bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAS isoform specific activities are disrupted by disease associated mutations during cell differentiation
Authors: Chippalkatti Rohan , Parisi Bianca , Kouzi Farah , Laurini Christina , Ben Fredj Nesrine , Abankwa Daniel Kwaku 
Published: October 2023

AbstractThe Ras-MAPK pathway is aberrantly regulated in cancer and developmental diseases called RASopathies. While typically the impact of Ras on the proliferation of various cancer cell lines is assessed, it is poorly established how Ras affects cellular differentiation.Here we implement the C2C12 myoblast cell line to systematically study the effect of Ras mutants and Ras-pathway drugs on differentiation. We first provide evidence that a minor pool of Pax7+ progenitors replenishes a major pool of transit amplifying cells that are ready to differentiate. Our data indicate that Ras isoforms have distinct roles in the differentiating culture, where K-Ras is more important than N-Ras to maintain the progenitor pool and H-Ras is significant for terminal differentiation. This assay could therefore provide significant new insights into Ras biology and Ras-driven diseases.In line with this, we found that all oncogenic Ras mutants block terminal differentiation of transit amplifying cells. Notably, while RASopathy K-Ras variants that are also NF1-GAP resistant also block differentiation, albeit less than their oncogenic counterparts. Profiling of targeted Ras-pathway drugs on oncogenic Ras mutants revealed their distinct abilities to restore normal differentiation as compared to triggering cell death. In particular, the MEK-inhibitor trametinib could broadly restore differentiation, while the mTOR-inhibitor rapamycin broadly suppressed differentiation.We expect that this quantitative assessment of the impact of Ras-pathway mutants and drugs on cellular differentiation has great potential to complement cancer cell proliferation data.
Predicting Suitable Habitats Of Critically Endangered Chinese Pangolin In Assam, India
Authors: Sarma Kuladip , Krishna Murali , Boro Barin Kumar , Saikia Malabika Kakati , Sarania Bidyut , Basumatary Himolin , Saikia Bhrigu Prasad , Saikia Prasanta Kumar 
Published: October 2023

AbstractChinese pangolin is a least known species in terms of its ecology and population status in India. The present study of Chinese pangolin in Kaziranga-Karbi-Anglong landscape aimed to gather information on species distribution and population status and also an account of threats of the species was investigated. A total of 24 occurrence points were collected from all over Assam and used to get a predictive potential distribution map for the species via Maxent and Random Forest models. To understand the knowledge level of the local people, a total of 13 villages in the north east boundary of North Karbi Anglong Wildlife Sactuary have been surveyed and 160 respondents were interviewed. The AUC values for the two models namely Maxent (0.736) and Random Forest (0.87) were different. Out of the six environmental parameters chosen, the altitude clarified the maximum variation in the model (62 %) followed by the seasonal temperature (bio4; 19.6 %) in the Maxent model. At the same time, these two variables were also found to be of greater significance in the Random Forest model. The species has been least seen by most of the respondents in the last 10 years (43.7%). Most of the respondent of age class 18-24 years never saw a pangolin (82.5%) in the area which depict the population decline of the spcies. Scales were the most used body parts for traditional medicine (58.8%) especially for exceesive saliva secretion in children. The resultant potential habitat in the predictive distribution map in Assam needs to be confirmed with ground verification and accordingly inclusion in the priority conservation zone for Chinese pangolin in Assam should be done.
Ecology and not phylogeny influences sensitivity to climate change in Muscicapidae Flycatchers in Eastern Himalayan and Indo-Burman hotspots
Authors: Dhanda Aavika , Jezierski Michał T. , Coulson Tim , Clegg Sonya 
Published: October 2023

