bluuebunny/crossref_metadata_2025_split huggingface dataset:
GPR41/43 regulates blood pressure by improving gut epithelial barrier integrity to prevent TLR4 activation and renal inflammation
Authors: Muralitharan Rikeish R. , Zheng Tenghao , Dinakis Evany , Xie Liang , Barbaro-Wahl Anastasia , Jama Hamdi A. , Nakai Michael , Patterson Madeleine , Johnson Chad , Salimova Ekaterina , Bitto Natalie , Liaskos Maria-Kaparakis , Kaye David M. , O’Donnell Joanne A. , Mackay Charles R. , Marques Francine Z. 
Published: March 2023

AbstractFermentation of dietary fibre by the gut microbiota leads to the production of metabolites called short-chain fatty acids (SCFAs), which have emerged as potent regulators of immune, metabolic, and tissue barrier functions. More recently, a high fibre diet and SCFA supplementation were shown to lower blood pressure and be cardio-protective. SCFAs activate host signalling responses via the receptors GPR41 and GPR43, which have redundancy in their signalling pathways. Whether these receptors play a role in hypertension or mediate the cardio-protective effects of fibre remains unknown. Using an experimental model that lacks both GPR41 and GPR43, we show that lack of signalling via these receptors increases risk to high blood pressure and leads to cardiorenal fibrosis and hypertrophy.Moreover, we demonstrate that GPR41/43 signalling is essential in maintaining gut epithelial barrier, which prevents the translocation of the bacterial toxins lipopolysaccharides (LPS) from entering the peripheral circulation. In the absence of GPR41/43, this is accompanied by macrophage infiltration to the kidneys, resulting in pro-inflammatory cytokine production.Using an antagonist against the LPS’ receptor, TLR4, a potent pro-inflammatory signalling pathway, we were able to rescue the cardiovascular phenotype in GPR41/43 knockout mice. We also demonstrate that GPR41/43 are, at least partially, responsible for the blood pressure- lowering and cardio-protective effects of a high fibre diet; however, improvements of gut barrier integrity and macrophages in the kidney were independent of GPR41/43 signalling.Finally, using the UK Biobank, we provide translational evidence that variants associated with lower expression of both GPR41/43 are more prevalent in hypertensive patients. Our findings highlight that lack of SCFA-receptor signalling via both GPR41/43 increases risk of high blood pressure, suggesting these receptors could be targeted as a new treatment.
The genome of medicinal plantSophora flavescenshas undergone significant expansion of both transposons and genes
Authors: Qu Zhipeng , Wang Wei , Adelson David L. 
Published: March 2023

AbstractPurposeSophora flavescensis a medicinal plant in the genus Sophora of the Fabaceae family. The root ofS. flavescensis known in China as Kushen and has a long history of wide use in multiple formulations of Traditional Chinese Medicine (TCM). However, there is little genomic information available forS. flavescens.MethodsIn this study, we used third-generation Nanopore long-read sequencing technology combined with Hi-C scaffolding technology to de novo assemble the S. flavescens genome.ResultsWe obtained a chromosomal level high-qualityS. flavescensdraft genome. The draft genome size is approximately 2.08 Gb, with more than 80% annotated as Transposable Elements (TEs), which have recently and rapidly proliferated. This genome size is ∼5x larger than its closest sequenced relativeLupinus albus l.. We annotated 60,485 genes and examined their expression profiles in leaf, stem and root tissues, and also characterised the genes and pathways involved in the biosynthesis of major bioactive compounds, including alkaloids, flavonoids and isoflavonoids.ConclusionThe assembled genome highlights the very different evolutionary trajectories that have occurred in recently diverged Fabaceae, leading to smaller duplicated genomes vs larger genomes resulting from TE expansion. Our assembly provides valuable resources for conservation, genetic research and breeding ofS. flavescens.
Multitrophic assembly: a perspective from modern coexistence theory
Authors: Song Chuliang , Spaak Jurg W. 
Published: March 2023

