bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct Gene Regulatory Dynamics Drive Skeletogenic Cell Fate Convergence During Vertebrate Embryogenesis
Authors: Wang Menghan , Di Pietro-Torres Ana , Feregrino Christian , Luxey Maëva , Moreau Chloé , Fischer Sabrina , Fages Antoine , Tschopp Patrick
Published: March 2024

Cell type repertoires have expanded extensively in metazoan animals, with some clade-specific cells being paramount to their evolutionary success. A prime example are the skeletogenic cells of vertebrates that form the basis of their developing endoskeletons. Depending on anatomical location, these cells originate from three different embryonic precursor lineages – the neural crest, the somites, and the lateral plate mesoderm – yet they converge developmentally towards similar cellular phenotypes. Furthermore, these lineages have gained ‘skeletogenic competency’ at distinct timepoints during vertebrate evolution, thus questioning to what extent different parts of the vertebrate skeleton rely on truly homologous cell types.

Here, we investigate how lineage-specific molecular properties of the three precursor pools are integrated at the gene regulatory level, to allow for phenotypic convergence towards a skeletogenic cell fate. Using single-cell transcriptomics and chromatin accessibility profiling along the precursor-to-skeletogenic cell continuum, we examine the gene regulatory dynamics associated with this cell fate convergence. We find that distinct transcription factor profiles are inherited from the three precursor states, and that lineage-specific enhancer elements integrate these different inputs at thecis-regulatory level, to execute a core skeletogenic program.

We propose a lineage-specific gene regulatory logic for skeletogenic convergence from three embryonic precursor pools. Early skeletal cells in different body parts thus share only a partial ‘deep homology’. This regulatory uncoupling may render them amenable to individualized selection, to help to define distinct morphologies and biomaterial properties in the different parts of the vertebrate skeleton.
Temporal prediction captures retinal spiking responses across animal species
Authors: Taylor Luke , Zenke Friedemann , King Andrew J. , Harper Nicol S.
Published: March 2024

The retina’s role in visual processing has been viewed as two extremes: an efficient compressor of incoming visual stimuli akin to a camera, or as a predictor of future stimuli. Addressing this dichotomy, we developed a biologically-detailed spiking retinal model trained on natural movies under metabolic-like constraints to either encode the present or to predict future scenes. Our findings reveal that when optimized for efficient prediction∼100 ms into the future, the model not only captures retina-like receptive fields and their mosaic-like organizations, but also exhibits complex retinal processes such as latency coding, motion anticipation, differential tuning, and stimulus-omission responses. Notably, the predictive model also more accurately predicts the way retinal ganglion cells respond across different animal species to natural images and movies. Our findings demonstrate that the retina is not merely a compressor of visual input, but rather is fundamentally organized to provide the brain with foresight into the visual world.
Cytosolic sodium accumulation is a common danger signal triggering endocytic dysfunction and NLRP3 inflammasome activation
Authors: Mangan Matthew S.J. , Akbal Anil , Rivara Sophie , Schröder Agnes , Horvath Gabor , Walch Philipp , Hegermann Jan , Kaiser Romina , Duthie Fraser , Selkrig Joel , Jantsch Jonathan , Gerhard Ralf , Wachten Dagmar , Latz Eicke
Published: March 2024

Detecting and responding to noxious molecules internalized within the endolysosomal system, including bacterial toxins and particulate matter, is essential to prevent cellular intoxication and damage. Here, we demonstrate that the NLRP3 inflammasome detects perturbations of the endolysosomal system by large clostridial toxins, including toxin B fromClostridioides difficile, as well as monosodium urate and silica crystals in human macrophages. These molecules cause sodium efflux from the endolysosomal system into the cytosol, driving cytosolic sodium accumulation. The rapid increase in cytosolic sodium subsequently triggers cell swelling and inhibits endocytic trafficking to activate the NLRP3 inflammasome. Furthermore, we demonstrate that cytosolic sodium accumulation is a common trigger for NLRP3 activation by non-particulate stimuli, including nigericin and inhibition of the Na+/K+ATPase. Our findings reveal that accumulation of cytosolic sodium is the common denominator underlying activation of the NLRP3 inflammasome upon exposure to different danger signals.
Selective regulation of corticostriatal synapses by astrocytic phagocytosis
Authors: Kim Ji-young , Kim Hyeyeon , Chung Won-Suk , Park Hyungju
Published: March 2024

