bluuebunny/crossref_metadata_2025 huggingface dataset:
Kidney Transplantation in Patients With aHUS: A Comparison of Eculizumab Prophylaxis Versus Rescue Therapy
Authors: Duineveld Caroline , Glover Emily K. , Bouwmeester Romy N. , van de Kar Nicole C.A.J. , Kavanagh David , Wetzels Jack F.M. , Sheerin Neil S.
Published: July 2024

Background.

Guidelines advise eculizumab prophylaxis for most kidney transplant recipients with atypical hemolytic uremic syndrome (aHUS). However, recurrence rates may be overestimated, and starting eculizumab at relapse (“rescue therapy”) may prevent graft loss. Randomized controlled trials have not compared the efficacy, safety, and costs of different treatment strategies. We performed a comparative study, including a previously described Dutch cohort treated with rescue therapy and a UK cohort using eculizumab prophylaxis.

Methods.

In the Netherlands, we selected all adult patients with aHUS who received a kidney transplant between 2010 and 2021 in the Radboud University Medical Center (n = 30) and enriched this cohort with 8 patients who received rescue therapy in other centers. The UK cohort included all adult patients with aHUS at moderate or high risk of recurrence, transplanted between 2013 and 2017 with prophylactic eculizumab.

Results.

We included 38 Dutch patients and 35 UK patients. Characteristics were comparable, although the UK cohort included more patients with a complement factor H SCR20 mutation or hybrid gene (31% versus 5%; P < 0.01), and more Dutch patients received living donor kidneys (66% versus 20%; P < 0.001). Follow-up was comparable (the Dutch patients 70.8 mo, range, 10–134; UK patients 55.4 mo, range, 2–95). Eighteen (47%) Dutch patients received rescue therapy. Death-censored graft survival was not significantly different (the Dutch patients 1 y, 3 y, and 6 y: 97.4%, 91.2%, and 87.1%, respectively; UK patients 1 y, 3 y, and 6 y: 97.1%, 88.2%, and 65.6%, respectively, log-rank P = 0.189).

Conclusions.

In a population characterized by low prevalence of “very high risk” genes, who were predominantly transplanted using an endothelial protective regime, death-censored graft survival with eculizumab rescue therapy was not inferior to prophylaxis.
Congenital myasthenic syndromes: increasingly complex
Authors: Ramdas Sithara , Beeson David , Dong Yin Yao
Published: July 2024

Purpose of review

Congenital myasthenia syndromes (CMS) are treatable, inherited disorders affecting neuromuscular transmission. We highlight that the involvement of an increasing number of proteins is making the understanding of the disease mechanisms and potential treatments progressively more complex.

Recent findings

Although early studies identified mutations of proteins directly involved in synaptic transmission at the neuromuscular junction, recently, next-generation sequencing has facilitated the identification of many novel mutations in genes that encode proteins that have a far wider expression profile, some even ubiquitously expressed, but whose defective function leads to impaired neuromuscular transmission. Unsurprisingly, mutations in these genes often causes a wider phenotypic disease spectrum where defective neuromuscular transmission forms only one component. This has implications for the management of CMS patients.

Given the widening nonneuromuscular junction phenotypes in the newly identified forms of CMS, new therapies need to include disease-modifying approaches that address not only neuromuscular weakness but also the multisystem involvement. Whilst the current treatments for CMS are highly effective for many subtypes there remains, in a proportion of CMS patients, an unmet need for more efficacious therapies.
Co-development of gut microbial metabolism and visual neural circuitry over human infancy
Authors: Bonham Kevin S. , Margolis Emma T. , Bottino Guilherme Fahur , Sobrino Ana , Patel Fadheela , McCann Shelley , Zieff Michal R. , Miles Marlie , Herr Donna , Davel Lauren , Bosco Cara ,   Khula South Africa Data Collection Team, Huttenhower Curtis , Pini Nicolò , Alexander Daniel C. , Jones Derek K. , Williams Steve C. R. , Amso Dima , Gladstone Melissa , Fifer William P. , Donald Kirsten A. , Gabard-Durnam Laurel J. , Klepac-Ceraj Vanja
Published: July 2024

Infancy is a time of elevated neuroplasticity supporting rapid brain and sensory development. The gut microbiome, also undergoing extensive developmental changes in early life, may influence brain development through metabolism of neuroactive compounds. Here, we leverage longitudinal data from 194 infants across the first 18 months of life to show that microbial genes encoding enzymes play a key role in modulating early neuroplasticity are associated with visual cortical neurodevelopment, measured by the Visual-Evoked Potential (VEP). Neuroactive compounds included neurotransmitters GABA and glutamate, the amino acid tryptophan, and short-chain fatty acids involved in myelination, including acetate and butyrate. Microbial gene sets around 4 months of age were strongly associated with the VEP from around 9 to 14 months of age and showed more associations than concurrently measured gene sets, suggesting microbial metabolism in early life may affect subsequent neural plasticity and development.
FhlA is a Formate Binding Protein
Authors: Al Fardan Abrar Abdullah , Koestler Benjamin James
Published: July 2024

