bluuebunny/crossref_metadata_2025 huggingface dataset:
George Yeats
Authors: Mills Harper Margaret
Published: July 2023

Many stories swirl about George Yeats, even though she did not write or speak much for public consumption. In the last several decades, this least known of the women in Yeats’s circle has received an increasing amount of scholarly attention, and her massive contributions to her husband’s life and work are more appreciated than has been true for the longer part of the history of Yeats studies. For the first generation or two of scholarship after his death, George was mentioned publicly and frequently in acknowledgements and copyright pages of works by and about her husband. And she did produce thousands of pages of written texts, most in the form of automatic writing, occult notebooks of varying types, and private letters. She also consulted with publishers to edit much of WBY’s poetry, drama, and prose. She was a brilliant woman who led a long and active life.
Yeats’s Visionary Comedy
Authors: Campbell Matthew
Published: July 2023

This chapter explores various aspects of reading Yeats as a sort of comedian, or, if not that, someone who wrote a visionary comedy, albeit one passing through ‘general humanity’ to the figure of the ‘The Fool’. He was an experimenter with comedic forms in his plays and poetry, as well as in his depictions of historical events: ‘Easter, 1916’ is the only one of Yeats’s poems to use the word ‘comedy’. Later in life, he reverted often to the example of Jonathan Swift and a sort of classical Fescennine poetry, a satire of the body, often obscene and bawdy. In all of these versions, comedy comports with serious matter, and Yeats certainly thought of it as such: the idea of joy as the most important consummating achievement to which so many of his later poems aspire may be partly the comedic joy of divine knowledge and partly the tragic joy of the Nietzschean hero. But comedy is also something that features in usual Yeatsian subject matter, the sensible, the ethical, the everyday, our feelings about what it is to be in good humour, to have an equable and not obsessive temperament.
Imperfect Forms
Authors: Burt Stephanie
Published: July 2023

We can learn more about poetic form, about W. B. Yeats’s forms, and about Yeats’s notions of perfection and imperfection, repetition and variation, order and disorder, when Yeats rejects the norm: from poems in which the metre, or the rhyme scheme, as well as the imaginative logic, change midway through. As discussed in this chapter, these poems—most of them lesser known or less often discussed—can help us think about recent models of form, and recent definitions of lyric poetry, as well as helping us to view and appreciate the aesthetic effects and choices that set Yeats’s poems apart.
Editing Yeats
Authors: Gould Warwick
Published: July 2023

This chapter focuses upon the achievements of major editorial projects undertaken during the past sixty-five years. There are as many means of editing Yeats as there are imagined audiences for his work, but future scholarly editing of his work should apply Yeats’s own sense of a hierarchy of his audiences, and the various opportunities this implied for his editorial self-shaping. Yeats as an editor and self-editor continues to clarify the task for those who might take the editing of his work into the digital future. The chapter ends with a bibliography of principal editions of W. B. Yeats works edited by others, in approximately chronological order, followed by modern editions of works by Yeats, and then scholarly studies in alphabetical order by author and chronological order as to date.
Talking Back to History
Authors: Higgins Geraldine
Published: July 2023

‘History’ for Yeats is personal—not simply in the sense that he sees his own biography and that of the nation as intertwined—but also in his belief that the writer reshapes history itself. Famously a poet who constantly remakes himself, Yeats also fashions useable versions of the past that inform his symbolic historical schema. Rejecting the poetry of witness, he sometimes inhabits the role of prophet, but rarely, if ever, can he be said to be a reliable historical chronicler. How then has he come to be known as the poet without whom the age cannot be understood? This chapter argues that Yeats’s status as a poet of history rests on the key questions embedded in his best-known public poems. These questions ‘talk back’ to received ideas about the past, to political bromides about history and to Yeats’s own earlier work.
‘Cast A Cold Eye’
Authors: Piette Adam
Published: July 2023

This chapter first considers the reception of Yeats’s late work in the aftermath of his death in January 1939, looking in particular at the reaction of his fellow modernists, and then the judgements made on his lifetime achievement by Irish writers of different persuasions. The second section considers another thrust to Yeats’s epitaph: his injunction to those passing by to treat death lightly, and explores psychoanalytical ideas about ‘the death drive’ to unpack its implications. The chapter ends by seeking to winkle out from the verse the lineaments of prophecy as foreboding, as weird contact with the war dead of the future.
The Scientific Revolution
Authors: Ebury Katherine
Published: July 2023

Yeats’s reading in modern science post-relativity has recently come strongly into the light, placing him in a fascinating position among modern writers, open to scientific thinking that appears to challenge the empiricism that Yeats himself abhorred. This chapter reappraises previous critical work on Yeats and science, especially in relation to the ‘Two Cultures’ debate (and its ancestors) and highlights missed opportunities to engage with the potential of his thought. Subsections address Yeats’s experience of science before Einstein through his education, as well as how his engagement with science was transformed after the Einsteinian revolution. Yeats’s thought will ultimately be found to be less of an outlier and more in harmony with a particular strand of ‘New Age’ popular science, from Einstein’s Cosmic Religion (1931) to Gary Zukav’s The Dancing Wu Li Masters (1979), which combined Eastern philosophy with the new physics.
W. B. Yeats
Authors: Hanna Adam
Published: July 2023

