bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Relationship Between Intra-articular Fracture Energy and a Patient's Inflammatory Response
Authors: Haller Justin M. , Fink Diane , Smith Hannah , Olsen Zachary , Jacobs Cale , Anderson Donald 
Published: March 2024

OBJECTIVES:
Prior studies have demonstrated elevated inflammatory cytokine concentrations in the synovial fluid of articular fracture patients postinjury. Similarly, CT-based fracture energy measurements have been correlated with posttraumatic osteoarthritis risk after pilon fracture. The purpose of this study was to determine the associations between synovial fluid cytokine levels, fracture energy, and overall trauma to the body in articular fracture patients.

METHODS:
Acute tibial plateau, tibial plafond, and rotational ankle fracture patients were prospectively enrolled from December 2011 through January 1, 2019. Synovial fluid concentrations of interleukin-1 beta, interleukin-1 receptor antagonist, IL-6, IL-8, IL-10, matrix metallopeptidase-1, MMP-3, and MMP-13 were quantified. Patient CT scans were used to calculate fracture energy. The Injury Severity Score (ISS) was used to relate cytokine levels to whole-body injury severity. Spearman rho correlation coefficients were calculated to assess the relationship between injury severity metrics and synovial fluid cytokine, chemokine, and matrix metallopeptidase concentrations.

RESULTS:
Eighty-seven patients were enrolled with 42 had a tibial plateau fractures (OTA/AO 41B1-2, 41B2-14, 41B3-3, 41C1-3, 41C2-4, 41C3-16), 24 patients had a tibial plafond fracture (OTA/AO 43B1-2, 43B2-4, 43B3-5, 43C1-2, 43C2-3, 43C3-8), and 21 had a rotational ankle fracture (OTA/AO 44B1-3, 44B2-3, 44B3-6, 44C1-4, 44C2-5). Fracture energy significantly differed between fracture patterns, with ankle fractures involving substantially less fracture energy (median = 2.92 J) than plafond (10.85 J, P < 0.001) and plateau fractures (13.05 J, P < 0.001). After adjustment for multiple comparisons, MMP-3 was significantly correlated with transformed fracture energy (r = 0.41, 95% confidence interval [CI], 0.22–0.58, P < 0.001), while IL-1β was significantly correlated with the Injury Severity Score (Spearman ρ = 0.31, 95% CI, 0.08–0.49, P = 0.004).

CONCLUSIONS:
Synovial fluid MMP-3 concentration was significantly correlated with CT-quantified fracture energy in intra-articular fracture patients. Given that in clinical practice fracture energy tends to correlate with posttraumatic osteoarthritis risk, MMP-3 may warrant further investigation for its role in posttraumatic osteoarthritis development after articular fracture.

LEVEL OF EVIDENCE:
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Reframing the Morbidity and Mortality Conference: The Impact of a Just Culture
Authors: Brook Karolina , Agarwala Aalok V. , Tewfik George L. 
Published: March 2024

Abstract
Morbidity and mortality (M&M) conferences are prevalent in all fields of medicine. Historically, they arose out a desire to improve medical care. Nevertheless, the goals of M&M conferences are often poorly defined, at odds with one another, and do not support a just culture. We differentiate among the various possible goals of an M&M and review the literature for strategies that have been shown to achieve these goals. Based on the literature, we outline an ideal M&M structure within the context of just culture: The process starts with robust adverse event and near miss reporting, followed by careful case selection, excluding cases solely attributable to individual error. Prior to the M&M, the case should be openly discussed with involved members and should be reviewed using a selected framework. The goal of the M&M should be selected and clearly defined, and the presentation format and rules of conduct should all conform to the selected presentation goal. The audience should ideally be multidisciplinary and multispecialty. The M&M should conclude with concrete tasks and assigned follow-up. The entire process should be conducted in a peer review protected format within an environment promoting psychological safety. We conclude with future directions for M&Ms.
Maternal Alcohol Drinking Patterns Predict Offspring Neurobehavioral Outcomes
Authors: Myrick Abbey , Jimenez Diane , Jacquez Belkis , Sun Melody S. , Noor Shahani , Milligan Erin D. , Valenzuela C. Fernando , Linsenbardt David N. 
Published: March 2024

