bluuebunny/crossref_metadata_2025_split huggingface dataset:
ChAdOx1 COVID vaccines express RBD open prefusion SARS-CoV-2 spikes on the cell surface
Authors: Ni Tao , Mendonça Luiza , Zhu Yanan , Howe Andrew , Radecke Julika , Shah Pranav M. , Sheng Yuewen , Krebs Anna-Sophia , Duyvesteyn Helen M. E. , Allen Elizabeth , Lambe Teresa , Bisset Cameron , Spencer Alexandra , Morris Susan , Stuart David I. , Gilbert Sarah , Zhang Peijun 
Published: May 2023

AbstractVaccines against SARS-CoV-2 have been proven to be an effective means of decreasing COVID-19 mortality, hospitalization rates, and transmission. One of the vaccines deployed worldwide is ChAdOx1 nCoV-19, which uses an adenovirus vector to drive the expression of the original SARS-CoV-2 spike on the surface of transduced cells. Using cryo-electron tomography and subtomogram averaging, we determined the native structures of the vaccine product expressed on cell surfacesin situ. We show that ChAdOx1-vectored vaccines expressing the Beta SARS-CoV-2 variant produce abundant native prefusion spikes predominantly in one-RBD-up conformation. Furthermore, the ChAdOx1 vectored HexaPro stabilized spike yields higher cell surface expression, enhanced RBD exposure, and reduced shedding of S1 compared to the wild-type. We demonstratein situstructure determination as a powerful means for studying antigen design options in future vaccine development against emerging novel SARS-CoV-2 variants and broadly against other infectious viruses.
Compression strategies for large-scale electrophysiology data
Authors: Buccino Alessio P. , Winter Olivier , Bryant David , Feng David , Svoboda Karel , Siegle Joshua H. 
Published: May 2023

AbstractWith the rapid adoption of high-density electrode arrays for recording neural activity, electrophysiology data volumes within labs and across the field are growing at unprecedented rates. For example, a one-hour recording with a 384-channel Neuropixels probe generates over 80 GB of raw data. These large data volumes carry a high cost, especially if researchers plan to store and analyze their data in the cloud. Thus, there is a pressing need for strategies that can reduce the data footprint of each experiment. Here, we establish a set of benchmarks for comparing the performance of various compression algorithms on experimental and simulated recordings from Neuropixels 1.0 (NP1) and 2.0 (NP2) probes. For lossless compression, audio codecs (FLACandWavPack) achieve compression ratios 6% higher for NP1 and 10% higher for NP2 than the best general-purpose codecs, at the expense of a slower decompression speed. For lossy compression, theWavPackalgorithm in “hybrid mode” increases the compression ratio from 3.59 to 7.08 for NP1 and from 2.27 to 7.04 for NP2 (compressed file size of∼14% for both types of probes), without adverse effects on spike sorting accuracy or spike waveforms. Along with the tools we have developed to make compression easier to deploy, these results should encourage all electrophysiologists to apply compression as part of their standard analysis workflows.
Domain-specific cognitive impairment reflects prefrontal dysfunction in aged common marmosets
Authors: Glavis-Bloom Courtney , Vanderlip Casey R , Asch Payton A , Reynolds John H 
Published: May 2023

