bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serological responses to COVID-19 booster vaccine in England
Authors: Ireland Georgina , Whitaker Heather , Ladhani Shamez N , Baawuah Frances , Subbarao Vani , Linley Ezra , Warrener Lenesha , O’Brien Michelle , Whillock Corinne , Moss Paul , Ramsay Mary E , Amirthalingam Gayatri , Brown Kevin E 
Published: November 2021

AbstractIntroductionThere are limited data on immune responses after COVID-19 vaccine boosters in individuals receiving primary immunisation with BNT162b2 (Pfizer-BioNTech) or AZD1222 (AstraZeneca).MethodsA prospective, cohort study to assess SARS-CoV-2 antibody responses before and after booster vaccination with BNT162b2 in adults receiving either (i) two BNT162b2 doses <30 days apart (BNT162b2-control), (ii) two BNT162b2 doses ≥30 days apart (BNT162b2-extended) or (iii) two AZD1222 doses ≥30 days apart (AZD1222-extended) in London, England. SARS-CoV-2 spike protein antibody geometric mean titres (GMTs) before and 2-4 weeks after booster were compared.ResultsOf 750 participants, 626 provided serum samples for up to 38 weeks after their second vaccine dose. Antibody GMTs peaked at 2-4 weeks after the second dose, before declining by 68% at 36-38 weeks after dose 2 for BNT162b2-control participants, 85% at 24-29 weeks for BNT162b2-extended participants and 78% at 24-29 weeks for AZD1222-extended participants. Antibody GMTs was highest in BNT162b2-extended participants (942 [95%CI, 797-1113]) than AZD1222-extended (183 [124-268]) participants at 24-29 weeks or BNT162b2-control participants at 36-38 weeks (208; 95%CI, 150-289). At 2-4 weeks after booster, GMTs were significantly higher than after primary vaccination in all three groups: 18,104 (95%CI, 13,911-23,560; n=47) in BNT162b2-control (76.3-fold), 13,980 (11,902-16,421; n=118) in BNT162b2-extended (15.9-fold) and 10,799 (8,510-13,704; n=43) in AZD1222-extended (57.2-fold) participants. BNT162b2-control participants (median:262 days) had a longer interval between primary and booster doses than BNT162b2-extended or AZD1222-extended (both median:186 days) participants.ConclusionsWe observed rapid serological responses to boosting with BNT162b2, irrespective of vaccine type or schedule used for primary immunisation, with higher post-booster responses with longer interval between primary immunisation and boosting. Boosters will not only provide additional protection for those at highest risk of severe COVID-19 but also prevent infection and, therefore, interrupt transmission, thereby reducing infections rates in the population. Ongoing surveillance will be important for monitoring the duration of protection after the booster.
Germany’s low SARS-CoV-2 seroprevalence confirms effective containment in 2020: Results of the nationwide RKI-SOEP study
Authors: Neuhauser Hannelore , Rosario Angelika Schaffrath , Butschalowsky Hans , Haller Sebastian , Hoebel Jens , Michel Janine , Nitsche Andreas , Poethko-Müller Christina , Prütz Franziska , Schlaud Martin , Steinhauer Hans W. , Wilking Hendrik , Wieler Lothar H. , Schaade Lars , Liebig Stefan , Gößwald Antje , Grabka Markus M. , Zinn Sabine , Ziese Thomas 
Published: November 2021