AbstractEcological communities encompass rich diversity across multiple trophies. While modern coexistence theory has been useful in understanding community assembly, its traditional formalism only allows for the study of assembly within a single trophic level. Here, using an expanded definition of niche and fitness differences applicable to multi-trophic communities, we study how diversity within and across trophics affect species coexistence. Specifically, we investigate how assembly in one trophic level impacts the coexistence of three types of communities: (1) the single-trophic subcommunity with species at that level, (2) the single-trophic subcommunity with species at an adjacent level, and (3) the entire multitrophic community. We find that while coexistence mechanisms are similar for single-trophic communities, they differ for multitrophic ones. We also find that fitness differences primarily constrain diversity in lower-level tropics, while niche differences primarily constrain diversity in higher-level tropics. Empirical data corroborates our predictions about multitrophic structures. Our work provides needed theoretical expectation of multitrophic communities within modern coexistence theory.
Psidium guajavaderived carbon nanoparticles: A promising red emissive cellular bioimaging agent
Authors: Mehta Shivani , Singh Udisha , Barve Ketki , Bhatia Dhiraj 
Published: March 2023

AbstractWe report a simple, cost-effective, microwave-assisted green synthesis route of red-emitting fluorescence carbon nanoparticles (CNPs) usingPsidium guajava(Guava leaves). The synthesis of CNPs is a simple, affordable, and rapid method of producing carbon nanoparticles. The CNPs were characterized by various spectroscopic and microscopic techniques. Atomic force microscopy studies showed that the average size of CNPs is approximately 50 nm. The CNPs exhibited excellent photoluminescence properties with a maximum emission at 677 nm, making them suitable for bioimaging applications. The Ionic, photostability, and thermal stability of CNPs were also checked to understand their robustness. Retinal pigment epithelium (RPE) cells were exposed to these nanoparticles and showed very efficient uptake, some fraction of it also getting targeted to the nucleus, indicating that CNPs are non-toxic and biocompatible for future biological experiments. The results indicate that guava leaves can be a promising source for the synthesis of red emissive CNPs through the very simple method of synthesis and with bioimaging applications.
Effect of acetic acid bacteria colonization on oviposition and feeding site choice inDrosophila suzukiiand its related species
Authors: Sato Airi , Yew Joanne Y. , Takahashi Aya 
Published: March 2023

AbstractOviposition site choice has a large impact on offspring performance. Unlike other vinegar flies that colonize decaying fruits,Drosophila suzukiilay eggs into hard ripening fruits by using their enlarged and serrated ovipositors (oviscapts). This behavior has an advantage over other species by providing access to the host fruit earlier and avoiding competition. However, the larvae are not fully adapted to a low-protein diet, and the availability of intact healthy fruits is seasonally restricted. Thus, to investigate oviposition site preference for microbial growth in this species, we conducted an oviposition assay using single species of commensalDrosophilaacetic acid bacteria,AcetobacterandGluconobacter. The oviposition site preferences for media with or without bacterial growth were quantified in multiple strains ofD. suzukiiand its closely related species,D. subpulchrellaandD. biarmipes, and a typical fermenting-fruit consumer,D. melanogaster. Our comparisons demonstrated a continuous degree of preference for sites withAcetobactergrowth both within and across species, suggesting that the niche separation is notable but not complete. The preference forGluconobactershowed large variations among replicates and no clear differences between the strains. In addition, the lack of interspecific differences in feeding site preference forAcetobacter-containing media implies that the interspecific divergence in oviposition site preference occurred independently from the feeding site preference. Our oviposition assays measuring the preference of multiple strains from each fly species for acetic acid bacteria growth revealed intrinsic properties of shared resource usage among these fruit fly species.
Managing very small scale objective structured clinical examinations - can we ensure reliability of pass/fail decisions with low candidate numbers? A feasibility study of global score only decision making
Authors: Gray James , Darling-Pomranz Claire , Rone James , Spencer David 
Published: March 2023

