bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural and Functional Characterization of the Aorta in Hypertrophic Obstructive Cardiomyopathy
Authors: Ibrahim AM. , Latif N. , Roshdy M. , Sarathchandra P. , Hosny M. , Elsawy A. , Hekal S. , Attia A. , Elmozy W. , Elaithy A. , Elguindy A. , Afifi A. , Aguib Y. , Yacoub M. 
Published: May 2023

AbstractBackground and aimsChanges in the phenotype and genotype in Hypertrophic Obstructive Cardiomyopathy (HOCM) are thought to involve the myocardium as well as extracardiac tissues. The extent and significance of extra-myocardial changes has not been adequately studied. We here describe the structural and functional changes in the ascending aorta of HOCM patients.MethodsChanges in the aortic wall were studied in a cohort of 102 consecutive HOCM patients undergoing myectomy, and 10 normal controls. Biopsies were examined histologically, immunohistochemically and by electron microscopy. Changes in protein expression were quantified using morphometry and western blotting. Pulse wave velocity (PWV) was measured using Cardiac Magnetic Resonance (CMR), in 86 HCM patients compared to 166 age-matched normal controls.ResultsIn HCM, the number of medial lamellar units (MLU) was significantly decreased, associated with an increase in the interlamellar distance and a preserved thickness of the aortic wall, as compared to controls. Electron microscopy showed an altered lamellar structure with disorientation of elastin fibers from the circumferential direction. There was an altered composition and orientation of smooth muscle cells. In addition, there was a significant decrease in alpha-smooth muscle actin, smooth muscle myosin, smooth muscle 22 and integrin beta1, and a significant increase in calponin and caspase3. Fibulins 1, 2 and 5, had a reduced expression in HOCM aortic biopsies. Functionally, PWV was significantly higher in HOCM patients compared to healthy controls.ConclusionIn HOCM patients, specific molecular and structural changes in the composition and organisation of the arterial wall have been identified. This was associated with increased stiffness of the arterial wall.Translational PerspectiveThis study sheds light for the first time on the altered lamellar organization in the aorta of Hypertrophic Obstructive Cardiomyopathy (HOCM), in addition to the Smooth muscle cells and Extracellular Matrix abnormalities, to explain the increased wall stiffness associated with patients clinical phenotype. The data provide insights on extra-myocardial targets that can have potential value for risk stratification and personalized therapeutics for HOCM patients.
A pilot clinical study to estimate intracranial pressure utilising cerebral photoplethysmograms in traumatic brain injury patients
Authors: Roldan Maria , Abay Tomas Ysehak , Uff Christopher , Kyriacou Panayiotis A. 
Published: May 2023

AbstractObjectiveIn this research a non-invasive ICP optical sensor has been developed and evaluated in a clinical pilot study. The technology is based on infrared light interrogating brain tissue, including photodetectors used to detect the backscattered light, which is modulated by vascular pulsations in the brain vascular tissue. The hypothesis underpinning this research is based on the expected changes in the extramural arterial pressure affecting the morphology of the recorded optical signals (photoplethysmograms (PPGs)), therefore analysis of the acquired signals using a bespoke algorithm could enable the calculation of the intracranial pressure non-invasively (nICP).MethodsThis pilot study is the first evaluation of the nICP probe in patients in whom the gold standard comparator of invasive ICP was available. nICP monitoring was performed for up to 48 hours in each of the 40 patients undergoing invasive ICP monitoring as part of their prescribed medical treatment. The quality of the recorded PPG signals was analysed, and time-based features were extracted off-line. Data from all ICP levels were randomly allocated into two groups to train (80%) and test (20%) a machine learning algorithm. A Bland Altman analysis and ROC curve were calculated to evaluate the accuracy of the estimated nICP value compared to the gold standard of synchronously acquired invasive ICP data.ResultsThe successful acquisition of cerebral PPG signals from TBI patients for the subsequent extraction of morphological features allowed the generation of a bagging tree model to estimate ICP non-invasively. The non-invasive estimation of ICP was achieved with 95% limits of agreement of 3.8 mmHg and a negligible bias. Furthermore, the model achieved a good correlation coefficient of 82.54% compared to standard clinical invasive ICP monitoring. Finally, the ROC curve analysis showed good diagnostic capability with a sensitivity of 80% and specificity of 89%.ConclusionClinical evaluation of this novel optical nICP sensor demonstrated for the first time that it could estimate ICP non-invasively to an acceptable and clinically useful accuracy and paves the way for further technology optimisation and larger clinical studies.
Interhelical E@g-N@aInteractions Modulate Coiled Coil Stability within aDe NovoSet of Orthogonal Peptide Heterodimers
Authors: Perez Anthony R. , Lee Yumie , Colvin Michael E. , Merg Andrea D. 
Published: May 2023