AimsSpecies’ distributional responses to climate change can depend on ecology and phylogeny. The degree of habitat specialism is potentially important because habitat generalists with wider distributions are assumed to be less sensitive to environmental changes compared to narrowly-distributed habitat specialists. Additionally, predicting which aspects of the changing climate impacts species with different habitat associations may be particularly challenging in complex environments such as those of tropical mountains. We explore the effects of climate change on potential distributions of Muscicapidae Flycatchers in parts of the Eastern Himalayan Mountains and the Indo-Burman range, and relate predictions to the level of ecological habitat specialism, while accounting for phylogenetic relatedness.LocationBhutan and Northeast IndiaMethodsWe used Maxent to develop ecological niche models of 60 Muscicapidae Flycatchers under different climatic scenarios by collating presences from Global Biodiversity Information Facility, Bioclimatic variables from WorldClim, and elevation from ASTER. Species were scored as habitat specialists or generalists using the Species Specialism Index. Variables with high contributions to Maxent models were extracted to explore sensitivity to climate change based on habitat specialism while testing for phylogenetic signal using Phylogenetic Generalised Least Squares.ResultsMaxent models had the highest contributions from variable bio8 (mean temperature of wettest quarter) under present climate, and tmax (maximum temperature) under future climatic scenarios. Phylogenetic Generalised Least Squares revealed that habitat generalists had higher sensitivity to climate change than specialists. We did not detect strong phylogenetic signal in sensitivity to abiotic variables under all climate scenarios.Main conclusionsPotential distributions of Muscicapidae Flycatchers were sensitive to temperature variable in the month of the highest precipitation, and to maximum temperature. Potential distributions of habitat generalists were particularly sensitive to these abiotic variables, and those of habitat specialists less so. Sensitivity to abiotic variables did not show a pattern of phylogenetic niche conservatism. climate change, Muscicapidae Flycatchers, phylogenetic niche conservatism, habitat specialism, tropical mountains, Maxent
Learning modifies attention during bumblebee visual search
Authors: Robert Théo , Tarapata Karolina , Nityananda Vivek 
Published: October 2023

AbstractThe role of visual search during bee foraging is relatively understudied compared to the choices made by bees. As bees learn about rewards, we predicted that visual search would be modified to prioritise rewarding flowers. To test this, we ran an experiment testing how bee search differs in the initial and later part of training as they learn about flowers with either higher-or lower-quality rewards. We then ran an experiment to see how this prior training with reward influences their search on a subsequent task with different flowers. We used the time spent inspecting flowers as a measure of attention and found that learning increased attention to rewards and away from distractors. Higher quality rewards led to decreased attention to non-flower regions, but lower quality rewards did not. Prior experience of lower rewards also led to more attention to higher rewards compared to distractors and non-flower regions. Our results suggest that flowers would elicit differences in bee search behaviour depending on the sugar content of their nectar. They also demonstrate the utility of studying visual search and have important implications for understanding the pollination ecology of flowers with different qualities of reward.Significance StatementStudies investigating how foraging bees learn about reward typically focus on the choices made by the bees. How bees deploy attention and visual search during foraging is less well studied. We analysed flight videos to characterise visual search as bees learn which flowers are rewarding. We found that learning increases the focus of bees on flower regions. We also found that the quality of the reward a flower offers influences how much bees search in non-flower areas. This means that a flower with lower reward attracts less focussed foraging compared to one with a higher reward. Since flowers do differ in floral reward, this has important implications for how focussed pollinators will be on different flowers. Our approach of looking at search behaviour and attention thus advances our understanding of the cognitive ecology of pollination.
Neural Correlates of Self-Referential Belief Processes
Authors: Bruns Emily , Scholz Immanuel , Koppe Georgia , Kirsch Peter , Gerchen Martin Fungisai 
Published: October 2023

