bluuebunny/crossref_metadata_2025_split huggingface dataset:
Screening macrocyclic peptide libraries by yeast display allows control of selection process and affinity ranking
Authors: Linciano Sara , Mazzocato Ylenia , Romanyuk Zhanna , Vascon Filippo , Soler Lluc Farrera , Will Edward , Xing Yuyu , Chen Shiyu , Kumada Yoichi , Simeoni Marta , Scarso Alessandro , Cendron Laura , Heinis Christian , Angelini Alessandro 
Published: August 2024

AbstractMacrocyclic peptides provide an attractive modality for drug development due to their ability to bind challenging targes, their small size, and amenability to powerfulin vitroevolution techniques such as phage or mRNA display. While these technologies proved capable of generating and screening extremely large libraries and yielded ligands to already many targets, they often do not identify the best binders within a library due to the difficulty of monitoring performance and controlling selection pressure. Furthermore, only a small number of enriched ligands can typically be characterised due to the need of chemical peptide synthesis and purification prior to characterisation. In this work, we address these limitations by developing a yeast display-based strategy for the generation, screening and characterisation of structurally highly diverse disulfide-cyclised peptides. Analysis and sorting by quantitative flow cytometry enabled monitoring the performance of millions of individual macrocyclic peptides during the screening process and allowed us identifying macrocyclic peptide ligands with affinities in the low micromolar to high picomolar range against five highly diverse protein targets. X-ray analysis of a selected ligand in complex with its target revealed optimal shape complementarity, large interaction surface, constrained peptide backbones and multiple inter- and intra-molecular interactions, rationalising the high affinity and exquisite selectivity. The novel technology described here offers a facile, quantitative and cost-effective alternative to rapidly and efficiently generate and characterise fully genetically encoded macrocycle peptide ligands with sufficiently good binding properties to even therapeutically relevant targets.
Temperature and Pressure Shaped the Evolution of Antifreeze Proteins in Polar and Deep Sea Zoarcoid Fishes
Authors: Bogan Samuel N. , Surendran Nathan , Hotaling Scott , Desvignes Thomas , Bista Iliana , Lins Luana S.F. , Eilertsen Mari H. , Le François Nathalie R. , Algayer Tait , Hamilton Scott L. , Frandsen Paul B. , Hoffmann Federico G. , Kelley Joanna L. 
Published: August 2024

AbstractAntifreeze proteins (AFPs) have enabled teleost fishes to repeatedly colonize polar seas. Four AFP types have convergently evolved in several fish lineages. AFPs inhibit ice crystal growth and lower cellular freezing point. In lineages with AFPs, species inhabiting colder environments may possess more AFP copies. Elucidating how differences in AFP copy number evolve is challenging due to the genes’ tandem array structure and consequently poor resolution of these repetitive regions. Here we explore the evolution of type III AFPs (AFP III) in the globally distributed suborder Zoarcoidei, leveraging six new long-read genome assemblies. Zoarcoidei has fewer genomic resources relative to other polar fish clades while it is one of the few groups of fishes adapted to both the Arctic and Southern Oceans. Combining these new assemblies with additional long-read genomes available for Zoarcoidei, we conducted a comprehensive phylogenetic test of AFP III evolution and modeled the effects of thermal habitat and depth on AFP III gene family evolution. We confirm a single origin of AFP III via neofunctionalization of the enzyme sialic acid synthase B and show that AFP gains and losses were not only correlated with temperature, but also with depth, which reduces freezing point via pressure. Associations between the environment and AFP III copy number were driven by duplications of paralogs that were translocated out of the ancestral locus at which Zoarcoidei AFP arose. Our results reveal novel environmental effects on AFP evolution and demonstrate the value of high-quality genomic resources for studying how structural genomic variation shapes convergent adaptation.
Your Blood is Out for Delivery: Considerations of Shipping Time and Temperature on Degradation of RNA from Stabilized Whole Blood
Authors: Stefanovic Filip , Brown Lauren G. , MacDonald James , Bammler Theo , Rinchai Darawan , Nguyen Serena , Zeng Yuting , Shinkawa Victoria , Adams Karen , Chausabel Damien , Berthier Erwin , Haack Amanda J. , Theberge Ashleigh B. 
Published: August 2024

