bluuebunny/crossref_metadata_2025_split huggingface dataset:
Continuous bedside neuroimaging using high-density diffuse optical tomography in a pediatric patient on extracorporeal support
Authors: McMorrow Sophia R. , Park Sung Min , George Tessa G. , Sobolewski Chloe M. , Yang Dalin , King Kelsey T. , Kenley Jeanette , Smyser Christopher D. , Culver Joseph P. , Guilliams Kristin P. , Said Ahmed S. , Eggebrecht Adam T. 
Published: August 2024

ABSTRACTBackgroundExtracorporeal membrane oxygenation (ECMO) provides life support for severe, reversible cardiac or respiratory failure, yet is associated with significant neurological risks including stroke. Currently available neuroimaging methods have limited sensitivity or specificity to detect early brain injury, have little real-time ability to assess interventions, and/or pose additional risks. Here, we present a case study of high-density diffuse optical tomography (HD-DOT) for bedside neuroimaging in pediatric ECMO.MethodsA young infant supported on ECMO following cardiac surgery underwent continuous HD-DOT imaging over a two-hour duration that included baseline support and a clamp trial to test the ability to separate from ECMO. After stringent data quality assessments, we estimated cortical parcel-based brain functional connectivity (FC), evaluated spatial correlations between neighboring temporal epochs throughout the recording to evaluate test-retest reliability of brain FC, and calculated paired t-tests between the brain-wide set of test-retest values to test for significant changes in brain FC.ResultsHigh-fidelity bedside HD-DOT data were acquired without disruptions to patient care. During the baseline period, we observed strong test-retest with consistent bilateral FC patterns. Significant disruptions in cortical FC reflected concurrent changes in cerebral blood flow during the clamp trial and persisted after ECMO resumed.ConclusionsOur results demonstrate the feasibility of continuous bedside HD-DOT neuroimaging in pediatric ECMO. HD-DOT can potentially provide clinically relevant information on cortical FC during ECMO support.
Automated Coronary Artery Calcium Scoring Using Convolutional Neural Networks: Enhancing Cardiovascular Risk Assessment in Chest CT Scans
Authors: Mansoor Masab A. , Grindem David J. 
Published: August 2024

AbstractBackgroundCoronary artery calcium (CAC) scoring is valuable for cardiovascular risk assessment but often time-consuming and subject to variability. This study aimed to develop and validate a convolutional neural network (CNN) model for automated CAC scoring in chest CT scans, potentially enhancing efficiency and accuracy.MethodsWe utilized 10,000 chest CT scans from a public dataset, split into training (n=7,000), validation (n=1,500), and testing (n=1,500) sets. A 3D CNN model based on ResNet-50 was developed and trained for CAC detection and quantification. Performance was evaluated on the test set and compared to manual scoring by three experienced radiologists.ResultsThe CNN model achieved 93.7% accuracy in detecting CAC, with 87.4% sensitivity and 92.1% specificity for identifying clinically significant CAC (Agatston score >100) in the test set (n=1,500). The model showed strong correlation with manual CAC scores (r=0.89, p<0.001). Automated scoring reduced processing time by 78% compared to manual techniques, averaging 18.3 seconds per scan. The model demonstrated consistent performance across diverse patient demographics and CT types. In a subset of patients with follow-up data (n=500), the model’s risk stratification was comparable to the Framingham Risk Score in predicting cardiovascular events (AUC 0.76 vs 0.74, p=0.09).ConclusionsThe CNN-based automated CAC scoring system demonstrated high accuracy and efficiency, potentially enabling more widespread cardiovascular risk assessment in routine chest CT scans. Future research should focus on prospective validation and investigation of long-term patient outcomes when integrating this technology into clinical practice.
Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma
Authors: Rendo Veronica , Lee Eudocia Q. , Bossi Connor , Khuu Nicholas , Rudek Michelle A. , Pal Sangita , Reynolds Abigail R. N. , Fassinou Auriole C.R. , Ayoub Georges , Lapinskas Emily , Pisano William , Jeang John , Stopka Sylwia A. , Regan Michael S. , Spetz Johan , Desai Arati , Lieberman Frank , Fisher Joy D. , Pelton Kristine , Huang Raymond Y. , Nabors Louis B. , Holdhoff Matthias , Danda Neeraja , Strowd Roy , Desideri Serena , Walbert Tobias , Ye Xiaobu , Agar Nathalie Y. R. , Grossman Stuart A. , Alexander Brian M. , Wen Patrick Y. , Ligon Keith L. , Beroukhim Rameen 
Published: August 2024

