bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resolving the pharmacological redox-sensitivity of SARS-CoV-2 PLpro in drug repurposing screening enabled identification of the competitive GRL-0617 binding site inhibitor CPI-169
Authors: Kuzikov Maria , Morasso Stefano , Reinshagen Jeanette , Wolf Markus , Monaco Vittoria , Cozzolino Flora , Grdadolnik Simona Golič , Šket Primož , Plavec Janez , Iaconis Daniela , Summa Vincenzo , Esposito Francesca , Tramontano Enzo , Monti Maria , Beccari Andrea R. , Windshügel Björn , Gribbon Philip , Storici Paola , Zaliani Andrea 
Published: October 2023

AbstractThe SARS CoV-2 Papain-Like protease has multiple roles in the viral replication cycle, related to both its polypeptide cleavage function and its capacity to antagonize host immune response. Targeting PLpro function is recognized as a promising mechanism to modulate viral replication whilst supporting host immune responses. However, development of PLpro specific inhibitors remains challenging. Upcoming studies revealed the limitation of reported inhibitors by profiling them through a pipeline of enzymatic, binding and cellular activity assays showing unspecific activity. GRL-0617 remained the only validated molecule with demonstrated anti-viral activity in cells. In this study we refer to the pitfalls of redox-sensitivity of PLpro. Using a screening-based approach to identify inhibitors of PLpro proteolytic activity, we made extensive efforts to validate the active compounds over a range of conditions and readouts, emphasising the need for comprehensive orthogonal data when profiling putative PLpro inhibitors. The remaining active compound CPI-169, showed to compete with GRL-0617 in NMR-based experiments, suggesting to share a similar binding mode, opening novel design opportunities for further developments as antiviral agents.Author summaryThe increasing knowledge about SARS-CoV-2 allowed the development of multiple strategies to contain the spread of COVID-19 infection. Nevertheless, effective antiviral pharmacological treatments are still rare and viral evolution allowed a fast adaptation and escape from available containment methods. The papain like protease (PLpro) has now become the next most promising SARS-CoV-2 therapeutic due to its multiple functions in virus replication cycle and antagonization of host immune response. However, due to inherent flexibility and sensitivity of this enzyme specific inhibitors are rare. Here we report on a screening strategy using repurposing of known drugs that takes into account PLpro characteristics to identify new inhibitors, showing the success of the approach by identifying CPI-169 that competitive targets the well described GRL-0617 inhibitor binding pocket of PLpro and helping to design further antiviral agents.
Partial information transfer from peripheral visual streams to foveal visual streams is mediated through local primary visual circuits
Authors: Costantino Andrea I. , Turner Benjamin O. , Williams Mark A. , Crossley Matthew J. 
Published: October 2023

AbstractA classic view holds that visual object recognition is driven through thewhatpathway in which perceptual features of increasing abstractness are computed in a sequence of different visual cortical regions. The cortical origin of this pathway, the primary visual cortex (V1), has a retinotopic organization such that neurons have receptive fields tuned to specific regions of the visual field. That is, a neuron that responds to a stimulus in the center of the visual field will not respond to a stimulus in the periphery of the visual field, and vice versa. However, despite this fundamental design feature, the overall processing of stimuli in the periphery – while clearly dependent on processing by neurons in the peripheral regions of V1 – can be clearly altered by the processing of neurons in the fovea region of V1. For instance, it has been shown that task-relevant, non-retinotopic feedback information about peripherally presented stimuli can be decoded in the unstimulated foveal cortex, and that the disruption of this feedback – through Transcranial Magnetic Stimulation or behavioral masking paradigms – has detrimental effects on same/different discrimination behavior. Here, we used fMRI multivariate decoding techniques and functional connectivity analyses to assess the nature of the information that is encoded in the periphery-to-fovea feedback projection and to gain insight into how it may be anatomically implemented. Participants performed a same/different discrimination task on images of real-world stimuli (motorbikes, cars, female and male faces) displayed peripherally. We were able to decode only a subset of these categories from the activity measured in peripheral V1, and a further reduced subset from the activity measured in foveal V1, indicating that the feedback from periphery to fovea may be subject to information loss. Functional connectivity analysis revealed that foveal V1 was functionally connected only to the peripheral V1 and not to later-stage visual areas, indicating that the feedback from peripheral to foveal V1 is likely implemented by neural circuits local to V1.
Finding regulatory modules of chemical reaction systems
Authors: Yamauchi Yuhei , Hishida Atsuki , Okada Takashi , Mochizuki Atsushi 
Published: October 2023

