bluuebunny/crossref_metadata_2025_split huggingface dataset:
Degree of Cyclooxygenase-2 Inhibition Modulates Blood Pressure Response to Celecoxib and Naproxen
Authors: Theken Katherine N. , Ghosh Soumita , Skarke Carsten , Fries Susanne , Lahens Nicholas F. , Sarantopoulou Dimitra , Grant Gregory R. , FitzGerald Garret A. , Grosser Tilo 
Published: June 2024

AbstractBackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of adverse cardiovascular events via suppression of cyclooxygenase (COX)-2-derived prostacyclin (PGI2) formation in heart, vasculature, and kidney. The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial and other large clinical studies compared the cardiovascular risk of traditional NSAIDs (i.e. naproxen), which inhibit both COX isozymes, with NSAIDs selective for COX-2 (i.e. celecoxib). However, whether pharmacologically equipotent doses were used - that is, whether a similar degree of COX-2 inhibition was achieved - was not considered. We compared drug target inhibition and blood pressure response to celecoxib at the dose used by most patients in PRECISION with the lowest recommended naproxen dose for osteoarthritis, which is lower than the dose used in PRECISION.MethodsSixteen healthy participants (19-61 years) were treated with celecoxib (100 mg every 12h), naproxen (250 mg every 12h), or placebo administered twice daily for seven days in a double-blind, crossover design randomized by order. On Day 7 when drug levels had reached steady state, the degree of COX inhibition was assessedex vivoandin vivo. Ambulatory blood pressure was measured throughout the final 12h dosing interval.ResultsBoth NSAIDs inhibited COX-2 activity relative to placebo, but naproxen inhibited COX-2 activity to a greater degree (62.9±21.7%) than celecoxib (35.7±25.2%; p<0.05). Similarly, naproxen treatment inhibited PGI2formationin vivo(48.0±24.9%) to a greater degree than celecoxib (26.7±24.6%; p<0.05). Naproxen significantly increased blood pressure compared to celecoxib (differences in least-square means of mean arterial pressure: 2.5 mm Hg (95% CI: 1.5, 3.5); systolic blood pressure: 4.0 mm Hg (95% CI: 2.9, 5.1); diastolic blood pressure: 1.8 mm Hg (95% CI: 0.8, 2.8); p<0.05 for all). The difference in systolic blood pressure relative to placebo was associated with the degree of COX-2 inhibition (p<0.05).ConclusionsCelecoxib 200 mg/day inhibited COX-2 activity to a lesser degree than naproxen 500 mg/day, resulting in a less pronounced blood pressure increase. While the PRECISION trial concluded the non-inferiority of celecoxib regarding cardiovascular risk, this is based on a comparison of doses that are not equipotent.ClinicalTrials.govidentifier:NCT02502006(https://clinicaltrials.gov/study/NCT02502006)Clinical PerspectiveNaproxen 250 mg twice a day inhibited COX-2 activity to a greater degree than celecoxib 100 mg twice a day.The degree of COX-2 inhibition was associated with the increase in systolic blood pressure with NSAID treatment relative to placebo.Dose and its pharmacological potency achievedin vivoshould be considered when evaluating the relative cardiovascular safety of COX-2-selective vs. non-selective NSAIDs.
Protection of Omicron bivalent vaccine, previous infection, and their induced neutralizing antibodies against symptomatic infection with Omicron XBB.1.16 and EG.5.1
Authors: Yamamoto Shohei , Matsuda Kouki , Maeda Kenji , Mizoue Tetsuya , Horii Kumi , Okudera Kaori , Tan Tomofumi , Oshiro Yusuke , Inamura Natsumi , Nemoto Takashi , Takeuchi Junko S. , Konishi Maki , Sugiyama Haruhito , Aoyanagi Nobuyoshi , Sugiura Wataru , Ohmagari Norio 
Published: June 2024

