bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose optimization of an adjuvanted peptide-based personalized neoantigen melanoma vaccine
Authors: Valega-Mackenzie Wencel , Rodriguez Messan Marisabel , Yogurtcu Osman N. , Nukala Ujwani , Sauna Zuben E. , Yang Hong 
Published: June 2023

AbstractThe advancements in next-generation sequencing have made it possible to effectively detect somatic mutations, which has led to the development of personalized neoantigen cancer vaccines that are tailored to the unique variants found in a patient’s cancer. These vaccines can provide significant clinical benefit by leveraging the patient’s immune response to eliminate malignant cells. However, determining the optimal vaccine dose for each patient is a challenge due to the heterogeneity of tumors. To address this challenge, we formulated a mathematical dose optimization problem that aims to find the optimal personalized vaccine doses for a given fixed vaccination schedule, based on a previous mathematical model that encompasses the immune response cascade produced by the vaccine in a patient. To validate our approach, we performedin silicoexperiments on six patients with advanced melanoma. We compared the results of applying an optimal vaccine dose to those of a suboptimal dose (dose used in the clinical trial and its deviations). Our simulations revealed that an optimal vaccine may lead to a reduction in tumor size for certain patients, with higher initial doses and lower final doses. Our mathematical dose optimization offers a promising approach to determining the optimal vaccine dose for each patient and improving clinical outcomes.
Novel topological methods for identifying surprising protein tertiary structure relationships
Authors: Bale Arron , Rambo Robert , Prior Christopher 
Published: June 2023

AbstractWe present fast and simple-to-implement measures of the entanglement of protein tertiary structures which are appropriate for highly flexible structure comparison. These quantities are based on the writhing and crossing numbers heavily utilised in DNA topology studies which and which have shown some promising results when applied to proteins recently. Here we show how they can be applied in a novel manner across various scales of the protein’s backbone to identify similar topologies which can be missed by more common RMSD, secondary structure or primary sequence based comparison methods. We derive empirical bounds on the entanglement implied by these measures and show how they can be used to constrain the search space of a protein for solution scattering, a method highly suited to determining the likely structure of proteins in solution where crystal structure or machine learning based predictions often fail to match experimental data. In addition we identify large scale helical geometries present in a large array of proteins, which are consistent across a number of different protein structure types and sequences. This is used in one specific case to demonstrate significant structural similarity between Rossmann fold and TIM Barrel proteins, a link which is potentially significant as attempts to engineer the latter have in the past produced the former. Finally we provide the SWRITHE python notebook to calculate these metrics.Author summaryThere is much interest in developing quantitative methods to compare different protein structures or identify common sub-structures across protein families. We present novel methods for studying and comparing protein structures based on the entanglement of their amino-acid backbone and demonstrate a number of their critical properties. First, they are shown to be especially useful in identifying similar protein entanglement for structures which may be seen as distinct via more established methods. Second, by studying the distribution of entanglement across a wide sample of proteins, we show that there exists a minimum expected amount (a lower bound) of entanglement given the protein’s length. This bound is shown to be useful in ensuring realistic predictions from experimental structural determination methods. Third, using fundamental properties of this entanglement measure, we identify two common classes of protein sub-structure. The first are large scale helices, which provide stability to the structure. These helical structures indicate strong structural similarity of two protein families usually regarded as differing significantly. The second class of substructure is one which, though complex, has a small net entanglement. This configuration is physically useful in other disciplines, but its function in proteins is not yet clear. Finally, we provide an interactive python notebook to compute these measures for a given protein.
The evolutionary history of the common bean (Phaseolus vulgaris) revealed by chloroplast and nuclear genomes
Authors: Frascarelli Giulia , Galise Teresa R. , D’Agostino Nunzio , Cafasso Donata , Cozzolino Salvatore , Cortinovis Gaia , Sparvoli Francesca , Bellucci Elisa , Vittori Valerio Di , Nanni Laura , Pieri Alice , Rossato Marzia , Vincenzi Leonardo , Benazzo Andrea , Delledonne Massimo , Bitocchi Elena , Papa Roberto 
Published: June 2023