AbstractThe designability of orthogonal coiled coil (CC) dimers, which draw on well-established design rules, plays a pivotal role in fueling the development of CCs as synthetically versatile assembly-directing motifs for the fabrication of bionanomaterials. Here, we aim to expand the synthetic CC toolkit through establishing a “minimalistic” set of orthogonal,de novoCC peptides that comprise 3.5 heptads in length and a single buried Asn to prescribe dimer formation. The designed sequences display excellent partner fidelity, confirmed via circular dichroism (CD) spectroscopy, and are corroboratedin silicousing molecular dynamics (MD) simulation. Detailed analysis of the MD conformational data highlights the importance of interhelical E@g-N@ainteractions in coordinating an extensive 6-residue hydrogen bonding network that “locks” the interchain Asn-Asn’ contact in place. The enhanced stability imparted to the Asn-Asn’ bond elicits an increase in thermal stability of CCs up to ∼15°C and accounts for significant differences in stability within the collection of similarly designed orthogonal CC pairs. The presented work underlines the utility of MD simulation as a tool for constructingde novo, orthogonal CCs, and presents an alternative handle for modulating the stability of orthogonal CCs via tuning the number of interhelical E@g-N@acontacts. Expansion of CC design rules is a key ingredient for guiding the design and assembly of more complex, intricate CC-based architectures for tackling a variety of challenges within the fields of nanomedicine and bionanotechnology.
Functional and metagenomic level diversities of human gut symbiont-derived glycolipids
Authors: Yoo Ji-Sun , Goh Byoungsook , Heo Kyoo , Jung Da-Jung , Zheng Wen , Lee ChangWon C. , Geva-Zatorsky Naama , Wu Meng , Park Seung Bum , Kasper Dennis L. , Oh Sungwhan F. 
Published: May 2023

SummaryBioactive metabolites produced by symbiotic microbiota causally impact host health and disease, nonetheless, incomplete functional annotation of genes as well as complexities and dynamic nature of microbiota make understanding species-level contribution in production and actions difficult. Alpha-galactosylceramides produced byBacteroides fragilis(BfaGC) are one of the first modulators of colonic immune development, but biosynthetic pathways and the significance of the single species in the symbiont community still remained elusive.To address these questions at the microbiota level, we have investigated the lipidomic profiles of prominent gut symbionts and the metagenome-level landscape of responsible gene signatures in the human gut. We first elucidated the chemical diversity of sphingolipid biosynthesis pathways of major bacterial species. In addition to commonly shared ceramide backbone synthases showing two distinct intermediates, alpha-galactosyltransferase (agcT), the necessary and sufficient component for BfaGC production and host colonic type I natural killer T (NKT) cell regulation byB. fragilis,was characterized by forward-genetics based targeted metabolomic screenings. Phylogenetic analysis of agcT in human gut symbionts revealed that only a few ceramide producers have agcT and hence can produce aGCs, on the other hand, structurally conserved homologues of agcT are widely distributed among species lacking ceramides. Among them, alpha-glucosyl-diacylglycerol(aGlcDAG)-producing glycosyltransferases with conserved GT4-GT1 domains are one of the most prominent homologs in gut microbiota, represented byEnterococcus bgsB. Of interest, aGlcDAGs produced by bgsB can antagonize BfaGC-mediated activation of NKT cells, showing the opposite, lipid structure-specific actions to regulate host immune responses. Further metagenomic analysis of multiple human cohorts uncovered that theagcTgene signature is almost exclusively contributed byB. fragilis, regardless of age, geographical and health status, where thebgsBsignature is contributed by >100 species, of which abundance of individual microbes is highly variable. Our results collectively showcase the diversities of gut microbiota producing biologically relevant metabolites in multiple layers-biosynthetic pathways, host immunomodulatory functions and microbiome-level landscapes in the host.
Ferroptosis induced by phenolic compound-iron complex
Authors: Sui Xinyue , Wang Jichao , Zhao Zhiqiang , Liu Bin , Liu Miaomiao , Liu Min , Shi Cong , Feng Xinjun , Fu Yingxin , Shi Dayong , Li Shengying , Qi Qingsheng , Xian Mo , Zhao Guang 
Published: May 2023