AbstractBackgroundThis study assesses a change to pass/fail decision making from an Angoff method to one based on examiner global judgements in very small scale Objective Structured Clinical Examinations (OSCE).ApproachData was collected from a Physician Associate OSCE in which two examiners marked each station one utilising a global rating based mark scheme and the other the original, Angoff based, mark scheme. Alternative global ratings were used to try and improve the judgement decision of examiners and checklists significantly reduced into a small number of broader domains. Examiners were also asked to provide some feedback on the new rating scales.EvaluationMann-Whitney U tests were used to evaluate the data. Overall there was fairly good correlation of candidate performance between the two methods. Some anomalies were found with the use of the word safe in the global ratings creating a “killer” station. Examiners had mixed views but most were positive about the change in approach.ImplicationsThe initial results seem promising suggesting that global rating scales alone may be suitable to determine pass/fail decisions in very small scale OSCE with implications for all educators managing such assessments. We intend to keep the adjusted global rating scales.
Impact of Obesity on Catheter Ablation of Atrial fibrillation: Patient Characteristics, Procedural Complications, Outcomes and Quality of Life
Authors: Tabaja Chadi , Younis Arwa , Santageli Pasquale , Farwati Medhat , Braghieri Lorenzo , Nakagawa Hiroshi , Saliba Walid I. , Madden Ruth , Bouscher Patricia , Kanj Mohamed , Callahan Thomas D. , Martin David , Bhargava Mandeep , Chung Mina , Baranowski Bryan , Nakhla Shady , Sroubek Jakub , Lee Justin , Taigen Tyler , Tchou Patrick J. , Wazni Oussama M. , Hussein Ayman A. 
Published: March 2023

AbstractBackgroundObesity is a well-known risk factor for atrial fibrillation (AF).ObjectiveTo evaluate the effect of baseline obesity on procedural complications, AF recurrence, and symptoms following catheter ablation (CA).MethodsA total of 5841 patients undergoing AF ablation (2013-2021) were enrolled in a prospectively maintained registry. Primary endpoint was AF recurrence based on electrocardiographic documentation. Patients were categorized into 5 groups according to their baseline body mass index (BMI). Patients survey at baseline and at follow-up were used to calculate AF severity score (AFSS) as well as AF burden.ResultsMajor procedural complications were low (1.5%) among BMI sub-groups. At 3 years AF recurrence was highest in Class III obesity patients (48%) followed by Class II (43%), whereas Class I, normal, and overweight had similar results with lower recurrence (35%). In multivariable analyses, Class III obesity was independently associated with increased risk for AF recurrence (HR=1.30, P=0.01), whereas other groups had similar risk in comparison to normal weight. Baseline AFSS was lowest in normal weight, and highest in Obesity-III, median [interquartile range] 10 [5-16] vs 15 [10-21]. In all groups, CA resulted in improvement in their AFSS with a similar magnitude among the groups. At follow-up, AF burden was minimal and did not differ significantly between the groups.ConclusionAF ablation is safe with a low complication rate across all BMI groups. Morbid obesity (BMI ≥40) was significantly associated with reduced AF ablation success. However, ablation resulted in improvement in QOL including reduction of the AFSS, and AF burden.What is known?Obesity is an independent risk factor of atrial fibrillation (AF)Catheter ablation (CA) has emerged as a standard of care in arrhythmia management, leading to improvements in quality of life, reductions in hospitalizations, and potential reductions in major adverse clinical outcomes.More obese patients are being referred to catheter ablation of AF.What is new?AF ablation is safe with low complication rates across all BMI sub-groups (<1.5%)Morbid obesity (BMI ≥40) was associated with increased risk of AF recurrence after ablationUsing patient reported outcomes, AF Ablation resulted in improvement of quality of life regardless of BMI
Integration of DNA methylation datasets for individual prediction
Authors: Merzbacher Charlotte , Ryan Barry , Goldsborough Thibaut , Hillary Robert F , Campbell Archie , Murphy Lee , McIntosh Andrew M , Liewald David , Harris Sarah E , McRae Allan F , Cox Simon R , Cannings Timothy I , Vallejos Catalina , McCartney Daniel L , Marioni Riccardo E 
Published: March 2023

