bluuebunny/crossref_metadata_2025 huggingface dataset:
Microglial depletion decreases Müller cell maturation and inner retinal vascular density
Authors: Rowthorn-Apel Nathaniel , Vridhachalam Naveen , Connor Kip M. , Bonilla Gracia M. , Sadreyev Ruslan , Singh Charandeep , Gnanaguru Gopalan
Published: May 2024

The neuroretinal vascular system is comprised of three interconnected layers. The initial superficial vascular plexus formation is guided by astrocytes around birth in mice. The formation of the deep and intermediate vascular plexuses occurs in the second postnatal week and is driven by Müller-cell-derived angiogenic signaling. Previously, we reported that microglia play an important role in regulating astrocyte density during superficial vascular plexus formation. Here, we investigated the role for microglia in regulating Müller-cell-dependent inner retinal vascular development. Results from this study show that microglia closely interact with Müller cells and the growing inner retinal vasculature. Depletion of microglia resulted in reduced inner retinal vascular layers densities and decreased Vegfa isoforms transcript levels. RNA-seq analysis further revealed that microglial depletion significantly reduced specific Müller cell maturation markers including glutamine synthetase, responsible for glutamine biosynthesis, which is needed for angiogenesis. Thus, our study reveals an important role for microglia in Müller cell maturation and inner retinal angiogenesis.
Theoretical Models of Obligate Mutualism to Link Micro- with Macro-Coevolutionary Dynamics
Authors: Eaton Carrie Diaz , Moore Christopher M.
Published: May 2024

There is a need to link micro- and macro-coevolution to bridge mechanistic theory and observations of micro-coevolutionary change with observations of macro-coevolutionary patterns. This need is particularly conspicuous in theoretical models of obligate mutualism, where phylogenetic matching is the predicted outcome. However, these theoretical models of obligate mutualism create a mismatch with empirical studies of obligate mutualism, which experience extensive phylogenetic discordance. Although environmental variation on geographic scales is often invoked, there are other, non-mutually exclusive mechanisms that can possibly explain genetic diversity and co-phylogenetic patterns in mutualistic communities. In this study, we use a genetic-explicit mathematical model of obligate mutualism that explain host-switching outcomes and, consequently, discordance in cophylogenies. We then explore the role of temporal variation in maintenance of genetic variation (i.e., phenology), which can further account for phylogenetic discordance. These insights are possible due to the focus on initial conditions and short-term behavior of model results. This work ultimately supports the continued importance of theoretical work which expands its analysis of outcomes beyond asymptotic behavior.
Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MASLD patients
Authors: Schinderle Joseph D. , Wu Anqi , Bochkis Irina M.
Published: May 2024

Mutations of nuclear lamina-associated proteins LMNA and ZMPSTE24 have been associated with fatty liver. We report that the changes at the nuclear envelope we described in MASLD patients are caused by downregulation of ZMPSTE24, an enzyme that processes prelamin to mature lamin A. In addition,Zmpste24mutant mice develop hepatic steatosis and exhibit upregulation of p53 target genes. p53 activity is also induced in genes differentially expressed in MASLD patients. Furthermore, p53 regulates genes bound by FOXA2 in these individuals, corresponding to observations inZmpste24mutants. In contrast, expression of glucose and insulin regulated genes is reduced in MASLD patients, suggesting altered glucose metabolism and insulin resistance, hallmarks of type 2 diabetes (T2D). Hence, our genomics data show that MASLD patients with severe steatosis but yet without MASH are already suffering from severe metabolic consequences and underscore the need for treatment at this stage of the disease.
fmo-4promotes longevity and stress resistance via ER to mitochondria calcium regulation inC. elegans
Authors: Tuckowski AM , Beydoun S , Kitto ES , Bhat A , Howington MB , Sridhar A , Bhandari M , Chambers K , Leiser SF
Published: May 2024

Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports thatC. elegans fmo-2promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are fiveC. elegansFMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression ofC. elegans fmo-4promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression offmo-4in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream offmo-4expression. Highlighting the importance of calcium homeostasis in this pathway,fmo-4overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression offmo-4and/or interact withfmo-4to affect lifespan and stress resistance. Further analysis supports a pathway wherefmo-4modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requiresfmo-4expression. Together, our data identifyfmo-4as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.
Morphological single-cell analysis of peripheral blood mononuclear cells from 390 healthy blood donors with Blood Cell Painting
Authors: Högel-Starck Caroline , Timonen Veera A. , Atarsaikhan Gantugs , Mogollon Isabel , Polso Minttu , Hassinen Antti , Honkanen Jarno , Soini Julius , Ruokoranta Tanja , Ahlnäs Toveann , Juvila Julianna , Miettinen Juho J. , Rodosthenous Rodosthenis S. , Arvas Mikko ,   FinnGen, Heckman Caroline A. , Partanen Jukka , Daly Mark , Palotie Aarno , Paavolainen Lassi , Pietiäinen Vilja , Pitkänen Esa
Published: May 2024

