bluuebunny/crossref_metadata_2025_split huggingface dataset:
Environmental determinants of suitable habitat and the prediction of a southern shift in the future distribution of spiny lobsters, genusJasus
Authors: Tepker Jason H. E. , Strugnell Jan M. , Silva Catarina N. S. 
Published: April 2023

AbstractClimate change is altering environmental conditions which is affecting species habitats globally. As a result, many species are shifting their habitat ranges poleward to ensure that they remain within their optimal thermal range. On average, marine species have shifted their ranges poleward by approximately 72km to track their optimal thermal conditions compared to 17km for terrestrial species. These range shifts are pushing some species out of their currently fished areas. This will require nations and fishery companies to predict the most likely areas their target species could move to and obtain permits to fish in those new areas. Spiny lobsters (genusJasus) are likely to shift their ranges poleward as they are distributed within a relatively tight latitudinal band, but there is limited information about the extent of any potential range shifts. The aims of this study were to identify the environmental variables that characterise the current habitat locations of lobsters within the genusJasus, and to predict their potential distribution by modelling future suitable habitat under the RCP45, RCP60, and RCP85 climate scenarios using MaxEnt. There were 16 environmental variables used for modelling suitable habitat for the present (2000-2014), while only four environmental variables were available for modelling in two future time periods (2040-2050 and 2090-2100). There was a predicted overall southern shift in suitable habitat locations for all species. The most important environmental variable identified for species distributed along continental shelves (J. edwardsiiandJ. lalandii) was benthic temperature. Benthic nutrients (silicate, nitrate, and phosphate) were the most important variables for species distributed around islands and on seamounts (J. paulensis, J. frontalis,andJ. tristani). Approximately 90% ofJasuslobsters’ present range contained highly suitable habitat locations. The percent of highly suitable locations under the RCP45 and RCP60 scenarios were higher than the present percentages for each species, while under the RCP85 scenario, there was a decrease of highly suitable habitat for most species in 2040-2050 period, while for the 2090- 2100 period, there was an increase in the percent of highly suitable habitats. This study provides evidence thatJasuspopulations might become more abundant in the southern extents of their current range as they track their optimum habitat conditions.
Phylogenetic variations in a novel family of hyperstable apple snail egg proteins: insights into structural stability and functional trends
Authors: Pasquevich M. Y. , Dreon M. S. , Diupotex-Chong M. E. , Heras H. 
Published: April 2023

ABSTRACTThe relationship between protein stability and function evolution has not been explored in proteins from natural sources. Here, we investigate the phylogenetic differences of Perivitellin-1 (PV1) a novel family of hyperstable egg carotenoproteins crucial to the reproductive success ofPomaceasnails, as they have evolved clade-specific protective functions.We studiedP. patulaPV1 (PpaPV1) from Flagellata clade eggs, the most basal ofPomaceaand compared it with PV1s orthologs from derived clades. PpaPV1 stands as the most stable, with longer unfolding half-life, resistance to detergent unfolding, and therefore higher kinetic stability than PV1s from derived clades. In fact, PpaPV1 is among the most hyperstable proteins described in nature. In addition, its spectral characteristics providing a pale egg coloration, mild lectin activity and glycan specificity are narrower than derived clades.Our results provide evidence indicating large structural and functional changes along the evolution of the genus.Notably, the lectin binding of PpaPV1 is less pronounced, and its glycan specificity is narrower compared to PV1s in the sister Bridgesii clade. Our findings underscore the phylogenetic disparities in terms of structural and kinetic stability, as well as defensive traits like a potent lectin activity affecting the gut morphology of potential predators within the Bridgesii clade or a conspicuous, likely warning coloration, within the Canaliculata clade.This work provides a comprehensive comparison of the structural attributes, stability profiles, and functional roles of apple snail egg PV1s from multiple species within a phylogenetic context. Furthermore, it proposes an evolutionary hypothesis suggesting a trade-off between structural stability and the functional aspects of apple snail’s major egg defense protein.
Atomic Models of All Major Trans-Envelope Complexes Involved in Lipid Trafficking inEscherichia ColiConstructed Using a Combination of AlphaFold2, AF2Complex, and Membrane Morphing Simulations
Authors: McDonnell Robert T. , Patel Nikhil , Wehrspan Zachary J. , Elcock Adrian H. 
Published: April 2023