AbstractPre-vaccine SARS-CoV-2 seroprevalence data from Germany are scarce outside hotspots, and socioeconomic disparities remained largely unexplored. The nationwide RKI-SOEP study with 15,122 adult participants investigated seroprevalence and testing in a supplementary wave of the Socio-Economic-Panel conducted predominantly in October-November 2020. Self-collected oral-nasal swabs were PCR-positive in 0.4% and Euroimmun anti-SARS-CoV-2-S1-IgG ELISA from dry capillary blood in 1.3% (95% CI 0.9-1.7%, population-weighted, corrected for sensitivity=0.811, specificity=0.997). Seroprevalence was 1.7% (95% CI 1.2-2.3%) when additionally adjusting for antibody decay. Overall infection prevalence including self-reports was 2.1%. We estimate 45% (95% CI 21-60%) undetected cases and analyses suggest lower detection in socioeconomically deprived districts. Prior SARS-CoV-2 testing was reported by 18% from the lower educational group compared to 25% and 26% from the medium and high educational group (p<0.0001). Symptom-triggered test frequency was similar across educational groups. However, routine testing was more common in low-educated adults, whereas travel-related testing and testing after contact with an infected person was more common in highly educated groups. In conclusion, pre-vaccine SARS-CoV-2-seroprevalence in Germany was very low. Notified cases appear to capture more than half of infections but may underestimate infections in lower socioeconomic groups. These data confirm the successful containment strategy of Germany until winter 2020.
Cocaine exacerbates neurological impairments and neuropathologies in the iTat model of HIV-associated neurocognitive disorder through genome-wide alterations of DNA methylation and gene expression
Authors: Zhao Xiaojie , Zhang Fan , Kandel Suresh R. , Brau Frédéric , He Johnny J. 
Published: November 2021

ABSTRACTHIV infection of the central nervous system causes HIV-associated neurocognitive disease (HAND) in up to 50% HIV-infected individuals. Cocaine use is prevalent in the HIV-infected population and has been shown to facilitate the HAND progression. However, the cellular and molecular mechanism of the cocaine-facilitated HAND progression remains largely unknown. In this study, we took advantage of the doxycycline inducible and brain-specific HIV Tat transgenic mouse model (iTat) of HAND and characterized effects of chronic cocaine exposure and long- term Tat expression on HAND-associated neurology and neuropathology. We found that cocaine exposure worsened the learning and memory of iTat mice, coupled with dendritic spine swelling, increased synaptophysin expression, and diminished microglia and astrocyte activation. We then employed the single-base resolution whole genome bisulfate sequencing and RNA sequencing and identified 14,838 hypermethylated CpG-related differentially methylated regions (DMR) and 15,800 hypomethylated CpG-related DMR that were linked to 52 down- and 127 up-regulated genes by cocaine and Tat. We further uncovered these genes to be mostly enriched at neuronal function- and cell morphology- and synapse formation-relatedECM-receptor interactionpathway, and to be linked to behavioral and pathological changes altered by cocaine and Tat. Eight mostly affected genes included four in microgliaIft172,Eif2ak4,Pik3c2a,andPhf8, two in astrocytesGarem1andAdgrb3, and two in neuronsDcun1d4andAdgrb3. These findings demonstrated for the first time that cocaine and Tat interactively contributed to HAND neurology and neuropathology through genome-wide changes of DNA methylation and gene expression and suggest that targeting epigenetic changes serves as a potentially new therapeutic strategy to treat cocaine use disorder in people living with HAND.
Genomic variation across a clinical Cryptococcus population linked to disease outcome
Authors: Sephton-Clark Poppy , Tenor Jennifer L. , Toffaletti Dena L. , Meyers Nancy , Giamberardino Charles , Molloy Síle F. , Palmucci Julia R. , Chan Adrienne , Chikaonda Tarsizio , Heyderman Robert , Hosseinipour Mina , Kalata Newton , Kanyama Cecilia , Kukacha Christopher , Lupiya Duncan , Mwandumba Henry C. , Harrison Thomas , Bicanic Tihana , Perfect John R. , Cuomo Christina A. 
Published: November 2021