Abstract Yeats described his Senate work as ‘the slow exciting work of creating the institutions of a new nation’. Both The Tower and A Vision were written during a period in which many of the legal and institutional structures in which Irish society operated fell and were built again, and they reflect both of these phases. In particular, Yeats’s ambivalent attitude to his new role as a legislator contributes to his strong thematic preoccupation with divided, multiple selfhood. The Tower is not just a lament for a former time, it is a paean to the very fact of change; it is not only a hymn to self-assertion but a reflection on just what a fugitive and fluid thing a self can be. As ‘Among School Children’ shows, Yeats’s renewed consciousness of division within himself enabled him to make great poetry out of a state of disjunction.
The Effect of Mobile Stroke Unit Care on Functional Outcomes: An Application of the Front-door Formula
Authors: Piccininni Marco , Kurth Tobias , Audebert Heinrich J. , Rohmann Jessica L.
Published: July 2023

Background:

The Berlin-based B_PROUD study was designed to assess the effect of mobile stroke unit (MSU) dispatch among ischemic stroke and transient ischemic attack (TIA) patients without contraindications to reperfusion treatments. However, a large proportion of patients for whom the MSU was dispatched did not ultimately receive MSU care. We estimated the causal effect of additional MSU care on 3-month functional outcomes among B_PROUD patients for whom an MSU was dispatched.

Methods:

We used data from the B_PROUD study (1 February 2017–8 May 2019). Given the presence of exposure–outcome unmeasured confounding, we used the front-door formula to identify the distribution of modified Rankin scale (mRS) outcomes under two hypothetical interventions: (1) receiving additional MSU care and (2) only receiving conventional care. We considered the time from dispatch to thrombolysis as the full mediator and adjusted for exposure–mediator and mediator–outcome confounding. We used a parametric estimator to estimate the common odds ratio (cOR) and 95% bootstrapped confidence intervals (CI).

Results:

We included in total 768 ischemic stroke/TIA patients with MSU dispatch. The MSU was canceled for 180 (23%) patients, whereas 588 (77%) received MSU care. The unadjusted association between the care group and mRS favored conventional care (cOR = 1.7; 95% CI = 1.2, 2.3); however, after applying the front-door formula, the mRS distribution favored MSU care (cOR = 0.88; 95% CI = 0.81, 0.96).

Conclusions:

Receiving MSU care was associated with better functional outcomes than conventional care only, compatible with the hypothesized beneficial effect of MSU care on poststroke outcomes, among stroke and TIA patients without contraindications to reperfusion treatments.
Recurrent Episodes of Encephalopathy/Encephalitis Secondary to Influenza Virus in a Pediatric Patient
Authors: Huq Rifah , Bolumen Ariana , Chalwadi Uday Kumar , Pichilingue-Reto Patricia , Vancherie John
Published: July 2023

Influenza virus commonly causes acute upper respiratory tract infections in pediatrics. Rarely, influenza-associated encephalopathy/encephalitis may occur in 4 of 100,000 children annually in the United States. North American literature, however, is sparse regarding the incidence of recurrent episodes. This report characterizes the clinical manifestations and identifies genetic, virologic and/or epidemiologic factors making children susceptible for recurring episodes of influenza-associated encephalopathy/encephalitis.
Factors influencing surgical performance and learning progress in minimally invasive surgery – results of an interdisciplinary muticenter study
Authors: Ackermann Johannes , Baumann Jorun , Pape Julian , Pahls Julia , Ruchay Zino , Spüntrup Carolin , Holthaus Bernd , Noé Günter , Anapolski Michael , Meinhold-Heerlein Ivo , Peters Göntje , Willer Damaris , Westermann Anna , Brügge Sandra , Günther Veronika , Maass Nicolai , Mettler Liselotte , Alkatout Ibrahim
Published: July 2023

Background:

Advancing surgical techniques require a high level of adaptation and learning skills on the part of surgeons. We need selection procedures and decision support systems for the recruitment of medical students and young surgeons. We aimed to investigate factors influencing the surgical performance and learning abilities of surgeons and medical students.

Material and Methods:

The training scores of persons attending 16 standardized training courses (at three training centers) of the German Working Group for Gynecological Endoscopy (AGE e.V.) from 2017 to 2020, individual characteristics, and the results of psychomotor tests of three-dimensional imagination and hand-eye coordination were correlated. Similar analyses were performed for medical students in their final clinical year from 2019 to 2020. The training concept was evaluated in a prospective, multicenter, interdisciplinary, multinational setting.