Recent molecular profiling and phenotyping methods combined with machine learning based analyses enable genotype-phenotype discovery at an unprecedented scale. The challenge now lies in unraveling the biological mechanisms underpinning these associations. High content imaging is a cost-effective approach for morphological and functional profiling of single cells that has provided insight into mechanisms of disease phenotypes, and consequences of genetic and drug perturbations. However, the morphological variability of healthy immune cells − instrumental to understanding disease-specific deviations from the healthy state − is still relatively uncharacterized. To elucidate this variability at scale, we generated high-resolution fluorescent confocal imaging data of peripheral blood mononuclear cell (PBMC) samples from 390 healthy blood donors with the Blood Cell Painting protocol. The protocol, developed here from the popular Cell Painting morphological profiling assay, optimizes for efficiency and throughput, and includes PBMC thawing, plating and fluorescence marker staining of non-adherent blood cells, followed by confocal and widefield imaging with a high content microscope. We assigned cell types based on cellular features with a classifier trained expert annotations, and observed monocytes to be five-fold more frequent in imaging data compared to flow cytometry baseline, with B and T cells being two-fold less frequent. We hypothesize this discrepancy is due to differential adherence between the cell types. We also evaluated three computational methods for correcting batch effects in imaging data, and found Harmony to perform the best, compatible with previous reports. Finally, we performed the Blood Cell Painting protocol on PBMCs in acute myeloid leukemia, and showed the protocol to be able to distinguish between AML FAB subtypes. Our study highlights the utility of high-content imaging with Cell Painting in characterizing and understanding health and disease phenotypes, opening avenues to further studies with integrated imaging and molecular profiling data.

This manuscript is a work in progress, and we anticipate incorporating additional results into subsequent versions.
Previously unmeasured genetic diversity explains part of Lewontin’s paradox in ak-mer-based meta-analysis of 112 plant species
Authors: Roberts Miles , Josephs Emily B.
Published: May 2024

At the molecular level, most evolution is expected to be neutral. A key prediction of this expectation is that the level of genetic diversity in a population should scale with population size. However, as was noted by Richard Lewontin in 1974 and reaffirmed by later studies, the slope of the population size-diversity relationship in nature is much weaker than expected under neutral theory. We hypothesize that one contributor to this paradox is that current methods relying on single nucleotide polymorphisms (SNPs) called from aligning short reads to a reference genome underestimate levels of genetic diversity in many species. To test this idea, we calculated nucleotide diversity (π) andk-mer-based metrics of genetic diversity across 112 plant species, amounting to over 205 terabases of DNA sequencing data from 27,488 individual plants. We then compared how these different metrics correlated with proxies of population size that account for both range size and population density variation across species. We found that our population size proxies scaled anywhere from about 3 to over 20 times faster withk-mer diversity than nucleotide diversity after adjusting for evolutionary history, mating system, life cycle habit, cultivation status, and invasiveness. The relationship betweenk-mer diversity and population size proxies also remains significant after correcting for genome size, whereas the analogous relationship for nucleotide diversity does not. These results suggest that variation not captured by common SNP-based analyses explains part of Lewontin’s paradox in plants.

Lay Summary

Even after many revolutions in our ability to sequence and understand DNA, many important biological questions remain unsolved. One such problem is Lewontin’s paradox, named after Richard Lewontin who first described it in 1974. The core of the paradox is a simple idea: species with more individuals should be more genetically diverse. The reasoning is that more individuals means more replication of DNA, and thus more opportunities for mutation to create new variation. However, species that differ massively in population size often have similar diversity levels. Lewontin’s paradox has several potential, previously investigated mechanisms but what if one contributor is simply that our measurements of genetic diversity are off? Most studies estimate diversity by comparing sample genomes to a standard reference genome. While this approach is useful, it is impossible to measure variation in DNA that is not represented in the reference - a phenomenon known as reference bias. We estimate metrics of diversity that are free of reference-bias and re-investigate Lewontin’s paradox in plants. Overall, we find that reference-free diversity metrics scale more with population size, compared to the reference-biased approach. While it is unlikely that reference-bias fully explains Lewontin’s paradox, our analyses suggest that reference-bias plays an important role.
Digital Twin Brain Simulator: Harnessing Primate ECoG Data for Real-Time Consciousness Monitoring and Virtual Intervention
Authors: Takahashi Yuta , Idei Hayato , Komatsu Misako , Tani Jun , Tomita Hiroaki , Yamashita Yuichi
Published: May 2024

At the forefront of bridging computational brain modeling with personalized medicine, this study introduces a novel, real-time, electrocorticogram (ECoG) simulator based on the digital twin brain concept. Utilizing advanced data assimilation techniques, specifically a Variational Bayesian Recurrent Neural Network model with hierarchical latent units, the simulator dynamically predicts ECoG signals reflecting real-time brain latent states. By assimilating broad ECoG signals from Macaque monkeys across awake and anesthetized conditions, the model successfully updated its latent states in real-time, enhancing the precision of ECoG signal simulations. Behind the successful data assimilation, a self-organization of latent states in the model was observed, reflecting brain states and individuality. This self-organization facilitated simulation of virtual drug administration and uncovered functional networks underlying changes in brain function during anesthesia. These results show that the proposed model is not only capable of simulating brain signals in real-time with high accuracy, but is also useful for revealing underlying information processing dynamics.
Dynamic changes in mitochondria support phenotypic flexibility of microglia
Authors: Espinoza Katherine , Schaler Ari W. , Gray Daniel T. , Sass Arielle R. , Moore Kamilia , Yu Megan E. , Chamorro Casandra G. , De Biase Lindsay M.
Published: May 2024