In the adult brain, neural circuit homeostasis depends on the constant turnover of synapses via astrocytic phagocytosis mechanisms. However, it remains unclear whether this process occurs in a circuit-specific manner. Here, we reveal that astrocytes target and reorganize excitatory synapses in the striatum. Using model mice lacking astrocytic phagocytosis receptors in the dorsal striatum, we found that astrocytes constantly remove corticostriatal synapses rather than thalamostriatal synapses. This preferential elimination suggests that astrocytes play a selective role in modulating corticostriatal plasticity and functions via phagocytosis mechanisms. Supporting this notion, corticostriatal long-term potentiation (LTP) and the early phase of motor sequence learning are dependent on astrocytic phagocytic receptors. Together, our findings demonstrate that astrocytes contribute to the connectivity and plasticity of the striatal circuit by preferentially engulfing a specific subset of excitatory synapses within brain regions innervated by multiple excitatory sources.
An adverse rearing environment alters maternal responsiveness to infant ultrasonic vocalizations
Authors: Rekapalli Alekhya K. , Roman Isabel C. , Brenhouse Heather C. , Cody Caitlyn R.
Published: March 2024

Rodent pups use a variety of ultrasonic vocalizations (USVs) to facilitate maternal care. Importantly, infant USV repertoires are dependent on both the age and early life experiences of the pups. We have shown that an adverse rearing environment modeled with the maternal separation (MS) paradigm alters caregiving behavior, but little is known about how pup USVs differentially elicit maternal attention. In the present study, maternal approach towards a vocalizing pup over a non-vocalizing pup was tested in a Y-maze apparatus at two developmental time points over the course of MS. At the postnatal day (P) 10, dams engaged in longer interaction times with the vocalizing pup compared to the non-vocalizing pup. This effect was modulated by rearing environment and the sex of the pup, with only MS dams spending more time with vocalizing male pups. As expected at P20, dams did not show a preference for either the vocalizing or non-vocalizing pups regardless of rearing environment, however, MS dams spent a greater amount of time in the center of the apparatus as compared to control dams, which can be interpreted as a measure of uncertainty and indecision. These effects are important considering the sex specific effects of MS exposure across all developmental stages. Our novel findings support the hypothesis that sex-specific pup-dam interactions may drive later life outcomes following adversity.
A Multiparametric Analysis Reveals Differential Behavior of Spheroid Cultures on Distinct Ultra-Low Attachment Plates Types
Authors: Vitacolonna Mario , Bruch Roman , Agaçi Ane , Nürnberg Elina , Cesetti Tiziana , Keller Florian , Padovani Francesco , Sauer Simeon , Schmoller Kurt M. , Reischl Markus , Hafner Mathias , Rudolf Rüdiger
Published: March 2024

Spheroids have become principal three-dimensional biological models to study cancer, developmental processes, and drug efficacy. For spheroid generation, ultra-low attachment plates are noteworthy due to their simplicity, compatibility with automation, and experimental and commercial accessibility. Nonetheless, it is unknown whether and to what degree the plate type impacts spheroid formation and biology. This study employed automated brightfield microscopy to systematically compare the size and eccentricity of spheroids formed in six different plate types using four distinct human cell lines, i.e., CCD-1137Sk fibroblasts, HaCaT keratinocytes, and MDA-MB-231 and HT-29 cancer cells. Results showed that all plate types exhibited similar sphe-roid-forming capabilities, and the gross patterns of growth or shrinkage during four days after seeding were comparable. Yet, size and eccentricity varied systematically among specific cell lines and plate types. A confocal wholemount analysis by a novel pipeline of AI-based 3D-image analysis procedures revealed changes in cell proliferation, cell number, nuclear volume, and keratino-cyte differentiation, which were accompanied by altered YAP1-signals. The findings show that the plate type may influence the outcome of experimental campaigns. It is advisable to scan different plate types for the optimal configuration for a specific investigation instead of using one standard plate for all kinds of applications.
Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age
Authors: Sarver Dylan C. , Saqib Muzna , Chen Fangluo , Wong G. William
Published: March 2024

Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: 1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; 2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; 3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; 4) age-effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and 5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.
Butyrate and propionate are microbial danger signals that activate the NLRP3-inflammasome in human macrophages in the presence of TLR stimulation
Authors: Wang Wei , Dernst Alesya , Martin Bianca , Lorenzi Lucia , Cadefau Maria , Phulphagar Kshiti , Wagener Antonia , Budden Christina , Stair Neil , Wagner Theresa , Färber Harald , Jaensch Andreas , Stahl Rainer , Duthie Fraser , Schmidt Susanne V. , Coll Rebecca C. , Meissner Felix , Cuartero Sergi , Mangan Matthew S.J. , Latz Eicke
Published: March 2024

Short chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through fermentation of dietary fibre. Although they are generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) have shown poor tolerance to fibre-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of toll-like receptor agonists. In contrast to their anti-inflammatory effects under steady state conditions, we observed that the SCFAs butyrate and propionate triggered the activation of the NLRP3 inflammasome when added in conjunction with TLR agonists. Mechanistically, butyrate and propionate activated NLRP3 by inhibiting HDACs 1-3 and 10, leading to an uneven distribution of histone hyperacetylation that resulted in alterations in the transcriptome. Specifically, there was a lack of hyperacetylation at the loci of theCFLARandIL10genes, two important inhibitors of NLRP3 inflammasome activation. The concurrent loss of transcription and protein expression of cFLIP and IL-10 enabled caspase-8-dependent NLRP3-inflammasome activation. SCFA-driven NLRP3 activation did not require potassium efflux and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially-derived, viability-dependent danger signals (vita-PAMPs) that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.