AbstractWe investigated the effectiveness of navtemadlin (KRT-232) in treating recurrent glioblastoma. A surgical window-of-opportunity trial (NCT03107780) was conducted on 21 patients to determine achievable drug concentrations within tumor tissue and examine mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact. Sequencing of three recurrent tumors revealed an absence ofTP53-inactivating mutations, indicating alternative mechanisms of resistance. In patient-derived GBM models, the lower range of clinically achieved navtemadlin concentrations induced partial tumor cell death as monotherapy. However, combining navtemadlin with temozolomide increased apoptotic rates while sparing normal bone marrow cells in vitro, which in return underwent reversible growth arrest. These results indicate that clinically achievable doses of navtemadlin generate significant pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy is a route to durable survival benefits.Statement of significanceTissue sampling during this clinical trial allowed us to assess mechanisms of response and resistance associated with navtemadlin treatment in recurrent GBM. We report that clinically achievable doses of navtemadlin induce pharmacodynamic effects in tumor tissue, and suggest combinations with standard-of-care chemotherapy for durable clinical benefit.
Pemivibart is less active against recent SARS-CoV-2 JN.1 sublineages
Authors: Wang Qian , Guo Yicheng , Ho Jerren , Ho David D. 
Published: August 2024

AbstractProtection from COVID-19 vaccination is suboptimal in many immunocompromised individuals. In March 2024, the Food and Drug Administration issued an Emergency Use Authorization for pemivibart (Permagard/VYD222), an engineered human monoclonal antibody, for pre-exposure prophylaxis in this vulnerable population. However, SARS-CoV-2 has since evolved extensively, resulting in multiple Omicron JN.1 sublineages. We therefore evaluated the in vitro neutralizing activity of pemivibart against the prevalent forms of JN.1, including KP.2, KP.3, KP.2.3, LB.1, and, importantly, KP.3.1.1, which is now expanding most rapidly. A panel of VSV-based pseudoviruses representing major JN.1 sublineages was generated to assess their susceptibility to pemivibart neutralization in vitro. Structural analyses were then conducted to understand the impact of specific spike mutations on the virus-neutralization results. Pemivibart neutralized both JN.1 and KP.2 in vitro with comparable activity, whereas its potency was decreased slightly against LB.1, KP.2.3, and KP.3 but substantially against KP.3.1.1. Critically, the 50% inhibitory concentration of pemivibart against KP.3.1.1 was ∼6 µg/mL, or ∼32.7 fold higher than that of JN.1 in our study. Structural analyses suggest that Q493E and the S31-deletion mutations in viral spike contribute to the antibody evasion, with the latter having a more pronounced effect. Our findings show that pemivibart has lost substantial neutralizing activity in vitro against KP.3.1.1, the most rapidly expanding lineage of SARS-CoV-2 today. Close monitoring of its clinical efficacy is therefore warranted. These results also highlight the imperative to expand our arsenal of preventive agents to protect millions of immunocompromised individuals who could not respond robustly to COVID-19 vaccines.
Mechanism that regulates the mutual inhibition controls functional switch of UNC-13
Authors: Liu Haowen , Li Lei , Wang Jiafan , Hu Jiayi , Xia Jingyao , Ma Cong , Kang Lijun , Hu Zhitao 
Published: August 2024

