bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remote homolog detection places insect chemoreceptors in a cryptic protein superfamily spanning the tree of life
Authors: Himmel Nathaniel J. , Moi David , Benton Richard 
Published: September 2023

SummaryMany proteins exist in the so-called “twilight zone” of sequence alignment, where low pairwise sequence identity makes it difficult to determine homology and phylogeny1, 2. As protein tertiary structure is often more conserved3, recent advances inab initioprotein folding have made structure-based identification of putative homologs feasible4–6. However, structural screening and phylogenetics are in their infancy, particularly for twilight zone proteins. We present a pipeline for the identification and characterization of distant homologs, and apply it to 7-transmembrane domain ion channels (7TMICs), a protein group founded by insect Odorant and Gustatory receptors. Previous sequence and limited structure-based searches identified putatively-related proteins, mainly in other animals and plants7–10. However, very few 7TMICs have been identified in non-animal, non-plant taxa. Moreover, these proteins’ remarkable sequence dissimilarity made it uncertain if disparate 7TMIC types (Gr/Or, Grl, GRL, DUF3537, PHTF and GrlHz) are homologous or convergent, leaving their evolutionary history unresolved. Our pipeline identified thousands of new 7TMICs in archaea, bacteria and unicellular eukaryotes. Using graph-based analyses and protein language models to extract family-wide signatures, we demonstrate that 7TMICs have structure and sequence similarity, supporting homology. Through sequence and structure-based phylogenetics, we classify eukaryotic 7TMICs into two families (Class-A and Class-B), which are the result of a gene duplication predating the split(s) leading to Amorphea (animals, fungi and allies) and Diaphoretickes (plants and allies). Our work reveals 7TMICs as a cryptic superfamily with origins close to the evolution of cellular life. More generally, this study serves as a methodological proof of principle for the identification of extremely distant protein homologs.
Stimulation of median raphe terminals in dorsal CA2 reduces social investigation in male mice specifically investigating social stimulus of ovariectomized female mice
Authors: Lee Su Hyun , Cilz Nicholas I. , Avram Sarah K. Williams , Cymerblit-Sabba Adi , Song June , Courey Karis , Howley Austin , Cooke Michaela E. , Young W. Scott 
Published: September 2023

AbstractThe cornu ammonis area 2 (CA2) region is essential for social behaviors, especially in social aggression and social memory. Recently, we showed that targeted CA2 stimulation of vasopressin presynaptic fibers from the paraventricular nuclei of hypothalamus strongly enhances social memory in mice. In addition, the CA2 area of the mouse hippocampus receives neuronal inputs from other regions including the septal nuclei, the diagonal bands of Broca, supramammillary nuclei, and median raphe nucleus. However, the functions of these projections have been scarcely investigated. A functional role of median raphe (MR) – CA2 projection is supported by the MR to CA2 projections and 82% reduction of hippocampal serotonin (5-HT) levels following MR lesions. Thus, we investigated the behavioral role of presynaptic fibers from the median raphe nucleus projecting to the dorsal CA2 (dCA2). Here, we demonstrate the optogenetic stimulation of 5-HT projections to dCA2 from the MR do not alter social memory, but instead reduce social interaction. We show that optical stimulation of MR fibers excites interneurons in the stratum radiatum (SR) and stratum lacunosum moleculare (SLM) of CA2 region. Consistent with these observations, we show that bath application of 5-HT increases spontaneous GABA release onto CA2 pyramidal neurons and excites presumed interneurons located in the SR/SLM. This is the first study, to our knowledge, which investigates the direct effect of 5-HT release from terminals onto dCA2 neurons on social behaviors. This highlights the different roles for these inputs (i.e., vasopressin inputs regulating social memory versus serotonin inputs regulating social interaction).
Natural gene variation inCannabis sativaunveils a key region of cannabinoid synthase enzymes
Authors: Villard Cloé , Bayer Christian , Medici Nora Pasquali , van de Peppel Arjen C. , Cankar Katarina , Verstappen Francel , Kappers Iris F. , Schranz M. Eric , Daniel Bastian , van Velzen Robin 
Published: September 2023