AbstractBackgroundBelief processing as well as self-referential processing have both been consistently associated with cortical midline structures. In addition, seminal neuroimaging papers have implicated cortical regions such as the vmPFC ingeneralbelief processing. However, the neural correlates ofself-referentialbelief are yet to be investigated in functional magnetic resonance imaging (fMRI).MethodsIn this fMRI study, we presented 120 statements with trait adjectives as target words to N=27 young healthy participants and asked them to judge whether they believed that these trait adjectives applied to themselves, a self-chosen close person, or a public person (the German chancellor at that time). Participants subsequently rated how certain (0-100%) they were in their judgment.ResultsAs expected, self-referential processing evoked a large cluster in the vmPFC, ACC and dmPFC. For belief, we found an activated cluster in the vmPFC during statement presentation, which partly overlapped with the cluster for self-referential processing. The cluster for self-belief vs. disbelief was similar in location and size to the cluster for general belief processing and distinct from the cluster for self-referential processing. We also found dmPFC activation for uncertainty in belief evaluations.DiscussionWe successfully replicated vmPFC involvement in belief processing and found a common neural correlate for belief and self-belief in the vmPFC. The activation clusters for self-belief versus self-referential processing were distinct, implying distinct neural processes. This insight will prove relevant for investigations in clinical populations with aberrant (self-)belief processing. Furthermore, we replicated the role of the dmPFC in uncertainty, supporting a dual neural process model of belief and certainty.
High-resolution label-free transcranial imaging ofin vivoneural activity via interferometric measurement of tissue deformation
Authors: Lefebvre Austen T. , Rodriguez Carissa L. , Bar-Kochba Eyal , Steiner Nicole E. , Mirski Marek , Blodgett David W. 
Published: October 2023

AbstractRapid sub-nanometer neuronal deformations have been shown to occur as a consequence of action potentialsin vitro, allowing for registration of discrete axonal and synaptic depolarizations and thus providing a novel signature for recording neural activity (1–3). We demonstrate that this signature can be extended toin vivomeasurements through recording of rapid neuronal deformations on the population level with optical phase-based recordings. Complicating these measurements is the optical phase noise due to microvascular flow as well as the presence of significant tissue clutter (deformation) associated with physiologic processes (e.g., heart and respiratory rate). These recordings were acquired using a full-field holographic imaging system with spatiotemporal resolutions of less than 1 ms and 0.1 mm3over a 3 mm diameter field of view (FOV). Our system demonstrates, for the first time, the ability to non-invasively recordin vivotissue deformation associated with population level neuronal activity. We confirmed this technique across a range of neural activation models, including direct epidural focal electrical stimulation (FES), activation of primary somatosensory cortex via whisker barrel stimulation, and pharmacologically-induced seizures. Calibrated displacement measurements of the associated tissue deformations provided additional insight into the underlying neural activation mechanisms. Collectively, we show that holographic imaging provides a pathway for high-resolution, label-free, non-invasive recording of transcranialin vivoneural activity at depth, making it highly advantageous for studying neural function and signaling.
CELL-E 2: Translating Proteins to Pictures and Back with a Bidirectional Text-to-Image Transformer
Authors: Khwaja Emaad , Song Yun S. , Agarunov Aaron , Huang Bo 
Published: October 2023

AbstractWe present CELL-E 2, a novel bidirectional transformer that can generate images depicting protein subcellular localization from the amino acid sequences (andvice versa). Protein localization is a challenging problem that requires integrating sequence and image information, which most existing methods ignore. CELL-E 2 extends the work of CELL-E, not only capturing the spatial complexity of protein localization and produce probability estimates of localization atop a nucleus image, but also being able to generate sequences from images, enablingde novoprotein design. We train and finetune CELL-E 2 on two large-scale datasets of human proteins. We also demonstrate how to use CELL-E 2 to create hundreds of novel nuclear localization signals (NLS). Results and interactive demos are featured athttps://bohuanglab.github.io/CELL-E_2/.
Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer’s disease and cerebral amyloid angiopathy
Authors: Yang Yang , Murzin Alexey G. , Peak-Chew Sew , Franco Catarina , Newell Kathy L. , Ghetti Bernardino , Goedert Michel , Scheres Sjors H.W. 
Published: October 2023