AbstractMunc13 plays a crucial role in short-term synaptic plasticity by regulating synaptic vesicle (SV) exocytosis and neurotransmitter release at the presynaptic terminals. However, the intricate mechanisms governing these processes have remained elusive due to the presence of multiple functional domains within Munc13, each playing distinct roles in neurotransmitter release. Here we report a coordinated mechanism in theC. elegansMunc13 homolog UNC-13 that controls the functional switch of UNC-13 during synaptic transmission. Mutations disrupting the interactions of C1 and C2B with diacylglycerol (DAG) and phosphatidylinositol 4,5-bisphosphate (PIP2) on the plasma membrane induced the gain-of-function state of UNC-13L, the long UNC-13 isoform, resulting in enhanced SV release. Concurrent mutations in both domains counteracted this enhancement, highlighting the functional interdependence of C1 and C2B. Intriguingly, the individual C1 and C2B domains exhibited significantly stronger facilitation of SV release compared to the presence of both domains, supporting a mutual inhibition of C1 and C2B under basal conditions. Moreover, the N-terminal C2A and X domains exhibited opposite regulation on the functional switch of UNC-13L. Furthermore, we identified the polybasic motif in the C2B domain that facilitates SV release. Finally, we found that disruption of C1 and C2B membrane interaction in UNC-13S, the short isoform, leads to functional switch between gain-of-function and loss-of-function. Collectively, our findings provide a novel mechanism for SV exocytosis wherein UNC-13 undergoes functional switches through the coordination of its major domains, thereby regulating synaptic transmission and short-term synaptic plasticity.
Inference technique for the synaptic conductances in rhythmically active networks and application to respiratory central pattern generation circuits
Authors: Molkov Yaroslav I. , Borgmann Anke , Koizumi Hidehiko , Hama Noriyuki , Zhang Ruli , Smith Jeffrey C. 
Published: August 2024

AbstractUnraveling synaptic interactions between excitatory and inhibitory interneurons within rhythmic neural circuits, such as central pattern generation (CPG) circuits for rhythmic motor behaviors, is critical for deciphering circuit interactions and functional architecture, which is a major problem for understanding how neural circuits operate. Here we present a general method for extracting and separating patterns of inhibitory and excitatory synaptic conductances at high temporal resolution from single neuronal intracellular recordings in rhythmically active networks. These post-synaptic conductances reflect the combined synaptic inputs from the key interacting neuronal populations and can reveal the functional connectome of the active circuits. To illustrate the applicability of our analytic technique, we employ our method to infer the synaptic conductance profiles in identified rhythmically active interneurons within key microcircuits of the mammalian (mature rat) brainstem respiratory CPG and provide a perspective on how our approach can resolve the functional interactions and circuit organization of these interneuron populations. We demonstrate the versatility of our approach, which can be applied to any other rhythmic circuits where conditions allow for neuronal intracellular recordings.
Estimating the burden of mpox among MSM in South Africa
Authors: McCabe Ruth , Johnson Leigh F. , Whittles Lilith 
Published: August 2024

AbstractDespite seeing few cases during the 2022-23 mpox global outbreak, recent reports of 22 cases among men-who-have-sex-with-men (MSM) in South Africa, including three deaths, have raised concerns about underreported community transmission. We used a Monte Carlo simulation model to estimate the true epidemic size, considering increased severity of mpox among MSM living with advanced HIV (MSMLAHIV), documented overrepresentation of people living with HIV (PLHIV) among mpox cases, and HIV prevalence in South Africa. We estimate there have been between 220-450 cases among MSM LHIV in South Africa, implying a total of 290-560 cases among all MSM. We provide an upper bound of 750-1,600 cases as a sensitivity analysis where the prevalence of HIV among mpox patients is the same as population prevalence among MSM in South Africa. Estimates in both scenarios suggest a substantial number of undetected cases, with case ascertainment rates estimated between 1% and 8%. Our findings underscore the need for enhanced surveillance, targeted public health interventions, and awareness campaigns to mitigate the outbreak’s impact at a population-level.
Preoperative Exposure to Fine Particulate Matter and Risk of Postoperative Complications: A Single Center Observational Cohort Bayesian Analysis
Authors: Pearson John F. , Jacobson Cameron K. , Riss Calvin S. , Strickland Matthew J. , Lee Longyin , Wan Neng , Benney Tabitha M. , Pace Nathan L. , Goodrich Ben K. , Gabry Jonah S. , Pham John V. , Kartchner Cade K. , Wood Jake S. , Andreae Michael H. 
Published: August 2024

