bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating cancer cell line and patient-derived xenograft recapitulation of tumor and non-diseased tissue gene expression profilesin silico
Authors: Williams Avery S. , Wilk Elizabeth J. , Fisher Jennifer L. , Lasseigne Brittany N. 
Published: April 2023

AbstractPreclinical models like cancer cell lines and patient-derived xenografts (PDXs) are vital for studying disease mechanisms and evaluating treatment options. It is essential that they accurately recapitulate the disease state of interest to generate results that will translate in the clinic. Prior studies have demonstrated that preclinical models do not recapitulate all biological aspects of human tissues, particularly with respect to the tissue of origin gene expression signatures. Therefore, it is critical to assess how well preclinical model gene expression profiles correlate with human cancer tissues to inform preclinical model selection and data analysis decisions. Here we evaluated how well preclinical models recapitulate human cancer and non-diseased tissue gene expression patternsin silicowith respect to the full gene expression profile as well as subsetting by the most variable genes, genes significantly correlated with tumor purity, and tissue-specific genes by using publicly available gene expression profiles across multiple sources. We found that using the full gene set improves correlations between preclinical model and tissue global gene expression profiles, confirmed that GBM PDX global gene expression correlation to GBM tumor global gene expression outperforms GBM cell line to GBM tumor global gene expression correlations, and demonstrated that preclinical models in our study often failed to reproduce tissue-specific expression. While including additional genes for global gene expression comparison between cell lines and tissues decreases the overall correlation, it improves the relative rank between a cell line and its tissue of origin compared to other tissues. Our findings underscore the importance of using the full gene expression set measured when comparing preclinical models and tissues and confirm that tissue-specific patterns are better preserved in GBM PDX models than in GBM cell lines. Future studies can build on these findings to determine the specific pathways and gene sets recapitulated by particular preclinical models to facilitate model selection for a given study design or goal.
Sidestream bio-P and mainstream anammox in a BNR process with upstream carbon capture
Authors: McCullough Kester , Klaus Stephanie , Wilson Christopher , Vanrolleghem Peter A. , Gu April Z. , Bott Charles 
Published: April 2023

AbstractThe integration of biological phosphorus removal (bio-P) and shortcut nitrogen removal (SNR) processes is challenging because of the conflicting demands on influent carbon: SNR allows for upstream carbon diversion but this reduction of influent carbon (especially volatile fatty acids (VFA) prevents or limits bio-P The objective of this study was to achieve SNR, either via partial nitritation/anammox (PNA) or partial denitrification/anammox (PdNA), simultaneously with biological phosphorus removal in a process with upstream carbon capture. This study took place in a pilot scale A/B process with a sidestream bio-P reactor and tertiary anammox polishing. Despite low influent rbCOD concentrations from the A-stage effluent, bio-P occurred in the B-stage thanks to the addition of A-stage WAS fermentate to the sidestream reactor. Nitrite accumulation occurred in the B-stage via partial denitrification and partial nitritation (NOB out-selection), depending on operational conditions, and was removed along with ammonia by the tertiary anammox MBBR, with the ability to achieve effluent TIN less than 2 mg/L.
Conformational dynamics of lipid transfer domains provide a general framework to decode their functional mechanism
Authors: Srinivasan Sriraksha , Di Luca Andrea , John Peter Arun T. , Gehin Charlotte , Lone Museer A. , Hornemann Thorsten , D’Angelo Giovanni , Vanni Stefano 
Published: April 2023

AbstractLipid Transfer Proteins (LTPs) are key players in cellular homeostasis and regulation, as they coordinate the exchange of lipids between different cellular organelles. Despite their importance, our mechanistic understanding of how LTPs function at the molecular level is still in its infancy, mostly due to the large number of existing LTPs and to the low degree of conservation at the sequence and structural level. In this work, we use molecular simulations to characterize dynamical and mechanistic aspects of a representative dataset of Lipid Transport Domains (LTDs) of 12 LTPs that belong to 8 distinct families. We find that LTDs display common dynamical, rather than structural, features despite no sequence homology nor structural conservation. These dynamical features correlate with their mechanistic mode of action, allowing to interpret and design experimental strategies to further dissect their mechanism. Our findings indicate the existence of a conserved, fold-independent mechanism of lipid transfer across LTPs of various families and offer a general framework for understanding their functional mechanism.
A scale-invariant log-normal droplet size distribution below the critical concentration for protein phase separation
Authors: Amico Tommaso , Dada Samuel , Lazzari Andrea , Brezinova Michaela , Trovato Antonio , Vendruscolo Michele , Fuxreiter Monika , Maritan Amos 
Published: April 2023