AbstractThe remarkable evolutionary history of the common bean (Phaseolus vulgaris L.) has led to the emergence of three wild main genepools corresponding to three different ecogeographic areas: Mesoamerica, the Andes and northern Peru/Ecuador. Recent works proposed novel scenarios and the northern Peru/Ecuador population has been described as a new species calledP. debouckii,rekindling the debate about the origin ofP. vulgaris. Here we shed light on the origin ofP. vulgarisby analysing the chloroplast and nuclear genomes of a large varietal collection representing the entire geographical distribution of wild forms. We assembled 37 chloroplast genomesde novoand used them to construct a time frame for the divergence of the genotypes under investigation, revealing that the separation of the Mesoamerican and northern Peru/Ecuador genepools occurred ∼0.15 Mya. Our results clearly support a Mesoamerican origin of the common bean and reject the recentP. deboukiihypothesis. These results also imply two independent migratory events from Mesoamerica to the North and South Andes, probably facilitated by birds. Our work represents a paradigmatic example of the importance of taking into account recombination events when investigating phylogeny and of the analysis of wild forms when studying the evolutionary history of a crop species.
African Swine Fever Virus major capsid p72 Trimers function as a pH sensor during uncoating process of virus endocytosis
Authors: Meng Kaiwen , Huyan Yangnan , Liu Qi , Li Junyi , Xiang Ye , Meng Geng 
Published: June 2023

AbstractAfrican swine fever virus (ASFV) belongs to nucleocytoplasmic large DNA viruses (NCLDVs), the only member of Asfarviridae. So far, it is revealed that the ASFV uncoating is a pH-dependent process undergone in late endosomes. But, the research on how pH affects capsid stability is limited, and which protein plays an essential role in pH sensing remains unknown. In this study, we identified the main component of the ASFV capsid -- major capsid protein p72, as a pH sensitive residue abundance protein, and it is speculated that the conformational change of the p72 trimer is possibly responsible for the ASFV uncoating process. To test this speculation, we obtained recombinant p72 trimers, treated with the acidic environment that simulated endosomes and displayed structural analysis. The results showed that the p72 trimer depolymerized at low pH. The depolymerization of trimers rationally explains the disassembly mechanism of the ASFV icosahedral capsid in endosomes.
mRNA vaccine induces protective immunity against the type III secretory virulence ofPseudomonas aeruginosa
Authors: Kawaguchi Ken , Kinoshita Mao , Sudo Kazuki , Inoue Keita , Naito Yoshifumi , Oba Makoto , Uchida Satoshi , Sawa Teiji 
Published: June 2023

AbstractFew studies have addressed mRNA vaccination against bacteria despite the desperate need to control antimicrobial resistance. Herein, we developed mRNA vaccines targeting the type III secretion system ofPseudomonas aeruginosa, which plays a critical role in the pathogenesis. Vaccination with a nucleoside-modified mRNA encapsulated in lipid nanoparticles improved mouse survival, reduced the bacterial load in the lung, and alleviated pathological changes in the lungs after bacterial challenge.
Information-theoretic analysis of a model of CAR-4-1BB-mediated NFκB activation
Authors: Tserunyan Vardges , Finley Stacey 
Published: June 2023