AbstractPhenolic compounds are the most ubiquitously distributed pollutants, and are highly toxic to living organisms, however the detailed mechanism how phenols exert toxic effects remains elusive. Here,Escherichia coliand phloroglucinol are adapted as proxy to elucidate the molecular mechanism of phenols’ toxicity. We demonstrated that phloroglucinol complexed with iron and promoted the generation of hydroxyl radicals in Fenton reaction, leading to reducing power depletion and lipid peroxidation, and further leading to ferroptosis-like cell death ofE. coli. This ferroptotic death can be triggered by various phenols in diverse organisms, from bacteria to mammalian cells. Furthermore, we demonstrated that phloroglucinol-induced ferroptosis suppressed tumor growth in mice effectively, indicating phloroglucinol as promising drug for therapy-resistant cancers. It’s also discovered that repression of this ferroptosis-like cell death benefited microbial degradation or production of desired phenolic compounds, showing great application potential in biotechnology field.
Cardiomyocyte-restricted expression of IL11 causes cardiac fibrosis, inflammation, and dysfunction
Authors: Sweeney Mark , O’Fee Katie , Villanueva-Hayes Chelsie , Rahman Ekhlas , Lee Michael , Vanezis Konstantinos , Andrew Ivan , Lim Wei-Wen , Widjaja Anissa , Barton Paul JR , Cook Stuart A 
Published: May 2023

AbstractBackground: Cardiac fibrosis is a common pathological process in heart disease and represents a therapeutic target. TGFβ is the canonical driver of cardiac fibrosis and was recently shown to be dependent on IL11 for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and also anti- inflammatory in the mouse heart. Objectives: In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. Methods: We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murineIl11expression. Using protein assays, bulk RNA-sequencing, andin vivoimaging we analysed the effects of IL11 on myocardial fibrosis, inflammation and cardiac function and challenge previous reports suggesting cardioprotective potential of IL11. Results: TGFβ stimulation of cardiomyocytes causedIl11upregulation. As compared to wild-type controls,Il11expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors and increased inflammatory cells. IL11 expression also activated a programme of endothelial-to- mesenchymal transition and resulted in left ventricular dysfunction. Conclusion: Our data define species matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.
Exploring the Chain Release Mechanism from an Atypical Apicomplexan Polyketide Synthase
Authors: Keeler Aaron M. , Petruzziello Porter E. , Boger Elizabeth G. , D’Ambrosio Hannah K. , Derbyshire Emily R. 
Published: May 2023

ABSTRACTPolyketide synthases (PKSs) are megaenzymes that form chemically diverse polyketides and are found within the genomes of nearly all classes of life. We recently discovered the type I PKS from the apicomplexan parasiteToxoplasma gondii, TgPKS2, which contains a unique putative chain release mechanism that includes ketosynthase (KS) and thioester reductase (TR) domains. Our bioinformatic analysis of the thioester reductase ofTgPKS2,TgTR, suggests differences in putative apicomplexan reductase domains compared to other systems and hints at a possibly conserved release mechanism within the apicomplexan subclass Coccidia. To evaluate this release module, we first isolatedTgTR and observed that it is capable of 4 electron (4e-) reduction of octanoyl-CoA to the primary alcohol, octanol, utilizing NADH as a cofactor.TgTR was also capable of generating octanol in the presence of octanal and NADH, but no reactions were observed when NADPH was supplied as a cofactor. To biochemically characterize the protein, we measured the catalytic efficiency ofTgTR using a fluorescence assay and determined theTgTR binding affinity for cofactor and substrates using isothermal titration calorimetry (ITC). We additionally show thatTgTR is capable of reducing an acyl carrier protein (ACP)-tethered substrate by liquid chromatography mass spectrometry and determine thatTgTR binds to holo-TgACP4, its predicted cognate ACP, with aKDof 5.75 ± 0.77 µM. Finally, our transcriptional analysis shows thatTgPKS2 is upregulated ∼4-fold in the parasite’s cyst-forming bradyzoite stage compared to tachyzoites. Our study identifies features that distinguishTgPKS2 from well-characterized systems in bacteria and fungi, and suggests it aids theT. gondiicyst stage. Together, this work increases our knowledge of PKS thioester reductase domains and advances our understanding of unconventional polyketide chain termination mechanisms.
Mapping Niche-specific Two-Component System Requirements in UropathogenicEscherichia coli
Authors: Brannon John R. , Reasoner Seth A. , Bermudez Tomas A. , Dunigan Taryn L. , Wiebe Michelle A. , Beebout Connor J. , Ross Tamia , Bamidele Adebisi , Hadjifrangiskou Maria 
Published: May 2023

