bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysphagia as a missing link between post-surgical- and opioid-related pneumonia
Authors: Frazure Michael , Greene Clinton L. , Iceman Kimberly E. , Howland Dena R. , Pitts Teresa 
Published: October 2023

AbstractObjectivePostoperative pneumonia remains a common complication of surgery, despite increased attention. The purpose of our study was to determine the effects of routine surgery and post-surgical opioid administration on airway protection risk.MethodsEight healthy adult cats were evaluated for dysphagia in 2 experiments. 1) In 4 female cats airway protection status was tracked following routine abdominal surgery (spay surgery) plus low-dose opioid administration (buprenorphine 0.015mg/kg, IM, q8-12h;n=5). 2) Using a cross-over design (2 male, 2 female) cats were treated with moderate (0.02mg/kg) or high (0.04mg/kg) dose buprenorphine (IM, q8-12h;n=5) to determine changes in airway protection status or evidence of dysphagia.ResultsAirway protection was significantly affected in both experiments, but most severely post-surgically where 75% of the animals exhibited silent aspiration.ConclusionOropharyngeal swallow is impaired by the partial mu-opioid receptor agonist buprenorphine, most remarkably in the post-operative setting. These findings have implications for the prevention and management of aspiration pneumonia in vulnerable populations.
Diffusion Deep Learning for Brain Age Prediction and Longitudinal Tracking in Children Through Adulthood
Authors: Zapaishchykova Anna , Tak Divyanshu , Ye Zezhong , Liu Kevin X. , Likitlersuang Jirapat , Vajapeyam Sridhar , Chopra Rishi B. , Seidlitz Jakob , Bethlehem Richard AI ,   Lifespan Brain Chart Consortium, Mak Raymond H. , Mueller Sabine , Haas-Kogan Daphne A. , Poussaint Tina Y. , Aerts Hugo J.W.L. , Kann Benjamin H. 
Published: October 2023

AbstractDeep learning (DL)-based prediction of biological age in the developing human from a brain magnetic resonance image (MRI) (“brain age”) may have important diagnostic and therapeutic applications as a non-invasive biomarker of brain health, aging, and neurocognition. While previous deep learning tools for predicting brain age have shown promising capabilities using single-institution, cross-sectional datasets, our work aims to advance the field by leveraging multi-site, longitudinal data with externally validated and independently implementable code to facilitate clinical translation and utility. This builds on prior foundational efforts in brain age modeling to enable broader generalization and individual’s longitudinal brain development. Here, we leveraged 32,851 T1-weighted MRI scans from healthy children and adolescents aged 3 to 30 from 16 multisite datasets to develop and evaluate several DL brain age frameworks, including a novel regression diffusion DL network (AgeDiffuse). In a multisite external validation (5 datasets), we found that AgeDiffuse outperformed conventional DL frameworks, with a mean absolute error (MAE) of 2.78 years (IQR:[1.2-3.9]). In a second, separate external validation (3 datasets), AgeDiffuse yielded an MAE of 1.97 years (IQR: [0.8-2.8]). We found that AgeDiffuse brain age predictions reflected age- related brain structure volume changes better than biological age (R2=0.48 vs R2=0.37). Finally, we found that longitudinal predicted brain age tracked closely with chronological age at the individual level. To enable independent validation and application, we made AgeDiffuse publicly available and usable for the research community.HighlightsDiffusion regression models trained with a large dataset (AgeDiffuse) enable accurate pediatric brain age prediction.AgeDiffuse demonstrates relatively stable performance on multiple external validation sets across people aged 3 – 30.Our pipeline is made publicly accessible, encouraging collaboration and progress in pediatric brain research.
Cancer-on-a-chip model shows that the adenomatous polyposis coli mutation impairs T cell engagement and killing of cancer spheroids
Authors: Bonnet Valentin , Maikranz Erik , Madec Marianne , Vertti-Quintero Nadia , Cuche Céline , Mastrogiovanni Marta , Alcover Andrés , Bartolo Vincenzo Di , Baroud Charles N. 
Published: October 2023

