bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scalable gradients enable Hamiltonian Monte Carlo sampling for phylodynamic inference under episodic birth-death-sampling models
Authors: Shao Yucai , Magee Andrew F. , Vasylyeva Tetyana I. , Suchard Marc A. 
Published: November 2023

AbstractBirth-death models play a key role in phylodynamic analysis for their interpretation in terms of key epidemiological parameters. In particular, models with piecewiseconstant rates varying at different epochs in time, to which we refer as episodic birthdeath-sampling (EBDS) models, are valuable for their reflection of changing transmission dynamics over time. A challenge, however, that persists with current time-varying model inference procedures is their lack of computational efficiency. This limitation hinders the full utilization of these models in large-scale phylodynamic analyses, especially when dealing with high-dimensional parameter vectors that exhibit strong correlations. We present here a linear-time algorithm to compute the gradient of the birth-death model sampling density with respect to all time-varying parameters, and we implement this algorithm within a gradient-based Hamiltonian Monte Carlo (HMC) sampler to alleviate the computational burden of conducting inference under a wide variety of structures of, as well as priors for, EBDS processes. We assess this approach using three different real world data examples, including the HIV epidemic in Odesa, Ukraine, seasonal influenza A/H3N2 virus dynamics in New York state, America, and Ebola outbreak in West Africa. HMC sampling exhibits a substantial efficiency boost, delivering a 10to 200-fold increase in minimum effective sample size per unit-time, in comparison to a Metropolis-Hastings-based approach. Additionally, we show the robustness of our implementation in both allowing for flexible prior choices and in modeling the transmission dynamics of various pathogens by accurately capturing the changing trend of viral effective reproductive number.
Sensory Feedback and Central Neuronal Interactions in Mouse Locomotion
Authors: Molkov Yaroslav I. , Yu Guoning , Ausborn Jessica , Bouvier Julien , Danner Simon M. , Rybak Ilya A. 
Published: November 2023

AbstractLocomotion is a complex process involving specific interactions between the central neural controller and the mechanical components of the system. The basic rhythmic activity generated by locomotor circuits in the spinal cord defines rhythmic limb movements and their central coordination. The operation of these circuits is modulated by sensory feedback from the limbs providing information about the state of the limbs and the body. However, the specific role and contribution of central interactions and sensory feedback in the control of locomotor gait and posture remain poorly understood. We use biomechanical data on quadrupedal locomotion in mice and recent findings on the organization of neural interactions within the spinal locomotor circuitry to create and analyze a tractable mathematical model of mouse locomotion. The model includes a simplified mechanical model of the mouse body with four limbs and a central controller composed of four rhythm generators, each operating as a state machine controlling the state of one limb. Feedback signals characterize the load and extension of each limb as well as postural stability (balance). We systematically investigate and compare several model versions and compare their behavior to existing experimental data on mouse locomotion. Our results highlight the specific roles of sensory feedback and some central propriospinal interactions between circuits controlling fore and hind limbs for speed-dependent gait expression. Our models suggest that postural imbalance feedback may be critically involved in the control of swing-to-stance transitions in each limb and the stabilization of walking direction.
Multi-spectral Fluorescent Reporter Influenza A Viruses Allow forin vivoStudies of Innate Immune Function in Zebrafish
Authors: Soos Brandy-Lee , Ballinger Alec , Weinstein Mykayla , Foreman Haley , Grampone Julianna , Weafer Samuel , Aylesworth Connor , King Benjamin L. 
Published: November 2023