Microglial capacity to adapt to local tissue needs is a hallmark feature of these cells. Yet, a full understanding of the intracellular machinery that allows them to rapidly adjust their cellular phenotype is lacking. New studies show that macrophage ability to alter cellular phenotype is critically regulated by their mitochondria. Indeed, mitochondria are increasingly recognized as key intracellular signaling and regulatory hubs, in addition to their well-established role as ATP producers. Surprisingly little is known about microglial mitochondriain vivoand whether they play similar roles in regulating microglial capacity to alter cellular phenotype. Here, we generated novel transgenic crosses for accurate visualization of microglial mitochondria and found, unexpectedly, that mitochondria did not appear to regulate microglial tissue surveillance. However, brain regions where microglia show early responses to aging also showed early changes in microglial mitochondria. Microglial mitochondria were also altered within hours of LPS injections and microglial expression of inflammation-, trophic-, and phagocytosis-relevant genes was strongly correlated with expression levels of specific mitochondria-relevant genes. Finally, direct genetic manipulation of microglial mitochondria altered microglial morphology and led to brain-region specific effects on microglial gene expression. Overall, this study provides foundational information about microglial mitochondria and their relationship to differences in cell phenotype that occur across brain region, during pathological insults, and during aging.
Identification of distinct rodent-associated adenovirus lineages from a mixed-use landscape in the Western Ghats biodiversity hotspot
Authors: Ansil B.R. , Sanyal Avirup , Sreenivas Darshan , Garg Kritika M. , Ramakrishnan Uma , Chattopadhyay Balaji
Published: May 2024

Shifts in land-use patterns and increased human-livestock-wildlife interactions have generated numerous possibilities for pathogen spillover. This demands increased efforts of pathogen surveillance in wildlife, especially in changing landscapes with high biodiversity. We investigated adenovirus diversity in small mammals, an understudied host taxon, from a forest-plantation mosaic in the Western Ghats biodiversity hotspot. Using PCR-based screening followed by Sanger sequencing and phylogenetic analyses, we attempted to detect and characterize adenovirus diversity in seven species of small mammals. We observed high prevalence (up to 38.8%) and identified five lineages of adenoviruses with unique mutations in the endemic and dominant small mammal species,Rattus satarae. These lineages significantly differed from other known Murine adenoviruses (p-distance > 25%), indicating the likelihood of novel adenovirus diversity in this endemic small mammal. Collectively, our results highlight the potential for unexplored diversity of DNA viruses like adenovirus in poorly explored host taxa inhabiting human-used landscapes and its zoonotic implications.
Renal L-2-hydroxyglutarate dehydrogenase activity promotes hypoxia tolerance and mitochondrial metabolism inDrosophila melanogaster
Authors: Mahmoudzadeh Nader H. , Heidarian Yasaman , Tourigny Jason P. , Fitt Alexander J. , Beebe Katherine , Li Hongde , Luhur Arthur , Buddika Kasun , Mungcal Liam , Kundu Anirban , Policastro Robert A. , Brinkley Garrett J. , Zentner Gabriel E. , Nemkov Travis , Pepin Robert , Chawla Geetanjali , Sudarshan Sunil , Rodan Aylin R. , D’Alessandro Angelo , Tennessen Jason M.
Published: May 2024

The mitochondrial enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH) regulates the abundance of L-2-hydroxyglutarate (L-2HG), a potent signaling metabolite capable of influencing chromatin architecture, mitochondrial metabolism, and cell fate decisions. Loss of L2hgdh activity in humans induces ectopic L-2HG accumulation, resulting in neurodevelopmental defects, altered immune cell function, and enhanced growth of clear cell renal cell carcinomas. To better understand the molecular mechanisms that underlie these disease pathologies, we used the fruit flyDrosophila melanogasterto investigate the endogenous functions of L2hgdh. Our studies revealed that while L2hgdh is not essential for growth or viability under standard culture conditions,L2hgdhmutants are hypersensitive to hypoxia and expire during the reoxygenation phase with severe disruptions of mitochondrial metabolism. Moreover, we find that the fly renal system (Malpighian tubules; MTs) is a key site of L2hgdh activity, asL2hgdhmutants that express a rescuing transgene within the MTs survive hypoxia treatment and exhibit normal levels of mitochondrial metabolites. We also demonstrate that even under normoxic conditions,L2hgdhmutant MTs experience significant metabolic stress and are sensitized to aberrant growth upon Egfr activation. Overall, our findings present a model in which renal L2hgdh activity limits systemic L-2HG accumulation, thus indirectly regulating the balance between glycolytic and mitochondrial metabolism, enabling successful recovery from hypoxia exposure, and ensuring renal tissue integrity.
Circadian Coupling Orchestrates Cell Growth
Authors: Gutu Nica , Nordentoft Malthe S. , Kuhn Marlena , Ector Carolin , Finger Anna-Marie , Heltberg Mathias Spliid , Jensen Mogens Høgh , Keilholz Ulrich , Kramer Achim , Herzel Hanspeter , Granada Adrián E.
Published: May 2024

