bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multivariate analysis of a missense variant inCREBRFreveals associations with measures of adiposity in people of Polynesian ancestries
Authors: Zhang Jerry Z. , Heinsberg Lacey W. , Krishnan Mohanraj , Hawley Nicola L. , Major Tanya J. , Carlson Jenna C. , Harré Hindmarsh Jennie , Watson Huti , Qasim Muhammad , Stamp Lisa K. , Dalbeth Nicola , Murphy Rinki , Sun Guangyun , Cheng Hong , Naseri Take , Reupena Muagututi’a S. , Kershaw Erin E. , Deka Ranjan , McGarvey Stephen T. , Minster Ryan L. , Merriman Tony R. , Weeks Daniel E. 
Published: September 2022

ABSTRACTBackgroundThe Pacific-specific minor allele of rs373863828, a missense variant in CREB3 Regulatory Factor (CREBRF), is associated with several cardiometabolic phenotypes in Polynesian peoples, but the variant’s function remains poorly understood. To broaden our understanding of this variant, we used joint multivariate and network analyses to examine the relationships between rs373863828 and a panel of correlated anthropometric and lipid phenotypes.MethodsWe tested the association of rs373863828 with a panel of phenotypes (body mass index [BMI], weight, height, HDL cholesterol, triglycerides, and total cholesterol) under a multivariate Bayesian association model in a cohort from Samoa (N = 1 632), a Māori and Pacific Island (Polynesian) cohort from Aotearoa New Zealand (N = 1 419), and the combined cohort (N = 2 976). An expanded set of phenotypes (adding estimated fat and fat-free mass, abdominal circumference, hip circumference, and abdominal-hip ratio) was also tested in the Samoa cohort (N = 1 496). Bayesian networks were learned to further understand the structure of the relationships.ResultsIn the Samoa cohort, significant associations (log10Bayes factor ≥5.0) were found between rs373863828 and the overall phenotype panel (7.97), weight (8.35) and BMI (6.39). In the Aotearoa New Zealand cohort, suggestive associations (log10Bayes factor between 1.5 and 5) were found between rs373863828 and the overall phenotype panel (3.64), weight (3.30), and BMI (1.79). In the combined cohort, concordant signals with stronger magnitudes were observed. In the expanded phenotype analyses among the Samoa cohort, significant associations were also observed between rs373863828 and fat mass (5.68), abdominal circumference (5.37), and hip circumference (5.15).Bayesian networks provided evidence for a direct association of rs373863828 with weight and indirect associations with height and BMI.ConclusionsWhen correlation structures were considered, multivariate Bayesian analyses provided additional evidence of rs373863828’s pleiotropic effects and highlighted a strong direct effect only on weight.
Reduced stress perfusion in myocardial infarction with nonobstructive coronary arteries
Authors: Johansson Rebecka Steffen , Tornvall Per , Sörensson Peder , Nickander Jannike 
Published: September 2022

