bluuebunny/crossref_metadata_2025_split huggingface dataset:
Left ventricular mass and global wall thickness – prognostic utility and characterization of left ventricular hypertrophy
Authors: Lundin Magnus , Heiberg Einar , Nordlund David , Gyllenhammar Tom , Steding-Ehrenborg Katarina , Engblom Henrik , Carlsson Marcus , Atar Dan , van der Pals Jesper , Erlinge David , Borgquist Rasmus , Khoshnood Ardavan , Ekelund Ulf , Nickander Jannike , Themudo Raquel , Nordin Sabrina , Kozor Rebecca , Bhuva Anish N , Moon James C , Maret Eva , Caidahl Kenneth , Sigfridsson Andreas , Sörensson Peder , Schelbert Erik B , Arheden Håkan , Ugander Martin 
Published: October 2022

AbstractAIMSCardiovascular magnetic resonance (CMR) can accurately measure left ventricular (LV) mass, which is associated with morbidity and mortality. Several measures related to LV wall thickness exist, with uncertain relative prognostic strength. We hypothesized that prognosis can be used to select an optimal measure of wall thickness for characterizing LV hypertrophy.METHODS AND RESULTSSubjects having undergone CMR were studied (cardiac patients, n=2543; healthy volunteers, n=100). A new measure, global wall thickness (GT, GTI if indexed to body surface area), and related measures, including mass/volume and mass/volume2/3, were calculated. GT was accurately calculated from LV mass and LV end-diastolic volume. Among patients with follow-up (n=1575, median follow-up 5.4 years), the most predictive measure of death or hospitalization for heart failure was LV mass index (LVMI) (hazard ratio (HR)[95% confidence interval] 1.16[1.12–1.20], p<0.001), followed by GTI (HR 1.14[1.09–1.19], p<0.001). Among patients with normal mass, volume, systolic function and absence of scar (n=326, median follow-up 5.8 years), the most predictive measure was GT (HR 1.62[1.35–1.94], p<0.001). GT and LVMI could characterize patients as having a normal LV mass and wall thickness, or concentric remodeling, concentric hypertrophy, or eccentric hypertrophy, and the three abnormal groups had worse prognosis than the normal group (p<0.05 for all).CONCLUSIONSLV mass is highly prognostic when mass is elevated (advanced disease), but global wall thickness is easily and accurately calculated, and adds value and discrimination amongst those with normal mass (early disease). The combination of these two measures can be used to characterize hypertrophy.
Three-dimensional cranial ultrasound and functional near infrared spectroscopy for bedside monitoring of intraventricular hemorrhage in preterm neonates
Authors: Kebaya Lilian M N , Stubbs Kevin , Lo Marcus , Al-Saoud Sarah , Karat Bradley , St Lawrence Keith , de Ribaupierre Sandrine , Duerden Emma G. 
Published: October 2022

AbstractGerminal Matrix-Intraventricular hemorrhage (GMH-IVH) remains a significant cause of adverse neurodevelopment in preterm infants. Current management relies on 2-dimensional cranial ultrasound (2D cUS) ventricular measurements. Reliable biomarkers are needed to aid in the early detection of posthemorrhagic ventricular dilatation (PHVD) and subsequent neurodevelopment. In a prospective cohort study, we incorporated 3-dimensional (3D) cUS and functional infrared spectroscopy (fNIRS) to monitor neonates with GMH-IVH. Preterm neonates (<32 weeks’ gestation) were enrolled following a GMH-IVH diagnosis. Neonates underwent sequential measurements: 3D cUS images were manually segmented using in-house software, and the ventricle volumes (VV) were extracted. Multichannel fNIRS data were acquired using a high-density system, and spontaneous functional connectivity (sFC) was calculated. Of the 30 neonates enrolled in the study, 21 (70%) had grade I-II and 12 (40%) grade III-IV GMH-IVH, and 23 neonates (77%) underwent surgical interventions to divert cerebrospinal fluid (CSF). Infants with severe GMH-IVH who underwent CSF diversion had larger VV and significantly decreased sFC (p<0.001). Our findings of increased VV and reduced sFC suggest that regional disruptions of ventricular size may impact the development of the underlying grey matter. Hence, 3D cUS and fNIRS are promising bedside tools for monitoring the progression of GMH-IVH in preterm neonates.
Parental COVID-19 vaccine hesitancy and vaccine uptake among children and adolescents in the US: Findings from a prospective national cohort
Authors: Rane Madhura S. , Robertson McKaylee , Westmoreland Drew , Zimba Rebecca , Kulkarni Sarah G. , Shen Yanhan , Berry Amanda , Chang Mindy , You William , Grov Christian , Nash Denis ,   the CHASING COVID Cohort Team
Published: October 2022

