bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pooled PPIseq: screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform
Authors: Miller Darach , Dziulko Adam , Levy Sasha 
Published: February 2024

AbstractProtein-ProteinInteractions (PPIs) are a key interface between virus and host, and these interactions are important to both viral reprogramming of the host and to host restriction of viral infection. In particular, viral-host PPI networks can be used to further our understanding of the molecular mechanisms of tissue specificity, host range, and virulence. At higher scales, viral-host PPI screening could also be used to screen for small-molecule antivirals that interfere with essential viral-host interactions, or to explore how the PPI networks between interacting viral and host genomes co-evolve. Current high-throughput PPI assays have screened entire viral-host PPI networks. However, these studies are time consuming, often require specialized equipment, and are difficult to further scale. Here, we develop methods that make larger-scale viral-host PPI screening more accessible. This approach combines the mDHFR split-tag reporter with the iSeq2 interaction-barcoding system to permit massively-multiplexed PPI quantification by simple pooled engineering of barcoded constructs, integration of these constructs into budding yeast, and fitness measurements by pooled cell competitions and barcode-sequencing. We applied this method to screen for PPIs between SARS-CoV-2 proteins and human proteins, screening in triplicate >180,000 ORF-ORF combinations represented by >1,000,000 barcoded lineages. Our results complement previous screens by identifying 74 putative PPIs, including interactions between ORF7A with the taste receptors TAS2R41 and TAS2R7, and between NSP4 with the transmembrane KDELR2 and KDELR3. We show that this PPI screening method is highly scalable, enabling larger studies aimed at generating a broad understanding of how viral effector proteins converge on cellular targets to effect replication.
Current Research On Epigenetic Age and Cellular Senescence: A Bibliometric and Visual Analysis
Authors: Mureti kahaer M.M , Wang Hao B.M , Zhi-Guo Sun M.M , Kuo Xu M.M , Dilimulati Aikeremu M.M 
Published: February 2024

ABSTRACTThe aim of this study is to summarize and visualize the current state of research on epigenetic age and cellular senescence over the last two decades using bibliometric methods and to explore the current research priorities and future development directions. Relevant literature on the topic Epigenetic age and cellular senescence data published between January 2000 and January 2024 were searched in the Web of Science core database and three bibliometric mapping tools (Biblimetrix R Package, VOS Viewer and CiteSpace) were used to provide an overview of the Literature to give and analyze keywords, the co-occurrence of reference citations, authors and institutions, to analyze the current status of epigenetic aging research and hot changes in recent years. A total of 2,193 relevant studies were included, and the co-occurrence network identified seven clusters of associations between epigenetic age and cellular senescence, including effects on human tissues, genetic clock analyses, the relationship of age-related diseases, precise genetic changes and accelerated cellular senescence, localized cellular transformations, and genetic immune regulation. The analysis shows that research in this area has shifted from disease-level studies to mechanism-based studies, with cancer being the main disease and the main pathogenic mechanism being related to DNA methylation. The research direction in recent years has focused on the mechanism study of epigenetic age and cellular senescence as well as target therapy. The bibliometric and visualization analyzes provide a comprehensive understanding of the research progress and the role between epigenetic age and human cellular senescence and enrich the review literature in this field.
Structure, function and assembly of soybean primary cell wall cellulose synthases
Authors: Ho Ruoya , Purushotham Pallinti , Wilson Louis F. L. , Wan Yueping , Zimmer Jochen 
Published: February 2024

AbstractPlant cell walls contain a meshwork of cellulose fibers embedded into a matrix of other carbohydrate and non-carbohydrate-based biopolymers. This composite material exhibits extraordinary properties, from stretchable and pliable cell boundaries to solid protective shells. Cellulose, a linear glucose polymer, is synthesized and secreted across the plasma membrane by cellulose synthase (CesA), of which plants express multiple isoforms. Different subsets of CesA isoforms are necessary for primary and secondary cell wall biogenesis. Here, we structurally and functionally characterize theGlycine max(soybean) primary cell wall CesAs CesA1, CesA3, and CesA6. The CesA isoforms exhibit robustin vitrocatalytic activity. Cryo-electron microscopy analyses reveal their assembly into homotrimeric complexesin vitroin which each CesA protomer forms a cellulose-conducting transmembrane channel with a large lateral opening. Biochemical and co-purification analyses demonstrate that different CesA isoforms interactin vitro, leading to synergistic cellulose biosynthesis. Interactions between CesA trimers are only observed between different CesA isoforms and require the class-specific region (CSR). The CSR forms a hook-shaped extension of CesA’s catalytic domain at the cytosolic water-lipid interface. Negative stain and cryo-electron microscopy analyses of mixtures of different CesA isoform trimers reveal their side-by-side arrangement into loose clusters. Our data suggest a model by which CesA homotrimers of different isoforms assemble into cellulose synthase complexes to synthesize and secrete multiple cellulose chains for microfibril formation. Inter-trimer interactions are mediated by fuzzy interactions between their CSR extension.
Development of subunit selective proteasome substrates forSchistosoma species
Authors: Jiang Zhenze , Silva Elany B. , Liu Chenxi , Fajtová Pavla , Liu Lawrence J. , El-Sakkary Nelly , Skinner Danielle E. , Syed Ali , Wang Steven C , Caffrey Conor R. , O’Donoghue Anthony J. 
Published: February 2024