Single-cell circadian oscillators exchange extracellular information to sustain coherent circadian rhythms at the tissue level. Within cells, the circadian clock and the cell cycle couple, yet the mechanisms governing this interplay remain poorly elucidated. Here, we study the role of extracellular circadian communication in the intracellular coordination between the circadian clock and the cell cycle. We demonstrate that the loss of extracellular circadian synchronization disrupts circadian and cell cycle coordination within individual cells, impeding collective tissue growth. Coherent circadian rhythms yield oscillatory growth patterns, unveiling a global timing regulator of tissue dynamics. Knocking down core circadian elements abolishes observed effects, highlighting the central role of circadian clock regulation. Our research underscores the significance of tissue-level circadian disruption in regulating proliferation, thereby linking disrupted circadian clocks with oncogenic processes. These findings illuminate the intricate interplay between circadian rhythms, cellular signaling, and tissue physiology, enhancing our understanding of tissue homeostasis and growth regulation in both health and disease contexts.
WITHDRAWN: Prevalence ofkatGandinhAmutations in genes associated with isoniazid resistance inMycobacterium tuberculosisclinical isolates in Cameroon
Authors: Nono Vanessa Ninkeh , Nantia Edouard Akono , Mutshembele Awelani Miranda , Teagho Sorelle Nguimfack , Simo Yannick Willy Kamdem , Takong Brenda Shile , Djieugoue Yvonne Josiane , Assolo Yannick Patrick , Ongboulal Suzanne Magloire , Awungafac Stanley Nkemnji , Eyangoh Sara , Makhado Ndivuhu Agnes , Mensah Eric , Donfack Valerie Flore Donkeng
Published: May 2024

Withdrawal statement

This manuscript has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. 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.
Fructosamine and Triglycerides - Developing an Index for Assessing Insulin Resistance
Authors: de Oliveira Andrade Luís Jesuíno , Matos de Oliveira Gabriela Correia , Matos de Oliveira Luísa Correia , Moreno de Brito Luiz Felipe , Matos de Oliveira Luís
Published: May 2024

Introduction

Insulin resistance (IR) is a metabolic condition where cells become less responsive to insulin, affecting glucose absorption and leading to diseases like type 2 diabetes. Factors like obesity and high triglycerides worsen IR. Fructosamine is a key marker for short-term glycemic control and can indicate IR. Various methods, like the euglycemic clamp and HOMA-IR index, assess IR, with the TyG index emerging as a simple and reliable tool due to its strong correlation with IR.

Objective

To develop and evaluate a novel IR index that incorporates both fructosamine and triglyceride levels, aiming to improve the accuracy of IR assessment compared to existing methods.

Methods

This study investigated IR using established methods and proposed a novel TrigFruc index incorporating fructosamine. Data from 200 individuals was analyzed to assess the TrigFruc index’s performance compared to existing methods (HOMA-IR and TyG index). Descriptive statistics summarized participant demographics, and Pearson’s correlation evaluated the relationship between TrigFruc and HOMA-IR and between TrigFruc and TyG index. A receiver operating characteristic (ROC) analysis identified the optimal TrigFruc cut-off point for IR detection, comparing its sensitivity and specificity to HOMA-IR and TyG index.

Results

Study with 200 participants (63% female, avg. age 46.6 years), the established HOMA-IR index identified IR in 32% (64 individuals) while the TyG index found it in 66% (132). The new TrigFruc index showed a weaker correlation with HOMA-IR (r=0.28) compared to the TyG index (r=0.44). For detecting IR based on HOMA-IR, the optimal TrigFruc cut-off (Ln 4.57) had just 50% sensitivity (correctly identifying half of true IR cases) but low specificity (23%, high misclassification of non-IR cases). When compared to the TyG index, the optimal TrigFruc cut-off (Ln 4.74) showed excellent performance with high sensitivity (85%, strong ability to identify true IR) and specificity (95%, low misclassification of non-IR).

Conclusion

The TrigFruc index, incorporating fructosamine, shows promise for IR assessment. Compared to HOMA-IR, it exhibits better correlation with the TyG index and superior sensitivity and specificity for IR detection when using the TyG index as a reference.
Use of assistive technology to assess distal motor function in subjects with neuromuscular disease
Authors: Vincent-Genod Dominique , Roche Sylvain , Barrière Aurélie , de Lattre Capucine , Tinat Marie , Venema Eelke , Lagrange Emmeline , de Souza Adriana Gomes Lisboa , Thomann Guillaume , Coton Justine , Gautheron Vincent , Féasson Léonard , Rippert Pascal , Vuillerot Carole
Published: May 2024

Purpose

Among the 32 items of the Motor Function Measure scale, 3 concern the assessment of hand function on a paper-based support. Their characteristics make it possible to envisage the use of a tablet instead of the original paper-based support for their completion. This would then make it possible to automate the score to reduce intra- and inter-individual variability.