AbstractSIGNIFICANCEThe timing, rate, and quantity of gestational alcohol consumption, collectively referred to here as Maternal Drinking Patterns (MDPs), are of known importance to fetal developmental outcomes. Though studies in rodents exist that have investigated the impact of gestational alcohol drinking characteristics, few have sought to determine the impact of MDPs on offspring behavioral outcomes.METHODSWe first used specialized equipment to record the precise amount and timing of binge alcohol consumption in pregnant mouse dams, and then characterized MDPs using Principle Component Analysis (PCA). We focused these analyses on the first fifteen minutes of every gestational drinking session when dams consumed the majority of each session’s alcohol (a phenomenon known as front-loading), as well as the entire 2 hour session across all days of gestation. We next tested offspring in open field and rotarod assays and evaluated these behavioral results in the context of MDPs.RESULTSMale alcohol exposed mice exhibited longer latencies to fall on the rotarod compared to their controls, which we attribute to a delayed decrease in body weight-gain not observed in females. This effect was found to be associated with MDPs within the first fifteen minutes of drinking, but not other MDPs. Female alcohol exposed mice had significantly reduced total locomotor activity in the open field compared to controls, and this effect was also associated with MDPs but only of the entire drinking session. Surprisingly, total gestational alcohol consumption alone was not associated with any particular behavioral outcome. Furthermore, we replicated robust behavioral data demonstrating development of allodynia in alcohol exposed mice where it did not develop in controls.CONCLUSIONSTo our knowledge, this report represents the highest resolution assessment of alcohol drinking throughout gestation, and one of few to have identified relationships between specific alcohol MDPs and neurobehavioral outcomes in offspring. Specifically, based on characteristics of the PCA groups, we found evidence that the rate of alcohol front-loading leads to developmental delays in males, whereas an interaction of front-loading rate and duration, overall persistence, and total amount consumed lead to a female-only decrease in locomotor activity. Beyond these results, we provide a method for precise and accessible tracking of such data.
Motor Hotspot Localization Based on Electroencephalography Using Convolutional Neural Network in Patients with Stroke
Authors: Choi Ga-Young , Seo Jeong-Kweon , Kim Kyoung Tae , Chang Won Kee , Paik Nam-Jong , Kim Won-Seok , Hwang Han-Jeong 
Published: March 2024

AbstractBackgroundAlthough transcranial magnetic stimulation (TMS) is the optimal tool for identifying individual motor hotspots for transcranial electrical stimulation (tES), it requires a cumbersome procedure in which patients must visit the hospital each time and rely on expert judgment to determine the motor hotspot. Therefore, in previous study, we proposed electroencephalography (EEG)-based machine learning approach to automatically identify individual motor hotspots. In this study, we proposed an advanced EEG-based motor hotspot identification algorithm using a deep learning model and assessed its clinical feasibility and benefits by applying it to stroke patient EEGs.MethodsEEG data were measured from thirty subjects as they performed a simple hand movement task. We utilized the five types of input data depending on the processing levels to assess the signal processing capability of our proposed deep learning model. The motor hotspot locations were estimated using a two-dimensional convolutional neural network (CNN) model. The error distance between the 3D coordinate information of the individual motor hotspots identified by the TMS (ground truth) and EEGs was calculated using the Euclidean distance. Additionally, we confirmed the clinical benefits of our proposed deep-learning algorithm by applying the EEG of stroke patients.ResultsA mean error distance between the motor hotspot locations identified by TMS and our approach was 2.34 ± 0.19 mm when using raw data from only 9 channels around the motor area. When it was tested on stroke patients, the mean error distance was 1.77 ± 0.15 mm using only 5 channels around the motor area.ConclusionWe have demonstrated that an EEG-based deep learning approach can effectively identify the individual motor hotspots. Moreover, we validated the clinical benefits of our algorithm by successfully implementing it in stroke patients. Our algorithm can be used as an alternative to TMS for identifying motor hotspots and maximizing rehabilitation effectiveness.
NeuralPlayground: A Standardised Environment for Evaluating Models of Hippocampus and Entorhinal Cortex
Authors: Dominé Clémentine C. J. , Carrasco-Davis Rodrigo , Hollingsworth Luke , Sirmpilatze Nikoloz , Tyson Adam L. , Jarvis Devon , Barry Caswell , Saxe Andrew M. 
Published: March 2024