AbstractBackgroundMyocardial infarction with nonobstructive coronary arteries (MINOCA) is a working diagnosis with several possible underlying causes. Early cardiovascular magnetic resonance imaging (CMR) is recommended, however cannot provide a diagnosis in 25% of cases. One pathophysiological mechanism may be coronary microvascular dysfunction (CMD) not possible to detect using standard CMR. Quantitative stress CMR perfusion mapping can be used to identify CMD, however it is currently unknown if CMD is present during long-term follow-up of MINOCA patients. Therefore, the aim of this study was to evaluate presence of CMD during long-term follow-up in MINOCA patients with an initial normal CMR scan.MethodsMINOCA patients from the second multicenter Stockholm Myocardial Infarction with Normal Coronaries study (SMINC-2), with a normal CMR scan a median 3 days after hospitalization were investigated with comprehensive stress CMR median 5 years after the acute event, together with age- and sex-matched volunteers without symptomatic ischemic heart disease. Cardiovascular risk factors, medication and symptoms of myocardial ischemia measured by the Seattle Angina Questionnaire 7, were registered.ResultsIn total, 15 patients with MINOCA and an initial normal CMR scan (59±7 years old, 60% female), and 15 age- and sex-matched volunteers, underwent CMR. Patients with MINOCA and an initial normal CMR scan had lower global stress perfusion compared to volunteers (2.83±1.8 vs 3.53±0.7 ml/min/g,p=0.02). There were no differences in other CMR parameters including global rest perfusion and myocardial perfusion reserve, hemodynamic parameters, or cardiovascular risk factors, except for a higher statin use in the MINOCA patient group compared to volunteers.ConclusionsGlobal stress perfusion is lower in MINOCA patients during follow-up, compared to age- and sex-matched volunteers, suggesting CMD as a possible pathophysiological mechanism in MINOCA.Clinical Trial RegistrationClinicaltrials.govidentifierNCT02318498. Registered 2014-12-17.
The Nanog epigenetic remodeling complex was essential to vertebrate mesoderm evolution
Authors: Simpson Luke A. , Crowley Darren , Forey Teri , Acosta Helena , Ferjentsik Zoltan , Chatfield Jodie , Payne Alexander , Simpson Benjamin S. , Redwood Catherine , Dixon James E. , Holmes Nadine , Sang Fei , Alberio Ramiro , Loose Mathew , Johnson Andrew D. 
Published: September 2022

AbstractPluripotency defines the unlimited potential of cells in the primitive ectoderm of vertebrate embryos, from which all adult somatic cells and germ cells are derived. Understanding how the programing of pluripotency evolved has been obscured by the study of early development in models from lower vertebrates in which pluripotency is not conserved. Here we investigated how the axolotl ortholog of the mammalian core pluripotency factor NANOG, programs pluripotency during axolotl development to model the tetrapod ancestor from which terrestrial vertebrates evolved. We show that in axolotl primitive ectoderm (animal caps; AC) NANOG synergizes with NODAL activity and the epigenetic modifying enzyme DPY30 to direct the deposition of H3K4me3 in chromatin prior to the waves of transcription required for lineage commitment and developmental progression. We show that the interaction of NANOG and NODAL with DPY30 is required to direct development downstream of pluripotency and this is conserved in axolotls and human. These data demonstrate that the interaction of NANOG and NODAL signaling represents the basal state of vertebrate pluripotency.
A novel fluorobenzothiazole RBx 10080758 as a dual inhibitor against bacterial GyraseB (GyrB) and Topoisomerase IV (parE) of Gram-positive pathogens causing skin and respiratory infections
Authors: Barman Tarani Kanta , Kumar Manoj , Chaira Tridib , Singhal Smita , Mathur Tarun , Kalia Vandana , Gangadharan Ramkumar , Rao Madhvi , Pandya Manisha , Bhateja Pragya , Sood Ruchi , Upadhyay Dilip J. , Varughese Shibu , Yadav Ajay , Sharma Lalima , Kumar Naresh , Sattigeri Jitendra , Bhatnagar Pradip K. , Raj V. Samuel 
Published: September 2022

AbstractDevelopment of a novel inhibitor targeting Gyrase B and Topoisomerase IV offers a potential opportunity to combat the drug resistance. In the present study, we extensively investigated the efficacy of RBx 10080758, a novel fluorobenzothiazole, against skin and respiratory infections caused by Staphylococci and Streptococci in in vitro and in vivo models. RBx 10080758 showed a potent IC50 of 0.06 μM against Gyrase and Topoisomerase IV and also exhibited a strong whole cell in vitro activity with MIC ranges of 0.015-0.06, 0.015-0.03, 0.008-0.03, 0.008-0.03, 0.008-0.0.06, 0.015-0.06 μg/ml against Staphylococcus. aureus, Streptococcus pneumoniae, Coagulase negative Staphylococci, Streptococcus viridans, Streptococcus pyogenes and Enterococcus, respectively. As expected from the novel class of molecule, it retains potent even against linezolid and vancomycin resistant strains. Interesting, in mouse systemic infection 10 mg/kg, IV dose protected 100% mice from lethal infections. In rat thigh infection model with MRSA WCUH29 at 45 mg/kg exhibited >3-log10 cfu reduction in thigh muscles. RBx 10080758 displayed potent in vitro and in vivo activity against a panel of MDR Gram-positive bacteria. As a novel chemical class, the fluorobenzothiazoles have the potential to become clinically viable antibiotics, to address the drug resistance problem by its unique dual targeting mechanism of action.
Increasing number of long-lived ancestors associates with up to a decade of healthspan extension and a healthy metabolomic profile in mid-life
Authors: van den Berg Niels , Rodríguez-Girondo Mar , van Dijk Ingrid K , Slagboom P. Eline , Beekman Marian 
Published: September 2022