AbstractSystems biology utilizes computational approaches to examine an array of biological processes, such as cell signaling, metabolomics and pharmacology. This includes mathematical modeling of CAR T cells, a modality of cancer therapy by which genetically engineered immune cells recognize and combat a cancerous target. While successful against hematologic malignancies, CAR T cells have shown limited success against other cancer types. Thus, more research is needed to understand their mechanisms of action and leverage their full potential. In our work, we set out to apply information theory on a mathematical model of cell signaling of CAR-mediated activation following antigen encounter. First, we estimated channel capacity for CAR-4-1BB-mediated NFκB signal transduction. Next, we evaluated the pathway’s ability to distinguish contrasting “low” and “high” antigen concentration levels, depending on the amount of intrinsic noise. Finally, we assessed the fidelity by which NFκB activation reflects the encountered antigen concentration, depending on the prevalence of antigen-positive targets in tumor population. We found that in most scenarios, fold change in the nuclear concentration of NFκB carries a higher channel capacity for the pathway than NFκB’s absolute response. Additionally, we found that most errors in transducing the antigen signal through the pathway skew towards underestimating the concentration of encountered antigen. Finally, we found that disabling IKKβ deactivation could increase signaling fidelity against targets with antigen-negative cells. Our information-theoretic analysis of signal transduction can provide novel perspectives on biological signaling, as well as enable a more informed path to cell engineering.
Innovative approach for vaccinating Nile tilapia,Oreochromis niloticusagainstStreptococcus agalactiaeusing an ozone nanobubble pre-treatment, VAC in BAG and VAC in FEED
Authors: Vinh Nguyen Tien , Dong Ha Thanh , Senapin Saengchan , Pumpuang Suntree , Lan Nguyen Giang Thu , Wilairat Bulakorn , Garud Pradnya R. , St-Hilaire Sophie , Linh Nguyen Vu , Phanphut Wattana , Shinn Andrew P. 
Published: June 2023

AbstractThe treatment of Nile tilapia with ozone nanobubbles (ONb) prior to vaccination with an immersible heat-killedStreptococcus agalactiae(Sa) vaccine has been reported to modulate and enhance both innate and specific immunity. The efficacy of this novel vaccination strategy is explored further in field trials. This strategy involved a short-term treatment of ONb to activate the fish’s immunity prior to immersion vaccination during their transportation in oxygenated plastic bags (VAC in BAG), followed by two oral boosters during the grow-out stage mixing vaccine in feed (VAC in FEED). The field trial was conducted over 112 days in open cages, comprising four groups: normal aeration control (AC), normal aeration + vaccine (AV), ONb control (NC), and ONb + vaccine (NV). The efficacy of the vaccine was evaluated by measuring specific antibodies forS. agalactiae, monitoring expressions ofIgMandIgTtranscripts in the gills and head kidney every two weeks, and a laboratory pathogen challenge. Results found that fish in the NV group had significant increases in anti-S. agalactiaeantibodies after the primary dose, whereas fish in the AV group required an oral booster dose to produce significant anti-S. agalactiaeantibodies. In the vaccinated groups (AV and NV), onlyIgMwas observed to be upregulated at 14 days post-immersion (dpi), while this gene was upregulated in both gills and head kidney in the NC group. No statistically significant upregulation ofIgTwas recorded in any group at any time point. Despite a decline in the levels of specific antibodies among the vaccinated groups at the time of challenge (88 dpi), the NV and AV groups demonstrated a relative percent survival (RPS) of 50% and 46.7%, respectively, following a relatively high injection dose ofS. agalactiaeinjection (0.1 mL of 108CFU/mL). In summary, this ONb, VAC in BAG and VAC in FEED vaccination strategy represents a promising alternative to the undesirable handling and costly injection approach used within the Nile tilapia industry.
Trained immunity in human monocyte enhances myeloid-T-cell pathogenic crosstalk in Ankylosing Spondylitis
Authors: Zhao Jinyi , Liu Feng , Worth Claudia , Simone Davide , Penkava Frank , Shi Hui , Li Jiaqi , Lama Shristi , Fang Hai , Lee Jeong Seok , Kim Tae-Jong , Duan Lihua , Bowness Paul , Chen Liye 
Published: June 2023