AbstractMany proteins have been recently shown to undergo a process of phase separation that leads to the formation of biomolecular condensates. Intriguingly, it has been observed that some of these proteins form dense droplets of sizeable dimensions already below the critical concentration, which is the concentration at which phase separation occurs. To understand this phenomenon, which is not readily compatible with classical nucleation theory, we investigated the properties of the droplet size distributions as a function of protein concentration. We found that these distributions can be described by a scale-invariant log-normal function with an average that increases progressively as the concentration approaches the critical concentration from below. The results of this scaling analysis suggest the existence of a universal behaviour independent of the sequences and structures of the proteins undergoing phase separation. While we refrain from proposing a theoretical model here, we suggest that any model of protein phase separation should predict the scaling exponents that we reported here from the fitting of experimental measurements of droplet size distributions. Furthermore, based on these observations, we show that it is possible to use the scale invariance to estimate the critical concentration for protein phase separation.
Computational Screen for Sex-Specific Drug Effects in a Cardiac Fibroblast Network Model
Authors: Watts Kelsey M. , Nichols Wesley , Richardson William J. 
Published: April 2023

AbstractHeart disease is the leading cause of death in both men and women. Cardiac fibrosis is the uncontrolled accumulation of extracellular matrix proteins which can exacerbate the progression of heart failure, and there are currently no drugs approved specifically to target matrix accumulation in the heart. Computational signaling network models (SNMs) can be used to facilitate discovery of novel drug targets. However, the vast majority of SNMs are not sex-specific and/or are developed and validated using data skewed towards male in vitro and in vivo samples. Biological sex is an important consideration in cardiovascular health and drug development. In this study, we integrate a previously constructed cardiac fibroblast SNM with estrogen signaling pathways to create sex-specific SNMs. The sex-specific SNMs maintained previously high validation when compared toin vitroexperimental studies in the literature. A sex-specific perturbation analysis and drug screen uncovered several potential pathways that warrant further study in the pursuit of sex-specific treatment recommendations for cardiac fibrosis.Author SummaryHeart failure is a leading cause of death for both men and women, but we still do not have adequate therapies to prevent or reverse this disease. One factor that contributes to heart failure is scarring of cardiac tissue, also known as fibrosis. Computer models can help find new heart failure drugs by simulating hundreds of biological reactions that regulate fibrosis at the molecular level. Unfortunately, the differences in male and female patients are not usually considered for these drug discovery simulations, which can result in drugs that work well for some individuals but not for other individuals. In our study, we added sex-specific biological reactions to a computer model in order to identify drugs that could treat fibrosis differently in male and female patients. Our simulations also predicted why premenopausal women may generally develop less fibrosis than men, while post-menopausal women may develop similar levels of fibrosis as men.
A comparison between Greengenes, SILVA, RDP, and NCBI reference databases in four published microbiota datasets
Authors: Ceccarani Camilla , Severgnini Marco 
Published: April 2023