AbstractEvaluating the ability of cytotoxic T lymphocytes (CTLs) to eliminate tumor cells is crucial, for instance to predict the efficiency of cell therapy in personalized medicine. However, the destruction of a tumor by CTLs involves CTL migration in the extra-tumoral environment, accumulation on the tumor, antigen recognition, and cooperation in killing the cancer cells. Therefore, identifying the limiting steps in this complex process requires spatio-temporal measurements of different cellular events over long periods. Here, we use a cancer-on-a-chip platform to evaluate the impact of adenomatous polyposis coli (APC) mutation on CTL migration and cytotoxicity against 3D tumor spheroids. The APC mutated CTLs are found to have a reduced ability to destroy tumor spheroids compared with control cells, even though APC mutants migrate in the extra-tumoral space and accumulate on the spheroids as efficiently as control cells. Once in contact with the tumor however, mutated CTLs display reduced engagement with the cancer cells, as measured by a new metric that distinguishes different modes of CTL migration. Realigning the CTL trajectories around localized killing cascades reveals that all CTLs transition to high engagement in the two hours preceding the cascades, which confirms that the low engagement is the cause of reduced cytotoxicity. Beyond the study of APC mutations, this platform offers a robust way to compare cytotoxic cell efficiency of even closely related cell types, by relying on a multiscale cytometry approach to disentangle complex interactions and to identify the steps that limit the tumor destruction.
Extracellular matrix sulfation in the tumor microenvironment stimulates cancer stemness and invasiveness
Authors: Kuşoğlu Alican , Örnek Deniz , Dansık Aslı , Uzun Ceren , Özkan Sena Nur , Sarıca Sevgi , Yangın Kardelen , Özdinç Şevval , Sorhun Duygu Turan , Solcan Nuriye , Doğanalp Efe Can , Arlov Øystein , Cunningham Katherine , Karaoğlu İsmail C. , Kizilel Seda , Solaroglu Ihsan , Bulutay Pınar , Fırat Pınar , Erus Suat , Tanju Serhan , Dilege Şükrü , Vunjak-Novakovic Gordana , Tuncbag Nurcan , Öztürk Ece 
Published: October 2023

AbstractTumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, we demonstrate that PGs are heavily expressed in lung adenocarcinoma patients in correlation with invasive phenotype and poor prognosis. We developed a bioengineered human lung tumor model which recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density and porosity. Our model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition and stemness in cancer cells. We identified the FAK-PI3K-mTOR signaling axis as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. We demonstrate that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG-rich patient tumors through employing integrative omics and network modeling approaches.
Supercharged Fluorescent Protein-Apoferritin Cocrystals for Lighting Applications
Authors: Patrian Marta , Shaukat Ahmed , Nieddu Mattia , Banda-Vázquez Jesús A. , Timonen Jaakko V. I. , Fuenzalida-Werner JP , Anaya□Plaza Eduardo , Kostiainen Mauri A. , Costa Rubén D. 
Published: October 2023

AbstractThe design of lighting sources based on fluorescent proteins (FPs) has been limited by the lack of protocols to stabilize FPs under preparation (deposition techniques, organic solvents,etc.) and working (temperature, irradiation,etc.) conditions. As a critical bottleneck, photo-induced heat generation due to FP motion and quick heat transfer leads to working device temperatures ofca. 70 °C, resulting in a quick FP-denaturation and, in turn, a quick loss of the device performance. Herein, we showcase FP stabilization for lighting devices with an electrostatically self-assembled FP-apoferritin cocrystals embedded in a silicone-based color down-converting filter. This strategy highlights three major advances:i) engineering of positively supercharged FPs (+22) without losing photoluminescence and thermal stability compared to its native form,ii) a crystallization protocol resulting in highly emissive cocrystals keeping the photoluminescence features of the FPs, andiii) a 40-fold increase of the lighting device stability compared to reference devices due to the reduction of the device working temperatures to 40 °C. Thus, the success of this multidisciplinary approach contributes toward developing stable energy-related protein-based optoelectronics.
An RNAi screen for conserved kinases that enhance microRNA activity after dauer inC. elegans
Authors: Pun Himal Roka , Karp Xantha 
Published: October 2023