The main objective of the present study was to validate the digital completion of items 18, 19, and 22 by measuring the agreement of the scores obtained using a digital tablet with those obtained using the original paper-based support in children and adults with various neuromuscular diseases (NMD). The secondary objective is to calibrate an algorithm for the automatic items scoring.

Design

Prospective, multicentre, non-interventional study.

Methods

Ninety-eight subjects aged 5 to 60 years with a confirmed NMD completed MFM items 18, 19, and 22 both on a paper support and a digital tablet.

Results

The median age of included subjects was 16.2 years. Agreement between scores as assessed using the weighted Kappa coefficient was almost perfect for the scores of items 18 and 22 (K=0.93, and 0.95, respectively) and substantial for item 19 (K=0.70). In all cases of disagreement, the difference was of 1 point. The most frequent disagreement concerned item 19; mainly in the direction of a scoring of 1 point less on the tablet. An automatic analysis algorithm was tested on 82 recordings to suggest improvements.

Conclusion

The switch from original paper-based support to the tablet results in minimal and acceptable differences, and maintains a valid and reproducible measure of the 3 items. The developed algorithm for automatic scoring appears feasible with the perspective to include them in a digital application that will make it easier to monitor patients.
Viral methyltransferase inhibitors: berbamine, venetoclax, and ponatinib as efficacious antivirals against Chikungunya virus
Authors: Bhutkar Mandar , Saha Ankita , Tomar Shailly
Published: May 2024

Chikungunya virus (CHIKV), transmitted by mosquitoes, poses a significant global health threat. Presently, no effective treatment options are available to reduce the disease burden. The lack of approved therapeutics against CHIKV and the complex spectrum of chronic musculoskeletal and neurological manifestations raise significant concerns, and repurposing drugs could offer swift avenues in the development of effective treatment strategies. RNA capping is a crucial step meditated by non-structural protein 1 (nsP1) in CHIKV replication. In this study, FDA-approved antivirals targeting CHIKV nsP1 methyltransferase (MTase) have been identified by structure-based virtual screening. Berbamine Hydrochloride (BH), ABT199/Venetoclax (ABT), and Ponatinib (PT) were the top hits, which exhibited robust binding energies. Tryptophan fluorescence spectroscopy-based assay confirmed binding of BH-, ABT-, and PT to purified nsP1 with KDvalues ∼5.45 μM, ∼161.3 μM, and ∼3.83μM, respectively. A dose-dependent decrease in CHIKV nsP1 MTase activity was observed in a capillary electrophoresis-based assay. Treatment with BH, ABT, and PT lead to a dose-dependent reduction in the virus titer with IC50<100, ∼3.46, and <3.9 nM, respectively, and reduced viral mRNA levels. The nsP1 MTases are highly conserved among alphaviruses; therefore, BH, ABT, and PT, as expected, inhibited replication machinery in Sindbis virus (SINV) replicon assay with IC50∼1.94, ∼0.23, and >1.25 μM, respectively. These results underscore the efficacy and promise of repurposing drugs as rapid and effective antiviral therapeutics against CHIKV.

Highlights

Berbamine Hydrochloride (BH), ABT199/Venetoclax (ABT), and Ponatinib (PT) identified as inhibitors of Chikungunya virus (CHIKV) nsP1

Molecules BH, ABT and PT make moelcular interactions with nsP1: KDvalues ∼5.45, ∼161.3, and ∼3.83 in μM, respectively and effectively inhibit methyltransferase activity.

BH, ABT, and PT exhibited potent antiviral activity against CHIKV in cell-based assays, with IC50<100, ∼3.46, and <3.9 nM.

BH, ABT, and PT also inhibit Sindbis virus, the prototype alphavirus with IC50∼1.94, ∼0.23, and >1.25 μM respectively demonstrating broad spectrum antiviral efficacy.

Graphical Abstract
The exoproteome and surfaceome of toxigenicCorynebacterium diphtheriae1737 and its response to iron-restriction and growth on human hemoglobin
Authors: Goring Andrew K. , Hale Scott T. , Dasika Poojita , Chen Yu , Clubb Robert T. , Loo Joseph A.
Published: May 2024

Toxin-producingCorynebacterium diphtheriaestrains are the etiological agent of the severe upper respiratory disease, diphtheria. A global phylogenetic analysis revealed that biotype gravis is particularly lethal as it produces diphtheria toxin and a range of other virulence factors, particularly when it encounters low levels of iron at sites of infection. To gain insight into how it colonizes its host we have identified iron-dependent changes in the exoproteome and surfaceome ofC. diphtheriaestrain 1737 using a combination of whole-cell fractionation, intact cell surface proteolysis, and quantitative proteomics. In total, we identified 1,425 of the predicted 2,265 (63%) proteins encoded by its reference genome. For each protein we quantified its degree of secretion and surface-exposure, revealing that exoproteases and hydrolases predominate in the exoproteome, while the surfaceome is enriched with adhesins, particularly DIP2093. Our analysis provides insight into how components in the heme-acquisition system are positioned, showing pronounced surface-exposure of the strain-specific ChtA/ChtC paralogues and high secretion of the species-conserved heme-binding HtaA protein suggesting it functions as a hemophore. Profiling the response of the exoproteome and surfaceome after microbial exposure to human hemoglobin and iron limitation reveals potential virulence factors that may be expressed at sites of infection. Data are available via ProteomeXchange with identifier PXD051674.
Alzheimer’s disease and neurodegeneration in symptomatic cerebral small vessel disease
Authors: Arndt Philipp , Pfister Malte , Perosa Valentina , Mattern Hendrik , Bernal Jose , John Anna-Charlotte , Dörner Marc , Müller Patrick , Braun-Dullaeus Rüdiger C. , Garz Cornelia , Nelke Christopher , Kokott Alma , Jansen Robin , Gliem Michael , Meuth Sven G. , Henneicke Solveig , Vielhaber Stefan , Neumann Katja , Schreiber Stefanie
Published: May 2024

Background

Co-occurrence of cerebral small vessel disease (CSVD) is common in aging and Alzheimer’s disease (AD) dementia, but, in symptomatic CSVD prevalence and role of AD and neurodegenerative co-pathologies have been less explored.

Methods

In vivodetermination of prevalence, predictors and relevance for cognition of AD and neurodegenerative co-pathologies in symptomatic CSVD, including deep perforator arteriopathy (DPA) and cerebral amyloid angiopathy (CAA), utilizing cerebrospinal fluid (CSF) biomarkers. Cross-sectional study from October 2010 to September 2021 of participants with magnetic resonance imaging (MRI) and CSF biomarkers (amyloid-β 42/40 ratio, phosphorylated-tau, total-tau, neurofilament light). Biomarker levels were compared among groups; prevalence of ATN classification subtypes was estimated and related to clinical phenotype, CSVD MRI markers and global cognition.

Results

The study comprised 229 individuals (median age 74 years; 47% females), 70 with AD dementia, 79 with probable CAA, 62 with DPA patients and 18 healthy controls. Participants were categorized based on the ATN classification: normal biomarkers (A-T-N-), AD pathology continuum (A+T±N±), and non-AD pathological changes, including primary age-related tauopathy (PART, A-T+N+) or isolated neurodegeneration (A-T-N+). Of 141 CSVD patients, 43 (30%) were A-T-N-, 39 (28%) A+T±N±, with lower prevalence in DPA than CAA (15% vs. 38%, p = .003), 18 (13%) A-T+N+, and 41 (29%) A-T-N+, with higher prevalence in DPA than CAA (42% vs. 19%, p = .002). A+T±N± was associated with increasing age, female sex, lobar hemorrhages and low burden of deep white matter hyperintensities and lacunes. A-T-N+ was related to younger age, symptomatic stroke and lacunes. A-T+N+ had no specific predictors, except advanced age. Each pathological ATN profile was independently related to lower Mini Mental State Examination scores (A+T±N±: B = -2.7, p = .013; A-T+N+: B = -4.6, p = .002; A-T-N+: B = -2.3, p = .034), accounting for demographics, clinical phenotype and MRI CSVD severity.

Conclusions

Using biomarkers, this study confirmsin vivothat CSVD frequently co-occurs with AD or neurodegenerative pathologies, exerting independent effects on cognitive health. As disease-modifying therapies emerge, integrating interacting biomarkers will be crucial for the selection of patients with the greatest benefit.
All-optical source size and emittance measurements of laser-accelerated electron beams
Authors: Salgado F. C. , Kozan A. , Seipt D. , Hollatz D. , Hilz P. , Kaluza M. , Sävert A. , Seidel A. , Ullmann D. , Zhao Y. , Zepf M.
Published: May 2024

Novel schemes for generating ultralow emittance electron beams have been developed in past years and promise compact particle sources with excellent beam quality suitable for future high-energy physics experiments and free-electron lasers. Recent theoretical work has proposed a laser-based method capable of resolving emittances in the sub 0.1 mm mrad regime by modulating the electron phase space ponderomotively. Here we present the first experimental demonstration of this scheme using a laser wakefield accelerator. The observed emittance and source size are consistent with published values. We also show calculations demonstrating that tight bounds on the upper limit for emittance and source size can be derived from the “laser-grating” method even in the presence of low signal to noise and uncertainty in laser-grating parameters.

Published by the American Physical Society
2024
QCD Kondo effect for single heavy quark in chiral-symmetry broken phase
Authors: Yasui Shigehiro , Suenaga Daiki , Suzuki Kei
Published: May 2024

We consider the quantum chromodynamics (QCD) Kondo effect for a single heavy quark in quark matter composed of light quarks with chiral symmetry breaking. Introducing several spinor structures in QCD Kondo condensates, i.e., particle-projected condensate, antiparticle-projected condensate, and normal condensate without projection, we calculate the attractive energy gained by the heavy quark within the mean-field approximation in the path-integral formalism. We show that the normal condensate is favored at low density and the particle-projected condensate is favored at high density, when the light quark has a nonzero mass. We interpret such a density-dependent transition between the two condensates in terms of the Kondo resonances.