ABSTRACTInaccurate bacterial taxonomic assignment in 16S-based microbiota experiments could have deleterious effects on research results, as all downstream analyses heavily rely on the accurate assessment of microbial taxonomy: a bias in the choice of the reference database can deeply alter microbiota biodiversity (alpha-diversity), composition (beta-diversity), and taxa profile (bacterial relative abundances).In this paper, we explored the influence of the reference 16S rRNA collection by performing a classification against four of the main databases used by the scientific community (i.e. Greengenes, SILVA, RDP, NCBI); the consequences of database clustering at 97% were also explored. To investigate the effects of the database choice on real and representative microbiome samples from different ecosystems, we performed a comparative analysis on four already published datasets from various sources: stools from a mouse model experiment, bovine milk, human gut microbiota stool samples, and swabs from the human vaginal environment. We took into consideration the computational time needed to perform the taxonomic classification as well.Although values in both alpha- and beta-diversity varied a lot, sometimes even statistically, according to the dataset chosen and the eventual clustering, the final outcome of the analysis was a concordance in the capability to retrieve the original experimental group differences over the various datasets. However, in the taxonomy classification, we found several inconsistencies with taxonomies correctly assigned in only some of the four databases. The degree of concordance among the databases was related to both the complexity of the environment and its degree of completeness in the reference databases.IMPORTANCE16S rRNA sequencing is, nowadays, the most commonly used strategy for microbiota profiling in many different ecosystems, ranging from human-associated to animal models, food matrices, and environmental samples. The ability of this kind of analysis to correctly capture differences in the microbiota composition is related to the taxonomic classification of the fragments obtained from sequencing and, thus, to the choice of the best reference database. This paper deals with four of the most popular microbial databases, which were evaluated in their ability to reproduce the experimental evidence from four already published datasets. The knowledge of the advantages and drawbacks of the database choice can be pivotal for planning future experiments in the field, making researchers aware of the repercussions of such a choice according to the different environments under scrutiny.Moreover, this work can also shed new light upon past results, partially explaining discordant evidence.
Plasmodium falciparumexploits CD44 as a co-receptor for erythrocyte invasion
Authors: Baro-Sastre Barbara , Kim Chi Yong , Lin Carrie , Kongsomboonvech Angel K. , Tetard Marilou , Salinas Nichole D. , Tolia Niraj H. , Egan Elizabeth S. 
Published: April 2023

ABSTRACTThe malaria parasitePlasmodium falciparuminvades and replicates asexually within human erythrocytes. CD44 expressed on erythrocytes was previously identified as an important host factor forP. falciparuminfection through a forward genetic screen, but little is known about its regulation or function in these cells, nor how it may be utilized by the parasite. We found that CD44 can be efficiently deleted from primary human hematopoietic stem cells using CRISPR/Cas9 genome editing, and that the efficiency of ex-vivo erythropoiesis to enucleated cultured red blood cells (cRBCs) is not impacted by lack of CD44. However, the rate ofP. falciparuminvasion was substantially reduced in CD44-null cRBCs relative to isogenic wild-type (WT) control cells, validating CD44 as an important host factor for this parasite. We identified twoP. falciparuminvasion ligands as binding partners for CD44, Erythrocyte Binding Antigen-175 (EBA-175) and EBA-140, and demonstrated that their ability to bind to human erythrocytes relies primarily on their canonical receptors-glycophorin A and glycophorin C, respectively. We further show that EBA-175 induces phosphorylation of erythrocyte cytoskeletal proteins in a CD44-dependent manner. Our findings support a model whereP. falciparumexploits CD44 as a co-receptor during invasion of human erythrocytes, stimulating CD44-dependent phosphorylation of host cytoskeletal proteins that alter host cell deformability and facilitate parasite entry.
Disulfide bridge-dependent dimerization triggers FGF2 membrane translocation into the extracellular space
Authors: Lolicato F , Steringer JP , Saleppico R , Beyer D , Fernandez-Sobaberas J , Unger S , Klein S , Riegerová P , Wegehingel S , Müller HM , Schmitt XJ , Kaptan S , Freund C , Hof M , Šachl R , Chlanda P , Vattulainen I , Nickel W 
Published: April 2023