ABSTRACTWe used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer’s disease and cerebral amyloid angiopathy. In agreement with previously reported structures, which were solved to a resolution of 4.4 Å, we found three types of filaments. However, our new structures, solved to a resolution of 2.4 Å resolution, revealed differences in the sequence assignment that redefine the fold of Aβ40 peptides and their interactions. Filaments are made of pairs of protofilaments, the ordered core of which comprises D1-G38. The different filament types comprise one, two or three protofilament pairs. In each pair, residues H14-G37 of both protofilaments adopt an extended conformation and pack against each other in an anti-parallel fashion, held together by hydrophobic interactions and hydrogen bonds between main chains and side chains. Residues D1-H13 fold back on the adjacent parts of their own chains through both polar and non-polar interactions. There are also several additional densities of unknown identity. Sarkosyl extraction and aqueous extraction gave the same structures. By cryo-EM, parenchymal deposits of Aβ42 and blood vessel deposits of Aβ40 have distinct structures, supporting the view that Alzheimer’s disease and cerebral amyloid angiopathy are different Aβ proteinopathies.
Early nuclear phenotypes and reactive transformation in human iPSC-derived astrocytes from ALS patients withSOD1mutations
Authors: Soubannier Vincent , Chaineau Mathilde , Gursu Lale , Lepine Sarah , Kalaydjian David , Haghi Ghazal , Rouleau Guy , Durcan Thomas M. , Stifani Stefano 
Published: October 2023

AbstractAmyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the progressive death of motor neurons (MNs). MN degeneration in ALS involves both cell-autonomous and non-cell autonomous mechanisms, with glial cells playing important roles in the latter. More specifically, astrocytes with mutations in the ALS-associated geneCu/Zn superoxide dismutase 1(SOD1) promote MN death. The mechanisms by whichSOD1-mutated astrocytes reduce MN survival are incompletely understood. In order to characterize the impact ofSOD1mutations on astrocyte physiology, we generated astrocytes from human induced pluripotent stem cell (iPSC) derived from ALS patients carryingSOD1mutations, together with control isogenic iPSCs. We report that astrocytes harbouringSOD1(A4V) andSOD1(D90A) mutations exhibit molecular and morphological changes indicative of reactive astrogliosis when compared to matching isogenic astrocytes. We show further that a number of nuclear phenotypes precede, or coincide with, reactive transformation. These include increased nuclear oxidative stress and DNA damage, and accumulation of the SOD1 protein in the nucleus. These findings reveal early cell-autonomous phenotypes inSOD1-mutated astrocytes that may contribute to the acquisition of a reactive phenotype involved in alterations of astrocyte-MN communication in ALS.
Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR
Authors: Zilberg Gregory , Parpounas Alexandra K. , Warren Audrey L. , Fiorillo Bianca , Provasi Davide , Filizola Marta , Wacker Daniel 
Published: October 2023

AbstractSerotonin (5-hydroxytryptamine, 5-HT) acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT1eR have confirmed roles in native tissue and are validated drug targets. Despite 5-HT1eR’s therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT1eR’s pharmacology in relation to the highly homologous 5-HT1FR, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT1e/1FR agonism by multicyclic drugs described as pan-antagonists at 5-HT receptors. Potent agonism by tetracyclic antidepressants mianserin, setiptiline, and mirtazapine suggests a mechanism for their clinically observed anti-migraine properties. Using cryoEM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT1eR distinct from similar drug scaffolds in inactive-state 5-HTR structures. Together with computational studies, our data suggest that these binding poses alongside receptor-specific allosteric coupling in 5-HT1eR and 5-HT1FR contribute to the agonist activity of these antidepressants.
Trehalose-based coacervates for local bioactive protein delivery to the central nervous system
Authors: Hassan Laboni F , Sen Riya , O’Shea Timothy M 
Published: October 2023

AbstractTherapeutic outcomes of local biomolecule delivery to the central nervous system (CNS) using bulk biomaterials are limited by inadequate drug loading, neuropil disruption, and severe foreign body responses. Effective CNS delivery requires addressing these issues and developing well-tolerated, highly-loaded carriers that are dispersible within local neural parenchyma. Here, we synthesized biodegradable trehalose-based polyelectrolyte oligomers using facile A2:B3:AR thiol-ene Michael addition reactions that form complex coacervates upon mixing of oppositely charged oligomers. Coacervates permit high concentration loading and controlled release of bioactive growth factors, enzymes, and antibodies, with modular formulation parameters that confer tunable release kinetics. Coacervates are cytocompatible with cultured neural cellsin vitroand can be formulated to either direct intracellular protein delivery or sequester media containing proteins and remain extracellular. Coacervates serve as effective vehicles for precisely delivering biomolecules, including bioactive neurotrophins, to the mouse striatum following intraparenchymal injection. These results support the use of trehalose-based coacervates as part of therapeutic protein delivery strategies for CNS disorders.
Collagen Tubular Airway-on-Chip for Extended Epithelial Culture and Investigation of Ventilation Dynamics
Authors: Gao Wuyang , Kanagarajah Kayshani R. , Graham Emma , Soon Kayla , Veres Teodor , Moraes Theo J. , Bear Christine E. , Veldhuizen Ruud A. , Wong Amy P. , Günther Axel 
Published: October 2023

AbstractThe lower respiratory tract is a hierarchical network of compliant tubular structures that are made from extracellular matrix proteins with a wall lined by an epithelium. While microfluidic airway-on-a-chip models incorporate the effects of shear and stretch on the epithelium, week-long air-liquid-interface (ALI) culture remains limited to static conditions. The circular cross-section and substrate compliance associated with intact airways have yet to be recapitulated to allow studies of epithelial injuries under physiological and ventilation conditions. To overcome these limitations, we present a collagen tube-based airway model. Sustaining a functional human bronchial epithelium during two-week perfusion is accomplished by continuously supplying warm, humid air at the apical side and culture medium at the basal side. The model faithfully recapitulates human airways in size, composition, and mechanical microenvironment, allowing for the first time dynamic studies of elastocapillary phenomena associated with regular breathing as well as mechanical ventilation, along with the impact on epithelial cells. Findings reveal the epithelium to become increasingly damaged when subjected to repetitive collapse and reopening as opposed to overdistension and suggest expiratory flow resistance to reduce atelectasis. We expect the model to find broad potential applications in organ-on-a-chip applications for various tubular tissues.
Genome-wide impact of codon usage bias on translation optimization inDrosophila melanogaster
Authors: Wu Xinkai , Yang Jian-Rong , Lu Jian 
Published: October 2023

AbstractAccuracy and efficiency are fundamental characteristics of the translational process. Codon usage bias is widespread across species. Despite the long-standing association between codon optimization and improved translation, our understanding of the evolutionary basis and functional effects of codon optimization is limited.Drosophilahas been widely used to study codon usage bias, but genome-scale experimental data on codon optimization and translation are scarce. We examined high-resolution mass spectrometry datasets fromD. melanogasterdevelopment and employed different strategies to reduce bias when comparing translation error rates. We demonstrated that optimal codons have lower translation errors than nonoptimal codons after accounting for these biases. Our findings also shed light on codon-anticodon mismatches in translation errors. Through genomic-scale analysis of ribosome profiling data, we showed that optimal codons are translated more rapidly than nonoptimal codons inD. melanogaster. While we did not find conclusive evidence that natural selection favored synonymous mutations during the long-term evolution of theD. melanogaster lineage after its divergence fromD. simulans, we did find that positive selection drives codon optimization-related mutations in theD. melanogasterpopulation. This study expands our understanding of the functional consequences of codon optimization, and serves as a foundation for future investigations into the molecular mechanisms governing gene expression evolution at the translation level.