AbstractObjectivesOur aim was to measure COVID-19 vaccine uptake among children aged 5-17 years old via parents participating in the CHASING COVID Cohort and identify sociodemographic factors associated with it.MethodsIn this longitudinal study, parents of school-aged children were asked about their own vaccination status and that of their children at three time points between June 2021-January 2022, along with reasons for vaccinating immediately or delaying vaccinations for their children. Multivariable log binomial models were used to identify correlates of vaccine uptake among children.ResultsOf the 1,583 children aged 5-17 years, 64.9% were vaccinated. Over 40% of parents of 5-11 year old children who intended to delay vaccinating their child in June 2021 had still not vaccinated them by January 2022, including 30% of the parents who were vaccinated. After adjusting for measured confounders, parents’ vaccination status was associated with higher likelihood of children’s vaccine uptake (age-specific adjusted odds ratios [aORs]: aOR16-173.7, 95% CI 2.3, 5.9, aOR12-153.7, 95% CI 2.6, 5.3; aOR5-1110.6, 95% CI 5.4, 20.9). Parents’ education (aOR16-171.4, 95% CI 1.1, 1.8, aOR12-151.5, 95% CI 1.2, 1.9; aOR5-112.1, 95% CI 1.5, 2.9) and worry about others getting infected (aOR5-111.4, 95% CI 1.1, 1.6) were also associated with higher vaccine uptake among children. A higher proportion of parents of 5-11 year olds (vs. 12-17 year olds) had concerns about vaccine safety and effectiveness.ConclusionTo increase vaccination coverage among young children, vaccination campaigns should focus on both vaccinated and unvaccinated parents and messaging should be specific to the child’s age.
Rapid quantitative electrochemical detection of SARS-CoV-2 antibodies in plasma and dried blood spot samples
Authors: Timilsina Sanjay S. , Durr Nolan , Jolly Pawan , Ingber Donald E. 
Published: October 2022

ABSTRACTCoronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a highly contagious disease with several variants, continues to spread as part of the global pandemic. With the roll-out of vaccines and development of new therapeutics that may be targeted to distinct viral molecules, there is a need to screen populations for viral antigen-specific SARS-CoV-2 antibodies. Here, we describe a rapid, multiplexed, electrochemical (EC) platform with on-chip control that enables detection of SARS-CoV-2 antibodies in less than 10 min using 1.5 µL of a patient sample. The EC biosensor demonstrated 100% sensitivity and specificity, and an area under the receiver operating characteristic curve of 1, when evaluated using 93 clinical samples, including plasma and dried blood spot samples from 54 SARS-CoV-2 positive and 39 negative patients. This EC biosensor platform enables simple, cost-effective, sensitive, and rapid detection of anti-SARS-CoV-2 antibodies in complex clinical samples, which is convenient for monitoring host humoral responses to vaccination or viral infection in broad population testing, including applications in low-resource settings. We also demonstrate the feasibility of using dried blood spot samples that can be collected locally and transported to distant clinical laboratories at ambient temperature for detection of anti-SARS-CoV-2 antibodies which can be used for serological surveillance and demonstrate the utility of remote sampling.
High levels of serum cholesterol positively correlate with the risk of the development of vessel co-opting tumours in colorectal cancer liver metastases
Authors: Rada Miran , Krzywon Lucyna , Kapelanski-Lamoureux Audrey , Petrillo Stephanie , Reynolds Andrew R. , Lazaris Anthoula , Seidah Nabil , Metrakos Peter 
Published: October 2022