Results:

In all, 180 of 206 physicians (response rate 87.4%) and 261 medical students (response rate 100%) completed the multi-stage training concept successfully. Of personal characteristics, the strongest correlation was noted for good surgical performance and learning success, and the absolute number of performed laparoscopic surgeries (r=0.28-0.45, P<0.001/r=0.1-0.28, P<0.05). A high score on the spatial visualization ability test was also correlated with good surgical performance (r=0.18-0.27, P<0.01). Among medical students with no surgical experience, however, age was negatively correlated with surgical performance, i.e. the higher the age, the lower the surgical performance (r=0.13/r=0.22, P<0.05/P<0.001).

Conclusion:

Individual factors (e.g. surgical experience, self-assessment, spatial visualization ability, eye-hand coordination, age) influence surgical performance and learning. Further research will be needed to create better decision support systems and selection procedures for prospective physicians. The possibilities of surgical training should be improved, promoted, and made accessible to a maximum number of surgical trainees because individual learning curves can be overcome even by less talented surgeons. Training options should be institutionalized for those attending medical school.
The invisible string of coagulation, complement, iron, and inflammation in sickle cell disease
Authors: Beckman Joan D. , Sparkenbaugh Erica M.
Published: July 2023

Purpose of review

This review provides an update on recent advances in mechanistic studies of thromboinflammatory mechanisms that contribute to the disease pathology in sickle cell disease (SCD). There is a focus on novel pathways, clinical relevance, and translational potential of these findings. We hope to encourage more advances in this area to reduce organ damage in young patients prior to gene therapy, and to serve the aging SCD patient population.

Recent findings

Novel insights into the roles of neutrophils, the ADAMTS-13/VWF axis, oxidative stress, and the intrinsic coagulation cascade, as well as relevant clinical trials, are discussed.

Several studies implicate dysregulation of the ADAMTS-13/VWF axis as playing a major role in vaso-occlusive events (VOE) in SCD. Another highlight is reducing iron overload, which has beneficial effects on erythrocyte and neutrophil function that reduce VOE and inflammation. Multiple studies suggest that targeting HO-1/ROS in erythrocytes, platelets, and endothelium can attenuate disease pathology. New insights into coagulation activation identify intrinsic coagulation factor XII as a central regulator of many thromboinflammatory pathologies in SCD. The complement cascade and modulators of neutrophil function and release of neutrophil extracellular traps are also discussed.
Nucleus basalis of Meynert degeneration signals earliest stage of Alzheimer’s disease progression
Authors: Shafiee Neda , Fonov Vladimir , Dadar Mahsa , Spreng R. Nathan , Collins D. Louis
Published: July 2023

The Nucleus Basalis of Meynert (NbM) is the main source of cholinergic projection to the entorhinal cortex (EC) and hippocampus (HC), where acetylcholine plays a key role in their function. Both cholinergic cells of NbM and their receptive targets in the EC and HC show sensitivity to neurofibrillary degeneration during the early stages of Alzheimer’s disease. Precise delineation of the NbM region on T1w scans is challenging due to limited spatial resolution and contrast. Using deformation-based morphometry (DBM), we sought to quantify NbM degeneration along the Alzheimer’s disease trajectory and confirm recent studies suggesting that NbM degeneration happens before degeneration in the EC or HC.

MRI scans of 1447 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI1, 2 and GO) were up-sampled to 0.5 mm voxel-size in each direction (0.125 mm3) before non-linear registration to an ADNI-based unbiased symmetric average MRI template. A subgroup of 677 amyloid-positive participants were chosen for volume time course analysis where the resulting deformation fields were used to compute a high-resolution Jacobian determinant map for each participant as a proxy for local volume change within NbM, EC, and HC masks. Scores of volume change were corrected for age and sex and z-scored using normative data from cognitively healthy amyloid-negative (CN-) participants (n = 219). Two-sample t-tests were then used to compare the baseline differences between NbM, EC, and HC for amyloid-positive cognitively normal controls (CN+), amyloid-positive early mild cognitive impairment (eMCI), and amyloid-positive late mild cognitive impairment (lMCI). Longitudinal linear mixed-effect models were used to compare trajectories of volume change after realigning all participants into a common timeline based on their cognitive decline.

Results showed a significant cross-sectional difference at baseline between CN+ and eMCI, and eMCI and lMCI for both left and right Z-scored NbM volumes. There was no difference in z-scored EC and HC volumes between CN+ and eMCI groups but results from eMCI and lMCI differed significantly in these regions. Longitudinal analysis, with a focus on the early disease stages showed the earliest deviation from the CN- trajectory in the NbM and HC in the subject-specific time realigned data.