AbstractNeural processes in the hippocampus and entorhinal cortex are thought to be crucial for spatial cognition. A growing variety of theoretical models have been proposed to capture the rich neural and behavioral phenomena associated with these circuits. However, systematic comparison of these theories, both against each other and against empirical data, remains challenging. To address this gap, we present NeuralPlayground, an open-source standardised software framework for comparisons between theory and experiment in the domain of spatial cognition. This Python software package offers a reproducible way to compare models against a centralised library of published experimental results, including neural recordings and animal behavior. The framework implements threeAgentsembodying different computational models; threeExperimentscomprising publicly available neural and behavioral datasets; a customisable 2-dimensionalArena(continuous and discrete) able to generate common and novel spatial layouts; and aComparisontool that facilitates systematic comparisons between models and data. Each module can also be used separately, allowing standardised and flexible access to influential models and data sets. We hope NeuralPlayground, available on GitHub3, provides a starting point for a shared, standardized, open, and reproducible computational understanding of the role of the hippocampus and entorhinal cortex in spatial cognition.
HSV-1 infection induces a downstream shift of the +1 nucleosome
Authors: Weiß Elena , Whisnant Adam W. , Hennig Thomas , Djakovic Lara , Dölken Lars , Friedel Caroline C. 
Published: March 2024

AbstractHerpes simplex virus 1 (HSV-1) infection induces a loss of host transcriptional activity and widespread disruption of host transcription termination, which leads to an induction of open chromatin downstream of genes. In this study, we show that lytic HSV-1 infection also leads to an extension of chromatin accessibility at promoters into downstream regions. This is most prominent for highly expressed genes and independent of the immediate-early proteins ICP0, ICP22, and ICP27 and the virion host shutoff proteinvhs.ChIPmentation of the noncanonical histone variant H2A.Z, which is strongly enriched at +1 and −1 nucleosomes, indicated that these chromatin accessibility changes are linked to a downstream shift of +1 nucleosomes. In yeast, downstream shifts of +1 nucleosomes are induced by RNA Polymerase II (Pol II) degradation. Accordingly, irreversible depletion of Pol II from genes in human cells using α-amanitin altered +1 nucleosome positioning similar to lytic HSV-1 infection. Consequently, treatment with phosphonoacetic acid (PAA) and knockout of ICP4, which both prevent viral DNA replication and alleviate the loss of Pol II from host genes, largely abolished the downstream extension of accessible chromatin in HSV-1 infection. In the absence of viral DNA replication, doxycycline-induced expression of ICP27, which redirects Pol II from gene bodies into intergenic regions by disrupting transcription termination, induced an attenuated effect that was further enhanced by co-expression of ICP22. In summary, our study provides strong evidence that HSV-1-induced depletion of Pol II from the host genome leads to a downstream shift of +1 nucleosomes at host promoters.ImportanceLytic herpes simplex virus 1 (HSV-1) infection leads to a profound host transcription shutoff. Loss of RNA Polymerase II (Pol II) in yeast has previously been shown to relax +1 nucleosome positioning to more thermodynamically favorable sites downstream of transcription start sites. Here, we show that a similar phenomenon is likely at play in lytic HSV-1 infection. Sequencing of accessible chromatin revealed a widening of nucleosome-free regions at host promoters into downstream regions. By mapping genome-wide positions of the noncanonical histone variant H2A.Z enriched at +1 and −1 nucleosomes, we demonstrate a downstream shift of +1 nucleosomes for most cellular genes in lytic HSV-1 infection. As chemical depletion of Pol II from genes also leads to a downstream shift of +1 nucleosomes in human cells, changes in chromatin architecture at promoters in HSV-1 infection are likely a consequence of HSV-1-induced loss of Pol II activity from the host genome.
The protective roles of Eugenol on type 1 diabetes mellitus through NRF2 mediated oxidative stress pathway
Authors: Jiang Yalan , He Pingping , Sheng Ke , Peng Yongmiao , Wu Huilan , Qian Songwei , Ji Weiping , Guo Xiaoling , Shan Xiaoou 
Published: March 2024