ABSTRACTSensory systems allow pathogens to differentiate between different niches and respond to stimuli within them. A major mechanism through which bacteria sense and respond to stimuli in their surroundings is two-component systems (TCSs). TCSs allow for the detection of multiple stimuli to lead to a highly controlled and rapid change in gene expression. Here, we provide a comprehensive list of TCSs important for the pathogenesis of uropathogenicEscherichia coli(UPEC). UPEC accounts for >75% of urinary tract infections (UTIs) worldwide. UTIs are most prevalent among people assigned female at birth, with the vagina becoming colonized by UPEC in addition to the gut and the bladder. In the bladder, adherence to the urothelium triggersE. coliinvasion of bladder cells and an intracellular pathogenic cascade. IntracellularE. coliare safely hidden from host neutrophils, competition from the microbiota, and antibiotics that kill extracellularE. coli.To survive in these intimately connected, yet physiologically diverse nichesE. colimust rapidly coordinate metabolic and virulence systems in response to the distinct stimuli encountered in each environment. We hypothesized that specific TCSs allow UPEC to sense these diverse environments encountered during infection with built-in redundant safeguards. Here, we created a library of isogenic TCS deletion mutants that we leveraged to map distinct TCS contributions to infection. We identify – for the first time – a comprehensive panel of UPEC TCSs that are critical for infection of the genitourinary tract and report that the TCSs mediating colonization of the bladder, kidneys, or vagina are distinct.IMPORTANCEWhile two-component system (TCS) signaling has been investigated at depth in model strains ofE. coli, there have been no studies to elucidate – at a systems level – which TCSs are important during infection by pathogenicEscherichia coli. Here, we report the generation of a markerless TCS deletion library in a uropathogenicE. coli(UPEC) isolate that can be leveraged for dissecting the role of TCS signaling in different aspects of pathogenesis. We use this library to demonstrate, for the first time in UPEC, that niche-specific colonization is guided by distinct TCS groups.
Long-range repression by ecdysone receptor on complex enhancers of the insulin receptor gene
Authors: Thompson Katie , Suber Will , Nicholas Rachel , Arnosti David N. 
Published: May 2023

