bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding Molecular Links of Vascular Cognitive Impairment: Selective Interaction between Mutant APP, TP53, and MAPKs
Authors: Zeylan Melisa Ece , Senyuz Simge , Keskin Ozlem , Gursoy Attila 
Published: December 2023

AbstractVascular cognitive impairment (VCI) is an understudied cerebrovascular disease. As it can result in a significant amount of functional and cognitive disabilities, it is vital to reveal proteins related to it. Our study focuses on revealing proteins related to this complex disease by deciphering the crosstalk between cardiovascular and cognitive diseases. We build protein-protein interaction networks related to cardiovascular and cognitive diseases. After merging these networks, we analyze the network to extract the hub proteins and their interactors. We found the clusters on this network and built the structural protein-protein interaction network of the most connected cluster on the network. We analyzed the interactions of this network with molecular modeling via PRISM. PRISM predicted several interactions that can be novel in the context of VCI-related interactions. Two mutant forms of APP (V715M and L723P), previously not connected to VCI, were discovered to interact with other proteins. Our findings demonstrate that two mutant forms of APP interact differently with TP53 and MAPK’s. Furthermore, TP53, AKT1, PARP1, and FGFR1 interact with MAPKs through their mutant conformations. We hypothesize that these interactions might be crucial for VCI. We suggest that these interactions and proteins can act as early VCI markers or as possible therapeutic targets.
pyRBDome: A comprehensive computational platform for enhancing and interpreting RNA-binding proteome data
Authors: Chu Liang-Cui , Christopoulou Niki , McCaughan Hugh , Winterbourne Sophie , Cazzola Davide , Wang Shichao , Litvin Ulad , Brunon Salomé , Harker Patrick J.B. , McNae Iain , Granneman Sander 
Published: December 2023

AbstractHigh-throughput proteomics approaches have revolutionised the identification of RNA-binding proteins (RBPome) and RNA-binding sequences (RBDome) across organisms. Yet the extent of noise, including false-positives, associated with these methodologies, is difficult to quantify as experimental approaches for validating the results are generally low throughput. To address this, we introduce pyRBDome, a pipeline for enhancing RNA-binding proteome datain silico. It aligns the experimental results with RNA-binding site (RBS) predictions from distinct machine learning tools and integrates high-resolution structural data when available. Its statistical evaluation of RBDome data enables quick identification of likely genuine RNA-binders in experimental datasets. Furthermore, by leveraging the pyRBDome results, we have enhanced the sensitivity and specificity of RBS detection through training new ensemble machine learning models. pyRBDome analysis of a human RBDome dataset, compared with known structural data, revealed that while UV cross-linked amino acids were more likely to contain predicted RBSs, they infrequently bind RNA in high-resolution structures. This discrepancy underscores the limitations of structural data as benchmarks, positioning pyRBDome as a valuable alternative for increasing confidence in RBDome datasets.
Human rhinovirus 16 infection modifies the microRNA landscape during epithelial cell infection
Authors: Bosner Pax , Cappleman Victoria , Tomicic Alka , Kyyaly Aref , Jubrail Jamil 
Published: December 2023

AbstractHuman rhinovirus is a major driver of disease exacerbations for patients with asthma and chronic obstructive pulmonary disease. Importantly, the virus can disrupt immune cell functioning leading to secondary bacterial infections in these patients. MicroRNAs are important regulators of gene expression and control viral pathogenesis and immune cell functions. However, the role of different miRNAs during rhinovirus infections remains poorly defined. The aim of this study was to analyze the impact of RV16 on epithelial cell responses and identify miRNAs with altered expression levels in response to the viral infection and their target genes. HeLa-Ohio cells exposed to RV16 showed deficiencies in bacterial clearance and induced changes in the expression of several novel miRNAs identified using a custom panel of 88 different miRNAs and further analyzed using our newly developed computer program. Our experiments identified a panel of 9 differentially regulated miRNAs and our computer program narrowed this down to two that could represent biomarkers for RV16 infection. Our results also showed that upon upregulation of these miRNAs (miR-101-3p and miR-30b-5p) by RV16 there was a downregulation in EZH2, RARG and PTPN13 that could correlate with a productive viral infection and a worsened immune response. Taken together, our findings suggest that RV16 modifies the miRNA landscape in epithelial cells and that miR-101-3p and miR-30b-5p could represent key biomarkers for either early or late RV16 infection.
Proton Relaxometry of Tree Leaves at Hypogeomagnetic Fields
Authors: Fabricant Anne M. , Put Piotr , Barskiy Danila A. 
Published: December 2023