AbstractWithin a cell, numerous chemical reactions form chemical reaction networks (CRNs), which are the origins of cellular functions. We previously developed a theoretical method called structural sensitivity analysis (SSA) [1], which enables us to determine, solely from the network structure, the qualitative changes in the steady-state concentrations of chemicals resulting from the perturbations to a parameter. Notably, if a subnetwork satisfies specific topological conditions, it is referred to as a buffering structure, and the effects of perturbations to the parameter within the subnetwork are localized to the subnetwork (the law of localization) [2, 3]. A buffering structure can be the origin of modularity in the regulation of cellular functions generated from CRNs. However, an efficient method to search for buffering structures in a large CRN has not yet been established. In this study, we proved the “inverse theorem” of the law of localization, which states that a certain subnetwork exhibiting a confined response range is always a buffering structure. In other words, we are able to identify buffering structures in terms of sensitivities rather than the topological conditions. By leveraging this property, we developed an algorithm to enumerate all buffering structures for a given network by calculating the sensitivity. In addition, using the inverse theorem, we demonstrated that the hierarchy among nonzero responses is equivalent to the hierarchy of buffering structures. Our method will be a powerful tool for understanding the regulation of cellular functions generated from CRNs.
Hidden evolutionary constraints dictate the retention of coronavirus accessory genes
Authors: Goldstein Stephen A. , Feeley Teagan M. , Babler Kristina M. , Hilbert Zoë A. , Downhour Diane M. , Moshiri Niema , Elde Nels C. 
Published: October 2023

SummaryCoronaviruses exhibit many mechanisms of genetic innovation, including the acquisition of accessory genes that originate by capture of cellular genes or through duplication of existing viral genes. Accessory genes influence viral host range and cellular tropism, but little is known about how selection acts on these variable regions of virus genomes. We used experimental evolution of mouse hepatitis virus (MHV) encoding a cellular AKAP7 phosphodiesterase and an inactive native phosphodiesterase, NS2 to model the evolutionary fate of accessory genes. After courses of serial infection, the gene encoding inactive NS2, ORF2, unexpectedly remained intact, suggesting it is under cryptic constraint uncoupled from the function of NS2. In contrast, AKAP7 was retained under strong selection but rapidly lost under relaxed selection. Experimental evolution also led to altered viral replication in a cell type-specific manner and changed the relative proportions of subgenomic viral RNA in plaque-purified viral isolates, revealing additional mechanisms of adaptation. Guided by the retention of ORF2 and similar patterns in related betacoronaviruses, we analyzed ORF8 of SARS-CoV-2, which arose via gene duplication and contains premature stop codons in several globally successful lineages. As with MHV ORF2, the coding-defective SARS-CoV-2 ORF8 gene remains largely intact, mirroring patterns observed during MHV experimental evolution, challenging assumptions on the dynamics of gene loss in virus genomes and extending these findings to viruses currently adapting to humans.
Adaptive genomic variation is linked to a climatic gradient in a social wasp
Authors: Cook Hannah L. , Miller Sara E. , Giri Gilbert , Loope Kevin J. , Sheehan Michael J. , Uy Floria M.K. 
Published: October 2023

ABSTRACTSpecies vary in their ability to adapt to rapid changes, with the presence of genetic variation often facilitating long-term evolutionary responses. Given the impending threat of climate change, it is critical to investigate how genetic variation facilitates persistence and possible range expansion in animals. Here, we combine genomic and climatic data to characterize the drivers of local adaptation in the widely distributed, social waspMischocyttarus mexicanus cubicola. Using whole genome sequence data, we show that adaptive genomic variation is linked to a climatic gradient across the broad distribution of this species. We found strong population structure, dividing the species into two genetic clusters that follow subtropical and temperate regions. Patterns of gene flow across the range deviate from those expected by isolation by distance alone with climatic differences resulting in reduced gene flow even between adjacent populations. Importantly, genotype-environment analyses reveal candidate single nucleotide polymorphism (SNPs) associated with temperature and rainfall, suggesting adaptation for thermal and desiccation tolerance. In particular, candidate SNPs in or near mitochondrial genesND5,CO1, andCOIIIare linked to cold tolerance and metabolism. Similarly, theGldnuclear gene shown to mediate cold hardiness and cuticle formation, shows two candidate SNPs with non-synonymous mutations unique to temperate populations. Together, our results reveal candidate SNPs consistent with local adaptation to distinct climatic conditions. Thus, the integration of genomic and climatic data can be a powerful approach to predict vulnerability and persistence of species under rapid climate change.
Storage cell proliferation during somatic growth establishes that tardigrades are not eutelic organisms
Authors: Quiroga-Artigas Gonzalo , Moriel-Carretero María 
Published: October 2023