AbstractCannabinoids are well-known specialised metabolites from the plantCannabis sativaL. (cannabis). They exhibit various therapeutical to intoxicating psychoactive effects and have potential for medicinal applications. Among the enzymes involved in cannabinoid biosynthesis, cannabinoid oxidocyclases such as the tetrahydrocannabinolic acid (THCA) synthase play a key role in determining cannabis chemotype. To improve our understanding of cannabinoid oxidocyclase structure-function relationship, we proposed a new approach to targeted mutagenesis. By reviewing cannabis natural variation, three cannabinoid oxidocyclase mutations (S355N, CONF, G376R) associated to atypical plant chemotypes were selected.In-vitrocharacterization of THCA synthase mutants demonstrated these mutations significantly impact enzyme activity, correlating with the associated chemotype: S355N nearly inactivated the THCA synthase, CONF impaired CBGA metabolization and altered product specificity, while G376R drastically reduced enzyme activity and altered product specificity.In-silicodocking experiments permitted to model the successive steps of THCA synthase substrate metabolization, revealing that the three mutations hamper substrate binding. Collectively, our results demonstrated how plant diversity can be leveraged to guide enzyme targeted mutagenesis, highlighted a key region of cannabinoid oxidocyclases, and permitted the establishment of a new model of the THCA synthase catalytic mechanism. This provides new insights into enzyme function, which can ultimately help developing medicinal cannabis cultivars and cannabinoid biotechnological production.
Role of IL-6 and IL10 immune response genes against nematodeHaemonchus contortusin ovis aries- a novel report
Authors: Rawat Kavita , Pal Aruna , Banerjee Samiddha , Pal Abantika , Chatterjee Paresh Nath , Batabyal Subhasis 
Published: September 2023

AbstractHaemonchus contortusis one of the most deadly parasites affecting sheep industry causing heavy economic loss. In our earlier study, we have reported RIGI, an earlier established antiviral molecule and CD14 (an earlier established antibacterial molecule) to have potential role in antiparasitic immunity for the first time. In this current study, we aim to clone and sequence the IL-6 and IL10 genes in sheep (Ovis aries) and utilized bioinformatics methods to analyze and compare the functional and structural domains of peptides produced from IL6 and IL10. Furthermore, the study explored these domains in three-dimensional structures. The findings of this study provide molecular characterization of IL-6 and IL10 in sheep, which is essential for advancing our understanding of functional immune responses in this animal. We report IL6 and IL10 to have potential antiparasitic role against H. contortus for first time. The production of these molecules opens up possibilities for its potential use as recombinant proteins to manipulate the immune response. Evaluating its value in vaccine research and gaining a broader understanding of its role in immune responses becomes feasible with the availability of IL-6 and IL10. Moreover, the differential mRNA expression levels of IL-6, IL10 between healthy and diseased sheep indicate its crucial role in maintaining homeostasis and mounting immune responses. IL10 acts as receptor for H. contortus. The identification of this immune-responsive gene also offers new avenues for investigating long-term resistance to H. contortus infection in sheep.
Logistic tumor-population growth and ghost-points symmetry
Authors: Pasetto Stefano , Harshe Isha , Brady-Nicholls Renee , Gatenby Robert. A. , Enderling Heiko 
Published: September 2023

AbstractThe observed time evolution of a population is well approximated by a logistic function in many research fields, including oncology, ecology, chemistry, demography, economy, linguistics, and artificial neural networks. Initial growth is exponential at a constant rate and capped at a limit size, i.e., the carrying capacity. In mathematical oncology, the carrying capacity has been postulated to be co-evolving and thus patient-specific. As the relative tumor-over-carrying capacity ratio may be predictive and prognostic for tumor growth and treatment response dynamics, it is paramount to estimate it from limited clinical data.We show that exploiting the logistic function’s rotation symmetry can help estimate the population’s growth rate and carry capacity from fewer data points than conventional regression approaches. We test this novel approach against a classic oncology database of logistic tumor growth, achieving a 30% to 40% reduction in the time necessary to correctly estimate the logistic growth rate and carrying capacity. Our results will improve tumor dynamics forecasting and augment the clinical decision-making process.
Predicting RNA-seq coverage from DNA sequence as a unifying model of gene regulation
Authors: Linder Johannes , Srivastava Divyanshi , Yuan Han , Agarwal Vikram , Kelley David R. 
Published: September 2023