ABSTRACTInfluenza virus infection can cause severe respiratory disease and is estimated to cause millions of illnesses annually. Studies of the contribution of the innate immune response to influenza A virus (IAV) to viral pathogenesis may yield new antiviral strategies. Zebrafish larvae are useful models to study the innate immune response to pathogens, including IAV,in vivo. Here, we demonstrate how Color-flu, four fluorescent IAV strains originally developed for mice, can be used to study host-virus interactions by simultaneously monitoring virus particles, neutrophils, and macrophagesin vivo. Using this model, we show how the angiotensin-converting enzyme inhibitor, ramipril, and mitophagy inhibitor, MDIVI-1, improved survival, decreased viral burden, and improved the respiratory burst response to IAV infection. The Color-flu zebrafish model of IAV infection is complementary to other models as it is the only model where interactions between virus particles and host cells in an intact vertebrate can be visualizedin vivo.
Transcriptome and Mutant Analysis of Neuronal Genes for Memory Formation and Retrieval inCaenorhabditis elegans
Authors: Chen Yen-Ju , Wu Shyang-Jen , Tang Yu-Cheng , Wu Yu-Chun , Chiang Yueh-Chen , Pan Chun-Liang 
Published: November 2023

SummaryAlthough it is generally believed that the formation and retrieval of memory require distinct sets of genes, little is known about the identity and temporal specificity of genes that act at different memory stages. Here we characterize the transcriptomes for the formation and retrieval of stress-induced aversive memory in the nematodeCaenorhabditis elegans. Our RNA-sequencing analysis show that neuronal genes for calcium homeostasis, membrane excitability, synaptic function and signaling are progressively activated during the formation of aversive memory. Stage-specific transcriptomes further reveal that memory formation and retrieval display distinct gene activation patterns. We carried out a candidate screen of mutants for these memory genes and verified the temporal requirement of memory function for several of them. Further in-depth characterization ofcasy-1/calsyntenin show that while the short CASY-1B isoform acts in memory retrieval, the long CASY-1A isoform functions during memory formation, and its shed extracellular N-terminus fragment is likely a critical signal for memory regulation. Our work uncovers gene expression patterns associated with distinct memory stages and provides a foundation for future mechanistic interrogation of memory functions.
Predicting the subjective intensity of imagined sensory experiences from electrophysiological measures of oscillatory brain activity
Authors: Arnold Derek H. , Saurels Blake W. , Anderson Natasha , Andresen Isabella , Schwarzkopf Dietrich S. 
Published: November 2023

ABSTRACTMost people can conjure images and sounds that they experience in their minds. There are, however, marked individual differences. Some people report that they cannot generate imagined sensory experiences at all (aphantasics) and others report that they have unusually intense imagined experiences (hyper-phantasics). These individual differences have been linked to activity in sensory brain regions, driven by feedback. We would therefore expect imagined experiences to be associated with specific frequencies of oscillatory brain activity, as these can be a hallmark of neural interactions within and across regions of the brain. Replicating a number of other studies, relative to meditation we find that the act of engaging in imagining auditory or visual sensations is linked to reductions in the power of oscillatory brain activity across a broad range of frequencies, with prominent peaks in the alpha band (8-12 Hz). This oscillatory activity, however, did not predict individual differences in the subjective intensity of imagined experiences. For imagined audio experiences, these were rather predicted by reductions within the theta (6 – 9 Hz) and gamma (33 – 38 Hz) bands, and by increases in beta (15 – 17Hz) band activity. For imagined visual experiences these were predicted by reductions in lower (14 – 16Hz) and upper (29 – 32 Hz) beta band activity, and by an increase in mid-beta band (24 – 26 Hz) activity. Our data suggest that there is sufficient ground truth to the subjective reports that people use to describe the intensity of their imagined sensory experiences such that these can be predicted by the power of distinct rhythms of brain activity.
Distinct Activation Mechanisms of CXCR4 and ACKR3 Revealed by Single-Molecule Analysis of their Conformational Landscapes
Authors: Schafer Christopher T. , Pauszek Raymond F. , Gustavsson Martin , Handel Tracy M. , Millar David P. 
Published: November 2023