SummaryFibroblast Growth Factor 2 (FGF2) exits cells by direct translocation across the plasma membrane, a type I pathway of unconventional protein secretion. This process is initiated by PI(4,5)P2-dependent formation of highly dynamic FGF2 oligomers at the inner plasma membrane leaflet, inducing the formation of lipidic membrane pores. Cell surface heparan sulfate chains linked to glypican-1 (GPC1) capture FGF2 at the outer plasma membrane leaflet, completing FGF2 membrane translocation into the extracellular space. While the basic steps of this pathway are well understood, the molecular mechanism by which FGF2 oligomerizes on membrane surfaces remains unclear. In the current study, we demonstrate the initial step of this process to depend on C95-C95 disulfide-bridge-mediated FGF2 dimerization on membrane surfaces, producing the building blocks for higher FGF2 oligomers that drive the formation of membrane pores. We find FGF2 with a C95A substitution to be defective in oligomerization, pore formation, and membrane translocation. Consistently, we demonstrate a C95A variant of FGF2 to be characterized by a severe secretion phenotype. By contrast, while also important for efficient FGF2 secretion from cells, a second cysteine residue on the molecular surface of FGF2 (C77) is not involved in FGF2 oligomerization. Rather, we find C77 to be part of the protein-protein interaction interface through which FGF2 binds to the α1 subunit of the Na,K-ATPase, the landing platform for FGF2 at the inner plasma membrane leaflet. Using cross-linking mass spectrometry, atomistic molecular dynamics simulations combined with a machine learning analysis and cryo-electron tomography, we provide insights into a FGF2 dimerization interface that brings C95 residues in close proximity, resulting in disulfide bridged FGF2 dimers. We propose a mechanism by which they bind with high avidity to PI(4,5)P2on membrane surfaces. We further propose a tight coupling between FGF2 secretion and the formation of ternary signaling complexes on cell surfaces, hypothesizing that C95-C95 bridged FGF2 dimers are functioning as the molecular units triggering autocrine and paracrine FGF2 signaling.
Antioxidant Activity via Free Radical Scavenging of Pitavastatin and Its Hydroxylated Metabolites. A Quantum Chemical Attempt Aiming to Assist Drug Development
Authors: Bâldea Ioan 
Published: April 2023

AbstractStatins form a class of drugs often administered in a variety of cardiovascular diseases, for which their antioxidant capacity appears particularly relevant. Although experiments have long provided empirical evidence that statins can suppress various oxidation pathways, theoretical attempts to quantify the antioxidant activity of statins (read, atorvastatin ATV, because this is the only one studied so far) were not published until last year. Molecular and clinical differences of stains trace back to the ring attached to the statin’s active moiety. This can be, e.g., a pyrrole, as the case of the aforementioned ATV or a quinoline, as the case of pitavastatin (PVT), which represents the focus of the present work. Extensive results reported here for PVT and derivative include the thermodynamic antioxidant descriptors (bond dissociation enthalpy BDE, adiabatic ionization potential IP, proton dissociation enthalpy PDE, proton affinity PA, and electron transfer enthalpy ETE) related to the three antioxidant mechanisms (hydrogen atom transfer HAT, stepwise electron transfer proton transfer SETPT, sequential proton loss electron transfer SPLET). Our particular emphasis is on the PVT’s hydroxylated derivatives wherein a hydroxy group replaces a hydrogen atom either on the quinoline core (Q-hydroxylated metabolites) or on the fluorophenyl ring (F-hydroxylated metabolites). Our calculations indicate that both the Q- and F-hydroxylated metabolites possess antioxidant properties superior to the parent PVT molecule. Given the fact that, to the best of our knowledge, no experimental data for the antioxidant potency of PVT and its hydroxylated derivatives exist, this is a theoretical prediction, and we Given the fact that, to the best of our knowledge, no experimental data for the antioxidant potency of PVT and its hydroxylated derivatives exist, this is a theoretical prediction for the validation of which we aim hereby to stimulate companion experimental in vivo and in vitro investigations and inspire pharmacologists in further drug developments.
Eupatilin improves cilia defects in human CEP290 ciliopathy models
Authors: Corral-Serrano JC , Sladen PE , Ottaviani D , Rezek FO , Jovanovic K , Athanasiou D , van der Spuy J , Mansfield BC , Cheetham ME 
Published: April 2023

AbstractThe photoreceptor outer segment is a highly specialized primary cilium essential for phototransduction and vision. Biallelic pathogenic variants in the cilia-associated geneCEP290cause non-syndromic Leber congenital amaurosis 10 (LCA10) and syndromic diseases, where the retina is also affected. While RNA antisense oligonucleotides and gene editing are potential treatment options for the common deep intronic variant c.2991+1655A>G inCEP290, there is a need for variant-independent approaches that could be applied to a broader spectrum of ciliopathies. Here, we generated several distinct human models ofCEP290-related retinal disease and investigated the effects of the flavonoid eupatilin as a potential treatment. Eupatilin improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, in gene-editedCEP290knockout (CEP290 KO) RPE1 cells, and in both CEP290 LCA10 and CEP290 KO iPSCs-derived retinal organoids. Furthermore, eupatilin reduced rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids. Eupatilin altered gene transcription in retinal organoids, by modulating the expression of rhodopsin, and by targeting cilia and synaptic plasticity pathways. This work sheds light into the mechanism of action of eupatilin, and supports its potential as a variant-independent approach forCEP290-associated ciliopathies.Abstract Figure
Hippocampal subfield vulnerability to α-synuclein pathology precedes neurodegeneration and cognitive dysfunction
Authors: Dues Dylan J. , Nguyen An Phu Tran , Becker Katelyn , Ma Jiyan , Moore Darren J. 
Published: April 2023