AbstractSequence-based machine learning models trained on genome-scale biochemical assays improve our ability to interpret genetic variants by providing functional predictions describing their impact on the cis-regulatory code. Here, we introduce a new model, Borzoi, which learns to predict cell- and tissue-specific RNA-seq coverage from DNA sequence. Using statistics derived from Borzoi’s predicted coverage, we isolate and accurately score variant effects across multiple layers of regulation, including transcription, splicing, and polyadenylation. Evaluated on QTLs, Borzoi is competitive with, and often outperforms, state-of-the-art models trained on individual regulatory functions. By applying attribution methods to the derived statistics, we extract cis-regulatory patterns driving RNA expression and post-transcriptional regulation in normal tissues. The wide availability of RNA-seq data across species, conditions, and assays profiling specific aspects of regulation emphasizes the potential of this approach to decipher the mapping from DNA sequence to regulatory function.
Navigating Pubertal Goldilocks: The Optimal Pace for Hierarchical Brain Organization
Authors: Szakács Hanna , Mutlu Murat Can , Balestrieri Giulio , Gombos Ferenc , Braun Jochen , Kringelbach Morten L. , Deco Gustavo , Kovács Ilona 
Published: September 2023

AbstractAdolescence is a timed process with an onset, tempo, and duration. Nevertheless, the temporal dimension, especially the pace of maturation, remains an insufficiently studied aspect of developmental progression. This study focuses on the modifications due to the different timings of developmental shifts during adolescence and addresses the impact of adolescent maturation on brain development. To reveal potential relationships between pubertal pace and the advancement of brain organisation, we analyse the connection between skeletal age-based maturation stages and hierarchical organisation in the temporal dynamics of resting-state EEG recordings (alpha frequency range). By adopting skeletal maturity as a proxy for pubertal progress and employing entropy production to measure hierarchical brain organisation, our findings indicate that an average maturational trajectory optimally aligns with cerebral hierarchical order. Adaptive developmental plasticity may not fully compensate for accelerated or decelerated timelines, potentially increasing the risk of behavioural problems and psychiatric disorders consequent to such alterations.
CHARMM-GUI Multicomponent Assembler for Modeling and Simulation of Complex Multicomponent Systems
Authors: Kern Nathan R. , Lee Jumin , Choi Yeol Kyo , Im Wonpil 
Published: September 2023

AbstractAtomic-scale molecular modeling and simulation are powerful tools for computational biology. However, constructing models with large, densely packed molecules, non-water solvents, or with combinations of multiple biomembranes, polymers, and nanomaterials remains challenging and requires significant time and expertise. Furthermore, existing tools do not support such assemblies under the periodic boundary conditions (PBC) necessary for molecular simulation. Here, we describeMulticomponent Assemblerin CHARMM-GUI that automates complex molecular assembly and simulation input preparation under the PBC. We demonstrate its versatility by preparing 6 challenging systems with varying density of large components: (1) solvated proteins, (2) solvated proteins with a pre-equilibrated membrane, (3) solvated proteins with a sheet-like nanomaterial, (4) solvated proteins with a sheet-like polymer, (5) a mixed membrane-nanomaterial system, and (6) a sheet-like polymer with gaseous solvent.Multicomponent Assembleris expected to be a unique cyberinfrastructure to facilitate innovative studies of complex interactions between small (organic and inorganic) molecules, biomacromolecules, polymers, and nanomaterials.
Hybrid Amyloid Quantum Dot Nanoassemblies to Probe Neuroinflammatory Damage
Authors: Chiang Wesley , Urban Jennifer M. , Yanchik-Slade Francine , Stout Angela , Nilsson Bradley L. , Gelbard Harris A. , Krauss Todd D. 
Published: September 2023