AbstractCryptococcus neoformans is the causative agent of cryptococcosis, a disease with poor patient outcomes, accounting for approximately 180,000 deaths each year. Patient outcomes may be impacted by the underlying genetics of the infecting isolate; however, our current understanding of how genetic diversity contributes to clinical outcomes is limited. Here, we leverage clinical, in vitro growth and genomic data for 284 C. neoformans isolates to identify clinically relevant pathogen variants within a population of clinical isolates from patients with HIV-associated cryptococcosis in Malawi. Through a genome-wide association study (GWAS) approach, we identify variants associated with fungal burden and growth rate. We also find both small and large-scale variation, including aneuploidy, associated with alternate growth phenotypes, which may impact the course of infection. Genes impacted by these variants are involved in transcriptional regulation, signal transduction, glycosylation, sugar transport, and glycolysis. We show that growth within the CNS is reliant upon glycolysis in an animal model, and likely impacts patient mortality, as CNS yeast burden likely modulates patient outcome. Additionally, we find genes with roles in sugar transport are enriched in regions under selection in specific lineages of this clinical population. Further, we demonstrate that genomic variants in two genes identified by GWAS impact virulence in animal models. Our approach identifies links between genetic variation in C. neoformans and clinically relevant phenotypes and animal model pathogenesis; shedding light on specific survival mechanisms within the CNS and identifying pathways involved in yeast persistence.ImportanceInfection outcomes for cryptococcosis, most commonly caused by C. neoformans, are influenced by host immune responses, as well as host and pathogen genetics. Infecting yeast isolates are genetically diverse; however, we lack a deep understanding of how this diversity impacts patient outcomes. To better understand both clinical isolate diversity and how diversity contributes to infection outcome, we utilize a large collection of clinical C. neoformans samples, isolated from patients enrolled in a clinical trial across 3 hospitals in Malawi. By combining whole-genome sequence data, clinical data, and in vitro growth data, we utilize genome-wide association approaches to examine the genetic basis of virulence. Genes with significant associations display virulence attributes in both murine and rabbit models, demonstrating that our approach can identify potential links between genetic variants and patho-biologically significant phenotypes.
Is It Really Musculoskeletal Pain? Differential diagnosis and screening for referral in paediatric musculoskeletal disorders: a scoping review protocol
Authors: D’Aversa A , Bonetti F , Gallotti M , Maselli F 
Published: November 2021

ABSTRACTIntroductionMusculoskeletal disorders are common in children and adolescents. They could have a broad spectrum of causes, which the most are self-limiting and usually do not need a referral to specialistic care. It is mandatory for the healthcare professionals working primary care settings to be able to understand when to perform a “wait and see” approach or when further investigations are needed. This study aims to identify signs and symptoms reliable to serious or life-threatening conditions that could be detected during the screening process and the physical examination of children and adolescent with common musculoskeletal disorders by a healthcare professional in direct access clinical setting.Materials and MethodsThe scoping review (ScR) will be performed following the six-stage methodology suggested by Arksey and O’Malley and the extensions to the original framework that are recommended by the Joanna Briggs Institute. Fourteen electronic databases will be investigated since their inception. The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist will be used to meet the required standards of quality and reproducibility. Review tools will be used for the quality assessment of the included studies. This protocol received input from all authors who have expertise in research methodology and paediatric and musculoskeletal disorders.Ethics and DisseminationThe results of this ScR will be relevant given that screening for referral in paediatric musculoskeletal disorders has not been addressed in the literature properly yet. Dissemination will include submission to peer-reviewed journal. Ethical approval is not required for scoping reviews.PROTOCOL INFORMATIONAnticipated or actual start date: January 2021Anticipated completion date: December 2021
Atomic resolution Protein Allostery from the multi-state Structure of a PDZ Domain
Authors: Ashkinadze Dzmitry , Kadavath Harindranath , Chi Celestine N. , Friedmann Michael , Strotz Dean , Kumari Pratibha , Minges Martina , Cadalbert Riccardo , Königl Stefan , Güntert Peter , Vögeli Beat , Riek Roland 
Published: November 2021

AbstractRecent methodological advances in solution NMR allow the determination of multi-state protein structures and provide insights into correlated motion at atomic resolution as demonstrated here for the well-studied PDZ2 domain of protein human tyrosine phosphatase 1E for which protein allostery was predicted. Two-state protein structures were calculated for both the free form and in complex with the RA-GEF2 peptide using the exact nuclear Overhauser effect (eNOE) method. In the apo protein states an allosteric conformational preselection step comprising almost 60% of the domain was detected with an “open” ligand welcoming state and a “closed” state that obstructs the binding site by the distance between the β-sheet, α-helix 2 and sidechains of residues Lys38 and Lys72. Observed apo-holo structural rearrangements of induced fit-type are in line with previously published evolution-based analysis covering ~25% of the domain with only a partial overlap with the protein allostery of the open form. These presented structural studies highlight the presence of a dedicated highly optimized dynamic interplay of the complexity of the PDZ2 domain owed by the structure-dynamics landscape.
Cryo-EM structure of the octameric pore of Clostridium perfringens β-toxin
Authors: Bruggisser Julia , Iacovache Ioan , Musson Samuel C. , Degiacomi Matteo T. , Posthaus Horst , Zuber Benoît 
Published: November 2021