ABSTRACTRemote research studies are an invaluable tool for reaching populations in geographical regions with limited access to large medical centers or universities. To expand the remote study toolkit, we have previously developed homeRNA, which allows for at-home self-collection and stabilization of blood and demonstrated the feasibility of using homeRNA in high temperature climates. Here, we expand upon this work through a systematic study exploring the effects of high temperature on RNA integrity through in-lab and field experiments. Compared to the frozen controls (overall mean RIN of 8.2,n= 8), samples kept at 37°C for 2, 4, and 8 days had mean RINs of 7.6, 5.9, and 5.2 (n= 3), respectively, indicating that typical shipping conditions (∼2 days) yield samples suitable for downstream RNA sequencing. Shorter time intervals (6 hours) resulted in minimal RNA degradation (median RIN of 6.4,n= 3) even at higher temperatures (50°C) compared to the frozen control (mean RIN of 7.8,n= 3). Additionally, we shipped homeRNA-stabilized blood from a single donor to 14 different states and back during the summer with continuous temperature probes (7.1 median RIN,n= 42). Samples from all locations were analyzed with 3’ mRNA-seq to assess differences in gene counts, with the transcriptomic data suggesting that there was no preferential degradation of transcripts as a result of different shipping times, temperatures, and regions. Overall, our data support that homeRNA can be used in elevated temperature conditions, enabling decentralized sample collection for telemedicine, global health, and clinical research.
Benchmarking text-integrated protein language model embeddings and embedding fusion on diverse downstream tasks
Authors: Ko Young Su , Parkinson Jonathan , Wang Wei 
Published: August 2024

AbstractProtein language models (pLMs) have traditionally been trained in an unsupervised manner using large protein sequence databases with an autoregressive or masked-language modeling training paradigm. Recent methods have attempted to enhance pLMs by integrating additional information, in the form of text, which are referred to as “text+protein” language models (tpLMs). We evaluate and compare six tpLMs (OntoProtein, ProteinDT, ProtST, ProteinCLIP, ProTrek, and ESM3) against ESM2, a baseline text-free pLM, across six downstream tasks designed to assess the learned protein representations. We find that while tpLMs outperform ESM2 in five out of six benchmarks, no tpLM was consistently the best. Thus, we additionally investigate the potential of embedding fusion, exploring whether the combinations of tpLM embeddings can improve performance on the benchmarks by exploiting the strengths of multiple tpLMs. We find that combinations of tpLM embeddings outperform single tpLM embeddings in five out of six benchmarks, highlighting its potential as a useful strategy in the field of machine-learning for proteins. To facilitate the practical application of embedding fusion, we outline a heuristic framework to efficiently identify the optimal combination of embeddings, reducing the exponential time complexity of an exhaustive combination search down to a manageable linear time complexity. Using our embedding fusion framework, we achieve state-of-the-art performances on the protein-protein interaction prediction and homologous sequence recovery tasks without any specific model adjustments or hyperparameter tuning. Our experiments suggest embedding fusion is a useful tool in the machine-learning for proteins toolbox. Lastly, this study highlights the potential of future research on additional strategies for maximizing the utility of pLMs.
Identification of a mesodermal progenitor for the pro-definitive angio-hematopoietic lineage
Authors: Lazarov Tomi , Loyher Pierre-Louis , Yang Hairu , Choo Zi-Ning , Deng Zihou , Nowotschin Sonja , Kuo Ying-Yi , Zhou Ting , Alberdi-Gonzalez Araitz , Stumm Ralf , Mass Elvira , Gomez Perdiguero Elisa , Hadjantonakis Anna-Katerina , Geissmann Frederic 
Published: August 2024