ABSTRACTVarious oligomeric species of amyloid-beta have been proposed to play different immunogenic roles in the cellular pathology of Alzheimer’s Disease. However, investigating the role of a homogenous single oligomeric species has been difficult due to highly dynamic oligomerization and fibril formation kinetics that convert between many species. Here we report the design and construction of a quantum dot mimetic for larger spherical oligomeric amyloid species as an “endogenously” fluorescent proxy for this cytotoxic species to investigate its role in inducing inflammatory and stress response states in neuronal and glial cell types.
Myostatin is a major endocrine driver of follicle-stimulating hormone synthesis
Authors: Ongaro Luisina , Zhou Xiang , Wang Ying , Zhou Ziyue , Schultz Hailey , Buddle Evan R.S. , Brûlé Emilie , Lin Yeu-Farn , Schang Gauthier , Castonguay Roselyne , Liu Yewei , Su Gloria H. , Seidah Nabil , Ray Kevin C. , Karp Seth J. , Boehm Ulrich , Lee Se-Jin , Bernard Daniel J. 
Published: September 2023

AbstractMyostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. Here, we report a functional role for myostatin as an endocrine hormone directly promoting pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor β family, the activins. The results both challenge activin’s eponymous role in FSH synthesis and establish an endocrine axis between skeletal muscle and the pituitary gland. The data also suggest that efforts to antagonize myostatin to treat muscle wasting disorders may have unintended consequences on fertility.One-Sentence SummaryHormone synthesis and reproduction depend on crosstalk between skeletal muscle and the pituitary gland.
Chromatographic, Immuno-inflammatory, and nephrotoxic Assessment of selected culinary oils in Experimental Models
Authors: Okoye Jude Ogechukwu , Delu-Mozie Chiagoziem Moral , Nwachioma Maureen Ugochukwu , Modozie Uchenna Benjamin 
Published: September 2023

AbstractBackgroundDietary oils are crucial for everyday human nutrition. They contain essential fatty acids and support a range of physiological functions. However, concerns regarding their possible toxicity have been expressed, particularly concerning the elevation of cholesterol levels, particularly Low-Density Lipoprotein (LDL). This study investigated the composition of selected dietary oils and determined their physiologic effects and the micro-architectural integrity of the kidney.MethodsIn this experimental study, 30 Albino rats were used in this study. The animals were divided into 5 groups: Groups A, B, C, D, and E (n=6 each). Group A (control) received normal rat pellets only while Groups B, C, D, and E received rat pellets mixed with Avocado oil, Coconut oil, Palm oil, and Peanut oil. Blood samples were drawn, and kidneys were excised. Data generated from biochemical, haematological, and histological investigations were analyzed using ANOVA, Pearson’s correlation, andPost hoctest. Significance was set at p< 0.05.ResultsThe results indicated significant differences in fatty acid levels between oils (p< 0.05). Higher levels of oleic acid, lauric acid, palmitic acid, and oleic acid were found in coconut oil, Palm oil, Avocado oil, and Peanut oil, respectively. Significant differences in urea levels were observed between the control group and other treatment groups (p= 0.001). Group B had lower levels of triglyceride while groups C and D had higher levels of LDL and organ weight, respectively compared with the control group (p= 0.035, 0.042, and 0.008, respectively). Group E had a higher neutrophil-lymphocyte ratio, mean corpuscular haemoglobin concentration, lower lymphocyte-monocyte ratio, and red cell distribution width (p= 0.325, 0.025, 0.068, and 0.053, respectively). Kidney sections revealed varying degrees of necrosis and inflammation,ConclusionThe study provides valuable insights indicating potential oil-induced effects on health. It advises caution during the application of the oils in culinary activities.
Scoring alignments by embedding vector similarity
Authors: Ashrafzadeh Sepehr , Golding G. Brian , Ilie Silvana , Ilie Lucian 
Published: September 2023