AbstractColorectal cancer liver metastatic (CRCLM) tumours present as two main histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours obtain their blood supply by sprouting angiogenesis, whereas the RHGP tumours utilize an alternative vascularisation known as vessel co-option. In vessel co-option, the cancer cells hijack the mature sinusoidal vessels to obtain blood supply. Vessel co-option has been reported as an acquired mechanism of resistance to anti-angiogenic treatment in CRCLM. Here, we show the connection between the concentration of serum cholesterol and the development of vessel co-option in CRCLM. Our clinical data suggested that the elevation of serum cholesterol levels correlates with the risk of developing vessel co-opting tumours. Moreover, inhibition of the key modulators of cholesterol metabolism including HMGCR or PCSK9 attenuated the development of CRCLM tumours, as well as vessel co-option in vivo. Altogether, our data uncovered the importance of cholesterol in the development of vessel co-option tumours and demonstrated PCSK9 and HMGCR inhibitors as promising strategies to mitigate the development of vessel co-option tumours in CRCLM.
The Ycf48 accessory factor occupies the site of the oxygen-evolving manganese cluster during photosystem II biogenesis
Authors: Zhao Ziyu , Vercellino Irene , Knoppová Jana , Sobotka Roman , Murray James W. , Nixon Peter J. , Sazanov Leonid A. , Komenda Josef 
Published: October 2022

AbstractRobust oxygenic photosynthesis requires a suite of accessory factors to ensure efficient assembly and repair of the oxygen-evolving photosystem two (PSII) complex. The highly conserved Ycf48 assembly factor binds to the newly synthesized D1 reaction center polypeptide and promotes the initial steps of PSII assembly, but its binding site is unclear. Here we have used cryo-electron microscopy to determine the structure of a cyanobacterial PSII D1/D2 reaction center assembly complex with Ycf48 attached. Ycf48, a 7-bladed beta propeller, binds to the amino-acid residues of D1 that ultimately ligate the Mn4CaO5cluster that catalyzes water oxidation, thereby preventing the premature binding of Mn2+and Ca2+ions and protecting the site from damage. Interactions with D2 help explain how Ycf48 promotes assembly of the D1/D2 complex. Overall, our work provides new insights into the early stages of PSII assembly and the structural changes that create the binding site for the Mn4CaO5cluster.
Thumb-domain dynamics modulate the functional repertoire of DNA-Polymerase IV (DinB)
Authors: Okeke Damasus C. , Lidman Jens , Matečko-Burmann Irena , Burmann Björn M. 
Published: October 2022

ABSTRACTIn order to cope with the risk of stress-induced mutagenesis, cells in all kingdoms of life employ Y-family DNA polymerases to resolve resulting DNA lesions and thus maintaining the integrity of the genome. InEscherichia coli(E. coli) the DNA polymerase IV, or DinB, plays this crucial role in coping with these type of mutationsviathe so-called translesion DNA synthesis. Despite the availability of several high-resolution crystal structures important aspects of the functional repertoire of DinB remain elusive. In this study, we use advanced solution NMR spectroscopy methods in combination with biophysical characterization to elucidate the crucial role of the Thumb domain within DinB’s functional cycle. We find that the inherent dynamics of this domain guide the recognition of double-stranded (ds) DNA buried within the interior of the DinB domain arrangement and trigger allosteric signals through the DinB protein. Subsequently, we characterized the RNA polymerase interaction with DinB, revealing an extended outside surface of DinB and thus not mutually excluding the DNA interaction. Altogether the obtained results lead to a refined model of the functional repertoire of DinB within the translesion DNA synthesis pathway.
Diversity-oriented synthesis encoded by deoxyoligonucleotides
Authors: Hudson Liam , Mason Jeremy W. , Westphal Matthias V. , Richter Matthieu J. R. , Thielman Jonathan R. , Hua Bruce K. , Gerry Christopher J. , Xia Guoqin , Osswald Heather L. , Knapp John M. , Tan Zher Yin , Kokkonda Praveen , Tresco Ben I. C. , Liu Shuang , Reidenbach Andrew G. , Lim Katherine S. , Poirier Jennifer , Capece John , Bonazzi Simone , Gampe Christian M. , Smith Nichola J. , Bradner James E. , Coley Connor W. , Clemons Paul A. , Melillo Bruno , Hon C. Suk-Yee , Ottl Johannes , Dumelin Christoph E. , Schaefer Jonas V. , Faust Ann Marie E. , Berst Frédéric , Schreiber Stuart L. , Zécri Frédéric J. , Briner Karin 
Published: October 2022