AbstractAge-related cognitive impairment is not expressed uniformly across cognitive domains. Cognitive functions that rely on brain areas that undergo substantial neuroanatomical changes with age often show age-related impairment, while those that rely on brain areas with minimal age-related change typically do not. The common marmoset has grown in popularity as a model for neuroscience research, but robust cognitive phenotyping, particularly as a function of age and across multiple cognitive domains, is lacking. This presents a major limitation for the development and evaluation of the marmoset as a model of cognitive aging, and leaves open the question of whether they exhibit age-related cognitive impairment that is restricted to some cognitive domains, as in humans. In this study, we characterized stimulus-reward association learning and cognitive flexibility in young adults to geriatric marmosets using a Simple Discrimination and a Serial Reversal task, respectively. We found that aged marmosets show transient impairment in “learning-to-learn” but have conserved ability to form stimulus-reward associations. Furthermore, aged marmosets have impaired cognitive flexibility driven by susceptibility to proactive interference. Since these impairments are in domains critically dependent on the prefrontal cortex, our findings support prefrontal cortical dysfunction as a prominent feature of neurocognitive aging. This work positions the marmoset as a key model for understanding the neural underpinnings of cognitive aging.Significance StatementAging is the greatest risk factor for neurodegenerative disease development, and understanding why is critical for the development of effective therapeutics. The common marmoset, a short-lived non-human primate with neuroanatomical similarity to humans, has gained traction for neuroscientific investigations. However, the lack of robust cognitive phenotyping, particularly as a function of age and across multiple cognitive domains limits their validity as a model for age-related cognitive impairment. We demonstrate that aging marmosets, like humans, have impairment that is specific to cognitive domains reliant on brain areas that undergo substantial neuroanatomical changes with age. This work validates the marmoset as a key model for understanding region-specific vulnerability to the aging process.
Auditory brainstem responses are resistant to pharmacological modulation in Sprague Dawley wildtype and Neurexin1α knockout rats
Authors: Marashli Samuel , Janz Philipp , Redondo Roger 
Published: May 2023

AbstractSensory processing in the auditory brainstem can be studied with auditory brainstem responses (ABRs) across species. Although ABRs have been widely utilized to evaluate abnormalities in auditory brainstem physiology, there is limited understanding if ABRs can be useful tool to assess the effect of pharmacological interventions. Therefore, we set out to understand how pharmacological agents that target key transmitter systems of the auditory brainstem circuitry affect ABR physiology in rats. Given previous studies, demonstrating that Nrxn1α KO Sprague Dawley rats show substantial auditory processing deficits and altered sensitivity to GABAergic modulators, we used both Nrxn1α KO and wildtype littermates in our study. First, we probed how different commonly used anesthetics (isoflurane, ketamine/xylazine, medetomidine) affect ABRs waveforms. In the next step, we assessed the effects of different pharmacological compounds (diazepam, gaboxadol, retigabine, nicotine, baclofen and bitopertin) either under isoflurane or medetomidine anesthesia. We found that under our experimental conditions, ABRs are largely unaffected by diverse pharmacological modulation. Significant modulation was observed with i.) nicotine, affecting the late ABR components at 90 dB stimulus intensity under isoflurane anesthesia in both genotypes, and ii.) retigabine, showing a slight decrease in late ABRs deflections at 80 dB stimulus intensity, mainly in isoflurane-anesthetized Nrxn1α KO rats. Our study suggest that ABRs in anesthetized rats are resistant to a wide range of pharmacological modulators, which has important implications for the applicability of ABRs to study auditory brainstem physiology.
Inertial effect of cell state velocity on the quiescence-proliferation fate decision in breast cancer
Authors: Venkatachalapathy Harish , Brzakala Cole , Batchelor Eric , Azarin Samira M. , Sarkar Casim A. 
Published: May 2023

SummaryEnergy landscapes can provide intuitive depictions of population heterogeneity and dynamics. However, it is unclear whether individual cell behavior, hypothesized to be determined by initial position and noise, is faithfully recapitulated. Using the p21-/Cdk2-dependent quiescence-proliferation decision in breast cancer dormancy as a testbed, we examined single-cell dynamics on the landscape when perturbed by hypoxia, a dormancy-inducing stress. Combining trajectory-based energy landscape generation with single-cell time-lapse microscopy, we found that initial position on a p21/Cdk2 landscape did not fully explain the observed cell-fate heterogeneity under hypoxia. Instead, cells with higher cell state velocities prior to hypoxia, influenced by epigenetic parameters, tended to remain proliferative under hypoxia. Thus, the fate decision on this landscape is significantly influenced by “inertia”, a velocity-dependent ability to resist directional changes despite reshaping of the underlying landscape, superseding positional effects. Such inertial effects may markedly influence cell-fate trajectories in tumors and other dynamically changing microenvironments.
The phycobilisome linker protein ApcG interacts with photosystem II and regulates energy transfer to photosystem I inSynechocystis sp.PCC 6803
Authors: Espinoza-Corral Roberto , Iwai Masakazu , Zavřel Tomáš , Lechno-Yossef Sigal , Sutter Markus , Červený Jan , Niyogi Krishna K. , Kerfeld Cheryl A. 
Published: May 2023