AbstractBackgroundEpigenetic scores (EpiScores) can provide blood-based biomarkers of lifestyle and disease risk. Projecting a new individual onto a reference panel would aid precision medicine and risk communication but is challenging due to the separation of technical and biological sources of variation with array data. Normalisation methods can standardize data distributions but may also remove population-level biological variation.MethodsWe compared two independent birth cohorts (Lothian Birth Cohorts of 1921 and 1936 – nLBC1921= 387 and nLBC1936= 498) with DNA methylation assessed at the same chronological age (79 years) and processed in the same lab but in different years and experimental batches. We examined the effect of 15 normalisation methods on a BMI EpiScore (trained in an external cohort of 18,413 individuals) when the cohorts were normalised separately and together.ResultsThe BMI EpiScore explained a maximum variance of R2=24.5% in BMI in LBC1936 after SWAN normalisation. Although there were differences in the variance explained across cohorts, the normalisation methods made minimal differences to the estimates within cohorts. Conversely, a range of absolute differences were seen for individual-level EpiScore estimates when cohorts were normalised separately versus together. While within-array methods result in identical BMI EpiScores whether a cohort was normalised on its own or together with the second dataset, a range of differences were observed for between-array methods.ConclusionsUsing normalisation methods that give similar EpiScores whether cohorts are analysed separately or together will minimise technical variation when projecting new data onto a reference panel. These methods are especially important for cases where when raw data and joint normalisation of cohorts is not possible or is computationally expensive.
Selective Aurora A-TPX2 interaction inhibitors havein vivoefficacy as targeted anti-mitotic agents
Authors: Stockwell Simon R. , Scott Duncan E. , Fischer Gerhard , Guarino Estrella , Rooney Timothy P. C. , Feng Tzu-Shean , Moschetti Tommaso , Srinivasan Rajavel , Alza Esther , Asteian Alice , Dagostin Claudio , Alcaide Anna , Rocaboy Mathieu , Blaszczyk Beata , Higueruelo Alicia , Wang Xuelu , Rossmann Maxim , Perrior Trevor R. , Blundell Tom L. , Spring David R. , McKenzie Grahame , Abell Chris , Skidmore John , Venkitaraman Ashok R. , Hyvönen Marko 
Published: March 2023

AbstractThe protein kinase Aurora A, and its close relative, Aurora B, regulate human cell division. Aurora A is frequently overexpressed in cancers of the breast, ovary, pancreas and blood, provoking genome instability and resistance to anti-mitotic chemotherapy. Intracellular localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. Here, we have used fragment-based, structure-guided lead discovery to develop small-molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). These compounds act by novel mechanism compared to existing Aurora A inhibitors and they are highly specific to Aurora A over Aurora B. Our biophysically, structurally and phenotypically validated lead compound,CAM2602, exhibits oral bioavailability, favourable pharmacokinetics, pharmacodynamic biomarker modulation, and arrest of growth in tumour xenografts. Consistent with our original finding that Aurora A overexpression drives taxane-resistance in cancer cells, inhibition of Aurora A-TPX2 PPI synergizes with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.
Transcriptomic contributions to a modern cytoarchitectonic parcellation of the human cerebral cortex
Authors: King Leana , Weiner Kevin S. 
Published: March 2023

AbstractTranscriptomic contributions to the anatomical, functional, and network layout of the human cerebral cortex (HCC) has become a major interest in cognitive and systems neuroscience. Here, we tested if transcriptomic differences support a modern, algorithmic cytoarchitectonic parcellation of HCC. Using a data-driven approach, we identified a sparse subset of genes that differentially contributed to the cytoarchitectonic parcellation of HCC. A novel metric (cortical thickness/myelination ratio; CT/M ratio), as well as cell density, correlated with gene expression. Enrichment analyses showed that genes specific to the cytoarchitectonic parcellation of the HCC were related to molecular functions such as transmembrane transport and ion channel activity. Together, the novel relationship between transcriptomics and the CT/M ratio bridges the gap among i) gradients at the macroscale, ii) areas at the meso-scale, and iii) cell density at the microscale, as well as supports the recently proposed cortical spectrum theory.
Individual thalamic inhibitory interneurons are functionally specialized towards distinct visual features
Authors: Müllner Fiona E. , Roska Botond 
Published: March 2023

ABSTRACTInhibitory interneurons in the dorsolateral geniculate nucleus (dLGN) are situated at the first central synapse of the image-forming visual pathway but little is known about their function. Given their anatomy, they are expected to be multiplexors, integrating many different retinal channels along their dendrites. Here, using targeted single-cell-initiated rabies tracing, we found that mouse dLGN interneurons exhibit a degree of retinal input specialization similar to thalamocortical neurons. Some are anatomically highly specialized, for example, towards direction-selective information. Two-photon calcium imaging performedin vivorevealed that interneurons are also functionally specialized. In mice lacking retinal horizontal direction selectivity, horizontal direction selectivity is reduced in interneurons, suggesting a causal link between input and functional specialization. Functional specialization is not only present at interneuron somata, but also extends into their dendrites. Altogether, each inhibitory interneuron globally encodes one visual feature originating mostly in the retina and is ideally suited to perform feature-selective inhibition.
Homocysteine Metabolites Inhibit Autophagy and Elevate Amyloid Beta by Impairing Phf8/H4K20me1-dependent Epigenetic Regulation of mTOR in Cystathionine β-Synthase-Deficient Mice
Authors: Witucki Łukasz , Jakubowski Hieronim 
Published: March 2023