AbstractDiversity-oriented synthesis (DOS)is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here, we describe the design, synthesis, and validation experiments performed for a 3.7 million-member DEL, generated using diverse skeleton architectures with varying exit vectors, derived from DOS, to achieve structural diversity beyond what is possible by varying appendages alone. We will make this DEL available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.
A drug’s most potent target is not necessarily the source of its anti-cancer activity
Authors: Bhattacharjee Debanjan , Bakar Jaweria , Sausville Erin L. , Mendelson Brianna E. , Long Kaitlin , Smith Joan C. , Sheltzer Jason M. 
Published: October 2022

ABSTRACTThe small-molecule drug ralimetinib was developed as an inhibitor of the kinase p38α, and it has advanced to phase 2 clinical trials in oncology. Here, we apply a multi-modal approach to demonstrate that ralimetinib’s anti-cancer activity occurs due to its ability to inhibit EGFR, rather than p38α. We find that cancer cell lines driven by EGFR mutations exhibit the greatest sensitivity to ralimetinib treatment, and ralimetinib phenocopies established EGFR inhibitors in pharmacogenomic profiling experiments. We further demonstrate that ralimetinib inhibits EGFR kinase activityin vitroandin cellulo, albeit at >30-fold higher concentrations than it inhibits p38α. Finally, while deletion of the gene encoding p38α has no effect on ralimetinib sensitivity, expression of the EGFR-T790M gatekeeper mutation confers resistance to ralimetinib treatment. These findings suggest that future clinical trials involving ralimetinib could incorporate EGFR mutation status as a biomarker to identify sensitive patients. Moreover, our results demonstrate that a compound’s anti-cancer effects should not necessarily be attributed to the protein that it inhibits most strongly, and instead, comprehensive cellular and genetic profiling is required to understand a drug’s mechanism-of-action.
Eleven key measures for monitoring general practice clinical activity during COVID-19 using federated analytics on 48 million adults’ primary care records through OpenSAFELY
Authors: Fisher Louis , Curtis Helen J. , Croker Richard , Wiedemann Milan , Speed Victoria , Wood Christopher , Brown Andrew , Hopcroft Lisa EM , Higgins Rose , Massey Jon , Inglesby Peter , Morton Caroline E. , Walker Alex J. , Morley Jessica , Mehrkar Amir , Bacon Seb , Hickman George , Macdonald Orla , Lewis Tom , Wood Marion , Myers Martin , Samuel Miriam , Conibere Robin , Baqir Wasim , Sood Harpreet , Drury Charles , Collison Kiren , Bates Chris , Evans David , Dillingham Iain , Ward Tom , Davy Simon , Smith Rebecca M. , Hulme William , Green Amelia , Parry John , Hester Frank , Harper Sam , Cockburn Jonathan , O’Hanlon Shaun , Eavis Alex , Jarvis Richard , Avramov Dima , Griffiths Paul , Fowles Aaron , Parkes Nasreen , MacKenna Brian , Goldacre Ben 
Published: October 2022

AbstractBackgroundThe COVID-19 pandemic has had a significant impact on delivery of NHS care. We have developed the OpenSAFELY Service Restoration Observatory (SRO) to describe this impact on primary care activity and monitor its recovery.ObjectivesTo develop key measures of primary care activity and describe the trends in these measures throughout the COVID-19 pandemic.MethodsWith the approval of NHS England we developed an open source software framework for data management and analysis to describe trends and variation in clinical activity across primary care electronic health record (EHR) data on 48 million adults.We developed SNOMED-CT codelists for key measures of primary care clinical activity selected by a expert clinical advisory group and conducted a population cohort-based study to describe trends and variation in these measures January 2019-December 2021, and pragmatically classified their level of recovery one year into the pandemic using the percentage change in the median practice level rate.ResultsWe produced 11 measures reflective of clinical activity in general practice. A substantial drop in activity was observed in all measures at the outset of the COVID-19 pandemic. By April 2021, the median rate had recovered to within 15% of the median rate in April 2019 in six measures. The remaining measures showed a sustained drop, ranging from a 18.5% reduction in medication reviews to a 42.0% reduction in blood pressure monitoring. Three measures continued to show a sustained drop by December 2021.ConclusionsThe COVID-19 pandemic was associated with a substantial change in primary care activity across the measures we developed, with recovery in most measures. We delivered an open source software framework to describe trends and variation in clinical activity across an unprecedented scale of primary care data. We will continue to expand the set of key measures to be routinely monitored using our publicly available NHS OpenSAFELY SRO dashboards with near real-time data.
Reconstruction of SARS-CoV-2 outbreaks in a primary school using epidemiological and genomic data
Authors: Kremer Cécile , Torneri Andrea , Libin Pieter J. K. , Meex Cécile , Hayette Marie-Pierre , Bontems Sébastien , Durkin Keith , Artesi Maria , Bours Vincent , Lemey Philippe , Darcis Gilles , Hens Niel , Meuris Christelle 
Published: October 2022