AbstractClostridium perfringens is one of the most widely distributed and successful pathogens. It causes multiple severe diseases in animals and humans and produces an impressive arsenal of toxins with pore-forming properties, most of them belonging to the hemolysin-like family of β-pore forming toxins (β-PFTs). One of the most potent toxins produced by C. perfringens is β-toxin (CPB). This toxin is the main virulence factor of type C strains and essential for the development of a fatal necrotic enteritis in humans and newborn animals. In the present study, we describe the cryo-electron microscopy (cryo-EM) structure of CPB in styrene maleic acid (SMA) discs, which represents the membrane-inserted pore form, at near atomic resolution. We show that CPB forms a homo-oligomeric pore with eightfold symmetry and similar conformation to the hetero-oligomeric pores of the bi-component leukocidins, with important differences in the receptor binding region and the N-terminal latch domain. Intriguingly, the octameric CPB pore complex contains a second 16-stranded β-barrel protrusion atop of the cap domain that is formed by the N-termini of the eight protomers. We propose that CPB defines a new subclass of the hemolysin-like family of β-PFTs s. In addition, we show that the β-barrel protrusion domain can be changed or modified without affecting the pore forming ability, thus making the pore particularly attractive for macromolecule sensing and nanotechnology. The cryo-EM structure of the octameric pore of CPB will facilitate future developments in both nanotechnology and basic research.
HSFs drive stress type-specific transcription of genes and enhancers
Authors: Himanen Samu V , Puustinen Mikael C , Da Silva Alejandro J , Vihervaara Anniina , Sistonen Lea 
Published: November 2021

ABSTRACTReprogramming of transcription is critical for the survival under cellular stress. Heat shock has provided an excellent model to investigate nascent transcription in stressed cells, but the molecular mechanisms orchestrating RNA synthesis during other types of stress are unknown. We utilized PRO-seq and ChIP-seq to study how Heat Shock Factors, HSF1 and HSF2, coordinate transcription at genes and enhancers upon oxidative stress and heat shock. We show that pause-release of RNA polymerase II (Pol II) is a universal mechanism regulating gene transcription in stressed cells, while enhancers are activated at the level of Pol II recruitment. Moreover, besides functioning as conventional promoter-binding transcription factors, HSF1 and HSF2 bind to stress-induced enhancers to trigger Pol II pause-release from poised gene promoters. Importantly, HSFs act at distinct genes and enhancers in a stress type-specific manner. HSF1 binds to many chaperone genes upon oxidative and heat stress but activates them only in heat-shocked cells. Under oxidative stress, HSF1 and HSF2 trans-activate genes independently of each other, demonstrating, for the first time, that HSF2 is a bona fide transcription factor. Taken together, we show that HSFs function as multi-stress-responsive factors that activate specific genes and enhancers when encountering changes in temperature and redox state.
High-resolution mapping and digital atlas of subcortical regions in the macaque monkey based on matched MAP-MRI and histology
Authors: Saleem Kadharbatcha S , Avram Alexandru V , Glen Daniel , Yen Cecil Chern-Chyi , Ye Frank Q , Komlosh Michal , Basser Peter J 
Published: November 2021

AbstractSubcortical nuclei and other deep brain structures are known to play an important role in the regulation of the central and peripheral nervous systems. It can be difficult to identify and delineate many of these nuclei and their finer subdivisions in conventional MRI due to their small size, buried location, and often subtle contrast compared to neighboring tissue. To address this problem, we applied a multi-modal approach inex vivonon-human primate (NHP) brain that includes high-resolution mean apparent propagator (MAP)-MRI and five different histological stains imaged with high-resolution microscopy in the brain of the same subject. By registering these high-dimensional MRI data to high-resolution histology data, we can map the location, boundaries, subdivisions, and micro-architectural features of subcortical gray matter regions in the macaque monkey brain. At high spatial resolution, diffusion MRI in general, and MAP-MRI in particular, can distinguish a large number of deep brain structures, including the larger and smaller white matter fiber tracts as well as architectonic features within various nuclei. Correlation with histology from the same brain enables a thorough validation of the structures identified with MAP-MRI. Moreover, anatomical details that are evident in images of MAP-MRI parameters are not visible in conventional T1-weighted images. We also derived subcortical template “SC21” from segmented MRI slices in three-dimensions and registered this volume to a previously published anatomical template with cortical parcellation (Reveley et al., 2017; Saleem and Logothetis, 2012), thereby integrating the 3D segmentation of both cortical and subcortical regions into the same volume. This newly updated three-dimensional D99 digital brain atlas (V2.0) is intended for use as a reference standard for macaque neuroanatomical, functional, and connectional imaging studies, involving both cortical and subcortical targets. The SC21 and D99 digital templates are available as volumes and surfaces in standard NIFTI and GIFTI formats.
Selective Inhibitory Circuit Dysfunction after Chronic Frontal Lobe Contusion
Authors: Nolan Amber L. , Sohal Vikaas S. , Rosi Susanna 
Published: November 2021