AbstractCognitive dysfunction is a salient feature of Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). The onset of dementia reflects the spread of Lewy pathology throughout forebrain structures. The mere presence of Lewy pathology, however, provides limited indication of cognitive status. Thus, it remains unclear whether Lewy pathology is the de facto substrate driving cognitive dysfunction in PD and DLB. Through application of α-synuclein fibrilsin vivo, we sought to examine the influence of pathologic inclusions on cognition. Following stereotactic injection of α-synuclein fibrils within the mouse forebrain, we measured the burden of α-synuclein pathology at 1-, 3-, and 6-months post-injection within subregions of the hippocampus and cortex. Under this paradigm, the hippocampal CA2/3 subfield was especially susceptible to α- synuclein pathology. Strikingly, we observed a drastic reduction of pathology in the CA2/3 subfield across time-points, consistent with the consolidation of α-synuclein pathology into dense somatic inclusions followed by neurodegeneration. Silver-positive degenerating neurites were observed prior to neuronal loss, suggesting that this might be an early feature of fibril-induced neurotoxicity and a precursor to neurodegeneration. Critically, mice injected with α-synuclein fibrils developed progressive deficits in spatial learning and memory. These findings support that the formation of α-synuclein inclusions in the mouse forebrain precipitate neurodegenerative changes that recapitulate features of Lewy-related cognitive dysfunction.HighlightsMice injected with α-synuclein fibrils develop hippocampal and cortical α- synuclein pathology with a dynamic regional burden at 1-, 3-, and 6-months post-injection.Silver-positive neuronal processes are an early and enduring degenerative feature of the fibril model, while extensive neurodegeneration of the hippocampal CA2/3 subfield is detected at 6-months post-injection.Mice exhibit progressive hippocampal-dependent spatial learning and memory deficits.Forebrain injection of α-synuclein fibrils may be used to model aspects of Lewy-related cognitive dysfunction.
Crosstalk between the tRNA methyltransferase Trm1 and RNA chaperone La influences eukaryotic tRNA maturation
Authors: Porat Jennifer , Vakiloroayaei Ana , Remnant Brittney M. , Talebi Mohammadaref , Cargill Taylor , Bayfield Mark A. 
Published: April 2023

AbstracttRNAs undergo an extensive maturation process involving post-transcriptional modifications often associated with tRNA structural stability and promoting the native fold. Impaired post-transcriptional modification has been linked to human disease, likely through defects in translation, mitochondrial function, and increased susceptibility to degradation by various tRNA decay pathways. More recently, evidence has emerged that bacterial tRNA modification enzymes can act as tRNA chaperones to guide tRNA folding in a manner independent from catalytic activity. Here, we provide evidence that the fission yeast tRNA methyltransferase Trm1, which dimethylates nuclear– and mitochondrial-encoded tRNAs at G26, can also promote tRNA functionality in the absence of catalysis. We show that wild type and catalytic-dead Trm1 are active in anin vivotRNA-mediated suppression assay and possess RNA strand annealing and dissociation activityin vitro, similar to previously characterized RNA chaperones. Trm1 and the RNA chaperone La have previously been proposed to function synergistically in promoting tRNA maturation, yet we surprisingly demonstrate that La binding to nascent pre-tRNAs decreases Trm1 tRNA dimethylationin vivoandin vitro. Collectively, these results support the hypothesis for tRNA modification enzymes that combine catalytic and non-catalytic activities to promote tRNA maturation, as well as expand our understanding of how La function can influence tRNA modification.