AbstractBackgroundWhile exposure to fine particulate matter air pollution (PM2.5) is known to cause adverse health effects, its impact on postoperative outcomes in US adults remains understudied. Perioperative exposure to PM2.5may induce inflammation that interacts insidiously with the surgical stress response, leading to higher postoperative complications.MethodsWe conducted a single center, retrospective cohort study using data from 49,615 surgical patients living along Utah’s Wasatch Front and who underwent elective surgical procedures at a single academic medical center from 2016-2018. Patients’ addresses were geocoded and linked to daily Census-tract level PM2.5estimates. We hypothesized that elevated PM2.5concentrations in the week prior to surgery would be associated with an increase in a bundle of major postoperative complications. A hierarchical Bayesians regression model was fit adjusting for age, sex, season, neighborhood disadvantage, and the Elixhauser index of comorbidities.ResultsPostoperative complications increased in a dose-dependent manner with higher concentrations of PM2.5exposure, with a relative increase of 8% in the odds of complications (OR=1.082) for every 10ug/m3increase in the highest single-day 24-hr PM2.5exposure during the 7 days prior to surgery. For a 30 fold increase in PM2.5(1 ug/m3to 30ug/m3) the odds of complication rose to over 27% (95%CI: 4%-55%). The association persisted after controlling for comorbidities and confounders; our inferences were robust to modeling choices and sensitivity analysis.ConclusionsIn this large Utah cohort, exposure to elevated PM2.5concentrations in the week before surgery was associated with a dose-dependent increase in postoperative complications, suggesting a potential impact of air pollution on surgical outcomes. These findings merit replication in larger datasets to identify populations at risk and define the interaction and impact of different pollutants. PM2.5exposure is a potential perioperative risk factor and, given the unmitigated air pollution in urban areas, a global health concern.
Characterising grey-white matter relationships in recent-onset psychosis and its association with cognitive function
Authors: Saito Yoshito , Pantelis Christos , Cropley Vanessa , Laskaris Liliana , Wannan Cassandra M. J. , Syeda Warda T. 
Published: August 2024

ABSTRACTIndividuals with recent-onset psychosis (ROP) present widespread grey matter (GM) reductions and white matter (WM) abnormalities. However, relationships between GM and WM changes and their association with cognitive impairment, a key symptom of ROP, are unclear. Using a multiblock partial least squares correlation (MB-PLS-C) analysis, we examined multivariate GM-WM relationships and their association with cognitive abilities in ROP. We used T1 and diffusion-weighted images from 71 non-affective ROP individuals (age 22.1±3.2) and 71 matched controls. We performed MB-PLS-C between GM thickness and WM fractional anisotropy (FA) and between GM surface area and WM FA to identify multivariate GM-WM patterns and analysed correlations between these patterns and cognitive abilities. MB-PLS-C identified a ‘GM thickness’-‘WM FA’ pattern representing group differences, explaining 12.38% of the variance and associated with frontal and temporal GM regions and seven WM tracts, including the corticospinal tract. MB-PLS-C also identified a ‘GM surface area’-‘WM FA’ pattern showing group differences, explaining 18.92% and related with cingulate, frontal, temporal, and parietal GM regions and 15 WM tracts, including the inferior cerebellar peduncle. The ‘GM thickness’-‘WM FA’ pattern describing group differences was significantly correlated with processing speed in ROP. There was no association between cognition and the ‘GM surface area’-‘WM FA’ pattern. MB-PLS-C identified differential whole-brain GM-WM relationships, indicating a potential signature of brain alterations in ROP. Our findings of a relationship between cognitive function and GM-WM patterns for GM thickness rather than for surface area have implications for our understanding of brain-behaviour relationships neurodevelopmentally in psychosis.
Opto-CLIP reveals dynamic FMRP regulation of mRNAs upon CA1 neuronal activation
Authors: Singer Ruth A. , Rajchin Veronika , Park Kwanghoon , Heintz Nathaniel , Darnell Robert B. 
Published: August 2024