ABSTRACTTraumatic brain injury (TBI) is a leading cause of neurologic disability; the most common deficits affect prefrontal cortex-dependent functions such as attention, working memory, social behavior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology that develops in frontal cortical microcircuits after TBI. We investigated if alterations in subtype-specific inhibitory circuits are associated with cognitive inflexibility in a mouse model of frontal lobe contusion that recapitulates aberrant mental flexibility as measured by deficits in rule reversal learning. Using patch clamp recordings and optogenetic stimulation, we identified selective vulnerability in the non-fast spiking, somatostatin-expressing (SOM+) subtype of inhibitory neurons in layer V of the orbitofrontal cortex (OFC) two months after injury. These neurons exhibited reduced intrinsic excitability and a decrease in their synaptic output onto pyramidal neurons. By contrast, fast spiking, parvalbumin-expressing (PV+) interneurons did not show changes in intrinsic excitability or synaptic output. Impairments in SOM+ inhibitory circuit function were also associated with network hyperexcitability. These findings provide evidence for selective disruptions within specific inhibitory microcircuits that may guide the development of novel therapeutics for TBI.
Directed Evolution of Aptamer Discovery Technologies
Authors: Wu Diana , Gordon Chelsea K.L. , Shin John H. , Eisenstein Michael , Soh H. Tom 
Published: November 2021

ConspectusAlthough antibodies are a powerful tool for molecular biology and clinical diagnostics, there are many emerging applications for which nucleic acid-based aptamers can be advantageous. However, generating high-quality aptamers with sufficient affinity and specificity for biomedical applications is a challenging feat for most research laboratories. In this Account, we describe four techniques developed in our lab to accelerate the discovery of high quality aptamer reagents that can achieve robust binding even for challenging molecular targets. The first method is particle display, in which we convert solution-phase aptamers into aptamer particles that can be screened via fluorescence-activated cell sorting (FACS) to quantitatively isolate individual aptamer particles based on their affinity. This enables the efficient isolation of high-affinity aptamers in fewer selection rounds than conventional methods, thereby minimizing selection biases and reducing the emergence of artifacts in the final aptamer pool. We subsequently developed the multi-parametric particle display (MPPD) method, which employs two-color FACS to isolate aptamer particles based on both affinity and specificity, yielding aptamers that exhibit excellent target binding even in complex matrices like serum. The third method is a click chemistry-based particle display (click-PD) that enables the generation and high-throughput screening of “non-nattural” aptamers with a wide range of base modifications. We have shown that these base-modified aptamers can achieve robust affinity and specificity for targets that have proven challenging or inaccessible with natural nucleotide-based aptamer libraries. Lastly, we describe the non-natural aptamer array (N2A2) platform, in which a modified benchtop sequencing instrument is used to characterize base-modified aptamers in a massively parallel fashion, enabling the efficient identification of molecules with excellent affinity and specificity for their targets. This system first generates aptamer clusters on the flow-cell surface that incorporate alkyne-modified nucleobases, and then performs a click reaction to couple those nucleobases to an azide-modified chemical moiety. This yields a sequence-defined array of tens of millions of base-modified sequences, which can then be characterized in a high-throughput fashion. Collectively, we believe that these advancements are helping to make aptamer technology more accessible, efficient, and robust, thereby enabling the use of these affinity reagents for a wider range of molecular recognition and detection-based applications.