AbstractRecent studies in infectious, cardiovascular and neurodegenerative diseases have established the presence of memory in innate immune cells. This “trained immunity (TI)” leads to an enhanced response to a second challenge. Monocytes in Ankylosing Spondylitis (AS), a common form of inflammatory arthritis, are known to be hyper-responsive to microbial stimulus lipopolysaccharide (LPS). We asked if TI is present in AS monocytes and, if so, how it contributes to disease pathology.Using Single-cell RNA sequencing (scRNA-seq), flow cytometry and enzyme-linked immunosorbent assays (ELISA), we identify a subset of monocytes from AS patients exhibiting features of trained immunity and being hyperresponsive to LPS stimulation. Surprisingly, both trained monocytes in AS and β-glucan-trained monocytes from healthy donors are hyper-responsive to T-cell-induced activation. scRNA-seq of AS synovial mononuclear cells shows enrichment of a monocyte population with these/analogous features. Additionally, T cell-stimulated monocytes act back on T-cells to support Th17 responses (of established pathology in AS). Lastly, using genetic and chemical perturbations we show that ERN1, an AS risk gene enriched in this trained monocyte population, contributes to T-cell-induced monocyte activation.Our data provide strong evidence for the first time for the key role of TI in common human inflammatory arthritis.
Modulation of neuronal activity in cortical organoids with bioelectronic delivery of ions and neurotransmitters
Authors: Park Yunjeong , Hernandez Sebastian , Hernandez Cristian O. , Schweiger Hunter E. , Li Houpu , Voitiuk Kateryna , Dechiraju Harika , Hawthorne Nico , Muzzy Elana M. , Selberg John A. , Sullivan Frederika N. , Urcuyo Roberto , Salama Sofie R. , Aslankoohi Elham , Teodorescu Mircea , Mostajo-Radji Mohammed A. , Rolandi Marco 
Published: June 2023

ABSTRACTPrecise modulation of brain activity is fundamental for the proper establishment and maturation of the cerebral cortex. To this end, cortical organoids are promising tools to study circuit formation and the underpinnings of neurodevelopmental disease. However, the ability to manipulate neuronal activity with high temporal resolution in brain organoids remains limited. To overcome this challenge, we introduce a bioelectronic approach to control cortical organoid activity with the selective delivery of ions and neurotransmitters. Using this approach, we sequentially increased and decreased neuronal activity in brain organoids with the bioelectronic delivery of potassium ions (K+) and γ-aminobutyric acid (GABA), respectively, while simultaneously monitoring network activity. This works highlights bioelectronic ion pumps as tools for high-resolution temporal control of brain organoid activity toward precise pharmacological studies that can improve our understanding of neuronal function.
Mag-Net: Rapid enrichment of membrane-bound particles enables high coverage quantitative analysis of the plasma proteome
Authors: Wu Christine C. , Tsantilas Kristine A. , Park Jea , Plubell Deanna , Sanders Justin A. , Naicker Previn , Govender Ireshyn , Buthelezi Sindisiwe , Stoychev Stoyan , Jordaan Justin , Merrihew Gennifer , Huang Eric , Parker Edward D. , Riffle Michael , Hoofnagle Andrew N. , Noble William S. , Poston Kathleen L. , Montine Thomas J. , MacCoss Michael J. 
Published: June 2023

ABSTRACTMembrane-bound particles in plasma are composed of exosomes, microvesicles, and apoptotic bodies and represent ∼1-2% of the total protein composition. Proteomic interrogation of this subset of plasma proteins augments the representation of tissue-specific proteins, representing a “liquid biopsy,” while enabling the detection of proteins that would otherwise be beyond the dynamic range of liquid chromatography-tandem mass spectrometry of unfractionated plasma. We have developed an enrichment strategy (Mag-Net) using hyper-porous strong-anion exchange magnetic microparticles to sieve membrane-bound particles from plasma. The Mag-Net method is robust, reproducible, inexpensive, and requires <100 μL plasma input. Coupled to a quantitative data-independent mass spectrometry analytical strategy, we demonstrate that we can collect results for >37,000 peptides from >4,000 plasma proteins with high precision. Using this analytical pipeline on a small cohort of patients with neurodegenerative disease and healthy age-matched controls, we discovered 204 proteins that differentiate (q-value < 0.05) patients with Alzheimer’s disease dementia (ADD) from those without ADD. Our method also discovered 310 proteins that were different between Parkinson’s disease and those with either ADD or healthy cognitively normal individuals. Using machine learning we were able to distinguish between ADD and not ADD with a mean ROC AUC = 0.98 ± 0.06.
eIF4E1b is a non-canonical eIF4E required for maternal mRNA dormancy
Authors: Lorenzo-Orts Laura , Strobl Marcus , Steinmetz Benjamin , Leesch Friederike , Pribitzer Carina , Schutzbier Michael , Dürnberger Gerhard , Pauli Andrea 
Published: June 2023