AbstractThe canonical chemokine receptor CXCR4 and atypical receptor ACKR3 both respond to CXCL12 but induce different effector responses to regulate cell migration. While CXCR4 couples to G proteins and directly promotes cell migration, ACKR3 is G protein-independent and scavenges CXCL12 to regulate extracellular chemokine levels and maintain CXCR4 responsiveness, thereby indirectly influencing migration. The receptors also have distinct activation requirements. CXCR4 only responds to wild-type CXCL12 and is sensitive to mutation of the chemokine. By contrast, ACKR3 recruits GPCR kinases (GRKs) and β-arrestins and promiscuously responds to CXCL12, CXCL12 variants, other peptides and proteins, and is relatively insensitive to mutation. To investigate the role of conformational dynamics in the distinct pharmacological behaviors of CXCR4 and ACKR3, we employed single-molecule FRET to track discrete conformational states of the receptors in real-time. The data revealed that apo-CXCR4 preferentially populates a high-FRET inactive state, while apo-ACKR3 shows little conformational preference and high transition probabilities among multiple inactive, intermediate and active conformations, consistent with its propensity for activation. Multiple active-like ACKR3 conformations are populated in response to agonists, compared to the single CXCR4 active-state. This and the markedly different conformational landscapes of the receptors suggest that activation of ACKR3 may be achieved by a broader distribution of conformational states than CXCR4. Much of the conformational heterogeneity of ACKR3 is linked to a single residue that differs between ACKR3 and CXCR4. The dynamic properties of ACKR3 may underly its inability to form productive interactions with G proteins that would drive canonical GPCR signaling.
A distinctive family of L,D-transpeptidases catalyzing L-Ala-mDAP crosslinks in Alpha and Betaproteobacteria
Authors: Espaillat Akbar , Alvarez Laura , Torrens Gabriel , Beek Josy ter , Miguel-Ruano Vega , Irazoki Oihane , Gago Federico , Hermoso Juan A. , Berntsson Ronnie Per-Arne , Cava Felipe 
Published: November 2023

AbstractMost bacteria are surrounded by an essential protective mesh-like structure called peptidoglycan, made of glycan chains crosslinked through short peptides by enzymes known as transpeptidases. Of these, penicillin-binding DD-transpeptidases connect adjacent peptide stems between their 4thand 3rdamino acids (4,3-type), D-alanine and a meso-diaminopimelic acid (mDAP) in Gram negatives, whereas LD-transpeptidases make the 3,3-type between mDAP3residues. While these two processes explain the formation of crosslinks in most bacteria, recent investigations involving non-model species have brought to light novel crosslinking mechanisms that point to the existence of less-explored groups of peptidoglycan crosslinking enzymes. Here, we present the identification and characterization of a novel LD-transpeptidase found in the acetic acid bacterialGluconobacter oxydans, named LDTGo, which performs 1,3-type crosslinks between L-Ala1and mDAP3. LDTGo-like proteins are conserved among Alpha and Betaproteobacteria species that do not encode LD3,3-transpeptidases. Using a highly active ortholog, we demonstratedin vitrothat this enzyme can work with non-terminal peptide bonds in the crosslinking process. This property is different from the strict specificity of typical LD- and DD-transpeptidases, which only deal with terminal peptide bonds. The high-resolution crystal structure of LDTGorevealed significant distinctions when compared to 3,3-type LD-transpeptidases. These include a proline-rich region near the N-terminus that restricts substrate access to the active site, and an unprecedented cavity designed to accommodate both the glycan chain and the peptide stem from donor muropeptides, a feature that exhibits broad conservation among LD1,3-transpeptidases. Finally, we demonstrated the involvement of DD-crosslinking turnover in supplying the necessary substrate for LD1,3-transpeptidation. This phenomenon underscores the interplay between structurally distinct crosslinking mechanisms in maintaining cell wall integrity inG. oxydans.
Fast and robust 3D MINFLUX excitation with a variable phase plate
Authors: Deguchi Takahiro , Ries Jonas 
Published: November 2023