SummaryIn Gram-negative bacteria, several trans-envelope complexes (TECs) have been identified that span the periplasmic space in order to facilitate lipid transport between the inner- and outer- membranes. While partial or near-complete structures of some of these TECs have been solved by conventional experimental techniques, most remain incomplete. Here we describe how a combination of computational approaches, constrained by experimental data, can be used to build complete atomic models for four TECs implicated in lipid transport inEscherichia coli. We use DeepMind’s protein structure prediction algorithm, AlphaFold2, and a variant of it designed to predict protein complexes, AF2Complex, to predict the oligomeric states of key components of TECs and their likely interfaces with other components. After obtaining initial models of the complete TECs by superimposing predicted structures of subcomplexes, we use the membrane orientation prediction algorithm OPM to predict the likely orientations of the inner- and outer- membrane components in each TEC. Since, in all cases, the predicted membrane orientations in these initial models are tilted relative to each other, we devise a novel molecular mechanics-based strategy that we call “membrane morphing” that adjusts each TEC model until the two membranes are properly aligned with each other and separated by a distance consistent with estimates of the periplasmic width inE. coli. The study highlights the potential power of combining computational methods, operating within limits set by both experimental data and by cell physiology, for producing useable atomic structures of very large protein complexes.
Rational development of a small-molecule activator of CK1γ2 that decreases C99 and beta-amyloid levels
Authors: Bustos Victor Hugo , Sunkari Yashoda Krishna , Sinha Anjana , Pulina Maria , Bispo Ashley , Hopkins Maya , Lam Alison , Kriegsman Sydney F. , Mui Emily , Chang Emily , Jedlicki Ana , Rosenthal Hannah , Flajolet Marc , Greengard Paul , Sinha Subhash C. 
Published: April 2023

AbstractAlzheimer’s disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of beta-amyloid (Aβ), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aβ levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD.Our laboratory has discovered that CK1γ2 phosphorylates Presenilin 1 at the γ-secretase complex, leading to decreased C99 and Aβ levels. Thus, CK1γ2 activation appears as a promising therapeutic target to lower both C99 and Aβ levels.In this study, we demonstrate that CK1γ2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1γ2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1γ2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and Aβ levels.Using cultured cells, we investigated the impact of these compounds on C99 and Aβ concentrations and confirmed that CK1γ2 activation effectively reduces their levels. Our results provide proof of concept that CK1γ2 is an attractive therapeutic target for AD.Future studies should focus on the identification of specific compounds that can inhibit CK1γ2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment of AD.
Neural Signatures of Evidence Accumulation Encode Subjective Perceptual Confidence
Authors: Dou Wei , Martinez Arango Lleymi J. , Castaneda Olenka Graham , Arellano Leopoldo , Mcintyre Emily , Yballa Claire , Samaha Jason 
Published: April 2023

AbstractConfidence is an adaptive computation when environmental feedback is absent, yet there is little consensus regarding how perceptual confidence is computed in the brain. Difficulty arises because confidence correlates with other factors such as accuracy, response time (RT), or evidence quality. We investigated whether neural signatures of evidence accumulation during a perceptual choice predict subjective confidence independently of these factors. Using motion stimuli, a central-parietal EEG component (CPP) behaves as an accumulating decision variable that predicts evidence quality, RT, accuracy, and confidence (Experiment 1). Psychophysically varying confidence while holding accuracy constant (Experiment 2), the CPP still predicts confidence. Statistically controlling for RT, accuracy, and evidence quality (Experiment 3), the CPP still explains unique variance in confidence. The results indicate that evidence accumulation, indexed by the CPP, is tightly linked to the subjective perceptual experience of sensory information. Independent of other factors, pre-decision neural signatures of evidence accumulation encode subjective confidence.
Prefrontal projections modulate recurrent circuitry in insular cortex to support short-term memory
Authors: Yao Jian , Hou Ruiqing , Fan Hongmei , Hou Jincan , Cheng Qi , Li Chengyu T. 
Published: April 2023