AbstractBackgroundData are limited on the protective role of the Omicron BA bivalent vaccine, previous infection, and their induced neutralizing antibodies against Omicron XBB.1.16 and EG.5.1 infection.MethodsWe conducted a nested case-control analysis among tertiary hospital staff in Tokyo who had received three or more doses of COVID-19 vaccines and donated blood samples in June 2023 (1 month before Omicron XBB.1.16 and EG.5.1 wave). We identified 206 symptomatic cases between June and September 2023 and selected their controls with 1:1 propensity-score matching. We examined the association of vaccination, previous infection, and preinfection live-virus neutralizing antibody titers against Omicron XBB.1.16 and EG.5.1 with the risk of COVID-19 infection.ResultsPrevious infection during Omicron BA- or XBB-dominant phases was associated with a significantly lower infection risk during the XBB.1.16 and EG.5.1 dominant phase than infection-naïve with 70% and 100% protection, respectively, whereas Omicron BA bivalent vaccination showed no association. Preinfection-neutralizing titers against XBB.1.16 and EG.5.1 were 39% (95%CI: 8–60) and 28% (95%CI: 8–44), respectively, lower in cases than in matched controls. Neutralizing activity against XBB.1.16 and EG.5.1. were somewhat detectable in the sera of individuals with previous infection but barely detectable in those who were infection-naïve and received the Omicron bivalent vaccine.ConclusionsIn the era when the Omicron XBB vaccine was unavailable, the Omicron BA bivalent vaccine did not confer the neutralizing activity and protection against Omicron XBB.1.16 and EG.5.1 symptomatic infection. The previous infection afforded neutralizing titers and protection against symptomatic infection with these variants.Main pointsIn the era when the Omicron XBB vaccine was unavailable, the Omicron BA bivalent vaccine did not confer the neutralizing activity and protection against Omicron XBB.1.16 and EG.5.1 symptomatic infection. The previous infection afforded neutralizing titers and protection against symptomatic infection with these variants.
Characterizing a Lethal CAG-ACE2 Transgenic Mouse Model for SARS-CoV-2 infection with Using Cas9-Enhanced Nanopore Sequencing
Authors: Smirnov Alexander , Nurislamov Artem , Koncevaya Galina , Serova Irina , Kabirova Evelyn , Chuyko Eduard , Maltceva Ekaterina , Savoskin Maxim , Zadorozhny Daniil , Svyatchenko Victor A. , Protopopova Elena V. , Taranov Oleg S. , Legostaev Stanislav S. , Loktev Valery B. , Serov Oleg , Battulin Nariman 
Published: June 2024

AbstractThe SARS-CoV-2 pandemic has underscored the necessity for functional transgenic animal models for testing. Mouse lines with overexpression of the human receptor ACE2 serve as the primary animal model to study COVID-19 infection. Overexpression ofACE2under a strong ubiquitous promoter facilitates convenient and sensitive testing of COVID-19 pathology. We performed pronuclear microinjections using a 5 kb CAG-ACE2 linear transgene construct and identified three founder lines with 140, 72, and 73 copies, respectively. Two of these lines were further analyzed forACE2expression profiles and sensitivity to SARS-CoV-2 infection. Both lines expressedACE2in all organs analyzed. Embryonic fibroblast cell lines derived from transgenic embryos demonstrated severe cytopathic effects following infection, even at low doses of SARS-CoV-2 (0,1-1.0 TCID50). Infected mice from the two lines began to show COVID-19 symptoms three days post-infection and succumbed between days 4 and 7. Histological examination of lung tissues from terminally ill mice revealed severe pathological alterations. To further characterize the integration site in one of the lines, we applied Nanopore sequencing combined with Cas9 enrichment to examine the internal transgene concatemer structure. Oxford Nanopore sequencing (ONT) is becoming the gold standard for transgene insert characterization, but it is relatively inefficient without targeted region enrichment. We digested genomic DNA with Cas9 and gRNA against theACE2transgene to create ends suitable for ONT adapter ligation. ONT data analysis revealed that most of the transgene copies were arranged in a head-to-tail configuration, with palindromic junctions being rare. We also detected occasional plasmid backbone fragments within the concatemer, likely co-purified during transgene gel extraction, which is a common occurrence in pronuclear microinjections.
Discarded diversity: Novel megaphages, auxiliary metabolic genes, and virally encoded CRISPR-Cas systems in landfills
Authors: George Nikhil A. , Zhou Zhichao , Anantharaman Karthik , Hug Laura A. 
Published: June 2024