ABSTRACTPhotosynthetic organisms harvest light using pigment-protein super-complexes. In cyanobacteria, these are water-soluble antennae known as phycobilisomes (PBSs). The light absorbed by PBS is transferred to the photosystems in the thylakoid membrane to drive photosynthesis. The energy transfer between these super-complexes implies that protein-protein interactions allow the association of PBS with the photosystems. However, the specific proteins involved in the interaction of PBS with the photosystems are not fully characterized. Here, we show that the newly discovered PBS linker protein ApcG interacts specifically with photosystem II through its N-terminal region. Growth of cyanobacteria is impaired inapcGdeletion strains under light-limiting conditions. Furthermore, complementation of these strains using a phospho-mimicking version of ApcG exhibit reduced growth under normal growth conditions. Interestingly, the interaction of ApcG with photosystem II is affected when a phospho-mimicking version of ApcG is used, targeting the positively charged residues interacting with thylakoid membrane suggesting a regulatory role mediated by phosphorylation of ApcG. Low temperature fluorescence measurements showed increased photosystem I fluorescence inapcGdeletion and complementation strains. The photosystem I fluorescence was the highest in the phospho-mimicking complementation strain while pull-down experiment showed no interaction of ApcG with PSI under any tested condition. Our results highlight the importance of ApcG for selectively directing energy harvested by the PBS and implies that the phosphorylation status of ApcG plays a role in regulating energy transfer from PSII to PSI.
Basal UPR activity inAspergillus fumigatusregulates adaptation to nutrient stress and is critical for the establishment of corneal infection
Authors: Kamath Manali M. , Lightfoot Jorge D. , Adams Emily M. , Wells Becca L. , Fuller Kevin K. 
Published: May 2023

ABSTRACTTheAspergillus fumigatusunfolded protein response (UPR) is a two-component relay consisting of the ER-bound IreA protein, which splices and activates the mRNA of the transcription factor HacA. SplicedhacAaccumulates under conditions of acute ER stressin vitro, and UPR null mutants are hypovirulent in a murine model of invasive pulmonary infection. In this report, we demonstrate that ahacAdeletion mutant is completely unable to establish infection in a model of fungal keratitis, a corneal infection and an important cause of ocular morbidity and unilateral blindness worldwide. Contrary to our initial prediction, however, we demonstrate thathacAsplicing is not increased above baseline conditions in the cornea, nor is the expression of genes classically associated with UPR activation, such as protein chaperones. We employed transcriptomics on wild-type andΔhacAstrains in gelatin media, as a proxy for the corneal environment, and found thathacAsupports the expression of numerous primary and secondary metabolic processes that likely promote adaptation to nutrient limitation. Taken together, our results support a model in which the cornea, similar to growth on proteinin vitro, is a source of sub-acute ER stress forA. fumigatus, but one nevertheless that requires the UPR pathway for proper adaptation. The data also suggest that this pathway could be a target for novel antifungals that improve visual outcomes for fungal keratitis patients.AUTHOR SUMMARYFungal keratitis has emerged as a leading cause of ocular morbidity and unilateral blindness worldwide. Relative to other infectious contexts, however, little is known about the fungal genes or pathways that regulate invasive growth and virulence in the corneal environment. In this report, we demonstrate that genetic disruption of theAspergillus fumigatusunfolded protein response (UPR) abolishes the ability of the mold to establish infection in a mouse model of FK. Despite this critical role for virulence, however, we did not detect a concerted activation of the pathway beyond levels observed on standard medium, suggesting that the host environment is not an acute source of endoplasmic reticulum stress. Transcriptomic profiling of the wild-type and UPR-deficient strains under host-relevant nutrient conditions revealed a critical role for the pathway in regulating primary and secondary metabolism, cell wall biology, and mitochondrial function, all of which likely modulate fungal growth within and interactions with the host. These results expand our understanding of UPR regulation and function in this important mold pathogen and suggest the pathway could serve as a target for novel antifungals that improve visual outcomes in the setting of fungal keratitis.
Primary Care Post-COVID syndrome Diagnosis and Referral Coding
Authors: Willans Robert , Allsopp Gail , Jonsson Pall , Glen Fiona , Macleod John , Wei Yinghui , Greaves Felix , Bacon Sebastian , Mehrkar Amir , Walker Alex , MacKenna Brian , Fisher Louis , Goldacre Ben ,   The OpenSAFELY Collaborative,   The CONVALESCENCE Collaborative
Published: May 2023