Escherichia coliuses glycolysis and mixed acid fermentation and produces formate as by product. One systemE. coliuses for formate oxidation is formate hydrogen lyase complex (FHL). The expression of the FHL complex is dependent on formate and regulated by the transcriptional regulator FhlA. The structure of FhlA is composed of three domains. The N-terminal domain is putatively responsible for formate binding and FhlA oligomerization as a tetramer, the central portion of FhlA contains a AAA+ domain that hydrolyzes ATP, and the C-terminal domain binds DNA. Formate enhances FhlA-mediated expression of FHL; however, FhlA direct interaction with formate has never been demonstrated. Formate-protein interactions are challenging to assess, due to the small and ubiquitous nature of the molecule. Here, we have developed three techniques to assess formate-protein interaction. We use these techniques to confirm that FhlA binds formate in the N-terminal domainin vitro, and that this interaction is partially dependent on residues E183 and E363, consistent with previous reports. This study is a proof of concept that these techniques can be used to assess other formate-protein interactions.
Modeling Nitric Oxide Diffusion and Plasticity Modulation in Cerebellar Learning
Authors: Trapani Alessandra Maria , Sartori Carlo Andrea , Gambosi Benedetta , Pedrocchi Alessandra , Antonietti Alberto
Published: July 2024

Abstract

Nitric Oxide (NO) is a versatile signalling molecule with significant roles in various physiological processes, including synaptic plasticity and memory formation. In the cerebellum, NO is produced by neural NO Synthase and diffuses to influence synaptic changes, particularly at parallel fiber - Purkinje cell synapses. This study aims to investigate NO’s role in cerebellar learning mechanisms using a biologically realistic simulation-based approach. We developed the NO Diffusion Simulator (NODS), a Python module designed to model NO production and diffusion within a cerebellar spiking neural network framework. Our simulations focus on the Eye-Blink Classical Conditioning protocol to assess the impact of NO modulation on long-term potentiation and depression at parallel fiber - Purkinje cell synapses. The results demonstrate that NO diffusion significantly affects synaptic plasticity, dynamically adjusting learning rates based on synaptic activity patterns. This metaplasticity mechanism enhances the cerebellum’s capacity to prioritize relevant inputs and mitigate learning interference selectively modulating synaptic efficacy. Our findings align with theoretical models suggesting that NO serves as a contextual indicator, optimizing learning rates for effective motor control and adaptation to new tasks. The NODS implementation provides an efficient tool for large-scale simulations, facilitating future studies on NO dynamics in various brain regions and neurovascular coupling scenarios. By bridging the gap between molecular processes and network-level learning, this work underscores the critical role of NO in cerebellar function and offers a robust framework for exploring NO-dependent plasticity in computational neuroscience.
Muscle stem cells in Duchenne muscular dystrophy exhibit molecular impairments and altered cell fate trajectories impacting regenerative capacity
Authors: Granet Jules A. , Robertson Rebecca , Filippelli Romina L. , Cusmano Alessio , Li Shulei , Yaqubi Moein , Stratton Jo Anne , Chang Natasha C.
Published: July 2024

Satellite cells are muscle-resident stem cells that maintain and repair muscle. Increasing evidence supports the contributing role of satellite cells in Duchenne muscular dystrophy (DMD), a lethal degenerative muscle disease caused by loss of dystrophin. However, whether or not satellite cells exhibit dysfunction due to loss of dystrophin remains unresolved. Here, we used single cell RNA-sequencing (scRNA-seq) to determine how dystrophin deficiency impacts the satellite cell transcriptome and cellular composition by comparing satellite cells frommdxand the more severe D2-mdxDMD mouse models. DMD satellite cells were disproportionally found within myogenic progenitor clusters and a previously uncharacterized DMD enriched cluster. Despite exposure to different dystrophic environments,mdxand D2-mdxsatellite cells exhibited overlapping impairments indicating cell-autonomous defects due to dystrophin deficiency. When comparing satellite stem cell versus myogenic progenitor populations, we identified unique dysfunctions between DMD and healthy satellite cells including apoptotic cell death and senescence, respectively. Pseudotime analyses revealed differences in cell fate trajectories indicating that DMD satellite cells are stalled in their differentiation capacity.In vivoregeneration assays confirmed that DMD satellite cells exhibit impaired myogenic gene expression and cell fate dynamics during regenerative myogenesis. These defects in differentiation capacity are accompanied by impaired senescence and autophagy dynamics. Finally, we demonstrate that inducing autophagy can rescue differentiation of DMD progenitors. Our findings provide novel molecular evidence of satellite cell dysfunction in DMD, expanding on our understanding of their role in its pathology and suggesting pathways to target and enhance their regenerative capacity.
Multi-omics analysis of a traditional fermented food reveals a byproduct-associated subpopulation ofNeurospora intermediafor waste-to-food upcycling
Authors: Rekdal Vayu Maini , Villalobos-Escobedo José Manuel , Rodriguez-Valeron Nabila , Garcia Mikel Olaizola , Vásquez Diego Prado , Rosales Alexander , Sörensen Pia M. , Baidoo Edward E. K. , de Carvalho Ana Calheiros , Riley Robert , Lipzen Anna , He Guifen , Yan Mi , Haridas Sajeet , Daum Christopher , Yoshinaga Yuko , Ng Vivian , Grigoriev Igor V. , Munk Rasmus , Wijaya Christofora Hanny , Nuraida Lilis , Damayanti Isty , Morales Pablo-Cruz , Keasling Jay. D.
Published: July 2024