Under inflammatory conditions, SCFAs are bacterially-derived, viability-dependent danger signals that, through HDAC inhibition and epigenetic modification, prevent expression of the anti-cell death gene cFLIP to trigger activation of the NLRP3 inflammasome.
Two highly selected mutations in the tandemly duplicatedCYP6P4aandCYP6P4bdrive pyrethroid resistance inAnopheles funestus
Authors: Tatchou-Nebangwa Nelly M.T. , Mugenzi Leon M. J. , Muhammad Abdullahi , Nebangwa Derrick N. , Kouamo Mersimine F.M. , Tagne Carlos S. D. , Tekoh Theofelix A. , Tchouakui Magellan , Ghogomu Stephen M. , Ibrahim Sulaiman S. , Wondji Charles S.
Published: March 2024

Gaining a comprehensive understanding of the genetic mechanisms underlying insecticide resistance in malaria vectors is crucial for optimising the effectiveness of insecticide-based vector control methods and developing diagnostic tools for resistance management. Considering the heterogeneity of metabolic resistance in major malaria vectors, the implementation of tailored resistance management strategies is essential for successful vector control. In this study, we provide evidence demonstrating that two highly selected mutations in the tandemly duplicated cytochrome P450 genes namelyCYP6P4aandCYP6P4b, are driving pyrethroid insecticide resistance in the major malaria vectorAnopheles funestus,in West Africa. Through a continent-wide polymorphism survey, we observed heightened indications of directional selection in both genes between 2014 and 2021. By conductingin vitroinsecticide metabolism assays with recombinant enzymes expressed from both genes, we established that mutant alleles under selection exhibit higher metabolic efficiency compared to their wild-type counterparts. Furthermore, using the GAL4-UAS transgenic system, we demonstrated that transgenicDrosophila melanogasterflies overexpressing mutant alleles displayed an increased resistance to pyrethroids. These findings were in agreement within silicocharacterisation, which highlighted changes in enzyme active site architecture that enhance the affinity of mutant alleles for type I and II pyrethroids. Furthermore, we developed two DNA-based assays capable of detecting the CYP6P4a-M220I and CYP6P4b-D284E mutations, showing their current confinement to West Africa. Genotype/phenotype correlation analyses revealed that these markers are strongly associated with resistance to types I and II pyrethroids and combine to drastically reduce the efficacy of pyrethroid bednets. Overall, our study makes available two field-applicable insecticide resistance molecular markers that will help in the monitoring and better management of insecticide resistance in West Africa.

Teaser

Two field-applicable diagnostic tools for detecting metabolic resistance inAnopheles funestusto enhance insecticide resistance management in West Africa.
The Interplay Between Multisensory Processing and Attention in Working Memory: Behavioral and Neural Indices of Audio-Visual Object Storage
Authors: Arslan Ceren , Schneider Daniel , Getzmann Stephan , Wascher Edmund , Klatt Laura-Isabelle
Published: March 2024

Although real-life events are multisensory, how audio-visual objects are stored in working memory is an open question. At a perceptual level, evidence shows that both top-down and bottom-up attentional processes can play a role in multisensory interactions. To understand how attention and multisensory processes interact in working memory, we designed an audio-visual delayed match-to-sample task in which participants were presented with one or two audio-visual memory items, followed by an audio-visual probe. In three different blocks, participants were instructed to either (a) attend to the auditory features, (b) attend to the visual features, or (c) attend to both auditory and visual features. Participants were instructed to indicate whether the task-relevant features of the probe matched one of the task-relevant feature(s) or objects in working memory. Behavioral results showed interference from task-irrelevant features, suggesting bottom-up integration of audio-visual features and their automatic encoding into working memory, irrespective of their task relevance. Yet, ERP analyses revealed no evidence for active maintenance of these task-irrelevant features, while they clearly taxed greater attentional resources during recall. Notably, alpha oscillatory activity revealed that linking information between auditory and visual modalities required more attentional demands at retrieval. Overall, these results offer critical insights into how and at which processing stage multisensory interactions occur in working memory.