AbstractSchistosomiasis, or bilharzia, is a neglected tropical disease caused bySchistosomaspp. blood flukes that infects over 200 million people worldwide. Just one partially effective drug is available, and new drugs and drug targets would be welcome. The 20S proteasome is a validated drug target for many parasitic infections, including those caused byPlasmodiumandLeishmania. We previously showed that anticancer proteasome inhibitors that act through theSchistosoma mansoni20S proteasome (Sm20S) kill the parasitein vitro. To advance these initial findings, we employed Multiplex Substrate Profiling by Mass Spectrometry (MSP-MS) to define the substrate cleavage specificities of the three catalytic β subunits of purified Sm20S. The profiles in turn were used to design and synthesize subunit-specific optimized substrates that performed two to eight fold better than the equivalent substrates used to measure the activity of the constitutive human proteasome (c20S). These specific substrates also eliminated the need to purify Sm20S from parasite extracts - a single step enrichment was sufficient to accurately measure substrate hydrolysis and its inhibition with proteasome inhibitors. Finally, we show that the substrate and inhibition profiles for the 20S proteasome from the three medically important schistosome species are similar, suggesting that data arising from an inhibitor development campaign that focuses on Sm20S can be extrapolated to the other two targets with consequent time and cost savings.
Herbarium specimens reveal links betweenCapsella bursa-pastorisleaf shape and climate
Authors: Hightower Asia T , Chitwood Daniel H , Josephs Emily B 
Published: February 2024

SummaryStudies into the evolution and development of leaf shape have connected variation in plant form, function, and fitness. For species with consistent leaf margin features, patterns in leaf architecture are related to both biotic and abiotic factors. However, for species with inconsistent leaf margin features, quantifying leaf shape variation and the effects of environmental factors on leaf shape has proven challenging.To investigate leaf shape variation in species with inconsistent shapes, we analyzed approxi-mately 500 digitizedCapsella bursa-pastorisspecimens collected throughout the continental U.S. over a 100-year period with geometric morphometric modeling and deterministic techniques. We generated a morphospace ofC. bursa-pastorisleaf shapes and modeled leaf shape as a function of environment and time.Our results suggestC. bursa-pastorisleaf shape variation is strongly associated with temperature over theC. bursa-pastorisgrowing season, with lobing decreasing as temperature increases. While we expected to see changes in variation over time, our results show that level of leaf shape variation is consistent over the 100-year period.Our findings showed that species with inconsistent leaf shape variation can be quantified using geometric morphometric modeling techniques and that temperature is the main environmental factor influencing leaf shape variation.
Fraudulent studies are undermining the reliability of systematic reviews – a study of the prevalence of problematic images in preclinical studies of depression
Authors: Berrío Jenny P. , Kalliokoski Otto 
Published: February 2024

AbstractSystematic reviews are considered by many to constitute the highest level of scientific evidence. A caveat is that the methods used in a systematic review – combining information from multiple studies – are predicated on all of the reports being truthful. Currently, we do not know how frequent fraudulent studies are in systematic reviews, or how they affect the resulting evidence base. For a systematic review of preclinical studies of depression, we found that potentially fraudulent studies were not only common but also that they biased the findings of the review. In a sample of 1,035 studies, we found that 19 % of peer-reviewed reports displayed data in the form of problematic images. In a majority of the cases, images had been altered or recycled in a way that makes us suspect foul play. Making things worse, these studies reported larger effect sizes, on average, than did studies where we did not identify problems. Counter to commonly held beliefs, reports with problematic images were not cited less or published in lower-impact journals, nor were their authors isolated to any specific geographic area. The sheer prevalence of problematic studies, and the fact that we could not find a simple pattern for identifying them, undermines the validity of systematic reviews within our research field. We suspect that this is symptomatic of a broader problem that needs immediate addressing.
Angiogenin regulates mitochondrial stress and function via tRNA-derived fragments generation and impacting tRNA modifications
Authors: Al-Mesitef Shadi , Tominaga Keita , Mousa Abdulrahman , Begley Thomas J , Dedon Peter C , Rashad Sherif , Niizuma Kuniyasu 
Published: February 2024