AbstractBackgroundViruses are the most abundant microbial entity on the planet, impacting microbial community structure and ecosystem services. Despite outnumbering Bacteria and Archaea by an order of magnitude, viruses have been comparatively underrepresented in reference databases. Metagenomic examinations have illustrated that viruses of Bacteria and Archaea have been specifically understudied in engineered environments. Here we employed metagenomic and computational biology methods to examine the diversity, host interactions, and genetic systems of viruses predicted from 27 samples taken from three municipal landfills across North America.ResultsWe identified numerous viruses that are not represented in reference databases, including the third largest bacteriophage genome identified to date (∼678 kbp), and note a cosmopolitan diversity of viruses in landfills that are distinct from viromes in other systems. Host-virus interactions were examined via host CRISPR spacer to viral protospacer mapping which captured hyper-targeted viral populations and six viral populations predicted to infect across multiple phyla. Virally-encoded auxiliary metabolic genes (AMGs) were identified with the potential to augment hosts’ methane, sulfur, and contaminant degradation metabolisms, including AMGs not previously reported in literature. CRISPR arrays and CRISPR-Cas systems were identified from predicted viral genomes, including the two largest bacteriophage genomes to contain these genetic features. Some virally encoded Cas effector proteins appear distinct relative to previously reported Cas systems and are interesting targets for potential genome editing tools.ConclusionsOur observations indicate landfills, as heterogeneous contaminated sites with unique selective pressures, are key locations for diverse viruses and atypical virus-host dynamics.
The Associations of Mental Disorders in Children With Parents’ Subsequent Mental Disorders: A Nationwide Cohort Study From Finland and Denmark
Authors: Hakulinen Christian , Gutvilig Mai , Niemi Ripsa , Momen Natalie C. , Pulkki-Råback Laura , Böckerman Petri , Plana-Ripoll Oleguer , Komulainen Kaisla , Elovainio Marko 
Published: June 2024

ABSTRACTBackgroundIntergenerational transmission of mental disorders has been well established, but it is unclear whether exposure to a child’s mental disorder increases parents’ subsequent risk of mental disorders.AimsWe examined the association of mental disorders in children with their parents’ subsequent mental disorders.MethodsIn this population based-cohort study, we included all persons with children born in Finland or Denmark in 1990–2010. Information of mental disorder was acquired from national registers. The follow-up period began when the parent’s eldest child was 5 years old (for codes F10–F60 ICD-10) or 1 year old (for codes F70–F98 of the ICD-10) and ended on December 31st, 2019, or when the parent received a mental disorder diagnosis, died, or emigrated from Finland or Denmark. The association of mental disorders in children with their parents’ subsequent mental disorders was examined using Cox proportional hazards models.ResultsThe study cohort included 1 651 723 parents. In total, 248 328 women and 250 763 men had at least one child who was diagnosed with a mental disorder. The risk of a parent receiving a mental disorder diagnosis was higher among those who had a child with a mental disorder compared to those who did not. For both parents, the hazard ratios were greatest in the first six months after the child’s diagnosis (HR between 2.04-2.54), followed by a subtle decline in the risk (after two years, HR between 1.33-1.77).ConclusionMental disorders in children were associated with a greater risk of subsequent mental disorders among their parents. Additional support is needed for parents whose children have been recently diagnosed with a mental disorder.
Functional brain connectivity in early adolescence after hypothermia-treated neonatal hypoxic-ischemic encephalopathy
Authors: Håkansson Gustaf , Grossmann Katarina Robertsson , Ådén Ulrika , Blennow Mats , Fransson Peter 
Published: June 2024

AbstractAimNeonatal hypoxic-ischemic encephalopathy (HIE) injures the infant brain during the basic formation of the developing functional connectome. This study aimed to investigate long-term changes in the functional connectivity (FC) networks of the adolescent brain following neonatal HIE treated with therapeutic hypothermia (TH).MethodThis prospective, population-based cohort study included all infants (n=66) with TH-treated neonatal HIE in Stockholm during 2007-2009 and a control group (n=43) of children with normal neonatal course. Assessment with resting-state functional magnetic resonance imaging (fMRI) was performed at Karolinska Institutet, Stockholm at age 9-12 years.ResultsfMRI data met quality criteria for 35 children in the HIE-cohort (mean [SD] age at MRI: 11.2 [0.74] years, 46% male) and 30 children in the control group (mean [SD] age at MRI: 10.1 [0.78] years, 53% male). Clinical neurologic symptoms were present in 40% of children in the HIE-cohort. Non-parametric statistical analysis failed to detect any significant (p<0.001) alterations of FC networks in the HIE-cohort, nor between children in the HIE-cohort with or without neurological sequelae.InterpretationHT-treated HIE could not be associated with persistent alteration of the functional connectome. This indicates a notable resilience of the functional architecture of the brain against this type of early brain injury.
Multi-polygenic prediction of frailty highlights chronic pain and educational attainment as key risk and protective factors
Authors: Flint J P , Welstead M , Cox S R , Russ T C , Marshall A , Luciano M 
Published: June 2024