AbstractThe insulin signaling pathway is evolutionarily conserved throughout metazoans, playing key roles in development, growth, and metabolism. Misregulation of this pathway is associated with a multitude of disease states including diabetes, cancer, and neurodegeneration. Genome-wide association studies indicate that natural variants in putative intronic regulatory elements of the human insulin receptor gene (INSR)are associated with metabolic conditions, however, this gene’s transcriptional regulation remains incompletely studied.INSRis widely expressed throughout development and was previously described as a ‘housekeeping’ gene. Yet, there is abundant evidence that this gene is expressed in a cell-type specific manner, with dynamic regulation in response to environmental signals. The Drosophila insulin-like receptor gene (InR) is homologous to the humanINSRgene and was previously shown to be regulated by multiple transcriptional elements located primarily within the introns of the gene. These elements were roughly defined in ∼1.5 kbp segments, but we lack an understanding of the potential detailed mechanisms of their regulation, as well as the integrative output of the battery of enhancers in the entire locus. Using luciferase assays, we characterized the substructure of these cis-regulatory elements in Drosophila S2 cells, focusing on regulation through the ecdysone receptor (EcR) and the dFOXO transcription factor. The direct action of EcR on Enhancer 2 reveals a bimodal form of regulation, with active repression in the absence of the ligand, and positive activation in the presence of 20E. By identifying the location of activators of this enhancer, we characterized a long-range of repression acting over at least 475 bp, similar to the action of long-range repressors found in the embryo. dFOXO and 20E have contrasting effects on some of the individual regulatory elements, and for the adjacent enhancers 2 and 3, their influence was/was not found to be additive, indicating that enhancer action on this locus can/cannot be characterized in part by additive models. Other characterized enhancers from within this locus exhibited “distributed” or “localized” modes of action, suggesting that predicting the joint functional output of multiple regulatory regions will require a deeper experimental characterization. The noncoding intronic regions ofInRhave demonstrated dynamic regulation of expression and cell type specificity. This complex transcriptional circuitry goes beyond the simple conception of a ‘housekeeping’ gene. Further studies are aimed at identifying how these elements work together in vivo to generate finely tuned expression in tissue- and temporal-specific manners, to provide a guide to understanding the impact of natural variation in this gene’s regulation, applicable to human genetic studies.
S1basic leucine zipper transcription factors shape plant architecture by controlling C/N partitioning to apical and lateral organs
Authors: Kreisz Philipp , Hellens Alicia M. , Fröschel Christian , Krischke Markus , Maag Daniel , Feil Regina , Wildenhain Theresa , Draken Jan , Braune Gabriel , Erdelitsch Leon , Cecchino Laura , Wagner Tobias C. , Mueller Martin J. , Becker Dirk , Lunn John E. , Hanson Johannes , Beveridge Christine A. , Fichtner Franziska , Barbier Francois F. , Weiste Christoph 
Published: May 2023

AbstractPlants exhibit an immense plasticity in their architecture. While the impact of hormonal regulation is well-characterised, the importance of sugar-signalling has just recently emerged. Here, we addressed which sugar-signalling components mediate the trade-off between growth of apical versus lateral meristems and how they control organ sink-strength. Thereby, we unravelled a novel developmental function of the sugar-controlled S1basic-leucine-zipper (S1-bZIP) transcription factors in establishing global source-sink interactions. Applying comprehensive molecular, analytical, and genetic approaches, we demonstrate that S1-bZIPs operate in a redundant manner to control tissue-specific expression of definedSWEETsugar-transporters and theGAT1_2.1glutaminase. By these means, S1-bZIPs control carbohydrate (C)-channelling from source leaves to apical shoot and root organs and tune systemic organic nitrogen (N)-supply to restrict lateral organ formation by C/N depletion. Knowledge of the underlying mechanisms controlling plant C/N partitioning is of pivotal importance for breeding strategies to generate plants with desired architectural and nutritional characteristics.
Genomic potential and evolution of Dissimilatory Nitrate Reduction to Ammonium in Cyanobacteria
Authors: Ray Manisha , Manu Shivakumara , Rastogi Gurdeep , Umapathy Govindhaswamy 
Published: May 2023

AbstractCyanobacteria play an important role in primary production and nitrogen fixation. Although Cyanobacteria are well-known diazotrophic organisms, their role in other steps Nitrogen Cycle is obscure. Screening of Cyanobacterial genomes from cultured and unculturable species can help identify potentially novel functions. In this study, we assembled Cyanobacterial genomes from metagenomic data generated from environmental DNA isolated from a brackish water lagoon (Chilika, India). We annotated these Cyanobacterial metagenome-assembled genomes (MAG) for all the encoded functions using KEGG Orthology. We found two high-quality Cyanobacterial MAGs containing thenirBDgene andnifHandnifDgenes involved in the nitrogen cycle.nirBDencodes for the Dissimilatory Nitrate Reduction to Ammonium (DNRA) activity, a function previously not ascribed to Cyanobacteria. We validated the presence of NirBD in publicly available isolate genomes of Cyanobacteria and examined its evolution in the phylum by phylogenetic reconciliation of species and gene trees. Our analysis revealed that both horizontal gene transfers and speciation events contributed to the dispersal of thenirBDgene in Cyanobacteria. We observed that mostly filamentous Cyanobacteria served as ancestral donors in horizontal gene transfer events. Further, we found that thenirBDgene is under a purifying selection pressure in Cyanobacteria. This study demonstrates the genomic potential and evolution of DNRA activity in Cyanobacteria for the utilisation of nitrate in the ecosystem which can help these organisms to cope with extreme environmental conditions. It expands our overall comprehension of the contribution of Cyanobacteria in the biogeochemical cycling in aquatic ecosystems.