AbstractThe loss of cystathionine β-synthase (CBS), an important homocysteine (Hcy)-metabolizing enzyme or the loss of PHF8, an important histone demethylase participating in epigenetic regulation, causes severe mental retardation in humans. Similar neuropathies were also observed inCbs-/-andPhf8-/-mice. How CBS or PHF8 depletion can cause neuropathy was unknown. To answer this question, we examined a possible interaction between PHF8 and CBS usingCbs-/-mouse and neuroblastoma cell models. We quantified gene expression by RT-qPCR and Western blotting, mTOR-bound H4K20me1 by chromatin immunoprecipitation (CHIP) assay, and amyloid β (Aβ) by confocal fluorescence microscopy using anti-Aβ antibody. We found significantly reduced expression of Phf8, increased H4K20me1, increased mTOR expression and phosphorylation, and increased App, both on protein and mRNA levels in brains ofCbs-/-micevs. Cbs+/-sibling controls. Autophagy-related proteins Becn1, Atg5, and Atg7 were downregulated while p62 was upregulated on protein and mRNA levels, suggesting impaired autophagy inCbs-/-brains. In mouse neuroblastoma N2a or N2a-APPswe cells, treatments with Hcy-thiolactone,N-Hcy-protein or Hcy, orCbsgene silencing by RNA interference significantly reduced Phf8 expression and increased total H4K20me1 as well as mTOR promoter-bound H4K20me1. This led to transcriptional mTOR upregulation, autophagy downregulation, and significantly increased App and Aβ levels. ThePhf8gene silencing increased Aβ, but not App, levels. Taken together, our findings identify Phf8 as a regulator of Aβ synthesis and suggest that neuropathy of Cbs deficiency is mediated by Hcy metabolites, which transcriptionally dysregulate the Phf8->H4K20me1->mTOR->autophagy pathway thereby increasing Aβ accumulation.
Protective role of protease-activated receptor-2 in anaphylaxis model mice
Authors: Nakazawa Maho , Tochinai Ryota , Fujii Wataru , Yonezawa Tomohiro , Momoi Yasuyuki , Maeda Shingo 
Published: March 2023

AbstractAnaphylaxis is a severe life-threatening hypersensitivity reaction induced by mast cell degranulation. Among the various mediators of mast cells, little is known about the role of tryptase. Therefore, we aimed to elucidate the role of protease-activating receptor-2 (PAR-2), a receptor activated by tryptase, in murine anaphylactic models using PAR-2-deficient mice and newly generated tryptase-deficient mice. Anaphylaxis was induced by IgE-dependent and IgE-independent mast cell degranulation in mice. PAR-2 deficiency exacerbated the decrease in body temperature and hypotension during anaphylaxis; however, the number of skin mast cells, degree of mast cell degranulation, and systemic and local vascular hyperpermeability were comparable in PAR-2 knockout and wild-type mice. Nitric oxide, which is produced by endothelial nitric oxide synthase (eNOS), is an indispensable vasodilator in anaphylaxis. In the lungs of anaphylactic mice, PAR-2 deficiency promoted eNOS expression and phosphorylation, suggesting a protective effect of PAR-2 against anaphylaxis by downregulating eNOS activation and expression. Based on the hypothesis that the ligand for PAR-2 in anaphylaxis is mast cell tryptase, tryptase-deficient mice were generated using CRISPR-Cas9. In wild-type mice, the PAR-2 antagonist exacerbated the body temperature drop due to anaphylaxis; however, the effect of the PAR-2 antagonist was abolished in tryptase-deficient mice. These results suggest that tryptase is a possible ligand of PAR-2 in anaphylaxis and that the tryptase/PAR-2 pathway attenuates the anaphylactic response in mice.