SUMMARYShort-term memory (STM) maintains information during a short delay period. How long-range and local connections interact to support STM encoding remains elusive. Here we tackled the problem focusing on long-range projections from medial prefrontal cortex (mPFC) to anterior agranular insular cortex (aAIC) in head-fixed mice performing an olfactory delayed-response task. Optogenetic and electrophysiological experiments revealed behavioral importance of the two regions in encoding STM information. Spike-correlogram analysis revealed strong local and cross-region functional coupling (FC) between memory neurons encoding the same information. Optogenetic suppression of mPFC-aAIC projections during the delay period reduced behavioral performance, the proportion of memory neurons and memory-specific FC within aAIC, whereas optogenetic excitation enhanced all of them. MPFC-to-aAIC projections also bidirectionally modulated efficacy of STM-information transfer, measured by contribution of FC spiking pairs to coding ability of following neurons. Thus, prefrontal projections modulate functional connectivity and coding ability of insular neurons to support short-term memory.
Systematic Pan-cancer Functional Inference and Validation of Hyper, Hypo and Neomorphic Mutations
Authors: Tagore Somnath , Tsang Samuel , Mills Gordon B. , Califano Andrea 
Published: April 2023

AbstractWhile the functional effects of many recurrent cancer mutations have been characterized, the TCGA repository comprises more than 10M non-recurrent events, whose function is unknown. We propose that the context specific activity of transcription factor (TF) proteins—as measured by expression of their transcriptional targets—provides a sensitive and accurate reporter assay to assess the functional role of oncoprotein mutations. Analysis of differentially active TFs in samples harboring mutations of unknown significance—compared to established gain (GOF/hypermorph) or loss (LOF/hypomorph) of function—helped functionally characterize 577,866 individual mutational events across TCGA cohorts, including identification of mutations that are either neomorphic (gain of novel function) or phenocopy other mutations (mutational mimicry). Validation using mutation knock-in assays confirmed 15 out of 15 predicted gain and loss of function mutations and 15 of 20 predicted neomorphic mutations. This could help determine targeted therapy in patients with mutations of unknown significance in established oncoproteins.
Epigenetic fidelity in complex biological systems and implications for ageing
Authors: Duffield Thomas , Csuka Laura , Akalan Arda , Vega Magdaleno Gustavo , Senez Ludovic , Palmer Daniel , de Magalhães João Pedro 
Published: April 2023

AbstractThe study of age is plagued by a lack of delineation between the causes and effects within the ageing phenotype. This has made it difficult to fully explain the biological ageing process from first principles with a single definition. Lacking a clear description of the underlying root cause of biological age confounds clarity in this critical field. In this paper, we demonstrate that the epigenetic system has a built-in, unavoidable fidelity limitation and consequently demonstrate that there is a distinct class of DNA methylation loci that increases in variance in a manner tightly correlated with chronological age. We demonstrate the existence of epigenetic ‘activation functions’ and that topological features beyond these activation functions represent deregulation. We show that the measurement of epigenetic fidelity is an accurate predictor of cross-species age and present a deep-learning model that predicts chronological age exclusively from knowledge of variance. We find that the classes of epigenetic loci in which variation correlates with chronological age control genes that regulate transcription and suggest that the inevitable consequence of this is a feedback cycle of system-wide deregulation causing a progressive collapse into the phenotype of age. This paper represents a novel theory of biological systemic ageing with arguments as to why, how and when epigenetic ageing is inevitable.
iPSC-derived healthy human astrocytes selectively load miRNAs targeting neuronal genes into extracellular vesicles
Authors: Gordillo-Sampedro Sara , Antounians Lina , Wei Wei , Mufteev Marat , Lendemeijer Bas , Kushner Steven A. , M.S. de Vrij Femke , Zani Augusto , Ellis James 
Published: April 2023