Contrary to the notion that Alzheimer’s disease originates in EC, we found that NbM volume changes earlier in the disease trajectory than EC or HC. Converging evidence from cross-sectional and longitudinal models suggest that the NbM may be a focal target of early AD progression, which is often obscured by normal age-related decline.
Reaching the tumor: mobility of polymeric micelles inside anin vitrotumor-on-a-chip model with dual ECM
Authors: Olea Alis R. , Jurado Alicia , Slor Gadi , Tevet Shahar , Pujals Silvia , De La Rosa Victor R. , Hoogenboom Richard , Amir Roey J. , Albertazzi Lorenzo
Published: July 2023

Degradable polymeric micelles are promising drug delivery systems due to their hydrophobic core and responsive design. When applying micellar nanocarriers for tumor delivery, one of the bottlenecks encounteredin vivois the tumor tissue barrier – crossing the dense mesh of cells and extracellular matrix (ECM). Sometimes overlooked, the extracellular matrix can trap nanoformulations based on charge, size and hydrophobicity. Here we used a simple design of a microfluidic chip with two types of ECM and MCF7 spheroids to allow “high throughput” screening of the interactions between biological interfaces and polymeric micelles. To demostrarte the applicapility of the chip, a small library of fluorescently labelled polymeric micelles varying in their hydrophilic shell and hydrophobic core forming blocks was studied. Three widely used hydrophilic shells were tested and compared, poly(ethylene glycol), poly(2-ethyl-2-oxazoline), and poly(acrylic acid), along with two enzyamticaly degradable dendritic hydrophobic cores (based on Hexyl or Nonyl end-gorups). Using ratiometric imaging of unimer:micelle fluorescence and FRAP inside the chip model, we obtained the local assembly state and dynamics inside the chip. Notably, we observed different micelle behaviors in the basal lamina ECM, from avoidance of ECM structure to binding of the poly(acrylic acid) formulations. Binding to basal lamina correlated with higher uptake into MCF7 spheroids. Overall, we proposed a simple microfluidic chip containing dual ECM and spheroids for the assessment of the interactions of polymeric nanocarrires with biological interfaces and evaluating nanoformulations’ capacity to cross the tumor tissue barrier.
A Multimodal Vision Transformer for Interpretable Fusion of Functional and Structural Neuroimaging Data
Authors: Bi Yuda , Abrol Anees , Fu Zening , Calhoun Vince D.
Published: July 2023

Deep learning models, despite their potential for increasing our understanding of intricate neuroimaging data, can be hampered by challenges related to interpretability. Multimodal neuroimaging appears to be a promising approach that allows us to extract supplementary information from various imaging modalities. It’s noteworthy that functional brain changes are often more pronounced in schizophrenia, albeit potentially less reproducible, while structural MRI effects are more replicable but usually manifest smaller effects. Instead of conducting isolated analyses for each modality, the joint analysis of these data can bolster the effects and further refine our neurobiological understanding of schizophrenia. This paper introduces a novel deep learning model, the multimodal vision transformer (MultiViT), specifically engineered to enhance the accuracy of classifying schizophrenia by using structural MRI (sMRI) and functional MRI (fMRI) data independently and simultaneously leveraging the combined information from both modalities. This study uses functional network connectivity data derived from a fully automated independent component analysis method as the fMRI features and segmented gray matter volume (GMV) as the sMRI features. These offer sensitive, high-dimensional features for learning from structural and functional MRI data. The resulting MultiViT model is lightweight and robust, outperforming unimodal analyses. Our approach has been applied to data collected from control subjects and patients with schizophrenia, with the MultiViT model achieving an AUC of 0.833, which is significantly higher than the average 0.766 AUC for unimodal baselines and 0.78 AUC for multimodal baselines. Advanced algorithmic approaches for predicting and characterizing these disorders have consistently evolved, though subject and diagnostic heterogeneity pose significant challenges. Given that each modality provides only a partial representation of the brain, we can gather more comprehensive information by harnessing both modalities than by relying on either one independently. Furthermore, we conducted a saliency analysis to gain insights into the co-alterations in structural gray matter and functional network connectivity disrupted in schizophrenia. While it’s clear that the MultiViT model demonstrates differences compared to previous multimodal methods, the specifics of how it compares to methods such as MCCA and JICA are still under investigation, and more research is needed in this area. The findings underscore the potential of interpretable multimodal data fusion models like the MultiViT, highlighting their robustness and potential in the classification and understanding of schizophrenia.
The role of squid for food web structure and community-level metabolism
Authors: Denéchère Rémy , van Denderen P. Daniël , Andersen Ken H.
Published: July 2023