AbstractMammalian hematopoietic cells arise from mesodermal progenitors in a close developmental relationship with endothelium, and along three distinct cell lineages known as primitive, pro-definitive, and definitive hematopoiesis. However, the developmental hierarchy between mesodermal progenitors, endothelium, and blood cell lineages is incompletely understood. We report here the identification in mouse gastrula and human (h)iPSC cultures of a population of CXCR4+primitive streak stage mesodermal progenitors that give rise to yolk sac endothelium, blood islands, yolk sac hematopoiesis, and resident macrophages, corresponding to the pro-definitive lineage. Strikingy, this progenitor does not give rise to primitive erythropoiesis or to caudal endothelium and definitive hematopoiesis. Interestingly however, the pro-definitive progenitor population also gives rise to rostral endothelium that persists in adults. Finally, pro-definitive progenitor-derived endothelium is the first and main source of macrophages in embryo and hiPSC cultures, both directly and via previously described multipotent Erythro-Myeloid Progenitors. The identification and isolation of this mesodermal progenitor defines a revised pro-definitive angio-hematopoietic lineage and provides a framework for resident macrophage and endothelial differentiation relevant to disease pathophysiology and their manipulation for therapeutic purposes.One sentence summaryIdentification in gastrulating embryo and hiPSC cultures of a mesodermal progenitor for yolk sac and rostral endothelial cells, early macrophages, and Erythro-Myeloid Progenitors characterize pro-definitive hematopoiesis and provide a revised framework for early angio-hematopoietic development.Graphical abstractSchematic represents the progeny of angio-hematopoietic progenitors at the posterior primitive streak. Developmental timing of CXCR4 expression distinguishesi)CXCR4-primitive hematopoiesis,ii)Early CXCR4+angio-hematopoieticprogenitors (EXAP) (purple) whichexpressCXCR4 between E6.5 and E7.5 and give rise to rostral vessels and resident macrophages through YS hemogenic endothelium, andiii)late CXCR4+intraembryonic angio-hematopoietic progenitors (blue) which acquire expression of CXCR4 around E8 and give rise to definitive hematopoiesis through an intraembryonic hemogenic endothelium. Abbreviations: E (Mouse Embryonic Day); YS (Yolk Sac); Hemog. (Hemogenic); Endo. (Endothelium); Defi. (Definitive).
Effectiveness of Exercise Intervention in Preventing Active Arthritis Exacerbation in an SKG Mouse Model of Rheumatoid Arthritis
Authors: Ozone Kaichi , Kumagai Tatsunori , Arakawa Kouhei , Sugasawa Takehito , Gu Wenchao , Kawabata Sora , Shimada Naoki , Takahashi Haruna , Yoneno Moe , Minegishi Yuki , Takahata Kei , Sato Michiaki , Oka Yuichiro , Kanemura Naohiko 
Published: August 2024

AbstractObjectivesTo investigate the effects of low-intensity exercise on active arthritis in an SKG mouse model of human rheumatoid arthritis (RA) pathology.MethodsTwenty-four female SKG mice were divided into three groups: ‘sedentary’ (control), ‘AR’ (induced arthritis), and ‘AREx’ (induced arthritis plus low-intensity exercise). Arthritis was induced via intraperitoneal administration of mannan. After a 2-week inflammation period, low-intensity treadmill exercise was performed only in the AREx group. Arthritis was assessed weekly during the rearing period. After 4 weeks of exercise, histological and bone morphometric analyses of the right ankle joint were performed. A histological analysis of the gastrocnemius muscle was also performed. Bulk mRNA sequencing was conducted on the left synovial membrane-fat pad (SM-FP) complex.ResultsThe synovitis score showed no change; however, the arthritis score was significantly lower in the AREx group than in the AR group (p<0.05), indicating that low-intensity exercise suppressed arthritis exacerbation. The calcaneal and talar bone volumes decreased in the AR group, whereas the AREx group showed no significant change. In the SM-FP complex tissue, the gene expression of inflammatory cytokines decreased in the AREx group compared with the AR group, particularly the suppression of IL6/Jak/Stat3. Immunohistochemical analysis revealed significantly decreased expression of pro-inflammatory cytokines and increased expression of anti-inflammatory cytokines in the synovium of the AREx group compared with the AR group (p<0.05).ConclusionLow-intensity exercise therapy for active RA showed anti-inflammatory and suppressive effects on arthritis exacerbation in SKG mice, a mouse model of human RA pathology.Key messagesExercise had an anti-inflammatory effect on SKG mice, a mouse model of rheumatoid arthritis.Exercise suppresses pro-inflammatory cytokine pathways such as IL6/Jak/Stat3 signalling in the synovial-fat complex tissue.Exercise therapy is effective in improving the pathophysiology of active rheumatoid arthritis.
A Dimeric SINE Discovered in Shrew Mole is Structurally Similar to Primate Alu
Authors: Kosushkin Sergey A. , Vassetzky Nikita S. , Borodulina Olga R. , Kramerov Dmitri A. 
Published: August 2024