Public Significance Statement

Current working memory research is dominated by investigations of the visual domain. Yet, understanding how more complex representations, e.g., based on multisensory inputs, are formed, stored, and recalled is crucial to obtaining a more realistic understanding of working memory function. The present study shows that when confronted with audio-visual inputs at the same time and location, features from both modalities are combined into a working memory representation, irrespective of their task relevance. During maintenance, alpha oscillations serve to flexibly gate information flow in the cortex, allowing for the re-distribution of attentional resources between modalities depending on their task-relevance. Notably, when the task instructions explicitly involve the storage of audio-visual objects as a whole, recall requires more attentional resources.
The SAGA acetyltransferase module is required for the maintenance of MAF and MYC oncogenic gene expression programs in multiple myeloma
Authors: Chen Ying-Jiun C. , Bhaskara Govinal Badiger , Lu Yue , Lin Kevin , Dent Sharon Y. R.
Published: March 2024

Despite recent advances in therapeutic treatments, multiple myeloma (MM) remains an incurable malignancy. Epigenetic factors contribute to the initiation, progression, relapse, and clonal heterogeneity in MM, but our knowledge on epigenetic mechanisms underlying MM development is far from complete. The SAGA complex serves as a coactivator in transcription and catalyzes acetylation and deubiquitylation. Analyses of datasets in the Cancer Dependency Map Project revealed many SAGA components are selective dependencies in MM. To define SAGA-specific functions, we focused on ADA2B, the only subunit in the lysine acetyltransferase (KAT) module that specifically functions in SAGA. Integration of RNA-seq, ATAC-seq, and CUT&RUN results identified pathways directly regulated by ADA2B include MTORC1 signaling, MYC, E2F, and MM-specific MAF oncogenic programs. We discovered that ADA2B is recruited to MAF and MYC gene targets, and that MAF shares a majority of its targets with MYC in MM cells. Furthermore, we found the SANT domain of ADA2B is required for interaction with both GCN5 and PCAF acetyltransferases, incorporation into SAGA, and ADA2B protein stability. Our findings uncover previously unknown SAGA KAT module-dependent mechanisms controlling MM cell growth, revealing a vulnerability that might be exploited for future development of MM therapy.
Collective anti-predator escape manoeuvres through optimal attack and avoidance strategies
Authors: Bartashevich Palina , Herbert-Read James E. , Hansen Matthew J. , Dhellemmes Félicie , Domenici Paolo , Krause Jens , Romanczuk Pawel
Published: March 2024

The collective dynamics of self-organised systems emerge from the decision rules agents use to respond to each other and to external forces. This is evident in groups of animals under attack from predators, where understanding collective escape patterns requires evaluating the risks and rewards associated with particular social rules, prey escape behaviour, and predator attack strategies. Here, we find that the emergence of the ‘fountain effect’, a common collective pattern observed when animal groups evade predators, is the outcome of rules designed to maximise individual survival chances given predator hunting decisions. Using drone-based empirical observations of schooling sardine prey (Sardinops sagax caerulea) attacked by striped marlin (Kajikia audax), we first find the majority of attacks produce fountain effects, with the dynamics of these escapes dependent on the predator’s attack direction. Then, using a spatially-explicit agent-based model of predator-prey dynamics, we show that fountain manoeuvres can emerge from combining an optimal individual prey escape angle with social interactions. The escape rule appears to prioritise maximising the distance to the predator and creates conflict in the effectiveness of predators’ attacks and the prey’s avoidance, explaining the empirically observed predators’ attack strategies and the fountain evasions produced by prey. Overall, we identify the proximate and ultimate explanations for fountain effects and more generally highlight that the collective patterns of self-organised predatory-prey systems can be understood by considering both social escape rules and attack strategies.
Spns1-dependent endocardial lysosomal function drives valve morphogenesis through Notch1-signaling
Authors: Chávez Myra N. , Arora Prateek , Ernst Alexander , Meer Marco , Morales Rodrigo A. , Mercader Nadia
Published: March 2024

Autophagy-lysosomal degradation is an evolutionarily conserved process key to cellular homeostasis, differentiation, and stress survival, which is particularly important for the cardiovascular system. Furthermore, experimental and clinical observations indicate it affects cardiac morphogenesis, including valve development. However, the cell-specificity and functional role of autophagic processes during heart development remain unclear. Here, we introduce novel zebrafish models to visualize autophagic vesiclesin vivoand follow their temporal and cellular localization in the larval heart. We observed a significant accumulation of lysosomal vesicles in the developing atrioventricular and bulboventricular regions and their respective valves. Next, we addressed the role of lysosomal degradation using a Spinster homolog 1 (spns1) mutant.spns1mutants displayed morphological and functional cardiac defects, including abnormal endocardial organization, impaired valve formation and retrograde blood flow. Single-nuclear transcriptome analysis revealed endocardial-specific differences in the expression of lysosome-related genes and alterations ofnotch1-signalling in the mutant. Endocardial-specific overexpression ofspns1andnotch1rescued features of valve formation and function. Altogether, our study reveals a cell-autonomous role of lysosomal processing during cardiac valve formation upstream ofnotch1-signalling.
Sustained bias of spatial attention in a 3T MRI scanner
Authors: Smaczny Stefan , Behle Leonie , Kuppe Sara , Karnath Hans-Otto , Lindner Axel
Published: March 2024