Squid differ from fish by their high growth rate, short life span and feeding behaviour. Their fast life strategy is thought to impose a high predation pressure on zooplankton, fish and other squid preys, and a rapid transfer of energy to upper trophic-levels of marine food webs. However, there is a lack of understanding of how squid’s fast life cycle affects the food-web structure, which is needed to project squid biomass across marine regions under shifting climatic conditions. Here, we examine the role of squid on community metabolism and biomass by collecting data on squid somatic growth and incorporating squid in a size- and trait-based fish community model. We show that squid have a 5 times higher average somatic growth rate than fish. Due to their high food demands, squid are constrained to regions of high pelagic secondary production. The presence of squid in these systems is associated with a reduction in total upper trophic level biomass. This decline is caused by an increase in community-level respiration losses associated with squid. Our results indicate that squid might have a large impact on ecosystem structure even at relatively low standing stock biomasses. Consequently, the recent proliferation of squid in ecosystems around the world is likely to have significant ecological and socio-economic impacts.
Expression of Bovine Annexin A4 In E.coliRescues Cytokinesis Blocked by Beta-Lactam Antibiotics
Authors: Creutz Carl E.
Published: July 2023

Treatment of bacteria with beta-lactam antibiotics can impair the process of cytokinesis, the final step in cell division, leading to the formation of a filamentous form of the bacteria. The expression of a mammalian calcium-dependent, membrane-binding protein, bovine annexin A4, inE. coliwas found to reverse the inhibitory effects on cytokinesis of the beta-lactam antibiotics ampicillin, piperacillin, and cephalexin. This novel activity of the annexin was blocked by mutation of calcium binding sites in the annexin, indicating roles for calcium binding to the annexin and the binding of the annexin to membranes in restoring cytokinesis. The filamentous form of the bacteria has been reported to be more resistant to phagocytosis by cells of the immune system in eukaryotic hosts. Therefore, expression of annexins in pathogenic bacteria, by promoting the breakdown of the bacterial filaments, might serve as an adjuvant to enhance the efficacy of beta-lactam antibiotics.
Predicting Fixation Paths in the Moran Process:A Machine Learning Approach
Authors: Hajihashemi Mahdi
Published: July 2023

Path of Fixation in evolutionary process highly depends on structure of underlying population. In this paper, we apply a machine learning method to predict the path of fixation in several complex graphs and two regular graphs. In our approach, the path of fixation is not used as the target variable in the machine learning model. Rather, we focus on predicting the probability of progression forward (referred to asλin the literature) using the machine learning model. By using previous achievements in determining the fixation path for the Moran process, obtaining the path of fixation becomes straightforward. Due to the time and computational resources required for simulating an evolutionary process in a large population, utilizing a machine learning method can help us save both of these valuable resources. This approach can provide insights to researchers studying evolutionary processes in the context of meta-population problems.
POPSHIFT: A THERMODYNAMICALLY SOUND APPROACH TO ESTIMATE BINDING FREE ENERGIES BY ACCOUNTING FOR LIGAND-INDUCED POPULATION SHIFTS FROM A LIGAND-FREE MSM
Authors: Smith Louis G. , Novak Borna , Osato Meghan , Mobley David L. , Bowman Gregory R.
Published: July 2023

Obtaining accurate binding free energies fromin silicoscreens has been a longstanding goal for the computational chemistry community. However, accuracy and computational cost are at odds with one another, limiting the utility of methods that perform this type of calculation. Many methods achieve massive scale by explicitly or implicitly assuming that the target protein adopts a single structure, or undergoes limited fluctuations around that structure, to minimize computational cost. Others simulate each protein-ligand complex of interest, accepting lower throughput in exchange for better predictions of binding affinities. Here, we present the PopShift framework for accounting for the ensemble of structures a protein adopts and their relative probabilities. Protein degrees of freedom are enumerated once, and then arbitrarily many molecules can be screened against this ensemble. Specifically, we use Markov state models (MSMs) as a compressed representation of a protein’s thermodynamic ensemble. We start with a ligand-free MSM and then calculate how addition of a ligand shifts the populations of each protein conformational state based on the strength of the interaction between that protein conformation and the ligand. In this work we use docking to estimate the affinity between a given protein structure and ligand, but any estimator of binding affinities could be used in the PopShift framework. We test PopShift on the classic benchmark pocket T4 Lysozyme L99A. We find that PopShift is more accurate than common strategies, such as docking to a single structure and traditional ensemble docking—producing results that compare favorably with alchemical binding free energy calculations in terms of RMSE but not correlation—and may have a more favorable computational cost profile in some applications. In addition to predicting binding free energies and ligand poses, PopShift also provides insight into how the probability of different protein structures is shifted upon addition of various concentrations of ligand, providing a platform for predicting affinities and allosteric effects of ligand binding. Therefore, we expect PopShift will be valuable for hit finding and for providing insight into phenomena like allostery.
Dynamical properties of self-sustained and driven neural networks
Authors: Bouté Jules , Destexhe Alain
Published: July 2023