AbstractFamilies of Short Interspersed Elements (SINEs) originate from tRNA, 5S rRNA, and 7SL RNA molecules in the genomes of multicellular organisms. Families of 7SL RNA-derived SINEs are very rare; however, they have been best studied in primates and rodents. The rodent B1 SINE is a monomeric element, whereas the primate Alu is composed of two 7SL RNA-derived monomers.We found that in contrast to other members of the family Talpidae (moles), which possess a tRNA-derived Tal SINE, the shrew moleUropsilus graciliscontains 280,000 genomic copies of the previously unknown 7SL RNA-derived Urop SINE. Like Alu, Urop consists of two monomers connected by an A-rich linker. The origin of the Urop monomers, like that of the Alu and B1 monomers, was mediated by several essentially identical events - a long central deletion in the 7SL RNA, dimerization, and/or internal duplication. Urop copies can be divided into three subfamilies (a, b, and c), the latter being the most numerous and recent. Urop_c has more copies with poly(A) tails longer than 50 compared to other L1-mobilized SINEs. Urop and Alu illustrate an independent emergence in the evolutionary history of highly similar SINEs.
Mammalian retinal specializations for high acuity vision evolve in response to both foraging strategies and morphological constraints
Authors: Kopania Emily E. K. , Clark Nathan L. 
Published: August 2024

AbstractVision is a complex sensory system that requires coordination among cellular and morphological traits, and it remains unclear how functional relationships among traits interact with ecological selective pressures to shape the evolution of vision. Many species have specialized high visual acuity regions in the retina defined by patterns of ganglion cell density, which may evolve in response to ecological conditions. For example, ganglion cell density can increase radially towards the center of the retina to form an area centralis, which is thought to improve acuity towards the center of the visual field in predators. Another example is the horizontal streak, where ganglion cells are dense across the center of the retina, which is thought to be beneficial in horizon-dominated habitats. At the morphological level, many have proposed that predation selects for high orbit convergence angles, or forward-facing eyes. We tested these hypotheses in a phylogenetic framework across eutherian mammals and only found support for the association between the horizontal streak and horizon-dominated habitats. We also tested if retinal specializations evolve in response to orbit convergence angles. We found that horizontal streaks were associated with side-facing eyes, which may both facilitate panoramic vision. Previous studies observed that some species with side-facing eyes have an area centralis shifted towards the temporal side of the retina, such that the high acuity region would project forward, but this relationship had not been tested quantitatively. We found that the temporal distance of the area centralis from the center of the retina was inversely correlated with orbit convergence, as predicted. Our work shows a strong relationship between orbit convergence and retinal specializations. We find support that both visual ecology and functional interactions among traits play important roles in the evolution of some ocular traits across mammals.
Bats from the Colombian Caribbean Reveal a new subtype of Influenza A (H18N12)
Authors: Echeverri-De la Hoz Daniel , Martínez-Bravo Caty , Gastelbondo-Pastrana Bertha , Rivero Ricardo , Lopez Yesica , Hoyos Richard , Alemán Maira , Garay Evelin , Bertel Valeria , Arrieta Germán , Ramírez Juan David , Mattar Salim 
Published: August 2024

AbstractInfluenza viruses have an excellent capacity for mutation and adaptation in mammalian hosts, which makes them viruses of medical and veterinary importance. Influenzaviruses have been studied mainly in birds but minor in bats. It is unknown whether Chiroptera are reservoirs of influenza viruses. However, circulation in bats showed molecular divergence from H17N10 (Guatemala) and H18N11 (Peru), and they were designated as new subtypes. The study aimed to characterize the influenza A virus detected in the fishing batNoctilio albiventris. A surveillance study of pathogens of public health interest was carried out; rectal samples were taken from four fishing bats (N. albiventris) captured in Talaigua Nuevo, Bolívar, Colombia. The samples were sequenced by NGS using DNBseq (MGI-G50®) and analyzed with bioinformatics tools. Eight viral contigs associated with the Orthomyxoviridae family were obtained. The identified segments showed around 90% similarity with H18N11, except for the neuraminidase (N). The phylogenetic analysis of the N protein showed the appearance of a basal branch to the N11 subtype, and the molecular clock indicates that it does not share a recent common ancestor. 3D modeling indicates that the N protein ofN. albiventrispresents three mutations (K363R, T242K, and I139V) near the hypothetical active site of the protein. These mutations potentially increase the interaction with the HLA-DR of bats, which could have significant implications for the virus’s behavior. The phylogenetic, evolutionary, and antigenic divergence of the N protein ofN. albiventrissuggests a new subtype called H18N12. Its role as a pathogen must be studied.
Integrative genetic analysis reveals new relationships between intraocular pressure, glaucoma and ischemic stroke risk: A study based on combined SNP-to-gene, mendelian randomization and pathway investigations
Authors: Zhang Qi , Hu Di , Lin Zenan , Jiang Junhong 
Published: August 2024