AbstractFrailty is a complex trait. Twin studies and recent Genome-Wide Association Studies have demonstrated a strong genetic basis of frailty but there remains a lack of genetic studies exploring genetic prediction of Frailty. Previous work has shown that a single polygenic predictor – represented by a Frailty polygenic score - predicts Frailty, measured via the frailty index, in independent samples within the United Kingdom. We extended this work, using a multi-polygenic score (MPS) approach to increase predictive power. Predictor variables - twenty-six polygenic scores (PGS) were modelled in regularised Elastic net regression models, with repeated cross-validation, to estimate joint prediction of the polygenic scores and order the predictions by their contributing strength to Frailty in two independent cohorts aged 65+ - the English Longitudinal Study of Ageing (ELSA) and Lothian Birth Cohort 1936 (LBC1936). Results showed that the MPS explained 3.6% and 4.7% of variance compared to the best single-score prediction of 2.6% and 2.2% of variance in ELSA and LBC1936 respectively. The strongest polygenic predictors of worsening frailty came from PGS for Chronic pain, Frailty and Waist circumference; whilst PGS for Parental Death, Educational attainment, and Rheumatoid Arthritis were found to be protective to frailty. Results from the predictors remaining in the final model were then validated using the longitudinal LBC1936, with equivalent PGS scores from the same GWAS summary statistics. Thus, this MPS approach provides new evidence for the genetic contributions to frailty in later life and sheds light on the complex structure of the Frailty Index measurement.
A machine learning-based prediction of tau load and distribution in Alzheimer’s disease using plasma, MRI and clinical variables
Authors: Karlsson Linda , Vogel Jacob , Arvidsson Ida , Åström Kalle , Strandberg Olof , Seidlitz Jakob , Bethlehem Richard A. I. , Stomrud Erik , Ossenkoppele Rik , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Palmqvist Sebastian , Smith Ruben , Janelidze Shorena , La Joie Renaud , Rabinovici Gil D. , Binette Alexa Pichet , Mattsson-Carlgren Niklas , Hansson Oskar 
Published: June 2024

AbstractTau positron emission tomography (PET) is a reliable neuroimaging technique for assessing regional load of tau pathology in the brain, commonly used in Alzheimer’s disease (AD) research and clinical trials. However, its routine clinical use is limited by cost and accessibility barriers. Here we explore using machine learning (ML) models to predict clinically useful tau-PET composites from low-cost and non-invasive features, e.g., basic clinical variables, plasma biomarkers, and structural magnetic resonance imaging (MRI). Results demonstrated that models including plasma biomarkers yielded the most accurate predictions of tau-PET burden (best model: R-squared=0.66-0.68), with especially high contribution from plasma P-tau217. In contrast, MRI variables stood out as best predictors (best model: R-squared=0.28-0.42) of asymmetric tau load between the two hemispheres (an example of clinically relevant spatial information). The models showed high generalizability to external test cohorts with data collected at multiple sites. Based on these results, we also propose a proof-of-concept two-step classification workflow, demonstrating how the ML models can be translated to a clinical setting. This study uncovers current potential in predicting tau-PET information from scalable cost-effective variables, which could improve diagnosis and prognosis of AD.
Genetic Liability to Higher Muscle Strength Associates with a Lower Risk of Cardiovascular Disease Mortality in Men Irrespective of Physical Activity in Adulthood: A Longitudinal Cohort Study
Authors: Herranen Päivi , Waller Katja , Joensuu Laura , Palviainen Teemu , Laakkonen Eija K , Kaprio Jaakko , Sillanpää Elina 
Published: June 2024