In the awake brain, cerebral cortex displays asynchronous-irregular (AI) states, where neurons fire irregularly and with low correlation. Neural networks can display AI states that are self-sustained through recurrent connections, or in some cases, need an external input to sustain activity. In this paper, we aim at comparing these two dynamics and their consequences on responsiveness. We first show that the first Lyapunov exponent (FLE) can differ between self-sustained and driven networks, the former displaying a higher FLE than the late. Next, we show that this impact the dynamics of the system, leading to a tendency for self-sustained networks to be more responsive, both properties that can also be captured by mean-field models. We conclude that there is a dynamical and excitability difference between the two types of networks besides their apparent similar collective firing. The model predicts that calculating FLE from population activities in experimental data could provide a way to identify if real neural networks are self-sustained or driven.
Cell networks in the mouse liver during partial hepatectomy
Authors: Li Bin , Rodrigo-Torres Daniel , Pelz Carl , Innes Brendan , Canaday Pamela , Chai Sunghee , Zandstra Peter , Bader Gary D. , Grompe Markus
Published: July 2023

In solid tissues homeostasis and regeneration after injury involve a complex interplay between many different cell types. The mammalian liver harbors numerous epithelial and non-epithelial cells and little is known about the global signaling networks that govern their interactions. To better understand the hepatic cell network, we isolated and purified 10 different cell populations from normal and regenerative mouse livers. Their transcriptomes were analyzed by bulk RNA-seq and a computational platform was used to analyze the cell-cell and ligand-receptor interactions among the 10 populations. Over 50,000 potential cell-cell interactions were found in both the ground state and after partial hepatectomy. Importantly, about half of these differed between the two states, indicating massive changes in the cell network during regeneration. Our study provides the first comprehensive database of potential cell-cell interactions in mammalian liver cell homeostasis and regeneration. With the help of this prediction model, we identified and validated two previously unknown signaling interactions involved in accelerating and delaying liver regeneration. Overall, we provide a novel platform for investigating autocrine/paracrine pathways in tissue regeneration, which can be adapted to other complex multicellular systems.

Highlights

A platform predicting cell-cell interactions in liver regeneration was established

This platform identified the BMP4 pathway antagonist Fstl1 as a stimulator of hepatocyte proliferation

This platform also discovered the role of Wnt pathway inhibitor Sfrp1 delaying liver regeneration
Habitat correlates of cave-dwelling: A radiation-scale analysis of skin traits and comparative transcriptomics of theSinocyclocheiluscavefish
Authors: Luo Xiayue , Chen Bing , Mao Tingru , Liu Yewei , Yang Jian , Meegaskumbura Madhava
Published: July 2023

With 78 species,Sinocyclocheiluscavefish constitute the largest cavefish radiation in the world. They exhibit remarkable morphological diversity across three habitat types: surface (Surface morphs, Normal-eyed, variably colored), exclusively-cave-dwelling (Stygobitic morphs, Eyeless, depigmented), and intermediate between cave and surface (Stygophilic morphs, Micro-eyed, partially depigmented). Distinctive traits ofSinocyclocheilusinclude variations in eye and skin conditions associated with their habitat, despite the role of the skin in sensing environmental changes, its habitat correlates are less understood, compared to the well-studied eye conditions. Here, we analyzed the correlation betweenSinocyclocheilusskin morphology and its habitat, utilizing morphological and transcriptomics-based methods. We generated RNA-sequencing data for nine species and integrated those with existing data from five additional species. These 14 species represent the primary clades and major habitats of these cavefish. Data on skin color and scale morphology were generated and 7374 orthologous genes were identified. Using a comparative transcriptomics approach, we identified 1,348 differentially expressed genes (DEGs) in the three morphotypes. GO and KEGG enrichment analyses suggest that these species have evolved different strategies for energy metabolism, immunity, and oxidative stress in different habitats. We also found 329 positive selection genes (PSGs) in the skin of these species that are mainly involved in immunity, apoptosis, and necrosis, indicating potential adaptations to their habitats. The maximum likelihood phylogenetic tree, based on 1369 single-copy orthologous genes of the species, was largely concordant with the currently established RAD-seq and mt-DNA based phylogenies, but with a few exceptions. Species with higher cave dependence present lighter coloration, fewer dark blotches, and diminished scale morphology and coverage. PCA and cluster analysis suggested that cave-dwelling species, characterized by the absence of black blotches, have similar expression patterns, indicating convergence in cave adaptation. Variations in tyrosine metabolism may explain pigmentation differences among species in diverse habitats. Our study highlights the significance of habitat in shaping skin metabolism, pigmentation variation, and morphology while offering insights into the molecular mechanisms driving these habitat-specific adaptations inSinocyclocheilus. These findings underscore the transcriptional variation in adapting to diverse environments and contribute to future studies on the evolution and ecology of cavefish.
Intranasal CRMP2-Ubc9 Inhibitor Regulates NaV1.7 to Alleviate Trigeminal Neuropathic Pain
Authors: Loya-Lopez Santiago I. , Allen Heather N. , Duran Paz , Calderon-Rivera Aida , Gomez Kimberly , Kumar Upasana , Shields Rory , Zeng Rui , Dwivedi Akshat , Saurabh Saumya , Korczeniewska Olga A. , Khanna Rajesh
Published: July 2023