AbstractIntroductionGuidelines for diagnosing and managing Post-COVID syndrome have been rapidly developed. Consistency of the application of these guidelines in primary care is unknown. Electronic health records provide an opportunity to review the use of codes relating to Post-COVID syndrome. This paper explores the use of primary care records as a surrogate uptake measure for NICE’s rapid guideline “managing the long-term effects of COVID-19” by measuring the use of Post-COVID syndrome diagnosis and referral codes in the pathway.MethodWith the approval of NHS England we used routine clinical data from the OpenSafely-EMIS/-TPP platforms. Counts of Post-COVID syndrome diagnosis and referral codes were generated from a cohort of all adults, establishing numbers of diagnoses and referrals following diagnosis. The relationship between Post-COVID syndrome diagnosis and referral codes was explored with reference to NICE’s rapid guideline.ResultsOf over 45 million patients, 69,220 (0.15%) had a Post-COVID syndrome diagnostic code, and 67,741 (0.15%) had a referral code. 78% of referral codes did not have an associated diagnosis code. 79% of diagnosis codes had no subsequent referral code. Only 18,633 (0.04%) had both. There were higher rates of both diagnosis and referral in those who were more deprived, female and some ethnic groups.DiscussionThis study demonstrates variation in diagnosis and referral coding rates for Post-COVID syndrome across different patient groups. The results, with limited crossover of referral and diagnostic codes, suggest only one type of code is usually recorded. Recording one code limits the use of routine data for monitoring Post-COVID syndrome diagnosis and management, but suggests several areas for improvement in coding. Post-COVID syndrome coding, particularly diagnosis coding, needs to improve before administrators and researchers can use it to evaluate care pathways.
Can artificial intelligence help a clinical laboratory to draw useful information from limited data sets ? Application to Mixed Connective Tissue Disease
Authors: Bertin Daniel , Bongrand Pierre , Bardin Nathalie 
Published: May 2023

AbstractDiagnosis is a key step of patient management. During decades, refined decision algorithms and numerical scores based on conventional statistic tools were elaborated to ensure optimal reliability. Recently, a number of machine learning tools were developed and applied to process more and more extensive data sets, including up to million of items and yielding sophisticated classification models. While this approach met with impressive efficiency in some cases, practical limitations stem from the high number of parameters that may be required by a model, resulting in increased cost and delay of decision making. Also, information relative to the specificity of local recruitment may be lost, hampering any simplification of universal models. Here, we explored the capacity of currently available artificial intelligence tools to classify patients found in a single health center on the basis of a limited number of parameters. As a model, the discrimination between systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) on the basis of thirteen biological parameters was studied with eight widely used classifiers. It is concluded that classification performance may be significantly improved by a knowledge-based selection of discriminating parameters.
Parkinson’s Progression Markers Initiative: A Milestone-Based Strategy to Monitor PD Progression
Authors: Brumm Michael C. , Siderowf Andrew , Simuni Tanya , Burghardt Elliot , Choi Seung Ho , Caspell-Garcia Chelsea , Chahine Lana M. , Mollenhauer Brit , Foroud Tatiana , Galasko Douglas , Merchant Kalpana , Arnedo Vanessa , Hutten Samantha J. , O’Grady Alyssa N. , Poston Kathleen L. , Tanner Caroline M. , Weintraub Daniel , Kieburtz Karl , Marek Kenneth , Coffey Christopher S. 
Published: May 2023