AbstractMaternal mRNAs are essential for protein synthesis during oogenesis and early embryogenesis. To adapt translation to specific needs during development, maternal mRNAs are translationally repressed by shortening the polyA tails. While mRNA deadenylation is associated with decapping and degradation in somatic cells, maternal mRNAs with short polyA tails are stable. Here we report an essential role for the germline-specific paralog of the mRNA cap-binding factor eIF4E, known as eIF4E1b, in the storage and repression of maternal mRNAs with short polyA tails. eIF4E1b binds to the mRNA cap and is targeted to ribonucleoprotein complexes through its direct interaction with eIF4ENIF1/4E-T. In early embryos, eIF4E1b binds to a specific set of translationally repressed mRNAs with short or no polyA tails, such as histone mRNAs, which are translated later on during embryogenesis. Consistent with an important role in maternal mRNA dormancy, mutation ofeIF4E1bin zebrafish impairs female germline development. Understanding the mechanism and function of eIF4E1B provides new insights into fundamental post-transcriptional regulatory principles governing early vertebrate development.
Roadmap For The Expression Of Canonical and Extended Endocannabinoid System Receptors and Proteins in Peripheral Organs of Preclinical Animal Models
Authors: Rosado-Franco JJ , Ellison AL , White CJ , Price AS , Moore CF , Williams RE , Fridman LB , Weerts EM , Williams DW 
Published: June 2023

AbstractThe endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential ofCannabisand phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system has not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were only five receptors (CB2, GPR18, GPR55, TRPV2, and FAAH) that had identical expression patterns in mice, rats, and rhesus macaques. Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has profound implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.
Liquid-liquid phase separation and aggregation of a globular folded protein SUMO1
Authors: Arora Simran , Roy Debsankar Saha , Maiti Sudipta , Koti Ainavarapu Sri Rama 
Published: June 2023

AbstractMany studies in recent years have investigated the phenomenon of liquid-liquid phase separation (LLPS) in proteins. LLPS is reported in intrinsically disordered proteins (IDPs) or in proteins with intrinsically disordered regions (IDRs) lacking a well-defined three-dimensional structure. However, the occurrence of LLPS in folded proteins, that lacks IDRs is not widely known. It is generally assumed that the compact structure and limited flexibility of folded proteins hinder their ability to establish weak and dynamic interactions crucial for LLPS. Contrary to the prevailing understanding, we present direct evidence of rapid phase separation of a globular protein, SUMO1, occurring under crowded conditions at physiological pH and room temperature. The protein molecules in the liquid droplets undergo conformational changes with time, monitored by intrinsic tryptophan fluorescence. We also demonstrate the phase transition of SUMO1 droplets from liquid to solid state with maturation, ultimately leading to aggregation. The SUMO1 aggregates contain a significant amount of beta-sheet structure but have amorphous morphology, probed by several spectroscopic techniques (Thioflavin T fluorescence, Raman Spectroscopy, and TEM). Our findings provide insights into the behaviour of SUMO1 protein in crowded environment, albeit, the underlying mechanism is not well understood and may differ from those of IDPs. Furthermore, SUMO1 protein is known to colocalize in inclusion bodies of IDPs, and therefore, LLPS of SUMO1 may have important biological implications in neurodegenerative diseases.