AbstractGlobally, the lifespan of populations increases but the healthspan is lagging behind. Previous research showed that survival into extreme ages (longevity) clusters in families as illustrated by the increasing lifespan of study participants with each additional long-lived family member. Here we investigate whether the healthspan in such families follows a similar quantitative pattern using three-generational data from two databases, LLS (Netherlands), and SEDD (Sweden). We study healthspan in 2,143 families containing index persons and two ancestral generations, comprising 17,539 persons with 25 follow-up years. Our results provide strong evidence that an increasing number of long-lived ancestors associates with up to a decade of healthspan extension. Further evidence indicates that members of long-lived families have a delayed onset of medication use, multimorbidity and, in mid-life, healthier metabolomic profiles than their partners. We conclude that in longevity families, both lifespan and healthspan are quantitatively linked to ancestral longevity, making such families highly suitable to identify protective mechanisms of multimorbidity.
Systematic analysis of microtubule plus-end networks defines EB-cargo complexes critical for mitosis in budding yeast
Authors: Kornakov Nikolay , Westermann Stefan 
Published: September 2022

SummaryMicrotubules are ubiquitous cytoskeletal polymers with essential functions in chromosome segregation, intracellular transport and cellular morphogenesis. End-binding proteins (EBs) form the nodes of intricate microtubule plus-end interaction networks. Which EB binding partners are most critical for cell division, and how cells manage to organize a microtubule cytoskeleton in the absence of an EB protein, are open questions. Here we demonstrate that the budding yeast EB protein Bim1 executes its key mitotic functions as part of two cargo complexes-Bim1-Kar9 in the cytoplasm and Bim1-Cik1-Kar3 in the nucleus. Lack of Bim1-Kar9 during spindle orientation is compensated by accumulation of the CLIP-170 homolog Bik1 on the lattice of long cytoplasmic microtubules, which upregulates the Dynein-Dynactin nuclear migration pathway. In the nucleus a Bim1-Bik1-Cik1-Kar3 complex acts during initial metaphase spindle assembly and supports sister chromatid bi-orientation. Lack of Bim1 alters spindle association timing and the level of the microtubule crosslinkers Ase1/PRC1 and Slk19, which become essential for bi-orientation. Engineered plus-end targeting of Kinesin-14 Cik1-Kar3 efficiently restores major spindle-relatedbim1τιphenotypes. In addition to defining the key Bim1-cargo complexes our study also reveals compensatory mechanisms that allow cells to proliferate in the absence of Bim1.
The m6A reader IGF2BP2 directs immune-metabolic reprogramming in Leishmania amazonensis-infected macrophages
Authors: Zhang Sheng , Lecoeur Hervé , Varet Hugo , Legendre Rachel , Mahtal Nassim , Proux Caroline , Aulner Nathalie , Shorte Spencer , Granjean Capucine , Bousso Philippe , Prina Eric , Späth Gerald F. 
Published: September 2022