AbstractType 1 diabetes mellitus (T1DM), known as insulin-dependent diabetes mellitus, is characterized by persistent hyperglycemia resulting from damage to the pancreatic β cells and an absolute deficiency of insulin, leading to multi-organ involvement and a poor prognosis. The progression of T1DM is significantly influenced by oxidative stress and apoptosis. The natural compound eugenol (EUG) possesses anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, the potential effects of EUG on T1DM had not been investigated. In this study, we established the streptozotocin (STZ)-induced T1DM mouse modelin vivoand STZ-induced pancreatic β cell MIN6 cell modelin vitroto investigate the protective effects of EUG on T1DM, and tried to elucidate its potential mechanism. Our findings demonstrated that the intervention of EUG could effectively induce the activation of nuclear factor E2-related factor 2 (NRF2), leading to an up-regulation in the expressions of downstream proteins NQO-1 and HO-1, which are regulated by NRF2. Moreover, this intervention exhibited a significant amelioration in pancreatic β cell damage associated with T1DM, accompanied by an elevation in insulin secretion and a reduction in the expression levels of apoptosis and oxidative stress related markers. Furthermore, ML385, an NRF2 inhibitor, reversed these effects of EUG. The present study suggested that EUG exerted protective effects on pancreatic β cells in T1DM by attenuating apoptosis and oxidative stress through the activation of the NRF2 signaling pathway. Consequently, EUG holds great promise as a potential therapeutic candidate for T1DM.
Microbial Response to Natural Disturbances: Rare Biosphere often plays a role
Authors: Zhao Jianshu , Brandt Genevieve , Wang Zhao , Hunt Dana E. , Rodriguez-R Luis M. , Hatt Janet K. , Konstantinidis Konstantinos T. 
Published: March 2024

AbstractUnderstanding how microbial populations respond to disturbances represents a major goal for microbial ecology. While several theories have been advanced to explain microbial community compositional changes in response to disturbances, appropriate data to test these theories is scarce, especially when considering the challenges to define rare vs. abundant taxa and generalists vs. specialists, a prerequisite for testing the theories. Here, we define these two key concepts by employing the patterns of coverage of a (target) genome by a metagenome to define rare populations, and by borrowing concepts from macroecology, the proportional similarity index (PS index), to define generalists. Using these concepts, we found that coastal microbial communities are resilient to major perturbations such as tropical cyclones and (uncommon) cold or warm weather events snaps-in part-due to the response of rare populations, providing support for the insurance hypothesis (i.e., the rare biosphere has the buffering capacity to mitigate the effects of disturbances). Generalists appear to contribute proportionally more than specialists to community adaptation to perturbations like warming, supporting the disturbance-specialization hypothesis, i.e., disturbance favors generalists. Taken together, our results advance understanding of the mechanisms governing microbial populations dynamics under changing environmental conditions and have potential applications for ecosystem management.
Studying relative RNA localization From nucleus to the cytosol
Authors: Ntasis Vasilis F. , Guigó Roderic 
Published: March 2024

AbstractThe precise coordination of important biological processes, such as differentiation and development, is highly dependent on the regulation of expression of the genetic information. The flow of the genetic information is tightly regulated on multiple levels. Among them, RNA export to cytosol is an essential step for the production of proteins in eukaryotic cells. Hence, estimating the relative concentration of RNA molecules of a given transcript species in the nucleus and in the cytosol is of major significance as it contributes to the understanding of the dynamics of RNA trafficking between the nucleus and the cytosol. The most efficient way to estimate the levels of RNA species genome-wide is through RNA sequencing (RNAseq). While RNAseq can be performed separately in the nucleus and in the cytosol, because measured transcript levels are relative to the total volume of RNA in these compartments, and because this volume is usually unknown, the transcript levels in the nucleus and in the cytosol cannot be directly compared. Here we show theoretically that if, in addition to nuclear and cytosolic RNA-seq, whole cell RNA-seq is also performed, then accurate estimations of the localization of transcripts can be obtained. Based on this, we designed a method that estimates, first the fraction of the total RNA volume in the cytosol (nucleus), and then, this fraction for every transcript. We evaluate our methodology on simulated data and nuclear and cytosolic single cell data available. Finally, we use our method to investigate the cellular localization of transcripts using bulk RNAseq data from the ENCODE project.
TRPC6 is a mechanosensitive channel essential for ultrasound neuromodulation in mammalian brain
Authors: Matsushita Yumi , Yoshida Kaede , Yoshiya Miyuki , Shimizu Takahiro , Tsukamoto Satoshi , Takeuchi Yuichi , Higuchi Makoto , Shimojo Masafumi 
Published: March 2024