AbstractGene regulation in changing environments is critical for maintaining homeostasis. Some animals undergo a stress-resistant diapause stage to withstand harsh environmental conditions encountered during development. MicroRNAs (miRNAs) are one mechanism for regulating gene expression during and after diapause. MicroRNAs downregulate target genes post-transcriptionally through the activity of the miRNA-Induced Silencing Complex (miRISC). Argonaute is the core miRISC protein that binds to both the miRNA and to other miRISC proteins. The two major miRNA Argonautes in theC. eleganssoma are ALG-1 and ALG-2, which function partially redundantly. Loss ofalg-1 (alg-1(0))causes penetrant developmental phenotypes including vulval defects and the reiteration of larval cell programs in hypodermal cells. However, these phenotypes are essentially absent ifalg-1(0)animals undergo a diapause stage called dauer. Levels of the relevant miRNAs are not higher during or after dauer, suggesting that activity of the miRISC may be enhanced in this context. To identify genes that are required foralg-1(0)mutants to develop without vulval defects after dauer, we performed an RNAi screen of genes encoding conserved kinases. We focused on kinases because of their known role in modulating miRISC activity. We found RNAi knockdown of four kinase-encoding genes,air-2,bub-1,chk-1,andnekl-3, caused vulval defects and reiterative phenotypes inalg-1(0)mutants after dauer, and that these defects were more penetrant in analg-1(0)background than in wild type. Our results implicate these kinases as potential regulators of miRISC activity during post-dauer development inC. elegans.
Preventing extinction in an age of species migration and planetary change
Authors: Lundgren Erick J. , Wallach Arian D. , Svenning Jens-Christian , Schlaepfer Martin A. , Andersson Astrid L.A. , Ramp Daniel 
Published: October 2023

AbstractInternational and national conservation policies almost exclusively focus on conserving species in their historic native ranges, thus excluding species that have dispersed on their own accord or have been introduced by people. Given that many of these ‘migrant’ species are threatened in their native ranges, conservation goals that explicitly exclude these migrant populations may overlook opportunities to prevent extinctions and respond dynamically to rapidly changing environmental and climatic conditions. Focusing on terrestrial mammals, we quantified the extent to which migration, in this case via introductions, has provided new homes for threatened mammal species. We then devised alternative scenarios for the inclusion of migrant populations in mainstream conservation policy with the aim of preventing global species extinctions and used spatial prioritization algorithms to simulate how these scenarios could change global spatial conservation priorities. We found that 22% of all identified migrant mammals (70 species) are threatened in their native ranges, mirroring the 25% of all mammals that are threatened. Reassessing global threat statuses by combining native and migrant ranges reduced the threat status of 23 species (∼33% of threatened migrants). Thus, including migrant populations in threat assessments provides a more accurate assessment of actual global extinction risk among species. Spatial prioritization simulations showed that reimagining the role of migrant populations to prevent global species extinction could increase the importance of overlooked landscapes, particularly in central Australia. Our results indicate that these various and non-exhaustive ways to consider migrant populations, with due consideration for potential conservation conflicts with resident taxa, may provide unprecedented opportunities to prevent species extinctions. We present these alternatives and spatial simulations to stimulate discussion on how conservation ought to respond, both pragmatically and ethically, to rapid environmental change in order to best prevent extinctions.
Defining the Cell Surface Cysteinome using Two-step Enrichment Proteomics
Authors: Yan Tianyang , Boatner Lisa M. , Cui Liujuan , Tontonoz Peter , Backus Keriann M. 
Published: October 2023