ABSTRACTWe report on a cross-species proton-relaxometry study inex vivotree leaves using nuclear magnetic resonance (NMR) at 7 μT. Apart from the intrinsic interest of probing nuclear-spin relaxation in biological tissues at magnetic fields below Earth field, our setup enables comparative analysis of plant water dynamics without the use of expensive commercial spectrometers. In this work, we focus on leaves from common Eurasian evergreen and deciduous tree families: Pinaceae (pine, spruce), Taxaceae (yew), Betulaceae (hazel), Prunus (cherry), and Fagaceae (beech, oak). Using a nondestructive protocol, we measure their effective protonT2relaxation times as well as track the evolution of water content associated with leaf dehydration. Newly developed “gradiometric quadrature” detection and data-processing techniques are applied in order to increase the signal-to-noise ratio (SNR) of the relatively weak measured signals. We find that while measured relaxation times do not vary significantly among tree genera, they tend to increase as leaves dehydrate. Such experimental modalities may have particular relevance for future drought-stress research in ecology, agriculture, and space exploration.
Byproducts of inflammatory radical metabolism provide transient nutrient niches for microbes in the inflamed gut
Authors: Spiga Luisella , Winter Maria G. , Muramatsu Matthew K. , Rojas Vivian K. , Chanin Rachael B. , Zhu Wenhan , Hughes Elizabeth R. , Taylor Savannah J. , Faber Franziska , Porwollik Steffen , Carvalho Tatiane F. , Qin Tian , Santos Renato L. , Andrews-Polymenis Helene , McClelland Michael , Winter Sebastian E. 
Published: December 2023

SUMMARYLouis Pasteur’s experiments on tartaric acid laid the foundation for our understanding of molecular chirality, but major questions remain. By comparing the optical activity of naturally-occurring tartaric acid with chemically-synthesized paratartaric acid, Pasteur realized that naturally-occurring tartaric acid contained only L-tartaric acid while paratartaric acid consisted of a racemic mixture of D- and L-tartaric acid. Curiously, D-tartaric acid has no known natural source, yet several gut bacteria specifically degrade D-tartaric acid. Here, we investigated the oxidation of monosaccharides by inflammatory reactive oxygen and nitrogen species. We found that this reaction yields an array of alpha hydroxy carboxylic acids, including tartaric acid isomers. Utilization of inflammation- derived D- and L-tartaric acid enhanced colonization bySalmonellaTyphimurium andE. coliin murine models of gut inflammation. Our findings suggest that byproducts of inflammatory radical metabolism, such as tartrate and other alpha hydroxy carboxylic acids, create transient nutrient niches for enteric pathogens and other potentially harmful bacteria. Furthermore, this work illustrates that inflammatory radicals generate a zoo of molecules, some of which may erroneously presumed to be xenobiotics.
Assessment of ferroptosis inducers and Nrf2 inhibitors as radiosensitisers in 2D and 3D breast cancer cell cultures
Authors: Alzufairi AA , Souilhol C , Jordan-Mahy N , Cross NA 
Published: December 2023