AbstractUltrasound neuromodulation has become an innovative technology that enables non-invasive intervention in mammalian brain circuits with high spatiotemporal precision. Despite the expanding utility of ultrasound neuromodulation in the neuroscience research field and clinical applications, the molecular and cellular mechanisms by which ultrasound impacts neural activity in the brain are still largely unknown. Here, we report that transient receptor potential canonical 6 (TRPC6), a mechanosensitive non-selective cation channel, is essential for ultrasound neuromodulation of mammalian neuronsin vitroandin vivo. We first demonstrated that ultrasound irradiation elicited rapid and robust Ca2+transients mediated via extracellular Ca2+influx in cultured mouse cortical and hippocampal neurons. Ultrasound-induced neuronal responses were massively diminished by blocking either the generation of action potential or synaptic transmission. Importantly, both pharmacological inhibition and genetic deficiency of TRPC6 almost completely abolished neuronal responses to ultrasound. Furthermore, we found that intracerebroventricular administration of a TRPC6 blocker significantly attenuated the population of neuronal firings in the cerebral cortex evoked by transcranial ultrasound irradiation in mice. Our findings indicate that TRPC6 is an indispensable molecule of ultrasound neuromodulation in the intact mammalian brains, providing fundamental understanding of biophysical molecular mechanisms of ultrasound neuromodulation as well as insight into its future feasibility in neuroscience and translational researches in humans.
Application of mechanistic multiparameter optimization and large scale in vitro toin vivopharmacokinetics correlations to small molecule therapeutic projects
Authors: Broccatelli Fabio , Veeravalli Vijayabhaskar , Cashion Daniel , Baylon Javier L. , Lombardo Franco , Jia Lei 
Published: March 2024

ABSTRACTComputational chemistry and machine learning are used in drug discovery to predict target-specific and pharmacokinetic properties of molecules. Multiparameter optimization (MPO) functions are used to summarize multiple properties into a single score, aiding compound prioritization. However, over-reliance on subjective MPO functions risks reinforcing human bias. Mechanistic modeling approaches based on physiological relevance can be adapted to meet different potential key objectives of the project (e.g. minimizing dose, maximizing safety margins and/or minimized drug-drug interaction risk) while retaining the same underlying model structure. The current work incorporates recent approaches to predictin vivoPK properties and validatesin vitrotoin vivocorrelation analysis to support mechanistic PK MPO. Examples of use and impact in small molecule drug discovery projects are provided. Overall, the mechanistic MPO identifies 83% of the compounds considered as short-listed for clinical experiments in the top 2ndpercentile, and 100% in the top 10thpercentile, resulting in an area under the receiver operating characteristic curve (AUCROC) > 0.95. In addition, the MPO score successfully recapitulates the chronological progression of the optimization process across different scaffolds. Finally, the MPO scores for compounds characterized in pharmacokinetics experiments are markedly higher compared to the rest of the compounds synthesized, highlighting the potential of this tool to reduce the reliance onin vivotesting for compound screening.
Spatial targeting of the prostaglandin receptor EP2 to very early endosomes co-ordinates PGE2-mediated cAMP signaling in decidualizing human endometrium
Authors: Brighton Paul J. , Walker Abigail R. , Mann Oliver , Kong Chow-Seng , Lucas Emma S. , Vrljicak Pavle , Brosens Jan J. , Hanyaloglu Aylin C. 
Published: March 2024

SummaryDecidualization denotes the differentiation of endometrial stromal cells into specialized decidual cells, essential for embryo implantation and pregnancy. The process requires coordinated activation of both progesterone and cAMP signaling pathways, which converge on downstream transcription factors. PGE2 and relaxin, acting respectively through their Gαs-coupled GPCRs EP2 and RXFP1, are putative candidates responsible for generating cAMP in differentiating stromal cells. Here, we show that PGE2 is less efficacious than relaxin in elevating intracellular cAMP levels in primary stromal cells but more effective at driving the expression of canonical decidual genes. Both PGE2- and relaxin-induced cAMP generation involves receptor internalization, but EP2 is endocytosed into very early endosomes (VEEs). Perturbation of the VEE machinery dysregulates PGE2-dependent cAMP profiles and disrupts key decidual signaling pathways, resulting in a disordered differentiation response. We demonstrate that the spatial location of EP2 is essential for coordinated activation of the downstream signaling cascades that govern decidualization.