Fungal solid-state fermentation (SSF) of byproducts has promise for increasing food sustainability and security, but fungal waste-to-food upcycling remains poorly understood at the molecular level. Here we use a multi-omics approach to characterize oncom – a fermented food traditionally produced from byproducts in Java, Indonesia – as a model system for understanding fungal waste conversion. Metagenomic sequencing of two oncom types (red and black) indicated thatNeurospora intermediais the fungus dominating red oncom. Further transcriptomic, metabolomic, and phylogenomic analysis revealed that oncom-derivedN. intermediautilizes pectin and cellulose degradation for substrate conversion and belongs to a distinct byproduct-associated subpopulation that differs from wild strains at the genetic and biochemical level. Finally, we found thatN. intermediagrew on a range of industrially relevant byproducts, did not encode for any known mycotoxins, and could be used to create foods that were positively perceived by consumers outside Indonesia. This study uncovers the microbial and genetic basis of a traditional upcycled food, sheds light on human domestication of microbes for sustainability challenges, and establishes the edibleN. intermediaas a promising fungus for byproduct upcycling in SSF and beyond.
In vivoquantification of anterior and posterior chamber volumes in mice: implications for aqueous humor dynamics
Authors: Kim Daniel , Fang Raymond , Zhang Pengpeng , Sun Cheng , Li Guorong , Montgomery Christa , John Simon W.M. , Stamer W. Daniel , Zhang Hao F. , Ethier C. Ross
Published: July 2024

Purpose

Aqueous humor inflow rate, a key parameter influencing aqueous humor dynamics, is typically measured by fluorophotometery. Analyzing fluorophotometric data depends,inter alia, on the volume of aqueous humor in the anterior, but not the posterior, chamber. Previous fluorophotometric studies of aqueous inflow rate in mice have assumed the ratio of anterior:posterior volumes in mice to be similar to those in humans. Our goal was to measure anterior and posterior chamber volumes in mice to facilitate better estimates of aqueous inflow rates.

Methods

We used standard near-infrared optical coherence tomography (OCT) and robotic visible-light OCT (vis-OCT) to visualize, reconstruct and quantify the volumes of the anterior and posterior chambers of the mouse eyein vivo. We used histology and micro-CT scans to validate relevant landmarks fromex vivotissues to facilitatein vivomeasurement.

Results

Posterior chamber volume is 1.1 times the anterior chamber volume in BALB/cAnNCrl mice, i.e. the anterior chamber constitutes about 47% of the total aqueous humor volume, which is very dissimilar to the situation in humans. Anterior chamber volumes in 2-month-old BALB/cAnNCrl and 7-month-old C57BL6/J mice were 1.55 ± 0.36 µL (n=10) and 2.41 ± 0.29 µL (n=8), respectively. This implies that previous studies likely over-estimated aqueous inflow rate by approximately two-fold.

Conclusions

It is necessary to reassess previously reported estimates of aqueous inflow rates, and thus aqueous humor dynamics in the mouse. For example, we now estimate that only 0-15% of aqueous humor drains via the pressure-independent (unconventional) route, similar to that seen in humans and monkeys.
Identification of the trail-following pheromone receptor in termites
Authors: Diallo Souleymane , Kašparová Kateřina , Šulc Josef , Johny Jibin , Křivánek Jan , Nebesářová Jana , Sillam-Dussès David , Kyjaková Pavlína , Vondrášek Jiří , Machara Aleš , Lukšan Ondřej , Grosse-Wilde Ewald , Hanus Robert
Published: July 2024

Chemical communication is the cornerstone of eusocial insect societies since it mediates the social hierarchy, division of labor, and concerted activities of colony members. The chemistry of social insect pheromones received considerable attention in both major groups of social insects, the eusocial Hymenoptera and termites. By contrast, current knowledge on molecular mechanisms of social insect pheromone detection by odorant receptors (ORs) is limited to hymenopteran social insects and no OR was yet functionally characterized in termites, the oldest eusocial insect clade. Here, we present the first OR deorphanization in termites. Using the data from antennal transcriptome and genome of the termiteProrhinotermes simplex(Rhinotermitidae), we selected 4 candidate OR sequences, expressed them in Empty NeuronDrosophila, and functionally characterized using single sensillum recording (SSR) and a panel of termite semiochemicals. In one of the selected ORs, PsimOR14, we succeeded in obtaining strong and reliable responses to the main component ofP. simplextrail-following pheromone, the monocyclic diterpene neocembrene. PsimOR14 showed a narrow tuning to neocembrene; only one additional compound out of 72 tested (geranylgeraniol) generated non-negligible responses. Subsequently, we used SSR andP. simplexworkers to identify the olfactory sensillum specifically responding to neocembrene, thus likely expressingPsimOR14. We report on homology-based modelling of neocembrene binding by PsimOR14 and show how different ligands impact the receptor dynamicity using molecular dynamics simulations. Finally, we demonstrate thatPsimOR14is significantly more expressed in workers than in soldiers, which correlates with higher sensitivity of workers to neocembrene.
Evolution of novel mimicry polymorphisms through Haldane’s sieve and rare recombination
Authors: Deshmukh Riddhi , Baral Saurav , Kizhakke Athulya Girish , Kuwalekar Muktai , Kunte Krushnamegh
Published: July 2024