AbstractBackgroundIdentifying a meaningful progression metric for Parkinson’s disease (PD) that reflects heterogeneity remains a challenge.ObjectiveTo assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones.MethodsUsing data from the Parkinson’s Progression Markers Initiative (PPMI)de novoPD cohort, we monitored 25 milestones across six domains (“walking and balance”; “motor complications”; “cognition”; “autonomic dysfunction”; “functional dependence”; “activities of daily living”). Milestones were intended to be severe enough to reflect meaningful disability. We assessed the proportion of participants reaching any milestone; evaluated which occurred most frequently; and conducted a time-to-first-event analysis exploring whether baseline characteristics were associated with progression.ResultsHalf of participants reached at least one milestone within five years. Milestones within the cognitive, functional dependence, and autonomic dysfunction domains were reached most often. Among participants who reached a milestone at an annual follow-up visit and remained active in the study, 82% continued to meet criteria for any milestone at one or more subsequent annual visits and 55% did so at thenextannual visit. In multivariable analysis, baseline features predicting faster time to reaching a milestone included age (p<0.0001), greater MDS-UPDRS total scores (p<0.0001), higher GDS-15 depression scores (p=0.0341), lower dopamine transporter binding (p=0.0043), and lower CSF total α-synuclein levels (p=0.0033). Symptomatic treatment was not significantly associated with reaching a milestone (p=0.1639).ConclusionsClinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.
Antimicrobial peptide glatiramer acetate targetsPseudomonas aeruginosalipopolysaccharides to breach membranes without altering lipopolysaccharide modification
Authors: Murphy Ronan A. , Pizzato Jade , Cuthbertson Leah , Sabnis Akshay , Edwards Andrew , Nolan Laura M. , Vorup-Jensen Thomas , Larrouy-Maumus Gerald , Davies Jane C. 
Published: May 2023

ABSTRACTAntimicrobial peptides (AMPs) are key components of innate immunity across all kingdoms of life. Both natural and synthetic AMPs are receiving renewed attention in the efforts to combat the antimicrobial resistance (AMR) crisis and the loss of antibiotic efficacy. The gram-negative pathogenPseudomonas aeruginosais one of the most concerning infectious bacteria in AMR, particularly in people with cystic fibrosis (CF) where respiratory infections are difficult to eradicate and are associated with increased morbidity and mortality. Cationic AMPs exploit the negative charge of lipopolysaccharides (LPS) onP. aeruginosato bind to and disrupt the bacterial membrane(s) and cause lethal damage.P. aeruginosamodifies its LPS, via environmental or genetic factors, to neutralise the charge of the cell and evade AMP killing. Free-LPS is also a component of CF sputum, as is anionic extracellular DNA (eDNA), each of which can bind AMPs by electrostatic interaction. Both free LPS and eDNA also feed into pro-inflammatory cycles. Glatiramer acetate (GA) is a random peptide co-polymer of glycine, lysine, alanine, and tyrosine and used as drug in the treatment of multiple sclerosis (MS); we have previously shown GA to be an AMP which synergises with tobramycin againstP. aeruginosafrom CF, functioning via bacterial membrane disruption. Here, we demonstrate direct binding and sequestration/neutralisation ofP. aeruginosaLPS in keeping with GA’s ability to disrupt the outer membrane. Binding and neutralisation of eDNA was also seen. At CF-relevant concentrations, however, neither strongly inhibited membrane disruption by GA. Furthermore, in both type strains and clinical CF isolates ofP. aeruginosa, exposure to GA did not result in increased modification of the Lipid A portion of LPS or in increased expression of genetically encoded systems involved in AMP sensing and LPS modification. With this low selective pressure onP. aeruginosafor known AMP resistance mechanisms, the potential to neutralise pro-inflammatory CF sputum components, as well as the previously described enhancement of antibiotic function, GA is a promising candidate for drug repurposing.