The static magnetic field of MRI scanners induces magneto-hydrodynamic stimulation of the vestibular organ (MVS) in the inner ear. This not only causes a horizontal vestibular nystagmus but also induces a horizontal bias in spatial attention. In this study, we aimed to determine the time course of MVS-induced biases in both VOR and spatial attention inside a 3T MRI-scanner as well as their respective aftereffects after participants left the scanner. Eye movements and overt spatial attention in a visual search task were assessed in healthy volunteers before, during and after a one-hour MVS period. All participants exhibited a VOR inside the scanner, which declined over time but never vanished completely. Importantly, there was also an MVS-induced horizontal bias in spatial attention and exploration, which persisted throughout the entire hour within the scanner. Upon exiting the scanner, we observed aftereffects in the opposite direction manifested in both the VOR and in spatial attention, lasting for about 6 minutes. Sustained MVS effects on spatial attention have important implications for the design and interpretation of fMRI-studies and for the development of therapeutic interventions counteracting spatial neglect.
Robust encoding of sub-sniff temporal information in the mouse olfactory bulb
Authors: Warner Tom P. A. , Tootoonian Sina , Schaefer Andreas T.
Published: March 2024

The sensory world is highly dynamic, and the temporal structure of stimuli contains rich information about the environment. Odour plumes are shaped by complex airflow that imprint information about the nature and spatial organisation of the olfactory environment onto their temporal dynamics. Whilst insects and mammals alike can discern high-frequency information, how temporal properties of the olfactory environment are represented in the brain remains largely unknown. Here, we presented temporally rich and systematically varying odour stimuli whilst electrically recording from the output neurons of the mouse olfactory bulb, mitral and tufted cells (MTC). We found that temporal aspects of odour stimuli could readily be read out from MTC responses, with a temporal resolution of up to 20 ms. Remarkably, temporal representation was virtually identical across three different odours. To understand which temporal features are encoded, we developed a single-cell model accurately describing both single-cell and population responses. Temporal receptive fields of MTCs translated between different odours, indicating that MTC tuning to odour quality and dynamics are partially separable. Together, this suggests a stereotypical representation of odour dynamics across projection neurons and can serve as an entry point into dissecting mechanisms underlying how information about the environment is extracted from temporally fluctuating odour plumes.
De novo antibody discovery in human blood from full-length single B cell transcriptomics and matching haplotyped-resolved germline assemblies
Authors: Beaulaurier John , Ly Lynn , Duty J. Andrew , Tyer Carly , Stevens Christian , Hung Chuan-tien , Sookdeo Akash , Drong Alex W. , Kowdle Shreyas , Turner Daniel J. , Juul Sissel , Hickey Scott , Lee Benhur
Published: March 2024

Immunoglobulin (IGH, IGK, IGL) loci in the human genome are highly polymorphic regions that encode the building blocks of the light and heavy chain IG proteins that dimerize to form antibodies. The processes of V(D)J recombination and somatic hypermutation in B cells are responsible for creating an enormous reservoir of highly specific antibodies capable of binding a vast array of possible antigens. However, the antibody repertoire is fundamentally limited by the set of variable (V), diversity (D), and joining (J) alleles present in the germline IG loci. To better understand how the germline IG haplotypes contribute to the expressed antibody repertoire, we combined genome sequencing of the germline IG loci with single-cell transcriptome sequencing of B cells from the same donor. Sequencing and assembly of the germline IG loci captured the IGH locus in a single fully-phased contig where the maternal and paternal contributions to the germline V, D, and J repertoire can be fully resolved. The B cells were collected following a measles, mumps, and rubella (MMR) vaccination, resulting in a population of cells that were activated in response to this specific immune challenge. Single-cell, full-length transcriptome sequencing of these B cells resulted in whole transcriptome characterization of each cell, as well as highly-accurate consensus sequences for the somatically rearranged and hypermutated light and heavy chain IG transcripts. A subset of antibodies synthesized based on their consensus heavy and light chain transcript sequences demonstrated binding to measles antigens and neutralization of measles live virus.
Acute and sub-chronic toxicity of 6PPD-quinone to early-life stage lake trout (Salvelinus namaycush)
Authors: Roberts Catherine , Lin Junyi , Kohlman Evan , Jain Niteesh , Amekor Mawuli , Alcaraz Alper James , Hogan Natacha , Hecker Markus , Brinkmann Markus
Published: March 2024

N-(1,3-Dimethylbutyl)-N’-phenyl-p-phenylenediamine-quinone (6PPD-q) is a rubber-tire derivative which leaches into surface waters from roadway runoff, from tire particles and has been identified as a possible driver of urban runoff mortality syndrome in coho salmon. Sensitivity to this toxicant is highly variable across fish species and life stages. With environmental concentrations meeting or exceeding toxicity thresholds in sensitive fishes, the potential for ecologically relevant effects is significant. There is currently no data regarding the sensitivity of lake trout (Salvelinus namaycush) to 6PPD-q. As early-life stages of fishes are typically more sensitive than adults, the goal of these studies was to evaluate the acute and sub-chronic toxicity of 6PPD-q to early-life stage lake trout. Alevins exposed from hatch until 45 days post hatch (dph) to time-weighted average 6PPD-q concentrations ranging from 0.22-13.5 μg/L exhibited a 45-day median lethal dose (LC50) of 0.39 μg/L. Deformities throughout growth were observed, with a unique pooling of blood observed in the caudal fin and eye. A subsequent acute study with exogenously feeding lake trout fry determined a 96-hr LC50of 0.50 μg/L. From these studies we can conclude that lake trout alevins and exogenously feeding fry are sensitive to 6PPD-q, which underscores the relevance of this chemical to inland freshwater ecosystems.
Faster inference of complex demographic models from large allele frequency spectra
Authors: Dilber Enes , Terhorst Jonathan
Published: March 2024