AbstractBackgroundIschemic stroke (IS) is a leading cause of death in elderly people. Previous studies on exploring the association between intraocular pressure (IOP), glaucoma and the IS risk provided inconsistent results and unclear elucidations.MethodsHere, multiple genetic approaches were employed to investigate the possible causality between these traits. First, we performed the traditional bidirectional mendelian randomization (MR) study to explore the causal relationship between IOP, glaucoma and IS. Second, the SNPs selected as instrumental variables for IOP and primary open-angle glaucoma (POAG) were mapped to relevant genes by the novel combined SNP-to-gene (cS2G) method. The genes with significant causal effects on IS were then introduced to the gene ontology (GO), pathway and colocalization analyses. Third, the partitioned heritability analysis was also performed to evaluate the genome complexity with the Linkage Disequilibrium Score (LDSC) tool. Fourth, we also performed single SNP mendelian randomization (SSMR) study to find the SNPs of IOP and glaucoma, which had significant causal influence on IS risk. Then, they were introduced to the cytogenetic investigation. The multiple variable MR (MVMR) was applied to assess the independence of the causal effect of the exposures.ResultsThe MR results supported the view that the elevated IOP and POAG may contribute to the IS risk, but not vice versa. By using the cS2G approach, we identified 31 and 3 genes which may play key roles in the IOP- and POAG-induced IS risk, respectively. The GO and pathway analyses indicated the olfactory pathway to be a crucial pathway in the IOP-associated mechanism. The colocalization study strengthened the causal implications of genesCDKNA2AandCDKN2B-AS1between POAG and IS. The partitioned heritability analysis showed that the most enriched categories for both IOP and POAG were regulatory-associated terms such as the Super-enhancer. The SSMR study demonstrated that the IOP-associated SNPs with causal effects on IS were located majorly in chromosomes 1 and 11, while the POAG-associated ones were mostly found in chromosomes 9 and 4. The MVMR confirmed that the causal effects of IOP and POAG were not independent from each other.ConclusionsThis work provides novel evidences to support the causal implications between IOP, POAG and IS, and offered putative pathway and genes for managing IOP and POAG in IS.
Decomposing Imaginary-Time Feynman Diagrams Using Separable Basis Functions: Anderson Impurity Model Strong-Coupling Expansion
Authors: Kaye Jason , Huang Zhen , Strand Hugo U. R. , Golež Denis 
Published: August 2024

We present a deterministic algorithm for the efficient evaluation of imaginary-time diagrams based on the recently introduced discrete Lehmann representation (DLR) of imaginary-time Green’s functions. In addition to the efficient discretization of diagrammatic integrals afforded by its approximation properties, the DLR basis is separable in imaginary-time, allowing us to decompose diagrams into linear combinations of nested sequences of one-dimensional products and convolutions. Focusing on the strong-coupling bold-line expansion of generalized Anderson impurity models, we show that our strategy reduces the computational complexity of evaluating an Mth-order diagram at inverse temperature β and spectral width ωmax from O((βωmax)2M−1) for a direct quadrature to O(M(log(βωmax))M+1), with controllable high-order accuracy. We benchmark our algorithm using third-order expansions for multiband impurity problems with off-diagonal hybridization and spin-orbit coupling, presenting comparisons with exact diagonalization and quantum Monte Carlo approaches. In particular, we perform a self-consistent dynamical mean-field theory calculation for a three-band Hubbard model with strong spin-orbit coupling representing a minimal model of Ca2RuO4, demonstrating the promise of the method for modeling realistic strongly correlated multiband materials. For both strong and weak coupling expansions of low and intermediate order, in which diagrams can be enumerated, our method provides an efficient, straightforward, and robust blackbox evaluation procedure. In this sense, it fills a gap between diagrammatic approximations of the lowest order, which are simple and inexpensive but inaccurate, and those based on Monte Carlo sampling of high-order diagrams.

Published by the American Physical Society
2024