AbstractFerroptosis is a form of programmed cell death that is modulated in some cancer cells as a pro-survival mechanism. Induction of ferroptosis is a potential anti-cancer strategy, and enhancement of ferroptosis using ferroptosis inducers has the potential to enhance current anti-tumour mechanisms. In this study, we assessed the effect of the ferroptosis inducers Erastin, RSL-3 and FIN-56 on radiosensitivity in 2D cell culture, and in 3D alginate tumour spheroids from breast cancer cell lines. Since some tumours modulate ferroptosis via increased Nrf2 production, and MCF-7 and MDA-MB-231 both produce Nrf2 protein, we also assessed the effects of the Nrf2 inhibitor ML385 on radiosensitivity. MDA-MB-231 was highly sensitive to all ferroptosis inducers, and ferroptosis was reversed by the ferroptosis inhibitors Ferrostatin-1, Liproxstatin-1 and Deferoxamine. MCF-7 was resistant to all ferroptosis inducers. MDA-MB-231 and MCF-7 cells were sensitive to irradiation in 2D cell culture but resistant to irradiation in 3D alginate spheroids. Ferroptosis inducers did not synergistically enhance irradiation-induced cell death in 2D cell cultures. There was also no robust enhancement to irradiation effects with ferroptosis inducers in 2D or 3D cell culture. Ferroptosis inducers did, however, show a heterogeneous response in 3D cell culture, in that isogenic spheroids responded differently within the same spheroid. The Nrf2 inhibitor ML385 showed no synergistic enhancement of ferroptotic cell death when combined with irradiation. These studies suggest targeting ferroptosis does not induce short-term enhancement of ferroptotic cell death.
Targeted protein degradation systems to enhance Wnt signaling
Authors: Sampathkumar Parthasarathy , Jung Heekyung , Chen Hui , Zhang Zhengjian , Suen Nicholas , Yang Yiran , Huang Zhong , Lopez Tom , Benisch Robert , Lee Sung-Jin , Ye Jay , Yeh Wen-Chen , Li Yang 
Published: December 2023

AbstractMolecules that facilitate targeted protein degradation (TPD) offer great promise as novel therapeutics. The human hepatic lectin asialoglycoprotein receptor (ASGR) is selectively expressed on hepatocytes. We have previously engineered an anti-ASGR1 antibody-mutant RSPO2 (RSPO2RA) fusion protein (called SWEETSTM) to drive tissue-specific degradation of ZNRF3/RNF43 E3-ubiquitin ligases, which achieved hepatocyte-specific enhanced Wnt signaling, proliferation, and restored liver function in mouse models, and an antibody-RSPO2RA fusion molecule is currently in human clinical trials. In the current study, we identified two new ASGR1 and ASGR1/2 specific antibodies, 8M24 and 8G8. High-resolution crystal structures of ASGR1:8M24 and ASGR2:8G8 complexes revealed that these antibodies bind to distinct epitopes on opposing sides of ASGR, away from the substrate binding site. Both antibodies enhanced Wnt-activity when assembled as SWEETS molecules with RSPO2RA through specific effects sequestering E3 ligases. In addition, 8M24-RSPO2RA and 8G8-RSPO2RA efficiently downregulate ASGR1 through TPD mechanisms. These results demonstrate the possibility of combining different therapeutic effects and degradation mechanisms in a single molecule.
Hemispheric divergence of interoceptive processing across psychiatric disorders
Authors: Adamic Emily M. , Teed Adam R. , Avery Jason A. , de la Cruz Feliberto , Khalsa Sahib S. 
Published: December 2023

AbstractInteractions between top-down attention and bottom-up visceral inputs are assumed to produce conscious perceptions of interoceptive states, and while each process has been independently associated with aberrant interoceptive symptomatology in psychiatric disorders, the neural substrates of this interface are unknown. We conducted a preregistered functional neuroimaging study of 46 individuals with anxiety, depression, and/or eating disorders (ADE) and 46 propensity-matched healthy comparisons (HC), comparing their neural activity across two interoceptive tasks differentially recruiting top-down or bottom-up processing within the same scan session. During an interoceptive attention task, top-down attention was voluntarily directed towards cardiorespiratory or visual signals, whereas during an interoceptive perturbation task, intravenous infusions of isoproterenol (a peripherally-acting beta-adrenergic receptor agonist) were administered in a double-blinded and placebo-controlled fashion to drive bottom-up cardiorespiratory sensations. Across both tasks, neural activation converged upon the insular cortex, localizing within the granular and ventral dysgranular subregions bilaterally. However, contrasting hemispheric differences emerged, with the ADE group exhibiting (relative to HCs) an asymmetric pattern of overlap in the left insula, with increased or decreased proportions of co-activated voxels within the left or right dysgranular insula, respectively. The ADE group also showed less agranular anterior insula activation during periods of bodily uncertainty (i.e., when anticipating possible isoproterenol-induced changes that never arrived). Finally, post-task changes in insula functional connectivity were associated with anxiety and depression severity. These findings confirm the dysgranular mid-insula as a key cortical interface where attention and prediction meet real-time bodily inputs, especially during heightened awareness of interoceptive states. Further, the dysgranular mid-insula may indeed be a “locus of disruption” for psychiatric disorders.
Acetone-Butanol-Ethanol (ABE) fermentation with Clostridial Co-cultures for Enhanced Biobutanol Production
Authors: Kumar Karan , Jadhav Shraddha M. , Moholkar Vijayanand S. 
Published: December 2023