Dysregulation of voltage-gated sodium NaV1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/NaV1.7 interaction and increased functional activity of NaV1.7. Targeting this feed-forward regulation, we developed compound194, which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We further demonstrated that194effectively reduces the functional activity of NaV1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and neuropathic pain. Here, we employed a comprehensive array of investigative approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, and behavioral analyses, to assess the functional implications of NaV1.7 regulation by CRMP2 in trigeminal ganglia (TG) neurons. We confirmed the expression ofScn9a,Dpysl2, andUBE2Iwithin TG neurons. Furthermore, we found an interaction between CRMP2 and NaV1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation with compound194uncoupled the CRMP2/NaV1.7 interaction, impeded NaV1.7 diffusion on the plasma membrane, and subsequently diminished NaV1.7 activity. Compound194also led to a reduction in TG neuron excitability. Finally, when intranasally administered to rats with chronic constriction injury of the infraorbital nerve (CCI-ION),194significantly decreased nociceptive behaviors. Collectively, our findings underscore the critical role of CRMP2 in regulating NaV1.7 within TG neurons, emphasizing the importance of this indirect modulation in trigeminal neuropathic pain.
Protective intravenous BCG vaccination induces enhanced immune signaling in the airways
Authors: Peters Joshua M. , Irvine Edward B. , Rosenberg Jacob M. , Wadsworth Marc H. , Hughes Travis K. , Sutton Matthew , Nyquist Sarah K. , Bromley Joshua D. , Mondal Rajib , Roederer Mario , Seder Robert A. , Darrah Patricia A. , Alter Galit , Flynn JoAnne L. , Shalek Alex K. , Fortune Sarah M. , Bryson Bryan D.
Published: July 2023

Intradermal (ID) Bacillus Calmette–Guérin (BCG) is the most widely administered vaccine in the world. However, ID-BCG fails to achieve the level of protection needed in adults to alter the course of the tuberculosis epidemic. Recent studies in non-human primates have demonstrated high levels of protection againstMycobacterium tuberculosis(Mtb) following intravenous (IV) administration of BCG. However, the protective immune features that emerge following IV BCG vaccination remain incompletely defined. Here we used single-cell RNA-sequencing (scRNAseq) to transcriptionally profile 157,114 unstimulated and purified protein derivative (PPD)-stimulated bronchoalveolar lavage (BAL) cells from 29 rhesus macaques immunized with BCG across routes of administration and doses to uncover cell composition-, gene expression-, and biological network-level signatures associated with IV BCG-mediated protection. Our analyses revealed that high-dose IV BCG drove an influx of polyfunctional T cells and macrophages into the airways. These macrophages exhibited a basal activation phenotype even in the absence of PPD-stimulation, defined in part by IFN and TNF-α signaling up to 6 months following BCG immunization. Furthermore, intercellular immune signaling pathways between key myeloid and T cell subsets were enhanced following PPD-stimulation in high-dose IV BCG-vaccinated macaques. High-dose IV BCG also engendered quantitatively and qualitatively stronger transcriptional responses to PPD-stimulation, with a robust Th1-Th17 transcriptional phenotype in T cells, and augmented transcriptional signatures of reactive oxygen species production, hypoxia, and IFN-γ response within alveolar macrophages. Collectively, this work supports that IV BCG immunization creates a unique cellular ecosystem in the airways, which primes and enables local myeloid cells to effectively clearMtbupon challenge.
Developmental Manganese Exposure Causes Lasting Attention Deficits Accompanied by Dysregulation of mTOR Signaling and Catecholaminergic Gene Expression in Brain Prefrontal Cortex
Authors: Santiago N. A. , He B. , Howard S. L. , Beaudin S. , Strupp B. J. , Smith D. R.
Published: July 2023

Elevated manganese (Mn) exposure is associated with attentional deficits in children, and is an environmental risk factor for attention deficit hyperactivity disorder (ADHD). We have shown that developmental Mn exposure causes lasting attention and sensorimotor deficits in a rat model of early childhood Mn exposure, and that these deficits are associated with a hypofunctioning catecholaminergic system in the prefrontal cortex (PFC), though the mechanistic basis for these deficits is not well understood. To address this, male Long-Evans rats were exposed orally to Mn (50 mg/kg/d) over PND 1-21 and attentional function was assessed in adulthood using the 5-Choice Serial Reaction Time Task. Targeted catecholaminergic system and epigenetic gene expression, followed by unbiased differential DNA methylation and gene regulation expression transcriptomics in the PFC, were performed in young adult littermates. Results show that developmental Mn exposure causes lasting focused attention deficits that are associated with reduced gene expression of tyrosine hydroxylase, dopamine transporter, and DNA methyltransferase 3a. Further, developmental Mn exposure causes broader lasting methylation and gene expression dysregulation associated with epigenetic regulation, inflammation, cell development, and hypofunctioning catecholaminergic neuronal systems. Pathway enrichment analyses uncovered mTOR and Wnt signaling pathway genes as significant transcriptomic regulators of the Mn altered transcriptome, and Western blot of total, C1 and C2 phospho-mTOR confirmed mTOR pathway dysregulation. Our findings deepen our understanding of the mechanistic basis of how developmental Mn exposure leads to lasting catecholaminergic dysfunction and attention deficits, which may aid future therapeutic interventions of environmental exposure associated disorders.