Origins of phenotypic novelty represent a paradox. Maintenance of distinct, canalized morphs usually requires a complex array of polymorphisms, whose co-retention requires a genetic architecture resistant to recombination, involving inversions and master regulators. Here, we reveal how such a constraining architecture can still accommodate novel morphs in evolving polymorphisms using the classic polymorphic Batesian mimicry inPapilio polytes, whose supergene-like genetic architecture is maintained in a large inversion. We show that rapidly evolving alleles of the conserved gene,doublesex, within this inversion underlie the genetic basis of this polymorphism. Using precisely dated phylogeny and breeding experiments, we show that novel adaptive mimetic morphs and underlying alleles evolved in a sequentially dominant manner, undergoing selective sweeps in the mimetic species as predicted under Haldane’s sieve. Furthermore, we discovered that mimetic forms share precise inversion breakpoints, allowing rare exon swaps between the universally dominant and a recessive allele to produce a novel, persistent intermediate phenotype, ultimately facilitating the acquisition of phenotypic novelty. Thus, genetic dominance, selective sweeps, rapid molecular divergence, and rare recombination promote novel forms in this iconic evolving polymorphism, resolving the paradox of phenotypic novelty arising even in highly constrained genetic architectures.
Environmental “Wiggles” as Stabilizers of Species Range Limits Set by Interspecific Competition
Authors: Shirani Farshad , Freeman Benjamin G.
Published: July 2024

Whether interspecific competition is a major contributing factor in setting species’ range limits has been debated for a long time. Evolutionary models have helped propose a possible mechanism: interspecific competition interacts with the disruptive effects of gene flow along an environmental gradient to halt range expansion of species when they meet and compete with each other. However, the stability of such range limits has not previously been well-addressed. Here we use a deterministic evolutionary model to show that, when the environmental gradient varies linearly in space, range limits set by interspecific competition are unlikely to be evolutionarily stable. However, we demonstrate that step-like nonlinearities in the environmental optimum for a fitness-related phenotypic trait, or sharp changes in the steepness of the trait optimum, can stabilize competitively-formed range limits. We show that the stability of the range limits established at such nonlinearities is sufficiently robust against environmental perturbations such as climate change. We note that strong climatic changes can still destabilize the range limits, depending on how the relative dominance of the species changes across the environmental nonlinearities. Therefore, our results further highlight the importance of measuring the competitive ability of species when predicting their response to climate change.
ZIBGLMM: Zero-Inflated Bivariate Generalized Linear Mixed Model for Meta-Analysis with Double-Zero-Event Studies
Authors: Li Lu , Lin Lifeng , Cappelleri Joseph C. , Chu Haitao , Chen Yong
Published: July 2024

Double-zero-event studies (DZS) pose a challenge for accurately estimating the overall treatment effect in meta-analysis. Current approaches, such as continuity correction or omission of DZS, are commonly employed, yet these ad hoc methods can yield biased conclusions. Although the standard bivariate generalized linear mixed model can accommodate DZS, it fails to address the potential systemic differences between DZS and other studies. In this paper, we propose a zero-inflated bivariate generalized linear mixed model (ZIBGLMM) to tackle this issue. This two-component finite mixture model includes zero-inflation for a subpopulation with negligible or extremely low risk. We develop both frequentist and Bayesian versions of ZIBGLMM and examine its performance in estimating risk ratios (RRs) against the bivariate generalized linear mixed model and conventional two-stage meta-analysis that excludes DZS. Through extensive simulation studies and real-world meta-analysis case studies, we demonstrate that ZIBGLMM outperforms the bivariate generalized linear mixed model and conventional two-stage metaanalysis that excludes DZS in estimating the true effect size with substantially less bias and comparable coverage probability.
Rescuing behavioral flexibility in a mouse model for OCD by enhancing reward-cue salience
Authors: van den Boom Bastijn J.G. , Carlo Sara De , van Klaveren Jennifer , Denys Damiaan , Willuhn Ingo
Published: July 2024

Deficits in cognitive flexibility are a frequent symptom of obsessive-compulsive disorder (OCD) and have been hypothesized to underlie compulsive behavior. Sign- and goal-tracking behaviors are thought to be related to cognitive flexibility, yet have not been studied in this context. To investigate the relationship between sign- and goal-tracking behavior and cognitive flexibility, we tested SAPAP3 knockout mice (SAPAP3-/-) and wild-type littermate controls in a Pavlovian reversal-learning task with two conditioned stimuli, one predicting reward delivery and the other reward omission. SAPAP3-/-displayed a heterogenous reversal-learning performance: Half of the population failed to acquire the reversed cue-reward contingencies, whereas the other half reversed their approach behavior similar to control mice. Surprisingly, such behavioral inflexibility and compulsive-like grooming were unrelated, suggesting a non-causal relationship between these traits. Importantly, compromised reversal learning in impaired mice was associated with diminished sign-tracking behavior (and therefore presumably with an overreliance on goal-tracking behavior). Administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, the first-line pharmacological OCD treatment, ameliorated both anxiety-like behavior and compulsive-like grooming, but did not improve behavioral flexibility in SAPAP3-/-. In contrast, enhancing reward-cue salience by altering conditioned stimuli brightness improved behavioral flexibility through augmenting sign-tracking behavior. These findings suggest that deficits in behavioral flexibility are associated with imbalanced sign- and goal-tracking behaviors in SAPAP3-/-, and enhancing reward-cue salience can rescue behavioral flexibility by restoring the balance. Thus, sign- and goal-tracking behavior might be an underexplored cognitive mechanism that could potentially be exploited to improve cognitive flexibility in OCD patients.
Chemokines Kill Bacteria by Binding Anionic Phospholipids without Triggering Antimicrobial Resistance
Authors: Pontejo Sergio M. , Martinez Sophia , Zhao Allison , Barnes Kevin , de Anda Jaime , Alimohamadi Haleh , Lee Ernest Y. , Dishman Acacia F. , Volkman Brian F. , Wong Gerard C.L. , Garboczi David N. , Ballesteros Angela , Murphy Philip M.
Published: July 2024

Classically, chemokines coordinate leukocyte trafficking during immune responses; however, many chemokines have also been reported to possess direct antibacterial activity in vitro. Yet, the bacterial killing mechanism of chemokines and the biochemical properties that define which members of the chemokine superfamily are antimicrobial remain poorly understood. Here we report that the antimicrobial activity of chemokines is defined by their ability to bind phosphatidylglycerol and cardiolipin, two anionic phospholipids commonly found in the bacterial plasma membrane. We show that only chemokines able to bind these two phospholipids killEscherichia coliandStaphylococcus aureusand that they exert rapid bacteriostatic and bactericidal effects againstE. coliwith a higher potency than the antimicrobial peptide beta-defensin 3. Furthermore, our data support that bacterial membrane cardiolipin facilitates the antimicrobial action of chemokines. Both biochemical and genetic interference with the chemokine-cardiolipin interaction impaired microbial growth arrest, bacterial killing, and membrane disruption by chemokines. Moreover, unlike conventional antibiotics,E. colifailed to develop resistance when placed under increasing antimicrobial chemokine pressure in vitro. Thus, we have identified cardiolipin and phosphatidylglycerol as novel binding partners for chemokines responsible for chemokine antimicrobial action. Our results provide proof of principle for developing chemokines as novel antibiotics resistant to bacterial antimicrobial resistance mechanisms.
Assessing the Relative Contributions of Mosaic and Regulatory Developmental Modes from Single-Cell Trajectories
Authors: Song Solène , Villoutreix Paul
Published: July 2024

Development is a highly complex process consisting of coordinated cell proliferation, cell differentiation and spatial organization. Classically, two ways to specify cell types during development are hypothesized : mosaic and regulative modes. In the mosaic mode, a particular cell isolated from the rest of the embryo will nevertheless give rise to cells with a fate identical to the ones expected in normal development, thus relying on lineage-inherited factors. In the regulative mode, the fate of a cell depends on its interactions with its environment, and thus relies on space-dependant factors. Both modes often coexist in the development of a given animal. We propose to quantify their respective contributions from single-cell trajectories.C. elegansdevelopment provides a unique opportunity to elaborate such an approach. Indeed, its invariant lineage enables the integration of spatial positions, lineage relationships and protein expression data. Using the single cell protein expression profile as a readout of the cell state, we relate the contributions of the mosaic and the regulative modes to the following measurable quantities. The contribution of the mosaic mode, or lineage-inherited contribution is quantified by the strength of the relationship between the cell-celllineage distanceand the cell-cellexpression distance. Similarly, the contribution of the regulative mode, or context-dependent contribution is quantified by the strength of the relationship between the cell-cellcontext distanceand the cell-cellexpression distance. The cell-cellcontext distancemeasures the similarity between the spatial neighborhoods of two cells based on the gene expression profiles of their neighbours. We assess the significance of these contributions by comparing the empirical results obtained onC. elegansdata to artificial models generated using simple rules. With these measures, we show the co-existence of mosaic and regulative modes in the development ofC. elegans. The relative contribution of these two modes varies across the different tissues and in time. In particular, we see in the skin tissue that during early development, the mosaic mode dominates while at later stages, regulative mode dominates, suggesting a convergence of single cell trajectories. These measures are general and can be applied to other datasets that will be made available with the progress of spatial transcriptomics and lineage-tracing, paving the way for a quantitative, unbiased and perturbation-free study of fundamental concepts in developmental biology.
Advancing Liver Gene Therapy: Enhanced Transduction with GalNAc-Bioconjugated rAAV Capsids
Authors: Lalys Pierre-Alban , Bourdon Audrey , Bouzelha Mohammed , Alvarez-Dorta Dimitri , Pavageau Karine , Girard Tiphaine , Peumery Roxane , Bouchouireb Zakaria , Marchand Maia , Mellet Anthony , Ledevin Mireille , Depienne Sébastien , Guilbaud Mickaël , Croyal Mikaël , Gouin Sébastien G. , Roubinet Benoit , Landemarre Ludovic , Adjali Oumeya , Ayuso Eduard , Larcher Thibaut , Le Guiner Caroline , Mével Mathieu , Deniaud David
Published: July 2024

This study investigates novel approaches to improve targeted gene delivery to the liver, a crucial organ for metabolic processes that faces vulnerabilities from various pathologies. Adeno-associated virus (AAV)-based gene therapy has emerged as a promising approach for liver targeting, with numerous investigational avenues. However, administration of high doses of AAV vectors present safety concerns, often requiring the use of corticosteroids and immunosuppression to mitigate immune adverse events. To address this, substantial efforts are underway to engineer optimized capsids to enhance the efficiency and specificity of recombinant AAV (rAAV) targeting hepatocytes, aiming to reduce required dosages. In this study, we employed bioconjugation chemistry to target the Asialoglycoprotein receptor (ASGPR), a C-type lectin abundantly expressed at the surface of hepatocyte membranes. We demonstrated that covalently attaching carbohydrates derived from GalNAc (a known ASGPR ligand) to lysine amino-acids on the rAAV2 capsid significantly enhancedin vivoliver transduction efficiency in mice. These optimized vectors present a promising avenue for the treatment of a spectrum of liver diseases, providing an alternative solution within the framework of liver gene therapy.
A Rose by any Other Name: Towards a quantitative theory of memory in neuroimmune memories
Authors: Fadai Nabil T. , Turcanu Victor , Nicolau Dan V.
Published: July 2024

Humanity has known about – and been fascinated by – the connection between mind and body since time immemorial, yet we have only been able to begin to quantitatively explore their interactions in recent years. Even so, the field of neuroimmunology is categorically in its infancy. Despite myriad and diverse experimental reports, no coherent theoretical approach to the neuroimmune system has been even attempted, which makes it difficult to make sense of the emerging body of empirical findings. Here, we take the first steps towards this goal by introducing a mathematical framework that describes the triggering and control of neurological memories (engrams) of immune challenges. Using peanut allergies as a model system, we show how a simple differential equation model of coupled ‘immune-engram’ responses can explain a number of key observations regarding putative neurological control of focal inflammatory responses and failures thereof. Simulations of our model identify four areas of the parameter regime corresponding to distinct consequences of ‘fake’ immune stimulation: a) resolution b) finite oscillations of inflammation, followed by resolution c) sustained, self-amplifying oscillations (cytokine storm-like phenomena) and d) resolution followed by the permanent establishment of a chronic higher-baseline inflammatory state. Importantly, we then show how our model recapitulates the key qualitative features of a recent experimental description of immune engram encoding and re-activation (respectively, suppression) in a mouse model of colitis. We conclude with remarks around clinical implications as well as directions for future work in theoretical neuroimmunology.

Abstract Figure
Systematic Analysis of the Glucose-PTS inStreptococcus sanguinisHighlighted its Importance in Central Metabolism and Bacterial Fitness
Authors: Taylor Zachary A , Pham Danniel N , Zeng Lin
Published: July 2024

Previous work reported that deletion of the Enzyme IIAB subunits (EIIABMan,manL) of the glucose phosphotransferase system (glucose-PTS,manLMNO)inStreptococcus sanguinisimpacted carbon catabolite repression (CCR) and bacterial fitness. Here, a single nucleotide polymorphism in ManN, ManNA91E, produced the unusual phenotype of increased excretion of organic acids and H2O2, yet elevated PTS activities. To characterize the contributions of each component of the glucose-PTS to bacterial fitness, we performed genetic analyses by deleting fromS. sanguinisSK36 the entire operon and each EIIMansubunit individually; and genes encoding the catabolite control protein CcpA (ΔccpA) and the redox regulator Rex (Δrex) for comparison. Deletion of each subunit incurred a growth defect on glucose partly due to elevated excretion of H2O2; when supplemented with catalase this defect was rescued, instead resulting in a significantly higher yield than the parent. All glucose-PTS deletion mutants presented an increased antagonism against the oral pathobiontStreptococcus mutans, a phenotype absent in ΔccpAdespite increased H2O2output. A shift in the pyruvate node towards mixed acid fermentation and increased arginine deiminase activity enhanced pH homeostasis in glucose-PTS mutants, but not ΔccpA. Despite the purported ability of Rex to regulate central carbon metabolism, deletion ofrexhad no significant impact on most of the phenotypes discussed here. These findings place glucose-PTS in the pivotal position of controlling central carbon flux in streptococci, with critical outcomes impacting acidogenicity, aciduricity, pH homeostasis, and antagonism, highlighting its potential as a therapeutic target for treating diseases with a dysbiotic microbiome.
Mass and decay width of
Tccs
from symmetries
Authors: Tanaka Mitsuru , Yamaguchi Yasuhiro , Harada Masayasu
Published: July 2024

We analyze the mass and width of the doubly heavy tetraquark Tccs composed of a heavy diquark and a light-quark cloud with strangeness with assuming that a color antitriplet heavy diquark is a dominant component of the doubly charmed tetraquarks Tcc and Tccs. We construct an effective Lagrangian for masses of heavy hadrons based on the superflavor symmetry between the doubly heavy tetraquarks and the singly heavy baryons by including the terms that simultaneously break the heavy-quark and light-flavor symmetries, and predict the mass of Tccs as M(Tccs)=4047±11  MeV. The comparison of this prediction with future experimental observation will give a clue to understand the color structure of the heavy diquark. We also predict the mass of Ωcc as

M

(

Ω

c

c

)

=

370

6

−

15

+

14

 

 

MeV

. We next calculate the decay width of Tccs, based solely on the light-flavor symmetry, as Γ(Tccs)=42±24  MeV.

Published by the American Physical Society
2024
Weight fluctuations in deep linear neural networks and a derivation of the inverse-variance flatness relation
Authors: Gross Markus , Raulf Arne P. , Räth Christoph
Published: July 2024

We investigate the stationary (late-time) training regime of single- and two-layer underparameterized linear neural networks within the continuum limit of stochastic gradient descent (SGD) for synthetic Gaussian data. In the case of a single-layer network in the weakly underparameterized regime, the spectrum of the noise covariance matrix deviates notably from the Hessian, which can be attributed to the broken detailed balance of SGD dynamics. The weight fluctuations, are in this case, generally anisotropic but effectively experience an isotropic loss. For an underparameterized two-layer network, we describe the stochastic dynamics of the weights in each layer and analyze the associated stationary covariances. We identify the interlayer coupling as a distinct source of anisotropy for the weight fluctuations. In contrast to the single-layer case, the weight fluctuations are effectively subject to an anisotropic loss, the flatness of which is inversely related to the fluctuation variance. We thereby provide an analytical derivation of the recently observed inverse-variance flatness relation in a model of a deep linear neural network.

Published by the American Physical Society
2024
Characterizing electron-collecting CdTe for use in a 77 ns burst-rate imager
Authors: Franklin Lena A. , Brown Nicholas J. , Gruner Sol M. , Met-Hoxha Elida , Tate Mark W. , Thom-Levy Julia
Published: July 2024

The Keck-PAD (pixel array detector) was developed at Cornell as a burst-rate imager capable of recording images from successive electron bunches (153 ns period) from the Advanced Photon Source (APS). Both Si and hole-collecting Schottky CdTe have been successfully bonded to this ASIC (application-specific integrated circuit) and used with this frame rate. The facility upgrades at the APS will lower the bunch period to 77 ns, which will require modifications to the Keck-PAD electronics to image properly at this reduced period. In addition, operation at high X-ray energies will require a different sensor material having a shorter charge collection time. For the target energy of 40 keV for this project, simulations have shown that electron-collecting CdTe should allow >90% charge collection within 35 ns. This collection time will be sufficient to sample the signal from one frame and prepare for the next. 750 µm-thick electron-collecting Schottky CdTe has been obtained from Acrorad and bonded to two different charge-integrating ASICs developed at Cornell, the Keck-PAD and the CU-APS-PAD. Carrier mobility has been investigated using the detector response to single X-ray bunches at the Cornell High Energy Synchrotron Source and to a pulsed optical laser. The tests indicate that the collection time will meet the requirements for 77 ns imaging.
Synthesis of organotin(IV) heterocycles containing a xanthenyl group by a Barbier approach via ultrasound activation: synthesis, crystal structure and Hirshfeld surface analysis
Authors: García-González J. Viridiana , Alvarado-Rodríguez José G. , Andrade-López Noemí , Zamora-Martínez Esmeralda , Jancik Vojtech , Martínez-Otero Diego
Published: July 2024

A series of organotin heterocycles of general formula [{Me2C(C6H3CH2)2O}SnR
2] [R = methyl (Me, 4), n-butyl (n-Bu, 5), benzyl (Bn, 6) and phenyl (Ph, 7)] was easily synthesized by a Barbier-type reaction assisted by the sonochemical activation of metallic magnesium. The 119Sn{1H} NMR data for all four compounds confirm the presence of a central Sn atom in a four-coordinated environment in solution. Single-crystal X-ray diffraction studies for 17,17-dimethyl-7,7-diphenyl-15-oxa-7-stannatetracyclo[11.3.1.05,16.09,14]heptadeca-1,3,5(16),9(14),10,12-hexaene, [Sn(C6H5)2(C17H16O)], 7, at 100 and 295 K confirmed the formation of a mononuclear eight-membered heterocycle, with a conformation depicted as boat–chair, resulting in a weak Sn...O interaction. The Sn and O atoms are surrounded by hydrophobic C—H bonds. A Hirshfeld surface analysis of 7 showed that the eight-membered heterocycles are linked by weak C—H...π, π–π and H...H noncovalent interactions. The pairwise interaction energies showed that the cohesion between the heterocycles are mainly due to dispersion forces.
A thermo-mechanical fully coupled model for high-speed machining of Ti6Al4V
Authors: Zhou Zeyuan , Wang Ying , Xia Zhijie
Published: July 2024

Purpose

This study aims to further refine the model, explore the influence of cutting parameters on the machining process, and apply it to practical engineering to improve the efficiency and quality of titanium alloy machining.

Design/methodology/approach

This paper establishes a comprehensive thermo-mechanical fully coupled orthogonal cutting model. This paper aims to couple the modified Johnson–Cook constitutive model, damage model and contact model to construct a two-dimensional orthogonal cutting thermo-mechanical coupling model for high-speed cutting of Ti6Al4V. The model considers the evolution of microstructures such as plastic deformation, grain dislocation rearrangement, dynamic recrystallization, as well as stress softening and hardening occurring continuously in Ti6Al4V metal during high-speed cutting. Additionally, the model incorporates friction and contact between the tool and the workpiece. It can be used to predict parameters such as cutting process, cutting force, temperature distribution, stress and strain in titanium alloy machining. The study establishes the model and implements corresponding functions by writing Abaqus VUMAT and VFRICTION subroutines.

Findings

The use of different material constitutive models can significantly impact the prediction of the cutting process. Some models may more accurately describe the mechanical behavior of the material, thus providing more reliable prediction results, while other models may exhibit larger deviations. Compared to the Tanh model, the proposed model achieves a maximum improvement of 8.9% in the prediction of cutting force and a maximum improvement of 20.9% in the prediction of chip morphology parameters. Compared to experiments, the proposed model achieves a minimum prediction error of 2.8% for average cutting force and a minimum error of 0.57% for sawtooth parameters. This study provides a comprehensive theoretical foundation and practical guidance for orthogonal cutting of titanium alloys. The model not only helps engineers and researchers better understand various phenomena in the cutting process but also serves as an important reference for optimizing cutting processes.

Originality/value

The originality of this research is guaranteed, as it has not been previously published in any journal or publication.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/ILT-05-2024-0168/
Doxing: how a darknet shop created the blackmail as a service business model
Authors: Logie Kenji , Maras Marie-Helen
Published: July 2024

Purpose

The objective of this paper is to explore the development of the Blackmail-as-a-Service business model within the Digital Thrift Shop. This service model involves the sale of doxing files to customers, as well as the removal of the content from the shop and its dissemination to victims or individuals closely connected to them.

Design/methodology/approach

To access the Digital Thrift shop, this study relies on the Tor browser and a darknet indexing site. The authors then use an application to collect and store the web pages as PDFs. Finally, content analysis is performed on these PDFs to understand the Blackmail-as-a-Service business model developed by the Digital Thrift.

Findings

The doxing data available on the Digital Thrift is primarily targeted toward women. Digital Thrift has also established a way to value the purchase, sale and the removal of blackmail data. The presence of Blackmail-as-a-Service on darknet sites poses unique challenges for criminal justice agencies in terms of jurisdiction, due to the lack of harmonized laws and the obstacles involved in taking down content from darknet sites. Finally, the use of a service model for blackmail allows criminals without technical skills to engage in cyber-victimization using blackmail.

Originality/value

Research into Blackmail-as-a-Service from boutique providers has not been conducted. To the best of the authors’ knowledge, this is one of the first study seeking to understand the Blackmail-as-a-Service business model on the darknet when used to target adults. This study presents evidence of a lack of connection between the buyers of the compromising material and the potential victim, challenging preconceived notions about image-based sexual abuse and its connection to individuals involved in interpersonal relationships.
A social identity perspective on lesbian, gay, bisexual and transgender (LGBT) entrepreneurs’ networking behavior
Authors: Fletcher Luke , Incerti Valerio , Essers Caroline
Published: July 2024

Purpose

This study aims to draw upon entrepreneurial network resource and social identity theories to advance the understanding of LGBT entrepreneurial behavior. The authors focus on what resources are acquired by LGBT entrepreneurs from LGBT-specific networks, such as entrepreneurs’ associations or chambers of commerce, and why they might engage with them.

Design/methodology/approach

As an initial scoping exercise, Study 1 quantitatively examined the different resources acquired via a survey of 109 LGBT entrepreneurs from the UK, mainland Europe and North America. Building on these findings, Study 2 qualitatively explored why LGBT entrepreneurs acquire resources from and engage with LGBT-specific networks via interviews with 23 LGBT entrepreneurs (with representation from the UK, Mainland Europe and North America).

Findings

Study 1 indicates that being more involved in LGBT-specific networks is associated with stronger resource acquisition, particularly those that are relational and psychological in nature. Study 2 reveals that such networks can act as psychologically safe holding environments where resources that fulfil needs for belonging and uniqueness are acquired. However, certain challenges and issues arise when trying to meet all members' needs.

Practical implications

The findings underscore the need for LGBT networks that are run for, and by, LGBT entrepreneurs. Such networks allow LGBT entrepreneurs to be more authentic about, and empowered by, their LGBT identity in their business such that they can develop a stronger sense of individual and collective pride in being part of an LGBT entrepreneurial community. Yet, there is a need to understand the variety of identities and needs across the LGBT community.

Originality/value

The authors advance our understanding of LGBT entrepreneurs by connecting knowledge on entrepreneurship with that on applied psychology. The authors develop an original contribution by focusing on how LGBT entrepreneurs use LGBT-specific networks to meet important psychological and relational needs, thus speaking to the importance of developing an LGBT entrepreneurial community that enables LGBT entrepreneurs to express their LGBT and entrepreneurial identities.
Customer engagement, moral identity and oppositional brand loyalty in virtual communities
Authors: Cheng Guo , Han Xiaoyun , Yu Weiping , He Mingli
Published: July 2024

Purpose

Oppositional brand loyalty poses a challenge to the management of virtual communities. This study aims to categorize these loyalty behaviors into positive (willingness to pay a price premium and brand evangelism) and negative (schadenfreude and anti-brand actions) dimensions. It then explores how customer engagement and moral identity influence these dimensions in the context of brand competition.

Design/methodology/approach

Structural equation modeling was conducted to analyze the main and moderating effects, using survey data obtained from 498 valid responses out of a total of 636 responses from Xiaomi's virtual communities.

Findings

The results indicate that customer engagement significantly influences all four dimensions of oppositional brand loyalty. The relationship between customer engagement and brand evangelism is notably stronger among customers with a strong moral identity. Conversely, the effects of customer engagement on schadenfreude and anti-brand actions are attenuated for these customers.

Originality/value

Anchored in theories of brand tribalism, social identity and brand polarization, this study bifurcates oppositional brand loyalty into directions of preference and antagonism, empirically showcasing moral identity's moderating effect. It contributes to the literature on antagonistic loyalty and moral identity, offering strategic insights for companies to navigate schadenfreude and anti-brand actions in online communities.