ABSTRACTMacrophages are the major host cells of the protozoan parasiteLeishmaniain mammalian infection. These key innate immune cells display remarkable phenotypic plasticity ranging from pro-inflammatory M1 to anti-inflammatory M2 macrophages that can control infection and tissue homeostasis, respectively. It has been recognized thatLeishmaniaexploits macrophage phenotypic plasticity to establish chronic infection. However, the current notion that these parasites simply trigger an M2-like phenotype seems over-simplified considering the immunopathology observed during leishmaniasis – in particular in response toLeishmania amazonensis- which is often characterized by a mixed Th1/Th2 immune response. Here we combined a series of systems-level analyses to shed new light on the phenotype ofLeishmania-infected macrophages (LIMs) during short- and long-term infection,in vitroandin vivo. Immuno-metabolic profiling by RNA-seq, RT-qPCR, cytokine immunoassays, and real-time bioenergetic flux analysis ofL. amazonensis-infected bone marrow-derived macrophages (BMDMs) revealed a highly complex and unique phenotypic and bioenergetic signature.In vitroLIMs were characterized by co-expression of both M1 and M2 markers at RNA and protein levels and increased expression of glycolytic genes that matched a progressive metabolic switch from a M2-like respiratory to a M1-like glycolytic energy production observed for both long-termin vitroandin vivoinfected macrophages. Unlike in M1 macrophages, glycolytic gene expression did not correlate with increased expression of its key regulatory HIF-1α. In contrast, siRNA knock down experiments in primary BMDMs uncovered an essential role of the m6A reader protein IGF2BP2 in stabilizing m6A modified transcripts of the glycolytic pathway, contributing to HIF-1α-independent induction of glycolysis. In conclusion,L. amazonensisestablishes a complex and unique phenotypic shift in infected macrophagesin vitroandin vivothat combines M1-like and M2-like immuno-metabolomic characteristics and implicates differential mRNA stability in induction of aerobic glycolysis. Our data thus uncover epi-transcriptomic regulation as a novel target forLeishmaniaimmune subversion to establish a host cell phenotype beneficial for intracellular parasite development and chronic infection.
Mediator 1 ablation induces enamel-to-hair lineage conversion through enhancer dynamics
Authors: Thaler Roman , Yoshizaki Keigo , Nguyen Thai , Fukumoto Satoshi , Besten Pamela Den , Bikle Daniel D. , Oda Yuko 
Published: September 2022

ABSTRACTPostnatal cell fate has been postulated to be primarily determined by the local tissue microenvironment. Here, we found that Mediator 1 (Med1) dependent epigenetic mechanisms dictate tissue-specific lineage commitment and progression of dental epithelia. Deletion ofMed1, a key component of the Mediator complex linking enhancer activities to gene transcription, provokes a tissue extrinsic lineage shift, causing hair generation in the dental environment.Med1deficiency gives rise to unusual hair growth via primitive cellular aggregates on incisors. Mechanistically, we found that Med1 establishes super-enhancers that control enamel lineage transcription factors in dental stem cells and their progenies. However,Med1deficiency reshapes the enhancer landscapes and causes a switch from the dental epithelial transcriptional program towards hair and epidermis on incisorsin vivo, and in dental epithelial stem cellsin vitro. Med1loss also provokes an increase in the number and size of enhancers. Interestingly, control dental epithelia already exhibit enhancers for hair and epidermal key transcription factors; these expand in size and transform into active super-enhancers uponMed1loss suggesting that these epigenetic mechanisms cause the transcriptomic and phenotypic shift towards epidermal and hair lineages. Thus, we propose a role for Med1 in safeguarding lineage specific enhancers, highlight the central role of enhancer accessibility and usage in lineage reprogramming and provide new insights into ectodermal regeneration.
Evolution of predictive memory in the hippocampus
Authors: Miller Adam M. P. , Jacob Alex D. , Ramsaran Adam I. , De Snoo Mitchell L. , Josselyn Sheena A. , Frankland Paul W. 
Published: September 2022