AbstractMitochondrial stress and dysfunction play an important role in many diseases, such as cancer, diabetes, and neurodegenerative diseases. We previously observed that mitochondrial electron transport chain (ETC) inhibition can induce tRNA cleavage and tsRNAs (tRNA-derived small non-coding RNAs) generation. However, whether this process is mediated via Angiogenin (ANG), the canonical enzyme responsible for tRNA cleavage, and whether it has a role in regulating the mitochondrial stress response remains to be understood. ANG is linked to Amyotrophic Lateral Sclerosis (ALS) and other conditions where mitochondrial stress plays a role in pathophysiology. Here, we aimed to examine the role of ANG in regulating the translational response to mitochondrial stress. We observed that ANG protected the cells from respiratory complex III and V inhibition specifically. Furthermore, we validated that the tsRNAs generated during mitochondrial and oxidative stress are mediated by ANG, given that their production is abrogated after ANG knock-out (KO). In addition, we observed that ANG-KO altered the tRNA modification status. Namely, we observed that ANG-KO led to the downregulation of queuosine tRNA modifications (tRNA-Q). tRNA-Q itself is related to mitochondrial translation and function. Indeed, we observed that ANG-KO led to reduced mitochondrial respiration and function. ANG altered how the cells respond to mitochondrial stress by altering the dynamic tRNA modification changes occurring during the stress response. We further examined the impact of ANG-KO on stress granules (SG) assembly as well as the knockdown of G3BP1 (core protein of SGs) on tsRNAs generation. Our results indicate that ANG regulates mitochondrial function and stress via tsRNAs generation as well as altering tRNA modifications levels. Our data also indicate that there are no direct links between tRNA cleavage and SG assembly, and both could be parallel systems for translation repression during stress.
Inflammatory bowel disease and risk of more than 1500 comorbidities: A disease-wide pre- and post-diagnostic phenomic association study
Authors: Ebert Anthony C , Elmahdi Rahma , Verstockt Bram , Bøgsted Martin , Poulsen Gry , Sazonovs Aleksejs , Lees Charlie W , Jess Tine 
Published: February 2024

ABSTRACTIntroductionInflammatory bowel disease (IBD) is associated with various extra-intestinal manifestations. We aim to identify comorbidities in IBD and the timing of their development to provide valuable insight into the mechanisms under-lying IBD.MethodsWe conducted a population– and disease-wide phenomic association study in IBD, using>6 million ICD-10 coded healthcare contacts from 10 years before and up-to 17 years after IBD diagnosis to investigate associations with 1583 comorbidities. To explore diseases with potential aetiological significance, we compared association in the pre-diagnostic and the post-diagnostic periods. We corrected also for multiple-testing. These estimates were validated with publically available data from Finland.ResultsWe identified 312 significant associations with 125 appearing before diagnosis. Risk of immune-mediated diseases and extra-intestinal manifestations was increased up to 10 years prior to IBD diagnosis, such as psoriasis (ORCD: 2.58 95% CI: [2.00-3.31]; ORUC: 1.54 [1.26-1.88]) and reactive arthropathies (ORCD: 2.07 [1.42-2.96]; ORUC: 1.42 [1.08-1.84]). Risk of cardiometabolic and neuropsychological disorders was increased both pre– and post-diagnostically. Potential treatment sequelae, such as osteoporosis (HRCD: 2.56 [2.30-2.86]; HRUC: 1.92 [1.79-2.07]) were primarily seen post-diagnostically. In only 15.7% (44/281) and 11.4% (35/301) of comorbidities in CD and UC respectively did we observe heterogeneity between Denmark and Finland.ConclusionFindings demonstrate that IBD is a multisystemic disease, particularly manifesting with metabolic, im-mune, and neuropsychological disorders, up-to 10 years prior to diagnosis. We find evidence for the generality of these findings with an international comparison. Diseases of etiological interest warrant further investigation.STUDY HIGHLIGHTSWHAT IS KNOWNIBD is strongly associated with other diseasesIBD has a complex etiologyWHAT IS NEW HEREIBD appears to be a multiorgan systemic disease not confined to the gutAssociations between IBD and non-digestive disorders are present up to 10 years prior to diagnosis either reflecting a prolonged pre-diagnostic phase or common etiologiesThese findings are validated in an international comparison
Anti-inflammatory effects of oral prednisolone at stable state in people treated with mepolizumab: a proteomic and bulk transcriptomics analysis
Authors: Howell I. , Yang F. , Brown V. , Cane J. , Marchi E. , Azim A , Busby J. , McDowell P.J. , Diver S.E. , Borg C. , Heaney L. G. , Pavord I. D. , Brightling C. E. , Chaudhuri R. , Hinks T.S.C. 
Published: February 2024

AbstractMepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids have broad anti-inflammatory effects and remain the main treatment for these residual exacerbations. Our study aimed to explore the nature and corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms.The MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in patients treated with mepolizumab for SEA. We analysed sputum and plasma samples from the MAPLE trial using high-throughput Olink® proteomics. We also analysed plasma microRNA, sputum proteins using ELISA, and nasal mucosal bulk RNA sequencing.In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Tissue repair and neutrophilic pathways were upregulated. Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated. In the nasal transcriptome, prednisolone suppressed genes involved in leucocyte chemotaxis, mast cell tryptase, 15-lipoxygenase andMMP12. By contrast, mepolizumab differentially regulated only Galectin-10 in plasma and no sputum proteins, and in nasal tissue affected genes related to cilia, keratinisation, extracellular matrix formation, and IL-4/13 signalling.At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab.Graphical abstract
Perceptions of Complementary, Alternative, and Integrative Medicine Among Neurology Researchers and Clinicians: A Large-Scale, International Cross-Sectional Survey
Authors: Ng Jeremy Y. , Li Stephanie Y. , Cramer Holger 
Published: February 2024

AbstractBackgroundWhile many patients with neurological disorders and conditions use complementary, alternative, and integrative medicine (CAIM), little is known about the use and perceptions of CAIM among neurology researchers and clinicians. With the increasing popularity of CAIM, our objective was to assess practices, perceptions, and attitudes towards CAIM among neurology researchers and clinicians.MethodsWe conducted an anonymous online survey of authors who had published articles in neurology journals indexed in MEDLINE. We emailed potential participants our cross-sectional electronic survey after extracting their email addresses from one of their publications in our sample of journals. Basic descriptive statistics were drawn from quantitative data, and thematic content analysis was used to analyse qualitative data from any open-ended questions.ResultsThe survey was completed by 783 neurology researchers and/or clinicians (1.5% response rate, 83.9% completion rate). Overall, respondents perceived CAIM to be promising in preventing, treating, and/or managing neurological diseases. Mind-body therapies received the most positive responses, indicated by over half of respondents cumulatively agreeing that they are promising (n=368, 59.0%) and safe (n=280, 50.3%). Whole medical systems and biofield therapy were less favourable. Most neurology clinicians reported a lack of formal (n=211, 70.3%) and supplementary training (n=158, 52.5%) on CAIM. Nearly half of clinicians did not feel comfortable counselling patients about CAIM (n = 121, 44.5%), and over half did not feel comfortable recommending it (n=161, 59.3%). A lack of scientific evidence for CAIM’s safety and efficacy was reported as the greatest challenge to CAIM (n=515, 92.5%). The majority of respondents believed there is value to conducting research on this topic (n=461, 82.0%) and supported increasing allocation of research funding towards CAIM (n=241, 58.9%).ConclusionsAlthough many participants found CAIM to be promising to the field of neurology, the vast majority did not feel open to integrating CAIM into mainstream medical practices on account of a perceived lack of scientific evidence for its safety and efficacy. Future studies can use our findings to improve educational resources on CAIM within neurology, as well as examine what effects a tailored CAIM education has on the perceptions of neurology researchers and clinicians.
Shifting to biology promotes highly efficient iron removal in groundwater filters
Authors: Müller Simon , Corbera-Rubio Francesc , Schoonenberg-Kegel Frank , Laureni Michele , van Loosdrecht Mark C.M. , van Halem Doris 
Published: February 2024

AbstractRapid sand filters are established and widely applied technologies for groundwater treatment. Conventionally, intensive aeration is employed to provide oxygen for the oxidation and removal of the main groundwater contaminants. While effective, intensive aeration promotes flocculent iron removal, which results in iron flocs that rapidly clog the filter. In this study, we operated two parallel full-scale sand filters at different aeration intensities to resolve the relative contribution of homogeneous, heterogeneous and biological iron removal pathways, and identify their operational controls. Our results show that mild aeration in the LOW filter (5 mg/L O2pH 6.9) promoted biological iron removal and enabled iron oxidation at twice the rate compared to the intensively aerated HIGH filter (>10mg/L O2,pH 7.4). ESEM images showed distinctive twisted stalk-like Fe solids, biosignatures ofGallionella ferruginea, both in the LOW filter sand coatings as well as in its backwash solids. In accordance, 10 times higher DNA copy numbers ofG. ferrugineawere found in the LOW filter effluent. Clogging by biogenic FeOx was slower than by chemical FeOx flocs, resulting in lower backwash frequencies and yielding four times more water per run. Ultimately, our results reveal that biological Fe2+oxidation can be actively controlled and favoured over competing physico-chemical routes. The resulting operational benefits are only starting to be appreciated, with the counterintuitive higher oxidation rates and water yields at lower aeration regimes, and the production of more compact and practically valuable FeOx solids being of outmost interest.