Significance Statement

Attention deficit hyperactivity disorder (ADHD) is associated with environmental risk factors, including exposure to neurotoxic agents. Here we used a rodent model of developmental manganese (Mn) exposure producing lasting attention deficits to show broad epigenetic and gene expression changes in the prefrontal cortex, and to identify disrupted mTOR and Wnt signaling pathways as a novel mechanism for how developmental Mn exposure may induce lasting attention and catecholaminergic system impairments. Importantly, our findings establish early development as a critical period of susceptibility to lasting deficits in attentional function caused by elevated environmental toxicant exposure. Given that environmental health threats disproportionately impact communities of color and low socioeconomic status, our findings can aid future studies to assess therapeutic interventions for vulnerable populations.
Effects of surface geometry on light exposure, photoacclimation and photosynthetic energy acquisition in zooxanthellate corals
Authors: López-Londoño Tomás , Enríquez Susana , Iglesias-Prieto Roberto
Published: July 2023

Symbiotic corals display a great array of morphologies, each of which has unique effects on light interception and the photosynthetic performance ofin hospitezooxanthellae. Changes in light availability elicit photoacclimation responses to optimize the energy balances in primary producers, extensively documented for corals exposed to contrasting light regimes along depth gradients. Yet, response variation driven by coral colony geometry and its energetic implications on colonies with contrasting morphologies remain largely unknown. In this study, we assessed the effect of the inclination angle of coral surface on light availability, short- and long-term photoacclimation responses, and potential photosynthetic usable energy. Increasing surface inclination angle resulted in an order of magnitude reduction of light availability, following a linear relationship explained by the cosine law and relative changes in the direct and diffuse components of irradiance. The light gradient induced by surface geometry triggered photoacclimation responses comparable to those observed along depth gradients: changes in the quantum yield of photosystem II, photosynthetic parameters, and optical properties and pigmentation of the coral tissue. Differences in light availability and photoacclimation driven by surface inclination led to contrasting energetic performance. Horizontally and vertically oriented coral surfaces experienced the largest reductions in photosynthetic usable energy as a result of excessive irradiance and light-limiting conditions, respectively. This pattern is predicted to change with depth or local water optical properties. Our study concludes that colony geometry plays an essential role in shaping the energy balance and determining the light niche of zooxanthellate corals.
Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and contextual memory
Authors: Tan Ji-Wei , Xu Haifei , Liao Guey-Ying , An Juan Ji , Xu Baoji
Published: July 2023

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encodingNtf3gene in the DG during the 1sttwo postnatal weeks to generate aNtf3conditional knockout (Ntf3-cKO). Ntf3-cKO mice had normal hippocampal cytoarchitecture but displayed elevated anxiety level and impairments in contextual memory, spatial reference memory and nest building. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice showed impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.
Urine proteomic signatures of histological class, activity, chronicity, and treatment response in lupus nephritis
Authors: Fava Andrea , Buyon Jill , Magder Laurence , Hodgin Jeff , Rosenberg Avi , Demeke Dawit S. , Rao Deepak A. , Arazi Arnon , Celia Alessandra Ida , Putterman Chaim , Anolik Jennifer H. , Barnas Jennifer , Dall’Era Maria , Wofsy David , Furie Richard , Kamen Diane , Kalunian Kenneth , James Judith A. , Guthridge Joel , Atta Mohamed G. , Trujillo Jose Monroy , Fine Derek , Clancy Robert , Belmont H. Michael , Izmirly Peter , Apruzzese William , Goldman Daniel , Berthier Celine C. , Hoover Paul , Hacohen Nir , Raychaudhuri Soumya , Davidson Anne , Diamond Betty ,   Accelerating Medicines Partnership in RA/SLE network, Petri Michelle
Published: July 2023

Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 LN patients (573 samples) in the longitudinal Accelerating Medicines Partnership (AMP) in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PRTN3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.92, EGFR 0.9, CD163 0.89, proteinuria 0.8, p<0.01). Candidate biomarkers were validated and provide new potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN, guide treatment, and as surrogate endpoints for clinical trials. These findings provide new insights into the processes involved in LN activity. This dataset (matching other AMP omics) is a public resource to generate and test hypotheses and validate biomarkers.