Published by the American Physical Society
2024
γ5
schemes and the interplay of SMEFT operators in the Higgs-gluon coupling
Authors: Di Noi Stefano , Gröber Ramona , Heinrich Gudrun , Lang Jannis , Vitti Marco
Published: May 2024

We calculate the four-top-quark operator contributions to Higgs production via gluon fusion in the Standard Model effective field theory. The four-top operators enter for the first time via two-loop diagrams. Owing to their chiral structure they contain γ5, so special care needs to be taken when using dimensional regularization for the loop integrals. We use two different schemes for the continuation of γ5 to D space-time dimensions in our calculations and present a mapping for the parameters in the two schemes. This generically leads to an interplay of different operators, such as four-top operators, chromomagnetic operators, or Yukawa-type operators at the loop level. We validate our results by examples of matching onto UV models.

Published by the American Physical Society
2024
Verification of wave turbulence theory in the kinetic limit
Authors: Hrabski Alexander , Pan Yulin
Published: May 2024

Using the 1D Majda-McLaughlin-Tabak model as an example, we develop numerical experiments to study the validity of the wave kinetic equation (WKE) at the kinetic limit (i.e., small nonlinearity and large domain). We show that the dynamics converge to the WKE prediction, in terms of the closure model and energy flux, when the kinetic limit is approached. When the kinetic limit is combined with a process of widening the inertial range, the theoretical Kolmogorov constant can be recovered numerically to a very high precision.

Published by the American Physical Society
2024
Data-driven analysis of annual rain distributions
Authors: Ashkenazy Yosef , Smith Naftali R.
Published: May 2024

Rainfall is an important component of the climate system, and its statistical properties are vital for prediction purposes. In this study, we have developed a statistical method for constructing the distribution of annual precipitation. The method is based on the convolution of the measured monthly rainfall distributions and does not depend on any presumed annual rainfall distribution. Using a simple statistical model, we demonstrate that our approach allows for a better prediction of extremely dry or wet years with a recurrence time several times longer than the original time series. The method that has been proposed can be utilized for other climate variables as well.

Published by the American Physical Society
2024
Doping dependence of scattering rate for linear-in-temperature resistivity in cuprate superconductors
Authors: Qin Mingyang , Zhang Ruozhou , Miao Chaoran , Wei Zhongxu , Shi Yujun , Yao Yixuan , Wang Haowen , Li Yangmu , Jin Kui , Xiang Xiaodong
Published: May 2024

The origin of the linear-in-temperature (T-linear) resistivity in cuprate superconductors remains a profound mystery in condensed matter physics. Here, we investigate the dependence of the T-linear resistivity coefficient on doping, i.e., A1(p), for three typical regions in the temperature versus doping phase diagram of hole-doped cuprates, from which the doping dependence of the scattering rate, i.e., α1(p), is further derived. It is found that for region I (p
T*), α1(p) is almost a constant; for region II (p>p* and T>Tcoh), α1(p)∝p; for region III (p>p* and T<Tcoh), α1(p)∝p(pc−p), where T* is the onset temperature of the pseudogap phase, p* indicates the doping at which

T

*

goes to zero, Tcoh marks the onset of antinodal quasiparticle coherence, and pc is the doping where the low-temperature linear behavior in the overdoped regime vanishes. Moreover, the deduced α1(p) relations are verified with the experimental data from previous reports. The discovered scattering rate versus doping relationship will shed light on the scattering mechanism underlying the T-linear resistivity in cuprate superconductors.

Published by the American Physical Society
2024
Do climate disasters make farmers more willing to cooperate? Evidence from rural communities in southern China
Authors: Dai Zhe , Gong Yazhen , Kant Shashi , Ma Guodong
Published: May 2024

Purpose

This article aims to explore the impact of climate disasters on small-scale farmers’ willingness to cooperate and explore the mediating effect of social capital.

Design/methodology/approach

The study investigates farmers’ willingness to cooperate through a framed field approach and surveys the information of individuals and villages, including climate disasters and social capital, using a structured questionnaire from rural communities in Jiangxi and Sichuan, China.

Findings

The results show that climate disasters and social capital are significant and positive determinants of farmers’ willingness to cooperate. In specific types of climate disasters, drought is positively associated with farmers’ cooperation willingness. Moreover, the mediation effect of drought on farmers’ willingness to cooperate through social capital has been demonstrated to be significant although negative, whereas the mediation effect of flood on farmers’ willingness to cooperate through social capital is significant and positive.

Originality/value

First, given the limited studies focusing on the impact of climate disasters on small-scale farmers’ willingness to cooperate, the authors complement the existing literature through a framed field experiment approach by designing a scenario that every farmer may encounter in their production activities. Second, the study figures out the roles of drought and flood as different kinds of climate disasters in farmers’ decision-making of cooperation and sheds light on the positive impact of climate disasters on small-scale farmers. Finally, this paper provides empirical evidence of social capital as a potential channel through which climate disasters could possibly affect farmers’ willingness to cooperate.
A new approach to entrepreneurship and regional development: key roles of purpose and well-being in the Swansea Bay City Region
Authors: Bowen Robert , Burvill Samantha , Cummings Beth , Themelidis Leonie
Published: May 2024

Purpose

This paper critically evaluates regional development through the lens of well-being and purpose. The paper provides insight into the key roles that well-being and purpose play in regional development and the way in which various actors are engaged in this process. This paper focuses on the Swansea Bay City Region within Wales, a country at the forefront of well-being legislation.