ABSTRACTTardigrades, microscopic ecdysozoans renowned for their resilience to extreme environments, have long been thought to maintain a constant cell number after completing embryonic development, a phenomenon known as eutely. However, sporadic reports of dividing cells have raised questions about this assumption. In this study, we investigated whether tardigrades truly exhibit a fixed cell number during somatic growth using the model speciesHypsibius exemplaris. Comparing hatchlings to adults, we observed an overall increase in the number of storage cells, a tardigrade cell type involved in nutrient storage. To assess cell proliferation, we monitored DNA replication via the incorporation of the thymidine analog 5-ethynyl-2’-deoxyuridine (EdU). A significantly higher number of storage cells incorporated EdU while animals were still growing. Starvation halted both animal growth and storage cell proliferation, linking the two processes. Additionally, we found that EdU incorporation in storage cells is associated with molting, a critical process in tardigrade post-embryonic development, since it involves cuticle renewal to enable further growth. Finally, we show that hydroxyurea, a drug that slows down DNA replication progression, strongly reduces the number of EdU+cells and results in molting-related fatalities. Our data not only provide a comprehensive picture of replication events during tardigrade growth but also highlight the critical role of proper DNA replication in tardigrade molting and survival. This study definitively challenges the notion of eutely in tardigrades, offering promising avenues for exploring cell cycle, replication stress, and DNA damage management in these remarkable creatures as genetic manipulation techniques emerge within the tardigrade research field.SIGNIFICANCETardigrades, microscopic invertebrate animals renowned for their resilience in extreme conditions, have traditionally been considered eutelic, implying little to no somatic cell proliferation during their growth. However, a few isolated reports challenged this notion. In this study, using the emerging modelHypsibius exemplaris, we provide unequivocal molecular evidence of DNA replication and proliferation in a specific tardigrade cell type called ‘storage cells’, primarily involved in nutrient storage, throughout the animal’s growth. Furthermore, we demonstrate that this proliferation is associated with the timing of cuticle molting, and we highlight the critical role of proper DNA replication in tardigrade molting and survival. Our research definitively resolves the long-standing controversy surrounding tardigrade eutely, opening up uncharted territories in tardigrade research.
IDENTIFICATION OF CANDIDATE GENES AND PATHWAYS LINKED TO THE TEMPERAMENT TRAIT IN SHEEP
Authors: Romaniuk Estefanía , Vera Brenda , Peraza Pablo , Ciappesoni Gabriel , Damián Juan Pablo , van Lier Elize 
Published: October 2023

AbstractTemperament can be defined as the emotional variability among animals of the same species in response to the same stimulus, thus being able to group animals by reactivity as nervous, intermediate or calm. The main objective for this study was to identify genomic regions with the temperament phenotype measured by the Isolation Box Test (IBT) by single-step genome wide association studies (ssGWAS). The database used consisted of 4,317 animals with temperament records, and 1,697 genotyped animals with 38,268 effective SNP after quality control. We identified three genomic regions that explained the greatest percentage of the genetic variance, resulting in 25 SNP associated with candidate genes on chromosomes 6, 10 and 21. A total of nine candidate genes are reported for the temperament trait, which are:PYGM,SYVN1,CAPN1,FADS1,SYT7,GRID2,GPRIN3,EEF1A1andFRY, linked to energetic activity of the organism, synaptic transmission, meat tenderness and calcium associated activities. This is the first study to identify these genetic variants associated with temperament in sheep, leading the opportinuty to potential applications of these molecular markers in future behavioral research.
Low- and high-level information analyses of transcriptome connecting endometrial-decidua-placental origin of preeclampsia subtypes: A preliminary study
Authors: Sufriyana Herdiantri , Wu Yu-Wei , Su Emily Chia-Yu 
Published: October 2023