AbstractAstrocytes are in constant communication with neurons during the establishment and maturation of functional networks in the developing brain. Astrocytes release extracellular vesicles (EVs) containing microRNA (miRNA) cargo that regulates transcript stability in recipient cells. Astrocyte released factors are thought to be involved in neurodevelopmental disorders. Healthy astrocytes partially rescue Rett Syndrome (RTT) neuron function. EVs isolated from stem cell progeny also correct aspects of RTT. EVs cross the blood-brain barrier (BBB) and their cargo is found in peripheral blood which may allow non-invasive detection of EV cargo as biomarkers produced by healthy astrocytes. Here we characterize miRNA cargo and sequence motifs in healthy human astrocyte derived EVs (ADEVs). First, human induced Pluripotent Stem Cells (iPSC) were differentiated into Neural Progenitor Cells (NPCs) and subsequently into astrocytes using a rapid differentiation protocol. iPSC derived astrocytes expressed specific markers, displayed intracellular calcium transients and secreted EVs. miRNAs were identified by RNA-Seq on astrocytes and ADEVs and target gene pathway analysis detected brain related terms. The miRNA profile was consistent with astrocyte identity, and included approximately 80 miRNAs found in astrocytes that were relatively depleted in ADEVs suggestive of passive loading. About 120 miRNAs were relatively enriched in ADEVs and motif analysis discovered binding sites for RNA binding proteins FUS, SRSF7 and CELF5. miRNA-483-5p was the most significantly enriched in ADEVs. This miRNA regulates MECP2 expression in neurons and has been found differentially expressed in blood samples from RTT patients. Our results identify potential miRNA biomarkers selectively sorted into ADEVs and implicate RNA binding protein sequence dependent mechanisms for miRNA cargo loading.
Acetyl transferase EP300 deficiency leads to chronic replication stress mediated by defective fork protection at stalled replication forks
Authors: Barreto-Galvez Angelica , Niljikar Mrunmai , Gagliardi Julia , Zhang Ranran , Kumar Vasudha , Juruwala Aastha , Pradeep Archana , Shaikh Anam , Tiwari Priyanka , Sharma Kritika , Gerhardt Jeannine , Cao Jian , Kataoka Keisuke , Durbin Adam , Qi Jun , Ye B. Hilda , Madireddy Advaitha 
Published: April 2023

AbstractMutations in the epigenetic regulator and global transcriptional activator, E1A binding protein (EP300), is being increasingly reported in aggressive hematological malignancies including adult T-cell leukemia/lymphoma (ATLL). However, the mechanistic contribution of EP300 dysregulation to cancer initiation and progression are currently unknown. Independent inhibition of EP300 in human cells results in the differential expression of genes involved in regulating the cell cycle, DNA replication and DNA damage response. Nevertheless, specific function played by EP300 in DNA replication initiation, progression and replication fork integrity has not been studied. Here, using ATLL cells as a model to study EP300 deficiency and an p300-selective PROTAC degrader, degrader as a pharmacologic tool, we reveal that EP300-mutated cells display prolonged cell cycle kinetics, due to pronounced dysregulations in DNA replication dynamics leading to persistent genomic instability. Aberrant DNA replication in EP300-mutated cells is characterized by elevated replication origin firing due to increased replisome pausing genome-wide. We demonstrate that EP300 deficiency results in nucleolytic degradation of nascently synthesized DNA at stalled forks due to a prominent defect in fork stabilization and protection. This in turn results in the accumulation of single stranded DNA gaps at collapsed replication forks, in EP300-deficient cells. Inhibition of Mre11 nuclease rescues the ssDNA accumulation indicating a dysregulation in downstream mechanisms that restrain nuclease activity at stalled forks. Importantly, we find that the absence of EP300 results in decreased expression of BRCA2 protein expression and a dependency on POLD3-mediated error-prone replication restart mechanisms. The overall S-phase abnormalities observed lead to under-replicated DNA in G2/M that instigates mitotic DNA synthesis. This in turn is associated with mitotic segregation defects characterized by elevated micronuclei formation, accumulation of cytosolic DNA and transmission of unrepaired inherited DNA lesions in the subsequent G1-phase in EP300-deficient cells. We demonstrate that the DNA replication dynamics of EP300-mutated cells ATLL cells recapitulate features of BRCA-deficient cancers. Altogether these results suggest that mutations in EP300 cause chronic DNA replication stress and defective replication fork restart results in persistent genomic instability that underlie aggressive chemo-resistant tumorigenesis in humans.
Cardioprotective Activities ofArtemisia lactifloraExtract in Rat Cardiomyoblast (H9c2) Under Inflmmatory Sepsis
Authors: Kooltheat Nateelak , Chaiissarapap Amethyst , Jienthaisong Onanong , Mohlek Nutchanok , Kawinwanalai Wisa , Nokkaew Nuttikarn 
Published: April 2023

Withdrawal StatementThe authors have withdrawn their manuscript owing to add more results. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Bispecific antibody shuttles targeting CD98hc mediate efficient and long-lived brain delivery of IgGs
Authors: Pornnoppadol Ghasidit , Bond Layne G. , Lucas Michael J. , Zupancic Jennifer M. , Kuo Yun-Huai , Zhang Boya , Greineder Colin F. , Tessier Peter M. 
Published: April 2023

SUMMARYThe inability of antibodies and other biologics to penetrate the blood-brain barrier (BBB) is a key limitation to their use in diagnostic, imaging, and therapeutic applications. One promising strategy is to deliver IgGs using a bispecific BBB shuttle, which involves fusing an IgG with a second affinity ligand that engages a cerebrovascular endothelial target and facilitates transport across the BBB. Nearly all prior efforts have focused on the transferrin receptor (TfR-1) as the prototypical endothelial target despite inherent delivery and safety challenges. Here we report bispecific antibody shuttles that engage CD98hc (also known as 4F2 and SLC3A2), the heavy chain of the large neutral amino acid transporter (LAT1), and efficiently transport IgGs into the brain parenchyma. Notably, CD98hc shuttles lead to much longer-lived brain retention of IgGs than TfR-1 shuttles while enabling more specific brain targeting due to limited CD98hc engagement in the brain parenchyma. We demonstrate the broad utility of the CD98hc shuttles by reformatting three existing IgGs as CD98hc bispecific shuttles and delivering them to the mouse brain parenchyma that either agonize a neuronal receptor (TrkB) or target other endogenous antigens on specific types of brain cells (neurons and astrocytes).
Structural basis for excitatory neuropeptide signaling
Authors: Kalienkova Valeria , Dandamudi Mowgli , Paulino Cristina , Lynagh Timothy 
Published: April 2023

ABSTRACTRapid chemo-electric signaling between neurons is mediated by ligand-gated ion channels, cell-surface proteins with an extracellular ligand-binding domain and a membrane-spanning ion channel domain1. The degenerin/epithelial sodium channel (DEG/ENaC) superfamily, which occurs throughout the animal kingdom, is unique in its diversity of gating stimuli, with some DEG/ENaCs gated by conventional ligands such as neuropeptides, and others gated by e.g. pH, mechanical force, or enzymatic activity2-5. The mechanism by which ligands bind to and activate DEG/ENaCs is poorly understood. We have therefore dissected the structural basis for neuropeptide binding and gating in a neuropeptide-gated DEG/ENaC, FMRFamide-gated sodium channel 1 (FaNaC1) from the annelid wormMalacoceros fuliginosus6, using cryo-electron microscopy. High-resolution structures of FaNaC1 in the ligand-free resting state and in several ligand-bound states reveal the ligand-binding site and capture the ligand-induced conformational changes that mediate channel gating. Complementary mutagenesis experiments confirm the functional roles of particular amino acid residues implicated by the structures. Our results illuminate ligand-induced channel gating in DEG/ENaCs and offer a structural template for the experimental dissection of channel pharmacology and ion conduction in a characteristically metazoan ion channel superfamily.