AbstractSequence similarity is of paramount importance in biology, as similar sequences tend to have similar function and share common ancestry. Scoring matrices, such as PAM or BLO-SUM, play a crucial role in all bioinformatics algorithms for identifying similarities, but have the drawback that they are fixed, independent of context. We propose a new scoring method for amino acid similarity that remedies this weakness, being contextually dependent. It relies on recent advances in deep learning architectures that employ self-supervised learning in order to leverage the power of enormous amounts of unlabelled data to generate contextual embeddings, which are vector representations for words. These ideas have been applied to protein sequences, producing embedding vectors for protein residues. We propose theE-scorebetween two residues as the cosine similarity between their embedding vector representations. Thorough testing on a wide variety of reference multiple sequence alignments indicate that the alignments produced using the newE-score method, especially ProtT5-score, are significantly better than those obtained using BLOSUM matrices. The new method proposes to change the way alignments are computed, with far reaching implications in all areas of textual data that use sequence similarity. The program to compute alignments based on variousE-scores is available as a web server ate-score.csd.uwo.ca. The source code is freely available for download fromgithub.com/lucian-ilie/E-score.
Foodscapes for Salmon and Other Mobile Consumers in River Networks
Authors: Rossi Gabriel J. , Bellmore J. Ryan , Armstrong Jonathan B. , Jeffres Carson , Naman Sean M. , Carlson Stephanie M. , Grantham Theodore E. , Kaylor Matthew J. , White Seth , Katz Jacob , Power Mary E. 
Published: September 2023

ABSTRACTMobile consumers track fluctuating resources across heterogeneous landscapes to grow and survive. In river networks, the abundance and accessibility of food and the costs of foraging vary between habitats and through time, providing a shifting mosaic of growth opportunities for mobile consumers. However, a framework integrating the spatiotemporal dynamics of growth potential within riverscapes has been lacking. Here we present the concept of “foodscapes” to depict the dynamic changes in food abundance, food accessibility, and foraging costs that contribute to spatial and temporal variation of fish growth in rivers. Drawing on case studies of salmonid fishes from Alaska to California, we illustrate that “healthy” foodscapes provide a plethora of foraging opportunities—promoting diverse life history strategies that potentially enhance population stability. We identify knowledge gaps in understanding foodscapes, and approaches for management that focus on restoring trophic pathways which support diverse foraging and growth opportunities for fish in river networks.
Differential reaction norms to ocean acidification in two oyster species from contrasting habitats
Authors: Caillon Coline , Pernet Fabrice , Lutier Mathieu , Poi Carole Di 
Published: September 2023

ABSTRACTOcean acidification (OA), a consequence of the increase in anthropogenic emissions of carbon dioxide, causes major changes in the chemistry of carbonates in the ocean with deleterious effects on calcifying organisms. The pH/pCO2range to which species are exposed in nature is important to consider when interpreting the response of coastal organisms to OA. In this context, emerging approaches, which assess the reaction norms of organisms to a wide pH gradient, are improving our understanding of tolerance thresholds and acclimation potential to OA. In this study, we decipher the reaction norms of two oyster species living in contrasting habitats: the intertidal oysterCrassostrea gigasand the subtidal flat oysterOstrea edulis, which are two economically and ecologically valuable species in temperate ecosystems. Six-month-old oysters of each species were exposed in common garden for 48 days to a pH gradient ranging from 7.7 to 6.4 (total scale). Both species are tolerant down to a pH of 6.6 with high plasticity in fitness-related traits such as survival and growth. However, oysters undergo remodelling of membrane fatty acids to cope with decreasing pH along with shell bleaching impairing shell integrity and consequently animal fitness. Finally, our work reveals species-specific physiological responses and highlights that intertidalC. gigasseems to have a better acclimation potential to rapid and extreme OA changes thanO. edulis. Overall, our study provides important data about the phenotypic plasticity and its limits in two oyster species, which is essential for assessing the challenges posed to marine organisms by OA.