AbstractThis study investigates acetone-butanol-ethanol (ABE) fermentation, a process using solventogenicClostridiumspecies to produce acetone, butanol, and ethanol. Recent biotechnological advancements, such as omics, systems biology, and metabolic engineering, have reignited interest in butanol production, responding to the increasing gasoline costs and the demand for sustainable energy systems. This study unravels the distinct physiological attributes ofC. acetobutylicum(Cac) andC. pasteurianum(Cpa), significantly impacting sustainable bioenergy technologies. Employing response surface methodology (RSM), we embarked on a comprehensive statistical optimization journey in the co-culture system,CacMTCC 11274 andCpaMTCC 116, enhancing biobutanol production from mixed substrates. A spectrum of process parameters was scrutinized, encompassing the ratio ofCacandCpainoculum, sodium concentration, and the ratio of xylose to glucose. Statistical analysis revealed salt concentration’s profound influence on biomass, total alcohol, and butanol production. The culmination of these endeavors yielded highly promising outcomes: a butanol concentration of 12.1 ± 0.45 g L-1(model prediction: 11.87 g L-1), biomass of 4.15 ± 0.03 (model prediction: 4.06 OD600), and ABE concentration of 23.1 ± 0.55 g L-1(model prediction: 22.45 g L-1). These results represent a significant leap forward in bioenergy technologies, offering both practical insights and sustainable solutions for enhanced biofuel production.
Sequence types of EnteroaggregativeEscherichia colistrains recovered from human, animal, and environmental sources, India
Authors: Modgil Vinay , Kaur Harpreet , Mahindroo Jaspreet , Mohan Balvinder , Taneja Neelam 
Published: December 2023

AbstractObjectivesIn the current study, we report whole genome sequencing (WGS) data on EAEC strains from India to identify lineages and different sequence types (STs) in our geographical regions across North India.Material and methodsWe performed WGS comparative genomics characterization to examine the diversity of 122 EAEC strains collected from a large geographic area from clinical (Human sources) and non-clinical sources (animal and environmental sources). M-PCR for 21 virulence genes was performed. A triplex PCR detected phylogenetic groups A, B1, B2, and Dwas done. All strains were genome-sequenced, and bioinformatics analysis was performed.ResultsEAEC isolates belonged to 29 sequence types, further clustered into 11 clonal complexes, among which CC38 was the largest, containing 38 isolates mainly belonging to two ST types (ST38 and ST315). CC10 was the most diverse group, comprising 8 STs (ST43, ST2706, ST1286, ST 10, ST167, ST34, ST227, and ST4305). The most frequently detected virulence gene among the 96 clinical EAEC isolates wasastA (87.5%), followed by ORF3 (62.5%), andaap(54.1%).ConclusionThese findings indicate the high diversity of EAEC and different sources of unique ST types of EAEC. Such genetic relatedness may be a favorable factor in exchanging virulence factors and other genes. The results of this study provide genetic evidence that farmed animals may act as a reservoir of EAEC.
Structural Insights into The Role of MAGEA4 in RAD18 Regulation: Implications for Ubiquitin Ligase-Binding across the MAGE Protein Family
Authors: Griffith-Jones Simonne , Álvarez Lucía , Mukhopadhyay Urbi , Gharbi Sarah , Rettel Mandy , Adams Michael , Hennig Janosch , Bhogaraju Sagar 
Published: December 2023

