descriptive method and a scientometric approach. The statistical society includes 4,105 records produced by writers in the field of Qur’an during the time period of 2011–2020 indexed in the Scopus database. In this study, Pearson correlation coefficient test is used with aid of Excel and SPSS software.

Findings
Countries such as Malaysia, the USA and Indonesia, respectively, hold the highest number of scientific productions in the field of Qur’an. Iran holds the fourth place with a 544 record difference in comparison to Malaysia (866 documents). There is a positive and meaningful relation between measures of RG, readers, followers, citations and the H-index score regarding writers with received citations and the H-index score of scientific productions in the field of Qur’an in Scopus. However, no relation can be observed between the mentioned measures and indicators of the number of documents with cowriting.

Research limitations/implications
Because of some authors not using the same name in their articles, it was not possible to access their profile in RG. For this reason, the information of these authors was not accessible in RG.

Practical implications
The activity of researchers in social networks will receive feedback from readers. This will result in more citations. Contrary to expectations, the research results showed that Iran does not have a good position in publishing Qur’anic works. Therefore, researchers should publish their findings in international journals.

Social implications
Iranian writers should try to publish their scientific productions in international publications and also widely spread their content and research results across social networks to increase feedback and gain the attention of readers. This process leads to receiving reader feedback and publication of the Islamic teachings.

Originality/value
The relationship between the number of citations of Qur’anic works in Scopus and altmetric indicators in RG has not been investigated in previous researches. Therefore, this research is innovative in this field.
Spiritual intelligence and teachers' intention to quit: the mechanism roles of sanctification of work and job satisfaction
Authors: Vem Linus Jonathan , Ng Imm Siew , Sambasivan Murali , Kok Tee Keng 
Published: December 2023

PurposeThe main objective of this study is to analyze the impact of spiritual intelligence (SI) based on its four dimensions (critical existential thinking (CET), personal meaning production (PMP), transcendental awareness (TA) and conscious state expansion (CSE)) on teachers' turnover intention (TI) through sanctification of work (SoW) and job satisfaction (JS).Design/methodology/approachDrawing from multiple intelligence theory, this study adopted a cross-sectional design to explore the hypothesized relationships. Copies of the questionnaire were distributed to 367 teachers working in public schools in Plateau State, Nigeria, and 290 out of the retrieved copies were useable. The data collected were analyzed using variance-based structural equation modeling (SEM), Smart-PLS 4.FindingsThe results suggest that SI does not significantly influence TI, while SoW and JS mediate the relationship between SI and TI.Practical implicationsThe result suggests that SoW and JS are significant mechanisms through which SI predicts teachers' TI. This highlights the need for educational policymakers to integrate spiritual literature as well as imbibe spiritual practices such as prayers, meditations and yoga either at work or privately to enhance the development of SI among teachers.Originality/valueThe results offer an insightful understanding of SI and how it influences work outcomes. The mechanism roles of SoW and JS explain the process by which one's perceived numinous object, activity event and job experience influence a job decision.