MINFLUX has achieved record resolution in superresolution imaging and single fluorophore tracking. It is based on localizing single fluorophores by rapid probing with a patterned beam that features a local intensity minimum. Current implementations, however, are complex and expensive and are limited in speed and robustness.Here, we show that a combination of an electro-optical modulator with a segmented birefringent element such as a spatial light modulator produces a variable phase plate for which the phase can be scanned on the MHz timescale. Bisected or top-hat phase patterns generate high-contrast compact excitation point-spread functions for MINFLUX localization in the x,y, and z-direction, respectively, which can be scanned around a fluorophore within a microsecond and alternated among different excitation wavelengths.We discuss how to compensate for non-optimal performance of the components and present a robust 3D and multi-color MINFLUX excitation module with record speed, which we envision as an integral component of a high-performance and cost-effective open-source MINFLUX.
Genes acquired by horizontal gene transfer share common regulatory patterns inPhotorhabdus laumondii
Authors: Rili Lydia , Simoes Marcus , Ali Maythem , Findlay Brandon L. 
Published: November 2023

AbstractBiosynthetic gene clusters are readily transferred between microbes through horizontal gene transfer, but to provide benefit to their host they must be induced to high levels during times of stress. Working with the insect pathogenPhotorhabdus laumondii, here we study the effect of plasmid-induced stress on natural product biosynthesis. We find that the expression plasmid pARO190 alone was sufficient to induce production of an array of natural products, and that the induction could be increased with heterologous expression of either bacterial enhancer binding proteins or a random DNA sequence. Overall, this suggests that generalized stress may be an effective way to increase production of natural products inP. laumondii.
Synanthropic Culicidae (Diptera) in three fragments of Atlantic Forest in northern Parana, Brazil
Authors: Grossi Luiz Eduardo , da Silva Leticia Bernardete , Novaes Vinicius Martins , Golias Halison Correia , da Silva Mario Antonio Navarro , Zequi João Antonio Cyrino 
Published: November 2023

AbstractSynanthropic Culicidae were sampled using natural and artificial traps in three forest fragments (Daher Wood, Botanical Garden, and Mata dos Godoy State Park) in Londrina, Paraná, Brazil. To collect Culicidae, six traps were distributed in two separate transects of 70 m each, parallel, with a distance between them of 30 m. Three traps were natural (bamboo) and the other three were artificial (tires). In total, we collected 15,048 specimens distributed in eight species. The peri-urban fragments showed the highest richness. Tires were preferred as breeding sites. The seasons of highest and lowest sampling were summer and winter. The Daher Wood and Botanical Garden showed high similarity, and the Godoy Wood, an intact environment, showed the greatest dominance. The mosquitoes demonstrated varying degrees of synanthropy. Correlations were positive between temperature (0.53) and precipitation (0.40) with Culicid abundance. The Principal Component Analysis indicated that tires were most influenced by temperature, relative humidity, and bamboos by Total Dissolved Solids. Four of the collected species showed potential to be vectors of etiological agents. Abiotic factors directly influence the biology of mosquitoes, which is reflected in higher diversity in warmer and rainy periods. Urban and peri-urban areas showed more synanthropic mosquitoes due to their preference for modified sites. Vector species in these areas are of concern because they can modify disease cycles, and for this reason, it is essential to monitor these areas.
Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice
Authors: Hayashi Kazuhiro , Lesnak Joseph B. , Plumb Ashley N. , Janowski Adam J. , Smith Angela F. , Hill Joslyn K. , Sluka Kathleen A. 
Published: November 2023