BackgroundExisting proposed pathogenesis for preeclampsia (PE) was only applied for early onset subtype and did not consider pre-pregnancy and competing risks. We aimed to decipher PE subtypes by identifying related transcriptome that represents endometrial maturation and histologic chorioamnionitis.MethodsWe utilized eight arrays of mRNA expression for discovery (n=289), and other eight arrays for validation (n=352). Differentially expressed genes (DEGs) were overlapped between those of: (1) healthy samples from endometrium, decidua, and placenta, and placenta samples under histologic chorioamnionitis; and (2) placenta samples for each of the subtypes. They were all possible combinations based on four axes: (1) pregnancy-induced hypertension; (2) placental dysfunction-related diseases (e.g., fetal growth restriction [FGR]); (3) onset; and (4) severity.ResultsThe DEGs of endometrium at late-secretory phase, but none of decidua, significantly overlapped with those of any subtypes with: (1) early onset (p-values ≤0.008); (2) severe hypertension and proteinuria (p-values ≤0.042); or (3) chronic hypertension and/or severe PE with FGR (p-values ≤0.042). Although sharing the same subtypes whose DEGs with which significantly overlap, the gene regulation was mostly counter-expressed in placenta under chorioamnionitis (n=13/18, 72.22%; odds ratio [OR] upper bounds ≤0.21) but co-expressed in late-secretory endometrium (n=3/9, 66.67%; OR lower bounds ≥1.17). Neither the placental DEGs at first-nor second-trimester under normotensive pregnancy significantly overlapped with those under late-onset, severe PE without FGR.ConclusionsWe identified the transcriptome of endometrial maturation in placental dysfunction that distinguished early- and late-onset PE, and indicated chorioamnionitis as a PE competing risk. This study implied a feasibility to develop and validate the pathogenesis models that include pre-pregnancy and competing risks to decide if it is needed to collect prospective data for PE starting from pre-pregnancy including chorioamnionitis information.
Valuing carbon sequestration by Antarctic krill faecal pellets
Authors: Cavan E. L. , Mackay N. , Hill S.L. , Atkinson A. , Belcher A. , Visser A. 
Published: October 2023

AbstractMarine life contribute to carbon stores helping lock carbon away from the atmosphere. Open-ocean pelagic ecosystems are vastly under-reported in terms of carbon sequestration conservation potential, compared to coastal vegetation ‘blue carbon’ systems. Here we show that a harvested organism, Antarctic krill, has similar carbon sequestration potential through its sinking faecal pellets as coastal blue carbon stores, namely seagrasses, mangroves and marshes. Building upon recent advances in krill abundance and faecal pellet carbon flux data, and combining these with an ocean circulation model, we show that from Austral spring to early autumn Antarctic krill sequester 20 Mt C into the deep ocean for at least 100 years. This equates to USD$ 4 - 46 billion per spring/summer season depending on the price of carbon. The footprint of remineralised krill pellet carbon has a global extent, with some reaching as far as the North Pacific. The vast area of ocean krill inhabit and their high abundance make their total carbon sequestered each year similar to that from coastal vegetated blue carbon stores. As Antarctic krill are being impacted by rapid polar climate change and they are harvested, both krill populations and their habitat warrant protection to preserve this valuable carbon sink.
Metamorphosis reverses the behavioural phenotype inRana arvalisalong a latitudinal gradient
Authors: Cortazar-Chinarro Maria , Corral-Lopez Alberto , Lüdtke Deike U. , Tegner Fredrik , Luquet Emilien , Laurila Anssi 
Published: October 2023

ABSTRACTUnderstanding how demographic processes and environmental conditions shape behavioural variation across populations is pivotal in evolutionary ecology. However, the role that such processes play in the link between behaviour and life-history traits across populations remains largely unclear.The moor frog (Rana arvalis) has colonized Sweden via two distinct routes from south via Denmark and from north via Finland. We collectedR. arvaliseggs from multiple populations along a 1700 km latitudinal gradient across Northern Europe and raised tadpoles in a common garden experiment. We assessed developmental growth and proactivity levels in ca. 300 individuals at two key stages of anuran larval development: tadpoles (Gosner stage 32) and froglets (Gosner stage 46).We found strong behavioural differences along the latitudinal gradient and between developmental stages. Tadpoles from northernmost populations were bolder (shorter times to leave a shelter) and showed higher activity levels in an open field test compared to those from southern populations.However, these behavioural patterns reversed at the froglet stage, with individuals from northern populations showing reduced proactivity that those from southern populations. Further analyses indicated significant associations between developmental growth and boldness, with contrasting patterns across developmental stages and colonization routes.In line with recent revisitations of the pace-of-life syndrome theory (POLS) for animal personality, our findings suggest a decoupling of correlations between behaviour and life history traits across ontogeny, likely reflecting adaptive responses to divergent ecological and demographic constraints along the latitudinal gradient.
Amelioration of Functional and Histopathological Consequences after Spinal Cord Injury through Phosphodiesterase 4D (PDE4D) Inhibition
Authors: Schepers Melissa , Hendrix Sven , Mussen Femke , van Breedam Elise , Ponsaerts Peter , Lemmens Stefanie , Hellings Niels , Ricciarelli Roberta , Fedele Ernesto , Bruno Olga , Brullo Chiara , Prickaerts Jos , Van Broeckhoven Jana , Vanmierlo Tim 
Published: October 2023

AbstractSpinal cord injury (SCI) is a life-changing event that severely impacts the patient’s quality of life. Two key strategies are currently being considered to improve clinical outcomes after SCI: modulation of the neuroinflammatory response, which exacerbates the primary injury, and stimulation of neuro-regenerative repair mechanisms to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI.