bluuebunny/crossref_metadata_2025 huggingface dataset:
Le Schtroumpf civil
Authors: Simiand Guillaume
Published: January 2024

Le Schtroumpf civil est la première traduction intégrale des Codes civils français et québécois en langue schtroumpf. Si cette démarche, clin d’œil burlesque à la centralité historique du Code civil dans la sphère francophone, est sa propre fin, cet article revient sur la réflexion théorique sur les régularités de la langue du droit qu’a exigée cette traduction. Plus que sur la langue schtroumpf originelle inventée par Peyo, elle s’appuie sur sa réinterprétation systématique par Umberto Eco, qui s’est penché à plusieurs reprises au cours de sa carrière sur une langue dont l’ambiguïté permanente devrait obérer toute compréhension, mais qui reste parfaitement intelligible pour les lecteurs. C’est, raison de l’intérêt du linguiste, que la langue schtroumpf illustre parfaitement la place prépondérante de l’activité interprétative du lecteur, et notamment le renvoi hors texte à un encodage commun des références situationnelles et textuelles qui permet la restitution du sens. Par de multiples aspects, ce fonctionnement de la langue schtroumpf rappelle des difficultés similaires soulevées par l’interprétation de la langue du droit, liées à sa clarté, à sa lisibilité et à son intelligibilité. Pour générer automatiquement la traduction des Schtroumpfs civils, une stratégie fondée sur l’apprentissage machine est mise en œuvre ; pour chaque mot susceptible d’être remplacé par schtroumpf, on demande à un modèle de langue une prédiction ; si le texte du Code et la prédiction coïncident, le mot est schtroumpfé. Ce dispositif forme une variante automatisée du test de closure, utilisé depuis les années cinquante comme outil de mesure de la lisibilité et, pour certains auteurs, de l’intelligibilité des textes. Le Schtroumpf civil, quoique ce ne soit pas son objet principal, rendrait ainsi visible le degré de proximité syntactique de la langue des législateurs et de la langue générale, une approche potentiellement nouvelle d’un des versants de l’intelligibilité du texte législatif.
Эволюция уединенных гидроупругих волн деформации в двух коаксиальных цилиндрических оболочках с физической нелинейностью Шамеля
Authors: Блинков Юрий Анатольевич , Могилевич Лев Ильич , Попов Виктор Сергеевич , Попова Елизавета Викторовна
Published: January 2024

The paper considers the formulation and solution of the hydroelasticity problem for studying wave processes in the system of two coaxial shells containing fluids in the annular gap between them and in the inner shell. We investigate the axisymmetric case for Kirchhoff–Lave type shells whose material obeys a physical law with a fractional exponent of the nonlinear term (Schamel nonlinearity). The dynamics of fluids in the shells is considered within the framework of the incompressible viscous Newtonian fluid model. The derivation of the Schamel nonlinear equations of shell dynamics makes it possible to develop a mathematical formulation of the problem, which includes the obtained equations, the dynamics equations of two shells, the fluid dynamics equations and the boundary conditions at the shell-fluid interfaces and at the flow symmetry axis. The asymptotic analysis of the problem is performed using perturbation techniques, and the system of two generalized Schamel equations is obtained. This system describes the evolution of nonlinear solitary hydroelastic strain waves in the coaxial shells filled with viscous fluids, taking into account the inertia of the fluid motion. In order to determine the fluid stress at the shell-fluid interfaces, we perform linearization of the fluid dynamics equations for fluids in the annular gap and in the inner shell. The linearized equations are solved by the iterative method. The inertial terms are excluded from the equations in the first iteration, while, in the second iteration, these are the values found in the first iteration. A numerical solution of the system of nonlinear evolution equations is obtained by applying a new difference scheme developed using the Gröbner basis technique. Computational experiments are performed to investigate the effect of fluid viscosity and the inertia of fluid motion in the shells on the wave process. In the absence of fluids in the inner shell, the results of calculations demonstrate that the strain waves in the shells during elastic interactions do not change their shape and amplitude, i.e., they are solitons. The presence of viscous fluid in the inner shell leads to attenuation of the wave process.
Almost uniformly convergence on MV-algebra of intuitionistic fuzzy sets
Authors:   Mathematical Institute, Slovak Academy of Sciences, Čunderlíková Katarína
Published: January 2024

The aim of this contribution is to formulate some definitions of almost uniformly convergence for a sequence of observables in the MV-algebra of the intuitionistic fuzzy sets. We define a partial binary operation ⊖ called difference on MV-algebra of intuitionistic fuzzy sets. As an illustration of the use the almost uniformly convergence we prove a variation of Egorov’s theorem for the observables in MV-algebra of intuitionistic fuzzy sets.
Criticality supports cross-frequency cortical-thalamic information transfer during conscious states
Authors: Toker Daniel , Müller Eli , Miyamoto Hiroyuki , Riga Maurizio S , Lladó-Pelfort Laia , Yamakawa Kazuhiro , Artigas Francesc , Shine James M , Hudson Andrew E , Pouratian Nader , Monti Martin M
Published: January 2024

Consciousness is thought to be regulated by bidirectional information transfer between the cortex and thalamus, but the nature of this bidirectional communication - and its possible disruption in unconsciousness - remains poorly understood. Here, we present two main findings elucidating mechanisms of corticothalamic information transfer during conscious states. First, we identify a highly preserved spectral channel of cortical-thalamic communication that is present during conscious states, but which is diminished during the loss of consciousness and enhanced during psychedelic states. Specifically, we show that in humans, mice, and rats, information sent from either the cortex or thalamus via δ/θ/α waves (∼1–13 Hz) is consistently encoded by the other brain region by high γ waves (52–104 Hz); moreover, unconsciousness induced by propofol anesthesia or generalized spike-and-wave seizures diminishes this cross-frequency communication, whereas the psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) enhances this low-to-high frequency interregional communication. Second, we leverage numerical simulations and neural electrophysiology recordings from the thalamus and cortex of human patients, rats, and mice to show that these changes in cross-frequency cortical-thalamic information transfer may be mediated by excursions of low-frequency thalamocortical electrodynamics toward/away from edge-of-chaos criticality, or the phase transition from stability to chaos. Overall, our findings link thalamic-cortical communication to consciousness, and further offer a novel, mathematically well-defined framework to explain the disruption to thalamic-cortical information transfer during unconscious states.
Inhibitory CCK+ basket synapse defects in mouse models of dystroglycanopathy
Authors: Jahncke Jennifer N , Miller Daniel S , Krush Milana , Schnell Eric , Wright Kevin M
Published: January 2024

Dystroglycan (Dag1) is a transmembrane glycoprotein that links the extracellular matrix to the actin cytoskeleton. Mutations in Dag1 or the genes required for its glycosylation result in dystroglycanopathy, a type of congenital muscular dystrophy characterized by a wide range of phenotypes including muscle weakness, brain defects, and cognitive impairment. We investigated interneuron (IN) development, synaptic function, and associated seizure susceptibility in multiple mouse models that reflect the wide phenotypic range of dystroglycanopathy neuropathology. Mice that model severe dystroglycanopathy due to forebrain deletion of Dag1 or Pomt2, which is required for Dystroglycan glycosylation, show significant impairment of CCK+/CB1R+ IN development. CCK+/CB1R+ IN axons failed to properly target the somatodendritic compartment of pyramidal neurons in the hippocampus, resulting in synaptic defects and increased seizure susceptibility. Mice lacking the intracellular domain of Dystroglycan have milder defects in CCK+/CB1R+ IN axon targeting, but exhibit dramatic changes in inhibitory synaptic function, indicating a critical postsynaptic role of this domain. In contrast, CCK+/CB1R+ IN synaptic function and seizure susceptibility was normal in mice that model mild dystroglycanopathy due to partially reduced Dystroglycan glycosylation. Collectively, these data show that inhibitory synaptic defects and elevated seizure susceptibility are hallmarks of severe dystroglycanopathy, and show that Dystroglycan plays an important role in organizing functional inhibitory synapse assembly.
Molecular mechanisms of microbiome modulation by the eukaryotic secondary metabolite azelaic acid
Authors: Shibl Ahmed A , Ochsenkühn Michael A , Mohamed Amin R , Isaac Ashley , Coe Lisa SY , Yun Yejie , Skrzypek Grzegorz , Raina Jean-Baptiste , Seymour Justin R , Afzal Ahmed J , Amin Shady A
Published: January 2024

Photosynthetic eukaryotes, such as microalgae and plants, foster fundamentally important relationships with their microbiome based on the reciprocal exchange of chemical currencies. Among these, the dicarboxylate metabolite azelaic acid (Aze) appears to play an important, but heterogeneous, role in modulating these microbiomes, as it is used as a carbon source for some heterotrophs but is toxic to others. However, the ability of Aze to promote or inhibit growth, as well as its uptake and assimilation mechanisms into bacterial cells are mostly unknown. Here, we use transcriptomics, transcriptional factor coexpression networks, uptake experiments, and metabolomics to unravel the uptake, catabolism, and toxicity of Aze on two microalgal-associated bacteria, Phycobacter and Alteromonas, whose growth is promoted or inhibited by Aze, respectively. We identify the first putative Aze transporter in bacteria, a ‘C4-TRAP transporter’, and show that Aze is assimilated through fatty acid degradation, with further catabolism occurring through the glyoxylate and butanoate metabolism pathways when used as a carbon source. Phycobacter took up Aze at an initial uptake rate of 3.8×10–9 nmol/cell/hr and utilized it as a carbon source in concentrations ranging from 10 μM to 1 mM, suggesting a broad range of acclimation to Aze availability. For growth-impeded bacteria, we infer that Aze inhibits the ribosome and/or protein synthesis and that a suite of efflux pumps is utilized to shuttle Aze outside the cytoplasm. We demonstrate that seawater amended with Aze becomes enriched in bacterial families that can catabolize Aze, which appears to be a different mechanism from that in soil, where modulation by the host plant is required. This study enhances our understanding of carbon cycling in the oceans and how microscale chemical interactions can structure marine microbial populations. In addition, our findings unravel the role of a key chemical currency in the modulation of eukaryote-microbiome interactions across diverse ecosystems.
Conformational heterogeneity of the BTK PHTH domain drives multiple regulatory states
Authors: Lin David Yin-wei , Kueffer Lauren E , Juneja Puneet , Wales Thomas E , Engen John R , Andreotti Amy H
Published: January 2024

Full-length Bruton’s tyrosine kinase (BTK) has been refractory to structural analysis. The nearest full-length structure of BTK to date consists of the autoinhibited SH3–SH2–kinase core. Precisely how the BTK N-terminal domains (the Pleckstrin homology/Tec homology [PHTH] domain and proline-rich regions [PRR] contain linker) contribute to BTK regulation remains unclear. We have produced crystals of full-length BTK for the first time but despite efforts to stabilize the autoinhibited state, the diffraction data still reveal only the SH3–SH2–kinase core with no electron density visible for the PHTH–PRR segment. Cryo-electron microscopy (cryoEM) data of full-length BTK, on the other hand, provide the first view of the PHTH domain within full-length BTK. CryoEM reconstructions support conformational heterogeneity in the PHTH–PRR region wherein the globular PHTH domain adopts a range of states arrayed around the autoinhibited SH3–SH2–kinase core. On the way to activation, disassembly of the SH3–SH2–kinase core opens a new autoinhibitory site on the kinase domain for PHTH domain binding that is ultimately released upon interaction of PHTH with phosphatidylinositol (3,4,5)-trisphosphate. Membrane-induced dimerization activates BTK and we present here a crystal structure of an activation loop swapped BTK kinase domain dimer that likely represents the conformational state leading to trans-autophosphorylation. Together, these data provide the first structural elucidation of full-length BTK and allow a deeper understanding of allosteric control over the BTK kinase domain during distinct stages of activation.
Gle1 is required for tRNA to stimulate Dbp5 ATPase activity in vitro and promote Dbp5-mediated tRNA export in vivo in Saccharomyces cerevisiae
Authors: Arul Nambi Rajan Arvind , Asada Ryuta , Montpetit Ben
Published: January 2024

Cells must maintain a pool of processed and charged transfer RNAs (tRNA) to sustain translation capacity and efficiency. Numerous parallel pathways support the processing and directional movement of tRNA in and out of the nucleus to meet this cellular demand. Recently, several proteins known to control messenger RNA (mRNA) transport were implicated in tRNA export. The DEAD-box Protein 5, Dbp5, is one such example. In this study, genetic and molecular evidence demonstrates that Dbp5 functions parallel to the canonical tRNA export factor Los1. In vivo co-immunoprecipitation data further shows Dbp5 is recruited to tRNA independent of Los1, Msn5 (another tRNA export factor), or Mex67 (mRNA export adaptor), which contrasts with Dbp5 recruitment to mRNA that is abolished upon loss of Mex67 function. However, as with mRNA export, overexpression of Dbp5 dominant-negative mutants indicates a functional ATPase cycle and that binding of Dbp5 to Gle1 is required by Dbp5 to direct tRNA export. Biochemical characterization of the Dbp5 catalytic cycle demonstrates the direct interaction of Dbp5 with tRNA (or double-stranded RNA) does not activate Dbp5 ATPase activity, rather tRNA acts synergistically with Gle1 to fully activate Dbp5. These data suggest a model where Dbp5 directly binds tRNA to mediate export, which is spatially regulated via Dbp5 ATPase activation at nuclear pore complexes by Gle1.
Double and triple thermodynamic mutant cycles reveal the basis for specific MsbA-lipid interactions
Authors: Lyu Jixing , Zhang Tianqi , Marty Michael T. , Clemmer David , Russell David H. , Laganowsky Arthur
Published: January 2024

Structural and functional studies of the ATP-binding cassette transporter MsbA have revealed two distinct lipopolysaccharide (LPS) binding sites: one located in the central cavity and the other at a membrane-facing, exterior site. Although these binding sites are known to be important for MsbA function, the thermodynamic basis for these specific MsbA-LPS interactions is not well understood. Here, we use native mass spectrometry to determine the thermodynamics of MsbA interacting with the LPS-precursor 3-deoxy-D-
manno
-oct-2-ulosonic acid (Kdo)
2
-lipid A (KDL). The binding of KDL is solely driven by entropy, despite the transporter adopting an inward-facing conformation or trapped in an outward-facing conformation with adenosine 5’-diphosphate and vanadate. An extension of the mutant cycle approach is employed to probe basic residues that interact with KDL. We find the molecular recognition of KDL is driven by a positive coupling entropy (as large as -100 kJ/mol at 298K) that outweighs unfavorable coupling enthalpy. These findings indicate that alterations in solvent reorganization and conformational entropy can contribute significantly to the free energy of protein-lipid association. The results presented herein showcase the advantage of native MS to obtain thermodynamic insight into protein-lipid interactions that would otherwise be intractable using traditional approaches, and this enabling technology will be instrumental in the life sciences and drug discovery.
Response to comment on 'The clinical pharmacology of tafenoquine in the radical cure of Plasmodium vivax malaria: An individual patient data meta-analysis'
Authors: Watson James A , Commons Robert J , Tarning Joel , Simpson Julie A , Llanos Cuentas Alejandro , Lacerda Marcus VG , Green Justin A , Koh Gavin CKW , Chu Cindy S , Nosten François H , Price Richard N , Day Nicholas PJ , White Nicholas J
Published: January 2024

In our recent paper on the clinical pharmacology of tafenoquine (Watson et al., 2022), we used all available individual patient pharmacometric data from the tafenoquine pre-registration clinical efficacy trials to characterise the determinants of anti-relapse efficacy in tropical vivax malaria. We concluded that the currently recommended dose of tafenoquine (300 mg in adults, average dose of 5 mg/kg) is insufficient for cure in all adults, and a 50% increase to 450 mg (7.5 mg/kg) would halve the risk of vivax recurrence by four months. We recommended that clinical trials of higher doses should be carried out to assess their safety and tolerability. Sharma and colleagues at the pharmaceutical company GSK defend the currently recommended adult dose of 300 mg as the optimum balance between radical curative efficacy and haemolytic toxicity (Sharma et al., 2024). We contend that the relative haemolytic risks of the 300 mg and 450 mg doses have not been sufficiently well characterised to justify this opinion. In contrast, we provided evidence that the currently recommended 300 mg dose results in sub-maximal efficacy, and that prospective clinical trials of higher doses are warranted to assess their risks and benefits.
Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome
Authors: Lopes Filipa M , Grenier Celine , Jarvis Benjamin W , Al Mahdy Sara , Lène-McKay Adrian , Gurney Alison M , Newman William G , Waddington Simon N , Woolf Adrian S , Roberts Neil A
Published: January 2024

Rare early-onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2, the viral genome was detected in pelvic ganglia. Human HPSE2 was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders, whereas bladders were uniformly distended in mutant mice, a defect ameliorated by AAV9/HPSE2 treatment. Therapeutically, AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.
Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome
Authors: Lopes Filipa M. , Grenier Celine , Jarvis Benjamin W. , Mahdy Sara Al , McKay Adrian Lène- , Gurney Alison M. , Newman William G. , Waddington Simon N. , Woolf Adrian S. , Roberts Neil A.
Published: January 2024

Rare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of
HPSE2
, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of
Hpse2
mutant mice display impaired neurogenic relaxation. We hypothesized that
HPSE2
gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (
AAV
) vector-based approach.
AAV9/HPSE2,
carrying human
HPSE2
driven by
CAG
, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and
ex vivo
myography was undertaken to measure bladder function. In mice administered
AAV9/HPSE2
, the viral genome was detected in pelvic ganglia. Human
HPSE2
was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders whereas bladders were uniformly distended in mutant mice, a defect ameliorated by
AAV9/HPSE2
treatment. Therapeutically,
AAV9/HPSE2
significantly ameliorated impaired neurogenic relaxation of
Hpse2
mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.In the first gene therapy for genetic bladder disease, we cured autonomic neurons using AAV-mediated gene delivery in a mouse model of urofacial syndrome.
Agent-based model demonstrates the impact of nonlinear, complex interactions between cytokines on muscle regeneration
Authors: Haase Megan , Comlekoglu Tien , Petrucciani Alexa , Peirce Shayn M , Blemker Silvia S
Published: January 2024

Muscle regeneration is a complex process due to dynamic and multiscale biochemical and cellular interactions, making it difficult to identify microenvironmental conditions that are beneficial to muscle recovery from injury using experimental approaches alone. To understand the degree to which individual cellular behaviors impact endogenous mechanisms of muscle recovery, we developed an agent-based model (ABM) using the Cellular-Potts framework to simulate the dynamic microenvironment of a cross-section of murine skeletal muscle tissue. We referenced more than 100 published studies to define over 100 parameters and rules that dictate the behavior of muscle fibers, satellite stem cells (SSCs), fibroblasts, neutrophils, macrophages, microvessels, and lymphatic vessels, as well as their interactions with each other and the microenvironment. We utilized parameter density estimation to calibrate the model to temporal biological datasets describing cross-sectional area (CSA) recovery, SSC, and fibroblast cell counts at multiple timepoints following injury. The calibrated model was validated by comparison of other model outputs (macrophage, neutrophil, and capillaries counts) to experimental observations. Predictions for eight model perturbations that varied cell or cytokine input conditions were compared to published experimental studies to validate model predictive capabilities. We used Latin hypercube sampling and partial rank correlation coefficient to identify in silico perturbations of cytokine diffusion coefficients and decay rates to enhance CSA recovery. This analysis suggests that combined alterations of specific cytokine decay and diffusion parameters result in greater fibroblast and SSC proliferation compared to individual perturbations with a 13% increase in CSA recovery compared to unaltered regeneration at 28 days. These results enable guided development of therapeutic strategies that similarly alter muscle physiology (i.e. converting extracellular matrix [ECM]-bound cytokines into freely diffusible forms as studied in cancer therapeutics or delivery of exogenous cytokines) during regeneration to enhance muscle recovery after injury.
Agent-based model demonstrates the impact of nonlinear, complex interactions between cytokines on muscle regeneration
Authors: Haase Megan , Comlekoglu Tien , Petrucciani Alexa , Peirce Shayn M. , Blemker Silvia S.
Published: January 2024

Muscle regeneration is a complex process due to dynamic and multiscale biochemical and cellular interactions, making it difficult to determine optimal treatments for muscle injury using experimental approaches alone. To understand the degree to which individual cellular behaviors impact endogenous mechanisms of muscle recovery, we developed an agent-based model (ABM) using the Cellular Potts framework to simulate the dynamic microenvironment of a cross-section of murine skeletal muscle tissue. We referenced more than 100 published studies to define over 100 parameters and rules that dictate the behavior of muscle fibers, satellite stem cells (SSC), fibroblasts, neutrophils, macrophages, microvessels, and lymphatic vessels, as well as their interactions with each other and the microenvironment. We utilized parameter density estimation to calibrate the model to temporal biological datasets describing cross-sectional area (CSA) recovery, SSC, and fibroblast cell counts at multiple time points following injury. The calibrated model was validated by comparison of other model outputs (macrophage, neutrophil, and capillaries counts) to experimental observations. Predictions for eight model perturbations that varied cell or cytokine input conditions were compared to published experimental studies to validate model predictive capabilities. We used Latin hypercube sampling and partial rank correlation coefficient to identify
in silico
perturbations of cytokine diffusion coefficients and decay rates to enhance CSA recovery. This analysis suggests that combined alterations of specific cytokine decay and diffusion parameters result in greater fibroblast and SSC proliferation compared to individual perturbations with a 13% increase in CSA recovery compared to unaltered regeneration at 28 days. These results enable guided development of therapeutic strategies that similarly alter muscle physiology (i.e. converting ECM-bound cytokines into freely diffusible forms as studied in cancer therapeutics or delivery of exogenous cytokines) during regeneration to enhance muscle recovery after injury.
Comparative neuroimaging of sex differences in human and mouse brain anatomy
Authors: Guma Elisa , Beauchamp Antoine , Liu Siyuan , Levitis Elizabeth , Ellegood Jacob , Pham Linh , Mars Rogier B , Raznahan Armin , Lerch Jason P
Published: January 2024

In vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-specific brain development, there have been no attempts to formally compare human and mouse neuroanatomical sex differences to ascertain how well they translate. Addressing this question would shed critical light on the use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use structural magnetic resonance imaging to conduct the first comparative neuroimaging study of sex-specific neuroanatomy of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous regions (r=0.30). This cross-species congruence is greater in the cortex (r=0.33) than non-cortex (r=0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-specific brain development in mice to brain regions that best echo sex-specific brain development in humans.
The delayed kinetics of Myddosome formation explains why Aβ aggregates trigger TLR4 less efficiently than LPS
Authors: Li Bing , Suresh Prasanna , Brelstaff Jack , Kedia Shekhar , Bryant Clare , Klenerman David
Published: January 2024

The Myddosome is a key innate immune signalling platform. It forms at the cell surface and contains MyD88 and IRAK proteins which ultimately coordinate the production of pro-inflammatory cytokines. Toll-like receptor 4 signals via the Myddosome when triggered by Lipopolysaccharide (LPS) or Amyloid-Beta (Aβ) aggregates but the magnitude and time duration of the response are very different for reasons that are unclear. Here we followed the formation of Myddosomes in live macrophages using local delivery of TLR4 agonist to the cell surface and visualisation with 3D rapid light sheet imaging. This was complemented by super-resolution imaging of Myddosomes in fixed macrophages to determine the size of the signalling complex at different times after triggering. Myddosomes formed more rapidly after LPS than in response to sonicated Aβ 1-42 fibrils (80 seconds vs 372 seconds). The mean lifetimes of the Myddosomes was also shorter when triggered by LPS compared to sonicated Aβ fibrils (170 and 220 s) respectively. In both cases a range of Myddosome of different sizes (50-500 nm) were formed. In particular, small round Myddosomes around 100 nm in size formed at early time points, then reduced in proportion over time. Collectively our data suggests that compared to LPS the multivalency of Aβ fibrils leads to the formation of larger Myddosomes which form more slowly and, due to their size, take longer to disassemble. This explains why sonicated Aβ fibrils results in less efficient triggering of TLR4 signalling and may be a general property of protein aggregates.
Human DDX6 regulates translation and decay of inefficiently translated mRNAs
Authors: Weber Ramona , Chang Chung-Te
Published: January 2024

Recent findings indicate that the translation elongation rate influences mRNA stability. One of the factors that has been implicated in this link between mRNA decay and translation speed is the yeast DEAD-box helicase Dhh1p. Here, we demonstrated that the human ortholog of Dhh1p, DDX6, triggers the deadenylation-dependent decay of inefficiently translated mRNAs in human cells. DDX6 interacts with the ribosome through the Phe-Asp-Phe (FDF) motif in its RecA2 domain. Furthermore, RecA2-mediated interactions and ATPase activity are both required for DDX6 to destabilize inefficiently translated mRNAs. Using ribosome profiling and RNA sequencing, we identified two classes of endogenous mRNAs that are regulated in a DDX6-dependent manner. The identified targets are either translationally regulated or regulated at the steady-state-level and either exhibit signatures of poor overall translation or of locally reduced ribosome translocation rates. Transferring the identified sequence stretches into a reporter mRNA caused translation- and DDX6-dependent degradation of the reporter mRNA. In summary, these results identify DDX6 as a crucial regulator of mRNA translation and decay triggered by slow ribosome movement and provide insights into the mechanism by which DDX6 destabilizes inefficiently translated mRNAs.
Antimicrobial activity of iron-depriving pyoverdines against human opportunistic pathogens
Authors: Vollenweider Vera , Rehm Karoline , Chepkirui Clara , Pérez-Berlanga Manuela , Polymenidou Magdalini , Piel Jörn , Bigler Laurent , Kümmerli Rolf
Published: January 2024

The global rise of antibiotic resistance calls for new drugs against bacterial pathogens. A common approach is to search for natural compounds deployed by microbes to inhibit competitors. Here, we show that the iron-chelating pyoverdines, siderophores produced by environmental Pseudomonas spp., have strong antibacterial properties by inducing iron starvation and growth arrest in pathogens. A screen of 320 natural Pseudomonas isolates used against 12 human pathogens uncovered several pyoverdines with particularly high antibacterial properties and distinct chemical characteristics. The most potent pyoverdine effectively reduced growth of the pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Staphylococcus aureus in a concentration- and iron-dependent manner. Pyoverdine increased survival of infected Galleria mellonella host larvae and showed low toxicity for the host, mammalian cell lines, and erythrocytes. Furthermore, experimental evolution of pathogens combined with whole-genome sequencing revealed limited resistance evolution compared to an antibiotic. Thus, pyoverdines from environmental strains have the potential to become a new class of sustainable antibacterials against specific human pathogens.
Single-nucleus transcriptomics reveal the differentiation trajectories of periosteal skeletal/stem progenitor cells in bone regeneration
Authors: Perrin Simon , Ethel Maria , Bretegnier Vincent , Goachet Cassandre , Wotawa Cécile-Aurore , Luka Marine , Coulpier Fanny , Masson Cécile , Ménager Mickael , Colnot Céline
Published: January 2024

Bone regeneration is mediated by skeletal stem/progenitor cells (SSPCs) that are mainly recruited from the periosteum after bone injury. The composition of the periosteum and the steps of SSPC activation and differentiation remain poorly understood. Here, we generated a single-nucleus atlas of the periosteum at steady state and of the fracture site during the early stages of bone repair (https://fracture-repair-atlas.cells.ucsc.edu). We identified periosteal SSPCs expressing stemness markers (Pi16 and Ly6a/SCA1) and responding to fracture by adopting an injury-induced fibrogenic cell (IIFC) fate, prior to undergoing osteogenesis or chondrogenesis. We identified distinct gene cores associated with IIFCs and their engagement into osteogenesis and chondrogenesis involving Notch, Wnt, and the circadian clock signaling, respectively. Finally, we show that IIFCs are the main source of paracrine signals in the fracture environment, suggesting a crucial paracrine role of this transient IIFC population during fracture healing. Overall, our study provides a complete temporal topography of the early stages of fracture healing and the dynamic response of periosteal SSPCs to injury, redefining our knowledge of bone regeneration.
A conserved cell-pole determinant organizes proper polar flagellum formation
Authors: Arroyo-Pérez Erick Eligio , Hook John C. , Alvarado Alejandra , Wimmi Stephan , Glatter Timo , Thormann Kai M. , Ringgaard Simon
Published: January 2024

The coordination of cell cycle progression and flagellar synthesis is a complex process in motile bacteria. In γ-proteobacteria, the localization of the flagellum to the cell pole is mediated by the SRP-type GTPase FlhF. However, the mechanism of action of FlhF, and its relationship with the cell pole landmark protein HubP remain unclear. In this study, we discovered a novel protein called FipA that is required for normal FlhF activity and function in polar flagellar synthesis. We demonstrated that membrane-localized FipA interacts with FlhF and is required for normal flagellar synthesis in
Vibrio parahaemolyticus
,
Pseudomonas putida
, and
Shewanella putrefaciens
, and it does so independently of the polar localization mediated by HubP. FipA exhibits a dynamic localization pattern and is present at the designated pole before flagellar synthesis begins, suggesting its role in licensing flagellar formation. This discovery provides insight into a new pathway for regulating flagellum synthesis and coordinating cellular organization in bacteria that rely on polar flagellation and FlhF-dependent localization.
Evolutionary adaptation of an HP1-protein chromodomain integrates chromatin and DNA sequence signals
Authors: Baumgartner Lisa , Ipsaro Jonathan J , Hohmann Ulrich , Handler Dominik , Schleiffer Alexander , Duchek Peter , Brennecke Julius
Published: January 2024

Members of the diverse heterochromatin protein 1 (HP1) family play crucial roles in heterochromatin formation and maintenance. Despite the similar affinities of their chromodomains for di- and tri-methylated histone H3 lysine 9 (H3K9me2/3), different HP1 proteins exhibit distinct chromatin-binding patterns, likely due to interactions with various specificity factors. Previously, we showed that the chromatin-binding pattern of the HP1 protein Rhino, a crucial factor of the Drosophila PIWI-interacting RNA (piRNA) pathway, is largely defined by a DNA sequence-specific C2H2 zinc finger protein named Kipferl (Baumgartner et al., 2022). Here, we elucidate the molecular basis of the interaction between Rhino and its guidance factor Kipferl. Through phylogenetic analyses, structure prediction, and in vivo genetics, we identify a single amino acid change within Rhino’s chromodomain, G31D, that does not affect H3K9me2/3 binding but disrupts the interaction between Rhino and Kipferl. Flies carrying the rhinoG31D mutation phenocopy kipferl mutant flies, with Rhino redistributing from piRNA clusters to satellite repeats, causing pronounced changes in the ovarian piRNA profile of rhinoG31D flies. Thus, Rhino’s chromodomain functions as a dual-specificity module, facilitating interactions with both a histone mark and a DNA-binding protein.
Pain persists in mice lacking both Substance P and CGRPα signaling
Authors: MacDonald Donald Iain , Jayabalan Monessha , Seaman Jonathan , Balaji Rakshita , Nickolls Alec , Chesler Alexander
Published: January 2024

The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides and their receptors are expressed at high levels in pain-responsive neurons from the periphery to the brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve pain in clinical trials. Since Substance P and CGRPα are extensively co-expressed we hypothesized that their simultaneous inhibition would be required for effective analgesia. We therefore generated Tac1 and Calca double knockout (DKO) mice and assessed their behavior using a wide range of pain-relevant assays. As expected, Substance P and CGRPα peptides were undetectable throughout the nervous system of DKO mice. To our surprise, these animals displayed largely intact responses to mechanical, thermal, chemical, and visceral pain stimuli, as well as itch. Moreover, chronic inflammatory pain and neurogenic inflammation were unaffected by loss of the two peptides. Finally, neuropathic pain evoked by nerve injury or chemotherapy treatment was also preserved in peptide-deficient mice. Thus, our results demonstrate that even in combination, Substance P and CGRPα are not required for the transmission of acute and chronic pain.
A seven-sex species recognizes self and non-self mating-type via a novel protein complex
Authors: Yan Guanxiong , Ma Yang , Wang Yanfang , Zhang Jing , Cheng Haoming , Tan Fanjie , Wang Su , Zhang Delin , Xiong Jie , Yin Ping , Miao Wei
Published: January 2024

Although most species have two sexes, multisexual species (i.e., those with multiple mating types) are also widespread. However, it is unclear how mating-type recognition is achieved at the molecular level in multisexual species. The unicellular ciliate
Tetrahymena thermophila
has seven mating types, which are determined by the MTA and MTB proteins. In this study, we found that both proteins are essential for cells to send or receive complete mating-type information, and transmission of the mating-type signal requires both proteins to be expressed in the same cell. We found that MTA and MTB form a mating-type recognition complex that localizes to the plasma membrane, but not to the cilia. Stimulation experiments showed that the mating-type-specific regions of MTA and MTB mediate both self-and non-self-recognition, indicating that
T. thermophila
uses a dual approach to achieve mating-type recognition. Our results suggest that MTA and MTB form an elaborate multifunctional protein complex that can identify cells of both self and non-self mating types in order to inhibit or activate mating, respectively.A giant multifunctional protein complex mediates mating-type recognition through a non-ligand-receptor mechanism in a multisexual species.
SPARK regulates AGC kinases central to the Toxoplasma gondii asexual cycle
Authors: Herneisen Alice L. , Peters Michelle L. , Smith Tyler A. , Lourido Sebastian
Published: January 2024

Apicomplexan parasites balance proliferation, persistence, and spread in their metazoan hosts. AGC kinases, such as PKG, PKA, and the PDK1 ortholog SPARK, integrate environmental signals to toggle parasites between replicative and motile life stages. Recent studies have cataloged pathways downstream of apicomplexan PKG and PKA; however, less is known about the global integration of AGC kinase signaling cascades. Here, conditional genetics coupled to unbiased proteomics demonstrates that SPARK complexes with an elongin-like protein to regulate the stability of PKA and PKG in the model apicomplexan
Toxoplasma gondii
. Defects attributed to SPARK depletion develop after PKG and PKA are down-regulated. Parasites lacking SPARK differentiate into the chronic form of infection, which may arise from reduced activity of a coccidian-specific PKA ortholog. This work delineates the signaling topology of AGC kinases that together control transitions within the asexual cycle of this important family of parasites.
A mitochondrial carrier transports glycolytic intermediates to link cytosolic and mitochondrial glycolysis in the human gut parasite Blastocystis
Authors: Pyrihová Eva , King Martin S , King Alannah C , Toleco M Rey , van der Giezen Mark , Kunji Edmund RS
Published: January 2024

Stramenopiles form a clade of diverse eukaryotic organisms, including multicellular algae, the fish and plant pathogenic oomycetes, such as the potato blight Phytophthora, and the human intestinal protozoan Blastocystis. In most eukaryotes, glycolysis is a strictly cytosolic metabolic pathway that converts glucose to pyruvate, resulting in the production of NADH and ATP (Adenosine triphosphate). In contrast, stramenopiles have a branched glycolysis in which the enzymes of the pay-off phase are located in both the cytosol and the mitochondrial matrix. Here, we identify a mitochondrial carrier in Blastocystis that can transport glycolytic intermediates, such as dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, across the mitochondrial inner membrane, linking the cytosolic and mitochondrial branches of glycolysis. Comparative analyses with the phylogenetically related human mitochondrial oxoglutarate carrier (SLC25A11) and dicarboxylate carrier (SLC25A10) show that the glycolytic intermediate carrier has lost its ability to transport the canonical substrates malate and oxoglutarate. Blastocystis lacks several key components of oxidative phosphorylation required for the generation of mitochondrial ATP, such as complexes III and IV, ATP synthase, and ADP/ATP carriers. The presence of the glycolytic pay-off phase in the mitochondrial matrix generates ATP, which powers energy-requiring processes, such as macromolecular synthesis, as well as NADH, used by mitochondrial complex I to generate a proton motive force to drive the import of proteins and molecules. Given its unique substrate specificity and central role in carbon and energy metabolism, the carrier for glycolytic intermediates identified here represents a specific drug and pesticide target against stramenopile pathogens, which are of great economic importance.
LSPConv: local spatial projection convolution for point cloud analysis
Authors: Zhang Haoming , Wang Ke , Zhong Chen , Yun Kaijie , Wang Zilong , Yang Yifan , Tao Xianshui
Published: January 2024

This study introduces a novel approach, Local Spatial Projection Convolution (LSPConv), for point cloud classification and semantic segmentation. Unlike conventional methods utilizing relative coordinates for local geometric information, our motivation stems from the inadequacy of existing techniques for representing the intricate spatial organization of unconsolidated and irregular 3D point clouds. To address this limitation, we propose a Local Spatial Projection Module utilizing a vector projection strategy, designed to capture comprehensive local spatial information more effectively. Moreover, recent studies emphasize the importance of anisotropic kernels for point cloud feature extraction, considering the distinct contributions of individual neighboring points. To cater to this requirement, we introduce the Feature Weight Assignment (FWA) Module to assign weights to neighboring points, enhancing the anisotropy crucial for accurate feature extraction. Additionally, we introduce an Anisotropic Relative Feature Encoding Module that adaptively encodes points based on their relative features, further amplifying the anisotropic characteristics. Our approaches achieve remarkable results for point cloud classification and segmentation in several benchmark datasets based on extensive qualitative and quantitative evaluation.