AbstractThe plasma membrane proteome is a rich resource of functional and therapeutically relevant protein targets. Distinguished by high hydrophobicity, heavy glycosylation, disulfide-rich sequences, and low overall abundance, the cell surface proteome remains undersampled in established proteomic pipelines, including our own cysteine chemoproteomics platforms. Here we paired cell surface glycoprotein capture with cysteine chemoproteomics to establish a two-stage enrichment method that enables chemoproteomic profiling of cellSurfaceCysteinome. Our “Cys-Surf” platform captures >2,800 total membrane protein cysteines in 1,046 proteins, including 1,907 residues not previously captured by bulk proteomic analysis. By pairing Cys-Surf with an isotopic chemoproteomic readout, we uncovered 821 total ligandable cysteines, including known and novel sites. Cys-Surf also robustly delineates redox-sensitive cysteines, including cysteines prone to activation-dependent changes to cysteine oxidation state and residues sensitive to addition of exogenous reductants. Exemplifying the capacity of Cys-Surf to delineate functionally important cysteines, we identified a redox sensitive cysteine in the low-density lipoprotein receptor (LDLR) that impacts both the protein localization and uptake of LDL particles. Taken together, the Cys-Surf platform, distinguished by its two-stage enrichment paradigm, represents a tailored approach to delineate the functional and therapeutic potential of the plasma membrane cysteinome.
Accurate model and ensemble refinement using cryo-electron microscopy maps and Bayesian inference
Authors: Hoff S. E. , Thomasen F. E. , Lindorff-Larsen K. , Bonomi M. 
Published: October 2023

AbstractConverting cryo-electron microscopy (cryo-EM) data into high-quality structural models is a challenging problem of outstanding importance. Current refinement methods often generate unbalanced models in which physico-chemical quality is sacrificed for excellent fit to the data. Furthermore, these techniques struggle to represent the conformational heterogeneity averaged out in low-resolution regions of density maps. Here we introduce EMMIVox, a Bayesian inference approach to determine single-structure models as well as structural ensembles from cryo-EM maps. EMMIVox automatically balances experimental information with accurate physico-chemical models of the system and the surrounding environment, including waters, lipids, and ions. Explicit treatment of data correlation and noise as well as inference of accurate B-factors enable determination of structural models and ensembles with both excellent fit to the data and high stereochemical quality, thus outperforming state-of-the-art refinement techniques. EMMIVox represents a flexible approach to determine high-quality structural models that will contribute to advancing our understanding of the molecular mechanisms underlying biological functions.
Local structural flexibility drives oligomorphism in computationally designed protein assemblies
Authors: Khmelinskaia Alena , Bethel Neville P. , Fatehi Farzad , Antanasijevic Aleksandar , Borst Andrew J. , Lai Szu-Hsueh , Wang Jing Yang (John) , Mallik Bhoomika Basu , Miranda Marcos C. , Watkins Andrew M. , Ogohara Cassandra , Caldwell Shane , Wu Mengyu , Heck Albert J.R. , Veesler David , Ward Andrew B. , Baker David , Twarock Reidun , King Neil P. 
Published: October 2023

AbstractMany naturally occurring protein assemblies have dynamic structures that allow them to perform specialized functions. For example, clathrin coats adopt a wide variety of architectures to adapt to vesicular cargos of various sizes. Although computational methods for designing novel self-assembling proteins have advanced substantially over the past decade, most existing methods focus on designing static structures with high accuracy. Here we characterize the structures of three distinct computationally designed protein assemblies that each form multiple unanticipated architectures, and identify flexibility in specific regions of the subunits of each assembly as the source of structural diversity. Cryo-EM single-particle reconstructions and native mass spectrometry showed that only two distinct architectures were observed in two of the three cases, while we obtained six cryo-EM reconstructions that likely represent a subset of the architectures present in solution in the third case. Structural modeling and molecular dynamics simulations indicated that the surprising observation of a defined range of architectures, instead of non-specific aggregation, can be explained by constrained flexibility within the building blocks. Our results suggest that deliberate use of structural flexibility as a design principle will allow exploration of previously inaccessible structural and functional space in designed protein assemblies.
Vertebral level specific modulation of paraspinal muscle activity based on vestibular signals during walking
Authors: Li Yiyuan C. , Bruijn Sjoerd M. , Lemaire Koen K. , Brumagne Simon , van Dieën Jaap H. 
Published: October 2023