SummaryThe brain organizes experiences into memories that can be used to guide future behavior. Hippocampal CA1 population activity may reflect the retrieval of predictive models that contain information about future events, but little is known about how these kinds of memories develop with experience. We trained mice on a series of tone discrimination problems with or without a common statistical structure to observe how memories are formed and updated during learning. Mice that learned structured problems integrated their experiences into a predictive model that contained the solutions to upcoming novel problems. Retrieving the model during learning improved discrimination accuracy and facilitated learning by decreasing the amount of new information that needed to be acquired. Using calcium imaging to track the activity of thousands of CA1 neurons during learning on this task, we observed the emergence of a persistent hippocampal ensemble at the same time that mice formed a predictive model of their environment. This ensemble was reactivated during training and incorporated new neuronal activity patterns from each training problem. Interestingly, the degree to which mice reactivated the ensemble was related to how well their model predicted the content of the current problem, ensuring that the model was only updated with congruent information. In contrast, mice trained on unstructured problems did not form a predictive model or engage a persistent ensemble. These results show how hippocampal activity supports building predictive models by organizing newly learned information according to its congruence with existing memories.
Detailed evaluation of chromatic pupillometry and full-field stimulus testing to assess ultra-low vision in retinitis pigmentosa
Authors: Yamamoto Midori , Matsuyama Take , Maeda Tadao , Takagi Seiji , Motozawa Naohiro , Sakai Daiki , Hirami Yasuhiko , Maeda Akiko , Kurimoto Yasuo , Takahashi Masayo , Mandai Michiko 
Published: September 2022

AbstractPurposeNovel therapeutic options, such as regenerative medicine and gene therapy are now emerging as viable treatment options for patients with severe visual impairments, such as retinitis pigmentosa (RP). Gradable assessment of patients’ visual function is essential to consider treatment options and to evaluate treatment outcomes, however, evaluation of visual function in advanced low vision patients is often challenging due to patients’ poor and sometimes unpredictable responses. In this study, we attempted to accurately assess the visual capabilities and disease stage in RP patients with visual acuity of 0.01 or lower, using chromatic pupillometry and full-field stimulus testing (FST), combined with retinal structural features, as determined by spectral-domain OCT.DesignRetrospective analysis of visual function tests in 84 eyes of 43 patients with advanced RP with visual acuity of 0.01 and lower visited Kobe City Eye Hospital from 2019 to 2021.MethodsEighty-four eyes of 43 patients with advanced RP with visual acuity of 0.01 and lower were evaluated by chromatic pupillometry, FST, BCVA (best-corrected visual acuity), and OCT (optical coherence tomography). Hierarchical (multilevel) Bayesian modeling was used to estimate individual eye’s pupil response and FST, taking into account the ambiguity and randomness often observed in ultra-low vision patients. Using the estimated abilityobtained from each test, the correlation between each test and retinal thickness was further analyzed to make a comprehensive assessment of the data.ResultsFST and pupillometry measurements were moderately correlated with visual acuity, but exhibited a wide range of values within the same visual acuity groups. FST was not correlated with central retinal thickness at CF/HM VA range and seemed to reflect overall remaining photoreceptor function including peripheral retina. Pupillometry seemed to distinguish different levels inner retinal function.ConclusionThe combination of pupillometry and FST allowed for graded evaluation of visual function within patients grouped in the same visual acuity groups in advanced RP patients with ultra-low vision.
Modeling and characterization of capacitor storage circuit for piezoelectric vibration energy harvester
Authors: Wei Sheng 
Published: September 2022

Purpose
This paper aims to study a power management circuit for a piezoelectric vibration energy harvester. It presents how to accumulate energy and provide regulated DC voltage for practical applications.

Design/methodology/approach
Energy storage and extraction circuit are proposed. While the storage stage consists of a full wave rectifier and a storage capacitor, the extraction stage includes a voltage comparator and regulator, which may provide the load steady DC voltage when the voltage of the storage capacitor is higher than the threshold.

Findings
The numerical analysis and experimental results indicate that it takes a longer time to charge to a specified voltage for the greater storage capacitor and the net charge flowing into the storage capacitor during each period decreases when the voltage of the storage capacitor is higher. The higher threshold voltage of the capacitor has lower harvesting efficiency owing to the rate of charging of the storage capacitor slowing down over time.

Research limitations/implications
Because of the chosen research method, the power management circuit is only suitable for the piezoelectric vibration energy harvester under resonant conditions.

Practical implications
This study includes practically useful applications for users to build a power management circuit for piezoelectric energy harvester.

Originality/value
This study presents results that the charging efficiency of the storage circuit is relative to the storage capacitor and the threshold voltage.