AbstractMelanoma associated antigen 4 (MAGEA4) is a cancer-testis antigen (CTA) that is primarily expressed in the testes of healthy adults but is aberrantly overexpressed and also a poor prognostic marker in several human cancers. In its cancer-specific role, MAGEA4 interacts with RAD18 and activates trans-lesion DNA synthesis (TLS), potentially favouring tumour evolution. However, the precise mode of interaction between RAD18 and MAGEA4 and its implications on the ubiquitination activity of RAD18 are unknown. Here, we employed NMR and AlphaFold2 (AF) to reveal that the ubiquitin-conjugating enzyme RAD6-binding domain (R6BD) of RAD18 interacts with a groove in the C-terminal winged-helix subdomain (WH) of MAGEA4. Using cross-linking mass spectrometry (XL-MS), we found that MAGEA4 displaces RAD6 from the R6BD of RAD18 and inhibits degradative autoubiquitination of RAD18, which could be countered by a competing short peptide of the RAD18 R6B region. AF and XL-MS also revealed an evolutionary invariant intramolecular interaction within RAD18 between the catalytic RING and the DNA-binding SAP domains that is essential for the ubiquitination of PCNA. Using interaction proteomics, we revealed that another Type-I MAGE, MAGE-C2, interacts with the RING ubiquitin ligase TRIM28 in a similar fashion as the MAGEA4/RAD18 complex. We propose that the peptide-binding groove identified in the C-terminal WH of MAGEA4 exists in other type-I MAGE proteins and serves as a ligase-binding cleft. Our data reveal crucial insights into RAD18-mediated ubiquitination of PCNA and its regulation by MAGE-A4.
Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart
Authors: Tamiato Anita , Tombor Lukas S. , Fischer Ariane , Muhly-Reinholz Marion , Vanicek Leah Rebecca , Toğru Büşra Nur , Neitz Jessica , Glaser Simone Franziska , Merten Maximilian , Morales David Rodriguez , Kwon Jeonghyeon , Klatt Stephan , Schumacher Bianca , Günther Stefan , Abplanalp Wesley , John David , Fleming Ingrid , Wettschureck Nina , Dimmeler Stefanie , Luxán Guillermo 
Published: December 2023

AbstractBackgroundPericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. Although ageing is one of the main risk factors for cardiovascular disease, the consequences of ageing on cardiac pericytes are unknown.MethodsIn this study, we have combined single-nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of Regulator of G protein signalling 5 (RGS5) loss of function and finally have performed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 deletion in pericytes on the neighbouring fibroblasts.ResultsAgeing reduced the pericyte area and capillary coverage in the murine heart. Single nucleus RNA sequencing analysis further revealed that the expression ofRgs5was reduced in cardiac pericytes from aged mice. In vivo and in vitro studies showed that the deletion of RGS5 impaired cardiac function, fibrosis, and induced morphological changes and a pro-fibrotic gene expression signature in pericytes characterized by the expression of different extracellular matrix components and growth factors e.g.TGFB2andPDGFB.Indeed, culturing fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation as evidenced by the increased expression of α smooth muscle actin in a TGFβ2-dependent mechanism.ConclusionsOur results have identified RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.
Category-based attention facilitates memory search
Authors: Shang Linlin , Yeh Lu-Chun , Zhao Yuanfang , Wiegand Iris , Peelen Marius V. 
Published: December 2023

AbstractWe often need to decide whether the object we look at is also the object we look for. When we look for one specific object, this process can be facilitated by preparatory feature-based attention. However, when we look for multiple objects at the same time (e.g., the products on our shopping list) such a strategy may no longer be possible, as research has shown that we can actively prepare to detect only one object at a time. Therefore, looking for multiple objects may additionally involve search in long-term memory, slowing down decision making. Interestingly, however, previous research has shown that memory search can be very efficient when distractor objects are from a different category than the items in the memory set. Here, using EEG, we show that this efficiency is supported by top-down attention at the category level. In Experiment 1, human participants (both sexes) performed a memory search task on individually presented objects of the same or different category as the objects in the memory set. We observed category-level attentional modulation of distractor processing from ∼150 ms after stimulus onset, expressed both as an evoked response modulation and as an increase in decoding accuracy of same-category distractors. In Experiment 2, memory search was performed on two concurrently presented objects. When both objects were distractors, spatial attention (indexed by the N2pc component) was directed to the object that was of the same category as the objects in the memory set. Together, these results demonstrate how attention can facilitate memory search.Significance statementWhen we are in the supermarket, we repeatedly decide whether a product we look at (e.g., a banana) is on our memorized shopping list (e.g., apples, oranges, kiwis). This requires searching our memory, which takes time. However, when the product is of an entirely different category (e.g., dairy instead of fruit), the decision can be made quickly. Here, we used EEG to show that this between-category advantage in memory search tasks is supported by top-down attentional modulation of visual processing: The visual response evoked by distractor objects was modulated by category membership, and spatial attention was quickly directed to the location of within-category (vs. between-category) distractors. These results demonstrate a close link between attention and memory.