AbstractEvoking muscle responses by electrical vestibular stimulation (EVS) may help to understand the contribution of the vestibular system to postural control. Although paraspinal muscles play a role in postural stability, the vestibulo-muscular coupling of these muscles during walking has rarely been studied. This study aimed to investigate how vestibular signals affect paraspinal muscle activity at different vertebral levels during walking with preferred and narrow step width. Sixteen healthy participants were recruited. Participants walked on a treadmill for 8 minutes at 78 steps/min and 2.8 km/h, at two different step width, either with or without EVS. Bipolar electromyography was recorded bilaterally from the paraspinal muscles at eight vertebral levels from cervical to lumbar. Coherence, gain, and delay of EVS and EMG responses were determined. Significant EVS-EMG coupling (p<0.01) was found at ipsilateral and/or contralateral heel strikes. This coupling was mirrored between left and right relative to the midline of the trunk and between the higher and lower vertebral levels, i.e., a peak occurred at ipsilateral heel strike at lower levels, whereas it occurred at contralateral heel strike at higher levels. EVS-EMG coupling only partially coincided with peak muscle activity. EVS-EMG coherence slightly, but not significantly, increased when walking with narrow steps. No significant differences were found in gain and phase between the vertebral levels or step width conditions. In summary, vertebral level specific modulation of paraspinal muscle activity based on vestibular signals might allow a fast, synchronized, and spatially co-ordinated response along the trunk during walking.Key Points SummaryMediolateral stabilization of gait requires an estimate of the state of the body, which is affected by vestibular afference.During gait, the heavy trunk segment is controlled by phasic paraspinal muscle activity and in rodents the medial and lateral vestibulospinal tracts activate these muscles.To gain insight in vestibulospinal connections in humans and their role in gait, we recorded paraspinal surface EMG of cervical to lumbar paraspinal muscles, and characterized coherence, gain and delay between EMG and electrical vestibular stimulation, during slow walking.Vestibular stimulation caused phasic, vertebral level specific modulation of paraspinal muscle activity at delays of around 40 milliseconds, which was mirrored between left, lower and right, upper vertebral levels.Our results indicate that vestibular afference causes fast, synchronized, and spatially co-ordinated responses of the paraspinal muscles along the trunk, that simultaneously contribute to stabilizing the centre of mass trajectory and to keeping the head upright.
Ataxia-telangiectasia mutated(Atm) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas to radiation therapy
Authors: Mangoli Avani , Wu Sophie , Liu Harrison Q. , Aksu Michael , Jain Vaibhav , Foreman Bronwen E. , Regal Joshua A. , Weidenhammer Loren B. , Stewart Connor E. , Guerra Garcia Maria E. , Hocke Emily , Abramson Karen , Williams Nerissa T. , Luo Lixia , Deland Katherine , Attardi Laura , Abe Kouki , Hashizume Rintaro , Ashley David M. , Becher Oren J. , Kirsch David G. , Gregory Simon G. , Reitman Zachary J. 
Published: October 2023

SummaryDiffuse midline gliomas (DMGs) are lethal brain tumors characterized by p53-inactivating mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress, which presents therapeutic opportunities. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce K27M in the nativeH3f3aallele in a lineage- and spatially-directed manner, yielding primary mouse DMGs. Genetic or pharmacologic disruption of the DNA damage response kinase Ataxia-telangiectasia mutated (ATM) enhanced the efficacy of focal brain irradiation, extending mouse survival. This finding suggests that targeting ATM will enhance the efficacy of radiation therapy for p53-mutant DMG but not p53-wildtype DMG. We used spatialin situtranscriptomics and an allelic series of primary murine DMG models with different p53 mutations to identify transactivation-independent p53 activity as a key mediator of such radiosensitivity. These studies deeply profile a genetically faithful and versatile model of a lethal brain tumor to identify resistance mechanisms for a therapeutic strategy currently in clinical trials.