ABSTRACTNeuronal diversity and function are intricately linked to the dynamic regulation of RNA metabolism. Electrophysiologic studies of synaptic plasticity, models for learning and memory, are disrupted in Fragile X Syndrome (FXS). FXS is characterized by the loss of FMRP, an RNA-binding protein (RBP) known to suppress translation of specific neuronal RNAs. Synaptic plasticity in CA1 excitatory hippocampal neurons is protein-synthesis dependent, suggesting a role for FMRP in FXS-related synaptic deficits. To explore this model, we developed Opto-CLIP, integrating optogenetics with cell-type specific FMRP-CLIP and RiboTag in CA1 neurons, allowing investigation of activity-induced FMRP regulation. We tracked changes in FMRP binding and ribosome-associated RNA profiles 30 minutes after neuronal activation. Our findings reveal distinct temporal dynamics for FMRP transcript regulation in the cell body versus the synapse. In the cell body, FMRP binding to transcripts encoding nuclear functions is relieved, potentially allowing rapid transcriptional responses to neuronal activation. At the synapse, FMRP binding to transcripts encoding synaptic targets was relatively stable, with variability in translational control across target categories. These results offer fresh insights into the dynamic regulation of RNA by FMRP in response to neuronal activation and provide a foundation for future research into the mechanisms of RBP-mediated synaptic plasticity.
One-Pot Time-Induced Proteome Integral Solubility Alteration (OPTI-PISA) assay for automated and sensitive drug target identification
Authors: Meng Zhaowei , Saei Amir Ata , Lyu Hezheng , Gaetani Massimiliano , Zubarev Roman A. 
Published: August 2024

AbstractProteome Integral Solubility Alteration (PISA) assay is widely used for identifying drug targets, but it is labour-intensive and time-consuming, and requires a substantial amount of biological sample. Aiming at enabling automation and greatly reducing the sample amount, we developed One-Pot Time-Induced (OPTI)-PISA. Here we demonstrate OPTI-PISA performance on identifying targets of multiple drugs in cell lysate and scaling down the sample amount to sub-microgram levels, making PISA method suitable for NanoProteomics.
Increased autonomous bioluminescence emission from mammalian cells by enhanced cofactor synthesis
Authors: Brinker Theresa , Gregor Carola 
Published: August 2024

AbstractThe bacterial bioluminescence system has been successfully implemented in mammalian cell lines, enabling substrate-free luminescence imaging of living cells. One of the major limitations of the system is its comparatively low brightness. To improve light emission, we aimed at increasing the cellular production of FMNH2and NADPH which serve as cosubstrates in the bacterial bioluminescence reaction. We coexpressed different proteins involved in the synthesis of these two cofactors together with the proteins of the bacterial bioluminescence system in different mammalian cell lines. Combined expression of a riboflavin kinase (RFK) and a constitutively active Akt2 variant (Akt2CA) that participate in the cellular production of FMN and NADP+, respectively, increased bioluminescence emission up to 2.4–fold. The improved brightness allows autonomous bioluminescence imaging of mammalian cells at a higher signal-to-noise ratio and enhanced spatiotemporal resolution.
A Chemoenzymatic Strategy for Site-Specific Glyco-Tagging of Native Proteins for the Development of Biologicals
Authors: Gimeno Ana , Ehlers Anna M. , Delgado Sandra , Langenbach Jan-Willem H. , van den Bos Leendert J. , Kruijtzer John A.W. , Guigas Bruno G.A. , Boons Geert-Jan 
Published: August 2024

ABSTRACTGlycosylation is an attractive approach to enhance biological properties of pharmaceutical proteins, however, precise installation of glycans for structure-function studies remains challenging. Here, we describe a chemoenzymatic methodology for glyco-tagging of proteins by peptidoligase catalyzed modification of theN-terminus of a protein with a synthetic glycopeptide ester having anN-acetyl-glucosamine (GlcNAc) moiety to generate aN-GlcNAc modified protein. The GlcNAc moiety can be elaborated into complex glycans bytrans-glycosylation using a well-defined sugar oxazolines and mutant forms of endo β-N-acetylglucosaminidases (ENGases). The glyco-tagging methodology makes it possible to modifyon-demandtherapeutic proteins, including proteins heterologously expressed inE. coli,with diverse glycan structures. As a proof of principle, theN-terminus of interleukin (IL)-18 and interferon (IFN)α-2a was modified by a glycopeptide harboring a complexN-glycan without compromising biological potencies. The glyco-tagging methodology was also used to prepare several glycosylated insulin variants that exhibit reduced oligomerization, aggregation and fibrillization yet maintained cell signaling properties, which is attractive for the development of insulins with improved shelf-lives. It was found that by employing different peptidoligases, it is possible to modify either the A or both chains of human insulin.