AbstractActivity-induced muscle pain increases release of interleukin-1β (IL-1β) in muscle macrophages and the development of pain is prevented by blockade of IL-1β. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1β and mediates both inflammatory and neuropathic pain. Thus, we hypothesized that metabolites released during fatiguing muscle contractions activate macrophages to release IL-1β, which subsequently activate sensory neurons to secrete BDNF. To test this hypothesis, we used an animal model of activity-induced pain induced by repeated intramuscular acidic saline injections combined with fatiguing muscle contractions. Intrathecal or intramuscular injection of inhibitors of BDNF-Tropomyosin receptor kinase B (TrkB) signaling, ANA-12 or TrkB-Fc, reduced the decrease in muscle withdrawal thresholds in male, but not in female, mice when given before or 24hr after, but not 1 week after induction of the model. BDNF messenger ribonucleic acid (mRNA) was significantly increased in L4–L6 dorsal root ganglion (DRG), but not the spinal dorsal horn or gastrocnemius muscle, 24hr after induction of the model in either male or female mice. No changes in TrkB mRNA or p75 neurotrophin receptor mRNA were observed. BDNF protein expression via immunohistochemistry was significantly increased in L4–L6 spinal dorsal horn and retrogradely labelled muscle afferent DRG neurons, at 24hr after induction of the model in both sexes. In cultured DRG, fatigue metabolites combined with IL-1β significantly increased BDNF expression in both sexes. In summary, fatigue metabolites release, combined with IL-1β, BDNF from primary DRG neurons and contribute to activity-induced muscle pain only in males, while there were no sex differences in the changes in expression observed in BDNF.
Environment-organism feedbacks drive changes in ecological interactions
Authors: Meacock Oliver J. , Mitri Sara 
Published: November 2023

AbstractEcological interactions, the impact of one organism on the growth and death of another, underpin our understanding of the long-term composition and the functional properties of communities. In recent years, the context-dependency of interactions – their tendency to change values in different environments, locations and at different times – has become an increasingly important theme in ecological research. However, an overarching theoretical assumption has been that external environmental factors are responsible for driving these changes. Here, we derive a theoretical interaction framework which teases apart the separate roles played by these extrinsic environmental inputs and the intrinsic environmental changes driven by organisms within the environment itself. At the heart of our theory is the ‘instantaneous interaction’, a quantity that captures the feedback between environmental composition and the growth of organisms within it. In the limit that intrinsic, organismdriven environmental change dominates over external drivers, we find that this feedback can give rise to temporal and spatial context-dependencies as organisms modify the environment over time and/or space. We use small synthetic microbial communities as model ecosystems to demonstrate the power of this framework, using it to predict time-dependent intra-specific interactions in a toxin degradation system and to relate time and spatial dependencies in crossfeeding communities. Our framework helps to explain the ubiquity of interaction context-dependencies in systems where population changes are driven by environmental changes – such as microbial communities – by placing the environment on an equal theoretical footing as the organisms that inhabit it.
From average transient transporter currents to microscopic mechanism – A Bayesian analysis
Authors: George August , Zuckerman Daniel M. 
Published: November 2023

AbstractElectrophysiology studies of secondary active transporters have revealed quantitative, mechanistic insights over many decades of research. However, the emergence of new experimental and analysis approaches calls for investigation of the capabilities and limitations of the newer methods. We examine the ability of solid-supported membrane electrophysiology (SSME) to characterize discrete-state kinetic models with>10 rate constants. We use a Bayesian framework applied to synthetic data for three tasks: to quantify and check (i) the precision of parameter estimates under different assumptions, (ii) the ability of computation to guide selection of experimental conditions, and (iii) the ability of SSME data to distinguish among mechanisms. When the general mechanism – event order – is known in advance, we show that a subset of kinetic parameters can be “practically identified” within∼1 order of magnitude, based on SSME current traces that visually appear to exhibit simple exponential behavior. This remains true even when accounting for systematic measurement bias and realistic uncertainties in experimental inputs (concentrations) are incorporated into the analysis. When experimental conditions are optimized or different experiments are combined, the number of practically identifiable parameters can be increased substantially. Some parameters remain intrinsically difficult to estimate through SSME data alone, suggesting additional experiments are required to fully characterize parameters. We additionally demonstrate the ability to perform model selection and determine the order of events when that is not known in advance, comparing Bayesian and maximum-likelihood approaches. Finally, our studies elucidate good practices for the increasingly popular, but subtly challenging, Bayesian calculations for structural and systems biology.