AbstractBackgroundLow muscle strength predicts premature mortality. We determined whether genetic liability to muscle strength is associated with mortality and whether this association is influenced by long-term leisure-time physical activity (PA).Methods and ResultsWe estimated the effects of a polygenic score for hand grip strength (PGS HGS) on all-cause and cardiovascular disease (CVD) mortality risk in the older Finnish Twin Cohort (N=8815, 53% women). National registries provided dates and causes of death. PA volume was assessed longitudinally in 1975, 1981, and 1990 using validated questionnaires. During the 16.9-year median follow-up time (143,723 person-years), 2896 deaths occurred, of which 1089 were due to CVD. We found a significant interaction between sex and PGS HGS (P=0.016) for predicting all-cause mortality. In men, one standard deviation increase in the PGS HGS was associated with a decreased risk both of all-cause (hazard ratio, HR [95% confidence interval, CI]): 0.93 [0.89–0.98] and CVD mortality (HR 0.88 [0.81–0.96]). Associations persisted after adjusting for PA, but only with CVD mortality after adjusting for other lifestyle covariates (HR 0.85 [0.76–0.96]). The cumulative incidence rates by age 75 years were 4.3% lower for all-cause mortality and 2.1% lower for CVD mortality in the highest PGS HGS quintile compared to the lowest quintile. No PGS HGS×PA interactions were found. PGS HGS was not associated with mortality in women.ConclusionsHigher PGS HGS was associated with a decreased risk of all-cause and CVD mortality in men; however, long-term PA in adulthood did not potentiate this association.Clinical PerspectiveWhat Is New?To the best of our knowledge, this is the first study to use a genome-wide polygenic score for hand grip strength to investigate whether the association between genetic liability to muscle strength and lifespan is affected by physical activity.Our results suggest that individuals with a genetic predisposition for higher muscle strength have a modest decreased risk of cardiovascular disease mortality, independent of their lifestyle.What Are the Clinical Implications?Polygenic scores for muscle strength require further development but may help identify individuals who represent extreme ends of genetic predisposition and vulnerability to premature death.
No Electrophysiological Evidence for Semantic Processing During Inattentional Blindness
Authors: Hutchinson Brendan T. , Jack Bradley N. , Pammer Kristen , Canseco-Gonzalez Enriqueta , Pitts Michael 
Published: June 2024

AbstractA long-standing question concerns whether sensory input can reach semantic stages of processing in the absence of attention and awareness. Here, we examine whether the N400, an event related potential associated with semantic processing, can occur under conditions of inattentional blindness. By employing a novel three-phase inattentional blindness paradigm designed to maximise the opportunity for detecting an N400, we found no evidence for it when participants were inattentionally blind to the eliciting stimuli (related and unrelated word pairs). In contrast, when minimal attention was allocated to the same task-irrelevant word pairs, participants became aware of them, and a small N400 became evident. Finally, when the same stimuli were fully attended and relevant to the task, a robust N400 was observed. In addition to univariate ERP measures, multivariate decoding analyses were unable to classify related versus unrelated word pairs when observers were inattentionally blind to the words, with decoding reaching above-chance levels only when the words were (at least minimally) attended. Our results also replicated several previous studies by finding a “visual awareness negativity” (VAN) that distinguished task-irrelevant stimuli that were perceived compared with those that were not perceived, and a P3b (or “late positivity”) that was evident only when the stimuli were perceived and task relevant. Together, our findings suggest that semantic processing might require at least a minimal amount of attention.
Loss of the lysosomal protein CLN3 modifies the lipid content of the nuclear envelope leading to DNA damage and activation of YAP1 pro-apoptotic signaling
Authors: Domingues Neuza , Calcagni’ Alessia , Pires Joana , Freire Sofia Roque , Herz Niculin Joachim , Huynh Tuong , Wieciorek Katarzyna , Moreno Maria João , Outeiro Tiago Fleming , Girão Henrique , Milosevic Ira , Ballabio Andrea , Raimundo Nuno 
Published: June 2024

ABSTRACTBatten disease is characterized by early-onset blindness, juvenile dementia and death during the second decade of life. The most common genetic causes are mutations in theCLN3gene encoding a lysosomal protein. There are currently no therapies targeting the progression of the disease, mostly due to the lack of knowledge about the disease mechanisms.To gain insight into the impact of CLN3 loss on cellular signaling and organelle function, we generated CLN3 knock-out cells in a human cell line (CLN3-KO), and performed RNA sequencing to obtain the cellular transcriptome. Following a multi-dimensional transcriptome analysis, we identified the transcriptional regulator YAP1 as a major driver of the transcriptional changes observed in CLN3-KO cells.We further observed that YAP1 pro-apoptotic signaling is hyperactive as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of CLN3exΔ7/8mice, an established model of Batten disease. Loss of CLN3 activates YAP1 by a cascade of events that starts with the inability of releasing glycerophosphodiesthers from CLN3-KO lysosomes, which leads to perturbations in the lipid content of the nuclear envelope and nuclear dysmorphism. This results in increased number of DNA lesions, activating the kinase c-Abl, which phosphorylates YAP1, stimulating its pro-apoptotic signaling.Altogether, our results highlight a novel organelle crosstalk paradigm in which lysosomal metabolites regulate nuclear envelope content, nuclear shape and DNA homeostasis. This novel molecular mechanism underlying the loss of CLN3 in mammalian cells and tissues may open new c-Abl-centric therapeutic strategies to target Batten disease.