Design/methodology/approach

This paper analyses a case study of 4theRegion, a membership organisation that undertakes regional development activities underpinned by a social purpose and well-being across the Swansea Bay city region. 4theRegion has been selected due to (1) its unique business model; (2) its clear focus on well-being and purpose; and (3) the influence of its regional development actions bringing together various stakeholder groups under a common aim.

Findings

This paper extends existing debates on collaborative development approaches and underlines the unique emphasis on asset-based local development influenced by well-being, which seeks to engage with a variety of community stakeholders to derive “holistic flourishing”. This emphasises inclusive development activities across the region, through people, place, process and purpose, underpinned by well-being. The research also underlines debates about the subjectivity of well-being and how the impact of well-being legislation can be evaluated.

Originality/value

This research provides a new way of looking at regional development, through the lens of well-being and purpose and provides insight into the way in which various actors are engaged in this process. Implications of this research could influence policymaking in supporting regional development activities, as well as practical lessons for those involved in place-based development.
Scaling of social initiatives: the role of entrepreneurial skills and positions
Authors: van Lunenburg Marion
Published: May 2024

Purpose

The scaling of social initiatives is important to achieve broad social impact based on successful small-scale experiments. This paper focuses on the influence of the characteristics of the initiators of social initiatives on scaling processes. The limited literature on this topic highlights two critical actor characteristics: high entrepreneurial skills and a central position in the area. Both characteristics influence two critical components of the scaling process: mobilizing stakeholders and focusing on retaining effectiveness. The purpose of this paper is to explore these complex relationships in a deductive analysis and to use these findings for an inductive analysis to generate new insights and extend our academic understanding.

Design/methodology/approach

A comparative qualitative study of 20 social initiatives in the Dutch social sector was conducted, including 48 in-depth interviews with initiators and stakeholders in three different areas – mental health, debt and labour participation.

Findings

High entrepreneurial skills are more important for mobilizing stakeholders and focusing on retention of effectiveness than the position of the initiators, but these are a condition rather than a guarantee. Creating space for scaling and investing in measuring effectiveness in other contexts are also important.

Originality/value

By combining the literature on social entrepreneurship and public innovation and conducting an empirical study, our study provides a broad and nuanced picture and brings precision to our understanding of the relationships between initiators' entrepreneurial skills and position and the scaling process.
This is our Pearl Harbor: effects of a targeted solidarity call in Ukraine’s public diplomacy
Authors: Kim Seon-Woo
Published: May 2024

Purpose

This experiment examines targeted public diplomacy message effects during a crisis, focusing on effects of whether such messages provide a targeted solidarity call that build a sense of common purpose by comparing the other country’s past crises to Ukraine’s current crisis.

Design/methodology/approach

Using an experiment, this study investigates whether such targeting in Zelensky’s speeches increased foreign public policy support for Ukraine, the perceived agenda importance of the war and Ukraine’s legitimacy.

Findings

The results found that a targeted solidarity call in public diplomacy messages during an international crisis helps gain foreign public policy support. However, it does not significantly impact the perceived agenda importance and the country’s legitimacy.

Originality/value

There has been a lack of studies on whether targeted messaging is more effective than nontargeted one in public diplomacy literature. The study’s result implies that the inclusion of a solidarity call in public diplomacy messaging is more effective in achieving its strategic goal of receiving aid. This study, therefore, empirically answers the remaining question about the effectiveness of targeted messaging in public diplomacy and advances. It also advances theoretical connections among solidarity, targeted messaging and public diplomacy.
We don’t fire! Family firms and employment change during the COVID-19 pandemic
Authors: Cano-Rubio Myriam , Barroso Ascension , Sanguino Ramón , Valentino Alfredo , Calabrò Andrea , Basco Rodrigo
Published: May 2024

Purpose

By investigating the reactions of family businesses to COVID-19 pandemic this article aims to explaining how family firms are capable to preserve employment during hardship.

Design/methodology/approach

Stemming from resource-based-view, we theorise that familiness is not directly associated with new hiring but instead fully mediated by pivoting strategic decisions (the propensity to transform the business).

Findings

Our findings show that familiness triggers pivoting strategic decisions and consequently increases the likelihood of new hiring. Additionally, we found that the involvement of multiple generations strengthens this relationship.

Practical implications

Family firms must consolidate their family human and social resources (familiness) and assure the presence of multiple generations in the firm because they can leverage their entrepreneurial disposition and increase the need to preserve employment and new hires during crises.

Originality/value

The main contribution lies in the explanation of the mechanisms that family firms deploy to overcome a crisis and thus explains why some family firms are more resilient than others in relation to firm’s employment during hardship.