AbstractMathematical modeling studies have shown that repetitive screening can be used to mitigate SARS-CoV-2 transmission in primary schools while keeping schools open. However, not much is known about how transmission progresses within schools and whether there is a risk of importation to households. In this study, we reconstructed outbreaks observed during a prospective study in a primary school and associated households in Liège (Belgium) during the academic year 2020-2021. In addition we performed a simulation study to investigate how the accuracy of estimated weekly positivity rates in a school depends on the proportion of a school that is sampled in a repetitive screening strategy. We found that transmission occurred mainly within the school environment and that observed positivity rates are a good approximation to the true positivity rate, especially in children. This study shows that it is worthwile to implement repetitive testing in school settings, which in addition to reducing infections can lead to a better understanding of the extent of transmission in schools during a pandemic and importation risk at the community level.
The ER tether VAPA is required for proper cell motility and anchors ER-PM contact sites to focal adhesions
Authors: Siegfried Hugo , Le Borgne Rémi , Durieu Catherine , De Azevedo Laplace Thaïs , Verraes Agathe , Daunas Lucien , Verbavatz Jean-Marc , Heuzé Mélina L. 
Published: October 2022

ABSTRACTCell motility processes highly depend on the membrane distribution of Phosphoinositides (PInst), giving rise to cytoskeleton reshaping and membrane trafficking events. Membrane contact sites serve as platforms for lipid exchange and calcium fluxes between two organelles. Here, we show that VAPA, an ER membrane-resident contact site tether, plays a crucial role during cell motility. CaCo2 adenocarcinoma epithelial cells depleted for VAPA exhibit several collective and individual motility defects, disorganized actin cytoskeleton and altered protrusive activity. During migration, VAPA is required for the maintenance of PI(4,5)P2 levels at the plasma membrane, but not for PI(4)P homeostasis in the Golgi and endosomal compartments. Importantly, we show that VAPA regulates the dynamics of focal adhesions (FA) through its MSP domain, and is essential to stabilize and anchor ventral ER-PM contact sites to FA, thus mediating microtubule-dependent FA disassembly. To conclude, our results reveal unprecedented functions for VAPA-mediated membrane contact sites during cell motility and provides a dynamic picture of ER-PM contact sites connection with FA mediated by VAPA.
Centrosome amplification fine-tunes tubulin acetylation to differentially control intracellular organization
Authors: Monteiro Pedro , Yeon Bongwhan , Wallis Samuel S. , Godinho Susana A. 
Published: October 2022

AbstractIntracellular organelle organisation is conserved in eukaryotic cells and is primarily achieved through active transport by motor proteins along the microtubule cytoskeleton. Microtubule posttranslational modifications (PTMs) contribute to microtubule diversity and differentially regulate motor-mediated transport. Here we show that centrosome amplification induces a global change in organelle positioning towards the cell periphery and facilitates nuclear migration through confined spaces. This reorganisation requires kinesin-1 and is analogous to loss of dynein. Cells with amplified centrosomes display increased levels of acetylated tubulin, a PTM known to enhance kinesin-1 mediated transport. Depletion of α-tubulin acetyltransferase 1 (αTAT1) to block tubulin acetylation, which has no impact on control cells, rescues the displacement of centrosomes, mitochondria and vimentin, but not Golgi or endosomes. Analyses of the distribution of acetylated microtubules indicates that the polarisation of modified microtubules, rather than levels alone, plays an important role in organelle positioning. We propose that tubulin acetylation differentially impacts kinesin-1-mediated organelle displacement, suggesting that each organelle must have its own sensing and response mechanisms to ensure fine-tuning of its distribution in cells.