We presentmomi3, a new method for inferring complex demographic models using genetic variation data sampled from many populations.momi3 features many improvements over its predecessormomi2 (Kamm, Terhorst, Durbin, et al., 2020), including support for continuous migration, just-in-time compilation, and execution on GPUs; a standardized interface for specifying demographic models; and a novel importance sampling strategy that enables it to efficiently analyze data from a large number of samples. Together, these improvements lead to speedups of as much as 1000× over existing state-of-the-art methods such as ∂a∂i,moments, andmomi2. We illustrate the usefulness of our method by revisiting a model of archaic admixture using a large, recent dataset containing hundreds of human genomes from many populations.
Geographic variation in vulnerability to warming temperatures in an intertidal barnacle species
Authors: Gilman Sarah E. , Ober Gordon T. , Rognstad Rhiannon L. , Bunnenberg-Ross Madeleine , Man Tingyue
Published: March 2024

Vulnerability to warming temperatures under climate change arises when there is a gap between local climate and local physiology. Intertidal species are unique because they face two distinct thermal environments, and it is unclear which is the bigger driver of thermal physiology and vulnerability. Here we compare the thermal environments and physiology of three populations of the intertidal barnacleBalanus glandula, spanning 1460 km of its geographic range. We measured energy consumption in the laboratory across a 5-hour emersion and subsequent 6-hour immersion at 7 different emersion temperatures (10-38°C). We compared these results to one year of emersion and immersion temperature data from each location. Our results suggest that the temperatures experienced during emersion are a bigger driver of each population’s emersion thermal physiology than those experienced during immersion. We also estimated vulnerability to future warming in two ways: as the total annual energy demand and as the number of days above each population’s thermal peak. These produced conflicting results. The central population spent the most days over its thermal peak, but the northernmost population had the greatest total costs over a year. The higher energetic costs in the northernmost population may be explained in part by a strong latitudinal gradient in primary productivity that is selecting for higher energy demand in higher latitude populations. Thus, accurate predictions ofB. glandula’s response to warming temperatures will require knowledge of both future temperature and food availability.
Assessment of the efficacy of field and laboratory methods for the detection ofTropilaelaps spp
Authors: Gill Maggie C. , Chuttong Bajaree , Davies Paul , Etheridge Dan , Panyaraksa Lakkhika , Tomkies Victoria , Tonge George , Budge Giles E.
Published: March 2024

Tropilaelapsspp. are invasive mites that cause severe disease inApis melliferacolonies. The UK has deployed an elaborate surveillance system that seeks to detect these mites early in any invasion to allow the best opportunity to eradicate any incursion. Effective field and laboratory protocols, capable of reliably detecting low numbers of mites, are key to the success of any intervention. Here we compared the efficacy of established field monitoring using brood removal with an uncapping fork, and brood ‘bump’ methods with novel methods forTropilaelapsdetection modified fromVarroamonitoring schemes. In addition, we monitored the efficacy of the laboratory method for screening for mites in hive debris by floating mites in ethanol. Our results clearly indicated that novel methods such as uncapping infested brood with tweezers, catching mite drop using sticky traps and rolling adult bees in icing sugar were all significantly more likely to detectTropilaelapsthan existing methods such using an uncapping fork on infested brood, or the brood ‘bump’ method. Existing laboratory protocols that sieved hive debris and then floated the mite containing layer failed to detectTropilaelapsmites and new efficacious protocols were developed. Our results demonstrated that the national surveillance protocols forTropilaelapsmite detection required modification to improve the early detection of this damaging invasive mite.
Phosphodiesterase-5 inhibition inhibits epithelial ATP release and restores detrusor contractility in rats with type 2 diabetesviaan increase in bladder blood flow
Authors: Kabuto Takafumi , Inamura So , Kobayashi Hisato , Zha Xinmin , Nagase Keiko , Taga Minekatsu , Seki Masaya , Tanaka Nobuki , Okumura Yoshinaga , Yokoyama Osamu , Terada Naoki
Published: March 2024

Purpose

The bladder dysfunction associated with type 2 diabetes mellitus (T2DM) involves urine storage and voiding disorders. We evaluated the pathologic conditions of bladder wall in a rat model of T2DM and evaluated the effects of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil (TA).

Materials and Methods

Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats comprised T2DM and control groups. TA was orally administered for 12 weeks. The bladder blood flow and ATP released from the bladder epithelium were measured using laser speckle imaging and an organ bath bladder distention test. The expression levels of markers of hypoxia, pro-inflammatory cytokines, and growth factors in the bladder wall were measured by real-time PCR and ELISA. The contractions of bladder strips in response to KCl and carbachol were monitored in OLETF rats.

Results

The bladder blood flow was impaired and there was greater ATP release and vesicular nucleotide transporter (VNUT) expression in the OLETF rats than in the LETO rats, but these effects were suppressed by TA administration. Furthermore, the high expression of HIF-1α, 8-OHdG, IL-6, TNF-α, IGF-1, and bFGF in the OLETF rats was reduced by TA administration. In the OLETF rats, the contractile responses of bladder strips to KCl and carbachol were impaired, but were restored by TA administration.

Conclusions

The impairment of bladder blood flow in rats with T2DM is associated with greater ATP release and the upregulation of VNUT, markers of hypoxia, proinflammatory cytokines, and growth factors in the bladder epithelium. PDE5 inhibition has the potential to prevent the storage and voiding dysfunction associated with T2DM.
Cortisol levels, heart rate, and autonomic responses in horses during repeated road transport with different truck conditions trucks in a tropical environment
Authors: Lertratanachai Siengsaw , Poochipakorn Chanoknun , Sanigavatee Kanokpan , Huangsaksri Onjira , Wonghanchao Thita , Charoenchanikran Ponlakrit , Lawsirirat Chaipat , Chanda Metha
Published: March 2024

Horse’s stress responses have been reported during road transport in cold but not tropical environments. Therefore, this study estimated cortisol levels, heart rate (HR), and heart rate variability (HRV) in horses during medium-distance road transport with different truck conditions in a tropical environment. Six horses were repeatedly transported in either air-conditioned trucks with full (ATF) or space (ATS) loads or non-air-conditioned trucks with full (N-ATF) and space (N-ATS) loads. Blood cortisol was determined beforehand and 5, 30, and 90 minutes post-transport. HR and HRV were assessed pre-transport and at 15-minute intervals until 90 minutes post-transport. Cortisol levels increased significantly in N-ATS horses (but non-significantly in ATF, ATS, and N-ATF horses) at 5 minutes post-transport and returned to baseline by 30 minutes post-transport. Predominant parasympathetic nervous system (PNS) activity was observed during the first few hours and returned to baseline until the destination was reached. A recurrent, increased PNS activity was detected post-transport. Interaction effects of air condition-by-loading condition-by-time, air condition-by-time, and separate effects of air condition and time were observed on HR and various HRV variables during transport. A transient increase in beat-to-beat intervals, coinciding with decreased HR, was observed in ATF horses. The PNS index increased, corresponding to a decreased sympathetic nervous system index, in ATS horses during transport. We suggest that medium-distance road transport causes no stress for transport-experienced horses in a tropical environment. Air and loading conditions impacted hormonal and autonomic modulation, causing different responses in horses transported in differently conditioned trucks.
CD4+Trm sustain the chronic phase of auto-immune neuroinflammatory disease
Authors: Pignata Aurora , Frieser David , Hsiao Cheng-Chih , Engelenburg Hendrik J. , Alis Marine , Gonzalez-Fierro Carmen , Cazaentre Vincent , Miranda-Capet Romain , Dufourd Eloise , Vermeulen Thais , Aida Amel , Gisbergen Klaas Van , Blanchard Nicolas , Hamann Jörg , Smolders Joost , Liblau Roland S. , Masson Frederick
Published: March 2024

Therapeutic options against multiple sclerosis (MS) preventing T cell migration to the central nervous system (CNS) have remarkable clinical effects against the relapsing-remitting (RRMS) form of the disease, while they are poorly effective against its progressive form (PMS). Disability progression in PMS is thought to result from an interplay between smoldering local inflammation and neurodegeneration. We postulated that an ongoing inflammatory process mediated by CNS-resident memory CD4+T cells (CD4+Trm) could contribute to promote disease chronicity independently ofde novorecruitment of peripheral autoreactive T cells. Indeed, our results revealed the presence ofbona fideCD4+Trm expressing CD69, CXCR6, P2RX7, CD49a and the transcription factor Hobit in the CNS of mice with chronic experimental autoimmune encephalomyelitis (EAE) and in the brain of persons with PMS. Single-cell transcriptional analysis uncovered their transcriptional heterogeneity and inflammatory potential and, accordingly, CD4+Trm preferentially localized within inflammatory lesions. Finally, depletion of both the recirculating and the CNS-resident CD4+T cell compartments was required to alleviate neurological signs during the chronic phase of EAE. Our results, therefore, indicate that CD4+Trm actively contribute to maintain a chronic inflammatory state in the CNS, promoting damage and/or preventing repair, and suggest that new therapeutic strategies for the treatment of PMS should consider targeting the CNS-resident T cell compartment.
Emergent predictability in microbial ecosystems
Authors: Moran Jacob , Tikhonov Mikhail
Published: March 2024

Microbial ecosystems carry out essential functions for global climate, human health, and industry. These complex communities exhibit a surprising amount of functionally relevant diversity at all levels of taxonomic resolution, presenting a significant challenge for most modeling frameworks. A long-standing hope of theoretical ecology is that some patterns might persist despite community complexity – or perhaps even emerge because of it. A deeper understanding of such “emergent simplicity” could enable new approaches for predicting the behaviors of the complex ecosystems in nature. However, most examples described so far afford limited predictive power, as they focused on reproducibility rather than prediction. Here, we propose an information-theoretic framework for defining, nuancing and quantifying emergent simplicity in empirical data based on the ability of simple models to predict community-level functional properties. Applying this framework to two published datasets, we demonstrate that the majority of properties measured across both experiments exhibit robust evidence of emergent predictability: surprisingly, as community richness increases, simple compositional descriptions become more predictive. We show that this behavior is not typical within the standard modeling frameworks of theoretical ecology, and argue that improving our ability to predict and control natural microbial communities will require a shift of focus: away from complexity ofecosystems, and towards prediction complexity ofpropertiesof ecosystems.
Fast exploration is coupled with a less choosy but more reactive learning style in a generalist predator
Authors: Kuo Chi-Yun , Chen Yu-Hsi , Meng Ai-Ching , Wu Yu-Zhe , Yang Shan-Yu , Yeh Ching-Ning
Published: March 2024

The hypothesis of slow-fast syndromes predicts a correspondence between personality type and learning style; fast explorers would have a more proactive (fast but inflexible) learning style and slow explorers would be more reactive (slow but flexible) learners. Empirical evidence for this personality-cognition coupling remains inconclusive and heavily biased towards birds. Moreover, most studies did not examine the personality-cognition correlation when the cognitive task is discerning food quality, a scenario directly related to energy acquisition that underpins the evolution of slow-fast syndromes. In this study, we examined the exploration-cognition correlation in the context of avoidance learning in an opportunistic predator - the common sun skinkEutropis multifasciata. We quantified exploration tendencies of individuals in an unfamiliar environment and compared foraging behaviours when lizards associated prey colour and quality during the initial learning trials and subsequent reverse learning trials, where the prey colour-taste combinations were switched. We found that fast explorers were less choosy but more reactive foragers, whereas slow explorers exhibited the opposite learning style. Interestingly, there was no evidence for a learning speed-flexibility trade-off. Our findings are in contrast with conventional predictions and suggest that the two types of exploration-cognition coupling could be different viable responses to fast-changing environmental predictability.
Challenges in quantifying functional redundancy and selection in microbial communities
Authors: Ho Po-Yi , Huang Kerwyn Casey
Published: March 2024

Microbiomes can exhibit large variations in species abundances but high reproducibility in abundances of functional units, an observation often considered evidence for functional redundancy. Based on such reduction in functional variability, selection is hypothesized to act on functional units in these ecosystems. However, the link between functional redundancy and selection remains unclear. Here, we show that reduction in functional variability does not always imply selection on functional profiles. We propose empirical null models to account for the confounding effects of statistical averaging and bias toward environment-independent beneficial functions. We apply our models to existing data sets, and find that the abundances of metabolic groups within microbial communities from bromeliad foliage do not exhibit any evidence of the previously hypothesized functional selection. By contrast, communities of soil bacteria or human gut commensals grownin vitroare selected for metabolic capabilities. By separating the effects of averaging and functional bias on functional variability, we find that the appearance of functional selection in gut microbiome samples from the Human Microbiome Project is artifactual, and that there is no evidence of selection for any molecular function represented by KEGG orthology. These concepts articulate a basic framework for quantifying functional redundancy and selection, advancing our understanding of the mapping between microbiome taxonomy and function.
hoodscanR: profiling single-cell neighborhoods in spatial transcriptomics data
Authors: Liu Ning , Martin Jarryd , Bhuva Dharmesh D , Chen Jinjin , Li Mengbo , Lee Samuel C. , Kharbanda Malvika , Cheng Jinming , Mohamed Ahmed , Kulasinghe Arutha , Chen Yunshun , Tan Chin Wee , Davis Melissa J
Published: March 2024

Understanding complex cellular niches and neighborhoods are giving us new insights into tissue biology. Accurate neighborhood identification is crucial, yet existing methodologies often struggle to detect mixed neighborhoods and generate cell-specific neighborhood profiles. To address these limitations, we introduce hoodscanR, a Bioconductor package designed for neighborhood identification and downstream analyses using spatial data. Applying hoodscanR to breast and lung cancer datasets, we showcase its efficacy in conducting detailed neighborhood analyses and identify subtle transcriptional changes in tumor cells from different neighborhoods. Such analyses can help researchers gain valuable insights into disease mechanisms and potential therapeutic targets.